Eizaburo Ohno

Intraductal papillary mucinous neoplasms of the pancreas: differentiation of malignant and benign tumors by endoscopic ultrasound findings of mural nodules.

Background and Aim:Intraductal papillary mucinous neoplasms (IPMNs) have a wide pathologic spectrum and it is difficult to differentiate malignant from benign tumors. The aim of this study was to identify predictors of malignancy using contrast-enhanced endoscopic ultrasound (CE-EUS). Subjects and Methods:In our institute, main duct type and mixed type IPMNs, branch duct type IPMNs with mural nodules, and IPMNs with coexistent invasive ductal cancer were indications for surgery. Eighty-seven IPMNs (14 main duct, 25 mixed, and 48 branch duct type) were resected and CE-EUS findings were compared with pathologic findings. Twelve clinicopathological variables and CE-EUS morphologic findings were assessed. Mural nodules defined as blood flow supplied protrusions were classified into 4 types: type I: low papillary nodule, type II: polypoid nodule, type III: papillary nodule, and type IV: invasive nodule. Results:Forty-two, 26, 16, and 3 were pathologically diagnosed as adenoma, noninvasive carcinoma, invasive IPMNs, and coexistent invasive ductal cancer, respectively. Multivariable logistic regression analysis showed that types III/IV mural nodule (odds ratio = 10.8; 95% confidential intervals = 2.75–56.1) and symptomatic IPMNs (odds ratio = 4.31; 95% confidential intervals = 1.37–14.7) were significant for malignancy. For mural nodule diameter, invasive IPMNs were significantly larger, but types III and IV mural nodules were more frequently associated with malignancy, particularly invasive cancer, at 88.9% and 91.7%, respectively. The diagnosis of IPMNs with types III or IV mural nodule as malignant resulted in a sensitivity of 60%, specificity of 92.9%, and accuracy of 75.9%. Conclusions:In conclusion, new morphologic criteria were useful to identify the malignant potentials of IPMNs.

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/m2 (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.

Malignant transformation of branch duct-type intraductal papillary mucinous neoplasms of the pancreas based on contrast-enhanced endoscopic ultrasonography morphological changes: focus on malignant transformation of intraductal papillary mucinous neoplasm itself.

Objectives The natural history of branch duct–type intraductal papillary mucinous neoplasms (BD-IPMNs) of the pancreas remains unclear. We conducted a retrospective long-term follow-up study for malignant transformation (MT) of BD-IPMNs focusing on morphological changes. Methods The subjects consisted of 142 patients who underwent contrast-enhanced endoscopic ultrasonography for initial diagnosis from January 2001 with more than 12 months of follow-up. The MT rate, including the co-occurrence of invasive ductal cancer, was evaluated by univariate and multivariate analysis. In addition, on the basis of morphological changes in patients who underwent surgery, the predictive factors for malignant IPMNs were evaluated. Results Median follow-up term was 42.5 months (range, 12–105 months). Thirty patients who exhibited morphological changes underwent surgery. Malignant transformation occurred in 9 patients (6.3%), and 5-year MT rate was 10.7%. The co-occurrence of invasive ductal cancer was seen in 5 patients. Multivariate analysis showed that the existence of mural nodules at initial diagnosis and involvement of main pancreatic duct were significant predictors of MT of BD-IPMN. Conclusions Malignant transformation of BD-IPMN is not rare. The observation of morphological changes of main pancreatic duct and nodules, mainly on contrast-enhanced endoscopic ultrasonography, is practical and useful for predicting MT of BD-IPMN itself. Abbreviations IPMN - intraductal papillary mucinous neoplasm BD-IPMN - branch duct–type intraductal papillary mucinous neoplasm MT - malignant transformation IDC - invasive ductal cancer MPD - main pancreatic duct CE-EUS - contrast-enhanced endoscopic ultrasonography EUS-FNA - endoscopic ultrasonography–guided fine needle aspiration MD-IPMN - main duct–type intraductal papillary mucinous neoplasm MD-CT - multidetector row computed tomography HR - hazard ratio OR - odds ratio

Preoperative endoscopic nasobiliary drainage in 164 consecutive patients with suspected perihilar cholangiocarcinoma: a retrospective study of efficacy and risk factors related to complications.

