Role of Ulcerative Colitis Endoscopic Index of Severity (UCEIS) versus Mayo Endoscopic Subscore (MES) in Predicting Patients' Response to Biological Therapy and the Need for Colectomy.

BACKGROUND: The main goal in the treatment of ulcerative colitis (UC) is to achieve mucosal healing. Despite being unvalidated, the most widely used scoring system is the Mayo endoscopic subscore (MES). However, the recently established and validated Ulcerative Colitis Endoscopic Index of Severity (UCEIS) represents an interesting alternative method in assessing endoscopic disease activity. OBJECTIVE: Due to a lack of reliable prognostic factors, the aim of this study was to investigate the diagnostic accuracy of the UCEIS and the MES, in predicting response to biological therapy and the need for colectomy. METHODS: We conducted a retrospective, uncontrolled, single-center study on UC patients with endoscopically active disease even with concomitant conventional and/or biological therapy, who had already started or had been changed a biological treatment. RESULTS: Sixty-one UC patients were enrolled. At baseline, 71% were naive to biological therapies and 41% had an extensive colitis. At control time (median time of 11.5 months), MES and UCEIS scores significantly decreased from those at baseline (from 2.6 to 1.8 and 5 to 3.2, respectively, p < 0.001). UCEIS, but not MES, was found to be significantly associated with unresponsiveness to therapy (p = 0.040). Moreover, when UCEIS was ≥7, all patients underwent colectomy after a median time of 5 months (p < 0.001). CONCLUSION: UCEIS may be superior to MES because of its accuracy and predictive role. Therefore, UCEIS should be considered for use in daily clinical practice.

Genomic characterization of malignant progression in neoplastic pancreatic cysts.

Intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs) are non-invasive neoplasms that are often observed in association with invasive pancreatic cancers, but their origins and evolutionary relationships are poorly understood. In this study, we analyze 148 samples from IPMNs, MCNs, and small associated invasive carcinomas from 18 patients using whole exome or targeted sequencing. Using evolutionary analyses, we establish that both IPMNs and MCNs are direct precursors to pancreatic cancer. Mutations in SMAD4 and TGFBR2 are frequently restricted to invasive carcinoma, while RNF43 alterations are largely in non-invasive lesions. Genomic analyses suggest an average window of over three years between the development of high-grade dysplasia and pancreatic cancer. Taken together, these data establish non-invasive IPMNs and MCNs as origins of invasive pancreatic cancer, identifying potential drivers of invasion, highlighting the complex clonal dynamics prior to malignant transformation, and providing opportunities for early detection and intervention.

Histopathological and Immunophenotypic Changes of Pancreatic Neuroendocrine Tumors after Neoadjuvant Peptide Receptor Radionuclide Therapy (PRRT).

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.

DAXX mutations as potential genomic markers of malignant evolution in small nonfunctioning pancreatic neuroendocrine tumors.

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.

Risk of misdiagnosis and overtreatment in patients with main pancreatic duct dilatation and suspected combined/main-duct intraductal papillary mucinous neoplasms.

BACKGROUND: Segmental/diffuse dilatation of the main pancreatic duct (MPD) is the typical feature of combined/main-duct intraductal papillary mucinous neoplasms (CMD-IPMNs). MPD dilation in IPMNs may be also expression of mucus hypersecretion/obstructive chronic pancreatitis (OCP). The aim of this study was to evaluate the presence and extension of MPD involvement by tumor/OCP and assess the risk of overtreatment. METHODS: Retrospective analysis of suspected CMD-IPMNs resected between January 2009 and October 2014 were included. Pathologic correlations among MPD dilatation, IPMN, and OCP was searched. RESULTS: Overall, 93 patients were resected for suspected CMD-IPMNs. At pathology, CMD-IPMNs were found in 69 patients (74%). Branch-duct IPMNs (BD-IPMNs) were found in 8 cases (9%), pancreatic ductal adenocarcinoma (PDAC) in absence of IPMN in 9 (10%), cystic neuroendocrine tumor (NET G2) in 1 (1%), serous cystadenoma in 2 (2%), and OCP alone/mucinous metaplasia in 4 patients (4%). Overall, 18 patients (19%) underwent an overtreatment because unnecessary (2 BD-IPMNs, 2 serous cystadenomas, and 4 OCPs only) or too extensive resections (9 CMD-IPMNs and 1 PDAC with associated OCP). In these, total pancreatectomy was the most common procedure (67%). Median size of MPD in IPMN-involved area was 12 mm compared with 7 mm when only OCP was found (P < .05). CONCLUSION: There is a considerable risk of overtreatment in patients with a preoperative morphologic diagnosis of CMD-IPMNs. Partial pancreatectomy with margin examination should be performed instead of upfront total pancreatectomy. Radiologic observation can be considered in asymptomatic patients with "worrisome" MPD dilatation (5-9 mm) and lacking other high-risk stigmata.

