Federal Practitioner

Disruptions caused by the COVID-19 pandemic led to an estimated 619 missed cases of colorectal cancer (CRC) diagnoses among US veterans, and those whose cases were caught had larger tumors and more malignant bowel obstructions compared with a prepandemic period, a new longitudinal study finds.

The decline in diagnoses during the pandemic (March 2020-October 2023) represented a 5% decrease in anticipated cases compared with the prepandemic period (January 2017-February 2020) reported Veterans Health Administration (VHA) researchers in the Journal of Gastrointestinal Surgery.

Meanwhile, the percentage of cancers > 4 cm increased from 48.9% to 57.3% from the prepandemic to pandemic periods, and the percentage of patients with malignant bowel obstructions at presentation nearly doubled from 2.7% to 5.3%. 

“The COVID-19 pandemic resulted in a significant initial decrease in rates of colon cancer diagnosis, with a slow return to baseline,” Louise Davies, MD, MS, a head-and-neck surgeon at the University of Wisconsin-Madison and senior author of the study told Federal Practitioner. “The length of time it took for things to return to normal surprised us. Patterns of detection did not return to more normal baselines until 2023.”

The Pandemic’s Toll on Colonoscopies

While mortality and diagnosis rates have fallen significantly over the past 3 decades, an estimated 158,850 colorectal cancer cases will be diagnosed in the US in 2026, and 55,230 patients will die. Within the VHA, an estimated 4000 new cases of colorectal cancer are diagnosed annually. 

The pandemic disrupted medical care across the board, and colonoscopies were no exceptions. “There are various estimates that there were anywhere from 2 to 3 million missed exams,” said Timothy Pawlik, MD, PhD, MBA, MPH, a surgical oncologist and professor at The Ohio State University Wexner Medical Center, in an interview. 

“At the height of the pandemic, all nonurgent procedures were put on hold,” explained Pawlik, who was not involved in the new study. “I suspect that a number of procedures were missed because different institutions and GI practices simply weren't providing that service at that time. In addition, I'm sure there was some reticence among patients to seek care even after the procedures were restarted and reoffered, especially at a hospital.”

Inside the VHA Data

The researchers found that 22,256 VHA patients were diagnosed with CRC during the study period (mean age, 71 years; 95.6% male; 72.1% White, 19.3% Black, and 6.4% Hispanic). 

In a subset of 1087 patients, the percentage with an American Society of Anesthesiologists class ≥ 3 rose from 74.4% before the pandemic to 78.9% during it. 

In light of the study findings, “clinicians should encourage their eligible patients to get screened for colon cancer, especially if they delayed screening as a result of the pandemic,” Davies said. 

Why Colonoscopy Delays Matter

Pawlik, the Ohio State University Wexner Medical Center surgical oncologist, said even small delays in colonoscopies can be important. 

“There are data suggesting that even a delay beyond 6 to 12 months can significantly increase the risk of advanced-stage cancer. Longer delays of a year, which were associated with the pandemic, definitely increase the risk of presenting with later stages of disease and potentially have a meaningful impact on your prognosis and survival.”

However, he noted that the study findings are limited because the results don’t clarify when patients were due for colonoscopies. 

Still, in the big picture, the research “emphasizes the importance of timely colonoscopy compliance with national guidelines for screening of colon cancer,” he said. 

Lessons About At-Home Tests

Pawlik added that the research also highlights that in times of limited access such as pandemics, there can be value to pivoting to home-based screening methods.

Study coauthor Douglas Robertson, MD, MPH, national deputy director of the Colorectal Cancer Screening Program with the US Department of Veterans Affairs National Gastroenterology and Hepatology Program, said the pandemic spurred a shift toward fecal immunochemical testing (FIT) via mail. 

The VA is now mailing > 40,000 FIT tests per month to veterans. “This program was an outgrowth of and response to the pandemic and would enhance VA’s readiness to maintain CRC screening efforts should something similar occur in the future,” Robertson said in an interview.

The Department of Veterans Affairs funded the study. Davies, Robertson, and the other study authors have no disclosures. Pawlik is co-editor-in-chief of the Journal of Gastrointestinal Surgery and has no other disclosures. 

Disruptions caused by the COVID-19 pandemic led to an estimated 619 missed cases of colorectal cancer (CRC) diagnoses among US veterans, and those whose cases were caught had larger tumors and more malignant bowel obstructions compared with a prepandemic period, a new longitudinal study finds.

The decline in diagnoses during the pandemic (March 2020-October 2023) represented a 5% decrease in anticipated cases compared with the prepandemic period (January 2017-February 2020) reported Veterans Health Administration (VHA) researchers in the Journal of Gastrointestinal Surgery.

Meanwhile, the percentage of cancers > 4 cm increased from 48.9% to 57.3% from the prepandemic to pandemic periods, and the percentage of patients with malignant bowel obstructions at presentation nearly doubled from 2.7% to 5.3%. 

“The COVID-19 pandemic resulted in a significant initial decrease in rates of colon cancer diagnosis, with a slow return to baseline,” Louise Davies, MD, MS, a head-and-neck surgeon at the University of Wisconsin-Madison and senior author of the study told Federal Practitioner. “The length of time it took for things to return to normal surprised us. Patterns of detection did not return to more normal baselines until 2023.”

The Pandemic’s Toll on Colonoscopies

While mortality and diagnosis rates have fallen significantly over the past 3 decades, an estimated 158,850 colorectal cancer cases will be diagnosed in the US in 2026, and 55,230 patients will die. Within the VHA, an estimated 4000 new cases of colorectal cancer are diagnosed annually. 

The pandemic disrupted medical care across the board, and colonoscopies were no exceptions. “There are various estimates that there were anywhere from 2 to 3 million missed exams,” said Timothy Pawlik, MD, PhD, MBA, MPH, a surgical oncologist and professor at The Ohio State University Wexner Medical Center, in an interview. 

“At the height of the pandemic, all nonurgent procedures were put on hold,” explained Pawlik, who was not involved in the new study. “I suspect that a number of procedures were missed because different institutions and GI practices simply weren't providing that service at that time. In addition, I'm sure there was some reticence among patients to seek care even after the procedures were restarted and reoffered, especially at a hospital.”

Inside the VHA Data

The researchers found that 22,256 VHA patients were diagnosed with CRC during the study period (mean age, 71 years; 95.6% male; 72.1% White, 19.3% Black, and 6.4% Hispanic). 

In a subset of 1087 patients, the percentage with an American Society of Anesthesiologists class ≥ 3 rose from 74.4% before the pandemic to 78.9% during it. 

In light of the study findings, “clinicians should encourage their eligible patients to get screened for colon cancer, especially if they delayed screening as a result of the pandemic,” Davies said. 

Why Colonoscopy Delays Matter

Pawlik, the Ohio State University Wexner Medical Center surgical oncologist, said even small delays in colonoscopies can be important. 

“There are data suggesting that even a delay beyond 6 to 12 months can significantly increase the risk of advanced-stage cancer. Longer delays of a year, which were associated with the pandemic, definitely increase the risk of presenting with later stages of disease and potentially have a meaningful impact on your prognosis and survival.”

However, he noted that the study findings are limited because the results don’t clarify when patients were due for colonoscopies. 

Still, in the big picture, the research “emphasizes the importance of timely colonoscopy compliance with national guidelines for screening of colon cancer,” he said. 

Lessons About At-Home Tests

Pawlik added that the research also highlights that in times of limited access such as pandemics, there can be value to pivoting to home-based screening methods.

Study coauthor Douglas Robertson, MD, MPH, national deputy director of the Colorectal Cancer Screening Program with the US Department of Veterans Affairs National Gastroenterology and Hepatology Program, said the pandemic spurred a shift toward fecal immunochemical testing (FIT) via mail. 

The VA is now mailing > 40,000 FIT tests per month to veterans. “This program was an outgrowth of and response to the pandemic and would enhance VA’s readiness to maintain CRC screening efforts should something similar occur in the future,” Robertson said in an interview.

The Department of Veterans Affairs funded the study. Davies, Robertson, and the other study authors have no disclosures. Pawlik is co-editor-in-chief of the Journal of Gastrointestinal Surgery and has no other disclosures. 

Disruptions caused by the COVID-19 pandemic led to an estimated 619 missed cases of colorectal cancer (CRC) diagnoses among US veterans, and those whose cases were caught had larger tumors and more malignant bowel obstructions compared with a prepandemic period, a new longitudinal study finds.

The decline in diagnoses during the pandemic (March 2020-October 2023) represented a 5% decrease in anticipated cases compared with the prepandemic period (January 2017-February 2020) reported Veterans Health Administration (VHA) researchers in the Journal of Gastrointestinal Surgery.

Meanwhile, the percentage of cancers > 4 cm increased from 48.9% to 57.3% from the prepandemic to pandemic periods, and the percentage of patients with malignant bowel obstructions at presentation nearly doubled from 2.7% to 5.3%. 

“The COVID-19 pandemic resulted in a significant initial decrease in rates of colon cancer diagnosis, with a slow return to baseline,” Louise Davies, MD, MS, a head-and-neck surgeon at the University of Wisconsin-Madison and senior author of the study told Federal Practitioner. “The length of time it took for things to return to normal surprised us. Patterns of detection did not return to more normal baselines until 2023.”

The Pandemic’s Toll on Colonoscopies

While mortality and diagnosis rates have fallen significantly over the past 3 decades, an estimated 158,850 colorectal cancer cases will be diagnosed in the US in 2026, and 55,230 patients will die. Within the VHA, an estimated 4000 new cases of colorectal cancer are diagnosed annually. 

The pandemic disrupted medical care across the board, and colonoscopies were no exceptions. “There are various estimates that there were anywhere from 2 to 3 million missed exams,” said Timothy Pawlik, MD, PhD, MBA, MPH, a surgical oncologist and professor at The Ohio State University Wexner Medical Center, in an interview. 

“At the height of the pandemic, all nonurgent procedures were put on hold,” explained Pawlik, who was not involved in the new study. “I suspect that a number of procedures were missed because different institutions and GI practices simply weren't providing that service at that time. In addition, I'm sure there was some reticence among patients to seek care even after the procedures were restarted and reoffered, especially at a hospital.”

Inside the VHA Data

The researchers found that 22,256 VHA patients were diagnosed with CRC during the study period (mean age, 71 years; 95.6% male; 72.1% White, 19.3% Black, and 6.4% Hispanic). 

In a subset of 1087 patients, the percentage with an American Society of Anesthesiologists class ≥ 3 rose from 74.4% before the pandemic to 78.9% during it. 

In light of the study findings, “clinicians should encourage their eligible patients to get screened for colon cancer, especially if they delayed screening as a result of the pandemic,” Davies said. 

Why Colonoscopy Delays Matter

Pawlik, the Ohio State University Wexner Medical Center surgical oncologist, said even small delays in colonoscopies can be important. 

“There are data suggesting that even a delay beyond 6 to 12 months can significantly increase the risk of advanced-stage cancer. Longer delays of a year, which were associated with the pandemic, definitely increase the risk of presenting with later stages of disease and potentially have a meaningful impact on your prognosis and survival.”

However, he noted that the study findings are limited because the results don’t clarify when patients were due for colonoscopies. 

Still, in the big picture, the research “emphasizes the importance of timely colonoscopy compliance with national guidelines for screening of colon cancer,” he said. 

Lessons About At-Home Tests

Pawlik added that the research also highlights that in times of limited access such as pandemics, there can be value to pivoting to home-based screening methods.

Study coauthor Douglas Robertson, MD, MPH, national deputy director of the Colorectal Cancer Screening Program with the US Department of Veterans Affairs National Gastroenterology and Hepatology Program, said the pandemic spurred a shift toward fecal immunochemical testing (FIT) via mail. 

The VA is now mailing > 40,000 FIT tests per month to veterans. “This program was an outgrowth of and response to the pandemic and would enhance VA’s readiness to maintain CRC screening efforts should something similar occur in the future,” Robertson said in an interview.

The Department of Veterans Affairs funded the study. Davies, Robertson, and the other study authors have no disclosures. Pawlik is co-editor-in-chief of the Journal of Gastrointestinal Surgery and has no other disclosures. 

TOPLINE:

In a population-based study, human papillomavirus (HPV) vaccination in England was associated with a 100% reduction in mortality due to cervical cancer between 2020 and 2024 among women aged 20-24 years who were mostly vaccinated at the age of 12-13 years.

METHODOLOGY:

• Researchers conducted a population-based study using cervical cancer mortality data of women aged 20-24, 25-29, and 30-34 years from the National Disease Registration Service and Office for National Statistics in England from 2000 to 2024.
• The analysis included women from the first eligible birth cohort (born from September 1990 to August 1991) who were targeted by England's school-based HPV vaccination programme introduced in September 2008 for girls aged 12-13 years, with a catch-up programme for girls aged 14-18 years implemented in 2008-2010.
• HPV vaccination coverage by birth cohort was obtained from annual reports of the UK Health Security Agency and used to estimate the proportion of women vaccinated for each age group and calendar year.
• The relative risk reduction (RRR) in mortality among vaccinated women compared with expected rates in the absence of vaccination, assuming no herd immunity, was evaluated.

TAKEAWAY:

• Among women aged 20-24 years between 2020 and 2024 with approximately 88%-91% vaccination coverage, no deaths occurred compared with 23.1 expected deaths on the basis of the observed average rate from 2000 to 2014, corresponding to a reduction in mortality of 100% (95% CI, 84%-100%).
• Among vaccinated women, the RRR in mortality due to cervical cancer was estimated at 100% (P = .0008) in those aged 20-24 years, 100% (P < .0001) in those aged 25-29 years, and 63% (P = .094) in those aged 30-34 years.
• Mortality reductions of 80% (95% CI, 51%-94%) were observed in women aged 20-24 years during 2015-2019 and 69% (95% CI, 55%-79%) were observed in those aged 25-29 years during 2020-2024.
• Up until the end of 2024, the HPV vaccination programme in England was associated with a reduction of approximately 199.6 deaths due to cervical cancer (95% CI, 125.0-274.2) among cohorts offered vaccination.

IN PRACTICE:

The authors concluded that "we found a substantial reduction in cervical cancer mortality in women aged 20-29 years that was associated with high uptake of HPV vaccination." "This observation further supports the benefit of HPV vaccination in reducing not only the incidence of but also the mortality from a cancer that is globally still the second most common cause of cancer death in women younger than 65 years," they added. SOURCE: The study was led by Peter Sasieni, PhD, Centre for Cancer Screening, Prevention and Early Diagnosis, Wolfson Institute of Population Health, Queen Mary University of London, London, England. It was published online on June 17, 2026, in The Lancet.

LIMITATIONS:

The analysis relied on population-level vaccination coverage data instead of individual-level status; the researchers had access to mortality data in 5-year age groups only rather than single-year cohorts, and the study assumed no herd protection among unvaccinated women within birth cohorts.

DISCLOSURES:

The study was funded by the Cancer Research UK. One author reported serving as a lead investigator of a trial examining the HPV vaccine Gardasil 9 that was partially supported by a research grant from the Investigator-Initiated Studies Program of Merck Sharp & Dohme. Additional disclosures are listed in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article first appeared on Medscape.com.

TOPLINE:

In a population-based study, human papillomavirus (HPV) vaccination in England was associated with a 100% reduction in mortality due to cervical cancer between 2020 and 2024 among women aged 20-24 years who were mostly vaccinated at the age of 12-13 years.

METHODOLOGY:

• Researchers conducted a population-based study using cervical cancer mortality data of women aged 20-24, 25-29, and 30-34 years from the National Disease Registration Service and Office for National Statistics in England from 2000 to 2024.
• The analysis included women from the first eligible birth cohort (born from September 1990 to August 1991) who were targeted by England's school-based HPV vaccination programme introduced in September 2008 for girls aged 12-13 years, with a catch-up programme for girls aged 14-18 years implemented in 2008-2010.
• HPV vaccination coverage by birth cohort was obtained from annual reports of the UK Health Security Agency and used to estimate the proportion of women vaccinated for each age group and calendar year.
• The relative risk reduction (RRR) in mortality among vaccinated women compared with expected rates in the absence of vaccination, assuming no herd immunity, was evaluated.

TAKEAWAY:

• Among women aged 20-24 years between 2020 and 2024 with approximately 88%-91% vaccination coverage, no deaths occurred compared with 23.1 expected deaths on the basis of the observed average rate from 2000 to 2014, corresponding to a reduction in mortality of 100% (95% CI, 84%-100%).
• Among vaccinated women, the RRR in mortality due to cervical cancer was estimated at 100% (P = .0008) in those aged 20-24 years, 100% (P < .0001) in those aged 25-29 years, and 63% (P = .094) in those aged 30-34 years.
• Mortality reductions of 80% (95% CI, 51%-94%) were observed in women aged 20-24 years during 2015-2019 and 69% (95% CI, 55%-79%) were observed in those aged 25-29 years during 2020-2024.
• Up until the end of 2024, the HPV vaccination programme in England was associated with a reduction of approximately 199.6 deaths due to cervical cancer (95% CI, 125.0-274.2) among cohorts offered vaccination.

IN PRACTICE:

The authors concluded that "we found a substantial reduction in cervical cancer mortality in women aged 20-29 years that was associated with high uptake of HPV vaccination." "This observation further supports the benefit of HPV vaccination in reducing not only the incidence of but also the mortality from a cancer that is globally still the second most common cause of cancer death in women younger than 65 years," they added. SOURCE: The study was led by Peter Sasieni, PhD, Centre for Cancer Screening, Prevention and Early Diagnosis, Wolfson Institute of Population Health, Queen Mary University of London, London, England. It was published online on June 17, 2026, in The Lancet.

LIMITATIONS:

The analysis relied on population-level vaccination coverage data instead of individual-level status; the researchers had access to mortality data in 5-year age groups only rather than single-year cohorts, and the study assumed no herd protection among unvaccinated women within birth cohorts.

DISCLOSURES:

The study was funded by the Cancer Research UK. One author reported serving as a lead investigator of a trial examining the HPV vaccine Gardasil 9 that was partially supported by a research grant from the Investigator-Initiated Studies Program of Merck Sharp & Dohme. Additional disclosures are listed in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article first appeared on Medscape.com.

TOPLINE:

In a population-based study, human papillomavirus (HPV) vaccination in England was associated with a 100% reduction in mortality due to cervical cancer between 2020 and 2024 among women aged 20-24 years who were mostly vaccinated at the age of 12-13 years.

METHODOLOGY:

• Researchers conducted a population-based study using cervical cancer mortality data of women aged 20-24, 25-29, and 30-34 years from the National Disease Registration Service and Office for National Statistics in England from 2000 to 2024.
• The analysis included women from the first eligible birth cohort (born from September 1990 to August 1991) who were targeted by England's school-based HPV vaccination programme introduced in September 2008 for girls aged 12-13 years, with a catch-up programme for girls aged 14-18 years implemented in 2008-2010.
• HPV vaccination coverage by birth cohort was obtained from annual reports of the UK Health Security Agency and used to estimate the proportion of women vaccinated for each age group and calendar year.
• The relative risk reduction (RRR) in mortality among vaccinated women compared with expected rates in the absence of vaccination, assuming no herd immunity, was evaluated.

