Search

Supplementary Methods, Figures 1-3, Table 1. Supplementary Table S1. Cytotoxicity assessment of maytansine conjugates in RET-positive cell lines (IC50 {plus minus} SE [nM]); Supplementary Figure S1. Breast cancer patient survival was stratified based on RET expression by immunohistochemistry; Figure S2. In vitro investigation of Y078-DM4 bystander activity. Figure S3. ADCs elicit dose-dependent, reversible DM1-mediated alterations in clinical chemistry.

Purpose: The RET proto-oncogene has been implicated in breast cancer, and the studies herein describe the preclinical and safety assessment of an anti-RET antibody–drug conjugate (ADC) being developed for the treatment of breast cancer.Experimental Design: RET protein expression was analyzed in breast tumor samples using tissue microarrays. The fully human anti-RET antibody (Y078) was conjugated to the DM1 and DM4 derivatives of the potent cytotoxic agent maytansine using thioether and disulfide linkers, respectively. The resulting compounds, designated Y078-DM1 and Y078-DM4, were evaluated for antitumor activity using human breast cancer cell lines and established tumor xenograft models. A single-dose, 28-day, safety study of Y078-DM1 was performed in cynomolgus monkeys.Results: By immunohistochemistry, RET expression was detected in 57% of tumors (1,596 of 2,800 tumor sections) and was most common in HER2-positive and basal breast cancer subtypes. Potent in vitro cytotoxicity was achieved in human breast cancer cell lines that have expression levels comparable with those observed in breast cancer tissue samples. Dose-response studies in xenograft models demonstrated antitumor activity with both weekly and every-3-weeks dosing regimens. In cynomolgus monkeys, a single injection of Y078-DM1 demonstrated dose-dependent, reversible drug-mediated alterations in blood chemistry with evidence of on-target neuropathy.Conclusions: RET is broadly expressed in breast cancer specimens and thus represents a potential therapeutic target; Y078-DM1 and Y078-DM4 demonstrated antitumor activity in preclinical models. Optimization of the dosing schedule or an alternate cytotoxic agent with a different mechanism of action may reduce the potential risk of neuropathy. Clin Cancer Res; 21(24); 5552–62. ©2015 AACR.

BACKGROUND Socratic method, which is an educational method to promote critical thinking through a dialogue, has never been practiced in a large number of people at the academic societies. METHODS Modified Socratic method was performed for the first time as an educational seminar using an example case of moderate acute cholecystitis based on the evidence described in Tokyo Guidelines 2018. We adopted a method that Takada had been modifying for many years: the instructor first knows the degree of recognition of the audience, then the instructor gives a lecture in an easy-to-understand manner and receives questions from the audience, followed by repeated questions and answers toward a common recognition. RESULTS Using slides, video, and an answer pad, 281 participants including the audience, instructors and moderators came together to repeatedly ask and answer questions in the five sessions related to the case scenario. The recognition rate of the topic of Critical View of Safety increased significantly before vs after this method (53.0% vs 90.3%). The seminar had been successfully performed by receiving a lot of praise from the participants. CONCLUSION This educational method is considered to be adopted by many academic societies in the future as an effective educational method.

The modulation of pre‐mRNA splicing is proposed as an attractive anti‐neoplastic strategy, especially for the cancers that exhibit aberrant pre‐mRNA splicing. Here, we discovered that T‐025 functions as an orally available and potent inhibitor of Cdc2‐like kinases (CLKs), evolutionally conserved kinases that facilitate exon recognition in the splicing machinery. Treatment with T‐025 reduced CLK‐dependent phosphorylation, resulting in the induction of skipped exons, cell death, and growth suppression in vitro and in vivo . Further, through growth inhibitory characterization, we identified high CLK2 expression or MYC amplification as a sensitive‐associated biomarker of T‐025. Mechanistically, the level of CLK2 expression correlated with the magnitude of global skipped exons in response to T‐025 treatment. MYC activation, which altered pre‐mRNA splicing without the transcriptional regulation of CLKs, rendered cancer cells vulnerable to CLK inhibitors with synergistic cell death. Finally, we demonstrated in vivo anti‐tumor efficacy of T‐025 in an allograft model of spontaneous, MYC‐driven breast cancer, at well‐tolerated dosage. Collectively, our results suggest that the novel CLK inhibitor could have therapeutic benefits, especially for MYC‐driven cancer patients.

Background The present study analyzed biliary tract cancer patients registered from 2008 to 2013 in Japan and evaluated the outcomes of biliary tract cancer. Methods A total of 18,606 patients were registered from 2008 to 2013. Cases were analyzed with regard to patient survival according to contiguous extent of the primary tumor (T), node metastasis, and tumor stage using the 3rd English edition of the Japanese classification of the biliary tract cancers. Results Five-year survival rates were 39.8% for gallbladder cancer, 24.2% for perihilar bile duct cancer, 39.1% for distal bile duct cancer, and 61.3% for ampullary region cancer. Significant differences were observed between newly introduced subdivisions in the new Japanese classification for all tumoral sites except gallbladder cancer. The survival rate in patients with #13a metastasis was significantly higher than in patients with distant lymph node metastasis. Conclusions The new Japanese classification adopted the 7th edition of staging system developed by the Union for International Cancer Control staging system. However, numerous aspects of these classification systems remain unvalidated. The present analysis demonstrated the significance of a proportion of T factor subdivisions and classifications of regional lymph nodes in cases of gallbladder cancer in the new Japanese classification.

Background In 2008, the Japanese Society of Hepato-Biliary-Pancreatic Surgery (JSHBPS) launched the clinical practice guideline for the management of biliary tract cancers. JSHBPS decided to revise these guidelines for distribution of updated points concerning the treatment of biliary tract cancers. Methods To make clearer recommendations, we introduced the concepts of Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach, in which the strength of recommendations are decided considering not only quality of evidence, but also balance of benefits and harms/burdens, patients’ preferences, and cost benefits. Results We emphasize the importance of the dynamic contrast enhanced multiple row detector CT (MDCT) in the diagnosis of biliary tract and gallbladder carcinomas. For biliary drainage, we suggest to perform endoscopic approaches instead of percutaneous approach to avoid complications. Regarding the surgical treatments, we included new clinical questions about the importance of combined vascular resection, intraoperative histological examination of the bile duct resection margin, and the combined extrahepatic bile duct resection for the gallbladder carcinoma. We also discussed details about premalignant lesions and non-neoplastic lesions in pathology section. Conclusion With this major revision, we expect that the Japanese standards of treatments of these diseases are recorded and reported in the universal language.

