TGFß-Responsive Stromal Activation Occurs Early in Serrated Colorectal Carcinogenesis.

Activated TGFß signaling in the tumor microenvironment, which occurs independently of epithelial cancer cells, has emerged as a key driver of tumor progression in late-stage colorectal cancer (CRC). This study aimed to elucidate the contribution of TGFß-activated stroma to serrated carcinogenesis, representing approximately 25% of CRCs and often characterized by oncogenic BRAF mutations. We used a transcriptional signature developed based on TGFß-responsive, stroma-specific genes to infer TGFß-dependent stromal activation and conducted in silico analyses in 3 single-cell RNA-seq datasets from a total of 39 CRC samples and 12 bulk transcriptomic datasets consisting of 2014 CRC and 416 precursor samples, of which 33 were serrated lesions. Single-cell analyses validated that the signature was expressed specifically by stromal cells, effectively excluding transcriptional signals derived from epithelial cells. We found that the signature was upregulated during malignant transformation and cancer progression, and it was particularly enriched in CRCs with mutant BRAF compared to wild-type counterparts. Furthermore, across four independent precursor datasets, serrated lesions exhibited significantly higher levels of TGFß-responsive stromal activation compared to conventional adenomas. This large-scale analysis suggests that TGFß-dependent stromal activation occurs early in serrated carcinogenesis. Our study provides novel insights into the molecular mechanisms underlying CRC development via the serrated pathway.

[Regulation of the Tumor Microenvironment through HER2 Signaling-Insights from Gastric Cancer Cases with Heterogeneous HER2 Overexpression].

HER2, a member of the human epidermal growth factor receptor(HER)family, exhibits gene amplification, protein overexpression, or both in 13-27% of gastric cancer(GC)cases. Through the activation of downstream Akt and ERK pathways, HER2 promotes the survival and proliferation of gastric cancer cells. The impact of HER2 signaling on the tumor microenvironment(TME)in GC remains unclear, and the heterogeneity of HER2 overexpression in GC tissues is considered a contributing factor. In this study, we focused on differences in the TME between HER2-positive and HER2-negative areas in HER2-positive GC and found that HER2 signaling, particularly the HER2-Akt cascade, may suppress stimulator of interferon genes (STING)expression and reduce CD8+ T cell infiltration in tumor cells. Overall, our findings suggest the potential for a novel therapeutic approach to activate the anti-tumor immune response in HER2-positive GC.

The tumor cell-intrinsic cGAS-STING pathway is associated with the high density of CD8+ T cells after chemotherapy in esophageal squamous cell carcinoma.

BACKGROUND: Chemotherapy has the potential to induce CD8+ T-cell infiltration in the tumor microenvironment (TME) and activate the anti-tumor immune response in several cancers including esophageal squamous cell carcinoma (ESCC). The tumor cell-intrinsic cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway has been known as a critical component for regulating immune cell activation in the TME. However, its effect on the infiltration of immune cells induced by chemotherapy in the ESCC TME has not been investigated. METHODS: We examined the effect of the tumor-cell intrinsic cGAS-STING pathway on the infiltration of CD8+ T cells induced by chemotherapy in ESCC using ESCC cell lines and surgically resected ESCC specimens from patients who received neoadjuvant chemotherapy (NAC). RESULTS: We found that chemotherapeutic agents, including 5-fluorouracil (5-FU) and cisplatin (CDDP), activated the cGAS-STING pathway, consequently inducing the expression of type I interferon and T-cell-attracting chemokines in ESCC cells. Moreover, the tumor cell-intrinsic expression of cGAS-STING was significantly and positively associated with the density of CD8+ T cells in ESCC after NAC. However, the tumor cell-intrinsic expression of cGAS-STING did not significantly impact clinical outcomes in patients with ESCC after NAC. CONCLUSION: Our findings suggest that the tumor cell-intrinsic cGAS-STING pathway might contribute to chemotherapy-induced immune cell activation in the ESCC TME.

Systemic inflammation score as a preoperative prognostic factor for patients with pT2-T4 resectable gastric cancer: a retrospective study.

BACKGROUND: Systemic inflammation has been reported to be associated with cancer progression and metastasis. Systemic inflammation score (SIS), calculated from preoperative serum albumin level and lymphocyte-to-monocyte ratio, has been shown to be a novel prognostic factor for several types of tumors. This study aimed to evaluate the prognostic value of the SIS in patients with pT2-4 resectable gastric cancer (GC). METHODS: Total 97 patients with pT2-4 GC who underwent curative surgery from 322 cases between 2009 and 2015 in Fukushima Medical University Hospital were included. We performed univariate and multivariate analyses to evaluate the usefulness of preoperative SIS and other prognostic factors for relapse-free survival (RFS) and overall survival (OS). RESULTS: The higher SIS score was associated with undifferentiated cancer and recurrence. Univariate analysis of RFS identified deeper tumor invasion and higher SIS were significant risk factors and multivariate analysis revealed that both of them were independent prognostic factors for RFS. As for OS, age, tumor invasion, SIS and LNR were significantly correlated with RFS. In multivariate analysis, tumor invasion, SIS and LNR were independent prognostic factors for OS. CONCLUSIONS: SIS was an independent prognostic factor for RFS and OS in pT2-4 resectable gastric cancer patients who underwent curative gastrectomy.

