Treatment of delayed pancreatic fistula associated with anastomosis breakdown after pancreaticoduodenectomy using percutaneous interventions.

We here present a rare case of development of a postoperative pancreatic fistula and breakdown of the pancreaticojejunal anastomosis 8 months after pancreaticoduodenectomy. A 70-year-old man underwent pancreaticoduodenectomy for distal cholangiocarcinoma and initially recovered well. However, 8 months later, he developed abdominal pain and distention and was admitted to our institution with suspected pancreatitis. On the 17th day of hospitalization, he suddenly bled from the jejunal loop and a fluid collection was detected near the pancreaticojejunal anastomosis site. The fluid collection was drained percutaneously. Subsequent fistulography confirmed breakdown of the pancreaticojejunal anastomosis. Considering the patient's overall condition and the presence of postoperative adhesions, we decided to manage him conservatively. An additional drain tube was placed percutaneously from the site of the anastomotic breakdown into the lumen of the jejunum, along with the tube draining the fluid collection, creating a completely new fistula. This facilitated the flow of pancreatic fluid into the jejunum and was removed 192 days after placement. During a 6-month follow-up, there were no recurrences of pancreatitis or a pancreatic fistula. This case highlights the efficacy of percutaneous drainage and creation of an internal fistula as a management strategy for delayed pancreatic fistula and anastomotic breakdown following pancreaticoduodenectomy.

Gastric cancer complicated by paraneoplastic neurological syndrome which presented with extremity numbness: a case report.

BACKGROUND: Paraneoplastic neurological syndromes refer to a group of neurological disorders, which occur as distant effects of malignant tumors and are not caused by metastasis, nutritional disorders, or side effects of antitumor drugs. CASE PRESENTATION: A 70-year-old woman complained of a 1-month history of extremity numbness. Upon presentation to our hospital, she had worsening numbness, and experienced staggering and falling. Physical examination revealed diminished tendon reflexes in both lower limbs, stocking and glove-type abnormal sensation, and left-sided dominant high-steppage gait due to weakness of the bilateral tibialis anterior muscles. Blood tests indicated anemia, and upper gastrointestinal endoscopy revealed gastric cancer, leading to laparoscopic distal gastrectomy. A nerve conduction velocity test showed demyelinating peripheral neuropathy. Further blood tests and imaging studies ruled out nutritional disorders, such as vitamin deficiency, diabetes-related diseases, connective tissue diseases, and central nervous system metastasis, leading to the suspicion of paraneoplastic neurological syndrome. After laparoscopic distal gastrectomy, the progression of symptoms stopped, and with intravenous high-dose immunoglobulin and steroid therapy, the symptoms improved to only minor numbness in the peripheral limbs as of the 18-month follow-up. As of the 2-year follow-up, there has been no cancer recurrence or metastasis. CONCLUSIONS: When paraneoplastic neurological syndrome is suspected, early diagnosis and a multidisciplinary approach, including surgical treatment, are important before irreversible neurological damage occurs.

Pancreatic morphological abnormality that was challenging to differentiate from an ectopic pancreas: a case report.

BACKGROUND: Protrusion of the lateral contour of the pancreatic head is a pancreatic morphological abnormality, which is known as rare shape atypia. We present a rare case of protrusion of the lateral contour of the pancreatic head, which was challenging to distinguish from an ectopic pancreas. CASE PRESENTATION: The patient was a 40-year-old man with a history of acute pancreatitis that occurred twice in the past. He complained of epigastric pain since the day before the visit; his blood workup showed high serum amylase level and a CT scan revealed a 25-mm-large mass with contrast effect from the anterior wall of the gastric pylorus to the duodenum and increased surrounding fatty tissue density. Endoscopic ultrasonography revealed a mass lesion in the gastric pylorus with continuity with the gastric wall and suspected partial continuity with the pancreatic head. Thus, the possibility of pancreatic morphological abnormality or an ectopic pancreas was considered. Following which, resection was attempted and intraoperative findings showed a wide extension of the pancreatic parenchyma from the pancreatic head to the anterior wall of the gastric pylorus to the duodenal bulb. Since the patient only had mild pancreatitis, the resection was judged to be too invasive and was completed by exploratory laparoscopy. CONCLUSIONS: Even if the findings on preoperative CT are suspicious for an ectopic pancreas or tumor, a pancreatic morphological abnormality, such as a protrusion of the lateral contour of the pancreatic head, should be included in the differential diagnosis.

