Revealing and harnessing CD39 for the treatment of colorectal cancer and liver metastases by engineered T cells.

OBJECTIVE: Colorectal tumours are often densely infiltrated by immune cells that have a role in surveillance and modulation of tumour progression but are burdened by immunosuppressive signals, which might vary from primary to metastatic stages. Here, we deployed a multidimensional approach to unravel the T-cell functional landscape in primary colorectal cancers (CRC) and liver metastases, and genome editing tools to develop CRC-specific engineered T cells. DESIGN: We paired high-dimensional flow cytometry, RNA sequencing and immunohistochemistry to describe the functional phenotype of T cells from healthy and neoplastic tissue of patients with primary and metastatic CRC and we applied lentiviral vectors (LV) and CRISPR/Cas9 genome editing technologies to develop CRC-specific cellular products. RESULTS: We found that T cells are mainly localised at the front edge and that tumor-infiltrating T cells co-express multiple inhibitory receptors, which largely differ from primary to metastatic sites. Our data highlighted CD39 as the major driver of exhaustion in both primary and metastatic colorectal tumours. We thus simultaneously redirected T-cell specificity employing a novel T-cell receptor targeting HER-2 and disrupted the endogenous TCR genes (TCR editing (TCRED)) and the CD39 encoding gene (ENTPD1), thus generating TCREDENTPD1KOHER-2-redirected lymphocytes. We showed that the absence of CD39 confers to HER-2-specific T cells a functional advantage in eliminating HER-2+ patient-derived organoids in vitro and in vivo. CONCLUSION: HER-2-specific CD39 disrupted engineered T cells are promising advanced medicinal products for primary and metastatic CRC.

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.

Treatment with rapamycin can restore regulatory T-cell function in IPEX patients.

BACKGROUND: Immune-dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a lethal disease caused by mutations in a transcription factor critical for the function of thymus-derived regulatory T (Treg) cells (ie, FOXP3), resulting in impaired Treg function and autoimmunity. At present, hematopoietic stem cell transplantation is the therapy of choice for patients with IPEX syndrome. If not available, multiple immunosuppressive regimens have been used with poor disease-free survival at long-term follow-up. Rapamycin has been shown to suppress peripheral T cells while sparing Treg cells expressing wild-type FOXP3, thereby proving beneficial in the clinical setting of immune dysregulation. However, the mechanisms of immunosuppression selective to Treg cells in patients with IPEX syndrome are unclear. OBJECTIVE: We sought to determine the cellular and molecular basis of the clinical benefit observed under rapamycin treatment in 6 patients with IPEX syndrome with different FOXP3 mutations. METHODS: Phenotype and function of FOXP3-mutated Treg cells from rapamycin-treated patients with IPEX syndrome were tested by flow cytometry and in vitro suppression assays, and the gene expression profile of rapamycin-conditioned Treg cells by droplet-digital PCR. RESULTS: Clinical and histologic improvements in patients correlated with partially restored Treg function, independent of FOXP3 expression or Treg frequency. Expression of TNF-receptor-superfamily-member 18 (TNFRSF18, glucocorticoid-induced TNF-receptor-related) and EBV-induced-3 (EBI3, an IL-35 subunit) in patients' Treg cells increased during treatment as compared with that of Treg cells from untreated healthy subjects. Furthermore inhibition of glucocorticoid-induced TNF-receptor-related and Ebi3 partially reverted in vitro suppression by in vivo rapamycin-conditioned Treg cells. CONCLUSIONS: Rapamycin is able to affect Treg suppressive function via a FOXP3-independent mechanism, thus sustaining the clinical improvement observed in patients with IPEX syndrome under rapamycin treatment.

Histopathology of IBD Colitis. A practical approach from the pathologists of the Italian Group for the study of the gastrointestinal tract (GIPAD).

