Sara Freeman

A genomic prostate score (GPS) has little value in predicting adverse outcomes in men who have undergone a period of active surveillance before having a radical prostatectomy, according to a study published in the Journal of Clinical of Oncology.

The hazard ratio for adverse pathology using the 17-gene Oncotype DX Genomic Prostate Score did not reach statistical significance in a multivariate model (HR, 1.17; P = .066). This model took into account factors such as the prostate-specific antigen density (PSAD) and the Gleason grade group at diagnosis.

“In our study, the independent association of GPS with adverse pathology after initial active surveillance was not statistically significant,” Daniel W. Lin, MD, of the Fred Hutchinson Cancer Research Center in Seattle, and colleagues wrote.

There was also no association between the GPS and having upgraded biopsy findings during active surveillance.

Active surveillance is the “preferred management strategy” for men with low-risk prostate cancer, observed Dr. Lin and colleagues, but its use is often tempered by the worry that there may be underlying pathology that is not detected using routine clinical measures such as prostate-specific antigen testing. In their study, the investigators looked to see if using the GPS could help risk-stratify men undergoing active surveillance.

They noted that the biopsy-based genomic test had been shown to predict adverse surgical pathology and recurrence in men with low- and intermediate-risk prostate cancer who had undergone immediate radical prostatectomy. The team therefore wanted to clarify the test’s role in men who had been initially managed with a period of active surveillance.

To calculate the GPS, the investigators retrospectively analyzed diagnostic biopsy samples that had been prospectively collected from 432 men in the Canary Prostate Active Surveillance Study. The primary endpoint was adverse pathology in men who underwent radical prostatectomy after initial surveillance. Adverse pathology was defined as a Gleason grade of 3 or greater, a staging of pT3a or higher (with or without N1), or both.

After a median follow-up of 4.6 years, 167 (39%) men experienced upgrading of their prostate cancer at a surveillance biopsy, with 51 (12%) being upgraded to a Gleason grade group of 3 or higher. A total of 101 (23%) men had radical prostatectomy at a median of 2.1 years after their diagnostic biopsy, and just over half (n = 52; 51%) had adverse pathology at this time point.

GPS was associated with adverse pathology when the diagnostic Gleason grade group was taken into account (HR, 1.18; P = .030) but not when the investigators adjusted for both PSAD and diagnostic Gleason grade group. By contrast, PSAD (HR, 1.75; P = .025) was significantly associated with adverse pathology.

“Adding GPS to a model containing PSAD and diagnostic [Gleason grade group] did not significantly improve stratification of risk for [adverse pathology] over the clinical variables alone,” Dr. Lin and colleagues concluded.

This work was supported by the Canary Foundation, the Department of Defense, the National Institutes of Health, and Genomic Health. The authors disclosed relationships with Genomic Health and other companies.

SOURCE: Lin DW et al. J Clin Oncol. 2020 Mar 4. doi: 10.1200/JCO.19.02267.

A genomic prostate score (GPS) has little value in predicting adverse outcomes in men who have undergone a period of active surveillance before having a radical prostatectomy, according to a study published in the Journal of Clinical of Oncology.

The hazard ratio for adverse pathology using the 17-gene Oncotype DX Genomic Prostate Score did not reach statistical significance in a multivariate model (HR, 1.17; P = .066). This model took into account factors such as the prostate-specific antigen density (PSAD) and the Gleason grade group at diagnosis.

“In our study, the independent association of GPS with adverse pathology after initial active surveillance was not statistically significant,” Daniel W. Lin, MD, of the Fred Hutchinson Cancer Research Center in Seattle, and colleagues wrote.

There was also no association between the GPS and having upgraded biopsy findings during active surveillance.

Active surveillance is the “preferred management strategy” for men with low-risk prostate cancer, observed Dr. Lin and colleagues, but its use is often tempered by the worry that there may be underlying pathology that is not detected using routine clinical measures such as prostate-specific antigen testing. In their study, the investigators looked to see if using the GPS could help risk-stratify men undergoing active surveillance.

They noted that the biopsy-based genomic test had been shown to predict adverse surgical pathology and recurrence in men with low- and intermediate-risk prostate cancer who had undergone immediate radical prostatectomy. The team therefore wanted to clarify the test’s role in men who had been initially managed with a period of active surveillance.

To calculate the GPS, the investigators retrospectively analyzed diagnostic biopsy samples that had been prospectively collected from 432 men in the Canary Prostate Active Surveillance Study. The primary endpoint was adverse pathology in men who underwent radical prostatectomy after initial surveillance. Adverse pathology was defined as a Gleason grade of 3 or greater, a staging of pT3a or higher (with or without N1), or both.

After a median follow-up of 4.6 years, 167 (39%) men experienced upgrading of their prostate cancer at a surveillance biopsy, with 51 (12%) being upgraded to a Gleason grade group of 3 or higher. A total of 101 (23%) men had radical prostatectomy at a median of 2.1 years after their diagnostic biopsy, and just over half (n = 52; 51%) had adverse pathology at this time point.

GPS was associated with adverse pathology when the diagnostic Gleason grade group was taken into account (HR, 1.18; P = .030) but not when the investigators adjusted for both PSAD and diagnostic Gleason grade group. By contrast, PSAD (HR, 1.75; P = .025) was significantly associated with adverse pathology.

“Adding GPS to a model containing PSAD and diagnostic [Gleason grade group] did not significantly improve stratification of risk for [adverse pathology] over the clinical variables alone,” Dr. Lin and colleagues concluded.

This work was supported by the Canary Foundation, the Department of Defense, the National Institutes of Health, and Genomic Health. The authors disclosed relationships with Genomic Health and other companies.

SOURCE: Lin DW et al. J Clin Oncol. 2020 Mar 4. doi: 10.1200/JCO.19.02267.

A genomic prostate score (GPS) has little value in predicting adverse outcomes in men who have undergone a period of active surveillance before having a radical prostatectomy, according to a study published in the Journal of Clinical of Oncology.

The hazard ratio for adverse pathology using the 17-gene Oncotype DX Genomic Prostate Score did not reach statistical significance in a multivariate model (HR, 1.17; P = .066). This model took into account factors such as the prostate-specific antigen density (PSAD) and the Gleason grade group at diagnosis.

“In our study, the independent association of GPS with adverse pathology after initial active surveillance was not statistically significant,” Daniel W. Lin, MD, of the Fred Hutchinson Cancer Research Center in Seattle, and colleagues wrote.

There was also no association between the GPS and having upgraded biopsy findings during active surveillance.

Active surveillance is the “preferred management strategy” for men with low-risk prostate cancer, observed Dr. Lin and colleagues, but its use is often tempered by the worry that there may be underlying pathology that is not detected using routine clinical measures such as prostate-specific antigen testing. In their study, the investigators looked to see if using the GPS could help risk-stratify men undergoing active surveillance.

They noted that the biopsy-based genomic test had been shown to predict adverse surgical pathology and recurrence in men with low- and intermediate-risk prostate cancer who had undergone immediate radical prostatectomy. The team therefore wanted to clarify the test’s role in men who had been initially managed with a period of active surveillance.

To calculate the GPS, the investigators retrospectively analyzed diagnostic biopsy samples that had been prospectively collected from 432 men in the Canary Prostate Active Surveillance Study. The primary endpoint was adverse pathology in men who underwent radical prostatectomy after initial surveillance. Adverse pathology was defined as a Gleason grade of 3 or greater, a staging of pT3a or higher (with or without N1), or both.

After a median follow-up of 4.6 years, 167 (39%) men experienced upgrading of their prostate cancer at a surveillance biopsy, with 51 (12%) being upgraded to a Gleason grade group of 3 or higher. A total of 101 (23%) men had radical prostatectomy at a median of 2.1 years after their diagnostic biopsy, and just over half (n = 52; 51%) had adverse pathology at this time point.

GPS was associated with adverse pathology when the diagnostic Gleason grade group was taken into account (HR, 1.18; P = .030) but not when the investigators adjusted for both PSAD and diagnostic Gleason grade group. By contrast, PSAD (HR, 1.75; P = .025) was significantly associated with adverse pathology.

“Adding GPS to a model containing PSAD and diagnostic [Gleason grade group] did not significantly improve stratification of risk for [adverse pathology] over the clinical variables alone,” Dr. Lin and colleagues concluded.

This work was supported by the Canary Foundation, the Department of Defense, the National Institutes of Health, and Genomic Health. The authors disclosed relationships with Genomic Health and other companies.

SOURCE: Lin DW et al. J Clin Oncol. 2020 Mar 4. doi: 10.1200/JCO.19.02267.

No difference in the primary endpoint of the time to clinical improvement was seen in an open-label trial of the antiretroviral drug lopinavir-ritonavir versus standard of care in adult patients hospitalized with severe COVID-19.

The median time to clinical improvement – defined as the time from randomization to either an improvement of two points on a seven-category ordinal scale or discharge from the hospital, whichever was first – was 16 days in both groups (hazard ratio, 1.31; 95% confidence interval 0.95-1.85; P = .09).

Although a numerically lower number of deaths were recorded at 28 days (19.2% vs. 25%) with the antiretroviral treatment versus standard of care, a similar percentage of patients had detectable levels of viral RNA in throat swabs taken at various time points during the study, Chinese researchers reported in the New England Journal of Medicine.

Bai Cao, M.D, from the China-Japan Friendship Hospital and Chinese Academy of Medical Sciences, both in Beijing, and associates, performed a randomized, controlled, trial of 199 adult patients hospitalized at the Jin Yin-Tan Hospital in Wuhan in Hubei Province, China.

For inclusion, patients had to have laboratory confirmed infection with SARS-Cov-2, the virus that causes COVID-19; pneumonia confirmed by chest imaging; and severely reduced oxygen saturation (94% or less while breathing ambient air or a ratio of the partial pressure of oxygen to the fraction of inspired oxygen of less than 300 mm Hg).

Patients were randomized to receive either a combination of lopinavir (400 mg) and ritonavir (100 mg) twice a day on top of standard care (n = 99) or to standard care alone (n = 100) for 14 days. “Because of the emergency nature of the trial, placebos of lopinavir-ritonavir were not prepared,” Dr. Cao et al. explained, noting that standard care consisted of supplemental oxygen, ventilation, antibiotic treatment, vasopressor support, renal-replacement therapy, and extracorporeal membrane oxygenation.

While the trial did not meet its primary endpoint, Dr. Cao et al. reported that patients in the lopinavir-ritonavir group had a shorter stay in the intensive care unit than did those in the standard-care group, at a median of 6 versus 11 days. They also reported that the duration from randomization to hospital discharge was numerically shorter, at a median of 12 versus 14 days. Furthermore, there was a higher percentage of patients with clinical improvement at day 14 in the lopinavir-ritonavir group than in the standard-care group (45.5% vs. 30.0%)

“The trial was initiated in rapid response to the COVID-19 public health emergency, at which time there was very limited information about clinical outcomes in hospitalized patients with COVID-19,” the researchers observed. “The question of whether earlier lopinavir-ritonavir treatment in COVID-19 could have clinical benefit is an important one that requires further study,” they wrote.

Among the trial’s limitations are it was not blinded and the researchers do not have data on the lopinavir exposure levels in the trial participants.

“This was a heroic effort” in a “particularly challenging population,” Lindsey R. Baden, MD, and Eric J. Rubin, MD, stated in an editorial accompanying the article (Baden LR and Rubin EJ. New Engl J Med. March 18, 2020. doi: 10.1056/NEJMe2005477). “Unfortunately, the trial results were disappointing,” they noted.

“The secondary end points provide both reason for hope and reason for discouragement,” wrote Dr. Baden and Dr. Rubin. The lack of effect on viral shedding, however, “strongly [suggests] that it did not have the activity desired” they observed.

Dr. Baden and Dr. Rubin commented that one of the important takeaways from the trial is that “the investigators appropriately prioritized speed, designing a trial that could rapidly produce an answer.” They continued that the investigators had shown that “rapidly initiated, high-quality randomized clinical trials are possible in epidemic conditions” and that results of such trials, whether they are positive or negative, “will be central to clinical care as the dangerous coronavirus outbreak continues.”

As it stands, more than 100 trials are listed in the ClinicalTrials.gov database as testing a wide range of different treatment approaches for COVID-19. These include trials investigating if sarilumab, hydroxychloroquine, fingolimod, bevacizumab, and losartan might have a role to play. There are also trials looking at the potential of other antiviral agents, such as Gilead’s investigational drug remdesivir, which has shown to have in vitro and in vivo activity against many emerging viral pathogens that cause Ebola, Middle Eastern Respiratory Syndrome, and Severe Acute Respiratory Syndrome.

Dr. Cao’s trial was supported by grants from Major Projects of National Science and Technology on New Drug Creation and Development and from the Chinese Academy of Medical Sciences (CAMS) Emergency Project of Covid-19, and a National Science Grant for Distinguished Young Scholars.

All authors had no financial conflicts of interest to disclose.

Dr. Baden is the director of clinical research in the Division of Infectious Diseases at the Brigham and Women’s Hospital and the director of infectious diseases at the Dana-Farber Cancer Institute. He is a deputy editor of the New England Journal of Medicine and chair of the FDA’s Antimicrobial Drug Advisory Committee. He is involved in HIV vaccine clinical trials and has received research grants from the Ragon Institute, the National Institutes of Health/National Institute of Allergy and Infectious Diseases, and the Gates Foundation.

Dr. Rubin is employed by the New England Journal of Medicine as editor-in-chief. He is an associate physician at Brigham and Women’s Hospital and is chair and Irene Heinz Given Professor of Immunology and Infectious Diseases at the Harvard T.H. Chan School of Public Health.

SOURCE: Cao B et al. New Engl J Med. 2020 Mar 18. doi: 10.1056/NEJMoa2001282.

No difference in the primary endpoint of the time to clinical improvement was seen in an open-label trial of the antiretroviral drug lopinavir-ritonavir versus standard of care in adult patients hospitalized with severe COVID-19.

The median time to clinical improvement – defined as the time from randomization to either an improvement of two points on a seven-category ordinal scale or discharge from the hospital, whichever was first – was 16 days in both groups (hazard ratio, 1.31; 95% confidence interval 0.95-1.85; P = .09).

Although a numerically lower number of deaths were recorded at 28 days (19.2% vs. 25%) with the antiretroviral treatment versus standard of care, a similar percentage of patients had detectable levels of viral RNA in throat swabs taken at various time points during the study, Chinese researchers reported in the New England Journal of Medicine.

Bai Cao, M.D, from the China-Japan Friendship Hospital and Chinese Academy of Medical Sciences, both in Beijing, and associates, performed a randomized, controlled, trial of 199 adult patients hospitalized at the Jin Yin-Tan Hospital in Wuhan in Hubei Province, China.

For inclusion, patients had to have laboratory confirmed infection with SARS-Cov-2, the virus that causes COVID-19; pneumonia confirmed by chest imaging; and severely reduced oxygen saturation (94% or less while breathing ambient air or a ratio of the partial pressure of oxygen to the fraction of inspired oxygen of less than 300 mm Hg).

Patients were randomized to receive either a combination of lopinavir (400 mg) and ritonavir (100 mg) twice a day on top of standard care (n = 99) or to standard care alone (n = 100) for 14 days. “Because of the emergency nature of the trial, placebos of lopinavir-ritonavir were not prepared,” Dr. Cao et al. explained, noting that standard care consisted of supplemental oxygen, ventilation, antibiotic treatment, vasopressor support, renal-replacement therapy, and extracorporeal membrane oxygenation.

While the trial did not meet its primary endpoint, Dr. Cao et al. reported that patients in the lopinavir-ritonavir group had a shorter stay in the intensive care unit than did those in the standard-care group, at a median of 6 versus 11 days. They also reported that the duration from randomization to hospital discharge was numerically shorter, at a median of 12 versus 14 days. Furthermore, there was a higher percentage of patients with clinical improvement at day 14 in the lopinavir-ritonavir group than in the standard-care group (45.5% vs. 30.0%)

“The trial was initiated in rapid response to the COVID-19 public health emergency, at which time there was very limited information about clinical outcomes in hospitalized patients with COVID-19,” the researchers observed. “The question of whether earlier lopinavir-ritonavir treatment in COVID-19 could have clinical benefit is an important one that requires further study,” they wrote.

Among the trial’s limitations are it was not blinded and the researchers do not have data on the lopinavir exposure levels in the trial participants.

“This was a heroic effort” in a “particularly challenging population,” Lindsey R. Baden, MD, and Eric J. Rubin, MD, stated in an editorial accompanying the article (Baden LR and Rubin EJ. New Engl J Med. March 18, 2020. doi: 10.1056/NEJMe2005477). “Unfortunately, the trial results were disappointing,” they noted.

“The secondary end points provide both reason for hope and reason for discouragement,” wrote Dr. Baden and Dr. Rubin. The lack of effect on viral shedding, however, “strongly [suggests] that it did not have the activity desired” they observed.

Dr. Baden and Dr. Rubin commented that one of the important takeaways from the trial is that “the investigators appropriately prioritized speed, designing a trial that could rapidly produce an answer.” They continued that the investigators had shown that “rapidly initiated, high-quality randomized clinical trials are possible in epidemic conditions” and that results of such trials, whether they are positive or negative, “will be central to clinical care as the dangerous coronavirus outbreak continues.”

As it stands, more than 100 trials are listed in the ClinicalTrials.gov database as testing a wide range of different treatment approaches for COVID-19. These include trials investigating if sarilumab, hydroxychloroquine, fingolimod, bevacizumab, and losartan might have a role to play. There are also trials looking at the potential of other antiviral agents, such as Gilead’s investigational drug remdesivir, which has shown to have in vitro and in vivo activity against many emerging viral pathogens that cause Ebola, Middle Eastern Respiratory Syndrome, and Severe Acute Respiratory Syndrome.