[A Case of MSI-High Sigmoid Colon Cancer in Which Long-Term Survival Was Achieved by Pembrolizumab for Recurrent Lesions Resistant to Conventional Chemotherapy].

The patient underwent sigmoidectomy with D3 lymph node dissection and partial bladder resection for sigmoid colon cancer(cT4bN1M0, cStage Ⅲa), after preoperative chemotherapy with mFOLFOX plus panitumumab, and FOLFOXIRI plus bevacizumab. Postoperative adjuvant chemotherapy was performed by 8 courses of CAPOX. He relapsed hilar lymph nodes and peritoneal dissemination after 13 months after surgery, he underwent resection of the recurrent lesions. Four months after, he developed recurrence in liver and peritoneum. Although he was treated with FOLFIRI plus ramucirumab or aflibercept, resulted in progression of disease, then he received trifluridine tipiracil hydrochloride plus bevacizumab. At this point, the Japanese health insulance had started to cover pembrolizumab, this therapy was started as the fourth chemotherapy after the diagnosis of high frequency microsatellite instability(MSI), and then tumor markers rapidly declined. He underwent 38 courses of pembrolizumab, the recurrent lesions both liver and peritoneum disappeared. He had stoma closure, peritoneal dissemination disappeared not only intraoperatively but also in histologically from the peritoneal scar. He has received pembrolizumab for 4 years without another recurrence. Here, we report a case of MSI-high sigmoid colon cancer in which long-term survival was achieved by pembrolizumab for recurrent lesions resistant to conventional chemotherapy.

[A Case of Perforation of the Duodenum during Chemotherapy with Ramucirumab plus Nab-Paclitaxel for Advanced Gastric Cancer].

A 70-year-old male patient was diagnosed with advanced gastric cancer with para-aortic lymph node metastasis. After diagnostic laparoscopy, the patient received 2 courses of neoadjuvant chemotherapy. Subsequently, distal gastrectomy, D2 plus para-aortic lymph node dissection, and Roux-en-Y reconstruction were performed. An enlarged lymph node(No. 16b2)was identified during surgery. The histopathological diagnosis revealed ypT4b, ypN3b, cM1(LYM; No. 16), Stage ⅣB. Chemotherapy with ramucirumab plus nab-paclitaxel was administered at 6 weeks postoperatively. However, after 2 courses of chemotherapy, the patient developed an abscess discharge from the wound, which was confirmed by an abdominal CT scan and diagnosed as an intra-abdominal abscess derived from duodenal perforation. The abscess was drained percutaneously. Subsequently, chemotherapy with nab-paclitaxel, nivolumab, and trifluridine/tipiracil hydrochloride was administered. After the appearance of brain metastases, the treatment was shifted to palliative care. The patient died 2 years and 7 months later from the primary disease.

Thoracoscopic and endoscopic cooperative surgery for esophageal gastrointestinal stromal tumor: a case report.

BACKGROUND: Esophageal gastrointestinal stromal tumors (GISTs) are relatively rare, accounting for 2-5% of all GISTs. Typically, the treatment is surgery in nature. However, no standard procedure established for esophageal GISTs, and in many cases, subtotal esophagectomy or local resection via thoracoscopy or mediastinoscopy is performed. Thoracoscopic and endoscopic cooperative surgery (TECS) is a surgical approach similar to laparoscopic and endoscopic cooperative surgery used for gastric GIST; however, no reports of its use for esophageal GIST have been published to date. We herein report such a case along with a review of past literature. CASE PRESENTATION: The patient was a 60-year-old man. Upper gastrointestinal contrast imaging revealed a subepithelial lesion in the esophagus. An 18 × 17 mm subepithelial lesion was identified in the left wall, 35 cm from the upper incisors, during upper gastrointestinal endoscopy, and was diagnosed as a GIST through endoscopic ultrasound-guided fine needle biopsy. TECS was therefore performed. The patient was placed in a prone position with his face to the left. After confirming the lesion under endoscopy and left thoracoscopy, the periesophageal area of the lesion was dissected under thoracoscopy. Subsequently, an endoscopic full-layer resection was performed. Finally, the excision site of the lesion was sutured under thoracoscopy. The operation took a total of 3 h and 22 min, with a blood loss of 50 mL. CONCLUSIONS: The appropriate surgical procedure for esophageal GIST should be considered according to the location and size of the lesion. TECS ensures that the resection margins are secured using an endoscopic or thoracoscopic approach. Furthermore, TECS is minimally invasive, avoiding esophagectomy and reconstruction, which makes it a potential surgical option for esophageal GISTs.

