Complete Response To Tislelizumab In A Muscle-Invasive Urothelial Carcinoma After Surgery Associated With Tumor Mutational Burden High: A Case Report

Muscle-invasive urothelial carcinoma (MIUC) is a highly aggressive urothelial carcinoma. Radical cystectomy (RC) is standard of treatment, but still more than 50% patients with cancer invading the muscularis propria or involving the regional lymph nodes will have metastatic recurrence. In CheckMate274 study, programmed cell death-1 (PD-1) inhibitor nivolumab as adjuvant treatment has shown effective for patients with MIUC. Tislelizumab is an anti-human PD-1 monoclonal IgG4 antibody which was specifically engineered to minimize FcɣR macrophage binding to abrogate antibody-dependent phagocytosis. But there is no report of tislelizumab as adjuvant treatment in MIUC currently. Here, we report a case of MIUC in a patient with PD-L1-negative, microsatellite stable (MSS), high tumor mutational burden (TMB-H) obtained complete response (CR) receiving tislelizumab therapy after surgery. Progression-free survival (PFS) exceeded 6 months since tislelizumab treatment. To our knowledge, this is the first reported case of MIUC patient with PD-L1-negative, MSS and TMB-H who responded well to tislelizumab as adjuvant treatment. However, we still need more studies to assess the efficacy of tislelizumab as adjuvant treatment in MIUC and to confirm that TMB is a predicted biomarker of tislelizumab for efficacy.

Case Report: First Case of Consolidation Immunotherapy After Definitive Chemoradiotherapy in Mediastinal Lymph Node Metastatic Sarcomatoid Carcinoma

Sarcomatoid carcinoma (SC) is a rare lung cancer subtype with poor prognosis and lack of effective treatment regimens. Studies concerning SC indicated common programmed death ligand-1 (PD-L1) overexpression and higher tumor mutational burden, leading to potential benefits from immunotherapy. The present case is the first report employing PD-L1 inhibitor durvalumab following definitive concurrent chemoradiotherapy (cCRT) in a patient with mediastinal lymph node metastatic SC, which was considered as a high probability of pulmonary origin but unclear primary lesion. After the 19-month follow-up, there was neither local recurrence nor distant metastasis. The patient was in a good condition, with the thoracic lesion controlled at Partial response-Response Evaluation Criteria in Solid Tumors (PR-RECIST). Except for grade 2 esophagitis, none of the other adverse events was observed. Our first attempt to adopt the consolidation immunotherapy after cCRT in unresectable locally advanced mediastinal SC exhibited improved local control, manageable safety, and potential survival benefits, representing a novel and promising therapeutic option for SC and encouraging further research exploration of this regimen in the future.

Identification of an at-risk subpopulation with high immune infiltration based on the peroxisome pathway and TIM3 in colorectal cancer

Background Peroxisomes are pivotal metabolic organelles that exist in almost all eukaryote cells. A reduction in numbers and enzymatic activities of peroxisomes was found in colon adenocarcinomas. However, the role of peroxisomes or the peroxisome pathway in colorectal cancer (CRC) is not defined. Methods In the current study, a peroxisome score was calculated to indicate the activity of the peroxisome pathway using gene set variant analysis based on transcriptomic datasets. CIBERSORTx was chosen to infer enriched immune cells for tumors among subgroups. The SubMap algorithm was applied to predict its sensitivity to immunotherapy. Results The patients with a relatively low peroxisome score and high level of T-cell immunoglobulin and mucin domain 3 (TIM-3) presented the worse overall survival than others. Moreover, low peroxisome scores were associated with high infiltration of lymphocytes and poor prognosis in those CRC patients. Thus, a PERLowTIM3High CRC risk subpopulation was identified and characterized by high immune infiltration. The results also showed that CD8 T cells and macrophages highly infiltrated tumors of the PERLowTIM3High group, regardless of consortium molecular subtype and microsatellite instability status. This subgroup had the highest tumor mutational burden and overexpression of immune checkpoint genes. Further, the PERLowTIM3High group showed a higher probability of responding to programmed cell death protein-1-based immunotherapy. In addition, genes involved in peroxisomal metabolic processes in CRC were also investigated since peroxisome is a rather pleiotropic and highly metabolic organelle in cell. The results indicated that only those genes involved in fatty acid alpha oxidation could be used to stratify CRC patients as similar as peroxisome pathway genes. Conclusions We revealed the favorable prognostic value of the peroxisome pathway in CRC and provided a new CRC stratification based on peroxisomes and TIM3, which might be helpful for CRC diagnostics and personalized treatment.

