Artificial Intelligence Enabled Histological Prediction of Remission or Activity and Clinical Outcomes in Ulcerative Colitis.

BACKGROUND & AIMS: Microscopic inflammation has significant prognostic value in ulcerative colitis (UC); however, its assessment is complex with high interobserver variability. We aimed to develop and validate an artificial intelligence (AI) computer-aided diagnosis system to evaluate UC biopsies and predict prognosis. METHODS: A total of 535 digitalized biopsies (273 patients) were graded according to the PICaSSO Histologic Remission Index (PHRI), Robarts, and Nancy Histological Index. A convolutional neural network classifier was trained to distinguish remission from activity on a subset of 118 biopsies, calibrated on 42 and tested on 375. The model was additionally tested to predict the corresponding endoscopic assessment and occurrence of flares at 12 months. The system output was compared with human assessment. Diagnostic performance was reported as sensitivity, specificity, prognostic prediction through Kaplan-Meier, and hazard ratios of flares between active and remission groups. We externally validated the model in 154 biopsies (58 patients) with similar characteristics but more histologically active patients. RESULTS: The system distinguished histological activity/remission with sensitivity and specificity of 89% and 85% (PHRI), 94% and 76% (Robarts Histological Index), and 89% and 79% (Nancy Histological Index). The model predicted the corresponding endoscopic remission/activity with 79% and 82% accuracy for UC endoscopic index of severity and Paddington International virtual ChromoendoScopy ScOre, respectively. The hazard ratio for disease flare-up between histological activity/remission groups according to pathologist-assessed PHRI was 3.56, and 4.64 for AI-assessed PHRI. Both histology and outcome prediction were confirmed in the external validation cohort. CONCLUSION: We developed and validated an AI model that distinguishes histologic remission/activity in biopsies of UC and predicts flare-ups. This can expedite, standardize, and enhance histologic assessment in practice and trials.

PICaSSO Histologic Remission Index (PHRI) in ulcerative colitis: development of a novel simplified histological score for monitoring mucosal healing and predicting clinical outcomes and its applicability in an artificial intelligence system.

Histological remission is evolving as an important treatment target in UC. We aimed to develop a simple histological index, aligned to endoscopy, correlated with clinical outcomes, and suited to apply to an artificial intelligence (AI) system to evaluate inflammatory activity. METHODS: Using a set of 614 biopsies from 307 patients with UC enrolled into a prospective multicentre study, we developed the Paddington International virtual ChromoendoScopy ScOre (PICaSSO) Histologic Remission Index (PHRI). Agreement with multiple other histological indices and validation for inter-reader reproducibility were assessed. Finally, to implement PHRI into a computer-aided diagnosis system, we trained and tested a novel deep learning strategy based on a CNN architecture to detect neutrophils, calculate PHRI and identify active from quiescent UC using a subset of 138 biopsies. RESULTS: PHRI is strongly correlated with endoscopic scores (Mayo Endoscopic Score and UC Endoscopic Index of Severity and PICaSSO) and with clinical outcomes (hospitalisation, colectomy and initiation or changes in medical therapy due to UC flare-up). A PHRI score of 1 could accurately stratify patients' risk of adverse outcomes (hospitalisation, colectomy and treatment optimisation due to flare-up) within 12 months. Our inter-reader agreement was high (intraclass correlation 0.84). Our preliminary AI algorithm differentiated active from quiescent UC with 78% sensitivity, 91.7% specificity and 86% accuracy. CONCLUSIONS: PHRI is a simple histological index in UC, and it exhibits the highest correlation with endoscopic activity and clinical outcomes. A PHRI-based AI system was accurate in predicting histological remission.

An International Multicenter Real-Life Prospective Study of Electronic Chromoendoscopy Score PICaSSO in Ulcerative Colitis.

