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Purpose: To assess which magnetic resonance imaging (MRI) features are associated with pNETs (pancreatic neuroendocrine tumors) grade based on the WHO classification, as well as identify MRI features related to disease progression after surgery., Materials and Methods: In this Institutional Review Board (IRB)-approved study, 1.5T and 3.0T MRI scans of 80 patients with surgically verified pNETs were assessed. The images were evaluated for tumor location; size; pattern; predominant signal intensity on precontrast T 1 - and T 2 -weighted images, as well as on postcontrast arterial and portal venous phase T 1 -weighted sequences; presence of pancreatic duct dilatation; pancreatic atrophy; restricted diffusion; vascular involvement by the tumor; extrapancreatic tumor spread; and synchronous liver metastases. Tumors were graded based on the WHO classification and patients were followed-up with computed tomography (CT) or MRI after surgical resection. Data were analyzed with Student's t and chi-square tests, logistic regression, and Kaplan-Meier curves., Results: The MRI features that were associated with aggressive tumors were: size >2.0 cm (odds ratio [OR] = 4.8, P = 0.002), "T 2 nonbright lesions" on T 2 -weighted images (OR = 4.6, P = 0.008), presence of pancreatic ductal dilatation (OR = 4.9, P = 0.024), and restricted diffusion within the lesion (OR = 4.9, P = 0.013). Differences in progression-free survival distribution were found for patients whose pNETs were associated with the following MRI features: size >2.0 cm (χ 2 (1) = 6.0, P = 0.014), "nonbright lesions" on T 2 -weighted images (χ 2 (1) = 6.8, P = 0.009), and presence of pancreatic duct dilatation (χ 2 (1) = 10.9, P = 0.001)., Conclusion: MRI features can be used to assess pNETs aggressiveness and identify patients at risk for early disease progression after surgical resection., Level of Evidence: 3 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:425-432., (© 2017 International Society for Magnetic Resonance in Medicine.)

