Objective response to immune checkpoint inhibitor therapy in NRAS-mutant melanoma: A systematic review and meta-analysis.

Introduction: NRAS mutations are common in melanoma and confer a worse prognosis. Although most patients with metastatic melanoma receive immune checkpoint inhibitors (ICIs), the impact of NRAS mutational status on their efficacy remains under debate. Methods: We performed a comprehensive literature search across several large databases. Inclusion criteria were trials, cohorts, and large case series that analyzed the primary outcome of objective response rate by NRAS mutational status in patients with melanoma treated with any line of ICI. At least two reviewers independently screened studies using Covidence software, extracted data, and assessed risk of bias. Standard meta-analysis was performed in R with sensitivity analysis and tests for bias. Results: Data on 1770 patients from ten articles were pooled for meta-analysis, and the objective response rate to ICIs was calculated to compare NRAS-mutant and NRAS-wildtype melanoma. The objective response rate was 1.28 (95% confidence interval: 1.01-1.64). Sensitivity analysis identified the study by Dupuis et al. with influential impact on the pooled effect size and heterogeneity, favoring NRAS-mutant melanoma. Discussion: In this meta-analysis evaluating the impact of NRAS mutational status on objective response to ICIs in metastatic melanoma, NRAS-mutant cutaneous melanoma demonstrated an increased likelihood of partial or complete tumor response, relative to NRAS-wildtype cutaneous melanoma. Genomic screening for NRAS mutations in patients with metastatic melanoma may improve predictive ability when initiating ICIs.

Cutaneous immune-related adverse events are associated with longer overall survival in advanced cancer patients on immune checkpoint inhibitors: A multi-institutional cohort study.

BACKGROUND: Cutaneous immune-related adverse events (cirAEs) occur in up to 40% of immune checkpoint inhibitor (ICI) recipients. However, the association of cirAEs with survival remains unclear. OBJECTIVE: To investigate the association of cirAEs with survival among ICI recipients. METHODS: ICI recipients were identified from the Mass General Brigham healthcare system and Dana-Farber Cancer Institute. Patient charts were reviewed for cirAE development within 2 years after ICI initiation. Multivariate time-varying Cox proportional hazards models, adjusted for age, sex, race/ethnicity, Charlson Comorbidity Index, ICI type, cancer type, and year of ICI initiation were utilized to investigate the impact of cirAE development on overall survival. RESULTS: Of the 3731 ICI recipients, 18.1% developed a cirAE. Six-month landmark analysis and time-varying Cox proportional hazards models demonstrated that patients who developed cirAEs were associated with decreased mortality (hazardratio [HR] = 0.87, P = .027), particularly in patients with melanoma (HR = 0.67, P = .003). Among individual morphologies, lichenoid eruption (HR = 0.51, P < .001), psoriasiform eruption (HR = 0.52, P = .005), vitiligo (HR = 0.29, P = .007), isolated pruritus without visible manifestation of rash (HR = 0.71, P = .007), acneiform eruption (HR = 0.34, P = .025), and non-specific rash (HR = 0.68, P < .001) were significantly associated with better survival after multiple comparisons adjustment. LIMITATIONS: Retrospective design; single geography. CONCLUSION: CirAE development is associated with improved survival among ICI recipients, especially patients with melanoma.

Influence of melanoma type on incidence and downstream implications of cutaneous immune-related adverse events in the setting of immune checkpoint inhibitor therapy.

BACKGROUND: Emerging evidence suggests that cutaneous immune-related adverse events (cirAEs) are associated with a survival benefit in the setting of advanced melanoma treated with immune checkpoint inhibitor (ICI) therapy. Previous studies have not examined the role of melanoma subtypes on cirAE development and downstream therapeutic outcomes. OBJECTIVE: Examine the impact of melanoma subtypes on cirAE onset and survival among ICI recipients. METHODS: Retrospective multi-institutional cohort study. Multivariate time-series regressions were utilized to assess relationships between melanoma subtype, cirAE development, and survival. RESULTS: Among 747 ICI recipients, 236 (31.6%) patients developed a cirAE. Patients with acral melanoma were less likely to develop a cirAE (hazard ratio [HR] = 0.41, P = .016) compared to patients with nonacral cutaneous melanoma. Across all melanoma subtypes, cirAEs were associated with reduced mortality (HR = 0.76, P = .042). Patients with acral (HR = 2.04, P = .005), mucosal (HR = 2.30, P < .001), and uveal (HR = 4.09, P < .001) primaries exhibited the worst survival. LIMITATIONS: Retrospective cohort study. CONCLUSION: This is the first study to demonstrate differences in cirAE development among melanoma subtypes. The presence of cirAEs was associated with better survival. Further, the lower incidence of cirAEs may be a marker of immunotherapy response, which is reflected in the association between acral melanoma and mortality.

