Photo courtesy of the CDC

A large, retrospective study suggests patients with atrial fibrillation may have a lower risk of acute myocardial infarction (AMI) if they receive vitamin K antagonists (VKAs) rather than other anticoagulants.

Investigators found that patients taking direct oral anticoagulants (DOACs, rivaroxaban or dabigatran) had more than twice the AMI risk of patients taking VKAs.

And the AMI risk for patients taking low-dose aspirin was nearly double that of those taking VKAs.

Leo M. Stolk, PharmD, PhD, of Maastricht University Medical Centre in the Netherlands, and his colleagues reported these results in the British Journal of Clinical Pharmacology.

The investigators analyzed data on 30,146 adults with atrial fibrillation who were new users of DOACs (n=1266), VKAs (n=13,098), low-dose aspirin (n=15,400), or mixed anticoagulants (n=382). Most DOAC users were taking rivaroxaban (71.6%), but some were taking dabigatran (28.4%).

The mean follow-up was 0.95 years for DOAC users, 2.72 years for VKA users, 2.86 years for low-dose aspirin users, and 2.99 years for mixed medication users.

The investigators estimated the hazard ratio (HR) of AMI for users of DOACs, aspirin, or mixed medications versus VKAs. The team adjusted their analysis for age, sex, lifestyle, risk factors, comorbidities, and use of other medications.

Compared to VKA users, the risk of AMI was significantly higher for DOAC users (HR=2.11; 95% CI 1.08 – 4.12, P<0.05) and aspirin users (HR=1.91; 95% CI 1.45-2.51, P<0.05). The risk was not significantly higher for mixed medication users (HR=1.69; 95% CI 0.69, 4.16).

When patients were stratified by gender, there was a significantly increased risk of AMI for aspirin users who were male (HR=1.60; 95% CI 1.10, 2.33, P<0.05) or female (HR=2.33; 95% CI 1.55, 3.50, P<0.05), when compared to VKA users. Neither DOACs nor mixed medications were associated with a significantly increased risk of AMI in this analysis.

The investigators also stratified patients according to their CHA2DS2-VASc score at the index date.

Among patients with a high score (≥4), there was a significantly increased risk of AMI for aspirin users compared to VKA users (HR=2.21; 95% CI 1.37,3.55, P<0.05).

Among patients with a medium score (>1 and <4), the risk of AMI was significantly higher for DOAC users (HR=2.67; 95% CI 1.11, 6.40, P<0.05) and aspirin users (HR=1.82; 95% CI 1.23, 2.68, P<0.05) compared to VKA users.

The investigators said this study suggests VKAs probably have greater beneficial effects on AMI than DOACs, and ongoing research is needed as the use of DOACs increases.

Photo courtesy of the CDC

A large, retrospective study suggests patients with atrial fibrillation may have a lower risk of acute myocardial infarction (AMI) if they receive vitamin K antagonists (VKAs) rather than other anticoagulants.

Investigators found that patients taking direct oral anticoagulants (DOACs, rivaroxaban or dabigatran) had more than twice the AMI risk of patients taking VKAs.

And the AMI risk for patients taking low-dose aspirin was nearly double that of those taking VKAs.

Leo M. Stolk, PharmD, PhD, of Maastricht University Medical Centre in the Netherlands, and his colleagues reported these results in the British Journal of Clinical Pharmacology.

The investigators analyzed data on 30,146 adults with atrial fibrillation who were new users of DOACs (n=1266), VKAs (n=13,098), low-dose aspirin (n=15,400), or mixed anticoagulants (n=382). Most DOAC users were taking rivaroxaban (71.6%), but some were taking dabigatran (28.4%).

The mean follow-up was 0.95 years for DOAC users, 2.72 years for VKA users, 2.86 years for low-dose aspirin users, and 2.99 years for mixed medication users.

The investigators estimated the hazard ratio (HR) of AMI for users of DOACs, aspirin, or mixed medications versus VKAs. The team adjusted their analysis for age, sex, lifestyle, risk factors, comorbidities, and use of other medications.

Compared to VKA users, the risk of AMI was significantly higher for DOAC users (HR=2.11; 95% CI 1.08 – 4.12, P<0.05) and aspirin users (HR=1.91; 95% CI 1.45-2.51, P<0.05). The risk was not significantly higher for mixed medication users (HR=1.69; 95% CI 0.69, 4.16).

When patients were stratified by gender, there was a significantly increased risk of AMI for aspirin users who were male (HR=1.60; 95% CI 1.10, 2.33, P<0.05) or female (HR=2.33; 95% CI 1.55, 3.50, P<0.05), when compared to VKA users. Neither DOACs nor mixed medications were associated with a significantly increased risk of AMI in this analysis.

The investigators also stratified patients according to their CHA2DS2-VASc score at the index date.

Among patients with a high score (≥4), there was a significantly increased risk of AMI for aspirin users compared to VKA users (HR=2.21; 95% CI 1.37,3.55, P<0.05).

Among patients with a medium score (>1 and <4), the risk of AMI was significantly higher for DOAC users (HR=2.67; 95% CI 1.11, 6.40, P<0.05) and aspirin users (HR=1.82; 95% CI 1.23, 2.68, P<0.05) compared to VKA users.

The investigators said this study suggests VKAs probably have greater beneficial effects on AMI than DOACs, and ongoing research is needed as the use of DOACs increases.

Photo courtesy of the CDC

A large, retrospective study suggests patients with atrial fibrillation may have a lower risk of acute myocardial infarction (AMI) if they receive vitamin K antagonists (VKAs) rather than other anticoagulants.

Investigators found that patients taking direct oral anticoagulants (DOACs, rivaroxaban or dabigatran) had more than twice the AMI risk of patients taking VKAs.

And the AMI risk for patients taking low-dose aspirin was nearly double that of those taking VKAs.

Leo M. Stolk, PharmD, PhD, of Maastricht University Medical Centre in the Netherlands, and his colleagues reported these results in the British Journal of Clinical Pharmacology.

The investigators analyzed data on 30,146 adults with atrial fibrillation who were new users of DOACs (n=1266), VKAs (n=13,098), low-dose aspirin (n=15,400), or mixed anticoagulants (n=382). Most DOAC users were taking rivaroxaban (71.6%), but some were taking dabigatran (28.4%).

The mean follow-up was 0.95 years for DOAC users, 2.72 years for VKA users, 2.86 years for low-dose aspirin users, and 2.99 years for mixed medication users.

The investigators estimated the hazard ratio (HR) of AMI for users of DOACs, aspirin, or mixed medications versus VKAs. The team adjusted their analysis for age, sex, lifestyle, risk factors, comorbidities, and use of other medications.

Compared to VKA users, the risk of AMI was significantly higher for DOAC users (HR=2.11; 95% CI 1.08 – 4.12, P<0.05) and aspirin users (HR=1.91; 95% CI 1.45-2.51, P<0.05). The risk was not significantly higher for mixed medication users (HR=1.69; 95% CI 0.69, 4.16).

When patients were stratified by gender, there was a significantly increased risk of AMI for aspirin users who were male (HR=1.60; 95% CI 1.10, 2.33, P<0.05) or female (HR=2.33; 95% CI 1.55, 3.50, P<0.05), when compared to VKA users. Neither DOACs nor mixed medications were associated with a significantly increased risk of AMI in this analysis.

The investigators also stratified patients according to their CHA2DS2-VASc score at the index date.

Among patients with a high score (≥4), there was a significantly increased risk of AMI for aspirin users compared to VKA users (HR=2.21; 95% CI 1.37,3.55, P<0.05).

Among patients with a medium score (>1 and <4), the risk of AMI was significantly higher for DOAC users (HR=2.67; 95% CI 1.11, 6.40, P<0.05) and aspirin users (HR=1.82; 95% CI 1.23, 2.68, P<0.05) compared to VKA users.

The investigators said this study suggests VKAs probably have greater beneficial effects on AMI than DOACs, and ongoing research is needed as the use of DOACs increases.

Primary myelofibrosis

CTI BioPharma has withdrawn its application for marketing authorization of pacritinib (Enpaxiq) in the European Union, according to the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP).

The company was seeking approval for pacritinib, a JAK2/FLT3 inhibitor, to treat splenomegaly or symptoms of myelofibrosis (MF) in adults with primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF.

When the application was withdrawn, the CHMP was of the provisional opinion that pacritinib could not have been approved for this indication.