Pancreatic ductal adenocarcinoma (PDAC) has a 5-year relative survival rate of 8% and is projected to be the second leading cause of cancer death by 2030, underscoring the urgency to develop new strategies to improve current therapeutic modalities for PDAC. Targeting pancreatic cancer stem cells (PCSCs), which are resistant to radiation and chemotherapy, is a promising strategy. A novel approach which can be readily clinically translated is to repurpose disulfiram (DSF), a drug for treating alcoholism, to target PCSCs. Chemoradiation or the combination of chemotherapy agents FOLFIRINOX, currently standard care for PDAC, can increase stemness in some established or primary PDAC cell lines. However, DSF in the presence of exogenously or endogenously supplied copper (Cu), when combined with chemotherapy or chemoradiation, targets both PCSCs and nonstem PDAC cells. Previously, we demonstrated that DSF/Cu effectively targets breast cancer stem cells in the context of fractionated radiation (FIR) by inhibiting the NF-κB-stemness gene pathway. Therefore, the hypothesis that PCSCs can be effectively targeted by incorporating DSF/Cu into the standard chemoradiation regimen consisting of 5-FU and FIR was investigated and found to be effective in vitro in targeting PCSCs, identified as either ALDH bright or CD24+/CD44+/ESA+ or sphere-forming cells, as well as nonstem PDAC cells. In vivo, the combination of IR+5-FU+DSF/Cu was more effective (72.46%) than either IR+5-FU (30.32%) or IR+FOLFIRINOX therapy (43.04%) in inhibiting growth of the mouse Panc02 tumor. These encouraging results provide a solid foundation for clinical trials to improve the outcomes of the current standard chemoradiation therapy regimen for PDAC., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Gastrinomas are rare neuroendocrine tumors that ectopically secrete gastrin and classically originate within the duodenum or pancreas. The presence of primary lymph node gastrinoma is controversial. We report on a single institution's experience with gastrinoma, with focus on primary lymph node tumors., Methods: Patients who underwent operative resection of gastrinoma between 1992 and 2016 at a single institution were identified. A diagnosis of primary lymph node gastrinoma was defined as tumor confined to one or more resected peripancreatic lymph nodes, negative localization for any extra-nodal disease and normal gastrin postresection., Results: In the study, 39 consecutive patients underwent operative resection of gastrinoma. Mean age was 53 years and 49% were male. 93% of patients had successful preoperative localization. Furthermore, 19 patients (49%) underwent enucleation of their tumor and 14 (35.9%) a pancreatic resection. Overall 5- and 10-year survival for all patients was 80.8% and 60.7%, respectively. Primary lymph node gastrinoma was identified in 11 cases (28.2%). The presentation of primary lymph node and non-primary lymph node patients were similar. There was no significant difference in operation type, tumor size, or overall survival. At median follow-up of 59 months, patients with primary lymph node gastrinoma were less likely to have persistent or recurrent disease (9.1% vs 42.9%, P = .04)., Conclusion: This series supports the existence of primary lymph node gastrinomas, and indicates that as many as 1 in 4 patients with gastrinoma have this form of the disease. This entity should be considered when an isolated pathologic lymph node is identified, although thorough exploration is still recommended to exclude other occult disease., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: The impact of preoperative biliary drainage (PBD) on perioperative morbidity and mortality in pancreatic surgery is still under debate. The aim of this study was to investigate outcomes of stented vs. non-stented patients undergoing pancreatoduodenectomy (PD)., Methods: We retrospectively compared 500 consecutive patients who underwent PBD prior to PD with 500 patients who did not. Ninety-day mortality and morbidity were assessed., Results: The overall postoperative morbidity and mortality was 37% and 1.4%, respectively. Major complications (Clavien ≥ III) occurred in 16% of patients. The overall morbidity and mortality was not significantly higher in patients who underwent PBD. However, the rate of wound infection was significantly higher in patients who underwent PBD (19% vs. 9%, P = 0.001). When comparing intraoperative bile cultures of stented patients with and without wound infection, the presence of Enterobacter species (OR 2.4, 95% CI 1.5-4.1, P = 0.001) and Citrobacter species (OR 2.3, 95% CI 1.1-5.2, P = 0.037) in the bile significantly increased the likelihood of wound infection., Conclusion: Preoperative biliary drainage is associated with bactobilia and wound infection, but does not affect the overall morbidity and mortality of patients undergoing PD., (© 2016 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Background and Objective: Hospital admissions can be difficult for patients with autism spectrum disorder (ASD). We created an autism-specific care plan (ACP) to help improve the hospital experience for patients with ASD, and we tested feasibility and acceptability and compared the experience of care for children with and without an ACP., Methods: We performed a nonrandomized, retrospective chart review of all patients with ASD and a hospital admission from January 2013 to December 2013 (n = 142) to determine feasibility of the intervention. We then mailed surveys to all 142 families to measure experience with the ACP and to compare experience of care in those who did and did not have an ACP. Using multivariable linear regression we assessed the association of experience of care with ACP use while adjusting for covariates., Results: The ACP was well tolerated by parents and used frequently by staff. Compared with parents who did not use the ACP, parents who used the ACP reported a better experience relating to their general hospital experience (B = 1.48, P < .001) and staff attention to their child's ASD-specific needs (B = 3.07, P < .001)., Conclusions: According to this pilot study, care plans are feasible and hold promise to improve the experience of care for children with ASD and their families in the hospital setting., (Copyright © 2016 by the American Academy of Pediatrics.)

Objectives: To describe the characteristics of intraductal papillary mucinous neoplasms (IPMNs) with predominant involvement of the main pancreatic duct (MPD), analyzing predictors for survival and recurrence., Background: IPMNs involving the MPD harbor a high likelihood of malignancy and different biological features. The appropriateness of including cases with minimal noncircumferential MPD involvement has been challenged because these show clinicopathological features that are similar to branch duct IPMN. Accordingly, their exclusion has led to a redefinition of MPD IPMN (MD-IPMN)., Methods: Retrospective review of resected MD-IPMN from 1990 to 2013. All slides were reviewed by a single pancreatic pathologist and classified on the basis of epithelial type and invasive component., Results: A total of 223 patients underwent resection for IPMN involving the MPD. Of these, 50 were excluded because of minimal MPD involvement. Among the 173 patients analyzed, median age was 68 years and 55% were males. Predominant epithelial phenotype was intestinal (50%). Forty-eight patients (28%) had low- or intermediate-grade dysplasia, whereas 125 (72%) had either high-grade dysplasia (33%) or invasive carcinoma (39%). Of the 67 invasive IPMNs, 39 were tubular carcinomas (58%) and invasion was minimal (<5 mm) in 28 (42%). The 5-year overall survival rate was 69% and the disease-specific survival rate was 83%. The estimated recurrence rate at 10 years was 25%. Size and type of the invasive component, lymph node positivity, and a positive resection margin were predictors for both survival and recurrence (P < 0.05)., Conclusions: MD-IPMN is mainly intestinal-type and malignant. After resection, it has a very favorable prognosis, especially in the absence of macroscopic invasive carcinoma.

