Mapping functional to morphological variation reveals the basis of regional extracellular matrix subversion and nerve invasion in pancreatic cancer.

Intratumor morphological heterogeneity of pancreatic ductal adenocarcinoma (PDAC) predicts clinical outcomes but is only partially understood at the molecular level. To elucidate the gene expression programs underpinning intratumor morphological variation in PDAC, we investigated and deconvoluted at single cell level the molecular profiles of histologically distinct clusters of PDAC cells. We identified three major morphological and functional variants that co-exist in varying proportions in all PDACs, display limited genetic diversity, and are associated with a distinct organization of the extracellular matrix: a glandular variant with classical ductal features; a transitional variant displaying abortive ductal structures and mixed endodermal and myofibroblast-like gene expression; and a poorly differentiated variant lacking ductal features and basement membrane, and showing neuronal lineage priming. Ex vivo and in vitro evidence supports the occurrence of dynamic transitions among these variants in part influenced by extracellular matrix composition and stiffness and associated with local, specifically neural, invasion.

Delta Radiomic Features Predict Resection Margin Status and Overall Survival in Neoadjuvant-Treated Pancreatic Cancer Patients.

BACKGROUND: Neoadjuvant therapy (NAT) emerged as the standard of care for patients with pancreatic ductal adenocarcinoma (PDAC) who undergo surgery; however, surgery is morbid, and tools to predict resection margin status (RMS) and prognosis in the preoperative setting are needed. Radiomic models, specifically delta radiomic features (DRFs), may provide insight into treatment dynamics to improve preoperative predictions. METHODS: We retrospectively collected clinical, pathological, and surgical data (patients with resectable, borderline, locally advanced, and metastatic disease), and pre/post-NAT contrast-enhanced computed tomography (CT) scans from PDAC patients at the University of Texas Southwestern Medical Center (UTSW; discovery) and Humanitas Hospital (validation cohort). Gross tumor volume was contoured from CT scans, and 257 radiomics features were extracted. DRFs were calculated by direct subtraction of pre/post-NAT radiomic features. Cox proportional models and binary prediction models, including/excluding clinical variables, were constructed to predict overall survival (OS), disease-free survival (DFS), and RMS. RESULTS: The discovery and validation cohorts comprised 58 and 31 patients, respectively. Both cohorts had similar clinical characteristics, apart from differences in NAT (FOLFIRINOX vs. gemcitabine/nab-paclitaxel; p < 0.05) and type of surgery resections (pancreatoduodenectomy, distal or total pancreatectomy; p < 0.05). The model that combined clinical variables (pre-NAT carbohydrate antigen (CA) 19-9, the change in CA19-9 after NAT (∆CA19-9), and resectability status) and DRFs outperformed the clinical feature-based models and other radiomics feature-based models in predicting OS (UTSW: 0.73; Humanitas: 0.66), DFS (UTSW: 0.75; Humanitas: 0.64), and RMS (UTSW 0.73; Humanitas: 0.69). CONCLUSIONS: Our externally validated, predictive/prognostic delta-radiomics models, which incorporate clinical variables, show promise in predicting the risk of predicting RMS in NAT-treated PDAC patients and their OS or DFS.

Exploring a novel composite method using non-contrast EUS enhanced microvascular imaging and cyst fluid analysis to differentiate pancreatic cystic lesions.

