Erdheim-Chester Disease with Pancreatic Enlargement Observed Using Contrast-enhanced Endoscopic Ultrasonography.

We herein report an unusual case of Erdheim-Chester disease (ECD), a rare non-Langerhans cell histiocytosis, and emphasize its unique presentation and diagnostic challenges. Our patient exhibited uncommon symptoms and significant organ involvement, particularly pancreatic enlargement that is not typically associated with ECD. Contrast-enhanced harmonic endoscopic ultrasonography (CEH-EUS) and EUS-fine needle aspiration (EUS-FNA) play crucial roles in the comprehensive assessment of the disease, demonstrating their superiority in identifying and characterizing elusive ECD lesions. This is the first report to document pancreatic lesions in patients with ECD evaluated using CEH-EUS. EUS-FNA is valuable for diagnosing rare diseases, including ECD, with diffuse pancreatic enlargement.

[Pre-surgical diagnosis of neuroendocrine carcinoma of the extrahepatic bile duct: a case study].

A 70-year-old woman presented to our hospital with jaundice. Abdominal ultrasonography showed biliary duct dilatation. Blood tests revealed elevated total bilirubin and hepatobiliary enzyme levels. A contrast-enhanced computed tomography of the abdomen showed bile duct thickening with wall enhancement. Transpapillary bile duct biopsy showed an invasive carcinoma proliferating in a follicular pattern. Pathology revealed positive synaptophysin and chromogranin A and a Ki67 index >40%, consistent with a diagnosis of neuroendocrine carcinoma (NEC). After confirming the absence of distant metastases, a subtotal stomach-preserving pancreaticoduodenectomy was performed. The result of the postoperative pathology was the same as the preoperative biopsy. According to previous reports, 7 out of 28 cases with NEC/mixed adenoneuroendocrine carcinoma could be diagnosed as NEC before surgery. However, biliary cytology and bile duct scraping cytology were used in many cases;only 11 cases underwent bile duct biopsy. For the latter, 5 out of 11 cases could be diagnosed preoperatively. NEC of the extrahepatic duct often exhibits a submucosal tumor-like morphology, which may result in a false negative result with biliary cytology or bile duct scraping cytology. In our case, the transpapillary bile duct biopsy sample was sufficient to diagnose NEC. This method could be an attractive option for the diagnosis of these tumors.

Comparison of 8- and 10-mm diameter fully covered self-expandable metal stents: A multicenter prospective study in patients with distal malignant biliary obstruction.

OBJECTIVES: The time to recurrent biliary obstruction (TRBO) of unresectable distal malignant biliary obstruction is generally thought to be longer when a self-expandable metal stent (SEMS) with a thicker inner diameter is used for drainage, but the dependence on the inner diameter using a fully covered SEMS (FCSEMS) is uncertain. The objective of this multicenter prospective study was to compare TRBO and adverse events, such as cholecystitis and pancreatitis, in treatment of patients with unresectable malignant biliary obstruction using 8- and 10-mm diameter FCSEMS. METHODS: Eighteen tertiary-care centers participated in the study. Patients were allocated to the 8- and 10-mm diameter groups. TRBO, non-inferiority of the 8-mm FCSEMS, overall survival time, frequency and type of adverse events, and non-recurrent biliary obstruction (RBO) rate at the time of death were compared between the two groups. RESULTS: Median TRBO did not differ significantly between the 8-mm (n = 102) and 10-mm (n = 100) groups (275 vs 293 days, P = 0.971). The hazard ratio of the 8- to 10-mm groups was 0.90 (80% confidence interval, 0.77-1.04; upper limit lower than the acceptable hazard ratio [1.33] of the null hypothesis). Based on these findings, the 8-mm diameter stent was determined to be non-inferior to the 10-mm diameter stent. Survival time, incidence of adverse events and non-RBO rate at the time of death did not differ significantly between the two groups. CONCLUSIONS: Time to RBO with an 8-mm diameter FCSEMS was non-inferior to that with a 10-mm diameter FCSEMS. This finding is important for development of future SEMS.

Randomized Phase II Study of Consecutive-Day versus Alternate-Day Treatment with S-1 as Second-Line Chemotherapy in Advanced Pancreatic Cancer.

