Nonocclusive mesenteric ischemia (NOMI) on Roux limb after biliary reconstruction successfully treated by interventional radiology (IVR).

Nonocclusive mesenteric ischemia (NOMI) is a life-threatening disorder. Early diagnosis is challenging because NOMI lacks specific symptoms. A 52-year-old man who received extended cholecystectomy with Roux-en-Y hepaticojejunostomy for gallbladder cancer (GBC) presented to our hospital with nausea and vomiting. Neither tender nor peritoneal irritation sign was present on abdominal examination. Blood test exhibited marked leukocytosis (WBC:19,800/mm3). A contrast-enhanced abdominal computed tomography (CT) scan revealed remarkable wall thickening and lower contrast enhancement effect localized to Roux limb. On hospital day 2, abdominal arterial angiography revealed angio-spasm at marginal artery and arterial recta between 2nd jejunal artery and 3rd jejunal artery, leading us to the diagnosis of NOMI. We then administered continuous catheter-directed infusion of papaverine hydrochloride until hospital day 7. Furthermore, the patient was anticoagulated with intravenous unfractionated heparin and antithrombin agents for increasing D-dimer level and decreasing antithrombin III level. On hospital day 8, diluted oral nutrition diet was initiated and gradually advanced as tolerated. On hospital day 21, the patient was confirmed of improved laboratory test data and discharged with eating a regular diet. We experienced a rare case of NOMI on Roux limb after 2 years of extended cholecystectomy with hepaticojejunostomy for GBC, promptly diagnosed and successfully treated by interventional radiology (IVR).

Surveillance after resection of non-invasive intraductal papillary mucinous neoplasms (IPMN). A systematic review.

BACKGROUND: The ideal surveillance strategy after partial pancreatectomy for non-invasive IPMN remains undefined and existing guidelines provide conflicting recommendations. The present study was developed in anticipation of the joint meeting of the International Association of Pancreatology (IAP) and the Japan Pancreas Society (JPS) held in Kyoto in July 2022. METHODS: An international team of experts developed the four clinical questions (CQ) to operationalize issues pertaining to surveillance of patients in this context. A systematic review was designed following the PRISMA guidelines and registered in PROSPERO. The search strategy was executed in PubMed/Medline (Ovid), Embase, the Cochrane Library and Web of Science databases. Four investigators individually extracted data from the selected studies and drafted recommendations for each CQ. These were subsequently discussed and agreed upon that the IAP/JPS meeting. RESULTS: From a total of 1098 studies identified through the initial search, 41 studies were included in the review and informed the recommendations. No studies providing level one data were identified in this systematic review, all studies included were cohort or case-control studies. CONCLUSIONS: There is a lack of level 1 data addressing the issue of surveillance of patients following partial pancreatectomy for non-invasive IPMN. The definition of remnant pancreatic lesion in this setting is largely heterogeneous across all studies evaluated. Herein we propose an inclusive definition of remnant pancreatic lesions to guide future prospective efforts for reporting the natural history and long-term outcomes of these patients.

C4orf47 contributes to the dormancy of pancreatic cancer under hypoxic conditions.

In our comprehensive analysis of pancreatic cancer pathology, we found that the C4orf47 molecule was upregulated in hypoxic environments. C4orf47 is reported to be a centrosome-associated protein, but its biological significance in cancer is completely unknown; therefore, we assessed its role in pancreatic cancer. We found that C4orf47 was a direct target of HIF-1α and is upregulated in hypoxic conditions, in which it suppressed the cell cycle and inhibits cell proliferation through up-regulation of the cell cycle repressors Fbxw-7, P27, and p57; and the down-regulation of the cell cycle promoters c-myc, cyclinD1, and cyclinC. Furthermore, C4orf47 induced epithelial-mesenchymal transition and enhanced their cell plasticity and invasiveness. In addition, the p-Erk/p-p38 ratio was significantly enhanced and down-regulated CD44 expression by C4orf47 suppression, suggesting that C4orf47 is involved in pancreatic cancer dormancy under hypoxic conditions. Furthermore, the potential of C4orf47 expression was a good prognostic biomarker for pancreatic cancer. These results contribute to the elucidation of the pathology of refractory pancreatic cancer and the development of novel therapeutic strategies.

