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IgG4-related disease (IgG4-RD) can cause fibroinflammatory lesions in nearly any organ. Correlation among clinical, serological, radiological and pathological data is required for diagnosis. This work was undertaken to develop and validate an international set of classification criteria for IgG4-RD. An international multispecialty group of 86 physicians was assembled by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR). Investigators used consensus exercises; existing literature; derivation and validation cohorts of 1879 subjects (1086 cases, 793 mimickers); and multicriterion decision analysis to identify, weight and test potential classification criteria. Two independent validation cohorts were included. A three-step classification process was developed. First, it must be demonstrated that a potential IgG4-RD case has involvement of at least one of 11 possible organs in a manner consistent with IgG4-RD. Second, exclusion criteria consisting of a total of 32 clinical, serological, radiological and pathological items must be applied; the presence of any of these criteria eliminates the patient from IgG4-RD classification. Third, eight weighted inclusion criteria domains, addressing clinical findings, serological results, radiological assessments and pathological interpretations, are applied. In the first validation cohort, a threshold of 20 points had a specificity of 99.2% (95% CI 97.2% to 99.8%) and a sensitivity of 85.5% (95% CI 81.9% to 88.5%). In the second, the specificity was 97.8% (95% CI 93.7% to 99.2%) and the sensitivity was 82.0% (95% CI 77.0% to 86.1%). The criteria were shown to have robust test characteristics over a wide range of thresholds. ACR/EULAR classification criteria for IgG4-RD have been developed and validated in a large cohort of patients. These criteria demonstrate excellent test performance and should contribute substantially to future clinical, epidemiological and basic science investigations.

Hanna Jokinen tutkimusryhmän jäsenenä (VICCCS Grp) Introduction: Progress in understanding and management of vascular cognitive impairment (VCI) has been hampered by lack of consensus on diagnosis, reflecting the use of multiple different assessment protocols. A large multinational group of clinicians and researchers participated in a two-phase Vascular Impairment of Cognition Classification Consensus Study (VICCCS) to agree on principles (VICCCS-1) and protocols (VICCCS-2) for diagnosis of VCI. We present VICCCS-2. Methods: We used VICCCS-1 principles and published diagnostic guidelines as points of reference for an online Delphi survey aimed at achieving consensus on clinical diagnosis of VCI. Results: Six survey rounds comprising 65-79 participants agreed guidelines for diagnosis of VICCCS-revised mild and major forms of VCI and endorsed the National Institute of Neurological Disorders-Canadian Stroke Network neuropsychological assessment protocols and recommendations for imaging. Discussion: The VICCCS-2 suggests standardized use of the National Institute of Neurological Disorders-Canadian Stroke Network recommendations on neuropsychological and imaging assessment for diagnosis of VCI so as to promote research collaboration. (C) 2017 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

OBJECTIVE: To investigate if the association between MRI-detectable white matter hyperintensity (WMH) and cognitive status reported in previous studies persists at older ages (>80 years), when some white matter abnormality is almost universally reported in clinical practice. METHODS: Consecutive eligible patients from a population-based cohort of all TIA/nondisabling stroke (Oxford Vascular Study) underwent multimodal MRI, including fluid-attenuated inversion recovery and diffusion-weighted imaging, allowing automated measurement of WMH volume, mean diffusivity (MD), and fractional anisotropy (FA) in normal-appearing white matter using FSL tools. These measures were related to cognitive status (Montreal Cognitive Assessment) at age ≤80 vs >80 years. RESULTS: Of 566 patients (mean [range] age 66.7 [20-102] years), 107 were aged >80 years. WMH volumes and MD/FA were strongly associated with cognitive status in patients aged ≤80 years (all p < 0.001 for WMH, MD, and FA) but not in patients aged >80 years (not significant for WMH, MD, and FA), with age interactions for WMH volume (p interaction = 0.016) and MD (p interaction = 0.037). Voxel-wise analyses also showed that lower Montreal Cognitive Assessment scores were associated with frontal WMH in patients ≤80 years, but not >80 years. CONCLUSION: MRI markers of white matter damage are strongly related to cognition in patients with TIA/minor stroke at younger ages, but not at age >80 years. Clinicians and patients should not overinterpret the significance of these abnormalities at older ages.

Background: There are no established guidelines for pathologic diagnosis/reporting of intraductal papillary mucinous neoplasms (IPMNs). Design: An international multidisciplinary group, brought together by the Verona Pancreas Group in Italy-2013, was tasked to devise recommendations. Results: (1) Crucial to rule out invasive carcinoma with extensive (if not complete) sampling. (2) Invasive component is to be documented in a full synoptic report including its size, type, grade, and stage. (3) The term "minimally invasive" should be avoided; instead, invasion size with stage and substaging of T1 (1a, b, c; ≤0.5, >0.5-≤1, >1 cm) is to be documented. (4) Largest diameter of the invasion, not the distance from the nearest duct, is to be used. (5) A category of "indeterminate/(suspicious) for invasion" is acceptable for rare cases. (6) The term "malignant" IPMN should be avoided. (7) The highest grade of dysplasia in the non-invasive component is to be documented separately. (8) Lesion size is to be correlated with imaging findings in cysts with rupture. (9) The main duct diameter and, if possible, its involvement are to be documented; however, it is not required to provide main versus branch duct classification in the resected tumor. (10) Subtyping as gastric/intestinal/pancreatobiliary/oncocytic/mixed is of value. (11) Frozen section is to be performed highly selectively, with appreciation of its shortcomings. (12) These principles also apply to other similar tumoral intraepithelial neoplasms (mucinous cystic neoplasms, intra-ampullary, and intrabiliary/cholecystic). Conclusions: These recommendations will ensure proper communication of salient tumor characteristics to the management teams, accurate comparison of data between analyses, and development of more effective management algorithms.

Objective IgG4-related disease (IgG4-RD) can cause fibroinflammatory lesions in nearly any organ. Correlation among clinical, serologic, radiologic, and pathologic data is required for diagnosis. This work was undertaken to develop and validate an international set of classification criteria for IgG4-RD. Methods An international multispecialty group of 86 physicians was assembled by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR). Investigators used consensus exercises, existing literature, derivation and validation cohorts of 1,879 subjects (1,086 cases, 793 mimickers), and multicriterion decision analysis to identify, weight, and test potential classification criteria. Two independent validation cohorts were included. Results A 3-step classification process was developed. First, it must be demonstrated that a potential IgG4-RD case has involvement of at least 1 of 11 possible organs in a manner consistent with IgG4-RD. Second, exclusion criteria consisting of a total of 32 clinical, serologic, radiologic, and pathologic items must be applied; the presence of any of these criteria eliminates the patient from IgG4-RD classification. Third, 8 weighted inclusion criteria domains, addressing clinical findings, serologic results, radiology assessments, and pathology interpretations, are applied. In the first validation cohort, a threshold of 20 points had a specificity of 99.2% (95% confidence interval [95% CI] 97.2-99.8%) and a sensitivity of 85.5% (95% CI 81.9-88.5%). In the second, the specificity was 97.8% (95% CI 93.7-99.2%) and the sensitivity was 82.0% (95% CI 77.0-86.1%). The criteria were shown to have robust test characteristics over a wide range of thresholds. Conclusion ACR/EULAR classification criteria for IgG4-RD have been developed and validated in a large cohort of patients. These criteria demonstrate excellent test performance and should contribute substantially to future clinical, epidemiologic, and basic science investigations.

