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In this randomized phase 2 trial, blockade of cytotoxic T-lymphocyte protein 4 (CTLA-4) with continuation of programmed death protein 1 (PD-1) blockade in patients with metastatic melanoma who had received front-line anti-PD-1 or therapy against programmed cell death 1 ligand 1 and whose tumors progressed was tested in comparison with CTLA-4 blockade alone. Ninety-two eligible patients were randomly assigned in a 3:1 ratio to receive the combination of ipilimumab and nivolumab, or ipilimumab alone. The primary endpoint was progression-free survival. Secondary endpoints included the difference in CD8 T cell infiltrate among responding and nonresponding tumors, objective response rate, overall survival and toxicity. The combination of nivolumab and ipilimumab resulted in a statistically significant improvement in progression-free survival over ipilimumab (hazard ratio = 0.63, 90% confidence interval (CI) = 0.41–0.97, one-sided P  = 0.04). Objective response rates were 28% (90% CI = 19–38%) and 9% (90% CI = 2–25%), respectively (one-sided P  = 0.05). Grade 3 or higher treatment-related adverse events occurred in 57% and 35% of patients, respectively, which is consistent with the known toxicity profile of these regimens. The change in intratumoral CD8 T cell density observed in the present analysis did not reach statistical significance to support the formal hypothesis tested as a secondary endpoint. In conclusion, primary resistance to PD-1 blockade therapy can be reversed in some patients with the combination of CTLA-4 and PD-1 blockade. Clinicaltrials.gov identifier: NCT03033576 . Patients with stage 4 or unresectable stage 3 melanoma refractory to first-line anti-programmed death protein 1 (PD-1) or anti-programmed cell death 1 ligand 1 have longer progression-free survival when treated with a combination of anti-cytotoxic T-lymphocyte protein 4 (CTLA-4) and anti-PD-1 versus anti-CTLA-4 alone.

Adaptive immune responses contribute to the pathogenesis of melanoma by facilitating immune evasion. V-domain Ig suppressor of T-cell activation (VISTA) is a potent negative regulator of T-cell function and is expressed at high levels on monocytes, granulocytes, and macrophages, and at lower densities on T-cell populations within the tumor microenvironment. In this study, 85 primary melanoma specimens were selected from pathology tissue archives and immunohistochemically stained for CD3, PD-1, PD-L1, and VISTA. Pearson’s correlation coefficients identified associations in expression between VISTA and myeloid infiltrate (r = 0.28, p = 0.009) and the density of PD-1+ inflammatory cells (r = 0.31, p = 0.005). The presence of VISTA was associated with a significantly worse disease-specific survival in univariate analysis (hazard ratio = 3.57, p = 0.005) and multivariate analysis (hazard ratio = 3.02, p = 0.02). Our findings show that VISTA expression is an independent negative prognostic factor in primary cutaneous melanoma and suggests its potential as an adjuvant immunotherapeutic intervention in the future.

Asthma is a respiratory disorder caused by airway inflammation which may worsen after allergen exposure. Recent cohort studies demonstrate a positive association between skin cancer and asthma or hay fever (allergy to outdoor allergens such as pollen). Nationally-representative data for adults in the United States remains limited. We aimed to characterize skin cancer prevalence among individuals in the United States who have asthma or hay fever. To achieve this aim, we extracted nationwide cross-sectional data from 16,277 adult participants (total survey-weighted sample = 174,765,931) of the Third National Health and Nutrition Examination Survey from 1988 to 1994. This study uses survey-weighted regression to compare the nationwide prevalence of skin cancer among participants with or without a history of asthma or hay fever. Sensitivity analysis examined the influence of sex, 25-hydroxyvitamin D, chronic bronchitis or emphysema, geographical region, urban proximity, and oral glucocorticoid use. Of the included participants, the age-adjusted prevalence of skin cancer was 7.2%, similar to national estimates. Skin cancer prevalence was higher among participants who had asthma with hay fever (adjusted prevalence ratio, 1.79; 95% confidence interval, 1.16, 2.76), but not among participants with asthma only or hay fever only. Similarly, skin cancer prevalence was higher for those with asthma and positive pollen allergen skin prick testing (SPT), but not for those with hay fever and positive pollen SPT. No association was noted between skin cancer and wheezing triggered by pollen. Hay fever or immunoglobulin-E sensitization to pollen may increase skin cancer prevalence among individuals with a history of asthma.