Last year, CTI BioPharma withdrew its application for approval of pacritinib in the US.

Issues preventing approval

The CHMP said it had a number of concerns related to the PERSIST-1 trial, which was used to support the application for approval in the European Union. In this trial, researchers compared pacritinib to best available therapy, excluding JAK inhibitors, in patients with MF.

The CHMP said the reduction in spleen size, which was the main efficacy outcome in the study, appeared to be lower with pacritinib than with another medicine of its class, with no improvement in symptom scores.

In addition, the incidence of thrombocytopenia was higher in patients treated with pacritinib.

And more deaths occurred in patients taking pacritinib than in those receiving best available therapy, including deaths due to bleeding and adverse effects on the heart.

The CHMP also said it needs more information about the starting materials used in the manufacture of pacritinib and how the drug acts on target proteins.

Given these concerns, the CHMP was of the opinion that pacritinib’s benefits had not been shown to outweigh its risks.

CTI BioPharma said it could address the CHMP’s concerns by providing data from a second study of pacritinib, PERSIST-2.

However, there was not enough time in the current application procedure to provide the data, so the company decided to withdraw the application.

CTI BioPharma said it intends to integrate data from PERSIST-2 into its current dossier before approaching the European Medicines Agency to discuss a new application.

The company also said the withdrawal of its application will not affect patients currently enrolled in clinical trials of pacritinib or compassionate use programs for the drug.

Previous withdrawal, clinical hold

CTI BioPharma withdrew its application for approval of pacritinib in the US after the US Food and Drug Administration (FDA) placed a full clinical hold on trials of the drug.

The FDA placed the hold on pacritinib trials in February 2016 after results from PERSIST-1 and PERSIST-2 showed excess mortality in patients who received pacritinib.

The FDA lifted the hold in January 2017 after CTI BioPharma agreed to conduct dose-exploration studies for pacritinib, submit final study reports and data sets for PERSIST-1 and PERSIST-2, and make  modifications to protocols and study-related documents.

Primary myelofibrosis

CTI BioPharma has withdrawn its application for marketing authorization of pacritinib (Enpaxiq) in the European Union, according to the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP).

The company was seeking approval for pacritinib, a JAK2/FLT3 inhibitor, to treat splenomegaly or symptoms of myelofibrosis (MF) in adults with primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF.

When the application was withdrawn, the CHMP was of the provisional opinion that pacritinib could not have been approved for this indication.

Last year, CTI BioPharma withdrew its application for approval of pacritinib in the US.

Issues preventing approval

The CHMP said it had a number of concerns related to the PERSIST-1 trial, which was used to support the application for approval in the European Union. In this trial, researchers compared pacritinib to best available therapy, excluding JAK inhibitors, in patients with MF.

The CHMP said the reduction in spleen size, which was the main efficacy outcome in the study, appeared to be lower with pacritinib than with another medicine of its class, with no improvement in symptom scores.

In addition, the incidence of thrombocytopenia was higher in patients treated with pacritinib.

And more deaths occurred in patients taking pacritinib than in those receiving best available therapy, including deaths due to bleeding and adverse effects on the heart.

The CHMP also said it needs more information about the starting materials used in the manufacture of pacritinib and how the drug acts on target proteins.

Given these concerns, the CHMP was of the opinion that pacritinib’s benefits had not been shown to outweigh its risks.

CTI BioPharma said it could address the CHMP’s concerns by providing data from a second study of pacritinib, PERSIST-2.

However, there was not enough time in the current application procedure to provide the data, so the company decided to withdraw the application.

CTI BioPharma said it intends to integrate data from PERSIST-2 into its current dossier before approaching the European Medicines Agency to discuss a new application.

The company also said the withdrawal of its application will not affect patients currently enrolled in clinical trials of pacritinib or compassionate use programs for the drug.

Previous withdrawal, clinical hold

CTI BioPharma withdrew its application for approval of pacritinib in the US after the US Food and Drug Administration (FDA) placed a full clinical hold on trials of the drug.

The FDA placed the hold on pacritinib trials in February 2016 after results from PERSIST-1 and PERSIST-2 showed excess mortality in patients who received pacritinib.

The FDA lifted the hold in January 2017 after CTI BioPharma agreed to conduct dose-exploration studies for pacritinib, submit final study reports and data sets for PERSIST-1 and PERSIST-2, and make  modifications to protocols and study-related documents.

Primary myelofibrosis

CTI BioPharma has withdrawn its application for marketing authorization of pacritinib (Enpaxiq) in the European Union, according to the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP).

The company was seeking approval for pacritinib, a JAK2/FLT3 inhibitor, to treat splenomegaly or symptoms of myelofibrosis (MF) in adults with primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF.

When the application was withdrawn, the CHMP was of the provisional opinion that pacritinib could not have been approved for this indication.

Last year, CTI BioPharma withdrew its application for approval of pacritinib in the US.

Issues preventing approval

The CHMP said it had a number of concerns related to the PERSIST-1 trial, which was used to support the application for approval in the European Union. In this trial, researchers compared pacritinib to best available therapy, excluding JAK inhibitors, in patients with MF.

The CHMP said the reduction in spleen size, which was the main efficacy outcome in the study, appeared to be lower with pacritinib than with another medicine of its class, with no improvement in symptom scores.

In addition, the incidence of thrombocytopenia was higher in patients treated with pacritinib.

And more deaths occurred in patients taking pacritinib than in those receiving best available therapy, including deaths due to bleeding and adverse effects on the heart.

The CHMP also said it needs more information about the starting materials used in the manufacture of pacritinib and how the drug acts on target proteins.

Given these concerns, the CHMP was of the opinion that pacritinib’s benefits had not been shown to outweigh its risks.

CTI BioPharma said it could address the CHMP’s concerns by providing data from a second study of pacritinib, PERSIST-2.

However, there was not enough time in the current application procedure to provide the data, so the company decided to withdraw the application.

CTI BioPharma said it intends to integrate data from PERSIST-2 into its current dossier before approaching the European Medicines Agency to discuss a new application.

The company also said the withdrawal of its application will not affect patients currently enrolled in clinical trials of pacritinib or compassionate use programs for the drug.

Previous withdrawal, clinical hold

CTI BioPharma withdrew its application for approval of pacritinib in the US after the US Food and Drug Administration (FDA) placed a full clinical hold on trials of the drug.

The FDA placed the hold on pacritinib trials in February 2016 after results from PERSIST-1 and PERSIST-2 showed excess mortality in patients who received pacritinib.

The FDA lifted the hold in January 2017 after CTI BioPharma agreed to conduct dose-exploration studies for pacritinib, submit final study reports and data sets for PERSIST-1 and PERSIST-2, and make  modifications to protocols and study-related documents.

Clinical Question: Are alpha blockers efficacious in patients with ureteric stones?

Background: A multicenter, randomized controlled trial by Pickard and colleagues demonstrated an alpha blocker to be no more efficacious than placebo as medical expulsive therapy. There are no systematic reviews that include this recent study.

Dr. Ecker is the assistant director of education, Division of Hospital Medicine, University of Colorado School of Medicine, Aurora.

Clinical Question: Are alpha blockers efficacious in patients with ureteric stones?

Background: A multicenter, randomized controlled trial by Pickard and colleagues demonstrated an alpha blocker to be no more efficacious than placebo as medical expulsive therapy. There are no systematic reviews that include this recent study.

Dr. Ecker is the assistant director of education, Division of Hospital Medicine, University of Colorado School of Medicine, Aurora.

Clinical Question: Are alpha blockers efficacious in patients with ureteric stones?

Background: A multicenter, randomized controlled trial by Pickard and colleagues demonstrated an alpha blocker to be no more efficacious than placebo as medical expulsive therapy. There are no systematic reviews that include this recent study.

Dr. Ecker is the assistant director of education, Division of Hospital Medicine, University of Colorado School of Medicine, Aurora.

Clinical Question: How efficacious are interventions to reduce burnout in physicians?

Background: Burnout is characterized by emotional exhaustion, depersonalization, and a diminished sense of personal accomplishment. It is driven by workplace stressors and affects nearly half of physicians practicing in the U.S.

Dr. Ecker is the assistant director of education, Division of Hospital Medicine, University of Colorado School of Medicine, Aurora.

Clinical Question: How efficacious are interventions to reduce burnout in physicians?

Background: Burnout is characterized by emotional exhaustion, depersonalization, and a diminished sense of personal accomplishment. It is driven by workplace stressors and affects nearly half of physicians practicing in the U.S.

