Benefit, recurrence pattern, and toxicity to adjuvant anti-PD-1 monotherapy varies by ethnicity and melanoma subtype: An international multicenter cohort study.

Background: Anti-Program-Death-1 (PD-1) is a standard adjuvant therapy for patients with resected melanoma. We hypothesized that there are discrepancies in survival, recurrence pattern and toxicity to adjuvant PD-1 between different ethnicities and melanoma subtypes. Objective: We performed a multicenter cohort study incorporating 6 independent institutions in Australia, China, Japan, and the United States. The primary outcomes were recurrence free survival (RFS) and overall survival (OS). Secondary outcomes were disease recurrence patterns and toxicities. Results: In total 534 patients were included. East-Asian/Hispanic/African reported significantly poorer RFS/OS. Nonacral cutaneous or melanoma of unknown primary reported the best RFS/OS, followed by acral, and mucosal was the poorest. Within the nonacral cutaneous or melanoma of unknown primary subtypes, East-Asian/Hispanic/African reported significantly poorer RFS/OS than Caucasian. In the multivariate analysis incorporating ethnicity/melanoma-subtype/age/sex/stage/lactate dehydrogenase/BRAF (v-Raf murine sarcoma viral oncogene homolog B)-mutation/adjuvant radiotherapy, East-Asian/Hispanic/African had independently significantly poorer outcomes (RFS: HR, 1.71; 95% CI, 1.19-2.44 and OS: HR, 2.34; 95% CI, 1.39-3.95), as was mucosal subtype (RFS: HR, 3.25; 95% CI, 2.04-5.17 and OS: HR, 3.20; 95% CI, 1.68-6.08). Mucosal melanoma was an independent risk factor for distant metastasis, especially liver metastasis. East-Asian/Hispanic/African had significantly lower incidence of gastrointestinal/musculoskeletal/respiratory/other-rare-type-toxicities; but higher incidences of liver toxicities. Limitations: A retrospective study. Conclusions: Ethnicity and melanoma subtype are associated with survival and recurrence pattern in melanoma patients treated with adjuvant anti-PD-1. Toxicity profile differs by ethnicity and may require a precision toxicity surveillance strategy.

Patterns of Perioperative Hormone Therapy for Gender-Affirming Surgery.

INTRODUCTION: There is no consensus regarding perioperative hormone replacement therapy (HRT) for gender-affirming surgery (GAS). Common concerns for continuing perioperative HRT included risk of deep vein thrombosis (DVT) or hematoma. However, discontinuing HRT is not risk free and may cause mood swing or increased anxiety. Our study aimed to investigate current patterns of HRT before GAS worldwide. METHODS: The first stage of Delphi technique was implemented by sending a 27-item survey to all surgeons (total n = 150; 94 plastic surgeon, 35 urologist, and 21 gynecologists) of the World Professional Association for Transgender Health who perform GAS. Survey themes included the hormone type, duration, and usage of DVT prophylaxis. RESULTS: Overall survey response rate was 34% (total n = 51; 8 urologists, 35 plastic surgeons, and 8 gynecologists). The majority of surgeons are US-based (n = 39, 76%). The most common HRTs are in injection form (n = 28, 55%). The majority of surgeons do not stop HRT before GAS and do provide DVT prophylaxis to all patients <1 week after GAS. The most common procedure that surgeons discontinue HRT is feminizing bottom surgery (43%). For surgeons who discontinue HRT before GAS, there is a wide variation on discontinuation schedule. CONCLUSIONS: There is considerable variation in perioperative HRT patterns for GAS. Further research is needed to develop a data-driven consensus guideline to provide high quality of care for transgender and nonbinary patients.

Radiology in the immune checkpoint inhibitor era.

The field of oncology has undergone rapid changes following the introduction of immunotherapies and biologics. However, these changes have also created new roles for radiology in both diagnosis and treatment. Our article addresses the evolving role of radiology in the immune checkpoint inhibitor era of oncology. With the progression of new immunotherapies for cancer, imaging paradigms and image guided therapy options have changed. Multidisciplinary oncology teams should be aware of these opportunities for collaboration.