Methods The study received institutional review board approval and included cohorts of lung transplant recipients at a single institution. Factors associated with increased risk of SCC included UAP-V cohort, white race, age between 55 and 62 years, and pre-transplant diagnosis of keratinocyte cancer (data not shown). Characteristics of UCLA Lung Transplant Recipients by Cohort Cohort p-value1 UAP-P (N = 396) UAP-V (N = 176) TAP (N = 180) Age at Transplant, mean (SD) 58.9 (11.4) 59.4 (10.2) 58.2 (12.6) 0.6684 Sex, N (%) 0.4641 Female 169 (42.7) 73 (41.5) 67 (37.2) Male 227 (57.3) 103 (58.5) 113 (62.8) Race, N (%)  < 0.0001 Asian 25 (6.3) 6 (3.4) 7 (3.9) Black 26 (6.6) 9 (5.1) 12 (6.7) Hispanic 119 (30.0) 23 (13.1) 22 (12.2) Other 19 (4.8) 6 (3.4) 5 (2.8) White 207 (52.3) 132 (75.0) 132 (73.3) Missing – – 2 (1.1) Primary Diagnosis, N (%)  < 0.0001 Restrictive Parenchymal Lung Disease 294 (74.2) 118 (67.1) 107 (59.4) Obstructive Lung Disease 41 (10.4) 40 (22.7) 49 (27.2) Cystic Fibrosis/bronchiectasis 24 (6.1) 6 (3.4) 13 (7.2) Pulmonary Vascular Disease 26 (6.6) 2 (1.1) 5 (2.8) Other 10 (2.5) 9 (5.1) 3 (1.7) Missing 1 (0.2) 1 (0.6) 3 (1.7) Induction Type, N (%)  < 0.0001 Anti-thymocyte Globulin 43 (10.9) 51 (29.0) 91 (50.5) Basiliximab 353 (89.1) 121 (68.7) 86 (47.8) Other/none – 3 (1.7) – Missing – 1 (0.6) 3 (1.7) Discharge Antifungal, N (%)  < 0.0001 Voriconazole 4 (1.0) 162 (92.1) 40 (22.2) Posaconazole 358 (90.4) 9 (5.1) 2 (1.1) Isavuconazole 30 (7.6) – – Other2 – 5 (2.8) 16 (8.9) None 4 (1.0) – 122 (67.8) Pre-transplant KC, N (%) 0.0316 Yes 31 (7.8) 8 (4.5) 5 (2.8) No 354 (89.4) 168 (95.5) 175 (97.2) Missing/Unavailable 11 (2.8) – – Post-transplant SCC, N (%) 28 (7.1) 29 (16.5) 34 (18.9)  < 0.0001 Time to First SCC (years), median (IQR) 1.6 (1.7) 1.4 (0.9) 2.8 (1.7)  < 0.0001 Total follow-up time (years), median (IQR) 1.4 (2.1) 1.7 (1.9) 3.9 (4.1)  < 0.0001 SD standard deviation, KC keratinocyte cancer, SCC squamous cell carcinoma, IQR interquartile range 1p−values from chi-square tests for independence (Fisher’s exact when appropriate) for categorical variables, Kruskal–Wallis test for continuous variables 2Other antifungals include itraconazole and fluconazole [See PDF for image] Fig. 1 Cumulative Incidences of First Post-Transplant Squamous Cell Carcinoma by Cohort Discussion The findings of this study indicate that posaconazole may not be associated with an increased risk of post-transplant SCC in lung transplant recipients, while voriconazole may contribute to an elevated risk compared to both posconazole and a cohort with low overall antifungal exposure.