Ipilimumab alone or ipilimumab plus anti-PD-1 therapy in patients with metastatic melanoma resistant to anti-PD-(L)1 monotherapy: a multicentre, retrospective, cohort study.

BACKGROUND: Anti-PD-1 therapy (hereafter referred to as anti-PD-1) induces long-term disease control in approximately 30% of patients with metastatic melanoma; however, two-thirds of patients are resistant and will require further treatment. We aimed to determine the efficacy and safety of ipilimumab plus anti-PD-1 (pembrolizumab or nivolumab) compared with ipilimumab monotherapy in patients who are resistant to anti-PD-(L)1 therapy (hereafter referred to as anti-PD-[L]1). METHODS: This multicentre, retrospective, cohort study, was done at 15 melanoma centres in Australia, Europe, and the USA. We included adult patients (aged ≥18 years) with metastatic melanoma (unresectable stage III and IV), who were resistant to anti-PD-(L)1 (innate or acquired resistance) and who then received either ipilimumab monotherapy or ipilimumab plus anti-PD-1 (pembrolizumab or nivolumab), based on availability of therapies or clinical factors determined by the physician, or both. Tumour response was assessed as per standard of care (CT or PET-CT scans every 3 months). The study endpoints were objective response rate, progression-free survival, overall survival, and safety of ipilimumab compared with ipilimumab plus anti-PD-1. FINDINGS: We included 355 patients with metastatic melanoma, resistant to anti-PD-(L)1 (nivolumab, pembrolizumab, or atezolizumab), who had been treated with ipilimumab monotherapy (n=162 [46%]) or ipilimumab plus anti-PD-1 (n=193 [54%]) between Feb 1, 2011, and Feb 6, 2020. At a median follow-up of 22·1 months (IQR 9·5-30·9), the objective response rate was higher with ipilimumab plus anti-PD-1 (60 [31%] of 193 patients) than with ipilimumab monotherapy (21 [13%] of 162 patients; p<0·0001). Overall survival was longer in the ipilimumab plus anti-PD-1 group (median overall survival 20·4 months [95% CI 12·7-34·8]) than with ipilimumab monotherapy (8·8 months [6·1-11·3]; hazard ratio [HR] 0·50, 95% CI 0·38-0·66; p<0·0001). Progression-free survival was also longer with ipilimumab plus anti-PD-1 (median 3·0 months [95% CI 2·6-3·6]) than with ipilimumab (2·6 months [2·4-2·9]; HR 0·69, 95% CI 0·55-0·87; p=0·0019). Similar proportions of patients reported grade 3-5 adverse events in both groups (59 [31%] of 193 patients in the ipilimumab plus anti-PD-1 group vs 54 [33%] of 162 patients in the ipilimumab group). The most common grade 3-5 adverse events were diarrhoea or colitis (23 [12%] of 193 patients in the ipilimumab plus anti-PD-1 group vs 33 [20%] of 162 patients in the ipilimumab group) and increased alanine aminotransferase or aspartate aminotransferase (24 [12%] vs 15 [9%]). One death occurred with ipilimumab 26 days after the last treatment: a colon perforation due to immune-related pancolitis. INTERPRETATION: In patients who are resistant to anti-PD-(L)1, ipilimumab plus anti-PD-1 seemed to yield higher efficacy than ipilimumab with a higher objective response rate, longer progression-free, and longer overall survival, with a similar rate of grade 3-5 toxicity. Ipilimumab plus anti-PD-1 should be favoured over ipilimumab alone as a second-line immunotherapy for these patients with advanced melanoma. FUNDING: None.

Guideline for in vivo assessment of adherent and rolling leukocytes in human skin microvasculature via reflectance confocal videomicroscopy.

