Survival and treatment outcomes in patients with leptomeningeal disease from metastatic melanoma.

Background: Melanoma leptomeningeal disease (LMD) has a poor prognosis. However, the management of patients with advanced melanoma has evolved with time, including those with LMD. We reviewed a large cohort of melanoma LMD patients to assess factors associated with survival. Methods: Retrospective clinical data was collected on patients diagnosed with LMD at MD Anderson Cancer Center from 2015 to 2020. Overall survival (OS) was determined from LMD diagnosis to date of death or last follow-up. The Kaplan-Meier method and log-rank test were used to estimate OS and to assess univariate group differences, respectively. Multivariable associations of survival with variables of interest were determined using Cox proportional hazards regression models. Results: A total of 172 patients were identified. The median age at LMD diagnosis was 53 (range 20-79) years, and all patients had radiographic evidence of LMD on magnetic resonance imaging of either brain or spine. In total 143 patients previously received systemic therapy (83%), with a median of 2 prior treatments (range 0-5). 81 patients (47%) had concurrent uncontrolled systemic disease and 80 patients (53%) had elevated serum LDH at the time of diagnosis. With a median follow-up of 4.0 months (range 0.1-65.3 months), median OS for all patients from LMD diagnosis was 4.9 months. Patients (n = 45) who received intrathecal therapy or systemic immunotherapy for LMD had a median OS of 8.0 months and 10.2 months, respectively. On multivariable analysis, decreased performance status, positive CSF cytology, elevated LDH, and whole brain radiation were associated with worse OS. Conclusions: Despite many advances in therapeutic options, the outcomes of melanoma patients with LMD remains poor. However, a subset of patients appears to derive benefit from LMD-directed treatment.

Keratosis Pilaris-Like Reaction Associated With Chromatin Remodeling Complex Inhibition in Uveal Melanoma.

This case series describes a constellation of novel adverse reactions in 3 of 9 patients with uveal melanoma receiving treatment targeting activity of the Brahma-associated factor chromatin remodeling complex.

Utility of next-generation sequencing in the diagnosis of metastatic melanoma: A case report.

During routine dermatologic examination, a 77-year-old male was noted to have a firm blue subcutaneous nodule on his right lateral upper back. His past medical history included metastatic melanoma of unknown primary involving right and left axillary lymph nodes, treated with ipilimumab/nivolumab with complete response, and subsequent primary uveal melanoma. The subcutaneous nodule was located near his previous right axillary scar for metastatic melanoma. Excision of the nodule showed a plexiform neoplasm involving mid and deep dermis composed of spindle and epithelioid atypical cells admixed with numerous melanophages. Central necrosis was present. Immunohistochemical studies revealed the tumor cells to be diffusely positive for HMB45, with retained expression of BAP1 and p16. The tumor cells were negative for PRAME, nuclear expression of ß-catenin, LEF1, and BRAF V600E. Molecular studies demonstrated BAP1 and GNA11 somatic mutations, a profile different from that exhibited by his prior melanoma. Collectively, these data were interpreted as a metastasis from uveal melanoma and not a recurrence of his metastatic likely cutaneous melanoma after complete response to immunotherapy. This case emphasizes the importance of molecular studies for definitive diagnosis in challenging clinical situations, especially when there is discordance among histopathological, immunohistochemical, and molecular studies. Integration of clinical, histopathological, and molecular features is warranted.

The Nasal Microarchitecture: How Does Tracheostomy Affect it?

