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A survey of the clinicopathological and molecular characteristics of patients with suspected Lynch syndrome in Latin America.

ABSTRACT: Genetic counselling and testing for Lynch syndrome (LS) have recently been introduced in several Latin America countries. We aimed to characterize the clinical, molecular and mismatch repair (MMR) variants spectrum of patients with suspected LS in Latin America.Eleven LS hereditary cancer registries and 34 published LS databases were used to identify unrelated families that fulfilled the Amsterdam II (AMSII) criteria and/or the Bethesda guidelines or suggestive of a dominant colorectal (CRC) inheritance syndrome.We performed a thorough investigation of 15 countries and identified 6 countries where germline genetic testing for LS is available and 3 countries where tumor testing is used in the LS diagnosis. The spectrum of pathogenic MMR variants included MLH1 up to 54%, MSH2 up to 43%, MSH6 up to 10%, PMS2 up to 3% and EPCAM up to 0.8%. The Latin America MMR spectrum is broad with a total of 220 different variants which 80% were private and 20% were recurrent. Frequent regions included exons 11 of MLH1 (15%), exon 3 and 7 of MSH2 (17 and 15%, respectively), exon 4 of MSH6 (65%), exons 11 and 13 of PMS2 (31% and 23%, respectively). Sixteen international founder variants in MLH1, MSH2 and MSH6 were identified and 41 (19%) variants have not previously been reported, thus representing novel genetic variants in the MMR genes. The AMSII criteria was the most used clinical criteria to identify pathogenic MMR carriers although microsatellite instability, immunohistochemistry and family history are still the primary methods in several countries where no genetic testing for LS is available yet.The Latin America LS pathogenic MMR variants spectrum included new variants, frequently altered genetic regions and potential founder effects, emphasizing the relevance implementing Lynch syndrome genetic testing and counseling in all of Latin America countries.

SUBMITTER: Rossi BM

PROVIDER: S-EPMC5586063 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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A survey of the clinicopathological and molecular characteristics of patients with suspected Lynch syndrome in Latin America.

Rossi Benedito Mauro BM Palmero Edenir Inêz EI López-Kostner Francisco F Sarroca Carlos C Vaccaro Carlos Alberto CA Spirandelli Florencia F Ashton-Prolla Patricia P Rodriguez Yenni Y de Campos Reis Galvão Henrique H Reis Rui Manuel RM Escremim de Paula André A Capochin Romagnolo Luis Gustavo LG Alvarez Karin K Della Valle Adriana A Neffa Florencia F Kalfayan Pablo German PG Spirandelli Enrique E Chialina Sergio S Gutiérrez Angulo Melva M Castro-Mujica Maria Del Carmen MDC Sanchez de Monte Julio J Quispe Richard R da Silva Sabrina Daniela SD Rossi Norma Teresa NT Barletta-Carrillo Claudia C Revollo Susana S Taborga Ximena X Morillas L Lena LL Tubeuf Hélène H Monteiro-Santos Erika Maria EM Piñero Tamara Alejandra TA Dominguez-Barrera Constantino C Wernhoff Patrik P Martins Alexandra A Hovig Eivind E Møller Pål P Dominguez-Valentin Mev M

BMC cancer 20170905 1

<h4>Background</h4>Genetic counselling and testing for Lynch syndrome (LS) have recently been introduced in several Latin America countries. We aimed to characterize the clinical, molecular and mismatch repair (MMR) variants spectrum of patients with suspected LS in Latin America.<h4>Methods</h4>Eleven LS hereditary cancer registries and 34 published LS databases were used to identify unrelated families that fulfilled the Amsterdam II (AMSII) criteria and/or the Bethesda guidelines or suggestive ...[more]

