Multiplex profiling of peritoneal metastases from gastric adenocarcinoma identified novel targets and molecular subtypes that predict treatment response.

OBJECTIVE: Peritoneal carcinomatosis (PC) occurs frequently in patients with gastric adenocarcinoma (GAC) and confers a poor prognosis. Multiplex profiling of primary GACs has been insightful but the underpinnings of PC's development/progression remain largely unknown. We characterised exome/transcriptome/immune landscapes of PC cells from patients with GAC aiming to identify novel therapeutic targets. DESIGN: We performed whole-exome sequencing (WES) and whole transcriptome sequencing (RNA-seq) on 44 PC specimens (43 patients with PC) including an integrative analysis of WES, RNA-seq, immune profile, clinical and pathological phenotypes to dissect the molecular pathogenesis, identifying actionable targets and/or biomarkers and comparison with TCGA primary GACs. RESULTS: We identified distinct alterations in PC versus primary GACs, such as more frequent CDH1 and TAF1 mutations, 6q loss and chr19 gain. Alterations associated with aggressive PC phenotypes emerged with increased mutations in TP53, CDH1, TAF1 and KMT2C, higher level of 'clock-like' mutational signature, increase in whole-genome doublings, chromosomal instability (particularly, copy number losses), reprogrammed microenvironment, enriched cell cycle pathways, MYC activation and impaired immune response. Integrated analysis identified two main molecular subtypes: 'mesenchymal-like' and 'epithelial-like' with discriminating response to chemotherapy (31% vs 71%). Patients with the less responsive 'mesenchymal-like' subtype had high expression of immune checkpoint T-Cell Immunoglobulin And Mucin Domain-Containing Protein 3 (TIM-3), its ligand galectin-9, V-domain Ig suppressor of T cell activation (VISTA) and transforming growth factor-ß as potential therapeutic immune targets. CONCLUSIONS: We have uncovered the unique mutational landscape, copy number alteration and gene expression profile of PC cells and defined PC molecular subtypes, which correlated with PC therapy resistance/response. Novel targets and immune checkpoint proteins have been identified with a potential to be translated into clinics.

Periosteal Chondroma of the Pelvis: An Uncommon Tumor in an Unusual Location.

Periosteal chondromas (PCs) are rare tumors composed of hyaline cartilage that are typically present in long bones and tubular bones of the hand. These lesions are easily mistaken for other, more common tumors. This study reports a case of PC located in the posterior pelvis of a 24-year-old female. The patient initially presented with a four-month history of pelvic pain with a presumptive diagnosis of endometriosis. However, when an MRI was performed, a 6.0 cm x 5.6 cm x 4.5 cm mass was found along the right posterior ilium extending to the ipsilateral sacroiliac joint. The patient underwent intralesional excision and curettage of the mass. Histologic analysis of the excised lesion revealed a proliferation of chondrocytes and abundant hyaline cartilage without chondroblasts, further suggesting the diagnosis of PC. The current study highlights the unusual location of this rare tumor and alerts the physician of the clinical presentation and differential diagnosis.