Small and large intestinal cancer in patients with Crohn's disease studied by surgeons.

PURPOSE: The current study summarized the clinical course and treatment outcomes of intestinal cancer in CD seen in our department and explored the steps to take in the future. METHODS: Subjects were patients who had been diagnosed with CD at our hospital and who underwent surgery in our department from 1985 to 2020. RESULTS: Thirty-one patients had CD and intestinal cancer, including 6 with cancer of the small intestine and 25 with cancer of the large intestine. In all six patients with cancer of the small intestine, the site where cancer or a tumor developed was at or near the site of the anastomosis made at a previous surgery. Of the 25 patients with cancer of the large intestine, 22 developed cancer in the rectum or anal region. CONCLUSION: Many of the patients with cancer of the small intestine had previously undergone surgery, and the cancer developed at or near the site of the anastomosis. In patients who have previously undergone resection of the small intestine, the small intestine needs to be examined regularly. Cancer of the large intestine often developed in the rectum or anal region of our patients, so a detailed examination of the same site needs to be performed.

Endoplasmic stress-inducing variants in carboxyl ester lipase and pancreatic cancer risk.

BACKGROUND: Endoplasmic reticulum (ER) stress-inducing variants in several pancreatic secretory enzymes have been associated with pancreatic disease. Multiple variants in CEL, encoding carboxyl ester lipase, are known to cause maturity-onset diabetes of the young (MODY8) but have not been implicated in pancreatic cancer risk. METHODS: The prevalence of ER stress-inducing variants in the CEL gene was compared among pancreatic cancer cases vs. controls. Variants were identified by next-generation sequencing and confirmed by Sanger sequencing. Variants of uncertain significance (VUS) were assessed for their effect on the secretion of CEL protein and variants with reduced protein secretion were evaluated to determine if they induced endoplasmic reticulum stress. RESULTS: ER stress-inducing CEL variants were found in 34 of 986 cases with sporadic pancreatic ductal adenocarcinoma, and 21 of 1045 controls (P = 0.055). Most of the variants were either the CEL-HYB1 variant, the I488T variant, or the combined CEL-HYB1/I488T variant; one case had a MODY8 variant. CONCLUSION: This case/control analysis finds ER stress-inducing CEL variants are not associated with an increased likelihood of having pancreatic cancer.

Laparoscopic splenic vessel-preserving distal pancreatectomy after laparoscopic pylorus-preserving gastrectomy: A case report.

A 77-year-old woman who had undergone laparoscopic pylorus-preserving gastrectomy for gastric cancer showed dilatation of the main pancreatic duct in the distal pancreas on ultrasonography during postoperative surveillance. Detailed examination revealed that she had a main-duct type intraductal papillary mucinous neoplasm with high-risk stigmata. As invasive malignancy was not suggested, laparoscopic splenic vessel-preserving distal pancreatectomy was performed to preserve the remnant stomach. Although adhesions around the gastroduodenostomy and splenic artery were severe, the magnified laparoscopic view facilitated the identification of appropriate dissection layers, resulting in limited blood loss. The distal pancreas was successfully resected without sacrificing blood flow to the remnant stomach. The postoperative course was uneventful. The pathological diagnosis was low-grade intraductal papillary mucinous neoplasm. Laparoscopic splenic vessel-preserving distal pancreatectomy for benign or low-grade malignant disease of the distal pancreas can be useful for preserving the remnant stomach in patients with a history of gastrectomy.

Endoplasmic stress-inducing variants in CPB1 and CPA1 and risk of pancreatic cancer: A case-control study and meta-analysis.