Solid pseudopapillary neoplasms (SPN) of the pancreas are rare, low‐grade malignant neoplasms that metastasise to the liver or peritoneum in 10–15% of cases. They almost invariably present somatic activating mutations of CTNNB1. No comprehensive molecular characterisation of metastatic disease has been conducted to date. We performed whole‐exome sequencing and copy‐number variation (CNV) analysis of 10 primary SPN and comparative sequencing of five matched primary/metastatic tumour specimens by high‐coverage targeted sequencing of 409 genes. In addition to CTNNB1‐activating mutations, we found inactivating mutations of epigenetic regulators (KDM6A, TET1, BAP1) associated with metastatic disease. Most of these alterations were shared between primary and metastatic lesions, suggesting that they occurred before dissemination. Differently from mutations, the majority of CNVs were not shared among lesions from the same patients and affected genes involved in metabolic and pro‐proliferative pathways. Immunostaining of 27 SPNs showed that loss or reduction of KDM6A and BAP1 expression was significantly enriched in metastatic SPNs. Consistent with an increased transcriptional response to hypoxia in pancreatic adenocarcinomas bearing KDM6A inactivation, we showed that mutation or reduced KDM6A expression in SPNs is associated with increased expression of the HIF1α‐regulated protein GLUT1 at both primary and metastatic sites. Our results suggest that BAP1 and KDM6A function is a barrier to the development of metastasis in a subset of SPNs, which might open novel avenues for the treatment of this disease. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Objective Posterior cortical atrophy (PCA) is a neurodegenerative syndrome characterised by progressive impairment in visuospatial and perceptual function. Recent findings show that memory functioning can also be compromised early in the course of disease. In this study, we investigated the neural basis of memory impairment in PCA, and hypothesised that correlations would be observed with parietal cortex rather than classic medial temporal memory structures. Methods Eighteen PCA patients, 15 typical Alzheimer's disease (tAD) patients and 21 healthy controls underwent memory testing with the Rey Auditory Verbal Learning Test (RAVLT) word list and MRI. Voxel-based morphometry (VBM) was used to identify regions in the parietal and medial temporal lobes that correlated with memory performance. Results Compared with controls, PCA patients were impaired at learning, immediate and delayed recall and recognition of the RAVLT. Learning rate and immediate recall was significantly better in PCA compared to tAD, whereas there was no difference in delayed recall. Recognition memory also was not statistically different between patient groups, but PCA patients made significantly more false positive errors than tAD patients. VBM analysis in the PCA patients revealed a significant correlation between total learning and grey matter density in the right supramarginal gyrus, right angular gyrus and left postcentral gyrus. The left post central gyrus also significantly correlated with immediate and delayed recall and with recognition memory. No correlations were detected in the medial temporal lobe. Conclusions The findings provide novel evidence that early verbal memory impairment is frequently observed in PCA, and is associated with damage to lateral parietal structures. The results have implications for the diagnosis and management of PCA., Highlights • PCA patients were impaired in learning, recall and recognition memory. • Deficits were evident in the early stages of disease. • Memory impairment was associated with damage to lateral parietal structures. • No correlations were detected in the medial temporal lobe.

This paper gives practical guidelines for diagnosis and treatment of chronic pancreatitis. Statements have been elaborated by working teams of experts, by searching for and analysing the literature, and submitted to a consensus process by using a Delphi modified procedure. The statements report recommendations on clinical and nutritional approach, assessment of pancreatic function, treatment of exocrine pancreatic failure and of secondary diabetes, treatment of pain and prevention of painful relapses. Moreover, the role of endoscopy in approaching pancreatic pain, pancreatic stones, duct narrowing and dilation, and complications was considered. Recommendations for most appropriate use of various imaging techniques and of ultrasound endoscopy are reported. Finally, a group of recommendations are addressed to the surgical treatment, with definition of right indications, timing, most appropriate procedures and techniques in different clinical conditions and targets, and clinical and functional outcomes following surgery. © 2010 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. Keywords: Pancreatitis, chronic; Complications; Surgery; Radiography; Therapy; Ultrasonography; Cholangiopancreatography

Impaired visuospatial associative memory may be one of the earliest changes predicting cognitive impairment and Alzheimers disease. We explored the relationship between performance on a visuospatial associative memory task (the Placing Test) and brain structure and function in cognitively healthy older adults. First, we performed a voxel-based morphometry correlational analysis on structural magnetic resonance imaging (MRI) data from 144 healthy older adults with their scores on the Placing Test. Second, we carried out a functional MRI study on another group of 28 healthy older adults who performed a similar task during functional MRI. Decreased performance on the Placing Test was associated with increased atrophy in medial-temporal regions. Functional activation of the same regionscontrolling for the effect of atrophyoccurred during successful performance of the same task. The colocalization of structural and functional MRI correspondents of visuospatial associative test performance within medial-temporal regions validates multimodal imaging in describing behaviorally relevant variability in the aging brain and suggests that the Placing Test has the potential for detecting early cognitive changes occurring in preclinical phases of Alzheimer's disease. © 2013 Elsevier Inc.

The Italian Group of Gastrointestinal Pathologists has named a committee to develop recommendations concerning the surgical pathology report for pancreatic cancer. The committee, formed by individuals with special expertise, wrote the recommendations, which were reviewed and approved by council of the Group. The recommendations are divided into several areas including an informative gross description, gross specimen handling, histopathologic diagnosis, immunohistochemistry, molecular findings, and a checklist. The purpose of these recommendations is to provide a fully informative report for the clinician.

Osteogenesis Imperfecta is a genetic disorder of increased bone fragility and low bone mass. Most cases are caused by a mutation in one of the two genes coding for the type I collagen protein. The correct clinical diagnosis of OI can be difficult sometimes, because of the wide phenotypic range. Therefore collagen I genes mutation identification can be helpful. We screened 23 patients by direct sequencing of the exons encoding the collagen protein. We identified 18 different mutations, while 5 cases were negative because of an uncertain clinical diagnosis or an atypical form of OI not related to collagen I genes. The current medical and pharmaceutical treatments are only symptomatic and do not alter the course of collagen mutations. Cells and gene therapies as potential treatments for OI have therefore to be actively investigated.

Endometriosis represents a common and important clinical problem of women of childbearing age. It is a disabling disorder manifesting with pain and infertility. The exact pathogenesis of the disease remains unclear, despite the different theories that have been formulated. The literature on endometriosis is extensive, but often in regard to classic endometrioma. It is surprising that, to the best of our knowledge, the many radiologic features of extraovarian endometriosis have not been well documented thus far. Although ultrasound (US) remains the imaging modality of choice in the radiologic evaluation of female patients with pelvic pain, the role of magnetic resonance imaging (MRI) in the evaluation of abdominal pain is expanding. In the young patient, MRI may be performed if a gynecologic disorder is not suspected at first, especially if US findings are equivocal or the abnormality extends beyond the field of view of the sonographic probe. Moreover, MRI is useful whenever further characterization of pelvic disorder is required. In fact, many causes of pelvic disorders and of endometriosis in particular demonstrate characteristic MRI findings. For these reasons, in this work we describe the protean US and MRI appearances of endometrial foci as encountered in daily experience.

A high resolution allelotype for nonfunctional pancreatic endocrine tumors (NF-PETs) has been generated by microsatellite analysis of DNA from 16 frozen cases, each probed with 394 markers. Two subgroups of NF-PETs were found. Seven cases showed frequent, large allelic deletions [loss of heterozygosity (LOH)] with an average fractional allelic loss (FAL) of 0.55, whereas nine cases showed a small number of random losses with a FAL of 0.15. Designated high or low FAL, respectively, these genetic phenotypes showed correlation with the ploidy status: high-FAL tumors were aneuploid, low-FAL were diploid. Chromosomes 6q and 11q showed LOH in60% of cases. About 50% of cases had losses on 11p, 20q, and 21. Selected LOH analysis on an additional 16 paraffin-embedded NF-PETs confirmed the high frequency of 6q and 11q LOH. The allelotype of NF-PET is markedly different from that of either ductal or acinar tumors of the pancreas as well as from that of functional-PETs. Moreover, whereas deletions involving chromosome 11 also are a feature of functional-PETs, the involvement of chromosome 6q is characteristic of NF-PETs. Survival analysis showed that none of the single chromosomal alterations was associated with outcome, whereas ploidy status is an independent factor adding prognostic information to that furnished by the proliferative index measured by Ki-67 immunohistochemistry.