Dr. Ecker is the assistant director of education, Division of Hospital Medicine, University of Colorado School of Medicine, Aurora.

Clinical Question: How efficacious are interventions to reduce burnout in physicians?

Background: Burnout is characterized by emotional exhaustion, depersonalization, and a diminished sense of personal accomplishment. It is driven by workplace stressors and affects nearly half of physicians practicing in the U.S.

Dr. Ecker is the assistant director of education, Division of Hospital Medicine, University of Colorado School of Medicine, Aurora.

SEATTLE – Disease anatomy is the main determinant of subsequent quality of life (QOL) in patients with locally recurrent rectal cancer at both base line and in the long term, according to findings presented at the annual Society of Surgical Oncology Cancer Symposium.

Posterior recurrences were associated with the worst QOL scores and the most severe pain.

Recurrent rectal cancer is a morbid disease state, leading to pain and disability. “Patients experience a multitude of symptoms, including disability as a result of tumor growth in a confined space in the pelvis and invasion of adjacent organs as well as complications from surgery and neoadjuvant treatment,” said lead author Dr. Tarik Sammour of the University of Texas MD Anderson Cancer Center in Houston.

He noted, however, that “it is not all doom and gloom.” Survival outcomes have been improving in this population, with the median 5-year survival now approaching 40%-50%.

“Decade by decade, the 5-year survival outcomes are increasing,” explained Dr. Sammour.

Increasing survival also begs the question: “Are we helping patients or affording them the option of living longer with pain and disability? In other words, we need to measure patient-centered outcomes,” he said.

Data for recurrent rectal cancer are very limited, particularly when it comes to measuring patient outcomes. Most studies have been retrospective in design, making it difficult to gauge symptoms and quality of life.

The majority of studies also have focused on surgery, have short follow-up times, and may be missing data.

“Very few measure baseline quality of life, so it makes it difficult to measure trajectories,” Dr. Sammour said. “So overall we don’t know very much about the quality of life of these patients, so we thought to remedy that with a prospective study.”

Dr. Sammour and his colleagues examined the longitudinal trajectory of cancer survivorship in recurrent rectal cancer over a 7-year period. A total of 104 patients diagnosed with recurrent rectal cancer were enrolled between 2008 and 2015, and they prospectively self reported QOL using the validated EORTC QLQ-C30 and EORTC QLQ-CR29. Pain was measured by the Brief Pain Inventory.

Symptoms were measured at baseline and then every 6 months for 5 years or until death.

Within this cohort, 73 (70.2%) patients were amenable to salvage surgery with curative intent. A variety of types of surgery were performed, and R0 resection was achieved in 75% of cases.

The 30-day complication rate was 49% (21% with grade 3/4), and 5-year disease-free survival was 40%. There was no immediate mortality from the surgery.

When looking at differences between patients who underwent surgery and those who didn’t, there was a significant difference in the location of the disease. The nonsurgical group was more likely to have posterior recurrences (26%) than was the surgical group (19%).

“This makes sense since these are more difficult to achieve a R0 result with, so it may be less likely that they were offered the procedure,” Dr. Sammour said.

There was also a significant difference in estimated 5-year survival. Overall survival was 7.7% in the nonsurgical group vs. 50.9% in the surgical group (P less than .0001), and cancer-specific survival was 11.5% vs. 59.6% (P less than .0001).

As for pain and QOL scores, there were no differences between groups at baseline.

“So when they arrived at clinic they had roughly equivalent quality of life,” he said.

At follow-up, male patients were more likely to experience severe pain, but “we felt it was due to the anatomical location. Men have a narrower pelvis and don’t have the luxury of a uterus to protect the genitourinary organs,” he explained. “We suspect this may have played a role in the severity of their pain.”

Patients with posterior recurrences also had worse pain, and this was true for both surgical and nonsurgical patients.

The only determinant for QOL in those who underwent surgery was a positive margin (global health score 70.4 for negative margin and 61.9 for positive margins [P = .024]), but otherwise there were no differences by type of surgery or postoperative complications.

At a median follow-up of 33 months, patients who underwent surgery showed gradual sustained improvement in QOL but not pain scores.

“We were encouraged to see improvement,” concluded Dr. Sammour. “Surgery does improve quality of life in resectable cases.”

No funding source was disclosed. Dr. Sammour and his coauthors had no disclosures.

SEATTLE – Disease anatomy is the main determinant of subsequent quality of life (QOL) in patients with locally recurrent rectal cancer at both base line and in the long term, according to findings presented at the annual Society of Surgical Oncology Cancer Symposium.

Posterior recurrences were associated with the worst QOL scores and the most severe pain.

Recurrent rectal cancer is a morbid disease state, leading to pain and disability. “Patients experience a multitude of symptoms, including disability as a result of tumor growth in a confined space in the pelvis and invasion of adjacent organs as well as complications from surgery and neoadjuvant treatment,” said lead author Dr. Tarik Sammour of the University of Texas MD Anderson Cancer Center in Houston.

He noted, however, that “it is not all doom and gloom.” Survival outcomes have been improving in this population, with the median 5-year survival now approaching 40%-50%.

“Decade by decade, the 5-year survival outcomes are increasing,” explained Dr. Sammour.

Increasing survival also begs the question: “Are we helping patients or affording them the option of living longer with pain and disability? In other words, we need to measure patient-centered outcomes,” he said.

Data for recurrent rectal cancer are very limited, particularly when it comes to measuring patient outcomes. Most studies have been retrospective in design, making it difficult to gauge symptoms and quality of life.

The majority of studies also have focused on surgery, have short follow-up times, and may be missing data.

“Very few measure baseline quality of life, so it makes it difficult to measure trajectories,” Dr. Sammour said. “So overall we don’t know very much about the quality of life of these patients, so we thought to remedy that with a prospective study.”

Dr. Sammour and his colleagues examined the longitudinal trajectory of cancer survivorship in recurrent rectal cancer over a 7-year period. A total of 104 patients diagnosed with recurrent rectal cancer were enrolled between 2008 and 2015, and they prospectively self reported QOL using the validated EORTC QLQ-C30 and EORTC QLQ-CR29. Pain was measured by the Brief Pain Inventory.

Symptoms were measured at baseline and then every 6 months for 5 years or until death.

Within this cohort, 73 (70.2%) patients were amenable to salvage surgery with curative intent. A variety of types of surgery were performed, and R0 resection was achieved in 75% of cases.

The 30-day complication rate was 49% (21% with grade 3/4), and 5-year disease-free survival was 40%. There was no immediate mortality from the surgery.

When looking at differences between patients who underwent surgery and those who didn’t, there was a significant difference in the location of the disease. The nonsurgical group was more likely to have posterior recurrences (26%) than was the surgical group (19%).

“This makes sense since these are more difficult to achieve a R0 result with, so it may be less likely that they were offered the procedure,” Dr. Sammour said.

There was also a significant difference in estimated 5-year survival. Overall survival was 7.7% in the nonsurgical group vs. 50.9% in the surgical group (P less than .0001), and cancer-specific survival was 11.5% vs. 59.6% (P less than .0001).

As for pain and QOL scores, there were no differences between groups at baseline.

“So when they arrived at clinic they had roughly equivalent quality of life,” he said.

At follow-up, male patients were more likely to experience severe pain, but “we felt it was due to the anatomical location. Men have a narrower pelvis and don’t have the luxury of a uterus to protect the genitourinary organs,” he explained. “We suspect this may have played a role in the severity of their pain.”

Patients with posterior recurrences also had worse pain, and this was true for both surgical and nonsurgical patients.

The only determinant for QOL in those who underwent surgery was a positive margin (global health score 70.4 for negative margin and 61.9 for positive margins [P = .024]), but otherwise there were no differences by type of surgery or postoperative complications.

At a median follow-up of 33 months, patients who underwent surgery showed gradual sustained improvement in QOL but not pain scores.

“We were encouraged to see improvement,” concluded Dr. Sammour. “Surgery does improve quality of life in resectable cases.”

No funding source was disclosed. Dr. Sammour and his coauthors had no disclosures.

SEATTLE – Disease anatomy is the main determinant of subsequent quality of life (QOL) in patients with locally recurrent rectal cancer at both base line and in the long term, according to findings presented at the annual Society of Surgical Oncology Cancer Symposium.

Posterior recurrences were associated with the worst QOL scores and the most severe pain.