Dr. Cao’s trial was supported by grants from Major Projects of National Science and Technology on New Drug Creation and Development and from the Chinese Academy of Medical Sciences (CAMS) Emergency Project of Covid-19, and a National Science Grant for Distinguished Young Scholars.

All authors had no financial conflicts of interest to disclose.

Dr. Baden is the director of clinical research in the Division of Infectious Diseases at the Brigham and Women’s Hospital and the director of infectious diseases at the Dana-Farber Cancer Institute. He is a deputy editor of the New England Journal of Medicine and chair of the FDA’s Antimicrobial Drug Advisory Committee. He is involved in HIV vaccine clinical trials and has received research grants from the Ragon Institute, the National Institutes of Health/National Institute of Allergy and Infectious Diseases, and the Gates Foundation.

Dr. Rubin is employed by the New England Journal of Medicine as editor-in-chief. He is an associate physician at Brigham and Women’s Hospital and is chair and Irene Heinz Given Professor of Immunology and Infectious Diseases at the Harvard T.H. Chan School of Public Health.

SOURCE: Cao B et al. New Engl J Med. 2020 Mar 18. doi: 10.1056/NEJMoa2001282.

No difference in the primary endpoint of the time to clinical improvement was seen in an open-label trial of the antiretroviral drug lopinavir-ritonavir versus standard of care in adult patients hospitalized with severe COVID-19.

The median time to clinical improvement – defined as the time from randomization to either an improvement of two points on a seven-category ordinal scale or discharge from the hospital, whichever was first – was 16 days in both groups (hazard ratio, 1.31; 95% confidence interval 0.95-1.85; P = .09).

Although a numerically lower number of deaths were recorded at 28 days (19.2% vs. 25%) with the antiretroviral treatment versus standard of care, a similar percentage of patients had detectable levels of viral RNA in throat swabs taken at various time points during the study, Chinese researchers reported in the New England Journal of Medicine.

Bai Cao, M.D, from the China-Japan Friendship Hospital and Chinese Academy of Medical Sciences, both in Beijing, and associates, performed a randomized, controlled, trial of 199 adult patients hospitalized at the Jin Yin-Tan Hospital in Wuhan in Hubei Province, China.

For inclusion, patients had to have laboratory confirmed infection with SARS-Cov-2, the virus that causes COVID-19; pneumonia confirmed by chest imaging; and severely reduced oxygen saturation (94% or less while breathing ambient air or a ratio of the partial pressure of oxygen to the fraction of inspired oxygen of less than 300 mm Hg).

Patients were randomized to receive either a combination of lopinavir (400 mg) and ritonavir (100 mg) twice a day on top of standard care (n = 99) or to standard care alone (n = 100) for 14 days. “Because of the emergency nature of the trial, placebos of lopinavir-ritonavir were not prepared,” Dr. Cao et al. explained, noting that standard care consisted of supplemental oxygen, ventilation, antibiotic treatment, vasopressor support, renal-replacement therapy, and extracorporeal membrane oxygenation.

While the trial did not meet its primary endpoint, Dr. Cao et al. reported that patients in the lopinavir-ritonavir group had a shorter stay in the intensive care unit than did those in the standard-care group, at a median of 6 versus 11 days. They also reported that the duration from randomization to hospital discharge was numerically shorter, at a median of 12 versus 14 days. Furthermore, there was a higher percentage of patients with clinical improvement at day 14 in the lopinavir-ritonavir group than in the standard-care group (45.5% vs. 30.0%)

“The trial was initiated in rapid response to the COVID-19 public health emergency, at which time there was very limited information about clinical outcomes in hospitalized patients with COVID-19,” the researchers observed. “The question of whether earlier lopinavir-ritonavir treatment in COVID-19 could have clinical benefit is an important one that requires further study,” they wrote.

Among the trial’s limitations are it was not blinded and the researchers do not have data on the lopinavir exposure levels in the trial participants.

“This was a heroic effort” in a “particularly challenging population,” Lindsey R. Baden, MD, and Eric J. Rubin, MD, stated in an editorial accompanying the article (Baden LR and Rubin EJ. New Engl J Med. March 18, 2020. doi: 10.1056/NEJMe2005477). “Unfortunately, the trial results were disappointing,” they noted.

“The secondary end points provide both reason for hope and reason for discouragement,” wrote Dr. Baden and Dr. Rubin. The lack of effect on viral shedding, however, “strongly [suggests] that it did not have the activity desired” they observed.

Dr. Baden and Dr. Rubin commented that one of the important takeaways from the trial is that “the investigators appropriately prioritized speed, designing a trial that could rapidly produce an answer.” They continued that the investigators had shown that “rapidly initiated, high-quality randomized clinical trials are possible in epidemic conditions” and that results of such trials, whether they are positive or negative, “will be central to clinical care as the dangerous coronavirus outbreak continues.”

As it stands, more than 100 trials are listed in the ClinicalTrials.gov database as testing a wide range of different treatment approaches for COVID-19. These include trials investigating if sarilumab, hydroxychloroquine, fingolimod, bevacizumab, and losartan might have a role to play. There are also trials looking at the potential of other antiviral agents, such as Gilead’s investigational drug remdesivir, which has shown to have in vitro and in vivo activity against many emerging viral pathogens that cause Ebola, Middle Eastern Respiratory Syndrome, and Severe Acute Respiratory Syndrome.

Dr. Cao’s trial was supported by grants from Major Projects of National Science and Technology on New Drug Creation and Development and from the Chinese Academy of Medical Sciences (CAMS) Emergency Project of Covid-19, and a National Science Grant for Distinguished Young Scholars.

All authors had no financial conflicts of interest to disclose.

Dr. Baden is the director of clinical research in the Division of Infectious Diseases at the Brigham and Women’s Hospital and the director of infectious diseases at the Dana-Farber Cancer Institute. He is a deputy editor of the New England Journal of Medicine and chair of the FDA’s Antimicrobial Drug Advisory Committee. He is involved in HIV vaccine clinical trials and has received research grants from the Ragon Institute, the National Institutes of Health/National Institute of Allergy and Infectious Diseases, and the Gates Foundation.

Dr. Rubin is employed by the New England Journal of Medicine as editor-in-chief. He is an associate physician at Brigham and Women’s Hospital and is chair and Irene Heinz Given Professor of Immunology and Infectious Diseases at the Harvard T.H. Chan School of Public Health.

SOURCE: Cao B et al. New Engl J Med. 2020 Mar 18. doi: 10.1056/NEJMoa2001282.

Longer survival was observed in women who had a stronger immune response to an investigational human papillomavirus (HPV) vaccine while treated with standard chemotherapy for advanced, metastatic, or recurrent cervical cancer.

The results, from a phase 1/2 study, showed that women with a vaccine-induced immune response higher than the median had a median overall survival of 16.8 months, compared with a median overall survival of 11.2 months for women with an immune response lower than the median (hazard ratio, 0.491; P = .012).

Cornelis “Kees” Melief, MD, chief scientific officer of ISA Pharmaceuticals in Leiden, the Netherlands, and colleagues reported these findings in Science Translational Medicine.

The researchers previously evaluated the HPV16 vaccine, ISA101, in combination with carboplatin and paclitaxel in a pilot study. Results showed that carboplatin and paclitaxel reduced abnormally high numbers of immunosuppressive myeloid cells, which allowed for “much stronger” ISA101-induced tumor immunity.

To investigate further, the researchers tested the chemotherapy-ISA101 combination in a phase 1/2 study (NCT02128126) of 79 women with advanced, metastatic, or recurrent HPV16-positive cervical cancer.

The patients received the vaccine 2 weeks after starting the second, third, and fourth cycles of chemotherapy. They received various doses of the vaccine (20, 40, 100, or 300 mcg) with or without pegylated type 1 interferon (1 mcg/kg body weight).

“ISA101 was generally safe and well tolerated in that its safety profile was not different from chemotherapy alone,” Dr. Melief and colleagues wrote.

Chemotherapy-associated adverse events occurred in 98.9% of patients, with more than 80% of patients reporting adverse events possibly related to the vaccine or interferon-alpha. However, less than 16% of patients withdrew from the study because of an adverse event.

Of the 72 patients evaluable for efficacy, 43% experienced tumor regression, and 43% had stable disease. The researchers observed regression of the target lesion in 29 of 59 patients with a measurable target lesion.

The team noted that, since all patients received chemotherapy, it is “difficult to interpret short-term clinical outcomes as being due to chemotherapy alone or to the combination,” although they noted that the use of interferon-alpha did not seem to provide any additional benefit.

“Eleven of 14 patients still alive at the end of the study displayed a strong vaccine-induced response and included 9 patients with FIGO stage IVa/IVb cancer who had a mean OS [overall survival] of 3 years,” the researchers noted.

Considering that patients with higher vaccine-induced immune responses lived longer, the researchers concluded that “chemoimmunotherapy can be exploited to the benefit of patients with advanced cancer based on a defined mode of action.”

This trial was funded by ISA Pharmaceuticals and a Dutch Cancer Society grant. Investigators disclosed relationships with ISA Pharmaceuticals and other companies.

SOURCE: Melief CJM et al. Sci Transl Med. 2020;12:eaaz8235.

Longer survival was observed in women who had a stronger immune response to an investigational human papillomavirus (HPV) vaccine while treated with standard chemotherapy for advanced, metastatic, or recurrent cervical cancer.

The results, from a phase 1/2 study, showed that women with a vaccine-induced immune response higher than the median had a median overall survival of 16.8 months, compared with a median overall survival of 11.2 months for women with an immune response lower than the median (hazard ratio, 0.491; P = .012).

Cornelis “Kees” Melief, MD, chief scientific officer of ISA Pharmaceuticals in Leiden, the Netherlands, and colleagues reported these findings in Science Translational Medicine.

The researchers previously evaluated the HPV16 vaccine, ISA101, in combination with carboplatin and paclitaxel in a pilot study. Results showed that carboplatin and paclitaxel reduced abnormally high numbers of immunosuppressive myeloid cells, which allowed for “much stronger” ISA101-induced tumor immunity.

To investigate further, the researchers tested the chemotherapy-ISA101 combination in a phase 1/2 study (NCT02128126) of 79 women with advanced, metastatic, or recurrent HPV16-positive cervical cancer.

The patients received the vaccine 2 weeks after starting the second, third, and fourth cycles of chemotherapy. They received various doses of the vaccine (20, 40, 100, or 300 mcg) with or without pegylated type 1 interferon (1 mcg/kg body weight).

“ISA101 was generally safe and well tolerated in that its safety profile was not different from chemotherapy alone,” Dr. Melief and colleagues wrote.

Chemotherapy-associated adverse events occurred in 98.9% of patients, with more than 80% of patients reporting adverse events possibly related to the vaccine or interferon-alpha. However, less than 16% of patients withdrew from the study because of an adverse event.

Of the 72 patients evaluable for efficacy, 43% experienced tumor regression, and 43% had stable disease. The researchers observed regression of the target lesion in 29 of 59 patients with a measurable target lesion.

The team noted that, since all patients received chemotherapy, it is “difficult to interpret short-term clinical outcomes as being due to chemotherapy alone or to the combination,” although they noted that the use of interferon-alpha did not seem to provide any additional benefit.

“Eleven of 14 patients still alive at the end of the study displayed a strong vaccine-induced response and included 9 patients with FIGO stage IVa/IVb cancer who had a mean OS [overall survival] of 3 years,” the researchers noted.

Considering that patients with higher vaccine-induced immune responses lived longer, the researchers concluded that “chemoimmunotherapy can be exploited to the benefit of patients with advanced cancer based on a defined mode of action.”

This trial was funded by ISA Pharmaceuticals and a Dutch Cancer Society grant. Investigators disclosed relationships with ISA Pharmaceuticals and other companies.

SOURCE: Melief CJM et al. Sci Transl Med. 2020;12:eaaz8235.

Longer survival was observed in women who had a stronger immune response to an investigational human papillomavirus (HPV) vaccine while treated with standard chemotherapy for advanced, metastatic, or recurrent cervical cancer.

The results, from a phase 1/2 study, showed that women with a vaccine-induced immune response higher than the median had a median overall survival of 16.8 months, compared with a median overall survival of 11.2 months for women with an immune response lower than the median (hazard ratio, 0.491; P = .012).

Cornelis “Kees” Melief, MD, chief scientific officer of ISA Pharmaceuticals in Leiden, the Netherlands, and colleagues reported these findings in Science Translational Medicine.

The researchers previously evaluated the HPV16 vaccine, ISA101, in combination with carboplatin and paclitaxel in a pilot study. Results showed that carboplatin and paclitaxel reduced abnormally high numbers of immunosuppressive myeloid cells, which allowed for “much stronger” ISA101-induced tumor immunity.

To investigate further, the researchers tested the chemotherapy-ISA101 combination in a phase 1/2 study (NCT02128126) of 79 women with advanced, metastatic, or recurrent HPV16-positive cervical cancer.

The patients received the vaccine 2 weeks after starting the second, third, and fourth cycles of chemotherapy. They received various doses of the vaccine (20, 40, 100, or 300 mcg) with or without pegylated type 1 interferon (1 mcg/kg body weight).

“ISA101 was generally safe and well tolerated in that its safety profile was not different from chemotherapy alone,” Dr. Melief and colleagues wrote.

Chemotherapy-associated adverse events occurred in 98.9% of patients, with more than 80% of patients reporting adverse events possibly related to the vaccine or interferon-alpha. However, less than 16% of patients withdrew from the study because of an adverse event.

Of the 72 patients evaluable for efficacy, 43% experienced tumor regression, and 43% had stable disease. The researchers observed regression of the target lesion in 29 of 59 patients with a measurable target lesion.

The team noted that, since all patients received chemotherapy, it is “difficult to interpret short-term clinical outcomes as being due to chemotherapy alone or to the combination,” although they noted that the use of interferon-alpha did not seem to provide any additional benefit.

“Eleven of 14 patients still alive at the end of the study displayed a strong vaccine-induced response and included 9 patients with FIGO stage IVa/IVb cancer who had a mean OS [overall survival] of 3 years,” the researchers noted.

Considering that patients with higher vaccine-induced immune responses lived longer, the researchers concluded that “chemoimmunotherapy can be exploited to the benefit of patients with advanced cancer based on a defined mode of action.”

This trial was funded by ISA Pharmaceuticals and a Dutch Cancer Society grant. Investigators disclosed relationships with ISA Pharmaceuticals and other companies.

SOURCE: Melief CJM et al. Sci Transl Med. 2020;12:eaaz8235.

LONDON – Despite a number of recent trials testing various topical therapies for epidermolysis bullosa, none so far has been able to provide the data needed to gain regulatory approval.

Results from trials such as ESSENCE, with allantoin, and DELIVERS, with diacerein, were “disappointing,” Dédée Murrell, BMBCh, MD, pointed out at the EB World Congress, organized by the Dystrophic Epidermolysis Bullosa Association (DEBRA).

Those two topical agents were most likely let down by the trials’ design, said Dr. Murrell, of St. George Hospital, University of New South Wales, Sydney, but she noted that there were still some promising trials that were either ongoing, such as EASE, with Oleogel-S10, or that were about to be unblinded, such as SISTERS, with sirolimus.

Epidermolysis bullosa (EB) is a group of rare genetic diseases that can cause the skin to blister and peel away to varying degrees, causing itchy and painful skin, as well as recurrent wounds, some of which may seem never to heal and that increase the risk for squamous cell carcinoma. Although finding a cure for the disease is high on the research agenda, finding a reliable therapy that can soothe and protect the skin is of equal importance.
 

Trials and tribulations

Conducting trials in rare diseases can be difficult because the studies are often small and poorly controlled, Dr. Murrell said during an oral presentation at the meeting. To gain regulatory approval, trials need to have an active and a placebo arm, because “even though we’re dealing with a rare disease, we still have to show statistical significance between the two arms.”

However, it is not just about finding enough participants who meet the inclusion criteria and adequately controlling the study, as finding funding can also be a significant hurdle. That is the case particularly when an existing drug with no patent protection is proposed to be repurposed. As an example, Dr. Murrell said that many patients with EB may use gentian violet to treat their condition, but it has been around for so long and is so widely used, that funding a trial to formally prove its merit is unlikely. ­In addition, “there are special caveats that occur in dermatology clinical trials with topical drugs that don’t exist [in trials] with systemic treatments, one of which is that it is very important to keep other variables the same,” Dr. Murrell said. “So, for example, the dressings need to stay the same throughout a trial with a topical therapy, because if you improve the dressings [during the course of the trial], you could mask the effect of the treatment.” Similarly, the bathing and cleansing routines of the participants need to remain the same throughout the trial.

“We also need to have validated instruments to prove whether these treatments are working, and the instruments need to be objective as well as subjective,” Dr. Murrell advised. For example, inflammation and blistering need to be scored separately from scarring and skin damage. “You have to conduct a clinical trial to be able to verify that there is diminished scarring or damage, because those are the longer-term complications.” Inflammation and blistering are valid endpoints to use in shorter-term studies.

Dr. Murrell also cautioned on getting too enthused about the results of case reports. “We do get excited when we see a patient using something new and they seem to be getting much better,” but such reports do not have a placebo arm, or, if there is one, then there is no vehicle control, she said. It’s important to include a run-in period in a trial to establish a new baseline and to ensure that any effects seen with a topical agent are independent of the carrier substance or any altered bathing behavior or dressing habits, which could skew the results.
 

