Surgeon gender was not associated with maternal morbidity or severe blood loss after cesarean delivery, a large prospective cohort study from France reports. The results have important implications for the promotion of gender equality among surgeons, obstetricians in particular, wrote a team led by Hanane Bouchghoul, MD, PhD, of the department of obstetrics and gynecology at Bordeaux (France) University Hospital. The report is in JAMA Surgery.

“Our findings are significant in that they add substantially to the string of studies contradicting the age-old dogma that men are better surgeons than women,” the authors wrote. Previous research has suggested slightly better outcomes with female surgeons or higher complication rates with male surgeons.

The results support those of a recent Canadian retrospective analysis suggesting that patients treated by male or female surgeons for various elective indications experience similar surgical outcomes but with a slight, statistically significant decrease in 30-day mortality when treated by female surgeons.

“Policy makers need to combat prejudice against women in surgical careers, particularly in obstetrics and gynecology, so that women no longer experience conscious or unconscious barriers or difficulties in their professional choices, training, and relationships with colleagues or patients,” study corresponding author Loïc Sentilhes, MD, PhD, of Bordeaux University Hospital, said in an interview.

Facing such barriers, women may doubt their ability to be surgeons, their legitimacy as surgeons, and may not consider this type of career, he continued. “Moreover a teacher may not be as involved in teaching young female surgeons as young male surgeons, or the doctor-patient relationship may be more complicated in the event of complications if the patient thinks that a female surgeon has less competence than a male surgeon.”  

The analysis drew on data from the Tranexamic Acid for Preventing Postpartum Hemorrhage after Cesarean Delivery 2 trial, a multicenter, randomized, placebo-controlled study conducted from March 2018 through January 2020 in mothers from 27 French maternity hospitals.

Eligible participants had a cesarean delivery before or during labor at or after 34 weeks’ gestation. The primary endpoint was the incidence of a composite maternal morbidity variable, and the secondary endpoint was the incidence of postpartum hemorrhage, defined by a calculated estimated blood loss exceeding 1,000 mL or transfusion by day 2.

Among the 4,244 women included, male surgeons performed 943 cesarean deliveries (22.2%) and female surgeons performed 3,301 (77.8%). The percentage who were attending obstetricians was higher for men at 441 of 929 (47.5%) than women at 687 of 3,239 (21.2%).

The observed risk of maternal morbidity did not differ between male and female surgeons: 119 of 837 (14.2%) vs. 476 of 2,928 (16.3%), for an adjusted risk ratio (aRR) of 0.92 (95% confidence interval [CI], 0.77-1.13). Interaction between surgeon gender and level of experience with the risk of maternal morbidity was not statistically significant; nor did the groups differ specifically by risk for postpartum hemorrhage: aRR, 0.98 (95% CI, 0.85-1.13).

Despite the longstanding stereotype that men perform surgery better than women, and the traditional preponderance of male surgeons, the authors noted, postoperative morbidity and mortality may be lower after various surgeries performed by women.

The TRAAP2 trial

In an accompanying editorial, Amanda Fader, MD, of the department of obstetrics and gynecology at Johns Hopkins School of Medicine in Baltimore, and colleagues caution that the French study’s methodology may not fully account for the complex intersection of surgeon volume, experience, gender, clinical decision-making skills, and patient-level and clinical factors affecting outcomes.

That said, appraising surgical outcomes based on gender may be an essential step toward reducing implicit bias and dispelling engendered perceptions regarding gender and technical proficiency, the commentators stated. “To definitively dispel archaic, gender-based notions about performance in clinical or surgical settings, efforts must go beyond peer-reviewed research,” Dr. Fader said in an interview. “Medical institutions and leaders of clinical departments must make concerted efforts to recruit, mentor, support, and promote women and persons of all genders in medicine – as well as confront any discriminatory perceptions and experiences concerning sex, race and ethnicity, sexual orientation, or economic class.”

This study was supported by the French Ministry of Health under its Clinical Research Hospital Program. Dr. Sentilhes reported financial relationships with Dilafor, Bayer, GlaxoSmithKline, Sigvaris, and Ferring Pharmaceuticals. The editorial commentators disclosed no funding for their commentary or conflicts of interest.

Surgeon gender was not associated with maternal morbidity or severe blood loss after cesarean delivery, a large prospective cohort study from France reports. The results have important implications for the promotion of gender equality among surgeons, obstetricians in particular, wrote a team led by Hanane Bouchghoul, MD, PhD, of the department of obstetrics and gynecology at Bordeaux (France) University Hospital. The report is in JAMA Surgery.

“Our findings are significant in that they add substantially to the string of studies contradicting the age-old dogma that men are better surgeons than women,” the authors wrote. Previous research has suggested slightly better outcomes with female surgeons or higher complication rates with male surgeons.

The results support those of a recent Canadian retrospective analysis suggesting that patients treated by male or female surgeons for various elective indications experience similar surgical outcomes but with a slight, statistically significant decrease in 30-day mortality when treated by female surgeons.

“Policy makers need to combat prejudice against women in surgical careers, particularly in obstetrics and gynecology, so that women no longer experience conscious or unconscious barriers or difficulties in their professional choices, training, and relationships with colleagues or patients,” study corresponding author Loïc Sentilhes, MD, PhD, of Bordeaux University Hospital, said in an interview.

Facing such barriers, women may doubt their ability to be surgeons, their legitimacy as surgeons, and may not consider this type of career, he continued. “Moreover a teacher may not be as involved in teaching young female surgeons as young male surgeons, or the doctor-patient relationship may be more complicated in the event of complications if the patient thinks that a female surgeon has less competence than a male surgeon.”  

The analysis drew on data from the Tranexamic Acid for Preventing Postpartum Hemorrhage after Cesarean Delivery 2 trial, a multicenter, randomized, placebo-controlled study conducted from March 2018 through January 2020 in mothers from 27 French maternity hospitals.

Eligible participants had a cesarean delivery before or during labor at or after 34 weeks’ gestation. The primary endpoint was the incidence of a composite maternal morbidity variable, and the secondary endpoint was the incidence of postpartum hemorrhage, defined by a calculated estimated blood loss exceeding 1,000 mL or transfusion by day 2.

Among the 4,244 women included, male surgeons performed 943 cesarean deliveries (22.2%) and female surgeons performed 3,301 (77.8%). The percentage who were attending obstetricians was higher for men at 441 of 929 (47.5%) than women at 687 of 3,239 (21.2%).

The observed risk of maternal morbidity did not differ between male and female surgeons: 119 of 837 (14.2%) vs. 476 of 2,928 (16.3%), for an adjusted risk ratio (aRR) of 0.92 (95% confidence interval [CI], 0.77-1.13). Interaction between surgeon gender and level of experience with the risk of maternal morbidity was not statistically significant; nor did the groups differ specifically by risk for postpartum hemorrhage: aRR, 0.98 (95% CI, 0.85-1.13).

Despite the longstanding stereotype that men perform surgery better than women, and the traditional preponderance of male surgeons, the authors noted, postoperative morbidity and mortality may be lower after various surgeries performed by women.

The TRAAP2 trial

In an accompanying editorial, Amanda Fader, MD, of the department of obstetrics and gynecology at Johns Hopkins School of Medicine in Baltimore, and colleagues caution that the French study’s methodology may not fully account for the complex intersection of surgeon volume, experience, gender, clinical decision-making skills, and patient-level and clinical factors affecting outcomes.

That said, appraising surgical outcomes based on gender may be an essential step toward reducing implicit bias and dispelling engendered perceptions regarding gender and technical proficiency, the commentators stated. “To definitively dispel archaic, gender-based notions about performance in clinical or surgical settings, efforts must go beyond peer-reviewed research,” Dr. Fader said in an interview. “Medical institutions and leaders of clinical departments must make concerted efforts to recruit, mentor, support, and promote women and persons of all genders in medicine – as well as confront any discriminatory perceptions and experiences concerning sex, race and ethnicity, sexual orientation, or economic class.”

This study was supported by the French Ministry of Health under its Clinical Research Hospital Program. Dr. Sentilhes reported financial relationships with Dilafor, Bayer, GlaxoSmithKline, Sigvaris, and Ferring Pharmaceuticals. The editorial commentators disclosed no funding for their commentary or conflicts of interest.

Surgeon gender was not associated with maternal morbidity or severe blood loss after cesarean delivery, a large prospective cohort study from France reports. The results have important implications for the promotion of gender equality among surgeons, obstetricians in particular, wrote a team led by Hanane Bouchghoul, MD, PhD, of the department of obstetrics and gynecology at Bordeaux (France) University Hospital. The report is in JAMA Surgery.

“Our findings are significant in that they add substantially to the string of studies contradicting the age-old dogma that men are better surgeons than women,” the authors wrote. Previous research has suggested slightly better outcomes with female surgeons or higher complication rates with male surgeons.

The results support those of a recent Canadian retrospective analysis suggesting that patients treated by male or female surgeons for various elective indications experience similar surgical outcomes but with a slight, statistically significant decrease in 30-day mortality when treated by female surgeons.

“Policy makers need to combat prejudice against women in surgical careers, particularly in obstetrics and gynecology, so that women no longer experience conscious or unconscious barriers or difficulties in their professional choices, training, and relationships with colleagues or patients,” study corresponding author Loïc Sentilhes, MD, PhD, of Bordeaux University Hospital, said in an interview.

Facing such barriers, women may doubt their ability to be surgeons, their legitimacy as surgeons, and may not consider this type of career, he continued. “Moreover a teacher may not be as involved in teaching young female surgeons as young male surgeons, or the doctor-patient relationship may be more complicated in the event of complications if the patient thinks that a female surgeon has less competence than a male surgeon.”  

The analysis drew on data from the Tranexamic Acid for Preventing Postpartum Hemorrhage after Cesarean Delivery 2 trial, a multicenter, randomized, placebo-controlled study conducted from March 2018 through January 2020 in mothers from 27 French maternity hospitals.

Eligible participants had a cesarean delivery before or during labor at or after 34 weeks’ gestation. The primary endpoint was the incidence of a composite maternal morbidity variable, and the secondary endpoint was the incidence of postpartum hemorrhage, defined by a calculated estimated blood loss exceeding 1,000 mL or transfusion by day 2.

Among the 4,244 women included, male surgeons performed 943 cesarean deliveries (22.2%) and female surgeons performed 3,301 (77.8%). The percentage who were attending obstetricians was higher for men at 441 of 929 (47.5%) than women at 687 of 3,239 (21.2%).

The observed risk of maternal morbidity did not differ between male and female surgeons: 119 of 837 (14.2%) vs. 476 of 2,928 (16.3%), for an adjusted risk ratio (aRR) of 0.92 (95% confidence interval [CI], 0.77-1.13). Interaction between surgeon gender and level of experience with the risk of maternal morbidity was not statistically significant; nor did the groups differ specifically by risk for postpartum hemorrhage: aRR, 0.98 (95% CI, 0.85-1.13).

Despite the longstanding stereotype that men perform surgery better than women, and the traditional preponderance of male surgeons, the authors noted, postoperative morbidity and mortality may be lower after various surgeries performed by women.

The TRAAP2 trial

In an accompanying editorial, Amanda Fader, MD, of the department of obstetrics and gynecology at Johns Hopkins School of Medicine in Baltimore, and colleagues caution that the French study’s methodology may not fully account for the complex intersection of surgeon volume, experience, gender, clinical decision-making skills, and patient-level and clinical factors affecting outcomes.

That said, appraising surgical outcomes based on gender may be an essential step toward reducing implicit bias and dispelling engendered perceptions regarding gender and technical proficiency, the commentators stated. “To definitively dispel archaic, gender-based notions about performance in clinical or surgical settings, efforts must go beyond peer-reviewed research,” Dr. Fader said in an interview. “Medical institutions and leaders of clinical departments must make concerted efforts to recruit, mentor, support, and promote women and persons of all genders in medicine – as well as confront any discriminatory perceptions and experiences concerning sex, race and ethnicity, sexual orientation, or economic class.”

This study was supported by the French Ministry of Health under its Clinical Research Hospital Program. Dr. Sentilhes reported financial relationships with Dilafor, Bayer, GlaxoSmithKline, Sigvaris, and Ferring Pharmaceuticals. The editorial commentators disclosed no funding for their commentary or conflicts of interest.

THE COMPARISON

A Vitiligo in a young Hispanic female, which spared the area under a ring. The patient has spotty return of pigment on the hand after narrowband ultraviolet B (UVB) treatment.

B Vitiligo on the hand in a young Hispanic male.

Vitiligo is a chronic autoimmune disorder characterized by areas of depigmented white patches on the skin due to the loss of melanocytes in the epidermis. Various theories on the pathogenesis of vitiligo exist; however, autoimmune destruction of melanocytes remains the leading hypothesis, followed by intrinsic defects in melanocytes.¹

Vitiligo is associated with various autoimmune diseases but is most frequently reported in conjunction with thyroid disorders.²

Epidemiology

Vitiligo affects approximately 1% of the US population and up to 8% worldwide.² There is no difference in prevalence between races or genders. Females typically acquire the disease earlier than males. Onset may occur at any age, although about half of patients will have vitiligo by 20 years of age.¹

Key clinical features in people with darker skin tones

Bright white patches are characteristic of vitiligo. The patches typically are asymptomatic and often affect the hands (FIGURES A and B), perioral skin, feet, and scalp, as well as areas more vulnerable to friction and trauma, such as the elbows and knees.² Trichrome lesions—consisting of varying zones of white (depigmented), lighter brown (hypopigmented), and normal skin—are most commonly seen in individuals with darker skin. Trichrome vitiligo is considered an actively progressing variant of vitiligo.²

An important distinction when making the diagnosis is evaluating for segmental vs nonsegmental vitiligo. Although nonsegmental vitiligo—the more common subtype—is characterized by symmetric distribution and a less predictable course, segmental vitiligo manifests in a localized and unilateral distribution, often avoiding extension past the midline. Segmental vitiligo typically manifests at a younger age and follows a more rapidly stabilizing course.³

Worth noting

Given that stark contrasts between pigmented and depigmented lesions are more prominent in darker skin tones, vitiligo can be more socially stigmatizing and psychologically devastating in these patients.^4,5

Continue to: Treatment of vitiligo...

Treatment of vitiligo includes narrowband UVB (NB-UVB) light phototherapy, excimer laser, topical corticosteroids, topical calcineurin inhibitors such as tacrolimus and pimecrolimus, and surgical melanocyte transplantation.¹ In July 2022, ruxolitinib cream 1.5% was approved by the US Food and Drug Administration (FDA) for nonsegmental vitiligo in patients ages 12 years and older.^6,7 It is the only FDA-approved therapy for vitiligo. It is thought to work by inhibiting the Janus kinase–signal transducers and activators of the transcription pathway.⁶ However, topical ruxolitinib is expensive, costing more than $2000 for 60 g.⁸

Health disparity highlight

A 2021 study reviewing the coverage policies of 15 commercial health care insurance companies, 50 BlueCross BlueShield plans, Medicaid, Medicare, and Veterans Affairs plans found inequities in the insurance coverage patterns for therapies used to treat vitiligo. There were 2 commonly cited reasons for denying coverage for therapies: vitiligo was considered cosmetic and therapies were not FDA approved.⁷ In comparison, NB-UVB light phototherapy for psoriasis is not considered cosmetic and has a much higher insurance coverage rate.^9,10 The out-of-pocket cost for a patient to purchase their own NB-UVB light phototherapy is more than $5000.¹¹ Not all patients of color are economically disadvantaged, but in the United States, Black and Hispanic populations experience disproportionately higher rates of poverty (19% and 17%, respectively) compared to their White counterparts (8%).¹²

Final thoughts

FDA approval of new drugs or new treatment indications comes after years of research discovery and large-scale trials. This pursuit of new discovery, however, is uneven. Vitiligo has historically been understudied and underfunded for research; this is common among several conditions adversely affecting people of color in the United States.¹³

THE COMPARISON

A Vitiligo in a young Hispanic female, which spared the area under a ring. The patient has spotty return of pigment on the hand after narrowband ultraviolet B (UVB) treatment.

B Vitiligo on the hand in a young Hispanic male.

Vitiligo is a chronic autoimmune disorder characterized by areas of depigmented white patches on the skin due to the loss of melanocytes in the epidermis. Various theories on the pathogenesis of vitiligo exist; however, autoimmune destruction of melanocytes remains the leading hypothesis, followed by intrinsic defects in melanocytes.¹

Vitiligo is associated with various autoimmune diseases but is most frequently reported in conjunction with thyroid disorders.²

Epidemiology

Vitiligo affects approximately 1% of the US population and up to 8% worldwide.² There is no difference in prevalence between races or genders. Females typically acquire the disease earlier than males. Onset may occur at any age, although about half of patients will have vitiligo by 20 years of age.¹

Key clinical features in people with darker skin tones

Bright white patches are characteristic of vitiligo. The patches typically are asymptomatic and often affect the hands (FIGURES A and B), perioral skin, feet, and scalp, as well as areas more vulnerable to friction and trauma, such as the elbows and knees.² Trichrome lesions—consisting of varying zones of white (depigmented), lighter brown (hypopigmented), and normal skin—are most commonly seen in individuals with darker skin. Trichrome vitiligo is considered an actively progressing variant of vitiligo.²

An important distinction when making the diagnosis is evaluating for segmental vs nonsegmental vitiligo. Although nonsegmental vitiligo—the more common subtype—is characterized by symmetric distribution and a less predictable course, segmental vitiligo manifests in a localized and unilateral distribution, often avoiding extension past the midline. Segmental vitiligo typically manifests at a younger age and follows a more rapidly stabilizing course.³

Worth noting

Given that stark contrasts between pigmented and depigmented lesions are more prominent in darker skin tones, vitiligo can be more socially stigmatizing and psychologically devastating in these patients.^4,5

Continue to: Treatment of vitiligo...

Treatment of vitiligo includes narrowband UVB (NB-UVB) light phototherapy, excimer laser, topical corticosteroids, topical calcineurin inhibitors such as tacrolimus and pimecrolimus, and surgical melanocyte transplantation.¹ In July 2022, ruxolitinib cream 1.5% was approved by the US Food and Drug Administration (FDA) for nonsegmental vitiligo in patients ages 12 years and older.^6,7 It is the only FDA-approved therapy for vitiligo. It is thought to work by inhibiting the Janus kinase–signal transducers and activators of the transcription pathway.⁶ However, topical ruxolitinib is expensive, costing more than $2000 for 60 g.⁸

Health disparity highlight

A 2021 study reviewing the coverage policies of 15 commercial health care insurance companies, 50 BlueCross BlueShield plans, Medicaid, Medicare, and Veterans Affairs plans found inequities in the insurance coverage patterns for therapies used to treat vitiligo. There were 2 commonly cited reasons for denying coverage for therapies: vitiligo was considered cosmetic and therapies were not FDA approved.⁷ In comparison, NB-UVB light phototherapy for psoriasis is not considered cosmetic and has a much higher insurance coverage rate.^9,10 The out-of-pocket cost for a patient to purchase their own NB-UVB light phototherapy is more than $5000.¹¹ Not all patients of color are economically disadvantaged, but in the United States, Black and Hispanic populations experience disproportionately higher rates of poverty (19% and 17%, respectively) compared to their White counterparts (8%).¹²

Final thoughts

FDA approval of new drugs or new treatment indications comes after years of research discovery and large-scale trials. This pursuit of new discovery, however, is uneven. Vitiligo has historically been understudied and underfunded for research; this is common among several conditions adversely affecting people of color in the United States.¹³

THE COMPARISON

A Vitiligo in a young Hispanic female, which spared the area under a ring. The patient has spotty return of pigment on the hand after narrowband ultraviolet B (UVB) treatment.

B Vitiligo on the hand in a young Hispanic male.