Vanderbilt Mini-PROM-Breast for Breast Reconstruction: A Short-Form, Patient-Reported Outcomes Measure.

BACKGROUND: Breast reconstruction procedures are among the most commonly performed plastic surgery operations. Although there are well-validated patient-reported outcomes measures (PROMs) for breast reconstruction, there are several patient-, provider-, and service-level barriers to their implementation in routine clinical settings. Therefore, we developed a short-form PROM to evaluate breast reconstruction outcomes. METHODS: Using a mixed-methods approach, the Vanderbilt Mini-PROM-Breast (VMP-B) was constructed and validated to assess patient-reported outcomes from breast reconstruction. Classic test theory methods were used to evaluate acceptability, reliability, and validity. External validation was subsequently performed using the BREAST-Q as a reference standard. RESULTS: The VMP-B is a 16-item instrument composed of three domains: quality of life, body image, and breast satisfaction. Psychometric properties including acceptability, reliability, and validity exceeded reference criteria. When tested with 104 patients, the authors found significant benefits of breast reconstruction on quality of life, body image, and breast satisfaction. These results were associated with sizeable effect sizes (g) (g = 0.421, g = 0.520, and g = 1.25) demonstrative of clinically meaningful results. When tested concurrently in 70 patients, the VMP-B and the BREAST-Q showed similar results, exhibiting excellent convergent validity. CONCLUSIONS: The VMP-B is a validated short-form PROM that reliably assesses breast reconstruction outcomes. As a short form, the VMP-B decreases both patient and provider burden, which allows for routine, point-of-care collection of breast reconstruction outcomes.

Patient Perspectives on Selecting an Academic Aesthetic Surgeon: A Qualitative Analysis.

BACKGROUND: Growth of the aesthetic surgery marketplace has increased patient choice in provider selection. This study aimed to characterize how patients choose an aesthetic surgeon, identify knowledge gaps in this decision-making process, and understand why patients select academic aesthetic surgeons. METHODS: A qualitative interview study of aesthetic surgery patients from an academic center was conducted. Purposive sampling maximized representation regarding surgeon, surgery type, and patient demographics. An interview guide was developed in collaboration with content and methodology experts, then refined through pilot testing. Emergent themes were identified using a codebook constructed by grounded theory. RESULTS: Thematic saturation was achieved with 24 patients. When selecting a surgeon, participants valued bedside manner (24 of 24) and past patients' satisfaction (18 of 24). Most participants (16 of 24) ascribed low importance to board certification. Reasons given for choosing an academic practice included the institution's reputation (13 of 24) and the availability of medical records and other specialties if complications arise (8 of 24). Participants demonstrated knowledge gaps regarding medical training and licensure. No participant (0 of 24) was aware that any licensed physician can offer aesthetic surgery, and nearly all participants (23 of 24) expressed discomfort with this. CONCLUSIONS: Patients prioritize subjective elements when selecting an aesthetic surgeon, relying less on objective and meaningful qualifications like board certification and training background. Academic aesthetic practice is valued because of reputation and ability to function as a medical home. Given the lack of public understanding regarding physician training, initiatives promoting transparency are needed to ensure that patients can make safe, informed decisions.

Dabrafenib plus trametinib versus anti-PD-1 monotherapy as adjuvant therapy in BRAF V600-mutant stage III melanoma after definitive surgery: a multicenter, retrospective cohort study.

