Chemoprevention of esophageal adenocarcinoma in a rat surgical model by a cysteinyl leukotriene receptor­1 antagonist.

Reflux of gastroduodenal contents into the esophagus leads to the development of esophagitis and inflammation-associated pathologies, such as Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). The role of the lipoxygenase (LOX) pathway in carcinogenesis has been recently reported; however, its involvement in esophageal carcinogenesis remains unclear. To address this, the present study investigated the potential of pranlukast, a cysteinyl leukotriene receptor-1 antagonist, to suppress the progression of BE and EAC in a rat duodenogastroesophageal reflux (DGER) model. Male Wistar rats that underwent DGER were divided into two groups. One group was fed commercial chow (control group), and the other was fed experimental chow containing pranlukast (pranlukast group). The rats were sacrificed at 10, 20, 30 and 40 weeks after surgery, and their esophagi were examined. Expression levels of 5-LOX, CD68, IL-8, VEGF and Ki-67 were investigated using immunohistochemistry, and apoptosis was analyzed using the TUNEL method. In the pranlukast group, esophagitis was milder, and the incidence of BE and EAC was significantly lower (P<0.05) compared with that in the control group at 40 weeks after surgery. The number of cells positive for IL-8 and VEGF were significantly lower in the pranlukast group compared with the control group. Proliferative activity was also lower in the pranlukast group compared with the control group (P<0.05). Pranlukast treatment increased apoptosis (P<0.05). Overall, Pranlukast suppressed esophageal carcinogenesis in a rat DGER model, decreasing inflammatory cytokines such as IL-8 and VEGF.

Incidence of and risk factors for totally implantable vascular access device complications in patients with gastric cancer: A retrospective analysis.

Totally implantable vascular access devices (TIVADs) are often used to administer chemotherapy by prolonged intravenous infusion. The objective of the present study was to investigate the incidence of long-term complications and identify risk factors associated with TIVAD placement in patients with gastric cancer. A total of 121 patients with gastric cancer who had undergone 150 TIVAD placement procedures for chemotherapy or supportive care were enrolled in the present retrospective cohort study. A number of risk factors were analyzed, including age, sex, hypertension, diabetes mellitus, history of thrombosis, body mass index, disease stage, and site and purpose of TIVAD. In total, 40 TIVADs (26.7%) developed long-term complications, of which 27 (18.0%) were infections, seven (4.7%) were catheter-related deep vein thrombosis (CR-DVT), and six (4.0%) were obstructions. Chemotherapy was associated with an increased rate of infectious adverse events (odds ratio 2.925; 95% CI, 1.104-7.750; P=0.031) according to the multivariate analysis. CR-DVT occurred more frequently in upper arm ports than in chest wall ports; however, this difference was not statistically significant (7.5 vs. 0.0%; P=0.084) according to the univariable analysis. All CR-DVTs developed in the upper arm sites. Chemotherapy and the upper arm site were associated with long-term complications in patients with TIVAD. However, further studies are needed to confirm the findings of the present study and to determine the reasons for the high incidence of long-term complications in these patients.

Effect of Oral Branched-Chain Amino Acids and Glutamine Supplementation on Skeletal Muscle Atrophy After Total Gastrectomy in Rat Model.

BACKGROUND: Sarcopenia is closely related to short-term outcomes of surgery and long-term prognosis. After gastrectomy, a decrease in muscle strength occurs because of insufficient nutrient intake and disturbed digestive function. Branched-chain amino acids (BCAAs) and glutamine (Gln) play vital roles in the signaling pathways regulating protein synthesis and protein degradation. In this study, we investigated the effects of BCAA and Gln supplementation alone or in combination on skeletal muscle atrophy after total gastrectomy in a rat model. METHODS: Male Wistar rats were divided into five groups: (1) sham operation (n = 8); (2) total gastrectomized rats (TG [control group], n = 16); (3) TG with BCAA (TG-B, n = 16); (4) TG with Gln (TG-G, n = 16); and (5) TG with BCAA and Gln (TG-BG, n = 16). In all groups, body weight, muscle weight, and marker for muscle metabolism were examined. RESULTS: Weight gain was significantly greater in the TG-BG group (130.5%) than in the TG group (108.1%) at 15 wk (P < 0.05). The gastrocnemius muscle weight was significantly higher for TG-BG (2.84 g) than for TG (2.44 g) at 15 wk (P < 0.05). Western blotting indicated that atrogin-1 and MuRF1 levels were lower in the TG-BG group than in the TG group but were not suppressed in the TG-B or TG-G group. CONCLUSIONS: In a rodent sarcopenia model induced by TG, the administration of BCAA in combination with Gln more effectively inhibited muscle atrophy than the administration of BCAA or Gln alone.

