Artificial Intelligence to Predict the Risk of Lymph Node Metastasis in T2 Colorectal Cancer.

OBJECTIVE: To develop and externally validate an updated artificial intelligence (AI) prediction system for stratifying the risk of lymph node metastasis (LNM) in T2 colorectal cancer (CRC). SUMMARY BACKGROUND DATA: Recent technical advances allow complete local excision of T2 CRC, traditionally treated with surgical resection. Yet, the widespread adoption of this approach is hampered by the inability to stratify the risk of LNM. METHODS: Data from pT2 CRC patients undergoing surgical resection between April 2000 and May 2022 at one Japanese and one Italian center were analyzed. Primary goal was AI system development for accurate LNM prediction. Predictors encompassed seven variables: age, sex, tumor size and location, lympho-vascular invasion, histological differentiation, and carcinoembryonic antigen level. The tool's discriminating power was assessed via Area Under the Curve (AUC), sensitivity, and specificity. RESULTS: Out of 735 initial patients, 692 were eligible. Training and validation cohorts comprised of 492 and 200 patients, respectively. The AI model displayed an AUC of 0.75 in the combined validation dataset. Sensitivity for LNM prediction was 97.8% and specificity was 15.6%. The Positive and the Negative Predictive Value were 25.7% and 96% respectively. The False Negative (FN) rate was 2.2%, the False Positive was 84.4%. CONCLUSIONS: Our AI model, based on easily accessible clinical and pathological variables, moderately predicts LNM in T2 CRC. However, the risk of FN needs to be considered. The training of the model including more patients across Western and Eastern centers -differentiating between colon and rectal cancers- may improve its performance and accuracy.

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.

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.

FOXA2 controls the cis-regulatory networks of pancreatic cancer cells in a differentiation grade-specific manner.

Differentiation of normal and tumor cells is controlled by regulatory networks enforced by lineage-determining transcription factors (TFs). Among them, TFs such as FOXA1/2 bind naïve chromatin and induce its accessibility, thus establishing new gene regulatory networks. Pancreatic ductal adenocarcinoma (PDAC) is characterized by the coexistence of well- and poorly differentiated cells at all stages of disease. How the transcriptional networks determining such massive cellular heterogeneity are established remains to be determined. We found that FOXA2, a TF controlling pancreas specification, broadly contributed to the cis-regulatory networks of PDACs. Despite being expressed in both well- and poorly differentiated PDAC cells, FOXA2 displayed extensively different genomic distributions and controlled distinct gene expression programs. Grade-specific functions of FOXA2 depended on its partnership with TFs whose expression varied depending on the differentiation grade. These data suggest that FOXA2 contributes to the regulatory networks of heterogeneous PDAC cells via interactions with alternative partner TFs.

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.

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.

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.

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.

Ki-67 Index of 55% Distinguishes Two Groups of Bronchopulmonary Pure and Composite Large Cell Neuroendocrine Carcinomas with Distinct Prognosis.

