Imaging studies of intraductal tubulopapillary neoplasms of the pancreas: 2-tone duct sign and cork-of-wine-bottle sign as indicators of intraductal tumor growth.

OBJECTIVE: The objective of this study was to describe the imaging findings for intraductal tubulopapillary neoplasms of the pancreas. METHODS: Eleven pancreatic tumors pathologically confirmed as intraductal tubulopapillary neoplasm were retrospectively collected. The dynamic contrast-enhanced computed tomography (CT), magnetic resonance (MR) imaging including MR cholangiopancreatography (MRCP), ultrasound, and endoscopic retrograde cholangiopancreatography (ERCP) results were reviewed. The 2-tone duct sign and cork-of-wine-bottle sign were reviewed as indicators of intraductal tumor growth on CT/MR and MRCP/ERCP images, respectively. RESULTS: A 2-tone duct sign was noted on the dynamic CT images (7/10, 70%) and on the MR imaging (5/8, 63%). The distal main pancreatic duct was dilated in all the patients except one, who had a branch duct lesion. A cork-of-wine-bottle sign was observed on the MRCP image (3/8, 38%) and on the ERCP image (3/6, 50%). CONCLUSIONS: Intraductal tubulopapillary neoplasms are rare tumors showing characteristic imaging findings such as the 2-tone duct sign and the cork-of-wine-bottle sign that represent their intraductal growth.

Prognostic relevance of morphological types of intraductal papillary mucinous neoplasms of the pancreas.

OBJECTIVE: The clinicopathological significance of four morphological types of intraductal papillary mucinous neoplasms of the pancreas (IPMNs; gastric, intestinal, pancreatobiliary and oncocytic) was assessed. DESIGN: Retrospective multicentre analysis of 283 surgically resected IPMNs. RESULTS: Of the 283 IPMNs, 139 were of the gastric type, 101 were intestinal, 19 were pancreatobiliary and 24 were oncocytic. These types were significantly associated with clinicopathological factors including sex (p = 0.0032), age (p = 0.00924), ectatic duct size (p = 0.0245), detection of mural nodules (p = 4.09 × 10⁻6), histological grade (p < 2.20 × 10⁻¹6), macroscopic types with differential involvement of the pancreatic duct system (p = 3.91 × 10⁻5), invasive phenotypes (p = 3.34 × 10⁻¹²), stage (p < 2.20 × 10⁻¹6) and recurrence (p = 0.00574). Kaplan-Meier analysis showed significant differences in patient survival by morphological type (p = 5.24 × 10⁻6). Survival rates at 5 and 10 years, respectively, were 0.937 (95% CI 0.892 to 0.984) for patients with gastric-type IPMNs; 0.886 (95% CI 0.813 to 0.965) and 0.685 (95% CI 0.553 to 0.849) for those with intestinal-type IPMNs; 0.839 (95% CI 0.684 to 1.000) and 0.734 (95% CI 0.526 to 1.000) for those with oncocytic-type IPMNs; and 0.520 (95% CI 0.298 to 0.909) and undetermined for those with pancreatobiliary-type IPMNs. Analysis by the Cox proportional hazards model comparing prognostic risks determined by stage and the morphological and macroscopic types indicated that staging was the most significant predictor of survival (p = 3.68×10⁻8) followed by the morphological type (p = 0.0435). Furthermore, the morphological type remained a significant predictor in a subcohort of invasive cases (p = 0.0089). CONCLUSION: In this multicentre retrospective analysis, the morphological type of IPMN appears to be an independent predictor of patient prognosis.

Association of epidermal growth factor receptor and mitogen-activated protein kinase with cystic neoplasms of the pancreas.

The molecular pathobiology of pancreatic cystic neoplasms is poorly understood. The aim of this study was to know the involvement of epidermal growth factor receptor (EGFR) and its downstream targets in the serous cystic neoplasms and the mucinous cystic neoplasms of the pancreas. In a total of 72 pancreatic cystic neoplasms, including 39 serous cystic neoplasms and 33 mucinous cystic neoplasms, we examined the expression of native and phosphorylated EGFR, mitogen-activated protein kinase (MAPK), and AKT by immunohistochemistry and somatic mutations in EGFR, KRAS, BRAF, and PIK3CA, by direct sequencing. We also assessed the copy numbers of EGFR transcripts and the amplification of the EGFR gene in some of the samples. We found that EGFR, phosphorylated EGFR, MAPK, and phosphorylated MAPK were evidently expressed in 100, 54, 100, and 69% of the serous cystic neoplasms, and in 12%, none, 33, and 27% of the mucinous cystic neoplasms, respectively; the expression was significantly higher and more prevalent in the serous cystic neoplasms than in the mucinous cystic neoplasms. The expression of AKT and phosphorylated AKT was low in both the types of neoplasms. On average, EGFR transcripts in the serous cystic neoplasms and the mucinous cystic neoplasms increased 53.5- and 2.5-fold, respectively, as compared with that in normal tissues, with the increase in the former being significantly greater than that in the latter. Amplification of the EGFR gene was not detected in any of the examined serous cystic neoplasms. None of the tumors had mutations in any of the examined portions of the genes, except two mucinous cystic neoplasms with mutations in codon-12 of KRAS. These results indicate that EGFR and MAPK are actively involved in the pathobiology of serous cystic neoplasms and may therefore be potential diagnostic markers and therapeutic targets in patients with the above mentioned types of neoplasms.