Vitiligo is a chronic autoimmune disorder characterized by areas of depigmented white patches on the skin due to the loss of melanocytes in the epidermis. Various theories on the pathogenesis of vitiligo exist; however, autoimmune destruction of melanocytes remains the leading hypothesis, followed by intrinsic defects in melanocytes.¹

Vitiligo is associated with various autoimmune diseases but is most frequently reported in conjunction with thyroid disorders.²

Epidemiology

Vitiligo affects approximately 1% of the US population and up to 8% worldwide.² There is no difference in prevalence between races or genders. Females typically acquire the disease earlier than males. Onset may occur at any age, although about half of patients will have vitiligo by 20 years of age.¹

Key clinical features in people with darker skin tones

Bright white patches are characteristic of vitiligo. The patches typically are asymptomatic and often affect the hands (FIGURES A and B), perioral skin, feet, and scalp, as well as areas more vulnerable to friction and trauma, such as the elbows and knees.² Trichrome lesions—consisting of varying zones of white (depigmented), lighter brown (hypopigmented), and normal skin—are most commonly seen in individuals with darker skin. Trichrome vitiligo is considered an actively progressing variant of vitiligo.²

An important distinction when making the diagnosis is evaluating for segmental vs nonsegmental vitiligo. Although nonsegmental vitiligo—the more common subtype—is characterized by symmetric distribution and a less predictable course, segmental vitiligo manifests in a localized and unilateral distribution, often avoiding extension past the midline. Segmental vitiligo typically manifests at a younger age and follows a more rapidly stabilizing course.³

Worth noting

Given that stark contrasts between pigmented and depigmented lesions are more prominent in darker skin tones, vitiligo can be more socially stigmatizing and psychologically devastating in these patients.^4,5

Continue to: Treatment of vitiligo...

Treatment of vitiligo includes narrowband UVB (NB-UVB) light phototherapy, excimer laser, topical corticosteroids, topical calcineurin inhibitors such as tacrolimus and pimecrolimus, and surgical melanocyte transplantation.¹ In July 2022, ruxolitinib cream 1.5% was approved by the US Food and Drug Administration (FDA) for nonsegmental vitiligo in patients ages 12 years and older.^6,7 It is the only FDA-approved therapy for vitiligo. It is thought to work by inhibiting the Janus kinase–signal transducers and activators of the transcription pathway.⁶ However, topical ruxolitinib is expensive, costing more than $2000 for 60 g.⁸

Health disparity highlight

A 2021 study reviewing the coverage policies of 15 commercial health care insurance companies, 50 BlueCross BlueShield plans, Medicaid, Medicare, and Veterans Affairs plans found inequities in the insurance coverage patterns for therapies used to treat vitiligo. There were 2 commonly cited reasons for denying coverage for therapies: vitiligo was considered cosmetic and therapies were not FDA approved.⁷ In comparison, NB-UVB light phototherapy for psoriasis is not considered cosmetic and has a much higher insurance coverage rate.^9,10 The out-of-pocket cost for a patient to purchase their own NB-UVB light phototherapy is more than $5000.¹¹ Not all patients of color are economically disadvantaged, but in the United States, Black and Hispanic populations experience disproportionately higher rates of poverty (19% and 17%, respectively) compared to their White counterparts (8%).¹²

Final thoughts

FDA approval of new drugs or new treatment indications comes after years of research discovery and large-scale trials. This pursuit of new discovery, however, is uneven. Vitiligo has historically been understudied and underfunded for research; this is common among several conditions adversely affecting people of color in the United States.¹³

U.S. health officials want to simplify the recommended COVID-19 vaccine protocol, making it more like the process for annual flu shots.

The U.S. Food and Drug Administration is suggesting a single annual shot. The formulation would be selected in June targeting the most threatening COVID-19 strains, and then people could get a shot in the fall when people begin spending more time indoors and exposure increases. 

Some people, such as those who are older or immunocompromised, may need more than one dose.

A national advisory committee is expected to vote on the proposal at a meeting Jan. 26.

People in the United States have been much less likely to get an updated COVID-19 booster shot, compared with widespread uptake of the primary vaccine series. In its proposal, the FDA indicated it hoped a single annual shot would overcome challenges created by the complexity of the process – both in messaging and administration – attributed to that low booster rate. Nine in 10 people age 12 or older got the primary vaccine series in the United States, but only 15% got the latest booster shot for COVID-19.

About half of children and adults in the U.S. get an annual flu shot, according to Centers for Disease Control and Prevention data.

The FDA also wants to move to a single COVID-19 vaccine formulation that would be used for primary vaccine series and for booster shots.

COVID-19 cases, hospitalizations, and deaths are trending downward, according to the data tracker from the New York Times. Cases are down 28%, with 47,290 tallied daily. Hospitalizations are down 22%, with 37,474 daily. Deaths are down 4%, with an average of 489 per day as of Jan. 22.

A version of this article originally appeared on WebMD.com.

U.S. health officials want to simplify the recommended COVID-19 vaccine protocol, making it more like the process for annual flu shots.

The U.S. Food and Drug Administration is suggesting a single annual shot. The formulation would be selected in June targeting the most threatening COVID-19 strains, and then people could get a shot in the fall when people begin spending more time indoors and exposure increases. 

Some people, such as those who are older or immunocompromised, may need more than one dose.

A national advisory committee is expected to vote on the proposal at a meeting Jan. 26.

People in the United States have been much less likely to get an updated COVID-19 booster shot, compared with widespread uptake of the primary vaccine series. In its proposal, the FDA indicated it hoped a single annual shot would overcome challenges created by the complexity of the process – both in messaging and administration – attributed to that low booster rate. Nine in 10 people age 12 or older got the primary vaccine series in the United States, but only 15% got the latest booster shot for COVID-19.

About half of children and adults in the U.S. get an annual flu shot, according to Centers for Disease Control and Prevention data.

The FDA also wants to move to a single COVID-19 vaccine formulation that would be used for primary vaccine series and for booster shots.

COVID-19 cases, hospitalizations, and deaths are trending downward, according to the data tracker from the New York Times. Cases are down 28%, with 47,290 tallied daily. Hospitalizations are down 22%, with 37,474 daily. Deaths are down 4%, with an average of 489 per day as of Jan. 22.

A version of this article originally appeared on WebMD.com.

U.S. health officials want to simplify the recommended COVID-19 vaccine protocol, making it more like the process for annual flu shots.

The U.S. Food and Drug Administration is suggesting a single annual shot. The formulation would be selected in June targeting the most threatening COVID-19 strains, and then people could get a shot in the fall when people begin spending more time indoors and exposure increases. 

Some people, such as those who are older or immunocompromised, may need more than one dose.

A national advisory committee is expected to vote on the proposal at a meeting Jan. 26.

People in the United States have been much less likely to get an updated COVID-19 booster shot, compared with widespread uptake of the primary vaccine series. In its proposal, the FDA indicated it hoped a single annual shot would overcome challenges created by the complexity of the process – both in messaging and administration – attributed to that low booster rate. Nine in 10 people age 12 or older got the primary vaccine series in the United States, but only 15% got the latest booster shot for COVID-19.

About half of children and adults in the U.S. get an annual flu shot, according to Centers for Disease Control and Prevention data.

The FDA also wants to move to a single COVID-19 vaccine formulation that would be used for primary vaccine series and for booster shots.

COVID-19 cases, hospitalizations, and deaths are trending downward, according to the data tracker from the New York Times. Cases are down 28%, with 47,290 tallied daily. Hospitalizations are down 22%, with 37,474 daily. Deaths are down 4%, with an average of 489 per day as of Jan. 22.

A version of this article originally appeared on WebMD.com.

Fibroepithelioma of Pinkus (FeP), or Pinkus tumor, is a rare tumor with a presentation similar to benign neoplasms such as acrochordons and seborrheic keratoses. Classically, FeP presents as a nontender, solitary, flesh-colored, firm, dome-shaped papule or plaque with a predilection for the lumbosacral region rather than sun-exposed areas. This tumor typically develops in fair-skinned older adults, more often in females.¹

The association between cutaneous lesions and internal malignancies is well known to include dermatoses such as erythema repens in patients with lung cancer, or tripe palms and acanthosis nigricans in patients with gastrointestinal malignancy. Outside of paraneoplastic presentations, many syndromes have unique constellations of clinical findings that require the clinician to investigate for internal malignancy. Cancer-associated genodermatoses such as Birt-Hogg-Dubé, neurofibromatosis, and Cowden syndrome have key findings to alert the provider of potential internal malignancies.² Given the rarity and relative novelty of FeP, few studies have been performed that evaluate for an association with internal malignancies.

There potentially is a common pathophysiologic mechanism between FeP and other benign and malignant tumors. Some have noted a possible common embryonic origin, such as Merkel cells, and even a common gene mutation involving tumor protein p53 or PTCH1 gene.^3,4 Carcinoembryonic antigen is a glycoprotein often found in association with gastrointestinal tract tumors and also is elevated in some cases of FeP.⁵ A single-center retrospective study performed by Longo et al³ demonstrated an association between FeP and gastrointestinal malignancy by calculating a percentage of those with FeP who also had gastrointestinal tract tumors. Moreover, they noted that FeP preceded gastrointestinal tract tumors by up to 1 to 2 years. Using the results of this study, they suggested that a similar pathogenesis underlies the association between FeP and gastrointestinal malignancy, but a shared pathogenesis has not yet been elucidated.³

With a transition to preventive medicine and age-adjusted malignancy screening in the US medical community, the findings of FeP as a marker of gastrointestinal tract tumors could alter current recommendations of routine skin examinations and colorectal cancer screening. This study investigates the association between FeP and internal malignancy, especially gastrointestinal tract tumors.

Methods

Patient Selection—A single-center, retrospective, case-control study was designed to investigate an association between FeP and internal malignancy. The study protocol was approved by the institutional review board of the Naval Medical Center San Diego, California, in compliance with all applicable federal regulations governing the protection of human subjects. A medical record review was initiated using the Department of Defense (DoD) electronic health record to identify patients with a history of FeP. The query used a natural language search for patients who had received a histopathology report that included Fibroepithelioma of Pinkus, Pinkus, or Pinkus tumor within the diagnosis or comment section for pathology specimens processed at our institution (Naval Medical Center San Diego). A total of 45 patients evaluated at Naval Medical Center San Diego had biopsy specimens that met inclusion criteria. Only 42 electronic medical records were available to review between January 1, 2003, and March 1, 2020. Three patients were excluded from the study for absent or incomplete medical records.

Study Procedures—Data extracted by researchers were analyzed for statistical significance. All available data in current electronic health records prior to the FeP diagnosis until March 1, 2020, was reviewed for other documented malignancy or colonoscopy data. Data extracted included age, sex, date of diagnosis of FeP, location of FeP, social history, and medical and surgical history to identify prior malignancy. Colorectal cancer screening results were drawn from original reports, gastrointestinal clinic notes, biopsy results, and/or primary care provider documentation of colonoscopy results. If the exact date of internal tumor diagnosis could not be determined but the year was known, the value “July, year” was utilized as the diagnosis date.

Statistical Analysis—Data were reviewed for validity, and the Shapiro-Wilk test was used to test for normality. Graphical visualization assisted in reviewing the distribution of the data in relation to the internal tumors. The Fisher exact test was performed to test for associations, while continuous variables were assessed using the Student t test or the nonparametric Mann-Whitney U test. Analysis was conducted with StataCorp. 2017 Stata Statistical Software: Release 15 (StataCorp LLC). Significance was set at P<.05. 

 

 

Results

Patient Demographics—Of the 42 patients with FeP included in this study, 28 (66.7%) were male and 14 (33.3%) were female. The overall mean age at FeP diagnosis was 56.83 years. The mean age (SD) at FeP diagnosis for males was 59.21 (19.00) years and 52.07 (21.61) for females (P=.2792)(Table 1). Other pertinent medical history, including alcohol and tobacco use, obesity, and diabetes mellitus, is included in Table 1.

Characterization of Tumors—The classification of the number of patients with any other nonskin neoplasm is presented in Table 2. Fifteen (35.7%) patients had 1 or more gastrointestinal tubular adenomas. Three patients were found to have colorectal adenocarcinoma. Karsenti et al⁶ published a large study of colonic adenoma detection rates in the World Journal of Gastroenterology stratified by age and found that the incidence of adenoma for those aged 55 to 59 years was 28.3% vs 35.7% in our study (P=.2978 [Fisher exact test]).

Given the number of gastrointestinal tract tumors detected, most of which were found during routine surveillance, and a prior study⁶ suggesting a relationship between FeP and gastrointestinal tract tumors, we analyzed the temporal relationship between the date of gastrointestinal tract tumor diagnosis and the date of FeP diagnosis to assess if gastrointestinal tract tumor or FeP might predict the onset of the other (Figure 1). By assigning a temporal category to each gastrointestinal tract tumor as occurring either before or after the FeP diagnosis by 0 to 3 years, 3 to 10 years, 10 to 15 years, and 15 or more years, the box plot in Figure 1 shows that gastrointestinal adenoma development had no significant temporal relationship to the presence of FeP, excluding any outliers (shown as dots). Additionally, in Figure 1, the same concept was applied to assess the relationship between the dates of all gastrointestinal tract tumors—benign, precancerous, or malignant—and the date of FeP diagnosis, which again showed that FeP and gastrointestinal tract tumors did not predict the onset of the other. Figure 2 showed the same for all nonskin tumor diagnoses and again demonstrated that FeP and all other nondermatologic tumors did not predict the onset of the other.

Comment

Malignancy Potential—The malignant potential of FeP—characterized as a trichoblastoma (an adnexal tumor) or a basal cell carcinoma (BCC) variant—has been documented.¹ Haddock and Cohen¹ noted that FeP can be considered as an intermediate variant between BCC and trichoblastomas. Furthermore, they questioned the relevance of differentiating FeP as benign or malignant.¹ There are additional elements of FeP that currently are unknown, which can be partially attributed to its rarity. If we can clarify a more accurate pathogenic model of FeP, then common mutational pathways with other malignancies may be identified.

Screening for Malignancy in FeP Patients—Until recently, FeP has not been demonstrated to be associated with other cancers or to have increased metastatic potential.¹ In a 1985 case series of 2 patients, FeP was found to be specifically overlying infiltrating ductal carcinoma of the breast. After a unilateral mastectomy, examination of the overlying skin of the breast showed a solitary, lightly pigmented nodule, which was identified as an FeP after histopathologic evaluation.⁷ There have been limited investigations of whether FeP is simply a solitary tumor or a harbinger for other malignancies, despite a study by Longo et al³ that attempted to establish this temporal relationship. They recommended that patients with FeP be clinically evaluated and screened for gastrointestinal tract tumors.³ Based on these recommendations, textbooks for dermatopathology now highlight the possible correlation of FeP and gastrointestinal malignancy,⁸ which may lead to earlier and unwarranted screening.

Comparison to the General Population—Although our analysis showed a portion of patients with FeP have gastrointestinal tract tumors, we do not detect a significant difference from the general population. The average age at the time of FeP diagnosis in our study was 56.83 years compared with the average age of 64.0 years by Longo et al,³ where they found an association with gastrointestinal adenocarcinoma and neuroendocrine tumors. As the rate of gastrointestinal adenoma and malignancy increases with age, the older population in the study by Longo et al³ may have developed colorectal cancer independent of FeP development. However, the rate of gastrointestinal or other malignancies in their study was substantially higher than that of the general population. The Longo et al³ study found that 22 of 49 patients developed nondermatologic malignancies within 2 years of FeP diagnosis. Additionally, no data were provided in the study regarding precancerous lesions.

In our study population, benign gastrointestinal tract tumors, specifically tubular adenomas, were noted in 35.7% of patients with FeP compared with 28.3% of the general population in the same age group reported by Karsenti et al.⁶ Although limited by our sample size, our study demonstrated that patients with FeP diagnosis showed no significant difference in age-stratified incidence of tubular adenoma compared with the general population (P=.2978). Figures 1 and 2 showed no obvious temporal relationship between the development of FeP and the diagnosis of gastrointestinal tumor—either precancerous or malignant lesions—suggesting that diagnosis of one does not indicate the presence of the other.

Relationship With Colonoscopy Results—By analyzing those patients with FeP who specifically had documented colonoscopy results, we did not find a correlation between FeP and gastrointestinal tubular adenoma or carcinoma at any time during the patients’ available records. Although some patients may have had undocumented colonoscopies performed outside the DoD medical system, most had evidence that these procedures were being performed by transcription into primary care provider notes, uploaded gastroenterologist clinical notes, or colonoscopy reports. It is unlikely a true colorectal or other malignancy would remain undocumented over years within the electronic medical record.

Study Limitations—Because of the nature of electronic medical records at multiple institutions, the quality and/or the quantity of medical documentation is not standardized across all patients. Not all pathology reports may include FeP as the primary diagnosis or description, as FeP may simply be reported as BCC. Despite thorough data extraction by physicians, we were limited to the data available within our electronic medical records. Colonoscopies and other specialty care often were performed by civilian providers. Documentation regarding where patients were referred for such procedures outside the DoD was not available unless reports were transmitted to the DoD or transcribed by primary care providers. Incomplete records may make it more difficult to identify and document the number and characteristics of patients’ tubular adenomas. Therefore, a complete review of civilian records was not possible, causing some patients’ medical records to be documented for a longer period of their lives than for others.

Conclusion

Our data demonstrated no statistically significant temporal relationship between the development of FeP and other benign or malignant tumors. Additionally, the prevalence of tubular adenoma or gastrointestinal malignancy is not substantially higher in those with FeP than the age-adjusted population. Current guidelines recommend that patients with FeP should be treated and return for follow up at regular intervals, similar to patients with a history of BCC. This study does not establish FeP as a risk factor for development of any type of cancer that would require earlier or more frequent intervals beyond the established age-appropriate screening guidelines.

Given the discrepancies in our findings with the previous study,³ future investigations on FeP and associated tumors should focus on integrated health care systems with longitudinal data sets for all age-appropriate cancer screenings in a larger sample size. Another related study is needed to evaluate the pathophysiologic mechanisms of FeP development relative to known cancer lines.

Fibroepithelioma of Pinkus (FeP), or Pinkus tumor, is a rare tumor with a presentation similar to benign neoplasms such as acrochordons and seborrheic keratoses. Classically, FeP presents as a nontender, solitary, flesh-colored, firm, dome-shaped papule or plaque with a predilection for the lumbosacral region rather than sun-exposed areas. This tumor typically develops in fair-skinned older adults, more often in females.¹

The association between cutaneous lesions and internal malignancies is well known to include dermatoses such as erythema repens in patients with lung cancer, or tripe palms and acanthosis nigricans in patients with gastrointestinal malignancy. Outside of paraneoplastic presentations, many syndromes have unique constellations of clinical findings that require the clinician to investigate for internal malignancy. Cancer-associated genodermatoses such as Birt-Hogg-Dubé, neurofibromatosis, and Cowden syndrome have key findings to alert the provider of potential internal malignancies.² Given the rarity and relative novelty of FeP, few studies have been performed that evaluate for an association with internal malignancies.

There potentially is a common pathophysiologic mechanism between FeP and other benign and malignant tumors. Some have noted a possible common embryonic origin, such as Merkel cells, and even a common gene mutation involving tumor protein p53 or PTCH1 gene.^3,4 Carcinoembryonic antigen is a glycoprotein often found in association with gastrointestinal tract tumors and also is elevated in some cases of FeP.⁵ A single-center retrospective study performed by Longo et al³ demonstrated an association between FeP and gastrointestinal malignancy by calculating a percentage of those with FeP who also had gastrointestinal tract tumors. Moreover, they noted that FeP preceded gastrointestinal tract tumors by up to 1 to 2 years. Using the results of this study, they suggested that a similar pathogenesis underlies the association between FeP and gastrointestinal malignancy, but a shared pathogenesis has not yet been elucidated.³

With a transition to preventive medicine and age-adjusted malignancy screening in the US medical community, the findings of FeP as a marker of gastrointestinal tract tumors could alter current recommendations of routine skin examinations and colorectal cancer screening. This study investigates the association between FeP and internal malignancy, especially gastrointestinal tract tumors.