BACKGROUND: Little information is available concerning prognostic factors for bronchopulmonary large cell neuroendocrine carcinomas (BP-LCNECs) and even less is known about combined LCNECs (Co-LCNECs). We investigated whether an integrated morphological, immunohistochemical, and molecular approach could be used for their prognostic evaluation. METHODS: Morphological (including combined features), proliferative (mitotic count/Ki-67 index), immunohistochemical (napsin A, p40, TTF-1, CD44, OTP, SSTR2A, SSTR5, mASH1, p53, RB1, and MDM2), and genomic (TP53, RB1, ATM, JAK2, KRAS, and STK11) findings were analyzed in BP-LCNECs from 5 Italian centers, and correlated with overall survival (OS). The Ki-67 index was expressed as the percentage of positive cells in hot spots as indicated in the WHO 2019 Digestive System Tumors and, for Co-LCNECs, the Ki-67 index was evaluated only in the LCNEC component. RESULTS: A total of 111 LCNECs were distinguished into 70 pure LCNECs, 35 Co-LCNECs (27 with adenocarcinoma [ADC] and 8 with squamous cell carcinoma [SqCC]), and 6 LCNECs with only napsin A immunoreactivity. The Ki-67 index cutoff at 55% evaluated in the neuroendocrine component was the most powerful predictor of OS (log-rank p = 0.0001) in all LCNECs; 34 cases had a Ki-67 index <55% (LCNEC-A) and 77 had a Ki-67 index ≥55% (LCNEC-B). Statistically significant differences in OS (log-rank p = 0.0001) were also observed between pure and Co-LCNECs. A significant difference in OS was found between pure LCNECs-A and Co-LCNECs-A (p < 0.05) but not between pure LCNECs-B and Co-LCNECs-B. Co-LCNEC-ADC and LCNEC napsin A+ cases had longer OS than pure LCNEC and Co-LCNEC-SqCC cases (log-rank p = 0.0001). On multivariable analysis, tumor location, pure versus combined features, and napsin A, but no single gene mutation, were significantly associated with OS after adjustment for Ki-67 index and study center (p < 0.05). CONCLUSIONS: The Ki-67 proliferation index and the morphological characterization of combined features in LCNECs seem to be important tools for predicting clinical outcome in BP-LCNECs.

Digital Pathology During the COVID-19 Outbreak in Italy: Survey Study.

BACKGROUND: Transition to digital pathology usually takes months or years to be completed. We were familiarizing ourselves with digital pathology solutions at the time when the COVID-19 outbreak forced us to embark on an abrupt transition to digital pathology. OBJECTIVE: The aim of this study was to quantitatively describe how the abrupt transition to digital pathology might affect the quality of diagnoses, model possible causes by probabilistic modeling, and qualitatively gauge the perception of this abrupt transition. METHODS: A total of 17 pathologists and residents participated in this study; these participants reviewed 25 additional test cases from the archives and completed a final psychologic survey. For each case, participants performed several different diagnostic tasks, and their results were recorded and compared with the original diagnoses performed using the gold standard method (ie, conventional microscopy). We performed Bayesian data analysis with probabilistic modeling. RESULTS: The overall analysis, comprising 1345 different items, resulted in a 9% (117/1345) error rate in using digital slides. The task of differentiating a neoplastic process from a nonneoplastic one accounted for an error rate of 10.7% (42/392), whereas the distinction of a malignant process from a benign one accounted for an error rate of 4.2% (11/258). Apart from residents, senior pathologists generated most discrepancies (7.9%, 13/164). Our model showed that these differences among career levels persisted even after adjusting for other factors. CONCLUSIONS: Our findings are in line with previous findings, emphasizing that the duration of transition (ie, lengthy or abrupt) might not influence the diagnostic performance. Moreover, our findings highlight that senior pathologists may be limited by a digital gap, which may negatively affect their performance with digital pathology. These results can guide the process of digital transition in the field of pathology.

Dissection of transcriptional and cis-regulatory control of differentiation in human pancreatic cancer.

The histological grade of carcinomas describes the ability of tumor cells to organize in differentiated epithelial structures and has prognostic and therapeutic impact. Here, we show that differential usage of the genomic repertoire of transcriptional enhancers leads to grade-specific gene expression programs in human pancreatic ductal adenocarcinoma (PDAC). By integrating gene expression profiling, epigenomic footprinting, and loss-of-function experiments in PDAC cell lines of different grade, we identified the repertoires of enhancers specific to high- and low-grade PDACs and the cognate set of transcription factors acting to maintain their activity. Among the candidate regulators of PDAC differentiation, KLF5 was selectively expressed in pre-neoplastic lesions and low-grade primary PDACs and cell lines, where it maintained the acetylation of grade-specific enhancers, the expression of epithelial genes such as keratins and mucins, and the ability to organize glandular epithelia in xenografts. The identification of the transcription factors controlling differentiation in PDACs will help clarify the molecular bases of its heterogeneity and progression.

