Efficacy of pre-operative chemotherapy with docetaxel, cisplatin, and S-1 (DCS therapy) and curative resection for gastric cancer with pathologically positive para-aortic lymph nodes

Background: The prognosis of gastric cancer with para-aortic lymph node (PAN) metastasis is poor. We applied triple combination chemotherapy with docetaxel, cisplatin, and S-1 (DCS therapy) as pre-operative chemotherapy and investigated the outcome of the combination of this therapy and gastrectomy with para-aortic lymph node dissection (PAND). Methods: We retrospectively identified 44 patients with pathologically positive PAN who underwent curative surgery at Kanazawa University Hospital between 1990 and 2008. Among the 44 patients, 16 received pre-operative DCS therapy and subsequent surgical resection after two courses of the therapy. Results: Pre-operative DCS therapy showed high clinical response ratio (68.8%) and disease control ratio (100%). The pathological response ratio of resected specimen was 87.5%. At 2 years after surgery, the overall survival ratio was 93.8% and relapse-free survival was 75.0%. Pre-operative DCS therapy was only independent prognostic factor in multivariate analysis. Grade 3/4 toxicity was observed only in 25.0% of patients who underwent DCS therapy. Surgical complication was observed in 31.3% of patients, and this ratio was equal to that of patients who did not receive DCS therapy. Conclusion: Multimodal therapy comprising combined pre-operative DCS therapy and gastrectomy with PAND was extremely effective and feasible for advanced gastric cancer with PAN metastasis. J. Surg. Oncol © 2011 Wiley Periodicals, Inc

Serum cytokeratin 18 as a biomarker for gastric cancer

Cytokeratin 18 (CK18) fragments are released into circulation during epithelial cell death. M30 (reflects caspase-cleaved CK18 fragment) and M65 (reflects total CK18 fragment) enzyme-linked immunosorbent assay (ELISA) detect circulating CK18 fragments released during caspase-dependent or total cell death, respectively; thus, CK18 has the potential of being a biomarker for epithelial cancers. In the present study, we investigated the serum levels of M30 and M65 in patients with gastric cancer, determined correlation of these levels with clinical features, and evaluated the usefulness of these enzymes as diagnostic and prognostic markers. We enrolled 54 gastric cancer patients and 12 healthy volunteers in this study. We measured the serum levels of M30 and M65 by quantitative ELISA. The levels of M30 and M65 in gastric cancer patients were significantly higher than those in healthy volunteers (P = 0.001, P < 0.001). The enzyme levels were elevated with the progress of gastric cancer. The sensitivity and specificity of M30 as a diagnostic marker were 67.5 and 90.9 %, respectively, and those of M65 were 70.1 and 90.9 %, respectively. The serum levels of M30 and M65 in patient with early gastric cancer were elevated in 38.1 and 66.7 %, respectively. Further, increased serum level of M65 is an independent indicator of poor prognosis (P = 0.036). The serum levels of M30 and M65 may be useful biomarkers for gastric cancer as diagnostic markers that can reflect the extent of cancer. Moreover, M65 levels can be used as a prognostic indicator. © 2012 Springer-Verlag

Predictive factors for postoperative tachyarrhythmia after thoracoscopic esophagectomy and the usefulness of landiolol hydrochloride for its treatment

Background: Tachyarrhythmia after esophagectomy is a severe complication that should not be underestimated because of its negative impact. The aims of this study were to clarify the cause and impact of postoperative tachyarrhythmia after thoracoscopic esophagectomy. Additionally, we analyzed the usefulness of landiolol administration for postoperative tachyarrhythmia. Methods: We evaluated the predictive factors for tachyarrhythmia onset after surgery and its clinical impact in 127 patients who underwent thoracoscopic esophagectomy with extended lymphadenectomy. Moreover, we analyzed the efficacy of landiolol for postoperative tachyarrhythmia. Results: Tachyarrhythmia developed in 38 of the 127 patients. Multivariate analysis showed that advanced age, heart disease, and hyperlipidemia were associated with postoperative tachyarrhythmia. Hyponatremia, hypoalbuminemia, and leukocytosis on postoperative day 3 were significantly associated with tachyarrhythmia onset. The incidence of all complications and respiratory complications, including pneumonia, was significantly higher in patients with than in those without tachyarrhythmia. The mortality rate in the tachyarrhythmia group tended to be higher than that in the nontachyarrhythmia group. Landiolol as a treatment for tachyarrhythmia immediately decreased heart rate and safely reduced subsequent respiratory complications. Conclusion: In elderly patients with cardiac disease or hyperlipidemia, surgeons should be alert for the occurrence of tachyarrhythmia after esophagectomy. Postoperative tachyarrhythmia is a marker of morbidities with particular emphasis on respiratory complications. However, it can be adequately managed by landiolol, resulting in fewer respiratory complications. Landiolol might be a safe and convenient agent for managing postoperative tachyarrhythmia after thoracoscopic esophagectomy, resulting in lower mortality and morbidity rates. © 2013 The Japan Esophageal Society and Springer