Background: Both dabrafenib/trametinib (D/T) and anti-PD-1 monotherapy (PD-1) are approved adjuvant therapies for patients with stage III BRAF V600-mutant melanoma. However, there is still a lack of head-to-head comparative data. We aimed to describe efficacy and toxicity outcomes for these two standard therapies across melanoma centers. Methods: This multicenter, retrospective cohort study was conducted in 15 melanoma centers in Australia, China, Germany, Italy, Japan, UK, and US. We included adult patients with resected stage III BRAF V600-mutant melanoma who received either adjuvant D/T or PD-1 between Jul 2015 and Oct 2022. The primary endpoint was relapse-free survival (RFS). Secondary endpoints included overall survival (OS), recurrence pattern and toxicity. Findings: We included 598 patients with stage III BRAF V600-mutant melanoma who received either adjuvant D/T (n = 393 [66%]) or PD-1 (n = 205 [34%]) post definitive surgery between Jul 2015 and Oct 2022. At a median follow-up of 33 months (IQR 21-43), the median RFS was 51.0 months (95% CI 41.0-not reached [NR]) in the D/T group, significantly longer than PD-1 (44.8 months [95% CI 28.5-NR]) (univariate: HR 0.66, 95% CI 0.50-0.87, P = 0.003; multivariate: HR 0.58, 95% CI 0.39-0.86, P = 0.007), with comparable OS with PD-1 (multivariate, HR 0.90, 95% CI 0.48-1.70, P = 0.75). Similar findings were observed using a restricted-mean-survival-time model. Among those who experienced recurrence, the proportion of distant metastases was higher in the D/T cohort. D/T had a higher incidence of treatment modification due to adverse events (AEs) than PD-1, but fewer persistent AEs. Interpretation: In patients with stage III BRAF V600-mutant melanoma post definitive surgery, D/T yielded better RFS than PD-1, with higher transient but lower persistent toxicity, and comparable OS. D/T seems to provide a better outcome compared with PD-1, but a longer follow-up and ideally a large prospective trial are needed. Funding: Dr. Xue Bai was supported by the Beijing Hospitals Authority Youth Programme (QMS20211101) for her efforts devoted to this study. Dr. Keith T. Flaherty was funded by Adelson Medical Research Foundation for the efforts devoted to this study.

Multidimensional Assessment of Patient-Reported Outcomes After Gender-Affirming Surgeries Using a Validated Instrument.

INTRODUCTION: Limited literatures used validated instruments to evaluate patient-reported outcomes (PROs) for transgender and gender-diverse population undergoing gender-affirming surgeries (GASs). This study aimed to evaluate PROs using a newly validated psychometric instrument, Vanderbilt Mini Patient-Reported Outcome Measures-Gender (VMP-G). METHODS: Vanderbilt Mini Patient-Reported Outcome Measures-Gender assesses 4 scales: quality of life, self-concept, satisfaction, and gender dysphoria. Scores range from 20 to 100, with higher scores representing superior PROs. Descriptive analysis was performed, and outcomes were compared in different races/ethnicities, gender identities, age, types of GAS, and time. Patients seeking GAS at Vanderbilt University Medical Center from October 11, 2021, to October 11, 2022, were included. Data were collected anonymously via the Research Electronic Data Capture survey tool at preoperative or postoperative clinic visits. RESULTS: A total of 207 patients completed VMP-G. Average age was 31.8 years (SD, ±11.5 years). Fifty-three percent of patients were postoperative GAS. In bivariate and linear regression analyses, postoperative patients scored higher on all scales compared with preoperative patients ( P < 0.001). After adjustment, postoperative patients scored 12.5 higher on VMP-G compared with preoperative patients ( P < 0.01). In subset analyses, GAS was associated with improved PROs in White, non-White, binary, and nonbinary and patients younger than 21 years ( P < 0.05). After GAS, patients younger than 21 years reported similar outcomes, compared with patients older than 21 years ( P > 0.05). No PROs differences were reported between patients who underwent top versus bottom surgery ( P = 0.2). Postoperative patients reported low rates of regret (2.8%). Scores on the VMP-G were sustained even 1 year after GAS. Each month after GAS was associated with a score improvement of 0.02 in the gender dysphoria domain after adjusting for patient demographics ( P = 0.02). CONCLUSIONS: Using a validated GAS-specific measure, we found that surgery sustainably improves patients' self-reported outcomes including gender dysphoria.

Impact of Tissue Expander Surface Texture on Two-Stage Breast Reconstruction Outcomes: A Combined Analysis of Incidence, Timing, and Severity.