Recurrent rectal cancer is a morbid disease state, leading to pain and disability. “Patients experience a multitude of symptoms, including disability as a result of tumor growth in a confined space in the pelvis and invasion of adjacent organs as well as complications from surgery and neoadjuvant treatment,” said lead author Dr. Tarik Sammour of the University of Texas MD Anderson Cancer Center in Houston.

He noted, however, that “it is not all doom and gloom.” Survival outcomes have been improving in this population, with the median 5-year survival now approaching 40%-50%.

“Decade by decade, the 5-year survival outcomes are increasing,” explained Dr. Sammour.

Increasing survival also begs the question: “Are we helping patients or affording them the option of living longer with pain and disability? In other words, we need to measure patient-centered outcomes,” he said.

Data for recurrent rectal cancer are very limited, particularly when it comes to measuring patient outcomes. Most studies have been retrospective in design, making it difficult to gauge symptoms and quality of life.

The majority of studies also have focused on surgery, have short follow-up times, and may be missing data.

“Very few measure baseline quality of life, so it makes it difficult to measure trajectories,” Dr. Sammour said. “So overall we don’t know very much about the quality of life of these patients, so we thought to remedy that with a prospective study.”

Dr. Sammour and his colleagues examined the longitudinal trajectory of cancer survivorship in recurrent rectal cancer over a 7-year period. A total of 104 patients diagnosed with recurrent rectal cancer were enrolled between 2008 and 2015, and they prospectively self reported QOL using the validated EORTC QLQ-C30 and EORTC QLQ-CR29. Pain was measured by the Brief Pain Inventory.

Symptoms were measured at baseline and then every 6 months for 5 years or until death.

Within this cohort, 73 (70.2%) patients were amenable to salvage surgery with curative intent. A variety of types of surgery were performed, and R0 resection was achieved in 75% of cases.

The 30-day complication rate was 49% (21% with grade 3/4), and 5-year disease-free survival was 40%. There was no immediate mortality from the surgery.

When looking at differences between patients who underwent surgery and those who didn’t, there was a significant difference in the location of the disease. The nonsurgical group was more likely to have posterior recurrences (26%) than was the surgical group (19%).

“This makes sense since these are more difficult to achieve a R0 result with, so it may be less likely that they were offered the procedure,” Dr. Sammour said.

There was also a significant difference in estimated 5-year survival. Overall survival was 7.7% in the nonsurgical group vs. 50.9% in the surgical group (P less than .0001), and cancer-specific survival was 11.5% vs. 59.6% (P less than .0001).

As for pain and QOL scores, there were no differences between groups at baseline.

“So when they arrived at clinic they had roughly equivalent quality of life,” he said.

At follow-up, male patients were more likely to experience severe pain, but “we felt it was due to the anatomical location. Men have a narrower pelvis and don’t have the luxury of a uterus to protect the genitourinary organs,” he explained. “We suspect this may have played a role in the severity of their pain.”

Patients with posterior recurrences also had worse pain, and this was true for both surgical and nonsurgical patients.

The only determinant for QOL in those who underwent surgery was a positive margin (global health score 70.4 for negative margin and 61.9 for positive margins [P = .024]), but otherwise there were no differences by type of surgery or postoperative complications.

At a median follow-up of 33 months, patients who underwent surgery showed gradual sustained improvement in QOL but not pain scores.

“We were encouraged to see improvement,” concluded Dr. Sammour. “Surgery does improve quality of life in resectable cases.”

No funding source was disclosed. Dr. Sammour and his coauthors had no disclosures.

ORLANDO – A guideline published late last year for the diagnostic work-up of myeloproliferative neoplasms and for the management of myelofibrosis in particular is just the first in a series of National Comprehensive Cancer Network guidelines on this “family of myeloid neoplasms,” according to the guideline panel chair, Ruben A. Mesa, MD.

The myeloproliferative neoplasm (MPN) guideline panel first worked to develop a framework based on existing understanding of the MPNs. Members consulted with two other panels working in the area of chronic myeloid diseases, including chronic myeloid leukemia and myelodysplastic syndrome.

Sharon Worcester/Frontline Medical News

sworcester@frontlinemedcom.com

ORLANDO – A guideline published late last year for the diagnostic work-up of myeloproliferative neoplasms and for the management of myelofibrosis in particular is just the first in a series of National Comprehensive Cancer Network guidelines on this “family of myeloid neoplasms,” according to the guideline panel chair, Ruben A. Mesa, MD.

The myeloproliferative neoplasm (MPN) guideline panel first worked to develop a framework based on existing understanding of the MPNs. Members consulted with two other panels working in the area of chronic myeloid diseases, including chronic myeloid leukemia and myelodysplastic syndrome.

Sharon Worcester/Frontline Medical News

sworcester@frontlinemedcom.com

ORLANDO – A guideline published late last year for the diagnostic work-up of myeloproliferative neoplasms and for the management of myelofibrosis in particular is just the first in a series of National Comprehensive Cancer Network guidelines on this “family of myeloid neoplasms,” according to the guideline panel chair, Ruben A. Mesa, MD.

The myeloproliferative neoplasm (MPN) guideline panel first worked to develop a framework based on existing understanding of the MPNs. Members consulted with two other panels working in the area of chronic myeloid diseases, including chronic myeloid leukemia and myelodysplastic syndrome.

Sharon Worcester/Frontline Medical News

sworcester@frontlinemedcom.com

Antihemophilic factor

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization for nonacog beta pegol (N9-GP, Refixia®).

N9-GP is an extended half-life factor IX molecule intended for replacement therapy in patients with hemophilia B.

The CHMP has recommended N9-GP for use as prophylaxis, for on-demand treatment of bleeding, and for control of bleeding related to surgical procedures in adolescents (older than 12 years of age) and adults with hemophilia B.

The CHMP’s opinion has been forwarded to the European Commission, which will decide whether or not to grant marketing authorization for N9-GP. The product is being developed by Novo Nordisk.

Trial results

The CHMP’s recommendation for N9-GP is based on results from the paradigm™ clinical trials. Results from the paradigm 4 trial were published in Thrombosis Research in May 2016.

Paradigm 4 was an extension trial enrolling patients who had participated in a pair of phase 3 trials known as paradigm 2 and paradigm 3.

In paradigm 2, researchers assessed N9-GP as treatment and prophylaxis in previously treated patients with hemophilia B. In paradigm 3, researchers assessed N9-GP in hemophilia B patients undergoing surgical procedures.

Paradigm 4 included 71 patients (ages 13 to 70) who continued to receive N9-GP as on-demand treatment (40 IU/kg for mild/moderate bleeds and 80 IU/kg for severe bleeds) or prophylaxis (10 IU/kg or 40 IU/kg once-weekly). Sixty-five patients completed treatment.

Safety

None of the patients developed factor IX inhibitors. Two patients had transient binding antibodies to N9-GP, but there was no sign that these antibodies had an inhibitory effect.

Four patients developed anti-CHO antibodies, but only 2 of these patients were still positive for these antibodies at the end of the trial.

There were a total of 155 adverse events. However, only 4 of these (in 3 patients) were considered possibly or probably related to N9-GP.

These events consisted of an injection site rash in 1 patient, 2 overdoses in 1 patient, and neutropenia in 1 patient. The rash and neutropenia resolved, and the patient who overdosed recovered without complications.

Efficacy

The researchers said the success rate for the treatment of reported bleeds was 94.6%. Most bleeds (87.9%) were resolved with a single injection of N9-GP, but 9.2% required 2 injections, and 2.9% required 3 or 4 injections.

The median annualized bleeding rate for patients on prophylaxis was 1.05 (interquartile range [IQR], 0.00–2.20) overall. It was 1.36 (IQR, 0.00-2.23) for the 10 IU/kg arm and 1.00 (IQR, 0.00-2.03) for the 40 IU/kg arm.

There were 14 patients on prophylaxis who underwent 23 minor surgical procedures.

The hemostatic response was considered “excellent” (better than expected/predicted for the procedure in question) in 19 procedures and “good” (as expected) in 2 procedures. In the remaining 2 procedures, hemostatic responses were not determined.

Antihemophilic factor

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization for nonacog beta pegol (N9-GP, Refixia®).

N9-GP is an extended half-life factor IX molecule intended for replacement therapy in patients with hemophilia B.

The CHMP has recommended N9-GP for use as prophylaxis, for on-demand treatment of bleeding, and for control of bleeding related to surgical procedures in adolescents (older than 12 years of age) and adults with hemophilia B.