TAKEAWAY:

• Among women aged 20-24 years between 2020 and 2024 with approximately 88%-91% vaccination coverage, no deaths occurred compared with 23.1 expected deaths on the basis of the observed average rate from 2000 to 2014, corresponding to a reduction in mortality of 100% (95% CI, 84%-100%).
• Among vaccinated women, the RRR in mortality due to cervical cancer was estimated at 100% (P = .0008) in those aged 20-24 years, 100% (P < .0001) in those aged 25-29 years, and 63% (P = .094) in those aged 30-34 years.
• Mortality reductions of 80% (95% CI, 51%-94%) were observed in women aged 20-24 years during 2015-2019 and 69% (95% CI, 55%-79%) were observed in those aged 25-29 years during 2020-2024.
• Up until the end of 2024, the HPV vaccination programme in England was associated with a reduction of approximately 199.6 deaths due to cervical cancer (95% CI, 125.0-274.2) among cohorts offered vaccination.

IN PRACTICE:

The authors concluded that "we found a substantial reduction in cervical cancer mortality in women aged 20-29 years that was associated with high uptake of HPV vaccination." "This observation further supports the benefit of HPV vaccination in reducing not only the incidence of but also the mortality from a cancer that is globally still the second most common cause of cancer death in women younger than 65 years," they added. SOURCE: The study was led by Peter Sasieni, PhD, Centre for Cancer Screening, Prevention and Early Diagnosis, Wolfson Institute of Population Health, Queen Mary University of London, London, England. It was published online on June 17, 2026, in The Lancet.

LIMITATIONS:

The analysis relied on population-level vaccination coverage data instead of individual-level status; the researchers had access to mortality data in 5-year age groups only rather than single-year cohorts, and the study assumed no herd protection among unvaccinated women within birth cohorts.

DISCLOSURES:

The study was funded by the Cancer Research UK. One author reported serving as a lead investigator of a trial examining the HPV vaccine Gardasil 9 that was partially supported by a research grant from the Investigator-Initiated Studies Program of Merck Sharp & Dohme. Additional disclosures are listed in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article first appeared on Medscape.com.

Rapid-growing nontuberculous mycobacteria (NTM) were strongly associated with death or retransplantation in adult lung transplant patients, based on data from a new study of about 1000 individuals.

NTM are ubiquitous environmental organisms, but the clinical significance of isolating NTM posttransplant remains poorly defined, and previous studies have been mainly small and single center, said lead author Gabrielle Mezochow, MD, a pulmonology and critical care fellow at the University of Pennsylvania in Philadelphia.

“This is important because treatment is particularly challenging in lung transplant recipients, requiring prolonged multidrug regimens that can be toxic and interact with immunosuppression,” Mezochow said. “We conducted this study to better understand how often NTM is isolated after lung transplant, and whether isolation is associated with important outcomes such as chronic lung allograft dysfunction (CLAD) and death or retransplantation in a large multicenter cohort,” she said.

In the study, presented at the annual meeting of the International Society for Heart and Lung Transplantation (ISHLT), Mezochow et al reviewed data from 1044 adult lung transplant recipients in the Lung Transplant Outcomes Group cohort who underwent transplant between 2007 and 2022 at 3 centers.

The researchers evaluated the time from transplantation to graft failure (defined as death or retransplantation) and CLAD (as defined by the ISHLT). They used a proportional hazards model adjusted for age, diagnosis, BMI, primary graft dysfunction, postoperative extracorporeal membrane oxygenation, and transplant type.

A total of 136 patients (13%) had pulmonary growth of NTM within a year of their transplants; the most common types were Mycobacterium avium (88 patients) and Mycobacterium abscessus (16 patients).

Overall, the association between early growth of any NTM and the risk for graft failure did not reach statistical significance (adjusted hazard ratio [HR], 1.27). However, patients who had early growth of rapid-growing NTM (including M abscessus, Mycobacterium chelonae, Mycobacterium fortuitum, Mycobacterium immunogenum, Mycobacterium mageritense, and Mycobacterium mucogenicum) had an increased risk for graft failure compared to those with early growth of slow-growing NTM such as M avium (unadjusted HR, 2.36; adjusted HR, 2.49). The associations were consistent when patients with cystic fibrosis were excluded, and no significant association was observed between early NTM growth by slow or rapid types and increased risk for CLAD (adjusted HR, 1.09).

“One of the most interesting findings was that associations differed by NTM species,” Mezochow said. “Rapid-growing NTM were most strongly associated with death or retransplantation, whereas slow-growing NTM appeared to have a stronger association with CLAD,” she said. “We were also intrigued by the stronger associations with negative outcomes observed among recipients with ILD [interstitial lung disease], particularly those undergoing single lung transplantation,” Mezochow noted. “This raises the possibility that characteristics of the native lung or underlying lung disease may influence susceptibility and outcomes,” she said.

“Importantly, our study evaluated NTM isolation rather than NTM pulmonary disease, which is often difficult to define in lung transplant recipients,” said Mezochow. The results suggest that NTM isolation should not be dismissed as a benign microbiologic finding and could serve as an early marker of lung transplant recipients at increased risk for poor outcomes, even before disease can be definitively established, she noted. “Certain subgroups of recipients, including those with specific NTM species or underlying diagnoses, may be at a particularly elevated risk for poor outcomes, while not all patients with NTM isolation are likely to require treatment,” she added.

Limitations and Next Steps

The findings were limited by several factors including the observational design and lack of detailed patient-level medication data including longitudinal immunosuppression, antibiotic exposures, and azithromycin use for bronchiolitis obliterans syndrome prevention, any of which could influence both NTM isolation and downstream outcomes, Mezochow said.

The researchers also were unable to adjudicate NTM pulmonary disease according to current guideline-based definitions because of the lack of longitudinal radiographic and symptom data, she added. “That said, these diagnostic criteria were developed outside the transplant setting and have not been validated in lung transplant recipients, so their applicability here is uncertain,” she added. “Although we focused on the first posttransplant year, when surveillance bronchoscopy is relatively routine, some residual ascertainment bias is still likely,” she noted.

“Future research should focus on identifying which recipients with NTM isolation are most likely to progress to CLAD or death, understanding the biologic mechanisms linking NTM and allograft injury, and determining whether treatment strategies or immunosuppression modifications can improve outcomes,” said Mezochow. “Ultimately, the goal is to develop a framework that helps clinicians distinguish who may benefit from treatment from those who can be safely observed,” she said.

Added Value for Patient Assessment

The current study addresses major questions in lung transplantation, namely, whether isolation of NTM species in the first year after a lung transplant is a marker of airway vulnerability, structural airway defects, patient frailty, or a true contributor to allograft function and failure, said Jacqueline Burnell, MD, an associate professor of clinical medicine at the Lewis Katz School of Medicine at Temple University in Philadelphia, and a specialist in infections in transplant and immunocompromised patients. “This study separated rapidly growing NTM from slow growers to attempt to identify species associated with poor outcomes and provide prognostication,” said Burnell, who was not involved in the study. The association of rapidly growing NTM and poorer outcomes was not surprising, she noted. “Mycobacterium abscessus species, which accounted for the majority of rapidly growing isolates, are thought to be more aggressive and are certainly more challenging to treat,” she said. “The absence of association with CLAD is interesting, as this has been found in other studies looking at NTM infections post-lung transplant,” she added.

The results suggest that rapidly growing NTM should be risk-stratified separately from slow-growing NTM, said Burnell. “Early growth of rapid-growing NTM should prompt careful evaluation and assessment in a multidisciplinary fashion and not be deemed colonization without thorough evaluation,” she said. Routine posttransplant cultures also may have prognostic value in graft failure, she noted.

However, additional research with more granular detail regarding patient characteristics would be useful for risk stratification, said Burnell. “For example, information about pretransplant colonization, type of transplant (single vs double), immunosuppressive regimens, co-infections, and other factors would be useful,” she said. The current study did not address delineation between colonization, transient isolation, and infection, and data on treatment regimens and timing were lacking; therefore, collaborative studies are needed to assess these factors and their relationship to patient outcomes, Burnell noted.

The study was funded by institutional grants from the National Heart, Lung, and Blood Institute. Mezochow and Burnell had no financial conflicts to disclose.

A version of this article first appeared on Medscape.com.

Rapid-growing nontuberculous mycobacteria (NTM) were strongly associated with death or retransplantation in adult lung transplant patients, based on data from a new study of about 1000 individuals.

NTM are ubiquitous environmental organisms, but the clinical significance of isolating NTM posttransplant remains poorly defined, and previous studies have been mainly small and single center, said lead author Gabrielle Mezochow, MD, a pulmonology and critical care fellow at the University of Pennsylvania in Philadelphia.

“This is important because treatment is particularly challenging in lung transplant recipients, requiring prolonged multidrug regimens that can be toxic and interact with immunosuppression,” Mezochow said. “We conducted this study to better understand how often NTM is isolated after lung transplant, and whether isolation is associated with important outcomes such as chronic lung allograft dysfunction (CLAD) and death or retransplantation in a large multicenter cohort,” she said.

In the study, presented at the annual meeting of the International Society for Heart and Lung Transplantation (ISHLT), Mezochow et al reviewed data from 1044 adult lung transplant recipients in the Lung Transplant Outcomes Group cohort who underwent transplant between 2007 and 2022 at 3 centers.

The researchers evaluated the time from transplantation to graft failure (defined as death or retransplantation) and CLAD (as defined by the ISHLT). They used a proportional hazards model adjusted for age, diagnosis, BMI, primary graft dysfunction, postoperative extracorporeal membrane oxygenation, and transplant type.

A total of 136 patients (13%) had pulmonary growth of NTM within a year of their transplants; the most common types were Mycobacterium avium (88 patients) and Mycobacterium abscessus (16 patients).

Overall, the association between early growth of any NTM and the risk for graft failure did not reach statistical significance (adjusted hazard ratio [HR], 1.27). However, patients who had early growth of rapid-growing NTM (including M abscessus, Mycobacterium chelonae, Mycobacterium fortuitum, Mycobacterium immunogenum, Mycobacterium mageritense, and Mycobacterium mucogenicum) had an increased risk for graft failure compared to those with early growth of slow-growing NTM such as M avium (unadjusted HR, 2.36; adjusted HR, 2.49). The associations were consistent when patients with cystic fibrosis were excluded, and no significant association was observed between early NTM growth by slow or rapid types and increased risk for CLAD (adjusted HR, 1.09).

“One of the most interesting findings was that associations differed by NTM species,” Mezochow said. “Rapid-growing NTM were most strongly associated with death or retransplantation, whereas slow-growing NTM appeared to have a stronger association with CLAD,” she said. “We were also intrigued by the stronger associations with negative outcomes observed among recipients with ILD [interstitial lung disease], particularly those undergoing single lung transplantation,” Mezochow noted. “This raises the possibility that characteristics of the native lung or underlying lung disease may influence susceptibility and outcomes,” she said.

“Importantly, our study evaluated NTM isolation rather than NTM pulmonary disease, which is often difficult to define in lung transplant recipients,” said Mezochow. The results suggest that NTM isolation should not be dismissed as a benign microbiologic finding and could serve as an early marker of lung transplant recipients at increased risk for poor outcomes, even before disease can be definitively established, she noted. “Certain subgroups of recipients, including those with specific NTM species or underlying diagnoses, may be at a particularly elevated risk for poor outcomes, while not all patients with NTM isolation are likely to require treatment,” she added.

Limitations and Next Steps

The findings were limited by several factors including the observational design and lack of detailed patient-level medication data including longitudinal immunosuppression, antibiotic exposures, and azithromycin use for bronchiolitis obliterans syndrome prevention, any of which could influence both NTM isolation and downstream outcomes, Mezochow said.

The researchers also were unable to adjudicate NTM pulmonary disease according to current guideline-based definitions because of the lack of longitudinal radiographic and symptom data, she added. “That said, these diagnostic criteria were developed outside the transplant setting and have not been validated in lung transplant recipients, so their applicability here is uncertain,” she added. “Although we focused on the first posttransplant year, when surveillance bronchoscopy is relatively routine, some residual ascertainment bias is still likely,” she noted.

“Future research should focus on identifying which recipients with NTM isolation are most likely to progress to CLAD or death, understanding the biologic mechanisms linking NTM and allograft injury, and determining whether treatment strategies or immunosuppression modifications can improve outcomes,” said Mezochow. “Ultimately, the goal is to develop a framework that helps clinicians distinguish who may benefit from treatment from those who can be safely observed,” she said.

Added Value for Patient Assessment

The current study addresses major questions in lung transplantation, namely, whether isolation of NTM species in the first year after a lung transplant is a marker of airway vulnerability, structural airway defects, patient frailty, or a true contributor to allograft function and failure, said Jacqueline Burnell, MD, an associate professor of clinical medicine at the Lewis Katz School of Medicine at Temple University in Philadelphia, and a specialist in infections in transplant and immunocompromised patients. “This study separated rapidly growing NTM from slow growers to attempt to identify species associated with poor outcomes and provide prognostication,” said Burnell, who was not involved in the study. The association of rapidly growing NTM and poorer outcomes was not surprising, she noted. “Mycobacterium abscessus species, which accounted for the majority of rapidly growing isolates, are thought to be more aggressive and are certainly more challenging to treat,” she said. “The absence of association with CLAD is interesting, as this has been found in other studies looking at NTM infections post-lung transplant,” she added.

The results suggest that rapidly growing NTM should be risk-stratified separately from slow-growing NTM, said Burnell. “Early growth of rapid-growing NTM should prompt careful evaluation and assessment in a multidisciplinary fashion and not be deemed colonization without thorough evaluation,” she said. Routine posttransplant cultures also may have prognostic value in graft failure, she noted.

However, additional research with more granular detail regarding patient characteristics would be useful for risk stratification, said Burnell. “For example, information about pretransplant colonization, type of transplant (single vs double), immunosuppressive regimens, co-infections, and other factors would be useful,” she said. The current study did not address delineation between colonization, transient isolation, and infection, and data on treatment regimens and timing were lacking; therefore, collaborative studies are needed to assess these factors and their relationship to patient outcomes, Burnell noted.

The study was funded by institutional grants from the National Heart, Lung, and Blood Institute. Mezochow and Burnell had no financial conflicts to disclose.

A version of this article first appeared on Medscape.com.

Rapid-growing nontuberculous mycobacteria (NTM) were strongly associated with death or retransplantation in adult lung transplant patients, based on data from a new study of about 1000 individuals.

NTM are ubiquitous environmental organisms, but the clinical significance of isolating NTM posttransplant remains poorly defined, and previous studies have been mainly small and single center, said lead author Gabrielle Mezochow, MD, a pulmonology and critical care fellow at the University of Pennsylvania in Philadelphia.

“This is important because treatment is particularly challenging in lung transplant recipients, requiring prolonged multidrug regimens that can be toxic and interact with immunosuppression,” Mezochow said. “We conducted this study to better understand how often NTM is isolated after lung transplant, and whether isolation is associated with important outcomes such as chronic lung allograft dysfunction (CLAD) and death or retransplantation in a large multicenter cohort,” she said.

In the study, presented at the annual meeting of the International Society for Heart and Lung Transplantation (ISHLT), Mezochow et al reviewed data from 1044 adult lung transplant recipients in the Lung Transplant Outcomes Group cohort who underwent transplant between 2007 and 2022 at 3 centers.

The researchers evaluated the time from transplantation to graft failure (defined as death or retransplantation) and CLAD (as defined by the ISHLT). They used a proportional hazards model adjusted for age, diagnosis, BMI, primary graft dysfunction, postoperative extracorporeal membrane oxygenation, and transplant type.

A total of 136 patients (13%) had pulmonary growth of NTM within a year of their transplants; the most common types were Mycobacterium avium (88 patients) and Mycobacterium abscessus (16 patients).

Overall, the association between early growth of any NTM and the risk for graft failure did not reach statistical significance (adjusted hazard ratio [HR], 1.27). However, patients who had early growth of rapid-growing NTM (including M abscessus, Mycobacterium chelonae, Mycobacterium fortuitum, Mycobacterium immunogenum, Mycobacterium mageritense, and Mycobacterium mucogenicum) had an increased risk for graft failure compared to those with early growth of slow-growing NTM such as M avium (unadjusted HR, 2.36; adjusted HR, 2.49). The associations were consistent when patients with cystic fibrosis were excluded, and no significant association was observed between early NTM growth by slow or rapid types and increased risk for CLAD (adjusted HR, 1.09).

“One of the most interesting findings was that associations differed by NTM species,” Mezochow said. “Rapid-growing NTM were most strongly associated with death or retransplantation, whereas slow-growing NTM appeared to have a stronger association with CLAD,” she said. “We were also intrigued by the stronger associations with negative outcomes observed among recipients with ILD [interstitial lung disease], particularly those undergoing single lung transplantation,” Mezochow noted. “This raises the possibility that characteristics of the native lung or underlying lung disease may influence susceptibility and outcomes,” she said.

“Importantly, our study evaluated NTM isolation rather than NTM pulmonary disease, which is often difficult to define in lung transplant recipients,” said Mezochow. The results suggest that NTM isolation should not be dismissed as a benign microbiologic finding and could serve as an early marker of lung transplant recipients at increased risk for poor outcomes, even before disease can be definitively established, she noted. “Certain subgroups of recipients, including those with specific NTM species or underlying diagnoses, may be at a particularly elevated risk for poor outcomes, while not all patients with NTM isolation are likely to require treatment,” she added.

Limitations and Next Steps

The findings were limited by several factors including the observational design and lack of detailed patient-level medication data including longitudinal immunosuppression, antibiotic exposures, and azithromycin use for bronchiolitis obliterans syndrome prevention, any of which could influence both NTM isolation and downstream outcomes, Mezochow said.

The researchers also were unable to adjudicate NTM pulmonary disease according to current guideline-based definitions because of the lack of longitudinal radiographic and symptom data, she added. “That said, these diagnostic criteria were developed outside the transplant setting and have not been validated in lung transplant recipients, so their applicability here is uncertain,” she added. “Although we focused on the first posttransplant year, when surveillance bronchoscopy is relatively routine, some residual ascertainment bias is still likely,” she noted.

“Future research should focus on identifying which recipients with NTM isolation are most likely to progress to CLAD or death, understanding the biologic mechanisms linking NTM and allograft injury, and determining whether treatment strategies or immunosuppression modifications can improve outcomes,” said Mezochow. “Ultimately, the goal is to develop a framework that helps clinicians distinguish who may benefit from treatment from those who can be safely observed,” she said.

Added Value for Patient Assessment

The current study addresses major questions in lung transplantation, namely, whether isolation of NTM species in the first year after a lung transplant is a marker of airway vulnerability, structural airway defects, patient frailty, or a true contributor to allograft function and failure, said Jacqueline Burnell, MD, an associate professor of clinical medicine at the Lewis Katz School of Medicine at Temple University in Philadelphia, and a specialist in infections in transplant and immunocompromised patients. “This study separated rapidly growing NTM from slow growers to attempt to identify species associated with poor outcomes and provide prognostication,” said Burnell, who was not involved in the study. The association of rapidly growing NTM and poorer outcomes was not surprising, she noted. “Mycobacterium abscessus species, which accounted for the majority of rapidly growing isolates, are thought to be more aggressive and are certainly more challenging to treat,” she said. “The absence of association with CLAD is interesting, as this has been found in other studies looking at NTM infections post-lung transplant,” she added.