The liver surface as a favorable site for islet cell sheet transplantation in type 1 diabetes model mice.

INTRODUCTION: Islet transplantation is one of the most promising therapeutic approaches for patients with severe type 1 diabetes mellitus (T1DM). Transplantation of engineered islet cell sheets holds great potential for treating T1DM as it enables the creation of stable neo-islet tissues. However, a large mass of islet cell sheets is required for the subcutaneous transplantation to reverse hyperglycemia in diabetic mice. Here, we investigated whether the liver surface could serve as an alternative site for islet cell sheet transplantation. METHODS: Dispersed rat islet cells (0.8 × 106 cells) were cultured on laminin-332-coated thermoresponsive culture dishes. After 2 days of cultivation, we harvested the islet cell sheets by lowering the culture temperature using a support membrane with a gelatin gel. We transplanted two recovered islet cell sheets into the subcutaneous space or onto the liver surface of severe combined immunodeficiency (SCID) mice with streptozocin-induced diabetes. RESULTS: In the liver surface group, the non-fasting blood glucose level decreased rapidly within several days after transplantation. In marked contrast, the hyperglycemia state was maintained in the subcutaneous space transplantation group. The levels of rat C-peptide and insulin in the liver surface group were significantly higher than those in the subcutaneous space group. An immunohistological analysis confirmed that most of the islet cells engrafted on the liver surface were insulin-positive. The CD31-positive endothelial cells formed vascular networks within the neo-islets and in the surrounding tissues. In contrast, viable islet cells were not found in the subcutaneous space group. CONCLUSIONS: Compared with the subcutaneous space, a relatively small mass of islet cell sheets was enough to achieve normoglycemia in diabetic mice when the liver surface was selected as the transplantation site. Our results demonstrate that the optimization of the transplantation site for islet cell sheets leads to significant improvements in the therapeutic efficiency for T1DM.

A randomized controlled trial of comprehensive early intervention care in patients with first-episode psychosis in Japan: 1.5-year outcomes from the J-CAP study.

The first episode of psychosis represents a critical period wherein comprehensive early intervention in psychosis (EIP) may alter the course of illness. However, evidence from randomized controlled trials that have examined the impact of comprehensive EIP care on clinical and functional recovery assessed by independent blinded raters is limited. The objective of this study was to conduct a single-blinded multicenter trial comparing comprehensive EIP care and standard care in young patients with first-episode psychosis (FEP) in Japan (J-CAP Study). A total of 77 participants with FEP (aged 15-35 years) were randomized to receive standard care or specialized comprehensive EIP care and were followed up for 1.5 years (trial no.: UMIN000005092). Function (measured with the Global Assessment of Functioning) and clinical remission (defined by internationally standardized criteria proposed by the Remission in Schizophrenia Working Group) were evaluated by independent raters who were blinded to group assignment. Dropout rate and other secondary outcomes were also examined. The specialized EIP care group had a higher clinical remission rate (odds ratio, 6.3; 95% confidence interval, 1.0-37.9) and lower treatment dropout rate (odds ratio, 0.038; 95% confidence interval, 0.002-0.923) than the standard care group, even after adjusting for baseline characteristics. Functional improvement in the specialized EIP care group was slightly higher than that in the standard care group, but this difference was not statistically significant (p = 0.195). From the results, we conclude that comprehensive EIP care may provide advantages over standard care in patients with FEP.

Comprehensive early intervention for patients with first-episode psychosis in Japan (J-CAP): study protocol for a randomised controlled trial.

