BackgroundImmune related adverse events (irAEs) are common side effects of checkpoint inhibitory (CPI) therapies targeting CTLA-4 and PD-1/PD-L1. Grover’s disease is an uncommon dermatologic ...condition with unclear pathogenesis previously reported as an irAE with ipilimumab.Case PresentationWe report an additional case of ipilimumab-induced Grover’s disease. Interestingly, this dermatologic side effect did not appear with use of anti-PD-1 therapy in our patient. Immune analysis was performed and suggests a possible role of Th2 cells in its patholgenesis.ConclusionThis case suggests that Grover's disease is an irAE induced by Ipilimumab. Our immune analysis suggests that Th2 cells may be pathogenic mediators which warrants further study.
The gut microbiome modulates the immune system and responses to immunotherapy in patients with late-stage melanoma. It is unknown whether fecal microbiota profiles differ between healthy individuals ...and patients with melanoma or if microbiota profiles differ among patients with different stages of melanoma. Defining gut microbiota profiles in individuals without melanoma and those with early-stage and late-stage melanoma may reveal features associated with disease progression.
To characterize and compare gut microbiota profiles between healthy volunteers and patients with melanoma and between patients with early-stage and late-stage melanoma.
This single-site case-control study took place at an academic comprehensive cancer center. Fecal samples were collected from systemic treatment-naive patients with stage I to IV melanoma from June 1, 2015, to January 31, 2019, and from healthy volunteers from June 1, 2021, to January 31, 2022. Patients were followed up for disease recurrence until November 30, 2021.
Fecal microbiota was profiled by 16S ribosomal RNA sequencing. Clinical and pathologic characteristics, treatment, and disease recurrence were extracted from electronic medical records. Fecal microbiome diversity, taxonomic profiles and inferred functional profiles were compared between groups.
A total of 228 participants were enrolled (126 men 55.3%; median age, 59 range, 21-90 years), including 49 volunteers without melanoma, 38 patients with early-stage melanoma (29 with stage I or melanoma in situ and 9 with stage II), and 141 with late-stage melanoma (66 with stage III and 75 with stage IV). Community differences were observed between patients with melanoma and volunteers. Patients with melanoma had a higher relative abundance of Fusobacterium compared with controls on univariate analysis (0.19% vs 0.003%; P < .001), but this association was attenuated when adjusted for covariates (log2 fold change of 5.18 vs controls; P = .09). Microbiomes were distinct between patients with early-stage and late-stage melanoma. Early-stage melanoma had a higher alpha diversity (Inverse Simpson Index 14.6 IQR, 9.8-23.0 vs 10.8 IQR, 7.2-16.8; P = .003), and a higher abundance of the genus Roseburia on univariate analysis (2.4% vs 1.2%; P < .001) though statistical significance was lost with covariate adjustment (log2 fold change of 0.86 vs controls; P = .13). Multiple functional pathways were differentially enriched between groups. No associations were observed between the microbial taxa and disease recurrence in patients with stage III melanoma treated with adjuvant immunotherapy.
The findings of this case-control study suggest that fecal microbiota profiles were significantly different among patients with melanoma and controls and between patients with early-stage and late-stage melanoma. Prospective investigations of the gut microbiome and changes that occur with disease progression may identify future microbial targets for intervention.
Abstract
Background
Treatment options for patients with melanoma brain metastasis (MBM) have changed significantly in the last decade. Few studies have evaluated changes in outcomes and factors ...associated with survival in MBM patients over time. The aim of this study is to evaluate changes in clinical features and overall survival (OS) for MBM patients.
Methods
Patients diagnosed with MBMs from 1/1/2009 to 12/31/2013 (Prior Era; PE) and 1/1/2014 to 12/31/2018 (Current Era; CE) at The University of Texas MD Anderson Cancer Center were included in this retrospective analysis. The primary outcome measure was OS. Log-rank test assessed differences between groups; multivariable analyses were performed with Cox proportional hazards models and recursive partitioning analysis (RPA).
Results
A total of 791 MBM patients (PE, n = 332; CE, n = 459) were included in analysis. Median OS from MBM diagnosis was 10.3 months (95% CI, 8.9–12.4) and improved in the CE vs PE (14.4 vs 10.3 months, P < .001). Elevated serum lactate dehydrogenase (LDH) was the only factor associated with worse OS in both PE and CE patients. Factors associated with survival in CE MBM patients included patient age, primary tumor Breslow thickness, prior immunotherapy, leptomeningeal disease, symptomatic MBMs, and whole brain radiation therapy. Several factors associated with OS in the PE were not significant in the CE. RPA demonstrated that elevated serum LDH and prior immunotherapy treatment are the most important determinants of survival in CE MBM patients.
