Hereditary Diffuse Gastric Cancer Treated by Prophylactic Total Gastrectomy.

We herein report a rare case of hereditary diffuse gastric cancer in a Japanese man. A 41-year-old man underwent esophagogastroduodenoscopy which revealed a small gastric erosion. Biopsy specimens showed signet ring cell carcinoma, and endoscopic submucosal dissection was performed. The patient's elder sister had died of gastric cancer at 38 years old. Considering the family history, a genetic test was conducted and revealed a CDH1 germline mutation. Although no carcinomatous lesion was detected endoscopically, prophylactic total gastrectomy was performed. The resection specimen showed seven microlesions of signet ring cell carcinoma confined to the lamina propria mucosae.

Buried bumper syndrome in percutaneous endoscopic gastrostomy with a jejunal extension tube in patients undergoing levodopa-carbidopa intestinal gel treatment.

BACKGROUND: Levodopa-carbidopa intestinal gel (LCIG) treatment is an effective Parkinson's disease (PD) treatment that requires percutaneous endoscopic gastrostomy with a jejunal extension tube (PEG-J). Buried bumper syndrome (BBS) is an uncommon but significant complication of PEG-J for LCIG. Case presentation A 71-year-old man had been undergoing LCIG therapy for PD since a PEG-J was implemented at our department two years previously. He presented with appetite loss. Computed tomography showed that the gastrostomy bumper was buried in the gastric wall. The patient was surgically treated with the simultaneous removal and replacement of PEG-J. Postoperative gastrocutaneous fistula occurred, which was conservatively treated. CONCLUSIONS: Notably, patients and medical staff should be aware that patients with PD on LCIG treatment have a high risk of BBS in PEG-J and that there might be some patients with latent BBS. When simultaneous removal and replacement surgery is performed, establishing a new route at the stomach and abdominal wall is recommended.

EphA2 Proteolytic Fragment as a Sensitive Diagnostic Biomarker for Very Early-stage Pancreatic Ductal Carcinoma.

Cleavage of erythropoietin-producing hepatocellular ephrin receptor A2 (EphA2) triggers malignant progression and yields an N-terminal fragment (EphA2-NF) detectable in sera from patients with pancreatic ductal carcinoma. We established a quantitative automated chemiluminescence immunoassay for EphA2-NF and evaluated serum EphA2-NF levels as a biomarker to diagnose pancreatic ductal carcinoma in the test and validation cohorts. The EphA2-NF value was elevated (above the cutoff: mean ± SD) in more than half of the patients with stage I/II pancreatic ductal carcinoma. Among patients receiving standard chemotherapy for pancreatic ductal carcinoma [gemcitabine plus nab-paclitaxel (GnP)], the median survival time of patients with elevated serum EphA2-NF was half that of patients with values below the cutoff. Patients with intraductal papillary mucinous neoplasm (IPMN), a precancerous pancreatic ductal carcinoma lesion, also show high serum EphA2 levels, which are associated with an increase in pancreatic duct size and the development of pancreatic ductal carcinoma in some cases. IHC showed loss of EphA2-NF staining in IPMN with pancreatic ductal carcinoma, but not in the normal epithelium or IPMN without pancreatic ductal carcinoma, regardless of the histologic grade. These results suggest that EphA2 cleavage is an essential event that occurs very early in pancreatic ductal carcinoma development, and that the consequent release of EphA2-NF can be detected in the serum. Thus, serum EphA2-NF could be a diagnostic biomarker for very early-stage pancreatic ductal carcinoma and pancreatic ductal carcinoma development from high-risk IPMN and as a prognostic biomarker after chemotherapy with GnP. SIGNIFICANCE: EphA2 N-terminus deletion is involved in pancreatic ductal carcinoma development from high-risk IPMN and EphA2-NF produced by cleavage can be used as a serum biomarker to diagnose pancreatic ductal carcinoma and predict pancreatic ductal carcinoma development from high-risk IPMN.

Segmental cervical esophagectomy with free jejunal flap reconstruction for cervical esophageal cancer in patients with previous history of gastric surgery: a report of two cases.

