Efficacy of second-line chemotherapy in patients with pulmonary large cell neuroendocrine carcinoma.

The efficacy of second-line chemotherapy in patients with pulmonary large cell neuroendocrine carcinoma (LCNEC) is unclear. This study aimed to evaluate the efficacy of second-line chemotherapy in patients with pulmonary LCNEC. We retrospectively reviewed patients with pulmonary LCNEC or possible LCNEC (pLCNEC) who received platinum-based chemotherapy as the first-line treatment. Among these patients, we evaluated the efficacy of second-line treatment by comparing patients with small cell lung cancer (SCLC group). Of the 61 patients with LCNEC or pLCNEC (LCNEC group) who received first-line chemotherapy, 39 patients were treated with second-line chemotherapy. Among the 39 patients, 61.5% received amrubicin monotherapy. The median progression-free survival (PFS) and overall survival (OS) in the LCNEC groups were 3.3 and 8.3 months, respectively. No significant differences in the PFS (hazard ratio [HR]: 0.924, 95% confidence interval [CI] 0.647-1.320; P = 0.664) and OS (HR: 0.926; 95% CI 0.648-1.321; P = 0.670) were observed between the LCNEC and SCLC groups. In patients treated with amrubicin, the PFS (P = 0.964) and OS (P = 0.544) were not different between both the groups. Second-line chemotherapy, including amrubicin, may be considered as a treatment option for patients with pulmonary LCNEC.

Genetic and Immunological Characterization of Brain Metastases from Solid Cancers.

BACKGROUND/AIM: Brain metastasis, a leading cause of cancer death, is a clinical challenge. Recently, genetic characterization of brain metastatic lesions based on next generation sequencing-based advanced technologies, such as single-cell RNA sequencing, has been performed to develop novel efficient therapies. The present study aimed to investigate brain-metastasis-specific biomarkers as well as relevant prognostic factors. PATIENTS AND METHODS: The genetic profiles and expression levels of immune response-associated genes and 820 cancer-associated genes were compared between primary cancer lesions and metastatic cancer lesions obtained from nine cancer patients at the Shizuoka Cancer Center. Cytokine and chemokine marker genes were analyzed via quantitative PCR. T-cell receptor (TCR) repertoire profiling was performed for the same patients. For survival analysis, survival data of 52 cancer patients with brain metastases were utilized. RESULTS: Comparison of driver mutation profiling between primary and metastatic lesions revealed shared core mutations in both lesions and a few new mutations in metastatic lesions. A high tumor mutation burden (TMB) was detected in metastatic lesions. Volcano plot analysis revealed specific features of the metastatic tumor microenvironment, such as cancer signaling promotion and immune suppression due to decreased immune cell infiltration. Survival analysis revealed that three genes, the TREML2 gene, the BTLA gene on activated microglia and the CERS2 gene on metastatic tumor, were potent prognostic factors. CONCLUSION: High TMB in metastatic lesions indicates potential benefit from immune checkpoint inhibitor usage for brain metastasis and TREML2 and BTLA are factors associated with poor prognosis. Activated microglia may be novel targets for the treatment of brain metastasis.

Brain Metastasis of Non-small Cell Lung Cancer After Disease-Free Survival of 5 years: Case Series and Comprehensive Literature Review.

BACKGROUND: In the treatment of nonsmall cell lung cancer (NSCLC), a disease-free survival of 5 years is a criterion for cure. This study aimed to evaluate the characteristics and outcomes of patients with brain metastases of NSCLC after a disease-free survival of 5 years (late recurrent brain metastasis [LRBM]). METHODS: We reviewed 1281 consecutive patients with brain metastasis of lung cancer at a single institute between November 2014 and December 2022. Relevant articles were retrieved from PubMed. Only peer-reviewed journals published in English were included. RESULTS: Six patients (0.47%) showed LRBM. Three were male. The median age at lung cancer diagnosis was 45 years. The histological diagnosis of all patients was adenocarcinoma. Driver gene mutations were observed in five patients. The median latency period from lung cancer treatment to the development of brain metastasis was 13 years. All patients had no metastasis to any other organs and underwent craniotomies. The median follow-up duration after craniotomy was 3.5 years. No local intracranial recurrences were observed. Three patients had distant intracranial recurrences at 7, 2, and 0.6 years after craniotomy. Five patients survived for 8, 4, 3, 2, and 0.3 years after craniotomy. One patient experienced re-recurrence in the lung 4 years after craniotomy and died 3.7 years later. In our systematic review, only six studies described LRBM of NSCLC. CONCLUSIONS: LRBM is rare in patients with NSCLC. In our institution, many of these patients harbored driver gene mutations, and achieved long-term survival with aggressive local therapy. Multicenter analysis is mandatory.