This study aims to evaluate the histological changes in the nasal mucosa post Tracheostomy. A prospective observational study was done on 30 patients undergoing Tracheostomy after obtaining written informed consent from patients/legally accepted representatives. Prior to Tracheostomy, anterior rhinoscopy was done, and findings were noted; nasal mucosal biopsy was obtained from the inferior turbinate. The patients enrolled were followed up for four weeks, and in the patients still having Tracheostomy, repeat inferior turbinate biopsies were taken and compared. Statistically significant atrophy of lining epithelium was seen in 80% of the subjects, i.e., pseudostratified lining epithelium at Baseline with multilayered appearance changed to a single layer of flattened cells at follow-up. There was also a marked reduction in the number of seromucinous glands in the stroma at follow-up in 80% of the subjects. Additionally, fibrosis in the stroma was noted in 43.3% of subjects at follow-up. The results from this study indicate that Tracheostomy, likely as a result of nasal airflow deprivation, brings about significant changes in the microanatomy of the nasal airway. The extent of this causation and its implication in nasal pathology must be studied in larger populations with extended follow-up periods.

Imipridones inhibit tumor growth and improve survival in an orthotopic liver metastasis mouse model of human uveal melanoma.

Purpose: Uveal melanoma (UM) is a highly aggressive disease with very few treatment options. We previously demonstrated that mUM is characterized by high oxidative phosphorylation (OXPHOS). Here we tested the anti-tumor, signaling and metabolic effects of imipridones, CLPP activators which reduce OXPHOS indirectly and have demonstrated safety in patients. Experimental Design: We assessed CLPP expression in UM patient samples. We tested the effects of imipridones (ONC201, ONC212) on the growth, survival, signaling and metabolism of UM cell lines in vitro, and for therapeutic effects in vivo in UM liver metastasis models. Results: CLPP expression was confirmed in primary and mUM patient samples. ONC201/212 treatment of UM cell lines in vitro decreased OXPHOS effectors, inhibited cell growth and migration, and induced apoptosis. ONC212 increased metabolic stress and apoptotic pathways, inhibited amino acid metabolism, and induced cell death-related lipids. ONC212 also decreased tumor burden and increased survival in vivo in two UM liver metastasis models. Conclusion: Imipridones are a promising strategy for further testing and development in mUM.

Long-term outcomes (beyond 5 years) of liver transplant recipients-A transatlantic multicenter study.

The long-term (>5 y) outcomes following liver transplantation (LT) have not been extensively reported. The aim was to evaluate outcomes of LT recipients who have survived the first 5 years. A multicenter retrospective analysis of prospectively collected data from 3 high volume LT centers (Dallas-USA, Birmingham-UK, and Barcelona-Spain) was undertaken. All adult patients, who underwent LT since the inception of the program to December 31, 2010, and survived at least 5 years since their LT were included. Patient survival was the primary outcome. A total of 3682 patients who survived at least 5 years following LT (long-term survivors) were included. Overall, median age at LT was 52 years (IQR 44-58); 53.1% were males; and 84.6% were Caucasians. A total of 49.4% (n=1820) died during a follow-up period of 36,828 person-years (mean follow-up 10 y). A total of 80.2% (n=1460) of all deaths were premature deaths. Age-standardized all-cause mortality as compared to general population was 3 times higher for males and 5 times higher for females. On adjusted analysis, besides older recipients and older donors, predictors of long-term mortality were malignancy, cardiovascular disease, and dialysis. Implementation of strategies such as noninvasive cancer screening, minimizing immunosuppression, and intensive primary/secondary cardiovascular prevention could further improve survival.

Clarification of the margin status by the multidisciplinary tumor board following transoral robotic surgery for p16 positive oropharyngeal squamous cell carcinoma.

Objectives: Margin status interpretation following transoral robotic surgery (TORS) for oropharyngeal squamous cell carcinoma (OPSCC) is challenging. This study aims to assess the discrepancy between status of margins as reported by the pathologist versus as determined by multi-disciplinary team review (MDTB). Methods: A retrospective study of 57 patients with OPSCC who underwent TORS from January 2010 to December 2016 was conducted. Our primary outcome measure was the discrepancy between the surgical specimen margins as described in the pathology report versus final margin status that was determined after the multi-disciplinary team discussion. Fisher's exact test was used. Results: Based on the pathologist-report, 29 subjects (51%) had positive margins, compared to 2 (4%) after multi-disciplinary team discussion. Receipt of chemotherapy correlated with final margin status as determined by MDTB, not with initial main specimen margins (p = .02 and p = .08, respectively). With a median follow up of 28.4 months, two subjects (4%) had loco-regional recurrence. Conclusion: Following TORS, there was a significant discrepancy between status of margins as reported by the pathologist versus as determined by MDTB review. Chemotherapy was avoided in 93.1% of cases that were originally reported as positive margins by the pathologist with an acceptably low recurrence rate. Level of evidence: 4.