Progesterone receptors (PgR) have been immunocytochemically localized in the nuclei of several (40% to 75%) endocrine cells of the human pancreas and in a more variable number of neoplastic cells of 7 of 18 endocrine pancreatic tumors. Conversely the exocrine epithelial cells of the pancreas did not exhibit any PgR immunoreactivity in normal as well as in different pathologic conditions, including pancreatic adenocarcinomas. Estrogen receptors were not detected in any of the pancreatic samples investigated. Double immunocytochemical experiments have documented that PgR immunoreactivity in normal Langerhans islets is a consistent feature of most (75%) glucagon-producing A cells, of approximately 5% to 20% of insulin-producing B cells, and of a variable percentage of pancreatic polypeptide (PP)-producing cells, ranging from 5% to 70%. These figures were not affected by the sex, age, or underlying disease of the patients. The reported findings corroborate previous clinical and experimental evidence indicating that sex steroid hormones may have some regulatory effects on the functional activity of the endocrine pancreas.

White matter hyperintensities (WMH) are frequently divided into periventricular (PWMH) and deep (DWMH), and the two classes have been associated with different cognitive, microstructural, and clinical correlates. However, although this distinction is widely used in visual ratings scales, how to best anatomically define the two classes is still ambiguous. In fact, the methods used to define PWMH and DWMH vary significantly between studies, making results difficult to compare. The purpose of this study was twofold: first, to compare four current criteria used to define PWMH and DWMH in a cohort of healthy older adults (mean age: 69.58 ± 5.33 years) by quantifying possible differences in terms of estimated volumes; second, to explore associations between the two WMH sub-classes with cognition, tissue microstructure and cardiovascular risk factors, analyzing the impact of different criteria on the specific associations. Our results suggest that the classification criterion used for the definition of PWMH and DWMH should not be considered a major obstacle for the comparison of different studies. We observed that higher PWMH load is associated with reduced cognitive function higher mean arterial pressure and age. Higher DWMH load is associated with higher body mass index. PWMH have lower fractional anisotropy than DWMH, which also have more heterogeneous microstructure. These findings support the hypothesis that PWMH and DWMH are different entities and that their distinction can provide useful information about healthy and pathological aging processes.

Cancer of the papilla (ampulla) of Vater is an uncommon disease that kills 60% of affected patients. There is general agreement that local spread of the tumor (T stage) is the only significant and independent prognostic factor for this cancer, whereas the predictive value of tumor grade and lymph node metastases is controversial. The genetic anomalies involved in this process have the potential to serve as additional prognostic markers. We explored 25 ampullary cancers for the occurrence of instability at simple repeat DNA sequences (microsatellites) of the type seen in replication error phenotype (RER-positive) cancers. Ten microsatellites from five different chromosomes were amplified by PCR from both normal and cancer tissue DNA of the same patients. A tumor was defined as RER-positive when microsatellite instability was found in the majority (/=6) of the loci analyzed. Five cancers (20%) showed a RER phenotype and were associated with long survival of patients (32-96 months), whereas RER-negative cancers had a significantly poorer prognosis (Mantel-Cox test; P = 0.0084), with a median actuarial survival of 17 months. We also report that three (12%) patients belonged to cancer-prone families and four (16%) were cancer-prone individuals.

During our DNA fingerprinting studies of paired normal and pancreatic cancer tissues using arbitrarily primed PCR, we noticed a band showing an apparent homozygous deletion in a pancreatic cancer cell line and a decreased intensity in a number of primary cancers. That band was assigned to chromosome 7. Such information led us to analyze chromosome 7 loss of heterozygosity (LOH) in a panel of 12 cryostat-enriched primary pancreatic cancers and 2 pancreatic cancer cell lines, despite the reportedly low frequency of chromosome 7 LOH in xenograft-enriched pancreatic cancers. Seventeen PCR-amplified CA-microsatellite polymorphic sites were analyzed. One of the two cell lines and eight common-type cancers (including all five poorly differentiated and three of five moderately differentiated cancers) showed chromosome 7q LOH, whereas the two uncommon types of ductal cancer (one adenosquamous and one mucinous noncystic) scored negative. Our data suggest that chromosome 7q LOH is a frequent event (80%) in cryostat-enrichable common pancreatic ductal carcinomas, that is, those primarily of high cellularity. The chromosome 7q smallest common deleted region described by our cases was between 7q31.1 and 7q32.

Context.Lymphangioleiomyomatosis (LAM) is a cystic lung disease that can be included in the wide group of proliferative lesions named PEComas (perivascular epithelioid cell tumors). These proliferative tumors are characterized by the coexpression of myogenic and melanogenesis-related markers. In all these lesions, genetic alterations related to the tuberous sclerosis complex (TSC) have been demonstrated. Striking improvements in the understanding of the genetic basis of this autosomal dominant genetic disease are coupled to the understanding of the mechanisms that link the loss of TSC1 (9q34) or TSC2 (16p13.3) genes with the regulation of the Rheb/m-TOR/p70S6K pathway. These data have opened a new era in the comprehension of the pathogenesis of LAM and have also suggested new therapeutic strategies for this potentially lethal disease.Objective.To present and discuss the pathologic and molecular features of LAM within the spectrum of PEComas, providing a rational approach to their diagnosis.Data Sources.The published literature and personal experience.Conclusions.The inclusion of LAM within the PEComa category is supported by a variety of biologic data and can significantly help in providing a comprehensive view of this interesting and clinically relevant group of lesions. The demonstration of molecular alterations of the mTOR pathway in LAM and other PEComas represents a rational basis for innovative therapeutic approaches with inhibitors of mTOR signaling.

Thirty-four pancreatic adenocarcinomas were studied for the presence of p53 gene mutations by the single-strand conformation polymorphism method and by direct sequencing of PCR-amplified fragments. p53 protein expression was immunohistochemically evaluated using monoclonal PAb1801 and polyclonal CM1 antibodies. Mutations were detected in 14 cases. The transitions were six G to A and two A to G; the transversions were one C to G and two A to C; the remaining three were frameshift mutations. Immunostaining results were identical with both antibodies. Nuclear immunohistochemical p53-positive cells were found in nine p53 mutated cases and in 12 cases in which no mutation was detected. In most of these latter cases only a minority of cancer cells showed immunohistochemical positivity. Twenty-nine cases, including all p53 mutated cancers, were known to contain codon 12 Ki-ras gene mutations. Also in the light of the demonstrated cooperation of ras and p53 gene alterations in the transformation of cultured cells, our data suggest that p53 mutation is one of the genetic defects that may have a role in the pathogenesis of a proportion of pancreatic cancers.

Eleven tumors of the ampulla of Vater (5 stage IV and 2 stage II adenocarcinomas, 1 stage II papillary carcinoma, 1 neuroendocrine carcinoma, and 2 adenomas, one with foci of carcinoma) were examined for Ki-ras and p53 gene mutations by single-strand conformation polymorphism analysis and direct sequencing of polymerase chain reaction-amplified DNA fragments. Ki-ras mutations were found in one adenocarcinoma and in the adenoma with foci of carcinoma, both involving mainly the intraduodenal bile duct component of the ampulla. Seven cases showed p53 gene mutations: four advanced-stage adenocarcinomas, the papillary carcinoma, the neuroendocrine carcinoma, and the adenoma with foci of carcinoma. Nuclear accumulation of p53 protein was immunohistochemically detected in the morphologically high-grade areas of the five cancers harboring a p53 gene missense point mutation. The adenomas, the two frame shift-mutated cancers, and the adenomatous and low-grade cancer areas of mutated carcinomas were immunohistochemically negative. Our data suggest that in ampullary neoplasia 1) p53 mutations are common abnormalities associated with the transformation of adenomas and low-grade cancers into morphologically high-grade carcinomas, and 2) Ki-ras mutations are relatively less frequent and might be restricted to tumors originating from the bile duct component of the ampulla.

