Neoplastic spindle cells are an independent prognostic factor in pancreatic cancer.

OBJECTIVE: Several reports showed that neoplastic spindle cells (NSCs) may be strongly involved in the invasion, metastasis, and poor prognosis, as well as in epithelial-mesenchymal transition (EMT). It has not yet been investigated that NSCs relate to the recurrence and prognosis in various cancers. Furthermore, NSCs participate in EMT in pancreatic cancer (PC) too. We clinicopathologically investigated the association between NSCs and the recurrence, prognosis, and EMT in PC. METHODS: We studied 68 PC patients. Cancer cells with a spindle or oval shape that do not exhibit luminal structures were defined as NSCs. We graded NSCs regarding to an area of NSCs at hematoxylin and eosin stain (NSC grade) and examined the participation in NSCs and EMT by immunohistostaining of snail antibody and E-cadherin antibody. RESULTS: In multivariate analysis, NSC grade was an independent risk factor for disease-free survival and overall survival. This was independent of TNM stage and histological grade. Neoplastic spindle cells were related to EMT pattern in immunohistostaining significantly. CONCLUSIONS: Neoplastic spindle cell grade significantly related to the recurrence and prognosis of PC. The NSC grade assessment can be not only performed inexpensively and conveniently, but also used to guide future individualized therapeutic approaches. Furthermore, NSCs were found to relate to EMT profoundly.

Clinical practice guidelines for the management of biliary tract cancers 2015: the 2nd English edition.

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.

Classification of biliary tract cancers established by the Japanese Society of Hepato-Biliary-Pancreatic Surgery: 3(rd) English edition.

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.

Maximum standardized uptake value on 18F-fluoro-2-deoxy-glucose positron emission tomography/computed tomography and glucose transporter-1 expression correlates with survival in invasive ductal carcinoma of the pancreas.

OBJECTIVES: The purpose of this study was to assess the correlations among the maximum standardized uptake value (SUVmax) on 18F-fluoro-2-deoxy-glucose positron emission tomography/computed tomography (FDG-PET/CT); the expressions of glucose transporter 1 (GLUT-1), glucose transporter 3, and epidermal growth factor receptor (EGFR); as well as prognosis in patients with invasive ductal carcinoma of the pancreas. METHODS: A total of 41 patients with surgically resected and histologically proven invasive ductal carcinoma of the pancreas who underwent preoperative FDG-PET/CT were assessed. The SUVmax at the primary tumor site was measured by FDG-PET/CT, and immunohistochemical staining of tumor sections was performed for GLUT-1, glucose transporter 3, and EGFR. RESULTS: Higher FDG uptake (SUVmax, >3.40) and GLUT-1 expression were significantly associated with shorter overall survival (P < 0.05). The SUVmax was not found to be significantly correlated with clinicopathological characteristics such as TNM classification, lymph node metastasis, and tumor differentiation. The EGFR expression was significantly correlated with the SUVmax (P = 0.024). CONCLUSIONS: Higher FDG uptake and GLUT-1 expression in invasive ductal carcinoma of the pancreas seems to be an important prognostic factor. In addition, the EGFR expression was significantly correlated with the SUVmax.

[Current surgical management of cancer of the ampulla of Vater].

Pancreatoduodenectomy (PD) is the standard radical treatment for cancer of the ampulla of Vater. Among patients we have treated in whom lymph node metastasis of cancer of the ampulla of Vater occurred, more positive lymph nodes surrounding the superior mesenteric artery were seen in one (patient No. 14), whereas more positive lymph nodes surrounding the anterior and posterior pancreas head were seen in another (No. 13). Six patients with lymph node metastasis achieved long-term survival after PD with lymph node dissection. This appears to be an adequate surgical treatment for cancer of the ampulla of Vater. From the viewpoint of radical treatment, local resection (LR) of the ampulla of Vater cannot be selected as a less-invasive procedure. However, LR of the ampulla of Vater can be performed in very elderly patients and patients in poor general condition for whom PD is considered excessively invasive due to small tumor size.

Evaluation of endoscopic biliary stenting for obstructive jaundice caused by hepatocellular carcinoma.