[Investigation of Colorectal Cancer Cases among Patients Aged over 75 Years Who Received Postoperative Adjuvant Chemotherapy].

BACKGROUND: As the aging of the Japanese population progresses, the administration of postoperative adjuvant chemotherapy( AC)to the elderly is also expected to increase. OBJECTIVE: To examine the characteristics of AC in cases of colorectal cancer among elderly people aged over 75 years. PATIENTS: Forty-eight cases of colorectal cancer patients who received AC. METHODS: The clinicopathological factors, including 14 patient-related factors, 6 operation-related factors, and 2 AC-related factors, as well as the long-term outcomes, were compared between the elderly group of patients aged over 75 years(group O, 12 cases)and the non-elderly group(group Y, 36 cases). RESULTS: Significant differences were observed between groups in neutrophil count(p=0.044), operation time(p=0.044), AC regimen(p=0.006), and administration completion status (p=0.046). Compared to group Y, a higher proportion of oral drug alone(92% vs 39%)and completion rate of the initial setting dose(75% vs 39%)were observed in group O. There was no significant difference in the 2-year disease-free survival rate. CONCLUSION: Oral preparations of AC may be useful from the viewpoint of tolerability in the elderly.

Tumor budding and human chorionic gonadotropin-ß expression correlate with unfavorable patient outcome in colorectal carcinoma.

Tumor budding is thought to represent a manifestation of epithelial-to-mesenchymal transition (EMT) and it has been correlated with poor patient outcomes in colorectal cancer (CRC). Our group recently demonstrated that human chorionic gonadotropin-ß (hCGß) modulates EMT in CRC. In the current study, based on the likely relationships between tumor budding and hCGß expression, we examined their clinicopathologic significance in CRC. Twenty-eight of 80 (35.0%) CRC showed tumor budding. Tumor budding significantly correlated with lymph node metastasis (P < 0.01), pathologic stage (P < 0.01), lymphatic invasion (P = 0.044), and vascular invasion (P = 0.013). Thirteen of 80 (16.3%) CRC were hCGß positive on immunohistochemistry. More tumor buds were present in the hCGß-positive cases (P < 0.01), and tumor budding was significantly correlated with hCGß positivity (P < 0.01). Cases with both tumor budding and hCGß expression had the poorest prognosis compared with all other groups (P < 0.01). In conclusion, tumor budding and hCGß expression are closely associated with EMT, and they are independent prognostic factors in CRC. They identify patients with an "EMT phenotype" who may respond to targeted molecular therapies.

Chorionic Gonadotropin-ß Modulates Epithelial-Mesenchymal Transition in Colorectal Carcinoma Metastasis.

Ectopic production of free ß human chorionic gonadotropin (hCGß) has been associated with aggressive behavior in non-trophoblastic tumors. hCGß shares common evolutionary sequences with transforming growth factor-ß (TGF-ß), which represents a major driving force of epithelial-to-mesenchymal transition (EMT). In this study, we examined the biological roles of hCGß during EMT and its clinical significance in colorectal cancer (CRC) progression. Eighty CRC specimens and 54 preoperative serum samples were analyzed. hCGß-overexpressing human CRC cell lines were examined for invasiveness and tumorigenicity, and the expression of EMT-associated genes was investigated. In human CRC, histologic hCGß positivity [13/80 (16.3%)] was lower than serologic hCGß positivity [13/54 (24.1%)]. However, it was significantly correlated with several clinicopathological features and unfavorable outcome (P < 0.05). hCGß-overexpressing cell lines had increased invasiveness, migratory ability, and metastatic potential in mice (P < 0.01). Western blot, PCR, and microarray analyses showed hCGß altered expression of EMT-related genes, including E-cadherin, phosphorylated SMAD2, SNAIL, and TWIST. hCGß-induced SNAIL and TWIST overexpression levels were reversible by type I and type II TGF-ß receptor inhibitors (P < 0.05). hCGß thus induces EMT via the TGF-ß signaling pathway, and it may represent a molecular target in CRC treatment.