Trans-duodenal ampullectomy for ampullary neoplasms: early and long-term outcomes in 36 consecutive patients.

BACKGROUND: Trans-duodenal ampullectomy (TDA) is a surgical option for the treatment of selected ampullary neoplasms. The aim of this study was to evaluate our experience with TDA for the treatment of ampullary neoplasms, focusing on indications, technical aspects, and short- and long-term outcomes. METHODS: All TDAs for ampullary neoplasms performed between January 2010 and December 2018 at our institution were retrospectively evaluated. Patients had ampullary neoplasms with low-grade dysplasia or in situ carcinoma (Tis) not suitable for an endoscopic approach, ampullary carcinoma unfit for pancreaticoduodenectomy (PD), or ampullary neuroendocrine G1-tumours. RESULTS: Thirty-six patients were included in the study: 9 (25.0%) with neoplasms with low-grade dysplasia, 4 (11.1%) with G1 neuroendocrine tumours and 23 (63.9%) with Tis or invasive carcinoma. Mean operative time was 252.5 min. Overall and severe (Clavien-Dindo > IIIa) morbidity rate was 44.4% and 13.9%, respectively. No 90-day mortality was observed. At follow-up, no deaths were observed and local recurrence rate was 11.1% for patients with ampullary adenomas with low-grade dysplasia. Among four patients with neuroendocrine neoplasms, only one developed recurrence (pulmonary). Tis, T1 and T2 lesions were found in 16 (69.6%), 2 (8.7%) and 5 (21.7%) patients, respectively: recurrence occurred in 3 patients with Tis lesions (one malignant), no patients with T1 neoplasms and 2 patients with T2 lesions (3 patients had a survival of > 3 years). CONCLUSIONS: TDA is a feasible and effective surgical procedure for the treatment of ampullary adenomas with low-grade dysplasia when endoscopic approach is contraindicated or has failed. For lesions with evidence of malignancy, TDA seems to be an oncological safe procedure for Tis ampullary cancer and a good palliative procedure for patients unfit for PD. Moreover, TDA may be appropriate for the treatment of G1 ampullary neuroendocrine neoplasms. A large multicentre study of TDA for early ampullary cancers is needed.

Multi-band mucosectomy for neoplasia in patients with Barrett's esophagus: in vivo comparison between two different devices.

BACKGROUND: Multi-band mucosectomy (MBM) is effective and safe for Barrett's neoplasia. No studies have yet compared the efficacy and safety of the MBM devices commercially available: Duette™ (CookMedical) and Captivator™ (BostonScientific). Our aim is to compare the two devices. METHODS: This is a dual-center retrospective case-control study (Rozzano, Portsmouth) comparing efficacy, safety, and histology of resected specimens between Duette™ (DUE) and Captivator™ (CAPT). Efficacy was assessed by R0 and local recurrence (LR) rate. Bleedings, perforations, and strictures were recorded as safety outcomes. Moreover, the specimens were re-examined by two pathologists, blinded about the study group, to assess the maximum thickness of both the whole specimens and the resected submucosal layer. RESULTS: Seventy-six patients (38 per group) were included. The two groups did not differ in terms of baseline characteristics. R0 resection was achieved in 96.7% versus 96.3% (p = ns) and LR were recorded in 4/38 (10.5%) versus 3/38 (7.9%) in DUE and CAPT group, respectively (p = ns). Considering Duette™ versus Captivator™, 2 versus 3 patients developed a symptomatic stricture. Only one post-procedural bleeding occurred (Captivator™). Maximum medium thicknesses of specimens and of resected submucosa did not differ between the groups. CONCLUSIONS: MBM is safe and effective for resecting visible lesions using either of the two available devices.

Surveillance of neo-squamous epithelium after ablation of Barrett's esophagus: is it better to use jumbo over standard biopsy forceps?

