Treatment of oral graft-versus-host disease with intraoral nbUVB phototherapy.

PURPOSE: There are limited treatment options available for hematopoietic stem-cell transplant patients (HSCT) with oral graft-versus-host disease (GVHD). Intraoral phototherapy is a novel, yet promising therapeutic regimen. RESEARCH QUESTION: To assess the safety and effectiveness of intraoral narrowband UVB (nbUVB) phototherapy in the treatment of oral GVHD. METHODS: This case series evaluated 10 patients with refractory oral GVHD, who were treated at Northwestern Memorial Hospital with nbUVB between July 2019 and October 2023. Primary outcomes were to evaluate the safety and efficacy of phototherapy. Efficacy was measured by objective improvement in symptom scores and subjective improvement in patient reported symptoms. Safety was determined by the withdrawal due to adverse events. Total nbUVB exposure, number of treatments, and change in systemic immunosuppressive medications were also examined. RESULTS: The study cohort comprised 10 patients who developed oral GVHD at a median of 9.5 months after HSCT. The total median dose of nbUVB was 36 J/cm2, and the median number of sessions was 55. All 10 patients demonstrated some degree of improvement in symptoms. Notably, there was a reduction in the number of patients who reported symptoms of oral pain (83%), bleeding (67%), xerostomia (50%), and oral sensitivity (78%) after initiating phototherapy. There was also a statistically significant decrease in the levels of pain, erythema, and edema (p ≤ 0.001, < 0.001, 0.01, respectively). Most patients tolerated phototherapy well, but 1 patient withdrew from treatment due to adverse effects. Seventy-five percent of patients who were on immunosuppressive medications were able to decrease or stop these medications. CONCLUSION: This case series suggests that nbUVB phototherapy is well tolerated and efficacious in patients with oral GVHD.

Mucocutaneous toxicities from MEK inhibitors: a scoping review of the literature.

BACKGROUND: MEK inhibitors cause a wide spectrum of mucocutaneous toxicities which can delay or interrupt life-saving therapy. PURPOSE: To summarize the morphology, incidence, and clinical presentation of mucocutaneous toxicities from MEK inhibitors via a scoping review of the literature. METHODS: We conducted a scoping review of the published literature, including clinical trials, retrospective and prospective studies, reviews, and case reports and series. All included literature was analyzed by a panel of pediatric and adult oncodermatologists. RESULTS: Of 1626 initial citations, 227 articles met final inclusion criteria. Our review identified follicular reactions, ocular toxicities, xerosis, eczematous dermatitis, edema, and paronychia as the most common mucocutaneous side effects from MEK inhibitor therapy. Grade 1 and 2 reactions were the most prevalent and were typically managed while continuing treatment; however, grade 3 toxicities requiring dose reductions or treatment interruptions were also reported. CONCLUSION: Mucocutaneous toxicities to MEK inhibitor therapy are common and most often mild in severity. Early recognition and treatment can mitigate disruptions in oncologic therapy.

Peritoneal dialysis-associated peritonitis: A case first for Aquamicrobium.

Aquamicrobium is an aerobic gram-negative rod which until recently had only been isolated from wastewater and contaminated soil. In 2021, two cases of Aquamicrobium infection in humans were reported. Both were cases of endophthalmitis following cataract surgery. In this manuscript, we describe the presentation and treatment of a 56-year-old immunocompetent male who has peritoneal dialysis-associated peritonitis caused by Aquamicrobium lusatiense. To our knowledge, this is the third reported case of Aquamicrobium infection in humans and the first example of this agent causing peritonitis.

See One, Do One, Improve One's Wellness: Resident Autonomy in US General Surgery Programs, A Mixed-methods Study.