Methods

Patient Selection—A single-center, retrospective, case-control study was designed to investigate an association between FeP and internal malignancy. The study protocol was approved by the institutional review board of the Naval Medical Center San Diego, California, in compliance with all applicable federal regulations governing the protection of human subjects. A medical record review was initiated using the Department of Defense (DoD) electronic health record to identify patients with a history of FeP. The query used a natural language search for patients who had received a histopathology report that included Fibroepithelioma of Pinkus, Pinkus, or Pinkus tumor within the diagnosis or comment section for pathology specimens processed at our institution (Naval Medical Center San Diego). A total of 45 patients evaluated at Naval Medical Center San Diego had biopsy specimens that met inclusion criteria. Only 42 electronic medical records were available to review between January 1, 2003, and March 1, 2020. Three patients were excluded from the study for absent or incomplete medical records.

Study Procedures—Data extracted by researchers were analyzed for statistical significance. All available data in current electronic health records prior to the FeP diagnosis until March 1, 2020, was reviewed for other documented malignancy or colonoscopy data. Data extracted included age, sex, date of diagnosis of FeP, location of FeP, social history, and medical and surgical history to identify prior malignancy. Colorectal cancer screening results were drawn from original reports, gastrointestinal clinic notes, biopsy results, and/or primary care provider documentation of colonoscopy results. If the exact date of internal tumor diagnosis could not be determined but the year was known, the value “July, year” was utilized as the diagnosis date.

Statistical Analysis—Data were reviewed for validity, and the Shapiro-Wilk test was used to test for normality. Graphical visualization assisted in reviewing the distribution of the data in relation to the internal tumors. The Fisher exact test was performed to test for associations, while continuous variables were assessed using the Student t test or the nonparametric Mann-Whitney U test. Analysis was conducted with StataCorp. 2017 Stata Statistical Software: Release 15 (StataCorp LLC). Significance was set at P<.05. 

 

 

Results

Patient Demographics—Of the 42 patients with FeP included in this study, 28 (66.7%) were male and 14 (33.3%) were female. The overall mean age at FeP diagnosis was 56.83 years. The mean age (SD) at FeP diagnosis for males was 59.21 (19.00) years and 52.07 (21.61) for females (P=.2792)(Table 1). Other pertinent medical history, including alcohol and tobacco use, obesity, and diabetes mellitus, is included in Table 1.

Characterization of Tumors—The classification of the number of patients with any other nonskin neoplasm is presented in Table 2. Fifteen (35.7%) patients had 1 or more gastrointestinal tubular adenomas. Three patients were found to have colorectal adenocarcinoma. Karsenti et al⁶ published a large study of colonic adenoma detection rates in the World Journal of Gastroenterology stratified by age and found that the incidence of adenoma for those aged 55 to 59 years was 28.3% vs 35.7% in our study (P=.2978 [Fisher exact test]).

Given the number of gastrointestinal tract tumors detected, most of which were found during routine surveillance, and a prior study⁶ suggesting a relationship between FeP and gastrointestinal tract tumors, we analyzed the temporal relationship between the date of gastrointestinal tract tumor diagnosis and the date of FeP diagnosis to assess if gastrointestinal tract tumor or FeP might predict the onset of the other (Figure 1). By assigning a temporal category to each gastrointestinal tract tumor as occurring either before or after the FeP diagnosis by 0 to 3 years, 3 to 10 years, 10 to 15 years, and 15 or more years, the box plot in Figure 1 shows that gastrointestinal adenoma development had no significant temporal relationship to the presence of FeP, excluding any outliers (shown as dots). Additionally, in Figure 1, the same concept was applied to assess the relationship between the dates of all gastrointestinal tract tumors—benign, precancerous, or malignant—and the date of FeP diagnosis, which again showed that FeP and gastrointestinal tract tumors did not predict the onset of the other. Figure 2 showed the same for all nonskin tumor diagnoses and again demonstrated that FeP and all other nondermatologic tumors did not predict the onset of the other.

Comment

Malignancy Potential—The malignant potential of FeP—characterized as a trichoblastoma (an adnexal tumor) or a basal cell carcinoma (BCC) variant—has been documented.¹ Haddock and Cohen¹ noted that FeP can be considered as an intermediate variant between BCC and trichoblastomas. Furthermore, they questioned the relevance of differentiating FeP as benign or malignant.¹ There are additional elements of FeP that currently are unknown, which can be partially attributed to its rarity. If we can clarify a more accurate pathogenic model of FeP, then common mutational pathways with other malignancies may be identified.

Screening for Malignancy in FeP Patients—Until recently, FeP has not been demonstrated to be associated with other cancers or to have increased metastatic potential.¹ In a 1985 case series of 2 patients, FeP was found to be specifically overlying infiltrating ductal carcinoma of the breast. After a unilateral mastectomy, examination of the overlying skin of the breast showed a solitary, lightly pigmented nodule, which was identified as an FeP after histopathologic evaluation.⁷ There have been limited investigations of whether FeP is simply a solitary tumor or a harbinger for other malignancies, despite a study by Longo et al³ that attempted to establish this temporal relationship. They recommended that patients with FeP be clinically evaluated and screened for gastrointestinal tract tumors.³ Based on these recommendations, textbooks for dermatopathology now highlight the possible correlation of FeP and gastrointestinal malignancy,⁸ which may lead to earlier and unwarranted screening.

Comparison to the General Population—Although our analysis showed a portion of patients with FeP have gastrointestinal tract tumors, we do not detect a significant difference from the general population. The average age at the time of FeP diagnosis in our study was 56.83 years compared with the average age of 64.0 years by Longo et al,³ where they found an association with gastrointestinal adenocarcinoma and neuroendocrine tumors. As the rate of gastrointestinal adenoma and malignancy increases with age, the older population in the study by Longo et al³ may have developed colorectal cancer independent of FeP development. However, the rate of gastrointestinal or other malignancies in their study was substantially higher than that of the general population. The Longo et al³ study found that 22 of 49 patients developed nondermatologic malignancies within 2 years of FeP diagnosis. Additionally, no data were provided in the study regarding precancerous lesions.

In our study population, benign gastrointestinal tract tumors, specifically tubular adenomas, were noted in 35.7% of patients with FeP compared with 28.3% of the general population in the same age group reported by Karsenti et al.⁶ Although limited by our sample size, our study demonstrated that patients with FeP diagnosis showed no significant difference in age-stratified incidence of tubular adenoma compared with the general population (P=.2978). Figures 1 and 2 showed no obvious temporal relationship between the development of FeP and the diagnosis of gastrointestinal tumor—either precancerous or malignant lesions—suggesting that diagnosis of one does not indicate the presence of the other.

Relationship With Colonoscopy Results—By analyzing those patients with FeP who specifically had documented colonoscopy results, we did not find a correlation between FeP and gastrointestinal tubular adenoma or carcinoma at any time during the patients’ available records. Although some patients may have had undocumented colonoscopies performed outside the DoD medical system, most had evidence that these procedures were being performed by transcription into primary care provider notes, uploaded gastroenterologist clinical notes, or colonoscopy reports. It is unlikely a true colorectal or other malignancy would remain undocumented over years within the electronic medical record.

Study Limitations—Because of the nature of electronic medical records at multiple institutions, the quality and/or the quantity of medical documentation is not standardized across all patients. Not all pathology reports may include FeP as the primary diagnosis or description, as FeP may simply be reported as BCC. Despite thorough data extraction by physicians, we were limited to the data available within our electronic medical records. Colonoscopies and other specialty care often were performed by civilian providers. Documentation regarding where patients were referred for such procedures outside the DoD was not available unless reports were transmitted to the DoD or transcribed by primary care providers. Incomplete records may make it more difficult to identify and document the number and characteristics of patients’ tubular adenomas. Therefore, a complete review of civilian records was not possible, causing some patients’ medical records to be documented for a longer period of their lives than for others.

Conclusion

Our data demonstrated no statistically significant temporal relationship between the development of FeP and other benign or malignant tumors. Additionally, the prevalence of tubular adenoma or gastrointestinal malignancy is not substantially higher in those with FeP than the age-adjusted population. Current guidelines recommend that patients with FeP should be treated and return for follow up at regular intervals, similar to patients with a history of BCC. This study does not establish FeP as a risk factor for development of any type of cancer that would require earlier or more frequent intervals beyond the established age-appropriate screening guidelines.

Given the discrepancies in our findings with the previous study,³ future investigations on FeP and associated tumors should focus on integrated health care systems with longitudinal data sets for all age-appropriate cancer screenings in a larger sample size. Another related study is needed to evaluate the pathophysiologic mechanisms of FeP development relative to known cancer lines.

Fibroepithelioma of Pinkus (FeP), or Pinkus tumor, is a rare tumor with a presentation similar to benign neoplasms such as acrochordons and seborrheic keratoses. Classically, FeP presents as a nontender, solitary, flesh-colored, firm, dome-shaped papule or plaque with a predilection for the lumbosacral region rather than sun-exposed areas. This tumor typically develops in fair-skinned older adults, more often in females.¹

The association between cutaneous lesions and internal malignancies is well known to include dermatoses such as erythema repens in patients with lung cancer, or tripe palms and acanthosis nigricans in patients with gastrointestinal malignancy. Outside of paraneoplastic presentations, many syndromes have unique constellations of clinical findings that require the clinician to investigate for internal malignancy. Cancer-associated genodermatoses such as Birt-Hogg-Dubé, neurofibromatosis, and Cowden syndrome have key findings to alert the provider of potential internal malignancies.² Given the rarity and relative novelty of FeP, few studies have been performed that evaluate for an association with internal malignancies.

There potentially is a common pathophysiologic mechanism between FeP and other benign and malignant tumors. Some have noted a possible common embryonic origin, such as Merkel cells, and even a common gene mutation involving tumor protein p53 or PTCH1 gene.^3,4 Carcinoembryonic antigen is a glycoprotein often found in association with gastrointestinal tract tumors and also is elevated in some cases of FeP.⁵ A single-center retrospective study performed by Longo et al³ demonstrated an association between FeP and gastrointestinal malignancy by calculating a percentage of those with FeP who also had gastrointestinal tract tumors. Moreover, they noted that FeP preceded gastrointestinal tract tumors by up to 1 to 2 years. Using the results of this study, they suggested that a similar pathogenesis underlies the association between FeP and gastrointestinal malignancy, but a shared pathogenesis has not yet been elucidated.³

With a transition to preventive medicine and age-adjusted malignancy screening in the US medical community, the findings of FeP as a marker of gastrointestinal tract tumors could alter current recommendations of routine skin examinations and colorectal cancer screening. This study investigates the association between FeP and internal malignancy, especially gastrointestinal tract tumors.

Methods

Patient Selection—A single-center, retrospective, case-control study was designed to investigate an association between FeP and internal malignancy. The study protocol was approved by the institutional review board of the Naval Medical Center San Diego, California, in compliance with all applicable federal regulations governing the protection of human subjects. A medical record review was initiated using the Department of Defense (DoD) electronic health record to identify patients with a history of FeP. The query used a natural language search for patients who had received a histopathology report that included Fibroepithelioma of Pinkus, Pinkus, or Pinkus tumor within the diagnosis or comment section for pathology specimens processed at our institution (Naval Medical Center San Diego). A total of 45 patients evaluated at Naval Medical Center San Diego had biopsy specimens that met inclusion criteria. Only 42 electronic medical records were available to review between January 1, 2003, and March 1, 2020. Three patients were excluded from the study for absent or incomplete medical records.

Study Procedures—Data extracted by researchers were analyzed for statistical significance. All available data in current electronic health records prior to the FeP diagnosis until March 1, 2020, was reviewed for other documented malignancy or colonoscopy data. Data extracted included age, sex, date of diagnosis of FeP, location of FeP, social history, and medical and surgical history to identify prior malignancy. Colorectal cancer screening results were drawn from original reports, gastrointestinal clinic notes, biopsy results, and/or primary care provider documentation of colonoscopy results. If the exact date of internal tumor diagnosis could not be determined but the year was known, the value “July, year” was utilized as the diagnosis date.

Statistical Analysis—Data were reviewed for validity, and the Shapiro-Wilk test was used to test for normality. Graphical visualization assisted in reviewing the distribution of the data in relation to the internal tumors. The Fisher exact test was performed to test for associations, while continuous variables were assessed using the Student t test or the nonparametric Mann-Whitney U test. Analysis was conducted with StataCorp. 2017 Stata Statistical Software: Release 15 (StataCorp LLC). Significance was set at P<.05. 

 

 

Results

Patient Demographics—Of the 42 patients with FeP included in this study, 28 (66.7%) were male and 14 (33.3%) were female. The overall mean age at FeP diagnosis was 56.83 years. The mean age (SD) at FeP diagnosis for males was 59.21 (19.00) years and 52.07 (21.61) for females (P=.2792)(Table 1). Other pertinent medical history, including alcohol and tobacco use, obesity, and diabetes mellitus, is included in Table 1.

Characterization of Tumors—The classification of the number of patients with any other nonskin neoplasm is presented in Table 2. Fifteen (35.7%) patients had 1 or more gastrointestinal tubular adenomas. Three patients were found to have colorectal adenocarcinoma. Karsenti et al⁶ published a large study of colonic adenoma detection rates in the World Journal of Gastroenterology stratified by age and found that the incidence of adenoma for those aged 55 to 59 years was 28.3% vs 35.7% in our study (P=.2978 [Fisher exact test]).

Given the number of gastrointestinal tract tumors detected, most of which were found during routine surveillance, and a prior study⁶ suggesting a relationship between FeP and gastrointestinal tract tumors, we analyzed the temporal relationship between the date of gastrointestinal tract tumor diagnosis and the date of FeP diagnosis to assess if gastrointestinal tract tumor or FeP might predict the onset of the other (Figure 1). By assigning a temporal category to each gastrointestinal tract tumor as occurring either before or after the FeP diagnosis by 0 to 3 years, 3 to 10 years, 10 to 15 years, and 15 or more years, the box plot in Figure 1 shows that gastrointestinal adenoma development had no significant temporal relationship to the presence of FeP, excluding any outliers (shown as dots). Additionally, in Figure 1, the same concept was applied to assess the relationship between the dates of all gastrointestinal tract tumors—benign, precancerous, or malignant—and the date of FeP diagnosis, which again showed that FeP and gastrointestinal tract tumors did not predict the onset of the other. Figure 2 showed the same for all nonskin tumor diagnoses and again demonstrated that FeP and all other nondermatologic tumors did not predict the onset of the other.

Comment

Malignancy Potential—The malignant potential of FeP—characterized as a trichoblastoma (an adnexal tumor) or a basal cell carcinoma (BCC) variant—has been documented.¹ Haddock and Cohen¹ noted that FeP can be considered as an intermediate variant between BCC and trichoblastomas. Furthermore, they questioned the relevance of differentiating FeP as benign or malignant.¹ There are additional elements of FeP that currently are unknown, which can be partially attributed to its rarity. If we can clarify a more accurate pathogenic model of FeP, then common mutational pathways with other malignancies may be identified.

Screening for Malignancy in FeP Patients—Until recently, FeP has not been demonstrated to be associated with other cancers or to have increased metastatic potential.¹ In a 1985 case series of 2 patients, FeP was found to be specifically overlying infiltrating ductal carcinoma of the breast. After a unilateral mastectomy, examination of the overlying skin of the breast showed a solitary, lightly pigmented nodule, which was identified as an FeP after histopathologic evaluation.⁷ There have been limited investigations of whether FeP is simply a solitary tumor or a harbinger for other malignancies, despite a study by Longo et al³ that attempted to establish this temporal relationship. They recommended that patients with FeP be clinically evaluated and screened for gastrointestinal tract tumors.³ Based on these recommendations, textbooks for dermatopathology now highlight the possible correlation of FeP and gastrointestinal malignancy,⁸ which may lead to earlier and unwarranted screening.

Comparison to the General Population—Although our analysis showed a portion of patients with FeP have gastrointestinal tract tumors, we do not detect a significant difference from the general population. The average age at the time of FeP diagnosis in our study was 56.83 years compared with the average age of 64.0 years by Longo et al,³ where they found an association with gastrointestinal adenocarcinoma and neuroendocrine tumors. As the rate of gastrointestinal adenoma and malignancy increases with age, the older population in the study by Longo et al³ may have developed colorectal cancer independent of FeP development. However, the rate of gastrointestinal or other malignancies in their study was substantially higher than that of the general population. The Longo et al³ study found that 22 of 49 patients developed nondermatologic malignancies within 2 years of FeP diagnosis. Additionally, no data were provided in the study regarding precancerous lesions.

In our study population, benign gastrointestinal tract tumors, specifically tubular adenomas, were noted in 35.7% of patients with FeP compared with 28.3% of the general population in the same age group reported by Karsenti et al.⁶ Although limited by our sample size, our study demonstrated that patients with FeP diagnosis showed no significant difference in age-stratified incidence of tubular adenoma compared with the general population (P=.2978). Figures 1 and 2 showed no obvious temporal relationship between the development of FeP and the diagnosis of gastrointestinal tumor—either precancerous or malignant lesions—suggesting that diagnosis of one does not indicate the presence of the other.

Relationship With Colonoscopy Results—By analyzing those patients with FeP who specifically had documented colonoscopy results, we did not find a correlation between FeP and gastrointestinal tubular adenoma or carcinoma at any time during the patients’ available records. Although some patients may have had undocumented colonoscopies performed outside the DoD medical system, most had evidence that these procedures were being performed by transcription into primary care provider notes, uploaded gastroenterologist clinical notes, or colonoscopy reports. It is unlikely a true colorectal or other malignancy would remain undocumented over years within the electronic medical record.

Study Limitations—Because of the nature of electronic medical records at multiple institutions, the quality and/or the quantity of medical documentation is not standardized across all patients. Not all pathology reports may include FeP as the primary diagnosis or description, as FeP may simply be reported as BCC. Despite thorough data extraction by physicians, we were limited to the data available within our electronic medical records. Colonoscopies and other specialty care often were performed by civilian providers. Documentation regarding where patients were referred for such procedures outside the DoD was not available unless reports were transmitted to the DoD or transcribed by primary care providers. Incomplete records may make it more difficult to identify and document the number and characteristics of patients’ tubular adenomas. Therefore, a complete review of civilian records was not possible, causing some patients’ medical records to be documented for a longer period of their lives than for others.

Conclusion

Our data demonstrated no statistically significant temporal relationship between the development of FeP and other benign or malignant tumors. Additionally, the prevalence of tubular adenoma or gastrointestinal malignancy is not substantially higher in those with FeP than the age-adjusted population. Current guidelines recommend that patients with FeP should be treated and return for follow up at regular intervals, similar to patients with a history of BCC. This study does not establish FeP as a risk factor for development of any type of cancer that would require earlier or more frequent intervals beyond the established age-appropriate screening guidelines.

Given the discrepancies in our findings with the previous study,³ future investigations on FeP and associated tumors should focus on integrated health care systems with longitudinal data sets for all age-appropriate cancer screenings in a larger sample size. Another related study is needed to evaluate the pathophysiologic mechanisms of FeP development relative to known cancer lines.

The risk of health harms from alcohol is low for people who consume two standard drinks or fewer per week, but it’s higher with greater consumption, according to new guidance from the Canadian Centre on Substance Use and Addiction.

“Drinking less is better,” says the guidance, which replaces Canada’s 2011 Low-Risk Drinking Guidelines (LRDGs).

Developed in consultation with an executive committee from federal, provincial, and territorial governments; national organizations; three scientific expert panels; and an internal evidence review working group, the guidance presents the following findings:

• Consuming no drinks per week has benefits, such as better health and better sleep, and it’s the only safe option during pregnancy.
• Consuming one or two standard drinks weekly will likely not have alcohol-related consequences.
• Three to six drinks raise the risk of developing breast, colon, and other cancers.
• Seven or more increase the risk of heart disease or stroke.
• Each additional drink “radically increases” the risk of these health consequences.