Conclusions
OS and factors associated with OS have changed for MBM patients. This information can inform contemporary patient management and clinical investigations.
Abstract
PURPOSE
Patients with BRAF-mutant melanoma brain metastases (MBM) continue to have limited overall survival (OS), averaging 4 months, despite advancements in systemic therapies. Our study ...aims to identify patient-specific and treatment-related prognostic factors in BRAF-mutant MBM to inform treatment sequencing and patient selection in future studies and improve patient outcomes.
METHODS
The following data were manually curated from 100 patients with BRAF-mutant MBM diagnosed from 2009-2018, with primary cutaneous melanoma and who received initial MBM treatment at our institution: clinical and demographic, treatment, and OS outcomes. We compared OS with the log rank test using the Python package kaplanmeier between the various clinical, demographic and treatment (including treatment sequence) related variables.
RESULTS
Both elevated lactase dehydrogenase (LDH) was associated with shorter OS (p=0.023), as was leptomeningeal disease (p<0.001). Gender (male vs. female) and initial treatment modality (BRAFi vs. immunotherapy) did not significantly impact OS, (p=0.911 and 0.578, respectively). Breakthrough brain metastases were associated with shorter OS for patients who received initial systemic therapy for MBM (p<0.001), but breakthrough metastases did not significantly impact OS for the whole cohort (p=0.141). Additionally, patients who received BRAFi before MBM diagnosis had shorter OS (p=0.028).
CONCLUSION
In conclusion, we have identified some interesting relationships between OS and the sequencing of treatment modalities, as well as the timing of MBM presentation. These findings support further investigation of treatment sequencing to improve outcomes and the consideration of clinical variables, disease presentation, and treatment history to help refine patient selection for future trials for patients with BRAF-mutant MBM.
Pilot study of intratumoral Kim, Dae Won; Haymaker, Cara; McQuail, Natalie ...
Journal for immunotherapy of cancer,
11/2015, Letnik:
3, Številka:
Suppl 2
Journal Article
BackgroundCryo is an effective modality for pain palliation and local control of soft tissue and bone metastases. Cryo induces necrotic cell death, and combination cryo with anti-CTLA-4 generates ...potent systemic anti-tumor immune responses in preclinical models and small clinical studies. However, the clinical activity of cryo plus checkpoint blockade has not been evaluated in MM. In this pilot study, we report the safety and efficacy of IT cryo and systemic ipilimumab or pembrolizumab in patients with MM.MethodsA single-institution study of 16 MM patients who received IT cryo during systemic therapy of checkpoint blockade. Pts with at least 1 symptomatic lesion amenable for cryo were included. Cryo was performed under ultrasound or CT-guidance. Data of symptom control, toxicity assessment and responses were collected prospectively and continued after 12 weeks of treatment administration. Exploratory immune correlates from peripheral blood and tumor samples were obtained when available.Results12 out of 16 treated pts are evaluable at this time. Median age was 60 years (range: 58-82). All pts received cryo after 1 or 2 doses of either ipilimumab (N=8) or pembrolizumab (N=4). 8 patients had BRAF-V600 mutation and 3 had NRAS mutation. 10 pts had stage-IV disease (M1a: 2, M1b: 1, M1c: 7) and 2 had unresectable stage III. 4 pts were treatment naïve and 8 received 1-5 prior treatments. Objective response rates (ORR) of cryoablated (local) lesions were 75% (9/12), ORR of distant lesions were 40% (4/10) and total ORR (local+distant) were 50% (2 with local lesions only + 4 distant = 6/12) (ipilimumab-63% (5/8), pembrolizumab-25% (1/4)) by RECIST 1.1. Local disease control rates (DCR) were 83%, distant DCR were 60%, and overall DCR were 75%. With a median follow-up of 7 months, the progression-free survival rate at 6 months was 57%. At the time of the analysis, the median progression-free survival and overall survival have not been reached. Grade 3 immune related (irAE) toxicities were observed in 2 patients including colitis and hypophysitis. There were no other grade ¾ irAEs or toxicities related to cryo. Immunological analysis is ongoing.ConclusionsThe study results suggest that the combination of cryo with checkpoint blockades is safe, well-tolerated and could potentially be an effective strategy to enhance the anti-tumor activity. These findings, warrant further evaluation in a larger prospective trial.
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