Cutaneous adverse reactions in B-RAF positive metastatic melanoma following sequential treatment with B-RAF/MEK inhibitors and immune checkpoint blockade or vice versa. A single-institutional case-series

Background With the advent of immune-checkpoint inhibitors and targeted treatments (TT), there have been unprecedented response rates and survival in advanced melanoma, but the optimal sequencing of these two treatments modalities is unknown. Combining or sequencing these agents could potentially result in unique toxicities. Cutaneous adverse events (CAE) after sequential exposure to these agents represents one toxicity that needs further description. Methods After retrospectively reviewing charts of patients from 2015 to 2018, we identified six patients who experienced CAEs after recent exposure to sequential immunotherapy and TT or vice versa for the treatment for metastatic melanoma at the University of North Carolina, Chapel Hill. Skin biopsies were available in five patients. Results Five patients received TT after immunotherapy, and one patient received immunotherapy after TT. TT consisted of vemurafenib/cobimetinib (V/C) in five patients with four patients starting V/C immediately before manifesting with a CAE. In patients receiving V/C after immunotherapy, the median time from beginning V/C to development of CAE was 14.5 days. The clinical presentation of diffuse morbilliform rash, fevers, hypotension, and end-organ damage raised concern for Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome. Histopathological features of lympho-eosinophilic infiltrate were supportive of a drug eruption. Immunotherapy or TT were re-initiated in five patients within 1–8 weeks after resolution of the index CAE. This resulted in two patients re-experiencing the CAE. Both of these patients were off prednisone at the time of therapy re-initiation, whereas none of the patients who were restarted on targeted therapy with a steroid overlap had a rash recurrence. Conclusions Sequential treatment using immunotherapy and TT, especially the sequence of V/C after immunotherapy appears to be the most common trigger for CAE with a median time to onset of approximately 2 weeks. Although the clinical presentation of these CAEs can be dramatic, they respond well to prednisone therapy. This unique presentation suggests that it may be reasonably safe to re-challenge certain patients with a steroid overlap after rash resolution

The Psychological Harms of Screening: the Evidence We Have Versus the Evidence We Need

BACKGROUND: Systematic reviews for the US Preventive Services Task Force have found less high-quality evidence on psychological than physical harms of screening. To understand the extent of evidence on psychological harms, we developed an evidence map that quantifies the distribution of evidence on psychological harms for five adult screening services. We also note gaps in the literature and make recommendations for future research. METHODS: We systematically searched PubMed, PsycInfo, and CINAHL from 2002 to 2012 for studies of any research design that assessed the burden or frequency of psychological harm associated with screening for: prostate and lung cancers, osteoporosis, abdominal aortic aneurysm (AAA) and carotid artery stenosis (CAS). We also searched for studies that estimated rates of overdiagnosis (a marker for unnecessary labeling). We included studies published in English and used dual independent review to determine study inclusion and to abstract information on design, types of measures, and outcomes assessed. RESULTS: Sixty-eight studies assessing psychological harms met our criteria; 62 % concerned prostate cancer and 16 % concerned lung cancer. Evidence was scant for the other three screening services. Overall, only about one-third of the studies used both longitudinal designs and condition-specific measures (ranging from 0 % for AAA and CAS to 78 % for lung cancer), which can provide the best evidence on harms. An additional 20 studies that met our criteria estimated rates of overdiagnosis in lung or prostate cancer. No studies estimated overdiagnosis for the non-cancer screening services. DISCUSSION: Evidence on psychological harms varied markedly across screening services in number and potential usefulness. We found important evidence gaps for all five screening services. The evidence that we have on psychological harms is inadequate in number of studies and in research design and measures. Future research should focus more clearly on the evidence that we need for decision making about screening

Cutaneous adverse reactions in B-RAF positive metastatic melanoma following sequential treatment with B-RAF/MEK inhibitors and immune checkpoint blockade or vice versa. A single-institutional case-series

Abstract Background With the advent of immune-checkpoint inhibitors and targeted treatments (TT), there have been unprecedented response rates and survival in advanced melanoma, but the optimal sequencing of these two treatments modalities is unknown. Combining or sequencing these agents could potentially result in unique toxicities. Cutaneous adverse events (CAE) after sequential exposure to these agents represents one toxicity that needs further description. Methods After retrospectively reviewing charts of patients from 2015 to 2018, we identified six patients who experienced CAEs after recent exposure to sequential immunotherapy and TT or vice versa for the treatment for metastatic melanoma at the University of North Carolina, Chapel Hill. Skin biopsies were available in five patients. Results Five patients received TT after immunotherapy, and one patient received immunotherapy after TT. TT consisted of vemurafenib/cobimetinib (V/C) in five patients with four patients starting V/C immediately before manifesting with a CAE. In patients receiving V/C after immunotherapy, the median time from beginning V/C to development of CAE was 14.5-‰days. The clinical presentation of diffuse morbilliform rash, fevers, hypotension, and end-organ damage raised concern for Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome. Histopathological features of lympho-eosinophilic infiltrate were supportive of a drug eruption. Immunotherapy or TT were re-initiated in five patients within 1--8-‰weeks after resolution of the index CAE. This resulted in two patients re-experiencing the CAE. Both of these patients were off prednisone at the time of therapy re-initiation, whereas none of the patients who were restarted on targeted therapy with a steroid overlap had a rash recurrence. Conclusions Sequential treatment using immunotherapy and TT, especially the sequence of V/C after immunotherapy appears to be the most common trigger for CAE with a median time to onset of approximately 2 weeks. Although the clinical presentation of these CAEs can be dramatic, they respond well to prednisone therapy. This unique presentation suggests that it may be reasonably safe to re-challenge certain patients with a steroid overlap after rash resolution

