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Hemorrhoidal Disease Management: When and How to Intervene
according to Vincent de Parades, MD, PhD, of Hôpital Paris Saint-Joseph in France. In his presentation at France’s annual general medicine conference (JNMG 2024) on the management of hemorrhoidal disease, he noted, “this [NSAID and analgesic] treatment is highly effective, initially relieving pain and reducing edema, though the clot takes longer to resolve.” In cases where residual skin tags (marisques) remain after an episode, resection may be considered if they cause discomfort.
While patients often turn to over-the-counter topical treatments during flare-ups, de Parades noted that these have not been proven effective for hemorrhoidal disease. For hemorrhoidal thrombosis, however, a topical treatment with a corticosteroid and anesthetic may be prescribed.
No NSAIDs for Abscesses
In addition to NSAIDs, a local treatment may provide soothing benefits, especially when combined with topical application, as highlighted by Nadia Fathallah, MD, of Hôpital Paris Saint-Joseph, who joined de Parades in the presentation. “I recommend massaging the ointment to help dissolve the thrombus,” she added. However, “NSAIDs should not be prescribed in the case of an abscess,” cautioned de Parades, emphasizing that “any patient with a painful anal swelling needs an examination.” When in doubt, administer an analgesic and reexamine the patient 1-2 days later. If an abscess is present, it will not resolve on its own, and pain will persist.
The two proctologists reviewed various interventions for managing hemorrhoidal conditions, underscoring the benefits of minimally invasive surgery as an alternative to hemorrhoidectomy for treating grade 2 or 3 hemorrhoidal prolapse.
Hemorrhoidal disease involves abnormal dilation of the vascular system in the anus and rectum. External hemorrhoids affect the external vascular plexus, while internal hemorrhoids occur in the upper part of the anal canal at the internal plexus.
Hygiene and Dietary Guidelines
Common symptoms include light to heavy bleeding during bowel movements and the sensation of a lump inside the anus. In some cases, this is accompanied by throbbing pain, which suggests hemorrhoidal thrombosis, a condition often associated with a painful external swelling. Hemorrhoidal prolapse, meanwhile, is characterized by the protrusion of internal hemorrhoids and is classified into four grades:
- Grade 1: Hemorrhoids emerge during straining but do not protrude externally.
- Grade 2: Hemorrhoids protrude but spontaneously retract after straining.
- Grade 3: Hemorrhoids protrude with straining and require manual reinsertion.
- Grade 4: Prolapse is permanent.
In all cases, medical treatment is recommended as the initial approach. European guidelines recommend to first implement lifestyle and dietary measures, encouraging regular physical activity and adequate water and fiber intake to promote intestinal transit. Laxatives may also be recommended.
Elastic Band Ligation
For hemorrhoidal thrombosis, NSAIDs and nonopioid analgesics are recommended as first-line treatments. For patients with contraindications to NSAIDs, such as pregnant women, corticosteroid treatment may be administered, although it is less effective. Routine incision is no longer recommended, according to de Parades.
For prolapsed internal hemorrhoids, instrumental treatment is recommended as a second-line option if medical management fails for grades 1 and 2, or for isolated grade 3 hemorrhoids. With sclerotherapy injections largely phased out, two options remain: Infrared photocoagulation and elastic band ligation.
The objective of instrumental treatment is to create a scar at the top of the hemorrhoidal plexus to reduce vascularization and secure the hemorrhoid to the rectal wall. When correctly performed above the insensitive mucosal area in the anal canal, the procedure is painless.
Ligation involves placing an elastic band at the base of the hemorrhoid, with the intervention taking only a few minutes. “Within 4 weeks, the hemorrhoid disappears,” explained de Parades. Photocoagulation is a more superficial treatment requiring several spaced sessions, mainly to address bleeding.
Advances in Minimally Invasive Surgery
Surgery is recommended if instrumental treatment fails and as a first-line option for circular grade 3 hemorrhoids (multiple hemorrhoidal masses) and grade 4 cases.
Milligan-Morgan hemorrhoidectomy is considered the “gold standard” surgical technique and is used primarily for grades 2, 3, and 4 cases. This technique involves resecting the three main hemorrhoidal bundles while preserving surrounding tissue, providing a “radical and definitive” treatment.
While effective in the long term, hemorrhoid bundle resection requires a lengthy healing process and typically requires the patient to take 15-20 days off work. It is also not recommended for people who engage in anal intercourse, as “removing hemorrhoidal tissue can reduce flexibility and sensation in the anal canal,” Fathallah noted.
Another widely used technique in France is Doppler-guided hemorrhoidal artery ligation, which selectively reduces blood flow to the hemorrhoidal plexus. It is often combined with a mucopexy to secure the prolapse above the anal canal and restore normal anatomy.
Minimally invasive surgery is today increasingly considered an alternative to hemorrhoidectomy for treating grade 2 or 3 hemorrhoidal prolapse.
Laser and radiofrequency techniques induce submucosal coagulation, reducing arterial flow and creating fibrous tissue to retract the hemorrhoidal bundle. Because the procedure is applied above the anal canal, “it is associated with little or no pain.”
Hemorrhoidal Embolization
Recent studies have validated the benefits of minimally invasive surgery for this condition. In a French multicenter study, radiofrequency treatment significantly improved quality of life 3 months post operation, requiring only 4 days off work. The vast majority of patients said they were satisfied with the results.
The procedure is less uncomfortable than hemorrhoidectomy and allows for quicker recovery, but it carries a risk for recurrence. In the French study, nearly 8% of patients required reoperation within a year, mostly by hemorrhoidectomy. “The estimated recurrence rate is 20%-30% over 10 years,” said de Parades.
Overall, the specialist emphasized the value of surgery, including hemorrhoidectomy, in treating hemorrhoidal prolapse. With substantial benefits from minimally invasive options, “patients should be referred early” to prevent prolapse progression “that might leave no choice but hemorrhoidectomy.”
Finally, another technique is available for bleeding without prolapse: Hemorrhoidal embolization. Practiced for about a decade, the procedure involves blocking blood flow to the hemorrhoids by inserting tiny metal coils through a catheter, which is inserted via a transcutaneous route through an artery in the arm.
This story was translated from Medscape’s French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version appeared on Medscape.com.
according to Vincent de Parades, MD, PhD, of Hôpital Paris Saint-Joseph in France. In his presentation at France’s annual general medicine conference (JNMG 2024) on the management of hemorrhoidal disease, he noted, “this [NSAID and analgesic] treatment is highly effective, initially relieving pain and reducing edema, though the clot takes longer to resolve.” In cases where residual skin tags (marisques) remain after an episode, resection may be considered if they cause discomfort.
While patients often turn to over-the-counter topical treatments during flare-ups, de Parades noted that these have not been proven effective for hemorrhoidal disease. For hemorrhoidal thrombosis, however, a topical treatment with a corticosteroid and anesthetic may be prescribed.
No NSAIDs for Abscesses
In addition to NSAIDs, a local treatment may provide soothing benefits, especially when combined with topical application, as highlighted by Nadia Fathallah, MD, of Hôpital Paris Saint-Joseph, who joined de Parades in the presentation. “I recommend massaging the ointment to help dissolve the thrombus,” she added. However, “NSAIDs should not be prescribed in the case of an abscess,” cautioned de Parades, emphasizing that “any patient with a painful anal swelling needs an examination.” When in doubt, administer an analgesic and reexamine the patient 1-2 days later. If an abscess is present, it will not resolve on its own, and pain will persist.
The two proctologists reviewed various interventions for managing hemorrhoidal conditions, underscoring the benefits of minimally invasive surgery as an alternative to hemorrhoidectomy for treating grade 2 or 3 hemorrhoidal prolapse.
Hemorrhoidal disease involves abnormal dilation of the vascular system in the anus and rectum. External hemorrhoids affect the external vascular plexus, while internal hemorrhoids occur in the upper part of the anal canal at the internal plexus.
Hygiene and Dietary Guidelines
Common symptoms include light to heavy bleeding during bowel movements and the sensation of a lump inside the anus. In some cases, this is accompanied by throbbing pain, which suggests hemorrhoidal thrombosis, a condition often associated with a painful external swelling. Hemorrhoidal prolapse, meanwhile, is characterized by the protrusion of internal hemorrhoids and is classified into four grades:
- Grade 1: Hemorrhoids emerge during straining but do not protrude externally.
- Grade 2: Hemorrhoids protrude but spontaneously retract after straining.
- Grade 3: Hemorrhoids protrude with straining and require manual reinsertion.
- Grade 4: Prolapse is permanent.
In all cases, medical treatment is recommended as the initial approach. European guidelines recommend to first implement lifestyle and dietary measures, encouraging regular physical activity and adequate water and fiber intake to promote intestinal transit. Laxatives may also be recommended.
Elastic Band Ligation
For hemorrhoidal thrombosis, NSAIDs and nonopioid analgesics are recommended as first-line treatments. For patients with contraindications to NSAIDs, such as pregnant women, corticosteroid treatment may be administered, although it is less effective. Routine incision is no longer recommended, according to de Parades.
For prolapsed internal hemorrhoids, instrumental treatment is recommended as a second-line option if medical management fails for grades 1 and 2, or for isolated grade 3 hemorrhoids. With sclerotherapy injections largely phased out, two options remain: Infrared photocoagulation and elastic band ligation.
The objective of instrumental treatment is to create a scar at the top of the hemorrhoidal plexus to reduce vascularization and secure the hemorrhoid to the rectal wall. When correctly performed above the insensitive mucosal area in the anal canal, the procedure is painless.
Ligation involves placing an elastic band at the base of the hemorrhoid, with the intervention taking only a few minutes. “Within 4 weeks, the hemorrhoid disappears,” explained de Parades. Photocoagulation is a more superficial treatment requiring several spaced sessions, mainly to address bleeding.
Advances in Minimally Invasive Surgery
Surgery is recommended if instrumental treatment fails and as a first-line option for circular grade 3 hemorrhoids (multiple hemorrhoidal masses) and grade 4 cases.
Milligan-Morgan hemorrhoidectomy is considered the “gold standard” surgical technique and is used primarily for grades 2, 3, and 4 cases. This technique involves resecting the three main hemorrhoidal bundles while preserving surrounding tissue, providing a “radical and definitive” treatment.
While effective in the long term, hemorrhoid bundle resection requires a lengthy healing process and typically requires the patient to take 15-20 days off work. It is also not recommended for people who engage in anal intercourse, as “removing hemorrhoidal tissue can reduce flexibility and sensation in the anal canal,” Fathallah noted.
Another widely used technique in France is Doppler-guided hemorrhoidal artery ligation, which selectively reduces blood flow to the hemorrhoidal plexus. It is often combined with a mucopexy to secure the prolapse above the anal canal and restore normal anatomy.
Minimally invasive surgery is today increasingly considered an alternative to hemorrhoidectomy for treating grade 2 or 3 hemorrhoidal prolapse.
Laser and radiofrequency techniques induce submucosal coagulation, reducing arterial flow and creating fibrous tissue to retract the hemorrhoidal bundle. Because the procedure is applied above the anal canal, “it is associated with little or no pain.”
Hemorrhoidal Embolization
Recent studies have validated the benefits of minimally invasive surgery for this condition. In a French multicenter study, radiofrequency treatment significantly improved quality of life 3 months post operation, requiring only 4 days off work. The vast majority of patients said they were satisfied with the results.
The procedure is less uncomfortable than hemorrhoidectomy and allows for quicker recovery, but it carries a risk for recurrence. In the French study, nearly 8% of patients required reoperation within a year, mostly by hemorrhoidectomy. “The estimated recurrence rate is 20%-30% over 10 years,” said de Parades.
Overall, the specialist emphasized the value of surgery, including hemorrhoidectomy, in treating hemorrhoidal prolapse. With substantial benefits from minimally invasive options, “patients should be referred early” to prevent prolapse progression “that might leave no choice but hemorrhoidectomy.”
Finally, another technique is available for bleeding without prolapse: Hemorrhoidal embolization. Practiced for about a decade, the procedure involves blocking blood flow to the hemorrhoids by inserting tiny metal coils through a catheter, which is inserted via a transcutaneous route through an artery in the arm.
This story was translated from Medscape’s French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version appeared on Medscape.com.
according to Vincent de Parades, MD, PhD, of Hôpital Paris Saint-Joseph in France. In his presentation at France’s annual general medicine conference (JNMG 2024) on the management of hemorrhoidal disease, he noted, “this [NSAID and analgesic] treatment is highly effective, initially relieving pain and reducing edema, though the clot takes longer to resolve.” In cases where residual skin tags (marisques) remain after an episode, resection may be considered if they cause discomfort.
While patients often turn to over-the-counter topical treatments during flare-ups, de Parades noted that these have not been proven effective for hemorrhoidal disease. For hemorrhoidal thrombosis, however, a topical treatment with a corticosteroid and anesthetic may be prescribed.
No NSAIDs for Abscesses
In addition to NSAIDs, a local treatment may provide soothing benefits, especially when combined with topical application, as highlighted by Nadia Fathallah, MD, of Hôpital Paris Saint-Joseph, who joined de Parades in the presentation. “I recommend massaging the ointment to help dissolve the thrombus,” she added. However, “NSAIDs should not be prescribed in the case of an abscess,” cautioned de Parades, emphasizing that “any patient with a painful anal swelling needs an examination.” When in doubt, administer an analgesic and reexamine the patient 1-2 days later. If an abscess is present, it will not resolve on its own, and pain will persist.
The two proctologists reviewed various interventions for managing hemorrhoidal conditions, underscoring the benefits of minimally invasive surgery as an alternative to hemorrhoidectomy for treating grade 2 or 3 hemorrhoidal prolapse.
Hemorrhoidal disease involves abnormal dilation of the vascular system in the anus and rectum. External hemorrhoids affect the external vascular plexus, while internal hemorrhoids occur in the upper part of the anal canal at the internal plexus.
Hygiene and Dietary Guidelines
Common symptoms include light to heavy bleeding during bowel movements and the sensation of a lump inside the anus. In some cases, this is accompanied by throbbing pain, which suggests hemorrhoidal thrombosis, a condition often associated with a painful external swelling. Hemorrhoidal prolapse, meanwhile, is characterized by the protrusion of internal hemorrhoids and is classified into four grades:
- Grade 1: Hemorrhoids emerge during straining but do not protrude externally.
- Grade 2: Hemorrhoids protrude but spontaneously retract after straining.
- Grade 3: Hemorrhoids protrude with straining and require manual reinsertion.
- Grade 4: Prolapse is permanent.
In all cases, medical treatment is recommended as the initial approach. European guidelines recommend to first implement lifestyle and dietary measures, encouraging regular physical activity and adequate water and fiber intake to promote intestinal transit. Laxatives may also be recommended.
Elastic Band Ligation
For hemorrhoidal thrombosis, NSAIDs and nonopioid analgesics are recommended as first-line treatments. For patients with contraindications to NSAIDs, such as pregnant women, corticosteroid treatment may be administered, although it is less effective. Routine incision is no longer recommended, according to de Parades.
For prolapsed internal hemorrhoids, instrumental treatment is recommended as a second-line option if medical management fails for grades 1 and 2, or for isolated grade 3 hemorrhoids. With sclerotherapy injections largely phased out, two options remain: Infrared photocoagulation and elastic band ligation.
The objective of instrumental treatment is to create a scar at the top of the hemorrhoidal plexus to reduce vascularization and secure the hemorrhoid to the rectal wall. When correctly performed above the insensitive mucosal area in the anal canal, the procedure is painless.
Ligation involves placing an elastic band at the base of the hemorrhoid, with the intervention taking only a few minutes. “Within 4 weeks, the hemorrhoid disappears,” explained de Parades. Photocoagulation is a more superficial treatment requiring several spaced sessions, mainly to address bleeding.
Advances in Minimally Invasive Surgery
Surgery is recommended if instrumental treatment fails and as a first-line option for circular grade 3 hemorrhoids (multiple hemorrhoidal masses) and grade 4 cases.
Milligan-Morgan hemorrhoidectomy is considered the “gold standard” surgical technique and is used primarily for grades 2, 3, and 4 cases. This technique involves resecting the three main hemorrhoidal bundles while preserving surrounding tissue, providing a “radical and definitive” treatment.
While effective in the long term, hemorrhoid bundle resection requires a lengthy healing process and typically requires the patient to take 15-20 days off work. It is also not recommended for people who engage in anal intercourse, as “removing hemorrhoidal tissue can reduce flexibility and sensation in the anal canal,” Fathallah noted.
Another widely used technique in France is Doppler-guided hemorrhoidal artery ligation, which selectively reduces blood flow to the hemorrhoidal plexus. It is often combined with a mucopexy to secure the prolapse above the anal canal and restore normal anatomy.
Minimally invasive surgery is today increasingly considered an alternative to hemorrhoidectomy for treating grade 2 or 3 hemorrhoidal prolapse.
Laser and radiofrequency techniques induce submucosal coagulation, reducing arterial flow and creating fibrous tissue to retract the hemorrhoidal bundle. Because the procedure is applied above the anal canal, “it is associated with little or no pain.”
Hemorrhoidal Embolization
Recent studies have validated the benefits of minimally invasive surgery for this condition. In a French multicenter study, radiofrequency treatment significantly improved quality of life 3 months post operation, requiring only 4 days off work. The vast majority of patients said they were satisfied with the results.
The procedure is less uncomfortable than hemorrhoidectomy and allows for quicker recovery, but it carries a risk for recurrence. In the French study, nearly 8% of patients required reoperation within a year, mostly by hemorrhoidectomy. “The estimated recurrence rate is 20%-30% over 10 years,” said de Parades.
Overall, the specialist emphasized the value of surgery, including hemorrhoidectomy, in treating hemorrhoidal prolapse. With substantial benefits from minimally invasive options, “patients should be referred early” to prevent prolapse progression “that might leave no choice but hemorrhoidectomy.”
Finally, another technique is available for bleeding without prolapse: Hemorrhoidal embolization. Practiced for about a decade, the procedure involves blocking blood flow to the hemorrhoids by inserting tiny metal coils through a catheter, which is inserted via a transcutaneous route through an artery in the arm.
This story was translated from Medscape’s French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version appeared on Medscape.com.
Certain Pesticides Linked With Risk for Pancreatic Cancer
One of them, a case-control study, showed an elevated risk in individuals whose adipose tissue contained substances that are now banned.
“The association between pesticides and pancreatic cancer exists. It is of low magnitude but robust, concerning cumulative pesticides and three substances: Mancozeb, glyphosate, and sulfur in spray form,” said Mathias Brugel, MD, hospital practitioner at Basque Coast Hospital Center in Bayonne, France, during his presentation.
Regarding the four other liposoluble substances associated with an increased risk for pancreatic cancer in the second study, “their use has been banned since the 1990s, but they are still present in soils and in the air,” Dr. Brugel told this news organization.
For example, in Reims, France, the assessment of air quality by ATMO Grand Est revealed the presence of banned pesticides in the air, he added. However, Dr. Brugel stressed that a cause-effect relationship between pesticide exposure and the risk for pancreatic cancer cannot be established with these studies.
Incidence Rising Constantly
The incidence of pancreatic adenocarcinoma has been increasing steadily for more than 30 years. In France, nearly 16,000 new cases were reported in 2023, which represented an annual increase of about 2%. According to the National Cancer Institute, “pancreatic adenocarcinoma could become the second leading cause of cancer mortality by 2030.”
“This increase in incidence is particularly strong in France compared with other Western countries. The causes are still poorly understood. One might wonder whether environmental factors like pesticides are involved,” said Dr. Brugel.
Known to have a mechanism of action favoring oncogenesis, pesticides are suspected of being responsible for the rise in certain cancers, especially given their extensive use in France. In total, around 300 substances are authorized, and 65,000 tons are applied each year, making France the largest consumer of pesticides in Europe.
“Contamination is ubiquitous, meaning they are found in soil, water, air, and in individuals,” said Dr. Brugel. According to a study by the Institute for Scientific Expertise Research, pesticide residues were detected in 64% of hair samples taken from French volunteers.
The literature increasingly reported data suggesting a link between pesticide exposure and the development of certain diseases like cancer. A 2021 document by Inserm notably confirmed the strong presumption of a link between occupational pesticide exposure and pathologies such as non-Hodgkin’s lymphoma and prostate cancer.
