[A Case of Mixed Neuroendocrine-Non-Neuroendocrine Neoplasm of the Distal Bile Duct].

An 82-year-old male with jaundice was referred to our hospital for a detailed examination. The computed tomography (CT) examination detected an enhanced mass lesion of the distal bile duct. Endoscopic retrograde cholangiography showed a filling defect corresponding to the CT findings. Simultaneously, a forceps biopsy and an endoscopic retrograde biliary drainage were performed. We performed pancreatoduodenectomy, and adenocarcinoma was pathologically proven. The histopathological finding of the resected specimen was a mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) composed of large cell neuroendocrine carcinoma and well-differentiated adenocarcinoma. Although pathological R0 resection was achieved, liver metastasis was observed 6 months after the operation. Although neuroendocrine carcinoma (NEC) rarely develops in the bile duct, it manifests a higher degree of malignancy than other ordinary bile duct adenocarcinomas. Further investigation is needed to choose an appropriate treatment.

[A Case of Severe Hyperammonemic Encephalopathy in a Dialysis Patient Following mFOLFOX6 Therapy].

A 69-year-old man on hemodialysis for chronic renal failure was diagnosed with ascending colon cancer, and received surgical resection. Multiple liver metastases were detected after surgery. He was administered modified FOLFOX6 therapy (reducing the dose to 50%), and showed severe disturbance of consciousness due to hyperammonemia on treatment day 6. After treatment with daily hemodialysis, branched-chain amino acid solutions, lactulose and rifaximin, his conscious level improved on day 9. Intensive chemotherapy in dialysis patients should be carefully performed considering the serious adverse events including hyperammonemia.

[A Case Report of P0CY1 Gastric Cancer Achieved Long-Term Survival after Treated with Ramucirumab Monotherapy].

The patient was a woman in her early 60s with type 4 advanced cancer which spread throughout the entire stomach. Total gastrectomy with regional lymphadenectomy was performed. She was diagnosed as Stage Ⅳ scirrhous gastric cancer with positive lavage cytology pathologically without any macroscopic peritoneal metastasis(P0CY1). S-1 plus cisplatin therapy was carried out as first-line therapy, but must be stopped after 2 courses because of appetite loss. As the second-line, ramucirumab monotherapy was administered, due to the patient's denial of alopecia and numbness as side effects of paclitaxel. Tumor marker value of CA19-9 remained high 24 months after ramucirumab chemotherapy, but gradually decreased near the normal level with no proof of distant metastasis or peritoneal dissemination. However, after 74 courses, CA19-9 value was elevated and peritoneal dissemination was detected from CT scan. Nivolumab therapy was started as third-line, but only for 5 courses because of indefinite complaints. Afterwards, no chemotherapy has been performed as the patient's request until almost 5 years after surgery. The prognosis of patients with P0CY1 gastric cancer is generally poor, but in our case long-term survival was obtained from ramucirumab therapy only. Recently, ramucirumab monotherapy is administered for advanced HCC patients and expect to be effective in AFP producing gastric cancer. There is an urgent need to elucidate potential predictive biomarkers of ramucirumab efficacy.

[A Case of Metastatic Colorectal Cancer with Hyperammonemic Encephalopathy Induced by mFOLFOX6 and SOX Therapy].

A 77-year-old man was given a diagnosis of pT4aN0M1a(PUL2), stage Ⅳ, RAS mutant type, after the operation for advanced ascending colon cancer. He was administered mFOLFOX6 plus Bmab as first-line chemotherapy. He showed consciousness disturbance on the 2nd day during the 6 cycles. Because of head computed tomography and magnetic resonance imaging showing no abnormal findings, we diagnosed convulsive seizure. His consciousness level gradually improved after intravenous infusion. He showed consciousness disturbance on the 2nd day during the 7 cycles again. Because blood ammonia level were high at 400µg/dL, he was diagnosed as hyperammonemic encephalopathy. His consciousness level rapidly recovered after branched chain amino acid(BCAA)infusion. SOX plus Bmab therapy was started as a post-treatment, he developed hyperammonemia(NH3 288µg/dL)again, on the 4th day during the 3 cycles. After taking of oral administration of BCAA and lactulose, the recurrence of hyperammonemic encephalopathy was not found. Therefore, 3 cycles of SOX plus Bmab therapy and 12 cycles of IRIS plus Bmab therapy were administered.

Adrenal Rest Tumor of the Liver Preoperatively Diagnosed as Hepatocellular Carcinoma.