“Alcohol is more harmful than was previously thought and is a key component of the health of your patients,” Adam Sherk, PhD, a scientist at the Canadian Institute for Substance Use Research at the University of Victoria (B.C.), and a member of the scientific expert panel that contributed to the guidance, said in an interview. “Display and discuss the new guidance with your patients with the main message that drinking less is better.”

Peter Butt, MD, a clinical associate professor at the University of Saskatchewan, Saskatoon, and cochair of the guidance project, said in an interview: “The World Health Organization has identified over 200 ICD-coded conditions associated with alcohol use. This creates many opportunities to inquire into quantity and frequency of alcohol use, relate it to the patient’s health and well-being, and provide advice on reduction.”

“Canada’s Guidance on Alcohol and Health: Final Report” and a related infographic were published online Jan. 17.
 

Continuum of risk

The impetus for the new guidance came from the fact that “our 2011 LRDGs were no longer current, and there was emerging evidence that people drinking within those levels were coming to harm,” said Dr. Butt.

That evidence indicates that alcohol causes at least seven types of cancer, mostly of the breast or colon; is a risk factor for most types of heart disease; and is a main cause of liver disease. Evidence also indicates that avoiding drinking to the point of intoxication will reduce people’s risk of perpetrating alcohol-related violence.

Responding to the need to accurately quantify the risk, the guidance defines a “standard” drink as 12 oz of beer, cooler, or cider (5% alcohol); 5 oz of wine (12% alcohol); and 1.5 oz of spirits such as whiskey, vodka, or gin (40% alcohol).

Using different mortality risk thresholds, the project’s experts developed the following continuum of risk:

• Low for individuals who consume two standard drinks or fewer per week
• Moderate for those who consume from three to six standard drinks per week
• Increasingly high for those who consume seven standard drinks or more per week

The guidance makes the following observations:

• Consuming more than two standard drinks per drinking occasion is associated with an increased risk of harms to self and others, including injuries and violence.
• When pregnant or trying to get pregnant, no amount of alcohol is safe.
• When breastfeeding, not drinking is safest.
• Above the upper limit of the moderate risk zone, health risks increase more steeply for females than males.
• Far more injuries, violence, and deaths result from men’s alcohol use, especially for per occasion drinking, than from women’s alcohol use.
• Young people should delay alcohol use for as long as possible.
• Individuals should not start to use alcohol or increase their alcohol use for health benefits.
• Any reduction in alcohol use is beneficial.

Other national guidelines

“Countries that haven’t updated their alcohol use guidelines recently should do so, as the evidence regarding alcohol and health has advanced considerably in the past 10 years,” said Dr. Sherk. He acknowledged that “any time health guidance changes substantially, it’s reasonable to expect a period of readjustment.”

“Some will be resistant,” Dr. Butt agreed. “Some professionals will need more education than others on the health effects of alcohol. Some patients will also be more invested in drinking than others. The harm-reduction, risk-zone approach should assist in the process of engaging patients and helping them reduce over time.

“Just as we benefited from the updates done in the United Kingdom, France, and especially Australia, so also researchers elsewhere will critique our work and our approach and make their own decisions on how best to communicate with their public,” Dr. Butt said. He noted that Canada’s contributions regarding the association between alcohol and violence, as well as their sex/gender approach to the evidence, “may influence the next country’s review.”

Commenting on whether the United States should consider changing its guidance, Timothy Brennan, MD, MPH, chief of clinical services for the Addiction Institute of Mount Sinai Health System in New York, said in an interview, “A lot of people will be surprised at the recommended limits on alcohol. Most think that they can have one or two glasses of alcohol per day and not have any increased risk to their health. I think the Canadians deserve credit for putting themselves out there.”

Dr. Brennan said there will “certainly be pushback by the drinking lobby, which is very strong both in the U.S. and in Canada.” In fact, the national trade group Beer Canada was recently quoted as stating that it still supports the 2011 guidelines and that the updating process lacked full transparency and expert technical peer review.

Nevertheless, Dr. Brennan said, “it’s overwhelmingly clear that alcohol affects a ton of different parts of our body, so limiting the amount of alcohol we take in is always going to be a good thing. The Canadian graphic is great because it color-codes the risk. I recommend that clinicians put it up in their offices and begin quantifying the units of alcohol that are going into a patient’s body each day.”

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

The risk of health harms from alcohol is low for people who consume two standard drinks or fewer per week, but it’s higher with greater consumption, according to new guidance from the Canadian Centre on Substance Use and Addiction.

“Drinking less is better,” says the guidance, which replaces Canada’s 2011 Low-Risk Drinking Guidelines (LRDGs).

Developed in consultation with an executive committee from federal, provincial, and territorial governments; national organizations; three scientific expert panels; and an internal evidence review working group, the guidance presents the following findings:

• Consuming no drinks per week has benefits, such as better health and better sleep, and it’s the only safe option during pregnancy.
• Consuming one or two standard drinks weekly will likely not have alcohol-related consequences.
• Three to six drinks raise the risk of developing breast, colon, and other cancers.
• Seven or more increase the risk of heart disease or stroke.
• Each additional drink “radically increases” the risk of these health consequences.

“Alcohol is more harmful than was previously thought and is a key component of the health of your patients,” Adam Sherk, PhD, a scientist at the Canadian Institute for Substance Use Research at the University of Victoria (B.C.), and a member of the scientific expert panel that contributed to the guidance, said in an interview. “Display and discuss the new guidance with your patients with the main message that drinking less is better.”

Peter Butt, MD, a clinical associate professor at the University of Saskatchewan, Saskatoon, and cochair of the guidance project, said in an interview: “The World Health Organization has identified over 200 ICD-coded conditions associated with alcohol use. This creates many opportunities to inquire into quantity and frequency of alcohol use, relate it to the patient’s health and well-being, and provide advice on reduction.”

“Canada’s Guidance on Alcohol and Health: Final Report” and a related infographic were published online Jan. 17.
 

Continuum of risk

The impetus for the new guidance came from the fact that “our 2011 LRDGs were no longer current, and there was emerging evidence that people drinking within those levels were coming to harm,” said Dr. Butt.

That evidence indicates that alcohol causes at least seven types of cancer, mostly of the breast or colon; is a risk factor for most types of heart disease; and is a main cause of liver disease. Evidence also indicates that avoiding drinking to the point of intoxication will reduce people’s risk of perpetrating alcohol-related violence.

Responding to the need to accurately quantify the risk, the guidance defines a “standard” drink as 12 oz of beer, cooler, or cider (5% alcohol); 5 oz of wine (12% alcohol); and 1.5 oz of spirits such as whiskey, vodka, or gin (40% alcohol).

Using different mortality risk thresholds, the project’s experts developed the following continuum of risk:

• Low for individuals who consume two standard drinks or fewer per week
• Moderate for those who consume from three to six standard drinks per week
• Increasingly high for those who consume seven standard drinks or more per week

The guidance makes the following observations:

• Consuming more than two standard drinks per drinking occasion is associated with an increased risk of harms to self and others, including injuries and violence.
• When pregnant or trying to get pregnant, no amount of alcohol is safe.
• When breastfeeding, not drinking is safest.
• Above the upper limit of the moderate risk zone, health risks increase more steeply for females than males.
• Far more injuries, violence, and deaths result from men’s alcohol use, especially for per occasion drinking, than from women’s alcohol use.
• Young people should delay alcohol use for as long as possible.
• Individuals should not start to use alcohol or increase their alcohol use for health benefits.
• Any reduction in alcohol use is beneficial.

Other national guidelines

“Countries that haven’t updated their alcohol use guidelines recently should do so, as the evidence regarding alcohol and health has advanced considerably in the past 10 years,” said Dr. Sherk. He acknowledged that “any time health guidance changes substantially, it’s reasonable to expect a period of readjustment.”

“Some will be resistant,” Dr. Butt agreed. “Some professionals will need more education than others on the health effects of alcohol. Some patients will also be more invested in drinking than others. The harm-reduction, risk-zone approach should assist in the process of engaging patients and helping them reduce over time.

“Just as we benefited from the updates done in the United Kingdom, France, and especially Australia, so also researchers elsewhere will critique our work and our approach and make their own decisions on how best to communicate with their public,” Dr. Butt said. He noted that Canada’s contributions regarding the association between alcohol and violence, as well as their sex/gender approach to the evidence, “may influence the next country’s review.”

Commenting on whether the United States should consider changing its guidance, Timothy Brennan, MD, MPH, chief of clinical services for the Addiction Institute of Mount Sinai Health System in New York, said in an interview, “A lot of people will be surprised at the recommended limits on alcohol. Most think that they can have one or two glasses of alcohol per day and not have any increased risk to their health. I think the Canadians deserve credit for putting themselves out there.”

Dr. Brennan said there will “certainly be pushback by the drinking lobby, which is very strong both in the U.S. and in Canada.” In fact, the national trade group Beer Canada was recently quoted as stating that it still supports the 2011 guidelines and that the updating process lacked full transparency and expert technical peer review.

Nevertheless, Dr. Brennan said, “it’s overwhelmingly clear that alcohol affects a ton of different parts of our body, so limiting the amount of alcohol we take in is always going to be a good thing. The Canadian graphic is great because it color-codes the risk. I recommend that clinicians put it up in their offices and begin quantifying the units of alcohol that are going into a patient’s body each day.”

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

The risk of health harms from alcohol is low for people who consume two standard drinks or fewer per week, but it’s higher with greater consumption, according to new guidance from the Canadian Centre on Substance Use and Addiction.

“Drinking less is better,” says the guidance, which replaces Canada’s 2011 Low-Risk Drinking Guidelines (LRDGs).

Developed in consultation with an executive committee from federal, provincial, and territorial governments; national organizations; three scientific expert panels; and an internal evidence review working group, the guidance presents the following findings:

• Consuming no drinks per week has benefits, such as better health and better sleep, and it’s the only safe option during pregnancy.
• Consuming one or two standard drinks weekly will likely not have alcohol-related consequences.
• Three to six drinks raise the risk of developing breast, colon, and other cancers.
• Seven or more increase the risk of heart disease or stroke.
• Each additional drink “radically increases” the risk of these health consequences.

“Alcohol is more harmful than was previously thought and is a key component of the health of your patients,” Adam Sherk, PhD, a scientist at the Canadian Institute for Substance Use Research at the University of Victoria (B.C.), and a member of the scientific expert panel that contributed to the guidance, said in an interview. “Display and discuss the new guidance with your patients with the main message that drinking less is better.”

Peter Butt, MD, a clinical associate professor at the University of Saskatchewan, Saskatoon, and cochair of the guidance project, said in an interview: “The World Health Organization has identified over 200 ICD-coded conditions associated with alcohol use. This creates many opportunities to inquire into quantity and frequency of alcohol use, relate it to the patient’s health and well-being, and provide advice on reduction.”

“Canada’s Guidance on Alcohol and Health: Final Report” and a related infographic were published online Jan. 17.
 

Continuum of risk

The impetus for the new guidance came from the fact that “our 2011 LRDGs were no longer current, and there was emerging evidence that people drinking within those levels were coming to harm,” said Dr. Butt.

That evidence indicates that alcohol causes at least seven types of cancer, mostly of the breast or colon; is a risk factor for most types of heart disease; and is a main cause of liver disease. Evidence also indicates that avoiding drinking to the point of intoxication will reduce people’s risk of perpetrating alcohol-related violence.

Responding to the need to accurately quantify the risk, the guidance defines a “standard” drink as 12 oz of beer, cooler, or cider (5% alcohol); 5 oz of wine (12% alcohol); and 1.5 oz of spirits such as whiskey, vodka, or gin (40% alcohol).

Using different mortality risk thresholds, the project’s experts developed the following continuum of risk:

• Low for individuals who consume two standard drinks or fewer per week
• Moderate for those who consume from three to six standard drinks per week
• Increasingly high for those who consume seven standard drinks or more per week

The guidance makes the following observations:

• Consuming more than two standard drinks per drinking occasion is associated with an increased risk of harms to self and others, including injuries and violence.
• When pregnant or trying to get pregnant, no amount of alcohol is safe.
• When breastfeeding, not drinking is safest.
• Above the upper limit of the moderate risk zone, health risks increase more steeply for females than males.
• Far more injuries, violence, and deaths result from men’s alcohol use, especially for per occasion drinking, than from women’s alcohol use.
• Young people should delay alcohol use for as long as possible.
• Individuals should not start to use alcohol or increase their alcohol use for health benefits.
• Any reduction in alcohol use is beneficial.

Other national guidelines

“Countries that haven’t updated their alcohol use guidelines recently should do so, as the evidence regarding alcohol and health has advanced considerably in the past 10 years,” said Dr. Sherk. He acknowledged that “any time health guidance changes substantially, it’s reasonable to expect a period of readjustment.”

“Some will be resistant,” Dr. Butt agreed. “Some professionals will need more education than others on the health effects of alcohol. Some patients will also be more invested in drinking than others. The harm-reduction, risk-zone approach should assist in the process of engaging patients and helping them reduce over time.

“Just as we benefited from the updates done in the United Kingdom, France, and especially Australia, so also researchers elsewhere will critique our work and our approach and make their own decisions on how best to communicate with their public,” Dr. Butt said. He noted that Canada’s contributions regarding the association between alcohol and violence, as well as their sex/gender approach to the evidence, “may influence the next country’s review.”

Commenting on whether the United States should consider changing its guidance, Timothy Brennan, MD, MPH, chief of clinical services for the Addiction Institute of Mount Sinai Health System in New York, said in an interview, “A lot of people will be surprised at the recommended limits on alcohol. Most think that they can have one or two glasses of alcohol per day and not have any increased risk to their health. I think the Canadians deserve credit for putting themselves out there.”

Dr. Brennan said there will “certainly be pushback by the drinking lobby, which is very strong both in the U.S. and in Canada.” In fact, the national trade group Beer Canada was recently quoted as stating that it still supports the 2011 guidelines and that the updating process lacked full transparency and expert technical peer review.

Nevertheless, Dr. Brennan said, “it’s overwhelmingly clear that alcohol affects a ton of different parts of our body, so limiting the amount of alcohol we take in is always going to be a good thing. The Canadian graphic is great because it color-codes the risk. I recommend that clinicians put it up in their offices and begin quantifying the units of alcohol that are going into a patient’s body each day.”

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

The Diagnosis: Marjolin Ulcer

A skin biopsy during his prior hospital admission demonstrated an ulcer with granulation tissue and mixed inflammation, and the patient was discharged with close outpatient follow-up. Two repeat skin biopsies from the peripheral margin at the time of the outpatient follow-up confirmed an invasive, well-differentiated squamous cell carcinoma (Figure), consistent with a Marjolin ulcer. Radiography demonstrated multiple left iliac chain and inguinal lymphadenopathies with extensive subcutaneous disease overlying the left medial tibia. After tumor board discussion, surgery was not recommended due to the size and likely penetration into the muscle. The patient began treatment with cemiplimab-rwlc, a PD-1 inhibitor. Within 4 cycles of treatment, he had improved pain and ambulation, and a 3-month follow-up positron emission tomography scan revealed decreased lymph node and cutaneous metabolic activity as well as clinical improvement.

Marjolin ulcers are rare and aggressive squamous cell carcinomas that arise from chronic wounds such as burn scars or pressure ulcers.¹ Although an underlying well-differentiated squamous cell carcinoma is the most common etiology, patients also may present with underlying basal cell carcinomas, melanomas, or angiosarcomas.² The exact pathogenesis underlying the malignant degeneration is unclear but appears to be driven by chronic inflammation. Patients classically present with a nonhealing ulcer associated with raised, friable, or crusty borders, as well as surrounding scar tissue. There is a median latency of 30 years after the trauma, though acute transformation within 12 months of an injury is possible.³ The diagnosis is confirmed with a peripheral wound biopsy. Surgical excision with wide margins remains the most common and effective intervention, especially for localized disease.¹ The addition of lymph node dissection remains controversial, but treatment decisions can be guided by radiographic staging.⁴

The prognosis of Marjolin ulcers remains poor, with a predicted 5-year survival rate ranging from 43% to 58%.¹ Dermatologists and trainees should be aware of Marjolin ulcers, especially as a mimicker of other chronic ulcerating conditions. Among the differential diagnosis, ulcerative lichen planus is a condition that commonly affects the oral and genital regions; however, patients with erosive lichen planus may develop an increased risk for the subsequent development of squamous cell carcinoma in the region.⁵ Furthermore, arterial ulcers typically develop on the distal lower extremities with other signs of chronic ischemia, including absent peripheral pulses, atrophic skin, hair loss, and ankle-brachial indices less than 0.5. Conversely, a venous ulcer classically affects the medial malleolus and will have evidence of venous insufficiency, including stasis dermatitis and peripheral edema.⁶

The Diagnosis: Marjolin Ulcer

A skin biopsy during his prior hospital admission demonstrated an ulcer with granulation tissue and mixed inflammation, and the patient was discharged with close outpatient follow-up. Two repeat skin biopsies from the peripheral margin at the time of the outpatient follow-up confirmed an invasive, well-differentiated squamous cell carcinoma (Figure), consistent with a Marjolin ulcer. Radiography demonstrated multiple left iliac chain and inguinal lymphadenopathies with extensive subcutaneous disease overlying the left medial tibia. After tumor board discussion, surgery was not recommended due to the size and likely penetration into the muscle. The patient began treatment with cemiplimab-rwlc, a PD-1 inhibitor. Within 4 cycles of treatment, he had improved pain and ambulation, and a 3-month follow-up positron emission tomography scan revealed decreased lymph node and cutaneous metabolic activity as well as clinical improvement.

Marjolin ulcers are rare and aggressive squamous cell carcinomas that arise from chronic wounds such as burn scars or pressure ulcers.¹ Although an underlying well-differentiated squamous cell carcinoma is the most common etiology, patients also may present with underlying basal cell carcinomas, melanomas, or angiosarcomas.² The exact pathogenesis underlying the malignant degeneration is unclear but appears to be driven by chronic inflammation. Patients classically present with a nonhealing ulcer associated with raised, friable, or crusty borders, as well as surrounding scar tissue. There is a median latency of 30 years after the trauma, though acute transformation within 12 months of an injury is possible.³ The diagnosis is confirmed with a peripheral wound biopsy. Surgical excision with wide margins remains the most common and effective intervention, especially for localized disease.¹ The addition of lymph node dissection remains controversial, but treatment decisions can be guided by radiographic staging.⁴

The prognosis of Marjolin ulcers remains poor, with a predicted 5-year survival rate ranging from 43% to 58%.¹ Dermatologists and trainees should be aware of Marjolin ulcers, especially as a mimicker of other chronic ulcerating conditions. Among the differential diagnosis, ulcerative lichen planus is a condition that commonly affects the oral and genital regions; however, patients with erosive lichen planus may develop an increased risk for the subsequent development of squamous cell carcinoma in the region.⁵ Furthermore, arterial ulcers typically develop on the distal lower extremities with other signs of chronic ischemia, including absent peripheral pulses, atrophic skin, hair loss, and ankle-brachial indices less than 0.5. Conversely, a venous ulcer classically affects the medial malleolus and will have evidence of venous insufficiency, including stasis dermatitis and peripheral edema.⁶

The Diagnosis: Marjolin Ulcer

A skin biopsy during his prior hospital admission demonstrated an ulcer with granulation tissue and mixed inflammation, and the patient was discharged with close outpatient follow-up. Two repeat skin biopsies from the peripheral margin at the time of the outpatient follow-up confirmed an invasive, well-differentiated squamous cell carcinoma (Figure), consistent with a Marjolin ulcer. Radiography demonstrated multiple left iliac chain and inguinal lymphadenopathies with extensive subcutaneous disease overlying the left medial tibia. After tumor board discussion, surgery was not recommended due to the size and likely penetration into the muscle. The patient began treatment with cemiplimab-rwlc, a PD-1 inhibitor. Within 4 cycles of treatment, he had improved pain and ambulation, and a 3-month follow-up positron emission tomography scan revealed decreased lymph node and cutaneous metabolic activity as well as clinical improvement.