PMID: 28874130

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Project description:Airway management during the COVID-19 pandemic has been one of the most challenging aspects of care that anesthesiologists and intensivists face. This study was conducted to evaluate the management of tracheal intubation in patients with suspected or confirmed COVID-19 infection. This is a cross-sectional and international multicenter study based on a 37-item questionnaire. The survey was available to physicians who had performed intubations and tracheostomies in patients with suspected or confirmed COVID-19 and had provided informed consent to participate. The primary outcome is the preference to use a specific device for tracheal intubation. Secondary outcomes are clinical practice variables, use of video laryngoscopes, difficult airway management, and safety features to prevent cross-infection. This study included 2411 physicians who performed an average of 11.90 and 20.67 tracheal intubations in patients diagnosed or suspected of having COVID-19 disease, respectively. Physicians were mainly from the specialties of Anesthesiology (61.2%) and Intensive Care (7.4%). COVID-19 infection diagnosed by positive PCR or serology in physicians participating in intubation in this study was 15.1%. Respondents considered preoxygenation for more than three minutes very useful (75.7%). The preferred device for tracheal intubation was the video laryngoscope (64.8%). However, the direct laryngoscope (57.9%) was the most commonly used, followed by the video laryngoscope (37.5%). The preferred device to facilitate intubation was the Eschmann guide (34.2%). Percutaneous tracheostomy was the preferred technique (39.5%) over the open tracheostomy (22%). The predicted or unpredicted difficult airway management in these patients was preferably performed with a video laryngoscope (61.7% or 63.7, respectively). Intubation was mostly performed by two or more expert airway physicians (61.6%). The use of personal protective equipment increased the practitioners' discomfort during intubation maneuvers. The video laryngoscope is the preferred device for intubating patients with COVID-19, combined with the Eschmann guide, flexible stylet within the endotracheal tube, or Frova guide to facilitate intubation. The sub-analysis of the two groups of physicians by the level of intubation experience showed a higher use of the video laryngoscope (63.4%) in the experts group and no significant differences between the two groups in terms of cross-infection rates in physicians, in their preference for the use of the video laryngoscope or in the number of intubations performed in confirmed or suspected COVID-19 patients.

Project description:In this study, we compared the molecular, clinical, and pathological characteristics, as well as pedigrees, between patients with Lynch-like syndrome (LLS) and confirmed Lynch syndrome (LS) to develop appropriate management strategies for patients with LLS and their affected family members. Between June 2008 and September 2018, 81 patients with LLS and 47 patients with LS who developed colorectal cancer (CRC) were enrolled in this study. Multigene panel testing included 139 genes and was performed for all patients. The variants identified in each group were described, and clinicopathological characteristics and pedigrees were compared between the two groups. In the LLS group, a total of 52 variants were detected in 44 (54.3%) patients. Among the 52 variants, 17 were variants of unknown significance in mismatch repair genes, and the other most frequently mutated genes were MUYTH, POLE, BRCA2, and GJB2. The proportion of early-onset patients was significantly higher among the LS probands than among the LLS probands (74.5 and 53.1%, respectively; ?2 = 5.712, P = 0.017). On the other hand, the proportion of primary CRC developed in the rectum was higher in the LLS group than in the LS group (25.9 and 10.6%, respectively; ?2 = 2.358, P = 0.046). There were no significant differences in the occurrence of metachronous CRC (P = 0.632) and extra-colorectal cancer (extra-CRC) (P = 0.145) between the two groups. However, analysis of pedigrees showed that more patients developed CRC in the LS families (P = 0.013), whereas more patients with extra-CRC were observed in the LLS families (P = 0.045). A higher prevalence of male patients was observed in the LLS families (P = 0.036). In conclusion, LLS should be classified as a mixed entity, containing cases of LS, other hereditary cancer syndromes, and sporadic CRC. The high risks of CRC and extra-CRCs, which were found in this study, suggest tailored management policy and surveillance should be formulated based on individual and family risk. The surveillance regimen can be based on the presence of confirmed pathogenic/likely pathogenic germline variant(s) and family history.