Serosal Laceration During Firing of Powered Linear Stapler Is a Predictor of Staple Malformation.

BACKGROUND: Although several types of staplers have been developed, staple-line leaks have been a great problem in gastrointestinal surgery. Powered linear staplers were recently developed to further reduce the risk of tissue trauma during laparoscopic surgery. The aim of this study was to identify the factors that predict staple malformation and determine the effect of precompression and slow firing on the staple formation of this novel powered stapling method. METHODS: Porcine stomachs were divided using an endoscopic powered linear stapler with gold reloads. We divided the specimens into 9 groups according to the precompression time (0/60/180 seconds) and firing time (0/60/180 seconds). The occurrence and length of laceration and the shape of the staples were evaluated. We examined the factors influencing successful stapling and investigated the key factors for staple malformation. RESULTS: Precompression significantly decreased the occurrence and length of serosal laceration. Precompression and slow firing significantly improved the optimal stapling formation rate. Univariate analysis showed that the precompression time (0 seconds), firing time (0 seconds), and presence of serosal laceration were significantly associated with a low optimal formation rate. Multivariate analysis showed that these three factors were associated independently with low optimal formation rate and that the presence of serosal laceration was the only factor that could be detected during the stapling procedure. CONCLUSIONS: We have shown that serosal laceration is a predictor of staple malformation and demonstrated the importance of precompression and slow stapling when using the powered stapling method.

Clinical impacts of mesothelin expression in gastrointestinal carcinomas.

Mesothelin, C-ERC/mesothelin is a 40-kDa cell surface glycoprotein that is normally present on normal mesothelial cells lining the pleura, peritoneum, and pericardium. Moreover, mesothelin has been shown to be overexpressed in several human cancers, including virtually all mesothelioma and pancreatic cancer, approximately 70% of ovarian cancer and extra bile duct cancer, and 50% of lung adenocarcinomas and gastric cancer. The full-length human mesothelin gene encodes the primary product, a 71-kDa precursor protein. The 71-kDa mesothelin precursor is cleaved into two products, 40-kDa C-terminal fragment that remains membrane-bound via glycosylphosphatidylinositol anchor, and a 31-kDa N-terminal fragment, megakaryocyte potentiating factor, which is secreted into the blood. The biological functions of mesothelin remain largely unknown. However, results of recent studies have suggested that the mesothelin may play a role of cell proliferation and migration. In pancreatic cancer, mesothelin expression was immunohistochemically observed in all cases, but absent in normal pancreas and in chronic pancreatitis. Furthermore, the expression of mesothelin was correlated with an poorer patient outcome in several human cancers. The limited mesothelin expression in normal tissues and high expression in many cancers makes it an attractive candidate for cancer therapy. The present review discusses the expression and function of mesothelin in cancer cells and the utility of mesothelin as a target of cancer therapy.

Comparison of outcomes after everolimus-eluting stent implantation in diabetic versus non-diabetic patients in the Tokyo-MD PCI study.