The National Clinical Database (NCD) of Japan was established in April, 2010 with ten surgical subspecialty societies on the platform of the Japan Surgical Society. Registrations began in 2011 and over 4,000,000 cases from more than 4100 facilities were registered over a 3-year period. The gastroenterological section of the NCD collaborates with the American College of Surgeons’ National Surgical Quality Improvement Program, which shares a similar goal of developing a standardized surgical database for surgical quality improvement, with similar variables for risk adjustment. Risk models of mortality for eight procedures; namely, esophagectomy, partial/total gastrectomy, right hemicolectomy, low anterior resection, hepatectomy, pancreaticoduodenectomy, and surgery for acute diffuse peritonitis, have been established, and feedback reports to participants will be implemented. The outcome measures of this study were 30-day mortality and operative mortality. In this review, we examine the eight risk models, compare the procedural outcomes, outline the feedback reporting, and discuss the future evolution of the NCD.

The 3(rd) English edition of the Japanese classification of biliary tract cancers was released approximately 10 years after the 5(th) Japanese edition and the 2(nd) English edition. Since the first Japanese edition was published in 1981, the Japanese classification has been in extensive use, particularly among Japanese surgeons and pathologists, because the cancer status and clinical outcomes in surgically resected cases have been the main objects of interest. However, recent advances in the diagnosis, management and research of the disease prompted the revision of the classification that can be used by not only surgeons and pathologists but also by all clinicians and researchers, for the evaluation of current disease status, the determination of current appropriate treatment, and the future development of medical practice for biliary tract cancers. Furthermore, during the past 10 years, globalization has advanced rapidly, and therefore, internationalization of the classification was an important issue to revise the Japanese original staging system, which would facilitate to compare the disease information among institutions worldwide. In order to achieve these objectives, the new Japanese classification of the biliary tract cancers principally adopted the 7(th) edition of staging system developed by the International Union Against Cancer (UICC) and the American Joint Committee on Cancer (AJCC). However, because there are some points pending in these systems, several distinctive points were also included for the purpose of collection of information for the future optimization of the staging system. Free mobile application of the new Japanese classification of the biliary tract cancers is available via http://www.jshbps.jp/en/classification/cbt15.html.

The discovery of mutations within genes associated with autosomal recessive Parkinson’s disease allowed for the identification of PINK1/Parkin regulated mitophagy as an important pathway for the removal of damaged mitochondria. While recent studies suggest that AKT-dependent signalling regulates Parkin recruitment to depolarised mitochondria, little is known as to whether this can also regulate PINK1 mitochondrial accumulation and downstream mitophagy. Here, we demonstrate that inhibition of AKT signalling decreases endogenous PINK1 accumulation in response to mitochondria depolarisation, subsequent Parkin recruitment, phosphorylation of ubiquitin, and ultimately mitophagy. Conversely, we show that upon stimulation of AKT signalling via insulin, the mitophagy pathway is increased in SHSY5Y cells. These data suggest that AKT signalling is an upstream regulator of PINK1 accumulation on damaged mitochondria. Importantly, we show that the AKT pathway also regulates endogenous PINK1-dependent mitophagy in human iPSC-derived neurons.

Pancreaticobiliary maljunction (PBM) is a congenital anomaly, which can be defined as a union of the pancreatic and biliary ducts located outside off the duodenal wall. We herein investigate clinical features of PBM including as the 2nd report of a Japanese nationwide survey.During a period of 18 years (from 1990 to 2007), 2,561 patients with PBM were registered at 141 medical institutions in Japan. Among them, eligible patients (n = 2,529) were divided into two groups: adult (n = 1,511) and pediatric patients (n = 1,018). Comparisons of clinical features including associated biliary cancers were performed according to the biliary dilatation (BD), age factor, and time era.Only one case in pediatric patients with BD combined with a bile duct cancer (0.1 %). In adult patients, the bile duct cancer and the gallbladder cancer was seen in 6.9 and 13.4 % patients with BD and in 3.1 and 37.4 % patients without BD, respectively. In adult patients with BD, the occurrence rates of biliary cancers were increased in latter period (00'-07') compared with former period (90'-99'). The ratio of biliary cancer localization was changed between former and latter period, and the bile duct cancer was increased in latter period (from 5.5 to 9.3 %).The largest series of PBM were evaluated to clarify the clinical features including the associated biliary cancer in this Japan-nationwide survey. This report could be widely used in the future as a reference data for diagnosis and treatment of PBM.

It is important to predict the development of clinically relevant pancreatic fistula (grade B/C) in the early period after pancreaticoduodenectomy (PD). This study has been carried out as a project study of the Japanese Society of Hepato-Biliary-Pancreatic Surgery (JSHPBS) to evaluate the predictive factors associated with clinically relevant pancreatic fistula (grade B/C).The data of 1,239 patients from 11 medical institutions who had undergone PD between July 2005 and June 2009 were retrospectively analyzed to review patient characteristics and perioperative and postoperative parameters.A drain amylase level4,000 IU/L on postoperative day (POD) 1 was proposed as the cut-off level to predict clinical relevant pancreatic fistula by the receiver operating characteristic (ROC) curve. The sensitivity, specificity, and accuracy of this cut-off level were 62.2, 89.0, and 84.8%, respectively. A multivariate logistic regression analysis revealed that male [odds ratio (OR) 1.7, P = 0.039], intraoperative bleeding1,000 ml (OR 2.5, P = 0.001), soft pancreas (OR 2.7, P = 0.001), and drain amylase level on POD 14,000 IU/L (OR 8.6, P 0.001) were the significant predictive factors for clinical pancreatic fistula.The four predictive risk factors identified here can provide useful information useful for tailoring postoperative management of clinically relevant pancreatic fistula (grade B/C).

黄色肉芽腫性胆嚢炎（Xanthogranulomatous cholecystitis；以下，XGCと略記）は，進行胆嚢癌との鑑別が困難で胆嚢癌と診断された場合，過大手術を施行されることが多く正確な術前診断が重要である．我々の施設では，XGCと進行胆嚢癌の術前鑑別診断に一般的な画像検査に加え，多列検出器CTとカラードプラ断層法による胆嚢壁血流測定を用いている．多列検出器CTでは，XGCの特徴的な所見である胆嚢粘膜の連続性の保持や胆嚢壁内の微細なLow density spotの描出が認められ，これらの所見は進行胆嚢癌には認められないことから鑑別に有用であった．またカラードプラ断層法による胆嚢壁血流測定では，いずれのXGC症例においても胆嚢壁血流の最高流速は進行胆嚢癌と同等の高値を示した．胆嚢壁血管抵抗はXGCでは正常胆嚢と同等の低値であったのに対し，胆嚢癌症例では有意に高値で鑑別診断に有用であった．