BACKGROUND & AIMS: Endoscopic and histologic remission are important goals in the treatment of ulcerative colitis (UC). We investigated the correlation of the recently developed Paddington International Virtual ChromoendoScopy ScOre (PICaSSO) and other established endoscopic scores against multiple histological indices and prospectively assessed outcomes. METHODS: In this prospective multicenter international study, inflammatory activity was assessed with high-definition and virtual chromoendoscopy in the rectum and sigmoid using the Mayo Endoscopic Score (MES), UC Endoscopic Index of Severity (UCEIS), and PICaSSO. Targeted biopsies were taken for assessment using Robarts Histological Index (RHI), Nancy Histological index (NHI), ECAP (Extent, Chronicity, Activity, Plus score), Geboes, and Villanacci. Follow-up data were obtained at 6 and 12 months after colonoscopy. RESULTS: A total of 307 patients were recruited. There was strong correlation between PICaSSO and histology scores, significantly superior to correlation coefficients of MES and UCEIS with histology scores. A PICaSSO score of ≤3 detected histologic remission by RHI (≤3 + absence of neutrophils) with area under the receiver operating characteristic curve (AUROC) 0.90 (95% confidence interval [CI] 0.86-0.94) and NHI (≤1) AUROC 0.82 (95% CI 0.77-0.87). The interobserver agreement for PICaSSO was 0.88 (95% CI 0.83-0.92). At 6- and 12-months follow-up, PICaSSO score ≤3 predicted better outcomes than PICaSSO >3 (hazard ratio [HR] 0.19 [0.11-0.33] and 0.22 [0.13-0.34], respectively),} as well as PICaSSO 4-8 (HR 0.25 [0.12-0.53] and 0.22 (0.12-0.39), respectively) and similar to histologic remission. CONCLUSION: In this first real-life multicenter study, the PICaSSO score correlated strongly with multiple histological indices. Furthermore, PICaSSO score predicted specified clinical outcomes at 6 and 12 months, similar to histology. Thus, PICaSSO can be a useful endoscopic tool in the therapeutic management of UC.

Macroscopic and microscopic characteristics of low grade appendiceal mucinous neoplasms (LAMN) on appendectomy specimens and correlations with pseudomyxoma peritonei development risk.

Low grade appendiceal mucinous neoplasm (LAMN) is the primary source of pseudomyxoma peritonei (PMP). PMP may develop after seemingly complete resection of primary tumor by appendectomy, which is unpredictable due to lack of reliable prognostic indicators. We retrospectively reviewed 154 surgically resected LAMNs to explore if any of the macroscopic and microscopic characteristics may be associated with increasing risk of PMP development. Our major findings include: (1) As compared to those without PMP, the cases that developed PMP were more frequent to have (a) smaller luminal diameter (<1 cm) and thicker wall, separate mucin aggregations, and microscopic perforation/rupture, all suggestive of luminal mucin leakage; (b) microscopic acellular mucin presenting on serosal surface and not being confined to mucosa; and (c) neoplastic epithelium dissecting outward beyond mucosa, however, with similar frequency of neoplastic cells being present in muscularis propria. (2) Involvement of neoplastic cells or/and acellular mucin at surgical margin did not necessarily lead to tumor recurrence or subsequent PMP, and clear margin did not absolutely prevent PMP development. (3) Coexisting diverticulum, resulted from neoplastic or non-neoplastic mucosa being herniated through muscle-lacking vascular hiatus of appendiceal wall, was seen in a quarter of LAMN cases, regardless of PMP. The diverticular portion of tumor involvement was often the weakest point where rupture occurred. In conclusion, proper evaluation of surgical specimens with search for mucin and neoplastic cells on serosa and for microscopic perforation, which are of prognostic significance, should be emphasized.

Newly recognized non-adenomatous lesions associated with enteric carcinomas in inflammatory bowel disease - Report of six rare and unique cases.