Gene variants that encode pancreatic enzymes with impaired secretion can induce pancreatic acinar endoplasmic reticulum (ER) stress, cellular injury and pancreatitis. The role of such variants in pancreatic cancer risk has received little attention. We compared the prevalence of ER stress-inducing variants in CPA1 and CPB1 in patients with pancreatic ductal adenocarcinoma (PDAC cases), enrolled in the National Familial Pancreas Tumor Registry, to their prevalence in noncancer controls in the Genome Aggregation Database (gnomAD). Variants of unknown significance were expressed and variants with reduced secretion assessed for ER stress induction. In vitro assessments were compared with software predictions of variant function. Protein variant software was used to assess variants found in only one gnomAD control ("n-of-one" variants). A meta-analysis of prior PDAC case/control studies was also performed. Of the 1385 patients with PDAC, 0.65% were found to harbor an ER stress-inducing variant in CPA1 or CPB1, compared to 0.17% of the 64 026 controls (odds ratio [OR]: 3.80 [1.92-7.51], P = .0001). ER stress-inducing variants in the CPA1 gene were identified in 4 of 1385 PDAC cases vs 77 of 64 026 gnomAD controls (OR: 2.4 [0.88-6.58], P = .087), and variants in CPB1 were detected in 5 of 1385 cases vs 33 of 64 026 controls (OR: 7.02 [2.74-18.01], P = .0001). Meta-analysis demonstrated strong associations for pancreatic cancer and ER-stress inducing variants for both CPA1 (OR: 3.65 [1.58-8.39], P < .023) and CPB1 (OR: 9.51 [3.46-26.15], P < .001). Rare variants in CPB1 and CPA1 that induce ER stress are associated with increased odds of developing pancreatic cancer.

Primary gastric synovial sarcoma resected by laparoscopic endoscopic cooperative surgery of the stomach: a case report.

BACKGROUND: Primary gastric synovial sarcoma is extremely rare, only 44 cases have been reported so far, and there have been no reports of laparoscopic endoscopic cooperative surgery for this condition. CASE PRESENTATION: A 45-year-old male patient presented with gastric pain. Esophagogastroduodenoscopy was performed that led to the identification of an 8-mm submucosal tumor in the anterior wall of the antrum, and a kit-negative gastrointestinal stromal tumor was suspected following biopsy. On endoscopic ultrasonography, the boundary of the tumor, mainly composed of the second layer, was depicted as a slightly unclear low-echo region, and a pointless no echo region was scattered inside. A boring biopsy revealed synovial sarcoma. Positron emission tomography did not reveal fluorodeoxyglucose (18F-FDG) accumulation in the stomach or other organs. Thus, the patient was diagnosed with a primary gastric synovial sarcoma, and laparoscopic endoscopic cooperative surgery was performed. The tumor of the antrum could not be confirmed laparoscopically from the serosa, and under intraoperative endoscopy, it had delle on the mucosal surface, which was removed by a method that does not involve releasing the gastric wall. Immunohistochemistry showed that the spindle cells were positive for EMA, BCL-2 protein, TLE-1, and SS18-SSX fusion-specific antibodies but negative for KIT and DOG-1. The final pathological diagnosis was synovial sarcoma of the stomach. The postoperative course was good, and the patient was discharged from the hospital on the 11th postoperative day. CONCLUSION: Resection with laparoscopic endoscopic cooperative surgery (LECS), which has not been reported before, was effective for small synovial sarcomas that could not be confirmed laparoscopically. With the combination of laparoscopic and endoscopic approaches to neoplasia with a non-exposure technique (CLEAN-NET) procedure, it was possible to excise the tumor with the minimum excision range of the gastric serosa without opening the stomach.

Laparoscopic distal pancreatectomy for intraductal papillary mucinous neoplasm-associated pancreatic cancer: A case report.