Single-incision laparoscopic surgery (SILS) offers the potential advantages of reduced postoperative pain and a lower incidence of port-site complications. Moreover, careful attention to closure can reduce the scarring after surgery. Consequently, this method is a promising technique for reducing postoperative pain, decreasing complications, and improving cosmesis. We have performed cholecystectomy in eight patients by SILS. The umbilicus was the point of entry to the abdomen in all patients.Between May 2009 and October 2009, 31 patients underwent cholecystectomy at our hospital. The umbilicus was the point of entry to the abdomen in all patients. Three SILSs were performed using a new SILS port, and five SILSs were performed by the conventional method in which three ports are inserted into the umbilicus; the remaining ten patients underwent multiple-incision laparoscopic cholecystectomy (standard cholecystectomy). The results for the patients who underwent standard cholecystectomy, conventional SILS, and SILS using the new port were compared using the Mann-Whitney U test. The data are expressed as mean +/- standard deviation.Of the eight cholecystectomies carried out, three were performed by SILS using the new port. No complications or mortalities were associated with this technique. The mean operating times for conventional SILS, SILS with the new port, and standard cholecystectomy were 154 +/- 57, 120 +/- 11, and 100 +/- 51 min, respectively; these inter-group differences are not significant. The blood loss in conventional SILS, SILS with the new port, and standard cholecystectomy was 9 +/- 16, 1, and 6.1 +/- 11 g, respectively; these inter-group differences are not significant. All umbilical incisions were concealed within the umbilicus.Cholecystectomy performed using SILS with the new port is a safe and feasible approach with reasonable operation times.

During a pancreatoduodenectomy (PD) it is important that the anatomy of the arcade of blood vessels in the head of the pancreas is fully understood before the surgery in order to reduce intraoperative bleeding. In most of the patients our group has treated, the inferior pancreaticoduodenal artery (IPDA), one of the efferent arteries of the head of the pancreas, has formed a short common trunk with the first jejunal artery (FJA). Thus, by first locating the origin of the FJA, it was easier to locate the IPDA. There are two ways to locate the IPDA: (1) by measuring the distance between the origin of the superior mesenteric artery (SMA) and that of the FJA; (2) by measuring the distance between the origin of the middle colic artery (MCA) and that of the FJA. Here, we report our measurements of both distances using three-dimensional (3D) models of arteries constructed with multidetector-row computed tomography (MD-CT) images and discuss which is the better measurement to determine the location of the IPDA during PD. A total of 140 patients underwent 64-MD-CT imaging to acquire early and late arterial phase scans. The distance between the origin of the SMA and that of the FJA and the distance between the origin of the MCA and that of the FJA origin were measured. In patients whose IPDA formed either a common trunk with the FJA or arose directly from the SMA, the IPDA or the common truck was located in parallel with the SMA at a very short distance of approximately 18 mm from the MCA origin towards the center. The distance between the SMA origin and the IPDA was significantly longer (approximately 36 mm). Therefore, locating the MCA origin during PD helped determine the location of the IPDA. However, in patients whose anterior inferior pancreaticoduodenal artery (AIPDA) and posterior inferior pancreaticoduodenal artery (PIPDA) arose separately, the distance between the AIPDA origin and the MCA origin was approximately 18 mm, the distance between the AIPDA origin and the PIPDA origin was approximately 19 mm, and the distance between the PIPDA origin and the SMA origin was 19 mm. Thus, locating the SMA helped determine the location of the IPDA during PD in these patients. Based on our findings that the distance between the IPDA origin and the MCA origin was short, we have shown that it is effective to locate the MCA origin in order to determine the location of the IPDA.

To apply duodenum-preserving pancreatic head resection (DPPHR) as radical procedure for benign or low-grade malignant tumors, it needs the reconciliation of complete pancreatic head resection and preservation of the bile duct and peripancreatic vessels. Several modifications have been introduced and applied to remove these lesions, however, the techniques have not been made clear in the management of the peripancreatic vessels and the bile duct. The long-term outcomes of the DPPHR have been reported as extremely rare in comparison with pylorus preserving pancreatoduodenectomy (PPPD) in these pancreatic head tumors. The angiograms by multi-detector row CT (MD-CT) can be reconstructed more physiologically than selective angiography. The anterior arcade is predominant in 43% of 64 patients. Therefore, we modified the DPPHR to include a complete resection of the pancreatic head and the preservation of both anterior and posterior arterial arcades. The bile duct is covered by the pancreatic parenchyma in various ways. The techniques of the preservation of the bile duct are also introduced. We performed 21 DPPHRs and 19 PPPDs in the patients with benign or low-grade malignant pancreatic head tumor. There was no significant difference in operative factors. The postoperative death was one patient in PPPD, but none in DPPHR. The postoperative complications of PPPD were more often than that of DPPHR. There is no postoperative recurrence in DPPHR in the follow-up period from 2 to 216 months. Both exocrine and endocrine function and the long-term results following DPPHR were superior to those following PPPD. The DPPHR should be favored over the PPPD in benign or low-grade malignant tumors of the head of the pancreas if there is no compromise with oncologic radicality.

Recently, we demonstrated that islet transplantation from non-heart-beating donors (NHBDs) using the Kyoto islet isolation method (KIIM) successfully reversed patients' diabetes state. In this study, we evaluated the effects of donor- and isolation-related variables on islet isolation results from NHBDs by KIIM. Twenty-one islet preparations from the pancreata of NHBDs were isolated by KIIM. Islet preparations that met transplantation criteria and achieved improved patient diabetes control after transplantation were defined as successful isolations. Potential risk factors deemed to affect islet isolation results, such as age, gender, body mass index, hospital stay, donors' blood biochemical tests, a modified pancreata procurement method, and isolation and purification procedure-related variables, were analyzed. Seventeen out of 21 islet isolations (81%) were successful isolations. Postpurification islet yield was 447,639 ± 39,902 islet equivalents (IE) in the successful isolation group and 108,007 ± 31,532 IE in the failure group. Donor age was significantly younger in the success group (41.9 ± 4.0 years old in the success group vs. 57.5 ± 2.2 years old in the failure group, p = 0.003). Chronic pancreatitis significantly decreased islet yields (p = 0.006). Phase I time was significantly shorter (p = 0.010) and undigested tissue volume was significantly smaller (p = 0.020) in the success group. Purity was in positive correlation to postpurification islet yield, while donor age was in reverse correlation to postpurification islet yield. KIIM enables us to perform islet transplantation from NHBDs; however, the decision to use pancreata from older donors or those with chronic pancreatitis requires careful consideration.