Pathologic significance of peribiliary capillary plexus in gallbladder neoplasm.

AIMS: Significance of peribiliary capillary plexus (PCP) in gallbladder neoplasms remains unclear. Aims are to characterize high-grade biliary intraepithelial neoplasm (BilIN), pyloric gland adenoma (PGA), and intracholecystic papillary neoplasm (ICPN), precursors of gallbladder carcinoma, and to differentiate invasive carcinoma from pseudo-invasive lesions in gallbladder walls, referring to PCP. MATERIALS AND METHODS: High-grade BilIN (38 cases), PGA (5 cases), and ICPN (25 cases) were examined using capillary immunostaining. Non-neoplastic gallbladders were used as controls. RESULTS: In non-neoplastic gallbladders, a single layer of regularly dotted capillaries (PCP) was located beneath lining epithelia and around non-neoplastic glands (NNGs), including Rokitansky-Aschoff sinus (RAS), presenting a two-layer of lining epithelia and PCP. Intra-luminal components of all cases of high-grade BilIN and PGA and one-third of ICPNs presented a two-layer pattern. In the remaining ICPNs, capillaries were irregular and sparse in intraluminal neoplastic components presenting irregular and complicated lesions. Neoplastic glands in gallbladder walls of high-grade BilIN and ICPN were classifiable into 2 types: glands that were underlain by densely dotted capillaries and those that were not, with the latter suggestive of invasive carcinoma, while the former suggestive of non-invasive neoplasms involving NNGs intraepithelially and/or showing an expanding growth into gallbladder wall (pseudo-invasion). CONCLUSION: A two-layer pattern of lining epithelia and underlining capillaries were preserved in all cases of high-grade BilIN and PGA and one-third of ICPN cases. Presence or absence of dotted capillaries around neoplastic glands may be able to be added as a new pathologic feature to differentiate invasive carcinomas from pseudo-invasion in gallbladder wall.

Gastric inflammatory myofibroblastic tumor: a case report.

BACKGROUND: Inflammatory myofibroblastic tumor (IMT) of the stomach is an uncommon mesenchymal neoplasm. We present a case of gastric submucosal tumor (SMT) where the final diagnosis was IMT. CASE PRESENTATION: A 69-year-old man presented with a 24-mm SMT on the posterior wall of the middle third of the stomach that was detected by screening upper gastrointestinal endoscopy. Abdominal contrast-enhanced computed tomography showed that the tumor was well-enhanced. Although endoscopic ultrasonography-guided biopsy was performed, the histological diagnosis was not confirmed preoperatively. Since the tumor was clinically suspected to be a gastrointestinal stromal tumor, we performed gastric wedge resection by laparoscopic-endoscopic cooperative surgery. Pathologically, proliferative spindle cells with a positive reaction for smooth muscle actin, negativity for c-kit, desmin, s-100, CD34, STAT-6, ß-catenin and anaplastic lymphoma kinase 1 were identified. Hence, the tumor was finally diagnosed as an IMT originating from the stomach. CONCLUSIONS: When an SMT of the stomach is identified, the possibility of gastric IMT should be considered.

Impact of Mutations in Subunit Genes of the Mammalian SWI/SNF Complex on Immunological Tumor Microenvironment.