We examined 2 normal pancreata, 21 primary pancreatic ductal cancers, and 19 pancreatic cancer cell lines for Fhit expression and FHIT gene status. The normal pancreas expressed Fhit protein in the cytoplasm of ductular cells, whereas interlobular and larger ducts, acini, and insulae of Langerhans were negative. Fhit protein was detected by immunoblot assay in 11 pancreatic cancer cell lines; of the 8 cell lines lacking Fhit protein, 7 lacked FHIT mRNA and 1 showed an abnormally sized transcript. DNA from five of these eight cell lines showed homozygous loss of FHIT exon 5. In 8 of the 21 primary cancers, Fhit expression was detected by immunohistochemistry. Reverse transcription-PCR analysis of 6 of the 13 cases lacking Fhit showed normal-sized FHIT product in 3 cases and a mixture of normal and abnormal products in the other 3. Sequencing showed that abnormal bands were missing variable numbers of exons. Loss of microsatellite DNA markers internal to the FHIT gene was observed in 10 of 13 primary cancers lacking Fhit protein (homozygous in two cases) and in only 1 of the 8 cancers expressing Fhit protein. In nine primary cancers, four expressing and five lacking Fhit protein, it was possible to obtain pure cancer DNA by microdissection. Three of the five microdissected cases lacking Fhit protein exhibited homozygous deletion of FHIT exon 5. In conclusion, the lack of Fhit protein in pancreatic cancers correlated with absence or alteration of FHIT mRNA and was often associated with FHIT gene anomalies.

To gain a better understanding of the growth of athyreotic newborns in the first weeks of life, we evaluated auxological parameters and determined the serum levels of growth hormone (GH), insulin-like growth factor I (IGF-I) and free IGF-I, and IGF-binding protein-3 (IGFBP-3) in 15 hypothyroid infants (10 females) at a mean age of 25 d of life, immediately before the beginning of L-thyroxine therapy, and at 3 and 6 mo of life. Fourteen normal infants (9 females) of the same age were studied as controls. IGFBP-3 proteolytic activity was evaluated in 8 patients and in 8 controls at 25 d and 6 mo of life. There was no significant difference concerning weight and length between the patients and controls at birth, 25 d, 3 and 6 mo of life. The blood GH, IGF-I and IGFBP-3 levels were significantly lower in patients at diagnosis than in controls of the same age (p0.01 for all parameters), as well as IGFBP-3 studied by Western blotting. At diagnosis, the patients' free IGF-I level was within the control range, but the free IGF-I percentage of total IGF-I was higher than in the controls (p0.01). IGFBP-3 proteolytic activity was found to be greater in the patients (p0.01). At 6 mo of life, after therapy, none of these parameters was different from those of the controls.Increased IGFBP-3 proteolytic activity in our patients at diagnosis, favouring IGF-I bioavailability, could account for normal free IGF-I levels and in turn for their normal growth pattern during the first weeks of life and before the start of treatment.

Constitutional BRCA1/BRCA2 pathogenic or likely pathogenic variants (PVs) are associated with an increased risk for developing breast and ovarian cancers. Current evidence indicates that BRCA1/2 PVs are also associated with pancreatic cancer, and that BRCA2 PVs are associated with prostate cancer risk. The identification of carriers of constitutional PVs in the BRCA1/2 genes allows the implementation of individual and family prevention pathways, through validated screening programs and risk-reducing strategies. According to the relevant and increasing therapeutic predictive implications, the inclusion of BRCA testing in the routine management of patients with breast, ovarian, pancreatic and prostate cancers represent a key requirement to optimize medical or surgical therapeutic and prevention decision-making, and access to specific anticancer therapies. Therefore, accurate patient selection, the use of standardized and harmonized procedures, and adherence to homogeneous testing criteria, are essential elements to implement BRCA testing in clinical practice. This consensus position paper has been developed and approved by a multidisciplinary Expert Panel of 64 professionals on behalf of the AIOM-AIRO-AISP-ANISC-AURO-Fondazione AIOM-SIAPEC/IAP-SIBioC-SICO-SIF-SIGE-SIGU-SIU-SIURO-UROP Italian Scientific Societies, and a patient association (aBRCAdaBRA Onlus). The working group included medical, surgical and radiation oncologists, medical and molecular geneticists, clinical molecular biologists, surgical and molecular pathologists, organ specialists such as gynecologists, gastroenterologists and urologists, and pharmacologists. The manuscript is based on the expert consensus and reports the best available evidence, according to the current eligibility criteria for BRCA testing and counseling, it also harmonizes with current Italian National Guidelines and Clinical Recommendations.

none 33 no This report contains clinically oriented guidelines for the diagnostic work-up and follow-up of cystic pancreatic neoplasms in patients fit for treatment. The statements were elaborated by working groups of experts by searching and analysing the literature, and then underwent a consensus process using a modified Delphi procedure. The statements report recommendations regarding the most appropriate use and timing of various imaging techniques and of endoscopic ultrasound, the role of circulating and intracystic markers and the pathologic evaluation for the diagnosis and follow-up of cystic pancreatic neoplasms open Italian Association of Hospital Gastroenterologists and Endoscopists; Italian Association for the Study of the Pancreas; Buscarini E; Pezzilli R; Cannizzaro R; De Angelis C; Gion M; Morana G; Zamboni G; Arcidiacono P; Balzano G; Barresi L; Basso D; Bocus P; Calculli L; Capurso G; Canzonieri V; Casadei R; Crippa S; D'Onofrio M; Frulloni L; Fusaroli P; Manfredi G; Pacchioni D; Pasquali C; Rocca R; Ventrucci M; Venturini S; Villanacci V; Zerbi A; Falconi M; Cystic Pancreatic Neoplasm Study Group Italian Association of Hospital Gastroenterologists and Endoscopists; Italian Association for the Study of the Pancreas; Buscarini E; Pezzilli R; Cannizzaro R; De Angelis C; Gion M; Morana G; Zamboni G; Arcidiacono P; Balzano G; Barresi L; Basso D; Bocus P; Calculli L; Capurso G; Canzonieri V; Casadei R; Crippa S; D'Onofrio M; Frulloni L; Fusaroli P; Manfredi G; Pacchioni D; Pasquali C; Rocca R; Ventrucci M; Venturini S; Villanacci V; Zerbi A; Falconi M; Cystic Pancreatic Neoplasm Study Group

Background The possible benefit of frozen section (FS) analysis during (PD) for pancreatic ductal adenocarcinoma (PDAC) and of additional resection up to total pancreatectomy (TP) is debated. Aim of this work is to evaluate the prognostic role of positive FS analysis after PD for PDAC. Methods Multicentric retrospective analysis on prospective databases of three institutions. Based on FS analysis patients were classified as FS negative/FS positive. All positive FS patients underwent extended PD (EPD) or TP. Postoperative outcomes, disease-free (DFS) and disease-specific survival (DSS) were evaluated. Results Of 371 patients, 58 (16%) had positive FS. This resulted in 313 (84%) SPD (standard pancreatoduodenectomy), 22 (6%) EPD and 36 (10%) TP. Postoperative mortality was higher in patients undergoing TP (11% compared to 4.5% in EPD and 1% in SPD; p = 0.01). 26% of patients underwent neoadjuvant therapy, and it did not decrease the rate of positive FS. Systemic/local relapse rates were 59% and 41% in negative FS group, and 78% and 22% in positive FS group (p = 0.031). Median DFS and DSS were 20 and 37 months in negative FS group, and 12 and 23 months in positive FS patients (p = 0.001). Independent predictors of recurrence were G3, N1/N2 status and positive FS. R1 resection, G3, N1/N2 status, perineural invasion and positive FS were independent predictors of DSS. Conclusions Positive FS analysis is a poor prognostic factor after PD for PDAC. It is significantly associated with a high rate of R1 resection at final histology, PDAC recurrence and poor survival.