Background: The molecular alterations that drive tumorigenesis in intrahepatic cholangiocarcinoma (ICC) remain poorly defined. We sought to determine the incidence and prognostic significance of mutations associated with ICC among patients undergoing surgical resection., Methods: Multiplexed mutational profiling was performed using nucleic acids that were extracted from 200 resected ICC tumor specimens from 7 centers. The frequency of mutations was ascertained and the effect on outcome was determined., Results: The majority of patients (61.5 %) had no genetic mutation identified. Among the 77 patients (38.5 %) with a genetic mutation, only a small number of gene mutations were identified with a frequency of >5 %: IDH1 (15.5 %) and KRAS (8.6 %). Other genetic mutations were identified in very low frequency: BRAF (4.9 %), IDH2 (4.5 %), PIK3CA (4.3 %), NRAS (3.1 %), TP53 (2.5 %), MAP2K1 (1.9 %), CTNNB1 (0.6 %), and PTEN (0.6 %). Among patients with an IDH1-mutant tumor, approximately 7 % were associated with a concurrent PIK3CA gene mutation or a mutation in MAP2K1 (4 %). No concurrent mutations in IDH1 and KRAS were noted. Compared with ICC tumors that had no identified mutation, IDH1-mutant tumors were more often bilateral (odds ratio 2.75), while KRAS-mutant tumors were more likely to be associated with R1 margin (odds ratio 6.51) (both P < 0.05). Although clinicopathological features such as tumor number and nodal status were associated with survival, no specific mutation was associated with prognosis., Conclusions: Most somatic mutations in resected ICC tissue are found at low frequency, supporting a need for broad-based mutational profiling in these patients. IDH1 and KRAS were the most common mutations noted. Although certain mutations were associated with ICC clinicopathological features, mutational status did not seemingly affect long-term prognosis.

Objectives: The purpose of this study was to investigate the prevalence of depression diagnoses and related clinical data in an outpatient sample of youth with autistic disorder., Methods: Records of 123 psychiatrically referred children and adolescents with a Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR) diagnosis of autistic disorder were examined. Mood disorder diagnoses and chief complaints along with family mood disorder history were the primary variables analyzed., Results: Four subjects (3%) presented with depressed mood. Irritability complaints were frequent (n=78, 63%). Six subjects (5%) received a mood disorder diagnosis; all with mood disorder, not otherwise specified. No subjects received a depressive disorder diagnosis. Family history of mood disorders was common., Conclusions: Findings raise questions about the appropriate characterization and potential misdiagnoses of depression in youth with autistic disorder.

The goal of this study was to determine the frequency of HLA class II antigen expression in colorectal carcinoma (CRC) tumors, its association with the clinical course of the disease, and the underlying mechanism(s). Two tissue microarrays constructed with 220 and 778 CRC tumors were stained with HLA-DR, DQ, and DP antigen-specific monoclonal antibody LGII-612.14, using the immunoperoxidase staining technique. The immunohistochemical staining results were correlated with the clinical course of the disease. The functional role of HLA class II antigens expressed on CRC cells was analyzed by investigating their in vitro interactions with immune cells. HLA class II antigens were expressed in about 25% of the 220 and 21% of the 778 tumors analyzed with an overall frequency of 23%. HLA class II antigens were detected in 19% of colorectal adenomas. Importantly, the percentage of stained cells and the staining intensity were significantly lower than those detected in CRC tumors. However, HLA class II antigen staining was weakly detected only in 5.4% of 37 normal mucosa tissues. HLA class II antigen expression was associated with a favorable clinical course of the disease. In vitro stimulation with interferon gamma (IFNγ) induced HLA class II antigen expression on two of the four CRC cell lines tested. HLA class II antigen expression on CRC cells triggered interleukin-1β (IL-1β) production by resting monocytes. HLA class II antigen expression in CRC tumors is a favorable prognostic marker. This association may reflect stimulation of IL-1β production by monocytes.

We determined whether bone mineral density (BMD) is lower in boys with autism spectrum disorders (ASD) than controls, and also assessed variables that may affect BMD in ASD. BMD was measured using dual energy X-ray absorptiometry (DXA) in 18 boys with ASD and 19 controls 8-14 years old. Boys with ASD had lower BMD Z-scores at the spine, hip and femoral neck, and differences at the hip and femoral neck persisted after controlling for maturity and BMI. Vitamin D intake from food and in serum were lower in ASD subjects, as was exercise activity. We conclude that BMD is lower in peripubertal boys with ASD and may be associated with impaired vitamin D status and lower exercise activity.