BACKGROUND/AIM: Recently, inactivating somatic mutations of SWI/SNF chromatin-remodeling genes in cancers have been reported. However, few studies have been performed regarding the immunological analysis of the tumor microenvironment (TME) in chromatin remodeling complex gene-mutated tumors. In the present study, we identified cancer patients harboring various mammalian SWI/SNF complex mutations and investigated the immunological features in those mutated cancers. PATIENTS AND METHODS: Cancer patients harboring any type of chromatin remodeling complex gene mutation were selected and clinicopathological features were compared between chromatin remodeling complex gene expression-low and expression-high groups. Specifically, expression levels of immune response-associated genes and cancer-associated genes were compared between the SMARCA4 expression-low and expression-high groups using volcano plot analysis. RESULTS: Among cancers harboring PBRM1, SAMRACA4 and ARID2 gene mutations, T-cell marker and mature B-cell marker genes were up-regulated in the tumor. Specifically, T-cell effector genes (CD8B, CD40LG), central memory marker genes (CD27, CCR7) and mature B-cell marker genes (CD20, CD38, CD79 and IRF4) were up-regulated, and cancer-associated genes including MYB, MYC and AURKB genes were down-regulated in the SMARCA4 expression-low group. Remarkably, heatmap of gene expression and immunohistochemistry (IHC) data demonstrated that the tertiary lymphoid structure (TLS) gene signature of mature B cells was up-regulated in SMACA4 gene-mutated stomach cancers. CONCLUSION: These results suggest that immune tumor microenvironment status, such as mature B cell recruitment featuring the TLS gene signature and immune activation mediated by cancer signal down-regulation, might contribute to the classification of SMARCA4 gene-mutated tumors as immune checkpoint blockade therapy-sensitive target tumors.

A novel low-power pure-cut hot snare polypectomy for 10-14 mm colorectal adenomas: An ex vivo and a clinical prospective feasibility study (SHARP trial).

BACKGROUND AND AIM: Hot snare polypectomy using blend or coagulation current is widely used; however, it causes deeper tissue heat injury, leading to adverse events. We hypothesized that hot polypectomy using low-power pure cut current (PureCut, effect 1 10 W) could reduce deeper tissue heat injury. We conducted animal experiments to evaluate the deeper tissue heat injury and conducted a prospective clinical study to examine its cutting ability. METHODS: In a porcine rectum, hot polypectomy using Blend current (EndoCut, effect 3 40 W) and low-power pure cut current was performed. The deepest part of heat destruction and thickness of the non-burned submucosal layer were evaluated histologically. Based on the results, we performed low-power pure cut current hot polypectomy for 10-14 mm adenoma. The primary endpoint was complete resection defined as one-piece resection with negative for adenoma in quadrant biopsies from the defect margin. RESULTS: In experiments, all low-power pure-cut resections were limited within the submucosal layer whereas blend current resections coagulated the muscular layer in 13% (3/23). The remaining submucosal layer was thicker in low-power pure cut current than in blend current resections. In the clinical study, low-power pure-cut hot polypectomy removed all 100 enrolled polyps. For 98 pathologically neoplastic polyps, complete resection was achieved in 84 (85.7%, 95% confidence interval, 77-92%). The lower limit of the 95% confidence interval was not more than 15% below the pre-defined threshold of 86.6%. No severe adverse events occurred. CONCLUSIONS: A novel low-power pure-cut hot polypectomy may be feasible for adenoma measuring 10-14 mm. (UMIN000037678).

An autopsy case of primary gliosarcoma with multiple extracranial metastases: pathology after administration of bevacizumab and genetic profile.

Gliosarcoma (GS), a morphological variant of glioblastoma, pathologically shows a biphasic pattern with gliomatous and sarcomatous components. It has been reported that GS has much higher metastatic capacity than glioblastoma. A few reports on the pathology of the extracranial metastasis of GS have shown that metastatic lesions had a sarcomatous component alone or a mixture of gliomatous and sarcomatous ones. Therefore, it is considered that GS tends to disseminate hematogenously due to its mesenchymal sarcomatous component. Herein, we report an autopsy case of GS with multiple extracranial metastases treated by craniotomy, radiotherapy, and bevacizumab. In this case, metastatic lesions at autopsy contained a gliomatous component alone, but no sarcomatous component. In addition, the sarcomatous component disappeared from the intracranial lesion at autopsy after the administration of bevacizumab. In this report, we discuss the clinical course and pathological findings at the initial state, recurrence, and autopsy, including the results of whole-genome analysis.