Roles of the hexosamine biosynthetic pathway and pentose phosphate pathway in bile acid-induced cancer development.

Esophageal squamous cell carcinomas (ESCCs) as well as adenocarcinomas (EACs) were developed in rat duodenal contents reflux models (reflux model). The present study aimed to shed light on the mechanism by which bile acid stimulation causes cancer onset and progression. Metabolomics analyses were performed on samples of neoplastic and nonneoplastic tissues from reflux models, and K14D, cultivated from a nonmetastatic, primary ESCC, and ESCC-DR, established from a metastatic thoracic lesion. ESCC-DRtca2M was prepared by treating ESCC-DR cells with taurocholic acid (TCA) to accelerate cancer progression. The lines were subjected to comprehensive genomic analyses. In addition, protein expression levels of glucose-6-phosphate dehydrogenase (G6PD), nuclear factor kappa B (NF-κB) (p65) and O-linked N-Acetylglucosamine (O-GlcNAc) were compared among lines. Cancers developed in the reflux models exhibited greater hexosamine biosynthesis pathway (HBP) activation compared with the nonneoplastic tissues. Expression of O-GlcNAc transferase (OGT) increased considerably in both ESCC and EAC compared with nonneoplastic squamous epithelium. Conversely, cell line-based experiments revealed the greater activation of the pentose phosphate pathway (PPP) at higher degrees of malignancy. G6PD overexpression in response to TCA exposure was observed. Both NF-κB (p65) and O-GlcNAc were expressed more highly in ESCC-DRtca2M than in the other cell lines. Moreover, ESCC-DRtca2M cells had additional chromosomal abnormalities in excess of ESCC-DR cells. Overall, glucose metabolism was upregulated in both esophageal cancer tissue and cell lines. While bile acids are not mutagenic, chronic exposure seems to trigger NF-κB(p65) activation, potentially inducing genetic mutations as well as facilitating carcinogenesis and cancer progression. Glucose metabolism was upregulated in both esophageal cancer tissue and cell lines, and the HBP was activated in the former. The cell line-based experiments demonstrated upregulation of the pentose phosphate pathway (PPP) at higher degrees of malignancy. While bile acids are not mutagenic, chronic exposure seems to trigger G6PD overexpression and NF-κB (p65) activation, potentially inducing genetic mutations as well as facilitating carcinogenesis and cancer progression.

A randomized controlled trial of postoperative intravenous acetaminophen plus thoracic epidural analgesia vs. thoracic epidural analgesia alone after gastrectomy for gastric cancer.

BACKGROUND: Acetaminophen is used in multimodal therapy for postoperative pain management. However, the additional effects of acetaminophen in combination with thoracic epidural analgesia (TEA) are not well understood. This prospective, multicenter randomized study was conducted to evaluate the efficacy of routine intravenous (i.v.) acetaminophen in combination with TEA for the management of postoperative pain in gastric cancer surgery. METHODS: A total of 120 patients who underwent distal gastrectomy were randomly assigned in a 1:1 ratio to receive i.v. acetaminophen every 6 h and TEA during the first 3 postoperative days (acetaminophen group) or TEA alone (control group). The primary endpoint was the sum of TEA rescue doses during the first 2 postoperative days. RESULTS: Final analysis included 58 patients in the acetaminophen group and 56 patients in the control group. The median number of TEA rescue doses was significantly lower in the acetaminophen group compared with the control group (3.0 vs. 8.0, p = 0.013). The median area under the curve (AUC) of the pain scores at coughing was significantly less in the acetaminophen group compared with the control group (285 vs. 342, p = 0.046) without an increase in postoperative complications. TEA rescue doses and pain score AUCs were significantly reduced by acetaminophen in patients who underwent open gastrectomy (p = 0.037 and 0.045), whereas there was no significant difference between patients who underwent laparoscopic gastrectomy in the two groups. CONCLUSIONS: In gastric cancer surgery patients, routine i.v. acetaminophen in combination with TEA provides superior postoperative pain management compared with TEA alone.