OBJECTIVE: To evaluate the efficacy and safety of alternate-day administration of S-1 as second-line chemotherapy for unresectable pancreatic cancer in a multicenter, randomized, phase II study. METHODS: Patients with histologically proven, unresectable pancreatic cancer treated with chemotherapy not including S-1 as first-line therapy were randomly assigned to receive either daily or alternate-day treatment with S-1. The primary end point was overall survival (OS), and the secondary end points were progression-free survival (PFS), time to treatment failure (TTF), response rate, and adverse events. RESULTS: A total of 77 patients were enrolled, of which 75 were included in the final analysis. The median OS was 4.5 months in the daily group and 4.4 months in the alternate-day group (HR 1.178; 95% CI 0.741-1.875), with no significance in PFS and TTF. The response rate was 2.8% in the daily group and 0% in the alternate-day group. Grade 3 or higher adverse events occurred with significantly higher incidence in the daily group (47.2 vs. 25.6%, p = 0.044). CONCLUSION: As a second-line chemotherapy for unresectable pancreatic cancer, although the efficacy in both groups was comparable and we can expect fewer toxicities with alternate-day administration of S-1, the noninferiority of alternate-day treatment to daily treatment with S-1 was not verified.

Natural history of pancreatic cystic lesions: A multicenter prospective observational study for evaluating the risk of pancreatic cancer.

BACKGROUND AND AIM: The aim of this study is to elucidate the natural history of pancreatic cystic lesions (PCLs), including branch duct-type intraductal papillary mucinous neoplasm (BD-IPMN), via midterm follow-up analysis of a multicenter prospective observational study (NSPINAL study). METHODS: From July 2011 to October 2016, 881 patients with PCLs were enrolled in NSPINAL study, and 664 patients with > 12 months of follow up were analyzed. Every patient was asymptomatic, and endoscopic ultrasound was performed at the initial diagnosis to exclude high-risk individuals. Follow up included endoscopic ultrasound, computed tomography, or magnetic resonance imaging at least once a year. Serial morphological changes and the pancreatic cancer (PC) incidence, including malignant progression of PCLs, were evaluated. RESULTS: The 664 patients (358 men) were followed for a median of 33.5 months (interquartile range 29). The cyst and main pancreatic duct sizes were 16.6 ± 9.3 and 2.3 ± 1.0 mm, respectively. Morphologically, 518 cases were multilocular, 137 were unilocular, and 9 had a honeycomb pattern; 269 cases involved multifocal lesions. Ninety-six patients (14.5%) showed worsening progression on imaging. There were two resectable and four unresectable cases of pancreatic ductal adenocarcinoma and three cases of malignant BD-IPMN. The 3-year risk of developing PC was 1.2%. The standardized incidence ratio for PC among PCLs was 10.0 (95% confidence interval 3.5-16.5), and the standardized incidence ratio among BD-IPMN was 16.6 (95% confidence interval 5.1-28.1). Multivariate analysis showed that development of symptoms and worsening progression were significant predictors of PC. CONCLUSIONS: Malignant progression of PCLs, including PC development, is not uncommon. Patients with PCLs should be carefully monitored to detect pancreatic ductal adenocarcinoma at early stages.

Prospective multicenter phase II study of gemcitabine plus cisplatin in patients with unresectable gallbladder cancer.

PURPOSE: To evaluate the efficacy and safety of gemcitabine plus cisplatin in Japanese patients with unresectable gallbladder cancer (GBC). METHODS: Chemo-naïve patients with histologically proven unresectable GBC were enrolled in this study. The patients received gemcitabine (1000 mg/m2) and cisplatin (25 mg/m2) on days 1 and 8, every 21 days. A response assessment was done by CT scan every 4 weeks. The primary end points were to determine the response rates [RR; complete response (CR) + partial response (PR)] and the disease control rate [DCR; CR + PR + stable disease (SD)]. The secondary end points were to evaluate toxicity, progression-free survival (PFS), and overall survival (OS). RESULTS: From March 2012 to February 2015, 14 patients from seven different institutions were enrolled in the study, and 13 cases were evaluable for assessment. Eleven cases (84.6%) had distant metastases, and 8 cases (61.5%) had obstructive jaundice. There was no CR, 1 PR (7.7%), 11 SD (84.6%), and 1 progressive disease (PD) (7.7%). The RR was 7.7%, whereas the DCR was 92.3%. The median PFS was 3.1 months, the median OS was 6.2 months, and the one-year survival rate was 0%. Grade 3 hematologic toxicity was observed in three cases (23%), but all of them recovered upon drug withdrawal, and there was no treatment-related death. CONCLUSION: Although gemcitabine plus cisplatin has a high DCR (92.3%) and relatively low toxicity, the RR is less than 10%, and development of new therapies is desired for the treatment of unresectable GBC.

A preliminary result of three-dimensional microarray technology to gene analysis with endoscopic ultrasound-guided fine-needle aspiration specimens and pancreatic juices.