OBJECTIVE: To develop a guideline that reliably identifies cutaneous adherent and rolling leukocytes from mimicking scenarios via in vivo reflectance confocal videomicroscopy. METHODS: We used a clinical reflectance confocal microscope, the VivaScope 1500, to acquire 1522 videos of the upper dermal microcirculation from 12 healthy subjects and 60 patients after allogeneic hematopoietic cell transplantation. Blinded to clinical information, two trained raters independently counted the number of adherent and rolling leukocytes in 88 videos. Based on discrepancies in the initial assessments, we developed a guideline to identify both types of leukocyte-endothelial interactions via a modified Delphi method (without anonymity). To test the guideline's ability to improve the inter-rater reliability, the two raters assessed the remaining 1434 videos by using the guideline. RESULTS: We demonstrate a guideline that consists of definitions, a step-by-step flowchart, and corresponding visuals of adherent and rolling leukocytes and mimicking scenarios. The guideline improved the inter-rater reliability of the manual assessment of both interactions. The intraclass correlation coefficient (ICC) of adherent leukocyte counts increased from 0.056 (95% confidence interval: 0-0.236, n = 88 videos, N = 10 subjects) to 0.791 (0.770-0.809, n = 1434, N = 67). The ICC of rolling leukocyte counts increased from 0.385 (0.191-0.550, n = 88, N = 10) to 0.626 (0.593-0.657, n = 1434, N = 67). Intra-rater ICC post-guideline was 0.953 (0.886-0.981, n = 20, N = 12) and 0.956 (0.894-0.983, n = 20, N = 12) for adherent and rolling, respectively. CONCLUSION: The guideline aids in the manual identification of adherent and rolling leukocytes via in vivo reflectance confocal videomicroscopy.

The Paramedian Forehead Flap: A Retrospective Clinical Model for Understanding the Connection Between Supraorbital and Supratrochlear Nerve Pathology and Headaches.

Background: In the later stages of a paramedian forehead flap (PMFF) surgery, the supratrochlear (STN) and branches of the supraorbital nerve (SON) are transected during flap inset above the supraorbital rim. This can lead to either a nerve release if the compression point was previously distal to the transection point or a new nerve compression through neuroma or scar tissue formation. We inferred that PMFF could be a model for understanding the correlation between STN/SON pathology and migraines headaches (MH). We hypothesized that patients undergoing PMFF would experience either a change in severity or an onset of a new headache (HA) or MH. Methods: One hundred ninety-nine patients who underwent a PMFF at a tertiary medical centre were identified and contacted by phone. Patients were asked about the presence of MH or HA before and after the procedure. If a patient reported a perioperative history of MH/HA, their pre- and postoperative MH/HA characteristics were recorded. Results: Of the 199 patients contacted, 74 reported no perioperative HA/MH history and 14 reported a perioperative history of HA/MH. Of these 14 patients, 5 had stable HA/MH pre- and post-surgery, and 9 reported a change in HA/MH post-surgery. In this subset of 9 patients, 3 reported change in HA/MH quality post-surgery, 1 reported HA/MH resolution post-surgery, and 5 reported new onset HA/MH post-surgery. Conclusion: Sixty-four percent of patients with perioperative HA/MH experienced a change in headache quality following surgery. These results suggest a potential connection between SON and STN pathology and HA/MH pathophysiology; further work is warranted.

Historique: Dans les dernières phases de l'opération du lambeau frontal paramédian (LFPM), le nerf supratrochléaire (NST) et les rameaux du nerf supraorbital (NSO) sont sectionnés pour installer le lambeau au-dessus de l'arcade sourcilière. Cette intervention peut libérer le nerf si le point de compression se trouvait auparavant dans la partie distale de l'incision ou provoquer une nouvelle compression nerveuse par la formation d'un névrome ou de tissu cicatriciel. Les chercheurs ont présumé que le LFPM pouvait servir de modèle pour comprendre la corrélation entre la pathologie du NST ou du NSO et les migraines. Les chercheurs ont postulé que les patients qui se font greffer un LFPM présenteraient soit un changement de la gravité de leurs migraines ou de leurs céphalées ou de nouvelles migraines ou céphalées. Méthodologie: Les chercheurs ont communiqué par téléphone avec 191 patients qui se sont fait greffer un LFPM dans un centre de soins tertiaires. Ils leur ont demandé s'ils souffraient de migraines ou de céphalées avant et après l'intervention. Si le patient déclarait des antécédents périopératoires de migraines ou de céphalées, les chercheurs en consignaient les caractéristiques. Résultats: Des 199 patients, 74 n'ont déclaré aucun antécédent de migraines ou de céphalées, mais 14 ont signalé une histoire périopératoire de ces symptômes. De ces 14 patients, cinq présentaient une migraine ou une céphalée avant et après l'opération et neuf, un changement à ces manifestations. Dans ce sous-groupe de neuf patients, trois ont déclaré un changement de la qualité des migraines et des céphalées après l'opération, un en a signalé la résolution après l'opération et cinq, l'apparition après l'opération. Conclusion: Au total, 64% des patients ayant des migraines et des céphalées ont ressenti un changement à la qualité de leurs symptômes après l'opération. Ces résultats laissent croire à un lien potentiel entre la pathologie du NSO et du NST et la physiopathologie des migraines et des céphalées. D'autres travaux s'imposent sur le sujet.