High-Incidence Zones
To explore the link between pesticide exposure and pancreatic cancer, Dr. Brugel and his colleagues conducted the EcoPESTIPAC and PESTIPAC studies, the results of which were presented at this year’s conference.
In EcoPESTIPAC, researchers conducted a national ecological regression by dividing the entire French territory into 5529 spatial units. The number of pancreatic cancer cases per spatial unit per year (disease-mapping) was determined using the National Health Data System.
Nine chemicals, including glyphosate, were included, thus covering half of pesticide purchases in France. The cumulative quantity of pesticides, regardless of molecule, was also examined. Pesticide exposure was estimated by the median ratio between pesticide purchase and agricultural area per spatial unit over an 11-year period from early 2011 to the end of 2021.
Mor than 134,000 cases of pancreatic cancer were reported during this period. The analysis revealed three high-incidence zones located around Paris, in central France, and in the Mediterranean basin, while spatial units in the western region showed the lowest incidences.
The heterogeneous distribution of the disease suggests the involvement of risk factors, said Dr. Brugel. After adjusting for confounding factors such as smoking, the study showed an increased risk for pancreatic cancer associated with the cumulative quantity of pesticides and three specific substances: Sulfur in spray form, mancozeb, and glyphosate.
Risk Increases
A dose-response relationship was evident. For an increase in pesticide use of 2.5 kg/hectare over 11 years, the risk for pancreatic adenocarcinoma increased from 0.9% to 1.4%. “The increase is relatively small, but one must not forget that this risk applies to all of France,” said Dr. Brugel. Indeed, the risk appeared homogeneous across the entire territory.
This was the first study to explore this link at the national level. Although the association between the four identified factors and pancreatic risk was robust, the study had some limitations. It relied on the quantities of pesticides purchased to estimate the quantities used, Dr. Brugel pointed out.
The second study, PESTIPAC, was a case-control study conducted at the Reims University Hospital to explore the association between pancreatic adenocarcinoma and concentrations of organochlorine pesticides in fat and urine.
The study included 26 patients with pancreatic cancer who had abdominal surgery that allowed for adipose tissue sampling (minimum 10 g). Urine was collected in the morning on an empty stomach.
A control group was formed by including 26 other patients who underwent surgery for a benign abdominal condition such as gallstones or hernia, thus allowing for the same sampling. Individuals in both groups were matched for age and body mass index, two risk factors for pancreatic cancer.
Banned Substances
In total, 345 substances were searched for using chromatography and mass spectrometry. Analyses revealed the presence of five banned substances in all patients, while nine substances were found in half of the samples.
“Contamination is very widespread, both in patients with pancreatic cancer and in the controls,” said Dr. Brugel. Consequently, for this study, between-group comparisons of substances present in all individuals could not be performed.
After adjustment, an association with an increased risk for pancreatic cancer was nonetheless observed with four liposoluble substances: 4,4-DDE, mirex or perchlordecone, trans-nonachlor, and cis-nonachlor. All four substances are herbicides that have been banned for at least 30 years.
The study also aimed to assess the effect of pesticide presence in the body on survival after pancreatic cancer. The results showed no significant difference for overall survival or progression-free survival.
“Pesticides are a credible candidate to explain the increase in the incidence of pancreatic adenocarcinoma,” said Dr. Brugel. However, “if associations between pancreatic cancer and pesticides exist, they remain poorly understood, and it is difficult to establish clear causality.”
Further large-scale studies will be needed to confirm these associations. An evaluation of the general population’s exposure to banned substances also appears justified, according to the researchers.
This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
One of them, a case-control study, showed an elevated risk in individuals whose adipose tissue contained substances that are now banned.
“The association between pesticides and pancreatic cancer exists. It is of low magnitude but robust, concerning cumulative pesticides and three substances: Mancozeb, glyphosate, and sulfur in spray form,” said Mathias Brugel, MD, hospital practitioner at Basque Coast Hospital Center in Bayonne, France, during his presentation.
Regarding the four other liposoluble substances associated with an increased risk for pancreatic cancer in the second study, “their use has been banned since the 1990s, but they are still present in soils and in the air,” Dr. Brugel told this news organization.
For example, in Reims, France, the assessment of air quality by ATMO Grand Est revealed the presence of banned pesticides in the air, he added. However, Dr. Brugel stressed that a cause-effect relationship between pesticide exposure and the risk for pancreatic cancer cannot be established with these studies.
Incidence Rising Constantly
The incidence of pancreatic adenocarcinoma has been increasing steadily for more than 30 years. In France, nearly 16,000 new cases were reported in 2023, which represented an annual increase of about 2%. According to the National Cancer Institute, “pancreatic adenocarcinoma could become the second leading cause of cancer mortality by 2030.”
“This increase in incidence is particularly strong in France compared with other Western countries. The causes are still poorly understood. One might wonder whether environmental factors like pesticides are involved,” said Dr. Brugel.
Known to have a mechanism of action favoring oncogenesis, pesticides are suspected of being responsible for the rise in certain cancers, especially given their extensive use in France. In total, around 300 substances are authorized, and 65,000 tons are applied each year, making France the largest consumer of pesticides in Europe.
“Contamination is ubiquitous, meaning they are found in soil, water, air, and in individuals,” said Dr. Brugel. According to a study by the Institute for Scientific Expertise Research, pesticide residues were detected in 64% of hair samples taken from French volunteers.
The literature increasingly reported data suggesting a link between pesticide exposure and the development of certain diseases like cancer. A 2021 document by Inserm notably confirmed the strong presumption of a link between occupational pesticide exposure and pathologies such as non-Hodgkin’s lymphoma and prostate cancer.
High-Incidence Zones
To explore the link between pesticide exposure and pancreatic cancer, Dr. Brugel and his colleagues conducted the EcoPESTIPAC and PESTIPAC studies, the results of which were presented at this year’s conference.
In EcoPESTIPAC, researchers conducted a national ecological regression by dividing the entire French territory into 5529 spatial units. The number of pancreatic cancer cases per spatial unit per year (disease-mapping) was determined using the National Health Data System.
Nine chemicals, including glyphosate, were included, thus covering half of pesticide purchases in France. The cumulative quantity of pesticides, regardless of molecule, was also examined. Pesticide exposure was estimated by the median ratio between pesticide purchase and agricultural area per spatial unit over an 11-year period from early 2011 to the end of 2021.
Mor than 134,000 cases of pancreatic cancer were reported during this period. The analysis revealed three high-incidence zones located around Paris, in central France, and in the Mediterranean basin, while spatial units in the western region showed the lowest incidences.
The heterogeneous distribution of the disease suggests the involvement of risk factors, said Dr. Brugel. After adjusting for confounding factors such as smoking, the study showed an increased risk for pancreatic cancer associated with the cumulative quantity of pesticides and three specific substances: Sulfur in spray form, mancozeb, and glyphosate.
Risk Increases
A dose-response relationship was evident. For an increase in pesticide use of 2.5 kg/hectare over 11 years, the risk for pancreatic adenocarcinoma increased from 0.9% to 1.4%. “The increase is relatively small, but one must not forget that this risk applies to all of France,” said Dr. Brugel. Indeed, the risk appeared homogeneous across the entire territory.
This was the first study to explore this link at the national level. Although the association between the four identified factors and pancreatic risk was robust, the study had some limitations. It relied on the quantities of pesticides purchased to estimate the quantities used, Dr. Brugel pointed out.
The second study, PESTIPAC, was a case-control study conducted at the Reims University Hospital to explore the association between pancreatic adenocarcinoma and concentrations of organochlorine pesticides in fat and urine.
The study included 26 patients with pancreatic cancer who had abdominal surgery that allowed for adipose tissue sampling (minimum 10 g). Urine was collected in the morning on an empty stomach.
A control group was formed by including 26 other patients who underwent surgery for a benign abdominal condition such as gallstones or hernia, thus allowing for the same sampling. Individuals in both groups were matched for age and body mass index, two risk factors for pancreatic cancer.
Banned Substances
In total, 345 substances were searched for using chromatography and mass spectrometry. Analyses revealed the presence of five banned substances in all patients, while nine substances were found in half of the samples.
“Contamination is very widespread, both in patients with pancreatic cancer and in the controls,” said Dr. Brugel. Consequently, for this study, between-group comparisons of substances present in all individuals could not be performed.
After adjustment, an association with an increased risk for pancreatic cancer was nonetheless observed with four liposoluble substances: 4,4-DDE, mirex or perchlordecone, trans-nonachlor, and cis-nonachlor. All four substances are herbicides that have been banned for at least 30 years.
The study also aimed to assess the effect of pesticide presence in the body on survival after pancreatic cancer. The results showed no significant difference for overall survival or progression-free survival.
“Pesticides are a credible candidate to explain the increase in the incidence of pancreatic adenocarcinoma,” said Dr. Brugel. However, “if associations between pancreatic cancer and pesticides exist, they remain poorly understood, and it is difficult to establish clear causality.”
Further large-scale studies will be needed to confirm these associations. An evaluation of the general population’s exposure to banned substances also appears justified, according to the researchers.
This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
One of them, a case-control study, showed an elevated risk in individuals whose adipose tissue contained substances that are now banned.
“The association between pesticides and pancreatic cancer exists. It is of low magnitude but robust, concerning cumulative pesticides and three substances: Mancozeb, glyphosate, and sulfur in spray form,” said Mathias Brugel, MD, hospital practitioner at Basque Coast Hospital Center in Bayonne, France, during his presentation.
Regarding the four other liposoluble substances associated with an increased risk for pancreatic cancer in the second study, “their use has been banned since the 1990s, but they are still present in soils and in the air,” Dr. Brugel told this news organization.
For example, in Reims, France, the assessment of air quality by ATMO Grand Est revealed the presence of banned pesticides in the air, he added. However, Dr. Brugel stressed that a cause-effect relationship between pesticide exposure and the risk for pancreatic cancer cannot be established with these studies.
Incidence Rising Constantly
The incidence of pancreatic adenocarcinoma has been increasing steadily for more than 30 years. In France, nearly 16,000 new cases were reported in 2023, which represented an annual increase of about 2%. According to the National Cancer Institute, “pancreatic adenocarcinoma could become the second leading cause of cancer mortality by 2030.”
“This increase in incidence is particularly strong in France compared with other Western countries. The causes are still poorly understood. One might wonder whether environmental factors like pesticides are involved,” said Dr. Brugel.
Known to have a mechanism of action favoring oncogenesis, pesticides are suspected of being responsible for the rise in certain cancers, especially given their extensive use in France. In total, around 300 substances are authorized, and 65,000 tons are applied each year, making France the largest consumer of pesticides in Europe.
“Contamination is ubiquitous, meaning they are found in soil, water, air, and in individuals,” said Dr. Brugel. According to a study by the Institute for Scientific Expertise Research, pesticide residues were detected in 64% of hair samples taken from French volunteers.
The literature increasingly reported data suggesting a link between pesticide exposure and the development of certain diseases like cancer. A 2021 document by Inserm notably confirmed the strong presumption of a link between occupational pesticide exposure and pathologies such as non-Hodgkin’s lymphoma and prostate cancer.
High-Incidence Zones
To explore the link between pesticide exposure and pancreatic cancer, Dr. Brugel and his colleagues conducted the EcoPESTIPAC and PESTIPAC studies, the results of which were presented at this year’s conference.
In EcoPESTIPAC, researchers conducted a national ecological regression by dividing the entire French territory into 5529 spatial units. The number of pancreatic cancer cases per spatial unit per year (disease-mapping) was determined using the National Health Data System.
Nine chemicals, including glyphosate, were included, thus covering half of pesticide purchases in France. The cumulative quantity of pesticides, regardless of molecule, was also examined. Pesticide exposure was estimated by the median ratio between pesticide purchase and agricultural area per spatial unit over an 11-year period from early 2011 to the end of 2021.
Mor than 134,000 cases of pancreatic cancer were reported during this period. The analysis revealed three high-incidence zones located around Paris, in central France, and in the Mediterranean basin, while spatial units in the western region showed the lowest incidences.
The heterogeneous distribution of the disease suggests the involvement of risk factors, said Dr. Brugel. After adjusting for confounding factors such as smoking, the study showed an increased risk for pancreatic cancer associated with the cumulative quantity of pesticides and three specific substances: Sulfur in spray form, mancozeb, and glyphosate.
Risk Increases
A dose-response relationship was evident. For an increase in pesticide use of 2.5 kg/hectare over 11 years, the risk for pancreatic adenocarcinoma increased from 0.9% to 1.4%. “The increase is relatively small, but one must not forget that this risk applies to all of France,” said Dr. Brugel. Indeed, the risk appeared homogeneous across the entire territory.
This was the first study to explore this link at the national level. Although the association between the four identified factors and pancreatic risk was robust, the study had some limitations. It relied on the quantities of pesticides purchased to estimate the quantities used, Dr. Brugel pointed out.
The second study, PESTIPAC, was a case-control study conducted at the Reims University Hospital to explore the association between pancreatic adenocarcinoma and concentrations of organochlorine pesticides in fat and urine.
The study included 26 patients with pancreatic cancer who had abdominal surgery that allowed for adipose tissue sampling (minimum 10 g). Urine was collected in the morning on an empty stomach.
A control group was formed by including 26 other patients who underwent surgery for a benign abdominal condition such as gallstones or hernia, thus allowing for the same sampling. Individuals in both groups were matched for age and body mass index, two risk factors for pancreatic cancer.
Banned Substances
In total, 345 substances were searched for using chromatography and mass spectrometry. Analyses revealed the presence of five banned substances in all patients, while nine substances were found in half of the samples.
“Contamination is very widespread, both in patients with pancreatic cancer and in the controls,” said Dr. Brugel. Consequently, for this study, between-group comparisons of substances present in all individuals could not be performed.
After adjustment, an association with an increased risk for pancreatic cancer was nonetheless observed with four liposoluble substances: 4,4-DDE, mirex or perchlordecone, trans-nonachlor, and cis-nonachlor. All four substances are herbicides that have been banned for at least 30 years.
The study also aimed to assess the effect of pesticide presence in the body on survival after pancreatic cancer. The results showed no significant difference for overall survival or progression-free survival.
“Pesticides are a credible candidate to explain the increase in the incidence of pancreatic adenocarcinoma,” said Dr. Brugel. However, “if associations between pancreatic cancer and pesticides exist, they remain poorly understood, and it is difficult to establish clear causality.”
Further large-scale studies will be needed to confirm these associations. An evaluation of the general population’s exposure to banned substances also appears justified, according to the researchers.
This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
Hair-Straightening Products Entail Acute Kidney Failure Risk
The observation was made by a team of French researchers who tested the suspected straightening product on animals. The product is believed to be the cause of several episodes of renal damage in a young woman.
“The results on mice are striking,” said study author Emmanuel Letavernier, MD, a nephrologist at Tenon Hospital in Paris. “They develop extremely severe acute kidney failure within 24 hours of applying the straightening cream. Samples show the presence of calcium oxalate crystals in all renal tubules.”
Given the potential nephrotoxicity of glyoxylic acid through topical application, products containing this compound should be avoided and ideally withdrawn from the market, the researchers suggested in a letter published in The New England Journal of Medicine. The appropriate departments of the French Agency for Food, Environmental, and Occupational Health and Safety have been alerted, Dr. Letavernier added.
Replacing Formaldehyde
Glyoxylic acid has recently been introduced into certain cosmetic products (such as shampoo, styling lotion, and straightening products), often as a replacement for formaldehyde, which is irritating and possibly carcinogenic. Glyoxylic acid is praised for its smoothing qualities. However, it is recommended to avoid contact with the scalp.
Cases of renal complications could be underdiagnosed, according to the researchers, who are preparing a nationwide survey. Renal failure can be silent. Among the signs that should raise concern are “scalp irritation accompanied by nausea or vomiting after a hair salon visit,” said Dr. Letavernier.
Similar cases have already been reported in the literature. An Israeli team recently described 26 patients treated for acute renal injuries after hair straightening in hair salons. Biopsies revealed calcium oxalate crystals in the kidneys.
The Israeli researchers suspected an effect of glycolic acid, another substance found in many cosmetic products, including straightening products. However, they could not provide evidence.
Glycolic Acid Safe?
By conducting a second animal study, which should be published soon, Dr. Letavernier and his team were able to rule out this hypothesis. “Glycolic acid does not pose a problem. Unlike glyoxylic acid, the application of glycolic acid on the skin of mice does not induce the formation of oxalate crystals in the kidneys, nor acute kidney failure.”
The French clinical case reported in the correspondence concerns a 26-year-old woman with no prior health history who had three episodes of acute renal damage 1 year apart. It turned out that each episode occurred shortly after hair straightening at a hair salon in Marseille.
The patient reported feeling a burning sensation during the hair treatment. Scalp irritations appeared. She then experienced vomiting, diarrhea, fever, and back pain. Analyses revealed high levels of plasma creatinine during each episode, indicating renal failure.
A CT scan showed no signs of urinary tract obstruction. However, the patient had a small kidney stone. Further analysis revealed the presence of blood and leukocytes in the urine. But there was no proteinuria or urinary infection.
Chronic Renal Failure
After each episode, renal function rapidly improved. “The repetition of episodes of acute renal failure is, however, a major risk factor for developing chronic renal failure in the long term,” said Dr. Letavernier.
The cream used in the hair salon to straighten hair was retrieved by the researchers. It contained a significant amount of glyoxylic acid but no glycolic acid.
To explore its potential nephrotoxic effect, they conducted a study on 10 mice. The animals were divided into two groups to test on one side topical application of the product and a gel without active product (control group) on the other.
Mice exposed to the product had oxalate crystals in their urine, unlike mice in the control group. A scan confirmed calcium oxalate deposits in the kidneys. Plasma creatinine levels increased significantly after exposure to glyoxylic acid.
“After passing through the epidermis, glyoxylic acid is rapidly converted in the blood to glyoxylate. In the liver and probably in other organs, glyoxylate is metabolized to become oxalate, which upon contact with calcium in the urine forms calcium oxalate crystals,” explained the specialist.
Excess calcium oxalate crystals causing renal failure are observed in rare conditions such as primary hyperoxaluria, a genetic disease affecting liver metabolism, or enteric hyperoxaluria, which is linked to increased intestinal permeability to oxalate: an anion naturally found in certain plants.
This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
The observation was made by a team of French researchers who tested the suspected straightening product on animals. The product is believed to be the cause of several episodes of renal damage in a young woman.
“The results on mice are striking,” said study author Emmanuel Letavernier, MD, a nephrologist at Tenon Hospital in Paris. “They develop extremely severe acute kidney failure within 24 hours of applying the straightening cream. Samples show the presence of calcium oxalate crystals in all renal tubules.”
Given the potential nephrotoxicity of glyoxylic acid through topical application, products containing this compound should be avoided and ideally withdrawn from the market, the researchers suggested in a letter published in The New England Journal of Medicine. The appropriate departments of the French Agency for Food, Environmental, and Occupational Health and Safety have been alerted, Dr. Letavernier added.
Replacing Formaldehyde
Glyoxylic acid has recently been introduced into certain cosmetic products (such as shampoo, styling lotion, and straightening products), often as a replacement for formaldehyde, which is irritating and possibly carcinogenic. Glyoxylic acid is praised for its smoothing qualities. However, it is recommended to avoid contact with the scalp.
Cases of renal complications could be underdiagnosed, according to the researchers, who are preparing a nationwide survey. Renal failure can be silent. Among the signs that should raise concern are “scalp irritation accompanied by nausea or vomiting after a hair salon visit,” said Dr. Letavernier.
Similar cases have already been reported in the literature. An Israeli team recently described 26 patients treated for acute renal injuries after hair straightening in hair salons. Biopsies revealed calcium oxalate crystals in the kidneys.
The Israeli researchers suspected an effect of glycolic acid, another substance found in many cosmetic products, including straightening products. However, they could not provide evidence.
Glycolic Acid Safe?
By conducting a second animal study, which should be published soon, Dr. Letavernier and his team were able to rule out this hypothesis. “Glycolic acid does not pose a problem. Unlike glyoxylic acid, the application of glycolic acid on the skin of mice does not induce the formation of oxalate crystals in the kidneys, nor acute kidney failure.”