[Secondary osteoporosis. Bone metabolism disorder after gastrointestinal surgery.]

Bone metabolism disorder caused by surgery and diseases of the gastrointestinal tract has been reported formerly, however the awareness of these disorder is not high. Calcium is absorbed mainly from the duodenum to the upper jejunum, moreover gastric acid plays an important role in digestion and absorption of calcium. Therefore, it is easy to imagine that gastrectomy will cause bone metabolism disorder. Furthermore, bone metabolism disorder accompanies with inflammatory bowel disease is drawing attention in recent years. Bone metabolic disorder accompanying with gastrointestinal dysfunction is not rare, accordingly clinician needs to understand the pathological condition. In this report, we will outline bone metabolism disorder caused by gastrointestinal surgery and diseases.

Multidisciplinary therapy for scirrhous gastric cancer: a retrospective analysis and proposal of new treatment strategy.

BACKGROUND: Scirrhous gastric cancer (SGC) is highly invasive and metastatic because of its interactions with stromal cells, such as fibroblasts and macrophages, and extracellular matrix, leading to a higher incidence of peritoneal metastasis (PM) than other gastric cancers (GCs). Taxane-based intraperitoneal chemotherapy (IPC) is a promising therapy for PM. We retrospectively analyzed outcomes of multidisciplinary therapies that included IPC for SGC. PATIENTS AND THERAPY: Of 1,679 GC patients treated between 1990 and 2012, we analyzed 119 patients who underwent multidisciplinary therapy for SGC. Patients without PM received gastrectomy with lymphadenectomy and resection of involved adjacent organs followed by intraoperative IPC using cisplatin. Patients with PM received chemotherapy using fluorouracil, with or without methotrexate plus IPC using cisplatin before 2000, and S-1 plus IPC using paclitaxel or docetaxel since 2000. RESULTS: Of the 119 patients, 73 (61%) had PM and 63 (53%) had positive peritoneal lavage cytology. Of the 89 gastrectomy patients, 30 (34%) had macroscopic residual tumors (R2). Of the patients treated since 2000, 66 (100%) received S-1 plus taxanes and 44 patients (67%) received taxane-based IPC. Median survival time was significantly longer in the post-2000 group (22.8 months) than in the pre-2000 group (9.5 months). In univariate analysis, lavage cytology, PM, taxane-based IPC, gastrectomy, and R2 resection were significant prognostic factors. However, only R2 resection was an independent prognostic factor in multivariate analysis (hazard ratio: 5.53, 95% CI: 2.05-14.93). CONCLUSION: As use of taxane-based IPC is not an independent prognostic factor, new multidisciplinary therapies are necessary to avoid R2 resections.

Low-dose eribulin mesylate exerts antitumor effects in gastric cancer by inhibiting fibrosis via the suppression of epithelial-mesenchymal transition and acts synergistically with 5-fluorouracil.