ESSENCE and allantoin

So what went wrong in the phase 3 ESSENCE trial with allantoin, which was halted early in September 2017? The trial had included 169 patients with any type of EB – simplex, recessive dystrophic, and junctional non-Herlitz – who were randomized to treatment with the allantoin-containing cream SD-101 or a placebo cream containing only the vehicle. The creams were applied daily to the entire body for 3 months, with the primary endpoint being total wound closure at the end of the treatment period. Total wound closure was a requirement of the Food and Drug Administration, Dr. Murrell said, but it is now known that 100% closure is not always likely, which the agency itself now concedes.

“Most disappointingly, no significant difference was found [between the study drug and placebo], therefore it didn’t meet the primary endpoint, and you’re not even allowed to consider secondary endpoints – those are the rules of the game,” she said. As a result, the trial was stopped in 2017.

For inclusion in the study, patients had to have at least one target wound that had been present for at least 3 weeks, but there was no stratification on the duration of wounds in the randomization process. That meant that some individuals with wounds of shorter duration had unintentionally ended up in the placebo arm – favoring healing – and those with more chronic wounds had been in the allantoin arm. So, because the study arms might not have been equally balanced at baseline, it would have been harder for the actual treatment to demonstrate a benefit, Dr. Murrell suggested.

Another problem with the trial was that the vehicle cream contained elements, such as lanolin, already associated with wound healing. That would have given patients in the placebo arm an advantage because anyone applying the cream every day would probably get better or improve to some degree.

The patients were also required to have daily dressing changes and baths and, “if you give any patient that advice and they comply with it for a period of time, they are going to improve,” whether or not they are applying the study drug. Dr. Murrell said that the researchers likely should have done a run-in period first and then established a new baseline to randomize the patients.

“Lastly, no one had ever done a study of what we essentially tell eczema patients to do every day … to moisturize, because that will provide extra protection and barrier to their skin. So, if anything, the ESSENCE study shows that moisturizing has a protective effect of the vehicle for patients with EB,” she said.
 

DELIVERS and diacerein

Another trial that was stopped prematurely was the phase 2 DELIVERS study, which was set up to assess the benefits of topical diacerein in people with EB simplex. Diacerein, an extract of rhubarb root, was tested in 54 patients, who were randomized to apply either diacerein or vehicle ointment for 8 weeks.

Initially, the results “looked very promising,” Dr. Murrell said, because there was a trend toward improved EB simplex lesions, with the primary endpoint of at least a 60% reduction in lesions met by 57.1% of diacerein-treated and 53.8% of vehicle-treated patients.

However, the trial included use of the Investigator’s Global Assessment Scale at the FDA’s behest, but the tool had not been validated in previous EB trials, and which didn’t seem to show any benefit of the active over the placebo ointment. (The Investigator’s Global Assessment is a 5-point scale used for overall clinical assessment of severity of disease, ranging from 0 to 4, where a higher score denotes worse outcome.)In a poster presented separately at the meeting, the DELIVERS researchers noted that “the lack of statistical significance in the primary endpoint could be explained in part by milder disease in the diacerein group.” The mean body surface area of EB simplex lesions within the assessment area at baseline was 5.76% in the diacerein group and 7.13% in the vehicle group. The researchers proposed that perhaps a higher concentration of diacerein than the 1% used in the trial might have been needed.


 

Sirolimus and EB simplex

Dr. Murrell noted that a pilot study, known as the SISTERS trial, had been conducted with a 2% sirolimus topical ointment at her institution and at Stanford (Calif.) University. This prospective, double-blind study had involved 16 patients with EB simplex, in which blisters tend to be confined to the palms of the hands and soles of the feet. The patients were assigned to treat both feet with either topical sirolimus or a placebo cream for 12 weeks. After a 4-week wash-out period, the patients switched to using the opposite cream for an additional 12 weeks.

Sirolimus is an inhibitor of the mTOR pathway, and, according to a description of the study on ClinicalTrials.gov, the researchers’ aim was to inhibit “the mTOR pathway to down-regulate the translation of defective keratin proteins.” That would allow a transition from supportive care, which is the current practice for EB simplex, to using a targeted molecular therapy to improve patient mobility and quality of life, they note on the site.

“We look forward to having that study unblinded,” Dr. Murrell said, adding that “data should be ready in a few months.”
 

EASE and Oleogel-S10

Oleogel-S10 is a gel that contains a birch bark extract dissolved in sunflower oil. It is already approved in Europe (Episalvan) for the treatment of partial-thickness skin wounds, but its use in EB remains investigational.

In a poster presentation at the meeting, Stella Gewert, MD, of the University of Freiburg (Germany) and colleagues discussed their experience using Oleogel-S10 in the treatment of four patients – each with a different type of EB – who applied the gel for between 6 days and 3 months.

Promising effects were seen, including reduced pruritus and pain, wounds healing more quickly, and reductions in lesion size. “During treatment, dressing requirements were reduced, and patient quality of life improved,” the researchers observed.

Mark Sumeray, MD, the chief medical officer of Amryt Pharmaceuticals, which is developing Oleogel-S10, said it was important to emphasize that Oleogel-S10 is a gel and not a cream. Gels are mixed with oil and are easier to apply – an important consideration for those with EB, he explained, whereas creams tend to be mixed with water and are stickier.

The phase 3 EASE trial is looking at the efficacy and safety of the gel in patients with junctional and dystrophic EB, and recruitment is ongoing, Dr. Murrell said. The primary endpoint is the proportion of patients with the first complete closure of a target wound within 45 days of treatment initiation. The estimated primary completion date for the trial is June 2020, and it is projected to end by 2022.

Scioderm, in collaboration with Amicus, funded the ESSENCE trial; Castle Creek financed the DELIVERS study; Amryt is supporting the EASE study; and Stanford University is sponsor of the SISTERS study. Dr. Murrell has been the principal investigator for trials run by Amicus, Amryt, Castle Creek, and Shire, and she acknowledged receipt of honoraria or consultation fees from those companies and others. Dr. Gewert did not report any financial disclosures. Dr. Sumeray is an employee and shareholder of Amryt.

LONDON – Despite a number of recent trials testing various topical therapies for epidermolysis bullosa, none so far has been able to provide the data needed to gain regulatory approval.

Results from trials such as ESSENCE, with allantoin, and DELIVERS, with diacerein, were “disappointing,” Dédée Murrell, BMBCh, MD, pointed out at the EB World Congress, organized by the Dystrophic Epidermolysis Bullosa Association (DEBRA).

Those two topical agents were most likely let down by the trials’ design, said Dr. Murrell, of St. George Hospital, University of New South Wales, Sydney, but she noted that there were still some promising trials that were either ongoing, such as EASE, with Oleogel-S10, or that were about to be unblinded, such as SISTERS, with sirolimus.

Epidermolysis bullosa (EB) is a group of rare genetic diseases that can cause the skin to blister and peel away to varying degrees, causing itchy and painful skin, as well as recurrent wounds, some of which may seem never to heal and that increase the risk for squamous cell carcinoma. Although finding a cure for the disease is high on the research agenda, finding a reliable therapy that can soothe and protect the skin is of equal importance.
 

Trials and tribulations

Conducting trials in rare diseases can be difficult because the studies are often small and poorly controlled, Dr. Murrell said during an oral presentation at the meeting. To gain regulatory approval, trials need to have an active and a placebo arm, because “even though we’re dealing with a rare disease, we still have to show statistical significance between the two arms.”

However, it is not just about finding enough participants who meet the inclusion criteria and adequately controlling the study, as finding funding can also be a significant hurdle. That is the case particularly when an existing drug with no patent protection is proposed to be repurposed. As an example, Dr. Murrell said that many patients with EB may use gentian violet to treat their condition, but it has been around for so long and is so widely used, that funding a trial to formally prove its merit is unlikely. ­In addition, “there are special caveats that occur in dermatology clinical trials with topical drugs that don’t exist [in trials] with systemic treatments, one of which is that it is very important to keep other variables the same,” Dr. Murrell said. “So, for example, the dressings need to stay the same throughout a trial with a topical therapy, because if you improve the dressings [during the course of the trial], you could mask the effect of the treatment.” Similarly, the bathing and cleansing routines of the participants need to remain the same throughout the trial.

“We also need to have validated instruments to prove whether these treatments are working, and the instruments need to be objective as well as subjective,” Dr. Murrell advised. For example, inflammation and blistering need to be scored separately from scarring and skin damage. “You have to conduct a clinical trial to be able to verify that there is diminished scarring or damage, because those are the longer-term complications.” Inflammation and blistering are valid endpoints to use in shorter-term studies.

Dr. Murrell also cautioned on getting too enthused about the results of case reports. “We do get excited when we see a patient using something new and they seem to be getting much better,” but such reports do not have a placebo arm, or, if there is one, then there is no vehicle control, she said. It’s important to include a run-in period in a trial to establish a new baseline and to ensure that any effects seen with a topical agent are independent of the carrier substance or any altered bathing behavior or dressing habits, which could skew the results.
 

ESSENCE and allantoin

So what went wrong in the phase 3 ESSENCE trial with allantoin, which was halted early in September 2017? The trial had included 169 patients with any type of EB – simplex, recessive dystrophic, and junctional non-Herlitz – who were randomized to treatment with the allantoin-containing cream SD-101 or a placebo cream containing only the vehicle. The creams were applied daily to the entire body for 3 months, with the primary endpoint being total wound closure at the end of the treatment period. Total wound closure was a requirement of the Food and Drug Administration, Dr. Murrell said, but it is now known that 100% closure is not always likely, which the agency itself now concedes.

“Most disappointingly, no significant difference was found [between the study drug and placebo], therefore it didn’t meet the primary endpoint, and you’re not even allowed to consider secondary endpoints – those are the rules of the game,” she said. As a result, the trial was stopped in 2017.

For inclusion in the study, patients had to have at least one target wound that had been present for at least 3 weeks, but there was no stratification on the duration of wounds in the randomization process. That meant that some individuals with wounds of shorter duration had unintentionally ended up in the placebo arm – favoring healing – and those with more chronic wounds had been in the allantoin arm. So, because the study arms might not have been equally balanced at baseline, it would have been harder for the actual treatment to demonstrate a benefit, Dr. Murrell suggested.

Another problem with the trial was that the vehicle cream contained elements, such as lanolin, already associated with wound healing. That would have given patients in the placebo arm an advantage because anyone applying the cream every day would probably get better or improve to some degree.

The patients were also required to have daily dressing changes and baths and, “if you give any patient that advice and they comply with it for a period of time, they are going to improve,” whether or not they are applying the study drug. Dr. Murrell said that the researchers likely should have done a run-in period first and then established a new baseline to randomize the patients.

“Lastly, no one had ever done a study of what we essentially tell eczema patients to do every day … to moisturize, because that will provide extra protection and barrier to their skin. So, if anything, the ESSENCE study shows that moisturizing has a protective effect of the vehicle for patients with EB,” she said.
 

DELIVERS and diacerein

Another trial that was stopped prematurely was the phase 2 DELIVERS study, which was set up to assess the benefits of topical diacerein in people with EB simplex. Diacerein, an extract of rhubarb root, was tested in 54 patients, who were randomized to apply either diacerein or vehicle ointment for 8 weeks.

Initially, the results “looked very promising,” Dr. Murrell said, because there was a trend toward improved EB simplex lesions, with the primary endpoint of at least a 60% reduction in lesions met by 57.1% of diacerein-treated and 53.8% of vehicle-treated patients.

However, the trial included use of the Investigator’s Global Assessment Scale at the FDA’s behest, but the tool had not been validated in previous EB trials, and which didn’t seem to show any benefit of the active over the placebo ointment. (The Investigator’s Global Assessment is a 5-point scale used for overall clinical assessment of severity of disease, ranging from 0 to 4, where a higher score denotes worse outcome.)In a poster presented separately at the meeting, the DELIVERS researchers noted that “the lack of statistical significance in the primary endpoint could be explained in part by milder disease in the diacerein group.” The mean body surface area of EB simplex lesions within the assessment area at baseline was 5.76% in the diacerein group and 7.13% in the vehicle group. The researchers proposed that perhaps a higher concentration of diacerein than the 1% used in the trial might have been needed.


 

Sirolimus and EB simplex

Dr. Murrell noted that a pilot study, known as the SISTERS trial, had been conducted with a 2% sirolimus topical ointment at her institution and at Stanford (Calif.) University. This prospective, double-blind study had involved 16 patients with EB simplex, in which blisters tend to be confined to the palms of the hands and soles of the feet. The patients were assigned to treat both feet with either topical sirolimus or a placebo cream for 12 weeks. After a 4-week wash-out period, the patients switched to using the opposite cream for an additional 12 weeks.

Sirolimus is an inhibitor of the mTOR pathway, and, according to a description of the study on ClinicalTrials.gov, the researchers’ aim was to inhibit “the mTOR pathway to down-regulate the translation of defective keratin proteins.” That would allow a transition from supportive care, which is the current practice for EB simplex, to using a targeted molecular therapy to improve patient mobility and quality of life, they note on the site.

“We look forward to having that study unblinded,” Dr. Murrell said, adding that “data should be ready in a few months.”
 

EASE and Oleogel-S10

Oleogel-S10 is a gel that contains a birch bark extract dissolved in sunflower oil. It is already approved in Europe (Episalvan) for the treatment of partial-thickness skin wounds, but its use in EB remains investigational.

In a poster presentation at the meeting, Stella Gewert, MD, of the University of Freiburg (Germany) and colleagues discussed their experience using Oleogel-S10 in the treatment of four patients – each with a different type of EB – who applied the gel for between 6 days and 3 months.

Promising effects were seen, including reduced pruritus and pain, wounds healing more quickly, and reductions in lesion size. “During treatment, dressing requirements were reduced, and patient quality of life improved,” the researchers observed.

Mark Sumeray, MD, the chief medical officer of Amryt Pharmaceuticals, which is developing Oleogel-S10, said it was important to emphasize that Oleogel-S10 is a gel and not a cream. Gels are mixed with oil and are easier to apply – an important consideration for those with EB, he explained, whereas creams tend to be mixed with water and are stickier.

The phase 3 EASE trial is looking at the efficacy and safety of the gel in patients with junctional and dystrophic EB, and recruitment is ongoing, Dr. Murrell said. The primary endpoint is the proportion of patients with the first complete closure of a target wound within 45 days of treatment initiation. The estimated primary completion date for the trial is June 2020, and it is projected to end by 2022.

Scioderm, in collaboration with Amicus, funded the ESSENCE trial; Castle Creek financed the DELIVERS study; Amryt is supporting the EASE study; and Stanford University is sponsor of the SISTERS study. Dr. Murrell has been the principal investigator for trials run by Amicus, Amryt, Castle Creek, and Shire, and she acknowledged receipt of honoraria or consultation fees from those companies and others. Dr. Gewert did not report any financial disclosures. Dr. Sumeray is an employee and shareholder of Amryt.

LONDON – Despite a number of recent trials testing various topical therapies for epidermolysis bullosa, none so far has been able to provide the data needed to gain regulatory approval.

Results from trials such as ESSENCE, with allantoin, and DELIVERS, with diacerein, were “disappointing,” Dédée Murrell, BMBCh, MD, pointed out at the EB World Congress, organized by the Dystrophic Epidermolysis Bullosa Association (DEBRA).

Those two topical agents were most likely let down by the trials’ design, said Dr. Murrell, of St. George Hospital, University of New South Wales, Sydney, but she noted that there were still some promising trials that were either ongoing, such as EASE, with Oleogel-S10, or that were about to be unblinded, such as SISTERS, with sirolimus.

Epidermolysis bullosa (EB) is a group of rare genetic diseases that can cause the skin to blister and peel away to varying degrees, causing itchy and painful skin, as well as recurrent wounds, some of which may seem never to heal and that increase the risk for squamous cell carcinoma. Although finding a cure for the disease is high on the research agenda, finding a reliable therapy that can soothe and protect the skin is of equal importance.
 

Trials and tribulations

Conducting trials in rare diseases can be difficult because the studies are often small and poorly controlled, Dr. Murrell said during an oral presentation at the meeting. To gain regulatory approval, trials need to have an active and a placebo arm, because “even though we’re dealing with a rare disease, we still have to show statistical significance between the two arms.”

However, it is not just about finding enough participants who meet the inclusion criteria and adequately controlling the study, as finding funding can also be a significant hurdle. That is the case particularly when an existing drug with no patent protection is proposed to be repurposed. As an example, Dr. Murrell said that many patients with EB may use gentian violet to treat their condition, but it has been around for so long and is so widely used, that funding a trial to formally prove its merit is unlikely. ­In addition, “there are special caveats that occur in dermatology clinical trials with topical drugs that don’t exist [in trials] with systemic treatments, one of which is that it is very important to keep other variables the same,” Dr. Murrell said. “So, for example, the dressings need to stay the same throughout a trial with a topical therapy, because if you improve the dressings [during the course of the trial], you could mask the effect of the treatment.” Similarly, the bathing and cleansing routines of the participants need to remain the same throughout the trial.

“We also need to have validated instruments to prove whether these treatments are working, and the instruments need to be objective as well as subjective,” Dr. Murrell advised. For example, inflammation and blistering need to be scored separately from scarring and skin damage. “You have to conduct a clinical trial to be able to verify that there is diminished scarring or damage, because those are the longer-term complications.” Inflammation and blistering are valid endpoints to use in shorter-term studies.

Dr. Murrell also cautioned on getting too enthused about the results of case reports. “We do get excited when we see a patient using something new and they seem to be getting much better,” but such reports do not have a placebo arm, or, if there is one, then there is no vehicle control, she said. It’s important to include a run-in period in a trial to establish a new baseline and to ensure that any effects seen with a topical agent are independent of the carrier substance or any altered bathing behavior or dressing habits, which could skew the results.
 