The French clinical case reported in the correspondence concerns a 26-year-old woman with no prior health history who had three episodes of acute renal damage 1 year apart. It turned out that each episode occurred shortly after hair straightening at a hair salon in Marseille.
The patient reported feeling a burning sensation during the hair treatment. Scalp irritations appeared. She then experienced vomiting, diarrhea, fever, and back pain. Analyses revealed high levels of plasma creatinine during each episode, indicating renal failure.
A CT scan showed no signs of urinary tract obstruction. However, the patient had a small kidney stone. Further analysis revealed the presence of blood and leukocytes in the urine. But there was no proteinuria or urinary infection.
Chronic Renal Failure
After each episode, renal function rapidly improved. “The repetition of episodes of acute renal failure is, however, a major risk factor for developing chronic renal failure in the long term,” said Dr. Letavernier.
The cream used in the hair salon to straighten hair was retrieved by the researchers. It contained a significant amount of glyoxylic acid but no glycolic acid.
To explore its potential nephrotoxic effect, they conducted a study on 10 mice. The animals were divided into two groups to test on one side topical application of the product and a gel without active product (control group) on the other.
Mice exposed to the product had oxalate crystals in their urine, unlike mice in the control group. A scan confirmed calcium oxalate deposits in the kidneys. Plasma creatinine levels increased significantly after exposure to glyoxylic acid.
“After passing through the epidermis, glyoxylic acid is rapidly converted in the blood to glyoxylate. In the liver and probably in other organs, glyoxylate is metabolized to become oxalate, which upon contact with calcium in the urine forms calcium oxalate crystals,” explained the specialist.
Excess calcium oxalate crystals causing renal failure are observed in rare conditions such as primary hyperoxaluria, a genetic disease affecting liver metabolism, or enteric hyperoxaluria, which is linked to increased intestinal permeability to oxalate: an anion naturally found in certain plants.
This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
The observation was made by a team of French researchers who tested the suspected straightening product on animals. The product is believed to be the cause of several episodes of renal damage in a young woman.
“The results on mice are striking,” said study author Emmanuel Letavernier, MD, a nephrologist at Tenon Hospital in Paris. “They develop extremely severe acute kidney failure within 24 hours of applying the straightening cream. Samples show the presence of calcium oxalate crystals in all renal tubules.”
Given the potential nephrotoxicity of glyoxylic acid through topical application, products containing this compound should be avoided and ideally withdrawn from the market, the researchers suggested in a letter published in The New England Journal of Medicine. The appropriate departments of the French Agency for Food, Environmental, and Occupational Health and Safety have been alerted, Dr. Letavernier added.
Replacing Formaldehyde
Glyoxylic acid has recently been introduced into certain cosmetic products (such as shampoo, styling lotion, and straightening products), often as a replacement for formaldehyde, which is irritating and possibly carcinogenic. Glyoxylic acid is praised for its smoothing qualities. However, it is recommended to avoid contact with the scalp.
Cases of renal complications could be underdiagnosed, according to the researchers, who are preparing a nationwide survey. Renal failure can be silent. Among the signs that should raise concern are “scalp irritation accompanied by nausea or vomiting after a hair salon visit,” said Dr. Letavernier.
Similar cases have already been reported in the literature. An Israeli team recently described 26 patients treated for acute renal injuries after hair straightening in hair salons. Biopsies revealed calcium oxalate crystals in the kidneys.
The Israeli researchers suspected an effect of glycolic acid, another substance found in many cosmetic products, including straightening products. However, they could not provide evidence.
Glycolic Acid Safe?
By conducting a second animal study, which should be published soon, Dr. Letavernier and his team were able to rule out this hypothesis. “Glycolic acid does not pose a problem. Unlike glyoxylic acid, the application of glycolic acid on the skin of mice does not induce the formation of oxalate crystals in the kidneys, nor acute kidney failure.”
The French clinical case reported in the correspondence concerns a 26-year-old woman with no prior health history who had three episodes of acute renal damage 1 year apart. It turned out that each episode occurred shortly after hair straightening at a hair salon in Marseille.
The patient reported feeling a burning sensation during the hair treatment. Scalp irritations appeared. She then experienced vomiting, diarrhea, fever, and back pain. Analyses revealed high levels of plasma creatinine during each episode, indicating renal failure.
A CT scan showed no signs of urinary tract obstruction. However, the patient had a small kidney stone. Further analysis revealed the presence of blood and leukocytes in the urine. But there was no proteinuria or urinary infection.
Chronic Renal Failure
After each episode, renal function rapidly improved. “The repetition of episodes of acute renal failure is, however, a major risk factor for developing chronic renal failure in the long term,” said Dr. Letavernier.
The cream used in the hair salon to straighten hair was retrieved by the researchers. It contained a significant amount of glyoxylic acid but no glycolic acid.
To explore its potential nephrotoxic effect, they conducted a study on 10 mice. The animals were divided into two groups to test on one side topical application of the product and a gel without active product (control group) on the other.
Mice exposed to the product had oxalate crystals in their urine, unlike mice in the control group. A scan confirmed calcium oxalate deposits in the kidneys. Plasma creatinine levels increased significantly after exposure to glyoxylic acid.
“After passing through the epidermis, glyoxylic acid is rapidly converted in the blood to glyoxylate. In the liver and probably in other organs, glyoxylate is metabolized to become oxalate, which upon contact with calcium in the urine forms calcium oxalate crystals,” explained the specialist.
Excess calcium oxalate crystals causing renal failure are observed in rare conditions such as primary hyperoxaluria, a genetic disease affecting liver metabolism, or enteric hyperoxaluria, which is linked to increased intestinal permeability to oxalate: an anion naturally found in certain plants.
This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
Bladder Cancer: Is Active Surveillance the Way Forward?
PARIS — Should clinicians promote active surveillance for non–muscle-invasive bladder tumors (NMIBT) and establish it as a comprehensive management approach, as with prostate and kidney cancers?
During the 117th congress of the French Association of Urology (AFU), Benjamin Pradère, MD, urologic surgeon at Croix du Sud Clinic in Quint-Fonsegrives, France, advocated for this approach, suggesting that the use of biomarkers could enhance its effectiveness.
However, it requires careful patient selection, proper information, and relevant follow-up,” said Dr. Pradère, who is a member of the AFU Cancer Committee (CCAFU).
Low-Grade Tumors
NMIBTs are precancerous lesions and constitute 70%-80% of diagnosed bladder tumors. The remaining tumors are more severe invasive tumors that infiltrate deep tissues. NMIBTs, however, entail a high risk for recurrence (reaching 80% after endoscopic resection), as well as a high risk for progression.
As a result, the diagnosis of NMIBT involves follow-up that significantly impacts patients’ quality of life due to repeated cystoscopies and endovesical treatments. “Tumors with the most impact are low-grade Ta tumors”, with longer-term monitoring required for these low-risk tumors.
Hematuria is the most frequent clinical sign. NMIBT diagnosis occurs after endoscopic tumor resection via transurethral resection, followed by an anatomopathological analysis to determine cell grade and tumor stage. Treatment depends on the risk of recurrence and progression, as well as the risk of therapeutic failure after the initial resection.
Risk stratification distinguishes the following four levels:
- Low-risk tumors: Low-grade pTa urothelial tumors, unifocal, < 3 cm, no history of bladder tumors. Low risk of recurrence and progression.
- Intermediate-risk tumors: Other low-grade pTa urothelial tumors with no high-risk criteria. Low risk of progression but high risk of recurrence.
- High-risk tumors: Tumors with at least one risk factor: Stage pT1, high grade, presence of carcinoma in situ. High risks of progression and recurrence.
- Very high-risk tumors: Tumors combining all risk factors (pT1 grade with carcinoma in situ). Very high and early risk of progression.
“We know that low-grade NMIBTs have no impact on survival,” said Dr. Pradère. For these tumors, which represent 60% of diagnosed NMIBTs, or approximately 250,000 new cases annually in France, specific survival is > 99%, meaning that most diagnosed patients will not die of bladder cancer.
The recurrence rate for low-grade tumors is 50%, but recurrences are “almost always low-grade and rarely invade the basement membrane,” said Pradère. Implementing active surveillance to limit surgical intervention to more advanced forms seems to be relevant for these tumors.
Cystoscopy Every 3 Months
According to CCAFU recommendations, “active surveillance is a therapeutic alternative that can be proposed for patients with recurrent low-risk NMIBT after the initial diagnosis.” Criteria include low-grade pTa, fewer than five tumors, size ≤ 15 mm, negative urinary cytology, asymptomatic nature, and the patient’s acceptance of closer monitoring.
While active surveillance has become the standard treatment for low-risk prostate cancer, this therapeutic option remains marginal in bladder cancer, as in kidney cancer. The goal is to defer or avoid surgical treatment by closely monitoring the natural progression of the disease.
For NMIBTs, follow-up modalities are not yet specifically recommended because of a lack of data, said Dr. Pradère. According to a consensus, cystoscopy should be repeated every 3 months for a year and then every 6 months. Unlike standard follow-up, it includes cytology “to not miss the transition to high grade.”
CCAFU recommends discontinuing active surveillance if any of the following criteria are present:
- More than 10 lesions
- Size > 30 mm
- Positive cytology
- Symptoms (hematuria, micturition disorders, and recurring infections).
Literature on the benefits of active surveillance in bladder tumors is still limited. Only seven studies are available. Overall, for nearly 600 included patients, tumors progressed in about 12% of cases. Progression to invasive tumors occurred in 0.8% of patients (n = 5).
13 Months’ Surveillance
According to a long-term study (median follow-up of 38 months), patients mostly exit active surveillance in the first year. The median duration of active surveillance is 13 months. Active surveillance is discontinued to surgically treat tumors that turn out to be low-grade Ta tumors in 70% of cases.
The following factors predicting recurrence and progression of tumors have been identified: Multiple tumors, early recurrence (within a year of initial diagnosis), frequent recurrence (more than one recurrence per year), tumors > 3 cm, and failure of previous endovesical treatment.
Recent studies have shown that with at least three of these recurrence and progression factors, the median duration under active surveillance is 15 months compared with 28 months in the absence of such factors. “Considering these factors, it is possible to assess the benefit of active surveillance for the patient,” said Dr. Pradère.
If active surveillance for bladder tumors is still not widely practiced, then the contribution of imaging (MRI and ultrasound) and biomarkers could promote its adoption. “The use of biomarkers should change the game and encourage active surveillance in patients with small polyps,” said Dr. Pradère.
ADXBladder Test Utility
A study highlighted the importance of evaluating minichromosome maintenance protein 5 expression during active surveillance using the ADXBladder ELISA test on a urine sample. This test is usually used in bladder cancer diagnosis.
“This study showed that a negative result in two consecutive tests during active surveillance is associated with an almost zero recurrence risk. After two negative tests, most patients do not exit active surveillance,” said Dr. Pradère. But the positive predictive value of biomarkers remains low for low-grade tumors.
The future of active surveillance in bladder cancer should involve better patient selection that relies on risk factors, enhanced modalities through imaging and biomarkers, and the advent of artificial intelligence to analyze cystoscopy results, concluded Dr. Pradère.
This article was translated from the Medscape French edition. A version of this article appeared on Medscape.com.
PARIS — Should clinicians promote active surveillance for non–muscle-invasive bladder tumors (NMIBT) and establish it as a comprehensive management approach, as with prostate and kidney cancers?
During the 117th congress of the French Association of Urology (AFU), Benjamin Pradère, MD, urologic surgeon at Croix du Sud Clinic in Quint-Fonsegrives, France, advocated for this approach, suggesting that the use of biomarkers could enhance its effectiveness.
However, it requires careful patient selection, proper information, and relevant follow-up,” said Dr. Pradère, who is a member of the AFU Cancer Committee (CCAFU).
Low-Grade Tumors
NMIBTs are precancerous lesions and constitute 70%-80% of diagnosed bladder tumors. The remaining tumors are more severe invasive tumors that infiltrate deep tissues. NMIBTs, however, entail a high risk for recurrence (reaching 80% after endoscopic resection), as well as a high risk for progression.
As a result, the diagnosis of NMIBT involves follow-up that significantly impacts patients’ quality of life due to repeated cystoscopies and endovesical treatments. “Tumors with the most impact are low-grade Ta tumors”, with longer-term monitoring required for these low-risk tumors.
Hematuria is the most frequent clinical sign. NMIBT diagnosis occurs after endoscopic tumor resection via transurethral resection, followed by an anatomopathological analysis to determine cell grade and tumor stage. Treatment depends on the risk of recurrence and progression, as well as the risk of therapeutic failure after the initial resection.
Risk stratification distinguishes the following four levels:
- Low-risk tumors: Low-grade pTa urothelial tumors, unifocal, < 3 cm, no history of bladder tumors. Low risk of recurrence and progression.
- Intermediate-risk tumors: Other low-grade pTa urothelial tumors with no high-risk criteria. Low risk of progression but high risk of recurrence.
- High-risk tumors: Tumors with at least one risk factor: Stage pT1, high grade, presence of carcinoma in situ. High risks of progression and recurrence.
- Very high-risk tumors: Tumors combining all risk factors (pT1 grade with carcinoma in situ). Very high and early risk of progression.
“We know that low-grade NMIBTs have no impact on survival,” said Dr. Pradère. For these tumors, which represent 60% of diagnosed NMIBTs, or approximately 250,000 new cases annually in France, specific survival is > 99%, meaning that most diagnosed patients will not die of bladder cancer.
The recurrence rate for low-grade tumors is 50%, but recurrences are “almost always low-grade and rarely invade the basement membrane,” said Pradère. Implementing active surveillance to limit surgical intervention to more advanced forms seems to be relevant for these tumors.
Cystoscopy Every 3 Months
According to CCAFU recommendations, “active surveillance is a therapeutic alternative that can be proposed for patients with recurrent low-risk NMIBT after the initial diagnosis.” Criteria include low-grade pTa, fewer than five tumors, size ≤ 15 mm, negative urinary cytology, asymptomatic nature, and the patient’s acceptance of closer monitoring.
While active surveillance has become the standard treatment for low-risk prostate cancer, this therapeutic option remains marginal in bladder cancer, as in kidney cancer. The goal is to defer or avoid surgical treatment by closely monitoring the natural progression of the disease.
For NMIBTs, follow-up modalities are not yet specifically recommended because of a lack of data, said Dr. Pradère. According to a consensus, cystoscopy should be repeated every 3 months for a year and then every 6 months. Unlike standard follow-up, it includes cytology “to not miss the transition to high grade.”
CCAFU recommends discontinuing active surveillance if any of the following criteria are present:
- More than 10 lesions
- Size > 30 mm
- Positive cytology
- Symptoms (hematuria, micturition disorders, and recurring infections).
Literature on the benefits of active surveillance in bladder tumors is still limited. Only seven studies are available. Overall, for nearly 600 included patients, tumors progressed in about 12% of cases. Progression to invasive tumors occurred in 0.8% of patients (n = 5).
13 Months’ Surveillance
According to a long-term study (median follow-up of 38 months), patients mostly exit active surveillance in the first year. The median duration of active surveillance is 13 months. Active surveillance is discontinued to surgically treat tumors that turn out to be low-grade Ta tumors in 70% of cases.
The following factors predicting recurrence and progression of tumors have been identified: Multiple tumors, early recurrence (within a year of initial diagnosis), frequent recurrence (more than one recurrence per year), tumors > 3 cm, and failure of previous endovesical treatment.
Recent studies have shown that with at least three of these recurrence and progression factors, the median duration under active surveillance is 15 months compared with 28 months in the absence of such factors. “Considering these factors, it is possible to assess the benefit of active surveillance for the patient,” said Dr. Pradère.
If active surveillance for bladder tumors is still not widely practiced, then the contribution of imaging (MRI and ultrasound) and biomarkers could promote its adoption. “The use of biomarkers should change the game and encourage active surveillance in patients with small polyps,” said Dr. Pradère.
ADXBladder Test Utility
A study highlighted the importance of evaluating minichromosome maintenance protein 5 expression during active surveillance using the ADXBladder ELISA test on a urine sample. This test is usually used in bladder cancer diagnosis.
“This study showed that a negative result in two consecutive tests during active surveillance is associated with an almost zero recurrence risk. After two negative tests, most patients do not exit active surveillance,” said Dr. Pradère. But the positive predictive value of biomarkers remains low for low-grade tumors.
The future of active surveillance in bladder cancer should involve better patient selection that relies on risk factors, enhanced modalities through imaging and biomarkers, and the advent of artificial intelligence to analyze cystoscopy results, concluded Dr. Pradère.
This article was translated from the Medscape French edition. A version of this article appeared on Medscape.com.
PARIS — Should clinicians promote active surveillance for non–muscle-invasive bladder tumors (NMIBT) and establish it as a comprehensive management approach, as with prostate and kidney cancers?
During the 117th congress of the French Association of Urology (AFU), Benjamin Pradère, MD, urologic surgeon at Croix du Sud Clinic in Quint-Fonsegrives, France, advocated for this approach, suggesting that the use of biomarkers could enhance its effectiveness.
However, it requires careful patient selection, proper information, and relevant follow-up,” said Dr. Pradère, who is a member of the AFU Cancer Committee (CCAFU).
Low-Grade Tumors
NMIBTs are precancerous lesions and constitute 70%-80% of diagnosed bladder tumors. The remaining tumors are more severe invasive tumors that infiltrate deep tissues. NMIBTs, however, entail a high risk for recurrence (reaching 80% after endoscopic resection), as well as a high risk for progression.
As a result, the diagnosis of NMIBT involves follow-up that significantly impacts patients’ quality of life due to repeated cystoscopies and endovesical treatments. “Tumors with the most impact are low-grade Ta tumors”, with longer-term monitoring required for these low-risk tumors.
Hematuria is the most frequent clinical sign. NMIBT diagnosis occurs after endoscopic tumor resection via transurethral resection, followed by an anatomopathological analysis to determine cell grade and tumor stage. Treatment depends on the risk of recurrence and progression, as well as the risk of therapeutic failure after the initial resection.
Risk stratification distinguishes the following four levels:
- Low-risk tumors: Low-grade pTa urothelial tumors, unifocal, < 3 cm, no history of bladder tumors. Low risk of recurrence and progression.
- Intermediate-risk tumors: Other low-grade pTa urothelial tumors with no high-risk criteria. Low risk of progression but high risk of recurrence.
- High-risk tumors: Tumors with at least one risk factor: Stage pT1, high grade, presence of carcinoma in situ. High risks of progression and recurrence.
- Very high-risk tumors: Tumors combining all risk factors (pT1 grade with carcinoma in situ). Very high and early risk of progression.
“We know that low-grade NMIBTs have no impact on survival,” said Dr. Pradère. For these tumors, which represent 60% of diagnosed NMIBTs, or approximately 250,000 new cases annually in France, specific survival is > 99%, meaning that most diagnosed patients will not die of bladder cancer.
The recurrence rate for low-grade tumors is 50%, but recurrences are “almost always low-grade and rarely invade the basement membrane,” said Pradère. Implementing active surveillance to limit surgical intervention to more advanced forms seems to be relevant for these tumors.
Cystoscopy Every 3 Months
According to CCAFU recommendations, “active surveillance is a therapeutic alternative that can be proposed for patients with recurrent low-risk NMIBT after the initial diagnosis.” Criteria include low-grade pTa, fewer than five tumors, size ≤ 15 mm, negative urinary cytology, asymptomatic nature, and the patient’s acceptance of closer monitoring.
While active surveillance has become the standard treatment for low-risk prostate cancer, this therapeutic option remains marginal in bladder cancer, as in kidney cancer. The goal is to defer or avoid surgical treatment by closely monitoring the natural progression of the disease.
For NMIBTs, follow-up modalities are not yet specifically recommended because of a lack of data, said Dr. Pradère. According to a consensus, cystoscopy should be repeated every 3 months for a year and then every 6 months. Unlike standard follow-up, it includes cytology “to not miss the transition to high grade.”
CCAFU recommends discontinuing active surveillance if any of the following criteria are present:
- More than 10 lesions
- Size > 30 mm
- Positive cytology
- Symptoms (hematuria, micturition disorders, and recurring infections).
Literature on the benefits of active surveillance in bladder tumors is still limited. Only seven studies are available. Overall, for nearly 600 included patients, tumors progressed in about 12% of cases. Progression to invasive tumors occurred in 0.8% of patients (n = 5).