Cutaneous immune-related adverse events are associated with longer overall survival in advanced cancer patients on immune checkpoint inhibitors: a multi-institutional cohort study.

Background: Cutaneous immune-related adverse events (cirAEs) occur in up to 40% of immune checkpoint inhibitor (ICI) recipients. However, the association of cirAEs with survival remains unclear. Objective: To investigate the association of cirAEs with survival among ICI recipients. Methods: ICI recipients were identified from the Mass General Brigham healthcare system (MGB) and Dana-Farber Cancer Institute (DFCI). Patient charts were reviewed for cirAE development within 2 years after ICI initiation. Multivariate time-varying Cox proportional hazards models, adjusted for age, sex, race/ethnicity, Charlson Comorbidity Index, ICI type, cancer type, and year of ICI initiation were utilized to investigate the impact of cirAE development on overall survival. Results: Of the 3,731 ICI recipients, 18.1% developed a cirAE. 6-month landmark analysis and time-varying Cox proportional hazards models demonstrated that patients who developed cirAEs were associated with decreased mortality (HR=0.87,p=0.027), particularly in melanoma patients (HR=0.67,p=0.003). Among individual morphologies, lichenoid eruption (HR=0.51,p<0.001), psoriasiform eruption (HR=0.52,p=0.005), vitiligo (HR=0.29,p=0.007), isolated pruritus without visible manifestation of rash (HR=0.71,p=0.007), acneiform eruption (HR =0.34,p=0.025), and non-specific rash (HR=0.68, p<0.001) were significantly associated with better survival after multiple comparisons adjustment. Limitations: Retrospective design; single geography. Conclusion: CirAE development is associated with improved survival among ICI recipients, especially melanoma patients. Capsule Summary: Patients on immune checkpoint inhibitors (ICIs) who developed cutaneous immune-related adverse events (cirAEs) had favorable outcomes. This was especially notable for melanoma patients who had cirAEs, both those with vitiligo and other morphologies.Development of cirAEs in ICI-treated patients can be used to prognosticate survival and guide treatment decisions.

Association of Cutaneous Immune-Related Adverse Events With Increased Survival in Patients Treated With Anti-Programmed Cell Death 1 and Anti-Programmed Cell Death Ligand 1 Therapy.

IMPORTANCE: Despite the efficacy of immune checkpoint inhibitors (ICIs), cutaneous immune-related adverse events (cirAEs) occur in 20% to 40% of all treated patients. To our knowledge, little is known about the predictive value of these cutaneous eruptions and their subtypes regarding cancer survival. OBJECTIVE: To determine the association of developing cirAEs following treatment with anti-programmed cell death 1 (PD-1) or anti-programmed cell death ligand 1 (PD-L1) therapy with patient survival. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study used data from the TriNetX Diamond Network, a database of health records and claims data from more than 200 million US and European patients, to conduct a population-level cohort analysis. The study included 7008 eligible patients who developed cirAEs after treatment with anti-PD-1 or anti-PD-L1 therapy for malignant neoplasms of digestive organs, bronchus or lung, melanoma of skin, and urinary tract who were identified through the TriNetX Diamond Network along with 7008 matched controls. EXPOSURES: Development of cirAEs within 6 months following anti-PD-1 or anti-PD-L1 therapy. MAIN OUTCOMES AND MEASURES: A 6-month analysis using a Cox proportional hazards model was performed to determine the association of cirAEs with overall survival after adjusting for demographic characteristics, cancer type, and cancer stage. RESULTS: A total of 7008 patients (3036 women [43.3%]; mean [SD] age, 68.2 [11.2] years) were matched to 7008 (3044 women [43.4%]; mean [SD] age, 68.3 [11.1] years) controls. Pruritus (hazard ratio [HR], 0.695; 95% CI, 0.602-0.803; P < .001), drug eruption (HR, 0.755; 95% CI, 0.635-0.897; P = .001), xerosis (HR, 0.626; 95% CI, 0.469-0.834; P = .001), nonspecific rashes (HR, 0.704; 95% CI, 0.634-0.781; P < .001), and appearance of any cirAE (HR, 0.778; 95% CI, 0.726-0.834; P < .001) were significantly protective of mortality using a Benjamini-Hochberg correction with a significance level of .05. Additionally, psoriasis (HR, 0.703; 95% CI, 0.497-0.994; P = .045) and lichen planus/lichenoid dermatitis (HR, 0.511; 95% CI, 0.279-0.939; P = .03) were significant. Eczematous dermatitis (HR, 0.612; 95% CI, 0.314-1.195), vitiligo (HR, 0.534; 95% CI, 0.254-1.123), bullous pemphigoid (HR, 0.524; 95% CI, 0.140-1.956), and Grover disease (HR, 0.468; 95% CI, 0.115-1.898) were all associated with strong protective clinical effects. CONCLUSIONS AND RELEVANCE: The results of this cohort study suggest that the development of cirAEs is strongly associated with response to ICI therapy and patient survival.