Inflammatory bowel diseases (IBDs) are lifelong disorders in which an interaction between genetic and environmental factors is involved. IBDs include two entities: Crohn's disease (CD) and ulcerative colitis (UC); these can be adequately diagnosed and distinguished with a correct methodological approach based on communicating exhaustive clinical, endoscopic and laboratory information to the pathologist and performing adequate bioptic sampling and precise morphological signs including crypt architecture, distribution of inflammation and granulomas, when present. IBD needs to be distinguished from non-IBD colitis, mostly at its onset. Moreover, IBDs are associated with an increased risk of developing colorectal adenocarcinoma. In daily pathological practice, correct diagnosis of IBD and its subclassification as well as a correct detection of dysplasia is imperative to establish the best therapeutic approach.

Histopathology of Non-IBD Colitis. A practical approach from the Italian Group for the study of the gastrointestinal tract (GIPAD).

Non-IBD colitides (NIBDC) are intestinal diseases clinically and endoscopically overlapping with Inflammatory Bowel Diseases (IBD), sometimes with a similar histological picture. NIBDC include entities such as infectious colitis, ischemic colitis, pseudomembranous colitis, eosinophilic colitis, autoimmune enterocolitis, segmental colitis associated with diverticulosis, drug-induced colitis, radiation-induced colitis, diversion colitis, and microscopic colitis, this last including two entities: collagenous and lymphocytic colitis. The knowledge of the most useful histological features and the main clinical data for each entity is mandatory in daily clinical practice, for correct pathological diagnosis and clinical management.

Competitive Testing of the WHO 2010 versus the WHO 2017 Grading of Pancreatic Neuroendocrine Neoplasms: Data from a Large International Cohort Study.

BACKGROUND: The World Health Organization (WHO) and the American Joint Cancer Committee (AJCC) modified the grading of pancreatic neuroendocrine neoplasms from a three-tier (WHO-AJCC 2010) to a four-tier system by introducing the novel category of NET G3 (WHO-AJCC 2017). OBJECTIVES: This study aims at validating the WHO-AJCC 2017 and identifying the most effective grading system. METHOD: A total of 2,102 patients were enrolled; entry criteria were: (i) patient underwent surgery; (ii) at least 2 years of follow-up; (iii) observation time up to 2015. Data from 34 variables were collected; grading was assessed and compared for efficacy by statistical means including Kaplan-Meier method, Cox regression analysis, Harrell's C statistics, and Royston's explained variation in univariable and multivariable analyses. RESULTS: In descriptive analysis, the two grading systems demonstrated statistically significant differences for the major category sex but not for age groups. In Cox regression analysis, both grading systems showed statistically significant differences between grades for OS and EFS; however, no statistically significant difference was observed between the two G3 classes of WHO-AJCC 2017. In multivariable analysis for the two models fitted to compare efficacy, the two grading systems performed equally well with substantially similar optimal discrimination and well-explained variation for both OS and EFS. The WHO-AJCC 2017 grading system retained statistically significant difference between the two G3 classes for OS but not for EFS. CONCLUSIONS: The WHO-AJCC 2017 grading system is at least equally performing as the WHO-AJCC 2010 but allows the successful identification of the most aggressive PanNET subgroup. Grading is confirmed as probably the most powerful tool for predicting patient survival.

T cell neoepitope discovery in colorectal cancer by high throughput profiling of somatic mutations in expressed genes.