BACKGROUND: Hepatic adrenal rest tumors are rare and show similar findings to hepatocellular carcinoma (HCC). It is difficult to distinguish an adrenal rest tumor from HCC due to radiological similarity. We report a case of an adrenal rest tumor in the liver that mimicked HCC radiologically. CASE PRESENTATION: A 67-year-old female was referred to our hospital due to the finding of a hepatic mass. Enhanced computed tomography revealed a 17 mm well-defined tumor that was enhanced in the arterial phase and washed out in the portal and delayed phase in the posterosuperior subsegment of the right hepatic lobe, and HCC was suspected. We performed a subsegmental resection of the liver. Microscopic findings showed that the tumor was composed of pale cells, and tumor cells were aligned in alveolar or fascicular arrangements in a similar manner to features of adrenocortical tissue. Immunohistochemically, the tumor expressed synaptophysin and CD56. The final histopathologic diagnosis in this case was an adrenal rest tumor of the liver. CONCLUSIONS: An adrenal rest tumor is similar to HCC in radiological findings. This hepatic tumor should be added to the list of radiological differential diagnoses of hypervascular hepatic tumors.

[A case of advanced gastric cancer treated with curative resection after preoperative combined chemotherapy with docetaxel, cisplatin, and S-1].

A 67-year-old woman with epigastralgia was admitted to our hospital and was diagnosed with type 3 advanced gastric cancer with lymph node metastases.The clinical diagnosis was Stage III A(cT3, N2, M0).Since curative surgery was not feasible, we administered preoperative combination chemotherapy with docetaxel, cisplatin(CDDP), and S-1.After 3 courses of chemotherapy, the lymph nodes became undetectable on computed tomography(CT).Distal gastrectomy was performed with curative intent, and the final diagnosis was Stage IIA(ypT3, N0, M0).There has been no recurrence for 1 year and 4 months after the operation.

Clinical outcomes of laparoscopy-assisted gastrectomy for patients with heart disease.

Laparoscopy-assisted gastrectomy (LG) is an established treatment for early gastric cancer. However, CO2 pneumoperitoneum during laparoscopic surgery can adversely affect cardiac function in the presence of heart disease (HD). We performed LG in 546 patients and conventional open gastrectomy (OG) in 448 patients. Patients with preoperatively diagnosed and treated HD were identified. The clinical outcomes of patients with HD who underwent LG (HD-LG) were compared with those of patients with HD who underwent OG (HD-OG), as well as those of patients with no operative risk who underwent LG (NR-LG). Variables of cardiac function were similar in the HD-LG and HD-OG groups. Postoperative cardiac complications did not differ between the groups (8.3% vs. 13.6%, P = 0.51). The HD-LG group had significantly more cardiac and abdominal complications than the NR-LG group (P = 0.0011 and 0.0070, respectively). LG was tolerated in patients with gastric cancer and mild or moderate HD, similar to OG.

Bilateral pleural fluid caused by a pancreaticopleural fistula requiring surgical treatment.

A 53-year-old man developed bilateral pleural effusion with respiratory failure. The amylase level in the pleural effusion was elevated. He had neither abdominal symptoms nor abdominal physical findings. Abdominal computed tomography (CT) also showed no abnormalities. Magnetic resonance cholangiopancreatography (MRCP) was non-diagnostic, but endoscopic retrograde cholangiopancreatography (ERCP) and subsequent CT showed a fistula connecting the pancreatic duct with the right pleural cavity. The pleural effusion was refractory to drug therapy, leading to the need for surgical intervention. The pathological findings revealed chronic pancreatitis without pseudocysts. The elevated pancreatic amylase in the pleural effusion offered an important clue to the correct diagnosis.

Influence of CT-measured appendiceal diameter on operation time of laparoscopic appendectomy.

Laparoscopic appendectomy (LA) is considered as an uncomplicated procedure, so residents are frequently chosen as LA operators. The aim of this study was to identify preoperative factors influencing operation time in LA. We proposed patient selection criteria to help choose an adequately skilled resident for performing LA. The medical records of 117 patients who underwent LA between April 2008 and August 2009 were retrospectively reviewed. Univariate and multivariate analyses were performed to identify factors influencing operation time. Accordingly multivariate analysis indicated that operation time was significantly influenced by C-reactive protein and computed tomography-measured appendiceal diameter. Appendiceal diameter was a better predicting factor for differentiating the longer and shorter operation time groups. The cut-off value for appendiceal diameter was 12 mm. We concluded that preoperative computed tomography findings of appendiceal diameter of more than 12 mm in patients suggested that LA would be technically challenging for the less experienced resident.

Vimentin expression is associated with decreased survival in gastric cancer.