Cutaneous adverse reactions in B-RAF positive metastatic melanoma following sequential treatment with B-RAF/MEK inhibitors and immune checkpoint blockade or vice versa. A single-institutional case-series

BackgroundWith the advent of immune-checkpoint inhibitors and targeted treatments (TT), there have been unprecedented response rates and survival in advanced melanoma, but the optimal sequencing of these two treatments modalities is unknown. Combining or sequencing these agents could potentially result in unique toxicities. Cutaneous adverse events (CAE) after sequential exposure to these agents represents one toxicity that needs further description.MethodsAfter retrospectively reviewing charts of patients from 2015 to 2018, we identified six patients who experienced CAEs after recent exposure to sequential immunotherapy and TT or vice versa for the treatment for metastatic melanoma at the University of North Carolina, Chapel Hill. Skin biopsies were available in five patients.ResultsFive patients received TT after immunotherapy, and one patient received immunotherapy after TT. TT consisted of vemurafenib/cobimetinib (V/C) in five patients with four patients starting V/C immediately before manifesting with a CAE. In patients receiving V/C after immunotherapy, the median time from beginning V/C to development of CAE was 14.5-‰days. The clinical presentation of diffuse morbilliform rash, fevers, hypotension, and end-organ damage raised concern for Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome. Histopathological features of lympho-eosinophilic infiltrate were supportive of a drug eruption. Immunotherapy or TT were re-initiated in five patients within 1--8-‰weeks after resolution of the index CAE. This resulted in two patients re-experiencing the CAE. Both of these patients were off prednisone at the time of therapy re-initiation, whereas none of the patients who were restarted on targeted therapy with a steroid overlap had a rash recurrence.ConclusionsSequential treatment using immunotherapy and TT, especially the sequence of V/C after immunotherapy appears to be the most common trigger for CAE with a median time to onset of approximately 2 weeks. Although the clinical presentation of these CAEs can be dramatic, they respond well to prednisone therapy. This unique presentation suggests that it may be reasonably safe to re-challenge certain patients with a steroid overlap after rash resolution

Cutaneous adverse reactions in B-RAF positive metastatic melanoma following sequential treatment with B-RAF/MEK inhibitors and immune checkpoint blockade or vice versa. A single-institutional case-series

Abstract Background With the advent of immune-checkpoint inhibitors and targeted treatments (TT) , there have been unprecedented response rates and survival in advanced melanoma , but the optimal sequencing of these two treatments modalities is unknown. Combining or sequencing these agents could potentially result in unique toxicities. Cutaneous adverse events (CAE) after sequential exposure to these agents represents one toxicity that needs further description. Methods After retrospectively reviewing charts of patients from 2015 to 2018 , we identified six patients who experienced CAEs after recent exposure to sequential immunotherapy and TT or vice versa for the treatment for metastatic melanoma at the University of North Carolina , Chapel Hill. Skin biopsies were available in five patients. Results Five patients received TT after immunotherapy , and one patient received immunotherapy after TT. TT consisted of vemurafenib/cobimetinib (V/C) in five patients with four patients starting V/C immediately before manifesting with a CAE. In patients receiving V/C after immunotherapy , the median time from beginning V/C to development of CAE was 14.5€‰days. The clinical presentation of diffuse morbilliform rash , fevers , hypotension , and end-organ damage raised concern for Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome. Histopathological features of lympho-eosinophilic infiltrate were supportive of a drug eruption. Immunotherapy or TT were re-initiated in five patients within 1-8€‰weeks after resolution of the index CAE. This resulted in two patients re-experiencing the CAE. Both of these patients were off prednisone at the time of therapy re-initiation , whereas none of the patients who were restarted on targeted therapy with a steroid overlap had a rash recurrence. Conclusions Sequential treatment using immunotherapy and TT , especially the sequence of V/C after immunotherapy appears to be the most common trigger for CAE with a median time to onset of approximately 2 weeks. Although the clinical presentation of these CAEs can be dramatic , they respond well to prednisone therapy. This unique presentation suggests that it may be reasonably safe to re-challenge certain patients with a steroid overlap after rash resolution