Extravasated platelet aggregation in liver zone 3 may correlate with the progression of sinusoidal obstruction syndrome following living donor liver transplantation: A case report

Sinusoidal obstruction syndrome (SOS), previously known as veno-occlusive disease, is relatively rare subsequent to liver transplantation (LT). SOS refractory to medical therapy, however, can result in centrilobular fibrosis, portal hypertension and liver failure. Although sinusoidal endothelial cell damage around central venules (zone 3) occurs early in the development of SOS, the detailed mechanism of SOS development and its association with thrombocytopenia are not yet completely understood. The present report describes a patient who experienced SOS with unexplained thrombocytopenia following living donor LT. The progression of SOS resulted in graft dysfunction and the patient succumbed. The presence of platelets in the liver allograft was assayed immunohistochemically using antibody to the platelet marker cluster of differentiation 42b (platelet glycoprotein Ib). Platelet aggregates were found attached to hepatocytes along the sinusoid and within the cytoplasm of hepatocytes, particularly in zone 3. By contrast, no staining was observed in zone 1. These findings suggested that extravasated platelet aggregation in the space of Disse and the phagocytosis of platelets by hepatocytes were initiated by sinusoidal endothelial cell damage due to the toxicity of the immunosuppressant tacrolimus or a corticosteroid pulse, and that platelet activation and degranulation may be at least partially involved in the mechanism responsible for SOS

Angiotensin II enhances epithelial-to-mesenchymal transition through the interaction between activated hepatic stellate cells and the stromal cell-derived factor-1/CXCR4 axis in intrahepatic cholangiocarcinoma

金沢大学医薬保健研究域医学系We previously reported that hepatic stellate cells (HSCs) activated by angiotensin II (AngII) facilitate stromal fibrosis and tumor progression in intrahepatic cholangiocarcinoma (ICC). AngII has been known as a growth factor which can promote epithelial-to-mesenchymal transition (EMT) in renal epithelial cells, alveolar epithelial cells and peritoneal mesothelial cells. However, in the past, the relationship between AngII and stromal cell-derived factor-1 (SDF-1) in the microenvironment around cancer and the role of AngII on EMT of cancer cells has not been reported in detail. SDF-1 and its specific receptor, CXCR4, are now receiving attention as a mechanism of cell progression and metastasis. In this study, we examined whether activated HSCs promote tumor fibrogenesis, tumor progression and distant metastasis by mediating EMT via the AngII/AngII type 1 receptor (AT-1) and the SDF-1/CXCR4 axis. Two human ICC cell lines and a human HSC line, LI-90, express CXCR4. Significantly higher concentration of SDF-1αwas released into the supernatant of LI-90 cells to which AngII had been added. SDF-1α increased the proliferative activity of HSCs and enhanced the activation of HSCs as a growth factor. Furthermore, addition of SDF-1α and AngII enhanced the increase of the migratory capability and vimentin expression, reduced E-cadherin expression, and translocated the expression of β-catenin into the nucleus and cytoplasm in ICC cells. Co-culture with HSCs also enhanced the migratory capability of ICC cells. These findings suggest that SDF-1α, released from activated HSCs and AngII, play important roles in cancer progression, tumor fibrogenesis, and migration in autocrine and paracrine fashion by mediating EMT. Our mechanistic findings may provide pivotal insights into the molecular mechanism of the AngII and SDF-1α-initiated signaling pathway that regulates fibrogenesis in cancerous stroma, tumor progression and metastasis of tumor cells expressing AT-1 and CXCR4.Embargo Period 6 month