Management of ampullary neoplasms: A tailored approach between endoscopy and surgery.

Ampullary neoplasms, although rare, present distinctive clinical and pathological features from other neoplastic lesions of the periampullary region. No specific guidelines about their management are available, and they are often assimilated either to biliary tract or to pancreatic carcinomas. Due to their location, they tend to become symptomatic at an earlier stage compared to pancreatic malignancies. This behaviour results in a higher resectability rate at diagnosis. From a pathological point of view they arise in a zone of transition between two different epithelia, and, according to their origin, may be divided into pancreatobiliary or intestinal type. This classification has a substantial impact on prognosis. In most cases, pancreaticoduodenectomy represents the treatment of choice when there is an overt or highly suspicious malignant behaviour. The rate of potentially curative resection is as high as 90% and in high-volume centres an acceptable rate of complications is reported. In selected situations less invasive approaches, such as ampullectomy, have been advocated, although there are some concerns mainly because of a higher recurrence rate associated with limited resections for invasive carcinomas. Importantly, these methods have the drawback of not including an appropriate lymphadenectomy, while nodal involvement has been shown to be frequently present also in apparently low-risk carcinomas. Endoscopic ampullectomy is now the procedure of choice in case of low up to high-grade dysplasia providing a proper assessment of the T status by endoscopic ultrasound. In the present paper the evidence currently available is reviewed, with the aim of offering an updated framework for diagnosis and management of this specific type of disease.

The role of (18)fluoro-deoxyglucose positron emission tomography/computed tomography in resectable pancreatic cancer.

BACKGROUND: The role of (18)fluoro-deoxyglucose positron emission tomography/computed tomography in pancreatic ductal adenocarcinoma is debated. We retrospectively assessed the value of (18)fluoro-deoxyglucose positron emission tomography/computed tomography in addition to conventional imaging as a staging modality in pancreatic cancer. METHODS: (18)Fluoro-deoxyglucose positron emission tomography/computed tomography was performed in 72 patients with resectable pancreatic carcinoma after multi-detector computed tomography positron emission tomography was considered positive for a maximum standardized uptake value >3. RESULTS: Overall, 21% of patients had a maximum standardized uptake value ≤ 3, and 60% of those had undergone neoadjuvant treatment (P=0.0001). Furthermore, 11% of patients were spared unwarranted surgery since positron emission tomography/computed tomography detected metastatic disease. All liver metastases were subsequently identified with contrast-enhanced ultrasound. Sensitivity and specificity of positron emission tomography/computed tomography for distant metastases were 78% and 100%. The median CA19.9 concentration was 48.8 U/mL for the entire cohort and 292 U/mL for metastatic patients (P=0.112). CONCLUSIONS: The widespread application of (18)fluoro-deoxyglucose positron emission tomography/computed tomography in patients with resectable pancreatic carcinoma seems not justified. It should be considered in selected patients at higher risk of metastatic disease (i.e. CA19.9>200 U/mL) after undergoing other imaging tests. Neoadjuvant treatment is significantly associated with low metabolic activity, limiting the value of positron emission tomography in this setting.

Targeted next-generation sequencing of cancer genes dissects the molecular profiles of intraductal papillary neoplasms of the pancreas.

Intraductal neoplasms are important precursors to invasive pancreatic cancer and provide an opportunity to detect and treat pancreatic neoplasia before an invasive carcinoma develops. The diagnostic evaluation of these lesions is challenging, as diagnostic imaging and cytological sampling do not provide accurate information on lesion classification, the grade of dysplasia or the presence of invasion. Moreover, the molecular driver gene mutations of these precursor lesions have yet to be fully characterized. Fifty-two intraductal papillary neoplasms, including 48 intraductal papillary mucinous neoplasms (IPMNs) and four intraductal tubulopapillary neoplasms (ITPNs), were subjected to the mutation assessment in 51 cancer-associated genes, using ion torrent semiconductor-based next-generation sequencing. P16 and Smad4 immunohistochemistry was performed on 34 IPMNs and 17 IPMN-associated carcinomas. At least one somatic mutation was observed in 46/48 (96%) IPMNs; 29 (60%) had multiple gene alterations. GNAS and/or KRAS mutations were found in 44/48 (92%) of IPMNs. GNAS was mutated in 38/48 (79%) IPMNs, KRAS in 24/48 (50%) and these mutations coexisted in 18/48 (37.5%) of IPMNs. RNF43 was the third most commonly mutated gene and was always associated with GNAS and/or KRAS mutations, as were virtually all the low-frequency mutations found in other genes. Mutations in TP53 and BRAF genes (10% and 6%) were only observed in high-grade IPMNs. P16 was lost in 7/34 IPMNs and 9/17 IPMN-associated carcinomas; Smad4 was lost in 1/34 IPMNs and 5/17 IPMN-associated carcinomas. In contrast to IPMNs, only one of four ITPNs had detectable driver gene (GNAS and NRAS) mutations. Deep sequencing DNA from seven cyst fluid aspirates identified 10 of the 13 mutations detected in their associated IPMN. Using next-generation sequencing to detect cyst fluid mutations has the potential to improve the diagnostic and prognostic stratification of pancreatic cystic neoplasms.