We report two cases of pneumatosis intestinalis and hepatic portal venous gas. The first case was in a 67-year-old woman who complained of strong right lower abdominal pain and high fever on the twelfth day after pancreatoduodenectomy (PD) with portal vein (PV) resection. Abdominal X-ray and computed tomography showed hepatic portal venous gas and pneumatosis intestinalis. The emergency laparotomy performed disclosed extensive necrosis of the bowel from the jejunum to the ascending colon. All necrotic parts of the bowel were resected and a jejunostomy was performed. The residual intact small intestine was 30 cm in length. Her postoperative course was stable. This is a rare complication after PD and cannot be cured by any other treatment but surgery. The second case was in a 45-year-old woman with the chief complaint of abdominal pain and constipation. She had a past history of chronic toluene inhalation. Abdominal X-ray and computed tomography also showed hepatic portal venous gas and pneumatosis intestinalis, as well as free air, but no physical examination or laboratory test results supported a diagnosis of bowel necrosis. Hyperbaric oxygen (HBO) therapy effectively controlled the symptoms and signs.

When a pancreatoduodenectomy is to be conducted, preoperative understanding of the vascular anatomy of the pancreatic head is important in order to reduce intraoperative bleeding. Using multislice computed tomography (MS-CT), we investigated the depiction rate and branching of the inferior pancreaticoduodenal artery (IPDA) and dorsal pancreatic artery (DPA), afferent arteries to the pancreatic head.In 109 patients (68 with pancreatic cancer, 21 with biliary tract cancer, 15 with intraductal papillary mucinous tumor of the pancreas, and 5 others), images were taken, using 64-row MS-CT, in the early and late arterial phases.The depiction rates were 98.2% for the IPDA and 96.3% for the DPA. Branching of the IPDA was categorized into three types: a type in which the IPDA formed a common vessel with the first jejunal branch (72.0%), a type in which the IPDA branched directly from the superior mesenteric artery (18.7%), and a type in which the anterior inferior pancreaticoduodenal artery (AIPDA) and posterior inferior pancreaticoduodenal artery (PIPDA) branched separately (9.3%). DPA branching was categorized into five types, in which the DPA branched from the splenic artery (40.0%), from the common hepatic artery (25.7%), from the superior mesenteric artery (20.0%), and from the celiac artery (8.6%), and a type in which the DPA branching did not follow any of the above patterns (5.7%).MS-CT images of vascular architecture enable evaluation from any angle, which is not possible with conventional angiography, making MS-CT a useful diagnostic imaging technique for understanding the vascular anatomy of the pancreatic head prior to conducting pancreatoduodenectomy for diseases of the pancreatic head region.

Apart from periampullary carcinoma, the prognosis of biliary tract carcinomas, including hilar cholangiocarcinoma, extrahepatic biliary tract carcinoma, and gallbladder carcinoma, remains poor. Sophisticated diagnostic skills and treatment methods and their application are naturally required to achieve better treatment results for biliary tract carcinomas. However, it is not too much to say that, due to the paucity of high-level evidence for the management of these carcinomas, medical care by healthcare providers in clinics and at medical institutes throughout the world is currently delivered without common consensus and common standards. The clinical practice guidelines for the management of biliary carcinoma outlined here were produced with the aim that they could be used by physicians involved in the care of biliary tract carcinomas, as indicators that could help them provide their patients with the most appropriate care possible at this time. Also, the guidelines were prepared to provide measures that could assure patients with biliary tract carcinomas of safe medical care. The present guidelines are characterized by their clarification of clinical questions assumed to be often shared by healthcare professionals. For clarity, we divided the contents of the guidelines into eight areas. In each area, clinical questions are presented, together with recommendations of clinical actions in response to the question. As mentioned already, there is a paucity of high-level evidence in this area; therefore, the recommendations are classified into grades, of which there are five: A, strongly recommend performing the clinical action; B, recommend performing the clinical action; C1, the clinical action may be useful, although there is a lack of high-level scientific evidence; C2, clinical action not definitively recommended because of insufficient scientific evidence; D, recommend not performing the clinical action. The grading of the recommendations is based on the determination of the level of evidence in references on which the recommendation is based.

The only curative treatment in biliary tract cancer is surgical treatment. Therefore, the suitability of curative resection should be investigated in the first place. In the presence of metastasis to the liver, lung, peritoneum, or distant lymph nodes, curative resection is not suitable. No definite consensus has been reached on local extension factors and curability. Measures of hepatic functional reserve in the jaundiced liver include future liver remnant volume and the indocyanine green (ICG) clearance test. Preoperative portal vein embolization may be considered in patients in whom right hepatectomy or more, or hepatectomy with a resection rate exceeding 50%–60% is planned. Postoperative complications and surgery-related mortality may be reduced with the use of portal vein embolization. Although hepatectomy and/or pancreaticoduodenectomy are preferable for the curative resection of bile duct cancer, extrahepatic bile duct resection alone is also considered in patients for whom it is judged that curative resection would be achieved after a strict diagnosis of its local extension. Also, combined caudate lobe resection is recommended for hilar cholangiocarcinoma. Because the prognosis of patients treated with combined portal vein resection is significantly better than that of unresected patients, combined portal vein resection may be carried out. Prognostic factors after resection for bile duct cancer include positive surgical margins, especially in the ductal stump; lymph node metastasis; perineural invasion; and combined vascular resection due to portal vein and/or hepatic artery invasion. For patients with suspected gallbladder cancer, laparoscopic cholecystectomy is not recommended, and open cholecystectomy should be performed as a rule. When gallbladder cancer invading the subserosal layer or deeper has been detected after simple cholecystectomy, additional resection should be considered. Prognostic factors after resection for gallbladder cancer include the depth of mural invasion; lymph node metastasis; extramural extension, especially into the hepatoduodenal ligament; perineural invasion; and the degree of curability. Pancreaticoduodenectomy is indicated for ampullary carcinoma, and limited operation is also indicated for carcinoma in adenoma. The prognostic factors after resection for ampullary carcinoma include lymph node metastasis, pancreatic invasion, and perineural invasion.