Although free-flap jejunal reconstruction is frequently performed after cervical esophagectomy for cervical esophageal cancer, the procedure after gastric surgery has not been reported. We encountered two patients with esophageal cancer and previous gastric surgeries who eventually underwent segmental esophagectomy with free-flap jejunal reconstruction. Case one involved a 75-year-old man who underwent abdominal abscess and duodenal ulcer perforation surgeries (abdominal drainage and subsequent gastrojejunal bypass). A type 0-IIa tumor was located posterior to the cervical esophagus's right wall, 21 cm from the incisor, without lymph node swelling or distant metastasis. The left lobe of the thyroid gland was mobilized to ensure an oral resection margin. Severe abdominal adhesions required careful adhesiolysis to harvest the jejunum (20 cm long) 40 cm from the jejunojejunostomy. An end-to-side and side-to-end esophagojejunostomy were performed for the proximal and distal ends, respectively. Case two involved a 75-year-old male with a history of distal gastrectomy with Billroth I reconstruction for early gastric cancer. A submucosal tumor-like lesion was located on the cervical esophageal wall on the left side, 21 cm from the incisor. The distal esophagus required additional segmental resection because the anal resection line was close to the tumor. Jejunum (10 cm long) 30 cm from Ligament of Treitz was harvested. An end-to-side and end-to-end esophagojejunostomy for the proximal and distal ends, respectively, was performed. This surgery requires a thorough preoperative examination to ensure an adequate surgical margin and a careful free-flap harvest based on post-gastric surgery anatomy.

Therapeutic strategy aiming at R0 resection for borderline-resectable esophageal squamous cell carcinoma using induction chemotherapy with docetaxel, cisplatin, and 5-fluorouracil.

OBJECTIVE: Treatment for borderline resectable (cT3br) esophageal squamous cell carcinoma (SCC) is currently undefined. This study aimed to analyze the outcome of treatment strategies including induction chemotherapy with docetaxel, cisplatin, and 5-fluorouracil (DCF) against T3br esophageal SCC. METHODS: A total of 32 patients with cT3br esophageal SCC enrolled in this study were treated with two cycles of DCF induction therapy. RESULTS: The overall response rate to DCF induction therapy was 62.5%, while the disease control rate was 93.8% (complete response (CR), three; partial response (PR), 17; stable disease (SD), 10; progressive disease (PD), 2). After DCF induction chemotherapy, 27 patients underwent conversion surgery (CS) and five patients underwent definitive chemoradiotherapy (CRT). Out of 27 patients who underwent CS, 17 underwent transthoracic esophagectomy and 10 underwent thoracoscopic esophagectomy. Anastomotic leakage occurred in five patients (18.5%) and pneumonia in four (14.8%). Recurrent laryngeal nerve paralysis and arrhythmia were observed in two patients (7.4%). The R0 resection rate was 81.5%. Among the five patients who underwent definitive CRT, only one patient (20.0%) achieved CR. Two patients (40.0%) had PR and two (40.0%) had PD. Salvage esophagectomy was performed in one patient after definitive CRT. The 1-, 3-, and 5-year overall survival rates were 75.0, 50.6, and 46.4%, respectively, whereas the 1-, 3-, and 5-year disease-free survival rates were 54.9, 38.8, and 38.8%, respectively. CONCLUSION: DCF induction therapy and subsequent CS or definitive CRT are promising treatment strategies for cT3br esophageal SCC.

Successful combined laparoscopic and thoracoscopic surgery for esophago-mediastinal fistulae.

Minimally invasive surgeries have been developed, not only for gastrointestinal cancer, but also for benign or emergency cases. We report the case of a 62-year-old male who underwent laparoscopic and thoracoscopic combined surgery for an esophago-mediastinal fistula caused by a press-through package. In the initial laparoscopic phase, transhiatal dissection of the lower thoracic esophagus and harvesting of the greater omentum were performed. In the thoracoscopic phase, resection of the fistula and esophageal wall closure were performed. Thereafter, the greater omentum was lifted via the esophageal hiatus and wrapped around the repaired part of the esophagus for reinforcement. The total operative time was 371 min, with 163 and 208 min for the laparoscopic and thoracoscopic phases, respectively. In total, 20 ml of blood was lost. No perioperative complications or recurrences were observed. Laparoscopic and thoracoscopic combined omentoplasty was effective for refractory esophago-mediastinal fistula.

Clinical evaluation of urine laminin-γ2 monomer as a potent biomarker for non-muscle invasive bladder cancer.