BACKGROUND AND AIMS: Differentiating pancreatic cystic lesions (PCLs) remains a diagnostic challenge. The use of high-definition imaging modalities which detect tumor microvasculature have been described in solid lesions. We aim to evaluate the usefulness of cystic microvasculature when used in combination with cyst fluid biochemistry to differentiate PCLs. METHODS: We retrospectively analyzed 110 consecutive patients with PCLs from 2 Italian Hospitals who underwent EUS with H-Flow and EUS fine needle aspiration to obtain cystic fluid. The accuracy of fluid biomarkers was evaluated against morphological features on radiology and EUS. Gold standard for diagnosis was surgical resection. A clinical and radiological follow up was applied in those patients who were not resected because not surgical indication and no signs of malignancy were shown. RESULTS: Of 110 patients, 65 were diagnosed with a mucinous cyst, 41 with a non-mucinous cyst, and 4 with an undetermined cyst. Fluid analysis alone yielded 76.7% sensitivity, 56.7% specificity, 77.8 positive predictive value (PPV), 55.3 negative predictive value (NPV) and 56% accuracy in diagnosing pancreatic cysts alone. Our composite method yielded 97.3% sensitivity, 77.1% specificity, 90.1% PPV, 93.1% NPV, 73.2% accuracy. CONCLUSIONS: This new composite could be applied to the holistic approach of combining cyst morphology, vascularity, and fluid analysis alongside endoscopist expertise.

Early Age of Onset Is an Independent Predictor for a Worse Response to Neoadjuvant Therapies in Sporadic Rectal Cancer Patients.

The incidence of rectal cancer (RC) is increasing in the population aged ≤ 49 (early-onset RC-EORC). EORC patients are more likely to present with locally advanced disease at diagnosis than late-onset RC (LORC; aged ≥ 50) patients. As a consequence, more EORC patients undergo neoadjuvant therapies. The response to treatment in EORC patients is still unknown. This study aims to explore the effect of age of onset on the pathological response to neoadjuvant therapies in sporadic locally advanced RC (LARC) patients. Based on an institutional prospectively maintained database, LARC patients undergoing neoadjuvant therapies and radical surgery between January 2010 and December 2022 were allocated to the EORC and LORC groups. The primary endpoint was the rate of incomplete response (Dworak 0-2). A total of 326 LORC and 79 EORC patients were included. Pre-neoadjuvant tumor features were comparable. A significantly higher rate of incomplete response was observed in EORC patients (49% vs. 35%; p = 0.028). From multivariable analysis, early age of onset, smoking and extramural invasion presented as independent risk factors for a worse response. This study demonstrates that an early age of onset is related to a worse response and calls for different multimodal strategies in this group of patients.

Ampullary Cancer: Histological Subtypes, Markers, and Clinical Behaviour-State of the Art and Perspectives.

There are different cancers in the peri-ampullary region, including pancreatic ductal adenocarcinoma (PDAC), duodenum cancers (DCs), and ampullary adenocarcinoma (AAC). Here, significant morphological-molecular characterizations should be necessary for the distinction of primary tumours and classifications of their subtypes of cancers. The sub classification of AACs might include up to five different variants, according to different points of view, concerning the prevalence of the two more-cellular components found in the ampulla. In particular, regarding the AACs, the most important subtypes are represented by the intestinal (INT) and the pancreato-biliary (PB) ones. The subtyping of AACs is essential for diagnosis, and their identifications have been impacting clinical management responses to treatments and overall survival (os) after surgery. Pb is associated with a worse clinical outcome. Otherwise, the criteria, through which are possible to attribute its subtype classification, are not well established. A triage of immune markers represented by CK7, CK20, and CDX-2 seem to represent the best compromise in order to split the cohort of AAC patients in the INT and PB groups. The test of choice for the sub-classification of AACs is represented by the immuno-histochemical approach, in which its molecular classification acquires its diagnostic, predictive, and prognostic value for both the INT and PB patients.

Neutrophil-only Histological Assessment of Ulcerative Colitis Correlates with Endoscopic Activity and Predicts Long-term Outcomes in a Multicentre Study.