The Psychological Harms of Screening: the Evidence We Have Versus the Evidence We Need

BACKGROUND: Systematic reviews for the US Preventive Services Task Force have found less high-quality evidence on psychological than physical harms of screening. To understand the extent of evidence on psychological harms, we developed an evidence map that quantifies the distribution of evidence on psychological harms for five adult screening services. We also note gaps in the literature and make recommendations for future research. METHODS: We systematically searched PubMed, PsycInfo, and CINAHL from 2002 to 2012 for studies of any research design that assessed the burden or frequency of psychological harm associated with screening for: prostate and lung cancers, osteoporosis, abdominal aortic aneurysm (AAA) and carotid artery stenosis (CAS). We also searched for studies that estimated rates of overdiagnosis (a marker for unnecessary labeling). We included studies published in English and used dual independent review to determine study inclusion and to abstract information on design, types of measures, and outcomes assessed. RESULTS: Sixty-eight studies assessing psychological harms met our criteria; 62 % concerned prostate cancer and 16 % concerned lung cancer. Evidence was scant for the other three screening services. Overall, only about one-third of the studies used both longitudinal designs and condition-specific measures (ranging from 0 % for AAA and CAS to 78 % for lung cancer), which can provide the best evidence on harms. An additional 20 studies that met our criteria estimated rates of overdiagnosis in lung or prostate cancer. No studies estimated overdiagnosis for the non-cancer screening services. DISCUSSION: Evidence on psychological harms varied markedly across screening services in number and potential usefulness. We found important evidence gaps for all five screening services. The evidence that we have on psychological harms is inadequate in number of studies and in research design and measures. Future research should focus more clearly on the evidence that we need for decision making about screening. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11606-014-2996-5) contains supplementary material, which is available to authorized users

Blood spot–based measures of glucose homeostasis and diabetes prevalence in a nationally representative population of young US adults

PURPOSE: We investigated under-studied, biomarker-based diabetes among young U.S. adults, traditionally characterized by low cardiovascular disease risk. METHODS: We examined 15,701 participants aged 24–32 years at Wave IV of the National Longitudinal Study of Adolescent Health (Add Health, 2008). The study used innovative and relatively non-invasive methods to collect capillary whole blood via finger prick at in-home examinations in all fifty states. RESULTS: Assays of dried blood spots produced reliable and accurate values of HbA1c. Reliability was lower for fasting glucose and lowest for random glucose. Mean (standard deviation) HbA1c was 5.6% (0.8%). More than a quarter (27.4%) had HbA1c-defined pre-diabetes. HbA1c was highest in the black, non-Hispanic race/ethnic group; inversely associated with education; and more common among the overweight/obese, and physically inactive. The prevalence of diabetes defined by previous diagnosis or use of anti-diabetic medication was 2.9%. Further incorporating HbA1c and glucose values, the prevalence increased to 6.8%, and among these participants, 38.9% had a previous diagnosis of diabetes (i.e., aware). Among those aware, 37.6% were treated and 64.0% were controlled (i.e., HbA1c < 7%). CONCLUSIONS: A contemporary cohort of young adults faces a historically high risk of diabetes but there is ample opportunity for early detection and intervention

Development of a skin-directed scoring system for Stevens-Johnson syndrome and epidermal necrolysis: a Delphi consensus exercise

Importance Scoring systems for Stevens-Johnson syndrome and epidermal necrolysis (EN) only estimate patient prognosis and are weighted toward comorbidities and systemic features; morphologic terminology for EN lesions is inconsistent.Objectives To establish consensus among expert dermatologists on EN terminology, morphologic progression, and most-affected sites, and to build a framework for developing a skin-directed scoring system for EN.Evidence Review A Delphi consensus using the RAND/UCLA appropriateness criteria was initiated with a core group from the Society of Dermatology Hospitalists to establish agreement on the optimal design for an EN cutaneous scoring instrument, terminology, morphologic traits, and sites of involvement.Findings In round 1, the 54 participating dermatology hospitalists reached consensus on all 49 statements (30 appropriate, 3 inappropriate, 16 uncertain). In round 2, they agreed on another 15 statements (8 appropriate, 7 uncertain). There was consistent agreement on the need for a skin-specific instrument; on the most-often affected skin sites (head and neck, chest, upper back, ocular mucosa, oral mucosa); and that blanching erythema, dusky erythema, targetoid erythema, vesicles/bullae, desquamation, and erosions comprise the morphologic traits of EN and can be consistently differentiated.Conclusions and Relevance This consensus exercise confirmed the need for an EN skin-directed scoring system, nomenclature, and differentiation of specific morphologic traits, and identified the sites most affected. It also established a baseline consensus for a standardized EN instrument with consistent terminology