Sphingomyelin synthase 2 deficiency inhibits the induction of murine colitis-associated colon cancer.

Sphingomyelin synthase 2 (SMS2) is the synthetic enzyme of sphingomyelin (SM), which regulates membrane fluidity and microdomain structure. SMS2 plays a role in LPS-induced lung injury and inflammation; however, its role in inflammation-mediated tumorigenesis is unclear. We investigated the effect of SMS2 deficiency on dextran sodium sulfate (DSS)-induced murine colitis and found inhibition of DSS-induced inflammation in SMS2-deficient (SMS2-/-) mice. DSS treatment induced a significant increase in ceramide levels, with a decrease of SM levels in SMS2-/- colon tissue, and demonstrated attenuation of the elevation of both inflammation-related gene expression and proinflammatory cytokines and chemokines, leukocyte infiltration, and MAPK and signal transducer and activator of transcription 3 activation. After undergoing transplantation of wild-type bone marrow, SMS2-/- mice also exhibited inhibition of DSS-induced inflammation in the colon, which suggested that SMS2 deficiency in bone marrow-derived immune cells was not involved in the inhibition of colitis. Finally, in an azoxymethane/DSS-induced cancer model, SMS2 deficiency significantly decreased tumor incidence in the colon. Our results demonstrate that SMS2 deficiency inhibits DSS-induced colitis and subsequent colitis-associated colon cancer via inhibition of colon epithelial cell-mediated inflammation; therefore, inhibition of SMS2 may be a potential therapeutic target for human colitis and colorectal cancer.-Ohnishi, T., Hashizume, C., Taniguchi, M., Furumoto, H., Han, J., Gao, R., Kinami, S., Kosaka, T., Okazaki, T. Sphingomyelin synthase 2 deficiency inhibits the induction of murine colitis-associated colon cancer.

[Long-Term Survival Due to Combination Therapy in a Patient with Locally Advanced Body-Tail Pancreatic Cancer].

A 49-year-old man was referred to a neighboring hospital with a chief complaint of abdominal pain.He was diagnosed with locally advanced body-tail pancreatic cancer that had invaded the celiac artery and SMA.He came to our department after undergoing radiotherapy, 2.5 Gy×22 Fr, and chemotherapy with gemcitabine(GEM)and S-1.The same chemotherapy was continued for 15 months until DIC occurred.He was subsequently treated with GEM only and then S-1 only in sequence for 6 years.We decided to stop the chemotherapy because the original lesion had been stable for a long time.After 1 month, a hard nodule appeared in the subcutaneous layer of the navel.Although resection was performed and he received chemotherapy, he died after surviving a total of 7 years and 10 months.This case is important when considering whether to discontinue chemotherapy with a stable long-term pancreatic cancer patient.

[Prognosis of Conversion Gastrectomy Cases for Stage IV Gastric Cancer].

BACKGROUND: We evaluated the efficacy of surgical resection following response to primary chemotherapy for prospective registered Stage IV gastric cancer patients. PATIENTS AND METHODS: We analyzed the details and prognosis of 6 patients having advanced gastric cancer clinically diagnosed as resectable following primary chemotherapy between 2011 and 2015. RESULTS: The reason for being diagnosed as unresectable before chemotherapy was metastasis to distant sites, including paraaortic lymph node metastasis in 3 cases, peritoneal metastasis in 2 cases, and liver metastasis in 1 case.Two patients were able to undergo R0 resection, and the remaining 4 patients were unable to undergo complete resection.The median survival time (MST)of the patients who underwent R0 resection was 567.5 days, and the MST of the patients who could not undergo R0 resection was 474 days. CONCLUSION: Careful consideration of conversion gastrectomy may be important in inducing longterm survival in clinical Stage IV gastric cancer patients.

[Radical Resection of cT3a Gallbladder Cancer after Neoadjuvant Chemotherapy - A Case Report].

We report a case of a radical resection of cT3a gallbladder cancer after neoadjuvant chemotherapy(NAC). A 68-year-old man was referred to our hospital with a chief complaint of right hypochondralgia.Imaging findings were consistent with acute cholecystitis with a stone at the neck of the gallbladder, and advanced gallbladder cancer with infiltration into segments 4 and 5 from the fundus of the gallbladder, Gfb, cT3a(liver), cN1(8a), cM0, cStage III B, was diagnosed on staging laparoscopy. The patient received 3 courses of GEM plus CDDP NAC.The response to the treatment included reduction of the main tumor by 35%, diminished accumulation of FDG at the 8a lymph node, and decrease in serum CA19-9, from 163 U/mL to 75 U/mL. Cholecystectomy with the gallbladder bed and regional lymphadenectomy were performed.The histologic examination revealed extensive necrosis and degeneration of cancer cells in the infiltrating lesions, and the therapeutic effect was judged as Grade I b.The patient has now survived for 11 months without recurrence.

