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This study aimed to evaluate the outcome of patients with type 1 gastric neuroendocrine neoplasia (T1gNENs) treated with different endoscopic approaches.Patients were managed with endoscopic surveillance at regular intervals. Resection was performed by forceps or cold snare in tumours10 mm, otherwise mucosal resection (EMR) or submucosal dissection (ESD) were done.127 T1gNENs, detected in 80 patients, were included. 87.4% of them were5 mm, whereas 8.7% were 6-10 mm, 3.1% were 11-20 mm, and 0.8% was20 mm. Ki673%% was found in 85.8% tumours, whereas it was 3%-20% in the remaining 14.2% lesions. Noninterventional management (surveillance without radical resection) was performed in 15 patients (18.7%) with T1gNENs5 mm. None of them underwent disease progression during follow-up. among the 65 patients treated by radical endoscopic resection, 37 patients (56.9%) had disease recurrence. 48.5% T1gNENs were removed by forceps, 16.8% by cold snare, 31.7% by EMR and 3% by ESD. The recurrence rate was similar among the different endoscopic techniques used.The management of T1gNENs may be planned based on tumour size. T1gNENs5 mm for which the initial removal is not radical could be followed up by noninterventional endoscopic surveillance.

Background Autoimmune and multifocal atrophic gastritis (AG) are at risk for gastric neoplastic lesions. European guidelines recommend surveillance with high-quality endoscopy every 3 years. Aim To prospectively investigate the occurrence of gastric neoplastic lesions at the 3-year follow-up in patients with autoimmune and multifocal AG. Methods Longitudinal cohort study conducted between 2011 and 2019: consecutive patients with histological diagnosis of autoimmune or multifocal AG underwent follow-up gastroscopy 3 years after diagnosis with high-resolution-narrow-band-imaging endoscopes. Results Overall, 160 patients were included(F117(73.0%);median age 66(35–87)years). Autoimmune and multifocal AG were present in 122(76.3%) and 38(23.7%) patients, respectively. At the 3-year follow-up, 16(10.0%) patients presented 16 gastric neoplastic lesions: 3(18.7%) gastric cancers, 4(25.0%) low-grade dysplasia, 2(12.5%) low-grade dysplasia adenomas, 7(43.7%) type-1 neuroendocrine tumours. In these patients, OLGA and OLGIM III/IV stages were present in 4(25.0)% and 1(6.3%), respectively; 11(69.0%) presented autoimmune AG, and all but one(93.7%) had parietal cells antibodies positivity (p = 0.026 vs patients without lesions). All lesions were endoscopically(87.5%) or surgically(12.5%) treated with favourable outcome. Age>70 years was associated with a 9-fold higher probability of developing gastric epithelial neoplastic lesions (OR 9.6,95CI% 1.2–79.4,p = 0.0359). Conclusions The first endoscopic surveillance 3 years after diagnosis seems safe for autoimmune and multifocal AG patients and should be offered to elderly patients who are at higher risk for gastric neoplasia.

Background Laparoscopic resections for rectal cancer are routinely performed in high-volume centres. Despite short-term advantages have been demonstrated, the oncological outcomes are still debated. The aim of this study was to compare the oncological adequateness of the surgical specimen and the long-term outcomes between open (ORR) and laparoscopic (LRR) rectal resections. Methods Patients undergoing laparoscopic or open rectal resections from January 1, 2013, to December 31, 2019, were enrolled. A 1:2 propensity score matching was performed according to age, sex, BMI, ASA score, comorbidities, distance from the anal verge, and clinical T and N stage. Results Ninety-eight ORR were matched to 50 LRR. No differences were observed in terms of operative time (224.9 min. vs. 230.7; p = 0.567) and postoperative morbidity (18.6% vs. 20.8%; p = 0.744). LRR group had a significantly earlier soft oral intake (p p p p = 0.772). Clearance of the distal (99.0% vs. 100%; p = 0.474) and radial margins (91.8 vs. 90.0%, p = 0.709), and mesorectal integrity (94.9% vs. 98.0%, p = 0.365) were comparable between groups. No differences in local recurrence (6.1% vs.4.0%, p = 0.589), 3-year overall survival (82.9% vs. 91.4%, p = 0.276), and disease-free survival (73.1% vs. 74.3%, p = 0.817) were observed. Conclusions LRR is associated with good postoperative results, safe oncological adequateness of the surgical specimen, and comparable survivals to open surgery.

