The Synergistic Anti-Cancer Effects of NVP-BEZ235 and Regorafenib in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the most common type of liver cancer worldwide. Regorafenib is a multi-kinase inhibitor and the second-line treatment for HCC. Since the PI3K/Akt/mTOR signaling pathway is dysregulated in HCC, we evaluated the therapeutic effects of regorafenib combined with a dual PI3K/mTOR inhibitor BEZ235 in the human HCC cell lines (n = 3). The combined treatment with BEZ235 and regorafenib enhanced the inhibition of cell proliferation and increased the expression of cleaved caspase-3 and cleaved PARP in HCC cells. Moreover, the combined treatment suppressed HCC cell migration and invasion in the transwell assay. Further, the Western blot analyses confirmed the involvement of epithelial-mesenchymal transition (EMT)-related genes such as slug, vimentin, and matrix metalloproteinase (MMP)-9/-2. Additionally, the proteinase activity of MMP-9/-2 was analyzed using gelatin zymography. Furthermore, the inhibition of phosphorylation of the Akt, mTOR, p70S6K, and 4EBP1 after combined treatment was validated using Western blot analysis. Therefore, these results suggest that the combined treatment with BEZ235 and regorafenib benefits patients with HCC.

The Risk of Acute Pancreatitis and Selective Serotonin Reuptake Inhibitors Use: A Meta-Analysis of Case-Control Studies.

BACKGROUND/OBJECTIVE: Some case series and case report have shown the association between the risk of acute pancreatitis and use of selective serotonin reuptake inhibitors. The results of systematic studies were not consistent. METHODS: A meta-analysis was performed to investigate the risk of acute pancreatitis associated with use of selective serotonin reuptake inhibitors. RESULTS: There was no statistical association between the risk of acute pancreatitis and selective serotonin reuptake inhibitors use (odds ratio: 1.19, 95% confidence interval: 0.93-1.51). CONCLUSIONS: Despite reaching no statistical significance, the possibility of the association between the risk of acute pancreatitis and selective serotonin reuptake inhibitors use cannot be totally excluded.

Unroofing hepatectomy: a facilitating approach for resection of deep-seated hepatocellular carcinoma adjacent to major intrahepatic vessels in cirrhotic patients.

BACKGROUND AND OBJECTIVES: Unroofing hepatectomy, an alternative approach to remove a deep-seated hepatocellular carcinoma (HCC) adjacent to major intrahepatic vessels by peel-off technique after sacrificing the overlying noncancerous liver, may result in tumor exposure without resection margin. The aim of the study was to examine the value of this approach in cirrhotic patients. METHODS: Between 1998 and 2012, 51 cirrhotic patients underwent unroofing hepatectomy for deep-seated newly-diagnosed HCC adjacent to major intrahepatic vessels (group A). Another 274 cirrhotic patients with similar tumor size and without gross major vessel involvement in the same period were selected as the control cohort (group B). The patients' clinicopathological characteristics, the early and long-term outcomes of the two groups were compared. RESULTS: The HCCs in group A had a significantly higher rate of tumor encapsulation, smaller number of associated satellite nodules, and smaller amount of resected liver weight. Postoperative complication and 90-day mortality rates were similar, but group A patients had a significant better 5-year disease-free (56% vs. 32%, P = 0.011) and overall survival rates (82% vs. 53%, P = 0.008). CONCLUSIONS: In selected cirrhotic patients, unroofing hepatectomy facilitates resection of deep-seated HCC adjacent to major intrahepatic vessels with acceptable early and long-term results.

Intractable duodenal ulcer caused by transmural migration of gossypiboma into the duodenum--a case report and literature review.