INTRODUCTION AND IMPORTANCE: Intraductal papillary mucinous neoplasm (IPMN) of the pancreas is often found incidentally during examination for other diseases. In addition to the risk of malignant transformation, patients with IPMN are at risk of developing pancreatic cancer. We report a case of pancreatic tail cancer that developed separately from a preexisting IPMN after minimally invasive esophagectomy for cancer of the esophagogastric junction and was resected successfully by laparoscopic distal pancreatectomy. CASE PRESENTATION: A 72-year-old man underwent thoracoscopic and laparoscopic esophagectomy for esophagogastric junction cancer. He had undergone surgery for ascending colon cancer 20 years ago. At that time, IPMN was confirmed in the pancreatic body by a preoperative examination. Computed tomography was regularly performed for postoperative work-up and follow-up of the IPMN, and a solid lesion with cystic components was detected in the pancreatic tail 9 months after the operation. On detailed examination, pancreatic ductal adenocarcinoma concomitant with IPMN, accompanied by a retention cyst, was considered. Laparoscopic distal pancreatectomy was successfully performed after neoadjuvant chemotherapy. Pathological diagnosis of the lesion in the pancreatic tail was of an invasive intraductal papillary mucinous carcinoma (ypT3ypN0yM0 ypStageIIA). CLINICAL DISCUSSION: If an IPMN is detected during preoperative examination for malignancies of other organs, careful follow-up is necessary due to the high risk of pancreatic cancer development. Furthermore, initial operation with minimally invasive surgery may reduce adhesion and facilitate subsequent surgeries. CONCLUSION: We have provided evidence that supports the importance of a careful follow-up of IPMNs, even if they are low risk.

[A Case of Anastomotic Stenosis with Reconstructed Small Intestine Mucosal Damage during Taking S-1 Orally after Gastrectomy for Gastric Cancer].

An 83-year-old woman underwent laparoscopic distal gastrectomy and Billroth Ⅱ reconstruction for gastric cancer. Since histopathological examination revealed that the lesion was Stage ⅢA, she had started taking S-1 as an adjuvant chemotherapy 7 weeks after gastrectomy. Seventeen days later after taking S-1 administration, she felt nauseous and self-interrupted. Nineteen days later, she was urgently hospitalized. Esophagogastroduodenoscopy(EGD)showed anastomotic lumen was open, but reconstructed small intestine mucosal damage was found, and reconstructed small intestine muscle layer was fused to anastomotic region. On 50th day of hospitalization, mucosa was regenerated and endoscopic balloon dilatation (EBD)was performed from 78th day. She was discharged on 151th day of hospitalization after 7 times of EBD. One year later, she does not need EBD and can be taken orally and has no recurrence.

NFκB and TGFß contribute to the expression of PTPN3 in activated human lymphocytes.

We previously reported that protein tyrosine phosphatase non-receptor type 3 (PTPN3), which is upregulated in activated lymphocytes, acts as an immune checkpoint. However, the mechanism by which PTPN3 expression is enhanced in activated lymphocytes is unknown. In this study, we analyzed the mechanism of PTPN3 expression in activated lymphocytes with a view for developing a novel immune checkpoint inhibitor that suppresses PTPN3. Through the activation process, lymphocytes showed enhanced NFκB activation as well as increased PTPN3 expression. NFκB enhanced proliferation, migration, and cytotoxicity of lymphocytes. Furthermore, NFκB enhanced PTPN3 expression and tyrosine kinase activation. TGFß reduced PTPN3 expression and NFκB activation in the cancer microenvironment, and suppressed the biological activity of lymphocytes. The results of this study are expected to provide significant implications for improving existing immunotherapy and developing novel immunotherapy.

FAM115C could be a novel tumor suppressor associated with prolonged survival in pancreatic cancer patients.

Hypoxia is a characteristic feature of the tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC). We have recently explored new targeting molecules and pathways in PDAC cells under hypoxic conditions. In this study, we performed a microarray experiment to analyze the genes up-regulated in PDAC cell lines under hypoxia compared to normoxia, and identified human family with sequence similarity 115, member C (FAM115C) as a candidate gene for further study. Our data showed that FAM115C was overexpressed in PDAC cell lines under hypoxia, and FAM115C inhibition promoted PDAC cell migration and invasion in vitro. FAM115C inhibition did not affect tumor cell proliferation in PDAC. Immunohistochemically, FAM115C expression was observed ubiquitously in normal pancreas, pancreatic intraepithelial neoplasia (PanIN) and PDAC tissue, and it was located mainly in the nucleus but also in the cytoplasm of cells. In qPCR analysis, high expression of FAM115C was correlated with better prognosis in patients with PDAC. Our findings suggest that FAM115C could be a novel tumor suppressor associated with prolonged survival in patients with PDAC.