RNA dysregulation is a hallmark of most human cancers, including PDAC. We identify the RNA‐binding protein MEX3A as prognostic factor in PDAC. MEX3A regulates stability of transcripts for cell cycle proteins, such as CDK6, and promotes cell cycle progression and resistance to chemotherapeutic treatments., Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer. Most patients present with advanced disease at diagnosis, which only permits palliative chemotherapeutic treatments. RNA dysregulation is a hallmark of most human cancers, including PDAC. To test the impact of RNA processing dysregulation on PDAC pathology, we performed a bioinformatics analysis to identify RNA‐binding proteins (RBPs) associated with prognosis. Among the 12 RBPs associated with progression‐free survival, we focused on MEX3A because it was recently shown to mark an intestinal stem cell population that is refractory to chemotherapeutic treatments, a typical feature of PDAC. Increased expression of MEX3A was correlated with higher disease stage in PDAC patients and with tumor development in a mouse model of PDAC. Depletion of MEX3A in PDAC cells enhanced sensitivity to chemotherapeutic treatment with gemcitabine, whereas its expression was increased in PDAC cells selected upon chronic exposure to the drug. RNA‐sequencing analyses highlighted hundreds of genes whose expression is sensitive to MEX3A expression, with significant enrichment in cell cycle genes. MEX3A binds to its target mRNAs, like cyclin‐dependent kinase 6 (CDK6), and promotes their stability. Accordingly, knockdown of MEX3A caused a significant reduction in PDAC cell proliferation and in progression to the S phase of the cell cycle. These findings uncover a novel role for MEX3A in the acquisition and maintenance of chemoresistance by PDAC cells, suggesting that it may represent a novel therapeutic target for PDAC.

In patients with colonic diverticulosis, the prevalence of segmental colitis associated with diverticulosis (SCAD) is debated. The aim of this study was to assess the prevalence of SCAD in consecutive patients with diverticulosis in a single tertiary center. Over a six-month period, consecutive adult patients with colonic diverticulosis were included. Patients with endoscopic signs of interdiverticular mucosal inflammation (erythema, friability, and ulcerations) were considered suspected SCAD and underwent multiple biopsy samplings to confirm diagnosis. Clinical features were collected from diverticulosis and suspected SCAD patients. In total, 367 (26.5%) of 1383 patients who underwent colonoscopy presented diverticulosis. Among diverticulosis patients, 4.3% (n = 16) presented macroscopic signs of interdiverticular mucosal inflammation and were identified as suspected SCAD. Compared to that of patients with diverticulosis, the age of suspected SCAD patients was significantly lower (60 ± 12.9 years (41.0–86.0) vs. 70 ± 10.6 years (38.0–93.0)) (p = 0.047). Among patients with suspected SCAD, one patient received a new diagnosis of Crohn’s disease, one had spirochetosis infection, and one presented drug-induced colitis. The remaining patients with suspected SCAD (n = 13) were not confirmed by histology. This observational study suggests that SCAD diagnosis is a challenge in clinical practice due to the heterogeneity of endoscopic findings and lack of stated histological criteria.

Background Factors associated with rectal NENs prognosis are poorly investigated. Aim To evaluate the prognostic role of the ENETs staging and grading systems in rectal NENs. Methods Tertiary referral, multicenter, retrospective study. Factors associated with OS and PFS were investigated by Cox-regression analysis, with best size cut-offs calculated by ROC analysis. Results Of 100 patients (mean age 55, 45% male, mean size 16.2 mm) 62, 5, 10 and 23 were TNM stage 1 to 4, and 63, 15 and 22 were G1, G2 and G3. Primary treatment was endoscopic snare resection in 62%, endoscopic mucosal resection/endoscopic submucosal dissection in 10%, surgery in 20% and medical treatment in 8%. The best size cut-offs to predict OS and PFS were 10 and 12 mm. During a mean follow-up of 40.7 months 12% died and 26% progressed. The 5-year OS and PFS were 79.5% and 65.2%. Stage IV and G3 were associated with worse OS (HR 8.16; p = 0.002; HR 15.57; p = 0.0004) and PFS (HR 14.26 p Conclusion Both staging and grading accurately predict rectal NENs prognosis. Size alone has limited accuracy as 26% of patients with stage IV and 16% with G3 have a primary tumour≤10 mm.

We retrospectively collected a series of 82 endoscopically removed early colorectal cancers. Histological specimens were revised by two gastrointestinal pathologists, performing a re-evaluation of all risk factors for lymph node metastasis. The comparison between second opinion and first pathological report revealed that lymphovascular invasion and tumor grading showed a lower level of concordance than other parameters. Our results demonstrated that second opinion modified risk assessment in about 10% of cases. It was mainly due to a lack in reporting of some parameters at the first diagnosis and a different evaluation in second opinion for updated guidelines. Considering the subgroup of patients with modified risk assessment, clinical data revealed that tumors, re-classified as low risk, did not develop lymph node metastasis that, conversely, occurred in patients identified as high risk by second opinion. In conclusion, second opinion significantly alters risk perception of endoscopically removed early colorectal carcinomas representing a valuable tool for their appropriate clinical management.