Prognostic significance of tumor microenvironment assessed by machine learning algorithm in surgically resected non-small cell lung cancer.

BACKGROUND: A methodology to assess the immune microenvironment (IME) of non-small cell lung cancer (NSCLC) has not been established, and the prognostic impact of IME factors is not yet clear. AIMS: This study aimed to assess the IME factors and evaluate their prognostic values. METHODS AND RESULTS: We assessed CD8+ tumor-infiltrating lymphocyte (TIL) density, forkhead box protein P3+ (Foxp3+ ) TIL density, and programmed death receptor ligand-1 (PD-L1) tumor proportion score (TPS) using a machine-learning algorithm in whole-slide imaging (WSI). We dichotomized patients according to TIL density or TPS and compared their clinical outcomes. Between September 2014 and September 2015, 165 patients with NSCLC were enrolled in the study. We assessed IME factors in the epithelium, stroma, and their combination. An improvement in disease-free survival (DFS) was observed in the high CD8+ TIL density group in the epithelium, stroma, and the combination of both. Moreover, the group with high PD-L1 TPS in the epithelium showed better DFS than that with low PD-L1 TPS. In the multivariate analysis, the CD8+ TIL density in the combination of epithelium and stroma and PD-L1 TPS in the epithelium were independent prognostic factors (hazard ratio [HR] = 0.43; 95% confidence interval [CI] = 0.26-0.72; p = .001, HR = 0.49; 95% CI = 0.30-0.81; p = .005, respectively). CONCLUSION: Our approach demonstrated that the IME factors are related to survival in patients with NSCLC. The quantitative assessment of IME factors enables to discriminate patients with high risk of recurrence, who can be the candidates for adjuvant therapy. Assessing the CD8+ TIL density in the combination of epithelium and stroma might be more useful than their individual assessment because it is a simple and time-saving analysis of TILs in WSI.

A Primary Intraosseous Meningioma: A Rare Case of Malignancy with High Proliferative Ability.

Primary intraosseous meningioma (PIM) is a rare tumor that arises in the skull. Histopathologically, it is generally described as a slow-growing, benign lesion. However, on rare occasions, PIM presents as a malignancy with high proliferative ability, which requires maximal resection, adjuvant radiotherapy, and subsequent careful follow-up. Because of the rarity of such cases, they present a diagnostic challenge with unusual pathological findings. Herein, we report a case of a primary intraosseous anaplastic meningioma with extensive invasion inside and outside the skull, along with the results of whole-genome analysis. Histopathological diagnosis was a World Health Organization grade 3 anaplastic meningioma. In the literature, only two cases of anaplastic PIM have been reported, so its characteristics and treatment are poorly understood. Our patient was successfully treated with tumor resection, followed by intensity-modulated radiation therapy. Follow-up imaging studies revealed no recurrence or distant metastasis, including to lung, liver, and bone, at 8 months after the surgery.

ERBB2-Mutant Gastrointestinal Tumors Represent Heterogeneous Molecular Biology, Particularly in Microsatellite Instability, Tumor Mutation Burden, and Co-Mutated Genes: An In Silico Study.

During recent years, activating mutations in ERBB2 have been reported in solid tumors of various organs, and clinical trials targeting ERBB2-mutant tumors have been conducted. However, no effective treatment has been established for gastrointestinal tumors targeting ERBB2 mutations. ERBB2-mutant tumors have a higher tumor mutation burden (TMB) and microsatellite instability (MSI) than ERBB2 non-mutant tumors, but not all ERBB2-mutant tumors are TMB- and MSI-high. Thus, a more detailed classification of ERBB2-mutant tumors based on the underlying molecular mechanisms is required. Herein, we classified ERBB2 mutations into three groups-group 1: both ERBB2 mutations and amplifications; group 2: ERBB2 mutations annotated as putative driver mutations but without amplifications; group 3: ERBB2 mutations annotated as non-driver mutations (passenger mutations or unknown significance) and those that were not amplified in gastrointestinal tumors. Esophageal adenocarcinoma, gastric cancer, and colorectal cancer presented significantly higher MSI and TMB in the ERBB2-mutant group than in the ERBB2-wild-type group. The proportions of TMB- and MSI-high tumors and frequency of co-mutated downstream genes differed among the groups. We identified TMB- and MSI-high groups; this classification is considered important for guiding the selection of drugs for ERBB2-mutant tumors with downstream genetic mutations.