It is the current view that the inflammatory bowel disease (IBD)-associated precancerous lesions may be adenomatous (with classic cytologic dysplasia) and non-adenomatous (without frank cytologic dysplasia), and the latter ones are in various histomorphologies including serrated, mucinous, eosinophilic (goblet cell deficient), and differentiated (dysplasia with terminal epithelial differentiation) types. By retrospectively reviewing the surgically resected IBD-associated colorectal and ileal carcinomas (×53), analyzing the background epithelial changes/lesions in the mucosa surrounding and adjacent to invasive carcinomas, and testing the key molecular profile (KRAS, BRAF, PIK3CA, NRAS, p53, mismatch repair proteins, and SAT-B2) known to be involved in colorectal carcinogenesis, we identified 6 representative, rare and unique cases, in which non-adenomatous lesions were clearly in vicinity and in transition to invasive carcinomas. Furthermore, we identified certain colonic carcinoma-related molecular alterations, and thus further confirmed the neoplastic nature of various non-adenomatous lesions. It was also revealed that non-adenomatous lesions are heterogeneous in both morphology and molecular alterations, and that it is common to have more than one type of lesions be associated with a carcinoma. Moreover, mixed focal adenomatous dysplasia was common, which may be the necessary step in the malignant transformation of the non-adenomatous lesions.

A Randomized Trial Comparing High Definition Colonoscopy Alone With High Definition Dye Spraying and Electronic Virtual Chromoendoscopy for Detection of Colonic Neoplastic Lesions During IBD Surveillance Colonoscopy.

OBJECTIVES: Dye spraying chromoendoscopy (DCE) is recommended for the detection of colonic neoplastic lesions in inflammatory bowel disease (IBD). The majority of neoplastic lesions are visible endoscopically and therefore targeted biopsies are appropriate for surveillance colonoscopy. To compare three different techniques for surveillance colonoscopy to detect colonic neoplastic lesions in IBD patients: high definition (HD), (DCE), or virtual chromoendoscopy (VCE) using iSCAN image enhanced colonoscopy. METHODS: A randomized non-inferiority trial was conducted to determine the detection rates of neoplastic lesions in IBD patients with longstanding colitis. Patients with inactive disease were enrolled into three arms of the study. Endoscopic neoplastic lesions were classified by the Paris classification and Kudo pit pattern, then histologically classified by the Vienna classification. RESULTS: A total of 270 patients (55% men; age range 20-77 years, median age 49 years) were assessed by HD (n=90), VCE (n=90), or DCE (n=90). Neoplastic lesion detection rates in the VCE arm was non-inferior to the DCE arm. HD was non-inferior to either DCE or VCE for detection of all neoplastic lesions. In the lesions detected, location at right colon and the Kudo pit pattern were predictive of neoplastic lesions (OR 6.52 (1.98-22.5 and OR 21.50 (8.65-60.10), respectively). CONCLUSIONS: In this randomized trial, VCE or HD-WLE is not inferior to dye spraying colonoscopy for detection of colonic neoplastic lesions during surveillance colonoscopy. In fact, in this study HD-WLE alone was sufficient for detection of dysplasia, adenocarcinoma or all neoplastic lesions.

The Paddington International Virtual Chromoendoscopy Score in ulcerative colitis exhibits very good inter-rater agreement after computerized module training: a multicenter study across academic and community practice (with video).

BACKGROUND AND AIMS: Electronic virtual chromoendoscopy (EVC) can demonstrate ongoing disease activity in ulcerative colitis (UC), even when Mayo subscores suggest healing. However, applicability of EVC technology outside the expert setting has yet to be determined. METHODS: Fifteen participants across 5 centers reviewed a computerized training module outlining high-definition and EVC (iScan) colonoscopy modes. Interobserver agreement was then tested (Mayo score, Ulcerative Colitis Endoscopic Index of Severity [UCEIS], and the Paddington International Virtual Chromoendoscopy Score [PICaSSO] for UC), using a colonoscopy video library (30 cases reviewed pretraining and 30 post-training). Knowledge sustainability was retested in a second round (42 cases; 9/15 participants), 6 months after training provision. RESULTS: Pretraining intraclass correlation coefficients (ICC) were good for the Mayo endoscopic subscore (ICC, .775), UCEIS scoring erosions/ulcers (ICC, .770), and UCEIS overall (ICC, .786) and for mucosal (ICC, .754) and vascular components of PICaSSO (ICC, .622). For the vascular components of UCEIS, agreement was only moderate (ICC, .429) and did not enhance post-training (ICC, .417); conversely, use of PICaSSO improved post-training (mucosal ICC, .848; vascular, .746). Histologic correlation using the New York Mt. Sinai System was strong for both PICaSSO components (Spearman's ρ for mucosal: .925; vascular, .873; P < .001 for both). Moreover, accuracy in specifically discriminating quiescent from mild histologic strata was strongest for PICaSSO (area under the receiver operating characteristic curve [AUROC] for mucosal, .781; vascular, .715) compared with Mayo (AUROC, .708) and UCEIS (AUROC for UCEIS overall, .705; vascular, .562; bleeding, .645; erosions/ulcers, .696). Inter-rater reliability for PICaSSO was sustained by round 2 participants (round 1 and 2 ICC for mucosal, .873 and .869, respectively; vascular, .715 and .783, respectively), together with histologic correlation (ρ mucosal, .934; vascular, .938; P < .001 for both). CONCLUSIONS: PICaSSO demonstrates good interobserver agreement across all levels of experience, providing excellent correlation with histology. Given the ability to discriminate subtle endoscopic features, PICaSSO may be applied to refine stratified treatment paradigms for UC patients.