BACKGROUNDS AND AIMS: Absence of neutrophils is the minimum standard to consider histological remission of ulcerative colitis [UC]. The PICaSSO Histological Remission Index [PHRI] is a new simple index for UC, based only on the detection of neutrophils. We evaluate PHRI's correlation with endoscopy and its prognostic value compared with other established indices. METHODS: Consecutive patients with UC underwent colonoscopy at two referral centres [Birmingham, UK, and Milan, Italy,] and were followed up for 2 years. Correlation between histology (PHRI, Nancy [NHI], and Robarts [RHI] indexes) and endoscopy (Mayo Endoscopic Score [MES], Ulcerative Colitis Endoscopic Index of Severity [UCEIS], and PICaSSO index) was calculated as Spearman coefficients. Diagnostic performance of endoscopy was assessed with receiver operating characteristic [ROC] curves and outcome stratification with Kaplan-Meier curves. RESULTS: A total of 192 patients with UC was enrolled, representing all grades of endoscopic severity. Correlation between histology and endoscopy did not differ significantly when using PHRI instead of NHI or RHI. In particular, PHRI's correlation with MES, UCEIS, and PICaSSO was 0.745, 0.718, and 0.694, respectively. Endoscopically-assessed remission reflected the absence of neutrophils [PHRI = 0] with areas under the ROC curve of 0.905, 0.906, and 0.877 for MES, UCEIS, and PICaSSO, respectively. The hazard ratio for disease flare between patients in histological activity/remission was statistically similar [p >0.05] across indexes [2.752, 2.706, and 2.871 for RHI, NHI, and PHRI, respectively]. CONCLUSION: PHRI correlates with endoscopy and stratifies risk of relapse similarly to RHI and NHI. Neutrophil-only assessment of UC is a simple yet viable alternative to established histological scores.

Correlations between Molecular Alterations, Histopathological Characteristics, and Poor Prognosis in Esophageal Adenocarcinoma.

Esophageal adenocarcinoma (EAC) is a severe malignancy with increasing incidence, poorly understood pathogenesis, and low survival rates. We sequenced 164 EAC samples of naïve patients (without chemo-radiotherapy) with high coverage using next-generation sequencing technologies. A total of 337 variants were identified across the whole cohort, with TP53 as the most frequently altered gene (67.27%). Missense mutations in TP53 correlated with worse cancer-specific survival (log-rank p = 0.001). In seven cases, we found disruptive mutations in HNF1alpha associated with other gene alterations. Moreover, we detected gene fusions through massive parallel sequencing of RNA, indicating that it is not a rare event in EAC. In conclusion, we report that a specific type of TP53 mutation (missense changes) negatively affected cancer-specific survival in EAC. HNF1alpha was identified as a new EAC-mutated gene.

Relationships Between Intestinal Ultrasound Parameters and Histopathologic Findings in a Prospective Cohort of Patients With Crohn's Disease Undergoing Surgery.

OBJECTIVES: Recognition of intestinal lesions with substantial fibrosis is strategic for optimal management of patients with Crohn's disease (CD). We aimed to assess the relationships between intestinal ultrasound parameters and histopathologic findings in a prospective cohort of patients with CD undergoing surgery. METHODS: Seventeen consecutive adult CD patients with involvement of the terminal ileum or the sigmoid colon who underwent bowel resective surgeries were enrolled and performed intestinal ultrasound (IUS) within 30 days prior to surgery. Uni- and multivariable analyses were used to assess the relationships between IUS parameters and histopathological elements of lesions. RESULTS: Sensitivity, specificity, accuracy, PPV and NPV (95% CI) of IUS in detecting stricturing and penetrating complications (surgical specimen as reference standard) were 93% (68-100), 86% (42-100), 91% (71-99), 93% (68-100) and 86% (42-100), and 78% (40-97), 92% (64-100), 86% (65-97), 88% (47-100) and 86% (57-98), respectively. Only the presence of hyperechogenic spiculates was statistically significantly associated with collagen content (b = 7.29, 95% CI = 1.88/12.69, P = .012), while only the presence of vascular signals at color Doppler (Limberg score 3 or 4) was significantly associated with active inflammation (OR = 10.0, 95% CI = 0.9/108.6, P = .037). There was a strong correlation between IUS and histological measurements of the wall thickness (r = 0.67, P = .01). CONCLUSIONS: The presence of hyperechogenic spiculates was associated with the presence of fibrosis, while the presence of marked vascular signals was associated with the presence of inflammation. Wall thickness measured by IUS was reliable and reproducible in comparison with histological measurement.