BACKGROUND: Analysis of gene expression and gene mutation may add information to be different from ordinary pathological tissue diagnosis. Since samples obtained endoscopically are very small, it is desired that more sensitive technology is developed for gene analysis. We investigated whether gene expression and gene mutation analysis by newly developed ultra-sensitive three-dimensional (3D) microarray is possible using small amount samples from endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) specimens and pancreatic juices. METHODS: Small amount samples from 17 EUS-FNA specimens and 16 pancreatic juices were obtained. After nucleic acid extraction, the samples were amplified with labeling and analyzed by the 3D microarray. RESULTS: The analyzable rate with the microarray was 46% (6/13) in EUS-FNA specimens of RNAlater storage, and RNA degradations were observed in all the samples of frozen storage. In pancreatic juices, the analyzable rate was 67% (4/6) in frozen storage samples and 20% (2/10) in RNAlater storage. EUS-FNA specimens were classified into cancer and non-cancer by gene expression analysis and K-ras codon 12 mutations were also detected using the 3D microarray. CONCLUSIONS: Gene analysis from small amount samples obtained endoscopically was possible by newly developed 3D microarray technology. High quality RNA from EUS-FNA samples were obtained and remained in good condition only using RNA stabilizer. In contrast, high quality RNA from pancreatic juice samples were obtained only in frozen storage without RNA stabilizer.

A combination therapy of gemcitabine with immunotherapy for patients with inoperable locally advanced pancreatic cancer.

OBJECTIVES: Dendritic cell (DC) therapy frequently induces a measurable immune response. However clinical responses are seen in a minority of patients, presumably due to insufficient expansion of antigen-specific cytotoxic T lymphocytes (CTLs) capable of eradicating tumor cells. To increase therapeutic efficacy of DC-based vaccination, we have undertaken the first clinical trial involving a combination therapy of gemcitabine (GEM) with immunotherapy for patients with inoperable locally advanced pancreatic cancer. METHODS: Patients (n = 5) received the treatment course, which consisted of intravenous GEM administration at 1000 mg/m (day 1) and the endoscopic ultrasound-guided fine-needle injection of OK432-pulsed DCs into a tumor, followed by intravenous infusion of lymphokine-activated killer cells stimulated with anti-CD3 monoclonal antibody (CD3-LAKs) (day 4), at 2-week intervals. RESULTS: No serious treatment-related adverse events were observed during the study period. Three of the 5 patients demonstrated effective responses to this clinical trial; 1 had partial remission and 2 had long stable disease more than 6 months. In the patient with partial remission, it has been shown that DC-based vaccination combined with GEM administration induces tumor antigen-specific CTLs. CONCLUSION: This combined therapy was considered to be synergistically effective and may have a role in the therapy of pancreatic cancer for inducing tumor antigen-specific CTLs.

Feasibility of tissue elastography using transcutaneous ultrasonography for the diagnosis of pancreatic diseases.

OBJECTIVES: We investigated the feasibility of using real-time tissue elastography (EG) with transcutaneous ultrasonography (EG-US) for pancreatic diseases. METHODS: A preliminary study (phase I) and a prospective (phase II) study were conducted. Phase I: subjects were 10 volunteers, 5 with cancer, 2 with endocrine tumor, 5 with chronic pancreatitis, 14 with intraductal papillary-mucinous neoplasm. To determine the characteristic EG images (diagnostic criteria for phase II), B-mode images were compared with EG images and histopathologic findings. Phase II: 53 consecutive patients were enrolled. The visualization rate by EG-US in lesions visualized by B mode was assessed, and the correct diagnosis rate by B mode alone (B diagnosis) or in combination with EG-US was evaluated. RESULTS: Phase I: normal parenchyma was a homogeneous color. In cancer, EG-US showed a markedly hard area with soft spots inside. Endocrine tumor was uniform and soft comparable to parenchyma. Chronic pancreatitis showed a mixture of various colors. Phase II: we identified 77.4% (41/53) of the lesions and observed 60.0% (15/25) of the cancers, 100% (3/3) of the endocrine tumor, 92.0% (23/25) of the cases of chronic pancreatitis cases on EG-US. The B-diagnosis rates ranged from about 70% to 80%. The diagnosis rates of the combination were more than 90% of lesions of each type. CONCLUSIONS: The EG-US is feasible in the diagnosis of pancreatic diseases.

[A case of gallbladder adenoma with wide base].