13 Months’ Surveillance
According to a long-term study (median follow-up of 38 months), patients mostly exit active surveillance in the first year. The median duration of active surveillance is 13 months. Active surveillance is discontinued to surgically treat tumors that turn out to be low-grade Ta tumors in 70% of cases.
The following factors predicting recurrence and progression of tumors have been identified: Multiple tumors, early recurrence (within a year of initial diagnosis), frequent recurrence (more than one recurrence per year), tumors > 3 cm, and failure of previous endovesical treatment.
Recent studies have shown that with at least three of these recurrence and progression factors, the median duration under active surveillance is 15 months compared with 28 months in the absence of such factors. “Considering these factors, it is possible to assess the benefit of active surveillance for the patient,” said Dr. Pradère.
If active surveillance for bladder tumors is still not widely practiced, then the contribution of imaging (MRI and ultrasound) and biomarkers could promote its adoption. “The use of biomarkers should change the game and encourage active surveillance in patients with small polyps,” said Dr. Pradère.
ADXBladder Test Utility
A study highlighted the importance of evaluating minichromosome maintenance protein 5 expression during active surveillance using the ADXBladder ELISA test on a urine sample. This test is usually used in bladder cancer diagnosis.
“This study showed that a negative result in two consecutive tests during active surveillance is associated with an almost zero recurrence risk. After two negative tests, most patients do not exit active surveillance,” said Dr. Pradère. But the positive predictive value of biomarkers remains low for low-grade tumors.
The future of active surveillance in bladder cancer should involve better patient selection that relies on risk factors, enhanced modalities through imaging and biomarkers, and the advent of artificial intelligence to analyze cystoscopy results, concluded Dr. Pradère.
This article was translated from the Medscape French edition. A version of this article appeared on Medscape.com.
Testosterone Supplements: Overcoming Current Misconceptions
Underdiagnosis, reluctant doctors, patient preconceptions: Treating low testosterone levels is a tricky business in France despite the proven benefits of replacement therapy. About 20% of patients with symptomatic low testosterone levels are treated for the deficiency, said Eric Huygue, MD, PhD, urologic surgeon at Toulouse University Hospital in France, at the 117th annual conference of the French Urology Association (AFU).
, said Dr. Huygue, who was involved in drawing up the first French recommendations on treating low testosterone in 2021.
“We must keep up communication efforts to make patients and doctors aware” of the benefits of supplementation, he said.
Testosterone Levels
Testosterone deficiency mostly affects men older than 40 years. A drop in androgen levels, which varies by individual, can lead to sexual problems (such as erectile dysfunction and low libido), physical symptoms (fatigue, hot flashes, loss of muscle mass, and osteoporosis), and mental disorders (anxiety, irritability, and depression).
There are an estimated 340,000 men with symptomatic testosterone deficiency in France. Just 70,000 of these are receiving replacement therapy (see box), which accounts for only 20% of those affected. For Dr. Huygue, this low treatment rate is due to underdiagnosis, as well as reluctance on the part of doctors and patients.
Although routine screening of low testosterone in the general population is not recommended, some individuals are particularly at risk, noted the urologist.
This is especially true for patients with metabolic disorders associated with insulin resistance (such as obesity and type 2 diabetes), cardiovascular diseases (hypertension, heart failure, and atrial fibrillation), or other chronic conditions (chronic obstructive pulmonary disease, cancer, and depression). Some medications (corticosteroids, antipsychotics, chemotherapy drugs, and antiretroviral therapies) can also lead to low testosterone.
Per the French recommendations for managing low testosterone, diagnosis must be based on free or bioavailable testosterone and not total testosterone levels, which can give a skewed result. Levels must be tested twice, 1 month apart, in the morning and while fasting. The reference range is determined by taking the lower threshold level of young men as measured in the laboratory.
Threshold Values
The current practice of using the reference range associated with the patient’s age group undoubtedly contributes to the underdiagnosis of low testosterone, said Dr. Huygue. According to a survey of AFU members in 2021, the year in which the recommendations were published, 77% of urologists interviewed reported referring to reference ranges for patients of the same age.
In their defense, “this method has long been in use, but it has eventually become apparent that symptomatic patients with an undiagnosed deficiency could be in the reference patients’ group,” Dr. Huygue explained.
Once a deficiency has been diagnosed, doctors may be reluctant to prescribe replacement therapy due to the perceived risk of developing prostate cancer. Several international studies have shown that “the risk of prostate cancer is the single biggest reason for doctors refusing to prescribe testosterone,” said Dr. Huygue.
Despite this reluctance, numerous studies have clearly shown that there is no link between a high testosterone level and the risk of developing prostate cancer. It even seems that a low testosterone level might expose a person to an increased risk for an aggressive form of cancer.
“This is a time of many surprising discoveries concerning the link between the prostate and testosterone, which go against what we have thought up to now. It has been observed that men with low testosterone develop more serious types of cancer,” said Dr. Huygue at a previous meeting of the AFU, during which he announced the publication of the French recommendations.
Prostate Cancer Recurrence
Urologists are also wary of testosterone supplementation in patients with a previous history of prostate cancer. According to the AFU’s survey, 40% of urologists questioned think that testosterone is contraindicated in this population. One in two urologists prescribe testosterone after radical prostatectomy for low or intermediate risk and most commonly after 3 years of undetectable prostate-specific antigen (PSA) levels.
Nevertheless, “several retrospective studies show the safety of testosterone replacement therapy in men who have undergone radical prostatectomy or radiotherapy or who are under active monitoring,” said Dr. Huygue. Testosterone “does not appear to increase the risk of relapse” after treatment of prostate cancer.
Dr. Huygue invited prescribing physicians to refer to the French recommendations, which specify that 1 year of undetectable PSA after prostatectomy is sufficient before prescribing replacement therapy. “This is clearly indicated in the recommendations for patients with a previous history of prostate cancer.”
Neither prostate cancer nor benign prostatic hyperplasia is a contraindication. According to the recommendations, the only contraindications to testosterone prescription are the following:
- Hematocrit > 54%
- Current breast or prostate cancer
- Cardiovascular event less than 3-6 months prior
- Trying to conceive
Cardiovascular Benefits
Another more commonly used argument by general practitioners and endocrinologists to justify their reluctance to prescribe testosterone is the risk to cardiovascular health. In early 2010, a series of American studies alerted clinicians to this risk when taking testosterone. Since then, other studies have had reassuring findings.
In response to the alert issued by the United States, the European Medicines Agency specified that “the data are not sufficient for a warning,” before the American Heart Association colleagues concluded that testosterone should only be avoided in the first 6 months following a severe cardiovascular event.
Conversely, in 2021, the European Society of Cardiology put forward the benefits of testosterone in an article in favor of replacement therapy to prevent cardiovascular risk. In particular, the hormone is thought to have a beneficial effect on arterial stiffness, the appearance of calcified plaques, and coronary artery dilatation.
The final hurdle to overcome before a testosterone prescription is filled relates to patients themselves, who often regard such treatment unfavorably. Many wrongly believe that androgens are hormones that “increase the risk of cancer, make you aggressive, cause weight gain, lead to hair loss, and cause body hair growth,” said Dr. Huygue.
Finally, breaks in the supply chain for Androtardyl, the only injectable form available for reimbursement by French social security schemes, were reported in the country in 2023, said Dr. Huygue. This situation only complicates further the prescription and use of testosterone replacement therapy.
Which Supplement?
Testosterone replacement therapies are available on the market in the following formulations:
Via transcutaneous administration: Testosterone-based gels, not covered by the French social security system (Androgel and Fortigel), to be applied daily. Users must be careful to avoid any potential transfer of the product to women or children in case of contact with the site after application.
Via an injection: Androtardyl (testosterone enanthate), covered by French social security, to be administered intramuscularly once a month. Nebido (testosterone undecanoate), not covered by French social security, with a more beneficial bioavailability profile, to be administered once every 3 months.
Pantestone (testosterone undecanoate), administered orally, is not marketed since 2021. It had the major disadvantage of requiring a high-fat diet to ensure optimal absorption.
This article was translated from the Medscape French edition. A version of this article appeared on Medscape.com.
Underdiagnosis, reluctant doctors, patient preconceptions: Treating low testosterone levels is a tricky business in France despite the proven benefits of replacement therapy. About 20% of patients with symptomatic low testosterone levels are treated for the deficiency, said Eric Huygue, MD, PhD, urologic surgeon at Toulouse University Hospital in France, at the 117th annual conference of the French Urology Association (AFU).
, said Dr. Huygue, who was involved in drawing up the first French recommendations on treating low testosterone in 2021.
“We must keep up communication efforts to make patients and doctors aware” of the benefits of supplementation, he said.
Testosterone Levels
Testosterone deficiency mostly affects men older than 40 years. A drop in androgen levels, which varies by individual, can lead to sexual problems (such as erectile dysfunction and low libido), physical symptoms (fatigue, hot flashes, loss of muscle mass, and osteoporosis), and mental disorders (anxiety, irritability, and depression).
There are an estimated 340,000 men with symptomatic testosterone deficiency in France. Just 70,000 of these are receiving replacement therapy (see box), which accounts for only 20% of those affected. For Dr. Huygue, this low treatment rate is due to underdiagnosis, as well as reluctance on the part of doctors and patients.
Although routine screening of low testosterone in the general population is not recommended, some individuals are particularly at risk, noted the urologist.
This is especially true for patients with metabolic disorders associated with insulin resistance (such as obesity and type 2 diabetes), cardiovascular diseases (hypertension, heart failure, and atrial fibrillation), or other chronic conditions (chronic obstructive pulmonary disease, cancer, and depression). Some medications (corticosteroids, antipsychotics, chemotherapy drugs, and antiretroviral therapies) can also lead to low testosterone.
Per the French recommendations for managing low testosterone, diagnosis must be based on free or bioavailable testosterone and not total testosterone levels, which can give a skewed result. Levels must be tested twice, 1 month apart, in the morning and while fasting. The reference range is determined by taking the lower threshold level of young men as measured in the laboratory.
Threshold Values
The current practice of using the reference range associated with the patient’s age group undoubtedly contributes to the underdiagnosis of low testosterone, said Dr. Huygue. According to a survey of AFU members in 2021, the year in which the recommendations were published, 77% of urologists interviewed reported referring to reference ranges for patients of the same age.
In their defense, “this method has long been in use, but it has eventually become apparent that symptomatic patients with an undiagnosed deficiency could be in the reference patients’ group,” Dr. Huygue explained.
Once a deficiency has been diagnosed, doctors may be reluctant to prescribe replacement therapy due to the perceived risk of developing prostate cancer. Several international studies have shown that “the risk of prostate cancer is the single biggest reason for doctors refusing to prescribe testosterone,” said Dr. Huygue.
Despite this reluctance, numerous studies have clearly shown that there is no link between a high testosterone level and the risk of developing prostate cancer. It even seems that a low testosterone level might expose a person to an increased risk for an aggressive form of cancer.
“This is a time of many surprising discoveries concerning the link between the prostate and testosterone, which go against what we have thought up to now. It has been observed that men with low testosterone develop more serious types of cancer,” said Dr. Huygue at a previous meeting of the AFU, during which he announced the publication of the French recommendations.
Prostate Cancer Recurrence
Urologists are also wary of testosterone supplementation in patients with a previous history of prostate cancer. According to the AFU’s survey, 40% of urologists questioned think that testosterone is contraindicated in this population. One in two urologists prescribe testosterone after radical prostatectomy for low or intermediate risk and most commonly after 3 years of undetectable prostate-specific antigen (PSA) levels.
Nevertheless, “several retrospective studies show the safety of testosterone replacement therapy in men who have undergone radical prostatectomy or radiotherapy or who are under active monitoring,” said Dr. Huygue. Testosterone “does not appear to increase the risk of relapse” after treatment of prostate cancer.
Dr. Huygue invited prescribing physicians to refer to the French recommendations, which specify that 1 year of undetectable PSA after prostatectomy is sufficient before prescribing replacement therapy. “This is clearly indicated in the recommendations for patients with a previous history of prostate cancer.”
Neither prostate cancer nor benign prostatic hyperplasia is a contraindication. According to the recommendations, the only contraindications to testosterone prescription are the following:
- Hematocrit > 54%
- Current breast or prostate cancer
- Cardiovascular event less than 3-6 months prior
- Trying to conceive
Cardiovascular Benefits
Another more commonly used argument by general practitioners and endocrinologists to justify their reluctance to prescribe testosterone is the risk to cardiovascular health. In early 2010, a series of American studies alerted clinicians to this risk when taking testosterone. Since then, other studies have had reassuring findings.
In response to the alert issued by the United States, the European Medicines Agency specified that “the data are not sufficient for a warning,” before the American Heart Association colleagues concluded that testosterone should only be avoided in the first 6 months following a severe cardiovascular event.
Conversely, in 2021, the European Society of Cardiology put forward the benefits of testosterone in an article in favor of replacement therapy to prevent cardiovascular risk. In particular, the hormone is thought to have a beneficial effect on arterial stiffness, the appearance of calcified plaques, and coronary artery dilatation.
The final hurdle to overcome before a testosterone prescription is filled relates to patients themselves, who often regard such treatment unfavorably. Many wrongly believe that androgens are hormones that “increase the risk of cancer, make you aggressive, cause weight gain, lead to hair loss, and cause body hair growth,” said Dr. Huygue.
Finally, breaks in the supply chain for Androtardyl, the only injectable form available for reimbursement by French social security schemes, were reported in the country in 2023, said Dr. Huygue. This situation only complicates further the prescription and use of testosterone replacement therapy.
Which Supplement?
Testosterone replacement therapies are available on the market in the following formulations:
Via transcutaneous administration: Testosterone-based gels, not covered by the French social security system (Androgel and Fortigel), to be applied daily. Users must be careful to avoid any potential transfer of the product to women or children in case of contact with the site after application.
Via an injection: Androtardyl (testosterone enanthate), covered by French social security, to be administered intramuscularly once a month. Nebido (testosterone undecanoate), not covered by French social security, with a more beneficial bioavailability profile, to be administered once every 3 months.
Pantestone (testosterone undecanoate), administered orally, is not marketed since 2021. It had the major disadvantage of requiring a high-fat diet to ensure optimal absorption.
This article was translated from the Medscape French edition. A version of this article appeared on Medscape.com.
Underdiagnosis, reluctant doctors, patient preconceptions: Treating low testosterone levels is a tricky business in France despite the proven benefits of replacement therapy. About 20% of patients with symptomatic low testosterone levels are treated for the deficiency, said Eric Huygue, MD, PhD, urologic surgeon at Toulouse University Hospital in France, at the 117th annual conference of the French Urology Association (AFU).
, said Dr. Huygue, who was involved in drawing up the first French recommendations on treating low testosterone in 2021.
“We must keep up communication efforts to make patients and doctors aware” of the benefits of supplementation, he said.
Testosterone Levels
Testosterone deficiency mostly affects men older than 40 years. A drop in androgen levels, which varies by individual, can lead to sexual problems (such as erectile dysfunction and low libido), physical symptoms (fatigue, hot flashes, loss of muscle mass, and osteoporosis), and mental disorders (anxiety, irritability, and depression).
There are an estimated 340,000 men with symptomatic testosterone deficiency in France. Just 70,000 of these are receiving replacement therapy (see box), which accounts for only 20% of those affected. For Dr. Huygue, this low treatment rate is due to underdiagnosis, as well as reluctance on the part of doctors and patients.
Although routine screening of low testosterone in the general population is not recommended, some individuals are particularly at risk, noted the urologist.
This is especially true for patients with metabolic disorders associated with insulin resistance (such as obesity and type 2 diabetes), cardiovascular diseases (hypertension, heart failure, and atrial fibrillation), or other chronic conditions (chronic obstructive pulmonary disease, cancer, and depression). Some medications (corticosteroids, antipsychotics, chemotherapy drugs, and antiretroviral therapies) can also lead to low testosterone.
Per the French recommendations for managing low testosterone, diagnosis must be based on free or bioavailable testosterone and not total testosterone levels, which can give a skewed result. Levels must be tested twice, 1 month apart, in the morning and while fasting. The reference range is determined by taking the lower threshold level of young men as measured in the laboratory.
Threshold Values
The current practice of using the reference range associated with the patient’s age group undoubtedly contributes to the underdiagnosis of low testosterone, said Dr. Huygue. According to a survey of AFU members in 2021, the year in which the recommendations were published, 77% of urologists interviewed reported referring to reference ranges for patients of the same age.
In their defense, “this method has long been in use, but it has eventually become apparent that symptomatic patients with an undiagnosed deficiency could be in the reference patients’ group,” Dr. Huygue explained.
Once a deficiency has been diagnosed, doctors may be reluctant to prescribe replacement therapy due to the perceived risk of developing prostate cancer. Several international studies have shown that “the risk of prostate cancer is the single biggest reason for doctors refusing to prescribe testosterone,” said Dr. Huygue.
Despite this reluctance, numerous studies have clearly shown that there is no link between a high testosterone level and the risk of developing prostate cancer. It even seems that a low testosterone level might expose a person to an increased risk for an aggressive form of cancer.
“This is a time of many surprising discoveries concerning the link between the prostate and testosterone, which go against what we have thought up to now. It has been observed that men with low testosterone develop more serious types of cancer,” said Dr. Huygue at a previous meeting of the AFU, during which he announced the publication of the French recommendations.
Prostate Cancer Recurrence
Urologists are also wary of testosterone supplementation in patients with a previous history of prostate cancer. According to the AFU’s survey, 40% of urologists questioned think that testosterone is contraindicated in this population. One in two urologists prescribe testosterone after radical prostatectomy for low or intermediate risk and most commonly after 3 years of undetectable prostate-specific antigen (PSA) levels.
Nevertheless, “several retrospective studies show the safety of testosterone replacement therapy in men who have undergone radical prostatectomy or radiotherapy or who are under active monitoring,” said Dr. Huygue. Testosterone “does not appear to increase the risk of relapse” after treatment of prostate cancer.
Dr. Huygue invited prescribing physicians to refer to the French recommendations, which specify that 1 year of undetectable PSA after prostatectomy is sufficient before prescribing replacement therapy. “This is clearly indicated in the recommendations for patients with a previous history of prostate cancer.”
Neither prostate cancer nor benign prostatic hyperplasia is a contraindication. According to the recommendations, the only contraindications to testosterone prescription are the following:
- Hematocrit > 54%
- Current breast or prostate cancer
- Cardiovascular event less than 3-6 months prior
- Trying to conceive
Cardiovascular Benefits
Another more commonly used argument by general practitioners and endocrinologists to justify their reluctance to prescribe testosterone is the risk to cardiovascular health. In early 2010, a series of American studies alerted clinicians to this risk when taking testosterone. Since then, other studies have had reassuring findings.
In response to the alert issued by the United States, the European Medicines Agency specified that “the data are not sufficient for a warning,” before the American Heart Association colleagues concluded that testosterone should only be avoided in the first 6 months following a severe cardiovascular event.
Conversely, in 2021, the European Society of Cardiology put forward the benefits of testosterone in an article in favor of replacement therapy to prevent cardiovascular risk. In particular, the hormone is thought to have a beneficial effect on arterial stiffness, the appearance of calcified plaques, and coronary artery dilatation.
The final hurdle to overcome before a testosterone prescription is filled relates to patients themselves, who often regard such treatment unfavorably. Many wrongly believe that androgens are hormones that “increase the risk of cancer, make you aggressive, cause weight gain, lead to hair loss, and cause body hair growth,” said Dr. Huygue.
Finally, breaks in the supply chain for Androtardyl, the only injectable form available for reimbursement by French social security schemes, were reported in the country in 2023, said Dr. Huygue. This situation only complicates further the prescription and use of testosterone replacement therapy.
Which Supplement?
Testosterone replacement therapies are available on the market in the following formulations:
Via transcutaneous administration: Testosterone-based gels, not covered by the French social security system (Androgel and Fortigel), to be applied daily. Users must be careful to avoid any potential transfer of the product to women or children in case of contact with the site after application.
Via an injection: Androtardyl (testosterone enanthate), covered by French social security, to be administered intramuscularly once a month. Nebido (testosterone undecanoate), not covered by French social security, with a more beneficial bioavailability profile, to be administered once every 3 months.