The results suggest that rapidly growing NTM should be risk-stratified separately from slow-growing NTM, said Burnell. “Early growth of rapid-growing NTM should prompt careful evaluation and assessment in a multidisciplinary fashion and not be deemed colonization without thorough evaluation,” she said. Routine posttransplant cultures also may have prognostic value in graft failure, she noted.

However, additional research with more granular detail regarding patient characteristics would be useful for risk stratification, said Burnell. “For example, information about pretransplant colonization, type of transplant (single vs double), immunosuppressive regimens, co-infections, and other factors would be useful,” she said. The current study did not address delineation between colonization, transient isolation, and infection, and data on treatment regimens and timing were lacking; therefore, collaborative studies are needed to assess these factors and their relationship to patient outcomes, Burnell noted.

The study was funded by institutional grants from the National Heart, Lung, and Blood Institute. Mezochow and Burnell had no financial conflicts to disclose.

A version of this article first appeared on Medscape.com.

June 24 (Reuters) - The US military has resumed requiring flu vaccines for some service members in an exception to Defense Secretary Pete Hegseth’s guidance declaring the shots voluntary 2 months ago.

The decision follows a flu outbreak among recruits at Joint Base San Antonio-Lackland in Texas and sharp criticism of the policy from public health experts. More than 220 ‌recruits have been diagnosed with influenza and 4 hospitalized in the outbreak, according to media reports.

Hegseth said in April that the annual flu vaccine would become optional for all US military personnel under the Pentagon’s new vaccine policy. It ‌had previously been mandated and considered critical to troop preparedness.

The Under Secretary for War ‌Personnel and Readiness approved exception requests ‌for the Army, Navy, Air Force, National Security Agency, and Defense Health Agency, according to a statement from chief Pentagon spokesperson Sean Parnell on ‌Wednesday.

“The decisions were based upon thorough risk assessments and are designed to maximize operational readiness, lethality, ‌and force generation, while safeguarding at-risk populations,” Parnell said.

Each department is responsible for implementation, the spokesperson added.

The World Health Organization recommends the flu shot for those aged ≥ 6 months.

Trump administration Health Secretary Robert ‌F. ‌Kennedy Jr., a longtime antivaccine activist, has enacted policies that have decreased the use ‌of inoculations in the US, including dropping its 2025 flu vaccine campaign. Kennedy’s Make America Healthy Again movement has sought to weaken school enrollment mandates around the country.

Flu vaccines from Sanofi, CSL Seqirus, GSK and AstraZeneca are approved ‌in the United States.

(Reporting by Idrees Ali, Mariam Sunny and Mrinalika Roy; Editing by Caroline Humer and Bill Berkrot)

A version of this article first appeared on Medscape.com.

June 24 (Reuters) - The US military has resumed requiring flu vaccines for some service members in an exception to Defense Secretary Pete Hegseth’s guidance declaring the shots voluntary 2 months ago.

The decision follows a flu outbreak among recruits at Joint Base San Antonio-Lackland in Texas and sharp criticism of the policy from public health experts. More than 220 ‌recruits have been diagnosed with influenza and 4 hospitalized in the outbreak, according to media reports.

Hegseth said in April that the annual flu vaccine would become optional for all US military personnel under the Pentagon’s new vaccine policy. It ‌had previously been mandated and considered critical to troop preparedness.

The Under Secretary for War ‌Personnel and Readiness approved exception requests ‌for the Army, Navy, Air Force, National Security Agency, and Defense Health Agency, according to a statement from chief Pentagon spokesperson Sean Parnell on ‌Wednesday.

“The decisions were based upon thorough risk assessments and are designed to maximize operational readiness, lethality, ‌and force generation, while safeguarding at-risk populations,” Parnell said.

Each department is responsible for implementation, the spokesperson added.

The World Health Organization recommends the flu shot for those aged ≥ 6 months.

Trump administration Health Secretary Robert ‌F. ‌Kennedy Jr., a longtime antivaccine activist, has enacted policies that have decreased the use ‌of inoculations in the US, including dropping its 2025 flu vaccine campaign. Kennedy’s Make America Healthy Again movement has sought to weaken school enrollment mandates around the country.

Flu vaccines from Sanofi, CSL Seqirus, GSK and AstraZeneca are approved ‌in the United States.

(Reporting by Idrees Ali, Mariam Sunny and Mrinalika Roy; Editing by Caroline Humer and Bill Berkrot)

A version of this article first appeared on Medscape.com.

June 24 (Reuters) - The US military has resumed requiring flu vaccines for some service members in an exception to Defense Secretary Pete Hegseth’s guidance declaring the shots voluntary 2 months ago.

The decision follows a flu outbreak among recruits at Joint Base San Antonio-Lackland in Texas and sharp criticism of the policy from public health experts. More than 220 ‌recruits have been diagnosed with influenza and 4 hospitalized in the outbreak, according to media reports.

Hegseth said in April that the annual flu vaccine would become optional for all US military personnel under the Pentagon’s new vaccine policy. It ‌had previously been mandated and considered critical to troop preparedness.

The Under Secretary for War ‌Personnel and Readiness approved exception requests ‌for the Army, Navy, Air Force, National Security Agency, and Defense Health Agency, according to a statement from chief Pentagon spokesperson Sean Parnell on ‌Wednesday.

“The decisions were based upon thorough risk assessments and are designed to maximize operational readiness, lethality, ‌and force generation, while safeguarding at-risk populations,” Parnell said.

Each department is responsible for implementation, the spokesperson added.

The World Health Organization recommends the flu shot for those aged ≥ 6 months.

Trump administration Health Secretary Robert ‌F. ‌Kennedy Jr., a longtime antivaccine activist, has enacted policies that have decreased the use ‌of inoculations in the US, including dropping its 2025 flu vaccine campaign. Kennedy’s Make America Healthy Again movement has sought to weaken school enrollment mandates around the country.

Flu vaccines from Sanofi, CSL Seqirus, GSK and AstraZeneca are approved ‌in the United States.

(Reporting by Idrees Ali, Mariam Sunny and Mrinalika Roy; Editing by Caroline Humer and Bill Berkrot)

A version of this article first appeared on Medscape.com.

A retrospective cohort study links clomiphene citrate (CC) to significantly lower mortality rates when compared with testosterone replacement therapy (TRT) in male veterans with hypogonadism or infertility. CC is not approved by the US Food and Drug Administration (FDA) for hypogonadism but is often used off label. Patients taking clomiphene also had significantly lower risk of diseases of the circulatory system, brain, and bones. 

The study tracked matched cohorts of 2518 patients taking CC or TRT for a mean 3.5 years. All-cause mortality was lower in the CC group (1.83%) than the TRT group (10.13%, P < .001), reported researchers at the Kansas City Veterans Affairs Medical Center and University of Missouri-Kansas City School of Medicine, et al in Andrology.

The researchers also reported that outcomes were better in the CC group than the TRT group for new-onset hypertension (6.04% vs 10.48%, P < .001), cerebrovascular accident (0.52% vs 1.43%, P < .001), coronary artery disease (1.51% vs 2.26%, P < .048), polycythemia (1.07% vs 2.22%, P < .001), and osteoporosis (1.15% vs 2.07%, P = .009), respectively. 

“It seems like clomiphene is a good medication to be used long term, but we still need more investigation into this,” endocrinologist Mariana Garcia-Touza, MD said in an interview with Federal Practitioner. 

TRT is a common therapy for male hypogonadism, although the study notes it is linked to thickened blood, breast growth, infertility, fluid retention, obstructive sleep apnea, and cardiovascular and prostate problems. Guidelines recommend against its use in patients with prostate cancer, at high cardiovascular risk, and those trying to have children.

CC is a selective estrogen receptor modulator and used off-label to treat male hypogonadism because it can boost the production of testosterone. The study notes how many Veterans health Administration patients have low testosterone, with previous research reporting the rate among veterans aged ≥ 60 years at 34%. 

Garcia-Touza was especially interested in any effect clomiphene has on bones: “We’ve been hearing that it probably affects the bone and can cause osteoporosis, but no one has looked into it.”

The study tracked veterans from December 1990 to September 2024; follow-ups lasted up to 34 years. Patient mean ages were 46.5 and 47.5 years for the HRT and CC groups, respectively. Hypogonadism was the treatment indication for 98.4% and 64.5% and infertility was the indication for 1.6% and 35.5% for the HRT and CC groups, respectively. About 70% of both groups were White. 

There were no statistically significant gaps between the groups regarding hip fractures, pulmonary embolism, thrombosis, and vertebral fractures. Garcia-Touza said the all-cause mortality gap the study reported was surprising, although the study did not control for factors that may have differed between the groups.

“This needs to be more carefully examined to see if this is a real finding or if there is some bias in the study that is causing it,” she said.

Moving forward, Garcia-Touza said she hopes to launch a prospective study of TRT vs CC.

Parviz K. Kavoussi, MD, a reproductive urologist at the University of Texas at Austin who was not involved in the study, said in an interview the study’s findings highlight the importance of monitoring patients on TRT for an increase in hematocrit. 

“Not all testosterone replacement therapies are created equal from this standpoint,” he said, noting that risk depends on the delivery method. “There are multiple modalities — topical gels, patches, nasal gels, intramuscular injections, subcutaneous pellets, subcutaneous autoinjector pens, and oral testosterone pills. Each of these has a defined percentage risk of secondary erythrocytosis, with some being significantly higher than others.”

As for other potential risks from TRT such as a possible higher mortality rate, Kavoussi noted that a landmark 2023 trial of middle-aged and older men convinced the FDA to no longer require testosterone products to include a black-box warning about cardiovascular disease. 

Regarding the question of whether clomiphene works as well as testosterone, Kavoussi noted his group’s research has found clomiphene can normalize testosterone levels biochemically. However, “where clomiphene typically falls short in data and in clinical practice is the level of symptomatic improvement in testosterone deficiency symptoms that patients can achieve in comparison to exogenous testosterone replacement.” 

No funding was reported, and the authors – including Garcia-Touza – had no disclosures. Kavoussi discloses relationships with Halozyme and Verity.

A retrospective cohort study links clomiphene citrate (CC) to significantly lower mortality rates when compared with testosterone replacement therapy (TRT) in male veterans with hypogonadism or infertility. CC is not approved by the US Food and Drug Administration (FDA) for hypogonadism but is often used off label. Patients taking clomiphene also had significantly lower risk of diseases of the circulatory system, brain, and bones. 

The study tracked matched cohorts of 2518 patients taking CC or TRT for a mean 3.5 years. All-cause mortality was lower in the CC group (1.83%) than the TRT group (10.13%, P < .001), reported researchers at the Kansas City Veterans Affairs Medical Center and University of Missouri-Kansas City School of Medicine, et al in Andrology.

The researchers also reported that outcomes were better in the CC group than the TRT group for new-onset hypertension (6.04% vs 10.48%, P < .001), cerebrovascular accident (0.52% vs 1.43%, P < .001), coronary artery disease (1.51% vs 2.26%, P < .048), polycythemia (1.07% vs 2.22%, P < .001), and osteoporosis (1.15% vs 2.07%, P = .009), respectively. 

“It seems like clomiphene is a good medication to be used long term, but we still need more investigation into this,” endocrinologist Mariana Garcia-Touza, MD said in an interview with Federal Practitioner. 

TRT is a common therapy for male hypogonadism, although the study notes it is linked to thickened blood, breast growth, infertility, fluid retention, obstructive sleep apnea, and cardiovascular and prostate problems. Guidelines recommend against its use in patients with prostate cancer, at high cardiovascular risk, and those trying to have children.

CC is a selective estrogen receptor modulator and used off-label to treat male hypogonadism because it can boost the production of testosterone. The study notes how many Veterans health Administration patients have low testosterone, with previous research reporting the rate among veterans aged ≥ 60 years at 34%. 

Garcia-Touza was especially interested in any effect clomiphene has on bones: “We’ve been hearing that it probably affects the bone and can cause osteoporosis, but no one has looked into it.”

The study tracked veterans from December 1990 to September 2024; follow-ups lasted up to 34 years. Patient mean ages were 46.5 and 47.5 years for the HRT and CC groups, respectively. Hypogonadism was the treatment indication for 98.4% and 64.5% and infertility was the indication for 1.6% and 35.5% for the HRT and CC groups, respectively. About 70% of both groups were White. 

There were no statistically significant gaps between the groups regarding hip fractures, pulmonary embolism, thrombosis, and vertebral fractures. Garcia-Touza said the all-cause mortality gap the study reported was surprising, although the study did not control for factors that may have differed between the groups.

“This needs to be more carefully examined to see if this is a real finding or if there is some bias in the study that is causing it,” she said.

Moving forward, Garcia-Touza said she hopes to launch a prospective study of TRT vs CC.

Parviz K. Kavoussi, MD, a reproductive urologist at the University of Texas at Austin who was not involved in the study, said in an interview the study’s findings highlight the importance of monitoring patients on TRT for an increase in hematocrit. 

“Not all testosterone replacement therapies are created equal from this standpoint,” he said, noting that risk depends on the delivery method. “There are multiple modalities — topical gels, patches, nasal gels, intramuscular injections, subcutaneous pellets, subcutaneous autoinjector pens, and oral testosterone pills. Each of these has a defined percentage risk of secondary erythrocytosis, with some being significantly higher than others.”

As for other potential risks from TRT such as a possible higher mortality rate, Kavoussi noted that a landmark 2023 trial of middle-aged and older men convinced the FDA to no longer require testosterone products to include a black-box warning about cardiovascular disease. 

Regarding the question of whether clomiphene works as well as testosterone, Kavoussi noted his group’s research has found clomiphene can normalize testosterone levels biochemically. However, “where clomiphene typically falls short in data and in clinical practice is the level of symptomatic improvement in testosterone deficiency symptoms that patients can achieve in comparison to exogenous testosterone replacement.” 

No funding was reported, and the authors – including Garcia-Touza – had no disclosures. Kavoussi discloses relationships with Halozyme and Verity.

A retrospective cohort study links clomiphene citrate (CC) to significantly lower mortality rates when compared with testosterone replacement therapy (TRT) in male veterans with hypogonadism or infertility. CC is not approved by the US Food and Drug Administration (FDA) for hypogonadism but is often used off label. Patients taking clomiphene also had significantly lower risk of diseases of the circulatory system, brain, and bones. 

The study tracked matched cohorts of 2518 patients taking CC or TRT for a mean 3.5 years. All-cause mortality was lower in the CC group (1.83%) than the TRT group (10.13%, P < .001), reported researchers at the Kansas City Veterans Affairs Medical Center and University of Missouri-Kansas City School of Medicine, et al in Andrology.

The researchers also reported that outcomes were better in the CC group than the TRT group for new-onset hypertension (6.04% vs 10.48%, P < .001), cerebrovascular accident (0.52% vs 1.43%, P < .001), coronary artery disease (1.51% vs 2.26%, P < .048), polycythemia (1.07% vs 2.22%, P < .001), and osteoporosis (1.15% vs 2.07%, P = .009), respectively. 

“It seems like clomiphene is a good medication to be used long term, but we still need more investigation into this,” endocrinologist Mariana Garcia-Touza, MD said in an interview with Federal Practitioner. 

TRT is a common therapy for male hypogonadism, although the study notes it is linked to thickened blood, breast growth, infertility, fluid retention, obstructive sleep apnea, and cardiovascular and prostate problems. Guidelines recommend against its use in patients with prostate cancer, at high cardiovascular risk, and those trying to have children.

CC is a selective estrogen receptor modulator and used off-label to treat male hypogonadism because it can boost the production of testosterone. The study notes how many Veterans health Administration patients have low testosterone, with previous research reporting the rate among veterans aged ≥ 60 years at 34%. 

Garcia-Touza was especially interested in any effect clomiphene has on bones: “We’ve been hearing that it probably affects the bone and can cause osteoporosis, but no one has looked into it.”

The study tracked veterans from December 1990 to September 2024; follow-ups lasted up to 34 years. Patient mean ages were 46.5 and 47.5 years for the HRT and CC groups, respectively. Hypogonadism was the treatment indication for 98.4% and 64.5% and infertility was the indication for 1.6% and 35.5% for the HRT and CC groups, respectively. About 70% of both groups were White. 

There were no statistically significant gaps between the groups regarding hip fractures, pulmonary embolism, thrombosis, and vertebral fractures. Garcia-Touza said the all-cause mortality gap the study reported was surprising, although the study did not control for factors that may have differed between the groups.

“This needs to be more carefully examined to see if this is a real finding or if there is some bias in the study that is causing it,” she said.

Moving forward, Garcia-Touza said she hopes to launch a prospective study of TRT vs CC.

Parviz K. Kavoussi, MD, a reproductive urologist at the University of Texas at Austin who was not involved in the study, said in an interview the study’s findings highlight the importance of monitoring patients on TRT for an increase in hematocrit. 

“Not all testosterone replacement therapies are created equal from this standpoint,” he said, noting that risk depends on the delivery method. “There are multiple modalities — topical gels, patches, nasal gels, intramuscular injections, subcutaneous pellets, subcutaneous autoinjector pens, and oral testosterone pills. Each of these has a defined percentage risk of secondary erythrocytosis, with some being significantly higher than others.”

As for other potential risks from TRT such as a possible higher mortality rate, Kavoussi noted that a landmark 2023 trial of middle-aged and older men convinced the FDA to no longer require testosterone products to include a black-box warning about cardiovascular disease. 

Regarding the question of whether clomiphene works as well as testosterone, Kavoussi noted his group’s research has found clomiphene can normalize testosterone levels biochemically. However, “where clomiphene typically falls short in data and in clinical practice is the level of symptomatic improvement in testosterone deficiency symptoms that patients can achieve in comparison to exogenous testosterone replacement.” 

No funding was reported, and the authors – including Garcia-Touza – had no disclosures. Kavoussi discloses relationships with Halozyme and Verity.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is caused by the misfolding of the TTR protein, which results in aggregation of amyloid fibrils that deposit in the myocardium and causes restrictive cardiomyopathy. Though it remains underdiagnosed, ATTR-CM is increasingly being recognized as a cause of heart failure in geriatric patients.¹ There are 2 categories of ATTRCM: wild-type ATTR-CM (wtATTR-CM), in which there is no mutation in the TTR gene, and hereditary ATTR-CM (hATTR-CM), in which a mutation is present in the TTR gene. Research has shown that wtATTR-CM accounted for as many as 30% of cases of heart failure (HF) with preserved ejection fraction (HFpEF) in patients aged > 75 years.² A significant percentage of the veteran patient population consists of older males. Given their age, these patients are at greater risk for ATTR diagnosis.³

Identifying red flags for patients within this population may allow clinicians to make earlier diagnoses and improve outcomes. A high index of suspicion is needed to diagnose ATTR because many early signs and symptoms are extracardiac, which leads to delayed diagnoses and worse outcomes. This article describes 8 cases of ATTR-CM within the US Department of Veterans Affairs (VA) New York Harbor Healthcare System-Brooklyn (VANYHHSB).

