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Lung cancer screening via annual low-dose computed tomography (LDCT) has poor adoption. We conducted a prospective case-control study among 958 individuals eligible for lung cancer screening to develop a blood-based lung cancer detection test that when positive is followed by an LDCT. Changes in genome-wide cell-free DNA (cfDNA) fragmentation profiles (fragmentomes) in peripheral blood reflected genomic and chromatin characteristics of lung cancer. We applied machine learning to fragmentome features to identify individuals who were more or less likely to have lung cancer. We trained the classifier using 576 cases and controls from study samples, and then validated it in a held-out group of 382 cases and controls. The validation demonstrated high sensitivity for lung cancer, and consistency across demographic groups and comorbid conditions. Applying test performance to the screening eligible population in a five-year model with modest utilization assumptions suggested the potential to prevent thousands of lung cancer deaths.
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Adagrasib, an irreversible, selective KRASG12C inhibitor, may be an effective treatment in KRASG12C-mutated colorectal cancer, particularly when combined with an anti-EGFR antibody. In this analysis of the KRYSTAL-1 trial, patients with previously treated KRASG12C-mutated unresectable or metastatic colorectal cancer received adagrasib (600 mg twice daily) plus cetuximab. The primary endpoint was objective response rate (ORR) by blinded independent central review. Ninety-four patients received adagrasib plus cetuximab. With a median follow-up of 11.9 months, ORR was 34.0%, disease control rate was 85.1%, and median duration of response was 5.8 months (95% confidence interval [CI], 4.2-7.6). Median progression-free survival was 6.9 months (95% CI, 5.7-7.4) and median overall survival was 15.9 months (95% CI, 11.8-18.8). Treatment-related adverse events (TRAEs) occurred in all patients; grade 3-4 in 27.7% and no grade 5. No TRAEs led to adagrasib discontinuation. Exploratory analyses suggest circulating tumor DNA may identify features of response and acquired resistance. SIGNIFICANCE: Adagrasib plus cetuximab demonstrates promising clinical activity and tolerable safety in heavily pretreated patients with unresectable or metastatic KRASG12C-mutated colorectal cancer. These data support a potential new standard of care and highlight the significance of testing and identification of KRASG12C mutations in patients with colorectal cancer. This article is featured in Selected Articles from This Issue, p. 897.
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Protocolos de Quimioterapia Combinada Antineoplásica , Cetuximab , Neoplasias Colorretais , Mutação , Proteínas Proto-Oncogênicas p21(ras) , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Acetonitrilas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cetuximab/administração & dosagem , Cetuximab/efeitos adversos , Cetuximab/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Metástase Neoplásica , Piperazinas , Proteínas Proto-Oncogênicas p21(ras)/genética , Pirimidinas/administração & dosagem , Pirimidinas/uso terapêutico , Pirimidinas/efeitos adversos , Resultado do TratamentoRESUMO
OBJECTIVE: Studies addressing small and diminutive polyps and their potential of harboring advanced histologic features (AH) are scarce in Hispanics. We aimed to determine the prevalence of AH in a cohort of Hispanics. METHODS: A retrospective review of medical records of patients who had a colonoscopy from 2005 through 2010. The data collected included demographics, indications, history (personal/family) of colon cancer and/or polyps, and polyp histology. Polyps with high-grade dysplasia, prominent villous component, adenocarcinoma or serrated were classified as having AH. RESULTS: The population comprised 1884 patients, and 3835 polyps were evaluated; 63.3% were diminutive (1-5 mm), 22.7% small (6-9 mm), and 13.9% large (≥10 mm). The prevalence of AH for small and diminutive polyps were 4.9% and 1.1%, respectively. Of the polyps with AH, 11.9% were diminutive and 19.6% small. Small polyps were 5.04 times more likely to harbor AH than were diminutive polyps. Distal rather than proximal polyps were more likely to harbor AH. Furthermore, AH was >7 times more common in small (6-9 mm) polyps identified during diagnostic or surveillance colonoscopies compared to screening colonoscopies. CONCLUSION: The prevalence of AH was significantly associated with size, location (distal), and procedure indication. Although diminutive polyps (<6 mm) were less likely to harbor AH, the risk for non-Hispanics was higher than previously reported. The "resect and discard" strategy for polyps ≤ 1 cm should be used with caution in ethnically diverse cohorts, as the risk for AH may be higher in Hispanics than in non-Hispanic Whites.