BACKGROUND: To evaluate whether urine laminin-γ2 monomer (Ln-γ2m) offers a useful biomarker for patients with non-muscle-invasive bladder cancer (NMIBC). METHODS: Participants comprised 297 patients, including 111 patients with NMIBC, 136 patients with benign genitourinary disease (BD) and 50 healthy donors (HD). Urine Ln-γ2m was prospectively measured and accuracy was analyzed. Receiver operating characteristic (ROC) curves were determined and area under the ROC curve (AUC) was calculated for urine Ln-γ2m, and compared to those of traditional urine tumor markers such as nuclear matrix protein 22 (NMP22), bladder tumor antigen (BTA) and cytology. The net benefits of combining urine markers were analyzed by decision curve analysis. RESULTS: Mean urine Ln-γ2m was significantly higher in NMIBC than in BD or HD. The AUC for urine Ln-γ2m was significantly higher than those for urine NMP22, BTA or cytology when comparing NMIBC with HD. In patients with low-grade NMIBC, the AUC for urine Ln-γ2m was higher than the AUCs for NMP22, BTA or cytology. A net benefit of combined examination using urine Ln-γ2m/uCRN with NMP22 was demonstrated. CONCLUSION: These results suggest urine Ln-γ2m as a potentially useful biomarker for NMIBC, particularly in cases of low-grade cancer.

Strategy Treatment of cT4b Esophageal Squamous Cell Carcinoma Using Docetaxel, Cisplatin, and 5-Fluorouracil.

BACKGROUND/AIM: This study analyzed the outcomes of docetaxel, cisplatin, and 5-fluorouracil (DCF) therapy and DCF plus concurrent radiotherapy (DCF-RT), both followed by conversion surgery, if possible, in patients with cT4b esophageal cancer. PATIENTS AND METHODS: Forty-six patients with cT4b esophageal cancer, including borderline cT4b lesions, were eligible. Borderline cT4b lesions were treated with induction DCF therapy. For definitive cT4b lesions, definitive DCF-RT was administered. Patients unsuitable for induction DCF therapy or DCF-RT were treated with other therapies. After treatment, conversion surgery (CS) was performed for the residual tumor in resectable cases. RESULTS: Induction DCF therapy was administered to 12 patients (group A), and DCF-RT was provided to 18 patients (group B). Meanwhile, other therapies were provided to 16 patients (group C). The 1-, 3-, and 5-year overall survival (OS) rates were 66.7, 30.0, and 15.0%, respectively, in group A; 66.7, 37.5, and 37.5%, respectively, in group B; and 62.5, 0, and 0%, respectively, in group C. DCF-RT tended to prolong survival, albeit without significance (p=0.1040). The group A + B had significantly better overall survival than group C (p=0.0437). Fourteen patients underwent CS (30.4%), and patients who underwent CS had significantly better overall survival than those who did not undergo surgery (p=0.0291). CONCLUSION: Induction DCF or DCF-RT is promising for the treatment of cT4b esophageal cancer. Effective CS including combined resection of the invaded organ can contribute to improved therapeutic outcomes.

Dislocation of the gastric conduit reconstructed via the posterior mediastinal route is a significant risk factor for anastomotic disorder after McKeown esophagectomy.

BACKGROUND: Anastomotic disorder of the reconstructed gastric conduit is a life-threating morbidity after thoracic esophagectomy. Although there are various reasons for anastomotic disorder, the present study focused on dislocation of the gastric conduit (DGC). METHODS: The study cohort comprised 149 patients who underwent transthoracic esophagectomy. The relationships between DGC and peri- and postoperative morbidities were analyzed retrospectively. Data were analyzed to determine whether body mass index (BMI) and extension of the gastric conduit were related to DGC. Uni- and multivariate Cox regression analyses were performed to identify the factors associated with anastomotic disorder. RESULTS: DGC was significantly related to anastomotic leakage (P < .001), anastomotic stricture (P = .018), and mediastinal abscess/empyema (P = .031). Compared with the DGC-negative group, the DGC-positive group had a significantly larger mean preoperative BMI (23.01 ± 3.26 kg/m2 vs. 21.22 ± 3.13 kg/m2, P = .001) and mean maximum cross-sectional area of the gastric conduit (1024.75 ± 550.43 mm2 vs. 619.46 ± 263.70 mm2, P < .001). Multivariate analysis revealed that DGC was an independent risk factor for anastomotic leakage (odds ratio: 4.840, 95% confidence interval: 1.770-13.30, P < .001). Body weight recovery tended to be better in the DGC-negative group than in the DGC-positive group, although this intergroup difference was not significant. CONCLUSION: DGC reconstructed via the posterior mediastinal route is a significant cause of critical morbidities related to anastomosis. In particular, care is required when performing gastric conduit reconstruction via the posterior mediastinal route in patients with a high BMI.