Prior investigations suggest that birth order position may be associated with the risk for developing a pervasive developmental disorder. This retrospective chart review examined the birth order status of 29 psychiatrically-referred patients with Asperger's Syndrome (AS). Eighty-six percent of the subjects were first born. The finding was statistically significant when compared to an expected random distribution of AS subjects χ(2) (1, N = 29) = 9.18, p < 0.01. The reasons for such an association are unclear though birth stoppage, obstetric complications, and immunological mechanisms may play a role.

Objectives: To estimate the risk of malignancy in autoimmune pancreatitis (AIP)., Methods: We examined resected pancreata to compare the prevalence of pancreatic intraepithelial neoplasia (PanIN) in 28 cases of AIP and 30 cases of chronic pancreatitis not otherwise specified (CP-NOS). We also reviewed a cohort of 84 AIP cases., Results: The mean age of the AIP cohort (57 years) was significantly higher than that of the cohort of CP-NOS (47 years) (P = 0.01). Twenty-three cases (82%) of AIP showed PanIN, and 7 cases (25%) showed grade 2 PanIN. Grade 3 PanIN was identified in one case of AIP. There was no statistically significant difference in the number of cases with high-grade PanIN lesions between the cases of type 1 as opposed to type 2 AIP. In comparison to CP-NOS, a comparable percentage of patients with AIP had PanIN (82% of AIP cases vs 63% of CP-NOS cases) (P = NS) and PanIN 2 (25% AIP vs 20% CP-NOS) (P = NS). Of the 84 AIP cases at our institution (mean follow-up, 49 months), 2 cases of pancreatic carcinoma were identified 6 and 10 years after the diagnoses of AIP., Conclusions: These findings raise concern that AIP is associated with an elevated risk of malignancy and should prompt additional studies.

Pancreatic acinar cystadenomas (ACAs) are rare cystic lesions showing acinar differentiation with benign outcome. Although debated, ACAs are favored to be neoplastic and potentially the benign counterpart of acinar cystadenocarcinoma. We present the largest single institution series to date comprising 10 cases. The mean age was 49 years with a female predominance (M:F=1:2.3). Abdominal/flank pain was the most common presentation (n=6). Serum amylase/lipase and cyst fluid amylase were often elevated. All lesions had a benign outcome on follow-up (5 to 67 mo). The lesions were unilocular (n=3) or multilocular (n=7) with mean size of 3.8 cm (range, 2.9 to 5.0 cm) and 5.1 cm (range, 2.0 to 7.5 cm), respectively. Eight lesions were unifocal with locations as follows: head (n=2), head/neck (n=2), body (n=1), tail (n=1), predominantly extrapancreatic with a microscopic intrapancreatic component (n=1), and unspecified location (n=1). Two lesions were multifocal, involving the head/uncinate/body and pancreatic head, respectively. Two aspects of ACAs that may represent a diagnostic pitfall include the propensity for acinar epithelium to appear as nondescript flat/cuboidal epithelium (trypsin/chymotrypsin immunopositive) and epithelial heterogeneity, with focal mucinous and squamous epithelium, the latter particularly in multilocular variants. In addition, 2 cases with intracystic nodules were observed. Array comparative genomic hybridization performed on 1 of these cases showed multiple chromosomal gains involving 1p, 3p, 5q, 6p, 7q, 8, 10q, 11, 14, 20, and X. These findings provide preliminary evidence that ACAs represent a cystic neoplastic lesion.

Introduction: The prototypic pancreatic ductal adenocarcinoma shows small-caliber glands that are placed within an exuberant desmoplastic stromal reaction. A number of histologic patterns have been described, and the majority of these patterns are genetically and biologically related to conventional ductal adenocarcinomas. In this report we describe our experience with a heretofore undescribed histologic pattern of pancreatic adenocarcinoma that mimics intraductal papillary mucinous carcinoma, both morphologically and radiologically., Methods: We identified 10 cases of pancreatic adenocarcinoma with large-caliber malignant glands and an intraluminal papillary pattern. The demographic, clinical, radiologic, and outcome data were recorded. In addition to a review of the histologic features we also performed elastin stains, immunohistochemistry for selected oncogenes and tumor suppressor genes including SMAD4. Immunohistochemical staining for MUC proteins was also performed., Results: The median age of the patients was 67 years, and there were 6 women and 4 men. Grossly, the cut surface in 6 of these cases showed an admixture of solid and cystic areas. The papillary cystic architecture was intimately mixed with areas of conventional adenocarcinoma, the latter characterized by invasive small-caliber tubular structures. None of the tumors showed a pure papillary cystic pattern; however, in 8 cases, this was the predominant pattern (>50% of the tumor). The cysts and papillae were lined predominantly by tall columnar hypermucinous epithelium. Elastin fibers were not identified around these dilated malignant cysts and glands. The intratumoral stroma was paucicellular and hyalinized. Seven of the 10 tumors were negative for SMAD4. The lack of pericystic elastin fibers and loss of SMAD4 in the majority of cases argue against these lesions representing an intraductal papillary mucinous neoplasm. All 10 tumors stained for MUC1; focal MUC2 reactivity was noted in 1 case. The majority of cases were positive for MUC5AC (9/10) and MUC6 (8/10). Seven patients died of their disease, whereas 1 patient is alive with widely metastatic disease. Two patients were lost to follow up., Conclusions: The adenocarcinoma described herein is a unique morphologic pattern of pancreatic ductal adenocarcinoma. The biology and genetics (as estimated by immunohistochemistry) are no different from that of conventional ductal adenocarcinoma but are distinctly different from that of an intraductal papillary mucinous carcinoma, its closest morphologic mimic.