BACKGROUND/AIM Although genoproteomic and clinicopathological knowledge on Lynch syndrome (LS) and familial adenomatous polyposis (FAP) has notably increased during the past two decades and even though surgery represents the mainstay of treatment for both conditions, as of 2019, the surgical choice in terms of timing and procedure still appears controversial in the absence of definitive guidelines. MATERIALS AND METHODS Data were retrospectively analyzed of patients with colorectal cancer (CRC) surgically treated at our Institution between 1st January 2003 and 31st December 2018. Particular attention was given to patients with LS and FAP ≤45 years of age (young-onset CRC); for this category of patients, the surgical procedures performed were compared in terms of benefits and disadvantages. RESULTS A total of 1,878 primary CRCs were submitted to major surgery; young-onset malignancies accounted for 3.8% of all CRCs. Thirteen young-onset inherited CRCs were surgically removed from 11 patients with LS and two with FAP. Segmental colectomy and restorative proctocolectomy were the procedures most frequently performed in young patients with LS and FAP, respectively. CONCLUSION In the light of our retrospective results, we highlight the need for randomized controlled trials comparing the surgical options for LS- and FAP-related CRC developing in young patients. Defining the advantages and risks of each surgical option is of the utmost importance in order to improve prognosis of such patients and establish unanimous recommendations.

Background: Because of a lack of large-scale prospective studies there is no clear indication about the management of patients with small bowel adenocarcinoma (SBA). This study evaluated clinical outcome of patients diagnosed with SBA at our institution. Methods: Clinicopathologic features, treatments, and clinical outcome of patients diagnosed with SBA between 2006 and 2017 were retrospectively analyzed. Median time of survival was calculated and compared using the log-rank test. Multivariate Cox regression was used to test independence of significant factors in univariate analysis. Results: Forty patients were included in the study; the majority (82.5%) had a tumor in the duodenum (including ampulla of Vater) and an early stage disease at the diagnosis. Median overall survival (OS) in the whole study population was 26.5 months. Patients with a tumor of the lower part of the small intestine (jejunum, ileum, and appendix) showed a better OS compared with that of patients with upper SBA (40 months vs 26 months, respectively; P=0.09). Primary tumor site and stage were independent predictors of OS. Conclusions: Our results suggest a prognostic role for the primary tumor site. This finding deserves to be further investigated to ensure better classification as well as more effective management strategies for SBA.

Background Intestinal Ganglioneuromatosis (IG) is a rare disorder of the enteric nervous system. In pediatric age it is often associated with genetic syndromes such as Neurofibromatosis 1 (NF1), multiple endocrine neoplasia type 2B (MEN2B) and Cowden syndrome (PTEN mutation), and ganglioneuromas (GNs) may be sometimes the first sign of the disease. Isolated GNs are rare and sporadic. Clinical symptom vary and depend on the size and on the location of the GNs. This disorder affects intestinal motility and it, consequently, causes changes in bowel habits, abdominal pain, occlusive symptoms and rarely lower gastrointestinal bleeding secondary to ulceration of the intestinal mucosa. On the other hand, patients can remain asymptomatic for many years. Case presentation We describe a 9-year-old boy referred to our emergency department for right lower quadrant abdominal pain. No familial history for gastrointestinal disorders. No history of fever or weight loss. At physical examination, he had diffused abdominal pain. Abdominal ultrasonography showed a hypoechoic formation measuring 41.8 mm by 35 mm in the right lower quadrant of the abdomen. Routine blood tests were normal, but fecal occult blood test was positive. Abdominal TC confirmed the hypodense formation, of about 5 cm in transverse diameter, in the right hypochondrium that apparently invaginated in the caecum-last ileal loop. Colonoscopy showed in the cecum an invaginated polypoid lesion of the terminal ileal loop. Laparoscopic resection of the polypoid lesion was performed. Histological diagnosis of the large neoplasm observed in the terminal ileum was diffuse ganglioneuromatosis. NF1, RET and PTEN gene tests resulted negative for specific mutations. At the 1 year follow-up, the patient presented good general condition and blood tests, fecal occult blood test, esophagogastroduodenoscopy, colonoscopy and MR-enterography were negative. Conclusions Only few cases are reported in literature of IG in pediatric age. Although rare, the present case suggests that this disorder must be taken in consideration in every patient with GI symptoms such as abdominal pain, constipation, lower intestinal bleeding, in order to avoid a delayed diagnosis.

INTRODUCTION Corpus atrophic gastritis (CAG) is associated with intestinal metaplasia (IM) and pseudopyloric metaplasia (PPM). Prospective data on corpus mucosa PPM and its link to the development of gastric cancer (GC) are lacking. This study aimed to investigate the relationship between the presence of corpus mucosa PPM at baseline and the development of GC at follow-up in patients with CAG. METHODS A longitudinal cohort study was conducted on patients with consecutive CAG adhering to endoscopic-histological surveillance. Patients were stratified for the presence/absence of corpus PPM without concomitant corpus IM at baseline, and the occurrence of gastric neoplastic lesions at the longest available follow-up was assessed. RESULTS A total of 292 patients with CAG with a follow-up of 4.2 (3-17) years were included. At baseline, corpus PPM without corpus IM was diagnosed in 62 patients (21.2%). At the follow-up, GC was detected in 5 patients (1.7%) and gastric dysplasia (GD) in 4 patients (1.4%). In all these 9 patients with GC/GD at the follow-up, corpus IM was present at baseline and follow-up. Age

