Extended Follow-Up of Chronic Immune-Related Adverse Events Following Adjuvant Anti-PD-1 Therapy for High-Risk Resected Melanoma.

Importance: Anti-programmable cell death-1 (anti-PD-1) improves relapse-free survival when used as adjuvant therapy for high-risk resected melanoma. However, it can lead to immune-related adverse events (irAEs), which become chronic in approximately 40% of patients with high-risk melanoma treated with adjuvant anti-PD-1. Objective: To determine the incidence, characteristics, and long-term outcomes of chronic irAEs from adjuvant anti-PD-1 therapy. Design, Setting, and Participants: This retrospective multicenter cohort study analyzed patients treated with adjuvant anti-PD-1 therapy for advanced and metastatic melanoma between 2015 and 2022 from 6 institutions in the US and Australia with at least 18 months of evaluable follow-up after treatment cessation (range, 18.2 to 70.4 months). Main Outcomes and Measures: Incidence, spectrum, and ultimate resolution vs persistence of chronic irAEs (defined as those persisting at least 3 months after therapy cessation). Descriptive statistics were used to analyze categorical and continuous variables. Kaplan-Meier curves assessed survival, and Wilson score intervals were used to calculate CIs for proportions. Results: Among 318 patients, 190 (59.7%) were male (median [IQR] age, 61 [52.3-72.0] years), 270 (84.9%) had a cutaneous primary, and 237 (74.5%) were stage IIIB or IIIC at presentation. Additionally, 226 patients (63.7%) developed acute irAEs arising during treatment, including 44 (13.8%) with grade 3 to 5 irAEs. Chronic irAEs, persisting at least 3 months after therapy cessation, developed in 147 patients (46.2%; 95% CI, 0.41-0.52), of which 74 (50.3%) were grade 2 or more, 6 (4.1%) were grade 3 to 5, and 100 (68.0%) were symptomatic. With long-term follow-up (median [IQR], 1057 [915-1321] days), 54 patients (36.7%) experienced resolution of chronic irAEs (median [IQR] time to resolution of 19.7 [14.4-31.5] months from anti-PD-1 start and 11.2 [8.1-20.7] months from anti-PD-1 cessation). Among patients with persistent irAEs present at last follow-up (93 [29.2%] of original cohort; 95% CI, 0.25-0.34); 55 (59.1%) were grade 2 or more; 41 (44.1%) were symptomatic; 24 (25.8%) were using therapeutic systemic steroids (16 [67%] of whom were on replacement steroids for hypophysitis (8 [50.0%]) and adrenal insufficiency (8 [50.0%]), and 42 (45.2%) were using other management. Among the 54 patients, the most common persistent chronic irAEs were hypothyroid (38 [70.4%]), arthritis (18 [33.3%]), dermatitis (9 [16.7%]), and adrenal insufficiency (8 [14.8%]). Furthermore, 54 [17.0%] patients experienced persistent endocrinopathies, 48 (15.1%) experienced nonendocrinopathies, and 9 (2.8%) experienced both. Of 37 patients with chronic irAEs who received additional immunotherapy, 25 (67.6%) experienced no effect on chronic irAEs whereas 12 (32.4%) experienced a flare in their chronic toxicity. Twenty patients (54.1%) experienced a distinct irAE. Conclusions and Relevance: In this cohort study of 318 patients who received adjuvant anti-PD-1, chronic irAEs were common, affected diverse organ systems, and often persisted with long-term follow-up requiring steroids and additional management. These findings highlight the likelihood of persistent toxic effects when considering adjuvant therapies and need for long-term monitoring and management.

Measuring Biomechanical Properties Using a Noninvasive Myoton Device for Lymphedema Detection and Tracking: A Pilot Study.