The histopathological classification, diagnosis and differential diagnosis of mucinous appendiceal neoplasms, appendiceal adenocarcinomas and pseudomyxoma peritonei.

The vermiform appendix is the primary site of several distinctive benign and malignant neoplasms. Some can produce the clinical syndrome of pseudomyxoma peritonei (PMP). A consensus on their terminology was reached by an international panel of pathologists and clinicians working under the auspices of the Peritoneal Surface Oncology Group International (PSOGI), and this review discusses the application of the PSOGI classification to routine reporting. We discuss diagnosis and differential diagnosis together with implications for patient management, covering low-grade appendiceal mucinous neoplasms, high-grade appendiceal mucinous neoplasms, serrated polyps, adenomas and adenocarcinomas. We do not cover goblet cell tumours or neuroendocrine neoplasms in this paper.

Development and reliability of the new endoscopic virtual chromoendoscopy score: the PICaSSO (Paddington International Virtual ChromoendoScopy ScOre) in ulcerative colitis.

BACKGROUND AND AIMS: Endoscopic inflammation and healing are important therapeutic endpoints in ulcerative colitis (UC). We developed and validated a new electronic virtual chromoendoscopy (EVC) score that could reflect the full spectrum of mucosal and vascular changes including mucosal healing in UC. METHODS: Eight participants reviewed a 60-minute training module outlining 3 different i-SCAN modes demonstrating the entire spectrum of inflammatory mucosal and vascular changes in UC. Performance characteristics in endoscopic scoring and predicting the histologic inflammation with EVC (i-SCAN) by using 20 video clips before (pre-test) and after (post-test) were evaluated. Exploratory univariate factor analysis was performed on Paddington International Virtual Chromoendoscopy Score (PICaSSO) covariates for mucosal and vascular score separately. Subsequently, a proportional odds logistic regression model for the prediction of histologic scores was analyzed. RESULTS: The interobserver agreement for Mayo endoscopic score in the pre-test (κ = .85; 95% CI, .78-.90) and the post-test (κ = .85; 95% CI, .77-.90) evaluation were very good. This was also true for the Ulcerative Colitis Endoscopic Index of Severity in the pre-test and post-test score interobserver agreement (κ = .86; 95% CI, .77-.92; and κ = .84; 95% CI, .75-.91, respectively). The interobserver agreement of the PICaSSO endoscopic score was very good in the pre-test and post-test evaluations (κ = .92; 95% CI, .87-.96; and κ = .89; 95% CI, .84-.94, respectively). The accuracy of the overall PICaSSO in assessing histologic abnormalities and inflammation by Harpaz score was 57% (95% CI, 48%-65%), by Robarts Histological Index 72% (95% CI, 64%-79%), and by the extent, chronicity, activity, plus system (full spectrum of histologic changes) 83% (95% CI, 76%-88%). CONCLUSIONS: The EVC score "PICaSSO" showed very good interobserver agreement. The new EVC score may be used to define the endoscopic findings of mucosal and vascular healing in UC and reflected the full spectrum of histologic changes.

Beyond white light: optical enhancement in conjunction with magnification colonoscopy for the assessment of mucosal healing in ulcerative colitis.