OBJECTIVE: We sought to examine the factors associated with resident perceptions of autonomy and to characterize the relationship between resident autonomy and wellness. BACKGROUND: Concerns exist that resident autonomy is decreasing, impacting competence. METHODS: Quantitative data were collected through a cross-sectional survey administered after the 2020 ABSITE. Qualitative data were collected through interviews and focus groups with residents and faculty at 15 programs. RESULTS: Seven thousand two hundred thirty-three residents (85.5% response rate) from 324 programs completed the survey. Of 5139 residents with complete data, 4424 (82.2%) reported appropriate autonomy, and these residents were less likely to experience burnout [odds ratio (OR) 0.69; 95% CI 0.58-0.83], suicidality (OR 0.69; 95% CI 0.54-0.89), and thoughts of leaving their programs (OR 0.45; 95% CI 0.37-0.54). Women were less likely to report appropriate autonomy (OR 0.81; 95% CI 0.68-0.97). Residents were more likely to report appropriate autonomy if they also reported satisfaction with their workload (OR 1.65; 95% CI 1.28-2.11), work-life balance (OR 2.01; 95% CI 1.57-2.58), faculty engagement (OR 3.55; 95% CI 2.86-4.35), resident camaraderie (OR 2.23; 95% CI, 1.78-2.79), and efficiency and resources (OR 2.37; 95% CI 1.95-2.88). Qualitative data revealed that (1) autonomy gives meaning to the clinical experience of residency, (2) multiple factors create barriers to autonomy, and (3) autonomy is not inherent to the training paradigm, requiring residents to learn behaviors to "earn" it. CONCLUSION: Autonomy is not considered an inherent part of the training paradigm such that residents can assume that they will achieve it. Resources to function autonomously should be allocated equitably to support all residents' educational growth and wellness.

INDIVIDUAL ARTICLE: USCOM Algorithm for the Prevention and Management of Cutaneous Immunotherapy-Related Adverse Events.

BACKGROUND: In 2023, nearly 2 million patients will be diagnosed with cancer in the United States and at least 40% will be eligible for treatment with an immune checkpoint inhibitor (ICI). Cutaneous immune related adverse events (cirAEs) from ICIs are common and include pruritus as well as maculopapular, eczematous, bullous, lichenoid, and psoriasiform reactions. All clinicians interfacing with cancer patients must expedite proper evaluation and diagnosis, treatment, and/or consultation that supports the need for evidence-directed guidelines. MATERIALS AND METHODS: A panel of advisors was selected, and a systematic literature review generated foundational evidence to develop a treatment algorithm for cirAEs via a modified Delphi process. Iterations of the algorithm were performed until the group met consensus. RESULTS: An algorithm that tailors the management of cirAEs was developed based on the CTCAE v.5 grading of skin disorders. Representative clinical images and suggested diagnostic measures, supplement the algorithm. CONCLUSION: Recognition and treatment of cirAEs guided through a multidisciplinary, physician-developed algorithm will limit disruption of immunotherapy, optimize quality of life, and enhance overall outcomes in patients treated with ICIs. J Drugs Dermatol. 2023;22:11(Suppl 1):s3-10.

Untargeted Metabolomics Based Prediction of Therapeutic Potential for Apigenin and Chrysin.

The prominent flavonoids apigenin and chrysin have been demonstrated to have systemic benefits. Our previous work was first to establish the impact of apigenin and chrysin on cellular transcriptome. In the current study, we have revealed the ability of apigenin and chrysin to alter the cellular metabolome based on our untargeted metabolomics. Based on our metabolomics data, both these structurally related flavonoids demonstrate diverging and converging properties. Apigenin demonstrated the potential to possess anti-inflammatory and vasorelaxant properties through the upregulation of intermediate metabolites of alpha-linolenic acid and linoleic acid pathways. Chrysin, on the other hand, exhibited abilities to inhibit protein and pyrimidine synthesis along with downregulation of gluconeogenesis pathways based on the altered metabolites detected. Chrysin-mediated metabolite changes are mostly due to its ability to modulate L-alanine metabolism and the urea cycle. On the other hand, both the flavonoids also demonstrated converging properties. Apigenin and chrysin were able to downregulate metabolites involved in cholesterol biosynthesis and uric acid synthesis, namely 7-dehydrocholesterol and xanthosine, respectively. This work will provide understanding regarding the diverse therapeutic potential of these naturally occurring flavonoids and help us in curbing an array of metabolic complications.

Readability of Online Patient Education Materials for Graft-Versus-Host Disease.

