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Global DNA hypermethylation pattern and unique gene expression signature in liver cancer from patients with Indigenous American ancestry
No full textHepatocellular carcinoma (HCC) usually afflicts individuals in their maturity after a protracted liver disease. Contrasting with this pattern, the age structure of HCC in Andean people displays a bimodal distribution with half of the patients developing HCC in adolescence and early adulthood. To deepen our understanding of the molecular determinants of the disease in this population, we conducted an integrative analysis of gene expression and DNA methylation in HCC developed by 74 Peruvian patients, including 39 adolescents and young adults. While genome-wide hypomethylation is considered as a paradigm in human HCCs, our analysis revealed that Peruvian tumors are associated with a global DNA hypermethylation. Moreover, pathway enrichment analysis of transcriptome data characterized an original combination of signatures. Peruvian HCC forgoes canonical activations of IGF2, Notch, Ras/MAPK, and TGF-β signals to depend instead on Hippo/YAP1, MYC, and Wnt/β-catenin pathways. These signatures delineate a homogeneous subtype of liver tumors at the interface of the proliferative and non-proliferative classes of HCCs. Remarkably, the development of this HCC subtype occurs in patients with one of the four Native American mitochondrial haplogroups A-D. Finally, integrative characterization revealed that Peruvian HCC is apparently controlled by the PRC2 complex that mediates cell reprogramming with massive DNA methylation modulating gene expression and pinpointed retinoid signaling as a potential target for epigenetic therapy.This work was supported by the Alliance pour les Sciences de la Vie et de la Santé (AVIESAN), ITMO Cancer ENV201408 (to S.B.) and the Ligue Contre le Cancer (to P.P.). J.P.C. was a recipient of a doctoral scholarship from the Fondo Nacional de Desarrollo Científico, Tecnológico y de Innovación Tecnológica (FONDECYT) 212-2015-FONDECYT and was supported by a fellowship from Campus France 941211E; L.C. was supported by a doctoral fellowship from IRD ARTS-2016-878573B; I.L. was supported by a postdoctoral fellowship from the Fondation ARC pour la Recherche sur le Cancer PDF20170505624; J.J.F. has received funding from the Agence Nationale de la Recherche (ANR) under the Investments for the Future program 11-LABX-0068; S.C.Z. and E.R. have received funding from the World Bank Group and FONDECYT-CONCYTEC under the Research Infrastructure Improvement program 016-2018-FONDECYT/BM; and S.B. has received funding from the European Union’s Horizon 2020 Framework program under the Marie Skłodowska-Curie Actions 823935
Pembrolizumab for Persistent, Recurrent, or Metastatic Cervical Cancer
No full textBackground: Pembrolizumab has efficacy in programmed death ligand 1 (PD-L1)-positive metastatic or unresectable cervical cancer that has progressed during chemotherapy. We assessed the relative benefit of adding pembrolizumab to chemotherapy with or without bevacizumab. Methods: In a double-blind, phase 3 trial, we randomly assigned patients with persistent, recurrent, or metastatic cervical cancer in a 1:1 ratio to receive pembrolizumab (200 mg) or placebo every 3 weeks for up to 35 cycles plus platinum-based chemotherapy and, per investigator discretion, bevacizumab. The dual primary end points were progression-free survival and overall survival, each tested sequentially in patients with a PD-L1 combined positive score of 1 or more, in the intention-to-treat population, and in patients with a PD-L1 combined positive score of 10 or more. The combined positive score is defined as the number of PD-L1-staining cells divided by the total number of viable tumor cells, multiplied by 100. All results are from the protocol-specified first interim analysis. Results: In 548 patients with a PD-L1 combined positive score of 1 or more, median progression-free survival was 10.4 months in the pembrolizumab group and 8.2 months in the placebo group (hazard ratio for disease progression or death, 0.62; 95% confidence interval [CI], 0.50 to 0.77; P<0.001). In 617 patients in the intention-to-treat population, progression-free survival was 10.4 months and 8.2 months, respectively (hazard ratio, 0.65; 95% CI, 0.53 to 0.79; P<0.001). In 317 patients with a PD-L1 combined positive score of 10 or more, progression-free survival was 10.4 months and 8.1 months, respectively (hazard ratio, 0.58; 95% CI, 0.44 to 0.77; P<0.001). Overall survival at 24 months was 53.0% in the pembrolizumab group and 41.7% in the placebo group (hazard ratio for death, 0.64; 95% CI, 0.50 to 0.81; P<0.001), 50.4% and 40.4% (hazard ratio, 0.67; 95% CI, 0.54 to 0.84; P<0.001), and 54.4% and 44.6% (hazard ratio, 0.61; 95% CI, 0.44 to 0.84; P = 0.001), respectively. The most common grade 3 to 5 adverse events were anemia (30.3% in the pembrolizumab group and 26.9% in the placebo group) and neutropenia (12.4% and 9.7%, respectively). Conclusions: Progression-free and overall survival were significantly longer with pembrolizumab than with placebo among patients with persistent, recurrent, or metastatic cervical cancer who were also receiving chemotherapy with or without bevacizumab. (Funded by Merck Sharp and Dohme; KEYNOTE-826 ClinicalTrials.gov number, NCT03635567.)