Objective:To assess the clinical benefits of preoperative endoscopic nasobiliary drainage (ENBD) in patients with perihilar cholangiocarcinoma. Background:The advantages of ENBD have been previously reported. However, no studies to date have examined a large number of patients, including those with Bismuth-Corlette (B-C) type III to IV tumors. In addition, sufficient data on the risk factors associated with ENBD complications are not available. Methods:This study involved 164 consecutive patients with suspected perihilar cholangiocarcinoma (128 patients with B-C type III–IV tumors) who had undergone unilateral ENBD between January 2007 and December 2010. The success and efficacy of this procedure and the risk factors for post-ENBD cholangitis and pancreatitis were retrospectively evaluated. Results:The ENBD procedure was successful in 153 (93.3%) of the 164 patients. Of these 164 patients, 65 had serum total bilirubin (TB) levels of 2.0 mg/dL or more before the drainage. The first unilateral ENBD was successfully performed in 60 of the 65 patients, and the TB level decreased to less than 2.0 mg/dL after ENBD in 50 of these 60 patients (83.3%). The significant predictive factors for ENBD efficacy included the pre-ENBD TB level (P = 0.032; 95% confidence interval [CI], 1.01–1.23) and post-ENBD cholangitis (P = 0.012; 95% CI, 1.61–43.2). Post-ENBD cholangitis occurred in 47 (28.8%) of the 163 patients, and a previous endoscopic sphincterotomy (EST) was found to be a significant risk factor for post-ENBD cholangitis (P = 0.008; 95% CI, 1.30–5.46). Post-ENBD pancreatitis occurred in 33 (20.1%) of the 164 patients (26 grade 1 patients, 4 grade 2 patients, and 3 grade 3 patients). The significant risk factors included undergoing pancreatography (P < 0.001; 95% CI, 2.44–31.1) and the absence of previous EBS or ENBD (P < 0.001; 95% CI, 3.03–29.2). Conclusions:Unilateral ENBD of the future remnant lobe(s) exhibited a high success rate, suggesting that it is an effective and suitable preoperative drainage method for perihilar cholangiocarcinoma even in patients with B-C type III to IV tumors. To reduce the postprocedural complications, ENBD should be performed without EST or pancreatography.

Dynamic quantitative evaluation of contrast-enhanced endoscopic ultrasonography in the diagnosis of pancreatic diseases

Objectives: This study aimed to investigate the usefulness of contrast-enhanced endoscopic ultrasonography (EUS) with time-intensity curve (TIC) in differentiating pancreatic diseases. Methods: Patients who underwent contrast-enhanced EUS between January 2007 and June 2009 were analyzed retrospectively, including 48 with pancreatic ductal cancer (PC), 14 with autoimmune pancreatitis (AIP), 13 with mass-forming pancreatitis (MFP), and 16 with pancreatic endocrine tumor (PET). After intravenous injection of contrast agent, contrast imaging pattern, TIC-based quantitative evaluation, and diagnostic ability of EUS in combination with TIC to diagnose benignancy or malignancy were assessed. Results: Hypovascular and heterogeneous pattern (42/48) in PC, isovascular and homogenous (21/27) in AIP and MFP, and hypervascular and rapid stained (16/16) in PET were observed. The echo intensity reduction rate from the peak at 1 minute was the greatest in PC followed by MFP, AIP, and PET (P < 0.05). The diagnostic accuracies based on contrast imaging pattern (84.0%) and TIC (88.0%) were higher than those based on B-mode imaging (82.6%) and dynamic computed tomography (81.3%). In EUS in combination with TIC, sensitivity, specificity, and accuracy rose up to 95.8%, 92.6%, and 94.7%, respectively. Conclusions: Contrast-enhanced EUS with the dynamic quantitative analysis preparing TIC increased the diagnostic accuracy for pancreatic diseases.

Diagnosis of Pancreatic Disorders Using Contrast-Enhanced Endoscopic Ultrasonography and Endoscopic Elastography

Contrast-enhanced endoscopic ultrasonography (CE-EUS) and EUS-elastography are cutting-edge diagnostic modalities for pancreatic disorders. Each pancreatic disorder has characteristic hemodynamics. CE-EUS uses color Doppler flow imaging to classify pancreatic lesions into a spectrum of solid and cystic patterns. Although there is overlap in the patterns generated by specific types of tumors, some types of tumors tend to produce distinct flow images. EUS-elastography can assess tissue hardness by measuring its elasticity. This parameter appears to correlate with the malignant potential of the lesions. Tissue elasticity studies can provide information on both its pattern and distribution. The former is the conventional method of morphologic diagnosis, but it is restricted to observations made in a region of interest. The latter is an unbiased analysis that can be performed by image analysis software and is theoretically constant, regardless of regions of interest. The evolving modalities of CE-EUS and EUS-elastography might provide clinical utility in the diagnosis of pancreatic disorders.