ESSENCE and allantoin

So what went wrong in the phase 3 ESSENCE trial with allantoin, which was halted early in September 2017? The trial had included 169 patients with any type of EB – simplex, recessive dystrophic, and junctional non-Herlitz – who were randomized to treatment with the allantoin-containing cream SD-101 or a placebo cream containing only the vehicle. The creams were applied daily to the entire body for 3 months, with the primary endpoint being total wound closure at the end of the treatment period. Total wound closure was a requirement of the Food and Drug Administration, Dr. Murrell said, but it is now known that 100% closure is not always likely, which the agency itself now concedes.

“Most disappointingly, no significant difference was found [between the study drug and placebo], therefore it didn’t meet the primary endpoint, and you’re not even allowed to consider secondary endpoints – those are the rules of the game,” she said. As a result, the trial was stopped in 2017.

For inclusion in the study, patients had to have at least one target wound that had been present for at least 3 weeks, but there was no stratification on the duration of wounds in the randomization process. That meant that some individuals with wounds of shorter duration had unintentionally ended up in the placebo arm – favoring healing – and those with more chronic wounds had been in the allantoin arm. So, because the study arms might not have been equally balanced at baseline, it would have been harder for the actual treatment to demonstrate a benefit, Dr. Murrell suggested.

Another problem with the trial was that the vehicle cream contained elements, such as lanolin, already associated with wound healing. That would have given patients in the placebo arm an advantage because anyone applying the cream every day would probably get better or improve to some degree.

The patients were also required to have daily dressing changes and baths and, “if you give any patient that advice and they comply with it for a period of time, they are going to improve,” whether or not they are applying the study drug. Dr. Murrell said that the researchers likely should have done a run-in period first and then established a new baseline to randomize the patients.

“Lastly, no one had ever done a study of what we essentially tell eczema patients to do every day … to moisturize, because that will provide extra protection and barrier to their skin. So, if anything, the ESSENCE study shows that moisturizing has a protective effect of the vehicle for patients with EB,” she said.
 

DELIVERS and diacerein

Another trial that was stopped prematurely was the phase 2 DELIVERS study, which was set up to assess the benefits of topical diacerein in people with EB simplex. Diacerein, an extract of rhubarb root, was tested in 54 patients, who were randomized to apply either diacerein or vehicle ointment for 8 weeks.

Initially, the results “looked very promising,” Dr. Murrell said, because there was a trend toward improved EB simplex lesions, with the primary endpoint of at least a 60% reduction in lesions met by 57.1% of diacerein-treated and 53.8% of vehicle-treated patients.

However, the trial included use of the Investigator’s Global Assessment Scale at the FDA’s behest, but the tool had not been validated in previous EB trials, and which didn’t seem to show any benefit of the active over the placebo ointment. (The Investigator’s Global Assessment is a 5-point scale used for overall clinical assessment of severity of disease, ranging from 0 to 4, where a higher score denotes worse outcome.)In a poster presented separately at the meeting, the DELIVERS researchers noted that “the lack of statistical significance in the primary endpoint could be explained in part by milder disease in the diacerein group.” The mean body surface area of EB simplex lesions within the assessment area at baseline was 5.76% in the diacerein group and 7.13% in the vehicle group. The researchers proposed that perhaps a higher concentration of diacerein than the 1% used in the trial might have been needed.


 

Sirolimus and EB simplex

Dr. Murrell noted that a pilot study, known as the SISTERS trial, had been conducted with a 2% sirolimus topical ointment at her institution and at Stanford (Calif.) University. This prospective, double-blind study had involved 16 patients with EB simplex, in which blisters tend to be confined to the palms of the hands and soles of the feet. The patients were assigned to treat both feet with either topical sirolimus or a placebo cream for 12 weeks. After a 4-week wash-out period, the patients switched to using the opposite cream for an additional 12 weeks.

Sirolimus is an inhibitor of the mTOR pathway, and, according to a description of the study on ClinicalTrials.gov, the researchers’ aim was to inhibit “the mTOR pathway to down-regulate the translation of defective keratin proteins.” That would allow a transition from supportive care, which is the current practice for EB simplex, to using a targeted molecular therapy to improve patient mobility and quality of life, they note on the site.

“We look forward to having that study unblinded,” Dr. Murrell said, adding that “data should be ready in a few months.”
 

EASE and Oleogel-S10

Oleogel-S10 is a gel that contains a birch bark extract dissolved in sunflower oil. It is already approved in Europe (Episalvan) for the treatment of partial-thickness skin wounds, but its use in EB remains investigational.

In a poster presentation at the meeting, Stella Gewert, MD, of the University of Freiburg (Germany) and colleagues discussed their experience using Oleogel-S10 in the treatment of four patients – each with a different type of EB – who applied the gel for between 6 days and 3 months.

Promising effects were seen, including reduced pruritus and pain, wounds healing more quickly, and reductions in lesion size. “During treatment, dressing requirements were reduced, and patient quality of life improved,” the researchers observed.

Mark Sumeray, MD, the chief medical officer of Amryt Pharmaceuticals, which is developing Oleogel-S10, said it was important to emphasize that Oleogel-S10 is a gel and not a cream. Gels are mixed with oil and are easier to apply – an important consideration for those with EB, he explained, whereas creams tend to be mixed with water and are stickier.

The phase 3 EASE trial is looking at the efficacy and safety of the gel in patients with junctional and dystrophic EB, and recruitment is ongoing, Dr. Murrell said. The primary endpoint is the proportion of patients with the first complete closure of a target wound within 45 days of treatment initiation. The estimated primary completion date for the trial is June 2020, and it is projected to end by 2022.

Scioderm, in collaboration with Amicus, funded the ESSENCE trial; Castle Creek financed the DELIVERS study; Amryt is supporting the EASE study; and Stanford University is sponsor of the SISTERS study. Dr. Murrell has been the principal investigator for trials run by Amicus, Amryt, Castle Creek, and Shire, and she acknowledged receipt of honoraria or consultation fees from those companies and others. Dr. Gewert did not report any financial disclosures. Dr. Sumeray is an employee and shareholder of Amryt.

LONDON – Disrupting how microorganisms communicate with each other could be a way to overcome antibiotic resistance and to help heal chronic wounds in patients with epidermolysis bullosa (EB), according to presenters at the EB World Congress, organized by the Dystrophic Epidermolysis Bullosa Association (DEBRA).

The majority of chronic wounds in patients with EB are colonized with microorganisms, with a predominance of Staphylococcus species, said Erik Gerner, an industrial PhD student at Mölnlycke Health Care in Gothenburg, Sweden, and Gothenburg University.

Because of the growing problem of antibiotic resistance, alternative treatments are needed, and one possible alternative for treating infected wounds could be interfering with quorum sensing, the cell-to-cell communication used by bacteria, he said. He is hoping to explore this possibility as a novel treatment strategy for infected wounds.

“Quorum sensing is defined as the ability to detect and respond to population density,” Mr. Gerner said, noting that, when there is a sufficient density of bacteria, “they start to communicate with each other.” This enables them to act as a community and perform actions that they could not do as individual cells. Such actions include forming biofilms, which helps protect bacteria from their environment, such as the immune system. Other actions include collectively switching on the production of virulence factors and becoming resistant to treatments.

“Bacteria use quorum sensing to act collectively,” Mr. Gerner said. “If we could shut down this quorum sensing system, it would be very beneficial … and increase the chances to heal the wound.”

The quorum sensing system is based on the production of signaling molecules called AHL (N-acyl homoserine lactones), which are constantly produced at a low rate. This isn’t a problem until the level of bacteria increases and the level of quorum sensing breaches a threshold, he explained.

There are several benefits of inhibiting bacterial communication through disrupting quorum sensing, namely, “a low risk of resistance,” Mr. Gerner said. There is also potentially less toxin production by bacteria, and this could help the immune system in killing the invading bacteria.

One approach to disrupting quorum testing that Mr. Gerner has been investigating is the use of sodium salicylate (NaSa). So far, preclinical work shows that NaSa can reduce toxin production but not the growth rate of bacteria. The advantage of using NaSa is that it is nontoxic to human dermal fibroblasts, with similar results seen in human keratinocytes and immune cells. His work to date has shown that NaSa reduced activity of NF-kB (a proinflammatory signaling pathway) in differentiated and lipopolysaccharide-stimulated monocytes; NF-kB activated production of proinflammatory cytokines (such as interleukin-1 beta and IL-6) are elevated in EB wounds. “My studies support the bodies of evidence that bacteria use quorum sensing to coordinate … and to produce a large number of toxic factors,” Mr. Gerner concluded. Future studies will look at the potential of NaSa to disrupt this activity.
 

Skin microbiome of EB wounds

Understanding what bacteria most commonly colonize wounds in patients with EB was the subject of two unrelated presentations at the EB World Congress. Liat Samuelov, MD, of the department of molecular dermatology at Tel Aviv (Israel) Sourasky Medical Center, presented data on skin microbiome characteristics in eight patients with recessive dystrophic EB (RDEB). This showed that there was reduced bacterial diversity in wounds, and a “progressive development of dysbiosis across different stages of DEB wound formation.”

The skin microbiome has been implicated in several skin diseases, Dr. Samuelov and associates observed in a poster presentation. That includes the autoimmune blistering disease bullous pemphigoid (Exp Dermatol. 2017 Dec;26[12]:1221-7). “Colonization of DEB chronic wounds may lead to systemic infections, result in delayed healing, and possibly be involved in the development of squamous cell carcinoma,” they noted in the poster, “thus accurate delineation of the dysbiotic profile … may point to corrective measures of great therapeutic potential.”

The aim was to see what microorganisms were present in the chronic wounds of the patients. To be included in the study, patients must not have had any antibiotic treatment – oral or topical – in the past 6 months. Samples were taken from an untreated wound, around the wound, and from uninvolved skin, which were compared with samples taken from similar areas in age-matched controls.

Reduced bacterial diversity was observed in RDEB wounds, compared with uninvolved or perilesional areas and the skin of control subjects, Dr. Samuelov said in an oral presentation of the study results. There was increased abundance of Staphylococcus epidermidis and decreased Cutibacterium acnes, which she noted was in contrast to other studies where S. aureus was the most common colonizer in RDEB wounds.

Bacterial composition in each group was calculated using the beta-diversity score, while control samples showed similar microbial composition, the DEB samples had no microbial similarities among different samples. These data “suggest the need to ascertain the potential therapeutic benefit of interventions aimed at restoring normal microbiome composition in DEB,” Dr. Samuelov concluded.

Wound colonization and squamous cell carcinoma

Other research on wound microbiology was presented by Laura E. Levin, MD, a dermatologist at New York–Presbyterian, and associates. “Given the potential role of bacteria-induced inflammation in the development of wound-associated SCC [squamous cell carcinoma] in a subset of patients, we sought to improve our understanding of what microbes colonize and infect the wounds of patients with epidermolysis bullosa,” they explained in their poster.

The researchers, from New York–Presbyterian Morgan Stanley Children’s Hospital and Columbia University Irvine Medical Center, New York, presented data from a retrospective analysis of 739 wound cultures taken between 2001 and 2017 from 158 patients enrolled in the Epidermolysis Bullosa Clinical Characterization and Outcomes Database. In the analysis, just under 70% of patients had DEB, of which 90% were of the RDEB subtype; 13% had EB simplex, 14% had junctional EB, and 3% had an unknown EB subtype.

At least one organism grew in 87% of cultures, with the most common microorganism isolated being Staphylococcus aureus (84% of cultures). Other commonly isolated microbes were Pseudomonas aeruginosa in 35% of cultures, Streptococcus group A in 34% of cultures (of which 22% were Streptococcus pyogenes), Corynebacterium species in 31% of cultures, and Proteus species in 18% of cultures.

“Improved understanding of what microbes are colonizing the wounds of our patients may help improve antibiotic stewardship,” the researchers stated.

Looking at the antibiotic susceptibilities, Dr. Levin and associates found that 68% of 115 cultures were sensitive to methicillin and 60% of 15 cultures were sensitive to mupirocin. “Resistance to many systemic and topical antibiotic agents in EB patients supports surveillance cultures with routine testing for mupirocin susceptibility,” they suggested.

A total of 23 patients developed SCC of whom 10 had cultures that grew S. aureus (90%) and P. aeruginosa (50%), and Proteus species (20%). Among the patients who did not develop SCC, the respective cultures positive for each of those microorganisms were 83%, 34%, and 11%. Perhaps “gram-negative and flagellated organisms may be more common in wounds of patients at risk for SCC,” they observed, adding that further studies were needed to determine if “wound microbiome interventions inhibit the risk of development of SCC and improve outcomes.”

Mr. Gerner’s research is supported by Mölnlycke Health Care. Dr. Samuelov had no disclosures. The work by Dr. Levin and associates is supported by the Pediatric Dermatology Research Alliance, EB Research Partnership, and the Epidermolysis Bullosa Medical Research Foundation.

LONDON – Disrupting how microorganisms communicate with each other could be a way to overcome antibiotic resistance and to help heal chronic wounds in patients with epidermolysis bullosa (EB), according to presenters at the EB World Congress, organized by the Dystrophic Epidermolysis Bullosa Association (DEBRA).

The majority of chronic wounds in patients with EB are colonized with microorganisms, with a predominance of Staphylococcus species, said Erik Gerner, an industrial PhD student at Mölnlycke Health Care in Gothenburg, Sweden, and Gothenburg University.

Because of the growing problem of antibiotic resistance, alternative treatments are needed, and one possible alternative for treating infected wounds could be interfering with quorum sensing, the cell-to-cell communication used by bacteria, he said. He is hoping to explore this possibility as a novel treatment strategy for infected wounds.

“Quorum sensing is defined as the ability to detect and respond to population density,” Mr. Gerner said, noting that, when there is a sufficient density of bacteria, “they start to communicate with each other.” This enables them to act as a community and perform actions that they could not do as individual cells. Such actions include forming biofilms, which helps protect bacteria from their environment, such as the immune system. Other actions include collectively switching on the production of virulence factors and becoming resistant to treatments.

“Bacteria use quorum sensing to act collectively,” Mr. Gerner said. “If we could shut down this quorum sensing system, it would be very beneficial … and increase the chances to heal the wound.”

The quorum sensing system is based on the production of signaling molecules called AHL (N-acyl homoserine lactones), which are constantly produced at a low rate. This isn’t a problem until the level of bacteria increases and the level of quorum sensing breaches a threshold, he explained.

There are several benefits of inhibiting bacterial communication through disrupting quorum sensing, namely, “a low risk of resistance,” Mr. Gerner said. There is also potentially less toxin production by bacteria, and this could help the immune system in killing the invading bacteria.

One approach to disrupting quorum testing that Mr. Gerner has been investigating is the use of sodium salicylate (NaSa). So far, preclinical work shows that NaSa can reduce toxin production but not the growth rate of bacteria. The advantage of using NaSa is that it is nontoxic to human dermal fibroblasts, with similar results seen in human keratinocytes and immune cells. His work to date has shown that NaSa reduced activity of NF-kB (a proinflammatory signaling pathway) in differentiated and lipopolysaccharide-stimulated monocytes; NF-kB activated production of proinflammatory cytokines (such as interleukin-1 beta and IL-6) are elevated in EB wounds. “My studies support the bodies of evidence that bacteria use quorum sensing to coordinate … and to produce a large number of toxic factors,” Mr. Gerner concluded. Future studies will look at the potential of NaSa to disrupt this activity.
 

Skin microbiome of EB wounds

Understanding what bacteria most commonly colonize wounds in patients with EB was the subject of two unrelated presentations at the EB World Congress. Liat Samuelov, MD, of the department of molecular dermatology at Tel Aviv (Israel) Sourasky Medical Center, presented data on skin microbiome characteristics in eight patients with recessive dystrophic EB (RDEB). This showed that there was reduced bacterial diversity in wounds, and a “progressive development of dysbiosis across different stages of DEB wound formation.”

The skin microbiome has been implicated in several skin diseases, Dr. Samuelov and associates observed in a poster presentation. That includes the autoimmune blistering disease bullous pemphigoid (Exp Dermatol. 2017 Dec;26[12]:1221-7). “Colonization of DEB chronic wounds may lead to systemic infections, result in delayed healing, and possibly be involved in the development of squamous cell carcinoma,” they noted in the poster, “thus accurate delineation of the dysbiotic profile … may point to corrective measures of great therapeutic potential.”

The aim was to see what microorganisms were present in the chronic wounds of the patients. To be included in the study, patients must not have had any antibiotic treatment – oral or topical – in the past 6 months. Samples were taken from an untreated wound, around the wound, and from uninvolved skin, which were compared with samples taken from similar areas in age-matched controls.

Reduced bacterial diversity was observed in RDEB wounds, compared with uninvolved or perilesional areas and the skin of control subjects, Dr. Samuelov said in an oral presentation of the study results. There was increased abundance of Staphylococcus epidermidis and decreased Cutibacterium acnes, which she noted was in contrast to other studies where S. aureus was the most common colonizer in RDEB wounds.

Bacterial composition in each group was calculated using the beta-diversity score, while control samples showed similar microbial composition, the DEB samples had no microbial similarities among different samples. These data “suggest the need to ascertain the potential therapeutic benefit of interventions aimed at restoring normal microbiome composition in DEB,” Dr. Samuelov concluded.

Wound colonization and squamous cell carcinoma

Other research on wound microbiology was presented by Laura E. Levin, MD, a dermatologist at New York–Presbyterian, and associates. “Given the potential role of bacteria-induced inflammation in the development of wound-associated SCC [squamous cell carcinoma] in a subset of patients, we sought to improve our understanding of what microbes colonize and infect the wounds of patients with epidermolysis bullosa,” they explained in their poster.