Background & Aims The risk of malignancy is uncertain for intraductal papillary mucinous neoplasms (IPMNs) with main pancreatic duct (MPD) of 5-9 mm. No study has correlated MPD size and malignancy considering the anatomic site of the gland (head versus body-tail). Our aim was to analyze the significance of MPD in pancreatic head/body-tail as a predictor of malignancy in main-duct/mixed IPMNs. Methods Retrospective analysis of resected patients between 2009-2018 was performed. Malignancy was defined as high-grade dysplasia and invasive carcinoma. MPD diameter was measured with magnetic resonance imaging. Receiver operating characteristic curve (ROC) analysis was utilized to identify optimal MPD cut-off for malignancy. Independent predictors of malignancy were searched. Results Malignancy was detected in 74% of 312 identified patients. 213 patients (68.3%) had IPMNs of the pancreatic head and 99 (31.7%) of the body-tail. ROC analysis identified 9 and 7 mm as the optimal MPD cut-offs for malignancy in IPMNs of head and body-tail of the pancreas, respectively. Multivariate analysis confirmed that MPD ≥9 mm (pancreatic head) and ≥7 mm (body-tail) were independent predictors of malignancy along with macroscopic solid components, positive cytology and elevated CA 19-9. The risk of malignancy was low for IPMNs with MPD ≤8 mm (pancreatic head) or ≤6 mm (pancreatic body-tail) unless high-risk stigmata or multiple worrisome features were present. Conclusions Different thresholds of MPD dilation are associated with malignancy in IPMNs of the head and body-tail of the pancreas. The risk of malignancy for IPMNs with MPD ≤8 mm (pancreatic head) or ≤6 mm (pancreatic body-tail) lacking high-risk stigmata or multiple worrisome features is low.

European Cancer Organisation Essential Requirements for Quality Cancer Care (ERQCC) are written by experts representing all disciplines involved in cancer care in Europe. They give patients, health professionals, managers and policymakers a guide to essential care throughout the patient journey. Pancreatic cancer is an increasing cause of cancer mortality and has wide variation in treatment and care in Europe. It is a major healthcare burden and has complex diagnosis and treatment challenges. Care must be carried out only in pancreatic cancer units or centres that have a core multidisciplinary team (MDT) and an extended team of health professionals detailed here. Such units are far from universal in European countries. To meet European aspirations for comprehensive cancer control, healthcare organisations must consider the requirements in this paper, paying particular attention to multidisciplinarity and patient-centred pathways from diagnosis, to treatment, to survivorship.

IntroductionBRCA tumour testing is a crucial tool for personalised therapy of patients with ovarian cancer. Since different next-generation sequencing (NGS) platforms and BRCA panels are available, the NGS Italian Network proposed to assess the robustness of different technologies.MethodsSix centres, using four different technologies, provided raw data of 284 cases, including 75 cases with pathogenic/likely pathogenic variants, for a revision blindly performed by an external bioinformatic platform.ResultsThe third-party revision assessed that all the 284 raw data reached good quality parameters. The variant calling analysis confirmed all the 75 pathogenic/likely pathogenic variants, including challenging variants, achieving a concordance rate of 100% regardless of the panel, instrument and bioinformatic pipeline adopted. No additional variants were identified in the reanalysis of a subset of 41 cases.ConclusionsBRCA tumour testing performed with different technologies in different centres, may achieve the realibility and reproducibility required for clinical diagnostic procedures.

Peptide Receptor Radionuclide Therapy (PRRT) is an emerging therapeutic option for pancreatic neuroendocrine tumors (PanNETs). A possible role for PRRT as a neoadjuvant agent is still largely undetermined, explored only in case reports or small case series. Likewise, the histopathological and immunophenotypic changes induced by PRRT are poorly characterized. In the present study, 24 patients who underwent neoadjuvant PRRT on the basis of their disease’s characteristics were retrospectively matched with 24 patients who underwent upfront surgery. A comprehensive morphological and immunohistochemical evaluation was conducted to identify the differences in the two groups. The most significant findings were that the total percentage of stroma increased significantly in patients who underwent PRRT (p < 0.0001) and the characteristics of the stroma were different in the two groups. The somatostatin receptors type 2A (SSTR2A) were retained in most patients (87%) after PRRT. The density of CD163+ M2-polarized macrophages was greater in the PRRT group (p = 0.022), and M2-polarized macrophages tended to assume an epithelioid morphology (p = 0.043). In the neoadjuvant PRRT group, none of the histological parameters considered were associated with progression-free survival (PFS). Neoadjuvant PRRT in PanNETs is associated with reduced tumor diameter, an increased percentage of stroma, preserved SSTR2A expression in most of the cases, and an increased CD163+ M2-polarized macrophages density.

Background There is an increased interest in venous vascular resection associated with pancreatic resection for pancreatic ductal adenocarcinoma as an upfront procedure or after neoadjuvant treatment. The aim of this study was to evaluate the impact of venous vascular resection for pancreatic ductal adenocarcinoma on postoperative and long-term outcomes. Methods The study is a retrospective analysis of patients who underwent pancreatectomy for pancreatic head pancreatic ductal adenocarcinoma with and without venous vascular resection between January 2010 and April 2018. The impact of venous vascular resection on postoperative and pathologic data was analyzed. Univariate and multivariate analyses of predictors of disease-free and disease-specific survival were analyzed for the entire cohort. A propensity-score matched cohort analysis was subsequently performed to remove selection bias and improve homogeneity. Results Four hundred and eighty-one patients were included, and 126 (26%) underwent a venous vascular resection. Patients undergoing venous vascular resection had higher morbidity (64% vs 54%; P = .026) with no differences in 90-day postoperative mortality (3.1 vs 2.8%; P = .5). Venous vascular resections were also significantly associated with R1 resections (52% vs 37%; P = .002) and perineural invasion (87% vs 77%; P = .017). Five-year disease-free survival in patients with and without venous vascular resection were 7% and 20% (P = .018), respectively. Independent predictors of worse disease-free survival included venous vascular resection, positive lymph node status, and perineural invasion. Independent predictors of worse disease-specific survival were perineural invasion and positive nodal status, while adjuvant treatment was a protective factor. Five-year disease-specific survival in patients with and without venous vascular resection were 19% and 35% (P = .42). Conclusion Pancreatectomy with venous vascular resection can be accomplished safely. Venous vascular resections are associated with poor prognostic factors and with a worse clinical outcome, being a significant predictor of cancer recurrence.

Summary Pancreatic malignant exocrine tumors represent the most important cause of cancer-related death for pancreatic neoplasms. The most common tumor type in this category is represented by pancreatic ductal adenocarcinoma (PDAC), an ill defined, stroma-rich, scirrhous neoplasm with glandular differentiation. Here we present the relevant characteristics of the most important PDAC variants, namely adenosquamous carcinoma, colloid carcinoma, undifferentiated carcinoma, undifferentiated carcinoma with osteoclast-like giant cells, signet ring carcinoma, medullary carcinoma and hepatoid carcinoma. The other categories of malignant exocrine tumors, characterized by fleshy, stroma-poor, circumscribed neoplasms, include acinar cell carcinoma (pure and mixed), pancreatoblastoma, and solid pseudopapillary neoplasms. The most important macroscopic, histologic, immunohistochemical and molecular hallmarks of all these tumors, highlighting their key diagnostic/pathological features are presented. Lastly, standardized indications regarding gross sampling and how to compile a formal pathology report for pancreatic malignant exocrine tumors will be provided.