BACKGROUND: With ongoing investigations of the impact of device texturing on breast implant-related anaplastic large cell lymphoma (BIA-ALCL), studies have begun comparing complications profiles of tissue expanders. However, there is a paucity of timing and severity data of complications. The aim of this study is to provide a comparative survival analysis of post-operative complications between smooth (STE) and textured tissue expanders (TTE) in breast reconstruction. METHODS: A single institution experience with tissue expander breast reconstruction was reviewed for complications up to 1 year post 2nd stage reconstruction from 2014-2020. Demographics, comorbidities, operation-related variables, and complications were evaluated. Kaplan-Meier curves, cox proportional hazard models, and a consensus based ordinal logistic regression model were used to compare complication profiles. RESULTS: Of 919 ttal patients, 65.3% (n=600) received TTEs and 34.7% (n=319) received STEs. There was increased risk of infection (p<0.0001), seroma (p=0.046), expander malposition (p<0.0001), and wound dehiscence (p=0.019) in STEs compared to TTEs. However, there were also decreased risk of capsular contracture (p=0.005) in STEs compared to TTEs. Failure of breast reconstruction (p<0.001) and wound dehiscence (p=0.018) occurred significantly earlier in STEs compared to TTEs. Predictors for significantly higher severity complications included: smooth tissue expander use (p=0.007), shorter time to complication (p<0.0001), higher BMI (p=0.005), smoking history (p=0.025), and nipple sparing mastectomy (p=0.012). CONCLUSIONS: Differences in the timing and severity of complications contribute to the safety profiles of tissue expanders. STEs are associated increased odds of higher severity and earlier complications. Therefore, tissue expander selection may depend on underlying risk factors and severity predictors.

Comparison of Complication Rates Between Subpectoral vs Prepectoral Techniques in Prosthetic Breast Reconstruction.

BACKGROUND: The location of tissue expanders in implant-based breast reconstruction remains controversial due to variation in surgical techniques and devices. OBJECTIVES: The aim of this study was to provide a comprehensive assessment of early and late complication rates between prepectoral and subpectoral placement of tissue expanders. METHODS: A retrospective cohort study was conducted of all adult female patients who had undergone 2-stage implant-based breast reconstruction between 2013 and 2019 in our institution. Early complication was defined as complications that occurred within 30 days after surgery. Time-to-event analyses were performed and Cox proportional hazard models were used to adjust for confounders. RESULTS: In total, 854 patients were included; 76% of patients underwent a subpectoral tissue expander placement. After the first-stage procedure, the early complication rate was 34% and the late complication rate was 36.4%. After the second-stage procedure, the early complication rate was 16.3% and the late complication rate was 16.1%. Location of the tissue expander did not predict either overall early or late complication rates, regardless of the stages of reconstruction, after adjusting for confounders. Tissue expanders placed in prepectoral plane were associated with a higher hazard ratio (HR) for developing early and late infection after the first stage of reconstruction (HR, 2.1 and 2.4, respectively) as well as late infection after the second stage of reconstruction (HR, 5.3; all P < .05). CONCLUSIONS: Location of tissue expanders did not predict risk of complication. However, the prepectoral group was associated with an increased risk of developing infection.

Rare immune-related adverse events in patients with melanoma: incidence, spectrum, and clinical presentations.

Immune-related adverse events (irAEs) are side effects of immune checkpoint inhibitor therapy (ICI). While common irAEs have been well characterized, there are more limited data on rare immune related adverse events (RirAEs) due to low incidence. Lack of characterization of these entities has led to difficulties in accurate diagnosis and management. Here, we conducted a multi-institution analysis of all patients with stage III/IV melanoma who developed RirAEs after being treated with ICIs (anti-PD-1/L1, anti-CTLA-4, and combination PD-1/CTLA-4 blockade) at three institutions (Vanderbilt University Medical Center, Massachusetts General Hospital, and Melanoma Institute of Australia). RirAEs were defined as those occurring in approximately <1% of patients treated with anti-PD-1 or <2% with combination. Of 2834 patients who received ICIs, 82 developed RirAEs and were more common with combination PD-1/CTLA-4 blockade (4.6%) vs. anti-PD-1/L1 agents (2.8%). Overall median time from ICI start to RirAE was 86 days (interquartile range 42-235 days) with significantly earlier onset in combination therapy (p < 0.001). The spectrum of RirAEs spanned across several organ systems. Most RirAEs were grade 2 (57 [41.3%]) and grade 3 (40 [29.0%]) with relatively few grade 4 (11 [8.0%]) or 5 (5 [3.6%]) events. Steroid re-escalation (21.4%) or additional immunosuppression (13.8%) were commonly required. RirAE recurrence occurred in 22.6% with ICI rechallenge; 37.1% had new irAEs with rechallenge. In conclusion, RirAEs associated with ICIs in melanoma patients occurred, in aggregate, in 2-5% of patients treated with anti-PD-1-based therapy. Steroid re-escalation and alternative immunosuppression use were frequently required but fatal irAEs were fairly uncommon.