Contrast Enhanced EUS for Predicting Solid Pancreatic Neuroendocrine Tumor Grade and Aggressiveness.

Pancreatic neuroendocrine tumor (PNET) behavior assessment is a daily challenge for physicians. Modern PNET management varies from a watch-and-wait strategy to surgery depending on tumor aggressiveness. Therefore, the aggressiveness definition plays a pivotal role in the PNET work-up. The aggressiveness of PNETs is mainly based on the dimensions and histological grading, with sometimes a lack of specificity and sensibility. In the last twenty years, EUS has become a cornerstone in the diagnostic phase of PNET management for its high diagnostic yield and the possibility of obtaining a histological specimen. The number of EUS applications in the PNET work-up has been rapidly increasing with new and powerful possibilities. The application of contrast has led to an important step in PNET detection; in recent years, it has been gaining interesting applications in aggressiveness assessment. In this review, we underline the latest experiences and opportunities in the behavior assessment of PNETs using contact-enhanced EUS and contested enhanced harmonic EUS with a particular focus on the future application and possibility that these techniques could provide.

Dysfunctional Extracellular Matrix Remodeling Supports Perianal Fistulizing Crohn's Disease by a Mechanoregulated Activation of the Epithelial-to-Mesenchymal Transition.

BACKGROUND AND AIMS: Perianal fistula represents one of the most disabling manifestations of Crohn's disease (CD) due to complete destruction of the affected mucosa, which is replaced by granulation tissue and associated with changes in tissue organization. To date, the molecular mechanisms underlying perianal fistula formation are not well defined. Here, we dissected the tissue changes in the fistula area and addressed whether a dysregulation of extracellular matrix (ECM) homeostasis can support fistula formation. METHODS: Surgical specimens from perianal fistula tissue and the surrounding region of fistulizing CD were analyzed histologically and by RNA sequencing. Genes significantly modulated were validated by real-time polymerase chain reaction, Western blot, and immunofluorescence assays. The effect of the protein product of TNF-stimulated gene-6 (TSG-6) on cell morphology, phenotype, and ECM organization was investigated with endogenous lentivirus-induced overexpression of TSG-6 in Caco-2 cells and with exogenous addition of recombinant human TSG-6 protein to primary fibroblasts from region surrounding fistula. Proliferative and migratory assays were performed. RESULTS: A markedly different organization of ECM was found across fistula and surrounding fistula regions with an increased expression of integrins and matrix metalloproteinases and hyaluronan (HA) staining in the fistula, associated with increased newly synthesized collagen fibers and mechanosensitive proteins. Among dysregulated genes associated with ECM, TNFAI6 (gene encoding for TSG-6) was as significantly upregulated in the fistula compared with area surrounding fistula, where it promoted the pathological formation of complexes between heavy chains from inter-alpha-inhibitor and HA responsible for the formation of a crosslinked ECM. There was a positive correlation between TNFAI6 expression and expression of mechanosensitive genes in fistula tissue. The overexpression of TSG-6 in Caco-2 cells promoted migration, epithelial-mesenchymal transition, transcription factor SNAI1, and HA synthase (HAs) levels, while in fibroblasts, isolated from the area surrounding the fistula, it promoted an activated phenotype. Moreover, the enrichment of an HA scaffold with recombinant human TSG-6 protein promoted collagen release and increase of SNAI1, ITGA4, ITGA42B, and PTK2B genes, the latter being involved in the transduction of responses to mechanical stimuli. CONCLUSIONS: By mediating changes in the ECM organization, TSG-6 triggers the epithelial-mesenchymal transition transcription factor SNAI1 through the activation of mechanosensitive proteins. These data point to regulators of ECM as new potential targets for the treatment of CD perianal fistula.

Prognostic Factors across Poorly Differentiated Neuroendocrine Neoplasms: A Pooled Analysis.