Marjolin ulcers are rare and aggressive squamous cell carcinomas that arise from chronic wounds such as burn scars or pressure ulcers.¹ Although an underlying well-differentiated squamous cell carcinoma is the most common etiology, patients also may present with underlying basal cell carcinomas, melanomas, or angiosarcomas.² The exact pathogenesis underlying the malignant degeneration is unclear but appears to be driven by chronic inflammation. Patients classically present with a nonhealing ulcer associated with raised, friable, or crusty borders, as well as surrounding scar tissue. There is a median latency of 30 years after the trauma, though acute transformation within 12 months of an injury is possible.³ The diagnosis is confirmed with a peripheral wound biopsy. Surgical excision with wide margins remains the most common and effective intervention, especially for localized disease.¹ The addition of lymph node dissection remains controversial, but treatment decisions can be guided by radiographic staging.⁴

The prognosis of Marjolin ulcers remains poor, with a predicted 5-year survival rate ranging from 43% to 58%.¹ Dermatologists and trainees should be aware of Marjolin ulcers, especially as a mimicker of other chronic ulcerating conditions. Among the differential diagnosis, ulcerative lichen planus is a condition that commonly affects the oral and genital regions; however, patients with erosive lichen planus may develop an increased risk for the subsequent development of squamous cell carcinoma in the region.⁵ Furthermore, arterial ulcers typically develop on the distal lower extremities with other signs of chronic ischemia, including absent peripheral pulses, atrophic skin, hair loss, and ankle-brachial indices less than 0.5. Conversely, a venous ulcer classically affects the medial malleolus and will have evidence of venous insufficiency, including stasis dermatitis and peripheral edema.⁶

AURORA, COLO. – Only sparse evidence supports the use of dual-targeted therapy for patients with severe, refractory inflammatory bowel disease (IBD) -- and additional evidence will be hard to come by, according to a leading IBD researcher.

Dual-targeted therapy consists of either sequential or concomitant treatment with drugs from different classes of agents with distinct, specific mechanisms of action such as the use of a drug targeted against tumor necrosis factor (anti-TNFs) with an interleukin-12/23 inhibitor.

There have been only a handful of randomized clinical trials exploring such combinations, however. In addition, there are barriers to new trials, including the costs and risks of randomized trials, the need for cooperation rather than competition between pharmaceutical companies, and identifying patients who might optimally benefit from dual-targeted therapy, Laura Targownik, MD, said in a presentation at the annual Crohn’s & Colitis Congress®, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.

“In Canada we have absolutely no chance of getting coverage for this, and I imagine in hearing about the fights you have with insurers here in the [United] States, that you’re anticipating similar problems. So what do we do with this information? I think if we’re going to get answers on this question, it’s probably going to come from real-world evidence, from all of our experiences,” said Dr. Targownik of the Zane Cohen Centre for Digestive Diseases at Mount Sinai Hospital in Toronto.

Who might benefit?

Dual-targeted therapy has the potential to benefit patients with severe disease who may need intensive therapy upfront to prevent complications such as fistulas, strictures, or chronic abdominal pain. It may also benefit those who may require only short-term acute disease control; patients with meaningful yet incomplete responses to single-agent therapy who might have better outcomes with the addition of a second agent; and, patients with a unique phenotype that might be responsive to dual-targeted agents, Dr. Targownik said.

Another reason to consider dual-targeted therapy in IBD comes from applying data from recent clinical trials of upadacitinib (Rinvoq, Abbvie) for ulcerative colitis (UC) and risankizumab-rzaa (Skyrizi, Abbvie) for Crohn’s disease to hypothetical cohorts.

For example, of 1,000 persons with moderate to severe UC treated with upadacitinib, 736 would have a clinical response at the end of the induction, and at the end of the maintenance phase 191 would have endoscopic remissions, and 382 would remain in clinical remission.

Similarly, of 1,000 persons with moderate to severe Crohn’s disease treated with risankizumab, 434 would have a clinical response at the end of induction, and at the end of the maintenance phase, 172 would have endoscopic remissions, and 234 would remain in clinical remission.

“So, the vast majority of our patients are not achieving the targets that we want to hit,” she said.
 

Evidence from research clinical trials

Data from one of the few trials that have explored dual targeted therapy in IBD were presented at United European Gastroenterology Week in 2022.

The randomized double-blind phase 2a VEGA study looked at induction therapy with either a combination of the IL-23 inhibitor guselkumab (Tremfya, Janssen) and the anti-TNF monoclonal antibody golimumab (Simponi Aria, Janssen) followed by maintenance guselkumab, or each agent alone as induction monotherapy and maintenance.

The study population included 214 patients with moderate to severe UC with a modified Mayo Disease Activity Index scores of 6 or greater and endoscopy scores of 2 or 3 who had not received either anti-TNF or anti IL-23 agents.

At 12 weeks of follow-up, 36.6% of patients who started on combination therapy had clinical remissions, compared with 22.2% of patients on golimumab monotherapy and 22.1% of those on guselkumab alone, a clinically significant difference, Dr. Targownik said.

The combination also resulted in better endoscopic improvement over baseline (49.3% vs. 25% and 29.6%, respectively), although the study was not powered for this outcome.

At 38 weeks, 22.2% of patients who started on golimumab alone were in clinical remission, compared with 31% of those assigned to guselkumab monotherapy and 43.7% of those who started on the combination.

Endoscopic normalization at 38 weeks was seen in 6.9%, 15.5%, and 25.4% of patients, respectively.

“Even in the patients who went back on guselkumab monotherapy that were induced with dual therapy, there were statistically higher rates of clinical remission and endoscopic normalization at the end of the study,” Dr. Targownik said, although she noted that it’s unknown whether the benefit of the combination would be sustained over longer follow-up.

In the open-label EXPLORER Crohn’s disease trial, among 55 patients with high risk Crohn’s disease, within 24 months of diagnosis investigators looked at the triple combination therapy of the anti-integrin agent vedolizumab (Entyvio, Takeda), the anti-TNF agent adalimumab (Humira, Abbvie) and methotrexate. An interim analysis at week 26 of the 34-week trial showed clinical remissions in 54.5% of patients and endoscopic remissions in 34.5%, “which I would argue for an open-label study are not terribly high results,” she said.
 

Real-world experience

Dr. Targownik pointed to a systematic review and meta-analysis of the safety and effectiveness of combining biologic agents and small molecules in patients with IBD as evidence for how combinations work in the real world.

The analysis included data from 1 clinical trial and 12 observational studies on a total of 266 patients treated with one of seven different combinations. It showed estimates of clinical efficacy ranging from about 40% to 80%, albeit with wide and overlapping confidence intervals, making it difficult to come to any conclusions about the relatively superiority of one combination over another, Dr. Targownik said.

The authors of the meta-analysis did note, however, that the incidence of serious adverse events was relatively low, ranging from 9.6% for the combination of vedolizumab and anti-TNF, to just 1% for the JAK inhibitor tofacitinib (Xeljanz, Pfizer) plus vedolizumab.
 

Registry data may help

The use of registry data will shed more light on the potential benefits and drawbacks of dual-targeted therapy.

“If we can identify...the patient phenotypes that we want to evaluate dual therapy in, and try to catalog their experiences in a regimented way with defined outcomes and periods of follow-up, we may be able to get more meaningful information,” Dr. Targownik said.

Dr. Targownik disclosed fees, grant support, and/or scientific advisory board participation with multiple companies.

This article was updated 1/25/23.

AURORA, COLO. – Only sparse evidence supports the use of dual-targeted therapy for patients with severe, refractory inflammatory bowel disease (IBD) -- and additional evidence will be hard to come by, according to a leading IBD researcher.

Dual-targeted therapy consists of either sequential or concomitant treatment with drugs from different classes of agents with distinct, specific mechanisms of action such as the use of a drug targeted against tumor necrosis factor (anti-TNFs) with an interleukin-12/23 inhibitor.

There have been only a handful of randomized clinical trials exploring such combinations, however. In addition, there are barriers to new trials, including the costs and risks of randomized trials, the need for cooperation rather than competition between pharmaceutical companies, and identifying patients who might optimally benefit from dual-targeted therapy, Laura Targownik, MD, said in a presentation at the annual Crohn’s & Colitis Congress®, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.

“In Canada we have absolutely no chance of getting coverage for this, and I imagine in hearing about the fights you have with insurers here in the [United] States, that you’re anticipating similar problems. So what do we do with this information? I think if we’re going to get answers on this question, it’s probably going to come from real-world evidence, from all of our experiences,” said Dr. Targownik of the Zane Cohen Centre for Digestive Diseases at Mount Sinai Hospital in Toronto.

Who might benefit?

Dual-targeted therapy has the potential to benefit patients with severe disease who may need intensive therapy upfront to prevent complications such as fistulas, strictures, or chronic abdominal pain. It may also benefit those who may require only short-term acute disease control; patients with meaningful yet incomplete responses to single-agent therapy who might have better outcomes with the addition of a second agent; and, patients with a unique phenotype that might be responsive to dual-targeted agents, Dr. Targownik said.

Another reason to consider dual-targeted therapy in IBD comes from applying data from recent clinical trials of upadacitinib (Rinvoq, Abbvie) for ulcerative colitis (UC) and risankizumab-rzaa (Skyrizi, Abbvie) for Crohn’s disease to hypothetical cohorts.

For example, of 1,000 persons with moderate to severe UC treated with upadacitinib, 736 would have a clinical response at the end of the induction, and at the end of the maintenance phase 191 would have endoscopic remissions, and 382 would remain in clinical remission.

Similarly, of 1,000 persons with moderate to severe Crohn’s disease treated with risankizumab, 434 would have a clinical response at the end of induction, and at the end of the maintenance phase, 172 would have endoscopic remissions, and 234 would remain in clinical remission.

“So, the vast majority of our patients are not achieving the targets that we want to hit,” she said.
 

Evidence from research clinical trials

Data from one of the few trials that have explored dual targeted therapy in IBD were presented at United European Gastroenterology Week in 2022.

The randomized double-blind phase 2a VEGA study looked at induction therapy with either a combination of the IL-23 inhibitor guselkumab (Tremfya, Janssen) and the anti-TNF monoclonal antibody golimumab (Simponi Aria, Janssen) followed by maintenance guselkumab, or each agent alone as induction monotherapy and maintenance.

The study population included 214 patients with moderate to severe UC with a modified Mayo Disease Activity Index scores of 6 or greater and endoscopy scores of 2 or 3 who had not received either anti-TNF or anti IL-23 agents.

At 12 weeks of follow-up, 36.6% of patients who started on combination therapy had clinical remissions, compared with 22.2% of patients on golimumab monotherapy and 22.1% of those on guselkumab alone, a clinically significant difference, Dr. Targownik said.

The combination also resulted in better endoscopic improvement over baseline (49.3% vs. 25% and 29.6%, respectively), although the study was not powered for this outcome.

At 38 weeks, 22.2% of patients who started on golimumab alone were in clinical remission, compared with 31% of those assigned to guselkumab monotherapy and 43.7% of those who started on the combination.

Endoscopic normalization at 38 weeks was seen in 6.9%, 15.5%, and 25.4% of patients, respectively.

“Even in the patients who went back on guselkumab monotherapy that were induced with dual therapy, there were statistically higher rates of clinical remission and endoscopic normalization at the end of the study,” Dr. Targownik said, although she noted that it’s unknown whether the benefit of the combination would be sustained over longer follow-up.

In the open-label EXPLORER Crohn’s disease trial, among 55 patients with high risk Crohn’s disease, within 24 months of diagnosis investigators looked at the triple combination therapy of the anti-integrin agent vedolizumab (Entyvio, Takeda), the anti-TNF agent adalimumab (Humira, Abbvie) and methotrexate. An interim analysis at week 26 of the 34-week trial showed clinical remissions in 54.5% of patients and endoscopic remissions in 34.5%, “which I would argue for an open-label study are not terribly high results,” she said.
 

Real-world experience

Dr. Targownik pointed to a systematic review and meta-analysis of the safety and effectiveness of combining biologic agents and small molecules in patients with IBD as evidence for how combinations work in the real world.

The analysis included data from 1 clinical trial and 12 observational studies on a total of 266 patients treated with one of seven different combinations. It showed estimates of clinical efficacy ranging from about 40% to 80%, albeit with wide and overlapping confidence intervals, making it difficult to come to any conclusions about the relatively superiority of one combination over another, Dr. Targownik said.

The authors of the meta-analysis did note, however, that the incidence of serious adverse events was relatively low, ranging from 9.6% for the combination of vedolizumab and anti-TNF, to just 1% for the JAK inhibitor tofacitinib (Xeljanz, Pfizer) plus vedolizumab.
 

Registry data may help

The use of registry data will shed more light on the potential benefits and drawbacks of dual-targeted therapy.

“If we can identify...the patient phenotypes that we want to evaluate dual therapy in, and try to catalog their experiences in a regimented way with defined outcomes and periods of follow-up, we may be able to get more meaningful information,” Dr. Targownik said.

Dr. Targownik disclosed fees, grant support, and/or scientific advisory board participation with multiple companies.

This article was updated 1/25/23.

AURORA, COLO. – Only sparse evidence supports the use of dual-targeted therapy for patients with severe, refractory inflammatory bowel disease (IBD) -- and additional evidence will be hard to come by, according to a leading IBD researcher.

Dual-targeted therapy consists of either sequential or concomitant treatment with drugs from different classes of agents with distinct, specific mechanisms of action such as the use of a drug targeted against tumor necrosis factor (anti-TNFs) with an interleukin-12/23 inhibitor.

There have been only a handful of randomized clinical trials exploring such combinations, however. In addition, there are barriers to new trials, including the costs and risks of randomized trials, the need for cooperation rather than competition between pharmaceutical companies, and identifying patients who might optimally benefit from dual-targeted therapy, Laura Targownik, MD, said in a presentation at the annual Crohn’s & Colitis Congress®, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.

“In Canada we have absolutely no chance of getting coverage for this, and I imagine in hearing about the fights you have with insurers here in the [United] States, that you’re anticipating similar problems. So what do we do with this information? I think if we’re going to get answers on this question, it’s probably going to come from real-world evidence, from all of our experiences,” said Dr. Targownik of the Zane Cohen Centre for Digestive Diseases at Mount Sinai Hospital in Toronto.

Who might benefit?

Dual-targeted therapy has the potential to benefit patients with severe disease who may need intensive therapy upfront to prevent complications such as fistulas, strictures, or chronic abdominal pain. It may also benefit those who may require only short-term acute disease control; patients with meaningful yet incomplete responses to single-agent therapy who might have better outcomes with the addition of a second agent; and, patients with a unique phenotype that might be responsive to dual-targeted agents, Dr. Targownik said.

Another reason to consider dual-targeted therapy in IBD comes from applying data from recent clinical trials of upadacitinib (Rinvoq, Abbvie) for ulcerative colitis (UC) and risankizumab-rzaa (Skyrizi, Abbvie) for Crohn’s disease to hypothetical cohorts.

For example, of 1,000 persons with moderate to severe UC treated with upadacitinib, 736 would have a clinical response at the end of the induction, and at the end of the maintenance phase 191 would have endoscopic remissions, and 382 would remain in clinical remission.

Similarly, of 1,000 persons with moderate to severe Crohn’s disease treated with risankizumab, 434 would have a clinical response at the end of induction, and at the end of the maintenance phase, 172 would have endoscopic remissions, and 234 would remain in clinical remission.

“So, the vast majority of our patients are not achieving the targets that we want to hit,” she said.
 

Evidence from research clinical trials

Data from one of the few trials that have explored dual targeted therapy in IBD were presented at United European Gastroenterology Week in 2022.

The randomized double-blind phase 2a VEGA study looked at induction therapy with either a combination of the IL-23 inhibitor guselkumab (Tremfya, Janssen) and the anti-TNF monoclonal antibody golimumab (Simponi Aria, Janssen) followed by maintenance guselkumab, or each agent alone as induction monotherapy and maintenance.

The study population included 214 patients with moderate to severe UC with a modified Mayo Disease Activity Index scores of 6 or greater and endoscopy scores of 2 or 3 who had not received either anti-TNF or anti IL-23 agents.

At 12 weeks of follow-up, 36.6% of patients who started on combination therapy had clinical remissions, compared with 22.2% of patients on golimumab monotherapy and 22.1% of those on guselkumab alone, a clinically significant difference, Dr. Targownik said.

The combination also resulted in better endoscopic improvement over baseline (49.3% vs. 25% and 29.6%, respectively), although the study was not powered for this outcome.

At 38 weeks, 22.2% of patients who started on golimumab alone were in clinical remission, compared with 31% of those assigned to guselkumab monotherapy and 43.7% of those who started on the combination.

Endoscopic normalization at 38 weeks was seen in 6.9%, 15.5%, and 25.4% of patients, respectively.

“Even in the patients who went back on guselkumab monotherapy that were induced with dual therapy, there were statistically higher rates of clinical remission and endoscopic normalization at the end of the study,” Dr. Targownik said, although she noted that it’s unknown whether the benefit of the combination would be sustained over longer follow-up.

In the open-label EXPLORER Crohn’s disease trial, among 55 patients with high risk Crohn’s disease, within 24 months of diagnosis investigators looked at the triple combination therapy of the anti-integrin agent vedolizumab (Entyvio, Takeda), the anti-TNF agent adalimumab (Humira, Abbvie) and methotrexate. An interim analysis at week 26 of the 34-week trial showed clinical remissions in 54.5% of patients and endoscopic remissions in 34.5%, “which I would argue for an open-label study are not terribly high results,” she said.
 

Real-world experience

Dr. Targownik pointed to a systematic review and meta-analysis of the safety and effectiveness of combining biologic agents and small molecules in patients with IBD as evidence for how combinations work in the real world.

The analysis included data from 1 clinical trial and 12 observational studies on a total of 266 patients treated with one of seven different combinations. It showed estimates of clinical efficacy ranging from about 40% to 80%, albeit with wide and overlapping confidence intervals, making it difficult to come to any conclusions about the relatively superiority of one combination over another, Dr. Targownik said.

The authors of the meta-analysis did note, however, that the incidence of serious adverse events was relatively low, ranging from 9.6% for the combination of vedolizumab and anti-TNF, to just 1% for the JAK inhibitor tofacitinib (Xeljanz, Pfizer) plus vedolizumab.
 

Registry data may help

The use of registry data will shed more light on the potential benefits and drawbacks of dual-targeted therapy.

“If we can identify...the patient phenotypes that we want to evaluate dual therapy in, and try to catalog their experiences in a regimented way with defined outcomes and periods of follow-up, we may be able to get more meaningful information,” Dr. Targownik said.

Dr. Targownik disclosed fees, grant support, and/or scientific advisory board participation with multiple companies.

This article was updated 1/25/23.