Background: The most appropriate nodal staging for pancreatic neuroendocrine neoplasms (PanNENs) is unclear. Aim of the study was to evaluate the effect of the number of positive lymph nodes on prognosis after pancreaticoduodenectomy for PanNENs. Methods: A retrospective analysis of pancreaticoduodenectomies for nonfunctioning PanNENs was performed. PanNENs with nodal metastases (N+) were classified into N1 (1 to 3 positive lymph nodes) and N2 (4 or more positive lymph nodes). Univariate and multivariate analyses of disease-free survival were performed. Results: 157 patients were included. 99 patients (63%) had N0 PanNENs whereas 58 patients (37%) had nodal involvement (N+). Patients with N0 PanNENs had a 3-year disease-free survival rate of 89% compared with 83% and 75% in patients with N1 and N2 PanNENs, respectively (P < 0.0001). Independent predictors of disease-free survival were the presence of necrosis, lymph node ratio and nodal status. Factors positively correlated with the number of positive lymph nodes were the Ki67 value, the T stage and the number of examined lymph nodes. Similar percentage of N0 and N+ PanNENs was demonstrated for a cut-off of 13 examined lymph nodes. Conclusions: The number of positive lymph nodes is accurate in predicting recurrence for PanNENs. Thirteen examined lymph nodes seems to be the minimum number of lymph nodes to be resected/examined in patients who undergo pancreaticoduodenectomy for PanNENs.

Background/Aims: The annual incidence of pancreatic neuroendocrine tumors (PanNET) has been estimated to be around 0.8/100,000 inhabitants. The aim of this study was to determine the frequency of incidental histological diagnosis of PanNET in pancreatic specimen evaluation for a purpose other other than PanNET diagnosis. Methods: One thousand seventy-four histopathological examinations of pancreatic specimens performed in 3 centers in Italy were retrospectively reviewed. All cases with a main pathological diagnosis of PanNET were excluded. Results: An incidental associated diagnosis of PanNET was made in 41 specimens (4%). Among those 41 cases, 29 (71%) had a largest diameter p = 0.048). There was no association between incidental diagnosis of PanNET and age, gender, BMI, smoking habit, diabetes, and type of operation. Conclusions: The frequency of incidental histological diagnosis of PanNET is considerably high, suggesting that their real prevalence is probably underestimated. The present study suggests a possible correlation between the incidental occurrence of PanNET and IPMN.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease characterized by complex biological features and poor prognosis. A prognostic stratification of PDAC would help to improve patient management. The aim of this study was to analyse the expression of Ki-67 in relation to prognosis in a cohort of patients with PDAC who had surgical treatment.Patients who had pancreatic resection between August 2010 and October 2014 for PDAC at two Italian centres were reviewed retrospectively. Patients with metastatic or locally advanced disease, those who received neoadjuvant chemotherapy, patients with PDAC arising from intraductal papillary mucinous neoplasm and those with missing data were excluded. Clinical and pathological data were retrieved and analysed. Ki-67 expression was evaluated using immunohistochemistry and patients were stratified into three subgroups. Survival analyses were performed for disease-free (DFS) and disease-specific (DSS) survival outcomes according to Ki-67 expression and tumour grading.A total of 170 patients met the selection criteria. Ki-67 expression of 10 per cent or less, 11-50 per cent and more than 50 per cent significantly correlated with DFS and DSS outcomes (Ki-67 index could be of use in predicting the survival of patients with PDAC. Further investigation in larger cohorts is needed to validate these results.El adenocarcinoma ductal de páncreas (Se efectuó un análisis retrospectivo de pacientes sometidos a resección pancreática por PDAC en dos centros italianos entre agosto de 2010 y octubre de 2014. Se excluyeron los pacientes con enfermedad metastásica o localmente avanzada, los tratados con quimioterapia neoadyuvante, los pacientes con PDAC originado en una neoplasia papilar mucinosa intraductal y aquellos pacientes con datos incompletos. Se analizaron los datos clínicos y anatomopatológicos. La expresión de Ki‐67 se evaluó por inmunohistoquímica y los pacientes se estratificaron en tres grupos. Se calculó la supervivencia libre de enfermedad (Un total de 170 pacientes cumplió los criterios de selección. La expresión de Ki‐67 del ≤ 10%, 11‐50% y 50% mostró una correlación significativa con los resultados de DFS y DSS (El índice Ki‐67 se puede utilizar como predictor de supervivencia en pacientes con PDAC. Hace falta seguir investigando para validar estos resultados en cohortes más grandes.

Management of localized well-differentiated pancreatic neuroendocrine tumors (panNETs) is controversial and primarily dependent on tumor size. Upfront surgery is usually recommended for tumors larger than 2 cm in diameter since they frequently show metastatic potential, whereas smaller panNETs are generally characterized by an indolent clinical course, with a rate of relapse or metastasis below 15%. To explore whether increased tumor size is paralleled by genomic variations, we compared the rate and the mutational patterns of putative driver genes that are recurrently altered in these tumors by investigating differential cohorts of panNET surgical specimens smaller (n = 27) or larger than 2 cm (n = 29). We found that the cumulative number of mutations detected in panNETs >2 cm was significantly higher (p = 0.03) relative to smaller tumors, while mutations of DAXX were significantly more frequent in the cohort of larger tumors (p = 0.05). Moreover, mutations of DAXX were associated with features of malignancy including increased grade, nodal involvement and lymphovascular invasion, and independently predicted both relapse after surgery (p = 0.05) and reduced DFS in multivariable analysis (p = 0.02). Our data suggest that alterations of the DAXX/ATRX molecular machinery increase the malignant potential of panNETs, and that identification of mutations of DAXX/ATRX in small, nonfunctioning tumors can predict the malignant progression observed in a minority of them.

Background Intraductal papillary mucinous neoplasms (IPMN) have been reported to be associated with concurrent, distinct pancreatic ductal adenocarcinoma (con-PDAC) in about 8% (range, 4–10%) of resected branch duct (BD) lesions. In addition, other pancreatic and ampullary tumors are occasionally diagnosed with IPMN in patients undergoing pancreatic surgery. The objective of this study is to describe the prevalence, clinicopathologic characteristics and prognosis of IPMN with concurrent pancreatic and ampullary neoplasms, especially con-PDAC. Methods The combined databases of pancreatic resections from the Massachusetts General Hospital and the Negrar Hospital, Italy, were analyzed for patients who had been diagnosed with IPMN and concurrent pancreatic or ampullary neoplasms. Results 2762 patients underwent pancreatic surgery from January 2000 to December 2012. Sixteen percent (n = 441) had pathologically confirmed IPMN and 11% of these (n = 50) had a different distinct synchronous pancreatic neoplasm. The majority of these, 62%, were con-PDAC, followed by neuroendocrine neoplasms (10%) and ampullary carcinoma (10%). Less frequently, mucinous (6%) as well as serous cystic neoplasms (6%), adenosquamous carcinoma (4%) and distal bile duct cancer (2%) were diagnosed. Among all patients with synchronous neoplasms, 66% harbored BD-IPMN, 28% combined IPMN and 6% main duct IPMN. Abdominal pain and/or jaundice were the leading symptoms in half of patients. Conclusion IPMN, mainly BD-IPMN, are associated with con-PDAC in about 7% of patients and account for 62% of all concurrent pancreatic/ampullary neoplasms. Other synchronous neoplasms may be found sporadically with IPMN without a suspected association.