Background: Improved techniques for lymphedema detection and monitoring of disease progression are needed. This study aims to use the noninvasive MyotonPRO Device to detect differences in biomechanical skin characteristics in patients with breast cancer-related lymphedema (BCRL). Methods: The handheld Myoton device was used to measure skin parameters including dynamic skin stiffness, oscillation frequency (tone), mechanical stress relaxation time, and creep in 11 women diagnosed with BCRL. Seven anatomical sites were measured bilaterally for each participant. The average values in the affected arms were compared with those in the contralateral unaffected arms. Results: Among the 11 female participants with unilateral BCRL Stages 0 to II, the combined averages for dynamic skin stiffness and frequency measurements were decreased in the affected arms when compared with those for the contralateral control arms (ratio < 1). The median ratio of stiffness (affected to unaffected control arm) was 0.91 (interquartile range [IQR] 0.78-1.03) while frequency was 0.94 (IQR 0.89-1.0). Skin relaxation time and creep averages were increased in the affected arms. The relaxation time median ratio (affected to unaffected control arm) was 1.07 (IQR 1.02-1.14) and the median ratio of creep was 1.06 (IQR 1.03-1.16). Conclusions: This study suggests the Myoton can detect differences in skin biomechanical parameters of the affected and unaffected arms in patients with BCRL. Larger studies are needed to draw strong conclusions.

Combination anti-PD1 and ipilimumab therapy in patients with advanced melanoma and pre-existing autoimmune disorders.

BACKGROUND: Clinical trials of immunotherapy have excluded patients with pre-existing autoimmune disease. While the safety and efficacy of single agent ipilimumab and anti-PD1 antibodies in patients with autoimmune disease has been examined in retrospective studies, no data are available for combination therapy which has significantly higher toxicity risk. We sought to establish the safety and efficacy of combination immunotherapy for patients with advanced melanoma and pre-existing autoimmune diseases. METHODS: We performed a retrospective study of patients with advanced melanoma and pre-existing autoimmune disease who received combination ipilimumab and anti-PD1 at 10 international centers from March 2015 to February 2020. Data regarding the autoimmune disease, treatment, toxicity and outcomes were examined in patients. RESULTS: Of the 55 patients who received ipilimumab and anti-PD1, the median age was 63 years (range 23-83). Forty-six were treated with ipilimumab and nivolumab and nine with ipilimumab and pembrolizumab.Eighteen patients (33%) had a flare of their autoimmune disease including 4 of 7 with rheumatoid arthritis, 3 of 6 with psoriasis, 5 of 10 with inflammatory bowel disease, 3 of 19 with thyroiditis, 1 of 1 with Sjogren's syndrome, 1 of 1 with polymyalgia and 1 of 1 with Behcet's syndrome and psoriasis. Eight (44%) patients ceased combination therapy due to flare. Thirty-seven patients (67%) had an unrelated immune-related adverse event (irAE), and 20 (36%) ceased combination immunotherapy due to irAEs. There were no treatment-related deaths. Patients on immunosuppression (OR 4.59; p=0.03) had a higher risk of flare.The overall response rate was 55%, with 77% of responses ongoing. Median progression free survival and overall survival were 10 and 24 months, respectively. Patients on baseline immunosuppression had an overall survival of 11 months (95% CI 3.42 to 18.58) compared with 31 months without (95% CI 20.89 to 41.11, p=0.005). CONCLUSIONS: In patients with pre-existing autoimmune disease, not on immunosuppression and advanced melanoma, combination ipilimumab and anti-PD1 has similar efficacy compared with previously reported trials. There is a risk of flare of pre-existing autoimmune disorders, particularly in patients with inflammatory bowel disease and rheumatologic conditions, and patients on baseline immunosuppression.

The Importance of Financial Metrics in Physician Funding and Performance Evaluation.

