Masahiro Serikawa

Management of intraductal papillary-mucinous neoplasm of the pancreas: treatment strategy based on morphologic classification.

Goals The aim of this study was to examine and clarify the preoperative markers that are useful for differentiating between benign and malignant lesions of intraductal papillary-mucinous neoplasms (IPMN) of the pancreas, grouped according to morphologic classification. Background There are various stages of pathology in IPMN, ranging from benign to malignant lesions. Although the determination of appropriate treatment guidelines to deal with IPMN is a critical issue, no such guidelines have been established. Patients and Methods One hundred twenty cases of IPMN were classified morphologically into either main or branch duct types. We compared the morphologic classification with histopathologic diagnosis using indicators of malignancy detected by imaging such as main duct diameter, the number and diameter of cysts, and the presence or absence of mural nodules. We also examined the usefulness of pancreatic juice cytology and measurement of telomerase activity as indicators of malignancy. Finally, we performed a survival analysis on the basis of morphologic classification to determine prognosis of IPMN. Results Whereas a high incidence (64%) of malignant lesions was seen in main duct type IPMN, benign lesions were dominant (80.5%) in branch duct type IPMN. Survival analysis showed that the prognosis was significantly worse in main duct type than in branch duct type IPMN. The lesions were aggravated in all patients with main duct type who did not undergo resection, resulting in death due to progression of the pancreatic lesion. The incidence of mural nodules was a useful indicator in main duct type, whereas main duct diameter and incidence of mural nodules were useful indicators in branch duct type. Although pancreatic juice cytology showed a high accuracy rate with low sensitivity for determining malignancy, measurement of telomerase activity in this juice was very effective for differentiating between benign and malignant lesions. Conclusions The incidence of malignant lesions was extremely high in main duct type IPMN, indicating that surgery is required in all these patients. However, to determine whether surgery is indicated in branch duct type IPMN it is necessary to obtain an appropriate image diagnosis focusing on main duct diameter and mural nodules and also to carry out cytology and measurement of telomerase activity in samples of pancreatic juice.

Statins induce apoptosis and inhibit proliferation in cholangiocarcinoma cells

Given the poor prognosis for cholangiocarcinoma, new and effective treatments are urgently needed. HMG-CoA reductase inhibitors (statins) reportedly exert anticancer effects in a variety of diseases, but there have been no reports of these effects in cholangiocarcinoma. In this study, we investigated the utility of statins for cholangiocarcinoma treatment. Proliferation suppression by pitavastatin and atorvastatin was investigated in the human cholangiocarcinoma cell lines HuCCT1 and YSCCC while changes in the cell cycle and intracellular signals were examined by FACS and Western blotting, respectively. Additive proliferation suppression by statins and pre-existing anticancer drugs was also investigated. HuCCT1 and YSCCC cell proliferation was dramatically suppressed by incubation with statins for 72 h or longer. Cell cycle analysis revealed a reduction in the G2M fraction and an increase in the sub-G1 fraction in statin-treated cells, while Western blotting showed increased levels of cleaved caspase-3 and a reduction in p-ERK. Furthermore, statins in combination with gemcitabine, cisplatin and 5-FU showed additive proliferation suppression. In this study, treatment of human cholangiocarcinoma cells with statins induced apoptosis via suppression of the classical MAPK pathway. Together, these results suggest that statins may be a new cholangiocarcinoma treatment option that could potentially enhance the anticancer effect of pre-existing anticancer drugs.

Connective tissue growth factor is an indicator of bone involvement in multiple myeloma, but matrix metalloproteinase-9 is not.

Bone disease (BD) in multiple myeloma (MM) is because of the activation of osteoclasts and impairment of osteoblast differentiation. Connective tissue growth factor (CTGF) is known to participate in the differentiation of mesenchymal stem cells to committed osteoprogenitor cells. We analysed the concentration of circulating CTGF in 35 MM patients and 22 malignant lymphoma (ML) patients and 14 normal individuals. CTGF is protease‐sensitive and thus is found as both an N‐terminal half fragment (N‐half CTGF) and whole (W‐CTGF). Serum levels of W‐CTGF and N‐half CTGF + W‐CTGF were determined by separate sandwich enzyme‐linked immunosorbent assays. The level of W‐CTGF was significantly lower (P < 0·005) in MM patients compared with ML patients and normal individuals, while N‐half + W‐CTGF was similar in all groups. Furthermore, W‐CTGF was significantly lower in MM patients with BD compared with those without BD (P < 0·005) and this was independent of previous treatment. Matrix metalloproteinase (MMP)‐9 is produced by myeloma cells and is thought to be related to BD in MM. However, MMP‐9 does not cleave CTGF and serum MMP‐9 level was not related to BD in MM. Thus, CTGF is an indicator of BD in MM; its metabolism and function in MM should be clarified.