Desmin immunostaining is effective for improving interobserver variability in the depth assessment of the submucosal invasion of colorectal cancers.

Tumor depth evaluation is essential for pathological tumor staging because it affects clinical management as an independent risk factor for lymph node metastasis in colorectal cancers. However, poor interobserver variability of invasion depth has been reported. This study aimed to clarify the effectiveness of desmin immunostaining in the histological diagnosis of colorectal cancer. Overall, 63 sets of slides of colorectal cancer stained with hematoxylin and eosin (H&E) and desmin were prepared and independently reviewed by four examiners. After reviewing the desmin-stained slides, the interobserver variability of H&E slides alone was significantly improved for all examiners. For the assessment of Tis vs. T1, the sensitivity and accuracy were significantly improved for all examiners by combining H&E and desmin immunostaining. For the diagnosis of T1b vs. Tis or T1a, specificity and accuracy were significantly improved by adding desmin immunostaining. Ancillary desmin staining to assess submucosal invasion in colorectal cancers significantly improved interobserver agreement, led to efficient screening of T1 cancers, and reduced excessive T1b diagnoses. The combination of desmin immunostaining and H&E staining is highly recommended for diagnosing invasive colorectal cancer.

Local recurrence risk of esophageal squamous cell carcinoma due to intralesional damage during endoscopic submucosal dissection.

BACKGROUND AND AIM: It is unclear whether additional treatment should be considered given the recurrence risk after endoscopic submucosal dissection (ESD) for esophageal squamous cell carcinoma (ESCC) when the vertical margin is positive or unclear (VM1/VMX) due to intralesional damage. This study aimed to elucidate the local recurrence risk of ESCC caused by intralesional damage during ESD. METHODS: Among consecutive patients with pT1a ESCCs initially treated by ESD at our institution between January 2006 and December 2018, ESCCs diagnosed as VM1/VMX were retrospectively reviewed. Exclusion criteria were piecemeal resection and any additional treatment after ESD. Intralesional damage included the following three types: a macroscopic hole inside the lesion, an incision from the lateral margin of the specimen into the lesion, and crushing injury or burn effect into the deepest area of the lesion without an obvious hole. The local recurrence rate after ESD was primarily analyzed. RESULTS: Of 1174 pT1a ESCCs initially treated using ESD, 22 lesions were histopathologically diagnosed as VM1/VMX due to intralesional damage (1.9%; 95% confidence interval [CI], 1.2-2.8%). At a median follow-up period of 60.0 (interquartile range, 15.0-84.0) months, no local recurrence was observed (0.0%; 95% CI, 0.0-13.3%) among 21 lesions finally evaluated. CONCLUSIONS: The impact of intralesional damage during ESD for ESCC on local recurrence might be negligible. Follow-up without additional treatment may be acceptable even if intralesional damage occurs and results in VM1/VMX after ESD for pT1a ESCCs.

Generation of novel complete HLA class I monoallelic cell lines used in an MHC stabilization assay for neoantigen evaluation.