We posed six clinical questions (CQ) on preoperative biliary drainage and organized all pertinent evidence regarding these questions. CQ 1. Is preoperative biliary drainage necessary for patients with jaundice? The indications for preoperative drainage for jaundiced patients are changing greatly. Many reports state that, excluding conditions such as cholangitis and liver dysfunction, biliary drainage is not necessary before pancreatoduodenectomy or less invasive surgery. However, the morbidity and mortality of extended hepatectomy for biliary cancer is still high, and the most common cause of death is hepatic failure; therefore, preoperative biliary drainage is desirable in patients who are to undergo extended hepatectomy. CQ 2. What procedures are appropriate for preoperative biliary drainage? There are three methods of biliary drainage: percutaneous transhepatic biliary drainage (PTBD), endoscopic nasobiliary drainage (ENBD) or endoscopic retrograde biliary drainage (ERBD), and surgical drainage. ERBD is an internal drainage method, and PTBD and ENBD are external methods. However, there are no reports of comparisons of preoperative biliary drainage methods using randomized controlled trials (RCTs). Thus, at this point, a method should be used that can be safely performed with the equipment and techniques available at each facility. CQ 3. Which is better, unilateral or bilateral biliary drainage, in malignant hilar obstruction? Unilateral biliary drainage of the future remnant hepatic lobe is usually enough even when intrahepatic bile ducts are separated into multiple units due to hilar malignancy. Bilateral biliary drainage should be considered in the following cases: those in which the operative procedure is difficult to determine before biliary drainage; those in which cholangitis has developed after unilateral drainage; and those in which the decrease in serum bilirubin after unilateral drainage is very slow. CQ 4. What is the best treatment for post-drainage fever? The most likely cause of high fever in patients with biliary drainage is cholangitis due to problems with the existing drainage catheter or segmental cholangitis if an undrained segment is left. In the latter case, urgent drainage is required. CQ 5. Is bile culture necessary in patients with biliary drainage who are to undergo surgery? Monitoring of bile cultures is necessary for patients with biliary drainage to determine the appropriate use of antibiotics during the perioperative period. CQ 6. Is bile replacement useful for patients with external biliary drainage? Maintenance of the enterohepatic bile circulation is vitally important. Thus, preoperative bile replacement in patients with external biliary drainage is very likely to be effective when highly invasive surgery (e.g., extended hepatectomy for hilar cholangiocarcinoma) is planned.

症例は62歳，男性．2006年4月，検診にて血清アミラーゼ値の高値を指摘され受診．腹部CTにて膵頭部に造影不良腫瘤と主膵管の拡張，上腸間膜動脈（SMA）周囲神経叢浸潤を認めた．また，ERCPにて膵頭部主膵管の狭窄と尾側膵管の拡張を認めた．局所高度浸潤膵癌と診断し放射線化学療法として総照射線量50Gy及びGemcitabine（GEM）600mg/m2の投与を開始した．2コース目以降，800mg/m2のGEMをBi-weeklyで施行し，3コース終了時の腹部CTにて原発巣でPRとSMA周囲神経叢浸潤の軽快を認めたため膵頭十二指腸切除術を施行した．病理検査にて十二指腸粘膜下筋層内に少数の癌遺残を認めたが，膵頭部は腺房萎縮と広範な線維化を認めるのみで明らかな癌細胞は認めなかった．現在，外来にてGEMによる化学療法を継続中であり，明らかな再発·転移は認めていない． 今回，SMA周囲神経叢浸潤を伴う進行膵頭部癌に対しGEM併用放射線化学療法が奏功し膵頭十二指腸切除術を施行しえた1例を経験したため報告した．

Curative resection is the only treatment for biliary tract cancer that achieves long-term survival. However, patients with advanced biliary tract cancer have only a limited prognosis even after radical surgical resection. Thus, to improve the longterm results, the early detection of biliary tract cancer and subsequent cure seem to be essential. The purpose of this study was to review the literature concerning the risk factors for cancerous and precancerous lesions of the biliary tract, and prophylactic surgery for these factors. It has been reported that pancreaticobiliary maljunction (PBM) with bile duct dilatation is a risk factor for gallbladder cancer and bile duct cancer, while PBM without bile duct dilatation is a risk factor for gallbladder cancer. Thus, in the former group, a prophylactic excision of the common bile duct and gallbladder should be recommended, while in the later group, a prophylactic cholecystectomy without bile duct resection may be the appropriate surgical procedure. It has also been reported that primary sclerosing cholangitis (PSC) is a risk factor for cholangiocarcinoma. Patients with PSC often develop advanced cholangiocarcinoma with a poor prognosis. In patients with PSC, therefore, strict follow-up should be recommended. Adenoma and dysplasia have been regarded as precancerous lesions of gallbladder cancer. A polypoid lesion of the gallbladder that is sessile, has a diameter greater than 10 mm, and /or grows rapidly, is highly likely to be cancerous and should be resected. Although gallstones seem to be closely associated with gallbladder cancer, there is no evidence of a direct causal relationship between gallstones and gallbladder cancer. Thus, a cholecystectomy is not advised for asymptomatic cholecystolithiasis. Controversy remains as to whether adenomyomatosis of the gallbladder and porcelain gallbladder are associated with gallbladder cancer. With respect to ampullary carcinoma, adenoma of the ampulla is considered to be a precancerous lesion. This article discusses the risk factors for cancerous and precancerous lesions of the biliary tract and prophylactic treatment for these factors.

Pancreatoduodenectomy (PD) is one of the most difficult operations in gastrointestinal surgery. Standard PD ligates and cuts superior mesenteric vein (SMV) branches after the removal of the pancreas head, which leads to congestion and bleeding of these veins. In this study, we modified the standard PD and first ligated the efferent vessels (arteries); namely, the gastroduodenal artery and inferior pancreatoduodenal artery (IPDA), before ligating and cutting the corresponding afferent vessels (veins) of the pancreas head. By doing this, congestion of these veins was relieved and bleeding from the resected surface was substantially prevented. Thirty-six patients (18 underwent standard PD and 18 had modified PD) formed the study population. The amount of bleeding in the modified PD group was significantly lower than that in the standard PD group. (678 ± 329 g vs 1225 ± 375 g, respectively; P < 0.05) However, no difference in operation time was found between the two groups. We believe this modified PD procedure is valuable to enable the safe performance of PD.

Background The Japanese Society of Hepato-Biliary-Pancreatic Surgery launched the clinical practice guidelines for the management of biliary tract and ampullary carcinomas in 2008. Novel treatment modalities and handling of clinical issues have been proposed after the publication. New approaches for editing clinical guidelines, such as the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system, also have been introduced for better and clearer grading of recommendations. Methods Clinical questions (CQs) were proposed in seven topics. Recommendation, grade of recommendation and statement for each CQ were discussed and finalized by evidence-based approach. Recommendation was graded to grade 1 (strong) and 2 (weak) according to the concept of GRADE system. Results The 29 CQs covered seven topics: (1) prophylactic treatment, (2) diagnosis, (3) biliary drainage, (4) surgical treatment, (5) chemotherapy, (6) radiation therapy, and (7) pathology. In 27 CQs, 19 recommendations were rated strong and 11 recommendations weak. Each CQ included the statement of how the recommendation was graded. Conclusions This guideline provides recommendation for important clinical aspects based on evidence. Future collaboration with cancer registry will be a key for assessment of the guidelines and establishment of new evidence. Free full-text articles and a mobile application of this guideline are available via http://www.jshbps.jp/en/guideline/biliary-tract2.html.