Graft-versus-host disease (GVHD) is a complex systemic diagnosis which is associated with significant symptom distress in patients. Patient education has shown to mitigate uncertainty and distress, but to our knowledge, no studies have evaluated patient education materials on GVHD. We characterized the readability and understandability of patient education materials on GVHD available online. We conducted a Google search of the top 100 non-sponsored search results, selecting for full-text patient education that is not peer-reviewed or a news article. We evaluated the text of the eligible search results against the Flesch-Kincaid Reading Ease, Flesch Kincaid Grade Level, Gunning Fog, Automated Readability, Linsear Write Formula, Coleman-Liau Index, Smog Index, and Patient Education Materials Assessment Tool (PEMAT) for understandability. Among 52 included Web results, 17 (32.7%) were provider-authored and 15 (28.8%) were hosted on university Web sites. The total average scores on validated readability tools were Flesch-Kincaid Reading Ease (46.4), Flesch Kincaid Grade Level (11.6), Gunning Fog (13.6), Automated Readability (12.3), Linsear Write Formula (12.6), Coleman-Liau Index (12.3), Smog Index (10.0), and PEMAT Understandability (65.5). Provider-authored links scored poorer than non-provider-authored links on all metrics, with significant differences for the Gunning Fog index (p < 0.05). University-hosted links scored better than non-university-hosted links on all metrics. Evaluation of online patient education materials for GVHD demonstrates the need for more readable and understandable resources to mitigate the distress and uncertainty that patients may feel upon being diagnosed with GVHD.

A Competency-based Laparoscopic Cholecystectomy Curriculum Significantly Improves General Surgery Residents' Operative Performance and Decreases Skill Variability: Cohort Study.

OBJECTIVE: To demonstrate the feasibility of implementing a CBE curriculum within a general surgery residency program and to evaluate its effectiveness in improving resident skill. SUMMARY OF BACKGROUND DATA: Operative skill variability affects residents and practicing surgeons and directly impacts patient outcomes. CBE can decrease this variability by ensuring uniform skill acquisition. We implemented a CBE LC curriculum to improve resident performance and decrease skill variability. METHODS: PGY-2 residents completed the curriculum during monthly rotations starting in July 2017. Once simulator proficiency was reached, residents performed elective LCs with a select group of faculty at 3 hospitals. Performance at curriculum completion was assessed using LC simulation metrics and intraoperative operative performance rating system scores and compared to both baseline and historical controls, comprised of rising PGY-3s, using a 2-sample Wilcoxon rank-sum test. PGY-2 group's performance variability was compared with PGY-3s using Levene robust test of equality of variances; P < 0.05 was considered significant. RESULTS: Twenty-one residents each performed 17.52 ± 4.15 consecutive LCs during the monthly rotation. Resident simulated and operative performance increased significantly with dedicated training and reached that of more experienced rising PGY-3s (n = 7) but with significantly decreased variability in performance ( P = 0.04). CONCLUSIONS: Completion of a CBE rotation led to significant improvements in PGY-2 residents' LC performance that reached that of PGY-3s and decreased performance variability. These results support wider implementation of CBE in resident training.

Identifying Strategies for Struggling Surgery Residents.

BACKGROUND: Struggling residents are not uncommon in general surgery. Early identification of these residents and effective remediation remain imperfect. MATERIALS AND METHODS: We performed a survey of program directors (PD) across all general surgery residencies. Survey questions included the following: demographic information about the program and PD, 10 vignettes about hypothetical residents struggling in various ACGME milestones to assess how PDs would address these deficiencies, and self-reported PD preparedness and availability of resources to support struggling residents. RESULTS: In total, we received 82 responses to our survey. All PDs who participated in our study reported having struggling residents in their program. The three most common ways struggling residents are identified were faculty word-of-mouth, formal evaluations such as milestones and ABSITE performance, and resident word-of-mouth. Over 18% of PDs reported having little to no relevant training in addressing the needs of a struggling resident, and 65.9% of PDs did not feel that their program had 'completely adequate' resources to address these needs. In the majority of cases, PDs offer mentorship with themselves or other faculty as a remediation strategy with infrequent use of other resources. CONCLUSIONS: Strategies to identify struggling residents and remediation strategies varied widely across programs. Diversifying remediation approaches should be considered for more effective remediation.