Pantestone (testosterone undecanoate), administered orally, is not marketed since 2021. It had the major disadvantage of requiring a high-fat diet to ensure optimal absorption.
This article was translated from the Medscape French edition. A version of this article appeared on Medscape.com.
Chronic diarrhea management: Be wary of false diarrhea
PARIS – said gastroenterologist Nassim Hammoudi, MD, PhD, of the Lariboisière Hospital in Paris, during France’s annual general medicine conference (JNMG 2023). He said that doctors need to understand the characteristics of chronic diarrhea and adapt its management accordingly. In his presentation, Dr. Hammoudi highlighted the clinical signs that should be considered.
Mechanisms of chronic diarrhea
Chronic diarrhea can result from different mechanisms, such as motility disorders related to accelerated intestinal transit, malabsorption, osmotic diarrhea, and secretory diarrhea, which are often interlinked. When an endoscopy is performed, it is recommended to conduct multilevel biopsies to detect microscopic colitis, which Dr. Hammoudi believes is “probably underdiagnosed.”
Diarrhea is defined as the passage of frequent stools (more than three a day), soft to liquid in consistency, and a daily weight exceeding 300 g. It is considered chronic when it persists for more than a month.
Identifying false diarrhea
Practitioners must first distinguish between genuine and false diarrhea, with the latter presenting in most consultations. “Thorough questioning is fundamental,” Dr. Hammoudi emphasized. It is essential to determine the daily stool count, the presence of nocturnal stools, and stool consistency. “A soft stool passed once a day is not diarrhea,” he said.
The most challenging form of false diarrhea to identify is what he called “constipated person’s diarrhea.” These patients, who are typically elderly, reside in care homes, and are bed-bound and taking morphine, have daily liquid stools but are actually constipated. “Taking antidiarrheal medications makes the situation worse,” said Dr. Hammoudi.
Another type of false diarrhea is tenesmus, in which patients feel like they have a full rectum, even though it is physiologically empty. The recurring urge to defecate results in mucus discharges that resemble diarrhea. Inflammatory rectal involvement could be the cause, necessitating a gastroenterology consultation.
Anal incontinence can also cause false diarrhea. It is more common in elderly people residing in care homes and in women in the postpartum period. This condition is difficult to manage and requires referral to a gastroenterologist.
Chronic diarrhea: Could cancer be the culprit?
After ruling out false diarrhea, clinicians should be vigilant for warning signs. The first question to consider, said Dr. Hammoudi, is whether the chronic diarrhea is associated with a lesion. Several criteria should prompt a colonoscopy, especially to search for colorectal cancer lesions:
- Age greater than 50 years
- Personal or family history of colorectal cancer
- Recent changes in bowel habits
- Rectal bleeding
- Nighttime stools
- Unexplained weight loss
- Iron-deficiency anemia
Obvious causes of chronic diarrhea should be prioritized in the management plan. Medications top the list, with more than 500 treatments – for example, ACE inhibitors, proton pump inhibitors (PPIs), antidiabetic drugs, colchicine, magnesium, laxatives – known to have diarrhea as a side effect.
Certain dietary habits can also exacerbate diarrhea, such as milk consumption in cases of lactose intolerance, or excessive sugar intake, which can lead to osmotic diarrhea.
IBS is often at play
Once these causes have been ruled out, several etiological pathways should be investigated. The first relates to motility issues, which are the most common diarrhea-related problem, said Dr. Hammoudi.
This type of diarrhea is linked to rapid intestinal transit time and is characterized by postprandial bowel movements (occurring shortly after a meal). Here, patients experience urgency and notice identifiable food debris in their stools. It tends to stop when fasting and can be treated effectively with antidiarrheals.
Irritable bowel syndrome (IBS) is the main cause of rapid intestinal transit diarrhea. It is defined as recurrent abdominal pain (at least 1 day/week) over a period of 3 months, associated with two of the following criteria: pain eases or worsens on passing feces, change in frequency of bowel movements, change in the consistency of stools.
Symptoms may come on suddenly, sometimes after taking antibiotics, and may result in misdiagnosis.
IBS medications treat the symptoms. Antispasmodics, such as trimebutine, phloroglucinol (Spasfon), or pinaverium bromide (Dicetel) are recommended, even there can be a placebo effect. The antidiarrheal medication loperamide (Imodium) can also be used. Probiotics may be beneficial, as an imbalanced intestinal microbiota is often implicated.
Dietary changes can also have a positive impact. Encouraging a diet rich in fruit and vegetables to enhance fiber intake is advised. A low FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) diet, targeting short-chain carbohydrates, can also be tried to identify foods to avoid, although it may be challenging to stick to.
Postinfectious IBS is a frequent cause of rapid intestinal transit diarrhea. It generally follows an episode of acute infectious diarrhea. “Symptoms may come on suddenly, sometimes after taking antibiotics, and may result in misdiagnosis,” said Dr. Hammoudi. This type of IBS often resolves spontaneously within 6 months.
Consider the possibility of SIBO
Another cause of rapid intestinal transit diarrhea is small intestinal bacterial overgrowth (SIBO). It is difficult to distinguish between IBS and SIBO. Often, affected patients are diabetic, overweight, or have had bowel surgery.
The only way to diagnose SIBO is by conducting a breath test to measure the production of hydrogen and methane by the microbiota after ingesting sugar. However, the test is difficult to access and not fully covered by social security plans in France, said Dr. Hammoudi.
In cases of suspected SIBO and severe symptoms, a 7- to 10-day course of antibiotics can be attempted to provide relief, although a diagnosis should be confirmed before considering this option, Dr. Hammoudi said.
Malabsorption diarrhea
Another major cause of chronic diarrhea is malabsorption, characterized by large, fatty stools that are difficult to flush. Despite a normal diet, this type of diarrhea is associated with weight loss and nutritional deficiencies.
Its diagnosis involves measuring fat in the stools (steatorrhea) and possibly testing fecal elastase, an enzyme produced by the pancreas that is involved in digestion.
The most important causes of malabsorption diarrhea are pancreatic insufficiency, celiac disease, and Crohn’s disease. Generally, any lesion in the small intestine can lead to malabsorption-related diarrhea.
Celiac disease, or gluten intolerance, is an autoimmune condition triggered by a reaction to gluten proteins. Several antibodies can be produced in the presence of gluten proteins. Diagnosis is confirmed by positive antitransglutaminase antibodies and a duodenal biopsy through esophagogastroduodenoscopy.
The only treatment for celiac disease is a lifelong gluten-free diet. Celiac disease is increasingly diagnosed in adults, said Dr. Hammoudi, and should be considered as a possibility. This condition must be distinguished from gluten sensitivity, which can cause digestive issues, possibly leading to rapid intestinal transit diarrhea. “The only treatment for celiac disease is a lifelong gluten-free diet,” Dr. Hammoudi added.
Crohn’s disease, a type of inflammatory bowel disease, affects the entire digestive tract, particularly the terminal small intestine, which promotes malabsorption. In ulcerative colitis, another IBD affecting the rectum, any associated rectal syndrome can result in false diarrhea with stools containing blood and mucus.
Osmotic diarrhea, on the other hand, is linked to the presence of highly osmotic agents in the digestive tract. This type of diarrhea is watery and short-lived, stopping once the agents are no longer absorbed. The main culprits are lactose (in cases of lactose intolerance) and laxatives.
Drug-induced microscopic colitis
Secretory diarrhea is characterized by excessive secretions by the digestive tract, leading to significant potassium loss. This type of diarrhea is not related to food intake and is resistant to fasting.
Major causes of secretory diarrhea include microscopic colitis, parasitic infections, and endocrine tumors. Between 10% and 15% of patients with chronic diarrhea and apparently normal colonoscopy have microscopic colitis.
Dr. Hammoudi advised specialists seeking to determine the cause of chronic diarrhea to routinely collect multilevel bowel biopsies during colonoscopies from macroscopically normal mucosa to rule out microscopic colitis.
Microscopic colitis is mainly linked to the use of medications like PPIs and NSAIDs. These drugs can induce malabsorption-related diarrhea by damaging the intestinal wall.
In addition to discontinuing the implicated medication, the treatment for microscopic colitis includes low-dose budesonide (multiple brands). Biologics used in IBD may also be considered in cases of recurrent colitis.
Finally, exudative enteropathy can be a distinct cause of chronic diarrhea. It is characterized by albumin leakage (Waldmann’s disease) and manifests with edema, malnutrition, and significant hypoalbuminemia.
This article was translated from the Medscape French edition. A version of this article appeared on Medscape.com.
PARIS – said gastroenterologist Nassim Hammoudi, MD, PhD, of the Lariboisière Hospital in Paris, during France’s annual general medicine conference (JNMG 2023). He said that doctors need to understand the characteristics of chronic diarrhea and adapt its management accordingly. In his presentation, Dr. Hammoudi highlighted the clinical signs that should be considered.
Mechanisms of chronic diarrhea
Chronic diarrhea can result from different mechanisms, such as motility disorders related to accelerated intestinal transit, malabsorption, osmotic diarrhea, and secretory diarrhea, which are often interlinked. When an endoscopy is performed, it is recommended to conduct multilevel biopsies to detect microscopic colitis, which Dr. Hammoudi believes is “probably underdiagnosed.”
Diarrhea is defined as the passage of frequent stools (more than three a day), soft to liquid in consistency, and a daily weight exceeding 300 g. It is considered chronic when it persists for more than a month.
Identifying false diarrhea
Practitioners must first distinguish between genuine and false diarrhea, with the latter presenting in most consultations. “Thorough questioning is fundamental,” Dr. Hammoudi emphasized. It is essential to determine the daily stool count, the presence of nocturnal stools, and stool consistency. “A soft stool passed once a day is not diarrhea,” he said.
The most challenging form of false diarrhea to identify is what he called “constipated person’s diarrhea.” These patients, who are typically elderly, reside in care homes, and are bed-bound and taking morphine, have daily liquid stools but are actually constipated. “Taking antidiarrheal medications makes the situation worse,” said Dr. Hammoudi.
Another type of false diarrhea is tenesmus, in which patients feel like they have a full rectum, even though it is physiologically empty. The recurring urge to defecate results in mucus discharges that resemble diarrhea. Inflammatory rectal involvement could be the cause, necessitating a gastroenterology consultation.
Anal incontinence can also cause false diarrhea. It is more common in elderly people residing in care homes and in women in the postpartum period. This condition is difficult to manage and requires referral to a gastroenterologist.
Chronic diarrhea: Could cancer be the culprit?
After ruling out false diarrhea, clinicians should be vigilant for warning signs. The first question to consider, said Dr. Hammoudi, is whether the chronic diarrhea is associated with a lesion. Several criteria should prompt a colonoscopy, especially to search for colorectal cancer lesions:
- Age greater than 50 years
- Personal or family history of colorectal cancer
- Recent changes in bowel habits
- Rectal bleeding
- Nighttime stools
- Unexplained weight loss
- Iron-deficiency anemia
Obvious causes of chronic diarrhea should be prioritized in the management plan. Medications top the list, with more than 500 treatments – for example, ACE inhibitors, proton pump inhibitors (PPIs), antidiabetic drugs, colchicine, magnesium, laxatives – known to have diarrhea as a side effect.
Certain dietary habits can also exacerbate diarrhea, such as milk consumption in cases of lactose intolerance, or excessive sugar intake, which can lead to osmotic diarrhea.
IBS is often at play
Once these causes have been ruled out, several etiological pathways should be investigated. The first relates to motility issues, which are the most common diarrhea-related problem, said Dr. Hammoudi.
This type of diarrhea is linked to rapid intestinal transit time and is characterized by postprandial bowel movements (occurring shortly after a meal). Here, patients experience urgency and notice identifiable food debris in their stools. It tends to stop when fasting and can be treated effectively with antidiarrheals.
Irritable bowel syndrome (IBS) is the main cause of rapid intestinal transit diarrhea. It is defined as recurrent abdominal pain (at least 1 day/week) over a period of 3 months, associated with two of the following criteria: pain eases or worsens on passing feces, change in frequency of bowel movements, change in the consistency of stools.
Symptoms may come on suddenly, sometimes after taking antibiotics, and may result in misdiagnosis.
IBS medications treat the symptoms. Antispasmodics, such as trimebutine, phloroglucinol (Spasfon), or pinaverium bromide (Dicetel) are recommended, even there can be a placebo effect. The antidiarrheal medication loperamide (Imodium) can also be used. Probiotics may be beneficial, as an imbalanced intestinal microbiota is often implicated.
Dietary changes can also have a positive impact. Encouraging a diet rich in fruit and vegetables to enhance fiber intake is advised. A low FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) diet, targeting short-chain carbohydrates, can also be tried to identify foods to avoid, although it may be challenging to stick to.
Postinfectious IBS is a frequent cause of rapid intestinal transit diarrhea. It generally follows an episode of acute infectious diarrhea. “Symptoms may come on suddenly, sometimes after taking antibiotics, and may result in misdiagnosis,” said Dr. Hammoudi. This type of IBS often resolves spontaneously within 6 months.
Consider the possibility of SIBO
Another cause of rapid intestinal transit diarrhea is small intestinal bacterial overgrowth (SIBO). It is difficult to distinguish between IBS and SIBO. Often, affected patients are diabetic, overweight, or have had bowel surgery.
The only way to diagnose SIBO is by conducting a breath test to measure the production of hydrogen and methane by the microbiota after ingesting sugar. However, the test is difficult to access and not fully covered by social security plans in France, said Dr. Hammoudi.
In cases of suspected SIBO and severe symptoms, a 7- to 10-day course of antibiotics can be attempted to provide relief, although a diagnosis should be confirmed before considering this option, Dr. Hammoudi said.
Malabsorption diarrhea
Another major cause of chronic diarrhea is malabsorption, characterized by large, fatty stools that are difficult to flush. Despite a normal diet, this type of diarrhea is associated with weight loss and nutritional deficiencies.
Its diagnosis involves measuring fat in the stools (steatorrhea) and possibly testing fecal elastase, an enzyme produced by the pancreas that is involved in digestion.
The most important causes of malabsorption diarrhea are pancreatic insufficiency, celiac disease, and Crohn’s disease. Generally, any lesion in the small intestine can lead to malabsorption-related diarrhea.
Celiac disease, or gluten intolerance, is an autoimmune condition triggered by a reaction to gluten proteins. Several antibodies can be produced in the presence of gluten proteins. Diagnosis is confirmed by positive antitransglutaminase antibodies and a duodenal biopsy through esophagogastroduodenoscopy.
The only treatment for celiac disease is a lifelong gluten-free diet. Celiac disease is increasingly diagnosed in adults, said Dr. Hammoudi, and should be considered as a possibility. This condition must be distinguished from gluten sensitivity, which can cause digestive issues, possibly leading to rapid intestinal transit diarrhea. “The only treatment for celiac disease is a lifelong gluten-free diet,” Dr. Hammoudi added.
Crohn’s disease, a type of inflammatory bowel disease, affects the entire digestive tract, particularly the terminal small intestine, which promotes malabsorption. In ulcerative colitis, another IBD affecting the rectum, any associated rectal syndrome can result in false diarrhea with stools containing blood and mucus.
Osmotic diarrhea, on the other hand, is linked to the presence of highly osmotic agents in the digestive tract. This type of diarrhea is watery and short-lived, stopping once the agents are no longer absorbed. The main culprits are lactose (in cases of lactose intolerance) and laxatives.
Drug-induced microscopic colitis
Secretory diarrhea is characterized by excessive secretions by the digestive tract, leading to significant potassium loss. This type of diarrhea is not related to food intake and is resistant to fasting.
Major causes of secretory diarrhea include microscopic colitis, parasitic infections, and endocrine tumors. Between 10% and 15% of patients with chronic diarrhea and apparently normal colonoscopy have microscopic colitis.
Dr. Hammoudi advised specialists seeking to determine the cause of chronic diarrhea to routinely collect multilevel bowel biopsies during colonoscopies from macroscopically normal mucosa to rule out microscopic colitis.
Microscopic colitis is mainly linked to the use of medications like PPIs and NSAIDs. These drugs can induce malabsorption-related diarrhea by damaging the intestinal wall.
In addition to discontinuing the implicated medication, the treatment for microscopic colitis includes low-dose budesonide (multiple brands). Biologics used in IBD may also be considered in cases of recurrent colitis.
Finally, exudative enteropathy can be a distinct cause of chronic diarrhea. It is characterized by albumin leakage (Waldmann’s disease) and manifests with edema, malnutrition, and significant hypoalbuminemia.
This article was translated from the Medscape French edition. A version of this article appeared on Medscape.com.
PARIS – said gastroenterologist Nassim Hammoudi, MD, PhD, of the Lariboisière Hospital in Paris, during France’s annual general medicine conference (JNMG 2023). He said that doctors need to understand the characteristics of chronic diarrhea and adapt its management accordingly. In his presentation, Dr. Hammoudi highlighted the clinical signs that should be considered.
Mechanisms of chronic diarrhea
Chronic diarrhea can result from different mechanisms, such as motility disorders related to accelerated intestinal transit, malabsorption, osmotic diarrhea, and secretory diarrhea, which are often interlinked. When an endoscopy is performed, it is recommended to conduct multilevel biopsies to detect microscopic colitis, which Dr. Hammoudi believes is “probably underdiagnosed.”
Diarrhea is defined as the passage of frequent stools (more than three a day), soft to liquid in consistency, and a daily weight exceeding 300 g. It is considered chronic when it persists for more than a month.
Identifying false diarrhea
Practitioners must first distinguish between genuine and false diarrhea, with the latter presenting in most consultations. “Thorough questioning is fundamental,” Dr. Hammoudi emphasized. It is essential to determine the daily stool count, the presence of nocturnal stools, and stool consistency. “A soft stool passed once a day is not diarrhea,” he said.
The most challenging form of false diarrhea to identify is what he called “constipated person’s diarrhea.” These patients, who are typically elderly, reside in care homes, and are bed-bound and taking morphine, have daily liquid stools but are actually constipated. “Taking antidiarrheal medications makes the situation worse,” said Dr. Hammoudi.
Another type of false diarrhea is tenesmus, in which patients feel like they have a full rectum, even though it is physiologically empty. The recurring urge to defecate results in mucus discharges that resemble diarrhea. Inflammatory rectal involvement could be the cause, necessitating a gastroenterology consultation.
Anal incontinence can also cause false diarrhea. It is more common in elderly people residing in care homes and in women in the postpartum period. This condition is difficult to manage and requires referral to a gastroenterologist.
Chronic diarrhea: Could cancer be the culprit?
After ruling out false diarrhea, clinicians should be vigilant for warning signs. The first question to consider, said Dr. Hammoudi, is whether the chronic diarrhea is associated with a lesion. Several criteria should prompt a colonoscopy, especially to search for colorectal cancer lesions:
- Age greater than 50 years
- Personal or family history of colorectal cancer
- Recent changes in bowel habits
- Rectal bleeding
- Nighttime stools
- Unexplained weight loss
- Iron-deficiency anemia
Obvious causes of chronic diarrhea should be prioritized in the management plan. Medications top the list, with more than 500 treatments – for example, ACE inhibitors, proton pump inhibitors (PPIs), antidiabetic drugs, colchicine, magnesium, laxatives – known to have diarrhea as a side effect.
Certain dietary habits can also exacerbate diarrhea, such as milk consumption in cases of lactose intolerance, or excessive sugar intake, which can lead to osmotic diarrhea.
IBS is often at play
Once these causes have been ruled out, several etiological pathways should be investigated. The first relates to motility issues, which are the most common diarrhea-related problem, said Dr. Hammoudi.
This type of diarrhea is linked to rapid intestinal transit time and is characterized by postprandial bowel movements (occurring shortly after a meal). Here, patients experience urgency and notice identifiable food debris in their stools. It tends to stop when fasting and can be treated effectively with antidiarrheals.
Irritable bowel syndrome (IBS) is the main cause of rapid intestinal transit diarrhea. It is defined as recurrent abdominal pain (at least 1 day/week) over a period of 3 months, associated with two of the following criteria: pain eases or worsens on passing feces, change in frequency of bowel movements, change in the consistency of stools.
Symptoms may come on suddenly, sometimes after taking antibiotics, and may result in misdiagnosis.