The researchers, from New York–Presbyterian Morgan Stanley Children’s Hospital and Columbia University Irvine Medical Center, New York, presented data from a retrospective analysis of 739 wound cultures taken between 2001 and 2017 from 158 patients enrolled in the Epidermolysis Bullosa Clinical Characterization and Outcomes Database. In the analysis, just under 70% of patients had DEB, of which 90% were of the RDEB subtype; 13% had EB simplex, 14% had junctional EB, and 3% had an unknown EB subtype.

At least one organism grew in 87% of cultures, with the most common microorganism isolated being Staphylococcus aureus (84% of cultures). Other commonly isolated microbes were Pseudomonas aeruginosa in 35% of cultures, Streptococcus group A in 34% of cultures (of which 22% were Streptococcus pyogenes), Corynebacterium species in 31% of cultures, and Proteus species in 18% of cultures.

“Improved understanding of what microbes are colonizing the wounds of our patients may help improve antibiotic stewardship,” the researchers stated.

Looking at the antibiotic susceptibilities, Dr. Levin and associates found that 68% of 115 cultures were sensitive to methicillin and 60% of 15 cultures were sensitive to mupirocin. “Resistance to many systemic and topical antibiotic agents in EB patients supports surveillance cultures with routine testing for mupirocin susceptibility,” they suggested.

A total of 23 patients developed SCC of whom 10 had cultures that grew S. aureus (90%) and P. aeruginosa (50%), and Proteus species (20%). Among the patients who did not develop SCC, the respective cultures positive for each of those microorganisms were 83%, 34%, and 11%. Perhaps “gram-negative and flagellated organisms may be more common in wounds of patients at risk for SCC,” they observed, adding that further studies were needed to determine if “wound microbiome interventions inhibit the risk of development of SCC and improve outcomes.”

Mr. Gerner’s research is supported by Mölnlycke Health Care. Dr. Samuelov had no disclosures. The work by Dr. Levin and associates is supported by the Pediatric Dermatology Research Alliance, EB Research Partnership, and the Epidermolysis Bullosa Medical Research Foundation.

LONDON – Disrupting how microorganisms communicate with each other could be a way to overcome antibiotic resistance and to help heal chronic wounds in patients with epidermolysis bullosa (EB), according to presenters at the EB World Congress, organized by the Dystrophic Epidermolysis Bullosa Association (DEBRA).

The majority of chronic wounds in patients with EB are colonized with microorganisms, with a predominance of Staphylococcus species, said Erik Gerner, an industrial PhD student at Mölnlycke Health Care in Gothenburg, Sweden, and Gothenburg University.

Because of the growing problem of antibiotic resistance, alternative treatments are needed, and one possible alternative for treating infected wounds could be interfering with quorum sensing, the cell-to-cell communication used by bacteria, he said. He is hoping to explore this possibility as a novel treatment strategy for infected wounds.

“Quorum sensing is defined as the ability to detect and respond to population density,” Mr. Gerner said, noting that, when there is a sufficient density of bacteria, “they start to communicate with each other.” This enables them to act as a community and perform actions that they could not do as individual cells. Such actions include forming biofilms, which helps protect bacteria from their environment, such as the immune system. Other actions include collectively switching on the production of virulence factors and becoming resistant to treatments.

“Bacteria use quorum sensing to act collectively,” Mr. Gerner said. “If we could shut down this quorum sensing system, it would be very beneficial … and increase the chances to heal the wound.”

The quorum sensing system is based on the production of signaling molecules called AHL (N-acyl homoserine lactones), which are constantly produced at a low rate. This isn’t a problem until the level of bacteria increases and the level of quorum sensing breaches a threshold, he explained.

There are several benefits of inhibiting bacterial communication through disrupting quorum sensing, namely, “a low risk of resistance,” Mr. Gerner said. There is also potentially less toxin production by bacteria, and this could help the immune system in killing the invading bacteria.

One approach to disrupting quorum testing that Mr. Gerner has been investigating is the use of sodium salicylate (NaSa). So far, preclinical work shows that NaSa can reduce toxin production but not the growth rate of bacteria. The advantage of using NaSa is that it is nontoxic to human dermal fibroblasts, with similar results seen in human keratinocytes and immune cells. His work to date has shown that NaSa reduced activity of NF-kB (a proinflammatory signaling pathway) in differentiated and lipopolysaccharide-stimulated monocytes; NF-kB activated production of proinflammatory cytokines (such as interleukin-1 beta and IL-6) are elevated in EB wounds. “My studies support the bodies of evidence that bacteria use quorum sensing to coordinate … and to produce a large number of toxic factors,” Mr. Gerner concluded. Future studies will look at the potential of NaSa to disrupt this activity.
 

Skin microbiome of EB wounds

Understanding what bacteria most commonly colonize wounds in patients with EB was the subject of two unrelated presentations at the EB World Congress. Liat Samuelov, MD, of the department of molecular dermatology at Tel Aviv (Israel) Sourasky Medical Center, presented data on skin microbiome characteristics in eight patients with recessive dystrophic EB (RDEB). This showed that there was reduced bacterial diversity in wounds, and a “progressive development of dysbiosis across different stages of DEB wound formation.”

The skin microbiome has been implicated in several skin diseases, Dr. Samuelov and associates observed in a poster presentation. That includes the autoimmune blistering disease bullous pemphigoid (Exp Dermatol. 2017 Dec;26[12]:1221-7). “Colonization of DEB chronic wounds may lead to systemic infections, result in delayed healing, and possibly be involved in the development of squamous cell carcinoma,” they noted in the poster, “thus accurate delineation of the dysbiotic profile … may point to corrective measures of great therapeutic potential.”

The aim was to see what microorganisms were present in the chronic wounds of the patients. To be included in the study, patients must not have had any antibiotic treatment – oral or topical – in the past 6 months. Samples were taken from an untreated wound, around the wound, and from uninvolved skin, which were compared with samples taken from similar areas in age-matched controls.

Reduced bacterial diversity was observed in RDEB wounds, compared with uninvolved or perilesional areas and the skin of control subjects, Dr. Samuelov said in an oral presentation of the study results. There was increased abundance of Staphylococcus epidermidis and decreased Cutibacterium acnes, which she noted was in contrast to other studies where S. aureus was the most common colonizer in RDEB wounds.

Bacterial composition in each group was calculated using the beta-diversity score, while control samples showed similar microbial composition, the DEB samples had no microbial similarities among different samples. These data “suggest the need to ascertain the potential therapeutic benefit of interventions aimed at restoring normal microbiome composition in DEB,” Dr. Samuelov concluded.

Wound colonization and squamous cell carcinoma

Other research on wound microbiology was presented by Laura E. Levin, MD, a dermatologist at New York–Presbyterian, and associates. “Given the potential role of bacteria-induced inflammation in the development of wound-associated SCC [squamous cell carcinoma] in a subset of patients, we sought to improve our understanding of what microbes colonize and infect the wounds of patients with epidermolysis bullosa,” they explained in their poster.

The researchers, from New York–Presbyterian Morgan Stanley Children’s Hospital and Columbia University Irvine Medical Center, New York, presented data from a retrospective analysis of 739 wound cultures taken between 2001 and 2017 from 158 patients enrolled in the Epidermolysis Bullosa Clinical Characterization and Outcomes Database. In the analysis, just under 70% of patients had DEB, of which 90% were of the RDEB subtype; 13% had EB simplex, 14% had junctional EB, and 3% had an unknown EB subtype.

At least one organism grew in 87% of cultures, with the most common microorganism isolated being Staphylococcus aureus (84% of cultures). Other commonly isolated microbes were Pseudomonas aeruginosa in 35% of cultures, Streptococcus group A in 34% of cultures (of which 22% were Streptococcus pyogenes), Corynebacterium species in 31% of cultures, and Proteus species in 18% of cultures.

“Improved understanding of what microbes are colonizing the wounds of our patients may help improve antibiotic stewardship,” the researchers stated.

Looking at the antibiotic susceptibilities, Dr. Levin and associates found that 68% of 115 cultures were sensitive to methicillin and 60% of 15 cultures were sensitive to mupirocin. “Resistance to many systemic and topical antibiotic agents in EB patients supports surveillance cultures with routine testing for mupirocin susceptibility,” they suggested.

A total of 23 patients developed SCC of whom 10 had cultures that grew S. aureus (90%) and P. aeruginosa (50%), and Proteus species (20%). Among the patients who did not develop SCC, the respective cultures positive for each of those microorganisms were 83%, 34%, and 11%. Perhaps “gram-negative and flagellated organisms may be more common in wounds of patients at risk for SCC,” they observed, adding that further studies were needed to determine if “wound microbiome interventions inhibit the risk of development of SCC and improve outcomes.”

Mr. Gerner’s research is supported by Mölnlycke Health Care. Dr. Samuelov had no disclosures. The work by Dr. Levin and associates is supported by the Pediatric Dermatology Research Alliance, EB Research Partnership, and the Epidermolysis Bullosa Medical Research Foundation.

LONDON – A quarter of urgent contacts in 20 children with generalized severe recessive dystrophic epidermolysis bullosa (GS-RDEB) were tied to esophageal narrowing, according data from a 12-month review of electronic health records.

Urgent advice was sought 102 times outside of regular or scheduled appointments by the parents of 20 children with GS-RDEB, Christine Prodinger, MD, of the University Clinic of Dermatology at Paracelsus Medical University, Salzburg, Austria, and colleagues reported in a poster presentation at the EB World Congress, organized by the Dystrophic Epidermolysis Bullosa Association (DEBRA). The researchers looked at the records from the EB clinic at Great Ormond Street Hospital for Children NHS Foundation Trust, London, during April 2018–April 2019.

The mean number of urgent contacts with the specialist unit was 5.1 per patient per year, the researchers reported, with 24 of the 102 contacts (23.5%) resulting in the child being admitted to a hospital. Most of the contacts were made via email or telephone to EB nurses (94%), by contacts during home visits (3%), or in an appointment with the palliative or symptom care team (3%).

“The most common reason [for the urgent contact] was acute dysphagia,” which was experienced as choking, throat pain, difficulty eating, reflux, and vomiting, the researchers observed. Dysphagia affected children in 27 of the contacts (26.5%), and resulted in esophageal dilatation in 90% of the cases. Other reasons for urgent contact were skin infection (15.7% of contacts), uncontrolled pain (15.7% of the contacts), and eye problems (11.8%).
 

Esophageal dilatation

Strictures are just one of the esophageal manifestations of the disease, noted Anna Bruckner, MD, associate professor of dermatology and pediatrics in the department of dermatology at the University of Colorado at Denver, Aurora, during an oral presentation. Other possible manifestations include blisters and erosions, the formation of webs – a thin extension of esophageal tissue, perforations, and rupture. “These are primarily problems with dystrophic EB” but can occur with other EB subtypes, she noted.

“We don’t have great evidence” on whether the onset of esophageal strictures can be delayed or prevented, Dr. Bruckner observed. As for management, “fluoroscopy-guided balloon dilatation is probably best” for most patients, but the best procedural approach needs to be discussed on a patient-by-patient basis.

Citing a paper that documents her own experience on the use of esophageal dilatation in 24 children who underwent 231 fluoroscopy-guided balloon dilatation procedures, Dr. Bruckner noted that strictures were most commonly located in the proximal part of the esophagus, with a median distance of 13 cm down from the lips (J Pediatr Gastroenterol Nutr. 2018;67[6]:701-5).

The retrospective chart review reported by Dr. Bruckner showed that there were a median of seven dilatation procedures per patient, and 20 patients had repeated procedures at a median interval of 164 days. About 10% of procedures resulted in adverse events – mostly vomiting, pain, and fever – but there were no perforations or other serious effects, and the rate of subsequent hospitalization was 6.9%.
 

Dysphagia

Dysphagia was the predominant symptom caused by esophageal stricture in another dataset reported in a poster by Elena Pope, MD, MSc, of the Hospital for Sick Children at the University of Toronto, and colleagues.

Of 125 EB patients who had experienced at least 1 esophageal stricture episode, 497 esophageal stricture events were reported, and 85.5% of patients had difficulty swallowing at presentation, with 29.8% unable to swallow solids and 7.2% unable to swallow liquids. Other symptoms at presentation were painful swallowing (11%), food being stuck in the esophagus (8%), regurgitation (5%), coughing (4.8%), and dyspepsia (2.8%).

The aim of the retrospective, multicenter cohort study was to determine the prevalence of, and predisposing factors for, restenosis of esophageal strictures and factors that may predispose to restenosis. The study population consisted of 66 men and 59 women who had experienced their esophageal stricture at around ages 12-13 years. The majority (98.4%) had dystrophic EB, of which almost half (46.5%) had GS-RDEB.

The researchers found that the location of the esophageal stricture was important for restenosis, and that strictures occurring in the lower esophagus were 67.5% less likely to result in restenosis than if they occurred in the upper esophagus (P = .057; hazard ratio, 0.675).

A higher number of strictures was associated with a higher rate of restenosis, they reported. Indeed, patients who had two esophageal strictures had a 29.4% increased risk of restenosis, compared with those who had just one stricture (P = .038; HR, 1.294), and those with three or more strictures had an increased risk of 78.5%, compared with those having one stricture (P = .005; HR, 1.785).

Strictures longer than 1 cm also were associated with a greater (34.7%) risk of restenosis, compared with shorter strictures (P = .032; HR, 1.347). Various methods of resolving the stricture were used, from fluoroscopy-guided balloon dilatation to retro- or antegrade endoscopy. “Irrespective of method, dilatations are successful,” Dr. Pope and colleagues reported. The overall success of dilatation was 99.3%, with full dilatation achieved in almost all of the patients (96%). Of note is that there was a low risk (2.6%) of complications, they observed.

Medications were used in 46.8% of the patients, with the most popular choice being corticosteroids (90.3%), but the researchers noted that the “potential benefit of periprocedural corticosteroids use in decreasing the risk of restenosis needs further exploration.”

Dr. Bruckner had noted in her presentation that her group did not favor the use of periprocedural corticosteroids, but that antifibrotic therapy “could be attractive” for preventing future strictures.

Dr. Prodinger, Dr. Pope, and their colleagues did not provide disclosure information. Dr. Bruckner is the principal investigator for the Epidermolysis Bullosa Clinical Characterization and Outcomes Database. She disclosed the receipt of grants or research funding, honoraria, or consultation fees from a number of drug companies, as well as other support from the EB Research Partnership and the EB Medical Research Foundation.

SOURCES: Prodinger et al. EB 2020. Poster 3; Bruckner A et al. Pediatr Gastroenterol Nutr. 2018;67(6):701-5; Pope et al. EB 2020. Poster 8.

LONDON – A quarter of urgent contacts in 20 children with generalized severe recessive dystrophic epidermolysis bullosa (GS-RDEB) were tied to esophageal narrowing, according data from a 12-month review of electronic health records.

Urgent advice was sought 102 times outside of regular or scheduled appointments by the parents of 20 children with GS-RDEB, Christine Prodinger, MD, of the University Clinic of Dermatology at Paracelsus Medical University, Salzburg, Austria, and colleagues reported in a poster presentation at the EB World Congress, organized by the Dystrophic Epidermolysis Bullosa Association (DEBRA). The researchers looked at the records from the EB clinic at Great Ormond Street Hospital for Children NHS Foundation Trust, London, during April 2018–April 2019.

The mean number of urgent contacts with the specialist unit was 5.1 per patient per year, the researchers reported, with 24 of the 102 contacts (23.5%) resulting in the child being admitted to a hospital. Most of the contacts were made via email or telephone to EB nurses (94%), by contacts during home visits (3%), or in an appointment with the palliative or symptom care team (3%).

“The most common reason [for the urgent contact] was acute dysphagia,” which was experienced as choking, throat pain, difficulty eating, reflux, and vomiting, the researchers observed. Dysphagia affected children in 27 of the contacts (26.5%), and resulted in esophageal dilatation in 90% of the cases. Other reasons for urgent contact were skin infection (15.7% of contacts), uncontrolled pain (15.7% of the contacts), and eye problems (11.8%).
 

Esophageal dilatation

Strictures are just one of the esophageal manifestations of the disease, noted Anna Bruckner, MD, associate professor of dermatology and pediatrics in the department of dermatology at the University of Colorado at Denver, Aurora, during an oral presentation. Other possible manifestations include blisters and erosions, the formation of webs – a thin extension of esophageal tissue, perforations, and rupture. “These are primarily problems with dystrophic EB” but can occur with other EB subtypes, she noted.

“We don’t have great evidence” on whether the onset of esophageal strictures can be delayed or prevented, Dr. Bruckner observed. As for management, “fluoroscopy-guided balloon dilatation is probably best” for most patients, but the best procedural approach needs to be discussed on a patient-by-patient basis.

Citing a paper that documents her own experience on the use of esophageal dilatation in 24 children who underwent 231 fluoroscopy-guided balloon dilatation procedures, Dr. Bruckner noted that strictures were most commonly located in the proximal part of the esophagus, with a median distance of 13 cm down from the lips (J Pediatr Gastroenterol Nutr. 2018;67[6]:701-5).

The retrospective chart review reported by Dr. Bruckner showed that there were a median of seven dilatation procedures per patient, and 20 patients had repeated procedures at a median interval of 164 days. About 10% of procedures resulted in adverse events – mostly vomiting, pain, and fever – but there were no perforations or other serious effects, and the rate of subsequent hospitalization was 6.9%.
 

Dysphagia

Dysphagia was the predominant symptom caused by esophageal stricture in another dataset reported in a poster by Elena Pope, MD, MSc, of the Hospital for Sick Children at the University of Toronto, and colleagues.

Of 125 EB patients who had experienced at least 1 esophageal stricture episode, 497 esophageal stricture events were reported, and 85.5% of patients had difficulty swallowing at presentation, with 29.8% unable to swallow solids and 7.2% unable to swallow liquids. Other symptoms at presentation were painful swallowing (11%), food being stuck in the esophagus (8%), regurgitation (5%), coughing (4.8%), and dyspepsia (2.8%).