BACKGROUND: Characterized by aggressive proliferation, extensive stromal fibrosis, and resulting drug resistance, peritoneal dissemination in gastric cancer remains associated with poor prognosis. Interaction between cancer and stromal cells accelerates tumor progression via epithelial-mesenchymal transition (EMT), which is one of the major causes of tissue fibrosis, and human peritoneal mesothelial cells (HPMCs) play important roles as cancer stroma in peritoneal dissemination. Transforming growth factor-ß (TGF-ß) has a pivotal function in the progression of EMT, and Smad proteins play an important role in the TGF-ß signaling pathway. Eribulin mesylate (eribulin), a nontaxane microtubule dynamics inhibitor used for the treatment of advanced breast cancer, inhibits EMT changes in triple-negative breast cancer cells. We examined its ability to inhibit tumor progression and EMT changes resulting from the interaction between gastric cancer cells and HPMCs and to act synergistically with 5-fluorouracil (5-FU), a key drug for gastric cancer. MATERIALS AND METHODS: Proliferation of gastric cancer cells and HPMCs isolated from healthy omentum was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Following gastric cancer cell/HPMC coculture, EMT markers were detected by immunofluorescence, immunohistochemistry, and Western blotting; invasion assays were performed; and TGF-ß and Smad phosphorylation were assessed by Western blotting and enzyme-linked immunosorbent assay. A mouse fibrotic tumor xenograft model was established using gastric cancer cell/HPMC cocultures. The effect of eribulin and/or 5-FU was tested in each case. RESULTS: Eribulin significantly suppressed gastric cancer cell proliferation and EMT changes in MKN-45 gastric cancer cells and HPMCs induced by their interaction in vitro. Eribulin inhibited EMT at much lower concentrations (≥0.5 nM for MKN-45 and ≥0.1 nM for HPMCs) than its half maximal inhibitory concentrations (2.2 nM for MKN-45 and 8.1 nM for HPMCs), and this resulted, at least partly, from the downregulation of TGF-ß/Smad signaling. Eribulin administration of ≥0.1 mg/kg suppressed tumor progression (0.1 mg/kg, p=0.02), and fibrosis was inhibited by lower dose (0.05 mg/kg, p=0.008) in the xenograft model. Furthermore, 0.05 mg/kg administration with 5-FU brought about synergistic antitumor effects (p=0.006). CONCLUSION: Low-dose eribulin combined with 5-FU might be a promising therapy for peritoneal dissemination in gastric cancer.

The effect of HIF-1α and PKM1 expression on acquisition of chemoresistance.

BACKGROUND: In patients with gastric cancer, one of the greatest obstacles to effective chemotherapy is the development of chemoresistance. It has been previously reported that hypoxia-inducible factor-1 alpha (HIF-1α) is associated with acquisition of chemoresistance, and more recent studies have also noted an association of pyruvate kinase muscle 1 (PKM1) and chemoresistance. The purpose of this study was to identify the effect of HIF-1α and PKM1 expression on the development of acquired chemoresistance using a paclitaxel (PTX)-resistant gastric cancer cell line. MATERIALS AND METHODS: A cancer cell line resistant to PTX was established from MKN45 cells by stepwise exposure to drug (rMKN45-PTX). The expressions of HIF-1α, apoptosis, vascular endothelial growth factor (VEGF), multidrug transporters and glycolytic enzyme were examined by Western blotting, enzyme-linked immunosorbent assay and immunohistochemistry. We also assessed the tumor proliferation by subcutaneous tumor and peritoneal dissemination of mouse xenograft model. RESULTS: The resistance index was 6.1 by determining as the ratio of the 50% growth inhibition (IC50) of rMKN45-PTX/IC50 of MKN45. Expression of nuclear factor kappa B and HIF-1α was increased in rMKN45-PTX cells compared with the parent cells. Expression of Bax and caspase-3 was significantly downregulated, whereas expression of Bcl-xL, P-glycoprotein, multidrug resistance-associated protein and VEGF was increased in rMKN45-PTX. The expression level of PKM1 was upregulated in rMKN45-PTX, leading to an increase in the PKM1/PKM2 ratio. Using xenograft models, we demonstrated that mouse subcutaneous tumors derived from rMKN45-PTX were significantly larger than those derived from MKN45 cells. CONCLUSION: Under the stress of chemotherapeutic agent exposure, high expression of HIF-1α affects various downstream genes. Although the underlying mechanism is unknown, our data suggest that PKM1 is also a molecular target for gastric cancer treatment.

[A Case of Colon Cancer with Brain, Liver and Lung Metastasis Successfully Treated with Bevacizumab plus Xelox Therapy].