Purposes: To test the hypothesis that extensive use of La MaMa vocal technique may result in symptoms of vocal abuse, an evaluation of the acoustic and perceptual characteristics of voice for eight performers from the Great Jones Repertory Company of the La MaMa Experimental Theater was conducted. This vocal technique includes wide ranges of frequency from 46 to 2003 Hz and vocal intensity that is sustained at 90-108 dB sound pressure level with a mouth-to-microphone distance of 30 cm for 3-4 hours per performance., Methods: The actors rehearsed for 4 hours per day, 5 days per week for 14 weeks before the series of performances. Thirty-nine performances were presented in 6 weeks. Three pretraining, three posttraining, and two postperformance series data collection sessions were carried out for each performer. Speech samples were gathered using the CSL 4500 and analyzed using Real-Time Pitch program and Multidimensional Voice Program. Acoustic analysis was performed on 48 tokens of sustained vowel phonation for each subject. Statistical analysis was performed using the Friedman test of related samples. Perceptual analysis included professional listeners rating voice quality in pretraining, posttraining, and postperformance samples of the Rainbow Passage and sample lines from the plays., Results: The majority of professional listeners (11/12) judged that this technique would result in symptoms of vocal abuse; however, acoustic data revealed statistically stable or improved measurements for all subjects in most dependent acoustic variables when compared with both posttraining and postperformance trials., Conclusion: These findings add support to the notion that a technique that may be perceived as vocally abusive, generating 90-100 dB sound pressure level and sustained over 6 weeks of performances, actually resulted in improved vocal strength and flexibility., (Copyright © 2011 The Voice Foundation. Published by Mosby, Inc. All rights reserved.)

Chronic widespread pain (CWP) due to musculoskeletal conditions is a major social burden. The case definition of CWP relies on pain, chronicity (more than 3 months' duration) and widespread distribution (both sides of the body including the axial skeleton). Health Interview Survey (HIS) and Health Examination Survey (HES) have been used to assess the frequency of CWP in the general population. Unfortunately, both techniques are poorly standardised, which hampers comparison of data pertaining to different populations and countries. A major effort in the European Union (EU) is the development of common strategies to investigate musculoskeletal pain through HIS. Issues to be addressed include: (1) loss of daily life functions due to pain; (2) pain duration and rhythm; (3) affected sites; and (4) type of pain. We know that musculoskeletal pain affects between 13.5% and 47% of the general population, with CWP prevalence varying between 11.4% and 24%. Risk factors for musculoskeletal pain include age, gender, smoking, low education, low physical activity, poor social interaction, low family income, depression, anxiety and sleep disorders, as well as performing manual work, being a recent immigrant, non-Caucasian and widowed, separated or divorced., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: The genetics of advanced biliary tract cancers (BTC), which encompass intra- and extra-hepatic cholangiocarcinomas as well as gallbladder carcinomas, are heterogeneous and remain to be fully defined., Methods: To better characterize mutations in established known oncogenes and tumor suppressor genes we tested a mass spectrometric based platform to interrogate common cancer associated mutations across a panel of 77 formalin fixed paraffin embedded archived BTC cases., Results: Mutations among three genes, KRAS, NRAS and PIK3CA were confirmed in this cohort. Activating mutations in PIK3CA were identified exclusively in GBC (4/32, 12.5%). KRAS mutations were identified in 3 (13%) intra-hepatic cholangiocarcinomas and 1 (33%) perihillar cholangiocarcinoma but were not identified in gallbladder carcinomas and extra-hepatic cholangiocarcinoma., Conclusions: The presence of activating mutations in PIK3CA specifically in GBC has clinical implications in both the diagnosis of this cancer type, as well as the potential utility of targeted therapies such as PI3 kinase inhibitors.

