Increased genomic instability and reshaping of tissue microenvironment underlie oncogenic properties of Arid1a mutations.

Oncogenic mutations accumulating in many chromatin-associated proteins have been identified in different tumor types. With a mutation rate from 10 to 57%, ARID1A has been widely considered a tumor suppressor gene. However, whether this role is mainly due to its transcriptional-related activities or its ability to preserve genome integrity is still a matter of intense debate. Here, we show that ARID1A is largely dispensable for preserving enhancer-dependent transcriptional regulation, being ARID1B sufficient and required to compensate for ARID1A loss. We provide in vivo evidence that ARID1A is mainly required to preserve genomic integrity in adult tissues. ARID1A loss primarily results in DNA damage accumulation, interferon type I response activation, and chronic inflammation leading to tumor formation. Our data suggest that in healthy tissues, the increased genomic instability that follows ARID1A mutations and the selective pressure imposed by the microenvironment might result in the emergence of aggressive, possibly immune-resistant, tumors.

Laparoscopic Resection of Transverse Colon Cancer with an Anomaly of the Middle Colic Artery Originating from the Splenic Artery: A Case Report.

Introduction: We encountered a colon cancer case with a very rare anomaly of the middle colic artery (MCA) originating from the splenic artery (SA). Case Presentation: A woman was referred to our hospital for transverse colon cancer. Three-dimensional computed tomography (3D-CT) angiography showed an anomalous MCA originating from the SA rather than from the superior mesenteric artery (SMA) as is typical. Laparoscopic left hemicolectomy with D3 lymph node dissection was performed. The lymph nodes around the SMA were dissected from the caudal view, confirming the absence of a typical MCA. An anomalous SA-originating MCA was identified just below the pancreas, where it was clipped and ligated; subsequently, total mesenteric excision was achieved. Conclusion: As D3 lymph node dissection for transverse colon cancer is technically difficult, 3D-CT angiography is useful for identifying vascular anomalies preoperatively, thereby avoiding intraoperative injury. This is the first case report of laparoscopic colectomy associated with a SA-originating MCA anomaly.

Sporadic gastric juvenile polyposis with a novel SMAD4 nonsense mutation in a mosaic pattern.

A 50-year-old female was diagnosed with gastric hyperplastic polyps 7 years before and was followed up at another hospital. She was referred to our hospital because of the growth of gastric polyps and progression of anemia. She had no family history of polyposis. The polyps were observed only in the stomach, increased in size and number, and the erythematous edema got worse. Endoscopic mucosal resection (EMR) of the gastric polyp was performed. Pathologically, the gastric polyp was hamartomatous polyp, and the intervening mucosa between polyps showed no atypical structure without inflammation. Given that gastric juvenile polyposis (GJP) was clinically suspected, a genetic test using peripheral blood was performed. Target resequencing and Sanger sequencing analysis revealed a nonsense mutation in the SMAD4 gene at codon 169. The mutation was detected at a low frequency of 11%, and considered a mosaic mutation. Therefore, she was diagnosed with a sporadic GJP, and total gastrectomy was performed. Immunostaining of SMAD4 for the resected specimen showed a mixture of stained and unstained area in the epithelium of the polyp, indicating partial loss of SMAD4 expression. To our knowledge, this is the first reported case of GJP with a nonsense SMAD4 mutation at codon 169 in a mosaic pattern.

Pancreatic RECK inactivation promotes cancer formation, epithelial-mesenchymal transition, and metastasis.

RECK is downregulated in various human cancers; however, how RECK inactivation affects carcinogenesis remains unclear. We addressed this issue in a pancreatic ductal adenocarcinoma (PDAC) mouse model and found that pancreatic Reck deletion dramatically augmented the spontaneous development of PDAC with a mesenchymal phenotype, which was accompanied by increased liver metastases and decreased survival. Lineage tracing revealed that pancreatic Reck deletion induced epithelial-mesenchymal transition (EMT) in PDAC cells, giving rise to inflammatory cancer-associated fibroblast-like cells in mice. Splenic transplantation of Reck-null PDAC cells resulted in numerous liver metastases with a mesenchymal phenotype, whereas reexpression of RECK markedly reduced metastases and changed the PDAC tumor phenotype into an epithelial one. Consistently, low RECK expression correlated with low E-cadherin expression, poor differentiation, metastasis, and poor prognosis in human PDAC. RECK reexpression in the PDAC cells was found to downregulate MMP2 and MMP3, with a concomitant increase in E-cadherin and decrease in EMT-promoting transcription factors. An MMP inhibitor recapitulated the effects of RECK on the expression of E-cadherin and EMT-promoting transcription factors and invasive activity. These results establish the authenticity of RECK as a pancreatic tumor suppressor, provide insights into its underlying mechanisms, and support the idea that RECK could be an important therapeutic effector against human PDAC.