The patient was a 57-year-old woman. Preclinical examination of malignant lymphoma revealed 0-I sp type of early rectal cancer in the upper rectum, 20 cm from the anal margin. Endoscopic mucosal resection was performed and positive deep margins were pathologically diagnosed. Additional intestinal resection with lymph node dissection was deemed necessary, but ABVD therapy was initiated because the clinical stage of the malignant lymphoma was Stage III b or higher. Two months after detecting elevated CEA, S8 liver metastasis was pointed out, and examination of weakness of the right upper limb revealed nodular, multifocal brain metastasis. After chemotherapy for malignant lymphoma, bevacizumab(BV)plus Xelox therapy was initiated. After administering 4 courses, partial loss of multiple brain metastases and reduction of the liver metastatic lesion were confirmed; therefore, partial resection of the liver via laparoscopy was performed. After surgery, BV plus Xelox therapy was resumed, but since the lower lobular lung metastasis was confirmed after 8 courses, partial resection of the left lower lobe with thoracoscopy was performed. After lung resection, BV plus FOLFIRI therapy was administered, and 12 months after the onset of treatment for brain metastasis, recurrence was not detected.

Phase I study of third-line palliative chemotherapy with low dose paclitaxel for pancreatic cancer.

The prognosis of patients with unresectable or recurrent pancreatic cancers is very poor. Prior to development of nab-paclitaxel (PTX) plus gemcitabine (GEM) therapy and FOLFIRINOX therapy, there was no recommended third-line chemotherapy after 5-fluorouracil (5-FU) and GEM-based regimens. The present study conducted a Phase I clinical trial of weekly low-dose PTX as a third-line palliative chemotherapy for patients with pancreatic cancer. PTX was administered on days 1, 8, 15, and 22 of each cycle, repeated twice as follows: Level 1, 40 mg/m2 (n=6); Level 2, 50 mg/m2 (n=4). During the two cycles, three patients developed Grade 3 neutropenia in level 2; thus, the recommended dose was defined as 40 mg/m2. The disease control rate was 40.0% (stable disease, n=4). Median time to treatment failure of the four patients with stable disease was 5.5 months. In conclusion, palliative chemotherapy with low-dose PTX after failure of GEM and 5-FU is well tolerated and safe for unresectable or recurrent pancreatic cancer patients. The unique ID issues by UMIN: 000008148.

Preventive effect of oral hangeshashinto (TJ-14) on the development of reflux-induced esophageal cancer.

BACKGROUND: Prostaglandin E2 is one of the potential products that promotes development of tumors and also is a strong inducer of M2 phenotype macrophages, which contribute to tumor development in the immunosuppressed microenvironment. Hangeshashinto (TJ-14), a Japanese traditional medicine (Kampo medicine), has been reported to be effective in preventing chemotherapy-induced oral mucositis through the reduction of prostaglandin E2. We previously developed a surgical rat reflux model of esophageal cancer and used this well-established animal model to investigate the action of TJ-14 in preventing esophageal cancer. We also assessed the effect of TJ-14 on the downregulation of prostaglandin E2 production, utilizing esophageal squamous cell carcinoma cell line exposed to bile acid. METHODS: An end-to-side esophagojejunostomy was performed for the reflux model. A daily oral diet was subsequently administered, consisting of either diet-incorporated TJ-14 or standard diet as a control group. The rats were killed at 40 weeks after surgery. The incidence of esophageal cancer, Barrett's metaplasia, and proliferative hyperplasia were assessed histologically. CD163, a M2 phenotype macrophage marker, was assessed with immunohistochemistry. Prostaglandin E2 enzyme immunoassay and lactate dehydrogenase assay were performed on chenodeoxycholic acid or gastroesophageal reflux contents exposed to esophageal squamous cell carcinoma cell line. RESULTS: Sixty-seven percent of the controls (n = 12) developed esophageal cancer, but animals that received TJ-14 (n = 10) had a cancer incidence of 10% (P=.007). Barrett's metaplasia was found in 83% of the rats in the control group and 50% of the rats in the TJ-14 indicating a protective tendency of TJ-14 (P=.095). All of the rats developed proliferative hyperplasia. The number of M2 phenotype macrophage were significantly decreased in the TJ-14 group compared to the control group in both Barrett's metaplasia and esophageal cancer lesions. TJ-14 inhibited chenodeoxycholic acid or gastroesophageal reflux content-induced prostaglandin E2 production in esophageal squamous cell carcinoma cell. CONCLUSION: TJ-14 reduced the incidence of reflux-induced esophageal cancer and the infiltration of M2 macrophages in a surgical rat model or suppressed prostaglandin E2 production in esophageal squamous cell carcinoma cell. Further investigation is required regarding the potential clinical use of TJ-14 as an esophageal cancer chemopreventive agent.

