Increased Number of Colorectal Interval Cancers in Lynch Syndrome after the SARS-CoV-2 Pandemic: A Survey-Based Study

Background: Hereditary colorectal cancer syndromes require timely endoscopic surveillance. Methods: This study evaluated the approach of Italian gastroenterologists to the management of such patients. It then assessed the impact of SARS-CoV-2. All members affiliated with the leading Italian gastroenterology societies (AIGO, SIED, and SIGE) received an online questionnaire. Results: One hundred and twenty-one clinicians from 96 centers answered, not necessarily experts in the field (mean age 50.26 +/- 11.22 years). Many collected family history for genetic risk assessment (74.4%), but only 14.0% used an online predictive software. 65.6% discussed cases in multidisciplinary units. Genetic analysis was available to most centers, but only a few hospitals offered dedicated endoscopy (19.0%), outpatient clinics (33.9%), or surgeries (23.1%). Since the start of the SARS-CoV-2 pandemic, the number of clinicians with a high volume of patients decreased (from 38.8% to 28.1%). Almost half of the responders (45.5%) reported a delay in the surveillance (median: 4-12 months). Ultimately, 30.6% detected one interval colorectal cancer in at least one of their patients. Conclusion: The SARS-CoV-2 pandemic directly affected the surveillance of hereditary colorectal cancer syndromes in Italy. Endoscopic surveillance should resume in all centers to avoid the possible long-term consequences of its interruption, especially for inherited colorectal cancer syndromes

Delphi Initiative for Early-Onset Colorectal Cancer (DIRECt) International Management Guidelines

Background & aims: Patients with early-onset colorectal cancer (eoCRC) are managed according to guidelines that are not age-specific. A multidisciplinary international group (DIRECt), composed of 69 experts, was convened to develop the first evidence-based consensus recommendations for eoCRC. Methods: After reviewing the published literature, a Delphi methodology was used to draft and respond to clinically relevant questions. Each statement underwent 3 rounds of voting and reached a consensus level of agreement of ≥80%. Results: The DIRECt group produced 31 statements in 7 areas of interest: diagnosis, risk factors, genetics, pathology-oncology, endoscopy, therapy, and supportive care. There was strong consensus that all individuals younger than 50 should undergo CRC risk stratification and prompt symptom assessment. All newly diagnosed eoCRC patients should receive germline genetic testing, ideally before surgery. On the basis of current evidence, endoscopic, surgical, and oncologic treatment of eoCRC should not differ from later-onset CRC, except for individuals with pathogenic or likely pathogenic germline variants. The evidence on chemotherapy is not sufficient to recommend changes to established therapeutic protocols. Fertility preservation and sexual health are important to address in eoCRC survivors. The DIRECt group highlighted areas with knowledge gaps that should be prioritized in future research efforts, including age at first screening for the general population, use of fecal immunochemical tests, chemotherapy, endoscopic therapy, and post-treatment surveillance for eoCRC patients. Conclusions: The DIRECt group produced the first consensus recommendations on eoCRC. All statements should be considered together with the accompanying comments and literature reviews. We highlighted areas where research should be prioritized. These guidelines represent a useful tool for clinicians caring for patients with eoCRC

Ruolo delle mutazioni geniche e dei polimorfismi nella patogenesi delle malattie infiammatorie del pancreas