INTRODUCTION: Poorly differentiated neuroendocrine carcinomas (NECs) are characterized by aggressive clinical course and poor prognosis. No reliable prognostic markers have been validated to date; thus, the definition of a specific NEC prognostic algorithm represents a clinical need. This study aimed to analyze a large NEC case series to validate the specific prognostic factors identified in previous studies on gastro-entero-pancreatic and lung NECs and to assess if further prognostic parameters can be isolated. METHODS: A pooled analysis of four NEC retrospective studies was performed to evaluate the prognostic role of Ki-67 cut-off, the overall survival (OS) according to primary cancer site, and further prognostic parameters using multivariable Cox proportional hazards model and machine learning random survival forest (RSF). RESULTS: 422 NECs were analyzed. The most represented tumor site was the colorectum (n = 156, 37%), followed by the lungs (n = 111, 26%), gastroesophageal site (n = 83, 20%; 66 gastric, 79%) and pancreas (n = 42, 10%). The Ki-67 index was the most relevant predictor, followed by morphology (pure or mixed/combined NECs), stage, and site. The predicted RSF response for survival at 1, 2, or 3 years showed decreasing survival with increasing Ki-67, pure NEC morphology, stage III-IV, and colorectal NEC disease. Patients with Ki-67 <55% and mixed/combined morphology had better survival than those with pure morphology. Morphology pure or mixed/combined became irrelevant in NEC survival when Ki-67 was ≥55%. The prognosis of metastatic patients who did not receive any treatment tended to be worse compared to that of the treated group. The prognostic impact of Rb1 immunolabeling appears to be limited when multiple risk factors are simultaneously assessed. CONCLUSION: The most effective parameters to predict OS for NEC patients could be Ki-67, pure or mixed/combined morphology, stage, and site.

Interferon regulatory factor 1 (IRF1) controls the metabolic programmes of low-grade pancreatic cancer cells.

OBJECTIVE: Pancreatic ductal adenocarcinomas (PDACs) include heterogeneous mixtures of low-grade cells forming pseudoglandular structures and compact nests of high-grade cells organised in non-glandular patterns. We previously reported that low-grade PDAC cells display high expression of interferon regulatory factor 1 (IRF1), a pivotal transcription factor of the interferon (IFN) system, suggesting grade-specific, cell-intrinsic activation of IFN responses. Here, we set out to determine the molecular bases and the functional impact of the activation of IFN-regulated responses in human PDACs. DESIGN: We first confirmed the correlation between glandular differentiation and molecular subtypes of PDAC on the one hand, and the expression of IRF1 and IFN-stimulated genes on the other. We next used unbiased omics approaches to systematically analyse basal and IFN-regulated responses in low-grade and high-grade PDAC cells, as well as the impact of IRF1 on gene expression programmes and metabolic profiles of PDAC cells. RESULTS: High-level expression of IRF1 in low-grade PDAC cells was controlled by endodermal lineage-determining transcription factors. IRF1-regulated gene expression equipped low-grade PDAC cells with distinctive properties related to antigen presentation and processing as well as responsiveness to IFN stimulation. Notably, IRF1 also controlled the characteristic metabolic profile of low-grade PDAC cells, suppressing both mitochondrial respiration and fatty acid synthesis, which may in part explain its growth-inhibiting activity. CONCLUSION: IRF1 links endodermal differentiation to the expression of genes controlling antigen presentation and processing as well as to the specification of the metabolic profile characteristic of classical PDAC cells.

Combined Large Cell Neuroendocrine Carcinomas of the Lung: Integrative Molecular Analysis Identifies Subtypes with Potential Therapeutic Implications.