AIM: To review the usefulness of endoscopic biliary stenting for obstructive jaundice caused by hepatocellular carcinoma and identify problems that may need to be addressed. METHODS: The study population consisted of 36 patients with obstructive jaundice caused by hepatocellular carcinoma (HCC) who underwent endoscopic biliary stenting (EBS) as the initial drainage procedure at our hospital. The EBS technical success rate and drainage success rate were assessed. Drainage was considered effective when the serum total bilirubin level decreased by 50% or more following the procedure compared to the pre-drainage value. Survival time after the procedure and patient background characteristics were assessed comparatively between the successful drainage group (group A) and the non-successful drainage group (group B). The EBS stent patency duration in the successful drainage group (group A) was also assessed. RESULTS: The technical success rate was 100% for both the initial endoscopic nasobiliary drainage and EBS in all patients. Single stenting was placed in 21 patients and multiple stenting in the remaining 15 patients. The drainage successful rate was 75% and the median interval to successful drainage was 40 d (2-295 d). The median survival time was 150 d in group A and 22 d in group B, with the difference between the two groups being statistically significant (P < 0.0001). There were no statistically significant differences between the two groups with respect to patient background characteristics, background liver condition, or tumor factors; on the other hand, the two groups showed statistically significant differences in patients without a history of hepatectomy (P = 0.009) and those that received multiple stenting (P = 0.036). The median duration of stent patency was 43 d in group A (2-757 d). No early complications related to the EBS technique were encountered. Late complications occurred in 13 patients (36.1%), including stent occlusion in 7, infection in 3, and distal migration in 3. CONCLUSION: EBS is recommended as the initial drainage procedure for obstructive jaundice caused by HCC, as it appears to contribute to prolongation of survival time.

Contrast-enhanced ultrasonograpic studies on pancreatic carcinoma with special reference to staining and muscular arterial vessels.

Comparative study of contrast-enhanced ultrasonography (CE-US) and histopathology of surgically resected specimens in 13 patients with pancreatic carcinoma. A time intensity curve was used to determine the percentage brightness increase in cancerous and normal regions and the patients were divided into two groups, hyperperfusion, with a percentage brightness increase over 80% (n=6) and hypoperfusion, with an increase of less than 80% (n=7) on CE-US. The hyperperfusion group included well-differentiated tubular adenocarcinoma, adenosquamous cell carcinoma and acinar cell carcinoma, while all 7 patients in the hypoperfusion group had moderately differentiated tubular adenocarcinoma. Immunological staining (α-SMA and anti-CD34) of the resected specimens showed significantly higher microartery count (MAC) in the hyperperfusion group (p<0.005) than in the hypoperfusion group or normal pancreas. In the normal pancreas, the mean vessel diameter was significantly higher (over 100 µm) than in the hyperperfusion group (30 µm; p<0.005). It was concluded that a muscular arterial vessel density of less than 30 µm is an important factor in determining staining degree and carcinoma progression by CE-US in pancreatic carcinoma.

Side population cell fractions from hepatocellular carcinoma cell lines increased with tumor dedifferentiation, but lack characteristic features of cancer stem cells.

BACKGROUND AND AIM: Cancer stem cells (CSCs), a minority population with stem cell-like characteristics, play important roles in cancer development and progression. Putative CSC markers, such as CD13, CD90, CD133, and epithelial cell adhesion molecule (EpCAM), and side population (SP) technique are generally used in an attempt to isolate CSCs. We aimed to clarify the relationship between CSCs and clonal dedifferentiation in hepatocellular carcinoma (HCC). METHODS: We used a well-differentiated HCC cell line (HAK-1A) and a poorly differentiated HCC cell line (HAK-1B) established from a single nodule with histological heterogeneity. HAK-1B arose because of clonal dedifferentiation of HAK-1A. The SP cells and non-SP (NSP) cells were isolated from the two cell lines with a FACSAria II and used for the analyses. RESULTS: The SP cell fractions in HAK-1A and HAK-1B were 0.2% and 0.9%, respectively. CD90 or EpCAM was not expressed in either HAK-1A or HAK-1B, while CD13 and CD133 were expressed in HAK-1B alone. Although sphere forming ability, tumorigenicity, growth rate, and CD13 expression were higher in HAK-1B SP cells than HAK-1B NSP cells, there were no differences in drug resistance, colony forming ability, or cell cycle rates between HAK-1B SP and NSP cells, suggesting HAK-1B SP cells do not fulfill CSC criteria. CONCLUSIONS: Our findings suggested a possible relationship between the expression of CSC markers and clonal dedifferentiation. However, the complete features of CSC could not be identified in SP cells, and the concept of SP cells as a universal marker for CSC may not apply to HAK-1A and HAK-1B.

Influence of preoperative anti-cancer therapy on resectability and perioperative outcomes in patients with pancreatic cancer: project study by the Japanese Society of Hepato-Biliary-Pancreatic Surgery.