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.

Enteroscopic and radiologic diagnoses, treatment, and prognoses of small-bowel tumors.

BACKGROUND Small-bowel tumors (SBTs) represent a diagnostic challenge. OBJECTIVE To evaluate the usefulness of contrast-enhanced CT (CECT), fluoroscopic enteroclysis (FE), videocapsule endoscopy (VCE), and double-balloon endoscopy (DBE) and the outcome after treatment. DESIGN Single-center, retrospective study. SETTING Tertiary-care referral hospital. PATIENTS Between June 2003 and May 2011, 159 consecutive patients with SBTs (93 malignant and 66 benign) were enrolled. MAIN OUTCOME MEASUREMENTS Comparison of diagnostic yields among CECT, FE, VCE, and DBE and the prognosis. RESULTS CECT and FE had significantly lower diagnostic yields of SBTs ≤ 10 mm, but VCE and DBE had high yields of SBTs regardless of size. CECT had a significantly lower diagnostic yield of epithelial tumors compared with subepithelial tumors. When stratified by the site, the diagnostic yield of VCE for SBTs located only in the distal duodenum/the proximal jejunum (73%) was significantly lower than that for SBTs located in other areas (90%). Comparisons among the 4 methods revealed that VCE and DBE had significantly higher diagnostic yields than CECT, and DBE had significantly higher diagnostic yields than VCE, but a combination of CECT and VCE had a diagnostic yield similar to that of DBE. The histologic diagnostic yield of SBTs by DBE was 92%, and 25% of SBTs were enteroscopically treated. Metastatic tumors had the poorest overall survival, followed by adenocarcinomas and malignant lymphomas. LIMITATIONS Retrospective comparative study. CONCLUSION For the detection of SBTs, a combination screening method by using VCE and CECT is recommended. DBE is useful for histologic diagnosis and endoscopic treatment.

TRANSPAPILLARY BILIARY FORCEPS BIOPSY TO DISTINGUISH BENIGN BILIARY STRICTURE FROM MALIGNANCY: HOW MANY TISSUE SAMPLES SHOULD BE OBTAINED?

Background:  The sensitivity of transpapillary biliary forceps biopsy for malignancy has been reported as varying from 43–81%. Therefore, there are false negatives in more than 20% of patients, which makes it difficult to diagnose benign biliary stricture as benignancy in a clinical setting.

Endoscopic and imaging findings in protein-losing enteropathy.

Objectives: Protein-losing enteropathy (PLE) is often difficult to diagnose. We evaluated the diagnostic yields of underlying diseases of PLE among esophagogastroduodenoscopy, colonoscopy, fluoroscopic conventional enteroclysis (FCE), videocapsule endoscopy (VCE), and double-balloon enteroscopy (DBE) and prognosis after treatment. Methods: Between June 2003 and August 2010, 25 consecutive patients with PLE confirmed by fecal &agr;1-antitrypsin clearance (n=18) and technetium 99m human serum albumin scintigraphy (n=19) were enrolled, investigated, and treated. Results: Of 25 patients, 4 (16%) with intestinal lymphangiectasia secondary to macroglobulinemia (n=1), amyloidosis (n=2), and strongyloidiasis (n=1) were diagnosed at preceding esophagogastroduodenoscopy or colonoscopy, and 7 (32%) with primary intestinal lymphangiectasia and chronic nonspecific multiple ulcers unrelated to nonsteroidal anti-inflammatory drugs of the small intestine were newly diagnosed at FCE or VCE. Other 11 (44%) patients with primary intestinal lymphangiectasia, small-bowel tumors, amyloidosis, chronic nonspecific multiple ulcers unrelated to nonsteroidal anti-inflammatory drugs of the small intestine, Crohn’s disease, and small-bowel ulcers due to polyarteritis nodosa were diagnosed only at DBE with biopsy. Three patients with primary intestinal lymphangiectasia, cirrhosis after living donor liver transplantation, and congestive heart failure were not diagnosed at any small-bowel examination. The overall diagnostic yield of FCE, VCE, and DBE was 62% (8/13), 83% (14/17), and 88% (22/25), respectively. Eight patients (32%) died of underlying disorders regardless of medical treatment over the follow-up period. Conclusions: DBE with pathologic findings of biopsy specimens was useful for the differential diagnosis of PLE. Noninvasive VCE might be preferable and useful for screening and follow up of PLE without stricture. Prognosis of a subgroup of PLE was poor regardless of treatment.