Cutaneous T-cell lymphoma (CTCL) is a diverse group of skin-homing T-cell neoplasms with a wide array of clinical presentations, immunohistopathologic subtypes, and prognoses. The age-adjusted incidence of CTCL in the United States is 6.4 per million individuals.¹ In the early stages of CTCL, the malignant lymphocytes are isolated to the skin, while more advanced disease involves metastatic spread to the lymphatic and peripheral blood compartments. Mycosis fungoides (MF) is the most common subtype of CTCL, comprising roughly 50% of all cases. The etiology of CTCL and MF remains poorly understood and no unifying driver mutation has been identified.² However, recent sequencing efforts have revealed recurrent genomics alterations primarily in 3 pathways: constitutive T-cell activation, resistance to apoptosis/cell-cycle dysregulation, and DNA structural/gene expression dysregulation.^3-8 These studies, among others, support the assertion that CTCL may be an epigenetic phenomenon.^9-14

Most patients with MF will experience an indolent course of skin-limited disease with a favorable prognosis and a 5-year survival rate of 88%.^15-17 A large study of patients with MF (N=525) followed for more than 40 years determined that approximately 20% of early-stage (IA-IIA) patients with MF progress to develop tumors, metastasis to the lymphatic tissue, and/or leukemic blood disease.¹⁸

Cutaneous T-cell lymphoma is a chronic disease, and most treatment responses are partial and short-lived. Allogenic hematopoietic transplantation is the only potentially curative option, and all other therapies are aimed at arresting progression and achieving remission.¹⁹ Skin-directed therapies include topical steroids, topical nitrogen mustard, phototherapy, and radiation. Systemic therapies such as oral retinoids, chemotherapy, and immunotherapy may be used alone or in combination with skin-directed therapies based on the overall disease stage and clinical presentation. Unfortunately, complete response (CR) to therapy is rare and fleeting, and most patients require multiple sequential treatments over their lifetimes.²⁰

Across all stages of CTCL, there is a therapeutic push to combination and immune-based therapies to achieve more durable responses. The imidazoquinolines are a family of toll-like receptor (TLR) agonists including imiquimod (TLR7) and resiquimod (TLR7 and TLR8). Imiquimod (IMQ) is a topical immunomodulator, which increases the local cytotoxic helper T-cell profile (T_H1 marked by IFN-α, tumor necrosis factor α, IL-1α, IL-6, and IL-8), thereby enhancing both humoral and innate immune responses targeting tumor cells.^21-23 Several small studies evaluating topical TLR agonists have documented efficacy in patients with early and advanced stages of CTCL.^24-34

Skin-directed chemotherapy using 5-fluorouracil (5-FU) has shown activity against many cutaneous malignancies. 5-Fluorouracil is an antimetabolite drug that inhibits thymidylate synthase, resulting in interrupted DNA and RNA synthesis and leading to an apoptotic cell death (Figure 1). It has been administered via intravenous, oral (prodrug), intralesional (IL), and topical routes with well-documented success in treating cutaneous squamous cell carcinoma, keratoacanthoma, basal cell carcinoma, and precancerous actinic keratosis.³⁵ As a topical, 5-FU has been shown to provide a good response in 6 patients with early MF.³⁶ In late-stage MF, 5-FU has been used in combination with methotrexate as an infusion.³⁷ We present a single-center case series of 9 patients with CTCL who received combination IL 5-FU and IMQ cream 5%.

Methods

Patient Selection—Patients were selected from our multidisciplinary CTCL subspecialty clinic at the Inova Schar Cancer Institute (Fairfax, Virginia). Patients with single to few recalcitrant CTCL plaques or tumors that were symptomatic or otherwise bothersome were included. All patients had at least 2 prior skin-directed therapies that failed, and many had advanced-stage disease requiring systemic therapy. All patients provided verbal consent.

Study Materials and Evaluations—Patients received IL injections of 5-FU 50 mg/mL. The volume injected was approximately 0.2 cc per cubic centimeter of lesion tissue. Injections were repeated at 2- to 3-week intervals until the target lesions achieved an acute hemorrhagic phase characterized by erosion, flattening, and crust formation. The total number of serial injections administered ranged from 1 to 5. The patients concomitantly treated all lesions with IMQ cream 5% daily for a duration of 2 to 3 months.

Medical photography and physical examination were performed every 2 to 3 weeks until the hemorrhagic phase resolved and treated sites re-epithelialized. Index lesions were assessed using the Composite Assessment of Index Lesion Severity (CAILS) score by a single investigator for all patients.³⁸ Scores were retrospectively assigned using the investigator’s detailed physical examination descriptions and extensive medical photography. Any hyperpigmentation was scored as residual disease, despite the fair interpretation of it as procedure-related postinflammatory dyspigmentation. Complete response was strictly defined as a CAILS score of 0. The patients were screened for possible systemic effects of IMQ, including the presence of fever, chills, fatigue, and myalgia. Patients were evaluated every 6 to 12 weeks as a standing follow-up.

Statistical Analysis—Reductions were calculated using local regression from baseline to the 4- to 7-week follow-up. Patients with multiple lesions had their CAILS score averaged at ea

Results

Nine patients aged 28 to 91 years (median age, 66 years) with CTCL stages IA to IVA2, who had lesions located throughout their body, achieved CR; 3 patients were female (Table 1). The most common phenotype was CD8⁺ (n=3). All patients had at least 2 prior skin-directed therapies at treatment sites that failed, and 1 patient had 7 prior treatments that failed. Prior treatments included a variety of modalities, including all standard-of-care options and enrollment in clinical trials. One patient died from pneumonia following CR (Table 2). Seven patients had previously received systemic therapy for CTCL, and 1 patient was stable on romidepsin during our study. In patients who received more than 1 injection of 5-FU—1 injection: 3 patients; 2 injections: 3 patients; 3 injections: 1 patient; 4 injections: 1 patient; 5 injections: 1 patient—injections were spaced by 2 to 3 weeks. There was 1 patient who initially had an inadequate dosing of IL 5-FU and was restarted 14 months later; this was the patient with 5 total injections. This occurred in one of the first patients in the study, who presented with a facial lesion. The investigator used approximately 0.02 cc per cubic centimeter (dose reduction of nearly 90%), which was inadequate and did not achieve the requisite hemorrhagic phase.

Treatment was well tolerated overall. In all cases, a hemorrhagic phase was achieved, characterized by erosion and crusting that was rated as mildly uncomfortable by 7 patients and moderately uncomfortable by 2 patients. In total, 15 lesions in all 9 patients achieved a CR within 24 weeks of the final injection. The longest treatment course required 12 weeks of therapy with IMQ and 5 IL injections of 5-FU. The fastest CR was achieved in patient 6 within 6 weeks following a single IL injection of 5-FU and 2 applications of IMQ. The average time to CR was 14.78 weeks (95% CI, 1.75-27.81)(Figure 2), and the time to CR ranged from 4 to 24 weeks. On average, patients achieved more than 50% reduction in CAILS score by 3.53 weeks (95% CI, 1.55-5.51) and nearly a 4-fold (74.7%) reduction at the time of initial follow-up (occurring at 4–7 weeks). By 7 weeks, patient 3 had the most modest improvement in CAILS score with a 2.75-fold reduction, while patient 5 had the largest decrease with a 5-fold reduction. Figure 3 shows representative clinical photographs of 2 patients before and after treatment, with all patients having similar results.

Comment

Cutaneous T-cell lymphoma is a chronic skin cancer with a pattern of limited response to therapy and frequent recurrence. Currently available skin-directed therapies function as temporizing measures rather than curative treatments. Immunotherapy offers the promise of lasting disease control even after cessation of treatment, as it may essentially awaken cutaneous immune surveillance to malignant lymphocytes.

Several small observational studies have evaluated topical IMQ and TLR agonist therapy in CTCL. The construct of prior reports varies widely, including many different pretreatments, dosing schemes, and follow-up periods.^24-33 Dosing intervals with IMQ ranged from daily to 3 times per week and treatment duration from 2 weeks to 1 year. Complete response rates from 50% to 100% were reported, and partial responses were observed in all but 1 patient, with recurrence-free follow-up ranging from 6 months to 8 years. Comparatively, combining IL 5-FU and IMQ appears to be at least as effective as IMQ alone or in other sequential treatments and combinations.^24-33

Resiquimod, an experimental TLR7/8 agonist, has shown promising results in CTCL. Rook et al³⁴ conducted a phase 1 trial of topical resiquimod in 12 early-stage patients with CTCL, all of whom responded to therapy. Two patients achieved CR, and 9 achieved a partial response, including 5 patients with the folliculotropic subtype. Interestingly, an abscopal effect was observed in 92% (11/12) of patients. Molecular evidence of reduction of the malignant clone was observed in 90% of patients via high-throughput sequencing of lesional tissue.³⁴ These exciting findings suggest that topical immune therapy with TLR agonists may achieve robust, sustained, and possibly global disease control in CTCL.

Topical therapies are limited by depth of absorption, which can present a barrier to using these treatments for thicker plaques and tumors. Combining IL and topical routes was critical in our study design. Having good clinical experience using IL 5-FU in nonmelanoma skin cancers, we hypothesized that IL 5-FU would achieve a cytotoxic response through the full depth of thicker lesions and erode the surface of these lesions to facilitate penetration of topical IMQ. We additionally hypothesized that the combination of mechanisms of action would lead to an additive or synergistic response (Figure 1). By first inducing apoptotic cell death via 5-FU, we hoped to spill malignant lymphocyte neoantigens. Coupling that antigen exposure with an enhanced T_H1-biased immune response driven by IMQ should facilitate tumor clearance and immune education against malignant T cells.

In our case series, all 15 lesions in 9 patients completely cleared, and no recurrences were observed at 26-month follow-up. No patients encountered any major adverse events, and the procedure was well tolerated by all.

Study Limitations—Limitations of this small study certainly exist. It is impossible to prove that our mechanistic theory is accurate given our strictly clinical assessment tools. We speculate that if our results had been achieved with IL 5-FU alone, future investigation with a prospective study using multiple treatment arms including a control would be warranted. Kannangara et al³⁶ reported the use of topical 5-FU for MF and the drug’s utility in either topical or IL routes for CTCL, which deserves further study. It is less likely that results were achieved exclusively by IMQ because of the rapid tissue breakdown observed in the acute hemorrhagic phase. This phenomenon is best explained by the sudden apoptosis caused by DNA intercalation from 5-FU. The follow-up period is not uniform because this was a rolling enrollment study. Follow-up will be ongoing, and we aim to assess all patients up to at least the 5-year point. A final limitation of this study is the purely clinical end point. In the future, pretreatment and posttreatment biopsies would be useful in assessing proof of histologic response, and high-throughput sequencing may be used to look for molecular clearance via liquid biopsy. Lastly, careful observation for possible abscopal effect using the Severity-Weighted Assessment Tool score would be interesting and potentially contributory to our understanding of the impact of topical immune therapy on cutaneous tumor surveillance.

Conclusion

Combination IL 5-FU and topical IMQ is a well-tolerated, effective, and durable therapy for recalcitrant thick plaques and tumors of CTCL. This treatment is convenient and cost-effective. The procedure is performed in less than 5 minutes in an outpatient dermatology clinic. All patients received full insurance coverage for both drug and procedure fees under Medicare and commercial carriers.

Cutaneous T-cell lymphoma (CTCL) is a diverse group of skin-homing T-cell neoplasms with a wide array of clinical presentations, immunohistopathologic subtypes, and prognoses. The age-adjusted incidence of CTCL in the United States is 6.4 per million individuals.¹ In the early stages of CTCL, the malignant lymphocytes are isolated to the skin, while more advanced disease involves metastatic spread to the lymphatic and peripheral blood compartments. Mycosis fungoides (MF) is the most common subtype of CTCL, comprising roughly 50% of all cases. The etiology of CTCL and MF remains poorly understood and no unifying driver mutation has been identified.² However, recent sequencing efforts have revealed recurrent genomics alterations primarily in 3 pathways: constitutive T-cell activation, resistance to apoptosis/cell-cycle dysregulation, and DNA structural/gene expression dysregulation.^3-8 These studies, among others, support the assertion that CTCL may be an epigenetic phenomenon.^9-14

Most patients with MF will experience an indolent course of skin-limited disease with a favorable prognosis and a 5-year survival rate of 88%.^15-17 A large study of patients with MF (N=525) followed for more than 40 years determined that approximately 20% of early-stage (IA-IIA) patients with MF progress to develop tumors, metastasis to the lymphatic tissue, and/or leukemic blood disease.¹⁸

Cutaneous T-cell lymphoma is a chronic disease, and most treatment responses are partial and short-lived. Allogenic hematopoietic transplantation is the only potentially curative option, and all other therapies are aimed at arresting progression and achieving remission.¹⁹ Skin-directed therapies include topical steroids, topical nitrogen mustard, phototherapy, and radiation. Systemic therapies such as oral retinoids, chemotherapy, and immunotherapy may be used alone or in combination with skin-directed therapies based on the overall disease stage and clinical presentation. Unfortunately, complete response (CR) to therapy is rare and fleeting, and most patients require multiple sequential treatments over their lifetimes.²⁰

Across all stages of CTCL, there is a therapeutic push to combination and immune-based therapies to achieve more durable responses. The imidazoquinolines are a family of toll-like receptor (TLR) agonists including imiquimod (TLR7) and resiquimod (TLR7 and TLR8). Imiquimod (IMQ) is a topical immunomodulator, which increases the local cytotoxic helper T-cell profile (T_H1 marked by IFN-α, tumor necrosis factor α, IL-1α, IL-6, and IL-8), thereby enhancing both humoral and innate immune responses targeting tumor cells.^21-23 Several small studies evaluating topical TLR agonists have documented efficacy in patients with early and advanced stages of CTCL.^24-34

Skin-directed chemotherapy using 5-fluorouracil (5-FU) has shown activity against many cutaneous malignancies. 5-Fluorouracil is an antimetabolite drug that inhibits thymidylate synthase, resulting in interrupted DNA and RNA synthesis and leading to an apoptotic cell death (Figure 1). It has been administered via intravenous, oral (prodrug), intralesional (IL), and topical routes with well-documented success in treating cutaneous squamous cell carcinoma, keratoacanthoma, basal cell carcinoma, and precancerous actinic keratosis.³⁵ As a topical, 5-FU has been shown to provide a good response in 6 patients with early MF.³⁶ In late-stage MF, 5-FU has been used in combination with methotrexate as an infusion.³⁷ We present a single-center case series of 9 patients with CTCL who received combination IL 5-FU and IMQ cream 5%.

Methods

Patient Selection—Patients were selected from our multidisciplinary CTCL subspecialty clinic at the Inova Schar Cancer Institute (Fairfax, Virginia). Patients with single to few recalcitrant CTCL plaques or tumors that were symptomatic or otherwise bothersome were included. All patients had at least 2 prior skin-directed therapies that failed, and many had advanced-stage disease requiring systemic therapy. All patients provided verbal consent.

Study Materials and Evaluations—Patients received IL injections of 5-FU 50 mg/mL. The volume injected was approximately 0.2 cc per cubic centimeter of lesion tissue. Injections were repeated at 2- to 3-week intervals until the target lesions achieved an acute hemorrhagic phase characterized by erosion, flattening, and crust formation. The total number of serial injections administered ranged from 1 to 5. The patients concomitantly treated all lesions with IMQ cream 5% daily for a duration of 2 to 3 months.

Medical photography and physical examination were performed every 2 to 3 weeks until the hemorrhagic phase resolved and treated sites re-epithelialized. Index lesions were assessed using the Composite Assessment of Index Lesion Severity (CAILS) score by a single investigator for all patients.³⁸ Scores were retrospectively assigned using the investigator’s detailed physical examination descriptions and extensive medical photography. Any hyperpigmentation was scored as residual disease, despite the fair interpretation of it as procedure-related postinflammatory dyspigmentation. Complete response was strictly defined as a CAILS score of 0. The patients were screened for possible systemic effects of IMQ, including the presence of fever, chills, fatigue, and myalgia. Patients were evaluated every 6 to 12 weeks as a standing follow-up.

Statistical Analysis—Reductions were calculated using local regression from baseline to the 4- to 7-week follow-up. Patients with multiple lesions had their CAILS score averaged at ea

Results

Nine patients aged 28 to 91 years (median age, 66 years) with CTCL stages IA to IVA2, who had lesions located throughout their body, achieved CR; 3 patients were female (Table 1). The most common phenotype was CD8⁺ (n=3). All patients had at least 2 prior skin-directed therapies at treatment sites that failed, and 1 patient had 7 prior treatments that failed. Prior treatments included a variety of modalities, including all standard-of-care options and enrollment in clinical trials. One patient died from pneumonia following CR (Table 2). Seven patients had previously received systemic therapy for CTCL, and 1 patient was stable on romidepsin during our study. In patients who received more than 1 injection of 5-FU—1 injection: 3 patients; 2 injections: 3 patients; 3 injections: 1 patient; 4 injections: 1 patient; 5 injections: 1 patient—injections were spaced by 2 to 3 weeks. There was 1 patient who initially had an inadequate dosing of IL 5-FU and was restarted 14 months later; this was the patient with 5 total injections. This occurred in one of the first patients in the study, who presented with a facial lesion. The investigator used approximately 0.02 cc per cubic centimeter (dose reduction of nearly 90%), which was inadequate and did not achieve the requisite hemorrhagic phase.

Treatment was well tolerated overall. In all cases, a hemorrhagic phase was achieved, characterized by erosion and crusting that was rated as mildly uncomfortable by 7 patients and moderately uncomfortable by 2 patients. In total, 15 lesions in all 9 patients achieved a CR within 24 weeks of the final injection. The longest treatment course required 12 weeks of therapy with IMQ and 5 IL injections of 5-FU. The fastest CR was achieved in patient 6 within 6 weeks following a single IL injection of 5-FU and 2 applications of IMQ. The average time to CR was 14.78 weeks (95% CI, 1.75-27.81)(Figure 2), and the time to CR ranged from 4 to 24 weeks. On average, patients achieved more than 50% reduction in CAILS score by 3.53 weeks (95% CI, 1.55-5.51) and nearly a 4-fold (74.7%) reduction at the time of initial follow-up (occurring at 4–7 weeks). By 7 weeks, patient 3 had the most modest improvement in CAILS score with a 2.75-fold reduction, while patient 5 had the largest decrease with a 5-fold reduction. Figure 3 shows representative clinical photographs of 2 patients before and after treatment, with all patients having similar results.

Comment

Cutaneous T-cell lymphoma is a chronic skin cancer with a pattern of limited response to therapy and frequent recurrence. Currently available skin-directed therapies function as temporizing measures rather than curative treatments. Immunotherapy offers the promise of lasting disease control even after cessation of treatment, as it may essentially awaken cutaneous immune surveillance to malignant lymphocytes.

Several small observational studies have evaluated topical IMQ and TLR agonist therapy in CTCL. The construct of prior reports varies widely, including many different pretreatments, dosing schemes, and follow-up periods.^24-33 Dosing intervals with IMQ ranged from daily to 3 times per week and treatment duration from 2 weeks to 1 year. Complete response rates from 50% to 100% were reported, and partial responses were observed in all but 1 patient, with recurrence-free follow-up ranging from 6 months to 8 years. Comparatively, combining IL 5-FU and IMQ appears to be at least as effective as IMQ alone or in other sequential treatments and combinations.^24-33

Resiquimod, an experimental TLR7/8 agonist, has shown promising results in CTCL. Rook et al³⁴ conducted a phase 1 trial of topical resiquimod in 12 early-stage patients with CTCL, all of whom responded to therapy. Two patients achieved CR, and 9 achieved a partial response, including 5 patients with the folliculotropic subtype. Interestingly, an abscopal effect was observed in 92% (11/12) of patients. Molecular evidence of reduction of the malignant clone was observed in 90% of patients via high-throughput sequencing of lesional tissue.³⁴ These exciting findings suggest that topical immune therapy with TLR agonists may achieve robust, sustained, and possibly global disease control in CTCL.

Topical therapies are limited by depth of absorption, which can present a barrier to using these treatments for thicker plaques and tumors. Combining IL and topical routes was critical in our study design. Having good clinical experience using IL 5-FU in nonmelanoma skin cancers, we hypothesized that IL 5-FU would achieve a cytotoxic response through the full depth of thicker lesions and erode the surface of these lesions to facilitate penetration of topical IMQ. We additionally hypothesized that the combination of mechanisms of action would lead to an additive or synergistic response (Figure 1). By first inducing apoptotic cell death via 5-FU, we hoped to spill malignant lymphocyte neoantigens. Coupling that antigen exposure with an enhanced T_H1-biased immune response driven by IMQ should facilitate tumor clearance and immune education against malignant T cells.

In our case series, all 15 lesions in 9 patients completely cleared, and no recurrences were observed at 26-month follow-up. No patients encountered any major adverse events, and the procedure was well tolerated by all.