Cutaneous manifestations of chimeric antigen receptor T-cell therapy: An introduction for dermatologists.

Chimeric antigen receptor T-cell therapy is an emerging immunotherapy with promising efficacy for the treatment of previously refractory or relapsed malignancies. As a personalized medicine approach, T cells are genetically engineered to express a receptor designed to bind a specific tumor antigen, leading to selective immune-mediated destruction of tumor cells. Due to the novelty of chimeric antigen receptor T-cell therapy, the safety profile continues to evolve with limited information currently available on cutaneous adverse events. Improved understanding of the spectrum of cutaneous adverse events may facilitate earlier recognition and appropriate management of these toxicities. To explore this knowledge gap, we discuss the available case reports and clinical trial results of cutaneous reactions associated with chimeric antigen receptor T-cell therapy.

Chylous ascites in the setting of internal hernia: a reassuring sign.

BACKGROUND: Chylous ascites is often reported in cases with lymphatic obstruction or after lymphatic injuries such as intraabdominal malignancies or lymphadenectomies. However, chylous ascites is also frequently encountered in operations for internal hernias. We sought to characterize the frequency and conditions when chylous ascites is encountered in general surgery patients. METHODS: Data from patients who underwent operations for CPT codes related to open and laparoscopic abdominal and gastrointestinal surgery in our tertiary hospital from 2010 to 2019 were reviewed. Patients with the postoperative diagnosis of internal hernia were identified and categorized into three groups: Internal Hernia with chylous ascites, non-chylous ascites, and no ascites. Demographics, prior surgical history, CT findings, source of internal hernia, open or laparoscopic surgery, and preoperative labs were recorded and compared. RESULTS: Fifty-six patients were found to have internal hernias and were included in our study. 80.3% were female and 86% had a previous Roux-en-Y gastric bypass procedure (RYGBP). Laparoscopy was the main approach for all groups. Ascites was present in 46% of the cases. Specifically, chylous ascites was observed in 27% of the total operations and was exclusively (100%) found in patients with gastric-bypass history. Furthermore, it was more commonly associated with Petersen's defect (p < 0.001), while the non-chylous fluid group was associated with herniation through the mesenteric defect (p < 0.001). CONCLUSIONS: Chylous ascites is a common finding during internal hernia operations. Unlike other more morbid conditions, identification of chylous ascites during an internal hernia operation appears innocuous. However, in the context of a patient with a history of RYGBP, the presence of chylous fluid signifies the associated small bowel obstruction is likely related to an internal hernia through a patent Petersen's defect.

The Role of Personal Accomplishment in General Surgery Resident Well-being.

OBJECTIVE: To investigate the association of personal accomplishment (PA) with the other subscales, assess its association with well-being outcomes, and evaluate drivers of PA by resident level. BACKGROUND: Most studies investigating physician burnout focus on the emotional exhaustion (EE) and depersonalization (DP) subscales, neglecting PA. Therefore, the role of PA is not well understood. METHODS: General surgery residents were surveyed following the 2019 American Board of Surgery In-Training Examination regarding their learning environment. Pearson correlations of PA with EE and DP were assessed. Multivariable logistic regression models assessed the association of PA with attrition, job satisfaction, and suicidality and identified factors associated with PA by PGY. RESULTS: Residents from 301 programs were surveyed (85.6% response rate, N = 6956). Overall, 89.4% reported high PA, which varied by PGY-level (PGY1: 91.0%, PGY2/3: 87.7%, PGY4/5: 90.2%; P = 0.02). PA was not significantly correlated with EE (r = -0.01) or DP (r = -0.08). After adjusting for EE and DP, PA was associated with attrition (OR 0.60, 95%CI 0.46-0.78) and job satisfaction (OR 3.04, 95%CI 2.45-3.76) but not suicidality (OR 0.72, 95%CI 0.48-1.09). Although the only factor significantly associated with PA for interns was resident cooperation, time in operating room and clinical autonomy were significantly associated with PA for PGY2/3. For PGY4/5s, PA was associated with time for patient care, resident cooperation, and mentorship. CONCLUSION: PA is a distinct metric of resident well-being, associated with job satisfaction and attrition. Drivers of PA differ by PGY level and may be targets for intervention to promote resident wellness and engagement.