BACKGROUND: Financial key performance indicators are often used to evaluate performance. Understanding of key performance indicators can be crucial for career advancement and bargaining leverage in resource negotiations. This study aimed to identify the most important key performance indicators used in surgical funding requests and understand how to use these metrics in clinical practice. METHODS: In two tertiary medical centers, funding requests for surgeon gap support (2019 to 2020) and equipment (2017 to 2019) within departments of surgery were reviewed. The requesting department, approval status, and amount allotted were recorded. In requests for gap support, projections for contribution margin, operating room volume, charges, collections, and relative value units were tracked. Projected contribution margin and cost savings were recorded for equipment funding requests. RESULTS: There were 40 gap support and 24 equipment requests, and all were approved. Most gap support requests included collections (90.0 percent), charges (87.5 percent), operating room cases (80.0 percent), relative value units (77.5 percent), and hospital contribution margin (77.5 percent). The most represented departments were general surgery (37.5 percent), neurosurgery (22.5 percent), and plastic surgery (15.0 percent). The departments that submitted the most equipment requests were general surgery (28.0 percent) and neurosurgery (28.0 percent). Most requests included projections for contribution margin (95.8 percent) and cost savings (87.4 percent). Projected hospital contribution margin correlated with the amount of funds allotted for surgeon support (r = 0.409; p = 0.022). CONCLUSIONS: This multicenter study identified the importance of using key performance indicators for a successful financial outcome in funding requests. In addition, the authors demonstrate the need for surgeons to understand their own key performance indicators. Surgeons should advocate for increased transparency to better understand their financial contributions and performance.

Chronic Immune-Related Adverse Events Following Adjuvant Anti-PD-1 Therapy for High-risk Resected Melanoma.

Importance: Agents targeting programmed cell death 1 (PD-1)/PD ligand 1 (PD-L1) improve long-term survival across many advanced cancers and are now used as adjuvant therapy for resected stage III and IV melanomas. The incidence and spectrum of chronic immune-related adverse events (irAEs) have not been well defined. Objective: To determine the incidence, time course, spectrum, and associations of chronic irAEs arising from adjuvant anti-PD-1 therapy. Design, Setting, and Participants: This retrospective multicenter cohort study was conducted between 2015 and 2020 across 8 academic medical centers in the United States and Australia. Patients with stage III to IV melanomas treated with anti-PD-1 in the adjuvant setting were included. Main Outcomes and Measures: Incidence, types, and time course of chronic irAEs (defined as irAEs persisting at least 12 weeks after therapy cessation). Results: Among 387 patients, the median (range) age was 63 (17-88) years, and 235 (60.7%) were male. Of these patients, 267 (69.0%) had any acute irAE, defined as those arising during treatment with anti-PD-1, including 52 (19.5%) with grades 3 through 5 events; 1 patient each had fatal myocarditis and neurotoxicity. Chronic irAEs, defined as those that persisted beyond 12 weeks of anti-PD-1 discontinuation, developed in 167 (43.2%) patients, of which most (n = 161; 96.4%) were mild (grade 1 or 2) and most persisted until last available follow-up (n = 143; 85.6%). Endocrinopathies (73 of 88; 83.0%), arthritis (22 of 45; 48.9%), xerostomia (9 of 17; 52.9%), neurotoxicities (11 of 15; 73.3%), and ocular events (5 of 8; 62.5%) were particularly likely to become chronic. In contrast, irAEs affecting visceral organs (liver, colon, lungs, kidneys) had much lower rates of becoming chronic irAEs; for example, colitis became chronic in 6 of 44 (13.6%) cases, of which 4 of 6 (66.7%) resolved with prolonged follow-up. Age, gender, time of onset, and need for steroids were not associated with the likelihood of chronicity of irAEs. Conclusion and Relevance: In this multicenter cohort study, chronic irAEs associated with anti-PD-1 therapy appear to be more common than previously recognized and frequently persisted even with prolonged follow-up, although most were low grade. The risks of chronic irAEs should be integrated into treatment decision-making.