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Adenoma , Neoplasias do Colo , Pólipos do Colo , Neoplasias Colorretais , Humanos , Pólipos do Colo/epidemiologia , Pólipos do Colo/diagnóstico , Pólipos do Colo/patologia , Prevalência , Adenoma/epidemiologia , Adenoma/patologia , Colonoscopia/métodos , Neoplasias do Colo/epidemiologia , Neoplasias do Colo/patologia , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/epidemiologiaRESUMO
BACKGORUND: Colorectal cancer (CRC) is among the leading causes of cancer-related deaths among Hispanics living in the United States (USH). Understanding the most common carcinogenic molecular pathways that affect Hispanics with CRC is crucial to guide research efforts in developing new therapeutic modalities incorporating genomically diverse populations. Tumor profiling techniques help identify actionable alternatives to recommend treatment and improve survival in cancer patients. METHODS: We conducted a secondary data analysis to evaluate the mutational profile of 218 CRC tumors in Hispanics living in Puerto Rico (PRH) who underwent next-generation sequencing (NGS) testing from 2015 to 2020. We compared the prevalence of CRC tumor somatic mutations in PRHs with the mutational profiles reported for CRC from The Cancer Genome Atlas (TCGA) Pan-Cancer Clinical Data, the AACR Project Genomics Evidence Neoplasia Information Exchange (GENIE)-Non-Hispanic, and GENIE-Hispanic datasets. RESULTS: Among the top mutated genes in CRC tumors in PRHs were APC, TP53, and KRAS, which had significantly higher mutational frequencies in PRH compared to the examined datasets, including GENIE-Hispanics. The most frequent gene amplifications for PRH were CDX2, CDKN1B, and HNRNPA2B1. Targetable biomarkers for CRC, such as microsatellite instability-high (MSI), wild-type KRAS, wild-type NRAS, V600E BRAF, and ERBB2 gene amplifications were found in 2.0%, 43.8%, 97.8%, 3.9%, and 2.3%, respectively, of PRH patients. CONCLUSION: This is the first study to report the mutational profile of CRC tumors in PRHs and make comparisons to other non-Hispanic and USH populations.
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Neoplasias Colorretais , Proteínas Proto-Oncogênicas p21(ras) , Humanos , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias Colorretais/patologia , Mutação , Porto Rico/epidemiologia , Amplificação de GenesRESUMO
BACKGROUND: The incidence of sporadic colorectal cancer (CRC) among individuals <50 years (early-onset CRC) has been increasing in the United States (U.S.) and Puerto Rico. CRC is currently the leading cause of cancer death among Hispanic men and women living in Puerto Rico (PRH). The objective of this study was to characterize the molecular markers and clinicopathologic features of colorectal tumors from PRH to better understand the molecular pathways leading to CRC in this Hispanic subpopulation. METHODS: Microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and KRAS and BRAF mutation status were analyzed. Sociodemographic and clinicopathological characteristics were evaluated using Chi-squared and Fisher's exact tests. RESULTS: Of the 718 tumors analyzed, 34.2% (n = 245) were early-onset CRC, and 51.7% were males. Among the tumors with molecular data available (n = 192), 3.2% had MSI, 9.7% had BRAF, and 31.9% had KRAS mutations. The most common KRAS mutations observed were G12D (26.6%) and G13D (20.0%); G12C was present in 4.4% of tumors. A higher percentage of Amerindian admixture was significantly associated with early-onset CRC. CONCLUSIONS: The differences observed in the prevalence of the molecular markers among PRH tumors compared to other racial/ethnic groups suggest a distinct molecular carcinogenic pathway among Hispanics. Additional studies are warranted.