Methods

This retrospective case series was reviewed and approved by the VANYHHSB Institutional Review Board where it was conducted. Patients diagnosed with ATTR between 2017 and 2024 were identified using International Classification of Diseases, Tenth Revision codes. Eleven patients were identified; 3 were excluded due to insufficient medical records. The remaining 8 patient records were retrospectively reviewed and included.

Case 1

A 67-year-old male with a history of carpal tunnel syndrome (CTS) presented following a syncopal episode. Initial electrocardiogram (ECG) showed sinus rhythm, first-degree atrioventricular block, and a bifascicular block. Transthoracic echocardiogram (TTE) showed moderate asymmetric left ventricular (LV) hypertrophy (LVH) and biatrial enlargement with an ejection fraction (EF) > 55%. The patient was discharged with a loop recorder and an outpatient follow-up appointment scheduled. One month later, he presented with worsening dyspnea on exertion with clinical signs of hypervolemia. A repeat TTE showed global LV wall thickening, moderately reduced LV systolic function (EF 40%), and moderate pulmonary hypertension. Given these findings, the patient underwent cardiac magnetic resonance imaging (CMR), which suggested an infiltrative cardiomyopathy. Amyloid light-chain (AL) amyloidosis evaluation, technetium-99m (^99mTC) pyrophosphate imaging, and a fat pad biopsy were unrevealing. An endomyocardial biopsy was performed with electron microscopy, which confirmed amyloidosis. Genetic testing was negative, and the patient began taking tafamidis. There were no later admissions for decompensated HF; however, the patient developed atrial fibrillation (AF) and an interval TTE demonstrated no improvement in his EF. He died at age 73 years.

Case 2

A 78-year-old male with a history of CTS presented with lightheadedness. Initial ECG showed rate-controlled AF and TTE revealed a moderately thickened LV wall with normal LV size, mild left atrial enlargement, and an EF of 65%. The patient was discharged with a scheduled outpatient CMR appointment; however, he defaulted from follow-up. Two years later, he presented with recurrent syncopal episodes and physical examination was consistent with hypervolemia. Repeat TTE revealed moderate LVH, biatrial enlargement, and an EF of 55%. An inpatient CMR was suggestive of cardiac amyloidosis, and a pyrophosphate scan was diagnostic for ATTR. The patient started taking tafamidis, but continued to have recurrent admissions for HF exacerbation. He died at age 81 years.

Case 3

A 71-year-old male with a history of CTS presented with exertional dyspnea. The initial ECG showed sinus rhythm with left atrial enlargement and left axis deviation. Subsequent TTE revealed severe LVH, mildly reduced LV cavity size, moderate to severe biatrial enlargement, and an EF of 25% to 30%. Outpatient ^99mTC pyrophosphate imaging suggested cardiac amyloidosis, and laboratory testing showed no evidence of monoclonal proteins. The patient was started on tafamidis for ATTR. At 2-year follow-up, he had new AF and to date has had no further hospitalizations for acute decompensated HF.

Case 4

A 92-year-old male with a history of AF and bilateral CTS presented with lightheadedness. An ECG revealed AF with a slowed ventricular response. Subsequent Holter monitoring demonstrated pauses exceeding 3 seconds, and a permanent pacemaker was recommended. During his preoperative evaluation, TTE revealed severe concentric LVH with a speckled appearance of the myocardium, mild-tomoderate biatrial enlargement, and an EF of 50% to 55%. 99mTC pyrophosphate imaging was positive for amyloidosis and the patient started taking tafamidis. Recurrent hospital admissions for decompensated HF complicated his progression. The patient died at age 95 years.

Case 5

A 72-year-old male with a history of bilateral CTS and cervical spinal stenosis presented with dyspnea on exertion. An ECG revealed a normal sinus rhythm. A TTE found severely reduced systolic function with an EF ≤ 25%, mild concentric LVH, grade 3 diastolic dysfunction, mild-tomoderate biatrial enlargement, and moderate pulmonary hypertension (Figure 1). He was started on guideline-directed medical therapy (GDMT) for HF, which included sacubitril/valsartan, metoprolol succinate, and empagliflozin. The patient’s dyspnea improved, and a workup for nonischemic cardiomyopathy was initiated. 99mTC pyrophosphate imaging 1 year after his initial presentation was positive, leading to ATTR-CM diagnosis. The patient started taking tafamidis and he has since had a stable progression and continued to demonstrate good exercise tolerance with no hospitalizations. His most recent TTE indicated an EF of 40% to 45%.

Case 6

A 76-year-old male with a history of paroxysmal AF status after multiple ablations, bilateral CTS, and severe cervical spinal stenosis presented with dyspnea on exertion. The patient’s ECG showed normal sinus rhythm and left axis deviation with concern for left anterior hemiblock. A TTE revealed moderate LVH with a speckled appearance of the myocardium and grade 3 diastolic dysfunction with preserved EF. Before completing the workup for underlying cardiomyopathy, the patient underwent an interventional radiology procedure for an angiomyolipoma, and his postoperative course was complicated by pulmonary edema, requiring admission to the coronary care unit for diuresis. A repeat TTE revealed a reduced EF of 35%, and he was discharged on GDMT. No monoclonal protein was seen in the serum or urine. The patient’s progression was complicated by recurrent admissions for acute decompensated HF and supraventricular tachycardia despite being on amiodarone, which led to a delay in obtaining 99mTC pyrophosphate imaging. Due to hypotension, the patient was unable to tolerate GDMT. He eventually underwent 99mTC pyrophosphate imaging that confirmed ATTR-CM and was started on tafamidis. One year following initial presentation, the patient’s EF progressively declined to 20% to 25%, and he died shortly after discharge to subacute rehabilitation.

Case 7

A 95-year-old male with a history of longstanding persistent AF and bilateral CTS presented with dyspnea on exertion, bendopnea, and worsening bilateral pedal edema for a week. An ECG showed AF with a controlled ventricular response and low-voltage QRS waves (Figure 2). A TTE showed biatrial enlargement, LVH, and preserved EF > 55%. He started taking furosemide and was discharged with a diagnosis of HFpEF. The patient missed cardiology follow-up and presented 1 year later with decompensated HF. An amyloidosis workup was recommended, but due to intermittent periods of being lost to follow-up, the patient did not pursue this workup until 3 years after his initial presentation when 99mTC pyrophosphate imaging confirmed ATTR-CM. The patient declined tafamidis and continued to be followed by the cardiology team. His HF is managed with furosemide as needed due to intolerance to GDMT.

Case 8

A 74-year-old male with history of bilateral CTS presented with right-sided chest pain associated with shortness of breath, diaphoresis, dizziness, and worsening abdominal pain. He was found to have inferior wall myocardial infarction on ECG with later percutaneous coronary intervention to the left circumflex. His hospital course was complicated by decompensated HF (EF 45% to 50%) and AF with rapid ventricular response. He was treated and discharged with follow-up visits scheduled in the cardiology clinic. Multiple attempts were made to place him on GDMT; however, the patient was unable to tolerate these medications due to recurrent admissions for syncope. During a cardiology clinic visit 3 years after his initial presentation, an amyloidosis workup was initiated. 99mTC pyrophosphate imaging was positive for ATTR-CM, and he started taking tafamidis. Before this diagnosis, ECG indicated low-voltage QRS complexes. His progression has since been complicated by admissions for decompensated HF, recurrent episodes of AF requiring atrioventricular node ablation, and biventricular implantable cardioverter-defibrillator implantation after failed attempts at electrical cardioversion. He continued to follow up in the HF clinic.

Discussion

ATTR-CM is an underdiagnosed cause of cardiomyopathy, particularly in older adults. TTR is a transport protein produced in the liver, and misfolding can occur due to age-related instability of the wild-type protein (wtATTR) or pathologic variants in the TTR (hATTR). The misfolding leads to restrictive physiology, HF (often with preserved EF) arrhythmias, and conduction system disease.¹ It is likely that the predominantly older male veteran population would be predisposed to wtATTR cardiomyopathy given that misfolding in the condition is believed to be age-related.

Current criteria for ATTR diagnosis require a combination of clinical suspicion, imaging, laboratory testing, and, in some cases, tissue biopsy confirmation and genetic testing.^1,4,5 The diagnostic algorithm is as follows:

Clinical suspicion. Consider ATTR in patients with unexplained HFpEF, LV wall thickness ≥ 12 to 14 mm, discordance between ECG voltage and wall thickness, or associated extracardiac manifestations such as CTS, lumbar spinal stenosis, or peripheral/ autonomic neuropathy.

Exclusion of AL amyloidosis. Bone scintigraphy alone cannot distinguish between AL amyloidosis and ATTR, so patients with suspected amyloid cardiomyopathy should undergo serum and urine immunofixation electrophoresis and serum free light chain assay to rule out a monoclonal gammopathy as seen in AL amyloidosis.

Cardiac scintigraphy. Once AL amyloidosis is excluded, a positive 99mTC-labeled boneavid tracer image (such as a pyrophosphate scan) with grade 2 or grade 3 myocardial uptake is diagnostic of ATTR.

Tissue biopsy. If there is monoclonal gammopathy or equivocal imaging, tissue biopsy (eg, endomyocardial) with Congo red staining and amyloid typing by mass spectrometry or immunohistochemistry is necessary.

Genetic testing. Once ATTR is confirmed, genetic testing distinguishes hATTR from wtATTR, which impacts management and determines the need to screen family members.

Currently, there are 3 therapies approved by the US Food and Drug Administration (FDA) to treat ATTR-CM: tafamidis, acoramidis, and vutrisiran.^6-8 Tafamidis and acoramidis stabilize the TTR tetramer, preventing amyloid formation. Vutrisiran uses RNA interference to silence the gene that produces TTR. Tafamidis has been found to improve cardiovascular outcomes in ATTR-CM. In the ATTR-ACT trial, it reduced all-cause mortality and cardiovascular hospitalizations in patients with ATTR-CM and New York Heart Association class I-III symptoms.⁶ There are other disease-modifying therapies, such the TTR gene silencers inotersen and patisiran; however, these are only FDA-approved for hATTR polyneuropathy and not for ATTRCM; ongoing trials are evaluating their cardiac efficacy.

The mean age of ATTR-CM diagnosis in the patients described in this case series was 79 years, which is older than the mean age of 74 years reported in prior research.⁴ All patients were male, and the most common presenting symptom was dyspnea on exertion. Table 1 outlines baseline characteristics and associated comorbidities of patients in this case series. The patients presented with many red-flag signs of ATTR-CM (Figure 3). Among them included syncope (4 of 8 patients), spinal stenosis (2 of 8 patients), arrhythmia (7 of 8 patients), heart failure (7 of 8 patients), and bilateral CTS (all patients).

Bilateral CTS was diagnosed in all patients before their diagnosis of ATTR-CM. Patient 7 had a diagnosis of CTS 9 years before his ATTR-CM diagnosis, underscoring a subtle, yet important extracardiac sign that may increase clinical suspicion for ATTR-CM. Previous research found that the probability of having CTS is highest 5 to 9 years prior to the development of cardiomyopathy. Its presence is also a prognostic marker in ATTR, independent of cardiac involvement.⁹ The median interval between CTS diagnosis and cardiomyopathy diagnosis was 5 years in this series.

Although screening criteria for ATTR have been proposed, none have been incorporated into formal guidelines.^10,11 We propose that a baseline ECG and screening TTE be obtained in any patient aged > 65 years with cardiac risk equivalents such as hypertension and diabetes, presenting with ≥ 1 extracardiac red-flag signs, such as bilateral CTS and spinal stenosis. This will likely facilitate an earlier diagnosis of ATTR-CM, leading to earlier treatment initiation and better patient outcomes. This initiative can be started in the primary care setting and facilitates early cardiology referral. This recommendation is based on literature supporting clinical patterns and observations the authors have made in clinical practice.

Obstructive sleep apnea (OSA) was a comorbidity present in 50% of the patients described in this case series. The literature describing this association is sparse; however, a prospective observational study reported that disorders of sleep inclusive of OSA are frequent in patients with cardiac amyloidosis.¹² A theory behind this association is that amyloid deposits in the upper airway tissues lead to airway narrowing. ¹³ More research is needed to further assess the relationship between OSA and cardiac amyloidosis, particularly with respect to the timing of OSA prior to the development of cardiomyopathy as it may be a potential early sign for clinicians to acknowledge.

An important observation from this case series is the variability in the timing of tafamidis initiation relative to symptom onset and confirmed diagnosis of ATTR-CM (Table 2). Although tafamidis has been found to slow disease progression, several patients in this series began treatment at advanced stages or years after the onset of cardiac symptoms, potentially limiting its clinical benefit.

For example, patient 1 was diagnosed with ATTR 2 years before tafamidis became available on the market and was initially treated with diflunisal. Patients who started tafamidis earlier in the disease course (eg, patients 3 and 5) appeared to have better long-term outcomes, including an absence of heart failure hospitalizations after initiation. In contrast, patients with delayed treatment initiation (eg, patients 2, 6, and 8) experienced ongoing decompensations or early mortality. Patient 7 declined tafamidis, underscoring challenges in medication uptake among older adults. Randomized controlled trials are warranted to compare the effectiveness of tafamidis with other recently FDA-approved therapies, such as acoramidis and vutrisiran, particularly in terms of cardiovascular outcomes.

AF was the most common arrhythmia observed in these patients and may occur years before the development of HF symptoms in the setting of ATTR-CM. Due to inherent conduction system disease, AF in this population may have a controlled or slow ventricular response, as observed in patient 4. Patients with atrial fibrillation and cardiac amyloidosis should receive anticoagulation regardless of CHA2DS2- VASc score due to their high risk of intracardiac thrombus formation.⁴

Limitations

This case series lacked genetic testing following a confirmed ATTR-CM diagnosis. Although much of the treatment is the same regardless of the presence of a TTR mutation, knowing the specific subtype of ATTR-CM has implications for prognosis and for screening family members.

Conclusions

Following analysis of 8 patients diagnosed with ATTR, this case series could serve as a blueprint for research into ATTR in veterans. In clinical practice, following military service, veterans may not be routinely seen by an outpatient physician and may present with sequelae of advanced stages of ATTR. Early identification of red-flag symptoms can lead to a higher clinical suspicion, prompting early diagnostic evaluation and treatment initiation and ultimately mitigating adverse outcomes. Future research that includes genetic testing for those with confirmed ATTR-CM may prove useful as a foundation for detailed and informed discussions with patients and their families regarding prognosis and, if indicated, screening for family members.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is caused by the misfolding of the TTR protein, which results in aggregation of amyloid fibrils that deposit in the myocardium and causes restrictive cardiomyopathy. Though it remains underdiagnosed, ATTR-CM is increasingly being recognized as a cause of heart failure in geriatric patients.¹ There are 2 categories of ATTRCM: wild-type ATTR-CM (wtATTR-CM), in which there is no mutation in the TTR gene, and hereditary ATTR-CM (hATTR-CM), in which a mutation is present in the TTR gene. Research has shown that wtATTR-CM accounted for as many as 30% of cases of heart failure (HF) with preserved ejection fraction (HFpEF) in patients aged > 75 years.² A significant percentage of the veteran patient population consists of older males. Given their age, these patients are at greater risk for ATTR diagnosis.³

Identifying red flags for patients within this population may allow clinicians to make earlier diagnoses and improve outcomes. A high index of suspicion is needed to diagnose ATTR because many early signs and symptoms are extracardiac, which leads to delayed diagnoses and worse outcomes. This article describes 8 cases of ATTR-CM within the US Department of Veterans Affairs (VA) New York Harbor Healthcare System-Brooklyn (VANYHHSB).

Methods

This retrospective case series was reviewed and approved by the VANYHHSB Institutional Review Board where it was conducted. Patients diagnosed with ATTR between 2017 and 2024 were identified using International Classification of Diseases, Tenth Revision codes. Eleven patients were identified; 3 were excluded due to insufficient medical records. The remaining 8 patient records were retrospectively reviewed and included.

Case 1

A 67-year-old male with a history of carpal tunnel syndrome (CTS) presented following a syncopal episode. Initial electrocardiogram (ECG) showed sinus rhythm, first-degree atrioventricular block, and a bifascicular block. Transthoracic echocardiogram (TTE) showed moderate asymmetric left ventricular (LV) hypertrophy (LVH) and biatrial enlargement with an ejection fraction (EF) > 55%. The patient was discharged with a loop recorder and an outpatient follow-up appointment scheduled. One month later, he presented with worsening dyspnea on exertion with clinical signs of hypervolemia. A repeat TTE showed global LV wall thickening, moderately reduced LV systolic function (EF 40%), and moderate pulmonary hypertension. Given these findings, the patient underwent cardiac magnetic resonance imaging (CMR), which suggested an infiltrative cardiomyopathy. Amyloid light-chain (AL) amyloidosis evaluation, technetium-99m (^99mTC) pyrophosphate imaging, and a fat pad biopsy were unrevealing. An endomyocardial biopsy was performed with electron microscopy, which confirmed amyloidosis. Genetic testing was negative, and the patient began taking tafamidis. There were no later admissions for decompensated HF; however, the patient developed atrial fibrillation (AF) and an interval TTE demonstrated no improvement in his EF. He died at age 73 years.

Case 2

A 78-year-old male with a history of CTS presented with lightheadedness. Initial ECG showed rate-controlled AF and TTE revealed a moderately thickened LV wall with normal LV size, mild left atrial enlargement, and an EF of 65%. The patient was discharged with a scheduled outpatient CMR appointment; however, he defaulted from follow-up. Two years later, he presented with recurrent syncopal episodes and physical examination was consistent with hypervolemia. Repeat TTE revealed moderate LVH, biatrial enlargement, and an EF of 55%. An inpatient CMR was suggestive of cardiac amyloidosis, and a pyrophosphate scan was diagnostic for ATTR. The patient started taking tafamidis, but continued to have recurrent admissions for HF exacerbation. He died at age 81 years.

Case 3

A 71-year-old male with a history of CTS presented with exertional dyspnea. The initial ECG showed sinus rhythm with left atrial enlargement and left axis deviation. Subsequent TTE revealed severe LVH, mildly reduced LV cavity size, moderate to severe biatrial enlargement, and an EF of 25% to 30%. Outpatient ^99mTC pyrophosphate imaging suggested cardiac amyloidosis, and laboratory testing showed no evidence of monoclonal proteins. The patient was started on tafamidis for ATTR. At 2-year follow-up, he had new AF and to date has had no further hospitalizations for acute decompensated HF.

Case 4

A 92-year-old male with a history of AF and bilateral CTS presented with lightheadedness. An ECG revealed AF with a slowed ventricular response. Subsequent Holter monitoring demonstrated pauses exceeding 3 seconds, and a permanent pacemaker was recommended. During his preoperative evaluation, TTE revealed severe concentric LVH with a speckled appearance of the myocardium, mild-tomoderate biatrial enlargement, and an EF of 50% to 55%. 99mTC pyrophosphate imaging was positive for amyloidosis and the patient started taking tafamidis. Recurrent hospital admissions for decompensated HF complicated his progression. The patient died at age 95 years.