The Prognostic Significance of Plakophilin-1 Expression in Esophageal Cancer.

BACKGROUND/AIM: Plakophilin 1 (PKP1) expression is inversely related to cancer grade. This study aimed to evaluate whether PKP1 is a prognostic marker for esophageal cancer (EC). MATERIALS AND METHODS: We tested immunohistochemically for PKP1 in squamous cell carcinoma EC specimens from 99 patients, including cytoplasmic (C), membrane (M), and nuclear (N) cellular areas, and analyzed their relationships with clinicopathological factors. RESULTS: PKP1stains were stratified into strong and weak for all three cellular areas. Staining was inversely related to tumor depth (C: p=0.002, M: p=0.00007, N: p=0.02), lymph node metastasis (C: p=0.003, M: p=0.001, N: p=0.004) and pathological stage (C: p=0.0004, M: p=0.0001, N: p=0.006). Cytoplasmic and membrane staining were inversely related to vessel invasion. Patients with strong C stain had a better overall survival than those with weak C stains (p=0.01). Disease-free survival of patients with strong M stains was better than that of those with weak staining (p=0.01). CONCLUSION: Cytoplasmic and membrane PKP1 expression is a possible prognostic marker for EC.

Serum Laminin γ2 Monomer as a Diagnostic and Predictive Biomarker for Hepatocellular Carcinoma.

BACKGROUNDS AND AIMS: Structural dynamics of basement membrane components are still to be elucidated in the process of hepatocarcinogenesis. We evaluated the characteristics of HCC expressing laminin γ2 monomer (LG2m), a basement membrane component not detected in normal tissues, for HCC diagnosis. We further determined whether elevated serum LG2m is a risk factor for HCC development in patients with chronic hepatitis C (CHC). APPROACH AND RESULTS: In HCC cell lines, LG2m was expressed in alpha-fetoprotein (AFP)-negative, CD90-positive cells characterized by highly metastatic natures. Using 14 cell lines and 258 HCC microarray data, we identified that LG2m gene signature was associated with Hoshida's S1/Boyault's G3 molecular subclasses with poor prognosis, which could not be recognized by AFP. Serum LG2m was assessed in 24 healthy donors, 133 chronic liver disease patients, and 142 HCC patients, and sensitivity and specificity of LG2m testing for HCC diagnosis were 62.9% and 70.5%, respectively (cutoff, 30 pg/mL). We evaluated the consequence of LG2m elevation in two independent HCC cohorts (n = 47 and n = 81), and LG2m-high HCC showed poor prognosis with later development of distant organ metastasis (cutoff, 60 pg/mL). LG2m was slightly elevated in a subset of CHC patients, and Kaplan-Meier analysis indicated a high incidence of HCC (n = 70). For validation, we enrolled 399 CHC patients with sustained virological response (SVR) as a multicenter, prospective study, and serum LG2m elevation correlated with a high incidence of HCC in the CHC patients with SVR (P < 0.0001). CONCLUSIONS: LG2m is a predictive biomarker for the development of metastatic HCC. Elevated serum LG2m is an HCC risk in CHC patients who have achieved SVR.

Correction to: Perioperative chemotherapy for locally advanced gastric cancer in Japan: current and future perspectives.

The article Perioperative chemotherapy for locally advanced gastric cancer in Japan: current and future perspectives, written by Masanori Tokunaga, Yuya Sato, Masatoshi Nakagawa, Tomoki Aburatani, Takatoshi Matsuyama, Yasuaki Nakajima and Yusuke Kinugasa was originally published Online First without Open Access.

Surgical and nutritional outcomes of laparoscopic proximal gastrectomy versus total gastrectomy: a meta-analysis.

BACKGROUND: Laparoscopic proximal gastrectomy (LPG) is regarded as a less invasive surgery than laparoscopic total gastrectomy (LTG) for early gastric cancer located on the proximal side of the stomach. However, whether LPG is more effective than LTG remains unclear. METHODS: A systematic literature search of studies assessing short-term surgical and nutritional outcomes after LPG and LTG was conducted. A meta-analysis of surgical outcomes (operative time, intraoperative estimated blood loss, postoperative complications, and length of hospital stay) and nutritional outcomes (decrease in body weight, albumin, hemoglobin, total protein, and lymphocyte count) was then performed. All of 11 papers are a retrospective cohort study. RESULTS: Eleven studies reported assessments of the above-mentioned outcomes in 883 patients. There was a trend towards shorter operative time and lower blood loss for LPG compared to LTG though not reaching statistical significance. Other surgical outcomes showed no significant differences. Patients who underwent LTG had a significantly lower body weight (95% confidence interval, 3.01-6.05, [Formula: see text] = 4.53, p < 0.01) and hemoglobin level (95% confidence interval, 1.88-5.87, [Formula: see text] = 3.87, p < 0.01) than patients who underwent LPG at 1 year after surgery. There were no significant differences in other nutritional outcomes. CONCLUSIONS: These results indicate LPG had some advantages in postoperative nutrition. However, no significant differences in short-term surgical outcomes were noted between the two operations. Our analysis suggests that LPG may be more beneficial compared with LTG in terms of perioperative and nutritional outcomes for early-stage gastric cancer.

