Prevalence of Germline Mutations in Cancer Predisposition Genes in Patients with Pancreatic Cancer or Suspected Related Hereditary Syndromes: Historical Prospective Analysis.

We investigate the prevalence of germline mutations in cancer predisposition genes in patients with pancreatic ductal adenocarcinoma (PDAC) or suspected related hereditary syndromes. METHODS: we enrolled for NGS with an Illumina TrueSight Cancer panel comprising 19 CPGs and 113 consecutive subjects referred to cancer genetic clinics for metastatic PDAC, early onset PDAC, suspected hereditary syndrome, or positive family history. RESULTS: Overall, 23 (20.1%) subjects were carriers of 24 pathogenetic variants (PVs). We found 9 variants in BRCA2 (37.5%), 6 in CDKN2A (25%), 3 in ATM (12.5%), 2 in BRCA1 (8.3%), 1 in CHEK2 (4.1%), 1 in PALB2 (4.1%), 1 in MITF (4.1%), and 1 in FANCM (4.1%). A double PV (BRCA1 plus BRCA2) was found in 1 subject. We observed a nearly 30% (16/55) mutational rate in the subgroup of subjects tested for the suspected syndromes (PDAC and other synchronous or metachronous tumors or an indicative family history), and the frequency was significantly higher than that in patients with only metastatic PDAC (p = 0.05). In our cohort, 39 variants of unknown significance (VUS) were identified, most of which (16/39, 41%) in genes belonging to the Lynch syndrome spectrum. CONCLUSION: A clinically relevant proportion of pancreatic cancer is associated with mutations in known predisposition genes. Guidelines instructing on an adequate selection for accessing genetic testing are eagerly needed. The heterogeneity of mutations identified in this study reinforces the value of using a multiple-gene panel in pancreatic cancer.

An Unexpected Anemia Hiding a Rare Syndrome With Overlapping Phenotypes.

Gastric polyposis is a rare endoscopic finding that can imply genetic syndromes predisposing to cancer development. Among the possible conditions associated with gastric polyposis and early onset gastric cancer (younger than 45 years) is juvenile polyposis syndrome. We present a clinical case of early onset gastric cancer associated with a frameshift mutation in the gene SMAD4. Individuals carrying a pathogenic variant of this gene have a high risk of malignant transformation, especially of gastric cancer. Moreover, most of these patients present also with extraintestinal features of the hereditary hemorrhagic telangiectasia, and the first symptom prompting medical evaluation is anemia.

Juvenile polyposis syndrome: An overview.

Juvenile polyposis syndrome (JPS) is a rare precancerous condition that confers an increased risk of developing gastrointestinal cancers. The inheritance pattern is autosomal dominant. JPS should be clinically suspected when the other hamartomatous polyposis syndromes are excluded (i.e., Peutz- Jeghers and Cowden), in presence of numerous juvenile polyps in the colorectum or in other GI locations. Among the syndromic features, JPS can present with concomitant extra-intestinal manifestations, above all cutaneous manifestations such as telangiectasia, pigmented nevi, and skeletal stigmata. Pathogenic germline variants of either BMPR1A or SMAD4 cause the syndrome. In JPS a cumulative risk of CRC of 39-68% has been estimated. The oncological risk justifies and imposes prevention strategies that aim at the cancer risk reduction through endoscopic screening, as recommended by international scientific societies. The aim of this review is to summarize clinical and genetic features of JPS and to elucidate the steps of the clinical management from diagnosis to surveillance.

Early age of onset is an independent predictor for worse disease-free survival in sporadic rectal cancer patients. A comparative analysis of 980 consecutive patients.

BACKGROUND: while interest on early-onset colorectal cancer (age ≤49) is on the rise, studies on early-onset rectal cancer (EORC) are limited. The aim of this study was to compare predictors for disease progression/recurrence between sporadic EORC and late-onset RC patients (LORC). METHODS: 163 EORC and 830 LORC operated between January 1st, 2010 and April 30th, 2021 at a tertiary center were included. Demographics, tumor characteristics, microsatellite status, gene mutations (KRAS, BRAF, NRAS, PI3Kca) and oncologic outcomes were compared. A Cox proportional hazards regression analysis was performed to ascertain the effect of variables on recurrence/progression and death. Recurrence/Progression free survival (R/PFS) and cancer specific survival (CSS) were analyzed by the Kaplan-Meier estimator. RESULTS: Mean age of EORC was 42.16, (46% aged 45-49). A majority of EORC patients had a family history for CRC (p = 0.01) and underwent total neoadjuvant treatment (p = 0.01). EORC patients showed a higher rate of low-grade tumor differentiation (p < 0.0001), stage III-IV (p = 0.001), microsatellite instability (p = 0.02), locoregional nodal (p = 0.001) and distant metastases (p < 0.0001). Accordingly, more EORC patients underwent adjuvant treatment (p < 0.0001). Mutations were mostly reported among LORC cases (p = 0.04), whereas EORC patients showed a worse R/PFS (p = 0.02), even at stage I (p = 0.04). CSS did not differ (p = 0.11) across groups. Multivariate analysis indicated age of onset (p = 0.04) was an independent predictor for progression/recurrence. CONCLUSIONS: Age of onset was shown to be an independent unfavorable predictor. Delayed diagnosis could explain this effect in the more advanced stages, while the worse outcomes in stage I may suggest a more aggressive disease behavior.