Clear cell gastric cancer (CCGC) represents an extremely rare variant of adenocarcinoma of the stomach. It can be mistaken for a clear cell metastatic lesion arising from other anatomic parts, especially renal cell carcinoma.We describe the case of a 66-year-old woman who was operated for a pyloric adenocarcinoma which resulted to be a CCGC at definitive histology. Moreover, we offer a systematic review of the current pertinent literature on CCGC.Our case represents the 160th example of CCGC. Clear cell aspect is due to the intracytoplasmic accumulation of glycogen in most cases, followed by mucin, lipid or water; the reason of the underlying biochemical process is still unclear. Paralleling other epithelial clear cell malignancies (as ovarian, bladder, urothelial or pancreatic cancers), also CCGC shows a more aggressive clinical behavior over conventional neoplastic counterparts.Differently from clear cell carcinomas involving other organs, CCGC has been rarely investigated by the literature. Since, compared to non clear cell cancers, this particular phenotype of gastric cancer appears to be associated with poorer prognosis, further studies are needed in order to corroborate its real adverse prognostic significance and standardize the correct management and treatment.

A gluten-free diet (GFD) leads to a rapid improvement in gastrointestinal (GI) symptoms, biochemical alterations and duodenal histological damage in the majority of celiac disease (CD) patients. This study aimed to assess the frequency and factors associated with the persistence of GI symptoms/malabsorption signs and their relationship with duodenal histological findings among CD patients on an adequate GFD (mean duration 16 months, range 12–28 months). This longitudinal cohort study included 102 adult CD patients (median age 38.5 years, range 18–76 years, F = 71.6%) diagnosed between 2012 and 2018. A total of 36.3% of the included patients had persistent GI symptoms and/or malabsorption signs (Group 1), while the remaining patients had complete GI well-being without malabsorption signs (Group 2) at the time of histological re-evaluation. The persistence of GI symptoms/signs was associated with a long duration of symptoms/signs before CD diagnosis (≥5 years) (OR 5.3, 95% CI 1.3–21.8) and the presence of constipation at the time of CD diagnosis (OR 7.5, 95% CI 1.3–42) while for other variables, including age at CD diagnosis, sex, duration of GFD, comorbidities, CD serology positivity and severity of duodenal damage at histological re-evaluation, no association was found. According to our results, the persistence of symptoms/signs is not associated with histological findings, and their relationship could be a gray area in CD management.

Background. EndoFaster® analyzes gastric juice in real time during gastroscopy allowing the detection of hypo-achlorhydric conditions, like corpus atrophic gastritis. Narrow-band imaging (NBI) endoscopy allows to accurately detect and perform target biopsies in areas of intestinal metaplasia, a histological change often associated to corpus atrophic gastritis. Aims. To compare the diagnostic accuracy of EndoFaster® with histological evaluation for corpus atrophic gastritis through high-resolution (HR) NBI targeted biopsies. Methods. Prospective study on consecutive adult patients undergoing gastroscopy between April and November 2018. Patients in therapy with proton pump inhibitors, previous gastric surgery, and/or known gastric neoplasia were excluded. At the beginning of gastroscopy, gastric juice was aspirated and analyzed by EndoFaster® in 15 seconds. Endoscopists were blinded to the report of EndoFaster®. Evaluation of gastric mucosa in HR-white light was firstly performed, then with HR-NBI allowing to perform targeted biopsies on areas suspected for intestinal metaplasia; otherwise, biopsies were performed according to the updated Sydney System protocol and sent for histopathological evaluation. Results. Overall, 124 patients were included [64% F; 56 (18-85) years]. Corpus atrophic gastritis was present in 41.9% of patients. EndoFaster® showed an accuracy for corpus atrophic gastritis diagnosis, compared to histopathological evaluation as gold standard, of 87.1% and a sensitivity, specificity, PPV, and NPV of 78.8%, 93.1%, 89.1%, and 85.9%, respectively. pH showed a positive correlation with the severity score of atrophy ( r = 0.67 , 95% CI: 0.73-0.81, and p < 0.0001 ). EndoFaster® allowed to diagnose corpus atrophic gastritis in 3.7% of patients negative to NBI (corpus atrophic gastritis without intestinal metaplasia). Conclusion. EndoFaster® seems a promising tool to diagnose corpus atrophic gastritis. The evaluation of hypo-achlorhydria during gastroscopy can address bioptic sampling in corpus atrophic gastritis patients without intestinal metaplasia.