OBJECTIVE: Patient-specific (unique) tumour antigens, encoded by somatically mutated cancer genes, generate neoepitopes that are implicated in the induction of tumour-controlling T cell responses. Recent advancements in massive DNA sequencing combined with robust T cell epitope predictions have allowed their systematic identification in several malignancies. DESIGN: We undertook the identification of unique neoepitopes in colorectal cancers (CRCs) by using high-throughput sequencing of cDNAs expressed by standard cancer cell cultures, and by related cancer stem/initiating cells (CSCs) cultures, coupled with a reverse immunology approach not requiring human leukocyte antigen (HLA) allele-specific epitope predictions. RESULTS: Several unique mutated antigens of CRC, shared by standard cancer and related CSC cultures, were identified by this strategy. CD8+ and CD4+ T cells, either autologous to the patient or derived from HLA-matched healthy donors, were readily expanded in vitro by peptides spanning different cancer mutations and specifically recognised differentiated cancer cells and CSC cultures, expressing the mutations. Neoepitope-specific CD8+ T cell frequency was also increased in a patient, compared with healthy donors, supporting the occurrence of clonal expansion in vivo. CONCLUSIONS: These results provide a proof-of-concept approach for the identification of unique neoepitopes that are immunogenic in patients with CRC and can also target T cells against the most aggressive CSC component.

The Clinicopathologic Heterogeneity of Grade 3 Gastroenteropancreatic Neuroendocrine Neoplasms: Morphological Differentiation and Proliferation Identify Different Prognostic Categories.

BACKGROUND/AIMS: Gastroenteropancreatic (GEP) neuroendocrine carcinomas (NECs) are defined as neuroendocrine neoplasms (NENs) with a Ki-67 index >20% according to the 2010 WHO classification. Some reports suggest that this category is heterogeneous. We retrospectively studied a series of 136 patients affected by grade 3 GEP-NECs with the aim to clarify the prognostic role of tumor morphological differentiation, proliferation, defect in mismatch repair proteins (MMRd), CD117 expression, and site of origin. The primary endpoint was the correlation between these parameters and the overall survival (OS). METHODS: Univariate and multivariable Cox proportional hazards regression analyses were used to assess the prognostic significance of various clinical and histopathologic features. RESULTS: With a median follow-up of 81 months, the median OS was 12.9 months. At multivariate analysis, morphological differentiation, Ki-67 index, MMRd, stage, and CD117 expression were independent prognostic markers in NECs. Three different prognostic categories of NECs were identified according to the degree of morphologic differentiation (well vs. poorly differentiated) and Ki-67 index (<55% vs. ≥55%). On this basis, median OS was 43.6 months in well-differentiated neoplasms with a Ki-67 index 20-55% (named type A), 24.5 months in poorly differentiated neoplasms with a Ki-67 index 20-55% (type B), and 5.3 months (p < 0.0001) in poorly differentiated neoplasms with a Ki-67 index ≥55% (type C). CONCLUSIONS: The present study suggests that GEP-NECs represent a heterogeneous group of neoplasms which can be better classified in different prognostic categories using both tumor morphology and Ki-67 index.

Four Neuroendocrine Tumor Types and Neuroendocrine Carcinoma of the Duodenum: Analysis of 203 Cases.

BACKGROUND: Several types of neuroendocrine neoplasms (NENs) have been described in the duodenal tract, from low-grade tumors (NETs) to high-grade neuroendocrine carcinomas (NECs). A comprehensive analysis of histology, hormonal profile and prognostic parameters of a sufficiently large duodenal NEN series to cover all main kinds of neoplasms is however lacking. METHODS: We collected a retrospective series of 203 duodenal wall and ampullary region NENs, from six specialized endocrine pathology centers. All were characterized histopathologically and histochemically, and 190 were followed for a median of 9 years. RESULTS: Twenty-seven poorly differentiated NECs, mostly from the ampullary region, were identified and shown to lead to patient demise in a median of 10 months. Among 176 NETs, four subtypes were characterized, including 20 gastrinomas, 37 ampullary-type somatostatin-producing NETs (ASTs), 12 gangliocytic paragangliomas (GPs) and 106 nonfunctioning NETs (nfNETs). ASTs and GPs were mostly localized in the ampullary/periampullary region, while gastrinomas and nfNETs were mainly from the proximal duodenum. ASTs and gastrinomas showed high rates of local infiltration (especially lymphoinvasion and deep duodenal wall/pancreatic tissue invasion) and lymph node metastasis, while nfNETs had significantly lower and more size-dependent local invasive potential. Disease-specific survival differed significantly between NETs and NECs, though not among NET subtypes. NET cases with distant metastases (n = 23) were significantly associated with larger size, higher proliferative grade, lymphovascular invasion, deep invasion and local lymph node metastasis. CONCLUSION: Our careful analysis of a large series of duodenal NENs identified five histologically and prognostically different histotypes of potential clinical relevance.