Autoimmune pancreatitis (AIP) is a chronic inflammatory disease of the pancreas. Examination of pancreatic resection specimens from patients with AIP has shown that there are 2 subclasses of this disease. However, there is no widely accepted pathologic classification scheme and the clinical significance of such a classification remains to be established. In this study, we revisited the subclassification of AIP and examine whether this provides clinically and prognostically meaningful information. We evaluated 29 pancreatic resection specimens from patients with AIP. Demographic, clinical, and imaging data were recorded, as was evidence of extrapancreatic manifestations. In addition to a detailed and semiquantitative histologic evaluation, immunohistochemistry for IgG4 was performed on pancreatic and extrapancreatic tissues. We also evaluated 48 consecutive cases of chronic pancreatitis, not otherwise specified. The resected specimens could readily be subclassified into 2 subtypes: type 1 (n=11) and type 2 (n=18). In comparison with patients with type 2 disease, patients with type 1 disease were significantly more likely to be males (P=0.09), older (P=0.02), and present with jaundice (P=0.01), and less likely to be associated with abdominal pain (P=0.04). On imaging, the pancreatic tail cut-off sign was exclusively seen in patients with type 2 disease (4 of 10 cases). Hypercellular inflamed interlobular stroma was unique to type 1 pattern (91%), whereas significant ductal injury in the form of microabscesses and ductal ulceration was almost exclusively seen in type 2 pattern (78%). Eight of 10 patients with a type 1 pattern had evidence of a systemic disease. Three patients with type 2 disease had recurrent episodes of pancreatitis after their pancreatic resection. In comparison with the cohort of chronic pancreatitis, not otherwise specified, type 2 AIP cases were less likely to be associated with a history of alcohol abuse, and showed significantly more foci of periductal inflammation and neutrophilic microabscesses. Our review of pancreatic resection specimens shows 2 histologically distinct forms of AIP. Our data support the concept that type 1 AIP is a systemic disease and is the pancreatic manifestation of IgG4-related systemic disease. Type 2 disease is confined to the pancreas. The intensity of the periductal inflammatory infiltrate and the presence of ductal neutrophilic abscesses are features that assist in distinguishing type 2 AIP from chronic pancreatitis, not otherwise specified. Although imperfect, clinical and imaging features may help distinguish the 2 subtypes of AIP. On the basis of these significant differences between the 2 types of AIP, we advocate the position that all subsequent studies attempt to substratify their patients into these 2 groups.

Several connective tissue diseases, in particular systemic sclerosis (SSc), have Raynaud's phenomenon (RP) as their first clinical manifestation. Primary RP represents a benign condition often observed in otherwise healthy subjects, especially women: it is due to an exaggerated response to the physiological cold-induced vasospasm, whereas the secondary form of RP is typically associated with connective tissue diseases, especially SSc. Nailfold videocapillaroscopy (NVC), particulary after the recent technological advances, is a safe and reliable method to observe the microvascular structure and its early changes, especially during the transition from primary to secondary RP. In case of SSc, by considering validated patterns and scoring systems, NVC is the main tool that rheumatologists can rely on, besides the presence of specific auto-antibodies, to perform a very early diagnosis of the disease. This implies the possibility of early treatment of SSc, with an eye of predicting and preventing its major clinical complications.

Histopathologic examination reveals that most human tumors are associated with diverse immune cell infiltrates, but the roles of host reactions in disease pathogenesis and prognosis remain to be fully clarified. Recent investigations in genetically engineered murine tumor models have uncovered dual functions for immune responses during cancer development and progression. Alterations in tumor cell gene expression profiles and coding sequences may trigger the activation of cytotoxic lymphocytes, which act to restrain tumor growth. In contrast, persistent inflammatory reactions, which may be driven by infection, environmental toxins, or impaired immune regulation, create a microenvironment that fosters tumor cell growth, survival, invasion, and dissemination. The dynamic interplay of these competing responses appears to be a critical event in cancer pathogenesis, with tumor promotion and immune evasion proving dominant in clinically evident disease. Nonetheless, longitudinal studies of patient cohorts have demonstrated that particular histopathologic and genetic signatures of cytotoxic lymphocyte reactions provide important prognostic information. Here, we discuss the dual roles of immunity in cancer development, focusing on gastrointestinal malignancies, given the depth of recent insights into the mechanisms underlying these tumors.