BACKGROUND: Diabetes mellitus (DM), especially in those requiring insulin for treatment, is known to be a risk factor for adverse events after percutaneous coronary intervention using first-generation drug-eluting stents. However, the role of DM in patients treated with everolimus-eluting stents (EES) is less known. The purpose of the present analysis was to evaluate the outcomes of treatment with EES for DM patients both requiring and not requiring insulin, and to compare them with non-DM patients. METHODS: Of patients treated with EES in the Tokyo-MD PCI study, an all-comer, multicenter, observational cohort study, we identified 199 insulin-requiring diabetics (IRDM), 575 non-insulin requiring diabetics (NIRDM), and 1092 non-diabetics (non-DM). The main outcomes were major adverse cardiovascular events (MACE) defined as a composite of all-cause death, myocardial infarction, and stroke, and target lesion revascularization (TLR). RESULTS: The cumulative incidence of MACE and TLR was significantly greater in patients with IRDM than non-DM [MACE: hazard ratio 1.97, 95% confidence interval (CI) 1.31-2.90, p<0.01; TLR: hazard ratio 3.43, 2.07-5.55, p<0.0001] according to univariate Cox proportional hazards model. After adjusting for confounders using the multivariate Cox proportional hazard model, the risk of IRDM versus non-DM for TLR remained significant (hazard ratio 1.92, 1.10-3.29, p=0.02). The incidence of TLR in NIRDM was slightly greater than that in non-DM according to univariate analysis (hazard ratio 1.65, 1.07-2.54, p=0.02). However, the risk was not statistically different in the multivariate analysis (hazard ratio 1.52, 0.97-2.35, p=0.06). CONCLUSIONS: In this all-comer, observational study, the risk of TLR was greater in IRDM compared with non-DM after EES implantation, while the increased risk for TLR from NIRDM did not reach statistical significance.

A Study on Drug Interaction between Warfarin and Capecitabine with Special Reference to the Co-Administered Term or the Discontinuation Term of Capecitabine.

We used the prothrombin time international normalized ratio(PT-INR)to investigate the change in degree and term of warfarin following co-administration and after discontinuation of capecitabine. In this study, approximately 3 years of medical records of 7 patients receiving co-administration therapy of warfarin and capecitabine were obtained from 4 hospitals. We observed daily increases in PT-INR values up to peak PT-INR levels following co-administration of warfarin and capecitabine. Interestingly, the peak PT-INR values of 4 of the patients remained remarkably high despite discontinuation of capecitabine. The peak PT-INR values for concomitant warfarin and capecitabine were attained after an average of 31.3 days of usage. When compared with the average PT-INR values attained before co-administration, the PT-INR values following co-administration significantly increased by 3 times (p<0.05). After discontinuation of capecitabine for an average of 15.1 days, i. e., for approximately 14 days, the PT-INR values returned to the PT-INR values attained prior to co-administration. These results suggest that capecitabine has influence on the anticoagulant effect of warfarin during not only the co-administered term but also the discontinuation term, and that this influence occasionally continues after discontinuation of capecitabine. These findings also suggest that a period of approximately 14 days after discontinuation is necessary for the interaction of capecitabine to dissipate and the PT-INR values to return the levels attained before receiving concomitant warfarin and capecitabine.

Importance of luminal membrane mesothelin expression in intraductal papillary mucinous neoplasms.

The present study demonstrated that luminal membrane mesothelin expression is a reliable prognostic factor in gastric cancer. Intraductal papillary mucinous neoplasms (IPMNs) often exhibit a spectrum of dysplasia, ranging between adenoma and carcinoma. Therefore, an immunohistochemical analysis of mesothelin expression in IPMN was performed in the present study, focusing on the localization of mesothelin. IPMNs were classified into two groups, IPMNs associated with invasive carcinoma and low-high (L-H) grade dysplasias. The tumors were classified as mesothelin-positive or -negative and in the mesothelin-positive cases, the localization of mesothelin was evaluated as luminal membrane- or cytoplasmic-positive. Among the 37 IPMNs, mesothelin expression was observed in 21 samples (56.8%), including 46.2% (12 out of 26) of the L-H dysplasia and 81.8% (9 out of 11) of the invasive carcinoma samples (P=0.071). Luminal membrane localization was observed in 10 samples (27%), including 15.4% (4/26) of the L-H dysplasia samples and 54.5% (6 out of 11) of the invasive carcinoma samples (P=0.022). Six patients experienced post-operative recurrence, with five of the recurrent tumors exhibiting mesothelin expression and all six exhibiting luminal membrane localization. It was concluded that immunohistochemical examinations for mesothelin expression and localization are clinically useful for prognostic assessments and decision making regarding further treatment subsequent to surgical procedures in patients with IPMN.