The CHMP’s opinion has been forwarded to the European Commission, which will decide whether or not to grant marketing authorization for N9-GP. The product is being developed by Novo Nordisk.

Trial results

The CHMP’s recommendation for N9-GP is based on results from the paradigm™ clinical trials. Results from the paradigm 4 trial were published in Thrombosis Research in May 2016.

Paradigm 4 was an extension trial enrolling patients who had participated in a pair of phase 3 trials known as paradigm 2 and paradigm 3.

In paradigm 2, researchers assessed N9-GP as treatment and prophylaxis in previously treated patients with hemophilia B. In paradigm 3, researchers assessed N9-GP in hemophilia B patients undergoing surgical procedures.

Paradigm 4 included 71 patients (ages 13 to 70) who continued to receive N9-GP as on-demand treatment (40 IU/kg for mild/moderate bleeds and 80 IU/kg for severe bleeds) or prophylaxis (10 IU/kg or 40 IU/kg once-weekly). Sixty-five patients completed treatment.

Safety

None of the patients developed factor IX inhibitors. Two patients had transient binding antibodies to N9-GP, but there was no sign that these antibodies had an inhibitory effect.

Four patients developed anti-CHO antibodies, but only 2 of these patients were still positive for these antibodies at the end of the trial.

There were a total of 155 adverse events. However, only 4 of these (in 3 patients) were considered possibly or probably related to N9-GP.

These events consisted of an injection site rash in 1 patient, 2 overdoses in 1 patient, and neutropenia in 1 patient. The rash and neutropenia resolved, and the patient who overdosed recovered without complications.

Efficacy

The researchers said the success rate for the treatment of reported bleeds was 94.6%. Most bleeds (87.9%) were resolved with a single injection of N9-GP, but 9.2% required 2 injections, and 2.9% required 3 or 4 injections.

The median annualized bleeding rate for patients on prophylaxis was 1.05 (interquartile range [IQR], 0.00–2.20) overall. It was 1.36 (IQR, 0.00-2.23) for the 10 IU/kg arm and 1.00 (IQR, 0.00-2.03) for the 40 IU/kg arm.

There were 14 patients on prophylaxis who underwent 23 minor surgical procedures.

The hemostatic response was considered “excellent” (better than expected/predicted for the procedure in question) in 19 procedures and “good” (as expected) in 2 procedures. In the remaining 2 procedures, hemostatic responses were not determined.

Antihemophilic factor

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization for nonacog beta pegol (N9-GP, Refixia®).

N9-GP is an extended half-life factor IX molecule intended for replacement therapy in patients with hemophilia B.

The CHMP has recommended N9-GP for use as prophylaxis, for on-demand treatment of bleeding, and for control of bleeding related to surgical procedures in adolescents (older than 12 years of age) and adults with hemophilia B.

The CHMP’s opinion has been forwarded to the European Commission, which will decide whether or not to grant marketing authorization for N9-GP. The product is being developed by Novo Nordisk.

Trial results

The CHMP’s recommendation for N9-GP is based on results from the paradigm™ clinical trials. Results from the paradigm 4 trial were published in Thrombosis Research in May 2016.

Paradigm 4 was an extension trial enrolling patients who had participated in a pair of phase 3 trials known as paradigm 2 and paradigm 3.

In paradigm 2, researchers assessed N9-GP as treatment and prophylaxis in previously treated patients with hemophilia B. In paradigm 3, researchers assessed N9-GP in hemophilia B patients undergoing surgical procedures.

Paradigm 4 included 71 patients (ages 13 to 70) who continued to receive N9-GP as on-demand treatment (40 IU/kg for mild/moderate bleeds and 80 IU/kg for severe bleeds) or prophylaxis (10 IU/kg or 40 IU/kg once-weekly). Sixty-five patients completed treatment.

Safety

None of the patients developed factor IX inhibitors. Two patients had transient binding antibodies to N9-GP, but there was no sign that these antibodies had an inhibitory effect.

Four patients developed anti-CHO antibodies, but only 2 of these patients were still positive for these antibodies at the end of the trial.

There were a total of 155 adverse events. However, only 4 of these (in 3 patients) were considered possibly or probably related to N9-GP.

These events consisted of an injection site rash in 1 patient, 2 overdoses in 1 patient, and neutropenia in 1 patient. The rash and neutropenia resolved, and the patient who overdosed recovered without complications.

Efficacy

The researchers said the success rate for the treatment of reported bleeds was 94.6%. Most bleeds (87.9%) were resolved with a single injection of N9-GP, but 9.2% required 2 injections, and 2.9% required 3 or 4 injections.

The median annualized bleeding rate for patients on prophylaxis was 1.05 (interquartile range [IQR], 0.00–2.20) overall. It was 1.36 (IQR, 0.00-2.23) for the 10 IU/kg arm and 1.00 (IQR, 0.00-2.03) for the 40 IU/kg arm.

There were 14 patients on prophylaxis who underwent 23 minor surgical procedures.

The hemostatic response was considered “excellent” (better than expected/predicted for the procedure in question) in 19 procedures and “good” (as expected) in 2 procedures. In the remaining 2 procedures, hemostatic responses were not determined.

NATIONAL HARBOR, MD. – Surgical resection to the point of no residual macroscopic disease significantly improved survival among patients with low-grade serous ovarian carcinoma, based on the findings of a large multicenter retrospective cohort study.

Adjuvant platinum-based therapy, however, did not appear to boost survival in the analysis, Tamayaa May, MD, MSc, said at the annual meeting of the Society of Gynecologic Oncology. “Genotyping and targeted sequencing of low-grade serous ovarian carcinoma often identifies actionable mutations, and treatment with MEK-based combination therapy might be a viable therapeutic strategy in patients with KRAS or NRAS mutations,” added Dr. May of Princess Margaret Cancer Center at the University of Toronto. She and her associates plan to examine more subgroups to determine if genomic alterations predict systemic response, she said.

NATIONAL HARBOR, MD. – Surgical resection to the point of no residual macroscopic disease significantly improved survival among patients with low-grade serous ovarian carcinoma, based on the findings of a large multicenter retrospective cohort study.

Adjuvant platinum-based therapy, however, did not appear to boost survival in the analysis, Tamayaa May, MD, MSc, said at the annual meeting of the Society of Gynecologic Oncology. “Genotyping and targeted sequencing of low-grade serous ovarian carcinoma often identifies actionable mutations, and treatment with MEK-based combination therapy might be a viable therapeutic strategy in patients with KRAS or NRAS mutations,” added Dr. May of Princess Margaret Cancer Center at the University of Toronto. She and her associates plan to examine more subgroups to determine if genomic alterations predict systemic response, she said.

NATIONAL HARBOR, MD. – Surgical resection to the point of no residual macroscopic disease significantly improved survival among patients with low-grade serous ovarian carcinoma, based on the findings of a large multicenter retrospective cohort study.

Adjuvant platinum-based therapy, however, did not appear to boost survival in the analysis, Tamayaa May, MD, MSc, said at the annual meeting of the Society of Gynecologic Oncology. “Genotyping and targeted sequencing of low-grade serous ovarian carcinoma often identifies actionable mutations, and treatment with MEK-based combination therapy might be a viable therapeutic strategy in patients with KRAS or NRAS mutations,” added Dr. May of Princess Margaret Cancer Center at the University of Toronto. She and her associates plan to examine more subgroups to determine if genomic alterations predict systemic response, she said.

NATIONAL HARBOR, MD. – Combining a liquid-based Pap smear and cell-free DNA plasma testing can boost the sensitivity of screening for primary ovarian tumors, based on the results of a prospective study of 201 patients.

The approach, however, was most sensitive when women already had late-stage disease, Amanda Nickles Fader, MD, said at the annual meeting of the Society of Gynecologic Oncology. Nonetheless, she called combined Pap and plasma testing “a promising step toward a broadly applicable screening methodology for the early detection of ovarian cancer.”

Ovarian cancer is a “legal malignancy,” and detecting it at “earlier, more curable stages is a clinical imperative,” said Dr. Fader of the Johns Hopkins Kelly Gynecologic Oncology Service in Baltimore, Md.

Routine screening with ultrasound or the CA-125 test has not been shown to reduce deaths from ovarian cancer and can lead to unnecessary diagnostic surgeries. Therefore, population-based screening is not recommended by the U.S. Preventive Services Task Force, the American Cancer Society, the American Congress of Obstetricians and Gynecologists, or the National Comprehensive Cancer Network, Dr. Fader noted.