Patched 1-interacting Peptide Represses Fibrosis in Pancreatic Cancer to Augment the Effectiveness of Immunotherapy.

Pancreatic ductal adenocarcinoma (PDAC) is resistant to immunotherapy. As a factor of resistance, the dense fibrosis of this cancer acts as a barrier to inhibit immune cell infiltration into a tumor. We examined the influence of a Hedgehog signal inhibitor, Patched 1-interacting peptide, on fibrosis, infiltration of immune cells, and immunotherapeutic effects on PDAC. We found that this peptide inhibited proliferation and migration of cancer-associated fibroblasts and cancer cells. Furthermore, this peptide reduced the production of extracellular matrix and transforming growth factor ß1 in cancer-associated fibroblasts and induced expression of HLA-ABC in PDAC cells and interferon-γ in lymphocytes. In vivo, the peptide suppressed fibrosis of PDAC and increased immune cell infiltration into tumors. The combination of this peptide and an anti-programmed death-1 antibody augmented the antitumor effect, and this combination showed the same effect in experiments using cancer cells and autologous lymphocytes. These results indicate that, in addition to the direct effect of tumor suppression, the Patched 1-interacting peptide increases the infiltration of immune cells by reducing fibrosis of PDAC and consequently enhances the effect of immunotherapy. Therefore, treatment with this peptide may be a novel therapy with 2 different mechanisms: direct tumor suppression and enhancing the immune response against PDAC.

PTPN3 expressed in activated T lymphocytes is a candidate for a non-antibody-type immune checkpoint inhibitor.

It has been shown that protein tyrosine phosphatase non-receptor type (PTPN) 3 inhibits T-cell activation. However, there is no definitive conclusion about how the inhibition of PTPN3 in lymphocytes affects immune functions in human lymphocytes. In the present study, we showed that PTPN3 inhibition significantly contributes to the enhanced activation of activated human lymphocytes. The PTPN3 expression of lymphocytes was significantly increased through the activation process using IL-2 and anti-CD3 mAb. Interestingly, inhibiting the PTPN3 expression in activated lymphocytes significantly augmented the proliferation, migration, and cytotoxicity through the phosphorylation of zeta-chain-associated protein kinase 70 (ZAP-70), lymphocyte-specific protein tyrosine kinase (LCK), and extracellular signal-regulated kinases (ERK). Lymphocyte activation by PTPN3 inhibition was observed only in activated CD3+ T cells and not in NK cells or resting T cells. In therapy experiments using autologous tumors and lymphocytes, PTPN3 inhibition significantly augmented the number of tumor-infiltrated lymphocytes and the cytotoxicity of activated lymphocytes. Our results strongly imply that PTPN3 acts as an immune checkpoint in activated lymphocytes and that PTPN3 inhibitor may be a new non-antibody-type immune checkpoint inhibitor for cancer therapy.

Long-term survival of a patient with recurrent gallbladder carcinoma, treated with chemotherapy, immunotherapy, and surgery: a case report.