Colorectal and glioblastoma cancer stem‐like cells (CSCs) are essential for translational research. Cell line authentication by short tandem repeat (STR) profiling ensures reproducibility of results in oncology research. This technique enables to identify mislabeling or cross‐contamination of cell lines. In our study, we provide a reference dataset for a panel of colorectal and glioblastoma CSCs that allows authentication. Each cell line was entered into the cell Line Integrated Molecular Authentication database 2.1 to be compared to the STR profiles of 4485 tumor cell lines. This article also provides clinical data of patients from whom CSCs arose and data on the parent tumor stage and mutations. STR profiles and information of our CSCs are also available in the Cellosaurus database (ExPASy) as identified by unique research resource identifier codes., What's new? Human cell lines obtained from cancer stem‐like cells represent an invaluable model for studying tumor properties. Cell line authentication by short tandem repeat (STR) profiling is an important tool to identify the potential mislabeling or cross‐contamination of cell lines. Here, the authors characterized 18 colorectal cancer stem‐like cell lines from 17 patients and 103 glioblastoma cancer stem‐like cell lines from 95 patients by STR profiling to create a reference dataset that allows the authentication of these cell lines and their identification through a unique research resource identifier. The results will help further ensure the reliability and reproducibility of research experiments.

Simple Summary A comparative ultrastructural and flow cytometric analysis of colorectal cancer-derived spheroids and their mouse xenografts showed that they both contain the same cell types but with different ratios, reflecting the interaction of cancer cells, respectively, with the in vitro and in vivo microenvironment. Abstract Spheroids from primary colorectal cancer cells and their mice xenografts have emerged as useful preclinical models for cancer research as they replicate tumor features more faithfully as compared to cell lines. While 3D models provide a reliable system for drug discovery and testing, their structural complexity represents a challenge and their structure-function relationships are only partly understood. Here, we present a comparative ultrastructural and flow citometric analysis of patient colorectal cancer-derived spheroids and their mice xenografts. Ultrastructural observations highlighted that multicellular spheroids and their xenografts contain the same cancer cell types but with different ratios, specifically multicellular spheroids were enriched in cells with a stem-like phenotype, while xenografts had an increased amount of lipid droplets-containing cells. The flow cytometric analysis for stem cell marker and activity showed enrichment of stem-like cells presence and activity in spheroids while xenografts had the inverse response. Our results evidence the effects on cancer cells of different in vitro and in vivo microenvironments. Those differences have to be paid into account in designing innovative experimental models for personalized drug testing.

In corpus atrophic gastritis (CAG), hypochlorhydria makes plausible the overgrowth of intragastric bacteria, whose role in gastric carcinogenesis is under debate.To characterize the antrum/corpus composition of the gastric bacterial microbiota in CAG patients compared to controls without CAG.A cross-sectional monocentric study on consecutive patients with known histological diagnosis of CAG undergoing gastroscopy for gastric cancer surveillance and patients without CAG undergoing gastroscopy for dyspepsia or anemia (108 biopsies from 55 patients, median age 61.5). Genomic DNA from one antral and one corpus biopsy from each case (n = 23) and control (n = 32) was extracted. Gastric microbiota was assessed by sequencing hypervariable regions of the 16SrRNA gene.Bacterial abundance and diversity were significantly lower in CAG cases than in controls (p 0.001). Firmicutes were more frequent in cases, Bacteroidetes and Fusobacteria in controls (p 0.0001). Streptococcaceae were more abundant in cases (p 0.0001), Prevotellaceae in controls (p 0.0001). The genus Streptococcus was positively correlated with severe OLGA/OLGIM stages linked to a higher risk of gastric cancer.Gastric bacterial microbiota in CAG showed a reduced abundance and complexity but was characterized by higher colonization of Firmicutes, in particular Streptococcus, increased in subjects with severe atrophy/metaplasia stages at higher risk of gastric cancer.

Background: Although most of the analyses included transverse colon cancers (TCC) among right colon cancer (RCC), it is not completely clear if they present total similarities with RCC or if they have their specific features. Therefore, we present an observational study to evaluate clinicopathological characteristics and survival data of patients with TCC. Methods: We retrospectively reviewed 450 RCC, of whom 97 stages I&ndash, IV TCC were included in this multicenter study, clinicopathological and molecular parameters were analyzed to identify prognostic factors for disease-free survival (DFS) and overall survival (OS). Results: Most of TCC cases were male (61%), with &le, 70 years old (62%), and good performance status (ECOG PS 0, 68%). According to WHO classification, 41 (49%) and 40 (48%) tumors were classified as well to moderate and poorly/undifferentiated respectively, regardless of mucinous component (30%). About molecular data, 8 (26%), 45 (63%), and 14 (24%) were MSI-H, KRAS wild-type, and BRAF V600E mutant, respectively. With a median follow-up of 34 months, there were 29 and 50 disease recurrences and deaths respectively. Charlson comorbidity index &ge, 5 was a significant prognostic factor for DFS (HR = 7.67, 95% CI 2.27&ndash, 25.92). Colon obstruction/perforation (HR = 2.65, 95% CI 1.01&ndash, 7.01), and BRAF mutant (HR = 3.03, 95% CI 0.97&ndash, 9.50) cases showed a worst, despite not statistically significant, DFS. Whereas for OS, at the multivariate model, only tumor grade differentiation (HR = 5.26, 95% CI 1.98&ndash, 14.01) and BRAF mutation status (3.71, 95% CI 1.07&ndash, 12.89) were independent prognostic factors. Conclusions: Poorly/undifferentiated tumor grade and BRAF V600E mutation are independent prognostic factors for OS in TCC. Further prospective clinical trials are needed to better define TCC treatment in order to improve patient outcome.