Catalyzing Childhood Cancer Care in Peru After One Year of the Global Initiative for Childhood Cancer
No full textTesis desarrollada en el ámbito de la Ingeniería, orientada al análisis y/o solución de problemáticas técnicas propias de la disciplina
Concurrent Detection of Circulating Tumor Cells and Circulating Tumor DNA in Triple-negative Breast Cancer
No full textObjective: Circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) provide tumor information in breast cancer. Our objective was to characterize CTCs, and contrasted them with ctDNA PIK3CA mutation in 24 triple-negative breast cancer (TNBC).
Methods: CTCs genes were characterized by AdnaTest protocol and ctDNA by digital PCR.
Results: We found CTCs genes in 37.5% and ctDNA PIK3CA mutations in 29.16%. Three cases with CTCs genes had concurrent ctDNA PIK3CA mutations. MUC1 or GA733-2 were found in 4 cases, and 3 of them had concurrent ctDNA PIK3CA. CTCs ALDH1/TWIST1 were found in 2 cases, AKT2 in one and PI3Kα in another, and none had concurrent ctDNA PIK3CA mutations. There was no correlation between CTCs and ctDNA detection. All 3 cases with CTC & cDNA concurrent finding underwent death during follow-up.
Conclusion: Infrequent concurrent detection of CTC and ctDNA presence suggests that both represent independent processes in TNBC patients, and could identify worst prognosis cases.This work was supported by funding from CONCYTEC (contract 198-2015-FONDECYT)
Natural Occurrence of Mycotoxin-Producing Fusaria in Market-Bought Peruvian Cereals: A Food Safety Threat for Andean Populations
No full textConsumption of cereals contaminated by mycotoxins poses health risks. For instance, Fumonisins B, mainly produced by Fusarium verticillioides and Fusarium proliferatum, and the type B trichothecene deoxynivalenol, typically produced by Fusarium graminearum, are highly prevalent on cereal grains that are staples of many cultural diets and known to represent a toxic risk hazard. In Peru, corn and other cereals are frequently consumed on a daily basis under various forms, the majority of food grains being sold through traditional markets for direct consumption. Here, we surveyed mycotoxin contents of market-bought grain samples in order to assess the threat these mycotoxins might represent to Peruvian population, with a focus on corn. We found that nearly one sample of Peruvian corn out of six was contaminated with very high levels of Fumonisins, levels mostly ascribed to the presence of F. verticillioides. Extensive profiling of Peruvian corn kernels for fungal contaminants could provide elements to refine the potential risk associated with Fusarium toxins and help define adapted food safety standards.This research was funded by the French National Alliance for Life Sciences and Health, grant number ENV201408. S.B. has received funding from the European Union’s Horizon 2020 Framework program under the Marie Skłodowska-Curie Actions, agreement number 823935. P.V.O. was supported by a postdoctoral fellowship from the French National Research Institute for Sustain-able Development (IRD) (04077858). JPC was a recipient of a doctoral fellowship from the Peruvian National Council for Science and Technology (212-2015-FONDECYT)
Metallomic profile in non-cirrhotic hepatocellular carcinoma supports a phenomenon of metal metabolism adaptation in tumor cells
No full textWe have previously described a form of hepatocellular carcinoma (HCC) in non-cirrhotic liver (HCC-NC) developed by Peruvian patients. We analyzed the metallomic profile in hepatic tissues from two independent cohorts exhibiting HCC-NC. Clinical, histopathological data, and HCC and non-tumoral liver (NTL) samples of 38 Peruvian and 38 French HCC-NC patients, were studied. Twelve metals were quantified using ICP/MS: Mn, Fe, Cu, Co, Zn, As, Se, Rb, Mo, Cd, Pb, and Sn. Associations between metals and survival were assessed. Our data showed significant differences between cohorts. Mean ages were 40.6 ± 20, 67.5 ± 9 years old for Peruvians and French, respectively. Fifty percent of the Peruvian patients were positive for the HBsAg, versus 3% in French patients. Mn, Cu, Zn, As, Se, Rb, Mo, Cd, Sn metal concentrations were higher in NTL of Peruvians. Importantly, metal concentrations were lower in HCC areas compared to NTL tissues in both cohorts, except for Cu for which mean concentration was higher in HCC (p < 0.05). Se concentration in HCC was associated with extended survival only in Peruvians. Our data, obtained in Peruvian and French HCC-NC cohorts, highlights similarity in the metallomic profile of HCC compared to NTL during the hepatic tumorigenesis in these specific groups of patients.This study was funded by the French National Alliance for Life Sciences and Health (ENV201408)||LC was a recipient of a doctoral fellowship from French National Research Institute for Sustainable Development (IRD) (EMHE-ARTS-2016-878573B)||JPC was a recipient of a doctoral fellowship from the Peruvian National Council for Science and Technology (212-2015-FONDECYT)||SB has received funding from the European Union\u2019s Horizon 2020 Framework program under the Marie Sk\u0142odowska-Curie Actions 823935 and from the Alliance pour les Sciences de la Vie et de la Sant\u00E9 (AVIESAN), ITMO Cancer ENV201408, and LC, ER, and SCZ have received funding from the World Bank Group and FONDECYT-CONCYTEC 016-2018-FONDECYT/BM. The authors are grateful to Karina Cancino, Danny Cordova (INEN Cancer Research Biobank), Patricia Leroyer (NUMECAN), Alain Fautrel, Marine Seffals, Gevorg Ghukasyan (H2P2 platform). They also thank Dr Anne Corlu for the critical reviewing of the manuscript
