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.

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.

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.

Pancreatic metastasis of malignant melanoma presenting as a tumor occluding the main pancreatic duct.

Metastasis to the pancreas is rare, especially for malignant melanoma. In these scarce cases, tumors normally present in the parenchyma of the pancreas. A 70-year-old woman was referred to our hospital for an asymptomatic pancreatic tumor detected by contrast-enhanced computed tomography (CE-CT). She had undergone a pneumonectomy for primary malignant melanoma (MM) of the lung approximately 3 years prior and was receiving nivolumab for recurrent intrapulmonary metastasis. CE-CT revealed a hypo-vascular lesion occluding the main pancreatic duct (MPD) which was consequently dilated. On magnetic resonance imaging, the MPD lesion had high signal intensity on T1-weighted and diffusion-weighted images. Contrast-enhanced endoscopic ultrasonography revealed that the low echoic tumor had heterogenous enhancement in the early phase. Endoscopic retrograde pancreatography (ERP) was performed for evaluation of tumor area and histological diagnosis. A contrast agent defected lesion was observed in the dilated MPD from the pancreas body to tail suggesting the tumor totally occluded the MPD. Biopsy was performed and the specimens obtained from the defect lesion were black in color. Histopathological examination of the black specimens revealed substantial growth of tumor cells with eosinophilic cytoplasm and unequal nuclei size. The tumor cells had a brownish pigmentation of melanin. From these findings, the tumor was diagnosed as pancreatic metastasis of MM. The patient underwent chemotherapy with ipilimumab and nivolumab. The final diagnosis was pancreatic metastasis of MM occurring as a tumor occluding the MPD. ERP was useful for histological diagnosis and could be useful for future cases.

Rare hypervascular pancreatic tumors diagnosed as asynchronous metastases of central nervous system solitary fibrous tumor/hemangiopericytoma.

A 70-year-old woman was referred to our hospital for asymptomatic pancreatic tumors. She had a history of hemagiopericytoma (HPC) about 20 years ago, and no apparent recurrence has been observed. Contrast-enhanced computed tomography revealed two hypervascular tumors in the head and uncinate process of the pancreas, and no obvious neoplastic lesions were found in other organs. Endoscopic ultrasound guided fine-needle aspiration cytology was performed and histopathology showed that spindle-shaped tumor cells were arranged in a hemangiopericytoma-like pattern and positive for STAT6, which was a characteristic feature of solitary fibrous tumors (SFTs). Immunohistochemical staining for surgical pathology specimens from past HPC showed positive expression of STAT6, which was Grade 2 central nervous system solitary fibrous tumor/hemagiopericytoma (CNS SFT/HPC) according to the current WHO classification. From these findings, the pancreatic tumors were preoperatively diagnosed as pancreatic metastases of CNS SFT/HPC. She underwent pancreaticoduodenectomy. Histopathological examination of the surgically resected specimen proved that the both pancreatic tumors were SFT/HPC. Thus, pancreatic tumors were finally diagnosed as asynchronous pancreatic metastases from CNS SFT/HPC. Although extremely rare, metastatic pancreatic tumors derived from SFT/HPC should be considered as a differential diagnosis for hypervascular pancreatic tumors, especially when having a past history of brain tumors.

A rare case of malignant biliary stenosis due to retroperitoneal metastasis from breast invasive ductal carcinoma.