Summary Gastric biopsies represent one of the most frequent specimens that the pathologist faces in routine activity. In the last decade or so, the landscape of gastric pathology has been changing with a significant and constant decline of H. pylori-related pathologies in Western countries coupled with the expansion of iatrogenic lesions due to the use of next-generation drugs in the oncological setting. This overview will focus on the description of the elementary lesions observed in gastric biopsies and on the most recent published recommendations, guidelines and expert opinions.

Background Type 1 and 2 diabetes confer an increased risk of pancreatic cancer (PaC) of similar magnitude, suggesting a common mechanism. The recent finding that PaC incidence increases linearly with increasing fasting glucose levels supports a central role for hyperglycaemia, which is known to cause carbonyl stress and advanced glycation end-product (AGE) accumulation through increased glycolytic activity and non-enzymatic reactions. This study investigated the impact of hyperglycaemia on invasive tumour development and the underlying mechanisms involved. Methods Pdx1-Cre;LSL-KrasG12D/+ mice were interbred with mitosis luciferase reporter mice, rendered diabetic with streptozotocin and treated or not with carnosinol (FL-926-16), a selective scavenger of reactive carbonyl species (RCS) and, as such, an inhibitor of AGE formation. Mice were monitored for tumour development by in vivo bioluminescence imaging. At the end of the study, pancreatic tissue was collected for histology/immunohistochemistry and molecular analyses. Mechanistic studies were performed in pancreatic ductal adenocarcinoma cell lines challenged with high glucose, glycolysis- and glycoxidation-derived RCS, their protein adducts AGEs and sera from diabetic patients. Results Cumulative incidence of invasive PaC at 22 weeks of age was 75% in untreated diabetic vs 25% in FL-926-16-gtreated diabetic and 8.3% in non-diabetic mice. FL-926-16 treatment suppressed systemic and pancreatic carbonyl stress, extracellular signal-regulated kinases (ERK) 1/2 activation, and nuclear translocation of Yes-associated protein (YAP) in pancreas. In vitro, RCS scavenging and AGE elimination completely inhibited cell proliferation stimulated by high glucose, and YAP proved essential in mediating the effects of both glucose-derived RCS and their protein adducts AGEs. However, RCS and AGEs induced YAP activity through distinct pathways, causing reduction of Large Tumour Suppressor Kinase 1 and activation of the Epidermal Growth Factor Receptor/ERK signalling pathway, respectively. Conclusions An RCS scavenger and AGE inhibitor prevented the accelerating effect of diabetes on PainINs progression to invasive PaC, showing that hyperglycaemia promotes PaC mainly through increased carbonyl stress. In vitro experiments demonstrated that both circulating RCS/AGEs and tumour cell-derived carbonyl stress generated by excess glucose metabolism induce proliferation by YAP activation, hence providing a molecular mechanism underlying the link between diabetes and PaC (and cancer in general).

Purpose: BRAF mutations represent the main negative prognostic factor for metastatic colorectal cancer and a supposed negative predictive factor of response to standard chemotherapy. We have explored survival difference in right-sided colon cancer (RCC) patients according to BRAF mutations, with the aim to identify any predictive factors of response to targeted-based therapy. Methods: A retrospective study of RCC patients, with BRAF known mutation status, treated with chemotherapy (CT) from October 2008 to June 2019 in 5 Italian centers, was conducted. Results: We identified 207 advanced RCC patients: 20.3% BRAF mutant and 79.7% BRAF wild type (wt). BRAF-mutant cancers were more likely to be pT4 (50.0% v 25.7%, p = 0.016), undifferentiated (71.4% v 44.0%, p = 0.004), KRAS wt (90.5% v 38.2%, p < 0.001), and MSI-H (41.7% v 16.2%, p = 0.019) tumors, with synchronous (52.4% v 31.5%, p = 0.018) and peritoneal metastases (38.1% v 22.4%, p = 0.003). Median overall survival (OS) was 16 v 27months in BRAF mutant and BRAF wt (P = 0.020). In first-line setting, BRAF-mutant showed a 2ys OS of 80% in clinical trials, 32% in anti-VEGF, 14% in epidermial growth factor receptor (EGFR), and 0% in chemotherapy alone regimens (P = 0.009). BRAF-mutant patients demonstrated worse survival, regardless of targeted therapy administered. However, survival difference was statistically significant in the anti-EGFR-treated subgroup (16 v 28months, P = 0.005 in BRAF mutant v BRAF wt, respectively). Conclusions: Our study demonstrated that BRAF status makes the difference in treatment’s outcome. Therefore, the anti-EGFR should not be excluded in all advanced RCC but considered on a case-by-case basis.