Immunogenic neoantigens derived from somatic mutations in cancer have been identified through clinical studies with the cloning of tumor-infiltrating T cells, and cancer driver gene mutation-derived epitopes have been reported; however, these are rare. At present, the validation of epitopes predicted in silico is difficult as human T-cell clonal diversity cannot be reproduced in vitro or in experimental animal models. To confirm the epitope peptides presented by human leukocyte antigen (HLA) class I molecules predicted in silico, biochemical methods such as major histocompatibility complex (MHC) stabilization assays and mass spectrometry-mediated identification have been developed based on HLA-A*02:01 monoallelic T2 cells and HLA-C*01:02 monoallelic LCL721.221 cells. Therefore, in the present study, to prevent confusion due to peptide cross-presentation among HLA molecules, HLA class I monoallelic B-cell clones were generated from the TISI cell line by knocking out HLA-ABC and TAP2, and knocking in HLA alleles. To explore cancer driver mutations as potential targets for immunotherapy, exome sequencing data from 5,143 patients with cancer enrolled in a comprehensive genome analysis project at the Shizuoka Cancer Center were used to identify somatic amino acid substituted mutations and the 50 most frequent mutations in five genes, TP53, EGFR, PIK3CA, KRAS and BRAF, were identified. Using NetMHC4.1, the present study predicted whether epitopes derived from these mutations are presented on major HLA-ABC alleles in Japanese individuals and synthesized 138 peptides for MHC stabilization assays. The authors also attempted to examine the candidate epitopes at physiological temperatures by using antibody clone G46-2.6, which can detect HLA-ABC, independent of ß2-microglobulin association. In the assays, although the peptide-induced HLA expression levels were associated with the predicted affinities, the respective HLA alleles exhibited varying degrees of responsiveness, and unexpectedly, p53-mutant epitopes with predicted weak affinities exhibited strong responses. These results suggested that MHC stabilization assays using completely monoallelic HLA-expressing B-cell lines are useful for evaluating the presentation of neoantigen epitopes.

Molecular profiling of gastric neuroendocrine carcinomas.

Gastric neuroendocrine carcinoma (G-NEC) usually has NEC and adenocarcinoma components and is considered to have a common origin in gastric adenocarcinoma because common pathogenic mutations are shared. However, G-NEC without adenocarcinoma also exists, and it may have a different mechanism of tumorigenesis. We aimed to elucidate the tumorigenesis of G-NEC by focusing on the proportion of NEC components. Thirteen patients with G-NEC were included in this study. Comprehensive genetic analysis using whole-exome sequencing was performed. G-NEC without an adenocarcinoma component was defined as pure NEC. TP53 was detected as the most frequent gene mutation (85% of the patients), independent of classification. RB1, KMT2C, LTBP1, and RYR2 mutations were identified in two of three pure NEC patients but were not detected in other G-NEC patients. Pure NEC has different somatic mutation profile than other NECs. This study provides insights into the mechanism of tumorigenesis in G-NEC.

Liver abscess caused by Clostridium perfringens after left hepatic trisectionectomy for perihilar cholangiocarcinoma: a case report.

BACKGROUND: Clostridium perfringens sepsis has been reported to have a rapid onset and severe clinical outcome. We herein report a case of C. perfringens sepsis associated with massive intravascular hemolysis after left hepatic trisectionectomy for perihilar cholangiocarcinoma. CASE PRESENTATION: A 72-year-old woman underwent left hepatic trisectionectomy for perihilar cholangiocarcinoma. Her postoperative course was uneventful except for bile leakage. She was discharged on postoperative day (POD) 35. On POD 54, she was readmitted because of abdominal pain with a high fever. Although her vital signs were stable on arrival at the hospital, a laboratory examination showed a severe inflammatory reaction and hemolysis, and she had developed disseminated intravascular coagulation. Abdominal contrast-enhanced computed tomography showed a 70-mm irregular shape and low-density containing air in liver segment 6, which suggested a liver abscess. The abscess was immediately drained of pus containing air. The pus showed multiple Gram-positive bacilli, and two blood cultures showed Gram-positive bacilli and hemolysis. Empirical antibiotic therapy with vancomycin and meropenem was started because C. perfringens was detected from the preoperative bile culture. Four hours after arrival, tachypnea and decreased oxygen saturation were observed. Her general condition deteriorated rapidly with significant hypoglycemia, progressive acidosis, anemia, and thrombocytopenia. Despite rapid drainage and empiric therapy, she died six hours after her arrival. At autopsy, the abscess consisted of coagulation necrosis of liver cells with inflammatory cell infiltration, and clusters of Gram-positive large bacilli were observed in the necrotic debris. C. perfringens was detected in the drainage fluid and blood culture. She was diagnosed with a liver abscess and severe sepsis caused by C. perfringens and treated promptly, but the disease progressed rapidly and led to her death. CONCLUSIONS: Sepsis caused by C. perfringens can progress rapidly and lead to death in a few hours, so prompt treatment is needed. When patients who have undergone highly invasive hepatobiliary-pancreatic surgery show hemolysis and hepatic abscesses with gas, C. perfringens should be considered the most likely bacterium.