Gastric cancer: texture analysis from multidetector computed tomography as a potential preoperative prognostic biomarker.

OBJECTIVES: To investigate the association between preoperative texture analysis from multidetector computed tomography (MDCT) and overall survival in patients with gastric cancer. METHODS: Institutional review board approval and informed consent were obtained. Fifty-six patients with biopsy-proved gastric cancer were examined by MDCT and treated with surgery. Image features from texture analysis were quantified, with and without filters for fine to coarse textures. The association with survival time was assessed using Kaplan-Meier and Cox analysis. RESULTS: The following parameters were significantly associated with a negative prognosis, according to different thresholds: energy [no filter] - Logarithm of relative risk (Log RR): 3.25; p = 0.046; entropy [no filter] (Log RR: 5.96; p = 0.002); entropy [filter 1.5] (Log RR: 3.54; p = 0.027); maximum Hounsfield unit value [filter 1.5] (Log RR: 3.44; p = 0.027); skewness [filter 2] (Log RR: 5.83; p = 0.004); root mean square [filter 1] (Log RR: - 2.66; p = 0.024) and mean absolute deviation [filter 2] (Log RR: - 4.22; p = 0.007). CONCLUSIONS: Texture analysis could increase the performance of a multivariate prognostic model for risk stratification in gastric cancer. Further evaluations are warranted to clarify the clinical role of texture analysis from MDCT. KEY POINTS: • Textural analysis from computed tomography can be applied in gastric cancer. • Preoperative non-invasive texture features are related to prognosis in gastric cancer. • Texture analysis could help to evaluate the aggressiveness of this tumour.

Apparent diffusion coefficient by diffusion-weighted magnetic resonance imaging as a sole biomarker for staging and prognosis of gastric cancer.

OBJECTIVE: To investigate the role of apparent diffusion coefficient (ADC) from diffusion-weighted magnetic resonance imaging (DW-MRI) when applied to the 7th TNM classification in the staging and prognosis of gastric cancer (GC). METHODS: Between October 2009 and May 2014, a total of 89 patients with non-metastatic, biopsy proven GC underwent 1.5T DW-MRI, and then treated with radical surgery. Tumor ADC was measured retrospectively and compared with final histology following the 7th TNM staging (local invasion, nodal involvement and according to the different groups - stage I, II and III). Kaplan-Meier curves were also generated. The follow-up period is updated to May 2016. RESULTS: Median follow-up period was 33 months and 45/89 (51%) deaths from GC were observed. ADC was significantly different both for local invasion and nodal involvement (P<0.001). Considering final histology as the reference standard, a preoperative ADC cut-off of 1.80×10-3 mm2/s could distinguish between stages I and II and an ADC value of ≤1.36×10-3 mm2/s was associated with stage III (P<0.001). Kaplan-Meier curves demonstrated that the survival rates for the three prognostic groups were significantly different according to final histology and ADC cut-offs (P<0.001). CONCLUSIONS: ADC is different according to local invasion, nodal involvement and the 7th TNM stage groups for GC, representing a potential, additional prognostic biomarker. The addition of DW-MRI could aid in the staging and risk stratification of GC.

Preoperative locoregional staging of gastric cancer: is there a place for magnetic resonance imaging? Prospective comparison with EUS and multidetector computed tomography.