BACKGROUND: Combined large cell neuroendocrine carcinoma (CoLCNEC) is given by the association of LCNEC with adeno or squamous or any non-neuroendocrine carcinoma. Molecular bases of CoLCNEC pathogenesis are scant and no standardized therapies are defined. METHODS: 44 CoLCNECs: 26 with adenocarcinoma (CoADC), 7 with squamous cell carcinoma (CoSQC), 3 with small cell carcinoma (CoSCLC), 4 with atypical carcinoid (CoAC) and 4 napsin-A positive LCNEC (NapA+), were assessed for alterations in 409 genes and transcriptomic profiling of 20,815 genes. RESULTS: Genes altered included TP53 (n = 30), RB1 (n = 14) and KRAS (n = 13). Targetable alterations included six KRAS G12C mutations and ALK-EML4 fusion gene. Comparison of CoLCNEC transcriptomes with 86 lung cancers of pure histology (8 AC, 19 ADC, 19 LCNEC, 11 SCLC and 29 SQC) identified CoLCNEC as a separate entity of neuroendocrine tumours with three different molecular profiles, two of which showed a non-neuroendocrine lineage. Hypomethylation, activation of MAPK signalling and association to immunotherapy signature specifically characterized each of three CoLCNEC molecular clusters. Prognostic stratification was also provided. CONCLUSIONS: CoLCNECs are an independent histologic category. Our findings support the extension of routine evaluation of KRAS mutations, fusion genes and immune-related markers to offer new perspectives in the therapeutic management of CoLCNEC.

Invasive IPMN relapse later and more often in lungs in comparison to pancreatic ductal adenocarcinoma.

BACKGROUND: The different oncological outcomes of invasive intraductal papillary mucinous neoplasm (I-IPMN) and pancreatic ductal adenocarcinoma (PDAC) are debated. This study aimed to compare disease recurrence patterns and histopathological characteristics in patients with resected I-IPMN and PDAC. METHODS: Consecutive patients undergoing surgical resection for stage I-III I-IPMN or PDAC between 2010 and 2016 were retrospectively analyzed. Patients treated with neoadjuvant therapy or resected for Tis neoplasia were excluded. All surgical specimens were re-staged according to AJCC-8th-edition. RESULTS: A total of 330 patients were included, of whom 43 had I-IPMN and 287 had PDAC. Median follow-up time was 26.7 (1.3-92.3) months and estimated median disease-free survival (DFS) was 60.3 months (47.2-73.4) for I-IPMN and 23.8 (19.3-28.2) months for PDAC (p < 0.001). During follow-up, 32.6% of I-IPMN and 67.9% of PDAC patients experienced recurrence (p < 0.001). The sites of first recurrence were the lungs (38.5% vs 13.1%, p = 0.027), liver (28.6% vs 45.0%, p = 0.180) and local (15.4% vs 36.6%, p = 0.101) for I-IPMN and PDAC, respectively. At multivariate analysis, I-IPMN histology remained an independent predictive factor for longer DFS (OR 0.528, CI 95% 0.278-1.000, p = 0.050), regardless of stage or adjuvant chemotherapy. I-IPMN and PDAC differed in rates of neuroinvasion (51.2% vs 97.2%) and positive lymph node status (N+) (46.5% vs 82.7%), especially in patients with lower T status. CONCLUSION: I-IPMN showed a different recurrence pattern compared to PDAC, with a higher lung tropism, and longer DFS. This different biological behavior is associated with lower rates of neuroinvasion and nodal involvement, especially in early-stage disease.

Oncogenic KRAS-Induced Protein Signature in the Tumor Secretome Identifies Laminin-C2 and Pentraxin-3 as Useful Biomarkers for the Early Diagnosis of Pancreatic Cancer.

KRAS mutations characterize pancreatic cell transformation from the earliest stages of carcinogenesis, and are present in >95% of pancreatic ductal adenocarcinoma (PDAC) cases. In search of novel biomarkers for the early diagnosis of PDAC, we identified the proteins secreted by the normal human pancreatic cell line (HPDE) recently transformed by inducing the overexpression of the KRASG12V oncogene. We report a proteomic signature of KRAS-induced secreted proteins, which was confirmed in surgical tumor samples from resected PDAC patients. The putative diagnostic performance of three candidates, Laminin-C2 (LAMC2), Tenascin-C (TNC) and Pentraxin-3 (PTX3), was investigated by ELISA quantification in two cohorts of PDAC patients (n = 200) eligible for surgery. Circulating levels of LAMC2, TNC and PTX3 were significantly higher in PDAC patients compared to the healthy individuals (p < 0.0001). The Receiver Operating Characteristics (ROC) curve showed good sensitivity (1) and specificity (0.63 and 0.85) for LAMC2 and PTX3, respectively, but not for TNC, and patients with high levels of LAMC2 had significantly shorter overall survival (p = 0.0007). High levels of LAMC2 and PTX3 were detected at early stages (I−IIB) and in CA19-9-low PDAC patients. In conclusion, pancreatic tumors release LAMC2 and PTX3, which can be quantified in the systemic circulation, and may be useful in selecting patients for further diagnostic imaging.