Background and study aim The I-SCAN optical enhancement (OE) system with magnification is a recently introduced combination of optical and digital electronic virtual chromoendoscopy, which enhances mucosal and vascular details. The aim of this pilot study was to investigate the use of I-SCAN OE in the assessment of inflammatory changes in ulcerative colitis (UC). Patients and methods A total of 41 consecutive patients with UC and 9 control patients were examined by I-SCAN OE (Pentax Medical, Tokyo, Japan). Targeted biopsies of the imaged areas were obtained. A new optical enhancement score focusing on mucosal and vascular changes was developed. The diagnostic accuracy of I-SCAN OE was calculated against histology using two UC histological scores - Robarts Histopathology Index (RHI) and ECAP (Extent, Chronicity, Activity, Plus additional findings). Results The overall I-SCAN OE score correlated with ECAP (r = 0.70; P < 0.001). The accuracy of the overall I-SCAN OE score to detect abnormalities by ECAP was 80 % (sensitivity 78 %, specificity 100 %). I-SCAN OE vascular and mucosal scores correlated with ECAP (r = 0.65 and 0.71, respectively; P < 0.001). The correlation between overall I-SCAN OE score and RHI was r = 0.61 (P < 0.01), and the accuracy to detect abnormalities by RHI was 68 % (sensitivity 78 %, specificity 50 %). The majority of patients with Mayo 0 had abnormalities on I-SCAN OE. Conclusion In UC, the new I-SCAN OE technology accurately identified mucosal inflammation, and correlated well with histological scores of chronic and acute changes.

Synchronous Ovarian and Appendiceal Mucinous Neoplasms in the Absence of Pseudomyxoma Peritonei.

BACKGROUND: Synchronous ovarian/appendiceal mucinous neoplasms sometimes occur in the absence of clinical pseudomyxoma peritonei (PMP), which raises a question about whether the 2 tumors could be independent. METHODS: We identified 11 cases of synchronous ovarian/appendiceal mucinous neoplasms without PMP and subclassified them into groups 1 and 2 based on the presence or absence of microscopic peritoneal/ovarian surface mucin deposits. A 7-marker panel (CK7, CK20, CDX2, PAX8, MUC1, MUC2, and MUC5AC) immunohistochemistry was performed on both tumors. RESULTS: Between the 2 groups, there were no significant differences in age, laterality, size, and histology of ovarian/appendiceal tumors. In group 1, 2 of 4 cases developed PMP later, and both had ovarian surface and contralateral ovarian involvement and appendiceal perforation with microscopic mucin deposits on the peritoneum. No patients in group 2 developed PMP. All group 1 cases showed a high degree of concordance of immunoprofile between the synchronous tumors, with an identical expression of appendiceal pattern in greater than 90% of the markers. In group 2, only 1 of 7 cases showed concordance in all markers. CONCLUSIONS: If peritoneal mucin deposits present, even microscopic and acellular, the synchronous tumors are most likely of a single appendiceal origin. Otherwise, they are more heterogeneous, and some may be truly dual primaries.

Microscopic Colitis Evolved Into Inflammatory Bowel Diseases Is Characterized by Increased Th1/Tc1 Cells in Colonic Mucosal Lamina Propria.

BACKGROUND: An association between microscopic colitis (MC), i.e., lymphocytic colitis (LC) and collagenous colitis (CC), and inflammatory bowel diseases (IBD) has been noticed. A subset of MC cases may evolve into IBD, and IBD in remission may present as MC in a histologic pattern. Moreover, MC and IBD may coexist in different regions of the bowel. A link between MC and IBD in their pathogenesis is, therefore, suggested. Abnormal mucosal immunity is likely the key. METHODS: We reviewed 2324 MC cases in Calgary over 14 years and identified 20 cases evolved into IBD (IBD transformers). 13 of them were further investigated for colonic mucosal lamina propria mononuclear cells (LPMNCs), as opposed to 22 cases whose MC resolved. On their index colonic biopsy immunohistochemistry was performed to detect major T cell subsets characterized by key cytokines and master transcription factors (IFNγ and T-bet for Th1/Tc1, GATA-3 for Th2/Tc2, IL-17 and RORc for Th17/Tc17, FoxP3 for Treg/Tcreg) as well as TNFα+ cells (partly representing Th1). LPMNCs positive for each marker were counted (average number per high-power field). RESULTS: IBD transformers had increased IFNγ+, T-bet+, TNF-α+, and GATA-3+ LPMNCs compared to the MC-resolved cases. The LC-to-IBD subgroup had increased IFNγ+ and GATA-3+ cells compared to the LC-resolved subgroup. The CC-to-IBD subgroup had increased T-bet+, TNF-α+, and GATA-3+ cells compared to the CC-resolved subgroup. Among MC-resolved patients, more TNF-α+ and RORc+ cells were seen in LC than in CC. CONCLUSION: Th1/Tc1- and TNFα-producing cells, and likely a subset of Th2/Tc2 cells as well, may be involved in the MC-to-IBD transformation.