THBS1-producing tumor-infiltrating monocyte-like cells contribute to immunosuppression and metastasis in colorectal cancer.

Mesenchymal activation, characterized by dense stromal infiltration of immune and mesenchymal cells, fuels the aggressiveness of colorectal cancers (CRC), driving progression and metastasis. Targetable molecules in the tumor microenvironment (TME) need to be identified to improve the outcome in CRC patients with this aggressive phenotype. This study reports a positive link between high thrombospondin-1 (THBS1) expression and mesenchymal characteristics, immunosuppression, and unfavorable CRC prognosis. Bone marrow-derived monocyte-like cells recruited by CXCL12 are the primary source of THBS1, which contributes to the development of metastasis by inducing cytotoxic T-cell exhaustion and impairing vascularization. Furthermore, in orthotopically generated CRC models in male mice, THBS1 loss in the TME renders tumors partially sensitive to immune checkpoint inhibitors and anti-cancer drugs. Our study establishes THBS1 as a potential biomarker for identifying mesenchymal CRC and as a critical suppressor of antitumor immunity that contributes to the progression of this malignancy with a poor prognosis.

A case of hepatic reactive lymphoid hyperplasia: the review of 23 cases from the literatures.

A 70-year-old woman was referred to our hospital because of slight elevation of soluble interleukin-2 receptor (sIL-2R) and accumulation of 18F-fluorodeoxyglucose (FDG) in S8 of the liver on positron emission tomography. The mass was strongly suspected to be malignant because of contrast enhancement and enlargement in size of the mass, and suspicion of portal vein invasion. Hepatic S8 subsegmentectomy was performed for diagnostic and therapeutic purposes. Hematoxylin and eosin staining of the resected specimen showed small lymphocytes with no atypia and no formation of lymphoid follicles. Immunostaining showed CD3-positive cells in the interfollicular region and CD20-positive cells in the lymphoid follicles. Both CD10 and BCL-2 were negative in the follicular germinal center. CD138-positive plasma cells were observed and there was no light chain restriction. Based on polyclonal growth pattern of lymphocytes in the lymphoid follicles and interfollicular region, she was diagnosed with hepatic reactive lymphoid hyperplasia (RLH).Review of the English literature of hepatic RLH which referred to imaging findings yielded 23 cases, including this case. As a result, we suggest that liver biopsy should be performed for definitive diagnosis, when hepatic RLH is suspected by imaging findings and backgrounds.

Safety and efficacy of neoadjuvant chemoradiotherapy with moderately hypofractionated intensity-modulated radiotherapy for resectable pancreatic cancer: A prospective, open-label, phase II study.

BACKGROUND: Resectable pancreatic cancer (RPC) is potentially resectable on admission, and the impact of neoadjuvant therapy on these tumors is controversial. Moreover, the safety and efficacy of neoadjuvant chemoradiotherapy with moderately hypofractionated intensity-modulated radiation therapy (NACIMRT) for RPC have not been studied. Here, we conducted a phase II study to evaluate the safety and efficacy of hypofractionated NACIMRT for RPC. METHODS: A total of 54 RPC patients were enrolled and treated according to the study protocol. We used moderately hypofractionated (45 Gy in 15 fractions) IMRT with gemcitabine to shorten the duration of radiotherapy and reduce gastrointestinal toxicity. The primary endpoint was overall survival (OS), and we subsequently analyzed the microscopically margin-negative resection (R0) rate, disease-free survival (DFS), and histologic effects and safety of NACIMRT. RESULTS: Median OS for the cohort was 40.0 months. Forty-two patients (77.8%) underwent pancreatectomy after NACIMRT. Median DFS was 20.3 months. The R0 resection rate was 95.2% (40/42) per protocol and 85.2% (46/54) for the cohort. There were no intervention-related deaths during the study period. Local treatment response, as assessed by the CAP classification, showed no residual tumor in 4.8% of patients. Overall, 23.9% of patients experienced CTCAE grade 3 or 4 during NACIMRT. Adjuvant therapy was initiated in 88% of patients undergoing resection. Postoperative complications grade ≥3b on the Clavien-Dindo scale occurred in 4.8% of patients. CA19-9 level at enrollment was an independent prognostic factor for OS and DFS. CONCLUSIONS: This is the first prospective study of hypofractionated IMRT as neoadjuvant therapy for RPC. Hypofractionated NACIMRT for RPC could be safely introduced with a high induction rate of adjuvant chemotherapy, with an overall survival of 40.0 months.