Case 5

A 72-year-old male with a history of bilateral CTS and cervical spinal stenosis presented with dyspnea on exertion. An ECG revealed a normal sinus rhythm. A TTE found severely reduced systolic function with an EF ≤ 25%, mild concentric LVH, grade 3 diastolic dysfunction, mild-tomoderate biatrial enlargement, and moderate pulmonary hypertension (Figure 1). He was started on guideline-directed medical therapy (GDMT) for HF, which included sacubitril/valsartan, metoprolol succinate, and empagliflozin. The patient’s dyspnea improved, and a workup for nonischemic cardiomyopathy was initiated. 99mTC pyrophosphate imaging 1 year after his initial presentation was positive, leading to ATTR-CM diagnosis. The patient started taking tafamidis and he has since had a stable progression and continued to demonstrate good exercise tolerance with no hospitalizations. His most recent TTE indicated an EF of 40% to 45%.

Case 6

A 76-year-old male with a history of paroxysmal AF status after multiple ablations, bilateral CTS, and severe cervical spinal stenosis presented with dyspnea on exertion. The patient’s ECG showed normal sinus rhythm and left axis deviation with concern for left anterior hemiblock. A TTE revealed moderate LVH with a speckled appearance of the myocardium and grade 3 diastolic dysfunction with preserved EF. Before completing the workup for underlying cardiomyopathy, the patient underwent an interventional radiology procedure for an angiomyolipoma, and his postoperative course was complicated by pulmonary edema, requiring admission to the coronary care unit for diuresis. A repeat TTE revealed a reduced EF of 35%, and he was discharged on GDMT. No monoclonal protein was seen in the serum or urine. The patient’s progression was complicated by recurrent admissions for acute decompensated HF and supraventricular tachycardia despite being on amiodarone, which led to a delay in obtaining 99mTC pyrophosphate imaging. Due to hypotension, the patient was unable to tolerate GDMT. He eventually underwent 99mTC pyrophosphate imaging that confirmed ATTR-CM and was started on tafamidis. One year following initial presentation, the patient’s EF progressively declined to 20% to 25%, and he died shortly after discharge to subacute rehabilitation.

Case 7

A 95-year-old male with a history of longstanding persistent AF and bilateral CTS presented with dyspnea on exertion, bendopnea, and worsening bilateral pedal edema for a week. An ECG showed AF with a controlled ventricular response and low-voltage QRS waves (Figure 2). A TTE showed biatrial enlargement, LVH, and preserved EF > 55%. He started taking furosemide and was discharged with a diagnosis of HFpEF. The patient missed cardiology follow-up and presented 1 year later with decompensated HF. An amyloidosis workup was recommended, but due to intermittent periods of being lost to follow-up, the patient did not pursue this workup until 3 years after his initial presentation when 99mTC pyrophosphate imaging confirmed ATTR-CM. The patient declined tafamidis and continued to be followed by the cardiology team. His HF is managed with furosemide as needed due to intolerance to GDMT.

Case 8

A 74-year-old male with history of bilateral CTS presented with right-sided chest pain associated with shortness of breath, diaphoresis, dizziness, and worsening abdominal pain. He was found to have inferior wall myocardial infarction on ECG with later percutaneous coronary intervention to the left circumflex. His hospital course was complicated by decompensated HF (EF 45% to 50%) and AF with rapid ventricular response. He was treated and discharged with follow-up visits scheduled in the cardiology clinic. Multiple attempts were made to place him on GDMT; however, the patient was unable to tolerate these medications due to recurrent admissions for syncope. During a cardiology clinic visit 3 years after his initial presentation, an amyloidosis workup was initiated. 99mTC pyrophosphate imaging was positive for ATTR-CM, and he started taking tafamidis. Before this diagnosis, ECG indicated low-voltage QRS complexes. His progression has since been complicated by admissions for decompensated HF, recurrent episodes of AF requiring atrioventricular node ablation, and biventricular implantable cardioverter-defibrillator implantation after failed attempts at electrical cardioversion. He continued to follow up in the HF clinic.

Discussion

ATTR-CM is an underdiagnosed cause of cardiomyopathy, particularly in older adults. TTR is a transport protein produced in the liver, and misfolding can occur due to age-related instability of the wild-type protein (wtATTR) or pathologic variants in the TTR (hATTR). The misfolding leads to restrictive physiology, HF (often with preserved EF) arrhythmias, and conduction system disease.¹ It is likely that the predominantly older male veteran population would be predisposed to wtATTR cardiomyopathy given that misfolding in the condition is believed to be age-related.

Current criteria for ATTR diagnosis require a combination of clinical suspicion, imaging, laboratory testing, and, in some cases, tissue biopsy confirmation and genetic testing.^1,4,5 The diagnostic algorithm is as follows:

Clinical suspicion. Consider ATTR in patients with unexplained HFpEF, LV wall thickness ≥ 12 to 14 mm, discordance between ECG voltage and wall thickness, or associated extracardiac manifestations such as CTS, lumbar spinal stenosis, or peripheral/ autonomic neuropathy.

Exclusion of AL amyloidosis. Bone scintigraphy alone cannot distinguish between AL amyloidosis and ATTR, so patients with suspected amyloid cardiomyopathy should undergo serum and urine immunofixation electrophoresis and serum free light chain assay to rule out a monoclonal gammopathy as seen in AL amyloidosis.

Cardiac scintigraphy. Once AL amyloidosis is excluded, a positive 99mTC-labeled boneavid tracer image (such as a pyrophosphate scan) with grade 2 or grade 3 myocardial uptake is diagnostic of ATTR.

Tissue biopsy. If there is monoclonal gammopathy or equivocal imaging, tissue biopsy (eg, endomyocardial) with Congo red staining and amyloid typing by mass spectrometry or immunohistochemistry is necessary.

Genetic testing. Once ATTR is confirmed, genetic testing distinguishes hATTR from wtATTR, which impacts management and determines the need to screen family members.

Currently, there are 3 therapies approved by the US Food and Drug Administration (FDA) to treat ATTR-CM: tafamidis, acoramidis, and vutrisiran.^6-8 Tafamidis and acoramidis stabilize the TTR tetramer, preventing amyloid formation. Vutrisiran uses RNA interference to silence the gene that produces TTR. Tafamidis has been found to improve cardiovascular outcomes in ATTR-CM. In the ATTR-ACT trial, it reduced all-cause mortality and cardiovascular hospitalizations in patients with ATTR-CM and New York Heart Association class I-III symptoms.⁶ There are other disease-modifying therapies, such the TTR gene silencers inotersen and patisiran; however, these are only FDA-approved for hATTR polyneuropathy and not for ATTRCM; ongoing trials are evaluating their cardiac efficacy.

The mean age of ATTR-CM diagnosis in the patients described in this case series was 79 years, which is older than the mean age of 74 years reported in prior research.⁴ All patients were male, and the most common presenting symptom was dyspnea on exertion. Table 1 outlines baseline characteristics and associated comorbidities of patients in this case series. The patients presented with many red-flag signs of ATTR-CM (Figure 3). Among them included syncope (4 of 8 patients), spinal stenosis (2 of 8 patients), arrhythmia (7 of 8 patients), heart failure (7 of 8 patients), and bilateral CTS (all patients).

Bilateral CTS was diagnosed in all patients before their diagnosis of ATTR-CM. Patient 7 had a diagnosis of CTS 9 years before his ATTR-CM diagnosis, underscoring a subtle, yet important extracardiac sign that may increase clinical suspicion for ATTR-CM. Previous research found that the probability of having CTS is highest 5 to 9 years prior to the development of cardiomyopathy. Its presence is also a prognostic marker in ATTR, independent of cardiac involvement.⁹ The median interval between CTS diagnosis and cardiomyopathy diagnosis was 5 years in this series.

Although screening criteria for ATTR have been proposed, none have been incorporated into formal guidelines.^10,11 We propose that a baseline ECG and screening TTE be obtained in any patient aged > 65 years with cardiac risk equivalents such as hypertension and diabetes, presenting with ≥ 1 extracardiac red-flag signs, such as bilateral CTS and spinal stenosis. This will likely facilitate an earlier diagnosis of ATTR-CM, leading to earlier treatment initiation and better patient outcomes. This initiative can be started in the primary care setting and facilitates early cardiology referral. This recommendation is based on literature supporting clinical patterns and observations the authors have made in clinical practice.

Obstructive sleep apnea (OSA) was a comorbidity present in 50% of the patients described in this case series. The literature describing this association is sparse; however, a prospective observational study reported that disorders of sleep inclusive of OSA are frequent in patients with cardiac amyloidosis.¹² A theory behind this association is that amyloid deposits in the upper airway tissues lead to airway narrowing. ¹³ More research is needed to further assess the relationship between OSA and cardiac amyloidosis, particularly with respect to the timing of OSA prior to the development of cardiomyopathy as it may be a potential early sign for clinicians to acknowledge.

An important observation from this case series is the variability in the timing of tafamidis initiation relative to symptom onset and confirmed diagnosis of ATTR-CM (Table 2). Although tafamidis has been found to slow disease progression, several patients in this series began treatment at advanced stages or years after the onset of cardiac symptoms, potentially limiting its clinical benefit.

For example, patient 1 was diagnosed with ATTR 2 years before tafamidis became available on the market and was initially treated with diflunisal. Patients who started tafamidis earlier in the disease course (eg, patients 3 and 5) appeared to have better long-term outcomes, including an absence of heart failure hospitalizations after initiation. In contrast, patients with delayed treatment initiation (eg, patients 2, 6, and 8) experienced ongoing decompensations or early mortality. Patient 7 declined tafamidis, underscoring challenges in medication uptake among older adults. Randomized controlled trials are warranted to compare the effectiveness of tafamidis with other recently FDA-approved therapies, such as acoramidis and vutrisiran, particularly in terms of cardiovascular outcomes.

AF was the most common arrhythmia observed in these patients and may occur years before the development of HF symptoms in the setting of ATTR-CM. Due to inherent conduction system disease, AF in this population may have a controlled or slow ventricular response, as observed in patient 4. Patients with atrial fibrillation and cardiac amyloidosis should receive anticoagulation regardless of CHA2DS2- VASc score due to their high risk of intracardiac thrombus formation.⁴

Limitations

This case series lacked genetic testing following a confirmed ATTR-CM diagnosis. Although much of the treatment is the same regardless of the presence of a TTR mutation, knowing the specific subtype of ATTR-CM has implications for prognosis and for screening family members.

Conclusions

Following analysis of 8 patients diagnosed with ATTR, this case series could serve as a blueprint for research into ATTR in veterans. In clinical practice, following military service, veterans may not be routinely seen by an outpatient physician and may present with sequelae of advanced stages of ATTR. Early identification of red-flag symptoms can lead to a higher clinical suspicion, prompting early diagnostic evaluation and treatment initiation and ultimately mitigating adverse outcomes. Future research that includes genetic testing for those with confirmed ATTR-CM may prove useful as a foundation for detailed and informed discussions with patients and their families regarding prognosis and, if indicated, screening for family members.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is caused by the misfolding of the TTR protein, which results in aggregation of amyloid fibrils that deposit in the myocardium and causes restrictive cardiomyopathy. Though it remains underdiagnosed, ATTR-CM is increasingly being recognized as a cause of heart failure in geriatric patients.¹ There are 2 categories of ATTRCM: wild-type ATTR-CM (wtATTR-CM), in which there is no mutation in the TTR gene, and hereditary ATTR-CM (hATTR-CM), in which a mutation is present in the TTR gene. Research has shown that wtATTR-CM accounted for as many as 30% of cases of heart failure (HF) with preserved ejection fraction (HFpEF) in patients aged > 75 years.² A significant percentage of the veteran patient population consists of older males. Given their age, these patients are at greater risk for ATTR diagnosis.³

Identifying red flags for patients within this population may allow clinicians to make earlier diagnoses and improve outcomes. A high index of suspicion is needed to diagnose ATTR because many early signs and symptoms are extracardiac, which leads to delayed diagnoses and worse outcomes. This article describes 8 cases of ATTR-CM within the US Department of Veterans Affairs (VA) New York Harbor Healthcare System-Brooklyn (VANYHHSB).

Methods

This retrospective case series was reviewed and approved by the VANYHHSB Institutional Review Board where it was conducted. Patients diagnosed with ATTR between 2017 and 2024 were identified using International Classification of Diseases, Tenth Revision codes. Eleven patients were identified; 3 were excluded due to insufficient medical records. The remaining 8 patient records were retrospectively reviewed and included.

Case 1

A 67-year-old male with a history of carpal tunnel syndrome (CTS) presented following a syncopal episode. Initial electrocardiogram (ECG) showed sinus rhythm, first-degree atrioventricular block, and a bifascicular block. Transthoracic echocardiogram (TTE) showed moderate asymmetric left ventricular (LV) hypertrophy (LVH) and biatrial enlargement with an ejection fraction (EF) > 55%. The patient was discharged with a loop recorder and an outpatient follow-up appointment scheduled. One month later, he presented with worsening dyspnea on exertion with clinical signs of hypervolemia. A repeat TTE showed global LV wall thickening, moderately reduced LV systolic function (EF 40%), and moderate pulmonary hypertension. Given these findings, the patient underwent cardiac magnetic resonance imaging (CMR), which suggested an infiltrative cardiomyopathy. Amyloid light-chain (AL) amyloidosis evaluation, technetium-99m (^99mTC) pyrophosphate imaging, and a fat pad biopsy were unrevealing. An endomyocardial biopsy was performed with electron microscopy, which confirmed amyloidosis. Genetic testing was negative, and the patient began taking tafamidis. There were no later admissions for decompensated HF; however, the patient developed atrial fibrillation (AF) and an interval TTE demonstrated no improvement in his EF. He died at age 73 years.

Case 2

A 78-year-old male with a history of CTS presented with lightheadedness. Initial ECG showed rate-controlled AF and TTE revealed a moderately thickened LV wall with normal LV size, mild left atrial enlargement, and an EF of 65%. The patient was discharged with a scheduled outpatient CMR appointment; however, he defaulted from follow-up. Two years later, he presented with recurrent syncopal episodes and physical examination was consistent with hypervolemia. Repeat TTE revealed moderate LVH, biatrial enlargement, and an EF of 55%. An inpatient CMR was suggestive of cardiac amyloidosis, and a pyrophosphate scan was diagnostic for ATTR. The patient started taking tafamidis, but continued to have recurrent admissions for HF exacerbation. He died at age 81 years.

Case 3

A 71-year-old male with a history of CTS presented with exertional dyspnea. The initial ECG showed sinus rhythm with left atrial enlargement and left axis deviation. Subsequent TTE revealed severe LVH, mildly reduced LV cavity size, moderate to severe biatrial enlargement, and an EF of 25% to 30%. Outpatient ^99mTC pyrophosphate imaging suggested cardiac amyloidosis, and laboratory testing showed no evidence of monoclonal proteins. The patient was started on tafamidis for ATTR. At 2-year follow-up, he had new AF and to date has had no further hospitalizations for acute decompensated HF.

Case 4

A 92-year-old male with a history of AF and bilateral CTS presented with lightheadedness. An ECG revealed AF with a slowed ventricular response. Subsequent Holter monitoring demonstrated pauses exceeding 3 seconds, and a permanent pacemaker was recommended. During his preoperative evaluation, TTE revealed severe concentric LVH with a speckled appearance of the myocardium, mild-tomoderate biatrial enlargement, and an EF of 50% to 55%. 99mTC pyrophosphate imaging was positive for amyloidosis and the patient started taking tafamidis. Recurrent hospital admissions for decompensated HF complicated his progression. The patient died at age 95 years.

Case 5

A 72-year-old male with a history of bilateral CTS and cervical spinal stenosis presented with dyspnea on exertion. An ECG revealed a normal sinus rhythm. A TTE found severely reduced systolic function with an EF ≤ 25%, mild concentric LVH, grade 3 diastolic dysfunction, mild-tomoderate biatrial enlargement, and moderate pulmonary hypertension (Figure 1). He was started on guideline-directed medical therapy (GDMT) for HF, which included sacubitril/valsartan, metoprolol succinate, and empagliflozin. The patient’s dyspnea improved, and a workup for nonischemic cardiomyopathy was initiated. 99mTC pyrophosphate imaging 1 year after his initial presentation was positive, leading to ATTR-CM diagnosis. The patient started taking tafamidis and he has since had a stable progression and continued to demonstrate good exercise tolerance with no hospitalizations. His most recent TTE indicated an EF of 40% to 45%.

Case 6

A 76-year-old male with a history of paroxysmal AF status after multiple ablations, bilateral CTS, and severe cervical spinal stenosis presented with dyspnea on exertion. The patient’s ECG showed normal sinus rhythm and left axis deviation with concern for left anterior hemiblock. A TTE revealed moderate LVH with a speckled appearance of the myocardium and grade 3 diastolic dysfunction with preserved EF. Before completing the workup for underlying cardiomyopathy, the patient underwent an interventional radiology procedure for an angiomyolipoma, and his postoperative course was complicated by pulmonary edema, requiring admission to the coronary care unit for diuresis. A repeat TTE revealed a reduced EF of 35%, and he was discharged on GDMT. No monoclonal protein was seen in the serum or urine. The patient’s progression was complicated by recurrent admissions for acute decompensated HF and supraventricular tachycardia despite being on amiodarone, which led to a delay in obtaining 99mTC pyrophosphate imaging. Due to hypotension, the patient was unable to tolerate GDMT. He eventually underwent 99mTC pyrophosphate imaging that confirmed ATTR-CM and was started on tafamidis. One year following initial presentation, the patient’s EF progressively declined to 20% to 25%, and he died shortly after discharge to subacute rehabilitation.

Case 7

A 95-year-old male with a history of longstanding persistent AF and bilateral CTS presented with dyspnea on exertion, bendopnea, and worsening bilateral pedal edema for a week. An ECG showed AF with a controlled ventricular response and low-voltage QRS waves (Figure 2). A TTE showed biatrial enlargement, LVH, and preserved EF > 55%. He started taking furosemide and was discharged with a diagnosis of HFpEF. The patient missed cardiology follow-up and presented 1 year later with decompensated HF. An amyloidosis workup was recommended, but due to intermittent periods of being lost to follow-up, the patient did not pursue this workup until 3 years after his initial presentation when 99mTC pyrophosphate imaging confirmed ATTR-CM. The patient declined tafamidis and continued to be followed by the cardiology team. His HF is managed with furosemide as needed due to intolerance to GDMT.

Case 8

A 74-year-old male with history of bilateral CTS presented with right-sided chest pain associated with shortness of breath, diaphoresis, dizziness, and worsening abdominal pain. He was found to have inferior wall myocardial infarction on ECG with later percutaneous coronary intervention to the left circumflex. His hospital course was complicated by decompensated HF (EF 45% to 50%) and AF with rapid ventricular response. He was treated and discharged with follow-up visits scheduled in the cardiology clinic. Multiple attempts were made to place him on GDMT; however, the patient was unable to tolerate these medications due to recurrent admissions for syncope. During a cardiology clinic visit 3 years after his initial presentation, an amyloidosis workup was initiated. 99mTC pyrophosphate imaging was positive for ATTR-CM, and he started taking tafamidis. Before this diagnosis, ECG indicated low-voltage QRS complexes. His progression has since been complicated by admissions for decompensated HF, recurrent episodes of AF requiring atrioventricular node ablation, and biventricular implantable cardioverter-defibrillator implantation after failed attempts at electrical cardioversion. He continued to follow up in the HF clinic.