Increased E-selectin in hepatic ischemia-reperfusion injury mediates liver metastasis of pancreatic cancer

金沢大学医薬保健研究域医学系Several recent studies have reported that selectins are produced during ischemia-reperfusion injury, and that selectin ligands play an important role in cell binding to the endothelium and in liver metastasis. Portal clamping during pancreaticoduodenectomy with vessel resection for pancreatic head cancer causes hepatic ischemia-reperfusion injury, which might promote liver metastasis. We investigated the liver colonization of pancreatic cancer cells under hepatic ischemia-reperfusion and examined the involvement of E-selectin and its ligands. A human pancreatic cancer cell line (Capan-1) was injected into the spleen of mice after hepatic ischemia-reperfusion (I/R group). In addition, to investigate the effect of an anti-E-selectin antibody on liver colonization in the IR group, mice received an intraperitoneal injection of the anti-E-selectin antibody following hepatic ischemia-reperfusion and tumor inoculation (IR+Ab group). Four weeks later, mice were sacrificed and the number of tumor nodules on the liver was compared to mice without hepatic ischemia-reperfusion (control group). The incidence of liver metastasis in the I/R group was significantly higher (16 of 20, 80%) than that in the control group (6 of 20, 30%) (P<0.01). Moreover, mice in the I/R group had significantly more tumor nodules compared to those in the control group (median, 9.9 vs. 2.7 nodules) (P<0.01). In the I/R+Ab group, only 2 of 5 (40%) mice developed liver metastases. RT-PCR and southern blotting of the liver extracts showed that the expression of IL-1 and E-selectin mRNA after hepatic ischemia-reperfusion was significantly higher than the basal levels. Hepatic ischemia-reperfusion increases liver metastases and E-selectin expression in pancreatic cancer. These results suggest that E-selectin produced due to hepatic ischemia-reperfusion is involved in liver metastasis.Embargo Period 6 month

Multiple liver metastases of pancreatic solid pseudopapillary tumor treated with resection following chemotherapy and transcatheter arterial embolization: A case report

金沢大学医薬保健研究域医学系A 33-year-old female was diagnosed with a solid pseudopapillary tumor (SPT) of the pancreas and multiple liver metastases at the Department of Gastroenterological Surgery, Ishikawa Prefectural Central Hospital (Kanazawa, Japan). Distal pancreatectomy and postoperative systemic chemotherapy with gemcitabine (GEM) and S-1, an oral fluoropyrimidine derivative, was administered, however, liver metastases became enlarged and local recurrence occurred. Therefore, the patient was referred to the Department of Gastroenterologic Surgery at the Graduate School of Medicine (Kanazawa, Japan) for hepatic arterial infusion (HAI) chemotherapy. Oral S-1 (80 mg/m2) was administered as well as HAI chemotherapy with GEM (1,000 mg/standard liver volume). Following 18 cycles, tumor sizes were reduced and 18-fluorodeoxyglucose positron emission tomography (18FDG-PET) examination revealed obvious reduction of tumor FDG uptake. Transarterial tumor embolization (TAE) was performed for the previously unresectable right subphrenic liver tumor, and the other tumors were surgically resected. The resected tumors were diagnosed as liver metastases and a local recurrence of SPT in the postoperative pathological examination, which revealed that the resected tumors were composed of sheets of bland cells, which were positive for CD10, CD56, vimentin, neuron-specific enolase and α-antitrypsin. The postoperative course was uneventful, and the patient is currently under observation at an outpatient clinic; postoperative adjuvant chemotherapy with oral S-1 has continued, and additional TAE is planned. In the future, if the middle segment of the liver becomes enlarged, surgery for the residual right lobe tumor may be possible. This case demonstrates one method of SPT treatment: Preoperative HAI chemotherapy with GEM, plus oral S-1 and TAE. If complete resection can be achieved, the majority of patients with SPT have a favorable prognosis. In patients with unresectable metastases from SPT, it is crucial to conduct systematic multimodal treatment to maximize treatment success. © 2015, Spandidos Publications. All Rights Reserved.Embargo Period 6 month

