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Background: Mucinous epithelial ovarian cancers (mEOCs) respond poorly to conventional chemotherapy and have a poor prognosis in advanced stages. The genomic landscape for mEOC in the Asian settings is ill defined. We seek to identify various mutational aberrations present in mEOC and correlate them with clinical outcomes. Methods: A total of 199 cases of mEOC were identified from a prospectively maintained gynecologic oncology tumor database. DNA was extracted and analyzed for KRAS mutations by using Sanger sequencing. Further MassArray sequencing was performed on 45 samples. Clinicopathologic correlation was performed with the results obtained. Findings: KRAS mutation status was evaluable in 124 cases. Fifty-five percent (68/124) were KRAS negative, whereas 45% (56/124) harbored a KRAS mutation, lower than that in Western populations. Successful ascertainment of both KRAS and HER2 statuses by Sanger sequencing occurred for 105 cases. The proportion of the double-positive subtype (HER2+ and KRAS positive) was 8% (8/105); double-negative subtype (HER2j and KRAS negative), 34% (36/105); and cases with mutation in either KRAS or HER2, 58% (61/105). The KRAS mutation rate was 44%, 50%, and 29% among Chinese, Indians, and Malays, respectively. There was no significant difference in overall survival (P = 0.952) or progression-free survival (P = 0.635) between KRAS-positive and KRAS-negative patients. Similar results were observed for progression-free survival (P = 0.206) and overall survival (P = 0.440) when outcomes were examined between the 4 groups based on KRAS and HER2 mutation. Patients in the doublenegative mutation subgroup had higher risk for death/progression compared with patients in the other 3 mutation subgroups. FurtherMassARRAYmultiplexed profilingwas performed in patients with sufficientDNAmaterial (n = 45) and yielded KRAS mutations (n = 16), PDGFRAmutations (n = 3), PIK3CA (n = 1) and KIT (n = 1), and HRAS, FGFR, MET, and NRAS (n = 1 each). Conclusions: Our study provides further knowledge about the mutational aberrations in mEOC in Asian populations. Neither the presence of KRAS mutation nor their correlation with HER2 mutations influenced outcomes. [ABSTRACT FROM AUTHOR]

Objective Gastric cancer (GC) is a deadly malignancy for which new therapeutic strategies are needed. Three transcription factors, KLF5, GATA4 and GATA6, have been previously reported to exhibit genomic amplification in GC. We sought to validate these findings, investigate how these factors function to promote GC, and identify potential treatment strategies for GCs harbouring these amplifications. Design KLF5, GATA4 and GATA6 copy number and gene expression was examined in multiple GC cohorts. Chromatin immunoprecipitation with DNA sequencing was used to identify KLF5/GATA4/GATA6 genomic binding sites in GC cell lines, and integrated with transcriptomics to highlight direct target genes. Phenotypical assays were conducted to assess the function of these factors in GC cell lines and xenografts in nude mice. Results KLF5, GATA4 and GATA6 amplifications were confirmed in independent GC cohorts. Although factor amplifications occurred in distinct sets of GCs, they exhibited significant mRNA coexpression in primary GCs, consistent with KLF5/GATA4/GATA6 cross-regulation. Chromatin immunoprecipitation with DNA sequencing revealed a large number of genomic sites co-occupied by KLF5 and GATA4/GATA6, primarily located at gene promoters and exhibiting higher binding strengths. KLF5 physically interacted with GATA factors, supporting KLF5/ GATA4/GATA6 cooperative regulation on co-occupied genes. Depletion and overexpression of these factors, singly or in combination, reduced and promoted cancer proliferation, respectively, in vitro and in vivo. Among the KLF5/GATA4/GATA6 direct target genes relevant for cancer development, one target gene, HNF4a, was also required for GC proliferation and could be targeted by the antidiabetic drug metformin, revealing a therapeutic opportunity for KLF5/GATA4/GATA6 amplified GCs. Conclusions KLF5/GATA4/GATA6 may promote GC development by engaging in mutual crosstalk, collaborating to maintain a pro-oncogenic transcriptional regulatory network in GC cells. [ABSTRACT FROM AUTHOR]

The article presents a case study of a middle aged female who presented to physicians with raised liver enzymes and antibodies against the hepatitis B core antigen which were otherwise negative for hepatitis B surface antigen as well as antibodies against the hepatitis B surface antigen. A discussion of testing which was conducted on the patient, and resulted in her receiving a diagnosis of a focal nodular hyperplasia-like lesion in her cirrhotic liver which resembled cholangiocarcinoma, is presented.