The aim of the retrospective, multicenter cohort study was to determine the prevalence of, and predisposing factors for, restenosis of esophageal strictures and factors that may predispose to restenosis. The study population consisted of 66 men and 59 women who had experienced their esophageal stricture at around ages 12-13 years. The majority (98.4%) had dystrophic EB, of which almost half (46.5%) had GS-RDEB.

The researchers found that the location of the esophageal stricture was important for restenosis, and that strictures occurring in the lower esophagus were 67.5% less likely to result in restenosis than if they occurred in the upper esophagus (P = .057; hazard ratio, 0.675).

A higher number of strictures was associated with a higher rate of restenosis, they reported. Indeed, patients who had two esophageal strictures had a 29.4% increased risk of restenosis, compared with those who had just one stricture (P = .038; HR, 1.294), and those with three or more strictures had an increased risk of 78.5%, compared with those having one stricture (P = .005; HR, 1.785).

Strictures longer than 1 cm also were associated with a greater (34.7%) risk of restenosis, compared with shorter strictures (P = .032; HR, 1.347). Various methods of resolving the stricture were used, from fluoroscopy-guided balloon dilatation to retro- or antegrade endoscopy. “Irrespective of method, dilatations are successful,” Dr. Pope and colleagues reported. The overall success of dilatation was 99.3%, with full dilatation achieved in almost all of the patients (96%). Of note is that there was a low risk (2.6%) of complications, they observed.

Medications were used in 46.8% of the patients, with the most popular choice being corticosteroids (90.3%), but the researchers noted that the “potential benefit of periprocedural corticosteroids use in decreasing the risk of restenosis needs further exploration.”

Dr. Bruckner had noted in her presentation that her group did not favor the use of periprocedural corticosteroids, but that antifibrotic therapy “could be attractive” for preventing future strictures.

Dr. Prodinger, Dr. Pope, and their colleagues did not provide disclosure information. Dr. Bruckner is the principal investigator for the Epidermolysis Bullosa Clinical Characterization and Outcomes Database. She disclosed the receipt of grants or research funding, honoraria, or consultation fees from a number of drug companies, as well as other support from the EB Research Partnership and the EB Medical Research Foundation.

SOURCES: Prodinger et al. EB 2020. Poster 3; Bruckner A et al. Pediatr Gastroenterol Nutr. 2018;67(6):701-5; Pope et al. EB 2020. Poster 8.

LONDON – A quarter of urgent contacts in 20 children with generalized severe recessive dystrophic epidermolysis bullosa (GS-RDEB) were tied to esophageal narrowing, according data from a 12-month review of electronic health records.

Urgent advice was sought 102 times outside of regular or scheduled appointments by the parents of 20 children with GS-RDEB, Christine Prodinger, MD, of the University Clinic of Dermatology at Paracelsus Medical University, Salzburg, Austria, and colleagues reported in a poster presentation at the EB World Congress, organized by the Dystrophic Epidermolysis Bullosa Association (DEBRA). The researchers looked at the records from the EB clinic at Great Ormond Street Hospital for Children NHS Foundation Trust, London, during April 2018–April 2019.

The mean number of urgent contacts with the specialist unit was 5.1 per patient per year, the researchers reported, with 24 of the 102 contacts (23.5%) resulting in the child being admitted to a hospital. Most of the contacts were made via email or telephone to EB nurses (94%), by contacts during home visits (3%), or in an appointment with the palliative or symptom care team (3%).

“The most common reason [for the urgent contact] was acute dysphagia,” which was experienced as choking, throat pain, difficulty eating, reflux, and vomiting, the researchers observed. Dysphagia affected children in 27 of the contacts (26.5%), and resulted in esophageal dilatation in 90% of the cases. Other reasons for urgent contact were skin infection (15.7% of contacts), uncontrolled pain (15.7% of the contacts), and eye problems (11.8%).
 

Esophageal dilatation

Strictures are just one of the esophageal manifestations of the disease, noted Anna Bruckner, MD, associate professor of dermatology and pediatrics in the department of dermatology at the University of Colorado at Denver, Aurora, during an oral presentation. Other possible manifestations include blisters and erosions, the formation of webs – a thin extension of esophageal tissue, perforations, and rupture. “These are primarily problems with dystrophic EB” but can occur with other EB subtypes, she noted.

“We don’t have great evidence” on whether the onset of esophageal strictures can be delayed or prevented, Dr. Bruckner observed. As for management, “fluoroscopy-guided balloon dilatation is probably best” for most patients, but the best procedural approach needs to be discussed on a patient-by-patient basis.

Citing a paper that documents her own experience on the use of esophageal dilatation in 24 children who underwent 231 fluoroscopy-guided balloon dilatation procedures, Dr. Bruckner noted that strictures were most commonly located in the proximal part of the esophagus, with a median distance of 13 cm down from the lips (J Pediatr Gastroenterol Nutr. 2018;67[6]:701-5).

The retrospective chart review reported by Dr. Bruckner showed that there were a median of seven dilatation procedures per patient, and 20 patients had repeated procedures at a median interval of 164 days. About 10% of procedures resulted in adverse events – mostly vomiting, pain, and fever – but there were no perforations or other serious effects, and the rate of subsequent hospitalization was 6.9%.
 

Dysphagia

Dysphagia was the predominant symptom caused by esophageal stricture in another dataset reported in a poster by Elena Pope, MD, MSc, of the Hospital for Sick Children at the University of Toronto, and colleagues.

Of 125 EB patients who had experienced at least 1 esophageal stricture episode, 497 esophageal stricture events were reported, and 85.5% of patients had difficulty swallowing at presentation, with 29.8% unable to swallow solids and 7.2% unable to swallow liquids. Other symptoms at presentation were painful swallowing (11%), food being stuck in the esophagus (8%), regurgitation (5%), coughing (4.8%), and dyspepsia (2.8%).

The aim of the retrospective, multicenter cohort study was to determine the prevalence of, and predisposing factors for, restenosis of esophageal strictures and factors that may predispose to restenosis. The study population consisted of 66 men and 59 women who had experienced their esophageal stricture at around ages 12-13 years. The majority (98.4%) had dystrophic EB, of which almost half (46.5%) had GS-RDEB.

The researchers found that the location of the esophageal stricture was important for restenosis, and that strictures occurring in the lower esophagus were 67.5% less likely to result in restenosis than if they occurred in the upper esophagus (P = .057; hazard ratio, 0.675).

A higher number of strictures was associated with a higher rate of restenosis, they reported. Indeed, patients who had two esophageal strictures had a 29.4% increased risk of restenosis, compared with those who had just one stricture (P = .038; HR, 1.294), and those with three or more strictures had an increased risk of 78.5%, compared with those having one stricture (P = .005; HR, 1.785).

Strictures longer than 1 cm also were associated with a greater (34.7%) risk of restenosis, compared with shorter strictures (P = .032; HR, 1.347). Various methods of resolving the stricture were used, from fluoroscopy-guided balloon dilatation to retro- or antegrade endoscopy. “Irrespective of method, dilatations are successful,” Dr. Pope and colleagues reported. The overall success of dilatation was 99.3%, with full dilatation achieved in almost all of the patients (96%). Of note is that there was a low risk (2.6%) of complications, they observed.

Medications were used in 46.8% of the patients, with the most popular choice being corticosteroids (90.3%), but the researchers noted that the “potential benefit of periprocedural corticosteroids use in decreasing the risk of restenosis needs further exploration.”

Dr. Bruckner had noted in her presentation that her group did not favor the use of periprocedural corticosteroids, but that antifibrotic therapy “could be attractive” for preventing future strictures.

Dr. Prodinger, Dr. Pope, and their colleagues did not provide disclosure information. Dr. Bruckner is the principal investigator for the Epidermolysis Bullosa Clinical Characterization and Outcomes Database. She disclosed the receipt of grants or research funding, honoraria, or consultation fees from a number of drug companies, as well as other support from the EB Research Partnership and the EB Medical Research Foundation.

SOURCES: Prodinger et al. EB 2020. Poster 3; Bruckner A et al. Pediatr Gastroenterol Nutr. 2018;67(6):701-5; Pope et al. EB 2020. Poster 8.

LONDON – Median survival among patients with generalized severe recessive dystrophic epidermolysis bullosa (RDEB-GS) after a first diagnosis of mucocutaneous squamous cell carcinoma (SCC) was 2.4 years in an observational, retrospective study.

The study, conducted at St. Thomas’ Hospital and Great Ormond Street Hospital in London, was a review of all individuals with EB who had developed the skin cancer over a 28-year period, from 1991 to 2019.

A total of 44 subjects were identified who together had 221 primary SCCs. Considering all study subjects, the median age at first diagnosis of SCC was 32.6 years, with a mean of five tumors present. Almost 40% had metastatic tumors, and of the 57% who died during the observation period, 88% of deaths were attributable to the SCC.

“EB-associated SCCs differ from those in the general population,” the study’s investigators wrote in a poster presented at the EB World Congress, organized by the Dystrophic Epidermolysis Bullosa Association (debra). “They affect a younger age group, and there are often multiple primaries,” they added. Furthermore, “they behave aggressively and metastasize early despite being well differentiated.”

Most (31) of the study participants had RDEB-GS and tended to develop their first SCC at a younger age than the group overall, at a median of 29.5 years (compared with 32.6 years for the overall group). The mean number of tumors was 5.8 among those with RDEB-GS, with over half (53.4%) of the SCCs being well differentiated and located on the hands, upper arms, feet, and lower legs. Median survival after a first diagnosis in this group was 2.4 years. The short survival after a first diagnosis of SCC “underscores the poor prognosis in this group,” the researchers wrote.

“As the largest cohort of EB SCC patients with comprehensive data regarding clinical course and management to date, our data reinforce the need for regular clinical surveillance for SCCs in EB patients,” the team concluded. This surveillance should start in adolescence for those with the severe generalized RDEB subtype, they advise, and from the third or fourth decade for other at-risk groups.

These data also highlight “the pressing need for more effective treatments,” the investigators wrote. Most (86.4%) of the SCCs among the patients in the study had been surgically removed by wide local excision, with a few patients undergoing lymph node dissection, radiotherapy, chemotherapy, electrochemotherapy, or receiving targeted cancer therapies such as erlotinib, cetuximab, or cemiplimab.

Surgery may not be an option for many patients, Jemima Mellerio, MD explained in an oral presentation at the meeting. Dr. Mellerio, a consultant dermatologist and chief of St John’s Institute of Dermatology at Guy’s & St. Thomas’ NHS Foundation, London, noted that the location of the tumor was important, as sometimes it was not physically possible to excise it completely.

Guidelines on how to manage SCCs in patients with EB were published a few years ago (Br J Dermatol. 2016;174:56-67) and noted that the clinical detection of SCCs could be difficult because of chronic wound ulceration in these patients. The “possibility of malignancy should be borne in mind, with suspicious lesions biopsied for histological evaluation,” the document states. Evidence for many of the nonsurgical options – radiotherapy, conventional chemotherapy, biologic therapies – was poor, according to the guidelines, and effective nonsurgical options are still desperately needed.

Several avenues of research are being investigated, Dr. Mellerio noted, such as targeting the fibrotic process and perhaps using a micro-RNA inhibitor to stop the upregulation of certain microRNAs in fibroblasts. Targeting inflammatory mechanisms such as thrombospondin 1, which can lead to elevated levels of tumor necrosis factor–beta and contribute to extracellular matrix stiffness, also is under investigation. Raised interleukin-6 may be another target to consider.

Research shows that similar genes are mutated in EB-related and ultraviolet-related SCCs, Dr. Mellerio said. Indeed, mutations in HRAS, NOTCH1, TP53, and CDKN2A have been reported, but mutations in these genes occur much earlier in life in patients with EB. “Something else is going on,” she added, commenting that researchers are looking at apolipoprotein B editing complex (APOBEC) enzymes, which modulate DNA and can cause “particular types of genetic changes in EB cancers.”

One investigator who is studying the genetics of EB SCCs and how APOBEC enzymes might be involved is Andrew South, PhD, an associate professor at Thomas Jefferson University, Philadelphia. APOBEC enzymes are a very prominent source of mutations in RDEB. These mutations are found in 10%-20% of squamous cell carcinomas not associated with RDEB, and 80%-90% of head and neck cancers, he said during a separate talk at the meeting.

Dr. South observed that “RDEB squamous cell carcinoma does not show any particular somatic mutation or upregulation or downregulation of genes that differentiates it from other squamous cell carcinomas, which might be disappointing on the front of it, but actually it does mean that precision therapies that have been developed for other squamous cell carcinomas have application in RDEB.”

RDEB SCC shows the greatest similarity with head and neck SCC, Dr. South said. He also stressed that fibrosis is a major driver of cancer development, SCC tumors in RDEB are homogenous, and that frontline therapy is still unclear.

What is clear, however, is that interdisciplinary management of patients is crucial, said Leena Bruckner-Tuderman, MD, professor and chair of the department of dermatology at the University Medical Center, Albert Ludwig University of Freiburg, Germany.

“In severe RDEB, metastatic SCC is the leading cause of death at a young age. We need monitoring, careful diagnostics, and multidisciplinary treatment,” Dr. Bruckner-Tuderman said. The latter should be delivered by a coordinated team that consists of dermatologists, surgeons, radiologists, oncologists, pathologists, geneticists, and (molecular) tumor boards, she advised.

The study had no commercial funding. Dr. Mellerio disclosed financial relationships with Castle Creek Pharmaceuticals and ProQR Therapeutics, and acted as an unpaid advisor to Helpberby Therapeutics. Dr. South disclosed financial relationships with Krystal Biotech Inc. and Amryt Genetics and has been an advisory board member for Abeona Therapeutics and Sanofi Genzyme. Dr. Bruckner-Tuderman disclosed receiving grants or research support from Constant Pharmaceuticals/Tarix Orphan.

LONDON – Median survival among patients with generalized severe recessive dystrophic epidermolysis bullosa (RDEB-GS) after a first diagnosis of mucocutaneous squamous cell carcinoma (SCC) was 2.4 years in an observational, retrospective study.

The study, conducted at St. Thomas’ Hospital and Great Ormond Street Hospital in London, was a review of all individuals with EB who had developed the skin cancer over a 28-year period, from 1991 to 2019.

A total of 44 subjects were identified who together had 221 primary SCCs. Considering all study subjects, the median age at first diagnosis of SCC was 32.6 years, with a mean of five tumors present. Almost 40% had metastatic tumors, and of the 57% who died during the observation period, 88% of deaths were attributable to the SCC.

“EB-associated SCCs differ from those in the general population,” the study’s investigators wrote in a poster presented at the EB World Congress, organized by the Dystrophic Epidermolysis Bullosa Association (debra). “They affect a younger age group, and there are often multiple primaries,” they added. Furthermore, “they behave aggressively and metastasize early despite being well differentiated.”

Most (31) of the study participants had RDEB-GS and tended to develop their first SCC at a younger age than the group overall, at a median of 29.5 years (compared with 32.6 years for the overall group). The mean number of tumors was 5.8 among those with RDEB-GS, with over half (53.4%) of the SCCs being well differentiated and located on the hands, upper arms, feet, and lower legs. Median survival after a first diagnosis in this group was 2.4 years. The short survival after a first diagnosis of SCC “underscores the poor prognosis in this group,” the researchers wrote.

“As the largest cohort of EB SCC patients with comprehensive data regarding clinical course and management to date, our data reinforce the need for regular clinical surveillance for SCCs in EB patients,” the team concluded. This surveillance should start in adolescence for those with the severe generalized RDEB subtype, they advise, and from the third or fourth decade for other at-risk groups.

These data also highlight “the pressing need for more effective treatments,” the investigators wrote. Most (86.4%) of the SCCs among the patients in the study had been surgically removed by wide local excision, with a few patients undergoing lymph node dissection, radiotherapy, chemotherapy, electrochemotherapy, or receiving targeted cancer therapies such as erlotinib, cetuximab, or cemiplimab.

Surgery may not be an option for many patients, Jemima Mellerio, MD explained in an oral presentation at the meeting. Dr. Mellerio, a consultant dermatologist and chief of St John’s Institute of Dermatology at Guy’s & St. Thomas’ NHS Foundation, London, noted that the location of the tumor was important, as sometimes it was not physically possible to excise it completely.

Guidelines on how to manage SCCs in patients with EB were published a few years ago (Br J Dermatol. 2016;174:56-67) and noted that the clinical detection of SCCs could be difficult because of chronic wound ulceration in these patients. The “possibility of malignancy should be borne in mind, with suspicious lesions biopsied for histological evaluation,” the document states. Evidence for many of the nonsurgical options – radiotherapy, conventional chemotherapy, biologic therapies – was poor, according to the guidelines, and effective nonsurgical options are still desperately needed.

Several avenues of research are being investigated, Dr. Mellerio noted, such as targeting the fibrotic process and perhaps using a micro-RNA inhibitor to stop the upregulation of certain microRNAs in fibroblasts. Targeting inflammatory mechanisms such as thrombospondin 1, which can lead to elevated levels of tumor necrosis factor–beta and contribute to extracellular matrix stiffness, also is under investigation. Raised interleukin-6 may be another target to consider.

Research shows that similar genes are mutated in EB-related and ultraviolet-related SCCs, Dr. Mellerio said. Indeed, mutations in HRAS, NOTCH1, TP53, and CDKN2A have been reported, but mutations in these genes occur much earlier in life in patients with EB. “Something else is going on,” she added, commenting that researchers are looking at apolipoprotein B editing complex (APOBEC) enzymes, which modulate DNA and can cause “particular types of genetic changes in EB cancers.”