This paradigm, however, is starting to change with the advent of DNA-based tests for ovarian cancer, including the PapGene test and assays for circulating DNA released by apoptotic tumor cells (ctDNA), Dr. Fader said. In a previous pilot study, Pap testing identified oncogenic driver mutations in 41% of primary ovarian tumors. In another study, polymerase chain reaction (PCR) testing detected ctDNA in more than 75% of metastatic solid tumors.

Might combining Pap and plasma testing for ctDNA further boost sensitivity? To test this idea, Dr. Fader and her associates performed liquid-based Pap tests and collected plasma from patients just before they underwent surgery for primary ovarian cancer.

They purified DNA from the Pap tests and used a Safe SeqS assay to amplify for 18 genes with known driver mutations in ovarian cancer: AKT1, APC, BRAF, CDKN2A, CTNNB1, EGFR, FBXW7, FGFR2, KRAS, MAPK1, NRAS, PIK3CA, PIK3R1, POLE, PPP2R1A, PTEN, RN F43, and TP53. Plasma DNA was purified and amplified for 16 genes of interest: AKT1, APC, BRAF, CDKN2A, CTNNB1, EGFR, FBXW7, FGFR2, GNAS, HRAS, KRAS, NRAS, PIK3CA, PPP2R1A, PTEN, and TP53. Tests were considered positive if they identified at least one driver mutation.

By itself, the Pap test identified only 34% of cases of stage I or stage II ovarian cancer and only 37% of cases of stage III/IV cancers, for an overall sensitivity of 36%, Dr. Fader reported. Likewise, ctDNA plasma testing yielded sensitivity values of 34% in stage I/II disease and 54% in stage III/IV disease. But combining these assays yielded sensitivities of 64% for stage I/II ovarian cancer and 97% for stage III/IV cancer, for an overall sensitivity of 76%.

Driver mutations most often involved the TP53 gene, followed by PIK3CA and CDKN2A. Rarer mutations included those of PTEN, KRAS, NRAS, APC, POLE, and PPP2RIA, Dr. Fader said. Study participants were 20-79 years old, with a median age of 61, and about 70% had stage III or stage IV disease. Nearly three-quarters of tumors were serous adenocarcinomas, of which 65% were high grade. Other tumors were mucinous (10%), clear cell (5%), germ cell (3%), carcinosarcomas (2%), or sex cord stromal (1%).

There was less detection of early-stage disease in this study, even though the investigators used a sensitive test that identified relatively rare driver mutations, Dr. Fader said. So far, ctDNA testing seems to be more effective for detecting metastatic ovarian cancer, she said. Future studies should further refine DNA detection by adding Tao Brush testing and should evaluate Pap and plasma testing in a larger cohort of women with early-stage ovarian cancer or precursor lesions, including carriers of BRCA mutations, she added.

Dr. Fader did not acknowledge external funding sources. She reported having no conflicts of interest.

NATIONAL HARBOR, MD. – Combining a liquid-based Pap smear and cell-free DNA plasma testing can boost the sensitivity of screening for primary ovarian tumors, based on the results of a prospective study of 201 patients.

The approach, however, was most sensitive when women already had late-stage disease, Amanda Nickles Fader, MD, said at the annual meeting of the Society of Gynecologic Oncology. Nonetheless, she called combined Pap and plasma testing “a promising step toward a broadly applicable screening methodology for the early detection of ovarian cancer.”

Ovarian cancer is a “legal malignancy,” and detecting it at “earlier, more curable stages is a clinical imperative,” said Dr. Fader of the Johns Hopkins Kelly Gynecologic Oncology Service in Baltimore, Md.

Routine screening with ultrasound or the CA-125 test has not been shown to reduce deaths from ovarian cancer and can lead to unnecessary diagnostic surgeries. Therefore, population-based screening is not recommended by the U.S. Preventive Services Task Force, the American Cancer Society, the American Congress of Obstetricians and Gynecologists, or the National Comprehensive Cancer Network, Dr. Fader noted.

This paradigm, however, is starting to change with the advent of DNA-based tests for ovarian cancer, including the PapGene test and assays for circulating DNA released by apoptotic tumor cells (ctDNA), Dr. Fader said. In a previous pilot study, Pap testing identified oncogenic driver mutations in 41% of primary ovarian tumors. In another study, polymerase chain reaction (PCR) testing detected ctDNA in more than 75% of metastatic solid tumors.

Might combining Pap and plasma testing for ctDNA further boost sensitivity? To test this idea, Dr. Fader and her associates performed liquid-based Pap tests and collected plasma from patients just before they underwent surgery for primary ovarian cancer.

They purified DNA from the Pap tests and used a Safe SeqS assay to amplify for 18 genes with known driver mutations in ovarian cancer: AKT1, APC, BRAF, CDKN2A, CTNNB1, EGFR, FBXW7, FGFR2, KRAS, MAPK1, NRAS, PIK3CA, PIK3R1, POLE, PPP2R1A, PTEN, RN F43, and TP53. Plasma DNA was purified and amplified for 16 genes of interest: AKT1, APC, BRAF, CDKN2A, CTNNB1, EGFR, FBXW7, FGFR2, GNAS, HRAS, KRAS, NRAS, PIK3CA, PPP2R1A, PTEN, and TP53. Tests were considered positive if they identified at least one driver mutation.

By itself, the Pap test identified only 34% of cases of stage I or stage II ovarian cancer and only 37% of cases of stage III/IV cancers, for an overall sensitivity of 36%, Dr. Fader reported. Likewise, ctDNA plasma testing yielded sensitivity values of 34% in stage I/II disease and 54% in stage III/IV disease. But combining these assays yielded sensitivities of 64% for stage I/II ovarian cancer and 97% for stage III/IV cancer, for an overall sensitivity of 76%.

Driver mutations most often involved the TP53 gene, followed by PIK3CA and CDKN2A. Rarer mutations included those of PTEN, KRAS, NRAS, APC, POLE, and PPP2RIA, Dr. Fader said. Study participants were 20-79 years old, with a median age of 61, and about 70% had stage III or stage IV disease. Nearly three-quarters of tumors were serous adenocarcinomas, of which 65% were high grade. Other tumors were mucinous (10%), clear cell (5%), germ cell (3%), carcinosarcomas (2%), or sex cord stromal (1%).

There was less detection of early-stage disease in this study, even though the investigators used a sensitive test that identified relatively rare driver mutations, Dr. Fader said. So far, ctDNA testing seems to be more effective for detecting metastatic ovarian cancer, she said. Future studies should further refine DNA detection by adding Tao Brush testing and should evaluate Pap and plasma testing in a larger cohort of women with early-stage ovarian cancer or precursor lesions, including carriers of BRCA mutations, she added.

Dr. Fader did not acknowledge external funding sources. She reported having no conflicts of interest.

NATIONAL HARBOR, MD. – Combining a liquid-based Pap smear and cell-free DNA plasma testing can boost the sensitivity of screening for primary ovarian tumors, based on the results of a prospective study of 201 patients.

The approach, however, was most sensitive when women already had late-stage disease, Amanda Nickles Fader, MD, said at the annual meeting of the Society of Gynecologic Oncology. Nonetheless, she called combined Pap and plasma testing “a promising step toward a broadly applicable screening methodology for the early detection of ovarian cancer.”

Ovarian cancer is a “legal malignancy,” and detecting it at “earlier, more curable stages is a clinical imperative,” said Dr. Fader of the Johns Hopkins Kelly Gynecologic Oncology Service in Baltimore, Md.

Routine screening with ultrasound or the CA-125 test has not been shown to reduce deaths from ovarian cancer and can lead to unnecessary diagnostic surgeries. Therefore, population-based screening is not recommended by the U.S. Preventive Services Task Force, the American Cancer Society, the American Congress of Obstetricians and Gynecologists, or the National Comprehensive Cancer Network, Dr. Fader noted.

This paradigm, however, is starting to change with the advent of DNA-based tests for ovarian cancer, including the PapGene test and assays for circulating DNA released by apoptotic tumor cells (ctDNA), Dr. Fader said. In a previous pilot study, Pap testing identified oncogenic driver mutations in 41% of primary ovarian tumors. In another study, polymerase chain reaction (PCR) testing detected ctDNA in more than 75% of metastatic solid tumors.