Gastric cancer rich in stromal tissue, such as diffuse-type disease, carries a poor prognosis. In some cancers, expression of vimentin, a mesenchymal maker, is associated with poor survival. The expression of mesenchymal markers such as vimentin is observed after epithelial-mesenchymal transition (EMT), an important initial behavioral change related to the adhesion and migration properties of tumor cells that is required for local tumor invasion. A hallmark of EMT is the loss of E-cadherin. EMT-inducing regulators, including SIP1, Slug, and Twist, repress E-cadherin transcription by interacting with E-cadherin promoter. We investigated the expression of vimentin and EMT-related genes, including SIP1, Slug, and Twist, in frozen cancer tissues and normal tissues by real-time quantitative reverse-transcriptase polymerase chain reaction. Tumor samples were obtained from 106 patients with gastric adenocarcinomas who underwent a gastrectomy. The relation of the expression of these genes to clinicopathological factors and outcomes was studied. Vimentin mRNA was significantly higher in diffuse type compared to intestinal type according to Lauren's classification (p=0.048) and was significantly elevated in patients with recurrent or distant metastatic disease (p=0.049). Immunohistochemically, however, vimentin was detected only in cancer stroma. Twist mRNA expression significantly correlated with tumor depth (p=0.042) and advanced tumor stage (I-II vs. III-IV, p=0.030). E-cadherin immunohistochemical expression was significantly associated with Lauren's histopathological type (p<0.001). Univariate analysis of relapse-free survival showed that tumor depth, lymph node metastasis, Lauren's histopathological type, and vimentin mRNA expression were significant prognostic factors (p<0.001, p=0.013, p=0.011, and p=0.019). On multivariate analysis, vimentin mRNA expression was an independent prognostic factor [hazard ratio (HR)=2.1; 95% confidence interval (CI), 1.0-4.4; p=0.036], coming after tumor depth (HR=9.7; 95%CI, 3.7-24; p<0.001). Vimentin mRNA expression is associated with recurrence or distant metastasis and decreased survival in gastric cancer.

Prognostic value of co-expression of STAT3, mTOR and EGFR in gastric cancer.

Signal transducer and activator of transcription 3 (STAT3), the mammalian target of rapamycin (mTOR) and epidermal growth factor receptor (EGFR), proteins that mediate intracellular signaling related to cell growth, proliferation and differentiation, have received considerable interest as possible targets for cancer treatment. We examined whether the expression of STAT3, mTOR and EGFR correlates with clinicopathological features and patient outcome in gastric cancer. Tumor samples were obtained from 126 patients with gastric adenocarcinomas who underwent a radical gastrectomy between 1999 and 2002. The expression of phosphorylated STAT3 (p-STAT3), p-mTOR and EGFR was analyzed by immunohistochemical staining. The relations of these to clinicopathological factors and outcomes were assessed. The expression of p-STAT3 p-mTOR and EGFR positively correlated with the following variables related to tumor progression: the depth of tumor invasion (T1 vs. T2-4; p<0.001, p=0.036 and p<0.001, respectively), lymph node involvement (p=0.008, p=0.027 and p=0.007) and tumor stage (I vs. II-IV; p<0.001, p=0.041 and p<0.001). The expression of p-STAT3 and EGFR was significantly related to distant metastasis and recurrence (p=0.001 and p=0.039), as well as significantly poorer disease-specific survival (DSS; p=0.0018 and p=0.026). The expression of p-STAT3 was a marginally non-significant prognostic factor for DSS (hazard ratio=2.0, 95% CI 0.91-4.5, p=0.082). Increasing expression of p-STAT3, p-mTOR and EGFR was associated with progressively worse DSS. Interactions among p-STAT3, p-mTOR and EGFR may play an important role in tumor progression and outcomes in patients with gastric cancer.

Methylation of BNIP3 and DAPK indicates lower response to chemotherapy and poor prognosis in gastric cancer.

Aberrant promoter hypermethylation (methylation) is an epigenetic change that silences the expression of crucial genes, thus inactivating the apoptotic pathway in various cancers. Inactivation of the apoptotic pathway has been considered to be associated with chemoresistance. The objective of the present study was to clarify the effect of the methylation of the apoptosis-related genes, Bcl-2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3) and death-associated protein kinase (DAPK), on the response to chemotherapy in metastatic or recurrent gastric cancers. Tumor samples were obtained from 80 gastric cancer patients who were treated with fluoropyrimidine-based chemotherapy for distant metastatic or recurrent disease, after surgical resection of the primary tumor. The methylation status of the apoptosis-related genes, BNIP3 and DAPK, was investigated by methylation-specific PCR. Methylation in BNIP3 was detected in 31 tumors (39%) and in DAPK in 33 tumors (41%). There was no correlation between the methylation status of BNIP3 and that of DAPK. The response rate was significantly lower in patients with methylation of DAPK, than in those without (21 vs. 49% p=0.012). Progression-free survival time (PFS) was shorter in patients with methylation of DAPK than in those without (p=0.007). The overall survival time (OS) was shorter in patients with methylation of BNIP3 than in those without (p=0.031). The response rate was significantly lower in patients with methylation of either DAPK or BNIP3, or both, than in those without methylation (p=0.003). PFS and OS were significantly shorter in patients with methylation of either or both of these genes than in those without (p=0.002, p=0.001). The methylation of BNIP3 and DAPK can predict lower response to chemotherapy and poor prognosis in gastric cancer.