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Neoplasias Colorretais , Proteínas Proto-Oncogênicas B-raf , Masculino , Feminino , Humanos , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Metilação de DNA , Porto Rico/epidemiologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Instabilidade de Microssatélites , Biomarcadores/metabolismo , Hispânico ou Latino/genéticaRESUMO
PURPOSE: To assess whether MUC1 peptide vaccine produces an immune response and prevents subsequent colon adenoma formation. PATIENTS AND METHODS: Multicenter, double-blind, placebo-controlled randomized trial in individuals age 40 to 70 with diagnosis of an advanced adenoma ≤1 year from randomization. Vaccine was administered at 0, 2, and 10 weeks with a booster injection at week 53. Adenoma recurrence was assessed ≥1 year from randomization. The primary endpoint was vaccine immunogenicity at 12 weeks defined by anti-MUC1 ratio ≥2.0. RESULTS: Fifty-three participants received the MUC1 vaccine and 50 placebo. Thirteen of 52 (25%) MUC1 vaccine recipients had a ≥2-fold increase in MUC1 IgG (range, 2.9-17.3) at week 12 versus 0/50 placebo recipients (one-sided Fisher exact P < 0.0001). Of 13 responders at week 12, 11 (84.6%) responded to a booster injection at week 52 with a ≥2-fold increase in MUC1 IgG measured at week 55. Recurrent adenoma was observed in 31 of 47 (66.0%) in the placebo group versus 27 of 48 (56.3%) in the MUC1 group [adjusted relative risk (aRR), 0.83; 95% confidence interval (CI), 0.60-1.14; P = 0.25]. Adenoma recurrence occurred in 3/11 (27.3%) immune responders at week 12 and week 55 (aRR, 0.41; 95% CI, 0.15-1.11; P = 0.08 compared with placebo). There was no difference in serious adverse events. CONCLUSIONS: An immune response was observed only in vaccine recipients. Adenoma recurrence was not different than placebo, but a 38% absolute reduction in adenoma recurrence compared with placebo was observed in participants who had an immune response at week 12 and with the booster injection.
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Adenoma , Neoplasias do Colo , Neoplasias Colorretais , Adulto , Idoso , Humanos , Pessoa de Meia-Idade , Adenoma/prevenção & controle , Neoplasias Colorretais/prevenção & controle , Imunoglobulina G , Vacinas de Subunidades AntigênicasRESUMO
Chronic hepatitis C can lead to cirrhosis and hepatocellular carcinoma. We studied the safety and immunogenicity of a novel therapeutic hepatitis C virus (HCV) genotype 1a/1b consensus DNA vaccine, INO-8000, encoding HCV NS3, NS4A, NS4B, and NS5A proteins alone or co-administered with DNA-encoding IL12 (INO-9012), a human cytokine that stimulates cellular immune function, in individuals with chronic hepatitis C. This was a phase I, multisite dose-escalation trial with an expansion cohort evaluating doses of 0, 0.3, 1.0, and 3.0 mg of INO-9012 (IL12 DNA) as an addition to 6.0 mg of (INO-8000; HCV DNA vaccine). Vaccines were administered by intramuscular injection followed by electroporation at study entry and at weeks 4, 12, and 24. HCV-specific CD4+ and CD8+ T-cell immune responses were measured by IFNγ ELISpot and flow cytometry-based assays. Transient, mild-to-moderate injection site reactions unrelated to IL12 DNA dose were common. Increases in HCV-specific IFNγ production occurred in 15/20 (75%) participants. Increases in the frequency of HCV-specific CD4+ and CD8+ T cells occurred at all dose levels, with the greatest increases seen at 1.0 mg of INO-9012. HCV-specific CD8+ and CD4+ T-cell activities increased in 16/18 (89%) and 14/17 (82%) participants with available data, respectively. The vaccine regimen was safe and induced HCV-specific CD4+ and CD8+ cellular immune responses of modest magnitude in most HCV-infected participants. The addition of 1.0 mg of IL12 DNA provided the best enhancement of immune responses. The vaccine regimen had little effect on controlling HCV viremia. PREVENTION RELEVANCE: The administration of IL12 DNA along with a hepatitis C viral antigen DNA vaccine enhanced the HCV-specific immune responses induced by the vaccine in individuals with chronic hepatitis C, an important cause of hepatocellular carcinoma. IL12 could be an effective adjuvant in vaccines targeting HCV and other oncogenic viruses.