Co-Mutation of FAT3 and LRP1B in Lung Adenocarcinoma Defines a Unique Subset Correlated With the Efficacy of Immunotherapy

Immunotherapy based on immune checkpoint inhibitors (ICIs) have demonstrated remarkable survival benefits and gained regulatory approval in non-small cell lung cancer (NSCLC) patients without an actionable driver mutation, but currently there is no well-established standard for how to screen the most suitable population for ICIs treatment. Here, we conducted a comprehensive analysis of the somatic mutation landscape of lung adenocarcinoma (LUAD) samples. After the stepwise screening of high-frequency mutated genes, two genes with prominent significance, FAT3 and LRP1B, were finally screened out. Through further analysis, we discovered that the co-mutation of FAT3 and LRP1B was associated with an earlier age of onset and occurred more frequently in Black/African American. Furthermore, co-mutation defines a unique subgroup of lung adenocarcinoma that can increase tumor mutational burden (TMB), boost cytotoxicity and tumor immunogenicity, and facilitate lymphocyte infiltration. The results of gene set enrichment analysis (GSEA) indicated that co-mutation can influence tumorigenesis through a variety of mechanisms. More strikingly, the subset of LUAD with co-mutation of FAT3 and LRP1B exhibited significantly prolonged immunotherapy progression free survival (PFS). In summary, co-mutation of FAT3 and LRP1B is a promising useful biomarker for predicting the efficacy of immunotherapy, which can improve the clinical efficiency of practicing precision medicine in lung adenocarcinoma patients.

Systematic analysis of the role of SLC52A2 in multiple human cancers

Background In humans, riboflavin must be obtained through intestinal absorption because it cannot be synthesized by the body. SLC52A2 encodes a membrane protein belonging to the riboflavin transporter protein family and is associated with a variety of diseases. Here, we systematically explore its relevance to multiple human tumors. Methods We analyzed the association of SLC52A2 with 33 tumors using publicly available databases such as TCGA and GEO. We verified the SLC52A2 expression in hepatocellular carcinoma, gastric cancer, colon cancer, and rectal cancer using immunohistochemistry. Results We report that SLC52A2 was highly expressed in almost all tumors, and the immunohistochemical results in the hepatocellular, gastric, colon, and rectal cancers were consistent with the above. SLC52A2 expression was linked to patient overall survival, disease-specific survival, progression-free interval, diagnosis, mutations, tumor mutational burden, microsatellite instability, common immune checkpoint genes, and immune cells infiltration. Enrichment analysis showed that SLC52A2 was mainly enriched in oocyte meiosis, eukaryotic ribosome biogenesis, and cell cycle. In hepatocellular carcinoma, the SLC52A2 expression is an independent prognostic factor. The SNHG3 and THUMPD3-AS1/hsa-miR-139-5p-SLC52A2 axis were identified as potential regulatory pathways in hepatocellular carcinoma. Conclusion In conclusion, we have systematically described for the first time that SLC52A2 is closely associated with a variety of tumors, especially hepatocellular carcinoma.

Primary Hepatoid Adenocarcinoma of Gallbladder With MB21D2/GALNT12/ARID2 Mutations: A Case Report

BackgroundPrimary hepatoid adenocarcinoma of the gallbladder is a relatively rare type of extrahepatic adenocarcinoma. The genetic changes involved in this type of adenocarcinoma were unexplained so far. We reported a rare case of primary hepatoid adenocarcinoma of gallbladder with Mab-21 domain containing 2 (MB21D2), polypeptide N-acetylgalactosaminyltransferase 12 (GALNT12), and AT-rich interaction domain 2 (ARID2) mutations, which was confirmed after surgical resection pathologically.Case SummaryA 69-year-old female with distention of hypogastrium and constipation received enema treatment, but ineffectively. No abnormalities were found on relevant physical examination. Then, the CT and MRI demonstrated a 3.3–4-cm soft tissue mass shadow in the neck of the gallbladder. The primary lesions consisted of two components: high-grade intraepithelial neoplasia of glands and hepatoid glands microscopically after laparoscope cholecystectomy. Immunohistochemical staining showed the sameness and difference of the two areas. Furthermore, tumor mutational burden (TMB) shows that the MB21D2, GALNT12, and ARID2 genes were mutated.ConclusionThis is the first report of primary hepatoid adenocarcinoma of the gallbladder with MB21D2, GALNT12, and ARID2 mutations. This will provide a theoretical basis for genetic changes in rare tumors.

Intraventricular Meningiomas: Clinical-Pathological and Genetic Features of a Monocentric Series

Intraventricular meningiomas (IVMs) are rare (0.5–5%) and usually low-grade (90% grade I) brain neoplasms. Their recurrence rate is lower than that of extra-axial meningiomas, but their surgical resection can be burdened with life-threatening complications, which represent the major cause of the reported 4% mortality. The aim of this study is to characterize the molecular portrait of IVMs to identify potential therapeutic targets. For this, we explored mutations and copy number variations (CNV) of 409 cancer-related genes and tumor mutational burden (TMB) of six cases, using next-generation sequencing. Five IVMs were grade I and one was grade II; none recurred, in spite of partial surgical resection in one case. NF2 mutation was the only recurring alteration and was present in three of the six IVMs, in association with SMARCB1 mutation in one case. None of the cases was hypermutated (TMB > 10 mutations/Mb). NF2-mutant progressing or recurring IVMs could potentially be treated with targeted therapies applied to other NF2-mutant tumors, as an alternative to surgery or radiosurgery, while in view of their low TMB they are unlikely candidates to immune check-point inhibition.