Crossover Subsets of CD4+ T Lymphocytes in the Intestinal Lamina Propria of Patients with Crohn's Disease and Ulcerative Colitis.

BACKGROUND: Hovhannisyan et al. first showed evidence of plasticity between Treg and Th17 in the inflamed intestine of Crohn's disease (CD) patients. Our previous report suggests that the inflammatory cytokine milieu generates IL-17+ Foxp3+ CD4+ T lymphocytes which is a crossover population converting Treg subset to Th17 in the peripheral blood of IBD patients. This is considered as an evidence of Treg/Th17 plasticity. AIM: The aim of this study was to characterize a variety of helper T cell crossover population, not limited to IL-17+ Foxp3+ CD4+ T lymphocytes, in the lamina propria (LP) of IBD patients. METHODS: Fresh colonoscopic biopsies were obtained from patients with CD (n = 50) and ulcerative colitis (UC, n = 32) and from healthy controls (HC, n = 25). LP mononuclear cells were assessed for intracellular cytokines and transcription factors such as IFNγ, IL-13, IL-17, IL-22, T-bet, Gata-3, RORγt, and Foxp3 using multicolor flow cytometry to detect subsets of LP CD4+ T lymphocytes. RESULTS: Patients with IBD demonstrated increased crossover populations in IL-17+ Foxp3+, T-bet+ Foxp3+, Gata3+ Foxp3+, RORγt+ Foxp3+ populations compared to HC. There was an inverse correlation of Harvey-Bradshaw index with Gata3+ Foxp3+ population in CD patients, while IL-13+ Foxp3+ population was directly correlated with Mayo clinical scores in UC patients. Furthermore, total IL-22 expressing cells as well as Th22 and IL-22+ Th1 populations were decreased in UC compared to CD and HC. CONCLUSION: IBD patients exhibit the increased crossover populations in LP Treg cells toward Th2 and Th17 compared to HC. The prevalence of Treg/Th2 crossover populations is associated with clinical disease score of IBD.

Complete mucosal healing defined by endoscopic Mayo subscore still demonstrates abnormalities by novel high definition colonoscopy and refined histological gradings.

BACKGROUND AND STUDY AIMS: A novel high definition colonoscopy imaging technique (i-Scan) can characterize, in detail, colonic mucosa in patients with ulcerative colitis, and may provide additional information about mucosal healing. The aim of this study was to create a more refined histological and endoscopic criteria based on this novel technique in order to redefine inflammatory activity and mucosal healing. PATIENTS AND METHODS: A total of 78 patients with ulcerative colitis were assessed by high definition colonoscopy as well as by white light endoscopy (WLE). Mayo endoscopic subscores were assigned to patients according to WLE findings. Mucosal and vascular patterns on high definition colonoscopy were each graded from 1 - 4. A histological scoring system (ECAP system) was designed to reflect all histological changes in ulcerative colitis. RESULTS: The overall high definition imaging scores (mucosal and vascular patterns) were significantly correlated with Mayo endoscopic subscores (rs = 0.86, 95 % confidence interval [CI] 0.79 - 0.91; P < 0.0001). Of those with Mayo endoscopic subscore of 0, 30.4 % had an abnormal mucosal pattern and 73.9 % of them had an abnormal vascular pattern on high definition colonoscopy; a score of 6 or less had a sensitivity of 95.8 % (95 %CI 85.7 % - 99.3 %) and specificity of 75.9 % (95 %CI 56.5 % - 90.0 %) to detect mucosal healing as defined by Mayo endoscopy subscore of 0 or 1. Furthermore, mucosal and vascular pattern scores were also significantly correlated with most parameters of the proposed ECAP score. CONCLUSION: The subtle histological abnormalities underlying the apparently healed mucosa in ulcerative colitis could be detected using high definition colonoscopy and the refined ECAP histology scoring system. These techniques detect residual abnormalities in the majority of patients with seemingly complete mucosal healing by conventional Mayo criteria.

Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy: an emerging treatment option for advanced goblet cell tumors of the appendix.

BACKGROUND: The debate remains whether appendiceal goblet cell cancers behave as classical carcinoid or adenocarcinoma. Treatment options are unclear and reports of outcomes are scarce. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS+HIPEC) is considered optimal treatment for peritoneal involvement of other epithelial appendiceal tumors. METHODS: Prospective cohorts of patients treated for advanced appendiceal tumors from three peritoneal malignancy centres were collected (1994-2011). All patients underwent complete CRS+HIPEC, when possible, or tumor debulking. Demographic and outcome data for patients with goblet cell cancers were compared to patients with low- or high-grade epithelial appendiceal tumors treated during the same time period. RESULTS: Details on 45 goblet cell cancer patients were compared to 708 patients with epithelial appendix lesions. In the goblet cell group, 57.8 % were female, median age was 53 years, median peritoneal cancer index (PCI) was 24, and CRS+HIPEC was achieved in 71.1 %. These details were similar in patients with low- or high-grade epithelial tumors. Lymph nodes were involved in 52 % of goblet cell patients, similar to rates in high-grade cancers, but significantly higher than in low-grade lesions (6.4 %; p < 0.001). At 3 years, overall survival (OS) was 63.4 % for goblet cell patients, intermediate between that for high-grade (40.4-52.2 %) and low-grade (80.6 %) tumors. On multivariate analysis, tumor histology, PCI, and achievement of CRS+HIPEC were independently associated with OS. CONCLUSIONS: This data supports the concept that appendiceal goblet cell cancers behave more as high-grade adenocarcinomas than as low-grade lesions. These patients have reasonable long-term survival when treated using CRS+HIPEC, and this strategy should be considered.

Appendiceal goblet cell carcinoid and mucinous neoplasms are closely associated tumors: lessons from their coexistence in primary tumors and concurrence in peritoneal dissemination.

BACKGROUND: Goblet cell carcinoid (GCC) and appendiceal mucinous neoplasms (AMNs) are considered as different appendiceal tumors. Coexistence of both tumors was occasionally noted. We further observed the concurrence in both primary tumors and their peritoneal dissemination, that is, peritoneal carcinomatosis (PC) including pseudomyxoma peritonei (PMP). METHODS: Review of our 10-year file identified two subgroups of cases with such concurrence. Group 1 is 14 cases of PC/PMP treated by surgical cytoreduction. Morphologic components of GCC, low-grade mucinous neoplasm (LMN), mucinous adenocarcinoma (MCA), and non-mucinous adenocarcinoma (NMCA) were identified separately in different organs/tissues. Group 2 is eight cases of localized primary tumors of appendix and ileocecal junction. RESULTS: In Group 1, primary tumors (11 GCC, 1 GCC + LMN, 1 MCA, 1 NMCA) were identified in appendix (13) and in rectum (1). Further review identified mixed morphologic components in 7/12 GCC cases, including GCC + LMN (2), GCC + MCA (2), GCC + NMCA (1), and GCC + MCA + NMCA (2). Over peritoneal dissemination, GCC and/or other components were coexistent at different sites and in variable combinations. In Group 2, primary tumors were initially diagnosed as GCC (7) and MCA (1). Further review identified mixed components in all cases, including GCC + LMN (3), GCC + LMN + MCA (3), GCC + MCA + NMCA (2). CONCLUSIONS: GCC may present as a component mixed with AMNs and even with conventional adenocarcinoma in both primary tumors and metastatic lesions. AMN in any given single case may show a wide morphologic spectrum. GCC and AMN may share a common tumor stem cell with potential of multiple lineage differentiations.