BACKGROUND Recent advances in pancreatic islet transplantation (PIT) have contributed significantly to the treatment of patients with type 1 diabetes. The specific aim of this study was to develop an effective technique for the procurement of pancreas for PIT from nonheart-beating-donor (NHBDs). METHODS Between January 2004 and August 2004, eight human pancreata were procured and processed for isolation of islets at a cell processing center. After confirmation of brain death status, a double balloon catheter was inserted to prevent warm ischemic damage to the donor pancreas by using an in situ regional organ cooling system that was originally developed for procurement of kidneys. The catheter position of the cooling system was modified specifically for the pancreas and kidney. Furthermore, we worked in cooperation with a kidney procurement team to protect the pancreas during kidney procurement. RESULTS Warm ischemic time could be controlled with the modified in situ regional cooling system at 3.0 +/- 0.8 min (mean +/- SE). The operations for procurement of the kidneys and pancreata lasted 45.6 +/- 3.6 min and 10.6 +/- 1.8 min, respectively. Islet yield per isolation was 444,426 +/- 35,172 IE (islet equivalent). All eight cases met the criteria for PIT based on the Edmonton protocol. CONCLUSION We developed a novel procurement technique in cooperation with our kidney procurement team. This protocol for the procurement of pancreas and kidney from a NHBD enabled us to transplant islets into a type 1 diabetic patient and kidney into a renal failure patient.

症例は69歳,男性.心窩部痛を認め近医受診,腹部超音波検査で膵頭部に嚢胞を指摘され紹介となった.各種画像診断で下頭枝領域に限局した径3.5cmの膵管内乳頭粘液性腫瘍の診断であった.術中主膵管損傷を予防するため,術前日に内視鏡的経鼻的膵管ドレナージチューブを主膵管から副膵管に挿入した.触診と超音波で主膵管を確認しつつ,膵切離を行い,最後に責任膵管分枝である下頭枝を切離し,病変を摘出した.切除後の術中膵管造影で主膵管損傷なく,造影剤の漏出のないことも確認した. 膵管ドレナージチューブを留置し,主膵管を確認しながら,下頭枝領域のみを切除する膵頭下部切除術を行い良好な経過を得ることができた膵管内乳頭粘液性腫瘍の1例を報告する.

We raised monoclonal antibodies by immunizing mice with total chromosome proteins extracted from isolated human metaphase chromosomes. The indirect immunofluorescence screening of hybridoma cell lines provided 15 monoclonal antibodies against the chromosomal antigens. The antigen proteins of the mAbs were identified by immunoblotting as core histones or by immunoprecipitation followed by a peptide mass fingerprinting method as nuclear mitotic apparatus protein, heterogeneous nuclear ribonucleoprotein A2/B1, ribosomal protein S4, linker histone and β-actin. During mitosis, localizations of these proteins on chromosomes were clearly observed using the obtained antibodies. These results indicate that the current strategy is effective for obtaining monoclonal antibodies useful for immunoblotting and/or immunofluorescent staining of human proteins, using the antigens with high homology to mouse proteins.

Proper control of gene expression at the level of transcription and RNA processing is a fundamental process of tumor cell growth. Here we showed that a novel pre-mRNA splicing modulator, Cdc2-like kinase (CLK) inhibitor T-025, suppressed tumor cell growth in vitro and in vivo. To reveal the mechanisms linking aberrant splicing and tumor growth suppression by T-025, we combined transcriptomic RNA-seq and proteomic p-SILAC data. We identified MDM4 as a mediator for triggering p53-dependent apoptosis in response to T-025. CLK inhibition led to exon 6 skipping of MDM4 mRNA, a potential target for nonsense-mediated decay, decreasing MDM4 protein. Consistent with these results, overexpression of MDM4 or knockdown of p53 attenuated growth-suppressive effects of T-025. We then investigated the relationship between genomic features and sensitivity to T-025 by evaluating the antiproliferative effect of T-025 against 240 cancer cell lines. Strikingly, expression of MDM4 was correlated with that of CLK2 and cell sensitivity to T-025. In addition, we found that copy number variation and mRNA expression of MYC were correlated with cell sensitivity to T-025. T-025 exhibited greater sensitivity in MYC-expressing cells and MYC-driven spontaneous breast cancer models. Together, we demonstrated that MDM4-p53 signaling and MYC-activation have key roles in antitumor activity of CLK inhibitor. Citation Format: Kazuho Nishimura, Masahiro Yaguchi, Yukiko Yamamoto, Shunsuke Ebara, Kawakita Yoichi, Ryo Mizojiri, Yusuke Nakayama, Kozo Hayashi, Shuichi Miyakawa, Kenichi Iwai, Toshiyuki Nomura. Small molecule inhibitor of pre-mRNA splicing evokes antitumor activity via MDM4-p53 pathway [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B060.

Purpose: The RET proto-oncogene has been implicated in breast cancer, and the studies herein describe the preclinical and safety assessment of an anti-RET antibody–drug conjugate (ADC) being developed for the treatment of breast cancer. Experimental Design: RET protein expression was analyzed in breast tumor samples using tissue microarrays. The fully human anti-RET antibody (Y078) was conjugated to the DM1 and DM4 derivatives of the potent cytotoxic agent maytansine using thioether and disulfide linkers, respectively. The resulting compounds, designated Y078-DM1 and Y078-DM4, were evaluated for antitumor activity using human breast cancer cell lines and established tumor xenograft models. A single-dose, 28-day, safety study of Y078-DM1 was performed in cynomolgus monkeys. Results: By immunohistochemistry, RET expression was detected in 57% of tumors (1,596 of 2,800 tumor sections) and was most common in HER2-positive and basal breast cancer subtypes. Potent in vitro cytotoxicity was achieved in human breast cancer cell lines that have expression levels comparable with those observed in breast cancer tissue samples. Dose-response studies in xenograft models demonstrated antitumor activity with both weekly and every-3-weeks dosing regimens. In cynomolgus monkeys, a single injection of Y078-DM1 demonstrated dose-dependent, reversible drug-mediated alterations in blood chemistry with evidence of on-target neuropathy. Conclusions: RET is broadly expressed in breast cancer specimens and thus represents a potential therapeutic target; Y078-DM1 and Y078-DM4 demonstrated antitumor activity in preclinical models. Optimization of the dosing schedule or an alternate cytotoxic agent with a different mechanism of action may reduce the potential risk of neuropathy. Clin Cancer Res; 21(24); 5552–62. ©2015 AACR.