Elevated expression of cyclooxygenase-2 and microsomal prostaglandin E synthase-1 in primary sclerosing cholangitis : Implications for cholangiocarcinogenesis

Cholangiocarcinoma (CCA) occurs frequently in primary sclerosing cholangitis (PSC). Cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-1) induced by inflammation are believed to mediate prostaglandin E2 (PGE2) production thereby promoting carcinogenesis. Their expression in PSC-associated CCA tissues and non-neoplastic bile duct epithelial cells (BDECs) in PSC was investigated. COX-2 and mPGES-1 levels in 15 PSC patients (7 with CCA) were scored using immunohistochemical staining. The results were compared with those obtained in CCA tissues and non-neoplastic BDECs (controls) of 15 sporadic CCA patients. Non-neoplastic BDECs from large and small bile ducts were investigated separately. The mRNA expression levels of COX-2 and mPGES-1 in CCA tissues were analyzed by quantitative polymerase chain reaction. Ki-67 immunostaining was performed to evaluate cell proliferation. COX-2 was strongly expressed in PSC-associated CCA tissues and non-neoplastic BDECs in PSC. This expression was significantly upregulated in both compared with sporadic CCA tissues and non-neoplastic BDECs in sporadic CCA (both P<0.01). mPGES-1 was expressed at moderate to strong levels in PSC. Compared with controls, the expression was significantly higher in non-neoplastic small BDECs (P<0.01). COX-2 mRNA levels were significantly higher in PSC-associated tissues than in sporadic CCA tissues (P<0.01). Conversely, no differences were observed in mPGES-1 mRNA levels. Ki-67 labeling indices were higher in PSC-associated CCA tissues and non-neoplastic BDECs in PSC than in controls. In conclusion, COX-2 and mPGES-1 were highly expressed in PSC-associated CCA tissues and non-neoplastic BDECs in PSC, suggesting the involvement of COX-2 and mPGES-1 in cholangiocarcinogenesis.

A comparative study of 4 Fr versus 6 Fr nasobiliary drainage catheters: a randomized, controlled trial

Despite the benefits of endoscopic nasobiliary drainage (NBD) in endoscopic retrograde cholangiopancreatography (ERCP), post‐ERCP pancreatitis (PEP) and nose/throat discomfort can result. We aimed to determine whether the use of a smaller catheter alleviates these complications.

Assessment of trypsinogen-2 levels as an early diagnostic for post-endoscopic retrograde cholangiopancreatography pancreatitis.

Objectives: The objective of the present study was to assess the use of serum trypsinogen-2 (TRY-2) measurements in early diagnosis of pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP). Methods: In this prospective study, investigation 1 involved collection of blood serum both before and at 2, 4, and 18 hours after ERCP, whereas investigation 2 involved collection before and 1, 2, 3, 4, 6, and 18 hours after ERCP. Total amylase, pancreatic amylase, and TRY-2 levels were measured from serum samples, and values from patients with pancreatitis after ERCP were compared to those from healthy control patients after ERCP. Results: In investigation 1, 8 of the 68 cases examined were diagnosed as post-ERCP pancreatitis. In the healthy group, total- and pancreatic-amylase levels peaked 4 hours after ERCP, and TRY-2 levels peaked at 2 hours after ERCP. In contrast, cases of post-ERCP pancreatitis demonstrated prolonged periods of high total-amylase, pancreatic-amylase, and TRY-2 levels. In investigation 2, none of the 23 cases was diagnosed as post-ERCP pancreatitis: Pancreatic amylase levels peaked 4 to 6 hours after ERCP and TRY-2 levels peaked 1 hour after ERCP. Conclusion: These results suggest that TRY-2 is a more sensitive marker than amylase, and it can be useful in early diagnosis of post-ERCP pancreatitis.

Antibiotic prophylaxis for endoscopic retrograde chlangiopancreatography increases the detection rate of drug‐resistant bacteria in bile

No consensus has yet been reached regarding the utility of antibiotic prophylaxis for endoscopic retrograde cholangiopancreatography (ERCP). However, there has been little discussion of potential adverse effects of antibiotic use. This study investigated the impact of antibiotic prophylaxis on overall levels of bacterial infiltration of the biliary tract and the prevalence of drug‐resistance among that population.