Project description:BACKGROUND: Patients and physicians from three Latin American (LA) and six European countries were surveyed in order to describe differences in journey to diagnosis, impact, and management of fibromyalgia (FM). METHODS: 900 patients (300 LA; 600 Europe) and 1824 physicians (604 LA; 1220 Europe) were surveyed between October-December 2010 (LA) and February-April 2008 (Europe). Patients and physicians (GP or specialists) completed separate questionnaires, on symptoms, impact, and FM management. Interviews were conducted in local languages. Appropriate rating scales were used throughout. Data were analyzed using cross-tabulations and descriptive statistics. Significance was determined at P<0.05 (indicated by *). RESULTS: In LA versus Europe, patients reported having FM symptoms for longer (100.8 vs. 83.7* months), and taking longer to be diagnosed (42.3 vs. 31.1* months). FM was characterized by multiple symptoms (11.2 vs. 6.9), but more LA patients reported 14 common symptoms*, and rated pain higher on 11-point scale (8.0 vs. 7.2*). LA patients were taking fewer medications (3.3 vs. 4.0). Patients from both regions found common symptoms very/extremely disruptive to their quality of life, but symptoms impacted daily living and ability to work more significantly in LA. Physicians (GPs or specialists) from LA more often considered problems sleeping*, difficulty concentrating*, anxiety*, depression*, numbness/tingling*, and leg cramps* very/extremely disruptive vs. European physicians. Despite headache, heightened sensitivity to touch, difficulty concentrating, and joint pain being experienced by ?50% of patients from both regions, <15% of PCPs or specialists considered these typical FM symptoms. Patients also considered 12/14 symptoms more disruptive than PCPs or specialists in the same region. However, a higher proportion of PCPs or specialists considered FM to have a strong/very strong impact on aspects of daily living vs. patients within the same region. CONCLUSIONS: Patient- and physician-rated disease perception and impact was often higher in LA than in Europe. Patient and physician perspective concerning FM impact and disruption were often misaligned within the same region. Our observations may be representative of cultural differences in stoicism, expression, beliefs, and attitudes to pain perception and management. Better understanding of these complexities could help targeted educational/training programs incorporating cultural differences, to improve chronic care.

Project description:Background & aimsMultigene panels are commercially available tools for hereditary cancer risk assessment that allow for next-generation sequencing of numerous genes in parallel. However, it is not clear if these panels offer advantages over traditional genetic testing. We investigated the number of cancer predisposition gene mutations identified by parallel sequencing in individuals with suspected Lynch syndrome.MethodsWe performed germline analysis with a 25-gene, next-generation sequencing panel using DNA from 1260 individuals who underwent clinical genetic testing for Lynch syndrome from 2012 through 2013. All patients had a history of Lynch syndrome-associated cancer and/or polyps. We classified all identified germline alterations for pathogenicity and calculated the frequencies of pathogenic mutations and variants of uncertain clinical significance (VUS). We also analyzed data on patients' personal and family history of cancer, including fulfillment of clinical guidelines for genetic testing.ResultsOf the 1260 patients, 1112 met National Comprehensive Cancer Network (NCCN) criteria for Lynch syndrome testing (88%; 95% confidence interval [CI], 86%-90%). Multigene panel testing identified 114 probands with Lynch syndrome mutations (9.0%; 95% CI, 7.6%-10.8%) and 71 with mutations in other cancer predisposition genes (5.6%; 95% CI, 4.4%-7.1%). Fifteen individuals had mutations in BRCA1 or BRCA2; 93% of these met the NCCN criteria for Lynch syndrome testing and 33% met NCCN criteria for BRCA1 and BRCA2 analysis (P = .0017). An additional 9 individuals carried mutations in other genes linked to high lifetime risks of cancer (5 had mutations in APC, 3 had bi-allelic mutations in MUTYH, and 1 had a mutation in STK11); all of these patients met NCCN criteria for Lynch syndrome testing. A total of 479 individuals had 1 or more VUS (38%; 95% CI, 35%-41%).ConclusionsIn individuals with suspected Lynch syndrome, multigene panel testing identified high-penetrance mutations in cancer predisposition genes, many of which were unexpected based on patients' histories. Parallel sequencing also detected a high number of potentially uninformative germline findings, including VUS.

Dataset Information

A survey of the clinicopathological and molecular characteristics of patients with suspected Lynch syndrome in Latin America.

Publications

A survey of the clinicopathological and molecular characteristics of patients with suspected Lynch syndrome in Latin America.

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