Ampullary Neuroendocrine Neoplasms: Identification of Prognostic Factors in a Multicentric Series of 119 Cases.

Neuroendocrine neoplasms (NENs) of the major and minor ampulla are rare diseases with clinico-pathologic features distinct from non-ampullary-duodenal NENs. However, they have been often combined and the knowledge on prognostic factors specific to ampullary NENs (Amp-NENs) is limited. The aim of this study was to identify factors associated with metastatic potential and patient prognosis in Amp-NENs. We clinically and histologically investigated an international series of 119 Amp-NENs, comprising 93 ampullary neuroendocrine tumors (Amp-NETs) and 26 neuroendocrine carcinomas (Amp-NECs). Somatostatin-producing tubulo-acinar NET represented the predominant Amp-NET histologic subtype (58 cases, 62%, 12 associated with type 1 neurofibromatosis). Compared to Amp-NETs, Amp-NECs arose in significantly older patients and showed a larger tumor size, a more frequent small vessel invasion, a deeper level of invasion and a higher rate of distant metastasis, and, importantly, a tremendously worse disease-specific patient survival. In Amp-NETs, the WHO grade proved to be a strong predictor of disease-specific survival (hazard ratio: 12.61, p < 0.001 for G2 vs G1), as well as patient age at diagnosis > 60 years, small vessel invasion, pancreatic invasion, and distant metastasis at diagnosis. Although nodal metastatic disease was not associated with survival by itself, patients with > 3 metastatic lymph nodes showed a worse outcome in comparison with the remaining Amp-NET cases with lymphadenectomy. Tumor epicenter in the major ampulla, small vessel invasion, and tumor size > 16 mm were independent predictors of nodal metastases in Amp-NETs. In conclusion, we identified prognostic factors, which may eventually help guide treatment decisions in Amp-NENs.

Reproducibility of the electronic chromoendoscopy PICaSSO score (Paddington International Virtual ChromoendoScopy ScOre) in ulcerative colitis using multiple endoscopic platforms: a prospective multicenter international study (with video).

BACKGROUND AND AIMS: Endoscopic and histologic remission (HR) are key therapeutic targets in the management of ulcerative colitis (UC). The aim of this study was to evaluate the reproducibility of the Paddington International virtual ChromoendoScopy ScOre (PICaSSO), a virtual chromoendoscopy score originally validated by use of the iSCAN platform, with the narrow-band imaging (NBI), linked-color imaging (LCI), and blue-laser imaging (BLI) platforms. METHODS: We evaluated endoscopic activity using the Mayo Endoscopic Score (MES), the Ulcerative Colitis Endoscopic Index of Severity (UCEIS), and PICaSSO in 159 UC patients (78 NBI and 81 BLI/LCI) who underwent colonoscopy in 2 tertiary referral centers. HR was defined by the Robarts Histopathology Index (RHI) and the Nancy Histologic Index (NHI). Receiver operating characteristic curves were plotted to evaluate endoscopic scores for the prediction of HR. Intraclass correlation coefficients (ICC) between endoscopists were evaluated. RESULTS: PICaSSO had an ICC of 0.825 when the NBI and BLI/LCI cohorts were combined, higher than MES and UCEIS. The correlation between PICaSSO and RHI and NHI was 0.83 and 0.79 in the NBI cohort and between 0.63 and 0.65 in LCI/BLI. In the NBI cohort, the accuracy of MES, UCEIS, and PICaSSO was 0.936, 0.897, and 0.808 for HR measured by RHI and 0.897, 0.885, and 0.821 by NHI, respectively. In the BLI/LCI cohort, the accuracy of MES, UCEIS, LCI PICaSSO and BLI PICaSSO was 0.765, 0.778, 0.827, and 0.79 to predict HR with RHI and NHI, respectively. CONCLUSIONS: The PICaSSO score can be consistently and accurately reproduced with NBI and LCI/BLI and therefore can be applied to all virtual electronic chromoendoscopy platforms.