Multicentre analysis of nucleic acid quantification using aqueous humour liquid biopsy in uveal melanoma: implications for clinical testing.

OBJECTIVE: Uveal melanoma (UM) tumour biopsy is limited by size and intratumour heterogeneity. We explored the potential of aqueous humour (AH) liquid biopsy for UM by quantifying analytes in samples collected at diagnosis and after brachytherapy to look for clinical correlations with tumour features. DESIGN: Case-series study. PARTICIPANTS: Sixty-six UM patients and 16 control subjects from a tertiary care hospital. METHODS: The study included 119 UM AH samples and 16 control samples analyzed for unprocessed analytes (i.e., dsDNA, miRNA, and protein) using Qubit fluorescence assays. RESULTS: Analytes were widely quantifiable among available UM AH samples (dsDNA: 94.1%; miRNA: 88.0%; protein: 95.2%) at significantly higher concentrations than among control samples (dsDNA, p = 0.008; miRNA, p < 0.0001; protein, p = 0.007). In samples taken at diagnosis, concentrations were higher at more advanced American Joint Cancer Commission stages; when comparing most advanced stage III with least advanced stage I, median dsDNA was 4 times greater (p < 0.0001), miRNA was 2 times greater (p = 0.001), and protein was 3 times greater (p < 0.0001). Analytes were quantifiable in >70% of diagnostic samples from eyes with tumours <2 mm tall. Height had a positive association with diagnostic analyte concentrations (dsDNA: R = 0.43, p = 0.0007; miRNA: R = 0.35, p = 0.01; protein: R = 0.39, p = 0.005). Samples taken after brachytherapy showed significantly higher concentrations than diagnostic samples (p < 0.01 for all). CONCLUSIONS: UM AH is a rich repository of analytes. Samples from eyes with more advanced stage and larger tumours had higher concentrations, though analytes also were quantifiable in eyes with smaller, less advanced tumours. Future analysis of AH analytes may be informative in the pursuit of personalized UM treatments.

FlatWire Sternal Closure System technique for median sternotomy closure.

Sternal closure after median sternotomy traditionally uses a stainless steel wire cerclage. Sternal wires are placed through or around the sternum, and the wire ends are twisted together to bring the sternum back together. Complications of this technique include sternal instability, dehiscence, non-union, and increased pain. Compared to traditional wire cerclage, the Figure 8 FlatWire Sternal Closure System has been demonstrated to be stronger and significantly reduce sternal cut-through and postoperative pain. There was no significant difference in hospital length of stay or mean hospitalization cost. Operative time was slightly longer in the FlatWire group, but this difference has been attributed to the learning curve of mastering the FlatWire technique. This article and supplemental video will demonstrate the technique of FlatWire Sternal Closure System. Briefly, the FlatWire is placed around the sternum, and the FlatWire end is fed through the security box. Once all of the wires are placed, the Figure 8 tensioning device is used to tighten each wire through the security box to the appropriate tensile force. Next, the FlatWires are rotated 90 degrees to hold the sternal position temporarily. Once sternal approximation is achieved, each FlatWire is twisted 120 degrees, and any excess length of the FlatWire is clipped.

Proceedings from the Melanoma Research Foundation Mucosal Melanoma Meeting (December 16, 2022, New York, USA).