Genome-wide DNA methylation patterns in pancreatic ductal adenocarcinoma reveal epigenetic deregulation of SLIT-ROBO, ITGA2 and MET signaling.

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-ß, 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.

Specific glycoforms of MUC5AC and endorepellin accurately distinguish mucinous from nonmucinous pancreatic cysts.

Specific protein glycoforms may be uniquely informative about the pathological state of a cyst and may serve as accurate biomarkers. Here we tested that hypothesis using antibody-lectin sandwich arrays in broad screens of protein glycoforms and in targeted studies of candidate markers. We profiled 16 different glycoforms of proteins captured by 72 different antibodies in cyst fluid from mucinous and nonmucinous cysts (n = 22), and we then tested a three-marker panel in 22 addition samples and 22 blinded samples. Glycan alterations were not widespread among the proteins and were mainly confined to MUC5AC and endorepellin. Specific glycoforms of these proteins, defined by reactivity with wheat germ agglutinin and a blood group H antibody, were significantly elevated in mucinous cysts, whereas the core protein levels were not significantly elevated. A three-marker panel based on these glycoforms distinguished mucinous from nonmucinous cysts with 93% accuracy (89% sensitivity, 100% specificity) in a prevalidation sample set (n = 44) and with 91% accuracy (87% sensitivity, 100% specificity) in independent, blinded samples (n = 22). Targeted lectin measurements and mass spectrometry analyses indicated that the higher wheat germ agglutinin and blood group H reactivity was due to oligosaccharides terminating in GlcNAc or N-acetyl-lactosamine with occasional α1,2-linked fucose. The results show that MUC5AC and endorepellin glycoforms may be highly specific and sensitive biomarkers for the differentiation of mucinous from nonmucinous pancreatic cysts.

Precancerous lesions of the pancreas.

Pancreatic cancer has a very poor prognosis, with a five year survival of only 5%. New studies have shown that it takes over 11 years for cells to develop invasive capability. This provides an opportunity to intervene if precursor lesions can be detected. This paper reviews the molecular, pathological, clinical findings and management of pancreatic intraepithelial neoplasia (PanIN), intraductal pancreatic mucinous neoplasm (IPMN) and mucinous cystic neoplasm (MCN), three precursor lesions which can give rise to invasive carcinoma of the pancreas.

Primary retroperitoneal acinar cell cystadenoma.

In this report, we describe a case of hitherto unreported primary retroperitoneal acinar cell cystadenoma that morphologically and immunophenotypically resembled pancreatic acinar cell cystadenoma. Pancreatic acinar cell cystadenoma is a very uncommon benign lesion characterized by acinar cell differentiation, the evidence of pancreatic exocrine enzyme production, and the absence of cellular atypia. Our case occurred in a 55-year-old woman presenting a 10-cm multilocular cystic lesion in the retroperitoneum thought to be a mucinous cystic neoplasm. At laparotomy, the cystic mass, which showed no connection with any organ, was completely resected with a clinical diagnosis of cystic lymphangioma. The diagnosis of retroperitoneal acinar cell cystadenoma was based on the recognition of morphological acinar differentiation, the immunohistochemical demonstration of the acinar marker trypsin, and the absence of cellular atypia. These peculiar features can be used in the differential diagnosis with all the other cystic lesions of the retroperitoneum.

Ductal Adenocarcinoma of the Pancreas.

Pancreatic ductal adenocarcinoma (PDAC) and its variants comprise between 80% and 90% of all tumors of the exocrine pancreas. Because of its silent course, late clinical manifestation, and rapid growth, it is considered a silent killer. Only 10% to 15% of cases are resectable and the 5-year survival rate remains lower than 5%. The differential diagnosis between PDAC and chronic pancreatitis is a challenge for pathologists. This article provides a guide for pathologic evaluation of PDAC specimens with the macroscopic and microscopic features of common PDAC and its variants and discusses the differential diagnosis and morphologic and immunophenotypical prognostic parameters.

Analysis of cyclooxygenase-2 (COX-2) expression in different sites of endometriosis and correlation with clinico-pathological parameters.

