Correction: Microscopic distance from tumor invasion front to serosa might be a useful predictive factor for peritoneal recurrence after curative resection of T3-gastric cancer.

[This corrects the article DOI: 10.1371/journal.pone.0225958.].

Serine threonine kinase 11/liver kinase B1 mutation in sporadic scirrhous-type gastric cancer cells.

Scirrhous-type gastric carcinoma (SGC), which is characterized by the rapid proliferation of cancer cells accompanied by extensive fibrosis, shows extremely poor survival. A reason for the poor prognosis of SGC is that the driver gene responsible for SGC has not been identified. To identify the characteristic driver gene of SGC, we examined the genomic landscape of six human SGC cell lines of OCUM-1, OCUM-2M, OCUM-8, OCUM-9, OCUM-12 and OCUM-14, using multiplex gene panel testing by next-generation sequencing. In this study, the non-synonymous mutations of serine threonine kinase 11/liver kinase B1 (STK11/LKB1) gene were detected in OCUM-12, OCUM-2M and OCUM-14 among the six SGC cell lines. Capillary sequencing analysis confirmed the non-sense or missense mutation of STK11/LKB1 in the three cell lines. Western blot analysis showed that LKB1 expression was decreased in OCUM-12 cells and OCUM-14 cells harboring STK11/LKB1 mutation. The mammalian target of rapamycin (mTOR) inhibitor significantly inhibited the proliferation of OCUM-12 and OCUM-14 cells. The correlations between STK11/LKB1 expression and clinicopathologic features of gastric cancer were examined using 708 primary gastric carcinomas by immunochemical study. The low STK11/LKB1 expression group was significantly associated with SGC, high invasion depth and frequent nodal involvement, in compared with the high STK11/LKB1 expression group. Collectively, our study demonstrated that STK11/LKB1 mutation might be responsible for the progression of SGC, and suggested that mTOR signaling by STK11/LKB1 mutation might be one of therapeutic targets for patients with SGC.

Microscopic distance from tumor invasion front to serosa might be a useful predictive factor for peritoneal recurrence after curative resection of T3-gastric cancer.

BACKGROUND: Peritoneal recurrence is one of the most frequent recurrent diseases in gastric cancer. Although the exposure of cancer cells to the serosal surface is considered a common risk factor for peritoneal recurrence, there are some cases of peritoneal recurrence without infiltration to the serosal surface even after curative surgery. This study sought to clarify the risk factors of peritoneal recurrence in the absence of invasion to the serosal surface. MATERIALS AND METHODS: Ninety-six patients with gastric cancer who underwent curative surgery were enrolled. In all 96 cases, the depth of tumor invasion was subserosal (T3). The microscopic distance from the tumor invasion front to the serosa (DIFS) was measured using tissue slides by H&E staining and pan-cytokeratin staining. E-cadherin expression was evaluated by immunohistochemical staining. RESULTS: Among the 96 patients, 16 developed peritoneal recurrence after curative surgery. The DIFS of the tumors with peritoneal recurrence (156±220 µm) was significantly shorter (p = 0.011) than that without peritoneal recurrence (360±478 µm). Peritoneal recurrence was significantly correlated with DIFS ≤234 µm (p = 0.023), but not with E-cadherin expression. The prognosis of DIFS ≤234 µm was significantly poorer than that of DIFS >234 µm (log rank, p = 0.007). A multivariate analysis of the patients' five-year overall survival revealed that DIFS ≤234 µm and lymph node metastasis were significantly correlated with survival (p = 0.005, p = 0.032, respectively). CONCLUSION: The measurement of the DIFS might be useful for the prediction of peritoneal recurrence in T3-gastric cancer patients after curative surgery.

[Breast Cancer with Cancerous Ascites with Good QOL by KM-CART-A Case Report].

Patients with cancerous ascites often manifest with various symptoms, such as abdominal distension and poor appetite. Ascites puncture may offer temporary relief, but there is a consentration loss of important proteins, such as albumin and immunoglobulin. Cell-free and concentrated ascites reinfusion therapy(CART)is helpful to compensate for this loss of proteins. However, the volume of ascites that can be retrieved is small, and patients occasionally have high fever at the time of reinjection. CART modified by Keisuke Matsusaki(KM-CART)is an improved version of CART with respect to these points. We performed KM-CART for a woman with breast cancer with ascites arising from peritoneal dissemination, and she had a good QOL until she died. We hope that more patients will benefit from KM-CART.

The clinicopathological significance of Thrombospondin-4 expression in the tumor microenvironment of gastric cancer.

