Stomatin­like protein 2 induces metastasis by regulating the expression of a rate­limiting enzyme of the hexosamine biosynthetic pathway in pancreatic cancer.

Stomatin­like protein 2 (SLP­2) is associated with poor prognosis in several types of cancer, including pancreatic cancer (PC); however, the molecular mechanism of its involvement remains elusive. The present study aimed to elucidate the role of this protein in the development of PC. Human PC cell lines AsPC­1 and PANC­1 were transfected by a vector expressing SLP­2 shRNA. Analyses of cell proliferation, migration, invasion, chemosensitivity, and glucose uptake were conducted, while a mouse xenograft model was used to evaluate the functional role of SLP­2 in PC. Immunohistochemical analysis was retrospectively performed on human tissue samples to compare expression between the primary site (n=279) and the liver metastatic site (n=22). Furthermore, microarray analysis was conducted to identify the genes correlated with SLP­2. In vitro analysis demonstrated that cells in which SLP­2 was suppressed exhibited reduced cell motility and glucose uptake, while in vivo analysis revealed a marked decrease in the number of liver metastases. Immunohistochemistry revealed that SLP­2 was increased in liver metastatic sites. Microarray analysis indicated that this protein regulated the expression of glutamine­fructose­6­phosphate transaminase 2 (GFPT2), a rate­limiting enzyme of the hexosamine biosynthesis pathway. SLP­2 contributed to the malignant character of PC by inducing liver metastasis. Cell motility and glucose uptake may be induced via the hexosamine biosynthesis pathway through the expression of GFPT2. The present study revealed a new mechanism of liver metastasis and indicated that SLP­2 and its downstream pathway could provide novel therapeutic targets for PC.

Novel candidate factors predicting the effect of S-1 adjuvant chemotherapy of pancreatic cancer.

The collagen gel droplet-embedded drug sensitivity test (CD-DST) was revealed to be useful for predicting the effect of S-1 adjuvant chemotherapy for pancreatic ductal adenocarcinoma (PDAC). However, collection of an adequate number of PDAC cells is difficult due to the surrounding fibroblasts. Thus, the aim of this study was to discover novel biomarkers to predict chemosensitivity based on the CD-DST results. Proteomics analysis was performed using liquid chromatography tandem mass spectrometry (LC-MS/MS). Candidate proteins were validated in patients with 5-FU CD-DST results via immunohistochemistry (IHC). The relationships between the candidate proteins and the effect of the adjuvant S-1 were investigated via IHC. Among the 2696 proteins extracted by LC-MS/MS, C1TC and SAHH could accurately predict the CD-DST results. Recurrence-free survival (RFS) was significantly improved in the IHC-positive group compared with the IHC-negative group in both factors. The negative group did not show a significant difference from the group that did not receive S-1. The double-positive group was associated with significantly prolonged RFS compared to the no adjuvant chemotherapy group. C1TC and SAHH have been shown to be useful biomarkers for predicting 5-FU sensitivity as a substitute for the CD-DST in adjuvant chemotherapy for PDAC.

Conversion surgery for positive peritoneal washing cytology in pancreatic cancer.

Positive peritoneal washing cytology (PPC) of pancreatic carcinoma is defined as distant metastasis in the American Joint Committee on Cancer or Union for International Cancer Control's tumour, node, metastases classification. However, surgical resection was believed to be the only method that prolong survival; thus, many institutions perform pancreatectomy for PPC, despite the unfavourable prognosis. Therefore, a more preferable alternative treatment for PPC is required. A 64-year-old man with resectable pancreatic tail cancer presented to our hospital. PPC was detected at first laparotomy; thus, pancreatectomy was avoided and gemcitabine with nabpaclitaxel (GnP) was administered. After four courses of GnP treatment, PPC converted to negative, as evaluated by abdominal port cytology. Thus, distal pancreatectomy was performed, and R0 resection was achieved. He has been healthy for more than 24 months since the first laparotomy. Initial chemotherapy with the intention of converting the cytological status followed by surgical treatment might become a useful treatment strategy for PPC.

Collagen gel droplet-embedded culture drug sensitivity test (CD-DST) predicts the effect of adjuvant chemotherapy on pancreatic cancer.