IBS medications treat the symptoms. Antispasmodics, such as trimebutine, phloroglucinol (Spasfon), or pinaverium bromide (Dicetel) are recommended, even there can be a placebo effect. The antidiarrheal medication loperamide (Imodium) can also be used. Probiotics may be beneficial, as an imbalanced intestinal microbiota is often implicated.
Dietary changes can also have a positive impact. Encouraging a diet rich in fruit and vegetables to enhance fiber intake is advised. A low FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) diet, targeting short-chain carbohydrates, can also be tried to identify foods to avoid, although it may be challenging to stick to.
Postinfectious IBS is a frequent cause of rapid intestinal transit diarrhea. It generally follows an episode of acute infectious diarrhea. “Symptoms may come on suddenly, sometimes after taking antibiotics, and may result in misdiagnosis,” said Dr. Hammoudi. This type of IBS often resolves spontaneously within 6 months.
Consider the possibility of SIBO
Another cause of rapid intestinal transit diarrhea is small intestinal bacterial overgrowth (SIBO). It is difficult to distinguish between IBS and SIBO. Often, affected patients are diabetic, overweight, or have had bowel surgery.
The only way to diagnose SIBO is by conducting a breath test to measure the production of hydrogen and methane by the microbiota after ingesting sugar. However, the test is difficult to access and not fully covered by social security plans in France, said Dr. Hammoudi.
In cases of suspected SIBO and severe symptoms, a 7- to 10-day course of antibiotics can be attempted to provide relief, although a diagnosis should be confirmed before considering this option, Dr. Hammoudi said.
Malabsorption diarrhea
Another major cause of chronic diarrhea is malabsorption, characterized by large, fatty stools that are difficult to flush. Despite a normal diet, this type of diarrhea is associated with weight loss and nutritional deficiencies.
Its diagnosis involves measuring fat in the stools (steatorrhea) and possibly testing fecal elastase, an enzyme produced by the pancreas that is involved in digestion.
The most important causes of malabsorption diarrhea are pancreatic insufficiency, celiac disease, and Crohn’s disease. Generally, any lesion in the small intestine can lead to malabsorption-related diarrhea.
Celiac disease, or gluten intolerance, is an autoimmune condition triggered by a reaction to gluten proteins. Several antibodies can be produced in the presence of gluten proteins. Diagnosis is confirmed by positive antitransglutaminase antibodies and a duodenal biopsy through esophagogastroduodenoscopy.
The only treatment for celiac disease is a lifelong gluten-free diet. Celiac disease is increasingly diagnosed in adults, said Dr. Hammoudi, and should be considered as a possibility. This condition must be distinguished from gluten sensitivity, which can cause digestive issues, possibly leading to rapid intestinal transit diarrhea. “The only treatment for celiac disease is a lifelong gluten-free diet,” Dr. Hammoudi added.
Crohn’s disease, a type of inflammatory bowel disease, affects the entire digestive tract, particularly the terminal small intestine, which promotes malabsorption. In ulcerative colitis, another IBD affecting the rectum, any associated rectal syndrome can result in false diarrhea with stools containing blood and mucus.
Osmotic diarrhea, on the other hand, is linked to the presence of highly osmotic agents in the digestive tract. This type of diarrhea is watery and short-lived, stopping once the agents are no longer absorbed. The main culprits are lactose (in cases of lactose intolerance) and laxatives.
Drug-induced microscopic colitis
Secretory diarrhea is characterized by excessive secretions by the digestive tract, leading to significant potassium loss. This type of diarrhea is not related to food intake and is resistant to fasting.
Major causes of secretory diarrhea include microscopic colitis, parasitic infections, and endocrine tumors. Between 10% and 15% of patients with chronic diarrhea and apparently normal colonoscopy have microscopic colitis.
Dr. Hammoudi advised specialists seeking to determine the cause of chronic diarrhea to routinely collect multilevel bowel biopsies during colonoscopies from macroscopically normal mucosa to rule out microscopic colitis.
Microscopic colitis is mainly linked to the use of medications like PPIs and NSAIDs. These drugs can induce malabsorption-related diarrhea by damaging the intestinal wall.
In addition to discontinuing the implicated medication, the treatment for microscopic colitis includes low-dose budesonide (multiple brands). Biologics used in IBD may also be considered in cases of recurrent colitis.
Finally, exudative enteropathy can be a distinct cause of chronic diarrhea. It is characterized by albumin leakage (Waldmann’s disease) and manifests with edema, malnutrition, and significant hypoalbuminemia.
This article was translated from the Medscape French edition. A version of this article appeared on Medscape.com.
One in five men carries high-risk HPV in international study
Findings from a meta-analysis of 65 studies conducted in 35 countries indicate that These estimates provide further weight to arguments in favor of vaccinating boys against HPV to prevent certain types of cancer.
“Our results support that sexually active men, regardless of age, are an important reservoir of HPV genital infection,” wrote the authors in The Lancet Global Health . “These estimates emphasize the importance of incorporating men into comprehensive HPV prevention strategies to reduce HPV-related morbidity and mortality in men and ultimately achieve elimination of cervical cancer and other HPV-related diseases.”
Literature review
HPV infection is the most common sexually transmitted viral infection worldwide. More than 200 HPV types can be transmitted sexually, and at least 12 types are oncogenic. Previous studies have shown that most sexually active men and women acquire at least one genital HPV infection during their lifetime.
Although most HPV infections are asymptomatic, they can lead to cancer. Indeed, HPV is involved in the development of cervical, vulval, and vaginal cancers, as well as oropharyngeal and anal cancers, which also affect the male population. More than 25% of cancers caused by HPV occur in men.
Despite these observations, fewer epidemiologic studies have assessed HPV infection in men than in women. To determine the prevalence of HPV infection in the male population, Laia Bruni, MD, MPH, PhD, an epidemiologist at the Catalan Institute of Oncology in Barcelona, and her colleagues collated data from 65 studies conducted in 35 countries pertaining to males older than 15 years.
In this literature review, the researchers selected studies that reported infection rates in males without HPV-related symptoms. Studies conducted exclusively in populations that were considered at increased risk for sexually transmitted infections (STIs) were excluded. Overall, the analysis included close to 45,000 men.
Prevalent HPV genotype
Testing for HPV was conducted on samples collected from the anus and genitals. The results show a global pooled prevalence of HPV infection in males older than 15 years of 31% for any HPV and 21% for HR-HPV. One of these viruses, HPV-16, was the most prevalent HPV genotype (5% prevalence).
HPV prevalence was highest among young adults. It stabilized and decreased from age 50 years. Between ages 25 and 29 years, 35% of men are infected with HPV. It should be noted that prevalence is already high in the youngest group, reaching 28% in males between the ages of 15 and 19 years. The variations are similar for HR-HPV infections.
This age-related change is different from rates in women. Among the female population, HPV prevalence peaks soon after first sexual activity and declines with age, with a slight rebound after ages 50–55 years (i.e., often after or around the time of menopause), wrote the researchers.
The results also show country- and region-based disparities. The pooled prevalence for any HPV was highest in Sub-Saharan Africa (37%), followed by Europe and Northern America (36%). The lowest prevalence was in East and Southeast Asia (15%). Here again, the trends are similar with high-risk HPV.
Preventive measures
“Our study draws attention to the high prevalence, ranging from 20% to 30% for HR-HPV in men across most regions, and the need for strengthening HPV prevention within overall STI control efforts,” wrote the authors.
“Future epidemiological studies are needed to monitor trends in prevalence in men, especially considering the roll-out of HPV vaccination in girls and young women and that many countries are beginning to vaccinate boys.”
In France, the HPV vaccination program was extended in 2021 to include all boys between the ages of 11 and 14 years (two-dose schedule), with a catch-up course in males up to age 19 years (three-dose schedule). This is the same vaccine program as for girls. It is also recommended for men up to age 26 years who have sex with other men.
The 2023 return to school will see the launch of a general vaccination campaign aimed at seventh-grade students, both boys and girls, with parental consent, to increase vaccine coverage. In 2021, vaccine uptake was 43.6% in girls between the ages of 15 and 18 years and scarcely 6% in boys, according to Public Health France.
Two vaccines are in use: the bivalent Cervarix vaccine, which is effective against HPV-16 and HPV-18, and the nonavalent Gardasil 9, which is effective against types 16, 18, 31, 33, 45, 52, and 58. Both provide protection against HPV-16, the type most common in men, which is responsible for more than half of cases of cervical cancer.
This article was translated from the Medscape French Edition. A version appeared on Medscape.com.
Findings from a meta-analysis of 65 studies conducted in 35 countries indicate that These estimates provide further weight to arguments in favor of vaccinating boys against HPV to prevent certain types of cancer.
“Our results support that sexually active men, regardless of age, are an important reservoir of HPV genital infection,” wrote the authors in The Lancet Global Health . “These estimates emphasize the importance of incorporating men into comprehensive HPV prevention strategies to reduce HPV-related morbidity and mortality in men and ultimately achieve elimination of cervical cancer and other HPV-related diseases.”
Literature review
HPV infection is the most common sexually transmitted viral infection worldwide. More than 200 HPV types can be transmitted sexually, and at least 12 types are oncogenic. Previous studies have shown that most sexually active men and women acquire at least one genital HPV infection during their lifetime.
Although most HPV infections are asymptomatic, they can lead to cancer. Indeed, HPV is involved in the development of cervical, vulval, and vaginal cancers, as well as oropharyngeal and anal cancers, which also affect the male population. More than 25% of cancers caused by HPV occur in men.
Despite these observations, fewer epidemiologic studies have assessed HPV infection in men than in women. To determine the prevalence of HPV infection in the male population, Laia Bruni, MD, MPH, PhD, an epidemiologist at the Catalan Institute of Oncology in Barcelona, and her colleagues collated data from 65 studies conducted in 35 countries pertaining to males older than 15 years.
In this literature review, the researchers selected studies that reported infection rates in males without HPV-related symptoms. Studies conducted exclusively in populations that were considered at increased risk for sexually transmitted infections (STIs) were excluded. Overall, the analysis included close to 45,000 men.
Prevalent HPV genotype
Testing for HPV was conducted on samples collected from the anus and genitals. The results show a global pooled prevalence of HPV infection in males older than 15 years of 31% for any HPV and 21% for HR-HPV. One of these viruses, HPV-16, was the most prevalent HPV genotype (5% prevalence).
HPV prevalence was highest among young adults. It stabilized and decreased from age 50 years. Between ages 25 and 29 years, 35% of men are infected with HPV. It should be noted that prevalence is already high in the youngest group, reaching 28% in males between the ages of 15 and 19 years. The variations are similar for HR-HPV infections.
This age-related change is different from rates in women. Among the female population, HPV prevalence peaks soon after first sexual activity and declines with age, with a slight rebound after ages 50–55 years (i.e., often after or around the time of menopause), wrote the researchers.
The results also show country- and region-based disparities. The pooled prevalence for any HPV was highest in Sub-Saharan Africa (37%), followed by Europe and Northern America (36%). The lowest prevalence was in East and Southeast Asia (15%). Here again, the trends are similar with high-risk HPV.
Preventive measures
“Our study draws attention to the high prevalence, ranging from 20% to 30% for HR-HPV in men across most regions, and the need for strengthening HPV prevention within overall STI control efforts,” wrote the authors.
“Future epidemiological studies are needed to monitor trends in prevalence in men, especially considering the roll-out of HPV vaccination in girls and young women and that many countries are beginning to vaccinate boys.”
In France, the HPV vaccination program was extended in 2021 to include all boys between the ages of 11 and 14 years (two-dose schedule), with a catch-up course in males up to age 19 years (three-dose schedule). This is the same vaccine program as for girls. It is also recommended for men up to age 26 years who have sex with other men.
The 2023 return to school will see the launch of a general vaccination campaign aimed at seventh-grade students, both boys and girls, with parental consent, to increase vaccine coverage. In 2021, vaccine uptake was 43.6% in girls between the ages of 15 and 18 years and scarcely 6% in boys, according to Public Health France.
Two vaccines are in use: the bivalent Cervarix vaccine, which is effective against HPV-16 and HPV-18, and the nonavalent Gardasil 9, which is effective against types 16, 18, 31, 33, 45, 52, and 58. Both provide protection against HPV-16, the type most common in men, which is responsible for more than half of cases of cervical cancer.
This article was translated from the Medscape French Edition. A version appeared on Medscape.com.
Findings from a meta-analysis of 65 studies conducted in 35 countries indicate that These estimates provide further weight to arguments in favor of vaccinating boys against HPV to prevent certain types of cancer.
“Our results support that sexually active men, regardless of age, are an important reservoir of HPV genital infection,” wrote the authors in The Lancet Global Health . “These estimates emphasize the importance of incorporating men into comprehensive HPV prevention strategies to reduce HPV-related morbidity and mortality in men and ultimately achieve elimination of cervical cancer and other HPV-related diseases.”
Literature review
HPV infection is the most common sexually transmitted viral infection worldwide. More than 200 HPV types can be transmitted sexually, and at least 12 types are oncogenic. Previous studies have shown that most sexually active men and women acquire at least one genital HPV infection during their lifetime.
Although most HPV infections are asymptomatic, they can lead to cancer. Indeed, HPV is involved in the development of cervical, vulval, and vaginal cancers, as well as oropharyngeal and anal cancers, which also affect the male population. More than 25% of cancers caused by HPV occur in men.
Despite these observations, fewer epidemiologic studies have assessed HPV infection in men than in women. To determine the prevalence of HPV infection in the male population, Laia Bruni, MD, MPH, PhD, an epidemiologist at the Catalan Institute of Oncology in Barcelona, and her colleagues collated data from 65 studies conducted in 35 countries pertaining to males older than 15 years.
In this literature review, the researchers selected studies that reported infection rates in males without HPV-related symptoms. Studies conducted exclusively in populations that were considered at increased risk for sexually transmitted infections (STIs) were excluded. Overall, the analysis included close to 45,000 men.
Prevalent HPV genotype
Testing for HPV was conducted on samples collected from the anus and genitals. The results show a global pooled prevalence of HPV infection in males older than 15 years of 31% for any HPV and 21% for HR-HPV. One of these viruses, HPV-16, was the most prevalent HPV genotype (5% prevalence).
HPV prevalence was highest among young adults. It stabilized and decreased from age 50 years. Between ages 25 and 29 years, 35% of men are infected with HPV. It should be noted that prevalence is already high in the youngest group, reaching 28% in males between the ages of 15 and 19 years. The variations are similar for HR-HPV infections.
This age-related change is different from rates in women. Among the female population, HPV prevalence peaks soon after first sexual activity and declines with age, with a slight rebound after ages 50–55 years (i.e., often after or around the time of menopause), wrote the researchers.
The results also show country- and region-based disparities. The pooled prevalence for any HPV was highest in Sub-Saharan Africa (37%), followed by Europe and Northern America (36%). The lowest prevalence was in East and Southeast Asia (15%). Here again, the trends are similar with high-risk HPV.
Preventive measures
“Our study draws attention to the high prevalence, ranging from 20% to 30% for HR-HPV in men across most regions, and the need for strengthening HPV prevention within overall STI control efforts,” wrote the authors.
“Future epidemiological studies are needed to monitor trends in prevalence in men, especially considering the roll-out of HPV vaccination in girls and young women and that many countries are beginning to vaccinate boys.”
In France, the HPV vaccination program was extended in 2021 to include all boys between the ages of 11 and 14 years (two-dose schedule), with a catch-up course in males up to age 19 years (three-dose schedule). This is the same vaccine program as for girls. It is also recommended for men up to age 26 years who have sex with other men.
The 2023 return to school will see the launch of a general vaccination campaign aimed at seventh-grade students, both boys and girls, with parental consent, to increase vaccine coverage. In 2021, vaccine uptake was 43.6% in girls between the ages of 15 and 18 years and scarcely 6% in boys, according to Public Health France.
Two vaccines are in use: the bivalent Cervarix vaccine, which is effective against HPV-16 and HPV-18, and the nonavalent Gardasil 9, which is effective against types 16, 18, 31, 33, 45, 52, and 58. Both provide protection against HPV-16, the type most common in men, which is responsible for more than half of cases of cervical cancer.
This article was translated from the Medscape French Edition. A version appeared on Medscape.com.
FROM THE LANCET GLOBAL HEALTH
Breast cancer: Hope in sight for improved tamoxifen therapy?
A team at Lyon’s Cancer Research Center (CRCL) has revealed the role of an enzyme, PRMT5, in the response to tamoxifen, a drug used to prevent relapse in premenopausal women with breast cancer.
Muriel Le Romancer, MD, director of research at France’s Institute of Health and Medical Research, explained the issues involved in this discovery in an interview. She jointly led this research along with Olivier Trédan, MD, PhD, oncologist at Lyon’s Léon Bérard Clinic. The research concluded with the publication of a study in EMBO Molecular Medicine. The researchers both head up the CRCL’s hormone resistance, methylation, and breast cancer team.
Although the enzyme’s involvement in the mode of action of tamoxifen has been observed in close to 900 patients with breast cancer, these results need to be validated in other at-risk patient cohorts before the biomarker can be considered for routine use, said Dr. Le Romancer. She estimated that 2 more years of research are needed.
Can you tell us which cases involve the use of tamoxifen and what its mode of action is?
Dr. Le Romancer: Tamoxifen is a hormone therapy used to reduce the risk of breast cancer relapse. It is prescribed to premenopausal women with hormone-sensitive cancer, which equates to roughly 25% of women with breast cancer: 15,000 women each year. The drug, which is taken every day via oral administration, is an estrogen antagonist. By binding to these receptors, it blocks estrogen from mediating its biological effect in the breasts. Aromatase inhibitors are the preferred choice in postmenopausal women, as they have been shown to be more effective. These also have an antiestrogenic effect, but by inhibiting estrogen production.
Tamoxifen therapy is prescribed for a minimum period of 5 years. Despite this, 25% of women treated with tamoxifen relapse. Tamoxifen resistance is unique in that it occurs very late on, generally 10-15 years after starting treatment. This means that it’s really important for us to identify predictive markers of the response to hormone therapy to adapt treatment as best we can. For the moment, the only criteria used to prescribe tamoxifen are patient age and the presence of estrogen receptors within the tumor.
Exactly how would treatment be improved if a decisive predictive marker of response to tamoxifen could be identified?
Dr. Le Romancer: Currently, when a patient’s breast cancer relapses after several years of treatment with tamoxifen, we don’t know if the relapse is linked to tamoxifen resistance or not. This makes it difficult to choose the right treatment to manage such relapses, which remain complicated to treat. Lots of patients die because of metastases.
By predicting the response to tamoxifen using a marker, we will be able to either use another hormone therapy to prevent the relapse or prescribe tamoxifen alongside a molecule that stops resistance from developing. We hope that this will significantly reduce the rate of relapse.
You put forward PRMT5 as a potential predictive marker of response to tamoxifen. What makes you think it could be used in this way?
Dr. Le Romancer: Our research has allowed us to demonstrate that PRMT5, when present in the nuclei of tumor cells, is involved in the mechanisms of action of tamoxifen. Remember that estrogen receptors are located in cell nuclei. For tamoxifen to exert its antitumoral action, PRMT5, an enzyme, needs to enter the nucleus to modify the estrogen receptor. It’s this modification that allows tamoxifen to inhibit tumor growth. The proliferative effect induced by the estrogens is also blocked.
The results of our study showed that high nuclear expression of PRMT5, specifically in the nuclei of breast cancer cells, is associated with a prolonged survival of tamoxifen-treated patients. Until now, we thought this enzyme had an oncogenic role when present in the cytoplasm. It turns out that it also has the opposite effect when acting within the nucleus, at least in this patient cohort: women with hormone-sensitive breast cancer treated with tamoxifen.
What are the next steps in your research before we can begin to think about its use in clinical practice?
Dr. Le Romancer: Our next research will focus on understanding the circumstances surrounding PRMT5 entering and leaving the nucleus. We have also shown that in some patients, tamoxifen causes PRMT5 to enter the cell nucleus. This translocation is only seen in women who respond to tamoxifen, not in those who are resistant to treatment with the drug. All that remains is for us to work out how tamoxifen facilitates this translocation.
Once the elements promoting this translocation have been identified, we will be able to propose a treatment aimed at forcing the enzyme to enter the nucleus and stay there. Eventually, the idea is to combine treatment with antiestrogens with a medicinal product that promotes localization of PRMT5 in the nucleus to guarantee response to tamoxifen. It will be a few years of research before we can apply our findings to clinical practice.