Pancreatic metastasis from lung adenocarcinoma.

TTF-1 is a highly useful marker to assist in differentiating between pulmonary and nonpulmonary, nonthyroid adenocarcinomas. Our case shows that TTF-1 is highly useful in differentiating between pancreatic metastasis from lung adenocarcinoma and primary pancreatic cancer, especially when the clinical course and imaging findings are not helpful for differentiating them.

Simultaneous activation of Kras-Akt and Notch pathways induces extrahepatic biliary cancer via the mTORC1 pathway.

Biliary tract cancer (BTC) has poor prognosis. The Notch receptor is aberrantly expressed in extrahepatic cholangiocarcinoma (eCCA). However, the role of Notch signaling in the initiation and progression of eCCA and gallbladder (GB) cancer remains unknown. Therefore, we investigated the functional role of Notch signaling during tumorigenesis of the extrahepatic bile duct (EHBD) and GB. Activation of Notch signaling and oncogenic Kras resulted in the development of biliary intraepithelial neoplasia (BilINs) in the EHBD and GB, which were premalignant lesions that progressed to adenocarcinoma in mice. The expression of genes involved in the mTORC1 pathway was increased in biliary spheroids from Hnf1b-CreERT2; KrasLSL-G12D ; Rosa26LSL-NotchIC mice and inhibition of the mTORC1 pathway suppressed spheroid growth. Additionally, simultaneous activation of the PI3K-AKT and Notch pathways in EHBD and GB induced biliary cancer development in mice. Consistent with this, we observed a significant correlation between activated NOTCH1 and phosphorylated Ribosomal Protein S6 (p-S6) expression in human eCCA. Furthermore, inhibition of the mTORC1 pathway suppressed the growth of Notch-activated human biliary cancer cells in vitro and in vivo. Mechanistically, the Kras/Notch-Myc axis activated mTORC1 through TSC2 phosphorylation in mutant biliary spheroids. These data indicate that inhibition of the mTORC1 pathway could be an effective treatment strategy for Notch-activated human eCCA. © 2023 The Pathological Society of Great Britain and Ireland.

Hemophagocytic lymphohistiocytosis associated with hepatocellular carcinoma.

A man in his 60s was admitted because of abdominal pain and fatigue. Contrast enhanced computed tomography (CECT) showed a hypovascular tumor, 7 cm in size, in the left lobe of liver. He had no history of alcohol consumption. HBs antigen and HCV antibody were negative. For definitive diagnosis, biopsy of the hepatic tumor was performed. After the biopsy, the patient suddenly got high fever, and blood tests showed WBC 22,000/L, Hb 8.9 g/dL, Plts 11.6 × 104/L, AST 140 IU/L, ALT 93 IU/L, LDH 635 U/L. He died on the following day despite of supportive therapy. Autopsy revealed that the hepatic tumor was poorly differentiated hepatocellular carcinoma (HCC) and that hemophagocytic macrophages were found in the bone marrow and spleen. Based on the pathological findings of autopsy, he was finally diagnosed with hemophagocytic lymphohistiocytosis (HLH) associated with HCC. HLH is a rare and life-threaded disorder of immune overactivation. Malignancy-associated HLH is well-known; however, it is usually associated with malignant lymphoma. To our knowledge, this is the first reported case of HLH associated with HCC, which was diagnosed by autopsy. Although extremely rare, our case highlights that HLH should be considered as a differential diagnosis of unknown high fever and bicytopenia in patients with solid tumors, including HCC.