Defects in MMR Genes as a Seminal Example of Personalized Medicine: From Diagnosis to Therapy.

Microsatellite instability (MSI) is the landmark feature of DNA mismatch repair deficiency, which can be found in 15-20% of all colorectal cancers (CRC). This specific set of tumors has been initially perceived as a niche for geneticists or gastroenterologists focused on inherited predispositions. However, over the years, MSI has established itself as a key biomarker for the diagnosis, then extending to forecasting the disease behavior and prognostication, including the prediction of responsiveness to immunotherapy and eventually to kinase inhibitors, and possibly even to specific biological drugs. Thanks to the contribution of the characterization of MSI tumors, researchers have first acknowledged that a strong lymphocytic reaction is associated with a good prognosis. This understanding supported the prognostic implications in terms of the low metastatic potential of MSI-CRC and has led to modifications in the indications for adjuvant treatment. Furthermore, with the emergence of immunotherapy, this strong biomarker of responsiveness has exemplified the capability of re-activating an effective immune control by removing the brakes of immune evasion. Lately, a subset of MSI-CRC emerged as the ideal target for kinase inhibitors. This therapeutic scenario implies a paradox in which appropriate treatments for advanced disease are effective in a set of tumors that seldom evolve towards metastases.

EUS-guided core biopsies of pancreatic solid masses using a new fork-tip needle: A multicenter prospective study.

BACKGROUND AND AIM: Endoscopic ultrasound-guided sampling (EUS sampling) is a safe and effective technique. The study aim was to evaluate the presence of a histological core from pancreatic lesions using a new 25G fork-tip needle. METHODS: Observational multicenter prospective and analytical study, including consecutive patients with solid pancreatic masses referred for EUS-guided sampling. At each needle pass, the endoscopist performed macroscopic on-site evaluation (MOSE). The primary outcome was the histological core procurement rates. Secondary outcomes were the evaluation of interobserver agreement between endoscopists and pathologists, adequacy of EUS samples for the diagnosis and post-procedure adverse events. RESULTS: 100 patients were enrolled in 3 centers. The mean size of the lesions was 28.5 mm (SD 11.7). Final diagnoses were adenocarcinoma (68%), neuroendocrine tumor (21%), inflammatory mass/benign lesions (8.0%), and pancreatic metastasis (3.0%). The pathologists described the presence of a core in 67 samples (67.0% of patients), with poor agreement with MOSE (kappa, 0. 12; 95% CI: 0.03-0.28). The diagnostic accuracy was 93%. We observed 6% of mild adverse events. CONCLUSION: The new 25-gauge core needle showed good overall adequacy and a good rate of histological specimens during EUS sampling of solid pancreatic masses, with a minimum number of passes and no major complications. Clinicaltrial.gov number, NCT02946840.

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

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

Endoscopic Management of Benign Esophageal Ruptures and Leaks.

OPINION STATEMENT: Esophageal leaks (EL) and ruptures (ER) are rare conditions associated with a high risk of mortality and morbidity. Historically, EL and ER have been surgically treated, but current treatment options also include conservative management and endoscopy. Over the last decades, interventional endoscopy has evolved as an effective and less invasive alternative to primary surgery in these cases. A variety of techniques are currently available to re-establish the continuity of the digestive tract, prevent or treat infection related to the leak/rupture, prevent further contamination, drain potential collections, and provide nutritional support. Endoscopic options include clips, both through the scope (TTS) and over the scope (OTS), stent placement, vacuum therapy, tissue adhesive, and endoscopic suturing techniques. Theoretically, all of these can be used alone or with a multimodality approach. Endoscopic therapy should be combined with medical therapy but also with percutaneous drainage of collections, where present. There is robust evidence suggesting that this change of therapeutic paradigm in the form of endoscopic therapy is associated with improved outcome, better quality of life, and shortened length of hospital stay. Moreover, recent European guidelines on endoscopic management of iatrogenic perforation have strengthened and to some degree regulated and redefined the role of endoscopy in the management of conditions where there is a breach in the continuity of the GI wall. Certainly, due to the complexity of these conditions and the variety of available treatment options, a multidisciplinary approach is strongly recommended, with close clinical monitoring (by endoscopists, surgeons, and intensive care physicians) and special attention to signs of sepsis, which can lead to the need for urgent surgical management. This review article will critically discuss the literature regarding endoscopic modalities for esophageal leak and perforation management and attempt to place them in perspective for the physician.