BACKGROUND AND AIMS: As obtaining adequate tissue on biopsy is critical for the detection of residual and recurrent intestinal metaplasia/dysplasia in Barrett's esophagus (BE) patients undergone Barrett's endoscopic eradication therapy (BET), we decided to compare the adequacy of biopsy specimens using jumbo versus standard biopsy forceps. METHODS: This is a two-center study of patients' post-radiofrequency ablation of dysplastic BE. After BET, jumbo (Boston Scientific©, Radial Jaw 4, opening diameter 2.8 mm) or standard (Boston Scientific©, Radial Jaw 4, opening diameter 2.2 mm) biopsy forceps were utilized to obtain surveillance biopsies from the neo-squamous epithelium. Presence of lamina propria and proportion of squamous epithelium with partial or full thickness lamina propria was recorded by two experienced gastrointestinal pathologists who were blinded. Squamous epithelial biopsies that contained at least two-thirds of lamina propria were considered 'adequate'. RESULTS: In a total of 211 biopsies from 55 BE patients, 145 biopsies (29 patients, 18 males, mean age 61 years, interquartile range [IQR] 33-83) were obtained using jumbo forceps and 66 biopsies (26 patients, all males, mean age 65 years, IQR 56-76) using standard forceps biopsies. Comparing jumbo versus standard forceps, the proportion of specimens with any subepithelial lamina propria was 51.7% versus 53%, P = 0.860 and the presence of adequate subepithelial lamina propria was 17.9% versus 9.1%, P = 0.096 respectively. CONCLUSIONS: Use of jumbo forceps does not appear to have added advantage over standard forceps to obtain adequate biopsy specimens from the neo-squamous mucosa post-ablation.

Pancreatic serous cystoadenoma (CSA) showing increased tracer uptake at 68-GaDOTA-peptide Positron Emission Tomography (68Ga-DOTA-peptide PET-CT): a case report.

BACKGROUND: Serous cysto-adenoma (SCA) is a rare benign neoplasm of the pancreas. SCA can mimic other pancreatic lesions, such as neuroendocrine tumours. 68Gallium-DOTA-peptide Positron Emission Tomography (PET) is able to image in vivo the over-expression of the somatostatin receptors, playing an important role for the identification of neuroendocrine neoplasms. CASE PRESENTATION: We reported a case of 63-year-old man, with a solid lesion of 7 cm of diameter of the body-tail of the pancreas. Two fine-needle-aspirations (FNA) were inconclusive. A 68Ga-DOTA-peptide PET-CT revealed a pathological uptake of the pancreatic lesion. The diagnosis of a pancreatic neuroendocrine neoplasm was established and a laparoscopic distal splenopancreatectomy and cholecystectomy was performed. Final histopathological report revealed the presence of a micro-cystic SCA. CONCLUSIONS: The current case firstly reports a pancreatic SCA showing increased radiopharmaceutical uptake at 68Ga-DOTA-peptide PET-CT images. This unexpected finding should be taken into account during the diagnostic algorithm of a pancreatic lesion, in order to minimize the risk of misdiagnosis and overtreatment of SCA.

Gastro-esophageal reflux disease and Barrett's esophagus: an overview with an histologic diagnostic approach.

The first part of this overview on non-neoplastic esophagus is focused on gastro-esophageal reflux disease (GERD) and Barrett's esophagus. In the last 20 years much has changed in histological approach to biopsies of patients with gastro-esophageal reflux disease. In particular, elementary histologic lesions have been well defined and modality of evaluation and grade are detailed, their sensitivity and specificity has been evaluated and their use has been validated by several authors. Also if there is not a clinical indication to perform biopsies in patient with GERD, the diagnosis of microscopic esophagitis, when biopsies are provided, can be performed by following simple rules for evaluation which allow pathologists to make the diagnosis with confidence. On the other hand, biopsies are required for the diagnosis of Barrett's esophagus. This diagnosis is the synthesis of endoscopic picture (which has to be provided with the proper description on extent and with adequate biopsies number) and histologic pattern. The current guidelines and expert opinions for the correct management of these diagnosis are detailed.