BACKGROUND: The aim of this study was to prospectively compare the diagnostic performance of magnetic resonance imaging (MRI), multidetector computed tomography (MDCT) and endoscopic ultrasonography (EUS) in the preoperative locoregional staging of gastric cancer. METHODS: This study had Institutional Review Board approval, and informed consent was obtained from all patients. Fifty-two patients with biopsy-proven gastric cancer underwent preoperative 1.5-T MRI, 64-channel MDCT and EUS. All images were analysed blind, and the results were compared with histopathological findings according to the seventh edition of the TNM classification. After the population had been divided on the basis of the local invasion (T1-3 vs T4a-b) and nodal involvement (N0 vs N+), sensitivity, specificity, positive and negative predictive value, and accuracy were calculated and diagnostic performance measures were assessed using the McNemar test. RESULTS: For T staging, EUS showed higher sensitivity (94%) than MDCT and MRI (65 and 76%; p = 0.02 and p = 0.08). MDCT and MRI had significantly higher specificity (91 and 89%) than EUS (60%) (p = 0.0009 and p = 0.003). Adding MRI to MDCT or EUS did not result in significant differences for sensitivity. For N staging, EUS showed higher sensitivity (92%) than MRI and MDCT (69 and 73%; p = 0.01 and p = 0.02). MDCT showed better specificity (81%) than EUS and MRI (58 and 73%; p = 0.03 and p = 0.15). CONCLUSIONS: Our prospective study confirmed the leading role of EUS and MDCT in the staging of gastric cancer and did not prove, at present, the value of the clinical use of MRI.

Cancer-initiating cells from colorectal cancer patients escape from T cell-mediated immunosurveillance in vitro through membrane-bound IL-4.

Cancer-initiating cells (CICs) that are responsible for tumor initiation, propagation, and resistance to standard therapies have been isolated from human solid tumors, including colorectal cancer (CRC). The aim of this study was to obtain an immunological profile of CRC-derived CICs and to identify CIC-associated target molecules for T cell immunotherapy. We have isolated cells with CIC properties along with their putative non-CIC autologous counterparts from human primary CRC tissues. These CICs have been shown to display "tumor-initiating/stemness" properties, including the expression of CIC-associated markers (e.g., CD44, CD24, ALDH-1, EpCAM, Lgr5), multipotency, and tumorigenicity following injection in immunodeficient mice. The immune profile of these cells was assessed by phenotype analysis and by in vitro stimulation of PBMCs with CICs as a source of Ags. CICs, compared with non-CIC counterparts, showed weak immunogenicity. This feature correlated with the expression of high levels of immunomodulatory molecules, such as IL-4, and with CIC-mediated inhibitory activity for anti-tumor T cell responses. CIC-associated IL-4 was found to be responsible for this negative function, which requires cell-to-cell contact with T lymphocytes and which is impaired by blocking IL-4 signaling. In addition, the CRC-associated Ag COA-1 was found to be expressed by CICs and to represent, in an autologous setting, a target molecule for anti-tumor T cells. Our study provides relevant information that may contribute to designing new immunotherapy protocols to target CICs in CRC patients.

Prognostic utility of diffusion-weighted MRI in oesophageal cancer: is apparent diffusion coefficient a potential marker of tumour aggressiveness?