Recurrence of Hypophysitis After Immune Checkpoint Inhibitor Rechallenge.

Immune checkpoint inhibitor (ICI)-induced hypophysitis is an immune-mediated pituitary inflammation that tends to cause long-term pituitary deficiency. Management of ICI-induced hypophysitis includes corticosteroids for acute inflammation and long-term hormone replacement due to irreversible pituitary cell damage. We report a case of recurrent hypophysitis following ICI rechallenge for metastatic melanoma. A 33-year-old woman with recurrent metastatic melanoma with adrenal, pelvic, and inguinal metastases developed recurrent hypophysitis during treatment with ipilimumab and nivolumab which recurred with rechallenge >5 years later. In both cases, headache was the most notable symptom and brain MRI showed pituitary enlargement and edema without evidence of metastases. Central adrenal insufficiency and symptoms caused by mass effect were treated with acute high-dose corticosteroids and long-term replacement corticosteroids. Based on recurrence and failure of symptomatic treatment with continued steroid treatment, ICI was discontinued. This case illustrates that hypophysitis may recur with ICI rechallenge, challenging traditional assumptions that chronic, irreversible irAEs are unlikely to recur or flare. The regenerative potential of pituitary cells after ICI-induced damage or additional damage to previously unaffected cells may be more conceivable than previously realized. Additional research on the potential for recurrent ICI-induced endocrinopathies are needed.

Immune checkpoint inhibitors and their impact on liver enzymes and attenuation.

BACKGROUND: Immune related adverse events impacting the liver are common from immune checkpoint inhibitor (ICI) therapy; however, there is little data regarding the subclinical impact of ICIs on liver inflammation. The study aims to determine whether ICI therapy affects liver attenuation and liver enzymes in melanoma patients with and without hepatic steatosis. METHODS: A retrospective, cohort study was conducted of patients with advanced melanoma treated with ICI therapy who received serial PET-CT scans at the Vanderbilt University Medical Center (VUMC). Primary outcomes included: liver attenuation measured by PET-CT/non-contrast CT and liver enzymes. Hepatic steatosis was diagnosed by radiologists on clinical imaging. RESULTS: Among 839 patients with advanced melanoma treated with ICIs, 81 had serial PET-CT scans approximately 12 months apart and long-term survival; of these 11 patients had pre-existing steatosis/steatohepatitis. Overall, ICI was not associated with significant increases in liver enzymes in all patients; modest decreases in liver enzymes were observed in patients with pre-existing steatosis/steatohepatitis. Similarly, liver attenuation did not change from baseline to post-treatment (58.44 vs 60.60 HU, + 2.17, p = 0.055). CONCLUSIONS: ICIs may not chronically affect liver enzymes or liver attenuation, a non-invasive measure of liver fat content and inflammation, in the general population or in those with pre-existing steatosis/steatohepatitis.

The Reevaluation of AΩA: Updating the Outdated.

Medical schools across the country are reconsidering the place of Alpha Omega Alpha Medical Honor Society (AΩA) as evidence of disparities in membership selection continues to mount. Although AΩA national leadership responded to backlash with a reaffirmation of their motto "Be Worthy to Serve the Suffering," and their commitment to diversity, little meaningful progress has been made to this end. By continuing as an organization based on exclusivity, AΩA is an outdated institution that contributes to the structural racism observed in multiple domains of medical education. As we continue to move away from elements of medical education that perpetuate these inequities (e.g., USMLE Step 1 and USMLE Step 2 Clinical Skills Examinations), the place of AΩA in medical education must be re-examined. Several leaders in diversity and inclusion have led the charge by suspending AΩA participation at their institutions (at least 16 U.S. medical schools) and this trend should continue without drastic changes to AΩA. Rather than pushing responsibility to individual chapters, AΩA national leadership must make significant changes to national selection criteria in order to provide appropriate oversight. We propose that AΩA leadership: (1) convene a national task force to review current selection criteria and make actionable recommendations, (2) incorporate standardized diversity goals into selection criteria to hold chapters accountable and limit internal bias, and 3) report diversity and inclusivity statistics annually to the public to promote organizational accountability. Ultimately, meaningful action is necessary for AΩA to remain an honor and to support the development of inclusive leaders in medicine.