Whole-genome and Epigenomic Landscapes of Malignant Gastrointestinal Stromal Tumors Harboring KIT Exon 11 557-558 Deletion Mutations.

Gastrointestinal stromal tumors (GIST) with KIT exon 11 deletions involving in codons 557-558 (KIT Δ557-558) exhibit higher proliferation rates and shorter disease-free survival times compared with GISTs with other KIT exon 11 mutations. We analyzed 30 GIST cases and observed genomic instability and global DNA hypomethylation only in high-risk malignant GISTs with KIT Δ557-558. Whole-genome sequencing revealed that the high-risk malignant GISTs with KIT Δ557-558 (12 cases) had more structural variations (SV), single-nucleotide variants, and insertions and deletions compared with the low-risk, less malignant GISTs with KIT Δ557-558 (six cases) and the high-risk (six cases) or low-risk (6 cases) GISTs with other KIT exon 11 mutations. The malignant GISTs with KIT Δ557-558 showed higher frequency and significance in copy number (CN) reduction on chromosome arms 9p and 22q, and 50% of them had LOH or CN-dependent expression reduction in CDKN2A. In addition, SVs with driver potential were detected in 75% of them, in which AKT3 and MGMT were recurrently identified. Genome-wide DNA methylation and gene expression analyses showed global intergenic DNA hypomethylation, SNAI2 upregulation, and higher expression signatures, including p53 inactivation and chromosomal instability, as characteristics of malignant GISTs with KIT Δ557-558 that distinguished them from other GISTs. These genomic and epigenomic profiling results revealed that KIT Δ557-558 mutations are associated with increased genomic instability in malignant GISTs. Significance: We present genomic and epigenomic insights into the malignant progression of GISTs with KIT exon 11 deletions involving in 557-558, demonstrating their unique chromosomal instability and global intergenic DNA hypomethylation.

Molecular profile of poorly cohesive gastric carcinoma with special reference to survival.

BACKGROUND: Patients with poorly cohesive gastric carcinoma (PCC) are known to have poor survival. However, detailed molecular biology of PCC has not been elucidated, except for mutations in CDH1 and RHOA. Additionally, the molecular profiles of signet-ring cell carcinoma (SRC) have not been fully investigated. We aimed to investigate the association between molecular profiles and survival in PCC and PCC subtypes. METHODS: The present study included 455 patients with gastric adenocarcinoma underwent radical gastrectomy. Whole-exome sequencing and gene expression profiling were conducted. Patients were classified according to the WHO classification as PCC or non-PCC, with PCC being further classified into SRC, combined, and PCC not-otherwise-specified (NOS). Clinicopathological factors and survival were compared with molecular profiles. RESULTS: Of the patients, 159 were classified with PCC, while 296 were classified with non-PCC. Among PCC, 44 were classified with SRC, 64 with combined, and 51 with PCC-NOS. Mutations in CDH1 and RHOA were remarkably more frequent in PCC than in non-PCC. PCC had worse overall survival (OS) and disease-specific survival (DSS) compared to non-PCC. For PCC, the SRC group had good OS and DSS, whereas PCC-NOS classification with CDH1 mutations was associated with extremely poor survival. In the PCC-NOS and combined groups, patients with mutations in the extracellular domain 1 of CDH1 had poor survival. CONCLUSIONS: Our findings suggest that PCC has poorer survival than non-PCC. Accumulation of CDH1 and RHOA mutations are unique profiles in PCC. Among PCC, CDH1 mutations may play a crucial role in the survival of non-SRC PCC.