Objective Gastric cancer is a major gastrointestinal malignancy for which targeted therapies are emerging as treatment options. This study sought to identify the most prevalent molecular targets in gastric cancer and to elucidate systematic patterns of exclusivity and cooccurrence among these targets, through comprehensive genomic analysis of a large panel of gastric cancers. Design Using high-resolution single nucleotide polymorphism arrays, copy number alterations were profiled in a panel of 233 gastric cancers (193 primary tumours, 40 cell lines) and 98 primary matched gastric non-malignant samples. For selected alterations, their impact on gene expression and clinical outcome were evaluated. Results 22 recurrent focal alterations (13 amplifications and nine deletions) were identified. These included both known targets (FGFR2, ERBB2) and also novel genes in gastric cancer (KLF5, GATA6). Receptor tyrosine kinase (RTK)/RAS alterations were found to be frequent in gastric cancer. This study also demonstrates, for the first time, that these alterations occur in a mutually exclusive fashion, with KRAS gene amplifications highlighting a clinically relevant but previously underappreciated gastric cancer subgroup. FGFR2-amplified gastric cancers were also shown to be sensitive to dovitinib, an orally bioavailable FGFR/VEGFR targeting agent, potentially representing a subtype-specific therapy for FGFR2-amplified gastric cancers. Conclusion The study demonstrates the existence of five distinct gastric cancer patient subgroups, defined by the signature genomic alterations FGFR2 (9% of tumours), KRAS (9%), EGFR (8%), ERBB2 (7%) and MET (4%). Collectively, these subgroups suggest that at least 37% of gastric cancer patients may be potentially treatable by RTK/RAS directed therapies. [ABSTRACT FROM AUTHOR]

The article presents the case of a 65-year old Chinese man who had prostatic ductal adenocarcinoma which expressed thyroid transcription factor-1. A nodule and extracellular mucin was found in his prostate biopsy. He underwent a radical prostatectomy to remove the nodular lesion in his left prostate lobe. The patient had a nodule between the bladder and rectum which represents a hematoma after the surgery.

Background Combination therapy with radioembolization (yttrium-90)-resin microspheres) followed by nivolumab has shown a promising response rate of 30.6% in a Phase II trial (CA209-678) for advanced hepatocellular carcinoma (HCC); however, the response mechanisms and relevant biomarkers remain unknown.Methods By collecting both pretreatment and on-treatment samples, we performed multimodal profiling of tissue and blood samples and investigated molecular changes associated with favorable responses in 33 patients from the trial.Results We found that higher tumor mutation burden, NCOR1 mutations and higher expression of interferon gamma pathways occurred more frequently in responders. Meanwhile, non-responders tended to be enriched for a novel Asian-specific transcriptomic subtype (Kaya_P2) with a high frequency of chromosome 16 deletions and upregulated cell cycle pathways. Strikingly, unlike other cancer types, we did not observe any association between T-cell populations and treatment response, but tumors from responders had a higher proportion of CXCL9+/CXCR3+ macrophages. Moreover, biomarkers discovered in previous immunotherapy trials were not predictive in the current cohort, suggesting a distinctive molecular landscape associated with differential responses to the combination therapy.Conclusions This study unraveled extensive molecular changes underlying distinctive responses to the novel treatment and pinpointed new directions for harnessing combination therapy in patients with advanced HCC.

Introduction Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-associated mortality globally. Immune-checkpoint blockade (ICB) is one of the systemic therapy options for HCC. However, response rates remain low, necessitating robust predictive biomarkers. In the present study, we examined the expression of CD38, a molecule involved in the immunosuppressive adenosinergic pathway, on immune cells present in the tumor microenvironment. We then investigated the association between CD38 and ICB treatment outcomes in advanced HCC.Methods Clinically annotated samples from 49 patients with advanced HCC treated with ICB were analyzed for CD38 expression using immunohistochemistry (IHC), multiplex immunohistochemistry/immunofluorescence (mIHC/IF) and multiplex cytokine analysis.Results IHC and mIHC/IF analyses revealed that higher intratumoral CD38+ cell proportion was strongly associated with improved response to ICB. The overall response rates to ICB was significantly higher among patients with high proportion of total CD38+cells compared with patients with low proportion (43.5% vs 3.9%, p=0.019). Higher responses seen among patients with a high intratumoral CD38+cell proportion translated to a longer median progression-free survival (mPFS, 8.21 months vs 1.64 months, p=0.0065) and median overall survival (mOS, 19.06 months vs 9.59 months, p=0.0295). Patients with high CD38+CD68+macrophage density had a better mOS of 34.43 months compared with 9.66 months in patients with low CD38+CD68+ macrophage density. CD38hi macrophages produce more interferon γ (IFN-γ) and related cytokines, which may explain its predictive value when treated with ICB.Conclusions A high proportion of CD38+ cells, determined by IHC, predicts response to ICB and is associated with superior mPFS and OS in advanced HCC.