Occupational Radiation Exposure during Endoscopic Retrograde Cholangiopancreatography and Usefulness of Radiation Protective Curtains

Objective. To evaluate the effectiveness of radiation protective curtains in reducing the occupational radiation exposure of medical personnel. Methods. We studied medical staff members who had assisted in 80 consecutive therapeutic endoscopic retrograde cholangiopancreatography (ERCP) procedures. Use of radiation protective curtains mounted to the X-ray tube was determined randomly for each procedure, and radiation doses were measured with electronic pocket dosimeters placed outside the protective apron. Results. When protective curtains were not used, the mean radiation doses to endoscopists, first assistants, second assistants, and nurses were 340.9, 27.5, 45.3, and 33.1 µSv, respectively; doses decreased to 42.6, 4.2, 13.1, and 10.6 µSv, respectively, when protective curtains were used (P < 0.01). When the patient had to be restrained during ERCP (n = 8), the radiation dose to second assistants without protective curtains increased by a factor of 9.95 (P < 0.01) relative to cases in which restraint was not required. Conclusions. During ERCP, not only endoscopists, but also assistants and nurses were exposed to high doses of radiation. Radiation exposure to staff members during ERCP was reduced with the use of protective curtains.

Timing of radiological improvement after steroid therapy in patients with autoimmune pancreatitis.

Abstract Objective. We retrospectively studied the timing of radiological improvement after steroid therapy in patients with autoimmune pancreatitis (AIP). Material and methods. Patients with AIP (n = 31) received steroids followed by diagnostic imaging within 1 month. Pancreatic swelling, pancreatic and bile duct features, and apparent diffusion coefficient (ADC) were compared before and after treatment. The period from treatment initiation to evaluation was divided into five phases: early phase (days 3–5), week 1 (days 6 and 7), week 2 (days 8–14), week 3 (days 15–21), and week 4 (days 22–28). Five gastroenterologists evaluated pancreatic swelling and duct features (good/intermediate/no response), and the “good response” rate (response rate) was calculated for each phase. In addition, pancreatic volumes were measured with a 3D workstation before and after treatment, and the percentage change in volume was calculated. ADC values were calculated in 14 patients. Results. The median ratio of pancreatic volume after relative to before treatment was 0.89, 0.79, 0.67, 0.59, and 0.47 for early phase, week 1, week 2, week 3, and week 4, respectively. The response rate of the pancreatic swelling was 37.5%, 57.1%, 83.3%, 100%, and 100%; response rate of the pancreatic duct was 0%, 20%, 75%, 75% and 100%; and response rate of the bile duct was 0%, 66.7%, 83.3%, 100%, and 80%. The ADC increased after treatment in all 14 patients, including the 7 patients evaluated in the early phase. Conclusions. Evaluation of pancreatic swelling and duct features is recommended in week 2 and thereafter. The ADC increased soon after treatment initiation, suggesting its usefulness for evaluating early treatment responses.

Multicenter study of early pancreatic cancer in Japan

BACKGROUND/OBJECTIVES The diagnosis of early-stage pancreatic ductal adenocarcinoma (PDAC) is still challenging. We conducted a multicenter study to clarify the clinical features of early-stage PDAC in Japan. METHODS We collected patients with stage 0 and stage I PDAC according to the sixth edition of the Japanese Classification of Pancreatic Carcinoma. We retrospectively analyzed the clinical profiles including opportunities for medical examination, imaging modalities and findings, methods of cytological diagnosis, and prognosis according to the stages at diagnosis. RESULTS Two hundred cases with Stage 0 and stage I PDAC were reported from 14 institutions, which accounted for approximately 0.7% and 3% of all PDAC cases, respectively. Overall, 20% of the early-stage PDAC cases were symptomatic. Indirect imaging findings such as dilatation of the main pancreatic duct were useful to detect early-stage PDAC. In particular, local fatty changes may be specific to early-stage PDAC. For preoperative pathologic diagnosis, cytology during endoscopic retrograde cholangiopancreatography was more commonly applied than endoscopic ultrasound fine-needle aspiration. Although the overall prognosis was favorable, new PDAC lesions developed in the remnant pancreas in 11.5% cases. CONCLUSIONS This multicenter study revealed several key points concerning the diagnosis and management of early-stage PDAC, including screening of asymptomatic cases, importance of indirect imaging findings, application of cytology during endoscopic retrograde cholangiopancreatography, and the risk of carcinogenesis in the remnant pancreas.