Background The 3rd English edition of the Japanese classification of the biliary tract cancers (JC) is now available in this journal. The primary aim of this revision is to provide all clinicians and researchers with a common language of cancer staging at an international level. On the other hand, there are several important issues that should be solved for the optimization of the staging system. Methods Revision concepts and major revision points of the 3rd English edition of the JC were reviewed. Furthermore, comparing with the 7th edition of staging system developed by the Union for International Cancer Control (UICC) and the American Joint Committee on Cancer (AJCC), distinctive points in the JC was discussed. Results In this edition of the JC, the same stage groupings as those in the UICC/AJCC staging system were basically adopted. T, N, and M categories were also identical in principle with those in the UICC/AJCC staging system, although slight modifications were proposed as the “Japanese rules”. As distinctive points, perihilar cholangiocarcinomas and ampullary region carcinomas were clearly defined. Intraepithelial tumor was discriminated from invasive carcinoma at ductal resection margins. Classifications of site-specific surgical margin status remained in this edition. Histological classification was based on that in the former editions of the JC, but adopted some parts of the World Health Organization classification. Conclusions The JC now share its staging system of the biliary tact carcinomas with the UICC/AJCC staging system. Future validation of the “Japanese rules” could provide important evidence to make globally standardized staging system. © Japanese Society of Hepato-Biliary-Pancreatic Surgery

The 3(rd) English edition of the Japanese classification of biliary tract cancers was released approximately 10 years after the 5(th) Japanese edition and the 2(nd) English edition. Since the first Japanese edition was published in 1981, the Japanese classification has been in extensive use, particularly among Japanese surgeons and pathologists, because the cancer status and clinical outcomes in surgically resected cases have been the main objects of interest. However, recent advances in the diagnosis, management and research of the disease prompted the revision of the classification that can be used by not only surgeons and pathologists but also by all clinicians and researchers, for the evaluation of current disease status, the determination of current appropriate treatment, and the future development of medical practice for biliary tract cancers. Furthermore, during the past 10 years, globalization has advanced rapidly, and therefore, internationalization of the classification was an important issue to revise the Japanese original staging system, which would facilitate to compare the disease information among institutions worldwide. In order to achieve these objectives, the new Japanese classification of the biliary tract cancers principally adopted the 7(th) edition of staging system developed by the International Union Against Cancer (UICC) and the American Joint Committee on Cancer (AJCC). However, because there are some points pending in these systems, several distinctive points were also included for the purpose of collection of information for the future optimization of the staging system. Free mobile application of the new Japanese classification of the biliary tract cancers is available via http://www.jshbps.jp/en/classification/cbt15.html.

Detailed conditions of the fabrication of devices by SPM ultrafine oxidation are discussed and a new process is conceived for reducing the surface roughness compared with the conventional process. A single electron transistor (SET) with a side gate electrode is fabricated on an ultrathin Ti film deposited on an SiO2/Si substrate. Current oscillation with gate voltage is clearly observed for the first time in a Ti-based SET. © 1998 Scripta Technica, Electron Comm Jpn Pt 2, 81(10): 12–18, 1998

Optimal treatment types and prognosis for patients with borderline resectable pancreatic cancer (BRPC) remain unclear because of the lack of studies involving large series of patients. We retrospectively analyzed various prognostic factors for 624 BRPC (pancreatic head/body) patients treated from June 2002 to May 2007, by distributing questionnaires to member institutions of the Japanese Society of Pancreatic Surgery in 2010. BRPC was defined according to the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines (2009). Among 624 patients, 539 (86.4 %) underwent curative-intent resection, showing an R0 resection rate of 65.9 %. The 3- and 5-year survival rates were 16.1 and 9.9 % in all patients, 22.8 and 12.5 % in the resected patients, and 4.4 and 0 % (P

Using helical computed tomography (CT), we evaluated cystic pancreatic lesions in 11 patients and compared the imaging and the histopathologic findings. Helical CT allowed us to assess the tumor vasculature. Contrastenhanced images showed satisfactory details of the cysts, cyst walls, and intracystic structures. Helical CT is extremely useful for the evaluation of cystic pancreatic lesions.

Using the criteria of the Japanese Ministry of Health and Welfare for evaluation of the severity of acute pancreatitis based on computed tomography (CT), we assessed the CT grade of 104 patients with acute pancreatitis. The CT assessments were compared with the status of acute pancreatitis in these patients, assessed using Ranson’s system of objective prognostic signs by which acute pancreatitis is classified as “mild”, “moderate”, or “severe.” A CT grade of I corresponded to Ranson’s mild category; CT grades II and III corresponded to moderate, and CT grades IV and V corresponded to servere. Some patients with a CT grade of IV or V died, whereas none of the patients with CT grades of I, II, or III succumbed to the condition. This study confirmed that enhanced CT provides an accurate CT grading of acute pancreatitis. We emphasize the necessity of using enhanced CT for determining the severity of acute pancreatitis, not only on admission but also during hospitalization if the patient’s condition should become exacerbated.

We hypothesize that the presence of a few secretin-releasing cells sited in the upper jejunum may provoke a postprandial secretin response to meal loading in patients who have undergone the Whipple procedure. This procedure involves gastrectomy and total duodenectomy and requires gastrointestinal tract reconstruction by one of three methods: (i) choledocho-pancreatico-gastro alignment (PD-1), (ii) pancreatico-choledocho-gastro alignment (PD-2) (both these methods excluding the upper jejunum from the route of food passage), or (iii) gastro-pancreatico-choledocho alignment (PD-3), in which food passes through the upper jejunum. Fasting and postprandial plasma secretin and gastrin response were measured in 47 Whipple-treated patients, 16 given a PD-1, 15 given a PD-2, and 16 given a PD-3, and in 15 healthy controls. Plasma secretin response and integrated secretin release were higher, but not significantly, in the PD-3 group, and lower in all three Whipple-treated groups than in the control (P

A 76-year-old woman underwent combined resection of the gallbladder plus partial hepatectomy for early gallbladder cancer. From the pathology results, the surgical treatment was deemed to have been curative. However, 3 years later, the patient was readmitted to the hospital with an elevated carbohydrate antigen (CA) 19-9 level. Percutaneous transhepatic cholangiography demonstrated irregularity of the common hepatic duct and the left intrahepatic bile duct, and percutaneous transhepatic cholangioscopy revealed two separate papillary tumors at these sites. A diagnosis of multiple carcinomas of the bile duct was made and left hepatic lobectomy and resection of the extrahepatic bile duct was performed; reconstruction was carried out with a right hepatico-jejunostomy with Roux-en-Y anastomosis. Microscopic study revealed that both of the lesions were papillary adenocarcinomas, and normal biliary mucosa was confirmed to exist between them.

Background/aims Pancreatic body cancer often involves the common hepatic artery and/or the celiac axis, and is regarded as an unresectable disease. Hepatic blood flow must be monitored while performing distal pancreatectomy with en bloc celiac axis resection (DP-CAR) for managing the progression of pancreatic body cancer. We first confirmed a safe level of blood flow by monitoring hepatic venous oxygen saturation (ShvO2) to prevent hepatic ischemia caused by occlusion of the common hepatic artery. However, this method is technically difficult and a long period of time is required to insert the catheter. Thus, we monitored hepatic arterial flow by using a transonic flowmeter in the hepatic artery during operation. Methodology Between April 1992 and January 2011, 14 patients underwent DP-CAR. In 6 of these 14 patients we measured ShvO2. In 2 of the 14 patients, a transonic flowmeter was used for determining the hepatic arterial flow during operation. Results There were no complications during this operation. Operation time when the blood flow was monitored using a transonic flowmeter was less than that when ShvO2 was measured. Conclusions Monitoring the transonic flowmeter hepatic artery is a useful and quick method for real-time evaluation of hepatic circulation during operation.