Phosphodiesterase III inhibitor attenuates rat sinusoidal obstruction syndrome through inhibition of platelet aggregation in Disse's space.

BACKGROUND AND AIM: Sinusoidal obstruction syndrome (SOS) is a serious drug-induced liver injury. However, the pathophysiology of the disease remains unclear. This study investigated the effects of cilostazol (CZ), a phosphodiesterase III inhibitor, in a monocrotaline (MCT)-induced rat model of SOS. METHODS: Male Wistar rats were administrated MCT to induce SOS. Rats were divided into control, MCT, and MCT + CZ groups. In the MCT + CZ group, CZ was administered at 48 h, 24 h, and 30 min prior to and 8 h and 24 h after MCT administration. The MCT group was treated with water instead of CZ. At 48 h after MCT administration, blood and liver samples were collected to assess biochemistry and liver histology. Expression of rat endothelial cell antigen, CD34, CD41, P-selectin, and caspase-3 in the liver were analyzed. Plasminogen activator inhibitor-1 (PAI-1) in hepatocytes was analyzed using western blotting and polymerase chain reaction. RESULTS: In the MCT group, macroscopic findings showed a dark-red liver surface. Histological findings showed sinusoidal dilatation, coagulative necrosis of hepatocytes, and endothelial damage of the central vein. These changes were attenuated in the MCT + CZ group. Elevated serum transaminase and decreased platelet counts were observed in the MCT + CZ group compared with those in the MCT group. Treatment with CZ reduced MCT-induced damage to the liver sinusoidal endothelial cells, inhibited extravasated platelet aggregation, and suppressed hepatocyte apoptosis around the central vein. CZ attenuated hepatic PAI-1 protein and mRNA levels. CONCLUSIONS: Cilostazol attenuated MCT-induced SOS by preventing damage to liver sinusoidal endothelial cells and extravasated platelet aggregation. Hepatic PAI-1 levels were suppressed with CZ treatment.

Importance of human peritoneal mesothelial cells in the progression, fibrosis, and control of gastric cancer: inhibition of growth and fibrosis by tranilast.

BACKGROUND: Scirrhous gastric cancer is an intractable disease with a high incidence of peritoneal dissemination and obstructive symptoms (e.g., ileus, jaundice, and hydronephrosis) arising from accompanying marked fibrosis. Microenvironmental interactions between cancer cells and cancer-associated fibroblasts are the suggested cause of the disease. We elucidated the mechanisms of tumor growth and fibrosis using human peritoneal mesothelial cells (HPMCs) and investigated the effects of tranilast treatment on cells and a xenograft mouse model of fibrosis. METHODS: HPMCs were isolated from surgically excised omentum and their interaction with MKN-45 gastric cancer cells was investigated using co-culture. Furthermore, a fibrosis tumor model was developed based on subcutaneous transplantation of co-cultured cells into the dorsal side of nude mice to form large fibrotic tumors. Mice were subsequently treated with or without tranilast. RESULTS: The morphology of HPMCs treated with transforming growth factor (TGF)-ß1 changed from cobblestone to spindle-type. Moreover, E-cadherin was weakly expressed whereas high levels of α-smooth muscle actin expression were observed. TGF-ß-mediated epithelial-mesenchymal transition-like changes in HPMCs were inhibited in a dose-dependent manner following tranilast treatment through inhibition of Smad2 phosphorylation. In the mouse model, tumor size decreased significantly and fibrosis was inhibited in the tranilast treatment group compared with that in the control group. CONCLUSIONS: Tranilast acts on the TGF-ß/Smad pathway to inhibit interactions between cancer cells and cancer-associated fibroblasts, thereby inhibiting tumor growth and fibrosis. This study supports the hypothesis that tranilast represents a novel strategy to prevent fibrous tumor establishment represented by peritoneal dissemination.

[A Case of Spontaneous Esophageal Rupture That Required Operation during Adjuvant Chemotherapy for Transverse Colon Cancer].