A 50-year-old woman was referred to our hospital for elevated hepatobiliary enzymes. She had a medical history of mastectomy for left breast invasive ductal carcinoma about 10 years ago, and no apparent recurrence had been observed. Contrast-enhanced computed tomography (CT) revealed soft-tissue shadows surrounding the portal vein, celiac artery, and other vessels. The lesions involved the hilar bile duct, and the upstream bile ducts were dilated. Endoscopic retrograde cholangiography showed an obstruction in the hilar bile duct, and biopsies were taken at the site of biliary stenosis. H&E staining showed that cells with strong nuclear atypia and prominent chromatin staining infiltrated in the stroma. Immunohistochemical analysis revealed that the cells were positive for CK7, GATA3 and weakly positive for CK20. Based on these results, we made the diagnosis of biliary stenosis due to retroperitoneal metastasis from breast invasive ductal carcinoma. Biliary inside stents were placed across the biliary stricture, and she received chemotherapy plus endocrine therapy for breast cancer. So far, the partial response has been maintained for 1 year since the diagnosis of retroperitoneal metastasis. Although retroperitoneal metastasis from breast cancer, especially breast invasive ductal carcinoma, is extremely rare, it could be a differential diagnosis for biliary stenosis.

A rare cause of multiple liver masses.

Primary hepatic mucosa-associated lymphoid tissue (MALT) lymphoma is a rare disease. However, if atypical hepatic masses are observed, hepatic MALT lymphoma should be considered in the differential.

Chronic Gastritis Due to Helicobacter Pylori Associated with Increased Serum Levels of CA54/61: A Report of Three Cases.

BACKGROUND The bacterial pathogen Helicobacter pylori (H. pylori) can cause chronic gastritis. CA54/61 is a serum tumor marker that has been shown to be positive in the several types of human malignancy. However, the association of between chronic gastritis due to H. pylori and elevated serum levels of CA54/61 has not been previously reported. This report is of three cases of increased serum levels of CA54/61 associated with H. pylori chronic gastritis. CASE REPORT Case 1 was a 44-year-old Japanese woman with a serum CA54/61 level of 138 U/ml (normal level: 12 U/ml). Following treatment and eradication of H. pylori the serum CA54/61 level decreased to 14 U/ml. Case 2 was a 73-year-old Japanese man with a serum level of less than 2 U/ml before completion of successful eradication therapy of H. pylori with a small peak of 30 U/ml after therapy. Case 3 was a 54-year-old Japanese man who maintained a serum CA54/61 level of approximately 20 U/ml before and until 603 days after eradication therapy. None of the three patients had malignancy, which is usually suggested by this serum marker. CONCLUSIONS These three case reports suggest the possibility of an association between chronic gastritis involving H. pylori infection and an elevated serum level of CA54/61. It is possible that the inflammatory gastric mucosal cells supply CA54/61 to the bloodstream. However, further studies are required to confirm the association between serum levels of CA54/61 and H. pylori chronic gastritis and the underlying mechanisms of this association.

Co-occurrence of types 1 and 2 PrP(res) in sporadic Creutzfeldt-Jakob disease MM1.

The genotype (M/M, M/V, or V/V) at polymorphic codon 129 of the human prion protein (PrP) gene and the type (1 or 2) of protease-resistant PrP (PrP(res)) in the brain are major determinants of the clinicopathological phenotypes of sporadic Creutzfeldt-Jakob disease (sCJD). According to this molecular typing system, sCJD has been classified into six subgroups (MM1, MM2, MV1, MV2, VV1, and VV2). Besides these pure subgroups, mixed cases presenting mixed neuropathological phenotypes and more than one PrP(res) type have been found in sCJD. To investigate the frequency of the co-occurrence of types 1 and 2 PrP(res) in sCJD patients classified as MM1, we produced type 2 PrP(res)-specific antibody Tohoku 2 (T2) that can specifically detect the N-terminal cleavage site of type 2 PrP(res) after protease treatment and examined brain samples from 23 patients with sCJD-MM1. Western blot analysis using the T2 antibody revealed that the minority type 2 PrP(res) could be detected in all sCJD-MM1 brain samples including those of the cerebellum where sCJD-MM2 prions rarely accumulate. These results show that the co-occurrence of types 1 and 2 PrP(res) within a single sCJD-MM1 patient is a universal phenomenon. The general co-occurrence of multiple PrP(res) fragments within a single prion strain questions the validity of the conventional molecular typing system.