Tumor Infiltrating Effector Regulatory T Cells Express VEGF Receptor 2 in Patients With Colorectal Cancer.

BACKGROUND/AIM: Regulatory T cells (Tregs) suppress various anti-tumor immune responses in the tumor microenvironment (TME) and their control is considered essential to enhancing efficacy of cancer immunotherapy. The purpose of the study was to evaluate the strategy to regulate Tregs through the vascular endothelial growth factor (VEGF) pathway. MATERIALS AND METHODS: We evaluated VEGF receptor (VEGFR) expression in subtypes of Tregs by analysis of public databases and through flow cytometry by investigating surgically resected specimens and peripheral blood mononuclear cells (PBMCs) from 26 patients with advanced colorectal cancer (CRC). RESULTS: Analysis of The Cancer Genome Atlas colorectal adenocarcinoma dataset (n=592) showed that mRNA expression of both FLT1 (VEGFR1) and KDR (VEGFR2) was positively correlated with mRNA expression of FOXP3 as well as Treg signature. Clinical specimens revealed abundant VEGFR2 expression on Tregs, but very marginal VEGFR1 expression. The frequency of effector Tregs, the most immunosuppressive fraction of Tregs, was significantly higher in the tumor than in the PBMC and normal mucosa, and the majority of effector Tregs expressed VEGFR2. Furthermore, by using in vitro generated Tregs, the proportion of Tregs expressing IL-10 or TGF-ß1 was significantly inhibited by a VEGFR2 inhibitor. CONCLUSION: A therapeutic strategy targeting the VEGFR2 axis may have a potential to control effector Tregs in the CRC-TME.

Cardiac tamponade caused by a ruptured coronary aneurysm treated with open-chest hemostasis after esophageal cancer surgery: a case report.

Cardiac tamponade is a rare postoperative complication of esophagectomy, with no previous reports of association with coronary artery aneurysm rupture. We present a case of cardiac tamponade caused by coronary aneurysm rupture following esophageal cancer surgery. A 68-year-old man with no history of heart disease underwent robotic subtotal esophagectomy for esophageal squamous cell carcinoma. He experienced intermittent chest pain on postoperative day (POD) 17. Echocardiography revealed increasing pericardial fluid, and pericardiocentesis on POD 34 revealed bloody pericardial fluid. Contrast-enhanced computed tomography and coronary angiography revealed a ruptured coronary aneurysm causing cardiac tamponade. Emergency surgery with a median sternotomy achieved hemostasis, and the patient recovered successfully. Cardiac tamponade after esophageal surgery, particularly from coronary aneurysm rupture, is rare. Prompt diagnosis and treatment are crucial for patient survival. Despite its risks, median sternotomy was effective in achieving rapid hemostasis and patient recovery in this case.

The impact of CLDN18.2 expression on effector cells mediating antibody-dependent cellular cytotoxicity in gastric cancer.

Activating antibody-dependent cellular cytotoxicity (ADCC) by targeting claudin-18 isoform 2 (CLDN18.2) using zolbetuximab, a monoclonal antibody against CLDN18.2, has been considered a promising novel therapeutic strategy for gastric cancer (GC). However, the impact of CLDN18.2 expression on natural killer (NK) cells and monocytes/macrophages-crucial effector cells of ADCC-in GC has not been fully investigated. In the present study, we assessed the impact of CLDN18.2 expression on clinical outcomes, molecular features, and the frequencies of tumor-infiltrating NK cells and macrophages, as well as peripheral blood NK cells and monocytes, in GC by analyzing our own GC cohorts. The expression of CLDN18.2 did not significantly impact clinical outcomes of GC patients, while it was significantly and positively associated with Epstein-Barr virus (EBV) status and PD-L1 expression. The frequencies of tumor-infiltrating NK cells and macrophages, as well as peripheral blood NK cells and monocytes, were comparable between CLDN18.2-positive and CLDN18.2-negative GCs. Importantly, both CLDN18.2 expression and the number of tumor-infiltrating NK cells were significantly higher in EBV-associated GC compared to other molecular subtypes. Our findings support the effectiveness of zolbetuximab in CLDN18.2-positive GC, and offer a novel insight into the treatment of this cancer type, highlighting its potential effectiveness for CLDN18.2-positive/EBV-associated GC.