BACKGROUND: Gallbladder cancer (GBC) is one of the refractory diseases. Multidisciplinary approach including immunotherapy for such cancers has received much attention in recent years. CASE PRESENTATION: A 59-year-old man underwent an extended cholecystectomy for GBC (pathological stage II, T2 N0 M0, [per UICC 7th edition]) that was incidentally found during cholelithiasis surgery, and was then treated with adjuvant gemcitabine (GEM). Three months later, when a recurrence-suspected lesion was detected in segment 5 (S5) of his liver, we started adoptive immunotherapies with cytokine-activated killer (CAK) cell infusions, combined with chemotherapy. After a year of adjuvant immunochemotherapy, the S5 lesion disappeared on imaging, but lesions suspected metastatic recurrence again appeared in S7 and S8 at 4 years and 6 months post-surgery, for which GEM and cisplatin (CDDP) were administered as second-line chemotherapy. Immunochemotherapy produced stable disease (per RECIST) for 9 months, when tumor growth was detected; open microwave coagulo-necrotic therapy (MCN) was performed for these lesions. Three years after MCN, a solitary liver metastasis was detected in S4. MCN was conducted again, and peritoneal dissemination was found intraoperatively. A month after the second MCN, the patient's carcinoembryonic antigen (CEA) level had increased. Therefore, GEM and tegafur-gimeracil-oteracil potassium (TS-1) were administered as third-line chemotherapy. We also switched the adoptive immunotherapy for tumor-associated antigen-pulsed dendritic cell-activated killer (DAK) cell immunotherapy. After nine courses of GEM and TS-1 administration, CEA had decreased to a normal level. At the time of reporting, 9 years and 6 months have passed since the initial surgery, and 18 months have passed since the peritoneal metastasis was detected. GEM and CDDP are currently administered as fourth-line chemotherapy because of re-increased CEA. Although an undeniable metastasis was found in his para-aortic lymph node, this patient visits our clinic regularly for immunotherapy. CONCLUSION: We here report a rare case of long-term survival of recurrent GBC well controlled by multidisciplinary therapy. Immunotherapy may be a promising modality among multidisciplinary methods for advanced cancer.

Combined Gemcitabine and Metronidazole Is a Promising Therapeutic Strategy for Cancer Stem-like Cholangiocarcinoma.

BACKGROUND/AIM: Metronidazole (MNZ) is a common antibiotic that exerts disulfiram-like effects when taken together with alcohol. However, the relationship between MNZ and aldehyde dehydrogenase (ALDH) activity remains unclear. This study investigated whether MNZ reduces cancer stemness by suppressing ALDH activity and accordingly reducing the malignancy of cholangiocarcinoma (CCA). MATERIALS AND METHODS: We developed gemcitabine (GEM)-resistant TFK-1 cells and originally established CCA cell line from a patient with GEM-resistant CCA. Using these cell lines, we analyzed the impacts of MNZ for cancer stem cell markers, invasiveness, and chemosensitivity. RESULTS: MNZ reduced ALDH activity in GEM-resistant CCA cells, leading to decreased invasiveness and enhanced chemosensitivity. MNZ diminished the invasiveness by inducing mesenchymal-epithelial transition and enhancing chemosensitivity by increasing ENT1 (equilibrative nucleoside transporter 1) and reducing RRM1 (ribonucleotide reductase M1). CONCLUSION: MNZ reduced cancer stemness in GEM-resistant CCA cells. Combined GEM and MNZ would be a promising therapeutic strategy for cancer stem-like CAA.

The Novel Selective Pan-TRK Inhibitor ONO-7579 Exhibits Antitumor Efficacy Against Human Gallbladder Cancer In Vitro.

We previously reported that brain-derived neurotrophic factor (BDNF)/neurotrophic receptor tyrosine kinase 2 (NTRK2/TRKB) signaling contributes to induction of malignant phenotype of gallbladder cancer (GBC). Recently, pan-TRK inhibitors have been evaluated and their dramatic clinical activity is being shown for a variety of cancer types harboring an NTRK rearrangement in phase I trials. ONO-7579 is an oral pan-TRK inhibitor currently under investigation in phase I/II clinical trial for TRK-rearranged solid tumors. In this study, we evaluated the anticancer effect of ONO-7579 using GBC cells with or without KRAS mutant, NOZ, TYGBK-1. Our study showed that ONO-7579 had a suppressive effect on GBC proliferation in TYGBK-1, and on invasive potential and vascular endothelial growth factor expression in TYGBK-1 and NOZ. Our data indicated that ONO-7579 could be a promising treatment option for patients with GBC.

Liprin-α4 as a Possible New Therapeutic Target for Pancreatic Cancer.