BACKGROUND: Gossypiboma is a term used to describe a mass that forms around a cotton sponge or abdominal compress accidentally left in a patient during surgery. Transmural migration of an intra-abdominal gossypiboma has been reported to occur in the digestive tract, bladder, vagina and diaphragm. Open surgery is the most common approach in the treatment of gossypiboma. However, gossypibomas can be extracted by endoscopy while migrating into the digestive tract. We report a case of intractable duodenal ulcer caused by transmural migration of gossypiboma successfully treated by duodenorrhaphy. A systemic literature review is provided and a scheme of the therapeutic approach is proposed. CASE PRESENTATION: A 61-year-old Han Chinese man presented with intermittent epigastric pain for the last 10 months. He had undergone laparoscopic cholecystectomy conversion to open cholecystectomy for acute gangrenous cholecystitis 10 months ago at another hospital. Transmural migration of gossypiboma into the duodenum was found. Endoscopic intervention failed to remove the entire gauze, and duodenal ulcer caused by the gauze persisted. Surgical intervention was performed and the gauze was removed successfully. The penetrated ulcer was repaired with duodenorrhaphy. The postoperative period was uneventful.We systematically reviewed the literature on transmural migration of gossypiboma into duodenum and present an overview of published cases. Our PubMed search yielded seven reports of transmural migration of retained surgical sponge into the duodenum. Surgical interventions were necessary in two patients. CONCLUSION: Transmural migration of gossypiboma into the duodenum is a rare surgical complication. The treatment strategies include endoscopic extraction and surgical intervention. Prompt surgical intervention should be considered for emergent conditions such as active bleeding, gastrointestinal obstruction, or intra-abdominal sepsis. For non-emergent conditions, surgical intervention could be considered for intractable cases in which endoscopic extraction failed.

Is liver resection for hepatocellular carcinoma in cirrhotic patients with high preoperative serum alanine aminotransferase level unadvisable?

BACKGROUND/AIMS: High operative mortality has been reported after liver resection for hepatocellular carcinoma (HCC) in cirrhotic patients with high preoperative serum alanine aminotransferase (sALT) level. Their long-term prognosis has never been investigated. The aim of this study is to evaluate the benefit of liver resection for HCC in this subgroup of patients. METHODOLOGY: A retrospective review of the medical records of 978 cirrhotic patients who underwent curative liver resection for HCC between 2000 and 2012 was conducted. The preoperative sALT level of 218 patients was > 100 U/l (normal 5 -50) (group 1). The clinicopathological characteristics as well as early and long-term results after hepatectomy of group 1 were compared with those of the other 760 cirrhotic patients whose sALT was < 100 U/l (group 2). Liver resection extent was decided by tumor extent and a modified version of Makuuchi's criteria. RESULTS: Group 1 patients had a significantly higher indocyanine 15-minute retention rate, higher hepatitis infection rates and a higher rate of macronodular cirrhosis. Although group 1 patients had a higher postoperative complication rate, the complication severity and 90-day mortality did not significantly differ. In 81.2 % of group 1 patients, sALT level returned to the normal range within 12 weeks after operation. The 5-year disease-free and overall survival rates in group 1 and 2 were 55.1% and 57.5% (P = 0.540) and 51.5% and 60.9%, (P=0.485), respectively. CONCLUSIONS: Liver resection for HCC remains advisable in selected cirrhotic patients with preoperatively high sALT level when liver resection extent fulfills Makuuchi's criteria for cirrhotic liver resection.

MMP-9 -1562 Promoter Polymorphism Associated with Gastric Cancer Risk in Females.