PURPOSE: To investigate the role of the apparent diffusion coefficient (ADC) as a potential prognostic biomarker in the evaluation of the aggressiveness of oesophageal cancer. MATERIALS AND METHODS: Between November 2009 and December 2013, 43 patients with evidence of oesophageal or oesophago-gastric junction cancer were referred to our institution and prospectively entered in our database. The final study population consisted of 23 patients (18 men; 5 women; mean age, 64.62 ± 10.91 years) who underwent diffusion-weighted Magnetic Resonance before surgical intervention. Specifically, 14 were directly treated with surgery and 9 were addressed to chemo/radiotherapy beforehand. Two radiologists independently measured mean tumour ADC and inter-observer agreement (Spearman's and intraclass correlation coefficient [ICC]) was assessed. In the univariate analysis, overall survival curves related to pathological ADC, pT, pN, tumour location and histotype were fitted using the Kaplan-Meier method. Survival curves were then compared using the log-rank test. RESULTS: Inter-observer reproducibility was very good (Spearman's rho = 0.95; ICC = 0.94). At a total median follow-up of 19 months (2-49 months), 4 patients had died. The median follow-up was 18.50 months (5-49 months) for the surgery-only group (1/4 events, 25 %) and 24 months (2-34 months) for the chemo/radiotherapy group (3/4 events, 75 %). Survival time at 48 months for the overall population was 59 % (±0.11), while for the surgery-only group and the chemo/radiotherapy group was 90 % (±0.09) and 61 % (±0.34), respectively. In the univariate analysis, ADC values below or equal to 1.4 × 10(-3) mm(2)/s were associated with a negative prognosis both in the total population (P = 0.016) and in the surgery-only group (P < 0.001). CONCLUSION: Despite the biggest limitation of our study (i.e. the small study population), we were able to show that pathological ADC could be considered a prognostic factor for oesophageal cancer. DWI might be introduced into clinical practice as a promising and reliable technique in the diagnostic pathway of this tumour.

Prognostic Role of Diffusion-weighted MR Imaging for Resectable Gastric Cancer.

PURPOSE: To prospectively investigate the role of apparent diffusion coefficient (ADC) calculated from diffusion-weighted magnetic resonance (MR) imaging as a potential prognostic biomarker in the evaluation of the aggressiveness of gastric cancer. MATERIALS AND METHODS: This prospective study had institutional review board approval. Informed consent was obtained from all patients. Between October 2009 and December 2013, a total of 99 patients (65 men, 34 women; mean age, 62.02 years; age range, 32.33-85.15 years) with biopsy-proved cancer (28 esophagogastric junction and 71 gastric cancers) were examined with a 1.5-T MR imaging system, including T1-, T2-, and diffusion-weighted sequences. ADC measurements were obtained. Seventy-one patients were directly treated with surgery, while 28 underwent neoadjuvant chemotherapy beforehand. Pathologic ADC, pathologic T and N stages, tumor location, surgical approach, and histologic subtype were investigated with univariate and multivariate analyses by using the Cox regression model. RESULTS: At a total median follow-up period of 21 months, 31 patients had died. The median follow-up was 25 months for the surgery-only group (19 of 31 events [61%]) and 28 months for the chemotherapy group (12 of 31 events [39%]). In the multivariate analysis, ADC values of 1.5 × 10(-3) mm(2)/sec or lower were associated with a negative prognosis, both in the total population (log-relative risk, 1.73; standard error, 0.56; P = .002) and in the surgery-only (log-relative risk, 1.97; standard error, 0.66; P = .003) and chemotherapy (log-relative risk, 2.93; standard error, 1.41; P = .03) groups, along with other significant prognostic factors (in particular, pathologic T and N stages). CONCLUSION: Pathologic ADC represents a strong independent prognostic factor in the evaluation of the aggressiveness of gastric cancer, in addition to clinical and surgical variables.

Response to chemotherapy in gastric adenocarcinoma with diffusion-weighted MRI and (18) F-FDG-PET/CT: correlation of apparent diffusion coefficient and partial volume corrected standardized uptake value with histological tumor regression grade.