A 75-year-old male underwent adjuvant chemotherapy with tegafur uracil(UFT)plus Leucovorin(LV)after surgery for transverse colon cancer(pT3pN0M0, ly1, v2, pStageⅡ). Although he had diarrhea(Grade 3)and vomiting(Grade 2)from day 15, he continued to take the medicine at his own discretion. He visited a hospital because of acute renal failure from severe dehydration. He went into shock after evacuation, and the computed tomography(CT)finding suggested a diagnosis of spontaneous esophageal rupture at the lower esophagus. We made a diagnosis of intrathoracic perforation of the esophagus by using thoracic drainage. Then, we performed an operation for mediastinal drainage via a transabdominal approach and the lesser omentum. He started ingestion from POD36 and transferred to another hospital on POD85. He had no disease recurrence in our outpatient care. We think that the spontaneous esophageal rupture occurred because of the frequent vomiting caused by the continued chemotherapy despite the severe side effects. Treatments must be selected by considering patients' life background and medical compliance, and common guidance in taking medications must be provided to elderly patients at the start of chemotherapy.

Role for Neutrophil Extracellular Traps (NETs) and Platelet Aggregation in Early Sepsis-induced Hepatic Dysfunction.

BACKGROUND/AIM: Severe sepsis is associated with high morbidity and mortality rates. Inflammation and coagulation play pivotal roles in the pathogenesis of sepsis leading to multiple organ failure, especially in the liver. The aim of the present study was to assess the mechanism from sepsis to liver damage in a mouse model. MATERIALS AND METHODS: We created a sepsis model by injecting lipopolysaccharide (LPS) intraperitoneally in mice. At 0, 6, 12, and 24 h following intraperitoneal injection of LPS, mice were euthanised and analyzed. Primary antibodies against myeloperoxidase (MPO), hepatic sinusoidal endothelial cells (SE-1), and P-selectin (CD62p) were used. Expression and localization in neutrophil, sinusoidal endothelial, and platelet cells were assessed by immunohistochemistry. RESULTS: Immunohistochemical analyses revealed a positive staining for MPO, most abundantly in neutrophil granulocytes, within the hepatic sinusoids immediately after injection. Neutrophil extracellular trap (NET)-like structures stained for MPO, indicating the presence of neutrophils undergoing NETosis, were confirmed at 6 h after LPS administration. SE-1 staining for liver sinusoidal endothelial cells was significantly reduced at 12 h post-LPS administration through sinusoidal endothelial injury or detachment. Furthermore, the presence of extravasated platelets was confirmed in the space of Disse at 24 h after LPS administration. Blood sample analyses showed that white blood cell counts and platelet counts decreased gradually, while MPO amounts increased until 12 h after LPS administration. CONCLUSION: We conclude that NET formation and intravasated platelet aggregation are the first steps from sepsis to liver damage, and that extravasated platelet aggregation promoted by NET-facilitated detachment of sinusoidal endothelial cells is the origin of sepsis-induced liver dysfunction.

Efficacy of CO2 insufflation during thoracoscopic esophagectomy in the left lateral position.

OBJECTIVE: Thoracoscopic esophagectomy (TE) is widely performed as a minimally invasive technique in the management of esophageal cancer. The aim of this study was to estimate the efficacy of intrathoracic carbon dioxide (CO2) insufflation during TE in the left lateral position. METHODS: From January 2010 to April 2016, 58 patients with esophageal cancer underwent TE without intrathoracic CO2 insufflation (Group N) and 37 patients with esophageal cancer underwent TE with intrathoracic CO2 insufflation (Group C). The operation results and respiratory parameters during the thoracic procedure were compared in both groups. RESULTS: A satisfactory surgical field was obtained by CO2 insufflation. There was no difference in the duration of the thoracic procedure or number of dissected mediastinal lymph nodes between the two groups. The amount of thoracic blood loss in Group C was significantly less than that in Group N (P < 0.05). Intrathoracic CO2 insufflation did not affect oxygenation during single-lung ventilation. However, both end-tidal CO2 (ETCO2) 1 h after single-lung ventilation and maximum ETCO2 in Group C were significantly higher than those in Group N. Intraoperative hypercapnia in Group C was permissive. The rate of extubation in the operation room, mortality and morbidity were not different between the two groups. CONCLUSIONS: Intrathoracic CO2 insufflation is beneficial to make satisfactory surgical field and to reduce thoracic blood loss in TE. Application of intrathoracic CO2 insufflation may contribute to the widespread adoption of TE in the left lateral position.