Background/Aims: C to T transition at the matrix metalloproteinase-9 (MMP-9) promoter site -1562 abolishes a binding site of a putative transcription repressor protein to the C allelic promoter. The aim of this study is to elucidate the significance of MMP-9 genotypes in clinicopathological manifestations of gastric cancer. Methodology: We conducted a case-control study based on previously stored peripheral blood samples from 263 gastric cancer patients and 354 controls. MMP-9 genotyping was analyzed by PCR-RFLP method. Stratified analysis, logistic regression and Cox proportional hazards analysis were used to evaluate the associations between polymorphisms and gastric cancer development, invasiveness, and survival. Results: There was significant correlation between female patients with MMP-9 -1562 C/T or T/T genotype and higher risk of gastric cancer (OR=2.12, p=0.02). On stratified analysis, only elderly females with T allele had higher risk of gastric cancer (OR=2.64, p=0.04). On Cox proportional hazards analysis, serosal invasion (adjusted HR=3.47, p<0.001) and lymph node metastasis (adjusted HR=2.31, p=0.003), but not MMP-9 polymorphism, were independent prognostic factors for survival. Conclusions: MMP-9 -1562 promoter polymorphism with T allele may be used as a marker to predict gastric cancer development in female subjects, especially in the elderly.

Osteopontin promoter polymorphisms are associated with susceptibility to gastric cancer.

GOALS: To evaluate the significance of osteopontin (OPN) genotypes in the susceptibility to gastric cancer. BACKGROUND: The expression of OPN has been correlated with development, invasiveness, metastasis, and survival of gastric cancer, but the role of polymorphisms in the OPN promoter has not been investigated. STUDY: We enrolled 146 gastric cancer patients and 128 controls. DNA was extracted from peripheral blood leucocytes. Single-nucleotide polymorphisms (SNPs) in the OPN promoter (-66, -156, -443, -616, -1748, and -1776) were analyzed by pyrosequencing and direct sequencing methods. Logistic regression analyses were used to evaluate the associations between SNPs and development of gastric cancer. RESULTS: SNP -443 C/C and -616 T/T of the OPN promoter were significantly associated with gastric cancer [odds ratio (OR)=2.88; 95% confidence interval (CI), 1.16-7.12 and OR=1.95; 95% CI, 1.35-2.82, respectively]. Analysis of the combined effect of OPN promoter SNPs revealed that the combination of SNP -443 (T/C or C/C) and SNP -616 (T/T or T/G) had the most significant association with gastric cancer (OR=3.95; 95% CI, 1.58-9.90). CONCLUSIONS: Our results suggest that polymorphisms in the OPN promoter are associated with the development of gastric cancer, and the combination of SNP -443 (T/C or C/C) and -616 (T/T or T/G) most significantly increases susceptibility to gastric cancer.

Thick calcification from a GIST of the stomach penetrating into pericolic soft tissue--report of a case.

Thick calcification is a rare presentation of gastrointestinal stromal tumor (GIST). Penetration into gastric mucosa and pericolic soft tissue has never been reported. We report a case of gastric GIST with cystic degeneration and thick calcification in an 81-year old female, who presented with hematemesis and severe abdominal pain. Thick calcification of this tumor penetrating into pericolic soft tissue was noted and successfully treated by distal gastrectomy and partial colectomy. For gastrointestinal tumors with thick calcification, even with benign behavior, surgical intervention should be considered for both oncological considerations and prevention of catastrophes like perforation or penetration into surrounding soft tissue.

Hepatic failure-induced hypogonadism in a prostate cancer patient.

Hypogonadism owing to systemic diseases in prostate cancer is rare. Here, we present a patient with metastatic prostate cancer to the pericardium who had low serum testosterone level due to hepatic failure. The patient had cardiac tamponade, and pericardiocentesis revealed sanguineous exudate. Cytology revealed adenocarcinoma. High serum prostate-specific antigen level of 244 ng/mL was detected. The patient experienced complications of stress gastric and duodenal ulcer perforation and underwent subtotal gastrectomy. Perioperative intra-abdominal inflammatory process caused subsequent cholestasis and hepatic dysfunction. Transrectal ultrasound-guided prostate biopsy confirmed prostate cancer. Hypogonadism and a gradual decline in prostate-specific antigen were detected without any hormone therapy. The patient died due to hepatic failure in the 12(th) postoperative week.

Eosinophilic cholangitis with obstructive jaundice mimicking bile duct carcinoma.