[A case of complete response to multiple liver metastasis of gastric cancer after discontinuation of S-1 administration].

An 80-year-old man was diagnosed with advanced gastric cancer and underwent distal gastrectomy. Although the pathological Stage of the cancer was III A, he refused adjuvant chemotherapy. One year later, CT revealed multiple liver metastases. Therefore, he was started with S-1 administration and a complete response was obtained at 10 months after starting S-1 administration. He has maintained a complete response for 22 months after S-1 discontinuation.

Adenosine triphosphate-induced atrial fibrillation: the clinical significance and relevance to spontaneous atrial fibrillation.

PURPOSE: Adenosine triphosphate (ATP) frequently triggers atrial fibrillation (AF), but the clinical significance of this phenomenon is unknown. The purpose of this study was to reveal the relevance between spontaneous AF and ATP-induced AF. METHODS: In 81 AF patients undergoing pulmonary vein isolation (PVI), we injected 20 mg of ATP before PVI, and recorded triggering sites of the AF induced. We also injected 20 mg of ATP in 44 patients receiving ablation for atrioventricular reciprocating tachycardia (AVRT). RESULTS: ATP provoked AF in 24 (29.6 %) of the 81 PVI patients and atrial ectopic beats in a further 48 (59.3 %). The trigger site of the AF was in the PV and the right atrium in 22 (91.7 %) and 2 patients, respectively. In 14 of those 24 patients, spontaneous AF arose from the same triggering site as the ATP-induced AF. In the 48 patients with ATP-provoked ectopic beats, spontaneous AF arose from the same site in 13. Conversely, among the 34 patients demonstrating spontaneous AF initiation, AF or ectopic beats were provoked by ATP from the same site in 14 (41.2 %) and 13 patients (38.2 %), respectively. ATP provoked AF in only 2 (4.5 %) of the AVRT patients. In summary, ATP provoked AF or atrial ectopic beats in 88.9 % of PVI patients, 36.1 % of whose triggering sites matched that of the spontaneous AF, while 79.4 % of spontaneous AF trigger sites matched ATP-provoked AF or ectopic beat sites. CONCLUSIONS: ATP-induced AF was strongly associated with clinical AF, and ATP is useful for identifying arrhythmogenic sites.

Characterization of predictors of in-hospital cardiac complications of takotsubo cardiomyopathy: multi-center registry from Tokyo CCU Network.

BACKGROUND: Takotsubo cardiomyopathy (TC) is an acute cardiac syndrome characterized by transient left ventricular dysfunction and relatively good prognosis after discharge. However, cardiac complications during hospitalization remain to be fully determined. We attempted to determine features characterizing patients with adverse clinical outcome by comparing those with cardiac complication and without cardiac complication during hospitalization. METHODS AND RESULTS: We investigated 107 patients with TC from the Tokyo CCU Network database, comprising 67 cardiovascular centers in the metropolitan area during January 1 to December 31, 2010. Cardiac complications were defined as cardiac death, pump failure (Killip grade≥II), sustained ventricular tachycardia or fibrillation (SVT/VF), and advanced atrioventricular block (AVB). Cardiac complications were observed in 41 patients (37 pump failure complicated by 3 cardiac deaths and 2 SVT/VF and 2 AVB without pump failure), and there was no cardiac complication in the remaining 66 patients. There was no difference in age, peak creatinine kinase level, C-reactive protein level and ST elevation on electrocardiogram. Multiple logistic regression analysis showed that white blood cell count (p=0.039) and brain natriuretic peptide (p=0.001) were independent predictors of in-hospital adverse cardiac complications. CONCLUSIONS: Cardiac complications are relatively high in patients with TC during hospitalization. High white blood cell count and brain natriuretic peptide level are associated with poor clinical outcome in patients with TC.