Business Education in Dermatology Residency: A Survey of Program Directors.

With the rising cost of health care in the United States and an increasingly competitive market, dermatology residents would benefit from business training. We constructed an 8-part questionnaire for dermatology program directors (PDs) to determine the current perceptions of and resources available for business education. Of the 139 surveys distributed, 35 were completed (25.2%). Approximately one half of the respondents said their programs offered business training, primarily through seminars or lectures. Most PDs felt business education during residency was important and that programs should implement more training. The most important topics identified for inclusion in a business curriculum were economics or finance, management, and health care policy or government. Our survey identified a gap between the perceived importance and current supply of business education during dermatology residency training. Future efforts should aim to develop a standardized, dermatology-specific curriculum that is readily available to all programs and residents.

Risk of adverse events due to high volumes of local anesthesia during Mohs micrographic surgery.

General guidelines for the maximum amounts of locally injected lidocaine exist; however, there is a paucity of data in the Mohs micrographic surgery (MMS) literature. This study aimed to determine the safety and adverse effects seen in patients that receive larger amounts of locally injected lidocaine. A retrospective chart review of 563 patients from 1992 to 2016 who received over 30 mL of locally injected lidocaine was conducted. Patient records were reviewed within seven postoperative days for complications. The average amount of anesthesia received was 40 mL, and the average patient weight was 86.69 kg. 1.4% of patients had a complication on the day of surgery, and 4.4% of patients had a complication within 7 days of the surgery. The most common complications were excessive bleeding/hematoma formation and wound infection. Only two complications could be attributable to local anesthetics. Gender, heart disease, hypertension, diabetes, and smoking were not significant risk factors for the development of complications. MMS is a safe outpatient procedure for patients that require over 30 mL of locally injected anesthesia. The safety of high volumes of lidocaine extends to patients with risk factors such as heart disease, hypertension, diabetes, and smoking.

The Role of Anti-PD-1/PD-L1 in the Treatment of Skin Cancer.

Skin cancers remain the most common group of cancers globally, and the incidence continues to rise. Although localized skin cancers tend to have excellent outcomes following surgical excisions, the less common cases that become surgically unresectable or metastatic have been associated with poor prognosis and suboptimal treatment responses to cytotoxic chemotherapy. Development of monoclonal antibodies to programmed cell death-1 receptor and its ligand (PD-1/PD-L1) have transformed the management of metastatic melanoma, squamous cell carcinoma, and Merkel cell carcinoma. These agents, as monotherapies, are associated with response rates of approximately 40-60%, many of which persist durably. Further efficacy is observed with combination immunotherapy in advanced melanoma. Early reports suggest similar activity in locally advanced or metastatic basal cell carcinoma. In this review, we describe common molecular features of skin cancers that may render them particularly susceptible to anti-PD-1/PD-L1 and detail results from key clinical trials of these agents across skin cancers. Overall, the superior response rates of skin cancer to anti-PD-1/PD-L1 compared with other solid tumor types are likely due, at least in part, to a high mutational burden and, in Merkel cell carcinoma, viral etiology. Although melanoma has been rigorously studied in the setting of anti-PD-1/PD-L1 treatment, more research is needed for the other skin cancer types to establish toxicity profiles, responses, and quality-of-life outcomes.