A multicenter characterization of hepatitis associated with immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICI) predispose patients to immune-related adverse events (irAEs). Although hepatitis is a potentially lethal toxicity, the timing and outcomes have not been well described. In this retrospective study, patients from six international institutions were included if they were treated with ICIs and developed immune-related hepatitis. Patient and tumor characteristics, and hepatitis management and outcomes were evaluated. Of the 164 patients included, most were male (53.7%) with a median age of 63.0 years. Most patients had melanoma (83.5%) and stage IV disease (86.0%). Median follow-up was 585 days; median OS and PFS were not reached. The initial grade of hepatitis was most often grade 2 (30.5%) or 3 (45.7%) with a median time to onset of 61 days. Patients were most commonly asymptomatic (46.2%), but flu-like symptoms, including fatigue/anorexia (17.1%), nausea/emesis (14.0%), abdominal/back pain (11.6%), and arthralgias/myalgias (8.5%) occurred. Most patients received glucocorticoids (92.1%); the median time to improvement by one grade was 13.0 days, and the median time to complete resolution was 52.0 days. Second-line immunosuppression was required in 37 patients (22.6%), and steroid-dose re-escalation in 45 patients (27.4%). Five patients (3%) died of ICI-hepatitis or complications of hepatitis treatment. Ninety-one patients (58.6%) did not resume ICI; of 66 patients (40 grade 1/2, 26 grade 3/4) that were rechallenged, only 25.8% (n = 17) had recurrence. In this multi-institutional cohort, immune-related hepatitis was associated with excellent outcomes but frequently required therapy discontinuation, high-dose steroids, and second-line immunosuppression. Rechallenge was associated with a modest rate of hepatitis recurrence.

Trigger Finger Corticosteroid Injection With and Without Local Anesthetic: A Randomized, Double-Blind Controlled Trial.

Background: The first-line treatment for trigger finger is a corticosteroid injection. Although the injectable solution is often prepared with a local anesthetic, we hypothesize that patients receiving an injection with anesthetic will experience more pain at the time of injection. Methods: C Patients with trigger finger were prospectively randomized into 2 cohorts to receive triamcinolone (1 mL, 40 mg) plus 1% lidocaine with epinephrine (1 mL) or triamcinolone (1 mL, 40 mg) plus normal saline (1 mL, placebo). Both patient and surgeon were blinded to the treatment arm. The primary outcome was pain measured using a (VAS) immediately following the injection. Results: Seventy-three patients with a total of 110 trigger fingers were enrolled (57 lidocaine with epinephrine and 53 placebo). Immediate postinjection pain scores were significantly higher for injections containing lidocaine with epinephrine compared with placebo (VAS 3.5 vs 2.0). Conclusions: In the treatment of trigger finger, corticosteroid injections are effective and have relatively little associated pain. This study shows there is more injection-associated pain when lidocaine with epinephrine is included with the corticosteroid. Therefore, surgeons looking to decrease injection pain should exclude the anesthetic, but they should discuss the trade-off of foregoing short-term anesthesia with patients. Using only a single drug (ie, corticosteroid alone) is not only less painful but is also more simple, efficient, and safe; this has therefore become our preferred treatment method.

Supraorbital Neuralgia Associated With Thyroid Eye Disease.

PURPOSE: To identify the relationship between thyroid eye disease (TED) and supraorbital neuralgia (SON) and establish a reliable approach to the diagnosis and management of TED-associated SON. METHODS: This retrospective study included 1,126 patients. Demographics, active and inactive phase status and duration, and reactivation rate were noted. TED clinical activity was determined using the vision, inflammation, strabismus, and appearance assessment system, and TED severity was classified using the European Group of Graves' Orbitopathy system. Subtypes of periorbital pain were identified, and suspected SON was confirmed by supraorbital nerve block. RESULTS: Of the study's 1,126 patients, 935 (83%) were deemed "active" at some point during the follow up and 34 (3%) remained "active" at the study's conclusion. Of the 2,251 eyes studied, 1,193 (53%) underwent orbital decompression. Of the 1,126 patients, 946 (84%) reported a retrobulbar "pressure" or "aching," but a distinct, more debilitating pain suggestive of SON was reported in 91 (8%). All 91 patients were given a supraorbital nerve block, and all had complete pain resolution lasting from hours to weeks. Eighty-eight (97%) of the 91 patients with SON-type pain underwent orbital decompression compared to 496 (48%) of the 1,035 without SON-type pain (p < 0.00001). A difference was found in the rate of TED reactivation between those with SON-type symptoms (8%) as compared to those without (2%), p = 0.01. CONCLUSIONS: SON of uncertain etiology appears to be a previously underreported but significant pain associated with TED. Paradoxically, although the SON does not appear to be related to the type or severity of TED on standard rating scales, the presence of SON was found to be associated with increased likelihood of both orbital decompression and TED reactivation.

