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.

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.

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.

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.

Resisting imagination and confabulation: effects of metacognitive training.

False memory rejection is enhanced when individuals rely on memorability-based inferences (e.g., "I should remember this event well; if I don't, it must not have happened"). The present study investigated whether 8- and 9-year-olds and adults could be trained to engage in memorability-based inferences to reject false, but highly familiar (increased through imagination and confabulation), events. Across two experiments, participants enacted, imagined, or confabulated a series of actions differing in expected memorability. Two weeks later, half of the participants received memorability-based training before being administered an old/new recognition test in which they were asked to endorse only enacted actions. Thus, imagined and confabulated actions were to be rejected in the face of their high familiarity. Results indicated that adults, but not children, exhibited increased rejection of these false events if they were of high memorability following a training procedure that explained the functioning of memorability-based inferences (Experiment 1, N=100). Children's rejection of familiar events improved only when the training procedure closely mimicked the demands of the retrieval test (Experiment 2, N=125). Theoretical and practical implications are discussed.

COVID-19, Isolation, Quarantine: On the Efficacy of Internet-Based Eye Movement Desensitization and Reprocessing (EMDR) and Cognitive-Behavioral Therapy (CBT) for Ongoing Trauma.

Literature points to cognitive-behavioural therapy (CBT) and eye movement desensitization and reprocessing (EMDR) as evidence-based therapies for trauma-related disorders. Treatments are typically administered in a vis-à-vis setting with patients reporting symptoms of a previously experienced trauma. Conversely, online-therapies and ongoing trauma have not received adequate attention. This study aimed to compare the efficacy of two brief treatments for health professionals and individuals suffering from the circumstances imposed by the coronavirus disease 2019 (COVID-19) pandemic. The EMDR and the trauma focused-CBT were administered online during the earliest stage of distress to manage the ongoing trauma associated to quarantine or disease. Thirty-eight patients satisfying the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria for acute stress disorder were randomly assigned to the EMDR or CBT treatment. Both groups received a 7-session therapy, and psychometric tests were administered before, after the treatment and at one-month follow-up to assess traumatic symptoms, depression and anxiety. Results revealed that both treatments reduced anxiety by 30%, and traumatic and depressive symptoms by 55%. Present findings indicate the internet-based EMDR and CBT as equally effective brief treatments, also suggesting a maintenance of the effects as indicated by the follow-up evaluation. The EMDR and CBT might be considered as first line therapies to treat the ongoing trauma and to prevent the sensitization and accumulation of trauma memories.

Knowing about not remembering: developmental dissociations in lack-of-memory monitoring.

Children aged 7 and younger encounter great difficulty in assessing whether lack of memory for an event indicates that the event was not experienced. The present research investigated whether this difficulty results from a general inability to evaluate memory absence or from a specific inability to monitor one feature of memory absence that has been examined in previous studies, namely expected memorability. Seven-, 8- and 9-year-olds, and adults (N = 72) enacted, imagined and confabulated about bizarre and common actions. Two weeks later, participants were asked to recognize the actions that had been enacted. Even 7-year-olds monitored the relative familiarity of rejected distracters (i.e. reported higher confidence for the rejection of novel versus imagined and confabulated distracters). However, only older children and adults exhibited the ability to monitor expected memorability (e.g. reported higher confidence for the rejection of bizarre versus common distracters). These results suggest that young children exhibit specific, rather than general, deficits in monitoring memory absence, and provide an indication of the specific domains in which lack-of-memory monitoring improves during childhood.

A randomized controlled study of immediate versus delayed umbilical cord clamping in infants born by elective caesarean section.

BACKGROUND: Delayed umbilical cord clamping is associated with greater haemoglobin concentration and iron storage between 3 and 6 months of life and with less need of blood transfusion and lower incidence of neonatal hypotension compared to early umbilical cord clamping. METHODS: The aim was to test the hypothesis that delayed cord clamping is better than early cord clamping in term infants born by elective caesarean section. Group A was subjected to immediate cord clamping while in the Group B, the umbilical cord was clamped 1 min after birth. Primary aim was revealed the difference in pre-ductal saturation between two groups while secondary aim was investigating the difference in HR, Ht, bilirubin and glycaemia. Pre-ductal SpO2 and HR were recorded at 5 and 10 min after birth, T was analysed 10 min after birth, glycaemia was revealed at 120 min while Ht and bilirubin were collected at 72 h. RESULTS: 132 newborns were enrolled in the study and allocated in ratio 1:1 to group A or B. Delayed cord clamping did not improve SpO2, HR and T values compared to immediate cord clamping (p > 0,05). However, Group B showed greater haematocrit and bilirubin values at 72 h compared to Group A (56,71 ± 6663 vs 51,56 ± 6929; p < 0,05 and 8,54 ± 2,90 vs 7,06 ± 2,76; p < 0,05). Glycaemia value did not differ between two groups (p > 0,05). CONCLUSIONS: Group B did not reveal any differences in SpO2, HR, T and glycaemia compared to Group A. Group B showed greater values of haematocrit and bilirubin but without need of phototherapy. TRIAL REGISTRATION: Umbilical Cord Clamping: What Are the Benefits; NCT03878602. Registered 18 March 2019 retrospectively registered.

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.

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.

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.

Children's perceived emotional behavior at disclosure and prosecutors' evaluations.

The present study investigated the perceived emotional behavior of alleged child victims when disclosing sexual abuse in a forensic interview. It also addressed whether the perceived emotional behavior influenced prosecutors' evaluations of children's potential as witnesses and prosecutors' recommendations to press charges. Ninety-eight videotapes of forensic interviews with alleged child sexual abuse victims (4- to 17-year-olds) were coded for behavioral indicators of emotions. Case file information and district attorney evaluations were also coded. Results indicated that children were not generally perceived as being emotional (e.g., sad) during disclosure. However, the perceived intensity of expressed emotions was greater when children disclosed the alleged abuse compared to when they discussed more neutral topics in rapport building. Greater perceived emotional withdrawal by children at disclosure was associated with more negative evaluations of child witnesses by prosecutors. Moreover, children's emotional behaviors, as noted by prosecutors, were among the predictors of prosecutors' recommendations to file charges. Practical implications are discussed.

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.

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.

Developmental differences in false-event rejection: Effects of memorability-based warnings.

The present study investigated the development of the memorability-based strategy, a metacognitive process through which individuals reject the occurrence of false events if they do not remember the events and they expect them to be highly memorable. Previous research found that only older children spontaneously use this strategy. In the present study, we examined whether providing children with relevant information about expected event-memorability and inferences derived from it induced strategy use. Children aged 5, 7, and 9 (n = 144) were asked about true and false (high- and low-memorability) autobiographical events. Participants were either interviewed according to the standard "lost-in-the-mall" procedure, or were additionally provided with warnings. Warnings were either congruent or incongruent with assessments and decision processes involved in the strategy use. Results showed that receiving memorability-congruent warnings increased false-event rejection rates in 7- and 9-year-olds, but not in 5-year-olds. However, only older children were more likely to reject high-memorability compared with low-memorability false events. Developmental trajectories and factors affecting reliance on the memorability-based strategy are discussed.