BACKGROUND: Recent studies have demonstrated the overexpression of cyclooxygenase-2 (COX-2) in endometriosis. The aim of this study was to investigate the expression of COX-2 in different anatomical sites of endometriosis and its association with clinico-pathological parameters in a single institutional series of patients undergoing operative treatment. METHODS: COX-2 expression was analysed by immunohistochemistry in 136 samples of endometriotic tissue from 103 patients affected by endometriosis. RESULTS: COX-2 immunoreaction was observed in 78.5% of ovarian endometriotic cysts, in 11.1% of peritoneal implants and 13.3% of recto-vaginal nodules. COX-2 positivity was not distributed differently according to age, pre-operative serum levels of CA125 and AFS score. Moreover, COX-2 positivity did not show any significant variation according to the subjective intensity of pain, as dysmenorrhoea, chronic pelvic pain, lower urinary tract or gastrointestinal symptoms, or according to infertility. CONCLUSIONS: Increased COX-2 expression in the endometriotic ovarian cyst wall was observed with respect to other extraovarian localizations. No relevant correlations between COX-2 positivity and clinico-pathological characteristics and symptoms of patients were observed.

Estudios de la asociación genética de la apolipoproteína E con la longevidad, el deterioro cognoscitivo y la demencia / The association of apolipoprotein E with longevity, cognitive impairment and dementia

Las investigaciones recientes sugieren que el envejecimiento y el deterioro cognoscitivo son resultado de los cambios en la información a nivel molecular. Así, se han formulado teorías genéticas que han intentado explicar la pérdida neuronal que se produce con la edad. Sin embargo, un hallazgo reciente ha abierto un nuevo camino en esta área. Se trata de la asociación que hay entre el genotipo molecular de la apolipoproteína E (ApoE) y el aumento del riesgo de padecer demencia senil de tipo Alzheimer. La ApoE es una glicoproteína producida por una variedad de tejidos en el organismo, particularmente en el hígado y el cerebro, que interviene en el transporte y metabolismo de los lípidos, coordinando la movilización y redistribución del colesterol en los procesos de reparación de las membranas neuronales. Se ha estudiado cuál es su papel en el metabolismo de las lipoproteínas en el sistema nervioso y su importancia en la plasticidad cerebral. La presente revisión tiene por objeto describir la función de la ApoE en el metabolismo de los lípidos y por medio de su efecto biológico, profundizar en la relación de su genotipo molecular con la longevidad, el deterioro cognoscitivo y la demencia

A double-blind comparison of nefazodone and fluoxetine in the treatment of depressed outpatients

Antecedentes. La nefazodona es una antidepresivo desarrollado recientemente, que ha demostrado poseer una eficacia similar a la de los antidepresivos tricíclicos y a la de algunos de los inhibidores selectivos de la recaptura de la serotonina (ISRS). También ha demostrado tener mayor tolerancia que los tricíclicos y similar a la de los de los ISRS. Sin embargo, hasta este momento no han aparecido reportes en los que se les compare específicamente con la fluoxetina. Debido a que este último antidepresivo se utiliza de manera muy extendida alrededor del mundo, su comparación con la nefazodona por medio de un estudi clínico controlado, es de gran interés. Metodología. Un total de 74 pacientes de la consulta externa, diagnosticados como portadores de un episodio depresivo mayor de acuerdo a los criterios diagnósticos del DSM-III-R, fue reclutado para participar en un ensayo clínico con el objetivo de comparar la eficacia y la tolerancia entre la nefazodona y la fluoxetina. El estudio se llevó a cabo por medio de un procedimiento doble-ciego con asignación aleatoria de medicamento en dos grupos paralelos. Las evaluaciones se efectuaron con una periodicidad semanal, en las cuales se hizo una valoración clínica globar de cada paciente, que incluía la aplicación de las escalas de Hamilton para depresión (EDH) y ansiedad (EAH), la Escala de Impresión Clínica Global (ICG) y la Evaluación Global del Paciente (EGP) para determinar la eficacia del tratamiento. La tolerancia y seguridad de los tratamientos se compraró con la aplicación de escalas pertinentes para ello. El análisis de los resultados se efectuó utilizando dos procedimientos: el procedimiento de acarreo de la última observación (AUO) y el de los datos agrupados de cada visita. Los datos se analizaron por medio de un análisis de varianza (ANOVA) para medidas repetidas, con la finalidad de buscar diferencias entre los dos tratamientos, partiendo del momento del inicio (periodo basal) y a lo largo de las semanas consecutivas de tratamiento. Resultados. Treinta y siete pacientes recibieron fluoxetina (dosis diaria promedio 24 mgs) y 37 recibieron nefazodona (dosis diaria promedio 400 mgs), sin embargo un paciente del grupo de la nefazodona no alcanzó a tener por lo menos una evaluación de eficacia a lo largo del estudio, por lo que se excluyó del análisis