Might combining Pap and plasma testing for ctDNA further boost sensitivity? To test this idea, Dr. Fader and her associates performed liquid-based Pap tests and collected plasma from patients just before they underwent surgery for primary ovarian cancer.

They purified DNA from the Pap tests and used a Safe SeqS assay to amplify for 18 genes with known driver mutations in ovarian cancer: AKT1, APC, BRAF, CDKN2A, CTNNB1, EGFR, FBXW7, FGFR2, KRAS, MAPK1, NRAS, PIK3CA, PIK3R1, POLE, PPP2R1A, PTEN, RN F43, and TP53. Plasma DNA was purified and amplified for 16 genes of interest: AKT1, APC, BRAF, CDKN2A, CTNNB1, EGFR, FBXW7, FGFR2, GNAS, HRAS, KRAS, NRAS, PIK3CA, PPP2R1A, PTEN, and TP53. Tests were considered positive if they identified at least one driver mutation.

By itself, the Pap test identified only 34% of cases of stage I or stage II ovarian cancer and only 37% of cases of stage III/IV cancers, for an overall sensitivity of 36%, Dr. Fader reported. Likewise, ctDNA plasma testing yielded sensitivity values of 34% in stage I/II disease and 54% in stage III/IV disease. But combining these assays yielded sensitivities of 64% for stage I/II ovarian cancer and 97% for stage III/IV cancer, for an overall sensitivity of 76%.

Driver mutations most often involved the TP53 gene, followed by PIK3CA and CDKN2A. Rarer mutations included those of PTEN, KRAS, NRAS, APC, POLE, and PPP2RIA, Dr. Fader said. Study participants were 20-79 years old, with a median age of 61, and about 70% had stage III or stage IV disease. Nearly three-quarters of tumors were serous adenocarcinomas, of which 65% were high grade. Other tumors were mucinous (10%), clear cell (5%), germ cell (3%), carcinosarcomas (2%), or sex cord stromal (1%).

There was less detection of early-stage disease in this study, even though the investigators used a sensitive test that identified relatively rare driver mutations, Dr. Fader said. So far, ctDNA testing seems to be more effective for detecting metastatic ovarian cancer, she said. Future studies should further refine DNA detection by adding Tao Brush testing and should evaluate Pap and plasma testing in a larger cohort of women with early-stage ovarian cancer or precursor lesions, including carriers of BRCA mutations, she added.

Dr. Fader did not acknowledge external funding sources. She reported having no conflicts of interest.

Evaluate bone health no longer than 6 months after onset of functional hypothalamic amenorrhea (FHA), according to new guidance on its diagnosis and management.

The preferred measure of bone mineral density (BMD) is dual-energy x-ray absorptiometry (DXA), guidance lead author Catherine M. Gordon, MD, of Cincinnati Children’s Hospital Medical Center noted in an interview.

“Our group has tried to raise awareness with our guideline about bone health,” said Dr. Gordon. “Bone is unfortunately detrimentally affected in adolescents and adult women with FHA, [so] our guideline now formally recommends bone density screening after 6 months of amenorrhea.”

Among the available therapies to preserve or restore bone density is short-term use of transdermal E2 therapy, with cyclic oral progestin, only after conventional intervention with nurtritional and exercise modification has been attempted for a “reasonable” amount of time but menstrual cycles have not yet been reestablished. Bisphosphonates, denosumab, testosterone, and leptin also can be used to improve bone mineral density (BMD), with recombinant parathyroid hormone 1-34 (rPTH) recommended in rare cases of extremely low BMD.

“Patients should not use oral contraceptives as a way to induce menstruation or improve BMD,” she said.

“We anticipate that some clinicians will be surprised to see that combined oral contraceptive pills do not provide bone protection for patients with FHA,” Dr. Gordon explained. “Our guideline reviews data on this point, which led to our recommendation that short-term transdermal estrogen may be helpful in restoring menses for select patients with longstanding amenorrhea despite efforts to correct their ‘energy deficit.’ ”

Clinicians also should be aware that FHA can mask the signs and symptoms of polycystic ovary syndrome in some young women. It’s therefore important for providers to understand that a patient could carry both diagnoses: Such patients should have a baseline BMD measurement taken, along with “clinical monitoring for hyper-response in those treated with exogenous gonadotropins for infertility,” according to the guidelines.

In general, “FHA is a ‘diagnosis of exclusion,’ meaning that underlying anatomic or organic pathologies must first be ruled out. It is important to consider other etiologies first before the amenorrhea is attributed to inadequate intake, overexercise, or stress,” Dr. Gordon said.

According to the guidelines, patients should only undergo evaluation for FHA if menstrual cycle interval exceeds 45 days on a consistent basis, or if they present with amenorrhea for at least 3 months. Patients with suspected FHA should be screened for psychological stressors that could be inducing anovulation.

When trying to make a diagnosis of FHA, providers should be “obtaining a detailed personal history with a focus on diet; eating disorders; exercise and athletic training; attitudes, such as perfectionism and high need for social approval; ambitions and expectations for self and others; weight fluctuations; sleep patterns; stressors; mood; menstrual pattern; fractures; and substance abuse,” the guidelines state.

Family histories also should be evaluated, and patients should undergo a full physical. Once a diagnosis of FHA is made, however, clinicians should help educate patients about different menstrual cycles while letting women know that an irregular cycle does not necessarily prevent them from conceiving.

The most important aspect of managing FHA is to take a multidiscipinary approach, according to Dr. Gordon and her colleagues (J Clin Endocrinol Metab. May 2017;102[5]:1-27).

“We emphasize that the mainstay of therapy for these adolescents and women is close attention to nutrition, exercise, and alleviating stressors through psychological support, best achieved through a multidisciplinary team,” Dr. Gordon stated.

Any patient diagnosed with FHA who also develops severe bradycardia, hypotension, orthostasis, or electrolyte imbalance should be treated as an inpatient. Energy imbalances can affect the hypothalamic-pituitary-ovarian (HPO) axis function, so correcting that should be considered a priority.

Adolescents and women for whom pregnancy has been excluded are recommended to undergo a progestin challenge, which should indicate chronic estrogen exposure via induced withdrawal bleeding. A brain MRI also can be conducted if the patient complains about chronic headaches, vomiting, or problems with vision or thirst.

FHA patients who wish to conceive have a number of options outlined by the guidelines. Pulsatile gonadotropin-releasing hormone (GnRH) should be the first treatment, followed by gonadotropin therapy, which must be administered as carefully as possible. Clomiphene citrate also can be used in certain situations, and cognitive behavior therapy is also a viable option, although the guidelines note that only one relatively small study offered any evidence of its efficacy. Kisspeptin and leptin should not be used as a treatment for infertility under any circumstances.

These guidelines were created in conjunction with the American Society for Reproductive Medicine, the European Society of Endocrinology, and the Pediatric Endocrine Society. An evidence-based approach was undertaken by a panel of eight experts, a methodologist, and a medical writer.

“There is currently a lack of consistency in clinical practice regarding the evaluation for patients with FHA,” said Dr. Gordon. “Our guideline attempts to clarify for clinicians what the appropriate general, endocrine, and imaging work-up would entail.”

The creation of these guidelines was funded by the Endocrine Society.

dchitnis@frontlinemedcom.com

Evaluate bone health no longer than 6 months after onset of functional hypothalamic amenorrhea (FHA), according to new guidance on its diagnosis and management.

The preferred measure of bone mineral density (BMD) is dual-energy x-ray absorptiometry (DXA), guidance lead author Catherine M. Gordon, MD, of Cincinnati Children’s Hospital Medical Center noted in an interview.

“Our group has tried to raise awareness with our guideline about bone health,” said Dr. Gordon. “Bone is unfortunately detrimentally affected in adolescents and adult women with FHA, [so] our guideline now formally recommends bone density screening after 6 months of amenorrhea.”

Among the available therapies to preserve or restore bone density is short-term use of transdermal E2 therapy, with cyclic oral progestin, only after conventional intervention with nurtritional and exercise modification has been attempted for a “reasonable” amount of time but menstrual cycles have not yet been reestablished. Bisphosphonates, denosumab, testosterone, and leptin also can be used to improve bone mineral density (BMD), with recombinant parathyroid hormone 1-34 (rPTH) recommended in rare cases of extremely low BMD.

“Patients should not use oral contraceptives as a way to induce menstruation or improve BMD,” she said.