US Cutaneous Oncodermatology Management (USCOM): A Practical Algorithm.

BACKGROUND: An increasing number of patients survive or are living with cancer. Anticancer treatments frequently have cutaneous adverse events (cAEs) that may severely impact patients' quality of life and interrupt anticancer treatment. The US Cutaneous Oncodermatology Management (USCOM) project aims to improve cancer patients' and survivors' quality of life by offering tools for preventing and managing cAEs. METHODS: An algorithm was designed to reduce the incidence of cAEs, treat cAEs, and maintain healthy skin using general measures and over-the-counter agents to support all healthcare providers treating oncology patients, including physicians, nurses, pharmacists, and advanced providers. The panel used a modified Delphi approach, developed, discussed, and reached a consensus on statements and an evidence-based algorithm. RESULTS: The USCOM algorithm includes education on cAEs for patients and clinicians supporting prevention, treatment, and maintenance using skincare measures before, during, and after cancer treatment. A skincare regimen including hygiene, moisturization, and sun protection products should be safe and effective in helping to minimize cAEs and improving skin conditions such as erythema, xerosis, pruritus, and photosensitivity. The number and quality of studies evaluating skincare formulations and regimens for cAEs are increasing, but the evidence on the benefits of specific formulations is still scarce. CONCLUSIONS: The algorithm focuses on general measures and skincare to prevent or reduce the severity of cAEs. Increased awareness of cAEs by the multidisciplinary team treating and guiding the cancer patient throughout their care may improve patient outcomes. J Drugs Dermatol. 2021;20:9(Suppl):s3-19.

Not just carriers: experiences of X-linked female heterozygotes.

PURPOSE: To better understand the needs and experiences of the X-linked carrier community to improve future recognition, diagnosis, and treatment by bringing X-linked carrier voices together. METHODS: An anonymous survey link was distributed to members of Remember the Girls, a non-profit organization for female (XX) carriers of X-linked conditions, through its website, Facebook group, Instagram, and Twitter. The survey was developed to gather data on XX carriers of numerous X-linked conditions. RESULTS: One hundred and fifty individuals participated in the study. The majority (81/150) of individuals learned about their carrier status by giving birth to a son diagnosed with an X-linked condition. However, over 80% (120/145) believed that they should learn this information before the age of 18. Over 80% of participants (124/148) felt that they either have or may have symptoms attributable to their X-linked condition. Yet, only 10.1% (15/148) felt that they had sufficient access to knowledgeable healthcare providers and/or medical information. Additionally, 46.7% (70/150) of participants reported that healthcare providers did not discuss reproductive options with them. Improving carrier access to medical information, research studies, new treatments, and reproductive methods was found to be the top priority. CONCLUSION: Limited information exists on X-linked carriers' risk for symptoms and there is a lack of available treatments. This study demonstrates the need for more knowledgeable healthcare providers and medical information within the X-linked carrier community.

Claudin-1-Dependent Destabilization of the Blood-Brain Barrier in Chronic Stroke.