Introduction: Dysregulation of the mechanistic target of rapamycin complex 1 (mTORC1)-dependent pathways in pancreatic neuroendocrine neoplasms (PanNENs) underlies the introduction of the mTORC1 inhibitor everolimus as treatment of advanced progressive PanNENs. Although everolimus significantly increases progression-free survival, most patients acquire secondary resistance to the drug. This study aimed at identifying mechanisms involved in acquisition of resistance to everolimus. Methods: BON-1 and everolimus-resistant (ER) BON-1 cells were used as in vitro system of sensitivity and acquired resistance. Transcriptome changes occurring in BON-1 and ER-BON-1 were investigated by RNA sequencing and validated by quantitative PCR analysis. RNA extracted from patients’ biopsies was used to validate MYC upregulation. Drug screening and functional assays were performed using ER-BON-1 cells. Cell cycle progression was evaluated by FACS analysis. Results: Our results show that MYC overexpression is a key event in the development of secondary resistance to everolimus in PanNEN cell lines and in metastatic lesions from neuroendocrine neoplasm patients. MYC knockdown restored ER-BON-1 sensitivity to everolimus. Pharmacological inhibition of MYC mediated by the cyclin-dependent kinase inhibitor dinaciclib strongly reduced viability of ER-BON-1. Dinaciclib synergized with everolimus and inhibited ER-BON-1 cell cycle progression. Discussion: Our findings suggest that MYC upregulation drives the development of secondary resistance to everolimus in PanNENs and that its inhibition is an exploitable vulnerability. Indeed, our results indicate that combined treatments with cyclin-dependent kinase and mTOR inhibitors may counteract secondary resistance to everolimus in PanNENs and may pave the ground for new therapeutic regimens for these tumors.

Cytokine production is essential for follicular dendritic cell (FDC) maintenance and organization of germinal centres. In follicular lymphoma, FDCs are often disarrayed and may lack antigens indicative of terminal differentiation. We investigated the in situ distribution of cells producing lymphotoxin-beta (LTB), lymphotoxin-alpha (LTA), and tumour necrosis factor-alpha (TNFA) transcripts in human reactive lymph nodes and in follicular lymphomas with follicular or diffuse growth pattern. LTB was the cytokine most abundantly produced in germinal centres. LTB was present in nearly 90% of germinal centre cells whereas LTA and TNFA were detected in 30 and 50%, respectively. Moreover, the amount of LTB expressed in reactive germinal centre cells was 80-fold higher than that of LTA and 20-fold higher than that of TNFA. LTB-positive cells were more numerous in the germinal centre dark zone, whereas expression of the FDC proteins CD21, CD23, VCAM, and CXCL13 was more intense in the light zone. Tumour cells of follicular lymphomas produced less LTB than reactive germinal centre cells. The results of the in situ study were confirmed by RT-PCR; LTB was significantly more abundant in reactive lymph nodes than in follicular lymphoma, with the lowest values detected in predominantly diffuse follicular lymphoma. In neoplastic follicles, low production of LTB by tumour B cells was associated with weaker expression of CD21+/CD23+ by FDCs. Our findings detail for the first time the distribution of LTA-, LTB-, and TNFA-producing cells in human reactive germinal centres and in follicular lymphoma. They suggest the possibility that impaired tumour-cell LTB production may represent a determinant of FDC phenotype loss and for defective follicular organization in follicular lymphoma.

Availability of tumor and non-tumor patient-derived models would promote the development of more effective therapeutics for non-small cell lung cancer (NSCLC). Recently, conditionally reprogrammed cells (CRC) methodology demonstrated exceptional potential for the expansion of epithelial cells from patient tissues. However, the possibility to expand patient-derived lung cancer cells using CRC protocols is controversial. Here, we used CRC approach to expand cells from non-tumoral and tumor biopsies of patients with primary or metastatic NSCLC as well as pulmonary metastases of colorectal or breast cancers. CRC cultures were obtained from both tumor and non-malignant tissues with extraordinary high efficiency. Tumor cells were tracked in vitro through tumorigenicity assay, monitoring of tumor-specific genetic alterations and marker expression. Cultures were composed of EpCAM+ lung epithelial cells lacking tumorigenic potential. NSCLC biopsies-derived cultures rapidly lost patient-specific genetic mutations or tumor antigens. Similarly, pulmonary metastases of colon or breast cancer generated CRC cultures of lung epithelial cells. All CRC cultures examined displayed epithelial lung stem cell phenotype and function. In contrast, brain metastatic lung cancer biopsies failed to generate CRC cultures. In conclusion, patient-derived primary and metastatic lung cancer cells were negatively selected under CRC conditions, limiting the expansion to non-malignant lung epithelial stem cells from either tumor or non-tumor tissue sources. Thus, CRC approach cannot be applied for direct therapeutic testing of patient lung tumor cells, as the tumor-derived CRC cultures are composed of (non-tumoral) airway basal cells.