Could we use this biomarker as is just to identify tamoxifen resistance?
Dr. Le Romancer: In the short term, yes, we could use this biomarker to better guide treatment choices at time of diagnosis. We have demonstrated the role of PRMT5 in response to tamoxifen by studying two cohorts of 900 patients with breast cancer receiving treatment at the Léon Bérard Center, Lyon. Before moving on to routine testing, we need to replicate these results in other cohorts, especially in high-risk patients with, for example, greater cell proliferation or those who experience relapse.
The use of this biomarker is based on histological examination of cancer tissue. Single antibody tissue staining targeting PRMT5 reveals the localization of the enzyme in the cells and provides a score evaluating its presence in the nucleus. Using this score, it would be possible to determine the level of response to tamoxifen and decide whether the treatment should be used. This biomarker is the first of its kind undergoing validation as part of the examination of resistance to hormone therapy. We should be able to confirm the findings within the next 2 years.
If clinical tests using this biomarker predict tamoxifen resistance, what alternative treatments are available to these patients?
Dr. Le Romancer: We could give them an aromatase inhibitor or one of the new estrogen antagonists that are currently in development. In a phase 3 study, fulvestrant (Faslodex), for example, demonstrated a significant benefit in treating women with hormone-sensitive advanced breast cancer when administered via injection. The same goes for oral treatment, elacestrant (Orserdu), which has recently been approved by the Food and Drug Administration. These treatments are usually deemed second line after tamoxifen, but they could certainly be used as first-line therapy in resistant patients.
The results obtained from research into novel estrogen antagonists are certainly encouraging. Can tamoxifen retain its prominent position while still ensuring its efficacy?
Dr. Le Romancer: Keeping in mind the current trend for personalized medicine, we should keep as many treatment options open as possible. When a patient relapses, there need to be other treatments available to them. Tamoxifen has been ousted in favor of aromatase inhibitors for postmenopausal women, but it’s still the gold standard for premenopausal women and has been for over 20 years. Despite having been replaced by a novel estrogen antagonist, it will still have a prominent place in the therapeutic arsenal of premenopausal women with breast cancer.
With the development of PRMT5 as a predictive biomarker, we could even see tamoxifen being proposed as first-line therapy for postmenopausal women in whom high levels of PRMT5 are found in the nuclei of their cancer cells. By predicting their response, we could achieve greater efficacy of tamoxifen, compared with aromatase inhibitors. For now, this remains a hypothesis and must be verified in further clinical studies.
This article was translated from the Medscape French Edition. A version appeared on Medscape.com.
A team at Lyon’s Cancer Research Center (CRCL) has revealed the role of an enzyme, PRMT5, in the response to tamoxifen, a drug used to prevent relapse in premenopausal women with breast cancer.
Muriel Le Romancer, MD, director of research at France’s Institute of Health and Medical Research, explained the issues involved in this discovery in an interview. She jointly led this research along with Olivier Trédan, MD, PhD, oncologist at Lyon’s Léon Bérard Clinic. The research concluded with the publication of a study in EMBO Molecular Medicine. The researchers both head up the CRCL’s hormone resistance, methylation, and breast cancer team.
Although the enzyme’s involvement in the mode of action of tamoxifen has been observed in close to 900 patients with breast cancer, these results need to be validated in other at-risk patient cohorts before the biomarker can be considered for routine use, said Dr. Le Romancer. She estimated that 2 more years of research are needed.
Can you tell us which cases involve the use of tamoxifen and what its mode of action is?
Dr. Le Romancer: Tamoxifen is a hormone therapy used to reduce the risk of breast cancer relapse. It is prescribed to premenopausal women with hormone-sensitive cancer, which equates to roughly 25% of women with breast cancer: 15,000 women each year. The drug, which is taken every day via oral administration, is an estrogen antagonist. By binding to these receptors, it blocks estrogen from mediating its biological effect in the breasts. Aromatase inhibitors are the preferred choice in postmenopausal women, as they have been shown to be more effective. These also have an antiestrogenic effect, but by inhibiting estrogen production.
Tamoxifen therapy is prescribed for a minimum period of 5 years. Despite this, 25% of women treated with tamoxifen relapse. Tamoxifen resistance is unique in that it occurs very late on, generally 10-15 years after starting treatment. This means that it’s really important for us to identify predictive markers of the response to hormone therapy to adapt treatment as best we can. For the moment, the only criteria used to prescribe tamoxifen are patient age and the presence of estrogen receptors within the tumor.
Exactly how would treatment be improved if a decisive predictive marker of response to tamoxifen could be identified?
Dr. Le Romancer: Currently, when a patient’s breast cancer relapses after several years of treatment with tamoxifen, we don’t know if the relapse is linked to tamoxifen resistance or not. This makes it difficult to choose the right treatment to manage such relapses, which remain complicated to treat. Lots of patients die because of metastases.
By predicting the response to tamoxifen using a marker, we will be able to either use another hormone therapy to prevent the relapse or prescribe tamoxifen alongside a molecule that stops resistance from developing. We hope that this will significantly reduce the rate of relapse.
You put forward PRMT5 as a potential predictive marker of response to tamoxifen. What makes you think it could be used in this way?
Dr. Le Romancer: Our research has allowed us to demonstrate that PRMT5, when present in the nuclei of tumor cells, is involved in the mechanisms of action of tamoxifen. Remember that estrogen receptors are located in cell nuclei. For tamoxifen to exert its antitumoral action, PRMT5, an enzyme, needs to enter the nucleus to modify the estrogen receptor. It’s this modification that allows tamoxifen to inhibit tumor growth. The proliferative effect induced by the estrogens is also blocked.
The results of our study showed that high nuclear expression of PRMT5, specifically in the nuclei of breast cancer cells, is associated with a prolonged survival of tamoxifen-treated patients. Until now, we thought this enzyme had an oncogenic role when present in the cytoplasm. It turns out that it also has the opposite effect when acting within the nucleus, at least in this patient cohort: women with hormone-sensitive breast cancer treated with tamoxifen.
What are the next steps in your research before we can begin to think about its use in clinical practice?
Dr. Le Romancer: Our next research will focus on understanding the circumstances surrounding PRMT5 entering and leaving the nucleus. We have also shown that in some patients, tamoxifen causes PRMT5 to enter the cell nucleus. This translocation is only seen in women who respond to tamoxifen, not in those who are resistant to treatment with the drug. All that remains is for us to work out how tamoxifen facilitates this translocation.
Once the elements promoting this translocation have been identified, we will be able to propose a treatment aimed at forcing the enzyme to enter the nucleus and stay there. Eventually, the idea is to combine treatment with antiestrogens with a medicinal product that promotes localization of PRMT5 in the nucleus to guarantee response to tamoxifen. It will be a few years of research before we can apply our findings to clinical practice.
Could we use this biomarker as is just to identify tamoxifen resistance?
Dr. Le Romancer: In the short term, yes, we could use this biomarker to better guide treatment choices at time of diagnosis. We have demonstrated the role of PRMT5 in response to tamoxifen by studying two cohorts of 900 patients with breast cancer receiving treatment at the Léon Bérard Center, Lyon. Before moving on to routine testing, we need to replicate these results in other cohorts, especially in high-risk patients with, for example, greater cell proliferation or those who experience relapse.
The use of this biomarker is based on histological examination of cancer tissue. Single antibody tissue staining targeting PRMT5 reveals the localization of the enzyme in the cells and provides a score evaluating its presence in the nucleus. Using this score, it would be possible to determine the level of response to tamoxifen and decide whether the treatment should be used. This biomarker is the first of its kind undergoing validation as part of the examination of resistance to hormone therapy. We should be able to confirm the findings within the next 2 years.
If clinical tests using this biomarker predict tamoxifen resistance, what alternative treatments are available to these patients?
Dr. Le Romancer: We could give them an aromatase inhibitor or one of the new estrogen antagonists that are currently in development. In a phase 3 study, fulvestrant (Faslodex), for example, demonstrated a significant benefit in treating women with hormone-sensitive advanced breast cancer when administered via injection. The same goes for oral treatment, elacestrant (Orserdu), which has recently been approved by the Food and Drug Administration. These treatments are usually deemed second line after tamoxifen, but they could certainly be used as first-line therapy in resistant patients.
The results obtained from research into novel estrogen antagonists are certainly encouraging. Can tamoxifen retain its prominent position while still ensuring its efficacy?
Dr. Le Romancer: Keeping in mind the current trend for personalized medicine, we should keep as many treatment options open as possible. When a patient relapses, there need to be other treatments available to them. Tamoxifen has been ousted in favor of aromatase inhibitors for postmenopausal women, but it’s still the gold standard for premenopausal women and has been for over 20 years. Despite having been replaced by a novel estrogen antagonist, it will still have a prominent place in the therapeutic arsenal of premenopausal women with breast cancer.
With the development of PRMT5 as a predictive biomarker, we could even see tamoxifen being proposed as first-line therapy for postmenopausal women in whom high levels of PRMT5 are found in the nuclei of their cancer cells. By predicting their response, we could achieve greater efficacy of tamoxifen, compared with aromatase inhibitors. For now, this remains a hypothesis and must be verified in further clinical studies.
This article was translated from the Medscape French Edition. A version appeared on Medscape.com.
A team at Lyon’s Cancer Research Center (CRCL) has revealed the role of an enzyme, PRMT5, in the response to tamoxifen, a drug used to prevent relapse in premenopausal women with breast cancer.
Muriel Le Romancer, MD, director of research at France’s Institute of Health and Medical Research, explained the issues involved in this discovery in an interview. She jointly led this research along with Olivier Trédan, MD, PhD, oncologist at Lyon’s Léon Bérard Clinic. The research concluded with the publication of a study in EMBO Molecular Medicine. The researchers both head up the CRCL’s hormone resistance, methylation, and breast cancer team.
Although the enzyme’s involvement in the mode of action of tamoxifen has been observed in close to 900 patients with breast cancer, these results need to be validated in other at-risk patient cohorts before the biomarker can be considered for routine use, said Dr. Le Romancer. She estimated that 2 more years of research are needed.
Can you tell us which cases involve the use of tamoxifen and what its mode of action is?
Dr. Le Romancer: Tamoxifen is a hormone therapy used to reduce the risk of breast cancer relapse. It is prescribed to premenopausal women with hormone-sensitive cancer, which equates to roughly 25% of women with breast cancer: 15,000 women each year. The drug, which is taken every day via oral administration, is an estrogen antagonist. By binding to these receptors, it blocks estrogen from mediating its biological effect in the breasts. Aromatase inhibitors are the preferred choice in postmenopausal women, as they have been shown to be more effective. These also have an antiestrogenic effect, but by inhibiting estrogen production.
Tamoxifen therapy is prescribed for a minimum period of 5 years. Despite this, 25% of women treated with tamoxifen relapse. Tamoxifen resistance is unique in that it occurs very late on, generally 10-15 years after starting treatment. This means that it’s really important for us to identify predictive markers of the response to hormone therapy to adapt treatment as best we can. For the moment, the only criteria used to prescribe tamoxifen are patient age and the presence of estrogen receptors within the tumor.
Exactly how would treatment be improved if a decisive predictive marker of response to tamoxifen could be identified?
Dr. Le Romancer: Currently, when a patient’s breast cancer relapses after several years of treatment with tamoxifen, we don’t know if the relapse is linked to tamoxifen resistance or not. This makes it difficult to choose the right treatment to manage such relapses, which remain complicated to treat. Lots of patients die because of metastases.
By predicting the response to tamoxifen using a marker, we will be able to either use another hormone therapy to prevent the relapse or prescribe tamoxifen alongside a molecule that stops resistance from developing. We hope that this will significantly reduce the rate of relapse.
You put forward PRMT5 as a potential predictive marker of response to tamoxifen. What makes you think it could be used in this way?
Dr. Le Romancer: Our research has allowed us to demonstrate that PRMT5, when present in the nuclei of tumor cells, is involved in the mechanisms of action of tamoxifen. Remember that estrogen receptors are located in cell nuclei. For tamoxifen to exert its antitumoral action, PRMT5, an enzyme, needs to enter the nucleus to modify the estrogen receptor. It’s this modification that allows tamoxifen to inhibit tumor growth. The proliferative effect induced by the estrogens is also blocked.
The results of our study showed that high nuclear expression of PRMT5, specifically in the nuclei of breast cancer cells, is associated with a prolonged survival of tamoxifen-treated patients. Until now, we thought this enzyme had an oncogenic role when present in the cytoplasm. It turns out that it also has the opposite effect when acting within the nucleus, at least in this patient cohort: women with hormone-sensitive breast cancer treated with tamoxifen.
What are the next steps in your research before we can begin to think about its use in clinical practice?
Dr. Le Romancer: Our next research will focus on understanding the circumstances surrounding PRMT5 entering and leaving the nucleus. We have also shown that in some patients, tamoxifen causes PRMT5 to enter the cell nucleus. This translocation is only seen in women who respond to tamoxifen, not in those who are resistant to treatment with the drug. All that remains is for us to work out how tamoxifen facilitates this translocation.
Once the elements promoting this translocation have been identified, we will be able to propose a treatment aimed at forcing the enzyme to enter the nucleus and stay there. Eventually, the idea is to combine treatment with antiestrogens with a medicinal product that promotes localization of PRMT5 in the nucleus to guarantee response to tamoxifen. It will be a few years of research before we can apply our findings to clinical practice.
Could we use this biomarker as is just to identify tamoxifen resistance?
Dr. Le Romancer: In the short term, yes, we could use this biomarker to better guide treatment choices at time of diagnosis. We have demonstrated the role of PRMT5 in response to tamoxifen by studying two cohorts of 900 patients with breast cancer receiving treatment at the Léon Bérard Center, Lyon. Before moving on to routine testing, we need to replicate these results in other cohorts, especially in high-risk patients with, for example, greater cell proliferation or those who experience relapse.
The use of this biomarker is based on histological examination of cancer tissue. Single antibody tissue staining targeting PRMT5 reveals the localization of the enzyme in the cells and provides a score evaluating its presence in the nucleus. Using this score, it would be possible to determine the level of response to tamoxifen and decide whether the treatment should be used. This biomarker is the first of its kind undergoing validation as part of the examination of resistance to hormone therapy. We should be able to confirm the findings within the next 2 years.
If clinical tests using this biomarker predict tamoxifen resistance, what alternative treatments are available to these patients?
Dr. Le Romancer: We could give them an aromatase inhibitor or one of the new estrogen antagonists that are currently in development. In a phase 3 study, fulvestrant (Faslodex), for example, demonstrated a significant benefit in treating women with hormone-sensitive advanced breast cancer when administered via injection. The same goes for oral treatment, elacestrant (Orserdu), which has recently been approved by the Food and Drug Administration. These treatments are usually deemed second line after tamoxifen, but they could certainly be used as first-line therapy in resistant patients.
The results obtained from research into novel estrogen antagonists are certainly encouraging. Can tamoxifen retain its prominent position while still ensuring its efficacy?
Dr. Le Romancer: Keeping in mind the current trend for personalized medicine, we should keep as many treatment options open as possible. When a patient relapses, there need to be other treatments available to them. Tamoxifen has been ousted in favor of aromatase inhibitors for postmenopausal women, but it’s still the gold standard for premenopausal women and has been for over 20 years. Despite having been replaced by a novel estrogen antagonist, it will still have a prominent place in the therapeutic arsenal of premenopausal women with breast cancer.
With the development of PRMT5 as a predictive biomarker, we could even see tamoxifen being proposed as first-line therapy for postmenopausal women in whom high levels of PRMT5 are found in the nuclei of their cancer cells. By predicting their response, we could achieve greater efficacy of tamoxifen, compared with aromatase inhibitors. For now, this remains a hypothesis and must be verified in further clinical studies.
This article was translated from the Medscape French Edition. A version appeared on Medscape.com.
Expert calls for sparing oxygen use for dyspnea in the emergency department
PARIS – , as per the current guidelines. Florian Negrello, MD, an emergency medicine specialist at University Hospital of Martinique in Fort-de-France, reiterated this message at the 2023 conference held by France’s emergency medicine society (Urgences 2023). The recommendation is intended to prevent hyperoxia; increasing evidence indicates the harmful effects of such a state on the body.
“This is a real problem. Oxygen therapy is given all too readily despite studies now showing that excess oxygen is harmful, especially in patients with head trauma, ischemic stroke, or cardiac arrest,” stated the session’s moderator, Patrick Plaisance, MD, PhD, a doctor at Lariboisière Hospital in Paris.
No proven hypoxia
Described as difficulty breathing or shortness of breath, dyspnea is common in the emergency department, occurring in 5%-9% of patients. Close to 20% of intensive care unit admissions involve patients with dyspnea. “Since this is a very subjective symptom, it’s possible it’s being underdiagnosed,” said Dr. Negrello.
Lower respiratory tract infection, acute heart failure, chronic obstructive pulmonary disease, and exacerbation of asthma are the four main diagnoses linked to dyspnea, but this symptom is also seen in several medical conditions (gastrointestinal, metabolic, neurologic, etc.), he noted.
Often seen as a harmless treatment option, oxygen therapy is commonly administered to patients with breathing difficulties even when no hypoxemia is documented. This is particularly the case for patients brought into hospital via ambulance who are treated with oxygen without even having had their blood oxygen levels, SpO2, and partial pressure of oxygen checked.
In the United States, one of the few studies published on the topic showed that one-third of patients transported via ambulance are put on oxygen, with SpO2 being measured in just 5% of these cases. Finally, just 17% of patients receiving oxygen were experiencing hypoxia, defined as SpO2 < 94%.
Oxidative stress
Recently, several research studies have revealed the potential dangers of unjustified use of oxygen, which can lead to hyperoxia and increased mortality in hospitalized patients.
A meta-analysis reported a linear relationship between severe hyperoxia, in-hospital mortality, and length of stay in intensive care. Another study revealed a greater mortality rate in patients with acute respiratory distress syndrome (ARDS) experiencing an episode of hyperoxia, regardless of the severity of ARDS.
Oxygen toxicity in intensive care is said to be linked to oxidative stress caused by increased growth of reactive oxygen species but also to the systemic inflammation caused by hyperoxia, explained Dr. Negrello. Excess oxygen may also cause lung lesions with necrosis, the severity of which is proportional to the fraction of inspired oxygen and the length of exposure.
According to the most up-to-date international recommendations published in 2018 on the use of oxygen therapy in treating acute conditions, oxygen should not be used when SpO2 ≥ 93%. When treatment has been started, it must be stopped when SpO2 reaches 96%. SpO2 cannot be maintained above 96%, according to experts.
These threshold values can be found in the COVID-19 treatment guidelines produced by the French-Language Society of Respiratory Medicine, with oxygen therapy being recommended when SpO2 < 92%, added Dr. Negrello. The aim is to maintain normal oxygen levels, with SpO2 between 92% and 96%.
Use sparingly
For patients with COPD, the target levels are lower, due to the risk of hypercapnia (higher than normal carbon dioxide levels in the blood). Oxygen saturation levels should then be kept between 88% and 92%, “by using the minimum amount of oxygen necessary,” per the guidelines.
“Oxygen should be used sparingly,” concluded Dr. Negrello. “To treat our patients without harming them, we must be able to use it at the right time, meaning when a patient really has low blood oxygen, by focusing on normal saturation levels as the end goal.”
SpO2 measurement is the first step to be taken to determine oxygen requirements, followed by, if necessary, blood gas analysis once the patient has been admitted, he explained.
Questioned at the end of his session on how long oxygen therapy can be given for, Dr. Negrello reiterated that the risk for death is correlated with the length of time spent in a state of hyperoxia but that it is difficult to establish a maximum timeframe to be adhered to strictly.
Given that excess oxygen is harmful to patients in intensive care, “it would be better, when in doubt, to focus on physiological levels” and simply stop treatment when target saturation levels are reached.
This article was translated from the Medscape French Edition. A version appeared on Medscape.com.
PARIS – , as per the current guidelines. Florian Negrello, MD, an emergency medicine specialist at University Hospital of Martinique in Fort-de-France, reiterated this message at the 2023 conference held by France’s emergency medicine society (Urgences 2023). The recommendation is intended to prevent hyperoxia; increasing evidence indicates the harmful effects of such a state on the body.