Study Limitations—Limitations of this small study certainly exist. It is impossible to prove that our mechanistic theory is accurate given our strictly clinical assessment tools. We speculate that if our results had been achieved with IL 5-FU alone, future investigation with a prospective study using multiple treatment arms including a control would be warranted. Kannangara et al³⁶ reported the use of topical 5-FU for MF and the drug’s utility in either topical or IL routes for CTCL, which deserves further study. It is less likely that results were achieved exclusively by IMQ because of the rapid tissue breakdown observed in the acute hemorrhagic phase. This phenomenon is best explained by the sudden apoptosis caused by DNA intercalation from 5-FU. The follow-up period is not uniform because this was a rolling enrollment study. Follow-up will be ongoing, and we aim to assess all patients up to at least the 5-year point. A final limitation of this study is the purely clinical end point. In the future, pretreatment and posttreatment biopsies would be useful in assessing proof of histologic response, and high-throughput sequencing may be used to look for molecular clearance via liquid biopsy. Lastly, careful observation for possible abscopal effect using the Severity-Weighted Assessment Tool score would be interesting and potentially contributory to our understanding of the impact of topical immune therapy on cutaneous tumor surveillance.

Conclusion

Combination IL 5-FU and topical IMQ is a well-tolerated, effective, and durable therapy for recalcitrant thick plaques and tumors of CTCL. This treatment is convenient and cost-effective. The procedure is performed in less than 5 minutes in an outpatient dermatology clinic. All patients received full insurance coverage for both drug and procedure fees under Medicare and commercial carriers.

Cutaneous T-cell lymphoma (CTCL) is a diverse group of skin-homing T-cell neoplasms with a wide array of clinical presentations, immunohistopathologic subtypes, and prognoses. The age-adjusted incidence of CTCL in the United States is 6.4 per million individuals.¹ In the early stages of CTCL, the malignant lymphocytes are isolated to the skin, while more advanced disease involves metastatic spread to the lymphatic and peripheral blood compartments. Mycosis fungoides (MF) is the most common subtype of CTCL, comprising roughly 50% of all cases. The etiology of CTCL and MF remains poorly understood and no unifying driver mutation has been identified.² However, recent sequencing efforts have revealed recurrent genomics alterations primarily in 3 pathways: constitutive T-cell activation, resistance to apoptosis/cell-cycle dysregulation, and DNA structural/gene expression dysregulation.^3-8 These studies, among others, support the assertion that CTCL may be an epigenetic phenomenon.^9-14

Most patients with MF will experience an indolent course of skin-limited disease with a favorable prognosis and a 5-year survival rate of 88%.^15-17 A large study of patients with MF (N=525) followed for more than 40 years determined that approximately 20% of early-stage (IA-IIA) patients with MF progress to develop tumors, metastasis to the lymphatic tissue, and/or leukemic blood disease.¹⁸

Cutaneous T-cell lymphoma is a chronic disease, and most treatment responses are partial and short-lived. Allogenic hematopoietic transplantation is the only potentially curative option, and all other therapies are aimed at arresting progression and achieving remission.¹⁹ Skin-directed therapies include topical steroids, topical nitrogen mustard, phototherapy, and radiation. Systemic therapies such as oral retinoids, chemotherapy, and immunotherapy may be used alone or in combination with skin-directed therapies based on the overall disease stage and clinical presentation. Unfortunately, complete response (CR) to therapy is rare and fleeting, and most patients require multiple sequential treatments over their lifetimes.²⁰

Across all stages of CTCL, there is a therapeutic push to combination and immune-based therapies to achieve more durable responses. The imidazoquinolines are a family of toll-like receptor (TLR) agonists including imiquimod (TLR7) and resiquimod (TLR7 and TLR8). Imiquimod (IMQ) is a topical immunomodulator, which increases the local cytotoxic helper T-cell profile (T_H1 marked by IFN-α, tumor necrosis factor α, IL-1α, IL-6, and IL-8), thereby enhancing both humoral and innate immune responses targeting tumor cells.^21-23 Several small studies evaluating topical TLR agonists have documented efficacy in patients with early and advanced stages of CTCL.^24-34

Skin-directed chemotherapy using 5-fluorouracil (5-FU) has shown activity against many cutaneous malignancies. 5-Fluorouracil is an antimetabolite drug that inhibits thymidylate synthase, resulting in interrupted DNA and RNA synthesis and leading to an apoptotic cell death (Figure 1). It has been administered via intravenous, oral (prodrug), intralesional (IL), and topical routes with well-documented success in treating cutaneous squamous cell carcinoma, keratoacanthoma, basal cell carcinoma, and precancerous actinic keratosis.³⁵ As a topical, 5-FU has been shown to provide a good response in 6 patients with early MF.³⁶ In late-stage MF, 5-FU has been used in combination with methotrexate as an infusion.³⁷ We present a single-center case series of 9 patients with CTCL who received combination IL 5-FU and IMQ cream 5%.

Methods

Patient Selection—Patients were selected from our multidisciplinary CTCL subspecialty clinic at the Inova Schar Cancer Institute (Fairfax, Virginia). Patients with single to few recalcitrant CTCL plaques or tumors that were symptomatic or otherwise bothersome were included. All patients had at least 2 prior skin-directed therapies that failed, and many had advanced-stage disease requiring systemic therapy. All patients provided verbal consent.

Study Materials and Evaluations—Patients received IL injections of 5-FU 50 mg/mL. The volume injected was approximately 0.2 cc per cubic centimeter of lesion tissue. Injections were repeated at 2- to 3-week intervals until the target lesions achieved an acute hemorrhagic phase characterized by erosion, flattening, and crust formation. The total number of serial injections administered ranged from 1 to 5. The patients concomitantly treated all lesions with IMQ cream 5% daily for a duration of 2 to 3 months.

Medical photography and physical examination were performed every 2 to 3 weeks until the hemorrhagic phase resolved and treated sites re-epithelialized. Index lesions were assessed using the Composite Assessment of Index Lesion Severity (CAILS) score by a single investigator for all patients.³⁸ Scores were retrospectively assigned using the investigator’s detailed physical examination descriptions and extensive medical photography. Any hyperpigmentation was scored as residual disease, despite the fair interpretation of it as procedure-related postinflammatory dyspigmentation. Complete response was strictly defined as a CAILS score of 0. The patients were screened for possible systemic effects of IMQ, including the presence of fever, chills, fatigue, and myalgia. Patients were evaluated every 6 to 12 weeks as a standing follow-up.

Statistical Analysis—Reductions were calculated using local regression from baseline to the 4- to 7-week follow-up. Patients with multiple lesions had their CAILS score averaged at ea

Results

Nine patients aged 28 to 91 years (median age, 66 years) with CTCL stages IA to IVA2, who had lesions located throughout their body, achieved CR; 3 patients were female (Table 1). The most common phenotype was CD8⁺ (n=3). All patients had at least 2 prior skin-directed therapies at treatment sites that failed, and 1 patient had 7 prior treatments that failed. Prior treatments included a variety of modalities, including all standard-of-care options and enrollment in clinical trials. One patient died from pneumonia following CR (Table 2). Seven patients had previously received systemic therapy for CTCL, and 1 patient was stable on romidepsin during our study. In patients who received more than 1 injection of 5-FU—1 injection: 3 patients; 2 injections: 3 patients; 3 injections: 1 patient; 4 injections: 1 patient; 5 injections: 1 patient—injections were spaced by 2 to 3 weeks. There was 1 patient who initially had an inadequate dosing of IL 5-FU and was restarted 14 months later; this was the patient with 5 total injections. This occurred in one of the first patients in the study, who presented with a facial lesion. The investigator used approximately 0.02 cc per cubic centimeter (dose reduction of nearly 90%), which was inadequate and did not achieve the requisite hemorrhagic phase.

Treatment was well tolerated overall. In all cases, a hemorrhagic phase was achieved, characterized by erosion and crusting that was rated as mildly uncomfortable by 7 patients and moderately uncomfortable by 2 patients. In total, 15 lesions in all 9 patients achieved a CR within 24 weeks of the final injection. The longest treatment course required 12 weeks of therapy with IMQ and 5 IL injections of 5-FU. The fastest CR was achieved in patient 6 within 6 weeks following a single IL injection of 5-FU and 2 applications of IMQ. The average time to CR was 14.78 weeks (95% CI, 1.75-27.81)(Figure 2), and the time to CR ranged from 4 to 24 weeks. On average, patients achieved more than 50% reduction in CAILS score by 3.53 weeks (95% CI, 1.55-5.51) and nearly a 4-fold (74.7%) reduction at the time of initial follow-up (occurring at 4–7 weeks). By 7 weeks, patient 3 had the most modest improvement in CAILS score with a 2.75-fold reduction, while patient 5 had the largest decrease with a 5-fold reduction. Figure 3 shows representative clinical photographs of 2 patients before and after treatment, with all patients having similar results.

Comment

Cutaneous T-cell lymphoma is a chronic skin cancer with a pattern of limited response to therapy and frequent recurrence. Currently available skin-directed therapies function as temporizing measures rather than curative treatments. Immunotherapy offers the promise of lasting disease control even after cessation of treatment, as it may essentially awaken cutaneous immune surveillance to malignant lymphocytes.

Several small observational studies have evaluated topical IMQ and TLR agonist therapy in CTCL. The construct of prior reports varies widely, including many different pretreatments, dosing schemes, and follow-up periods.^24-33 Dosing intervals with IMQ ranged from daily to 3 times per week and treatment duration from 2 weeks to 1 year. Complete response rates from 50% to 100% were reported, and partial responses were observed in all but 1 patient, with recurrence-free follow-up ranging from 6 months to 8 years. Comparatively, combining IL 5-FU and IMQ appears to be at least as effective as IMQ alone or in other sequential treatments and combinations.^24-33

Resiquimod, an experimental TLR7/8 agonist, has shown promising results in CTCL. Rook et al³⁴ conducted a phase 1 trial of topical resiquimod in 12 early-stage patients with CTCL, all of whom responded to therapy. Two patients achieved CR, and 9 achieved a partial response, including 5 patients with the folliculotropic subtype. Interestingly, an abscopal effect was observed in 92% (11/12) of patients. Molecular evidence of reduction of the malignant clone was observed in 90% of patients via high-throughput sequencing of lesional tissue.³⁴ These exciting findings suggest that topical immune therapy with TLR agonists may achieve robust, sustained, and possibly global disease control in CTCL.

Topical therapies are limited by depth of absorption, which can present a barrier to using these treatments for thicker plaques and tumors. Combining IL and topical routes was critical in our study design. Having good clinical experience using IL 5-FU in nonmelanoma skin cancers, we hypothesized that IL 5-FU would achieve a cytotoxic response through the full depth of thicker lesions and erode the surface of these lesions to facilitate penetration of topical IMQ. We additionally hypothesized that the combination of mechanisms of action would lead to an additive or synergistic response (Figure 1). By first inducing apoptotic cell death via 5-FU, we hoped to spill malignant lymphocyte neoantigens. Coupling that antigen exposure with an enhanced T_H1-biased immune response driven by IMQ should facilitate tumor clearance and immune education against malignant T cells.

In our case series, all 15 lesions in 9 patients completely cleared, and no recurrences were observed at 26-month follow-up. No patients encountered any major adverse events, and the procedure was well tolerated by all.

Study Limitations—Limitations of this small study certainly exist. It is impossible to prove that our mechanistic theory is accurate given our strictly clinical assessment tools. We speculate that if our results had been achieved with IL 5-FU alone, future investigation with a prospective study using multiple treatment arms including a control would be warranted. Kannangara et al³⁶ reported the use of topical 5-FU for MF and the drug’s utility in either topical or IL routes for CTCL, which deserves further study. It is less likely that results were achieved exclusively by IMQ because of the rapid tissue breakdown observed in the acute hemorrhagic phase. This phenomenon is best explained by the sudden apoptosis caused by DNA intercalation from 5-FU. The follow-up period is not uniform because this was a rolling enrollment study. Follow-up will be ongoing, and we aim to assess all patients up to at least the 5-year point. A final limitation of this study is the purely clinical end point. In the future, pretreatment and posttreatment biopsies would be useful in assessing proof of histologic response, and high-throughput sequencing may be used to look for molecular clearance via liquid biopsy. Lastly, careful observation for possible abscopal effect using the Severity-Weighted Assessment Tool score would be interesting and potentially contributory to our understanding of the impact of topical immune therapy on cutaneous tumor surveillance.

Conclusion

Combination IL 5-FU and topical IMQ is a well-tolerated, effective, and durable therapy for recalcitrant thick plaques and tumors of CTCL. This treatment is convenient and cost-effective. The procedure is performed in less than 5 minutes in an outpatient dermatology clinic. All patients received full insurance coverage for both drug and procedure fees under Medicare and commercial carriers.

Introduction

The professional activity of physicians has traditionally consisted of patient care, teaching/education, and research in varying proportions. These aims, especially education and research, have traditionally been achieved in academic health settings. However, involvement with industry can afford all physicians an opportunity to increase patient referrals, gain exposure to colleagues through a variety of educational opportunities, and participate in meaningful research projects they could not initiate independently. This article will discuss a variety of ways that gastroenterologists can engage with industry to achieve a mutually beneficial relationship.

How to initiate relationships with industry

Here are several ways to initiate a collaboration with industry. A few of the most common ways are to become a site investigator of a multicenter device or pharmaceutical trial, participate as a member of a speaker’s bureau, or obtain training on a new technology and subsequently incorporate it into your clinical practice. To find out what trials are enrolling and looking for additional sites or new studies that are being planned, I would suggest contacting the company’s local representative and have them put you in touch the appropriate personnel in the clinical trials division. For individuals who become involved in trials, this can be a great way to improve your understanding of how to design and conduct clinical trials as well as gain exposure to colleagues with similar clinical and research interests. Some of my closest long-term collaborators and friends have been individuals who I initially met as part of industry trials at investigator meetings. Another approach is to participate in a speaker’s bureau, which can be an excellent way to improve one’s presentation skills as well as gain knowledge with respect to a specific disease state. It is also a great way to network, meet colleagues, and develop a local and regional reputation as a content expert on a specific topic. Methods to find out about such opportunities include touring the exhibit halls during educational meetings and reading scientific journals to identify new products that are launching. I have found these sorts of opportunities can significantly increase topic-based referrals. Finally, obtaining training on a new diagnostic or therapeutic technology (usually through an industry-sponsored course) can allow individuals an opportunity to offer a unique or distinctive service to their community. In addition, as further clinical expertise is gained, the relationship can be expanded to offer local, regional, or even national training courses to colleagues via either on-site or virtual courses. Similarly, opportunities to speak about or demonstrate the technology/technique at educational courses may also follow.

Navigating and expanding the relationship

Once an individual establishes a relationship with a company or has established a reputation as a key opinion leader, additional opportunities for engagement may become available. These include serving as a consultant, becoming a member of an advisory board, participating or directing educational courses for trainees/practitioners, or serving as the principal investigator of a future clinical trial. Serving as a consultant can be quite rewarding as it can highlight clinical needs, identify where product improvement can be achieved, and focus where research and development funds should be directed. Serving on the advisory board can afford an even higher level of influence where corporate strategy can be influenced. Such input is particularly impactful with smaller companies looking to enter a new field or expand a limited market share. There are also a variety of educational opportunities offered by industry including local, regional, and national courses that focus on utilizing a new technology or education concerning a specific disease state. These courses can be held locally at the physician’s clinical site or off site to attract the desired target audience. Finally, being involved in research studies, especially early-stage projects, can be critical as many small companies have limited capital, and it is essential for them to design studies with appropriate endpoints that will ideally achieve both regulatory approval as well as payor coverage. Of note, in addition to relationships directly involving industry, the American Gastroenterological Association Center for GI Innovation and Technology (CGIT) also offers the opportunity to be part of key opinion leader meetings arranged and organized by the AGA. This may allow for some individuals to participate who may be restricted from direct relationships with industry partners. The industry services offered by the CGIT also include clinical trial design and registry management services.

Entrepreneurship/intellectual property

A less commonly explored opportunity with industry involves the development of one’s own intellectual property. Some of the most impactful technologies in my advanced endoscopy clinical practice have been developed from the ideas of gastroenterology colleagues that have been successfully commercialized. These include radiofrequency ablation technology to treat Barrett’s esophagus and the development of lumen-apposing stents. There are several options for physicians with an idea for an innovation. These can include working with a university technology transfer department if they are in an academic setting, creation of their own company, or collaborating with industry to develop the device through a licensing/royalty agreement. The AGA CGIT offers extensive resources to physicians with new ideas on how to secure their intellectual property as well as to evaluate the feasibility of the aforementioned options to choose which may be most appropriate for them.

Important caveats

It is important that physicians with industry relations be aware of their local institutional policies. Some institutions may prohibit such activities while others may limit the types of relationships or the amount of income that can be received. It is the physician’s responsibility to be aware of their institution’s guidelines prior to formalizing industry agreements. If intellectual property is involved, it is essential to know the specific rules regarding physician remuneration, especially pertaining to royalty or equity agreements. Furthermore, with regard to presentations and publications, it is required to acknowledge industry relations and potential conflicts of interest. Failure to do so may adversely affect an individual’s reputation as well as lead to additional consequences such as the potential for retraction of publications or restrictions regarding future educational speaking opportunities. In addition, key opinion leaders often consult for several companies that may be in competition with each other. Therefore, it is essential that there is no disclosure of confidential proprietary information among companies. Finally, the financial incentives resulting from industry collaboration should never influence physician judgment when interpreting or speaking about data regarding product efficacy or safety.

Conclusions

In summary, there are numerous opportunities for physicians to collaborate with industry. These relationships can be very rewarding and can serve to expedite the introduction of new diagnostic or treatment modalities and provide the opportunity to network and interact with colleagues as well as to participate in important research that improves clinical practice. The nature of these relationships should always be transparent, and it is the physician’s responsibility to ensure that the types of relationships that are engaged in are permitted by their employer. Over the course of my career, I have participated in nearly all forms of these relationships and have seen that participation lead to important publications, changes in corporate strategy, the fostering of acquisitions, and the rapid development and utilization of new endoscopic technologies. It is my personal belief than industry relationships can improve professional satisfaction, enhance one’s brand, and most importantly, expedite clinical innovation to improve patient care.

Dr. Muthusamy is professor of clinical medicine at the University of California, Los Angeles, and medical director of endoscopy, UCLA Health System. He disclosed ties with Medtronic, Boston Scientific, Motus GI, Endogastric Solutions, and Capsovision.

Introduction

The professional activity of physicians has traditionally consisted of patient care, teaching/education, and research in varying proportions. These aims, especially education and research, have traditionally been achieved in academic health settings. However, involvement with industry can afford all physicians an opportunity to increase patient referrals, gain exposure to colleagues through a variety of educational opportunities, and participate in meaningful research projects they could not initiate independently. This article will discuss a variety of ways that gastroenterologists can engage with industry to achieve a mutually beneficial relationship.

How to initiate relationships with industry

Here are several ways to initiate a collaboration with industry. A few of the most common ways are to become a site investigator of a multicenter device or pharmaceutical trial, participate as a member of a speaker’s bureau, or obtain training on a new technology and subsequently incorporate it into your clinical practice. To find out what trials are enrolling and looking for additional sites or new studies that are being planned, I would suggest contacting the company’s local representative and have them put you in touch the appropriate personnel in the clinical trials division. For individuals who become involved in trials, this can be a great way to improve your understanding of how to design and conduct clinical trials as well as gain exposure to colleagues with similar clinical and research interests. Some of my closest long-term collaborators and friends have been individuals who I initially met as part of industry trials at investigator meetings. Another approach is to participate in a speaker’s bureau, which can be an excellent way to improve one’s presentation skills as well as gain knowledge with respect to a specific disease state. It is also a great way to network, meet colleagues, and develop a local and regional reputation as a content expert on a specific topic. Methods to find out about such opportunities include touring the exhibit halls during educational meetings and reading scientific journals to identify new products that are launching. I have found these sorts of opportunities can significantly increase topic-based referrals. Finally, obtaining training on a new diagnostic or therapeutic technology (usually through an industry-sponsored course) can allow individuals an opportunity to offer a unique or distinctive service to their community. In addition, as further clinical expertise is gained, the relationship can be expanded to offer local, regional, or even national training courses to colleagues via either on-site or virtual courses. Similarly, opportunities to speak about or demonstrate the technology/technique at educational courses may also follow.