Scoring system for evaluating functional disorders following laparoscopy-assisted distal gastrectomy.

BACKGROUND: Practical questionnaires for evaluating duodenogastric reflux following gastrectomy are currently unavailable. The present study evaluated the usefulness of the frequency scale for the symptoms of gastroesophageal reflux disease (FSSG) questionnaire in the diagnosis of duodenogastric reflux after laparoscopy-assisted distal gastrectomy (LADG), which minimizes the risk of adhesions affecting the gastrointestinal tract. METHODS: Subjects in this study comprised 163 patients who had undergone LADG (Billroth-I (B-I), n = 57, Roux-en-Y (R-Y), n = 106). All subjects underwent endoscopy at least 6 mo postoperatively. The FSSG questionnaire was administered a few weeks after endoscopy, and FSSG scores were compared with endoscopic findings. RESULTS: In the R-Y group, FSSG scores were significantly higher in subjects with remnant gastritis than in those without (P = 0.002), and a significant correlation was seen between FSSG scores and bile reflux (P = 0.046). In the B-I group, FSSG scores were significantly higher in subjects with reflux esophagitis than in those without (P = 0.01), but degree of remnant gastritis and residual food did not correlate significantly with FSSG scores. With a cut-off FSSG score of six points, sensitivity and specificity for predicting remnant gastritis in R-Y reconstruction were 71% and 76%, respectively. CONCLUSION: The FSSG questionnaire is a viable and less invasive alternative to other modalities for evaluating duodenogastric reflux in R-Y reconstruction, but is unsuitable for B-I reconstruction after LADG.

BubR1 and AURKB overexpression are associated with a favorable prognosis in gastric cancer.

The majority of human solid tumors exhibit aneuploidy caused by impairment of the mitotic checkpoint. Since the Mad2, BubR1 and Aurora kinase B (AURKB) proteins are involved in the mitotic checkpoint, we investigated Mad2, BubR1 and AURKB mRNA expression and its effect on clinicopathological parameters and prognosis in 100 consecutive patients who underwent surgical resection for gastric cancer. Mad2, BubR1 and AURKB mRNA expression levels in gastric cancer tissues and corresponding normal gastric mucosa were compared by real-time quantitative RT-PCR. The data were then correlated to clinicopathological parameters and prognosis. The expression of Mad2, BubR1 and AURKB mRNA was found to be significantly higher in cancer tissue compared to normal tissue. BubR1 and AURKB expression was significantly higher during the earlier stages of the disease. Patients with high BubR1 expression had improved relapse-free survival and overall survival compared to patients with low BubR1 expression. Multivariate analysis of stage II and III patients indicated that high expression of BubR1 and/or AURKB was associated with improved overall survival. We conclude that overexpression of BubR1 and AURKB is associated with a low risk of gastric cancer progression, and that overexpression of BubR1 and/or AURKB can therefore be used to identify gastric cancer patients with a favorable prognosis.

Localized small-bowel infarction caused by Aspergillus during chemotherapy for acute myeloid leukemia: report of a case.

Aspergillosis is a common fungal infection in immunocompromised patients undergoing chemotherapy. The incidence of invasive fungal infection in these patients has increased dramatically in recent years. We report a case of small-bowel infarction caused by Aspergillus in a 48-year-old man who was receiving chemotherapy for acute myeloid leukemia. On day 20 after the start of chemotherapy, right lower abdominal pain and rebound tenderness developed, with a high fever. A contrast-enhanced computed tomography scan showed a semicircular perfusion defect in the ileum. Thus, we performed partial resection of the ileum with primary anastomosis. Macroscopically, the ileum had mucosal ulcerations. Microscopically, there was transmural necrosis with microperforation and Aspergillus invading necrotic tissue and blood vessels. The patient had an uneventful postoperative course and was discharged 14 days after the procedure. Intestinal aspergillosis is rare and associated with high mortality. Thus, it should be considered in the differential diagnosis of neutropenic patients with sudden abdominal pain and fever.