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Carcinoma Hepatocelular , Hepatite C Crônica , Hepatite C , Neoplasias Hepáticas , Vacinas de DNA , Humanos , Vacinas de DNA/efeitos adversos , Vacinas de DNA/genética , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Carcinoma Hepatocelular/prevenção & controle , Proteínas não Estruturais Virais/genética , Neoplasias Hepáticas/prevenção & controle , Hepatite C/prevenção & controle , Hepacivirus/genética , DNA , Interleucina-12RESUMO
BACKGROUND AND AIMS: Disparities in gastric cancer incidence and mortality have been reported among ethnic/racial groups. While gastric cancer is not common in the U.S., it is among the top 10 causes of cancer-related death among Hispanics living in Puerto Rico (PRH). This study compared gastric cancer incidence rates during a 15-year period (2002-2006, 2007-2011, and 2012-2016) between PRH and racial/ethnic groups in the mainland U.S., including Non-Hispanic Whites (NHW), Non-Hispanics Blacks (NHB), Hispanics (USH), and Non-Hispanic Asian or Pacific Islanders (NHAPI). METHODS: Primary gastric cancer cases (ICD-O-3 codes C16.0 to C16.9) from the Puerto Rico Central Cancer Registry and SEER diagnosed from January 1, 2002 to December 31, 2016 were included in the analysis. The Joinpoint Regression Program and standardized rate ratios were used to estimate Annual Percent Changes (APC) and differences in gastric cancer incidence among racial/ethnic groups, respectively. RESULTS: Our analysis included 83,369 gastric cancer cases (PRH n = 4202; NHW n = 43,164; NHB n = 10,414; NHAPI n = 11,548; USH n = 14,041). USH had the highest number of cases among individuals <50 years, whereas NHW and PRH had the highest percentage among individuals ≥50 years. PRH and USH were the only groups with increasing APCs among individuals <50 years. CONCLUSIONS: Gastric cancer continues to be a common cancer among PRH, despite the overall decrease in incidence among other racial/ethnic groups. Studies evaluating the gastric cancer risk factors among high-risk groups are necessary to establish health policy and modify gastric cancer screening algorithms among Hispanics.
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Neoplasias Gástricas , Humanos , Estados Unidos/epidemiologia , Neoplasias Gástricas/epidemiologia , Grupos Raciais , Porto Rico/epidemiologia , Etnicidade , População Branca , IncidênciaRESUMO
IMPORTANCE: Patients with familial adenomatous polyposis (FAP) are at markedly increased risk for duodenal adenomas and cancer. Combination sulindac and erlotinib was previously shown to reduce duodenal polyp burden but was associated with a relatively high adverse event (AE) rate. OBJECTIVE: To evaluate if a once weekly dosing schedule for erlotinib intervention improves the AE profile, while still providing efficacy with respect to reduced polyp burden, in participants with FAP. DESIGN, SETTING AND PARTICIPANTS: Single-arm trial, enrolling 46 participants with FAP, conducted from October 2017 to September 2019 in eight academic cancer centres. EXPOSURES: Participants self-administered 350 mg of erlotinib by mouth, one time per week for 6 months. MAIN OUTCOMES AND MEASURES: Duodenal polyp burden (sum of polyp diameters) was assessed in the proximal duodenum by esophagogastroduodenoscopy performed at baseline and 6 months, with mean per cent change defined as the primary efficacy outcome of interest. Rate of grade 2-3 AEs was evaluated as a co-primary outcome. Secondary outcomes included changes in total duodenal polyp count, along with changes in lower gastrointestinal (GI) polyp burden and count (for participants examined by optional lower endoscopy). RESULTS: Forty-six participants (mean age, 44.1 years (range, 18-68); women, 22 (48%)) were enrolled; 42 participants completed 6 months of intervention and were included in the per-protocol analysis. Duodenal polyp burden was significantly reduced after 6 months of weekly erlotinib intervention, with a mean per cent change of -29.6% (95% CI, -39.6% to -19.7%; p<0.0001). Similar results were observed in subgroup analyses defined by participants with advanced duodenal polyposis (Spigelman 3) at baseline (mean, -27%; 95% CI, -38.7% to -15.2%; p<0.0001). Post-intervention Spigelman stage was downstaged in 12% of the participants. Lower GI polyp number was also decreased after 6 months of intervention (median, -30.8%; IQR, -47.4% to 0.0%; p=0.0256). Grade 2 or 3 AEs were reported in 71.7% of subjects, with only two experiencing grade 3 toxicity at least possibly related to intervention. CONCLUSION: In this single-arm, multi-centre trial of participants with FAP, erlotinib one time per week resulted in markedly lower duodenal polyp burden, and modestly reduced lower GI polyp burden, after 6 months of intervention. While AEs were still reported by nearly three-quarters of all participants, these events were generally lower grade and well-tolerated. These findings support further investigation of erlotinib as an effective, acceptable cancer preventive agent for FAP-associated GI polyposis. TRIAL REGISTRATION NUMBER: NCT02961374.