INTRODUZIONE Le patologie infiammatorie pancreatiche, pancreatite acuta, acuta ricorrente e cronica, hanno una patogenesi multifattoriale in cui risultano coinvolti fattori ambientali, abitudini voluttuarie e predisposizione genetica. La pancreatite acuta (PA) è una patologia associata ad una intensa risposta infiammatoria. La proteina MCP-1 (Monocyte Chemoattracting Protein-1) è una chemochina con un ruolo centrale nell’instaurare e nel mantenere il processo infiammatorio. Il polimorfismo -2518 G della regione regolatrice del gene per MCP-1 altera il livello di espressione di questa chemochina accrescendo la risposta infiammatoria. La pancreatite cronica (PC) è una malattia caratterizzata da alterazioni morfologiche e funzionali irreversibili della ghiandola pancreatica. Recentemente è risultato evidente come oltre ai già riconosciuti fattori ambientali associati alla patogenesi malattia (es. alcol, fumo), siano implicati anche fattori genetici (es. mutazioni del canale per l’efflusso di cloro CFTR, mutazioni per il gene dell’inibitore della tripsina SPINK-1, mutazioni del tripsinogeno cationico PRSS1). SCOPO DELLA TESI La presente tesi ha avuto lo scopo di valutare la presenza del polimorfismo -2518 della proteina MCP-1 nei pazienti affetti da malattie infiammatorie pancreatiche, ed investigare il ruolo della predisposizione genetica alla pancreatite cronica nella popolazione italiana per identificare, tramite analisi molecolare, i geni associati con un aumento della suscettibilità alla malattia. Sono stati indagati, previa accettazione di consenso informato, 342 pazienti italiani di cui: 118 affetti da pancreatite acuta, 64 affetti da pancreatite acuta ricorrente e 160 pazienti affetti da pancreatite cronica sporadica, inoltre sono stati indagati 150 soggetti sani di controllo. In particolare sono state valutate: 1) Mutazioni genetiche già descritte come implicate nella patogenesi della pancreatite cronica, in popolazioni non italiane. Sono state analizzate: • Mutazioni dell'inibitore della proteasi serinica (SPINK1), proteina che inibisce specificamente circa il 20% della tripsina attivata bloccando fisicamente il sito attivo. E' stato ipotizzato che un deficit a livello di questa proteina inibitrice possa condurre ad eccessiva attivazione tripsinica. • Mutazioni del gene codificante il canale del cloro (CFTR), che, se mutato, può contribuire a modificare le caratteristiche del secreto pancreatico, rendendolo più viscoso. • Mutazioni del gene tripsinogeno cationico (PRSS1) che con modalità autosomica dominante causa pancreatite ereditaria. 2) Il polimorfismo A/G del gene MCP-1 espresso nel siero di pazienti affetti dalle tre patologie pancreatiche in esame (pancreatite acuta, acuta ricorrente e cronica). RISULTATI I risultati della presente tesi dimostrano un’associazione tra pancreatite cronica e mutazioni a carico dei geni CFTR (p<0.001) e SPINK1 (p=0.05, Yates chi-square test), già descritte in popolazioni non italiane. Infine, nessuno dei 160 pazienti presenta alcuna delle mutazioni analizzate del gene per il tripsinogeno cationico (PRSS1). Questo risultato negativo era previsto in quanto le mutazioni del PRSS1 causano pancreatite cronica ereditaria in modo autosomico dominante. I livelli sierici di MCP-1 erano significativamente più alti in tutti i pazienti affetti da malattie infiammatorie del pancreas. Inoltre, abbiamo riscontrato una notevole sovrarappresentazione dell'allele MCP-1G nei pazienti affetti da ARP. CONCLUSIONI I risultati del nostro studio confermano l’associazione della pancreatite cronica con mutazioni a carico dei geni CFTR e SPINK1, nella popolazione italiana. Pertanto, la pancreatite cronica va considerata una patologia multifattoriale in cui fattori ambientali, quali ad esempio alcol e fumo, vanno ad agire su un possibile substrato genetico nel predisporre alla malattia, con effetto additivo. Inoltre i risultati della presente tesi supportano l’ipotesi per cui un aumento significativo dei livelli sierici di MCP-1 durante AP, ARP, e CP, potrebbe contribuire alla patogenesi dell’infiammazione del tessuto pancreatico. Per questo motivo l’analisi completa dei diversi potenziali fattori di suscettibilità è indispensabile nella definizione della patogenesi della malattia

The Role of Diet and Lifestyle in Early-Onset Colorectal Cancer: A Systematic Review

The incidence of early-onset colorectal cancer, defined as colorectal cancer occurring in young adults under the age of 50, is increasing globally. Knowledge of the etiological factors in young adults is far from complete. Questionable eoCRCs&rsquo; exogenous factors are represented by processed meat, sugary drinks, alcohol, Western dietary pattern, overweight and obesity, physical inactivity, and smoking, though with heterogeneous results. Therefore, we performed a systematic review to summarize the current evidence on the role of diet and lifestyle as eoCRC risk factors. We systematically searched PubMed, Scopus, and EMBASE up to July 2021, for original studies evaluating diet, alcohol, physical activity, BMI, and smoking in eoCRC and included twenty-six studies. Indeed, the exogenous factors could represent modifiable key factors, whose recognition could establish areas of future interventions through public health strategies for eoCRC primary prevention. Additionally, we discussed the role of additional non-modifiable risk factors, and of epigenetic regulation and microbiota as mediators of the eoCRC triggered by diet and lifestyle

Common variants in glyoxalase I do not increase chronic pancreatitis risk

Chronic pancreatitis (CP) may be caused by oxidative stress. An important source of reactive oxygen species (ROS) is the methylglyoxal-derived formation of advanced glycation endproducts (AGE). Methylglyoxal is detoxified by Glyoxalase I (GLO1). A reduction in GLO1 activity results in increased ROS. Single nucleotide polymorphisms (SNPs) of GLO1 have been linked to various inflammatory diseases. Here, we analyzed whether common GLO1 variants are associated with alcoholic (ACP) and non-alcoholic CP (NACP).Using melting curve analysis, we genotyped a screening cohort of 223 ACP, 218 NACP patients, and 328 controls for 11 tagging SNPs defined by the SNPinfo LD TAG SNP Selection tool and the functionally relevant variant rs4746. For selected variants the cohorts were extended to up to 1,441 patient samples.In the ACP cohort, comparison of genotypes for rs1937780 between patients and controls displayed an ambiguous result in the screening cohort (p = 0.08). However, in the extended cohort of 1,441 patients no statistically significant association was found for the comparison of genotypes (p = 0.11), nor in logistic regression analysis (p = 0.214, OR 1.072, 95% CI 0.961-1.196). In the NACP screening cohort SNPs rs937662, rs1699012, and rs4746 displayed an ambiguous result when patients were compared to controls in the recessive or dominant model (p = 0.08, 0.08, and 0.07, respectively). Again, these associations were not confirmed in the extended cohorts (rs937662, dominant model: p = 0.07, logistic regression: p = 0.07, OR 1.207, 95% CI 0.985-1.480) or in the replication cohorts for rs4746 (Germany, p = 0.42, OR 1.080, 95% CI 0.673-1.124; France, p = 0.19, OR 0.90, 95% CI 0.76-1.06; China, p = 0.24, OR 1.18, 95% CI 0.90-1.54) and rs1699012 (Germany, Munich; p = 0.279, OR 0.903, 95% CI 0.750-1.087).Common GLO1 variants do not increase chronic pancreatitis risk