Recent evidence suggests that blood-brain barrier (BBB) recovery and reestablishment of BBB impermeability after stroke is incomplete. This could influence stroke recovery, increase the risk of repeat stroke, and be a solid substrate for developing vascular dementia. Although accumulating evidence has defined morphological alterations and underlying mechanisms of tight junction (TJ) changes during BBB breakdown in acute stroke, very little is known about the type of alterations and mechanisms in BBB "leakage" found subacutely or chronically. The current study examined BBB structural alterations during the "BBB leakage" associated with the chronic phase of stroke in male mice and both genders of humans. We found significant upregulation of claudin-1 mRNA and protein, a nonspecific claudin for blood vessels, and downregulation in claudin-5 expression. Morphological and biochemical as well as fluorescence resonance energy transfer and fluorescence recovery after photobleaching analysis of postischemic brain endothelial cells and cells overexpressing claudin-1 indicated that newly synthesized claudin-1 was present on the cell membrane (∼45%), was incorporated into the TJ complex with established interaction with zonula occludens-1 (ZO-1), and was building homophilic cis- and trans-interactions. The appearance of claudin-1 in the TJ complex reduced claudin-5 strands (homophilic claudin-5 cis- and trans-interactions) and claudin-5/ZO-1 interaction affecting claudin-5 incorporation into the TJ complex. Moreover, claudin-1 induction was associated with an endothelial proinflammatory phenotype. Targeting claudin-1 with a specific C1C2 peptide improved brain endothelial barrier permeability and functional recovery in chronic stroke condition. This study highlights a potential "defect" in postischemic barrier formation that may underlie prolonged vessel leakiness.SIGNIFICANCE STATEMENT Although rarely expressed at the normal blood-brain barrier (BBB), claudin-1 is expressed in pathological conditions. Analyzing poststroke human and mouse blood microvessels we have identified that claudin-1 is highly expressed in leaky brain microvessels. Our results reveal that claudin-1 is incorporated in BBB tight junction complex, impeding BBB recovery and causing BBB leakiness during poststroke recovery. Targeting claudin-1 with a claudin-1 peptide improves brain endothelial barrier permeability and consequently functional neurological recovery after stroke.

Permanent chemotherapy-induced alopecia: awareness and attitudes among health care providers.

PURPOSE: Reports of permanent chemotherapy-induced alopecia (PCIA) are increasing in the field of oncodermatology, but there is a dearth of information regarding how it is recognized and managed by health care providers (HCPs) across different medical specialties (dermatology, oncology, and internal medicine). METHODS: A 25-question survey was designed to elicit general knowledge and awareness of PCIA, as well as attitudes about referral and treatment. Responses were collected via REDCap, a secure online application, and analyzed with descriptive statistics, chi-square, and ANOVA tests. RESULTS: There was a significant difference in the number of subjects who had heard of PCIA prior to starting the survey (Derm 79%, Onc 30%, IM 22%, p < 0.05). A larger percentage of dermatology and oncology HCPs knew the correct definition of the condition (alopecia persisting > 6 months) than IM (42% and 45% vs. 17%) and significantly more had encountered patients with the condition (47% and 45% vs. 17%). More providers in dermatology and IM knew how to diagnose PCIA compared with oncology (84% and 83% vs. 70%). Dermatology HCPs were the only participants who had attempted to treat patients with PCIA, and most providers believed that patients would accept similar types of treatment for PCIA. Dermatology HCPs were more likely to report higher confidence in their abilities to diagnose and manage PCIA than other providers. CONCLUSION: The results of this survey identify knowledge gaps about PCIA among health care providers. Therefore, education and multidisciplinary engagement should be pursued in order to improve awareness, diagnosis, referral, and management of PCIA as part of survivorship care.

Multinational Association of Supportive Care in Cancer (MASCC) 2020 clinical practice recommendations for the management of severe gastrointestinal and hepatic toxicities from checkpoint inhibitors.

Immune-related adverse events (IrAEs) affecting the gastrointestinal (GI) tract and liver are among the most frequent and most severe inflammatory toxicities from contemporary immunotherapy. Inflammation of the colon and or small intestines (entero)colitis is the single most common GI IrAE and is an important cause of delay of discontinuation of immunotherapy. The severity of these GI IrAEs can range from manageable with symptomatic treatment alone to life-threatening complications, including perforation and liver failure. The frequency and severity of GI IrAEs is dependent on the specific immunotherapy given, with cytotoxic T lymphocyte antigen (CTLA)-4 blockade more likely to induce severe GI IrAEs than blockade of either programmed cell death protein 1 (PD-1) or PD-1 ligand (PD-L1), and combination therapy showing the highest rate of GI IrAEs, particularly in the liver. To date, we have minimal prospective data on the appropriate diagnosis and management of GI IrAEs, and recommendations are based largely on retrospective data and expert opinion. Although clinical diagnoses of GI IrAEs are common, biopsy is the gold standard for diagnosis of both immunotherapy-induced enterocolitis and hepatitis and can play an important role in excluding competing, though less common, diagnoses and ensuring optimal management. GI IrAEs typically respond to high-dose corticosteroids, though a significant fraction of patients requires secondary immune suppression. For colitis, both TNF-α blockade with infliximab and integrin inhibition with vedolizumab have proved highly effective in corticosteroid-refractory cases. Detailed guidelines have been published for the management of low-grade GI IrAEs. In the setting of more severe toxicities, involvement of a GI specialist is generally recommended. The purpose of this review is to survey the available literature and provide management recommendations focused on the GI specialist.