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Polipose Adenomatosa do Colo , Neoplasias Duodenais , Humanos , Feminino , Adulto , Cloridrato de Erlotinib/efeitos adversos , Polipose Adenomatosa do Colo/tratamento farmacológico , Neoplasias Duodenais/tratamento farmacológico , Duodeno , Endoscopia GastrointestinalRESUMO
BACKGROUND: Tumor molecular profiling techniques, such as next-generation sequencing (NGS) to identify somatic genetic alterations, allow physicians to have a better understanding of the affected carcinogenic pathways and guide targeted therapy. The objective of our study was to characterize common somatic alterations and carcinogenic pathways among Puerto Rican Hispanics with solid tumors. METHODS: We conducted a single-institution, retrospective study to characterize molecular tumor profiles using a 592-gene NGS platform. Actionable mutations with current or developing therapies targeting affected genes/pathways were highlighted. RESULTS: Tumors from 50 Hispanic patients were evaluated using CARIS Life Science© NGS testing. The median age of our study population was 55 (range 21-84); 54% (n = 27) were males. The primary tumor sites were colorectal (n = 24), gastric (n = 5), breast (n = 4), and lung (n = 3). The most common genetic mutations identified were in TP53 (44%), APC (38%), and KRAS (32%); followed by alterations in EGFR (4%), HER2 (6%), and homologous recombinant deficiency genes (BRCA2, 6%). Genetic alterations were found in multiple signaling pathways particularly in the cell cycle control pathway, MAPK and Wnt/ß-Catenin signaling pathways. Targetable biomarkers were identified in 27/50 (54.0%) of tumors. DISCUSSION: Molecular profiling techniques, such as next-generation sequencing, have substantially expanded access to alterations in the cancer genome. Our findings demonstrated important actionable mutations in most of the tumors evaluated and support the integration of somatic mutation profiling in the evaluation of Hispanic cancer patients with advanced cancer to help guide therapeutic options.
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Equidade em Saúde , Neoplasias Pulmonares , Masculino , Humanos , Feminino , Neoplasias Pulmonares/patologia , Estudos Retrospectivos , Medicina de Precisão/métodos , Mutação , Biomarcadores Tumorais/genéticaRESUMO
The traditional approach of one-size-fits-all for colorectal cancer has been replaced by personalized interventions to an individual's unique genetic, molecular, and environmental profile, seeking to identify high-risk individuals who would benefit from individualized screening and surveillance. This change in approach is due, in part, to emerging technologies, such as next-generation DNA sequencing.