Chondroitin sulfate proteoglycan 4 (CSPG4), also known as High Molecular Weight-Melanoma Associated Antigen, is a cell surface proteoglycan which has been recently shown to be expressed not only by melanoma cells, but also by various types of human carcinoma and sarcoma. Furthermore, at least in squamous cell carcinoma of head and neck and in basal breast carcinoma, CSPG4 is expressed by cancer stem cells. CSPG4 plays an important role in tumor cell growth and survival. These CSPG4-associated functional properties of tumor cells are inhibited by CSPG4-specific monoclonal antibodies (mAb) in vitro. Moreover, CSPG4-specific mAb can also inhibit tumor growth and metastasis in vivo. The anti-tumor effects of CSPG4-specific mAb are likely to reflect the blocking of important migratory, mitogenic and survival signaling pathways in tumor cells. These results indicate that CSPG4 is a promising new target to implement mAb-based immunotherapy of various types of cancer.

Optical coherence tomography (OCT) has recently become one of the primary methods for noninvasive probing of the human retina. The pseudoimage formed by OCT (the so-called B-scan) varies probabilistically across pixels due to complexities in the measurement technique. Hence, sensitive automatic procedures of diagnosis using OCT may exploit statistical analysis of the spatial distribution of reflectance. In this paper, we perform a statistical study of retinal OCT data. We find that the stretched exponential probability density function can model well the distribution of intensities in OCT pseudoimages. Moreover, we show a small, but significant correlation between neighbor pixels when measuring OCT intensities with pixels of about 5 microm. We then develop a simple joint probability model for the OCT data consistent with known retinal features. This model fits well the stretched exponential distribution of intensities and their spatial correlation. In normal retinas, fit parameters of this model are relatively constant along retinal layers, but varies across layers. However, in retinas with diabetic retinopathy, large spikes of parameter modulation interrupt the constancy within layers, exactly where pathologies are visible. We argue that these results give hope for improvement in statistical pathology-detection methods even when the disease is in its early stages.

Objective: To investigate possible correlations between fingertip blood perfusion (FBP) status, assessed by laser Doppler flowmetry (LDF), and morphological microvascular abnormalities, detected by nailfold videocapillaroscopy (NVC), in patients with systemic sclerosis (SSc). The effects on FBP of intravenous (IV) treatment with the prostacyclin analog iloprost were also investigated., Methods: Thirty-four consecutive patients with SSc and 16 healthy subjects were evaluated. LDF was performed by analyzing blood perfusion at the fingertips in both hands. Patients with SSc were distributed into the appropriate NVC pattern of microangiopathy (early, active, and late). Iloprost was administered to inpatients with SSc by 24-hour IV infusion for 7 consecutive days (4 microg/h)., Results: FBP was significantly lower in patients with SSc (p < 0.05) compared to controls. Heating of the LDF probe at 36 degrees C induced a significant increase of FBP in all subjects (p < 0.001), but the slope of variation was significantly lower in patients with SSc compared to controls (p < 0.05). Patients with SSc showing the late NVC pattern of microangiopathy had significantly lower FBP than patients with the active and early NVC patterns (p < 0.05). A negative correlation was observed between FBP and NVC rating of the microvascular damage (p < 0.05). After iloprost treatment, a significant increase of FBP was observed in patients with SSc (p < 0.05)., Conclusion: Patients with SSc show a decreased FBP partially reversible by local skin heating. The FBP correlated negatively with the extent of nailfold microvascular damage, and IV iloprost treatment increased the FBP.

Objective: To describe the management and impact of pancreatic fistulas in a high-volume center., Design: Retrospective case series., Setting: Tertiary academic center., Patients: Five hundred eighty-one consecutive patients who underwent pancreaticoduodenectomy from January 2001 through June 2006., Main Outcome Measures: Development of a pancreatic fistula (defined as > 30 mL of amylase-rich fluid from drains on or after postoperative day 7, or discharge with surgical drains in place, regardless of amount); the need for additional interventions or total parenteral nutrition; other morbidity; and mortality., Results: Seventy-five patients (12.9%) developed a pancreatic fistula. Fistulas were managed with gradual withdrawal of surgical drains. This allowed for patient discharge and eventual closure at a mean of 18 days in 38.7% of cases; these were classified as low-impact fistulas. The remaining 46 patients (61.3%) had an associated abscess, required percutaneous drainage or total parenteral nutrition, or developed bleeding; these were classified as high-impact fistulas and closed a mean of 35 days after surgery. Standard 30-day in-hospital mortality was 1.9% for all pancreaticoduodenectomies and 6.7% for those who developed a pancreatic fistula. The overall fistula-related mortality was 9.3% (7 patients), all but 1 of which was related to major hemorrhage., Conclusions: More than one-third of pancreatic fistulas are clinically insignificant (low impact). The remaining 60% of fistulas have a high clinical impact and nearly an 8-fold increase in overall mortality.