“We anticipate that some clinicians will be surprised to see that combined oral contraceptive pills do not provide bone protection for patients with FHA,” Dr. Gordon explained. “Our guideline reviews data on this point, which led to our recommendation that short-term transdermal estrogen may be helpful in restoring menses for select patients with longstanding amenorrhea despite efforts to correct their ‘energy deficit.’ ”

Clinicians also should be aware that FHA can mask the signs and symptoms of polycystic ovary syndrome in some young women. It’s therefore important for providers to understand that a patient could carry both diagnoses: Such patients should have a baseline BMD measurement taken, along with “clinical monitoring for hyper-response in those treated with exogenous gonadotropins for infertility,” according to the guidelines.

In general, “FHA is a ‘diagnosis of exclusion,’ meaning that underlying anatomic or organic pathologies must first be ruled out. It is important to consider other etiologies first before the amenorrhea is attributed to inadequate intake, overexercise, or stress,” Dr. Gordon said.

According to the guidelines, patients should only undergo evaluation for FHA if menstrual cycle interval exceeds 45 days on a consistent basis, or if they present with amenorrhea for at least 3 months. Patients with suspected FHA should be screened for psychological stressors that could be inducing anovulation.

When trying to make a diagnosis of FHA, providers should be “obtaining a detailed personal history with a focus on diet; eating disorders; exercise and athletic training; attitudes, such as perfectionism and high need for social approval; ambitions and expectations for self and others; weight fluctuations; sleep patterns; stressors; mood; menstrual pattern; fractures; and substance abuse,” the guidelines state.

Family histories also should be evaluated, and patients should undergo a full physical. Once a diagnosis of FHA is made, however, clinicians should help educate patients about different menstrual cycles while letting women know that an irregular cycle does not necessarily prevent them from conceiving.

The most important aspect of managing FHA is to take a multidiscipinary approach, according to Dr. Gordon and her colleagues (J Clin Endocrinol Metab. May 2017;102[5]:1-27).

“We emphasize that the mainstay of therapy for these adolescents and women is close attention to nutrition, exercise, and alleviating stressors through psychological support, best achieved through a multidisciplinary team,” Dr. Gordon stated.

Any patient diagnosed with FHA who also develops severe bradycardia, hypotension, orthostasis, or electrolyte imbalance should be treated as an inpatient. Energy imbalances can affect the hypothalamic-pituitary-ovarian (HPO) axis function, so correcting that should be considered a priority.

Adolescents and women for whom pregnancy has been excluded are recommended to undergo a progestin challenge, which should indicate chronic estrogen exposure via induced withdrawal bleeding. A brain MRI also can be conducted if the patient complains about chronic headaches, vomiting, or problems with vision or thirst.

FHA patients who wish to conceive have a number of options outlined by the guidelines. Pulsatile gonadotropin-releasing hormone (GnRH) should be the first treatment, followed by gonadotropin therapy, which must be administered as carefully as possible. Clomiphene citrate also can be used in certain situations, and cognitive behavior therapy is also a viable option, although the guidelines note that only one relatively small study offered any evidence of its efficacy. Kisspeptin and leptin should not be used as a treatment for infertility under any circumstances.

These guidelines were created in conjunction with the American Society for Reproductive Medicine, the European Society of Endocrinology, and the Pediatric Endocrine Society. An evidence-based approach was undertaken by a panel of eight experts, a methodologist, and a medical writer.

“There is currently a lack of consistency in clinical practice regarding the evaluation for patients with FHA,” said Dr. Gordon. “Our guideline attempts to clarify for clinicians what the appropriate general, endocrine, and imaging work-up would entail.”

The creation of these guidelines was funded by the Endocrine Society.

dchitnis@frontlinemedcom.com

Evaluate bone health no longer than 6 months after onset of functional hypothalamic amenorrhea (FHA), according to new guidance on its diagnosis and management.

The preferred measure of bone mineral density (BMD) is dual-energy x-ray absorptiometry (DXA), guidance lead author Catherine M. Gordon, MD, of Cincinnati Children’s Hospital Medical Center noted in an interview.

“Our group has tried to raise awareness with our guideline about bone health,” said Dr. Gordon. “Bone is unfortunately detrimentally affected in adolescents and adult women with FHA, [so] our guideline now formally recommends bone density screening after 6 months of amenorrhea.”

Among the available therapies to preserve or restore bone density is short-term use of transdermal E2 therapy, with cyclic oral progestin, only after conventional intervention with nurtritional and exercise modification has been attempted for a “reasonable” amount of time but menstrual cycles have not yet been reestablished. Bisphosphonates, denosumab, testosterone, and leptin also can be used to improve bone mineral density (BMD), with recombinant parathyroid hormone 1-34 (rPTH) recommended in rare cases of extremely low BMD.

“Patients should not use oral contraceptives as a way to induce menstruation or improve BMD,” she said.

“We anticipate that some clinicians will be surprised to see that combined oral contraceptive pills do not provide bone protection for patients with FHA,” Dr. Gordon explained. “Our guideline reviews data on this point, which led to our recommendation that short-term transdermal estrogen may be helpful in restoring menses for select patients with longstanding amenorrhea despite efforts to correct their ‘energy deficit.’ ”

Clinicians also should be aware that FHA can mask the signs and symptoms of polycystic ovary syndrome in some young women. It’s therefore important for providers to understand that a patient could carry both diagnoses: Such patients should have a baseline BMD measurement taken, along with “clinical monitoring for hyper-response in those treated with exogenous gonadotropins for infertility,” according to the guidelines.

In general, “FHA is a ‘diagnosis of exclusion,’ meaning that underlying anatomic or organic pathologies must first be ruled out. It is important to consider other etiologies first before the amenorrhea is attributed to inadequate intake, overexercise, or stress,” Dr. Gordon said.

According to the guidelines, patients should only undergo evaluation for FHA if menstrual cycle interval exceeds 45 days on a consistent basis, or if they present with amenorrhea for at least 3 months. Patients with suspected FHA should be screened for psychological stressors that could be inducing anovulation.

When trying to make a diagnosis of FHA, providers should be “obtaining a detailed personal history with a focus on diet; eating disorders; exercise and athletic training; attitudes, such as perfectionism and high need for social approval; ambitions and expectations for self and others; weight fluctuations; sleep patterns; stressors; mood; menstrual pattern; fractures; and substance abuse,” the guidelines state.

Family histories also should be evaluated, and patients should undergo a full physical. Once a diagnosis of FHA is made, however, clinicians should help educate patients about different menstrual cycles while letting women know that an irregular cycle does not necessarily prevent them from conceiving.

The most important aspect of managing FHA is to take a multidiscipinary approach, according to Dr. Gordon and her colleagues (J Clin Endocrinol Metab. May 2017;102[5]:1-27).

“We emphasize that the mainstay of therapy for these adolescents and women is close attention to nutrition, exercise, and alleviating stressors through psychological support, best achieved through a multidisciplinary team,” Dr. Gordon stated.

Any patient diagnosed with FHA who also develops severe bradycardia, hypotension, orthostasis, or electrolyte imbalance should be treated as an inpatient. Energy imbalances can affect the hypothalamic-pituitary-ovarian (HPO) axis function, so correcting that should be considered a priority.

Adolescents and women for whom pregnancy has been excluded are recommended to undergo a progestin challenge, which should indicate chronic estrogen exposure via induced withdrawal bleeding. A brain MRI also can be conducted if the patient complains about chronic headaches, vomiting, or problems with vision or thirst.

FHA patients who wish to conceive have a number of options outlined by the guidelines. Pulsatile gonadotropin-releasing hormone (GnRH) should be the first treatment, followed by gonadotropin therapy, which must be administered as carefully as possible. Clomiphene citrate also can be used in certain situations, and cognitive behavior therapy is also a viable option, although the guidelines note that only one relatively small study offered any evidence of its efficacy. Kisspeptin and leptin should not be used as a treatment for infertility under any circumstances.

These guidelines were created in conjunction with the American Society for Reproductive Medicine, the European Society of Endocrinology, and the Pediatric Endocrine Society. An evidence-based approach was undertaken by a panel of eight experts, a methodologist, and a medical writer.

“There is currently a lack of consistency in clinical practice regarding the evaluation for patients with FHA,” said Dr. Gordon. “Our guideline attempts to clarify for clinicians what the appropriate general, endocrine, and imaging work-up would entail.”

The creation of these guidelines was funded by the Endocrine Society.

dchitnis@frontlinemedcom.com