Location of the meso-pancreatoduodenum as a regional lymphatic basin for pancreatic head carcinoma.

The meso-pancreatoduodenum is the primary site of tumor infiltration in patients with pancreatic head cancer, with numerous patients exhibiting lymph node metastases. Effective dissection of the regional lymphatic basin requires knowledge of the patterns of the arterial branches. The present study examined the patterns of the arteries feeding the pancreatic head and the distribution of the meso-pancreatoduodenum. The present study included 123 patients with pancreatic cancer who underwent contrast-enhanced preoperative 64-multidetector-computed tomography to determine the routes of the inferior pancreaticoduodenal and first jejunal arteries. Surgical specimens and cadavers were also evaluated histologically to clarify the distribution of the meso-pancreatoduodenum. The feeding arteries were divided into three types, with 64.2% of patients having type A, 28.4% having type B and 7.3% having type C branches. The branches emerged from the back or left side of the superior mesenteric artery and ran to the far side of the pancreatic head in an arc. Consequently, the meso-pancreatoduodenum had a roll-shaped appearance, surrounding the trunk arteries and extending to the left side of the superior mesenteric artery. Dissecting the right and left sides of the superior mesenteric artery during lymphadenectomy could improve the effectiveness of resection.

Phase I study of weekly palliative chemotherapy with low-dose third-line paclitaxel for biliary tract cancer.

The prognosis of patients with unresectable and recurrent biliary tract cancer (BTC) is very poor. Although gemcitabine (GEM) plus cisplatin therapy is useful for unresectable cases, the median overall survival (OS) of the patients is <1 year, and third-line chemotherapy following failure of 5-fluorouracil (5-FU) and GEM plus cisplatin is currently unavailable. The clinical efficacy and basic effects of low-dose paclitaxel (PTX) therapy for patients with BTC was previously reported. We herein present the results of a phase I clinical trial of weekly low-dose PTX as third-line palliative chemotherapy. PTX was administered on days 1, 8, 15 and 22 of each cycle and repeated twice as follows: Level 1, 40 mg/m2; level 2, 50 mg/m2 (n=3). During the two cycles, grade 1 or 2 adverse events were observed in 3 patients, whereas dose-limiting adverse events (grade 3 or 4) were not observed. The disease control rate was 83.3% (partial response, n=3; stable disease, n=2). The OS and median survival were 15.4 and 9.0 months, respectively. In conclusion, palliative chemotherapy with low-dose PTX following failure of GEM and 5-FU was well-tolerated, safe and effective for patients with unresectable or recurrent BTCs, and the optimal dose was 50 mg/m2.

Evaluation of the effects of gastrectomy on the development of metabolic bone disease.

BACKGROUND: Metabolic bone disease after gastrectomy is one of the complications leading to deterioration in quality of life. The exact mechanism of the metabolic bone disease remains unclear. To clarify the cause of metabolic bone disease after gastrectomy, we evaluated the associations between the method of gastrectomy and the development of metabolic bone disease in a rat model. METHODS: Rats were assigned to four groups as follows: (1) sham operation (control group); (2) resection of the glandular stomach with Billroth I reconstruction (RGBI group); (3) Roux-en-Y anastomosis preserving the secretory function of the whole stomach (PSRY group); and (4) total gastrectomy with Roux-en-Y reconstruction (TGRY group). In all groups, body weight, serum biochemistry (total protein, albumin, calcium, phosphorus, tartrate-resistant acid phosphatase, and bone alkaline phosphatase), bone density, and bone breaking strength were measured. RESULTS: Body weights and serum calcium levels were significantly lower in the three operation groups compared with the control group. Bone density was significantly lower in the PSRY and TGRY groups compared with the control group. Bone breaking strength was significantly lower in the three operation groups compared with the control group. CONCLUSIONS: Surgical methods led to metabolic bone disease. However, exclusion of the duodenum from food passage had major influence to reduction in bone density and breaking strength. A stomach-preserving procedure and physiological reconstruction which enable food passage through duodenum and proximal jejunum contribute to mitigation of metabolic bone disease.