Brg1 controls stemness and metastasis of pancreatic cancer through regulating hypoxia pathway.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease. We previously reported that chromatin remodeler Brg1 is essential for acinar cell-derived PDAC formation in mice. However, the functional role of Brg1 in established PDAC and its metastasis remains unknown. Here, we investigated the importance of Brg1 for established PDAC by using a mouse model with a dual recombinase system. We discovered that Brg1 was a critical player for the cell survival and growth of spontaneously developed PDAC in mice. In addition, Brg1 was essential for metastasis of PDAC cells by inhibiting apoptosis in splenic injection and peritoneal dissemination models. Moreover, cancer stem-like property was compromised in PDAC cells by Brg1 ablation. Mechanistically, the hypoxia pathway was downregulated in Brg1-deleted mouse PDAC and BRG1-low human PDAC. Brg1 was essential for HIF-1α to bind to its target genes to augment the hypoxia pathway, which was important for PDAC cells to maintain their stem-like properties and to metastasize to the liver. Human PDAC cells with high BRG1 expression were more susceptible to BRG1 suppression. In conclusion, Brg1 plays a critical role for cell survival, stem-like property and metastasis of PDAC through the regulation of hypoxia pathway, and thus could be a novel therapeutic target for PDAC.

A case of unresectable ectopic acinar cell carcinoma developed in the portal vein in complete response to FOLFIRINOX therapy.

A 56-year-old man presented to our hospital for close examination of a mass in the portal vein. CT showed a homogeneously enhanced mass occupying the portal vein. No other lesions suggestive of a primary tumor were detected. Endoscopic ultrasound-guided fine-needle aspiration revealed that the tumor was pathologically acinar cell carcinoma (ACC) based on the positive staining for both BCL-10 and trypsin. He was diagnosed with an ectopic ACC developed in the portal vein. Because the tumor invaded secondary branches of the right intrahepatic portal vein and the superior mesenteric vein, it was considered surgically un-resectable. Therefore, chemotherapy with gemcitabine plus nab-paclitaxel (GEM + nab-PTX) was started. After 2 courses, CT showed progressive disease, so the regimen was switched to FOLFIRINOX. After starting treatment with FOLFIRINOX, the tumor shrank gradually. After 29 courses, CT scan eventually showed disappearance of the tumor and complete response was achieved. After 34 courses, the chemotherapy was discontinued. Since then, the patient has been recurrence-free for 5 years. Our English literature review yielded 6 cases, including this case, of un-resectable ACC in which complete response was achieved by chemotherapy. Our case suggest that platinum-based regimen might be an effective therapy for un-resectable ACC, including ectopic ACC.

p53 protects against formation of extrahepatic biliary precancerous lesions in the context of oncogenic Kras.

KRAS and TP53 mutations are frequently observed in extrahepatic biliary cancer. Mutations of KRAS and TP53 are independent risk factors for poor prognosis in biliary cancer. However, the exact role of p53 in the development of extrahepatic biliary cancer remains elusive. In this study, we found that simultaneous activation of Kras and inactivation of p53 induces biliary neoplasms that resemble human biliary intraepithelial neoplasia in the extrahepatic bile duct and intracholecystic papillary-tubular neoplasm in the gall bladder in mice. However, inactivation of p53 was not sufficient for the progression of biliary precancerous lesions into invasive cancer in the context of oncogenic Kras within the observation period. This was also the case in the context of additional activation of the Wnt signaling pathway. Thus, p53 protects against formation of extrahepatic biliary precancerous lesions in the context of oncogenic Kras.

A case of dedifferentiated liposarcoma of the descending colon.

A 54-year-old man referred to our hospital for abdominal distension. He had no medical history. On physical examination, he complained lower abdominal distention, and had no spontaneous pain or tenderness. The blood tests showed that CEA and CA19-9 levels were within normal limits. Colonoscopy revealed a submucosal tumor with irregularities and mucosal defects in the descending colon. Computed tomography (CT) showed a 3-cm-diameter mass in the descending colon and ascites. Due to the presence of ascites, laparoscopic examination was performed, which revealed multiple peritoneal seeding of the tumor. Given the presence of peritoneal dissemination, the tumor was determined to be unresectable, and a histological examination was performed from the disseminated nodule. Pathologically, atypical spindle cells were observed and infiltrated into adipose tissue. Additional immunohistochemistry revealed positive expression for Murine double minute 2 (MDM2) and Cyclin-dependent kinase 4 (CDK4), and fluorescence in situ hybridization showed amplification of MDM2. Thus, the tumor was diagnosed with a dedifferentiated liposarcoma of the descending colon. Liposarcoma is a type of soft-tissue sarcoma that arises from soft tissues such as the extremities or retroperitoneum. Here, we report an extremely rare case of a dedifferentiated liposarcoma of the colon.