Cancer immunotherapy-related adverse events: causes and challenges.

Despite the success and ongoing promise of monoclonal antibody-targeted immune checkpoint inhibitor immunotherapy of advanced malignancies, in particular, antibodies directed against CTLA-4 and PD-1/PD-L1, the development of immune-related adverse events (irAEs) remains a constraint of this type of therapy. Although rarely fatal, the occurrence of irAEs may necessitate discontinuation of immunotherapy, as well as administration of corticosteroids or other immunosuppressive therapies that may not only compromise efficacy but also predispose for development of opportunistic infection. Clearly, retention of efficacy of immune checkpoint-targeted therapies with concurrent attenuation of immune-mediated toxicity represents a formidable challenge. In this context, the current brief review examines mechanistic relationships between these events, as well as recent insights into immunopathogenesis, and strategies which may contribute to resolving this issue. These sections are preceded by brief overviews of the discovery and functions of CTLA-4 and PD-1, as well as the chronology of the development of immunotherapeutic monoclonal antibodies which target these immune checkpoint inhibitors.

Multinational Association of Supportive Care in Cancer (MASCC) 2020 clinical practice recommendations for the management of immune-related adverse events: pulmonary toxicity.

The immune checkpoints associated with the CTLA-4 and PD-1 pathways are critical modulators of immune activation. These pathways dampen the immune response by providing brakes on activated T cells, thereby ensuring more uniform and controlled immune reactions and avoiding immune hyper-responsiveness and autoimmunity. Cancer cells often exploit these regulatory controls through a variety of immune subversion mechanisms, which facilitate immune escape and tumor survival. Immune checkpoint inhibitors (ICI) effectively block negative regulatory signals, thereby augmenting immune attack and tumor killing. This process is a double-edged sword in which release of regulatory controls is felt to be responsible for both the therapeutic efficacy of ICI therapy and the driver of immune-related adverse events (IrAEs). These adverse immune reactions are common, typically low-grade and may affect virtually every organ system. In the early clinical trials, lung IrAEs were rarely described. However, with ever-expanding clinical applications and more complex ICI-containing regimens, lung events, in particular, pneumonitis, have become increasingly recognized. ICI-related lung injury is clinically distinct from other types of lung toxicity and may lead to death in advanced stage disease. Thus, knowledge regarding the key characteristics and optimal treatment of lung-IrAEs is critical to good outcomes. This review provides an overview of lung-IrAEs, including risk factors and epidemiology, as well as clinical, radiologic, and histopathologic features of ICI-related lung injury. Management principles for ICI-related lung injury, including current consensus on steroid refractory pneumonitis and the use of other immune modulating agents in this setting are also highlighted.

Multinational Association of Supportive Care in Cancer (MASCC) 2020 clinical practice recommendations for the management of severe dermatological toxicities from checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) frequently result in cutaneous immune-related adverse events (IrAEs). Although the majority of these events are mild-to-moderate in severity, up to 5% are severe, which may lead to morbidity and dose interruption or discontinuation of ICI therapy. In addition, up to 25% of dermatologic IrAEs are corticosteroid-refractory or corticosteroid-dependent. These 2020 MASCC recommendations cover the diagnosis and management of cutaneous IrAEs with a focus on moderate-to-severe and corticosteroid-resistant events. Although the usage of immune-suppressive therapy has been advocated in this setting, there is a lack of randomized clinical trial data to provide a compelling level of evidence of its therapeutic benefit.