PURPOSE: We evaluated the clinical effectiveness of collagen gel droplet-embedded culture drug sensitivity tests (CD-DSTs) in predicting the efficacy of adjuvant chemo-therapeutic treatments for pancreatic cancer (PC). METHODS: The clinicopathological characteristics and prognoses of 22 PC patients who underwent CD-DST after pancreatectomy at Tohoku University between 2012 and 2016 were analyzed retrospectively. Eligibility criteria were resectable or borderline resectable PC, successful evaluation for 5-fluorouracil sensitivity by CD-DST, treatment with S-1 adjuvant chemotherapy, and no preoperative chemotherapy. RESULTS: The rate of successful evaluation by CD-DST was 52.3% in PC. The optimal T/C ratio, defined as the ratio of the number of cancer cells in the treatment group (T) to that in the control group (C), for 5-fluorouracil was 85% using receiver operating characteristic curve analysis. The sensitive group (T/C ratio < 85%; n = 11) had a better recurrence-free survival rate than the resistant group (T/C ratio ≥ 85%; n = 11; P = 0.029). A Cox proportional hazards regression model demonstrated that sensitivity to 5-fluorouracil was an independent predictor of recurrence on multivariate analysis (hazard ratio 3.28; 95.0% CI 1.20-9.84; P = 0.020). CONCLUSIONS: CD-DSTs helped to predict PC recurrence after S-1 adjuvant chemotherapy.

[Pancreatic Leiomyosarcoma with a Difficult Preoperative Diagnosis-A Case Report].

A 43-year-old man was referred to our hospital for examination of a pancreatic tumor. Imaging revealed a mass-like lesion with a cyst in the pancreatic tail. Histological examination by EUS-FNA showed a low grade spindle cell lesion for which laparoscopic distal pancreatectomy was performed. The neoplasm was histologically diagnosed as pancreatic leiomyosarcoma. The postoperative course was uneventful and no signs of recurrence at 8 months after the surgery. Pancreatic leiomyosarcoma is very rare. Only 7 previous cases were reported in Japan. In tumors with diameters exceeding 50 mm, bleeding and necrosis occur inside the tumor and a cyst-like form often develops, which is considered a characteristic imaging finding. Therefore, imaging is important for preoperative differential diagnosis of the disease.

[Neoadjuvant Chemoradiotherapy for Locally Advanced Carcinoma Associated with Anal Fistula].

The patient was a 59-year-old man. He was admitted to our hospital because of increasing anal pain with induration of the perianal region. There were large secondary orifices with mucous discharge on the left side of the perineal resion and buttock. We diagnosed adenocarcinoma on analysis of a biopsy specimen from induration of the perianal region. Pelvic CT and MRI showed that the tumor spreaded within the pelvis, with invasion of the prostate and sacrum. We performed neoadjuvant chemoradiotherapy preoperatively. After chemoradiotherapy, the tumor reduced in size greatly. We performed abdominoperineal resection and massive resection of skin of the perianal region. The defect of the pelvic floor and perianal skin was repaired using skin flap. The surgical margin was tumor free. Neoadjuvant chemoradiotherapy was considered effective for locally advanced carcinoma associated with anal fistula.

[Malignant Pleural Mesothelioma with Excessive Inflammation and High Level of Interleukin 6 - A Case Report].

Malignant mesothelioma is a rare aggressive solid tumor that is invariably incurable. A 23-year-old female patient with ascites, anemia, and high levels of ferritin and CRP was diagnosed with pleural mesothelioma by exploratory laparotomy. She remained asymptomatic, but 7 years later, she developed intractable diarrhea and fever. Systematic chemotherapy with both cisplatin and pemetrexed was administered. However, the treatment was discontinued due to side effects, after which time the diarrhea, ascites, and fever became progressively more severe. Hepatomegaly and hepatic siderosis also developed. At the same time, the patient's serum interleukin 6(IL-6)levels were abnormally high. Although there was a temporary symptomatic improvement after intraperitoneal injection of cisplatin, the intractable mesothelioma-associated symptoms returned a few days later. The patient died of liver failure 1 week later. The poor prognosis in this case was due to symptoms associated with the high IL-6 level. There are limited medically proven treatments, and it is important to develop new treatments. Therefore, "anti-IL-6 therapy" may have to be tested as a potential treatment for symptoms associated with high IL-6 levels.