Challenging Dermatologic Considerations Associated with Immune Checkpoint Inhibitors.

Immune checkpoint inhibitors have emerged as a new paradigm in oncologic care for many malignancies. However, nonspecific immune activation has led to "collateral damage" in the form of immune-related adverse events, with skin being a commonly affected organ. Cutaneous immune-related adverse events include a wide spectrum of clinical presentations and challenging considerations, often necessitating dermatology referral to support diagnosis and management, particularly for atypical presentations or more severe, cutaneous immune-related adverse events that may require specialized dermatologic evaluations including biopsy and histopathology. Close collaborations between oncologists and dermatologists may optimize clinical decision making in the following challenging management settings: non-steroidal therapies for corticosteroid-refractory, cutaneous immune-related adverse events, immune checkpoint inhibitor rechallenge, balancing cutaneous immune-related adverse events and treatments, and immune checkpoint inhibitors in patients with pre-existing autoimmune disease, skin conditions, and organ transplants. These complex clinical decisions that often lack rigorous data should be made in close collaboration with dermatologists to minimize unnecessary morbidity and mortality. This article provides a review of approaches to challenging dermatologic considerations associated with immune checkpoint inhibitor therapies.

Functional panniculectomy vs cosmetic abdominoplasty: Multicenter analysis of risk factors and complications.

BACKGROUND: Amidst the rising trend of bariatric surgical procedures being performed across the country and around the world, patients seeking functional panniculectomy after massive weight loss represent a different population than those seeking cosmetic abdominoplasty. The purpose of this study was to determine whether certain complications are more likely to occur in patients undergoing functional panniculectomy, as well as identify risk factors that are implicated in the occurrence of adverse events. METHODS: Retrospective cohort study was conducted of patients undergoing cosmetic abdominoplasty and functional panniculectomy in North America between 2015 and 2019 using the National Surgical Quality Improvement Program database sponsored by the American College of Surgeons. Comorbidities and postoperative complications between these two cohorts were analyzed with appropriate statistics. RESULTS: During the study interval, 11,137 patients underwent excision of excessive infraumbilical abdominal skin, including 57.4% (n = 6397) patients undergoing functional panniculectomy and 42.6% (n = 4740) patients undergoing cosmetic abdominoplasty. Patients undergoing functional panniculectomy were significantly more likely to have comorbidities than those undergoing cosmetic abdominoplasty (p < .001). Overall adverse events (p < .001), medical complications (p = .047), surgical complications (p < .001), related readmission (p < .001), and related reoperation (p < .001) were significantly higher in patients undergoing functional panniculectomy. Surgical complications significantly higher in functional panniculectomy included superficial incisional infection (p < .001), deep incisional infection (p < .001), organ/space infection (p < .001), dehiscence (p = .003), and bleeding requiring transfusion (p = .003). CONCLUSIONS: Patients undergoing functional panniculectomy are significantly more likely to have comorbidities and experience postoperative wound infection, dehiscence, sepsis, bleeding, related readmission, and related reoperation.

Hypersensitivity Reactions and Immune-Related Adverse Events to Immune Checkpoint Inhibitors: Approaches, Mechanisms, and Models.

Immune checkpoint inhibitors (ICI) are a major class of cancer therapeutics that may cause durable responses in a growing proportion of patients with metastatic cancer. These agents remove negative regulators on T cells and may cause autoimmunelike toxicities that affect all organ systems. Monoclonal antibodies are much less commonly associated with traditional hypersensitivity reactions. Herein, we discuss the pathophysiology, clinical presentation, and management of toxicities of ICI and discuss their broader context within drug hypersensitivity.