Discussion

ATTR-CM is an underdiagnosed cause of cardiomyopathy, particularly in older adults. TTR is a transport protein produced in the liver, and misfolding can occur due to age-related instability of the wild-type protein (wtATTR) or pathologic variants in the TTR (hATTR). The misfolding leads to restrictive physiology, HF (often with preserved EF) arrhythmias, and conduction system disease.¹ It is likely that the predominantly older male veteran population would be predisposed to wtATTR cardiomyopathy given that misfolding in the condition is believed to be age-related.

Current criteria for ATTR diagnosis require a combination of clinical suspicion, imaging, laboratory testing, and, in some cases, tissue biopsy confirmation and genetic testing.^1,4,5 The diagnostic algorithm is as follows:

Clinical suspicion. Consider ATTR in patients with unexplained HFpEF, LV wall thickness ≥ 12 to 14 mm, discordance between ECG voltage and wall thickness, or associated extracardiac manifestations such as CTS, lumbar spinal stenosis, or peripheral/ autonomic neuropathy.

Exclusion of AL amyloidosis. Bone scintigraphy alone cannot distinguish between AL amyloidosis and ATTR, so patients with suspected amyloid cardiomyopathy should undergo serum and urine immunofixation electrophoresis and serum free light chain assay to rule out a monoclonal gammopathy as seen in AL amyloidosis.

Cardiac scintigraphy. Once AL amyloidosis is excluded, a positive 99mTC-labeled boneavid tracer image (such as a pyrophosphate scan) with grade 2 or grade 3 myocardial uptake is diagnostic of ATTR.

Tissue biopsy. If there is monoclonal gammopathy or equivocal imaging, tissue biopsy (eg, endomyocardial) with Congo red staining and amyloid typing by mass spectrometry or immunohistochemistry is necessary.

Genetic testing. Once ATTR is confirmed, genetic testing distinguishes hATTR from wtATTR, which impacts management and determines the need to screen family members.

Currently, there are 3 therapies approved by the US Food and Drug Administration (FDA) to treat ATTR-CM: tafamidis, acoramidis, and vutrisiran.^6-8 Tafamidis and acoramidis stabilize the TTR tetramer, preventing amyloid formation. Vutrisiran uses RNA interference to silence the gene that produces TTR. Tafamidis has been found to improve cardiovascular outcomes in ATTR-CM. In the ATTR-ACT trial, it reduced all-cause mortality and cardiovascular hospitalizations in patients with ATTR-CM and New York Heart Association class I-III symptoms.⁶ There are other disease-modifying therapies, such the TTR gene silencers inotersen and patisiran; however, these are only FDA-approved for hATTR polyneuropathy and not for ATTRCM; ongoing trials are evaluating their cardiac efficacy.

The mean age of ATTR-CM diagnosis in the patients described in this case series was 79 years, which is older than the mean age of 74 years reported in prior research.⁴ All patients were male, and the most common presenting symptom was dyspnea on exertion. Table 1 outlines baseline characteristics and associated comorbidities of patients in this case series. The patients presented with many red-flag signs of ATTR-CM (Figure 3). Among them included syncope (4 of 8 patients), spinal stenosis (2 of 8 patients), arrhythmia (7 of 8 patients), heart failure (7 of 8 patients), and bilateral CTS (all patients).

Bilateral CTS was diagnosed in all patients before their diagnosis of ATTR-CM. Patient 7 had a diagnosis of CTS 9 years before his ATTR-CM diagnosis, underscoring a subtle, yet important extracardiac sign that may increase clinical suspicion for ATTR-CM. Previous research found that the probability of having CTS is highest 5 to 9 years prior to the development of cardiomyopathy. Its presence is also a prognostic marker in ATTR, independent of cardiac involvement.⁹ The median interval between CTS diagnosis and cardiomyopathy diagnosis was 5 years in this series.

Although screening criteria for ATTR have been proposed, none have been incorporated into formal guidelines.^10,11 We propose that a baseline ECG and screening TTE be obtained in any patient aged > 65 years with cardiac risk equivalents such as hypertension and diabetes, presenting with ≥ 1 extracardiac red-flag signs, such as bilateral CTS and spinal stenosis. This will likely facilitate an earlier diagnosis of ATTR-CM, leading to earlier treatment initiation and better patient outcomes. This initiative can be started in the primary care setting and facilitates early cardiology referral. This recommendation is based on literature supporting clinical patterns and observations the authors have made in clinical practice.

Obstructive sleep apnea (OSA) was a comorbidity present in 50% of the patients described in this case series. The literature describing this association is sparse; however, a prospective observational study reported that disorders of sleep inclusive of OSA are frequent in patients with cardiac amyloidosis.¹² A theory behind this association is that amyloid deposits in the upper airway tissues lead to airway narrowing. ¹³ More research is needed to further assess the relationship between OSA and cardiac amyloidosis, particularly with respect to the timing of OSA prior to the development of cardiomyopathy as it may be a potential early sign for clinicians to acknowledge.

An important observation from this case series is the variability in the timing of tafamidis initiation relative to symptom onset and confirmed diagnosis of ATTR-CM (Table 2). Although tafamidis has been found to slow disease progression, several patients in this series began treatment at advanced stages or years after the onset of cardiac symptoms, potentially limiting its clinical benefit.

For example, patient 1 was diagnosed with ATTR 2 years before tafamidis became available on the market and was initially treated with diflunisal. Patients who started tafamidis earlier in the disease course (eg, patients 3 and 5) appeared to have better long-term outcomes, including an absence of heart failure hospitalizations after initiation. In contrast, patients with delayed treatment initiation (eg, patients 2, 6, and 8) experienced ongoing decompensations or early mortality. Patient 7 declined tafamidis, underscoring challenges in medication uptake among older adults. Randomized controlled trials are warranted to compare the effectiveness of tafamidis with other recently FDA-approved therapies, such as acoramidis and vutrisiran, particularly in terms of cardiovascular outcomes.

AF was the most common arrhythmia observed in these patients and may occur years before the development of HF symptoms in the setting of ATTR-CM. Due to inherent conduction system disease, AF in this population may have a controlled or slow ventricular response, as observed in patient 4. Patients with atrial fibrillation and cardiac amyloidosis should receive anticoagulation regardless of CHA2DS2- VASc score due to their high risk of intracardiac thrombus formation.⁴

Limitations

This case series lacked genetic testing following a confirmed ATTR-CM diagnosis. Although much of the treatment is the same regardless of the presence of a TTR mutation, knowing the specific subtype of ATTR-CM has implications for prognosis and for screening family members.

Conclusions

Following analysis of 8 patients diagnosed with ATTR, this case series could serve as a blueprint for research into ATTR in veterans. In clinical practice, following military service, veterans may not be routinely seen by an outpatient physician and may present with sequelae of advanced stages of ATTR. Early identification of red-flag symptoms can lead to a higher clinical suspicion, prompting early diagnostic evaluation and treatment initiation and ultimately mitigating adverse outcomes. Future research that includes genetic testing for those with confirmed ATTR-CM may prove useful as a foundation for detailed and informed discussions with patients and their families regarding prognosis and, if indicated, screening for family members.

Atopic dermatitis (AD) is a chronic skin condition generally characterized by pruritic and erythematous papules and plaques.¹ While AD commonly manifests in childhood, 1 in 4 patients living with AD report adult onset of the disease.² The clinical presentation and prevalence of AD vary across age groups, skin tones, and racial and ethnic groups. Globally, AD is estimated to have a prevalence of 2.6%; however, rates vary widely by region.¹ Morphology and distribution of AD lesions also vary by population; therefore, defining one classic presentation of AD is not sufficient in diverse patient populations.³

Epidemiology

The prevalence of AD ranges from 0.2% to 24.6% worldwide, with higher rates in Africa and Oceania and lower rates in India and Northern and Eastern Europe.¹ In the United States, AD affects all racial and ethnic groups; however, prevalence and severity are increased in Black children compared with White children.⁴ In one prospective cohort study, Hispanic children and non-Hispanic Black children aged 3 years and younger had greater odds of AD persisting into mid childhood (approximately age 7 years) compared with non-Hispanic White children.^5,6

Key Clinical Features

Clinical features of AD are heterogeneous and may include differences in color, morphology, and distribution. Brown, hyperpigmented, gray, and/or violaceous plaques may predominate in patients with skin of color (SOC) compared with the erythematous plaques commonly described in lighter skin tones.^1,3 Established scoring systems for AD rely on erythema as a key diagnostic feature, but because erythema can be difficult to detect in darker skin tones, disease severity may be underestimated and diagnosis may be delayed in this population.⁴

Atopic dermatitis in SOC may manifest as lichenoid plaques,⁷ prurigo nodules,^7,8 lichenification,¹ and follicular accentuation.⁹ Lichen planus–like AD is a distinct variant characterized by lichenoid plaques with a predilection for the extensor surfaces and face in patients with darker skin tones^1,8 occurring in approximately 9% of patients in one study.¹⁰

Other key clinical features of AD in patients with SOC include pityriasis alba,¹⁰ increased risk for postinflammatory pigment alteration (including hyperpigmentation and/or hypopigmentation),¹ and greater trunk and extensor involvement.^1,11

Worth Noting

The scientific landscape for AD has grown rapidly, increasing our understanding of its pathophysiology, treatment, and social impact. Nonsteroidal treatments available for pediatric and adult patients with AD have increased in recent years, including crisaborole (approved for use in those ages ≥ 3 months), tacrolimus (≥ 2 years), and pimecrolimus (≥ 2 years). Injectable options include dupilumab (≥ 6 months), lebrikizumab (≥ 12 years), nemolizumab (≥ 12 years), and tralokinumab (≥ 12 years). Oral options include abrocitinib (≥ 12 years) and upadacitinib (≥ 12 years).¹² Topical options include roflumilast 0.15% cream (≥ 6 years)¹² and 0.05% cream (≥ 2-5 years),¹³ ruxolitinib 1.5% cream (≥ 2 years),¹⁴ and tapinarof 1% cream (≥ 2 years).¹²

For some patients, postinflammatory pigment alteration associated with AD has a higher impact on quality of life than the AD itself.⁷ In a study of 260 US adults with AD, the emotional impact of pigmentary changes was greatest in Black patients, with 53.3% reporting that pigment changes bothered them “a lot” or “very much.”¹⁵

Genome-wide association studies have not identified a single determinant that explains racial and ethnic differences in susceptibility to AD.⁴ Instead, social determinants of health are thought to play a role in the difference in AD prevalence and severity across groups in the United States.¹⁶

Health Disparity Highlight

In an analysis of 20 US metropolitan cities, urban and inner-city residence was associated with approximately 1.7-fold increased odds of AD.⁴ Among pediatric patients with moderate to severe AD, Black children were more likely to be exposed to tobacco smoke¹⁷ and traffic-related air pollution.¹⁸ Low socioeconomic status and low income also have been associated with moderate¹⁶ and severe¹⁹ AD. At the same education level, Black individuals in the United States receive less income than their White counterparts and have markedly less wealth at equivalent incomes.²⁰

In utero exposure to maternal stress is associated with AD.⁴ Increased IgE levels have been recorded in children who develop AD, with Black children having the highest IgE levels overall compared to other children.¹⁸

An analysis of medical records from an urban medical center in Baltimore, Maryland, from 2013 through 2018 showed that Black patients with AD were less likely to receive topical corticosteroids, topical calcineurin inhibitors, a topical phosphodiesterase 4 inhibitor, and a biologic compared to White patients with AD.²¹

Since the disproportionate burden experienced by patients with AD is not physiologic, it is imperative to address these systemic complexities and address the barriers impacting treatment availability to improve health outcomes for all patients living with AD.

Atopic dermatitis (AD) is a chronic skin condition generally characterized by pruritic and erythematous papules and plaques.¹ While AD commonly manifests in childhood, 1 in 4 patients living with AD report adult onset of the disease.² The clinical presentation and prevalence of AD vary across age groups, skin tones, and racial and ethnic groups. Globally, AD is estimated to have a prevalence of 2.6%; however, rates vary widely by region.¹ Morphology and distribution of AD lesions also vary by population; therefore, defining one classic presentation of AD is not sufficient in diverse patient populations.³

Epidemiology

The prevalence of AD ranges from 0.2% to 24.6% worldwide, with higher rates in Africa and Oceania and lower rates in India and Northern and Eastern Europe.¹ In the United States, AD affects all racial and ethnic groups; however, prevalence and severity are increased in Black children compared with White children.⁴ In one prospective cohort study, Hispanic children and non-Hispanic Black children aged 3 years and younger had greater odds of AD persisting into mid childhood (approximately age 7 years) compared with non-Hispanic White children.^5,6

Key Clinical Features

Clinical features of AD are heterogeneous and may include differences in color, morphology, and distribution. Brown, hyperpigmented, gray, and/or violaceous plaques may predominate in patients with skin of color (SOC) compared with the erythematous plaques commonly described in lighter skin tones.^1,3 Established scoring systems for AD rely on erythema as a key diagnostic feature, but because erythema can be difficult to detect in darker skin tones, disease severity may be underestimated and diagnosis may be delayed in this population.⁴

Atopic dermatitis in SOC may manifest as lichenoid plaques,⁷ prurigo nodules,^7,8 lichenification,¹ and follicular accentuation.⁹ Lichen planus–like AD is a distinct variant characterized by lichenoid plaques with a predilection for the extensor surfaces and face in patients with darker skin tones^1,8 occurring in approximately 9% of patients in one study.¹⁰

Other key clinical features of AD in patients with SOC include pityriasis alba,¹⁰ increased risk for postinflammatory pigment alteration (including hyperpigmentation and/or hypopigmentation),¹ and greater trunk and extensor involvement.^1,11

Worth Noting

The scientific landscape for AD has grown rapidly, increasing our understanding of its pathophysiology, treatment, and social impact. Nonsteroidal treatments available for pediatric and adult patients with AD have increased in recent years, including crisaborole (approved for use in those ages ≥ 3 months), tacrolimus (≥ 2 years), and pimecrolimus (≥ 2 years). Injectable options include dupilumab (≥ 6 months), lebrikizumab (≥ 12 years), nemolizumab (≥ 12 years), and tralokinumab (≥ 12 years). Oral options include abrocitinib (≥ 12 years) and upadacitinib (≥ 12 years).¹² Topical options include roflumilast 0.15% cream (≥ 6 years)¹² and 0.05% cream (≥ 2-5 years),¹³ ruxolitinib 1.5% cream (≥ 2 years),¹⁴ and tapinarof 1% cream (≥ 2 years).¹²

For some patients, postinflammatory pigment alteration associated with AD has a higher impact on quality of life than the AD itself.⁷ In a study of 260 US adults with AD, the emotional impact of pigmentary changes was greatest in Black patients, with 53.3% reporting that pigment changes bothered them “a lot” or “very much.”¹⁵

Genome-wide association studies have not identified a single determinant that explains racial and ethnic differences in susceptibility to AD.⁴ Instead, social determinants of health are thought to play a role in the difference in AD prevalence and severity across groups in the United States.¹⁶

Health Disparity Highlight

In an analysis of 20 US metropolitan cities, urban and inner-city residence was associated with approximately 1.7-fold increased odds of AD.⁴ Among pediatric patients with moderate to severe AD, Black children were more likely to be exposed to tobacco smoke¹⁷ and traffic-related air pollution.¹⁸ Low socioeconomic status and low income also have been associated with moderate¹⁶ and severe¹⁹ AD. At the same education level, Black individuals in the United States receive less income than their White counterparts and have markedly less wealth at equivalent incomes.²⁰

In utero exposure to maternal stress is associated with AD.⁴ Increased IgE levels have been recorded in children who develop AD, with Black children having the highest IgE levels overall compared to other children.¹⁸

An analysis of medical records from an urban medical center in Baltimore, Maryland, from 2013 through 2018 showed that Black patients with AD were less likely to receive topical corticosteroids, topical calcineurin inhibitors, a topical phosphodiesterase 4 inhibitor, and a biologic compared to White patients with AD.²¹

Since the disproportionate burden experienced by patients with AD is not physiologic, it is imperative to address these systemic complexities and address the barriers impacting treatment availability to improve health outcomes for all patients living with AD.

Atopic dermatitis (AD) is a chronic skin condition generally characterized by pruritic and erythematous papules and plaques.¹ While AD commonly manifests in childhood, 1 in 4 patients living with AD report adult onset of the disease.² The clinical presentation and prevalence of AD vary across age groups, skin tones, and racial and ethnic groups. Globally, AD is estimated to have a prevalence of 2.6%; however, rates vary widely by region.¹ Morphology and distribution of AD lesions also vary by population; therefore, defining one classic presentation of AD is not sufficient in diverse patient populations.³

Epidemiology

The prevalence of AD ranges from 0.2% to 24.6% worldwide, with higher rates in Africa and Oceania and lower rates in India and Northern and Eastern Europe.¹ In the United States, AD affects all racial and ethnic groups; however, prevalence and severity are increased in Black children compared with White children.⁴ In one prospective cohort study, Hispanic children and non-Hispanic Black children aged 3 years and younger had greater odds of AD persisting into mid childhood (approximately age 7 years) compared with non-Hispanic White children.^5,6

Key Clinical Features

Clinical features of AD are heterogeneous and may include differences in color, morphology, and distribution. Brown, hyperpigmented, gray, and/or violaceous plaques may predominate in patients with skin of color (SOC) compared with the erythematous plaques commonly described in lighter skin tones.^1,3 Established scoring systems for AD rely on erythema as a key diagnostic feature, but because erythema can be difficult to detect in darker skin tones, disease severity may be underestimated and diagnosis may be delayed in this population.⁴

Atopic dermatitis in SOC may manifest as lichenoid plaques,⁷ prurigo nodules,^7,8 lichenification,¹ and follicular accentuation.⁹ Lichen planus–like AD is a distinct variant characterized by lichenoid plaques with a predilection for the extensor surfaces and face in patients with darker skin tones^1,8 occurring in approximately 9% of patients in one study.¹⁰

Other key clinical features of AD in patients with SOC include pityriasis alba,¹⁰ increased risk for postinflammatory pigment alteration (including hyperpigmentation and/or hypopigmentation),¹ and greater trunk and extensor involvement.^1,11

Worth Noting

The scientific landscape for AD has grown rapidly, increasing our understanding of its pathophysiology, treatment, and social impact. Nonsteroidal treatments available for pediatric and adult patients with AD have increased in recent years, including crisaborole (approved for use in those ages ≥ 3 months), tacrolimus (≥ 2 years), and pimecrolimus (≥ 2 years). Injectable options include dupilumab (≥ 6 months), lebrikizumab (≥ 12 years), nemolizumab (≥ 12 years), and tralokinumab (≥ 12 years). Oral options include abrocitinib (≥ 12 years) and upadacitinib (≥ 12 years).¹² Topical options include roflumilast 0.15% cream (≥ 6 years)¹² and 0.05% cream (≥ 2-5 years),¹³ ruxolitinib 1.5% cream (≥ 2 years),¹⁴ and tapinarof 1% cream (≥ 2 years).¹²

For some patients, postinflammatory pigment alteration associated with AD has a higher impact on quality of life than the AD itself.⁷ In a study of 260 US adults with AD, the emotional impact of pigmentary changes was greatest in Black patients, with 53.3% reporting that pigment changes bothered them “a lot” or “very much.”¹⁵

Genome-wide association studies have not identified a single determinant that explains racial and ethnic differences in susceptibility to AD.⁴ Instead, social determinants of health are thought to play a role in the difference in AD prevalence and severity across groups in the United States.¹⁶

Health Disparity Highlight

In an analysis of 20 US metropolitan cities, urban and inner-city residence was associated with approximately 1.7-fold increased odds of AD.⁴ Among pediatric patients with moderate to severe AD, Black children were more likely to be exposed to tobacco smoke¹⁷ and traffic-related air pollution.¹⁸ Low socioeconomic status and low income also have been associated with moderate¹⁶ and severe¹⁹ AD. At the same education level, Black individuals in the United States receive less income than their White counterparts and have markedly less wealth at equivalent incomes.²⁰

In utero exposure to maternal stress is associated with AD.⁴ Increased IgE levels have been recorded in children who develop AD, with Black children having the highest IgE levels overall compared to other children.¹⁸

An analysis of medical records from an urban medical center in Baltimore, Maryland, from 2013 through 2018 showed that Black patients with AD were less likely to receive topical corticosteroids, topical calcineurin inhibitors, a topical phosphodiesterase 4 inhibitor, and a biologic compared to White patients with AD.²¹

Since the disproportionate burden experienced by patients with AD is not physiologic, it is imperative to address these systemic complexities and address the barriers impacting treatment availability to improve health outcomes for all patients living with AD.