“This is a real problem. Oxygen therapy is given all too readily despite studies now showing that excess oxygen is harmful, especially in patients with head trauma, ischemic stroke, or cardiac arrest,” stated the session’s moderator, Patrick Plaisance, MD, PhD, a doctor at Lariboisière Hospital in Paris.
No proven hypoxia
Described as difficulty breathing or shortness of breath, dyspnea is common in the emergency department, occurring in 5%-9% of patients. Close to 20% of intensive care unit admissions involve patients with dyspnea. “Since this is a very subjective symptom, it’s possible it’s being underdiagnosed,” said Dr. Negrello.
Lower respiratory tract infection, acute heart failure, chronic obstructive pulmonary disease, and exacerbation of asthma are the four main diagnoses linked to dyspnea, but this symptom is also seen in several medical conditions (gastrointestinal, metabolic, neurologic, etc.), he noted.
Often seen as a harmless treatment option, oxygen therapy is commonly administered to patients with breathing difficulties even when no hypoxemia is documented. This is particularly the case for patients brought into hospital via ambulance who are treated with oxygen without even having had their blood oxygen levels, SpO2, and partial pressure of oxygen checked.
In the United States, one of the few studies published on the topic showed that one-third of patients transported via ambulance are put on oxygen, with SpO2 being measured in just 5% of these cases. Finally, just 17% of patients receiving oxygen were experiencing hypoxia, defined as SpO2 < 94%.
Oxidative stress
Recently, several research studies have revealed the potential dangers of unjustified use of oxygen, which can lead to hyperoxia and increased mortality in hospitalized patients.
A meta-analysis reported a linear relationship between severe hyperoxia, in-hospital mortality, and length of stay in intensive care. Another study revealed a greater mortality rate in patients with acute respiratory distress syndrome (ARDS) experiencing an episode of hyperoxia, regardless of the severity of ARDS.
Oxygen toxicity in intensive care is said to be linked to oxidative stress caused by increased growth of reactive oxygen species but also to the systemic inflammation caused by hyperoxia, explained Dr. Negrello. Excess oxygen may also cause lung lesions with necrosis, the severity of which is proportional to the fraction of inspired oxygen and the length of exposure.
According to the most up-to-date international recommendations published in 2018 on the use of oxygen therapy in treating acute conditions, oxygen should not be used when SpO2 ≥ 93%. When treatment has been started, it must be stopped when SpO2 reaches 96%. SpO2 cannot be maintained above 96%, according to experts.
These threshold values can be found in the COVID-19 treatment guidelines produced by the French-Language Society of Respiratory Medicine, with oxygen therapy being recommended when SpO2 < 92%, added Dr. Negrello. The aim is to maintain normal oxygen levels, with SpO2 between 92% and 96%.
Use sparingly
For patients with COPD, the target levels are lower, due to the risk of hypercapnia (higher than normal carbon dioxide levels in the blood). Oxygen saturation levels should then be kept between 88% and 92%, “by using the minimum amount of oxygen necessary,” per the guidelines.
“Oxygen should be used sparingly,” concluded Dr. Negrello. “To treat our patients without harming them, we must be able to use it at the right time, meaning when a patient really has low blood oxygen, by focusing on normal saturation levels as the end goal.”
SpO2 measurement is the first step to be taken to determine oxygen requirements, followed by, if necessary, blood gas analysis once the patient has been admitted, he explained.
Questioned at the end of his session on how long oxygen therapy can be given for, Dr. Negrello reiterated that the risk for death is correlated with the length of time spent in a state of hyperoxia but that it is difficult to establish a maximum timeframe to be adhered to strictly.
Given that excess oxygen is harmful to patients in intensive care, “it would be better, when in doubt, to focus on physiological levels” and simply stop treatment when target saturation levels are reached.
This article was translated from the Medscape French Edition. A version appeared on Medscape.com.
PARIS – , as per the current guidelines. Florian Negrello, MD, an emergency medicine specialist at University Hospital of Martinique in Fort-de-France, reiterated this message at the 2023 conference held by France’s emergency medicine society (Urgences 2023). The recommendation is intended to prevent hyperoxia; increasing evidence indicates the harmful effects of such a state on the body.
“This is a real problem. Oxygen therapy is given all too readily despite studies now showing that excess oxygen is harmful, especially in patients with head trauma, ischemic stroke, or cardiac arrest,” stated the session’s moderator, Patrick Plaisance, MD, PhD, a doctor at Lariboisière Hospital in Paris.
No proven hypoxia
Described as difficulty breathing or shortness of breath, dyspnea is common in the emergency department, occurring in 5%-9% of patients. Close to 20% of intensive care unit admissions involve patients with dyspnea. “Since this is a very subjective symptom, it’s possible it’s being underdiagnosed,” said Dr. Negrello.
Lower respiratory tract infection, acute heart failure, chronic obstructive pulmonary disease, and exacerbation of asthma are the four main diagnoses linked to dyspnea, but this symptom is also seen in several medical conditions (gastrointestinal, metabolic, neurologic, etc.), he noted.
Often seen as a harmless treatment option, oxygen therapy is commonly administered to patients with breathing difficulties even when no hypoxemia is documented. This is particularly the case for patients brought into hospital via ambulance who are treated with oxygen without even having had their blood oxygen levels, SpO2, and partial pressure of oxygen checked.
In the United States, one of the few studies published on the topic showed that one-third of patients transported via ambulance are put on oxygen, with SpO2 being measured in just 5% of these cases. Finally, just 17% of patients receiving oxygen were experiencing hypoxia, defined as SpO2 < 94%.
Oxidative stress
Recently, several research studies have revealed the potential dangers of unjustified use of oxygen, which can lead to hyperoxia and increased mortality in hospitalized patients.
A meta-analysis reported a linear relationship between severe hyperoxia, in-hospital mortality, and length of stay in intensive care. Another study revealed a greater mortality rate in patients with acute respiratory distress syndrome (ARDS) experiencing an episode of hyperoxia, regardless of the severity of ARDS.
Oxygen toxicity in intensive care is said to be linked to oxidative stress caused by increased growth of reactive oxygen species but also to the systemic inflammation caused by hyperoxia, explained Dr. Negrello. Excess oxygen may also cause lung lesions with necrosis, the severity of which is proportional to the fraction of inspired oxygen and the length of exposure.
According to the most up-to-date international recommendations published in 2018 on the use of oxygen therapy in treating acute conditions, oxygen should not be used when SpO2 ≥ 93%. When treatment has been started, it must be stopped when SpO2 reaches 96%. SpO2 cannot be maintained above 96%, according to experts.
These threshold values can be found in the COVID-19 treatment guidelines produced by the French-Language Society of Respiratory Medicine, with oxygen therapy being recommended when SpO2 < 92%, added Dr. Negrello. The aim is to maintain normal oxygen levels, with SpO2 between 92% and 96%.
Use sparingly
For patients with COPD, the target levels are lower, due to the risk of hypercapnia (higher than normal carbon dioxide levels in the blood). Oxygen saturation levels should then be kept between 88% and 92%, “by using the minimum amount of oxygen necessary,” per the guidelines.
“Oxygen should be used sparingly,” concluded Dr. Negrello. “To treat our patients without harming them, we must be able to use it at the right time, meaning when a patient really has low blood oxygen, by focusing on normal saturation levels as the end goal.”
SpO2 measurement is the first step to be taken to determine oxygen requirements, followed by, if necessary, blood gas analysis once the patient has been admitted, he explained.
Questioned at the end of his session on how long oxygen therapy can be given for, Dr. Negrello reiterated that the risk for death is correlated with the length of time spent in a state of hyperoxia but that it is difficult to establish a maximum timeframe to be adhered to strictly.
Given that excess oxygen is harmful to patients in intensive care, “it would be better, when in doubt, to focus on physiological levels” and simply stop treatment when target saturation levels are reached.
This article was translated from the Medscape French Edition. A version appeared on Medscape.com.
CML: Preventing chemo-induced vascular toxicity
PARIS –
Cardiologist Gabrielle Sarlon, MD, PhD, a professor at Marseille (France) University Hospital, offered her recommendations at the European Days of the French Society of Cardiology Conference 2023.
In the literature, we find many hypotheses that seek to explain why these drugs bring about the formation of atheromatous plaque. The findings of one French study led Dr. Sarlon to state, “I firmly believe that, in some patients, these treatments make LDL cholesterol go up.” This would be the main cause of the coronary and peripheral arterial diseases that are being seen.
Therefore, “LDL-C should start being monitored when the therapy starts, and a statin may have to be prescribed,” she said.
Arterial diseases
By bringing about a marked improvement in patients’ chances of survival, TKIs “have revolutionized the management of chronic myeloid leukemia,” Dr. Sarlon added. But these treatments have side effects. The most common is high blood pressure, “an effect that attests to the efficacy of targeted therapies and that must be quickly treated” with antihypertensives.
It is well known that the targeted therapies cause the rise in blood pressure. What was unexpected, though, was the vascular toxicity seen with the latest generation of TKIs. “This is a real toxicity that we need to know about, detect, and manage,” said Dr. Sarlon.
The prevalence of arterial diseases induced by nilotinib, a second-generation TKI, can be as high as 10%. Single-center studies have indicated much higher numbers. In a small study that Dr. Sarlon and her team conducted at Marseille University Hospital, atherosclerotic-type arterial injuries were observed in more than 30% of patients treated with nilotinib.
Dr. Sarlon noted that the signs of arterial toxicity occurring with this treatment have not appeared in clinical trials. Observations of the real-life use of nilotinib led French and German teams to sound the alarm. They noticed that some patients treated for CML had developed claudication and progression to critical limb ischemia of the lower extremities.
Risk factors uncovered
The first retrospective analysis to explore this risk was carried out by a German team. They included 179 patients who received nilotinib and found that 11 (6.2%) developed severe and previously unrecognized lower-extremity peripheral arterial disease (PAD) that required invasive therapy. The mean time from initiation of nilotinib to the first PAD event was 105.1 weeks (range = 16-212 weeks).
The following have emerged as major risk factors for nilotinib-induced PAD: the presence of cardiovascular risk factors, age older than 60 years, and long duration of exposure to nilotinib. Some of these factors were confirmed in the more recent study conducted at Marseille University Hospital involving patients treated with nilotinib. According to other research, there seems to be a correlation between this risk and the dose administered.
In the case of ponatinib, the side effects are even more common – so much so that, a few months after this third-generation TKI was authorized, a warning was issued about its use. A long-term follow-up study reported a 28% prevalence of cardiovascular events, while arterial diseases were observed in 20% of cases after 1-2 years on the treatment.
In terms of pathophysiology, the Marseilles University Hospital study found that arterial injuries were associated with stenosis greater than 50% in almost half of cases. “The atheromatous plaques were found where they typically are,” with the carotid bulb being the most involved territory, according to the researchers. But they’re also found in other arteries – femoral, vertebral, even renal – “sometimes in patients without cardiovascular risk factors.”
One distinctive characteristic to keep in mind is that “lipid-rich atheromatous plaques appear very dark on imaging” and thus can go unnoticed during a Doppler ultrasound. And, Dr. Sarlon added, “surprisingly, the thickening can extend to the external carotid artery.”
Ankle-brachial index
Published last year, the first European Society of Cardiology Guidelines on Cardio-Oncology present specific baseline risk-assessment and monitoring recommendations regarding patients treated with nilotinib and ponatinib. One suggests that a cardiovascular risk assessment be done every 3 months during the first year and every 6-12 months thereafter. This assessment would include such items as ECGs, blood pressure measurements, and lipid profile tests.
In addition, it is advised that every 6 months an ankle-brachial index test be performed to check for PAD. At Marseille University Hospital, a Doppler ultrasound is also done at each follow-up appointment to look for arterial plaques, “even for patients at low risk for cardiovascular disease,” said Dr. Sarlon. “It seems, above all, absolutely necessary that hematologists order an LDL-C test and, if needed, consider statin therapy,” all the while keeping in mind that “the target LDL-C level is 1 gram per liter.”
This article was translated from the Medscape French edition. A version of this article first appeared on Medscape.com.
PARIS –
Cardiologist Gabrielle Sarlon, MD, PhD, a professor at Marseille (France) University Hospital, offered her recommendations at the European Days of the French Society of Cardiology Conference 2023.
In the literature, we find many hypotheses that seek to explain why these drugs bring about the formation of atheromatous plaque. The findings of one French study led Dr. Sarlon to state, “I firmly believe that, in some patients, these treatments make LDL cholesterol go up.” This would be the main cause of the coronary and peripheral arterial diseases that are being seen.
Therefore, “LDL-C should start being monitored when the therapy starts, and a statin may have to be prescribed,” she said.
Arterial diseases
By bringing about a marked improvement in patients’ chances of survival, TKIs “have revolutionized the management of chronic myeloid leukemia,” Dr. Sarlon added. But these treatments have side effects. The most common is high blood pressure, “an effect that attests to the efficacy of targeted therapies and that must be quickly treated” with antihypertensives.
It is well known that the targeted therapies cause the rise in blood pressure. What was unexpected, though, was the vascular toxicity seen with the latest generation of TKIs. “This is a real toxicity that we need to know about, detect, and manage,” said Dr. Sarlon.
The prevalence of arterial diseases induced by nilotinib, a second-generation TKI, can be as high as 10%. Single-center studies have indicated much higher numbers. In a small study that Dr. Sarlon and her team conducted at Marseille University Hospital, atherosclerotic-type arterial injuries were observed in more than 30% of patients treated with nilotinib.
Dr. Sarlon noted that the signs of arterial toxicity occurring with this treatment have not appeared in clinical trials. Observations of the real-life use of nilotinib led French and German teams to sound the alarm. They noticed that some patients treated for CML had developed claudication and progression to critical limb ischemia of the lower extremities.
Risk factors uncovered
The first retrospective analysis to explore this risk was carried out by a German team. They included 179 patients who received nilotinib and found that 11 (6.2%) developed severe and previously unrecognized lower-extremity peripheral arterial disease (PAD) that required invasive therapy. The mean time from initiation of nilotinib to the first PAD event was 105.1 weeks (range = 16-212 weeks).
The following have emerged as major risk factors for nilotinib-induced PAD: the presence of cardiovascular risk factors, age older than 60 years, and long duration of exposure to nilotinib. Some of these factors were confirmed in the more recent study conducted at Marseille University Hospital involving patients treated with nilotinib. According to other research, there seems to be a correlation between this risk and the dose administered.
In the case of ponatinib, the side effects are even more common – so much so that, a few months after this third-generation TKI was authorized, a warning was issued about its use. A long-term follow-up study reported a 28% prevalence of cardiovascular events, while arterial diseases were observed in 20% of cases after 1-2 years on the treatment.
In terms of pathophysiology, the Marseilles University Hospital study found that arterial injuries were associated with stenosis greater than 50% in almost half of cases. “The atheromatous plaques were found where they typically are,” with the carotid bulb being the most involved territory, according to the researchers. But they’re also found in other arteries – femoral, vertebral, even renal – “sometimes in patients without cardiovascular risk factors.”
One distinctive characteristic to keep in mind is that “lipid-rich atheromatous plaques appear very dark on imaging” and thus can go unnoticed during a Doppler ultrasound. And, Dr. Sarlon added, “surprisingly, the thickening can extend to the external carotid artery.”
Ankle-brachial index
Published last year, the first European Society of Cardiology Guidelines on Cardio-Oncology present specific baseline risk-assessment and monitoring recommendations regarding patients treated with nilotinib and ponatinib. One suggests that a cardiovascular risk assessment be done every 3 months during the first year and every 6-12 months thereafter. This assessment would include such items as ECGs, blood pressure measurements, and lipid profile tests.
In addition, it is advised that every 6 months an ankle-brachial index test be performed to check for PAD. At Marseille University Hospital, a Doppler ultrasound is also done at each follow-up appointment to look for arterial plaques, “even for patients at low risk for cardiovascular disease,” said Dr. Sarlon. “It seems, above all, absolutely necessary that hematologists order an LDL-C test and, if needed, consider statin therapy,” all the while keeping in mind that “the target LDL-C level is 1 gram per liter.”
This article was translated from the Medscape French edition. A version of this article first appeared on Medscape.com.
PARIS –
Cardiologist Gabrielle Sarlon, MD, PhD, a professor at Marseille (France) University Hospital, offered her recommendations at the European Days of the French Society of Cardiology Conference 2023.
In the literature, we find many hypotheses that seek to explain why these drugs bring about the formation of atheromatous plaque. The findings of one French study led Dr. Sarlon to state, “I firmly believe that, in some patients, these treatments make LDL cholesterol go up.” This would be the main cause of the coronary and peripheral arterial diseases that are being seen.
Therefore, “LDL-C should start being monitored when the therapy starts, and a statin may have to be prescribed,” she said.
Arterial diseases
By bringing about a marked improvement in patients’ chances of survival, TKIs “have revolutionized the management of chronic myeloid leukemia,” Dr. Sarlon added. But these treatments have side effects. The most common is high blood pressure, “an effect that attests to the efficacy of targeted therapies and that must be quickly treated” with antihypertensives.
It is well known that the targeted therapies cause the rise in blood pressure. What was unexpected, though, was the vascular toxicity seen with the latest generation of TKIs. “This is a real toxicity that we need to know about, detect, and manage,” said Dr. Sarlon.
The prevalence of arterial diseases induced by nilotinib, a second-generation TKI, can be as high as 10%. Single-center studies have indicated much higher numbers. In a small study that Dr. Sarlon and her team conducted at Marseille University Hospital, atherosclerotic-type arterial injuries were observed in more than 30% of patients treated with nilotinib.
Dr. Sarlon noted that the signs of arterial toxicity occurring with this treatment have not appeared in clinical trials. Observations of the real-life use of nilotinib led French and German teams to sound the alarm. They noticed that some patients treated for CML had developed claudication and progression to critical limb ischemia of the lower extremities.
Risk factors uncovered
The first retrospective analysis to explore this risk was carried out by a German team. They included 179 patients who received nilotinib and found that 11 (6.2%) developed severe and previously unrecognized lower-extremity peripheral arterial disease (PAD) that required invasive therapy. The mean time from initiation of nilotinib to the first PAD event was 105.1 weeks (range = 16-212 weeks).
The following have emerged as major risk factors for nilotinib-induced PAD: the presence of cardiovascular risk factors, age older than 60 years, and long duration of exposure to nilotinib. Some of these factors were confirmed in the more recent study conducted at Marseille University Hospital involving patients treated with nilotinib. According to other research, there seems to be a correlation between this risk and the dose administered.
In the case of ponatinib, the side effects are even more common – so much so that, a few months after this third-generation TKI was authorized, a warning was issued about its use. A long-term follow-up study reported a 28% prevalence of cardiovascular events, while arterial diseases were observed in 20% of cases after 1-2 years on the treatment.
In terms of pathophysiology, the Marseilles University Hospital study found that arterial injuries were associated with stenosis greater than 50% in almost half of cases. “The atheromatous plaques were found where they typically are,” with the carotid bulb being the most involved territory, according to the researchers. But they’re also found in other arteries – femoral, vertebral, even renal – “sometimes in patients without cardiovascular risk factors.”
One distinctive characteristic to keep in mind is that “lipid-rich atheromatous plaques appear very dark on imaging” and thus can go unnoticed during a Doppler ultrasound. And, Dr. Sarlon added, “surprisingly, the thickening can extend to the external carotid artery.”
Ankle-brachial index
Published last year, the first European Society of Cardiology Guidelines on Cardio-Oncology present specific baseline risk-assessment and monitoring recommendations regarding patients treated with nilotinib and ponatinib. One suggests that a cardiovascular risk assessment be done every 3 months during the first year and every 6-12 months thereafter. This assessment would include such items as ECGs, blood pressure measurements, and lipid profile tests.
In addition, it is advised that every 6 months an ankle-brachial index test be performed to check for PAD. At Marseille University Hospital, a Doppler ultrasound is also done at each follow-up appointment to look for arterial plaques, “even for patients at low risk for cardiovascular disease,” said Dr. Sarlon. “It seems, above all, absolutely necessary that hematologists order an LDL-C test and, if needed, consider statin therapy,” all the while keeping in mind that “the target LDL-C level is 1 gram per liter.”
This article was translated from the Medscape French edition. A version of this article first appeared on Medscape.com.