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Polipose Adenomatosa do Colo , Neoplasias Colorretais Hereditárias sem Polipose , Neoplasias Colorretais , Polipose Adenomatosa do Colo/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/prevenção & controle , Neoplasias Colorretais Hereditárias sem Polipose/genética , Predisposição Genética para Doença , Testes Genéticos , Humanos , Programas de RastreamentoRESUMO
Familial Adenomatous Polyposis (FAP) is an autosomal dominant disorder caused by mutation of the APC gene presenting with numerous colorectal adenomatous polyps and a near 100% risk of colon cancer. Preliminary research findings from our group indicate that FAP patients experience significant deficits across many cognitive domains. In the current study, fMRI brain metrics in a FAP population and matched controls were used to further the mechanistic understanding of reported cognitive deficits. This research identified and characterized any possible differences in resting brain networks and associations between neural network changes and cognition from 34 participants (18 FAP patients, 16 healthy controls). Functional connectivity analysis was performed using FSL with independent component analysis (ICA) to identify functional networks. Significant differences between cases and controls were observed in 8 well-established resting state networks. With the addition of an aggregate cognitive measure as a covariate, these differences were virtually non-existent, indicating a strong correlation between cognition and brain activity at the network level. The data indicate robust and pervasive effects on functional neural network activity among FAP patients and these effects are likely involved in cognitive deficits associated with this disease.
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The prevalence and contribution of BRCA1/2 (BRCA) pathogenic variants (PVs) to the cancer burden in Latin America are not well understood. This study aims to address this disparity. BRCA analyses were performed on prospectively enrolled Latin American Clinical Cancer Genomics Community Research Network participants via a combination of methods: a Hispanic Mutation Panel (HISPANEL) on MassARRAY; semiconductor sequencing; and copy number variant (CNV) detection. BRCA PV probability was calculated using BRCAPRO. Among 1,627 participants (95.2% with cancer), we detected 236 (14.5%) BRCA PVs; 160 BRCA1 (31% CNVs); 76 BRCA2 PV frequency varied by country: 26% Brazil, 9% Colombia, 13% Peru, and 17% Mexico. Recurrent PVs (seen ≥3 times), some region-specific, represented 42.8% (101/236) of PVs. There was no ClinVar entry for 14% (17/125) of unique PVs, and 57% (111/196) of unique VUS. The area under the ROC curve for BRCAPRO was 0.76. In summary, we implemented a low-cost BRCA testing strategy and documented a significant burden of non-ClinVar reported BRCA PVs among Latin Americans. There are recurrent, population-specific PVs and CNVs, and we note that the BRCAPRO mutation probability model performs adequately. This study helps address the gap in our understanding of BRCA-associated cancer in Latin America.
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BACKGROUND AND AIMS: Gastric cancer is the 5th leading cause of cancer mortality worldwide and the leading infection-associated cancer. Helicobacter pylori is the most common chronic bacterial infection in humans and the major predisposing factor for the development of gastric intestinal metaplasia (GIM), the principal preneoplastic lesion in the gastric carcinogenesis pathway. GIM surveillance is now recommended for individuals among high-risk subgroups by three major gastroenterology societies in Europe, England, and U.S. Our objective was to provide the initial epidemiologic data for GIM among Hispanics in Puerto Rico. METHODS: Using a cross-sectional study design, we analyzed an extensive pathology database (n = 43,993) that captured approximately 50% of all endoscopy biopsies taken during 2012-2014 at academic, public, and private sectors in Puerto Rico. Prevalence estimates of GIM, GIM subgroups, and H. pylori status were estimated using logistic regression models. RESULTS: A total of 4,707 GIM cases were identified during the study period for a prevalence rate of 10.7%. H. pylori was detected in 26.9% (95% CI: 25.7-28.2) of the GIM cases. The majority of the pathology reports lacked information regarding the high-risk subtypes (99.6%) and extension (71.2%). CONCLUSIONS: The prevalence of GIM among Hispanics living in Puerto Rico may be higher than in U.S. mainland non-Hispanic populations. The prevalence of H. pylori detected in our study population was comparable to the rates reported in the mainland U.S. Standardization of the endoscopy biopsy protocol and pathology reporting is needed to characterize and risk stratify GIM surveillance programs in Puerto Rico.