Background: The World Health Organization (WHO) and the American Joint Cancer Committee (AJCC) modified the grading of pancreatic neuroendocrine neoplasms from a three-tier (WHO-AJCC 2010) to a four-tier system by introducing the novel category of NET G3 (WHO-AJCC 2017). Objectives: This study aims at validating the WHO-AJCC 2017 and identifying the most effective grading system. Method: A total of 2,102 patients were enrolled; entry criteria were: (i) patient underwent surgery; (ii) at least 2 years of follow-up; (iii) observation time up to 2015. Data from 34 variables were collected; grading was assessed and compared for efficacy by statistical means including Kaplan-Meier method, Cox regression analysis, Harrell’s C statistics, and Royston’s explained variation in univariable and multivariable analyses. Results: In descriptive analysis, the two grading systems demonstrated statistically significant differences for the major category sex but not for age groups. In Cox regression analysis, both grading systems showed statistically significant differences between grades for OS and EFS; however, no statistically significant difference was observed between the two G3 classes of WHO-AJCC 2017. In multivariable analysis for the two models fitted to compare efficacy, the two grading systems performed equally well with substantially similar optimal discrimination and well-explained variation for both OS and EFS. The WHO-AJCC 2017 grading system retained statistically significant difference between the two G3 classes for OS but not for EFS. Conclusions: The WHO-AJCC 2017 grading system is at least equally performing as the WHO-AJCC 2010 but allows the successful identification of the most aggressive PanNET subgroup. Grading is confirmed as probably the most powerful tool for predicting patient survival.

Background: Peptide receptor radionuclide therapy is a valid therapeutic option for pancreatic neuroendocrine neoplasms. The aim of this study was to describe an initial experience with the use of peptide receptor radionuclide therapy as a neoadjuvant agent for resectable or potentially resectable pancreatic neuroendocrine neoplasms. Methods: The postoperative outcomes of 23 patients with resectable or potentially resectable pancreatic neuroendocrine neoplasms at high risk of recurrence who underwent neoadjuvant peptide receptor radionuclide therapy (peptide receptor radionuclide therapy group) were compared with 23 patients who underwent upfront surgical operation (upfront surgery group). Patients were matched for tumor size, grade, and stage. Median follow-up was 61 months. Results: The size (median greatest width) of the primary pancreatic neuroendocrine neoplasms decreased after neoadjuvant peptide receptor radionuclide therapy (59 to 50 mm; P =.047). There were no differences in intraoperative and postoperative outcomes and there were no operative deaths, but the risk of developing a pancreatic fistula tended to be less in the peptide receptor radionuclide therapy group when compared to the upfront surgery group (0/23 vs 4/23; P .2) differed between groups, but progression-free survival in the 31 patients who had an R0 resection seemed to be greater in the 15 patients in the peptide receptor radionuclide therapy group versus 16 patients the upfront group (median progression-free survival not reached vs 36 months; P

Background (18)fluoro-deoxyglucose positron emission tomography/computed tomography (18FDG-PET/CT) might be a useful tool in the management of pancreatic ductal adenocarcinoma (PDAC). Aims The aim of this study was to analyze maximum standard uptake value (SUVmax) after 18FDG-PET/CT as predictor of survival outcomes and method to determine treatment strategies. Methods A consecutive series of patients who underwent preoperative 18FDG-PET/CT and subsequent resection for PDAC were retrospectively reviewed. Patients who underwent neoadjuvant chemotherapy were excluded. Results 46 patients were included in the analysis. Median follow-up was 27 months (4–67). Patients who recurred within 12 months showed a significantly higher preoperative median SUVmax (8.1 vs 6.1, p = 0.039). Receiver operating characteristics (ROC) curves for disease-free survival (DFS) and disease-specific survival (DSS) identified SUVmax of 6.0 as optimal cut-off. Multivariate analysis showed that SUVmax ≥ 6.0 was an independent predictor of poor DFS (HR 2.288, p = 0.024) and DSS (HR 4.875, p < 0.001). The combination of SUVmax ≥6.0 with CA19.9 ≥200 U/ml was significantly associated with survival outcomes in comparison to patients without concordantly elevated values. Conclusion SUVmax ≥6.0 is an independent predictor of DFS and DSS in resected PDAC. 18FDG-PET/CT might be considered in the preoperative evaluation of patients with pancreatic cancer.

Limited data are available for pancreatic neuroendocrine carcinomas (NEC) defined by 2010 World Health Organization (WHO) criteria (mitotic count20 mitoses/10 high-power fields and/or a Ki67 index of20%), because most studies encompass heterogeneous cohorts of extrapulmonary/gastrointestinal NEC. Our aim was to evaluate the clinicopathologic characteristics, treatment, and prognosis of patients with pancreatic NEC defined by the 2010 WHO criteria.We conducted a retrospective analysis of 59 patients with a histologic diagnosis of NEC between 1990 and 2012. All cases were re-reviewed and classified according to the WHO 2010 classification and the WHO 2000 criteria.All patients had stage III pancreatic NEC (n = 34; 58%) or IV pancreatic NEC (n = 25; 43%). Overall, 49 (83%) had poorly differentiated (PD) and 10 (17%) had a well-differentiated (WD) morphology. Fifteen patients (26%) were operated with curative intent (R0/R1), and 8 (14%) were R2 resections. Median disease-specific survival (DSS) for the entire cohort was 14 months. Median DSS did not differ between patient not undergoing resection and those undergoing R2 resection (10 vs 12 months; P.46), but DSS was greater for patients who underwent R0/R1 resection compared with those with no resection/R2 resection (35 vs 11 months; P.005). WD morphologic NEC had a greater survival than PD ones (43 vs 12 months; P = .004). Performance status, R2 resection/no resection, PD morphologic NEC, and no medical treatment were independent predictors of poor survival.Pancreatic NEC constitute a heterogeneous group of tumors. Although NEC is an aggressive disease, curative resection in localized disease is associated with improved survival. Morphologic WD pancreatic NEC represents a subgroup with what seems to be a markedly improved survival. Within the NEC category, tumor treatment should be individualized considering tumor morphology as well as the other 2010 WHO criteria.

Neuroendocrine carcinomas (NEC) of the pancreas are defined by a mitotic count > 20 mitoses/10 high power fields and/or Ki67 index > 20%, and included all the tumors previously classified as poorly differentiated endocrine carcinomas. These latter are aggressive malignancies with a high propensity for distant metastases and poor prognosis, and they can be further divided into small- and large-cell subtypes. However in the NEC category are included also neuroendocrine tumors with a well differentiated morphology but ki67 index > 20%. This category is associated with better prognosis and does not significantly respond to cisplatin-based chemotherapy, which represents the gold standard therapeutic approach for poorly differentiated NEC. In this review, the differences between well differentiated and poorly differentiated NEC are discussed considering both pathology, imaging features, treatment and prognostic implications. Diagnostic and therapeutic flowcharts are proposed. The need for a revision of current classification system is stressed being well differentiated NEC a more indolent disease compared to poorly differentiated tumors.