One investigator who is studying the genetics of EB SCCs and how APOBEC enzymes might be involved is Andrew South, PhD, an associate professor at Thomas Jefferson University, Philadelphia. APOBEC enzymes are a very prominent source of mutations in RDEB. These mutations are found in 10%-20% of squamous cell carcinomas not associated with RDEB, and 80%-90% of head and neck cancers, he said during a separate talk at the meeting.

Dr. South observed that “RDEB squamous cell carcinoma does not show any particular somatic mutation or upregulation or downregulation of genes that differentiates it from other squamous cell carcinomas, which might be disappointing on the front of it, but actually it does mean that precision therapies that have been developed for other squamous cell carcinomas have application in RDEB.”

RDEB SCC shows the greatest similarity with head and neck SCC, Dr. South said. He also stressed that fibrosis is a major driver of cancer development, SCC tumors in RDEB are homogenous, and that frontline therapy is still unclear.

What is clear, however, is that interdisciplinary management of patients is crucial, said Leena Bruckner-Tuderman, MD, professor and chair of the department of dermatology at the University Medical Center, Albert Ludwig University of Freiburg, Germany.

“In severe RDEB, metastatic SCC is the leading cause of death at a young age. We need monitoring, careful diagnostics, and multidisciplinary treatment,” Dr. Bruckner-Tuderman said. The latter should be delivered by a coordinated team that consists of dermatologists, surgeons, radiologists, oncologists, pathologists, geneticists, and (molecular) tumor boards, she advised.

The study had no commercial funding. Dr. Mellerio disclosed financial relationships with Castle Creek Pharmaceuticals and ProQR Therapeutics, and acted as an unpaid advisor to Helpberby Therapeutics. Dr. South disclosed financial relationships with Krystal Biotech Inc. and Amryt Genetics and has been an advisory board member for Abeona Therapeutics and Sanofi Genzyme. Dr. Bruckner-Tuderman disclosed receiving grants or research support from Constant Pharmaceuticals/Tarix Orphan.

LONDON – Median survival among patients with generalized severe recessive dystrophic epidermolysis bullosa (RDEB-GS) after a first diagnosis of mucocutaneous squamous cell carcinoma (SCC) was 2.4 years in an observational, retrospective study.

The study, conducted at St. Thomas’ Hospital and Great Ormond Street Hospital in London, was a review of all individuals with EB who had developed the skin cancer over a 28-year period, from 1991 to 2019.

A total of 44 subjects were identified who together had 221 primary SCCs. Considering all study subjects, the median age at first diagnosis of SCC was 32.6 years, with a mean of five tumors present. Almost 40% had metastatic tumors, and of the 57% who died during the observation period, 88% of deaths were attributable to the SCC.

“EB-associated SCCs differ from those in the general population,” the study’s investigators wrote in a poster presented at the EB World Congress, organized by the Dystrophic Epidermolysis Bullosa Association (debra). “They affect a younger age group, and there are often multiple primaries,” they added. Furthermore, “they behave aggressively and metastasize early despite being well differentiated.”

Most (31) of the study participants had RDEB-GS and tended to develop their first SCC at a younger age than the group overall, at a median of 29.5 years (compared with 32.6 years for the overall group). The mean number of tumors was 5.8 among those with RDEB-GS, with over half (53.4%) of the SCCs being well differentiated and located on the hands, upper arms, feet, and lower legs. Median survival after a first diagnosis in this group was 2.4 years. The short survival after a first diagnosis of SCC “underscores the poor prognosis in this group,” the researchers wrote.

“As the largest cohort of EB SCC patients with comprehensive data regarding clinical course and management to date, our data reinforce the need for regular clinical surveillance for SCCs in EB patients,” the team concluded. This surveillance should start in adolescence for those with the severe generalized RDEB subtype, they advise, and from the third or fourth decade for other at-risk groups.

These data also highlight “the pressing need for more effective treatments,” the investigators wrote. Most (86.4%) of the SCCs among the patients in the study had been surgically removed by wide local excision, with a few patients undergoing lymph node dissection, radiotherapy, chemotherapy, electrochemotherapy, or receiving targeted cancer therapies such as erlotinib, cetuximab, or cemiplimab.

Surgery may not be an option for many patients, Jemima Mellerio, MD explained in an oral presentation at the meeting. Dr. Mellerio, a consultant dermatologist and chief of St John’s Institute of Dermatology at Guy’s & St. Thomas’ NHS Foundation, London, noted that the location of the tumor was important, as sometimes it was not physically possible to excise it completely.

Guidelines on how to manage SCCs in patients with EB were published a few years ago (Br J Dermatol. 2016;174:56-67) and noted that the clinical detection of SCCs could be difficult because of chronic wound ulceration in these patients. The “possibility of malignancy should be borne in mind, with suspicious lesions biopsied for histological evaluation,” the document states. Evidence for many of the nonsurgical options – radiotherapy, conventional chemotherapy, biologic therapies – was poor, according to the guidelines, and effective nonsurgical options are still desperately needed.

Several avenues of research are being investigated, Dr. Mellerio noted, such as targeting the fibrotic process and perhaps using a micro-RNA inhibitor to stop the upregulation of certain microRNAs in fibroblasts. Targeting inflammatory mechanisms such as thrombospondin 1, which can lead to elevated levels of tumor necrosis factor–beta and contribute to extracellular matrix stiffness, also is under investigation. Raised interleukin-6 may be another target to consider.

Research shows that similar genes are mutated in EB-related and ultraviolet-related SCCs, Dr. Mellerio said. Indeed, mutations in HRAS, NOTCH1, TP53, and CDKN2A have been reported, but mutations in these genes occur much earlier in life in patients with EB. “Something else is going on,” she added, commenting that researchers are looking at apolipoprotein B editing complex (APOBEC) enzymes, which modulate DNA and can cause “particular types of genetic changes in EB cancers.”

One investigator who is studying the genetics of EB SCCs and how APOBEC enzymes might be involved is Andrew South, PhD, an associate professor at Thomas Jefferson University, Philadelphia. APOBEC enzymes are a very prominent source of mutations in RDEB. These mutations are found in 10%-20% of squamous cell carcinomas not associated with RDEB, and 80%-90% of head and neck cancers, he said during a separate talk at the meeting.

Dr. South observed that “RDEB squamous cell carcinoma does not show any particular somatic mutation or upregulation or downregulation of genes that differentiates it from other squamous cell carcinomas, which might be disappointing on the front of it, but actually it does mean that precision therapies that have been developed for other squamous cell carcinomas have application in RDEB.”

RDEB SCC shows the greatest similarity with head and neck SCC, Dr. South said. He also stressed that fibrosis is a major driver of cancer development, SCC tumors in RDEB are homogenous, and that frontline therapy is still unclear.

What is clear, however, is that interdisciplinary management of patients is crucial, said Leena Bruckner-Tuderman, MD, professor and chair of the department of dermatology at the University Medical Center, Albert Ludwig University of Freiburg, Germany.

“In severe RDEB, metastatic SCC is the leading cause of death at a young age. We need monitoring, careful diagnostics, and multidisciplinary treatment,” Dr. Bruckner-Tuderman said. The latter should be delivered by a coordinated team that consists of dermatologists, surgeons, radiologists, oncologists, pathologists, geneticists, and (molecular) tumor boards, she advised.

The study had no commercial funding. Dr. Mellerio disclosed financial relationships with Castle Creek Pharmaceuticals and ProQR Therapeutics, and acted as an unpaid advisor to Helpberby Therapeutics. Dr. South disclosed financial relationships with Krystal Biotech Inc. and Amryt Genetics and has been an advisory board member for Abeona Therapeutics and Sanofi Genzyme. Dr. Bruckner-Tuderman disclosed receiving grants or research support from Constant Pharmaceuticals/Tarix Orphan.

LONDON – Preventive oral health should be high on the agenda when managing babies and children with dystrophic epidermolysis bullosa (DEB), pediatric dentist Susanne Krämer told attendees at the first EB World Congress.

Sara Freeman/MDedge News

While it may not be the first thing on the minds of families coming to terms with their children having a chronic and potentially debilitating skin disease, it is important to consider oral health early to ensure healthy dentition and mouth function, both of which will affect the ability to eat and thus nutrition.

When there are a lot of other health issues, “dentistry is not a priority,” Dr. Krämer acknowledged in an interview at the meeting, organized by the Dystrophic Epidermolysis Bullosa Association (DEBRA). 

Something as simple as brushing teeth can be very distressing for parents of a child with EB, she observed, especially if there is dysphagia and toothpaste may be getting into the airways accidentally.

Oral health was one of the topics that patients with EB and their families said would be good to have some guidance on when they were surveyed by DEBRA International. This led the charity to develop its first clinical practice guideline in 2012. Dr. Krämer was the lead author of the guidelines, which are about to be updated and republished.

The “Oral Health for Patients with Epidermolysis Bullosa – Best Clinical Practice Guidelines” (Int J Paediatr Dent. 2012;22 Suppl 1:1-35) are in the final stages of being revised, said Dr. Krämer, who is head of the department of pediatric dentistry at the University of Chile in Santiago. Although there is not much new evidence since the guidelines were first published, “we do have a lot of new technologies within dentistry that can aid the care of EB,” she said.

LONDON – Preventive oral health should be high on the agenda when managing babies and children with dystrophic epidermolysis bullosa (DEB), pediatric dentist Susanne Krämer told attendees at the first EB World Congress.

Sara Freeman/MDedge News

While it may not be the first thing on the minds of families coming to terms with their children having a chronic and potentially debilitating skin disease, it is important to consider oral health early to ensure healthy dentition and mouth function, both of which will affect the ability to eat and thus nutrition.

When there are a lot of other health issues, “dentistry is not a priority,” Dr. Krämer acknowledged in an interview at the meeting, organized by the Dystrophic Epidermolysis Bullosa Association (DEBRA). 

Something as simple as brushing teeth can be very distressing for parents of a child with EB, she observed, especially if there is dysphagia and toothpaste may be getting into the airways accidentally.

Oral health was one of the topics that patients with EB and their families said would be good to have some guidance on when they were surveyed by DEBRA International. This led the charity to develop its first clinical practice guideline in 2012. Dr. Krämer was the lead author of the guidelines, which are about to be updated and republished.

The “Oral Health for Patients with Epidermolysis Bullosa – Best Clinical Practice Guidelines” (Int J Paediatr Dent. 2012;22 Suppl 1:1-35) are in the final stages of being revised, said Dr. Krämer, who is head of the department of pediatric dentistry at the University of Chile in Santiago. Although there is not much new evidence since the guidelines were first published, “we do have a lot of new technologies within dentistry that can aid the care of EB,” she said.

LONDON – Preventive oral health should be high on the agenda when managing babies and children with dystrophic epidermolysis bullosa (DEB), pediatric dentist Susanne Krämer told attendees at the first EB World Congress.

Sara Freeman/MDedge News

While it may not be the first thing on the minds of families coming to terms with their children having a chronic and potentially debilitating skin disease, it is important to consider oral health early to ensure healthy dentition and mouth function, both of which will affect the ability to eat and thus nutrition.

When there are a lot of other health issues, “dentistry is not a priority,” Dr. Krämer acknowledged in an interview at the meeting, organized by the Dystrophic Epidermolysis Bullosa Association (DEBRA). 

Something as simple as brushing teeth can be very distressing for parents of a child with EB, she observed, especially if there is dysphagia and toothpaste may be getting into the airways accidentally.

Oral health was one of the topics that patients with EB and their families said would be good to have some guidance on when they were surveyed by DEBRA International. This led the charity to develop its first clinical practice guideline in 2012. Dr. Krämer was the lead author of the guidelines, which are about to be updated and republished.

The “Oral Health for Patients with Epidermolysis Bullosa – Best Clinical Practice Guidelines” (Int J Paediatr Dent. 2012;22 Suppl 1:1-35) are in the final stages of being revised, said Dr. Krämer, who is head of the department of pediatric dentistry at the University of Chile in Santiago. Although there is not much new evidence since the guidelines were first published, “we do have a lot of new technologies within dentistry that can aid the care of EB,” she said.

LONDON – Hardened feet are a major determinant of the clinical course of epidermolysis bullosa simplex (EBS), according to research presented by a German team of investigators at the EB World Congress.

In a study of 157 individuals with EBS, 75.8% had plantar keratoderma, a condition associated with a vicious circle of pain, reduced mobility, subsequent weight gain, and further foot problems.

“EBS has severe impacts on various aspects of everyday life,” Antonia Reimer, MD, and associates at the University of Freiburg, Germany, reported in a poster presentation. “Plantar involvement and [plantar keratoderma] are serious complications of all EBS subtypes, correlating with excessive weight gain, pain, local infections, and limited mobility.”

The researchers suggested that “targeting [plantar keratoderma] should be a priority in EBS therapy and research.”

In their retrospective cohort study, clinical and molecular data were retrieved from patient records, and major determinants of the clinical course of EBS investigated. As such, the researchers looked at how weight changes affected EBS, the effect of hardening skin on the feet, pain, mobility, and working life.

“EB simplex is generally regarded as the ‘mildest’ EB type,” Dr. Reimer and colleagues wrote, “however, individuals with EBS report a high disease burden and frequent pain.” The team found that just under 30% of patients (n = 46) experienced frequent pain, particularly those with localized and severe EBS. Of the patients experiencing pain, the majority (75.2%) had plantar keratoderma. Furthermore, those with blisters underneath the hardened skin reported having the most painful lesions.

Palmoplantar hyperhidrosis was present in slightly more than 40% of cases, and was especially common in individuals with localized EBS, Dr. Reimer and colleagues found. They also found that bacterial and fungal infections occurred in 14% and 7% of patients, respectively, and this correlated significantly with diffuse plantar keratoderma.

A third of patients experience mobility problems, and 8.2% required a wheelchair; 16.4% “were in occupational disability,” the team reported.

“Hyperkeratosis is important because it isn’t just about treating the hyperkeratosis, it’s also looking at the mechanical balance of the foot,” Tariq Khan, PhD, said during an unrelated oral presentation. Dr. Khan, a consultant podiatrist specializing in EB at Great Ormond Street Hospital NHS Foundation Trust in London, discussed how to best manage the feet of people with EB.

“Podiatry technology and how we treat can often be detrimental to an EB patient,” Dr. Khan cautioned at the meeting, which was organized by the Dystrophic Epidermolysis Bullosa Association (DEBRA).

For example, “certain devices, certain types of material, will add more friction and pressure and cause more blistering,” he added, making treatment challenging.

SOURCES: EB 2020. Reimer A et al. Poster 26; Khan T. oral presentation; O’Sullivan M et al. Poster 93; Hubbard L. Poster 19.

LONDON – Hardened feet are a major determinant of the clinical course of epidermolysis bullosa simplex (EBS), according to research presented by a German team of investigators at the EB World Congress.

In a study of 157 individuals with EBS, 75.8% had plantar keratoderma, a condition associated with a vicious circle of pain, reduced mobility, subsequent weight gain, and further foot problems.

“EBS has severe impacts on various aspects of everyday life,” Antonia Reimer, MD, and associates at the University of Freiburg, Germany, reported in a poster presentation. “Plantar involvement and [plantar keratoderma] are serious complications of all EBS subtypes, correlating with excessive weight gain, pain, local infections, and limited mobility.”

The researchers suggested that “targeting [plantar keratoderma] should be a priority in EBS therapy and research.”

In their retrospective cohort study, clinical and molecular data were retrieved from patient records, and major determinants of the clinical course of EBS investigated. As such, the researchers looked at how weight changes affected EBS, the effect of hardening skin on the feet, pain, mobility, and working life.

“EB simplex is generally regarded as the ‘mildest’ EB type,” Dr. Reimer and colleagues wrote, “however, individuals with EBS report a high disease burden and frequent pain.” The team found that just under 30% of patients (n = 46) experienced frequent pain, particularly those with localized and severe EBS. Of the patients experiencing pain, the majority (75.2%) had plantar keratoderma. Furthermore, those with blisters underneath the hardened skin reported having the most painful lesions.

Palmoplantar hyperhidrosis was present in slightly more than 40% of cases, and was especially common in individuals with localized EBS, Dr. Reimer and colleagues found. They also found that bacterial and fungal infections occurred in 14% and 7% of patients, respectively, and this correlated significantly with diffuse plantar keratoderma.

A third of patients experience mobility problems, and 8.2% required a wheelchair; 16.4% “were in occupational disability,” the team reported.

“Hyperkeratosis is important because it isn’t just about treating the hyperkeratosis, it’s also looking at the mechanical balance of the foot,” Tariq Khan, PhD, said during an unrelated oral presentation. Dr. Khan, a consultant podiatrist specializing in EB at Great Ormond Street Hospital NHS Foundation Trust in London, discussed how to best manage the feet of people with EB.

“Podiatry technology and how we treat can often be detrimental to an EB patient,” Dr. Khan cautioned at the meeting, which was organized by the Dystrophic Epidermolysis Bullosa Association (DEBRA).

For example, “certain devices, certain types of material, will add more friction and pressure and cause more blistering,” he added, making treatment challenging.

SOURCES: EB 2020. Reimer A et al. Poster 26; Khan T. oral presentation; O’Sullivan M et al. Poster 93; Hubbard L. Poster 19.

LONDON – Hardened feet are a major determinant of the clinical course of epidermolysis bullosa simplex (EBS), according to research presented by a German team of investigators at the EB World Congress.

In a study of 157 individuals with EBS, 75.8% had plantar keratoderma, a condition associated with a vicious circle of pain, reduced mobility, subsequent weight gain, and further foot problems.

“EBS has severe impacts on various aspects of everyday life,” Antonia Reimer, MD, and associates at the University of Freiburg, Germany, reported in a poster presentation. “Plantar involvement and [plantar keratoderma] are serious complications of all EBS subtypes, correlating with excessive weight gain, pain, local infections, and limited mobility.”