A 65-year-old man was referred for a gallbladder elevated lesion. Abdominal US showed a hypoechoic tumor with wide base at the gallbladder body. The maximum velocity of the gallbladder wall blood flow was 20 cm/s. The outermost hyperechoic layer was irregular, but not disrupted on EUS images. We diagnosed the lesion as gallbladder carcinoma with the depth of subserosa. Cholecystectomy was performed and the tumor was diagnosed as tubular adenoma of the gallbladder. The p53 immumostaining was negative. A gallbladder adenoma with wide base is rare, here we report this case with the several considerations.

Progress of endoscopic ultrasonography and intraductal ultrasonography in the diagnosis of malignant biliary diseases.

In recent years, ultrasound technology has made remarkable strides, and the application of these latest advances to endoscopic ultrasonography (EUS) and intraductal ultrasonography (IDUS) is crucially important. EUS equipped with electronic scanners (both radial and convex types) has been developed, and now EUS with the function of tissue harmonic imaging (THI) and color/power Doppler is applicable clinically. THI facilitates the acquisition of ultrasound images clearer than those of fundamental imaging, and color/power Doppler sonography demonstrates the precise hemodynamics with the use of a contrast agent. In addition, the progress of image processing technology has realized three-dimensional (3D) images in EUS and IDUS. Reconstruction of 3D images enables us to diagnose more objectively. Here we describe the roles of these new ultrasound technologies in the diagnosis of biliary malignancies.

Relationship between Lens culinaris agglutinin-reactive alpha-fetoprotein and pathologic features of hepatocellular carcinoma.

AIM: We investigated pathological features of Lens culinaris agglutinin-reactive alpha-fetoprotein (AFP-L3)-positive hepatocellular carcinoma (HCC) in order to seek a pathological basis of poor prognosis of HCC patients with elevated AFP-L3. METHODS: A total of 111 patients with HCC < or =5 cm in diameter who underwent hepatic resection were studied. Serum AFP-L3 concentration was measured within a month prior to surgery by lectin-affinity electrophoresis coupled with antibody-affinity blotting, and expressed as AFP-L3 percentage of total AFP. AFP-L3 of 10% or higher was judged to be positive. Pathologic features of resected HCC specimens were evaluated and classified concerning growth pattern (expansive or infiltrative growth), capsule formation, capsule infiltration, septal formation, portal vein invasion, hepatic vein invasion, bile duct invasion, and intrahepatic metastasis. These macroscopic and microscopic findings were compared between AFP-L3-positive and negative HCC specimens. RESULTS: Thirty-three (29.7%) were positive for AFP-L3. The prevalence of HCC with infiltrative growth, with capsule infiltration, with septum formation, with portal vein invasion, and with hepatic vein invasion was significantly higher in AFP-L3-positive group (P=0.0121, 0.0290, 0.0442, 0.0314, and 0.0433, respectively). These pathologic features reportedly indicate the progression of the tumor. CONCLUSIONS: AFP-L3-positive HCC had several pathologic features of progressed state of HCC, which accounted for the AFP-L3 as an indicator of poor prognosis of HCC.

Changes in the characteristics and survival rate of hepatocellular carcinoma from 1976 to 2000: analysis of 1365 patients in a single institution in Japan.

BACKGROUND: The authors analyzed changes in the characteristics and survival rate of patients with hepatocellular carcinoma (HCC) in the past 25 years. METHODS: Trends in clinical characteristics and survival rate of patients with HCC were evaluated retrospectively based on data from 1365 patients who were diagnosed, treated, and followed between 1976 and 2000. RESULTS: Between 1976-1995, the number of patients with smaller tumors, a less advanced tumor stage, and with a lower Child-Pugh class increased markedly. No differences were observed in the distributions of these three factors between the periods 1991-1995 and 1996-2000. The year of HCC diagnosis, tumor size, tumor stage, Child-Pugh class, and the kind of initial treatment received correlated significantly with patient survival rates by multivariate analysis. The year of HCC diagnosis was found to contribute independently to the improvement in patient survival rates. Using the Kaplan-Meier comparison, the time periods during which the highest patient survival rates occurred were found to be 1991-1995/1996-2000, 1986-1990, and 1976-1985, in that order. The authors did not observe a difference with regard to survival rates between patients in the 1991-1995 and 1996-2000 groups. CONCLUSIONS: The characteristics of patients with HCC changed dramatically from 1976 to 1995 (but not in the past 10 years) toward the earlier detection of HCC. This contributed to the improvement noted in patient survival rates during this period. The year of HCC diagnosis was found to be an independent factor for the improved survival rates by multivariate analysis. This indicated that the progress of treatment and care for patients with HCC contributed to the annual improvement in patient survival rates.