Post-chemotherapy Laparoscopic Retroperitoneal Lymph Node Dissection for Mixed Malignant Germ Cell Testicular Tumors.

INTRODUCTION: Retroperitoneal lymph node dissection (RPLND) is performed to treat residual disease following chemotherapy for stage II and III testicular cancer. Significant morbidity can be associated with open RPLND. As such, laparoscopic techniques have been demonstrated to be safe and effective in select cases. Outcomes following post-chemotherapy laparoscopic RPLND for mixed malignant germ cell testicular tumors (MMGCT) are limited in the literature. PATIENTS AND METHODS: We performed a retrospective chart review for patients who underwent laparoscopic RPLND at our institution for MMGCT from May 2006 to October 2016. Patient clinical data and perioperative and oncologic outcomes were recorded. RESULTS: Twenty-three patients underwent post-chemotherapy laparoscopic RPLND. Thirty-five percent (8/23) underwent bilateral template dissection, whereas 65% (15/23) underwent a modified unilateral template dissection. Robotic assistance was utilized in 22% (5/23) of cases. Bilateral template was inferior to unilateral template RPLND in operative time, estimated blood loss, open conversion rate, length of hospital stay, and complication rate. The mean follow-up was 35.1 months and 43.3 months for the bilateral and unilateral template groups, respectively. The mean lymph node yield and recurrence rate were similar between the 2 cohorts. One recurrence of mature teratoma was noted 67 months after unilateral laparoscopic RPLND. CONCLUSIONS: In select patients, laparoscopic RPLND for stage II and III MMGCT is safe and effective in the post-chemotherapy setting. Bilateral template laparoscopic RPLND was associated with inferior perioperative outcomes, but similar oncologic outcomes compared with unilateral template. Patients requiring bilateral template RPLND should be considered for an open approach.

The Accuracy of Prostate Magnetic Resonance Imaging Interpretation: Impact of the Individual Radiologist and Clinical Factors.

OBJECTIVE: To compare test performance of multiparametric magnetic resonance imaging (mpMRI) for detection of prostate cancer between individual radiologists using the Prostate Imaging Reporting and Data System (PI-RADS) and to identify clinical factors that may predict test performance. MATERIALS AND METHODS: We examined our database of consecutive men who received prostate mpMRI prior to biopsy between September 2014 and December 2016 (n = 459). Test performance (eg, sensitivity, specificity, positive predictive value [PPV] and negative predictive value) were defined with PI-RADS classification 4 or 5 considered test positive and Gleason score ≥7 on biopsy from any targeted core considered outcome positive. Multivariate logistic regression was performed to identify clinical variables that affect test performance. RESULTS: No significant differences in test performance were found among individual radiologists. Prior biopsy (odds ratio [OR] 0.10, P = .01), radiologist experience >500 prostate mpMRI (OR 0.18, P = .04), transition zone location (OR 0.10, P = .04), and posterior location (OR 0.04, P = .03) were predictors of diminished sensitivity. Location of the mpMRI lesion in the TZ was a predictor of improved specificity (OR 2.53, P = .04). Increasing age (OR 1.07, P <.01) and prostate-specific antigen (OR 1.10, P <.01) predicted increased PPV, while prior biopsy predicted decreased PPV (OR 0.50, P <.01). CONCLUSION: Although variation exists in test performance among individual radiologists using PI-RADS, significant differences were not observed. Additional prostate mpMRI experience was not beneficial in improving accuracy of interpretation. Nonmodifiable patient variables-including prostate lesion location, prior biopsy history, prostate-specific antigen, and age-are predictive of prostate mpMRI test performance.

Gastric Acid Secretion from Parietal Cells Is Mediated by a Ca2+ Efflux Channel in the Tubulovesicle.

Gastric acid secretion by parietal cells requires trafficking and exocytosis of H/K-ATPase-rich tubulovesicles (TVs) toward apical membranes in response to histamine stimulation via cyclic AMP elevation. Here, we found that TRPML1 (ML1), a protein that is mutated in type IV mucolipidosis (ML-IV), is a tubulovesicular channel essential for TV exocytosis and acid secretion. Whereas ML-IV patients are reportedly achlorhydric, transgenic overexpression of ML1 in mouse parietal cells induced constitutive acid secretion. Gastric acid secretion was blocked and stimulated by ML1 inhibitors and agonists, respectively. Organelle-targeted Ca2+ imaging and direct patch-clamping of apical vacuolar membranes revealed that ML1 mediates a PKA-activated conductance on TV membranes that is required for histamine-induced Ca2+ release from TV stores. Hence, we demonstrated that ML1, acting as a Ca2+ channel in TVs, links transmitter-initiated cyclic nucleotide signaling with Ca2+-dependent TV exocytosis in parietal cells, providing a regulatory mechanism that could be targeted to manage acid-related gastric diseases.