INTRODUCTION: Comprehensive approaches for patients with psychotic symptoms play essential roles in the symptomatic and functional outcomes of patients, especially during disease onset. In Japan, the shortage of mental health services, particularly for outpatients, and community-based supports has been a major problem. The purpose of this trial is to investigate the effectiveness and affordability of 18-month comprehensive early intervention services for patients with first-episode psychosis compared with typical treatment. METHODS: This interventional, parallel, single-blinded (open but blinded raters trial) was effectively designed. The participants are patients with a diagnosis of F2 or F3 (International Classification of Disease, 10 th revision), with psychotic symptoms. The inclusion criteria were an age of 15-35 years, onset of psychotic symptoms within 5 years, first-episode psychosis, and residence in the catchment area of each site. Allocation will be conducted equally between case management and standard care groups. After enrollment, standard care will be provided for both groups, and community-based care to promote recovery for 18 months will be provided for the comprehensive approach group. The primary outcome will be the function domain of the global assessment of functioning scores at 18 months after enrollment. Data assessment will be performed at enrollment and 18, 36, and 60 months after enrollment. The target sample size will be 150, and registration will occur from March 1, 2011, to September 30, 2012. DISCUSSION: This trial will provide promising results about the effectiveness and cost-effectiveness of early intervention services in Japan to improve the quality and quantity of community mental health services. TRIAL REGISTRATION: This trial was registered in The University Hospital Medical Information Network Clinical Trials Registry (No. UMIN000005092).

Duodenum-preserving total pancreatectomy for pancreatic neoplasms.

BACKGROUND/PURPOSE: Total pancreatectomy (TP) is sometimes performed to treat low-grade malignant neoplasms that are spreading to the entire pancreas. However, TP impairs quality of life, due to the resulting loss of pancreatic exocrine and endocrine function, and an organ-preserving procedure should be chosen to minimize the impact of pancreatic dysfunction. Recently, we performed four duodenum-preserving TPs (DPTPs) on patients with low-grade malignant neoplasms of the entire pancreas and we introduce our operative technique and results herein. METHODS: DPTP is performed with the objective of preserving the arterial arcade of the posterior pancreas so as to maintain good blood flow in the duodenum and common bile duct. Care must also be taken to preserve the splenic artery and vein to protect the spleen. When patients are also undergoing a bile duct resection, an end-to-side choledochoduodenostomy is also performed to reconstruct the biliary tract. RESULTS: Patient 1: DPTP with preservation of the spleen, conserving splenic vessels, was performed on a patient with hereditary pancreatic carcinoma with pancreatic intraepithelial neoplasia-3 (PanIN-3). Patient 2: DPTP with splenectomy was performed on a patient with multiple metastases of the entire pancreas from renal cell carcinoma. Patient 3: DPTP with preservation of the common bile duct and the spleen, conserving splenic vessels, was performed on a patient with minimally invasive carcinoma derived from intraductal papillary mucinous neoplasm (IPMN). Patient 4: DPTP with preservation of the spleen, conserving splenic vessels, was performed on a patient with minimally invasive carcinoma derived from IPMN. No deaths or morbidity occurred. All patients were placed on pancreatic enzyme replacement therapy and given a daily dose of insulin of approximately 30 U. Complete professional rehabiliation was achieved in all patients. All patients except one gained weight, and the hemoglobin A1c (HbA1c) levels have been maintained at around 7%. CONCLUSIONS: DPTP is a useful organ-preserving procedure for low-grade malignant neoplasms spreading within the entire pancreas. This procedure minimizes the impact of pancreatic dysfunction and allows the patient to maintain good nutrition after surgery.

Intraductal tubulopapillary neoplasms of the pancreas distinct from pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms.

We have encountered cases of unusual intraductal pancreatic neoplasms with predominant tubulopapillary growth. We collected data on 10 similar cases of "intraductal tubulopapillary neoplasms (ITPNs)" and analyzed their clinicopathologic and molecular features. Tumor specimens were obtained from 5 men and 5 women with a mean age of 58 years. ITPNs were solid and nodular tumors obstructing dilated pancreatic ducts and did not contain any visible mucin. The tumor cells formed tubulopapillae and contained little cytoplasmic mucin. The tumors exhibited uniform high-grade atypia. Necrotic foci were frequently observed, and invasion was observed in some cases. The ITPNs were immunohistochemically positive for cytokeratin 7 and/or cytokeratin 19 and negative for trypsin, MUC2, MUC5AC, and fascin. Molecular studies revealed abnormal expressions of TP53 and SMAD4 in 1 case, but aberrant expression of beta-catenin was not observed. No mutations in KRAS and BRAF were observed in the 8 cases that were examined. Eight patients are alive without recurrence, 1 patient died of liver metastases, and 1 patient is alive but had a recurrence and underwent additional pancreatectomy. The mitotic count and Ki-67 labeling index were significantly associated with invasion. All the features of ITPN were distinct from those of other known intraductal pancreatic neoplasms, including pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasm, and the intraductal variant of acinar cell carcinoma. Intraductal tubular carcinomas showed several features that were similar to those of ITPN, except for the tubulopapillary growth pattern. In conclusion, ITPNs can be considered to represent a new disease entity encompassing intraductal tubular carcinoma as a morphologic variant.