PURPOSE: To assess whether changes in diffusion-weighted MRI (DW-MRI) and (18) F-fluoro-2-deoxyglucose positron emission tomography/computed tomography ((18) F-FDG PET/CT), correlate with treatment response to neoadjuvant therapy (NT), as expressed by tumor regression grade (TRG), from locally advanced gastric adenocarcinoma (GA). MATERIALS AND METHODS: Seventeen patients underwent both DW-MRI and (18) F-FDG-PET/CT scans before and after the end of NT. Apparent diffusion coefficient (ADC) and mean standardized uptake value (SUV) corrected for partial volume effect (PVC-SUVBW-mean ) were evaluated and compared with histopathological TRG. RESULTS: Pre- and post-NT and percentage changes for ADC and PVC-SUVBW-mean were assessed. Post-NT ADC and ΔADC showed a significant inverse correlation with TRG (r = -0.71; P = 0.0011 and r = -0.78; P = 0.00020, respectively) and significant differences in their mean values were found between responders (TRG 1-2-3) and nonresponders (TRG 4-5) (P = 0.0009; P = 0.000082, respectively). No correlations with TRG were found for pre-NT ADC and for all PVC-SUVBW-mean values as well as between ΔADC and Δ PVC-SUVBW-mean . CONCLUSION: DW-MRI seems more accurate than (18) F-FDG-PET/CT and ADC modifications may represent a reproducible tool to assess tumor response for GA.

The Dual Lens of Endoscopy and Histology in the Diagnosis and Management of Eosinophilic Gastrointestinal Disorders-A Comprehensive Review.

Eosinophilic Gastrointestinal Disorders (EGIDs) are a group of conditions characterized by abnormal eosinophil accumulation in the gastrointestinal tract. Among these EGIDs, Eosinophilic Esophagitis (EoE) is the most well documented, while less is known about Eosinophilic Gastritis (EoG), Eosinophilic Enteritis (EoN), and Eosinophilic Colitis (EoC). The role of endoscopy in EGIDs is pivotal, with applications in diagnosis, disease monitoring, and therapeutic intervention. In EoE, the endoscopic reference score (EREFS) has been shown to be accurate in raising diagnostic suspicion and effective in monitoring therapeutic responses. Additionally, endoscopic dilation is the first-line treatment for esophageal strictures. For EoG and EoN, while the literature is more limited, common endoscopic findings include erythema, nodules, and ulcerations. Histology remains the gold standard for diagnosing EGIDs, as it quantifies eosinophilic infiltration. In recent years, there have been significant advancements in the histological understanding of EoE, leading to the development of diagnostic scores and the identification of specific microscopic features associated with the disease. However, for EoG, EoN, and EoC, precise eosinophil count thresholds for diagnosis have not yet been established. This review aims to elucidate the role of endoscopy and histology in the diagnosis and management of the three main EGIDs and to analyze their strengths and limitations, their interconnection, and future research directions.

Gastroenteric neuroendocrine neoplasms classification: comparison of prognostic models.

BACKGROUND: Gastroenteric neuroendocrine neoplasms (GE-NENs) display highly variable clinical behavior. In an attempt to assess a better prognostic description, in 2010, the World Health Organization (WHO) updated its previous classification, and the European Neuroendocrine Tumors Society (ENETS) proposed a new grading and TNM-based staging system. In the current study, the authors evaluated the prognostic significance of these models and compared their efficacy in describing patients' long-term survival to assess the best prognostic model currently available for clinicians. METHODS: The study cohort was composed of 145 patients with extrapancreatic GE-NEN who were observed from 1986 to 2008 at a single center and were classified according to the WHO and ENETS classifications. Survival evaluations were performed using Kaplan-Meyer analyses on 131 patients. Only deaths from neoplasia were considered. A P value < .05 was considered significant. Prognostic efficacy was assessed by determining the Harrell concordance index (c-index). RESULTS: Both the 2010 WHO and the ENETS classification were able to efficiently divide patients into classes with different prognoses. According to the model comparison, the ENETS TNM-based staging system appeared to be the strongest. All combined models were effective prognostic predictors, but the model that included the 2010 WHO classification plus ENETS staging had a higher c-index. CONCLUSIONS: Both the 2010 WHO classification and the ENETS staging system are valid instruments for GE-NENs prognostic assessment, with TNM-based stage appearing to be the best available choice for clinicians, both alone and in association with other classifications.

Apparent diffusion coefficient modifications in assessing gastro-oesophageal cancer response to neoadjuvant treatment: comparison with tumour regression grade at histology.