BACKGROUND/AIM: In pancreatic cancer, where the microenvironment is extremely hypoxic, analyzing signal transduction under hypoxia is thought to be significantly important. By investigating microarray analysis of pancreatic cancer cells cultured under both normoxia and hypoxia, we found that the expression of leukocyte common antigen-related (LAR)-interacting protein (liprin)-α4 was extremely increased under hypoxia compared to under normoxia. MATERIALS AND METHODS: In the present study, the biological significance of liprin-α4 in pancreatic cancer was investigated and whether liprin-α4 has potential as a therapeutic target for pancreatic cancer was estimated. RESULTS: Suppression of liprin-α4 reduced proliferation of pancreatic cancer cells both in vitro and in vivo. Inhibition of liprin-α4 also reduced invasiveness through the suppression of endothelial-mesenchymal transition. Stimulation by liprin-α4 was through phosphoinositide 3-kinase and mitogen-activated protein kinase signaling pathways. CONCLUSION: Liprin-α4 plays a pivotal role in inducing malignant phenotypes such as increased proliferation and invasion in pancreatic cancer, and that liprin-α4 could be a new effective therapeutic target for pancreatic cancer.

Stage IV gastric cancer successfully treated by multidisciplinary therapy including chemotherapy, immunotherapy, and surgery: a case report.

BACKGROUND: The prognosis of stage IV gastric cancer (GC) still remains unfavorable. Multidisciplinary approaches should therefore be considered to improve the survival of patients with stage IV GC. We report here a case of primary GC with potentially unresectable metastasis, successfully treated by a multidisciplinary approach including chemotherapy, immunotherapy, and surgery. CASE PRESENTATION: A 74-year-old man presented with multiple left neck masses. Abdominal computed tomography showed a thickened gastric wall and multiple lymphadenopathies including left supraclavicular lymph node. Gastroenterological endoscopy revealed tumor lesions in the gastric cardia. Tumor biopsy indicated a pathological diagnosis of poorly differentiated adenocarcinoma. Open left cervical lymph node biopsy showed histological features identical with the gastric tumor, indicating left clavicle lymph node metastasis of GC. After 2 years of chemo-immunotherapy with S-1/CDDP, paclitaxel, and cytokine-activated killer cells, lesions other than the stomach lesion had regressed to undetectable on imaging studies. The patient then underwent laparoscopy-assisted total gastrectomy with Roux-en-Y reconstruction followed by adjuvant chemo-immunotherapy with paclitaxel and S-1 for 1 year, and immunotherapy with tumor lysate-pulsed dendritic cell-activated killer cells for 5 years. The patient remained well after 5 years and 6 months of follow-up, with no signs of recurrence. CONCLUSION: Therapeutic combinations including immunotherapy may thus allow surgery to be performed in patients previously considered unsuitable for surgical intervention, potentially leading to a clinical cure, as in the current case.

Hedgehog Inhibition Upregulates TRK Expression to Antagonize Tumor Suppression in Small Cell Lung Cancer Cells.

BACKGROUND/AIM: Previously we have shown that tropomyosin-related kinase B (TRKB) and Hedgehog (Hh) signalling pathways induce malignant phenotypes in many cancer types. However, results from small cell lung cancer (SCLC) clinical trials using TRK and Hh inhibitors have been disappointing. One reason for this may be the existence of crosstalk between TRKB and Hh signalling pathways. In this study, we detected negative crosstalk between the TRKB and Hh-GLI1 signalling pathways. MATERIALS AND METHODS: The human small cell lung carcinoma cell line, SBC-5, was used. Using small interfering RNA to inhibit TRKB and Hh signalling, whether TRKB and Hh signaling contribute to proliferation and invasiveness in SBC-5 cells were investigated. RESULTS: TRKB expression in GLI1 siRNA-transfected SBC-5 cells was higher than that of control cells. GLI1-knockdown alone did not affect invasiveness of SBC-5 cells. However, combined knockdown of TRKB and GLI1 significantly decreased invasiveness. Moreover, combined TRKB and GLI1 knockdown inhibited proliferation and migration to a greater extent than when either was inhibited alone. CONCLUSION: These results suggest that Hh inhibition increases TrkB expression to counter tumor suppression in SBC-5 cells. The combined use of TRKB and Hh inhibitors may, therefore, be useful for the treatment of refractory SCLC.