Mucosal melanoma remains a rare cancer with high mortality and a paucity of therapeutic options. This is due in significant part to its low incidence leading to limited patient access to expert care and downstream clinical/basic science data for research interrogation. Clinical challenges such as delayed and at times inaccurate diagnoses, and lack of consensus tumor staging have added to the suboptimal outcomes for these patients. Clinical trials, while promising, have been difficult to activate and accrue. While individual institutions and investigators have attempted to seek solutions to such problems, international, national, and local partnership may provide the keys to more efficient and innovative paths forward. Furthermore, a mucosal melanoma coalition would provide a potential network for patients and caregivers to seek expert opinion and advice. The Melanoma Research Foundation Mucosal Melanoma Meeting (December 16, 2022, New York, USA) highlighted the current clinical challenges faced by patients, providers, and scientists, identified current and future clinical trial investigations in this rare disease space, and aimed to increase national and international collaboration among the mucosal melanoma community in an effort to improve patient outcomes. The included proceedings highlight the clinical challenges of mucosal melanoma, global clinical trial experience, basic science advances in mucosal melanoma, and future directions, including the creation of shared rare tumor registries and enhanced collaborations.

Development of artificial intelligence tools for invasive Doppler-based coronary microvascular assessment.

Aims: Coronary flow reserve (CFR) assessment has proven clinical utility, but Doppler-based methods are sensitive to noise and operator bias, limiting their clinical applicability. The objective of the study is to expand the adoption of invasive Doppler CFR, through the development of artificial intelligence (AI) algorithms to automatically quantify coronary Doppler quality and track flow velocity. Methods and results: A neural network was trained on images extracted from coronary Doppler flow recordings to score signal quality and derive values for coronary flow velocity and CFR. The outputs were independently validated against expert consensus. Artificial intelligence successfully quantified Doppler signal quality, with high agreement with expert consensus (Spearman's rho: 0.94), and within individual experts. Artificial intelligence automatically tracked flow velocity with superior numerical agreement against experts, when compared with the current console algorithm [AI flow vs. expert flow bias -1.68 cm/s, 95% confidence interval (CI) -2.13 to -1.23 cm/s, P < 0.001 with limits of agreement (LOA) -4.03 to 0.68 cm/s; console flow vs. expert flow bias -2.63 cm/s, 95% CI -3.74 to -1.52, P < 0.001, 95% LOA -8.45 to -3.19 cm/s]. Artificial intelligence yielded more precise CFR values [median absolute difference (MAD) against expert CFR: 4.0% for AI and 7.4% for console]. Artificial intelligence tracked lower-quality Doppler signals with lower variability (MAD against expert CFR 8.3% for AI and 16.7% for console). Conclusion: An AI-based system, trained by experts and independently validated, could assign a quality score to Doppler traces and derive coronary flow velocity and CFR. By making Doppler CFR more automated, precise, and operator-independent, AI could expand the clinical applicability of coronary microvascular assessment.

Ipilimumab with or without nivolumab in PD-1 or PD-L1 blockade refractory metastatic melanoma: a randomized phase 2 trial.

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 .

T-cell receptor beta variable gene polymorphism predicts immune-related adverse events during checkpoint blockade immunotherapy.

BACKGROUND: Immune checkpoint inhibitors have revolutionized cancer treatment. However, they are associated with a unique spectrum of side effects, called immune-related adverse events (irAEs), which can cause significant morbidity and quickly progress to severe or life-threatening events if not treated promptly. Identifying predictive biomarkers for irAEs before immunotherapy initiation is therefore a critical area of research. Polymorphisms within the T-cell receptor beta (TCRB) variable (TRBV) gene have been implicated in autoimmune disease and may be mechanistically linked to irAEs. However, the repetitive nature of the TCRB locus and incomplete genome assembly has hampered the evaluation of TRBV polymorphisms in the past. PATIENTS AND METHODS: We used a novel method for long-amplicon next generation sequencing of rearranged TCRB chains from peripheral blood total RNA to evaluate the link between TRBV polymorphisms and irAEs in patients treated with immunotherapy for cancer. We employed multiplex PCR to create amplicons spanning the three beta chain complementarity-determining regions (CDR) regions to enable detection of polymorphism within the germline-encoded framework and CDR1 and CDR2 regions in addition to CDR3 profiling. Resultant amplicons were sequenced via the Ion Torrent and TRBV allele profiles constructed for each individual was correlated with irAE annotations to identify haplotypes associated with severe irAEs (≥ grade 3). RESULTS: Our study included 81 patients who had irAEs when treated with immunotherapy for cancer. By using principal component analysis of the 81 TRBV allele profiles followed by k-means clustering, we identified six major TRBV haplotypes. Strikingly, we found that one-third of this cohort possessed a TRBV allele haplotype that appeared to be protective against severe irAEs. CONCLUSION: The data suggest that long-amplicon TCRB repertoire sequencing can potentially identify TRBV haplotype groups that correlate with the risk of severe irAEs. Germline-encoded TRBV polymorphisms may serve as a predictive biomarker of severe irAEs.