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There are well-established disparities in cancer incidence and outcomes by race/ethnicity that result from the interplay between structural, socioeconomic, socio-environmental, behavioural and biological factors. However, large research studies designed to investigate factors contributing to cancer aetiology and progression have mainly focused on populations of European origin. The limitations in clinicopathological and genetic data, as well as the reduced availability of biospecimens from diverse populations, contribute to the knowledge gap and have the potential to widen cancer health disparities. In this review, we summarise reported disparities and associated factors in the United States of America (USA) for the most common cancers (breast, prostate, lung and colon), and for a subset of other cancers that highlight the complexity of disparities (gastric, liver, pancreas and leukaemia). We focus on populations commonly identified and referred to as racial/ethnic minorities in the USA-African Americans/Blacks, American Indians and Alaska Natives, Asians, Native Hawaiians/other Pacific Islanders and Hispanics/Latinos. We conclude that even though substantial progress has been made in understanding the factors underlying cancer health disparities, marked inequities persist. Additional efforts are needed to include participants from diverse populations in the research of cancer aetiology, biology and treatment. Furthermore, to eliminate cancer health disparities, it will be necessary to facilitate access to, and utilisation of, health services to all individuals, and to address structural inequities, including racism, that disproportionally affect racial/ethnic minorities in the USA.
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Disparidades nos Níveis de Saúde , Grupos Minoritários/estatística & dados numéricos , Neoplasias/etnologia , Etnicidade/estatística & dados numéricos , Feminino , Humanos , Masculino , Estados Unidos/etnologiaRESUMO
OBJECTIVE: Colorectal cancer is the leading cause of cancer death in Puerto Rico and third among Hispanics in the USA. Up to 2-4% of colorectal cancer cases are a result of Lynch syndrome (LS), a hereditary cancer syndrome caused by a germline mutation in at least one of the DNA mismatch repair genes. The objective of this study was to determine the prevalence of LS in colorectal tumors during the first 15-months after the implementation of universal tumor-based screening for LS in Puerto Rico. METHODS: A total of 317 colorectal tumors were evaluated in a large private pathology laboratory from September 2014 to December 2015. Clinical characteristics were obtained from the pathology reports. Unadjusted and adjusted logistic regression models were used to estimate the magnitude of association (odds ratio [OR] with 95% confidence intervals [CI]) between absent MMR protein expression and patient characteristics. RESULTS: Most cases (93.4%) were analyzed by immunohistochemistry; 11.8% (35 of 296) had deficient mismatch repair protein expression. While 29 of the 317 cases were subjected to PCR-based microsatellite instability analysis of which 10.3% (3 of 317) had microsatellite instability. In total, 11.0% of the tumors were reported MMR deficient. These tumors were more likely from females and more likely localized in the proximal colon compared to those with proficient MMR expression. CONCLUSIONS: Our data is consistent with the results from other studies including US Hispanics, where approximately 10% of Hispanic individuals with colorectal cancer have microsatellite instability. Our results support universal tumor-based screening for LS among Hispanics in accordance with National Comprehensive Cancer Network guidelines.
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Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/etnologia , Detecção Precoce de Câncer , Hispânico ou Latino/genética , Assistência de Saúde Universal , Idoso , Neoplasias Colorretais Hereditárias sem Polipose/genética , Estudos Transversais , Reparo de Erro de Pareamento de DNA , Feminino , Hispânico ou Latino/estatística & dados numéricos , Humanos , Imuno-Histoquímica , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Porto RicoRESUMO
Aim: Acquired molecular changes in Lynch syndrome (LS) colorectal tumors have been largely unstudied. We identified methylated DNA markers (MDMs) for discrimination of colorectal neoplasia in LS and determined if these MDMs were comparably discriminant in sporadic patients. Patients & methods: For LS discovery, we evaluated DNA from 53 colorectal case and control tissues using next generation sequencing. For validation, blinded methylation-specific PCR assays to the selected MDMs were performed on 197 cases and controls. Results:OPLAH was the most discriminant MDM with areas under the receiver operating characteristic curve ≥0.97 for colorectal neoplasia in LS and sporadic tissues. ALKBH5, was uniquely hypermethylated in LS neoplasms. Conclusion: Highly discriminant MDMs for colorectal neoplasia in LS were identified with potential use in screening and surveillance.