INTRODUCTION: Thrombospondin-4 [1] is an extracellular glycoprotein involved in wound healing and tissue remodeling. Although THBS4 is reportedly frequently expressed in solid tumors, there are few reports of the clinicopathological features of carcinomas with THBS4 expression. We evaluated the clinicopathologic significance of THBS4 expression in gastric carcinoma (GC). MATERIALS AND METHODS: We retrospectively analyzed the cases of 584 GC patients. The expression of THBS4 in each tumor was evaluated by immunohistochemistry. We then divided the patients into the THBS4-high (n = 223, 38.2%) group and THBS4-low (n = 361, 61.8%) group. THBS4 expression in cancer-associated fibroblasts (CAFs), normal-associated fibroblasts (NFs) and gastric cancer cell lines was examined by western blotting. RESULTS: THBS4 is expressed on stromal cells with αSMA or Podoplanin expression in the GC microenvironment, but not expressed on cancer cells with cytokeratin expression. The western blot analysis results showed that CAFs (but not NFs and cancer cells) expressed THBS4. Compared to the THBS4-low expression status, the THBS4-high expression status was correlated with higher αSMA expression, higher invasion depth, lymph-node metastasis, lymphatic invasion, peritoneal cytology, peritoneal metastasis, larger tumor size, microscopic diffuse type, and the macroscopic diffuse infiltrating type. The THBS4-high group's 5-year overall survival rate was significantly poorer than that of the THBS4-low group. A multivariate analysis revealed that THBS4 expression was an independent prognostic factor. CONCLUSION: THBS4 is expressed on CAFs in the gastric cancer microenvironment. THBS4 from CAFs is associated with the metastasis of cancer cells, and is a useful prognostic indicator for gastric cancer patients.

Feasibility of Identifying Patients at High Risk of Hereditary Gastric Cancer Based on Clinicopathological Variables.

BACKGROUND/AIM: Multiplex gene panel tests using next-generation sequencing (NGS) are clinically available for gastric cancer (GC). The NGS tests can reveal unexpected pathogenic variants to be associated with hereditary diseases, i.e., secondary genetic findings. We investigated whether GC patients at high risk of having hereditary gastric cancer (HGC) can be identified by their clinicopathological variables before they undergo NGS cancer gene panel tests. PATIENTS AND METHODS: The cases of 2,286 patients with GC treated at our hospital during the years 1999-2017 were retrospectively analyzed; of them, 143 patients were identified as being at high risk of having HGC (HR-HGC), and the remaining 2,143 patients were classified as having sporadic gastric cancer (SGC). RESULTS: Compared to the SGC group, the HR-HGC status was significantly associated with younger age, female gender, macroscopic type IV and a histologically diffuse type. In a multivariate analysis, being young (i.e., ≤50 years old) was an independent risk factor for HR-HGC. CONCLUSION: Female and young patients with diffuse-type GC are closely associated with a high risk of having HGC, and these factors might predict the detection of secondary genetic findings by NGS testing.

[A 3mm Gastric Neuroendocrine Tumor That Metastasized to a Lymph Node].

A 46-year-old man underwent a medical check-up and gastrointestinal endoscopy, which revealed a brown lesion at the greater curvature of the gastric body. Biopsy was performed, and a gastric neuroendocrine tumor(NET)was diagnosed. The serum levels of gastrin and other tumor markers were not elevated. The preoperative diagnosis was Rindi type Ⅲ gastric NET, and laparoscopic distal gastrectomy with D1 plus lymph node dissection was performed. Histological examination showed that the resected specimen was positive for chromogranin A, CD56, and synaptophysin, which was consistent with the findings of NET. Even though the tumor diameter was only 3 mm, a metastatic #4d lymph node was found. This case suggests that Rindi type Ⅲ gastric NET has high malignant potential, and gastrectomy with lymph node dissection is necessary, regardless of tumor size.

[A Case of Appendiceal Adenocarcinoma with Vesico-Appendiceal Fistula Treated by Additional Laparoscopic Excision].

A 40-year-old woman was admitted to our hospital with the chief complaint of miction pain. MRI showed fundal wall thickening of the bladder in contact with the appendix. Under cystoscopy, redness of the mucous membrane was found in the posterior wall of the bladder. Therefore, laparo-appendectomy with partial cystectomy was performed. Microscopically, adenocarcinoma cells were observed in the lumen of the appendix, invading the wall of the urinary bladder at the fundus of the appendix. We performed laparo-ileocecal resection for a regional lymphadenectomy. Thus, the patient was diagnosed with adenocarcinoma of the appendix[V, type 3, 16×7 mm, tub2, pT4b(SI, urinary bladder), int, INF b, ly0, v0, pN0, cM0, pStage Ⅱ]. The patient has been receiving adjuvant chemotherapy using capecitabine for 6 months. There was no evidence of recurrence after 9 months of follow-up.