Feasibility of laparoscopic gastrectomy for patients with poor physical status: a retrospective cohort study based on a nationwide registry database in Japan.

BACKGROUND: Laparoscopic gastrectomy (LG) is an established minimally invasive procedure for gastric cancer. However, it is controversial whether LG is useful for patients with poor physical status classified into higher classes of the American Society of Anesthesiologists physical status (ASA-PS) classification. The aim of this study was to determine the feasibility of LG in patients with ASA-PS class ≥ 3. METHODS: We extracted data for a total of 28,160 patients with an ASA-PS class ≥ 3 who underwent distal or total gastrectomy for gastric cancer between January 2013 and December 2017 from the National Clinical Database Japan society for gastroenterological surgery registry. We developed a propensity score model from baseline demographics and comorbidities and matched patients undergoing LG to those undergoing open gastrectomy (OG) using a 1:1 ratio. Mortality and morbidities (within 30 days and in-hospital) were compared between the 6998 matched patient pairs. RESULTS: In-hospital mortality was significantly lower in patients undergoing LG than in those undergoing OG (2.3% vs. 3.0%, p = 0.01), while the 30-day mortality was similar (1.6% vs. 1.5%). The length of hospital stay was significantly shorter in the LG group (median, 14 days vs. 17 days, p < 0.001). The LG group had a significantly lower incidence of postoperative complications in patients with any grade complication (20.3% vs. 22.5%, p = 0.002) as well as those with ≥ grade 3 complications (8.7% vs. 9.8%, p = 0.03). CONCLUSION: LG was associated with decreased in-hospital mortality and a lower incidence of several postoperative complications when compared to OG among patients with poor physical condition.

Feasibility and Safety of Early Oral Intake and Discharge After Total or Proximal Gastrectomy: An Analysis of Consecutive Cases Without Exclusion Criteria.

BACKGROUND: Postoperative feeding is administered relatively early in gastric surgery, especially distal gastrectomy, but its feasibility and safety for proximal gastric surgery remains unclear. METHODS: We retrospectively analyzed 91 consecutive patients who underwent total or proximal gastrectomy between 2014 and 2019. Baseline and perioperative results were prospectively recorded in our dataset. In our clinical pathway, sips of water and a soft diet were allowed on postoperative days 1 and 3. Discharge was set at days 6-8, and clinical pathway completion was defined as discharge by postoperative day 8. RESULTS: Median patient age was 69 years, and 25 patients (27%) were aged ≥ 75 years. Fifty-nine patients (65%) had comorbidities. Esophageal involvement occurred in 12 patients (13%), and there were 28 cases (31%) of pathological stage IA. The open approach was applied in 22 patients (24%), laparoscopy was applied in 53 patients (58%), and the robotic approach was applied in 16 patients (18%). Total gastrectomy was performed in 56 patients (62%) and proximal gastrectomy was performed in 35 patients (38%). Overall and severe (Clavien-Dindo grade III or higher) complications occurred in 24 (26%) and 9 (10%) patients, respectively. There were four cases (4%) of esophagojejunal leakage (three with esophagogastric junction cancer, one with long-term corticosteroid use). Clinical pathway completion was achieved in 66 patients (73%), with readmission of five cases (5%). CONCLUSIONS: Early feeding and discharge for total or proximal gastrectomy is feasible and safe as long as it is carefully applied to high-risk patients, but we must be aware of the relatively higher readmission rate of this patient group.

Perioperative chemotherapy for locally advanced gastric cancer in Japan: current and future perspectives.