A 55-year-old male who presented with obstructive jaundice and radiographically documented extrahepatic biliary tract obstruction is reported. Eosinophilic infiltration of the gallbladder, common bile duct, intrahepatic bile ducts, and bone marrow was observed. Eosinophilic cholangitis, a rare inflammatory condition that clinically resembles a biliary malignancy, should be taken into consideration in the differential diagnosis in the evaluation of presumed neoplasm of the bile ducts.

Synchronous gastric gastrointestinal stromal tumor and signet-ring cell adenocarcinoma: a case report.

Synchronous tumors of the stomach are uncommon. We present a unique case of gastric synchronous tumors composed of signet-ring cell adenocarcinoma and gastrointestinal stromal tumor (GIST). The two tumors arose at the same site and were sharply juxtaposed without intermingling of morphologically distinct elements. Coincidence probably accounts for this occurrence, even if a common carcinogenic agent had been hypothesized. Preoperative imaging and endoscopic biopsy could lead to the suspicion of synchronous tumors, and an accurate histological identification of both tumors could be achieved by multiple deep endoscopic biopsies. The presence in our case of diffuse carcinomatosis indicates that the signet-ring cell adenocarcinoma had a greater adverse effect on the prognosis than the GIST.

Successful management of latrogenic aortoduodenal fistula by intraaortic endovascular stent-graft and duodenal diversion.

Aortoduodenal fistula is usually fatal if not treated promptly. Long-term results are also not always satisfactory. A 53-year-old female patient suffered from massive hematemesis and shock due to an iatrogenic aortoduodenal fistula which was made during a laparoscopic total colectomy. Immediate closure of fistula with duodenal diversion by occlusion of duodenal lumen proximal to the fistula, bilateral truncal vagotomy and pyloroduodenojejunostomy were performed. Endoluminal aortic stent graft was inserted 3 days later. The patient remained disease-free 3 years after operation. With a prompt diagnosis, duodenal diversion with endoluminal aortic stent may be a better option for iatrogenic aortoduodenal fistula.

Role of glucocorticoid receptor in serosa-involved gastric carcinoma after gastrectomy.

Glucocorticoid receptor (GR) was first found in the cytosol of gastric cancer tissue more than 15 years ago. At present, most gastric cancers are diagnosed at the advanced stage. To elucidate the role of GR in gastric cancer, the GR levels of the cancer tissue of 75 consecutive patients with grossly serosa-involved gastric carcinoma were determined by the dextran-coated charcoal method. The clinicopathologic characteristics and long-term survival duration were compared in patients with GR-positive and GR-negative cancer cells. We found that GR could be detected in the cytosol of cancer cells in 31 (41.3%) of the gastric cancer patients with a median concentration of 18.5 (range, 1.03-73.9) fmol/mg protein. No significant differences could be found in any clinicopathologic characteristic between the patients with GR-positive and GR-negative cancers. After multivariate analysis, gross Borrmann's type, metastatic lymph node number, and GR positivity were the independent prognostic factors after gastrectomy for serosa-involved gastric carcinoma. GR-positive gastric cancer had a worse survival rate than GR-negative gastric cancer. Multimodality adjuvant therapies should be considered in patients with GR-positive serosa-involved gastric carcinoma.

Small bowel obstruction caused by a congenital intestinal web with an enteric bezoar in an adult: report of a case.

An intestinal web is a rare congenital anomaly, typically reported in childhood, but often remaining asymptomatic throughout the entire life span of the individual. We report the case of a symptomatic intestinal web associated with an enteric bezoar in an adult, which to the best of our knowledge has never been documented before. A 25-year-old man presented with acute small bowel obstruction, and laparotomy revealed a stenotic area of the ileum as well as impaction of an enteric bezoar. We resected this segment of ileum and an intestinal web was subsequently found in the stenotic area. The patient recovered well and has remained asymptomatic for 3 years. Although rare, a congenital intestinal web may be a cause of adult small bowel obstruction requiring surgical resection.