Perioperative chemotherapy (p-ChT) with a fluorouracil plus leucovorin, oxaliplatin, and docetaxel (FLOT) scheme is the gold standard of care for locally advanced gastric cancer. We aimed to test CT radiomics performance in early response prediction for p-ChT. Patients with advanced gastric cancer who underwent contrast enhanced CT prior to and post p-ChT were retrospectively enrolled. Histologic evaluation of resected specimens was used as the reference standard, and patients were divided into responders (TRG 1a-1b) and non-responders (TRG 2-3) according to their Becker tumor regression grade (TRG). A volumetric region of interest including the whole tumor tissue was drawn from a CT portal-venous phase before and after p-ChT; 120 radiomic features, both first and second order, were extracted. CT radiomics performances were derived from baseline CT radiomics alone and ΔRadiomics to predict response to p-ChT according to the TRG and tested using a receiver operating characteristic (ROC) curve. The final population comprised 15 patients, 6 (40%) responders and 9 (60%) non-responders. Among pre-treatment CT radiomics parameters, Shape, GLCM, First order, and NGTDM features showed a significant ability to discriminate between responders and non-responders (p < 0.011), with Cluster Shade and Autocorrelation (GLCM features) having AUC = 0.907. ΔRadiomics showed significant differences for Shape, GLRLM, GLSZM, and NGTDM features (p < 0.007). MeshVolume (Shape feature) and LongRunEmphasis (GLRLM feature) had AUC = 0.889. In conclusion, CT radiomics may represent an important supportive approach for the radiologic evaluation of advanced gastric cancer patients.

Lung is the site of metastasis in about 15-25 % of colorectal cancer (CRC) patients. Lung metastasectomy of CRC represents a standard therapy in patients with resectable metastases. In this study we investigated both histological patterns of metastases and mutations in MAPkinase pathway genes and their relationship to prognosis. The study included 74 patients that underwent metastasectomy of colorectal lung metastasis (CLM). In patients that underwent surgical resection of more than one metastasis in the same operation the largest was chosen. In patients that had undergone multiple lung metastasectomy only the sample from the first metastasectomy was included. Histologically metastases were scored according to amount and distribution of necrosis and fibrosis and three patterns were identified: "pattern A", metastasis with extensive, confluent central necrosis surrounded by a rim of neoplastic glands; "pattern B", metastasis characterized by a proliferation of neoplastic glands in a dense stroma with focal necrosis mainly intraglandular; "pattern C", metastasis with a mixed A and B morphology. In all samples direct sequencing of exon 2 of KRAS and NRAS genes and exon 15 of BRAF genes was carried out.Histological patterns weren't related to metastasis size or other clinical features however pattern C metastases showed a significant worst disease free survival (DFS). KRAS mutations were observed in 39 % of patients. Mutations in KRAS codon 13 resulted significantly associated with synchronous metastasis and poor prognosis. No mutations were identified in exon 2 NRAS gene whilst 1.4 % harboured a mutation in BRAF. To our knowledge this is the first study that investigates in a large series of CLM histological growth patterns, molecular alterations and their relationship to prognosis. Our data suggest a prognostic role in CLM of KRAS specific mutations and histopathological patterns.

Background Early onset (≤50y) colorectal carcinomas (EO-CRCs) are increasing in incidence according to epidemiological data. We investigated clinical-pathological, molecular features and outcomes of 62 left sided EO-CRCs (EOLS-CRCs) and compared them to a group of late onset (≥65) LS-CRCs (LOLS-CRCs). Materials and methods Samples were evaluated for pathological features and microsatellite instability (MSI). Overall survival (OS), disease free survival (DFS) and disease specific survival were evaluated in both groups. Results Five out 62 (8%) EOLS-CRCs showed MSI phenotype. Interestingly these cases were aged 26–39y. Most EOLS-CRCs present at advanced stage and this was statistically significant when compared to LOLS-CRCs. OS was better in EOLS-CRCs whilst DFS showed a worst profile in EOLS-CRCs either in low and high stages even though young patients were treated more often with adjuvant chemotherapy compared to older ones at the same disease stage. Conclusions Most EOLS-CRCs are sporadic non Lynch, microsatellite stable (MSS) CRCs. Our data show that when compared with LOLS-CRCs the early group represents an aggressive disease with worst outcome underlining a possible different carcinogenic pathway.

Introduction Recently TRG, necrosis grade and the rate of viable cancer cells of colorectal liver metastases were correlated with the response to chemotherapy treatments, whereas K-RAS mutations and c-MET over-expression were correlated with the prognosis. Methods 58 resection specimens were assessed for regression grades. Patients undergone neo-adjuvant treatments were compared to patients who underwent therapy exclusively adjuvantly. We investigated the K-RAS mutational profile, the c-MET over-expression along with patients’ survivals curves. Results Patients undergone neo-adjuvant treatment presented significant higher fibrosis rates and lower rates of viable cells. 36.7% of the patients had a K-RAS mutation and the 26.7% presented c-MET over-expression, but these features did not correlate with patients’ clinical/pathological data. Survival analysis documented that K-RAS WT patients presenting c-MET over-expression had worse outcomes. Conclusion Fibrosis and the rate of viable cells significantly correlate with the response to chemotherapy treatments. c-MET is a promising marker in K-RAS WT patients.