PD-L1 Tumor Expression as a Predictive Biomarker of Immune Checkpoint Inhibitors' Response and Survival in Advanced Melanoma Patients in Brazil.

Immune checkpoint blockade (ICB) agents are prominent immunotherapies for the treatment of advanced melanoma. However, they fail to promote any durable clinical benefit in a large cohort of patients. This study assessed clinical and molecular predictors of ICB response and survival in advanced melanoma. A retrospective analysis was performed on 210 patients treated with PD-1 or CTLA-4 inhibitors at Barretos Cancer Hospital, Brazil. PD-L1 expression was assessed by immunohistochemistry using formalin-fixed paraffin-embedded tumor tissues collected prior to ICB therapy. Patients were divided into responders (complete and partial response and stable disease for more than 6 months) and non-responders (stable disease for less than 6 months and progressive disease). Among them, about 82% underwent anti-PD-1 immunotherapy, and 60.5% progressed after the ICB treatment. Patients that received ICB as first-line therapy showed higher response rates than previously treated patients. Higher response rates were further associated with superficial spreading melanomas and positive PD-L1 expression (>1%). Likewise, PD-L1 positive expression and BRAF V600 mutations were associated with a higher overall survival after ICB therapy. Since ICBs are expensive therapies, evaluation of PD-L1 tumor expression in melanoma patients should be routinely assessed to select patients that are most likely to respond.

Cancer immune profiling unveils biomarkers, immunological pathways, and cell type score associated with glioblastoma patients' survival.

Introduction: Glioblastoma (GBM), isocitrate dehydrogenase (IDH) wild-type (IDH wt), and grade 4 astrocytomas, IDH mutant (IDH mut), are the most common and aggressive primary malignant brain tumors in adults. A better understanding of the tumor immune microenvironment may provide new biomarkers and therapeutic opportunities. Objectives: We aimed to evaluate the expression profile of 730 immuno-oncology-related genes in patients with IDH wt GBM and IDH mut tumors and identify prognostic biomarkers and a gene signature associated with patient survival. Methods: RNA was isolated from formalin-fixed, paraffin-embedded sections of 99 tumor specimens from patients treated with standard therapy. Gene expression profile was assessed using the Pan-Cancer Immune Profiling Panel (Nanostring Technologies, Inc., Seattle, WA, USA). Data analysis was performed using nSolverSoftware and validated in The Cancer Genome Atlas. In addition, we developed a prognostic signature using the cox regression algorithm (Least Absolute Shrinkage and Selection Operator). Results: We found 88 upregulated genes, high immunological functions, and a high macrophage score in IDH wt GBM compared to IDH mut tumors. Regarding IDH wt GBM, we found 24 upregulated genes in short-term survivors (STS) and overexpression of CD274 (programmed death-ligand 1, PD-L1). Immune pathways, CD45, cytotoxic, and macrophage scores were upregulated in STS. Two different prognostic groups were found based on the 12-gene signature (CXCL14, PSEN2, TNFRSF13C, IL13RA1, MAP2K1, TNFSF14, THY1, CTSL, ITGAE, CHUK, CD207, and IFITM1). Conclusion: The elevated expression of immune-oncology-related genes was associated with worse outcome in IDH wt GBM patients. Increased immune functions, CD45, cytotoxic cells, and macrophage scores were associated with a more aggressive phenotype and may provide promising possibilities for therapy. Moreover, a 12 gene-based signature could predict patients' prognosis.

Low MGMT digital expression is associated with a better outcome of IDH1 wildtype glioblastomas treated with temozolomide.

INTRODUCTION: Glioblastoma (GBM) is the deadliest primary brain tumor. The standard treatment consists of surgery, radiotherapy, and temozolomide (TMZ). TMZ response is heterogeneous, and MGMT promoter (MGMTp) methylation has been the major predictive biomarker. We aimed to describe the clinical and molecular data of GBMs treated with TMZ, compare MGMT methylation with MGMT expression, and further associate with patient's outcome. METHODS: We evaluate 112 FFPE adult GBM cases. IDH1 and ATRX expression was analyzed by immunohistochemistry, hotspot TERT promoter (TERTp) mutations were evaluated by Sanger or pyrosequencing, and MGMTp methylation was assessed by pyrosequencing and MGMT mRNA expression using the nCounter® Vantage 3D™ DNA damage and repair panel. RESULTS: Of the 112 GBMs, 96 were IDH1WT, and 16 were IDH1MUT. Positive ATRX expression was found in 91.6% (88/96) of IDHWT and 43.7% (7/16) of IDHMUT. TERTp mutations were detected in 70.4% (50/71) of IDHWT. MGMTp methylation was found in 55.5% (35/63) of IDHWT and 84.6% (11/13) of IDHMUT, and as expected, MGMTp methylation was significantly associated with a better response to TMZ. MGMT expression was inversely correlated with MGMTp methylation levels (- 0.506, p < 0.0001), and MGMT low expression were significantly associated with better patient survival. It was also observed that integrating MGMTp methylation and expression, significantly improved the prognostication value. CONCLUSIONS: MGMT mRNA levels evaluated by digital expression were associated with the outcome of TMZ-treated GBM patients. The combination of MGMT methylation and mRNA expression may provide a more accurate prediction of TMZ response in GBM patients.

Matrix metalloproteinase-1 (MMP-1) and (MMP-8) gene polymorphisms promote increase and remodeling of the collagen III and V in posterior tibial tendinopathy.

Posterior tibial tendinopathy (PTT) can lead to acquired flatfoot in adults. Many patients develop PTT without any identifiable risk factors. Molecular changes in extracellular matrix (ECM) and matrix metalloproteinase (MMP) polymorphism may influence the risk of developing PTT. We aim to investigate the association between matrix metalloproteinase-1 (MMP-1) and (MMP-8) gene polymorphisms with changes in collagen I, III and V in PTT. A case-control study with 22 patients and 5 controls was performed. The MMP-1 (2G/2G) and MMP-8 (T/T) genotypes were determined by PCR-restriction fragment length polymorphism. Tendon specimens were evaluated by a histologic semiquantitative score, immunofluorescence and histomorphometry for collagen I, III and V. Tendon specimens from PTT demonstrated marked distortion of the architecture with necrosis, large basophilic areas with disruption of the normal linear orientation of collagen bundles, infiltration of inflammatory cells, dystrophic calcification and ossification. Under immunofluorescence, PTT tendon specimens showed weak green fluorescence and diffuse distribution of collagen I fibers, but strong fluorescence of collagen III and V. The collagen I fibers were significantly decreased whereas an increase of collagen III and V were found in PTT compared to control groups. In addition, PTT group presented a significant association with MMP-1 and MMP-8 gene polymorphisms. Patients with PTT matrix metalloproteinase-1 (MMP-1) and (MMP-8) gene polymorphisms presented an increase of the collagen III and V ratio, suggesting that the higher proportion in degenerated tendons could contribute to a decrease in the mechanical resistance of the tissue. Still, functional and association studies are needed to elucidate evident roles of MMPs in PTT.