This study documents the vocal characteristics of an actor before and after a series of eight performances involving extended voice use. The hypothesis was that this type of extended voice use would result in symptoms of vocal abuse and that damage to the actor's voice would be evident in measures made after the performance series. Three pre-performance and three post-performance speech samples were gathered and analyzed using the CSL and Visipitch II. Measurements taken included maximum phonational range; maximum sustained phonation; fundamental frequency during reading; maximum intensity levels; sound pressure levels for soft, moderate, and loud productions of sustained /a/; and perturbation including jitter, shimmer, harmonics-to-noise ratio, and an s/z ratio. Pre- and post-performance samples of the "Rainbow passage" and sustained vowel phonation were rated by a group of blinded listeners that included professional voice trainers and speech pathologists. In addition, sample lines from the performance were played for the listeners to judge whether this technique would result in symptoms of vocal abuse. Eleven out of 12 professional voice trainers rated that this technique would result in symptoms of vocal abuse. The data revealed post-performance improvement in phonational range, maximum intensity levels, perturbation measures, and s/z ratio. Measures of maximum sustained phonation, fundamental frequency, and sound pressure levels remained stable. Videoendoscopy revealed normal function of the larynx and vocal folds.

Eigtheen patients affected by metastatic renal cell carcinoma, 16 which were assesable, were treated with 1 g/m2 of Gemcitabine (GCB) on days 1, 8 and 15 of a 28-day treatment cycle up to a maximun of ten cycles. All patients in neoplastic progression were treated with chemo- and immunotherapy (5 FU, IL-2, IFN alpha d 13-cis-retinoic acid.) Out of the 16 assessable patients, 5/16 (31%) showed overall response (ICR, 4 PR), 5 (31%) stable disease (SD) and 6 (38%) progression of disease (PD). Toxicity was limited to WHO grades I only, primarily hematological.

nm23 genes encode proteins that participate in tumor metastasis regulation and in various fundamental cellular processes, although the mechanisms remain undefined. All Nm23 proteins contain nucleoside diphosphate kinase (NDPK) activity whose significance to these regulatory effects is not yet evident. The protein product of the human nm23-H2 gene functions in vitro both as a nucleoside diphosphate kinase enzyme (NDPK-B; Gilles, A.-M., Presecan, E., Vonica, A. and Lascu, I. (1991) J. Biol. Chem. 266, 8784-8789) and as a transcription factor (PuF; Postel, E. H., Berberich, S. J., Flint, S. J. and Ferrone, C. A. (1993) Science 261, 478-480). To understand the significance of these two biochemical activities to NM23-H2 function, we have investigated the relationship between the DNA binding and transcriptional activity of NM23-H2 and its NDPK function. Using site-directed mutagenesis of the cDNA encoding NM23-H2, we have created a mutant substituting for the amino acid histidine 118, the presumed site of phosphorylation in the formation of the phosphoenzyme intermediate, the nonphosphorylatable amino acid phenylalanine. The H118F mutant protein is shown to be catalytically inactive as measured both in a radioisotopic assay that detects formation of the phosphorylated enzyme intermediate and in a coupled enzyme assay that indicates nucleoside diphosphate formation. These results confirm that histidine 118 is the critical residue for NDPK-B activity. In addition, the H118F mutant protein lacking enzymatic activity displayed normal DNA binding affinity for the c-myc promoter in electrophoretic mobility shift assays, and retained full transcriptional activity using the c-myc gene in vitro. These results indicate a lack of correlation between nucleoside diphosphate kinase activity of nm23-H2 on the one hand, and its DNA binding and transcriptional activity on the other, suggesting that the nm23-H2 gene encodes a bifunctional protein molecule.

A human gene encoding the c-myc purine-binding transcription factor PuF was identified by screening of a cervical carcinoma cell complementary DNA library with a DNA fragment containing PuF binding sites. The 17-kilodalton bacterially produced PuF was shown to have biological activity and properties similar to that of human PuF. DNA sequence analysis of recombinant PuF revealed perfect identity with the human nm23-H2 nucleoside diphosphate kinase gene, a potential negative regulator of cancer metastasis. These results provide a link between nm23 and the c-myc oncogene and suggest that the nm23 protein can function in vitro in the transcriptional regulation of c-myc expression.