Presence of Circulating Tumor Cells Predates Imaging Detection of Relapse in Patients with Stage III Melanoma.

Stage III melanoma includes nodal metastasis or in-transit disease. Five-year survival rates vary between 32% and 93%. The identification of high-risk patients is important for clinical decision making. We demonstrated previously that ≥1 circulating tumor cells (CTCs) at baseline was associated with recurrence. In this study, we investigated how frequently CTCs were identified prior to radiologically detected recurrence. Stage III patients (n = 325) had imaging at baseline and q 3 months. Baseline and q 6-12 months blood draws (7.5 mL) were performed to identify CTCs up to 3.5 years from diagnosis. CTC assessment was performed using the immunomagnetic capture of CD146-positive cells and anti-MEL-PE. The presence of one or more CTCs was considered positive. We analyzed the cohort of patients with relapse confirmed by radiologic imaging. CTC collection dates were assessed to determine the lead time for CTC detection. CTC-negative patients were significantly less likely to relapse compared to patients positive for CTCs (p-value < 0.001). Within the 325-patient cohort, 143 patients (44%) had recurrence, with a median follow-up of 52 months from diagnosis. The cohort (n = 143) with positive imaging and CTC results revealed 76% of patients (108/143) had CTC+ results before the radiological identification of relapse. The median time between positive CTC and positive imaging was 9 months. CTCs were positive in >75% of patients prior to relapse at a median of 9 months before radiologic detection.

Immune Checkpoint Inhibitors Suppress Hepatitis C Virus Replication in Infected Patients With Solid Tumors.

INTRODUCTION: Data are scarce regarding the virologic impact and safety of immune checkpoint inhibitors (ICI) in patients with chronic hepatitis C virus (HCV) infection. We examined the virologic impact of ICI in HCV-infected patients with solid tumors and their safety. METHODS: HCV-infected patients with solid tumor treated with ICI at our institution between April 26, 2016, and January 5, 2022, were enrolled in a prospective observational study. The primary outcomes were ICI-induced changes in HCV viremia (HCV inhibition and HCV reactivation) and safety of ICI. RESULTS: We enrolled 52 consecutive patients with solid tumors treated with ICI. Most were men (41; 79%), White (31; 59%), without cirrhosis (34; 65%), and with HCV genotype 1 (40; 77%). Four patients (7.7%) experienced HCV inhibition while receiving ICI including 1 patient who developed undetectable viremia for 6 months in the absence of direct-acting antivirals (DAA). Two patients (4%) developed HCV reactivation, both while receiving immunosuppressive therapy for ICI-related toxic effects. Adverse events occurred in 36 patients (69%), and 39 of the 47 adverse events (83%) were grade 1-2. Grade 3-4 adverse events occurred in 8 patients (15%), and in all cases, they were related to ICI, not to HCV. No HCV-associated liver failure or death occurred. DISCUSSION: Inhibition of HCV replication with virologic cure can develop in patients receiving ICI without DAA. HCV reactivation occurs primarily in patients receiving immunosuppressants for ICI-related toxic effects. ICI are safe in HCV-infected patients with solid tumors. Chronic HCV infection should not be considered a contraindication for ICI therapy.