Survivorship in immune therapy: Assessing toxicities, body composition and health-related quality of life among long-term survivors treated with antibodies to programmed death-1 receptor and its ligand.

AIM: Antibodies to programmed death-1 receptor and its ligand (anti-PD-1/PD-L1) produce durable responses in many cancers. However, the long-term effects of anti-PD-1/PD-L1 blockade are not well defined. We identified the toxicities, health outcomes and health-related quality of life (HRQoL) amongst long-term survivors treated with anti-PD-1/PD-L1. METHODS: We assessed 217 patients who received anti-PD-1/PD-L1 for melanoma, renal cell carcinoma or non-small-cell lung carcinoma between 2009 and 2017, with survival greater than two years after treatment. Patient and tumour characteristics, immune-related adverse events (irAEs), cardiometabolic parameters (glucose, blood pressure, body mass index [BMI]), body composition (using automated body composition analyser, computed tomography and Slice-o-matic software) and HRQoL outcomes were tracked. RESULTS: Among the included patients, most were men (70.3%) and at anti-PD-1/PD-L1 initiation had an average age of 61.0 years and median BMI of 28.5. Median overall survival was not reached; 33 (15.2%) died during the follow-up primarily from progressive cancer (n = 28). At the last follow-up, most patients' Eastern Cooperative Oncology Group performance status was 0 (38%) or 1 (41%). There was no difference in blood pressure, glucose or BMI from baseline to two years after treatment initiation. Body composition showed increased adiposity (p = 0.05), skeletal muscle mass (p = 0.03) and skeletal muscle gauge (p = 0.04). We observed chronic irAEs at the last follow-up including hypothyroidism (10.6%), arthritis (3.2%), adrenal insufficiency (3.2%) and neuropathy (2.8%). New diagnoses of type 2 diabetes (6.5%) and hypertension (6.0%) were observed, with uncertain relationship to anti-PD-1/PD-L1. Patient-reported outcomes compared favourably with cancer and general populations, although younger age (p = 0.003) and need for subsequent therapy (p = 0.03) were associated with worse HRQoL outcomes. CONCLUSION: Durable responses to anti-PD-1/PD-L1 therapy and favourable HRQoL outcomes are encouraging. Chronic events may be more common than previously thought although no clear chronic adverse cardiometabolic effects were observed.

Acellular Dermal Matrix Performance Compared with Latissimus Dorsi Myocutaneous Flap in Expander-Based Breast Reconstruction.

Latissimus dorsi myocutaneous flap (LDMF) with tissue expander provides excellent results in breast reconstruction. Acellular dermal matrix (ADM) has been used in expander-based reconstruction (EBR) with good results. This study assesses how ADM compares to LDMF in EBR. METHODS: The cohorts comprised 124 patients (218 breasts) who had EBR using ADM between 2006 and 2012, and 242 patients (266 breasts) who had EBR using LDMF between 1994 and 2012. Postoperative complications, reoperations, Breast-Q scores, and objectively assessed aesthetic outcomes were compared. RESULTS: Median age was 55 years for both ADM (range 23-84) and LDMF (range 26-88) groups. No statistically significant differences were noted between the groups in the rates of major postoperative complications (P > 0.3). Forty-nine of the 218 (22.5%) in the ADM group and 67 of 266 (25.2%) in the LDMF group had a total of 63 and 84 reoperations, respectively (P = 0.52), with no significant differences in the reoperations rate (P > 0.3). No significant differences were observed in the Breast-Q scores. Some categorical differences were noted in the aesthetic outcomes; however, the difference between the overall outcomes was not significant (P = 0.54). CONCLUSION: Our study revealed no statistically significant differences in the complications or reoperation rates, patient satisfaction, or overall aesthetic outcomes when comparing the use of ADM to LDMF in EBR. In conclusion, this study supports the hypothesis that ADM performs as well as LDMF in EBR.