Multidisciplinary Approach for the Management of Metastatic Poorly Differentiated Neuroendocrine Carcinoma of the Pancreas: A Case Report of an Exceptional Responder.

ABSTRACT: Poorly differentiated pancreatic neuroendocrine carcinomas (pNECs) are rare, highly aggressive neoplasms. Frequently metastatic at diagnosis, prognosis is poor with median overall survival estimated to be less than 1 year. Although multidisciplinary management, including systemic medications and locoregional therapies aimed at reducing and preventing symptoms caused by mass effect, is the mainstay of treatment for patients with metastatic well-differentiated pancreatic neuroendocrine tumors, rapid progression, organ dysfunction, and poor performance status often preclude initiation of even single-modality palliative chemotherapy for patients with metastatic pNEC, limiting the use of and recommendation for multidisciplinary management.We describe the case of a 51-year-old male patient diagnosed with pNEC metastatic to liver and lymph nodes presenting with impending cholestatic liver failure for whom we were able to successfully initiate and dose-escalate cytotoxic chemotherapy with excellent radiographic response. After multidisciplinary review of his case, the patient underwent pancreaticoduodenectomy and hepatic wedge biopsies, with pathology demonstrating a pathologic complete response to chemotherapy in both the pancreas and liver. Surveillance scans at 2 years from initial diagnosis and 1 year from surgery remain without evidence of locoregional or distant recurrence, highlighting the importance and utility of multidisciplinary management in select cases.

Non-Canonical Activin A Signaling Stimulates Context-Dependent and Cellular-Specific Outcomes in CRC to Promote Tumor Cell Migration and Immune Tolerance.

We have shown that activin A (activin), a TGF-ß superfamily member, has pro-metastatic effects in colorectal cancer (CRC). In lung cancer, activin activates pro-metastatic pathways to enhance tumor cell survival and migration while augmenting CD4+ to CD8+ communications to promote cytotoxicity. Here, we hypothesized that activin exerts cell-specific effects in the tumor microenvironment (TME) of CRC to promote anti-tumoral activity of immune cells and the pro-metastatic behavior of tumor cells in a cell-specific and context-dependent manner. We generated an Smad4 epithelial cell specific knockout (Smad4-/-) which was crossed with TS4-Cre mice to identify SMAD-specific changes in CRC. We also performed IHC and digital spatial profiling (DSP) of tissue microarrays (TMAs) obtained from 1055 stage II and III CRC patients in the QUASAR 2 clinical trial. We transfected the CRC cells to reduce their activin production and injected them into mice with intermittent tumor measurements to determine how cancer-derived activin alters tumor growth in vivo. In vivo, Smad4-/- mice displayed elevated colonic activin and pAKT expression and increased mortality. IHC analysis of the TMA samples revealed increased activin was required for TGF-ß-associated improved outcomes in CRC. DSP analysis identified that activin co-localization in the stroma was coupled with increases in T-cell exhaustion markers, activation markers of antigen presenting cells (APCs), and effectors of the PI3K/AKT pathway. Activin-stimulated PI3K-dependent CRC transwell migration, and the in vivo loss of activin lead to smaller CRC tumors. Taken together, activin is a targetable, highly context-dependent molecule with effects on CRC growth, migration, and TME immune plasticity.

A novel rat model for the study of postoperative pancreatic fistula.

While over the past several decades mortality after pancreatic surgery has decreased to <5%, postoperative morbidity remains remarkably high, ranging from 15% to 65%. The development of a postoperative pancreatic fistula (POPF) is a significant contributor to morbidity in patients undergoing pancreatic surgery. POPF can lead to life-threatening conditions such as intra-abdominal abscess, uncontrolled hemorrhage, sepsis, and death. Rates of POPF have not significantly changed over time, despite the introduction of multiple technical and pharmacologic interventions aimed at their treatment and prevention. Unfortunately, there are few POPF experimental models that have been described in the literature and existing models are unable to reliably reproduce the clinical sequelae of POPF, limiting the development of new methods to prevent and treat POPF. Herein, we describe a new rat experimental model that reliably creates a POPF via transection of the common pancreatic duct.