The researchers suggested that “targeting [plantar keratoderma] should be a priority in EBS therapy and research.”

In their retrospective cohort study, clinical and molecular data were retrieved from patient records, and major determinants of the clinical course of EBS investigated. As such, the researchers looked at how weight changes affected EBS, the effect of hardening skin on the feet, pain, mobility, and working life.

“EB simplex is generally regarded as the ‘mildest’ EB type,” Dr. Reimer and colleagues wrote, “however, individuals with EBS report a high disease burden and frequent pain.” The team found that just under 30% of patients (n = 46) experienced frequent pain, particularly those with localized and severe EBS. Of the patients experiencing pain, the majority (75.2%) had plantar keratoderma. Furthermore, those with blisters underneath the hardened skin reported having the most painful lesions.

Palmoplantar hyperhidrosis was present in slightly more than 40% of cases, and was especially common in individuals with localized EBS, Dr. Reimer and colleagues found. They also found that bacterial and fungal infections occurred in 14% and 7% of patients, respectively, and this correlated significantly with diffuse plantar keratoderma.

A third of patients experience mobility problems, and 8.2% required a wheelchair; 16.4% “were in occupational disability,” the team reported.

“Hyperkeratosis is important because it isn’t just about treating the hyperkeratosis, it’s also looking at the mechanical balance of the foot,” Tariq Khan, PhD, said during an unrelated oral presentation. Dr. Khan, a consultant podiatrist specializing in EB at Great Ormond Street Hospital NHS Foundation Trust in London, discussed how to best manage the feet of people with EB.

“Podiatry technology and how we treat can often be detrimental to an EB patient,” Dr. Khan cautioned at the meeting, which was organized by the Dystrophic Epidermolysis Bullosa Association (DEBRA).

For example, “certain devices, certain types of material, will add more friction and pressure and cause more blistering,” he added, making treatment challenging.

SOURCES: EB 2020. Reimer A et al. Poster 26; Khan T. oral presentation; O’Sullivan M et al. Poster 93; Hubbard L. Poster 19.

London – A predictable course of hand contracture was seen in a U.K. study of children with recessive dystrophic epidermolysis bullosa (RDEB), with all children experiencing moderate or severe hand deformity by the age of 12 years.

Sara Freeman/MDedge News

This stark finding, reported at the EB World Congress, organized by the Dystrophic Epidermolysis Bullosa Association (DEBRA), highlighted the importance of intervening early with surgical methods that aim to prevent the pseudosyndactyly, or “mitten” hand deformity, which is an unfortunate characteristic of the genetic skin condition.

The investigative team, from the plastic and reconstructive surgery department at Great Ormond Street Hospital for Children NHS Trust, London, presented data from a retrospective case review of 24 children who attended their specialist pediatric EB center between 2010 and 2019. Of these, seven children had surgery to release hand contractures.

A total of 250 hand assessments were made via the novel Assessment of the Component Hand Contractures in Epidermolysis Bullosa (ACE). The assessment provides a hand deformity grade (HDG) – none, mild, moderate, and severe –based on the typical contractures that are seen in RDEB, such as between the fingers (web space contractures), finger flexion contractures, and thumb adduction contractures.

Using the ACE tool, “we found four significant time points regarding hand contracture development,” Catherine Miller, one of the team’s occupational therapists, said during a poster presentation. At birth, none of the children had any signs of hand deformity, but by 2 years of age half had mild hand contracture. By age 6, all children had some form of hand deformity, Ms. Miller said, and by age 12 all had moderate to severe hand deformity, “so adding to the data that hand deformities really are inevitable.”

Other findings were that the thumb and finger web spaces were the first to contract, Ms. Miller said. “So they tend to develop earlier and progress relatively slowly.” By contrast the finger flexion contractures occurred later on, “but progress more relatively rapidly,” she observed.

“Our data are limited as not every child is included at every age, and out tool has not yet been validated,” Ms. Miller and team acknowledged in the poster. “We assume that hand contractures do not improve, and therefore have included operated hands (mean age 6 years) at their last preoperative HDG in order to represent older children and more advanced hand deformities.”

In an interview, Ms. Miller noted that families have a lot going on when their newborn is diagnosed with RDEB, so introducing the idea that there will be substantial hand deformities in the future “is a difficult conversation. We have to take that gently.”

There are nonsurgical approaches to keeping the hands open, such as “encouraging them to open their hands in play, daily stretches; we can make splints with a silicon substance and other thermoplastic materials,” Ms. Miller said.

Hand surgery is a ‘blunt tool’

“The primary problem, of course, is the dermal fibrosis that we see that creates scarring and secondary problems,” said Gill Smith, a plastic surgery consultant who works with Ms. Miller at the hospital.

“In an ideal world, you would bandage up [the children] so that they could never injure their hands, but then they couldn’t use them, they couldn’t grow properly, and they could not develop,” Ms. Smith said in an oral presentation about hand surgery in children with RDEB. “You do not want them to get to the secondary stage, because the secondary stage is a real problem – you get all these impairments of hand function – pseudosyndactyly, finger contraction, and first web contracture, and ending up in a ‘mitten’ hand.”

Surgery is a very “crude” and “blunt tool,” Ms. Smith emphasized. Prevention is key, and perhaps in the future gene therapy, mesenchymal stem cells, and the like will mean that there is less need for hand surgery, she intimated. Until then, there are some things that can be done surgically – such as wrapping the hands, using gloves to protect the skin, stretching out the web spaces of the palm, and using splints. “All of these things we are trying to improve all the time, and come up with new ideas.”

The question is when to intervene? Ms. Smith said that in any other type of hand surgery, particularly in children where growth and function might be affected, the aim would be to “go in early.” In children with RDEB, however, the timing is not so clear: “Should we be going in early, before secondary joint changes, before we get secondary tendon shortening?” Perhaps this would result in less complex surgery, she suggested, but “it is a really huge deal for families and for children. For the moment we are still only really doing it when there [are] quite significant functional difficulties.”

When it comes to the type of surgery done to release the hands, “everyone has variants on the release technique,” but none are known to be better than any other, Ms. Smith said. Surgical release deals with consequences of dermal fibrosis but also creates more fibrosis, she cautioned.

Effects of hand surgery do not last long

How long the surgery’s effect will last is “what everyone wants to know, and I don’t think anyone has found a really good answer. It is variable, but unfortunately it’s a lot shorter than we’d like,” said Ms. Smith.

Indeed, data in another poster presentation by Ms. Smith and colleagues showed that the situation can be ‘back to square one’ within just a couple of years. Of the seven patients who had surgery at a mean 7 years of age (range 6-10 years), “most had returned to their original total score by 2 years post surgery,” the team wrote. All children “were initially happy with both appearance and function after surgery” they added; however, “happiness gradually decreased with time as they lost function and their scores increased with recurrence of contracture.”

The team noted that “sometimes after surgery a different component of the hand contracture worsened but function was preserved.”

While the ACE tool used by the team has not yet been validated, they believe it to be “a systematic tool with a structured method of administration.” As such it can help with informed decision making, they believe, and it could be used with functional measures to see how hand contractures might be impacting hand function and quality of life.

The ACE tool can be downloaded for free from the GOSH website.

SOURCE: Jessop N et al. EB 2020. Posters 42 and 43; Smith G et al. Poster 63.

London – A predictable course of hand contracture was seen in a U.K. study of children with recessive dystrophic epidermolysis bullosa (RDEB), with all children experiencing moderate or severe hand deformity by the age of 12 years.

Sara Freeman/MDedge News

This stark finding, reported at the EB World Congress, organized by the Dystrophic Epidermolysis Bullosa Association (DEBRA), highlighted the importance of intervening early with surgical methods that aim to prevent the pseudosyndactyly, or “mitten” hand deformity, which is an unfortunate characteristic of the genetic skin condition.

The investigative team, from the plastic and reconstructive surgery department at Great Ormond Street Hospital for Children NHS Trust, London, presented data from a retrospective case review of 24 children who attended their specialist pediatric EB center between 2010 and 2019. Of these, seven children had surgery to release hand contractures.

A total of 250 hand assessments were made via the novel Assessment of the Component Hand Contractures in Epidermolysis Bullosa (ACE). The assessment provides a hand deformity grade (HDG) – none, mild, moderate, and severe –based on the typical contractures that are seen in RDEB, such as between the fingers (web space contractures), finger flexion contractures, and thumb adduction contractures.

Using the ACE tool, “we found four significant time points regarding hand contracture development,” Catherine Miller, one of the team’s occupational therapists, said during a poster presentation. At birth, none of the children had any signs of hand deformity, but by 2 years of age half had mild hand contracture. By age 6, all children had some form of hand deformity, Ms. Miller said, and by age 12 all had moderate to severe hand deformity, “so adding to the data that hand deformities really are inevitable.”

Other findings were that the thumb and finger web spaces were the first to contract, Ms. Miller said. “So they tend to develop earlier and progress relatively slowly.” By contrast the finger flexion contractures occurred later on, “but progress more relatively rapidly,” she observed.

“Our data are limited as not every child is included at every age, and out tool has not yet been validated,” Ms. Miller and team acknowledged in the poster. “We assume that hand contractures do not improve, and therefore have included operated hands (mean age 6 years) at their last preoperative HDG in order to represent older children and more advanced hand deformities.”

In an interview, Ms. Miller noted that families have a lot going on when their newborn is diagnosed with RDEB, so introducing the idea that there will be substantial hand deformities in the future “is a difficult conversation. We have to take that gently.”

There are nonsurgical approaches to keeping the hands open, such as “encouraging them to open their hands in play, daily stretches; we can make splints with a silicon substance and other thermoplastic materials,” Ms. Miller said.

Hand surgery is a ‘blunt tool’

“The primary problem, of course, is the dermal fibrosis that we see that creates scarring and secondary problems,” said Gill Smith, a plastic surgery consultant who works with Ms. Miller at the hospital.

“In an ideal world, you would bandage up [the children] so that they could never injure their hands, but then they couldn’t use them, they couldn’t grow properly, and they could not develop,” Ms. Smith said in an oral presentation about hand surgery in children with RDEB. “You do not want them to get to the secondary stage, because the secondary stage is a real problem – you get all these impairments of hand function – pseudosyndactyly, finger contraction, and first web contracture, and ending up in a ‘mitten’ hand.”

Surgery is a very “crude” and “blunt tool,” Ms. Smith emphasized. Prevention is key, and perhaps in the future gene therapy, mesenchymal stem cells, and the like will mean that there is less need for hand surgery, she intimated. Until then, there are some things that can be done surgically – such as wrapping the hands, using gloves to protect the skin, stretching out the web spaces of the palm, and using splints. “All of these things we are trying to improve all the time, and come up with new ideas.”

The question is when to intervene? Ms. Smith said that in any other type of hand surgery, particularly in children where growth and function might be affected, the aim would be to “go in early.” In children with RDEB, however, the timing is not so clear: “Should we be going in early, before secondary joint changes, before we get secondary tendon shortening?” Perhaps this would result in less complex surgery, she suggested, but “it is a really huge deal for families and for children. For the moment we are still only really doing it when there [are] quite significant functional difficulties.”

When it comes to the type of surgery done to release the hands, “everyone has variants on the release technique,” but none are known to be better than any other, Ms. Smith said. Surgical release deals with consequences of dermal fibrosis but also creates more fibrosis, she cautioned.

Effects of hand surgery do not last long

How long the surgery’s effect will last is “what everyone wants to know, and I don’t think anyone has found a really good answer. It is variable, but unfortunately it’s a lot shorter than we’d like,” said Ms. Smith.

Indeed, data in another poster presentation by Ms. Smith and colleagues showed that the situation can be ‘back to square one’ within just a couple of years. Of the seven patients who had surgery at a mean 7 years of age (range 6-10 years), “most had returned to their original total score by 2 years post surgery,” the team wrote. All children “were initially happy with both appearance and function after surgery” they added; however, “happiness gradually decreased with time as they lost function and their scores increased with recurrence of contracture.”

The team noted that “sometimes after surgery a different component of the hand contracture worsened but function was preserved.”

While the ACE tool used by the team has not yet been validated, they believe it to be “a systematic tool with a structured method of administration.” As such it can help with informed decision making, they believe, and it could be used with functional measures to see how hand contractures might be impacting hand function and quality of life.

The ACE tool can be downloaded for free from the GOSH website.

SOURCE: Jessop N et al. EB 2020. Posters 42 and 43; Smith G et al. Poster 63.

London – A predictable course of hand contracture was seen in a U.K. study of children with recessive dystrophic epidermolysis bullosa (RDEB), with all children experiencing moderate or severe hand deformity by the age of 12 years.

Sara Freeman/MDedge News

This stark finding, reported at the EB World Congress, organized by the Dystrophic Epidermolysis Bullosa Association (DEBRA), highlighted the importance of intervening early with surgical methods that aim to prevent the pseudosyndactyly, or “mitten” hand deformity, which is an unfortunate characteristic of the genetic skin condition.

The investigative team, from the plastic and reconstructive surgery department at Great Ormond Street Hospital for Children NHS Trust, London, presented data from a retrospective case review of 24 children who attended their specialist pediatric EB center between 2010 and 2019. Of these, seven children had surgery to release hand contractures.

A total of 250 hand assessments were made via the novel Assessment of the Component Hand Contractures in Epidermolysis Bullosa (ACE). The assessment provides a hand deformity grade (HDG) – none, mild, moderate, and severe –based on the typical contractures that are seen in RDEB, such as between the fingers (web space contractures), finger flexion contractures, and thumb adduction contractures.

Using the ACE tool, “we found four significant time points regarding hand contracture development,” Catherine Miller, one of the team’s occupational therapists, said during a poster presentation. At birth, none of the children had any signs of hand deformity, but by 2 years of age half had mild hand contracture. By age 6, all children had some form of hand deformity, Ms. Miller said, and by age 12 all had moderate to severe hand deformity, “so adding to the data that hand deformities really are inevitable.”

Other findings were that the thumb and finger web spaces were the first to contract, Ms. Miller said. “So they tend to develop earlier and progress relatively slowly.” By contrast the finger flexion contractures occurred later on, “but progress more relatively rapidly,” she observed.

“Our data are limited as not every child is included at every age, and out tool has not yet been validated,” Ms. Miller and team acknowledged in the poster. “We assume that hand contractures do not improve, and therefore have included operated hands (mean age 6 years) at their last preoperative HDG in order to represent older children and more advanced hand deformities.”

In an interview, Ms. Miller noted that families have a lot going on when their newborn is diagnosed with RDEB, so introducing the idea that there will be substantial hand deformities in the future “is a difficult conversation. We have to take that gently.”

There are nonsurgical approaches to keeping the hands open, such as “encouraging them to open their hands in play, daily stretches; we can make splints with a silicon substance and other thermoplastic materials,” Ms. Miller said.

Hand surgery is a ‘blunt tool’

“The primary problem, of course, is the dermal fibrosis that we see that creates scarring and secondary problems,” said Gill Smith, a plastic surgery consultant who works with Ms. Miller at the hospital.

“In an ideal world, you would bandage up [the children] so that they could never injure their hands, but then they couldn’t use them, they couldn’t grow properly, and they could not develop,” Ms. Smith said in an oral presentation about hand surgery in children with RDEB. “You do not want them to get to the secondary stage, because the secondary stage is a real problem – you get all these impairments of hand function – pseudosyndactyly, finger contraction, and first web contracture, and ending up in a ‘mitten’ hand.”

Surgery is a very “crude” and “blunt tool,” Ms. Smith emphasized. Prevention is key, and perhaps in the future gene therapy, mesenchymal stem cells, and the like will mean that there is less need for hand surgery, she intimated. Until then, there are some things that can be done surgically – such as wrapping the hands, using gloves to protect the skin, stretching out the web spaces of the palm, and using splints. “All of these things we are trying to improve all the time, and come up with new ideas.”

The question is when to intervene? Ms. Smith said that in any other type of hand surgery, particularly in children where growth and function might be affected, the aim would be to “go in early.” In children with RDEB, however, the timing is not so clear: “Should we be going in early, before secondary joint changes, before we get secondary tendon shortening?” Perhaps this would result in less complex surgery, she suggested, but “it is a really huge deal for families and for children. For the moment we are still only really doing it when there [are] quite significant functional difficulties.”

When it comes to the type of surgery done to release the hands, “everyone has variants on the release technique,” but none are known to be better than any other, Ms. Smith said. Surgical release deals with consequences of dermal fibrosis but also creates more fibrosis, she cautioned.

Effects of hand surgery do not last long

How long the surgery’s effect will last is “what everyone wants to know, and I don’t think anyone has found a really good answer. It is variable, but unfortunately it’s a lot shorter than we’d like,” said Ms. Smith.

Indeed, data in another poster presentation by Ms. Smith and colleagues showed that the situation can be ‘back to square one’ within just a couple of years. Of the seven patients who had surgery at a mean 7 years of age (range 6-10 years), “most had returned to their original total score by 2 years post surgery,” the team wrote. All children “were initially happy with both appearance and function after surgery” they added; however, “happiness gradually decreased with time as they lost function and their scores increased with recurrence of contracture.”

The team noted that “sometimes after surgery a different component of the hand contracture worsened but function was preserved.”

While the ACE tool used by the team has not yet been validated, they believe it to be “a systematic tool with a structured method of administration.” As such it can help with informed decision making, they believe, and it could be used with functional measures to see how hand contractures might be impacting hand function and quality of life.

The ACE tool can be downloaded for free from the GOSH website.

SOURCE: Jessop N et al. EB 2020. Posters 42 and 43; Smith G et al. Poster 63.