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Neoplasias Colorretais Hereditárias sem Polipose/genética , Metilação de DNA , Adenoma/genética , Idoso , Biomarcadores , Estudos de Casos e Controles , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Familial Adenomatous Polyposis (FAP) is an autosomal dominant disorder caused by mutation of the APC gene presenting with numerous colorectal adenomatous polyps and a near 100% risk of colon cancer. Preliminary research findings from our group indicate that FAP patients experience significant deficits across many cognitive domains. In the current study, fMRI brain metrics in a FAP population and matched controls were used to further the mechanistic understanding of reported cognitive deficits. This research identified and characterized any possible differences in resting brain networks and associations between neural network changes and cognition from 34 participants (18 FAP patients, 16 healthy controls). Functional connectivity analysis was performed using FSL with independent component analysis (ICA) to identify functional networks. Significant differences between cases and controls were observed in 8 well-established resting state networks. With the addition of an aggregate cognitive measure as a covariate, these differences were virtually non-existent, indicating a strong correlation between cognition and brain activity at the network level. The data indicate robust and pervasive effects on functional neural network activity among FAP patients and these effects are likely involved in cognitive deficits associated with this disease.
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OBJECTIVES: Management of colorectal cancer warrants mutational analysis of KRAS/NRAS when considering anti-epidermal growth factor receptor therapy and BRAF testing for prognostic stratification. In this multicenter study, we compared a fully integrated, cartridge-based system to standard-of-care assays used by participating laboratories. METHODS: Twenty laboratories enrolled 874 colorectal cancer cases between November 2017 and December 2018. Testing was performed on the Idylla automated system (Biocartis) using the KRAS and NRAS-BRAF cartridges (research use only) and results compared with in-house standard-of-care testing methods. RESULTS: There were sufficient data on 780 cases to measure turnaround time compared with standard assays. In-house polymerase chain reaction (PCR) had an average testing turnaround time of 5.6 days, send-out PCR of 22.5 days, in-house Sanger sequencing of 14.7 days, send-out Sanger of 17.8 days, in-house next-generation sequencing (NGS) of 12.5 days, and send-out NGS of 20.0 days. Standard testing had an average turnaround time of 11 days. Idylla average time to results was 4.9 days with a range of 0.4 to 13.5 days. CONCLUSIONS: The described cartridge-based system offers rapid and reliable testing of clinically actionable mutation in colorectal cancer specimens directly from formalin-fixed, paraffin-embedded tissue sections. Its simplicity and ease of use compared with other molecular techniques make it suitable for routine clinical laboratory testing.
Assuntos
Neoplasias Colorretais/genética , GTP Fosfo-Hidrolases/genética , Proteínas de Membrana/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Análise Mutacional de DNA , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Padrão de Cuidado , Fatores de TempoRESUMO
BACKGROUND: Familial adenomatous polyposis (FAP) is an autosomal dominant disorder caused by germline mutations in the APC gene. Patients with FAP have multiple extraintestinal manifestations that follow a genotype-phenotype pattern; however, few data exist characterizing their cognitive abilities. Given the role of the APC protein in development of the central nervous system, we hypothesized that patients with FAP would show differences in cognitive functioning compared to controls. METHODS: Matched case-control study designed to evaluate cognitive function using the Test of Nonverbal Intelligence-4, the Bateria III Woodcock-Munoz, and the Behavior Rating Inventory of Executive Functions-Adult. Twenty-six individuals with FAP (mean age = 34.2 ± 15.0 years) and 25 age-gender and educational level matched controls (mean age = 32.7 ± 13.8 years) were evaluated. RESULTS: FAP-cases had significantly lower IQ (p = 0.005). Across all tasks of the Batería III Woodcock-Muñoz, FAP-cases performed significantly lower than controls, with all of the summary scores falling in the bottom quartile compared to controls (p < 0.0001). Patients with FAP scored within the deficient range for Long-Term Retrieval and Cognitive Fluency. CONCLUSION: APC protein has an important role in neurocognitive function. The pervasive nature of the observed cognitive dysfunction suggests that loss or dysfunction of the APC protein impacts processes in cortical and subcortical brain regions. Additional studies examining larger ethnically diverse cohorts with FAP are warranted.