Non gastro-esophageal reflux disease related esophagitis: an overview with a histologic diagnostic approach.

Several pathological conditions, other than gastro-esophageal reflux disease and its complications, can affect the esophagus. While some of these can present with unspecific lesions (i.e. ulcers and epithelial damage) and require clinico-pathological correlation for diagnosis (i.e. drug-induced esophagitis and corrosive esophagitis) other conditions show distinctive histological lesions which enable the pathologist to reach the diagnosis (i.e. some specific infectious esophagites and Crohn's disease). In this context eosinophilic esophagitis is the condition which has been increasingly studied in the last two decades, while lymphocytic esophagitis, a relatively new entity, still represents an enigma. This overview will focus on and describe histologic lesions which allow pathologists to differentiate between these conditions.

Lymphatic endothelium contributes to colorectal cancer growth via the soluble matrisome component GDF11.

Colorectal cancer (CRC) is one of the most malignant tumors worldwide. Stromal cells residing in the tumor microenvironment strongly contribute to cancer progression through their crosstalk with cancer cells and extracellular matrix. Here we provide the first evidence that CRC-associated lymphatic endothelium displays a distinct matrisome-associated transcriptomic signature, which distinguishes them from healthy intestinal lymphatics. We also demonstrate that CRC-associated human intestinal lymphatic endothelial cells regulate tumor cell growth via growth differentiation factor 11, a soluble matrisome component which in CRC patients was found to be associated with tumor progression. Our data provide new insights into lymphatic contribution to CRC growth, aside from their conventional role as conduits of metastasis.

Pancreatic Neuroendocrine Tumours: The Role of Endoscopic Ultrasound Biopsy in Diagnosis and Grading Based on the WHO 2017 Classification.

BACKGROUND: One of the controversial issues in the diagnosis of pancreatic neuroendocrine tumours (pNETs) is the accurate prediction of their clinical behaviour. OBJECTIVES: The aim of the study was to evaluate the role of endoscopic ultrasound (EUS) biopsy in the diagnosis and grading of pNETs in a certified ENETS Center. METHODS: A prospectively maintained database of EUS biopsy procedures was retrospectively reviewed to identify all consecutive patients referred to a certified ENETS Center with a suspicion of pNET between June 2014 and April 2017. The cytological and/or histological specimens were stained and the Ki-67 labeling index was evaluated. In patients undergoing surgery, the grade obtained with EUS-guided biopsy was compared with the final histological grade. The grade was evaluated according to the 2017 WHO classifications and grading. RESULTS: The study population included 59 patients. EUS biopsy material reached an adequacy of 98.3% and was adequate for Ki-67 evaluation in 84.7% of cases. Twenty-nine patients (49.2%) underwent surgery. Of these, 25 patients had Ki-67 evaluated on EUS biopsy: the agreement between EUS biopsy grading and surgical specimen grading was 84%. CONCLUSION: EUS biopsy is an accurate method for the diagnosis and grading of pNETs based on the WHO 2017 Ki-67 labelling scheme.

Regorafenib in patients with refractory metastatic pancreatic cancer: a Phase II study (RESOUND).

Aim: Regorafenib may be active in different cancer types. This Phase II trial included patients with various refractory cancer types treated with regorafenib. Here, we report the results of the pancreatic adenocarcinoma cohort. Methods: The primary end point was progression-free survival (PFS) rate at 8 weeks; further investigation of regorafenib would be warranted with a PFS rate ≥50%. Results: A total of 20 patients were enrolled. The best response was stable disease in four patients (20%). The 8-week PFS rate was 25% with a median PFS of 1.7 months (95% CI: 1.5-2.0). A total of 13 patients (65%) experienced grade 3-4 treatment-related adverse events. Conclusion: The study did not meet its primary end point. Further investigation of regorafenib monotherapy in this setting is not recommended. Clinical Trial Registration: NCT02307500.