[Treatment Outcomes of Advanced Gastric Cancer after Neoadjuvant Chemotherapy with S-1 and Cisplatin].

BACKGROUND: The prognosis after neoadjuvant chemotherapy(NAC)is expected to improve in patients with resectable advanced gastric cancer who are at high risk of recurrence or those with unfavorable prognostic factors. PATIENTS AND METHODS: This retrospective study examined treatment outcomes and survival of 25 patients with advanced gastric cancer who received NAC with S-1 and cisplatin(CDDP)between October 2008 and December 2015. RESULTS: Among patients with clinical Stage II (4 patients)and III (21 patients)tumors, 13 had partial response(PR)and 12 had stable disease(SD). Neither complete response(CR)nor progressive disease(PD)was noted. CR of lymph node metastases was observed in 6 patients, PR in 9 patients, and SD in 7 patients. R0 resection was performed in 16 patients, R1 in 3 patients, and R2 in 6 patients. Histologic grades of primary tumors were Grade 0(1 patient), Grade 1a(16 patients), Grade 1b(5 patients), Grade 2(3 patients), and Grade 3(none). The 3-year survival rate after R0 resection was 46%, 3-year progression-free survival rate was 68%, and 3-year recurrence-free survival rate was 69%. Significant differences were observed for pathologic stages ypN0/1, 2, and 3(p=0.04), tumor down-stage(p=0.02), and overall tumor fStage I , II / III , and IV (p<0.01). CONCLUSION: It is conceivable that R0 resection and downstaging after NAC will improve prognosis.

[A patient with invasive carcinoma derived from IPMN who achieved long-term survival despite lymph node metastasis].

A woman in her 70s was referred for examination of liver dysfunction. A cystic lesion with irregular contrast was observed at the pancreas head. The bile and pancreatic ducts were obstructed by the lesion. Part of the branch of the pancreatic duct at the pancreas head, continuous with the main pancreatic duct, was observed to be extended by using pancreatography. Pancreaticoduodenectomy was performed, and a diagnosis of invasive carcinoma from an intraductal papillary-mucinous neoplasm (IPMN) was made. Postoperative pathological diagnosis showed 16b1 inter-node metastasis. Liver and lung metastases were also detected after surgery; nevertheless, long-term survival was achieved for 5 years and 2 months by using various treatment modalities.

[Evaluation of combination chemotherapy with docetaxel and nedaplatin in patients with advanced or recurrent esophageal cancer].

BACKGROUND: There is no standard regimen after failure of 5-fluorouracil and cisplatin-based first-line chemotherapy in patients with advanced or recurrent esophageal cancer. The feasibility of combination chemotherapy with docetaxel (DOC) and nedaplatin (CDGP) for these patients was retrospectively evaluated. METHODS: Patients received DOC (30 mg/m² intra- venously) and CDGP (30-40 mg/m² intravenously) on days 1 and 15 of each 4-week period. The efficacy and toxicity of combination chemotherapy with DOC and CDGP in 13 patients was analyzed. RESULTS: The patients received a median of 2 cycles of treatment(range, 1-23). The response and disease control rates were 8% and 54%, respectively. Grade 3 or 4 hematological toxicities were neutropenia, anemia, and thrombocytopenia, observed in 4(31%), 11(15%), and 2 patients (15%), respectively. Non-hematological toxicity, anorexia, was detected in only 1 patient(8%). No treatment-related death was observed. The median progression-free survival and overall survival were 3.2 and 11.6 months, respectively. CONCLUSIONS: Combination chemotherapy with DOC and CDGP is considered a feasible regimen for refractory esophageal cancer.

[Evaluation of conversion gastrectomy for treatment of Stage IV advanced gastric cancer].