Poorly differentiated, resectable pancreatic ductal adenocarcinoma is associated with early recurrence and may benefit from neoadjuvant treatment. The aim of this study was to evaluate clinicopathologic characteristics and survival of patients with resectable pancreatic ductal adenocarcinoma according to histologic grading.A total of 502 patients who underwent resection for pancreatic ductal adenocarcinoma between 1990 and 2008 were analyzed via the use of different histologic grading.Well-differentiated (G1), moderately differentiated (G2), and poorly differentiated (G3) pancreatic ductal adenocarcinomas were found in 23 (4.5%), 310 (62%), and 169 (33.5%) patients. Adjuvant therapy, N status, grading, and R status were independent predictors of disease-specific survival for the entire cohort, with 1- and 5-year disease-specific survival rates of 81% and 21%, respectively. Only the presence of symptoms was a significant clinical predictor of G3 status (P = .035). G3 neoplasms were characterized by a greater rate of lymph node metastases, microvascular/perineural invasion, and R2 resections. Median disease-specific survival was 77, 26, and 20 months for G1, G2, and G3 neoplasms (P.0001). Median disease-free survival was 63, 14, and 9 months for G1, G2, and G3 pancreatic ductal adenocarcinoma (P.0001). Adjuvant therapy improved disease-specific survival in G2 (P.04) and G3 (P.0001) pancreatic ductal adenocarcinoma, with a greater survival benefit for G3 neoplasms (hazard ratio: 1.334 vs 2.116).G3 pancreatic ductal adenocarcinoma is associated with a lesser rate of disease-free survival after resection and with the presence of other poor prognostic factors. The benefit of adjuvant therapy is greater in G3 than in G1 and G2 neoplasms. On the basis of these findings, patients with resectable G3 PDAC can be considered as possible targets for neoadjuvant treatment.

Lesion and neuroimaging studies have demonstrated that the mesial temporal lobe is crucial for recognizing emotions from facial expressions. In humans, bilateral amygdala damage is followed by impaired recognition of facial expressions of fear. To evaluate the influence of unilateral mesial temporal lobe damage we examined recognition of facial expressions and functional magnetic resonance (fMRI) brain activation associated with incidental processing of fearful faces in thirteen mesial temporal lobe epilepsy (MTLE) patients (eight with right MTLE, five with left MTLE). We also examined the effect of early versus later damage, comparing subjects with hippocampal-amygdalar sclerosis (MTS) and seizures occurring before five years of age to epilepsy patients with late onset seizures. Fourteen healthy volunteers participated as controls. Neuropsychological testing demonstrated that the ability of right MTLE patients to recognize fearful facial expressions is impaired. Patients with early onset of seizures were the most severely impaired. This deficit was associated with defective activation of a neural network involved in the processing of fearful expressions, which in controls and left MTLE included the left inferior frontal cortex and several occipito-temporal structures of both hemispheres.

Body homeostasis and sleep homeostasis may both rely on the complex integrative activity carried out by the hypothalamus. Thus, the three main wake-sleep (WS) states (i.e. wakefulness, NREM sleep, and REM sleep) may be better understood if the different cardio-respiratory and metabolic parameters, which are under the integrated control of the autonomic and the endocrine systems, are studied during sleep monitoring. According to this view, many physiological events can be considered as an expression of the activity that physiological regulations should perform in order to cope with the need to fulfill body and sleep homeostasis. This review is aimed at making an assessment of data showing the existence of a physiological interplay between body homeostasis and sleep homeostasis, starting from the spontaneous changes observed in the somatic and autonomic activity during sleep, through evidence showing the deep changes occurring in the central integration of bodily functions during the different WS states, to the changes in the WS states observed when body homeostasis is challenged by the external environment and when the return to normal ambient conditions allows sleep homeo- stasis to run without apparent physiological restrictions. The data summarized in this review suggest that an approach to the dichotomy between NREM and REM sleep based on physiological regulations may offer a framework within which observations that a traditional behavioral approach may overlook can be interpreted. The study of the interplay between body and sleep homeostasis appears, therefore, to be a way to understand the function of complex organisms beyond that of the specific regulations.

Background: To generate a robust predictive model of Early (3 months) Graft Loss after liver transplantation, we used a Bayesian approach to combine evidence from a prospective European cohort (Liver-Match) and the United Network for Organ Sharing registry. Methods: Liver-Match included 1480 consecutive primary liver transplants performed from 2007 to 2009 and the United Network for Organ Sharing a time-matched series of 9740 transplants. There were 173 and 706 Early Graft Loss, respectively. Multivariate analysis identified as significant predictors of Early Graft Loss: donor age, donation after cardiac death, cold ischaemia time, donor body mass index and height, recipient creatinine, bilirubin, disease aetiology, prior upper abdominal surgery and portal thrombosis. Results: A Bayesian Cox model was fitted to Liver-Match data using the United Network for Organ Sharing findings as prior information, allowing to generate an Early Graft Loss-Donor Risk Index and an Early Graft Loss-Recipient Risk Index. A Donor-Recipient Allocation Model, obtained by adding Early Graft Loss-Donor Risk Index to Early Graft Loss-Recipient Risk Index, was then validated in a distinct United Network for Organ Sharing (year 2010) cohort including 2964 transplants. Donor-Recipient Allocation Model updating using the independent Turin Transplant Centre dataset, allowed to predict Early Graft Loss with good accuracy (c-statistic: 0.76). Conclusion: Donor-Recipient Allocation Model allows a reliable donor and recipient-based Early Graft Loss prediction. The Bayesian approach permits to adapt the original Donor-Recipient Allocation Model by incorporating evidence from other cohorts, resulting in significantly improved predictive capability. © 2013 Editrice Gastroenterologica Italiana S.r.l.

The importance of epigenetic modifications such as DNA methylation in tumorigenesis is increasingly being appreciated. To define the genome-wide pattern of DNA methylation in pancreatic ductal adenocarcinomas (PDAC), we captured the methylation profiles of 167 untreated resected PDACs and compared them to a panel of 29 adjacent nontransformed pancreata using high-density arrays. A total of 11,634 CpG sites associated with 3,522 genes were significantly differentially methylated (DM) in PDAC and were capable of segregating PDAC from non-malignant pancreas, regardless of tumor cellularity. As expected, PDAC hypermethylation was most prevalent in the 5' region of genes (including the proximal promoter, 5'UTR and CpG islands). Approximately 33% DM genes showed significant inverse correlation with mRNA expression levels. Pathway analysis revealed an enrichment of aberrantly methylated genes involved in key molecular mechanisms important to PDAC: TGF-β, WNT, integrin signaling, cell adhesion, stellate cell activation and axon guidance. Given the recent discovery that SLIT-ROBO mutations play a clinically important role in PDAC, the role of epigenetic perturbation of axon guidance was pursued in more detail. Bisulfite amplicon deep sequencing and qRT-PCR expression analyses confirmed recurrent perturbation of axon guidance pathway genes SLIT2, SLIT3, ROBO1, ROBO3, ITGA2 and MET and suggests epigenetic suppression of SLIT-ROBO signaling and up-regulation of MET and ITGA2 expression. Hypomethylation of MET and ITGA2 correlated with high gene expression, which was associated with poor survival. These data suggest that aberrant methylation plays an important role in pancreatic carcinogenesis affecting core signaling pathways with potential implications for the disease pathophysiology and therapy.

The aim of the present study was to determine the optimal number of lymph nodes (LN) examined to stage pN0 tumors after surgery for ampulla of Vater carcinoma (AVC).We reviewed retrospectively 127 patients with AVC who underwent pancreaticoduodenectomy (1990-2008). Univariate and multivariate analysis was performed.Fifty-nine patients (46.5 %) were pN0, whereas 68 patients (53.5 %) were pN1. The 5-year disease-specific survival (DSS) was worse for pN1 patients than for pN0 patients (46 vs. 77 %; P0.0001). In the pN0 cohort, the optimal cut-off number of LN analyzed was found to be 12. The 5-year DSS for patients with ≤ 12 LN was 50 %, compared with 89 % in those with12 LN (P = 0.001). By multivariate analysis, a LN count12 was the only independent predictor associated with improved survival (HR 0.16, P = 0.003) among pN0 patients. Among pN1 patients, a LN count12 was associated with a significantly better 5-year DSS (59 vs. 22 %; P = 0.027). Patients with a lymph node ratio (LNR)0.20 had a 5-year DSS of 24 %, compared with 58 % in those with 0LNR ≤ 0.20 (P = 0.038).Removal of more than 12 LN for examination is associated with improved survival rate after surgery for AVC in both pN0 and pN1 patients.