BACKGROUND: Little is known about the effects of neoadjuvant therapy on outcomes in patients with pancreatic cancer. This study evaluated the effects of neoadjuvant therapy on resectability and perioperative outcomes. METHODS: A total of 992 patients were enrolled, with 971 deemed eligible. Of these, 582 had resectable tumors and 389 had borderline resectable tumors, and 388 patients received neoadjuvant therapy. Demographic characteristics and peri- and postoperative parameters were assessed by a questionnaire survey. RESULTS: The R0 rate was significantly higher in patients with resectable tumors who received neoadjuvant therapy than in those who underwent surgery first, but no significant difference was noted in patients with borderline resectable tumors. Operation time was significantly longer and blood loss was significantly greater in patients who received neoadjuvant therapy than in those who underwent surgery first, but there were no significant differences in specific complications and mortality rates. The node positivity rate was significantly lower in the neoadjuvant than in the surgery-first group, indicating that the former had significantly lower stage tumors. CONCLUSIONS: Neoadjuvant therapy may not increase the mortality and morbidity rate and may be able to increase the chance for curative resection against resectable tumor.

Clinicopathological features and prognosis of mucin-producing bile duct tumor and mucinous cystic tumor of the liver: a multi-institutional study by the Japan Biliary Association.

BACKGROUND: The aim of this study was to determine the clinicopathological features and surgical outcomes of mucinous cystic neoplasm of the liver (MCN) and mucin-producing intraductal papillary neoplasm of the intrahepatic bile duct (M-IPNB). METHODS: We performed a multi-institutional, retrospective study of patients with MCN or M-IPNB pathologically defined by the presence or absence of an ovarian-like stroma. RESULTS: The M-IPNB and MCN were diagnosed in 119 and nine patients, respectively. MCN was observed in female patients, while M-IPNB produced symptoms of cholangitis. M-IPNBs were classed as low or intermediate grade in 53 cases, high grade in 23 and invasive carcinoma in 43. Fifty-one of the M-IPNBs were the pancreatobiliary type (PT), 33 were the intestinal type (IT), 23 were the oncocytic type (OT), and 12 were the gastric type (GT). The 1-, 5- and 10-year survival rates for the 105 patients with M-IPNB were 96%, 84% and 81%, respectively, while the 5-year survival rate for patients with MCN was 100%. OT and GT M-IPNB had better 10-year survival rates than PT and IT M-IPNB. CONCLUSIONS: Although MCN has different features from M-IPNB, both diseases have a good prognosis after resection. The cellular type of M-IPNB appears to predict outcome.

Noninvasive diagnosis of compensated cirrhosis using an analysis of the time-intensity curve portal vein slope gradient on contrast-enhanced ultrasonography.

PURPOSE: We measured the slope gradients (SGs) of the vascular time-intensity curves (TICs) of the intrahepatic vessels on contrast-enhanced ultrasonography (CEUS). The aim of this study was to assess the diagnostic accuracy of the SG of each hepatic vessel, particularly the portal vein (PV), for detecting cirrhosis and to compare this method with conventional modalities. METHODS: Fifty-one preoperative patients underwent CEUS, and the TICs were plotted. The SGs of the hepatic artery, PV and hepatic vein were obtained from the linear functions between the slope of the arrival time of the contrast agent and the peak enhancement time of each vessel. The transit times and levels of biochemical markers were also measured. The patients were divided into three groups according to the Metavir score: F0/1 group (n = 14), F2/3 group (n = 21) and F4 group (n = 16). RESULTS: The PVSG significantly decreased in the F4 group (F0/1: 29.1 ± 2.27, F2/3: 23.1 ± 1.86, F4: 14.7 ± 2.13). The PVSG demonstrated high accuracy for diagnosing cirrhosis and was correlated with the levels of ICG-R15 and hyaluronic acid (Spearman rank correlation; ρ = -0.5691, p < 0.001 and ρ = -0.4652, p = 0.0006). CONCLUSIONS: The PVSG has the potential to be a diagnostic marker for identifying patients with well-compensated cirrhosis.

Influence of splenectomy in patients with liver cirrhosis and hypersplenism.