BACKGROUND: The standard treatment for Stage IV advanced gastric cancer (AGC) is systemic chemotherapy. Because patients who respond to induction chemotherapy seem to have a good prognosis, we converted the treatment strategy to gastrectomy( termed as conversion gastrectomy) in such patients. In this study, we estimated the outcomes of patients who underwent conversion gastrectomy for Stage IV AGC. METHODS: We evaluated patients with Stage IV AGC who underwent conversion gastrectomy from October 2008 through September 2012 and retrospectively analyzed their clinicopathological variables and oncologic outcomes. RESULTS: Twenty patients underwent conversion gastrectomy with an R0 resection rate of 45% (9/20). The median survival time (MST) was 18.0 months overall and did not differ significantly between patients with clinically stable disease( SD) and those with a partial response( PR)( 22.0 months vs 18.0 months, p=0.64). The MST was longer in patients with pathological Grade 1b-3 tumors than in those with Grade 1a tumors (47.8 months vs 16.3 months), and this difference was significant (p=0.04). Patients with R0 resection had a significantly longer MST than those with R1-2 ( 47.8 months vs 14.1 months ). CONCLUSIONS: The present study provides evidence that patients with Stage IV AGC who undergo conversion gastrectomy with a histopathological response have a good prognosis and that R0 resection predicts longer survival.

[A case of jejnal cancer who was controlled peritoneal metastasis, successfully by combination therapy with docetaxel and S-1].

The patient was a 60-year-old man who had been admitted to our hospital because of elevated serum CA19-9 levels. Endoscopy revealed a Borrmann type 2 tumor of the jejunum. Computed tomography (CT) revealed lymph node metastases and peritoneal seeding. Hence, he was diagnosed with advanced jejunal cancer with distant metastasis (T4N1M0 stage). We performed partial resection of the jejunum, and he underwent chemotherapy with docetaxel( DOC) and S-1 for the peritoneal seeding postoperatively. Follow-up CT revealed that the chemotherapy was effective, and the patient achieved complete remission following 9 months of treatment.

[Surgical resection of multiple liver metastases of rectal neuroendocrine tumors].

We report a case of surgically resected multiple liver metastases of rectal neuroendocrine tumors (NET), which could not be controlled by medical treatment. A 66-year-old man was diagnosed as having multiple liver metastases of rectal NET 5 years after the initial diagnosis. Although we performed 5 rounds of transcatheter arterial infusion (TAI) and administered 4 cycles of 5-fluorouracil, Leucovorin, and oxaliplatin( mFOLFOX6), the metastasis gradually spread. The patient was admitted to our hospital to undergo hepatectomy. Extended right hepatectomy and partial resection of the lateral segment were performed. The pathological diagnosis was metastasis of rectal NET and it was classified as grade 2 NET according to the 2010 World Health Organization (WHO) classification. The patient received intramuscular injections of sustained-release octreotide( 30 mg every 4 weeks) after surgery. One year and 2 months after surgery, he shows no signs of recurrence.

[A case of port site recurrence after thoracoscopic resection for lung metastasis of cecal cancer].

We experienced a case of port site recurrence after thoracoscopic resection for lung metastasis of cecal cancer. The patient was a 57-year-old woman who underwent right hemicolectomy at the age of 51 following a diagnosis of cecal carcinoma. She underwent video-assisted thoracic surgery for pulmonary metastasis 2 years after the first surgery. She underwent local resection for a retroperitoneal pelvic wall recurrence 3.5 years after the first surgery. Chest wall port site recurrence occurred 5.5 years after the first surgery, and she underwent partial resection of the left lung and chest wall. Subsequent treatment has been performed with adjuvant chemotherapy, and she is healthy with no evidence of recurrence 7 years and 11 months after the initial surgery. In this case, a good prognosis was obtained by frequent local resection and adjuvant chemotherapy for metachronous multiple metastases.

[A case of gastric endocrine cell carcinoma that responded to chemotherapy with CPT-11+CDDP].

A 57-year-old male patient was referred to our department with a diagnosis of #3 lymph node recurrence of early gastric cancer after treatment of endoscopic submucosal dissection (ESD). The pathological diagnosis of the ESD specimen was neuroendocrine cell carcinoma of the stomach with positive immunohistochemical staining of chromogranin A. The diameter of the tumor was 10 mm and the depth of invasion was pSM2. Distal partial gastrectomy with standard lymph node dissection (D2) was performed. The pathological findings were negative for malignancy in the resected stomach and positive in 2 of the #3 lymph nodes. Adjuvant chemotherapy of S-1 was administered, but a recurrence in the paraaortic lymph nodes was revealed by follow up X-ray computed tomography (X-CT) 3 months later. The case was considered as a S-1 failure, and the chemotherapy was changed to the irinotecan(CPT-11) +cisplatin(CDDP). A clinical complete response (CR) was obtained after two courses and maintained for up to twenty months.

[A case of drug resistant recurrent gastrointestinal stromal tumor treated surgically by resection, partial hepatectomy and diaphragmectomy].