The standard treatment for locally advanced gastric cancer differs across the world. In western countries, perioperative chemotherapy or postoperative adjuvant chemoradiotherapy are the preferred treatment options, whereas in Asia, D2 gastrectomy followed by postoperative adjuvant chemotherapy is standard. In Japan, adjuvant chemotherapy with S-1 is the standard treatment for pStage II gastric cancer, whereas adjuvant chemotherapy with a doublet regimen is preferred for pStage III gastric cancer. The efficacy of preoperative neoadjuvant chemotherapy using S-1 plus cisplatin, has been investigated in selected patients with expected poor survival outcomes. To expand the indications for neoadjuvant chemotherapy, a clinical trial investigating the efficacy of preoperative S-1 plus oxaliplatin in patients with cStage III (cT3-4N1-3) gastric cancer (JCOG1509) is ongoing in Japan. The addition of immune checkpoint inhibitors to cytotoxic chemotherapy also seems promising and is being investigated in international randomized clinical trials. Although we have to await the final results of these studies, preoperative neoadjuvant chemotherapy is a promising treatment strategy and likely to become standard treatment for locally advanced gastric cancer in Japan.

A case of tracheal obstruction caused by reflux and aspiration of semi-solid nutrients via the nasogastric tube.

INTRODUCTION: Semi-solid nutrients have several advantages, including reduced cases of diarrhea and aspiration pneumonia, and are usually administered via percutaneous endoscopic gastrostomy owing to its high viscosity. Administering semi-solid nutrients via a nasogastric tube was recently introduced in clinical practice; however, its safety has not been well confirmed. PRESENTATION OF CASE: An 82-year-old man with a right occipital hemorrhage and severe diarrhea consulted the nutritional support team. Administrations of semi-solid nutrients (HINE E-GEL®) via the nasogastric tube was initiated, which gradually alleviated his symptoms. Fourteen days after initiation, he suddenly had pulmonary failure owing to a tracheal obstruction caused by the reflux and aspiration of semi-solid nutrients. Intubation and subsequent reflex cough expectorated sputum with gel-form particles, which quickly stabilized his pulmonary condition. After this, his hospital course was stable, and he was referred to another hospital for further rehabilitation. DISCUSSION: Semi-solid nutrients administered via the nasogastric tube have different ingredients compared with those administered via percutaneous endoscopic gastrostomy. HINE E-GEL®, for example, contains pectin and calcium phosphate that changes from liquid to semi-solid inside the stomach via chemical reactions under acidic conditions. Data on the viscosity of HINE E-GEL® in vivo are insufficient. Uncertainty regarding the form and viscosity of HINE E-GEL® inside the stomach complicates clinical practice. CONCLUSIONS: Although semi-solid nutrients have several advantages, including reduced diarrhea and gastroesophageal reflux, evidence on semi-solid nutrients via the nasogastric tube is insufficient. It should be noted that semi-solid nutrient reflux can be more fatal than liquid nutrients.

A subset of diffuse-type gastric cancer is susceptible to mTOR inhibitors and checkpoint inhibitors.

BACKGROUND: Mechanistic target of rapamycin (mTOR) pathway is essential for the growth of gastric cancer (GC), but mTOR inhibitor everolimus was not effective for the treatment of GCs. The Cancer Genome Atlas (TCGA) researchers reported that most diffuse-type GCs were genomically stable (GS). Pathological analysis suggested that some diffuse-type GCs developed from intestinal-type GCs. METHODS: We established patient-derived xenograft (PDX) lines from diffuse-type GCs, and searched for drugs that suppressed their growth. Diffuse-type GCs were classified into subtypes by their gene expression profiles. RESULTS: mTOR inhibitor temsirolimus strongly suppressed the growth of PDX-derived diffuse-type GC-initiating cells, which was regulated via Wnt-mTOR axis. These cells were microsatellite unstable (MSI) or chromosomally unstable (CIN), inconsistent with TCGA report. Diffuse-type GCs in TCGA cohort could be classified into two clusters, and GS subtype was major in cluster I while CIN and MSI subtypes were predominant in cluster II where PDX-derived diffuse-type GC cells were included. We estimated that about 9 and 55% of the diffuse-type GCs in cluster II were responders to mTOR inhibitors and checkpoint inhibitors, respectively, by identifying PIK3CA mutations and MSI condition in TCGA cohort. These ratios were far greater than those of diffuse-type GCs in cluster I or intestinal-type GCs. Further analysis suggested that diffuse-type GCs in cluster II developed from intestinal-type GCs while those in cluster I from normal gastric epithelial cells. CONCLUSION: mTOR inhibitors and checkpoint inhibitors might be useful for the treatment of a subset of diffuse-type GCs which may develop from intestinal-type GCs.