AIM: Splenectomy improves hypersplenic thrombocytopenia in cirrhotic patients with hypersplenism. However, the long-term influence of splenectomy has not been clarified. We examined whether splenectomy improved liver fibrosis and caused immunological changes. METHODS: We collected liver and spleen specimens and peripheral blood (PB) from 26 patients with hepatitis C virus-related liver cirrhosis. An immunohistochemical examination of CD4, CD8, forkhead box P3, granzyme B and transforming growth factor-ß1, and Masson-trichrome stain were performed in spleen and liver tissues and in seven cases of follow-up liver biopsy sections obtained after splenectomy. We obtained PB before and at various intervals after splenectomy. We also examined the ratio of CD4(+) and CD8(+) lymphocytes in PB using flow cytometry. RESULTS: We observed improvements in liver fibrosis in four biopsy specimens obtained after splenectomy, in which fibrotic areas significantly decreased from 19.5% to 8.2% (P < 0.05). Increases were also observed in the ratio of CD8(+) cells in PB after splenectomy, which resulted in a significant decrease in the CD4(+) /CD8(+) ratio (P < 0.001). The carcinogenic rate in patients with a CD4(+) : CD8(+) ratio that decreased by more than 0.5 at 1 month after splenectomy was significantly lower than that in patients with a ratio that decreased by less than 0.5 (P < 0.05). CONCLUSION: Splenectomy may improve liver fibrosis and cause beneficial immunological changes in cirrhotic patients with hepatitis. Improvements in antitumor mechanisms can be also expected.

Perioperative challenges and surgical treatment of large simple, and infectious liver cyst - a 12-year experience.

BACKGROUND: Cystic lesions of the liver consist of a heterogeneous group of disorders that can present diagnostic and therapeutic challenges. METHODS: A retrospective review of all medical records of adult patients diagnosed with large (>7 cm) cystic lesions of the liver between January 2000 and December 2011, at Kurume University Hospital. Cases with polycystic disease were excluded. RESULTS: Twenty three patients were identified. The mean size was 13.9 cm (range, 7-22cm). The majority of simple cysts were found in women (females: males, 2: 21). In 19 patients, the cyst was removed surgically by wide deroofing (laparoscopically in 16 cases, combined with ethanol sclerotherapy in 13 cases). Infection of the liver cyst occurred in one patient, who later underwent central bi-segmentectomy. CONCLUSION: Simple large cysts of the liver can be successfully treated by laparoscopic deroofing and alcohol sclerotherapy. Large hepatic cyst considered to need drainage should be removed surgically to avoid possible infection.

Potential usefulness of mucin immunohistochemical staining of preoperative pancreatic biopsy or juice cytology specimens in the determination of treatment strategies for intraductal papillary mucinous neoplasm.

We classified resected intraductal papillary mucinous neoplasms (IPMNs) into four subtypes (gastric, intestinal, pancreatobiliary and oncocytic) according to their morphological features and mucin expression, determined their clinicopathological characteristics and investigated the possibility of preoperatively diagnosing these subtypes. Sixty resected tumors, 4 preoperative tumor biopsies and 10 preoperative pancreatic juice cytology specimens were analyzed. The gastric and intestinal types accounted for the majority of IPMNs. Non-gastric type IPMNs were of high-grade malignancy. Many of the pancreatobiliary-type IPMNs were in an advanced stage and were associated with a poor prognosis. The results of mucin immunohistochemical staining of preoperative biopsy and surgically resected specimens were in agreement with each other, and in close agreement with those for pancreatic juice cytology specimens obtained from 10 patients during endoscopic retrograde cholangiopancreatography (ERCP). The immunostaining of preoperative biopsy specimens and ERCP-obtained pancreatic juice cytology specimens may be useful in the differential diagnosis of gastric and intestinal types of IPMN. If such techniques enable the preoperative diagnosis of IPMN subtypes, their use in combination with conventional preoperative imaging modalities may lead to surgical treatment best suited for the biological characteristics of the four subtypes.

Long-term outcome of splenectomy in advanced cirrhotic patients with hepatocellular carcinoma and thrombocytopenia.

Splenectomy may be a treatment option in hepatocellular carcinoma (HCC) and cirrhosis when there is no potential donor for liver transplantation. We retrospectively investigated the long-term outcome of splenectomy on survival in advanced cirrhotic patients with HCC and thrombocytopenia. Between 1999 and 2009, 46 cirrhotic patients with thrombocytopenia (Child-Pugh class B or C) who underwent splenectomy for the simultaneous or secondary treatment of HCC at our institute were evaluated. The 1-, 3-, and 5-year survival rates were 93.5, 76.0, and 37.9%, respectively. Splenectomy resulted in a significant reduction in mean portal venous pressure from 21.2 to 16.8 mmHg and improvements in liver function tests such as total bilirubin, prothrombin time, platelet count, Child-Pugh score for 3 years, and albumin for 2 years. The mean frequency of treatment for HCC recurrence after surgery was 3.0 times (range 1-11). Seven patients out of 16 scheduled for Interferon (IFN) therapy after surgery achieved a sustained virological response (SVR). Multivariate analysis identified SVR after IFN therapy as an independent significant prognostic factor (Hazard ratio 0.18, 95%CI 0.03-0.65, P=0.006). Postoperative complications including liver failure (n=1), portal thrombosis (n=7), ascites (n=5), and bacterial infections (n=4) were observed in 14 patients (30%). Splenectomy can be a feasible supportive therapy for the continuation of anticancer therapy and completion of IFN therapy based on improvements in liver function and thrombocytopenia with minimum complications in patients with HCC and advanced cirrhosis with no potential donor.