This 69-year-old man underwent a partial jejunectomy for gastrointestinal stromal tumor(GIST) at the age of 60, and subsequently hepatectomy of segment 5, 6, 7 for liver metastasis of GIST a year later. An irregular mass close to the cutting stump of the liver, and a mass that showed enhanced-effect at segment 4 was discovered 28 months after hepatectomy. In order to treat this second recurrence, we administered imatinib and sunitinib sequentially. The tumor subsequently became drug-resistant, so we removed it surgically together with the liver and a portion of right diaphragm, and a tumor in segment 4. The patient shows no recurrent sign 4 months after surgery. This case suggests that surgical resection should be considered for partially drug resistant GIST.

[A case of AGC with pCR after preoperative chemotherapy including S-1 plus cisplatin].

A 79-year-old man complaining of epigastralgia was examined and diagnosed with advanced gastric cancer (UML, Type 5, Ant-Less-Gre, cT4a, cN1, cH0, cP1, cStage IV). A poor prognosis was predicted, but we tried preoperative chemotherapy hoping for a down-staging of the tumor. We chose a regimen of S-1 plus cisplatin as follows: S-1 (60 mg/m2) was administered orally for 3 weeks followed 2 weeks of rest, and cisplatin (50 mg/m2) was administered by intravenous drip on day 8. After three cycles of treatment, diagnostic laparoscopic examination revealed a suspected serosal invasion of the main tumor, but peritoneal dissemination was not seen, and abdominal washing cytology was negative. After the fourth cycle of treatment, total gastrectomy with lymph node dissection (D1+No. 7, 8a, 9, R0) was performed. Histological examination of the resected specimens revealed no residual cancer cells in the primary lesion or regional lymph nodes, resulting in a diagnosis of complete response to chemotherapy according to the Japanese Classification of Gastric Carcinoma. The postoperative course was uneventful, and he has been fine as an outpatient.

[A case report of pathologically complete response with chemo-radiation for rectal cancer].

A 60-year-old female presented to a local hospital with a chief complaint of melena. Since she was found to have a neoplastic lesion in the rectum on endoscopy, she was referred to our hospital. Barium-enema examination and endoscopy showed a 5-cm type-2 lesion proximal to the dentate line, which was diagnosed by biopsy as a moderately differentiated adenocarcinoma. Pelvic CT and MRI showed lower rectal wall thickening with pararectal lymphadenopathy, and FDP-PET showed increased uptake in these sites. Under a diagnosis of cT3, cN2, M0, Stage III b cancer, she started with preoperative chemoradiotherapy, consisting of 50 Gy in 25 fractions and oral UFT (400 mg)/Uzel (75 mg). After therapy, the tumor showed only a 2-cm ulceration, and FDG-PET revealed no abnormal uptake. Under a diagnosis of cT1, cN0, M0, Stage I cancer, super-low anterior resection of the rectum with D2 lymphadenectomy was performed. Histopathological examination showed that cancer cells forming a glandular structure had completely disappeared, leaving a fibrous scar, consistent with a Grade 3 (pCR).

Efficacy of the fat-dissociation method for nodal harvesting in gastric cancer.

BACKGROUND: There is an increased need for accurate staging for gastric cancer treatment. Consequently, it is necessary to carefully examine all dissected lymph nodes for precise staging. Recently, the fat-dissociation method has been developed as a quick and accurate method for harvesting dissected lymph nodes of colorectal cancer cases. AIM: To investigate the usefulness of the fat-dissociation method for harvesting dissected lymph nodes of gastric cancer cases. METHODS: Fifty-six resected specimens from gastric cancer patients who underwent standard curative gastrectomy and lymph node dissection at our hospital were used. Group 2 lymph nodes were separated from each specimen, and the remaining adipose tissue containing the group 1 lymph nodes was used. Some resected specimens were subjected to the fat-dissociation method. One vial of Imofully® was dissolved in 50 mL of saline and injected into the tissue. The tissue was incubated for 1 h and the dissolved fat was removed. Subsequently, the nodes were identified, picked up with scissors, and mapped. The number of nodes in each lymphatic compartment and duration of lymph node harvest and mapping were compared. RESULTS: The fat-dissociation method was used for 24 samples, while the conventional dissection method was used for 32 samples. The total number of harvested lymph nodes was 45.9 in the fat dissociation group and 44.3 in the control group, and there was no significant difference between the two groups. There were also no significant differences in the number of lymph nodes between the two groups based on a comparison of the lymphatic compartments. However, the total median duration of the fat-dissociation method was 38.2 min, reflecting a reduced duration of approximately 60 min compared to the control group. CONCLUSION: Based on our results, the fat-dissociation method is effective in shortening the duration of lymph node harvest in gastric cancer surgery.