OBJECTIVES: To assess changes in apparent diffusion coefficient (ΔADC) and volume (ΔV) after neoadjuvant treatment (NT), and tumour regression grade (TRG) in gastro-oesophageal cancers (GEC), and to discriminate responders from non-responders. METHODS: Thirty-two patients with biopsy-proven locally-advanced GEC underwent diffusion weighted magnetic resonance imaging (DWI) pre- and post-NT. Lesion ADC, volume, ΔADC and ΔV were calculated. TRG 1-2-3 patients were classified as R; TRG 4-5 as non-responders. ΔADC-TRG and ΔV-TRG correlations, pre-NT and post-NT ADC, ΔADC and ΔV cut-off values for responders and non-responders were calculated. Two readers measured mean tumour ADCs and interobserver variability was calculated. (Spearman's and intraclass correlation coefficient [ICC]). RESULTS: The interobserver reproducibility was very good both for pre-NT (Spearman's rho = 0.8160; ICC = 0.8993) and post-NT (Spearman's rho = 0.8357; ICC = 0.8663). Responders showed lower pre-NT ADC (1.32 versus 1.63 × 10(-3) mm(2)/s; P = 0.002) and higher post-NT ADC (2.22 versus 1.51 × 10(-3) mm(2)/s; P = 0.001) than non-responders and ADC increased in responders (ΔADC, 85.45 versus -8.21 %; P = 0.00005). ΔADC inversely correlated with TRG (r = -0.71, P = 0.000004); no difference in ΔV between responders and non-responders (-50.92 % versus -14.12 %; P = 0.068) and no correlation ΔV-TRG (r = 0.02 P = 0.883) were observed. CONCLUSIONS: The ADC can be used to assess gastro-oesophageal tumour response to neoadjuvant treatment as a reliable expression of tumour regression. KEY POINTS: • DWI is now being used to assess many cancers. • Change in ADC measurements offer new information about oesophageal tumours. • ADC changes are more reliable than dimensional criteria in assessing neoadjuvant treatment. • Such ADC assessment could optimise management of locally advanced gastro-oesophageal cancers.

Ex-vivo investigation of radiofrequency ablation in pancreatic adenocarcinoma after neoadjuvant chemotherapy.

Objective: Endoscopic ultrasound (US)-guided radiofrequency ablation (RFA) has been investigated for pancreatic ductal adenocarcinoma (PDAC) but studies are limited and heterogeneous. Computed tomography (CT) scan features may predict RFA response after chemotherapy but their role is unexplored. The primary aim was to investigate the efficacy of ex-vivo application of a dedicated RFA system at three power on surgically resected PDAC in patients who underwent neoadjuvant chemotherapy. The secondary aim was to explore the association between pre-treatment CT-based quantitative features and RFA response. Methods: Fifteen ex-vivo PDAC samples were treated by RFA under US control at three power groups (10, 30, and 50 W). Short axis necrosis diameter was measured by two expert blinded pathologists as the primary outcome. Two radiologists independently reviewed preoperative CT images. Results: Eighty percent of specimens showed coagulative necrosis consisting of few millimeters: 5.7 ± 3.9 mm at 10 W, 3.7 ± 2.2 mm at 30 W, and 3.5 ± 2.4 mm at 50 W (p = 0.3), without a significant correlation between power setting and mean necrosis short axis (rho = -0.28; p = 0.30). Good agreement was seen between pathologists (k = 0.76; 95% confidence interval 0.55-0.98). Logistic regression analysis did not show associations between CT features and RFA response. Conclusions: RFA causes histologically evident damage with coagulative necrosis of a few millimeters in 80% of ex-vivo PDAC samples after chemotherapy and no clinical or pre-operative CT features can predict efficacy. Power settings do not correlate with the histological ablation area. These results are of relevance when employing RFA in vivo and planning clinical trials on its role in PDAC patients.