Pt/WO3 Nanoparticle-Dispersed Polydimethylsiloxane Membranes for Transparent and Flexible Hydrogen Gas Leakage Sensors

Hydrogen gas is a promising, clean, and highly efficient energy source. However, to use combustible H2 gas safety, high-performance and safe gas leakage sensors are required. In this study, transparent and flexible platinum-catalyst-loaded tungsten trioxide (Pt/WO3) nanoparticle-dispersed membranes were prepared as H2 gas leakage sensors. The nanoparticle-dispersed membrane with a Pt:W compositional ratio of 1:13 was transparent and exhibited a sufficient color change in response to H2 gas. The membrane containing 0.75 wt.% of Pt/WO3 nanoparticles exhibited high transparency over a wide wavelength range and the largest transmittance change in response to H2 gas among the others. The heat treatment of the particles at 573 K provided sufficient crystallinity and an accessible area for a gasochromic reaction, resulting in a rapid and sensitive response to the presence of H2 gas. The lower limit of detection of the optimized Pt/WO3 nanoparticle-dispersed membrane by naked eye was 0.4%, which was one-tenth of the minimum explosive concentration. This novel membrane was transparent as well as flexible and exhibited a clear and rapid color response to H2. Therefore, it is an ideal candidate sensor for the safe and easy detection of H2 gas leakage

Salvage treatment with temozolomide in refractory or relapsed primary central nervous system lymphoma and assessment of the MGMT status

High-dose methotrexate (HD-MTX) is effective in the initial treatment of primary central nervous system lymphoma (PCNSL). Since the treatment options in patients with progressive or recurrent PCNSL are limited, their prognosis is remains poor. Temozolomide, a well-tolerated oral alkylating agent that permeates the blood brain barrier, is effective against malignant glioma and recurrent PCNSL. The gene for the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT), which is closely related to cellular sensitivity to alkylating agents, is inactivated by promoter hypermethylation. We evaluated the results of temozolomide treatment and the methylation status of the promoter region of the MGMT gene in 17 patients (median age 68 years) with refractory or relapsed PCNSL. They were immunocompetent and had received initial treatment with HD-MTX (3.5 g/m2) with or without irradiation. All were treated with temozolomide 150 to 200 mg/m2, for 5 days in the course of 28 days; treatment was continued until disease progression. We observed 5 complete remissions, 5 partial responses and stable disease, and 7 disease progressions. Median overall survival after the temozolomide treatment was 6.7 months. One patient manifested grade 3 neutropenia and thrombocytopenia. Eleven tumor specimens were available for MGMT analysis. MGMT promoter methylation (mMGMT) in the tumor tissue was found in 4 (36.4%), the other 7 harbored a non-methylated MGMT promoter (nmMGMT). There was no statistically significant difference in median overall survival between patients with mMGMT (11.1 months) and nmMGMT (6.7 months)(p=0.63). Although some patients were elderly and had been heavily pre-treated, temozolomide produced a complete response in 29% and was well tolerated without any major toxicity

Therapy-associated secondary tumor in patients with non-germinomatous malignant germ cell tumors

We report 3 patients with non-germinomatous malignant germ cell tumor (NGMGCT) who developed therapy-associated secondary tumors. They were diagnosed as having NGMGCT by elevated serum levels of β-fetoprotein (AFP), human chorionic gonadotropin (HCG), or β-HCG. Preoperatively, all patients received a combination of etoposide and platinum-based chemotherapy and radiotherapy; neo-adjuvant therapy (NAT) was followed by complete excision of the residual tumor. Postoperatively, all underwent maintenance chemotherapy and all remained free of NGMGCT without recurrence. However, they developed therapy-associated secondary tumors, i.e. glioblastoma, meningioma, or cavernous angioma after an interval of 10.1-, 9.8-, and 8.2 years, respectively. The patient with gliobastoma died 1 year after its detection. The other 2 patients are currently alive; the meningioma was completely removed and the cavernous angioma is being monitored without additional treatment. To our knowledge, therapy-associated secondary tumors in patients treated for NGMGCT are rare