The heart is one of the organs least likely to develop cancer, a long-standing biologic puzzle that may now have an explanation. A study published in Science found that the mechanical load generated by the beating heart suppresses tumor cell proliferation through a molecular pathway that alters gene expression, raising the possibility of new therapeutic targets.

Mechanical Protection

Tumors that originate directly in the myocardium are exceptionally rare, occurring in < 1% of autopsies. Even cardiac metastases, which have been reported in up to 18% of autopsies, are often small, asymptomatic, and incidentally discovered. Although this phenomenon has long been recognized, its biologic basis remains unclear.

The heart is notable for its limited capacity for regeneration. After birth, cardiomyocytes stop dividing and subsequently renew at a rate of about 1% per year. However, when the mechanical load is reduced, such as in patients supported by left ventricular assist devices, cardiomyocytes once again show signs of proliferation.

This observation prompted researchers to investigate whether the same mechanical load that restrains normal cardiac cells might also suppress cancer growth.

More Load, Less Growth

To investigate this question, researchers introduced two genetic alterations commonly found in human cancers, activation of the KRAS oncogene and loss of the TP53, into the liver, skeletal muscle, and hearts of mice. Tumors developed in multiple organs, but not in the heart.

The researchers then used a heterotopic heart transplant model in which a donor mouse’s heart is surgically connected to the neck (cervical) or abdominal vessels of a recipient mouse. The transplanted heart remained perfused but lost its normal mechanical loading (constant beating).

When researchers injected lung adenocarcinoma cells into 2 different hearts of the same animal, they observed entirely different outcomes. The cancer cells did not grow in the native mechanically loaded heart. However, the same cells grew rapidly and extensively in the mechanically unloaded transplanted heart.

Tumor cells had replaced nearly all normal tissue in the unloaded heart, whereas they occupied only approximately 20% of the ventricle in the native heart in 14 days. This difference could not be explained by differences in the initial tumor engraftment or cell death. Instead, the findings pointed to substantial differences in tumor cell proliferation.

Similar results were observed in bioengineered cardiac tissues exposed to varying degrees of mechanical stress. Tumor cells proliferated under conditions of low mechanical load but ceased proliferating as the mechanical load increased. Tumor growth was lowest in regions exposed to the greatest mechanical stimulation of cardiomyocytes in vitro.

However, the possibility of metabolic competition between cardiac and tumor cells for nutrition was ruled out.

From Mechanics to Genes

Next, we examined the influence of mechanical forces on tumor cell behavior.

Gene expression analyses of both human cardiac metastases and mouse tumor cells showed that mechanical stimulation altered chromatin accessibility through the activation of genes involved in chromatin remodeling. These changes promoted the expression of genes that suppress cell division.

The study also identified Nesprin-2, a part of the linker of the nucleoskeleton and cytoskeleton complex, which acts as a physical bridge. It is a multitasking protein that connects the cell’s outer structural network (cytoskeleton) to its inner genetic storage (nucleus) and appears to play a significant role in converting mechanical signals into changes in gene expression.

When Nesprin-2 was inactivated, cancer cells resumed proliferation despite exposure to a mechanical load, both in engineered tissues and animal models.

“Collectively, these results shed light on the role of mechanical forces in protecting the heart from cancer and may pave the way to cancer therapies based on mechanical stimulation,” concluded the authors.

An Actively Protected Organ

Speaking with Univadis Italy, part of the Medscape Professional Network, Giorgio Scita, PhD, director of the Mechanisms of Tumor Cell Migration research unit at AIRC Institute of Molecular Oncology and professor of general pathology at the University of Milan in Milan, Italy, said, “The study addressed a simple but fundamental question: Why is the heart largely resistant to cancer despite being highly vascularized and continuously exposed to circulating tumor cells?

These findings suggest that the heartbeat itself creates a mechanical environment that is hostile to tumor growth. The compressive forces generated by rhythmic myocardial contraction are sensed by cancer cells and translated into biochemical signals that limit their proliferation.

In this view, the heart is not simply an organ that is unfavorable for cancer growth but a tissue actively protected by its own mechanical forces.”

Speaking with Univadis Italy, Serena Zacchigna, PhD, study coauthor and head of the Cardiovascular Biology Laboratory at the International Centre for Genetic Engineering and Biotechnology, Trieste, Italy, said, “Until now, however, attention had focused primarily on signals from the extracellular matrix, such as tissue stiffness. Our study adds a new element: even forces generated directly by the movement of an organ — in this case, cardiac contraction — can influence the growth of cancer cells.”

Beyond the Heart

Scita said the findings have implications that extend well beyond the heart.

“The most significant aspect is that this work identifies tissue mechanics as an active regulator of tumor behavior,” he said. Stiffness, compression, tension, and confinement are not merely consequences of tumor growth, but factors capable of influencing proliferation, invasion, and dormancy.

The concept may apply to many solid tumors. Scita noted that cancer cells growing in confined environments, such as ductal carcinoma in situ of the breast, are exposed to substantial mechanical constraints. Understanding why some tumor cells remain susceptible to these forces whereas others evade them and become invasive remains a major unanswered question in cancer biology.

Research on these mechanisms is expanding internationally and in Italy as well. One example is the AIRC “5 per mille” (5 per thousand) research programs on metastatic disease, which includes projects designed to clarify how the mechanical properties of tumor tissue influence cancer initiation, metastatic spread, and disease progression.

Therapeutic Potential

According to Zacchigna, these findings open 2 principal avenues for future research.

“The first focuses on mechanical stimulation itself. In collaboration with engineers at the University of Siena, including a group led by Domenico Prattichizzo, researchers are developing wearable robotic devices designed to mimic the heartbeat and deliver mechanical stimulation to superficial solid tumors such as certain skin cancers.

The second approach is pharmacology. Researchers are investigating whether epigenetic therapies capable of modifying chromatin remodeling can reproduce the effects of cardiac contraction and suppress tumor cell proliferation.

However, Zacchigna cautioned that this work remains at an early experimental phase.”

However, before therapeutic applications can be pursued, important mechanistic questions remain unanswered.

Zacchigna noted that although the linker of nucleoskeleton and cytoskeleton (LINC) complex and Nesprin-2 are involved in signal transduction leading to chromatin reorganization and activation of cell cycle inhibitory loci, the molecular intermediates involved have yet to be fully defined.

Researchers also need to determine which genes are most critical, whether the mechanism operates across different tumor types, and whether it can be safely manipulated for therapeutic purposes.

In an accompanying commentary published in Science, Wyatt G. Paltzer, PhD, and James F. Martin, MD, from the Department of Integrative Physiology at the Baylor College of Medicine in Houston, noted that the findings suggest enhancing LINC complex activity could potentially suppress tumor growth.

However, because the complex has broad biologic functions, it may prove difficult to target therapeutically. The authors suggested that future studies should focus on identifying proteins that interact with Nesprin-2 or other components of the LINC complex and play a more specific role in inhibiting cancer cell proliferation.

Looking Ahead

Despite these challenges, Scita said that the study’s conceptual significance is already clear.

“Even if therapeutic applications remain years away, the findings suggest that cancer may one day be targeted by altering how tumor cells perceive and interpret physical forces.”

Scita and Zacchigna reported having no relevant conflicts of interest.

This story was translated from Univadis Italy.

A version of this article first appeared on Medscape.com.

The heart is one of the organs least likely to develop cancer, a long-standing biologic puzzle that may now have an explanation. A study published in Science found that the mechanical load generated by the beating heart suppresses tumor cell proliferation through a molecular pathway that alters gene expression, raising the possibility of new therapeutic targets.

Mechanical Protection

Tumors that originate directly in the myocardium are exceptionally rare, occurring in < 1% of autopsies. Even cardiac metastases, which have been reported in up to 18% of autopsies, are often small, asymptomatic, and incidentally discovered. Although this phenomenon has long been recognized, its biologic basis remains unclear.

The heart is notable for its limited capacity for regeneration. After birth, cardiomyocytes stop dividing and subsequently renew at a rate of about 1% per year. However, when the mechanical load is reduced, such as in patients supported by left ventricular assist devices, cardiomyocytes once again show signs of proliferation.

This observation prompted researchers to investigate whether the same mechanical load that restrains normal cardiac cells might also suppress cancer growth.

More Load, Less Growth

To investigate this question, researchers introduced two genetic alterations commonly found in human cancers, activation of the KRAS oncogene and loss of the TP53, into the liver, skeletal muscle, and hearts of mice. Tumors developed in multiple organs, but not in the heart.

The researchers then used a heterotopic heart transplant model in which a donor mouse’s heart is surgically connected to the neck (cervical) or abdominal vessels of a recipient mouse. The transplanted heart remained perfused but lost its normal mechanical loading (constant beating).

When researchers injected lung adenocarcinoma cells into 2 different hearts of the same animal, they observed entirely different outcomes. The cancer cells did not grow in the native mechanically loaded heart. However, the same cells grew rapidly and extensively in the mechanically unloaded transplanted heart.

Tumor cells had replaced nearly all normal tissue in the unloaded heart, whereas they occupied only approximately 20% of the ventricle in the native heart in 14 days. This difference could not be explained by differences in the initial tumor engraftment or cell death. Instead, the findings pointed to substantial differences in tumor cell proliferation.

Similar results were observed in bioengineered cardiac tissues exposed to varying degrees of mechanical stress. Tumor cells proliferated under conditions of low mechanical load but ceased proliferating as the mechanical load increased. Tumor growth was lowest in regions exposed to the greatest mechanical stimulation of cardiomyocytes in vitro.

However, the possibility of metabolic competition between cardiac and tumor cells for nutrition was ruled out.

From Mechanics to Genes

Next, we examined the influence of mechanical forces on tumor cell behavior.

Gene expression analyses of both human cardiac metastases and mouse tumor cells showed that mechanical stimulation altered chromatin accessibility through the activation of genes involved in chromatin remodeling. These changes promoted the expression of genes that suppress cell division.

The study also identified Nesprin-2, a part of the linker of the nucleoskeleton and cytoskeleton complex, which acts as a physical bridge. It is a multitasking protein that connects the cell’s outer structural network (cytoskeleton) to its inner genetic storage (nucleus) and appears to play a significant role in converting mechanical signals into changes in gene expression.

When Nesprin-2 was inactivated, cancer cells resumed proliferation despite exposure to a mechanical load, both in engineered tissues and animal models.

“Collectively, these results shed light on the role of mechanical forces in protecting the heart from cancer and may pave the way to cancer therapies based on mechanical stimulation,” concluded the authors.

An Actively Protected Organ

Speaking with Univadis Italy, part of the Medscape Professional Network, Giorgio Scita, PhD, director of the Mechanisms of Tumor Cell Migration research unit at AIRC Institute of Molecular Oncology and professor of general pathology at the University of Milan in Milan, Italy, said, “The study addressed a simple but fundamental question: Why is the heart largely resistant to cancer despite being highly vascularized and continuously exposed to circulating tumor cells?

These findings suggest that the heartbeat itself creates a mechanical environment that is hostile to tumor growth. The compressive forces generated by rhythmic myocardial contraction are sensed by cancer cells and translated into biochemical signals that limit their proliferation.

In this view, the heart is not simply an organ that is unfavorable for cancer growth but a tissue actively protected by its own mechanical forces.”

Speaking with Univadis Italy, Serena Zacchigna, PhD, study coauthor and head of the Cardiovascular Biology Laboratory at the International Centre for Genetic Engineering and Biotechnology, Trieste, Italy, said, “Until now, however, attention had focused primarily on signals from the extracellular matrix, such as tissue stiffness. Our study adds a new element: even forces generated directly by the movement of an organ — in this case, cardiac contraction — can influence the growth of cancer cells.”

Beyond the Heart

Scita said the findings have implications that extend well beyond the heart.

“The most significant aspect is that this work identifies tissue mechanics as an active regulator of tumor behavior,” he said. Stiffness, compression, tension, and confinement are not merely consequences of tumor growth, but factors capable of influencing proliferation, invasion, and dormancy.

The concept may apply to many solid tumors. Scita noted that cancer cells growing in confined environments, such as ductal carcinoma in situ of the breast, are exposed to substantial mechanical constraints. Understanding why some tumor cells remain susceptible to these forces whereas others evade them and become invasive remains a major unanswered question in cancer biology.

Research on these mechanisms is expanding internationally and in Italy as well. One example is the AIRC “5 per mille” (5 per thousand) research programs on metastatic disease, which includes projects designed to clarify how the mechanical properties of tumor tissue influence cancer initiation, metastatic spread, and disease progression.

Therapeutic Potential

According to Zacchigna, these findings open 2 principal avenues for future research.

“The first focuses on mechanical stimulation itself. In collaboration with engineers at the University of Siena, including a group led by Domenico Prattichizzo, researchers are developing wearable robotic devices designed to mimic the heartbeat and deliver mechanical stimulation to superficial solid tumors such as certain skin cancers.

The second approach is pharmacology. Researchers are investigating whether epigenetic therapies capable of modifying chromatin remodeling can reproduce the effects of cardiac contraction and suppress tumor cell proliferation.

However, Zacchigna cautioned that this work remains at an early experimental phase.”

However, before therapeutic applications can be pursued, important mechanistic questions remain unanswered.

Zacchigna noted that although the linker of nucleoskeleton and cytoskeleton (LINC) complex and Nesprin-2 are involved in signal transduction leading to chromatin reorganization and activation of cell cycle inhibitory loci, the molecular intermediates involved have yet to be fully defined.

Researchers also need to determine which genes are most critical, whether the mechanism operates across different tumor types, and whether it can be safely manipulated for therapeutic purposes.

In an accompanying commentary published in Science, Wyatt G. Paltzer, PhD, and James F. Martin, MD, from the Department of Integrative Physiology at the Baylor College of Medicine in Houston, noted that the findings suggest enhancing LINC complex activity could potentially suppress tumor growth.

However, because the complex has broad biologic functions, it may prove difficult to target therapeutically. The authors suggested that future studies should focus on identifying proteins that interact with Nesprin-2 or other components of the LINC complex and play a more specific role in inhibiting cancer cell proliferation.

Looking Ahead

Despite these challenges, Scita said that the study’s conceptual significance is already clear.

“Even if therapeutic applications remain years away, the findings suggest that cancer may one day be targeted by altering how tumor cells perceive and interpret physical forces.”

Scita and Zacchigna reported having no relevant conflicts of interest.

This story was translated from Univadis Italy.

A version of this article first appeared on Medscape.com.

The heart is one of the organs least likely to develop cancer, a long-standing biologic puzzle that may now have an explanation. A study published in Science found that the mechanical load generated by the beating heart suppresses tumor cell proliferation through a molecular pathway that alters gene expression, raising the possibility of new therapeutic targets.

Mechanical Protection

Tumors that originate directly in the myocardium are exceptionally rare, occurring in < 1% of autopsies. Even cardiac metastases, which have been reported in up to 18% of autopsies, are often small, asymptomatic, and incidentally discovered. Although this phenomenon has long been recognized, its biologic basis remains unclear.

The heart is notable for its limited capacity for regeneration. After birth, cardiomyocytes stop dividing and subsequently renew at a rate of about 1% per year. However, when the mechanical load is reduced, such as in patients supported by left ventricular assist devices, cardiomyocytes once again show signs of proliferation.

This observation prompted researchers to investigate whether the same mechanical load that restrains normal cardiac cells might also suppress cancer growth.

More Load, Less Growth

To investigate this question, researchers introduced two genetic alterations commonly found in human cancers, activation of the KRAS oncogene and loss of the TP53, into the liver, skeletal muscle, and hearts of mice. Tumors developed in multiple organs, but not in the heart.

The researchers then used a heterotopic heart transplant model in which a donor mouse’s heart is surgically connected to the neck (cervical) or abdominal vessels of a recipient mouse. The transplanted heart remained perfused but lost its normal mechanical loading (constant beating).

When researchers injected lung adenocarcinoma cells into 2 different hearts of the same animal, they observed entirely different outcomes. The cancer cells did not grow in the native mechanically loaded heart. However, the same cells grew rapidly and extensively in the mechanically unloaded transplanted heart.

Tumor cells had replaced nearly all normal tissue in the unloaded heart, whereas they occupied only approximately 20% of the ventricle in the native heart in 14 days. This difference could not be explained by differences in the initial tumor engraftment or cell death. Instead, the findings pointed to substantial differences in tumor cell proliferation.

Similar results were observed in bioengineered cardiac tissues exposed to varying degrees of mechanical stress. Tumor cells proliferated under conditions of low mechanical load but ceased proliferating as the mechanical load increased. Tumor growth was lowest in regions exposed to the greatest mechanical stimulation of cardiomyocytes in vitro.

However, the possibility of metabolic competition between cardiac and tumor cells for nutrition was ruled out.

From Mechanics to Genes

Next, we examined the influence of mechanical forces on tumor cell behavior.

Gene expression analyses of both human cardiac metastases and mouse tumor cells showed that mechanical stimulation altered chromatin accessibility through the activation of genes involved in chromatin remodeling. These changes promoted the expression of genes that suppress cell division.

The study also identified Nesprin-2, a part of the linker of the nucleoskeleton and cytoskeleton complex, which acts as a physical bridge. It is a multitasking protein that connects the cell’s outer structural network (cytoskeleton) to its inner genetic storage (nucleus) and appears to play a significant role in converting mechanical signals into changes in gene expression.

When Nesprin-2 was inactivated, cancer cells resumed proliferation despite exposure to a mechanical load, both in engineered tissues and animal models.

“Collectively, these results shed light on the role of mechanical forces in protecting the heart from cancer and may pave the way to cancer therapies based on mechanical stimulation,” concluded the authors.