Navigating and expanding the relationship

Once an individual establishes a relationship with a company or has established a reputation as a key opinion leader, additional opportunities for engagement may become available. These include serving as a consultant, becoming a member of an advisory board, participating or directing educational courses for trainees/practitioners, or serving as the principal investigator of a future clinical trial. Serving as a consultant can be quite rewarding as it can highlight clinical needs, identify where product improvement can be achieved, and focus where research and development funds should be directed. Serving on the advisory board can afford an even higher level of influence where corporate strategy can be influenced. Such input is particularly impactful with smaller companies looking to enter a new field or expand a limited market share. There are also a variety of educational opportunities offered by industry including local, regional, and national courses that focus on utilizing a new technology or education concerning a specific disease state. These courses can be held locally at the physician’s clinical site or off site to attract the desired target audience. Finally, being involved in research studies, especially early-stage projects, can be critical as many small companies have limited capital, and it is essential for them to design studies with appropriate endpoints that will ideally achieve both regulatory approval as well as payor coverage. Of note, in addition to relationships directly involving industry, the American Gastroenterological Association Center for GI Innovation and Technology (CGIT) also offers the opportunity to be part of key opinion leader meetings arranged and organized by the AGA. This may allow for some individuals to participate who may be restricted from direct relationships with industry partners. The industry services offered by the CGIT also include clinical trial design and registry management services.

Entrepreneurship/intellectual property

A less commonly explored opportunity with industry involves the development of one’s own intellectual property. Some of the most impactful technologies in my advanced endoscopy clinical practice have been developed from the ideas of gastroenterology colleagues that have been successfully commercialized. These include radiofrequency ablation technology to treat Barrett’s esophagus and the development of lumen-apposing stents. There are several options for physicians with an idea for an innovation. These can include working with a university technology transfer department if they are in an academic setting, creation of their own company, or collaborating with industry to develop the device through a licensing/royalty agreement. The AGA CGIT offers extensive resources to physicians with new ideas on how to secure their intellectual property as well as to evaluate the feasibility of the aforementioned options to choose which may be most appropriate for them.

Important caveats

It is important that physicians with industry relations be aware of their local institutional policies. Some institutions may prohibit such activities while others may limit the types of relationships or the amount of income that can be received. It is the physician’s responsibility to be aware of their institution’s guidelines prior to formalizing industry agreements. If intellectual property is involved, it is essential to know the specific rules regarding physician remuneration, especially pertaining to royalty or equity agreements. Furthermore, with regard to presentations and publications, it is required to acknowledge industry relations and potential conflicts of interest. Failure to do so may adversely affect an individual’s reputation as well as lead to additional consequences such as the potential for retraction of publications or restrictions regarding future educational speaking opportunities. In addition, key opinion leaders often consult for several companies that may be in competition with each other. Therefore, it is essential that there is no disclosure of confidential proprietary information among companies. Finally, the financial incentives resulting from industry collaboration should never influence physician judgment when interpreting or speaking about data regarding product efficacy or safety.

Conclusions

In summary, there are numerous opportunities for physicians to collaborate with industry. These relationships can be very rewarding and can serve to expedite the introduction of new diagnostic or treatment modalities and provide the opportunity to network and interact with colleagues as well as to participate in important research that improves clinical practice. The nature of these relationships should always be transparent, and it is the physician’s responsibility to ensure that the types of relationships that are engaged in are permitted by their employer. Over the course of my career, I have participated in nearly all forms of these relationships and have seen that participation lead to important publications, changes in corporate strategy, the fostering of acquisitions, and the rapid development and utilization of new endoscopic technologies. It is my personal belief than industry relationships can improve professional satisfaction, enhance one’s brand, and most importantly, expedite clinical innovation to improve patient care.

Dr. Muthusamy is professor of clinical medicine at the University of California, Los Angeles, and medical director of endoscopy, UCLA Health System. He disclosed ties with Medtronic, Boston Scientific, Motus GI, Endogastric Solutions, and Capsovision.

Introduction

The professional activity of physicians has traditionally consisted of patient care, teaching/education, and research in varying proportions. These aims, especially education and research, have traditionally been achieved in academic health settings. However, involvement with industry can afford all physicians an opportunity to increase patient referrals, gain exposure to colleagues through a variety of educational opportunities, and participate in meaningful research projects they could not initiate independently. This article will discuss a variety of ways that gastroenterologists can engage with industry to achieve a mutually beneficial relationship.

How to initiate relationships with industry

Here are several ways to initiate a collaboration with industry. A few of the most common ways are to become a site investigator of a multicenter device or pharmaceutical trial, participate as a member of a speaker’s bureau, or obtain training on a new technology and subsequently incorporate it into your clinical practice. To find out what trials are enrolling and looking for additional sites or new studies that are being planned, I would suggest contacting the company’s local representative and have them put you in touch the appropriate personnel in the clinical trials division. For individuals who become involved in trials, this can be a great way to improve your understanding of how to design and conduct clinical trials as well as gain exposure to colleagues with similar clinical and research interests. Some of my closest long-term collaborators and friends have been individuals who I initially met as part of industry trials at investigator meetings. Another approach is to participate in a speaker’s bureau, which can be an excellent way to improve one’s presentation skills as well as gain knowledge with respect to a specific disease state. It is also a great way to network, meet colleagues, and develop a local and regional reputation as a content expert on a specific topic. Methods to find out about such opportunities include touring the exhibit halls during educational meetings and reading scientific journals to identify new products that are launching. I have found these sorts of opportunities can significantly increase topic-based referrals. Finally, obtaining training on a new diagnostic or therapeutic technology (usually through an industry-sponsored course) can allow individuals an opportunity to offer a unique or distinctive service to their community. In addition, as further clinical expertise is gained, the relationship can be expanded to offer local, regional, or even national training courses to colleagues via either on-site or virtual courses. Similarly, opportunities to speak about or demonstrate the technology/technique at educational courses may also follow.

Navigating and expanding the relationship

Once an individual establishes a relationship with a company or has established a reputation as a key opinion leader, additional opportunities for engagement may become available. These include serving as a consultant, becoming a member of an advisory board, participating or directing educational courses for trainees/practitioners, or serving as the principal investigator of a future clinical trial. Serving as a consultant can be quite rewarding as it can highlight clinical needs, identify where product improvement can be achieved, and focus where research and development funds should be directed. Serving on the advisory board can afford an even higher level of influence where corporate strategy can be influenced. Such input is particularly impactful with smaller companies looking to enter a new field or expand a limited market share. There are also a variety of educational opportunities offered by industry including local, regional, and national courses that focus on utilizing a new technology or education concerning a specific disease state. These courses can be held locally at the physician’s clinical site or off site to attract the desired target audience. Finally, being involved in research studies, especially early-stage projects, can be critical as many small companies have limited capital, and it is essential for them to design studies with appropriate endpoints that will ideally achieve both regulatory approval as well as payor coverage. Of note, in addition to relationships directly involving industry, the American Gastroenterological Association Center for GI Innovation and Technology (CGIT) also offers the opportunity to be part of key opinion leader meetings arranged and organized by the AGA. This may allow for some individuals to participate who may be restricted from direct relationships with industry partners. The industry services offered by the CGIT also include clinical trial design and registry management services.

Entrepreneurship/intellectual property

A less commonly explored opportunity with industry involves the development of one’s own intellectual property. Some of the most impactful technologies in my advanced endoscopy clinical practice have been developed from the ideas of gastroenterology colleagues that have been successfully commercialized. These include radiofrequency ablation technology to treat Barrett’s esophagus and the development of lumen-apposing stents. There are several options for physicians with an idea for an innovation. These can include working with a university technology transfer department if they are in an academic setting, creation of their own company, or collaborating with industry to develop the device through a licensing/royalty agreement. The AGA CGIT offers extensive resources to physicians with new ideas on how to secure their intellectual property as well as to evaluate the feasibility of the aforementioned options to choose which may be most appropriate for them.

Important caveats

It is important that physicians with industry relations be aware of their local institutional policies. Some institutions may prohibit such activities while others may limit the types of relationships or the amount of income that can be received. It is the physician’s responsibility to be aware of their institution’s guidelines prior to formalizing industry agreements. If intellectual property is involved, it is essential to know the specific rules regarding physician remuneration, especially pertaining to royalty or equity agreements. Furthermore, with regard to presentations and publications, it is required to acknowledge industry relations and potential conflicts of interest. Failure to do so may adversely affect an individual’s reputation as well as lead to additional consequences such as the potential for retraction of publications or restrictions regarding future educational speaking opportunities. In addition, key opinion leaders often consult for several companies that may be in competition with each other. Therefore, it is essential that there is no disclosure of confidential proprietary information among companies. Finally, the financial incentives resulting from industry collaboration should never influence physician judgment when interpreting or speaking about data regarding product efficacy or safety.

Conclusions

In summary, there are numerous opportunities for physicians to collaborate with industry. These relationships can be very rewarding and can serve to expedite the introduction of new diagnostic or treatment modalities and provide the opportunity to network and interact with colleagues as well as to participate in important research that improves clinical practice. The nature of these relationships should always be transparent, and it is the physician’s responsibility to ensure that the types of relationships that are engaged in are permitted by their employer. Over the course of my career, I have participated in nearly all forms of these relationships and have seen that participation lead to important publications, changes in corporate strategy, the fostering of acquisitions, and the rapid development and utilization of new endoscopic technologies. It is my personal belief than industry relationships can improve professional satisfaction, enhance one’s brand, and most importantly, expedite clinical innovation to improve patient care.

Dr. Muthusamy is professor of clinical medicine at the University of California, Los Angeles, and medical director of endoscopy, UCLA Health System. He disclosed ties with Medtronic, Boston Scientific, Motus GI, Endogastric Solutions, and Capsovision.

More than half of emergency department visits from U.S. patients with cancer are potentially preventable, a new analysis suggests.

Overall, researchers found that 18.3 million (52%) ED visits among patients with cancer between 2012 and 2019 were potentially avoidable. Pain was the most common reason for such a visit. Notably, the number of potentially preventable ED visits documented each year increased over the study period.

“These findings highlight the need for cancer care programs to implement evidence-based interventions to better manage cancer treatment complications, such as uncontrolled pain, in outpatient and ambulatory settings,” said the authors, led by Amir Alishahi Tabriz, MD, PhD, MPH, department of health outcomes and behavior, Moffitt Cancer Center, Tampa.

Authors of an accompanying editorial agree, noting that “patients at risk for having uncontrolled pain could potentially be identified earlier, and steps could be taken that would address their pain and help prevent acute care visits.”

The study and the editorial were published online Jan. 19, 2022, in JAMA Network Open.

Patients with cancer experience a range of side effects from their cancer and treatment. Many such problems can be managed in the ambulatory setting but are often managed in the ED, which is far from optimal for patients with cancer from both a complications and cost perspective. Still, little is known about whether ED visits among patients with cancer are avoidable.

To better understand unnecessary emergency care use by these patients, Dr. Tabriz and colleagues evaluated trends and characteristics of potentially preventable ED visits among adults with cancer who had an ED visit between 2012 and 2019. The authors used the Centers for Medicare & Medicaid Services definition for a potentially preventable ED visit among patients receiving chemotherapy.

Among the 35.5 million ED visits made by patients with cancer during the study period, 18.3 million (52%) were identified as potentially preventable. Nearly 5.8 million of these visits (21%) were classified as being of “high acuity,” and almost 30% resulted in unplanned hospitalizations.

Pain was the most common reason for potentially preventable ED visits, accounting for 37% of these visits.

The absolute number of potentially preventable ED visits among cancer patients increased from about 1.8 million in 2012 to 3.2 million in 2019. The number of patients who visited the ED because of pain more than doubled, from roughly 1.2 million in 2012 to 2.4 million in 2019.

“The disproportionate increase in the number of ED visits by patients with cancer has put a substantial burden on EDs that are already operating at peak capacity” and “reinforces the need for cancer care programs to devise innovative ways to manage complications associated with cancer treatment in the outpatient and ambulatory settings,” Dr. Tabriz and coauthors wrote.

The increase could be an “unintended” consequence of efforts to decrease overall opioid administration in response to the opioid epidemic, Dr. Tabriz and colleagues noted. For example, the authors point to a recent study that found that about half of patients with cancer who had severe pain did not receive outpatient opioids in the week before visiting the ED.

“Even access to outpatient care does not mean patients can get the care they need outside an ED,” wrote editorialists Erek Majka, MD, with Summerlin Hospital, Las Vegas, and N. Seth Trueger, MD, MPH, with Northwestern University, Chicago. Thus, “it is no surprise that patients are sent to the ED if the alternatives do not have the staff or diagnostic and therapeutic capabilities the patients need.”

Overall, however, the “goal is not to eliminate ED visits for their own sake; rather, the goal is better care of patients with cancer, and secondarily, in a manner that is cost-effective,” Dr. Majka and Dr. Trueger explained.

No specific funding for the study was reported. The authors disclosed no relevant financial relationships. Dr. Trueger is digital media editor of JAMA Network Open, but he was not involved in decisions regarding review of the manuscript or its acceptance.

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

More than half of emergency department visits from U.S. patients with cancer are potentially preventable, a new analysis suggests.

Overall, researchers found that 18.3 million (52%) ED visits among patients with cancer between 2012 and 2019 were potentially avoidable. Pain was the most common reason for such a visit. Notably, the number of potentially preventable ED visits documented each year increased over the study period.

“These findings highlight the need for cancer care programs to implement evidence-based interventions to better manage cancer treatment complications, such as uncontrolled pain, in outpatient and ambulatory settings,” said the authors, led by Amir Alishahi Tabriz, MD, PhD, MPH, department of health outcomes and behavior, Moffitt Cancer Center, Tampa.

Authors of an accompanying editorial agree, noting that “patients at risk for having uncontrolled pain could potentially be identified earlier, and steps could be taken that would address their pain and help prevent acute care visits.”

The study and the editorial were published online Jan. 19, 2022, in JAMA Network Open.

Patients with cancer experience a range of side effects from their cancer and treatment. Many such problems can be managed in the ambulatory setting but are often managed in the ED, which is far from optimal for patients with cancer from both a complications and cost perspective. Still, little is known about whether ED visits among patients with cancer are avoidable.

To better understand unnecessary emergency care use by these patients, Dr. Tabriz and colleagues evaluated trends and characteristics of potentially preventable ED visits among adults with cancer who had an ED visit between 2012 and 2019. The authors used the Centers for Medicare & Medicaid Services definition for a potentially preventable ED visit among patients receiving chemotherapy.

Among the 35.5 million ED visits made by patients with cancer during the study period, 18.3 million (52%) were identified as potentially preventable. Nearly 5.8 million of these visits (21%) were classified as being of “high acuity,” and almost 30% resulted in unplanned hospitalizations.

Pain was the most common reason for potentially preventable ED visits, accounting for 37% of these visits.

The absolute number of potentially preventable ED visits among cancer patients increased from about 1.8 million in 2012 to 3.2 million in 2019. The number of patients who visited the ED because of pain more than doubled, from roughly 1.2 million in 2012 to 2.4 million in 2019.

“The disproportionate increase in the number of ED visits by patients with cancer has put a substantial burden on EDs that are already operating at peak capacity” and “reinforces the need for cancer care programs to devise innovative ways to manage complications associated with cancer treatment in the outpatient and ambulatory settings,” Dr. Tabriz and coauthors wrote.

The increase could be an “unintended” consequence of efforts to decrease overall opioid administration in response to the opioid epidemic, Dr. Tabriz and colleagues noted. For example, the authors point to a recent study that found that about half of patients with cancer who had severe pain did not receive outpatient opioids in the week before visiting the ED.

“Even access to outpatient care does not mean patients can get the care they need outside an ED,” wrote editorialists Erek Majka, MD, with Summerlin Hospital, Las Vegas, and N. Seth Trueger, MD, MPH, with Northwestern University, Chicago. Thus, “it is no surprise that patients are sent to the ED if the alternatives do not have the staff or diagnostic and therapeutic capabilities the patients need.”

Overall, however, the “goal is not to eliminate ED visits for their own sake; rather, the goal is better care of patients with cancer, and secondarily, in a manner that is cost-effective,” Dr. Majka and Dr. Trueger explained.

No specific funding for the study was reported. The authors disclosed no relevant financial relationships. Dr. Trueger is digital media editor of JAMA Network Open, but he was not involved in decisions regarding review of the manuscript or its acceptance.

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

More than half of emergency department visits from U.S. patients with cancer are potentially preventable, a new analysis suggests.

Overall, researchers found that 18.3 million (52%) ED visits among patients with cancer between 2012 and 2019 were potentially avoidable. Pain was the most common reason for such a visit. Notably, the number of potentially preventable ED visits documented each year increased over the study period.

“These findings highlight the need for cancer care programs to implement evidence-based interventions to better manage cancer treatment complications, such as uncontrolled pain, in outpatient and ambulatory settings,” said the authors, led by Amir Alishahi Tabriz, MD, PhD, MPH, department of health outcomes and behavior, Moffitt Cancer Center, Tampa.

Authors of an accompanying editorial agree, noting that “patients at risk for having uncontrolled pain could potentially be identified earlier, and steps could be taken that would address their pain and help prevent acute care visits.”

The study and the editorial were published online Jan. 19, 2022, in JAMA Network Open.

Patients with cancer experience a range of side effects from their cancer and treatment. Many such problems can be managed in the ambulatory setting but are often managed in the ED, which is far from optimal for patients with cancer from both a complications and cost perspective. Still, little is known about whether ED visits among patients with cancer are avoidable.

To better understand unnecessary emergency care use by these patients, Dr. Tabriz and colleagues evaluated trends and characteristics of potentially preventable ED visits among adults with cancer who had an ED visit between 2012 and 2019. The authors used the Centers for Medicare & Medicaid Services definition for a potentially preventable ED visit among patients receiving chemotherapy.

Among the 35.5 million ED visits made by patients with cancer during the study period, 18.3 million (52%) were identified as potentially preventable. Nearly 5.8 million of these visits (21%) were classified as being of “high acuity,” and almost 30% resulted in unplanned hospitalizations.

Pain was the most common reason for potentially preventable ED visits, accounting for 37% of these visits.

The absolute number of potentially preventable ED visits among cancer patients increased from about 1.8 million in 2012 to 3.2 million in 2019. The number of patients who visited the ED because of pain more than doubled, from roughly 1.2 million in 2012 to 2.4 million in 2019.

“The disproportionate increase in the number of ED visits by patients with cancer has put a substantial burden on EDs that are already operating at peak capacity” and “reinforces the need for cancer care programs to devise innovative ways to manage complications associated with cancer treatment in the outpatient and ambulatory settings,” Dr. Tabriz and coauthors wrote.

The increase could be an “unintended” consequence of efforts to decrease overall opioid administration in response to the opioid epidemic, Dr. Tabriz and colleagues noted. For example, the authors point to a recent study that found that about half of patients with cancer who had severe pain did not receive outpatient opioids in the week before visiting the ED.

“Even access to outpatient care does not mean patients can get the care they need outside an ED,” wrote editorialists Erek Majka, MD, with Summerlin Hospital, Las Vegas, and N. Seth Trueger, MD, MPH, with Northwestern University, Chicago. Thus, “it is no surprise that patients are sent to the ED if the alternatives do not have the staff or diagnostic and therapeutic capabilities the patients need.”

Overall, however, the “goal is not to eliminate ED visits for their own sake; rather, the goal is better care of patients with cancer, and secondarily, in a manner that is cost-effective,” Dr. Majka and Dr. Trueger explained.

No specific funding for the study was reported. The authors disclosed no relevant financial relationships. Dr. Trueger is digital media editor of JAMA Network Open, but he was not involved in decisions regarding review of the manuscript or its acceptance.

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