Intraductal papillary mucinous neoplasm (IPMN) and pancreatic endocrine tumors can develop at multiple sites of the pancreas at the same time, sometimes necessitating total pancreatectomy. When low-grade pancreatic malignancy is treated surgically, preservation of function to improve long-term QOL is emphasized. For low grade malignancy tumor of the pancreatic head and tail, we performed middle- segment-preserving pancreatectomy (MSPP), with resection of the pancreatic head and tail alone, resulting in favorable QOL.MSPP was performed for 4 patients. Intraoperative blood loss, hospital stay, postoperative complications, histopathological findings and prognosis were examined.Mean intraoperative blood loss was 1255 +/- 365g, mean hospital stay 61 +/- 53 days, and mortality 0%. Postoperatively, pancreatic fistula was observed in 3 patients, but subsided with conservative treatment. In one patient with diabetes preoperatively, diabetes was exacerbated postoperatively, necessitating insulin treatment. No postoperative onset of diabetes was observed. Percent change in body weight during the postoperative 6 month period from preoperative weight was 93 +/- 6.3%. One patient died of malignant lymphoma 1 year and 4 months after surgery. The other patients are alive and socially active.MSPP enables maintenance of good QOL long after surgery for malignancy affecting the head and tail of the pancreas.

The ideal surgical procedure for treating pancreatic cancer achieves radical excision in a minimally invasive manner and allows rapid transition to adjuvant chemotherapy. If the afferent artery to the pancreatic head is not ligated until the latter half of the surgery, congestion of the pancreaticoduodenal vein may occur, leading to phleborrhagia and increased intraoperative hemorrhage. Ligation of the afferent artery, i.e., the inferior pancreaticoduodenal artery (IPDA), in the first half of the surgery may prevent the occurrence of hemorrhage due to congestion. Early ligation of the IPDA is also useful in ensuring the success of radical dissection of the plexus around the superior mesenteric artery or the no. 14 lymph node. We have been performing pancreaticoduodenectomies with antecedent IPDA ligation since 2005 and have found that the percentage of R0 versus R1 and R2 has increased compared with that when standard pancreaticoduodenectomies were performed. Preemptive ligation of the IPDA early in pancreaticoduodenectomy for invasive pancreatic cancer is a useful method for reducing blood loss and achieving R0 resection in a thorough yet efficient manner.

In the field of gastroenterological surgery, laparoscopic surgery has advanced remarkably, and now accounts for most gastrointestinal operations. This paper outlines the current status of and future perspectives on robot-assisted laparoscopic pancreatectomy.A review of the literature and authors' experience was undertaken.The da Vinci Surgical System is a robot for assisting laparoscopy and is safer than conventional endoscopes, thanks to the 3-dimensional hi-vision images it yields, high articular function with the ability to perform 7 types of gripping, scaling function enabling 2:1, 3:1, and 5:1 adjustment of surgeon hand motion and forceps motions, a filtering function removing shaking of the surgeon's hand, and visual magnification. By virtue of these functions, this system is expected to be particularly useful for patients requiring delicate operative manipulation.Issues of importance remaining in robot-assisted laparoscopic pancreatectomy include its time of operation, which is longer than that of open surgery, and the extra time needed for application of the da Vinci compared with ordinary laparoscopic surgery. These issues may be resolved through accumulation of experience and modifications of the procedure. Robot-assisted laparoscopic pancreatectomy appears likely to become a standard procedure in the near future.

The search for effective antibodies (Ab) for curable cancer immunotherapy has been a quest of many research groups in order to find an effective target that exists on the cancer cell surface. So far there have been no conclusive answers to shed light on the search. This study therefore aimed to bridge the gap of cancer therapy. Screening against 49 kinds of cell lines belonging to 11 kinds of solids cancers was performed. Isolation and characterization for approximately 4200 monoclonal antibodies (mAb) was also performed thereafter. Of those mAb 488 clones that turned out to bind to 29 tumor-associated antigens (TAA) were subjected to immunohistochemical (IHC) analyses. Selection of target antigens (Ag) and a potential antibody for cancer therapy was conducted prior to clinical examinations. In order to find predictably effective targets for therapeutic Ab against solid cancers, expression of the Ag on the surface of cancer and normal cells was extensively examined by IHC analyses using fresh cancer specimens resected from patients. In this study, the tendencies of all staining patterns and distribution of the Ab are reported. While all of the TAA appeared to be involved in tumorigenesis, their expression was not restricted to some specific tumor types but rather randomly distributed among various cancers. Some kinds of Ab including anti-epidermal growth factor receptor (EGFR) and anti-human epidermal growth factor receptor 2 (HER2) indicated the frequency of expression in normal cells was generally low. We concluded that identification of 488 mAb and the accumulated results of IHC analyses in this study could be the key for further therapeutic Ab against cancers. The targets that showed cancer-specific expression are expected to be better for therapeutic Ab than the other Ab. Moreover, further investigation into the growth of cancer cell lines using full human IgG form of Ab shows available efficacy in specific cases.

Robotic surgery is the most advanced development in minimally invasive surgery. However, the number of reports on robot-assisted endoscopic gastrointestinal surgery is still very small. In this article, we describe total laparoscopic pancreaticoduodenectomy (PD) undertaken using the da Vinci Surgical System® (Intutive Surgical). Three patients underwent robotic PD between November 2009 and February 2010. Following resection of the pancreatic head, duodenum, and the distal stomach, intracorporeal anastomosis was accomplished by Child’s method of reconstruction, which includes a two-layered end-to-side pancreaticojejunostomy, an end-to-side choledochojejunostomy, and a side-to-side gastrojejunostomy. The time required for surgery was 703 ± 141 min, and blood loss was 118 ± 72 mL. The average hospital stay period was 26 ± 12 days. As a postoperative complication, pancreatic juice leak occurred in one case, but it was managed with conservative treatment. Of the three patients, one had cancer of the papilla of Vater, one had cancer of the pancreatic head, and one had a solid pseudopapillary neoplasm. In all cases, the surgical margin was negative for tumor. Robot-assisted PD required a long time, but organ removal with less bleeding was able to be safely performed owing to the high degree of freedom associated with the forceps manipulation and the magnified view. Similarly, pancreatojejunostomy could certainly be conducted. No major postoperative complications were found. Accumulation of da Vinci PD experience in the future will lead to safer and faster PD.