Pancreatic ductal adenocarcinoma and invasive intraductal papillary mucinous tumor: Different prognostic factors for different overall survival.

BACKGROUND: It is unclear whether invasive intraductal papillary mucinous neoplasm (IPMN) has different clinical and prognostic characteristics, beyond histological factors, when compared to pancreatic ductal adenocarcinoma (PDAC). AIMS: compare prognostic features of resected PDAC and invasive IPMN METHODS: A retrospective study of patients resected for PDAC or invasive IPMN realized at Humanitas Cancer Center's Pancreatic Surgery Unit, Milan, Italy, between 2010 and 2016. Data recorded included patient demographics, onset symptoms, preoperative health status, tumor features, histology and surgical characteristics. Overall survival was estimated using Kaplan-Meier and prognostic factors for survival were assessed by multivariate Cox regression. RESULTS: A total of 332 patients were included (PDAC, n = 289; invasive IPMN, n = 43). Patients with invasive IPMN had better overall survival than PDAC patients (median: 76.6 versus 25.6 months; 5-year OS rate: 65.4% vs. 14.2%; p < 0.001). PDAC histology was associated with a significantly higher risk of death than IPMN (hazard ratio 1.815, 95% CI: 1.02, 3.24; p = 0.044). Survival was also worse with PDAC in early-stage disease (IA-IB-IIA, N0). In multivariate analysis, independent predictors of worse survival included perineural invasion, preoperative ASA physical status ≥3 and pain at diagnosis. CONCLUSIONS: Patients with IPMN had a better prognosis than PDAC patients, regardless of disease stage.

The Prognostic Impact of Histology in Esophageal and Esophago-Gastric Junction Adenocarcinoma.

Stage significantly affects survival of esophageal and esophago-gastric junction adenocarcinomas (EA/EGJAs), however, limited evidence for the prognostic role of histologic subtypes is available. The aim of the study was to describe a morphologic approach to EA/EGJAs and assess its discriminating prognostic power. Histologic slides from 299 neoadjuvant treatment-naïve EA/EGJAs, resected in five European Centers, were retrospectively reviewed. Morphologic features were re-assessed and correlated with survival. In glandular adenocarcinomas (240/299 cases-80%), WHO grade and tumors with a poorly differentiated component ≥6% were the most discriminant factors for survival (both p < 0.0001), distinguishing glandular well-differentiated from poorly differentiated adenocarcinomas. Two prognostically different histologic groups were identified: the lower risk group, comprising glandular well-differentiated (34.4%) and rare variants, such as mucinous muconodular carcinoma (2.7%) and diffuse desmoplastic carcinoma (1.7%), versus the higher risk group, comprising the glandular poorly differentiated subtype (45.8%), including invasive mucinous carcinoma (5.7%), diffuse anaplastic carcinoma (3%), mixed carcinoma (6.7%) (CSS p < 0.0001, DFS p = 0.001). Stage (p < 0.0001), histologic groups (p = 0.001), age >72 years (p = 0.008), and vascular invasion (p = 0.015) were prognostically significant in the multivariate analysis. The combined evaluation of stage/histologic group identified 5-year cancer-specific survival ranging from 87.6% (stage II, lower risk) to 14% (stage IVA, higher risk). Detailed characterization of histologic subtypes contributes to EA/EGJA prognostic prediction.