An Actively Protected Organ

Speaking with Univadis Italy, part of the Medscape Professional Network, Giorgio Scita, PhD, director of the Mechanisms of Tumor Cell Migration research unit at AIRC Institute of Molecular Oncology and professor of general pathology at the University of Milan in Milan, Italy, said, “The study addressed a simple but fundamental question: Why is the heart largely resistant to cancer despite being highly vascularized and continuously exposed to circulating tumor cells?

These findings suggest that the heartbeat itself creates a mechanical environment that is hostile to tumor growth. The compressive forces generated by rhythmic myocardial contraction are sensed by cancer cells and translated into biochemical signals that limit their proliferation.

In this view, the heart is not simply an organ that is unfavorable for cancer growth but a tissue actively protected by its own mechanical forces.”

Speaking with Univadis Italy, Serena Zacchigna, PhD, study coauthor and head of the Cardiovascular Biology Laboratory at the International Centre for Genetic Engineering and Biotechnology, Trieste, Italy, said, “Until now, however, attention had focused primarily on signals from the extracellular matrix, such as tissue stiffness. Our study adds a new element: even forces generated directly by the movement of an organ — in this case, cardiac contraction — can influence the growth of cancer cells.”

Beyond the Heart

Scita said the findings have implications that extend well beyond the heart.

“The most significant aspect is that this work identifies tissue mechanics as an active regulator of tumor behavior,” he said. Stiffness, compression, tension, and confinement are not merely consequences of tumor growth, but factors capable of influencing proliferation, invasion, and dormancy.

The concept may apply to many solid tumors. Scita noted that cancer cells growing in confined environments, such as ductal carcinoma in situ of the breast, are exposed to substantial mechanical constraints. Understanding why some tumor cells remain susceptible to these forces whereas others evade them and become invasive remains a major unanswered question in cancer biology.

Research on these mechanisms is expanding internationally and in Italy as well. One example is the AIRC “5 per mille” (5 per thousand) research programs on metastatic disease, which includes projects designed to clarify how the mechanical properties of tumor tissue influence cancer initiation, metastatic spread, and disease progression.

Therapeutic Potential

According to Zacchigna, these findings open 2 principal avenues for future research.

“The first focuses on mechanical stimulation itself. In collaboration with engineers at the University of Siena, including a group led by Domenico Prattichizzo, researchers are developing wearable robotic devices designed to mimic the heartbeat and deliver mechanical stimulation to superficial solid tumors such as certain skin cancers.

The second approach is pharmacology. Researchers are investigating whether epigenetic therapies capable of modifying chromatin remodeling can reproduce the effects of cardiac contraction and suppress tumor cell proliferation.

However, Zacchigna cautioned that this work remains at an early experimental phase.”

However, before therapeutic applications can be pursued, important mechanistic questions remain unanswered.

Zacchigna noted that although the linker of nucleoskeleton and cytoskeleton (LINC) complex and Nesprin-2 are involved in signal transduction leading to chromatin reorganization and activation of cell cycle inhibitory loci, the molecular intermediates involved have yet to be fully defined.

Researchers also need to determine which genes are most critical, whether the mechanism operates across different tumor types, and whether it can be safely manipulated for therapeutic purposes.

In an accompanying commentary published in Science, Wyatt G. Paltzer, PhD, and James F. Martin, MD, from the Department of Integrative Physiology at the Baylor College of Medicine in Houston, noted that the findings suggest enhancing LINC complex activity could potentially suppress tumor growth.

However, because the complex has broad biologic functions, it may prove difficult to target therapeutically. The authors suggested that future studies should focus on identifying proteins that interact with Nesprin-2 or other components of the LINC complex and play a more specific role in inhibiting cancer cell proliferation.

Looking Ahead

Despite these challenges, Scita said that the study’s conceptual significance is already clear.

“Even if therapeutic applications remain years away, the findings suggest that cancer may one day be targeted by altering how tumor cells perceive and interpret physical forces.”

Scita and Zacchigna reported having no relevant conflicts of interest.

This story was translated from Univadis Italy.

A version of this article first appeared on Medscape.com.

Oral nicotinamide was cost-effective for reducing keratinocyte carcinoma (KC) risk in US veterans with a history of the disease, according to an economic analysis of Veterans Health Administration (VHA) data.

The findings, published online June 10 in JAMA Dermatology, “support strong consideration of nicotinamide for KC prevention in high-risk populations like veterans, particularly given its safety and tolerability,” wrote senior author Rebecca I. Hartman, MD, chief of the Dermatology Section at VA Boston and assistant professor of dermatology at Brigham and Women’s Hospital and Harvard Medical School, Boston, and co-authors.

Nicotinamide supplementation is “not only a cost-effective and patient-centric strategy for KC prevention, but it also remains economically favorable under a range of assumptions and may become even more cost-effective under higher procedure costs and frequency,” noted the authors.

The analysis included 33,822 individuals from the VHA database, all with a history of one or more KCs, including those with nicotinamide exposure for 30 or more days (n = 12,287) and those without that exposure (n = 21,535).

The mean ages in the unexposed and exposed cohorts were 76.9 and 77.2 years, respectively, and 98% were men. Procedural US VHA costs for KC treatment were estimated from previous research and adjusted for inflation. Nicotinamide pricing was obtained from the VHA.

KC incidence among nicotinamide-exposed and unexposed individuals was 0.204 and 0.255 events per person-year, respectively, reflecting an absolute risk reduction of 0.051 and 624 KCs prevented annually with nicotinamide supplementation.

With an estimated cost of $843 per KC, the yearly KC treatment expense was estimated at approximately $2.64 million, and the annual nicotinamide cost was estimated at $161,451, resulting in net savings of $364,581 — a 19.9% reduction in cohort-specific costs.

Assuming a quality-adjusted life-year (QALY) decrement of -0.01 per KC, nicotinamide use yielded an annual gain of 6.24 QALYs across the cohort and a savings of $58,426 per QALY gained.

A calculation of non-VHA cost-effectiveness, estimated with civilian prices and distributions, showed savings of $14,407 per QALY gained.

The authors concluded that oral nicotinamide was “a cost-effective and patient-centric preventive approach for KC, particularly in individuals with KC history at high risk of multiple primary KC.”

In an accompanying editorial, Ivo Abraham, PhD, JAMA Dermatology’s associate editor for quantitative methods and chief scientist at Matrix45, a health economics research and consulting group in Tucson, Arizona, and co-authors noted that although nicotinamide “is inexpensive, widely available, and mechanistically plausible for chemoprevention of actinic keratoses and KCs…stronger evidence remains required to support clinical recommendations.”

“Broader nicotinamide implementation might impart substantial population health benefits and cost savings to the VHA,” they wrote, while also asking, “do we truly know whether nicotinamide is effective for KC chemoprevention in broader populations?” They suggested that only an adequately powered randomized clinical trial in representative nonimmunosuppressed populations would provide the answer.

“Additional randomized controlled trials in non-VHA populations would provide further insight into generalizability beyond the VA healthcare system,” Hartman told Medscape Medical News.

“We are aiming to conduct a large [randomized controlled trial] in the VA to provide a more definitive answer,” added Lee Wheless, MD, one of Hartman’s coauthors, from Vanderbilt University Medical Center and the Tennessee Valley Healthcare System VA Medical Center, both in Nashville, Tennessee. “Doing so would also give a much better estimate of any potential side effects, though we and others have found no increased rate, and sometimes even a decreased rate, of major adverse cardiovascular events.”

Sarah Arron, MD, dermatologic surgeon with Palo Alto Foundation Medical Group in Palo Alto, California, and Premier Aesthetic Dermatology in San Carlos, California, who was not involved in the research, said, “It is gratifying to see that in the veteran population, nicotinamide affords protection against nonmelanoma skin cancer and is a cost-effective intervention. For a healthcare system such as the VHA, providing this over-the-counter vitamin through pharmacy benefits is an excellent method for reducing the overall cost of skin cancer treatment.”

Although Arron agreed that a randomized trial would offer a higher level of evidence for this intervention, she said the real-world obstacle is that nicotinamide is such an easily available, low-cost vitamin with a high safety profile. “Patients are not likely to sign up for a possible placebo when they can purchase nicotinamide online or at the drugstore,” she said. “This was reflected in Australia; once the positive data from the ONTRAC trial was publicized, investigators on the ONTRANS trial had difficulty enrolling patients because they were already taking the vitamin. The second study closed without meeting its enrollment goals and thus did not have power to show statistical significance.”

Hartman is supported by the US Department of Defense and the US Department of Veterans Affairs. Wheless is also supported by the US Department of Veterans Affairs. Arron is a speaker for Regeneron and Castle Biosciences; a consultant for Regeneron, Replimune, Castle, Lumenis, and Enspectra Health; an unpaid ambassador for HarkenDerm, which makes sunscreen as well as a sun and eye health supplement that includes nicotinamide as one of the ingredients.

The study authors reported having no conflicts of interest. Of the editorial authors, Abraham disclosed owning stock in Matrix45, which has received contract funding from companies outside this work, one author had disclosures not related to the work, and the third author had no disclosures.

Kate Johnson is a Montreal-based freelance medical journalist who has been writing for > 30 years about all areas of medicine.

A version of this article first appeared on Medscape.com.

Oral nicotinamide was cost-effective for reducing keratinocyte carcinoma (KC) risk in US veterans with a history of the disease, according to an economic analysis of Veterans Health Administration (VHA) data.

The findings, published online June 10 in JAMA Dermatology, “support strong consideration of nicotinamide for KC prevention in high-risk populations like veterans, particularly given its safety and tolerability,” wrote senior author Rebecca I. Hartman, MD, chief of the Dermatology Section at VA Boston and assistant professor of dermatology at Brigham and Women’s Hospital and Harvard Medical School, Boston, and co-authors.

Nicotinamide supplementation is “not only a cost-effective and patient-centric strategy for KC prevention, but it also remains economically favorable under a range of assumptions and may become even more cost-effective under higher procedure costs and frequency,” noted the authors.

The analysis included 33,822 individuals from the VHA database, all with a history of one or more KCs, including those with nicotinamide exposure for 30 or more days (n = 12,287) and those without that exposure (n = 21,535).

The mean ages in the unexposed and exposed cohorts were 76.9 and 77.2 years, respectively, and 98% were men. Procedural US VHA costs for KC treatment were estimated from previous research and adjusted for inflation. Nicotinamide pricing was obtained from the VHA.

KC incidence among nicotinamide-exposed and unexposed individuals was 0.204 and 0.255 events per person-year, respectively, reflecting an absolute risk reduction of 0.051 and 624 KCs prevented annually with nicotinamide supplementation.

With an estimated cost of $843 per KC, the yearly KC treatment expense was estimated at approximately $2.64 million, and the annual nicotinamide cost was estimated at $161,451, resulting in net savings of $364,581 — a 19.9% reduction in cohort-specific costs.

Assuming a quality-adjusted life-year (QALY) decrement of -0.01 per KC, nicotinamide use yielded an annual gain of 6.24 QALYs across the cohort and a savings of $58,426 per QALY gained.

A calculation of non-VHA cost-effectiveness, estimated with civilian prices and distributions, showed savings of $14,407 per QALY gained.

The authors concluded that oral nicotinamide was “a cost-effective and patient-centric preventive approach for KC, particularly in individuals with KC history at high risk of multiple primary KC.”

In an accompanying editorial, Ivo Abraham, PhD, JAMA Dermatology’s associate editor for quantitative methods and chief scientist at Matrix45, a health economics research and consulting group in Tucson, Arizona, and co-authors noted that although nicotinamide “is inexpensive, widely available, and mechanistically plausible for chemoprevention of actinic keratoses and KCs…stronger evidence remains required to support clinical recommendations.”

“Broader nicotinamide implementation might impart substantial population health benefits and cost savings to the VHA,” they wrote, while also asking, “do we truly know whether nicotinamide is effective for KC chemoprevention in broader populations?” They suggested that only an adequately powered randomized clinical trial in representative nonimmunosuppressed populations would provide the answer.

“Additional randomized controlled trials in non-VHA populations would provide further insight into generalizability beyond the VA healthcare system,” Hartman told Medscape Medical News.

“We are aiming to conduct a large [randomized controlled trial] in the VA to provide a more definitive answer,” added Lee Wheless, MD, one of Hartman’s coauthors, from Vanderbilt University Medical Center and the Tennessee Valley Healthcare System VA Medical Center, both in Nashville, Tennessee. “Doing so would also give a much better estimate of any potential side effects, though we and others have found no increased rate, and sometimes even a decreased rate, of major adverse cardiovascular events.”

Sarah Arron, MD, dermatologic surgeon with Palo Alto Foundation Medical Group in Palo Alto, California, and Premier Aesthetic Dermatology in San Carlos, California, who was not involved in the research, said, “It is gratifying to see that in the veteran population, nicotinamide affords protection against nonmelanoma skin cancer and is a cost-effective intervention. For a healthcare system such as the VHA, providing this over-the-counter vitamin through pharmacy benefits is an excellent method for reducing the overall cost of skin cancer treatment.”

Although Arron agreed that a randomized trial would offer a higher level of evidence for this intervention, she said the real-world obstacle is that nicotinamide is such an easily available, low-cost vitamin with a high safety profile. “Patients are not likely to sign up for a possible placebo when they can purchase nicotinamide online or at the drugstore,” she said. “This was reflected in Australia; once the positive data from the ONTRAC trial was publicized, investigators on the ONTRANS trial had difficulty enrolling patients because they were already taking the vitamin. The second study closed without meeting its enrollment goals and thus did not have power to show statistical significance.”

Hartman is supported by the US Department of Defense and the US Department of Veterans Affairs. Wheless is also supported by the US Department of Veterans Affairs. Arron is a speaker for Regeneron and Castle Biosciences; a consultant for Regeneron, Replimune, Castle, Lumenis, and Enspectra Health; an unpaid ambassador for HarkenDerm, which makes sunscreen as well as a sun and eye health supplement that includes nicotinamide as one of the ingredients.

The study authors reported having no conflicts of interest. Of the editorial authors, Abraham disclosed owning stock in Matrix45, which has received contract funding from companies outside this work, one author had disclosures not related to the work, and the third author had no disclosures.

Kate Johnson is a Montreal-based freelance medical journalist who has been writing for > 30 years about all areas of medicine.

A version of this article first appeared on Medscape.com.

Oral nicotinamide was cost-effective for reducing keratinocyte carcinoma (KC) risk in US veterans with a history of the disease, according to an economic analysis of Veterans Health Administration (VHA) data.

The findings, published online June 10 in JAMA Dermatology, “support strong consideration of nicotinamide for KC prevention in high-risk populations like veterans, particularly given its safety and tolerability,” wrote senior author Rebecca I. Hartman, MD, chief of the Dermatology Section at VA Boston and assistant professor of dermatology at Brigham and Women’s Hospital and Harvard Medical School, Boston, and co-authors.

Nicotinamide supplementation is “not only a cost-effective and patient-centric strategy for KC prevention, but it also remains economically favorable under a range of assumptions and may become even more cost-effective under higher procedure costs and frequency,” noted the authors.

The analysis included 33,822 individuals from the VHA database, all with a history of one or more KCs, including those with nicotinamide exposure for 30 or more days (n = 12,287) and those without that exposure (n = 21,535).

The mean ages in the unexposed and exposed cohorts were 76.9 and 77.2 years, respectively, and 98% were men. Procedural US VHA costs for KC treatment were estimated from previous research and adjusted for inflation. Nicotinamide pricing was obtained from the VHA.

KC incidence among nicotinamide-exposed and unexposed individuals was 0.204 and 0.255 events per person-year, respectively, reflecting an absolute risk reduction of 0.051 and 624 KCs prevented annually with nicotinamide supplementation.

With an estimated cost of $843 per KC, the yearly KC treatment expense was estimated at approximately $2.64 million, and the annual nicotinamide cost was estimated at $161,451, resulting in net savings of $364,581 — a 19.9% reduction in cohort-specific costs.

Assuming a quality-adjusted life-year (QALY) decrement of -0.01 per KC, nicotinamide use yielded an annual gain of 6.24 QALYs across the cohort and a savings of $58,426 per QALY gained.

A calculation of non-VHA cost-effectiveness, estimated with civilian prices and distributions, showed savings of $14,407 per QALY gained.

The authors concluded that oral nicotinamide was “a cost-effective and patient-centric preventive approach for KC, particularly in individuals with KC history at high risk of multiple primary KC.”

In an accompanying editorial, Ivo Abraham, PhD, JAMA Dermatology’s associate editor for quantitative methods and chief scientist at Matrix45, a health economics research and consulting group in Tucson, Arizona, and co-authors noted that although nicotinamide “is inexpensive, widely available, and mechanistically plausible for chemoprevention of actinic keratoses and KCs…stronger evidence remains required to support clinical recommendations.”

“Broader nicotinamide implementation might impart substantial population health benefits and cost savings to the VHA,” they wrote, while also asking, “do we truly know whether nicotinamide is effective for KC chemoprevention in broader populations?” They suggested that only an adequately powered randomized clinical trial in representative nonimmunosuppressed populations would provide the answer.

“Additional randomized controlled trials in non-VHA populations would provide further insight into generalizability beyond the VA healthcare system,” Hartman told Medscape Medical News.

“We are aiming to conduct a large [randomized controlled trial] in the VA to provide a more definitive answer,” added Lee Wheless, MD, one of Hartman’s coauthors, from Vanderbilt University Medical Center and the Tennessee Valley Healthcare System VA Medical Center, both in Nashville, Tennessee. “Doing so would also give a much better estimate of any potential side effects, though we and others have found no increased rate, and sometimes even a decreased rate, of major adverse cardiovascular events.”

Sarah Arron, MD, dermatologic surgeon with Palo Alto Foundation Medical Group in Palo Alto, California, and Premier Aesthetic Dermatology in San Carlos, California, who was not involved in the research, said, “It is gratifying to see that in the veteran population, nicotinamide affords protection against nonmelanoma skin cancer and is a cost-effective intervention. For a healthcare system such as the VHA, providing this over-the-counter vitamin through pharmacy benefits is an excellent method for reducing the overall cost of skin cancer treatment.”

Although Arron agreed that a randomized trial would offer a higher level of evidence for this intervention, she said the real-world obstacle is that nicotinamide is such an easily available, low-cost vitamin with a high safety profile. “Patients are not likely to sign up for a possible placebo when they can purchase nicotinamide online or at the drugstore,” she said. “This was reflected in Australia; once the positive data from the ONTRAC trial was publicized, investigators on the ONTRANS trial had difficulty enrolling patients because they were already taking the vitamin. The second study closed without meeting its enrollment goals and thus did not have power to show statistical significance.”

Hartman is supported by the US Department of Defense and the US Department of Veterans Affairs. Wheless is also supported by the US Department of Veterans Affairs. Arron is a speaker for Regeneron and Castle Biosciences; a consultant for Regeneron, Replimune, Castle, Lumenis, and Enspectra Health; an unpaid ambassador for HarkenDerm, which makes sunscreen as well as a sun and eye health supplement that includes nicotinamide as one of the ingredients.

The study authors reported having no conflicts of interest. Of the editorial authors, Abraham disclosed owning stock in Matrix45, which has received contract funding from companies outside this work, one author had disclosures not related to the work, and the third author had no disclosures.

Kate Johnson is a Montreal-based freelance medical journalist who has been writing for > 30 years about all areas of medicine.

A version of this article first appeared on Medscape.com.