Plastic Surgeons as Institutional Leaders.

BACKGROUND: Physicians, especially plastic surgeons, are underrepresented in hospital leadership. As such, the steps an aspiring plastic surgeon should take toward assuming a high-level administrative role remain unclear. The authors aim to profile the chief executive officers and surgeons-in-chief at top-ranked U.S. hospitals with the goal of better characterizing the attributes of institutional leaders. METHODS: Chief executive officers and surgeons-in-chief at top-ranking hospitals in the 2019 to 2020 U.S. News and World Report "Best Hospitals Honor Roll" were included in this study. For each leader, sex, title, degrees, years of experience, total number of publications, practice specialty (for physician leaders), and previous leadership roles in national societies were reviewed. Descriptive statistical analyses were performed. RESULTS: A total of 99 leadership positions at 66 institutions were included. Of these, 67 were chief executive officers and 32 were surgeons-in-chief. Overall, 28 of 67 chief executive officers (42 percent) were physicians-23 nonsurgeons and five surgeons. Of all surgeon executives, only two were plastic surgeons, and both were surgeons-in-chief. The "average" physician-chief executive officer had 24 years of experience, no M.B.A., over 100 publications, zero to one fellowship, and was involved in national leadership. There was no difference in professional qualifications (defined as years of experience, business training, number of publications and fellowships, and leadership positions) between nonsurgeon- and surgeon-chief executive officers, or between plastic surgeons and other surgeons in leadership positions. CONCLUSIONS: Despite possessing adequate qualifications, plastic surgeons are underrepresented in American health care institutional leadership roles. Aspiring plastic surgeon leaders should lean on their peer credibility and experience delivering patient-centered care to succeed in leadership roles.

The Discrepancy Between Perceived Importance and Actual Delivery of Business Education in Residency: A Survey of Program Directors.

BACKGROUND: In the contemporary healthcare environment, there is a need for physicians to understand business fundamentals. Nonsurgical residencies have implemented formal business education, but surgical training programs have been slower to adapt. Further research is needed to evaluate the status of business education in plastic surgery residency. METHODS: A 12-question survey was created. Ninety program director (PD) e-mails were obtained and the survey was distributed using SurveyMonkey. The survey evaluated program demographics and current resources, commitments, and attitudes toward business training. The survey also identified the most important topics to include in a business curriculum. RESULTS: Thirty-six surveys were completed (response rate = 40%). Whereas most PDs agreed that business education in plastic surgery residency was important (78%) and that their programs should have more business training (73%), only 39% currently offered business training. Only 42% of PDs believed that their chief residents were competent to handle the business aspects of plastic surgery upon graduation. No programs offered a formal gap year to pursue a professional business degree. The most important topics identified for a business curriculum were economics and finance (83.3%), management (64%), and marketing (53%). CONCLUSIONS: There is disconnect between perceived importance and resources available for plastic surgery residents to receive business education. Increased attention is needed to resolve this discrepancy to ensure that future plastic surgeons are equipped to excel in their personal careers and stimulate the advancement of the field. Future research should aim to outline a business curriculum for plastic surgery trainees.