A case of cancer of the ampulla of Vater accompanied by malrotation.

Intestinal malrotation is caused by a developmental anomaly of the embryonic intestine. Most cases develop in neonates, and development in adulthood is rare and difficult to diagnose before surgery. Pancreaticoduodenectomy was performed for cancer of the ampulla of Vater accompanied by incomplete fixation in a 63-year-old male patient. A branch of the superior mesenteric artery was present on the resection line and was deemed likely to cause circulatory disorder in the small intestine, and the duodenum and jejunum were covered with a membranous structure making dissection, anatomical identification, and jejunectomy difficult. Herein, we report the case with a review of the literature.

[A long-term survivor of advanced gallbladder carcinoma treated with curative operation and hepatic arterial infusion].

60-year-old woman was referred to us for epigastralagia under the diagnosis of chronic cholecystitis. Cholecystectomy was performed, and gallbladder carcinoma was pinpointed by postoperative pathological diagnosis. Because liver invasion should have been detected by pathological diagnosis, we conducted liver S4a+S5 resection, extrahepatic bile duct resection and D2 lymphadenectomy. The pathological diagnosis was advanced gallbladder carcinoma with liver metastasis. We treated a patient with curative operation and hepatic arterial infusion adjuvant chemotherapy by low-dose FP therapy for advanced gallbladder carcinoma, and she is doing well now without disease recurrence eight years after surgery.

Evaluation of magnifying endoscopy using narrow band imaging using ex vivo bile duct (with video).

BACKGROUND AND AIM: Detailed endoscopic findings of the bile duct mucosa, even of the non-neoplastic mucosa, have not yet been established. The aim of the present study was to compare a currently used video cholangioscope (CCS) with a magnifying endoscope (ME) that is commonly used for the gastrointestinal tract, for visualization of the bile duct mucosa. METHODS: Ten freshly resected common bile ducts were used in this study. We observed the non-neoplastic bile duct mucosa with CCS and ME, and carried out both conventional white light imaging and narrow band imaging. After histological diagnosis, the 10 specimens were classified into three categories according to the degree of histological inflammation: normal to mild, moderate, and severe. Then, we examined the relationship between the magnifying endoscopic findings and the histopathological findings. RESULTS: In eight of the 10 cases, the visualization obtained with CCS was inferior to that obtained by ME. Five specimens were classified as normal to mild inflammation, and many oval-shaped, depressed areas and a fine, regular network of the microvessels were observed by ME on the mucosal surfaces of these specimens. The remaining specimens were classified as moderate or severe inflammation, and the aforementioned findings could not be clearly visualized. CONCLUSION: CCS does not allow visualization of the bile duct mucosa with high sensitivity. Oval-shaped depressed areas and a fine, regular network of microvessels are characteristic endoscopic features of non-neoplastic bile duct mucosa without inflammation.

Gallbladder bed resection or hepatectomy of segments 4a and 5 for pT2 gallbladder carcinoma: analysis of Japanese registration cases by the study group for biliary surgery of the Japanese Society of Hepato-Biliary-Pancreatic Surgery.

PURPOSE: Hepatectomy of segments 4a and 5 (S4a+5) is the recommended treatment for pT2 gallbladder cancer. However, gallbladder bed resection is also occasionally used. Using nationwide data from the Japanese Biliary Tract Cancer Registry and a questionnaire survey, we retrospectively compared these 2 methods of treatment. METHOD: The study involved 85 patients with pT2, pN0 gallbladder cancer (55 treated with gallbladder bed resection, and 30, with S4a+5 hepatectomy). The prognosis and mode of tumor recurrence following treatment were analyzed retrospectively, with overall survival as the endpoint. RESULTS: The 5-year survival rate did not differ significantly between the 2 groups. Univariate analysis showed that bile duct resection and perineural tumor invasion were significant prognostic factors, but the extent of hepatectomy, location of the major intramural tumor, regional lymph node excision, and histological type were not. Multivariate analysis identified perineural tumor invasion as a significant prognostic factor. Recurrence occurred most frequently in both lobes than S4a+5 of the liver following gallbladder bed resection. CONCLUSION: In the present study of cases of Japanese Biliary Tract Cancer Registry, it was not possible to conclude that S4a+5 hepatectomy was superior to gallbladder bed resection.