Neutrophil-to-lymphocyte ratio predicts early mortality in females with metastatic triple-negative breast cancer
No full textBackground: The aim of this study was to determine the utility of the neutrophil-to-lymphocyte ratio (NLR) as a biomarker for predicting early-mortality (<2 years) among females with metastatic triple-negative breast cancer (mTNBC). Methods: We reviewed 118 medical records of females with mTNBC. The cut-off value for the NLR (<2.5 and ≥2.5) was determined with receiver operating characteristic curves (area under the curve: 0.73; 95% CI: 0.62-0.85). Survival curves were estimated using the Kaplan-Meier method and compared with the Log-rank test. Multivariate Cox regression was used to identify the risk of mortality at two years. Moreover, we performed sensitivity analyses with different cut-off values and a subgroup analysis in females that only received chemotherapy. Results: The median follow-up was 24 months. Females with NLR ≥2.5 had a poor overall survival compared to females with NLR <2.5 (6% vs. 28%, p<0.001) at two years. This outcome remained when we stratified for females that only received chemotherapy (8% vs. 36%, p = 0.001). Multivariate analyses identified NLR ≥2.5 as a poor prognostic risk factor for mortality in the entire population (HR: 2.12, 95% CI: 1.32-3.39) and among females that received chemotherapy (HR: 2.68, 95% CI: 1.46-4.92). Conclusion: The NLR is an accessible and reliable biomarker that predicts early mortality among females with mTNBC. Our results suggest that females with high NLR values have poor prognosis despite receiving standard chemotherapy. Health providers should evaluate the possibility to enroll these patients in novel immunotherapy trials
Breast cancer early detection: A phased approach to implementation
No full textWhen breast cancer is detected and treated early, the chances of survival are very high. However, women in many settings face complex barriers to early detection, including social, economic, geographic, and other interrelated factors, which can limit their access to timely, affordable, and effective breast health care services. Previously, the Breast Health Global Initiative (BHGI) developed resource-stratified guidelines for the early detection and diagnosis of breast cancer. In this consensus article from the sixth BHGI Global Summit held in October 2018, the authors describe phases of early detection program development, beginning with management strategies required for the diagnosis of clinically detectable disease based on awareness education and technical training, history and physical examination, and accurate tissue diagnosis. The core issues address include finance and governance, which pertain to successful planning, implementation, and the iterative process of program improvement and are needed for a breast cancer early detection program to succeed in any resource setting. Examples are presented of implementation, process, and clinical outcome metrics that assist in program implementation monitoring. Country case examples are presented to highlight the challenges and opportunities of implementing successful breast cancer early detection programs, and the complex interplay of barriers and facilitators to achieving early detection for breast cancer in real-world settings are considered
Detection of Helicobacter pylori in gastric cancer tissue through histopathology, immunohistochemistry and real-time reverse transcription-PCR
No full textAim:Helicobacter pylori is usually detected based on hematoxylin-eosin (H-E) features, but, immunohistochemistry (IHC) and real-time PCR (RT-PCR) are more precise in chronic-gastritis. We evaluated the relevance of these tests in Peruvian gastric cancer samples. Materials & methods: We performed and evaluated H-E, IHC staining and RT-PCR in 288 gastric tumors. Slides were independently evaluated by three pathologists. Results:H. pylori was detected in 167/287 through H-E, 140/288 through IHC and 175/288 through RT-PCR, and positive-status were associated (p < 0.001). H. pylori detection by H-E had a good concordance with IHC (kappa index = 0.632) but poor with RT-PCR (kappa index = 0.317). Higher median gene-copies were found in high H. pylori density through H-E or IHC (p < 0.001). Conclusion: H-E evaluation is accurate in gastric cancer, and IHC and RT-PCR can complement its results.This study was supported by CONCYTEC, under contracts 197-2015-FONDECYT and 204-2015-FONDECYT. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript
Class D carbapenemases in clinical isolates of Acinetobacter baumannii
No full textLos hallazgos sugieren que A. baumanniiMDR productor de carbapenemasas clase D circula en el INEN||sin embargo, la información de su distribución e impacto en el paÃs es limitada. Por lo tanto, deben realizarse estudios de epi-demiologÃa molecular para desarrollar estrategias de control y manejo de las IAAS asociadas a A. baumannii.A todo el personal del Laboratorio de Microbiología del Instituto Nacional de Enfermedades Neoplásicas por su colaboración en el proceso de recolección de los aislamientos, al equipo de investigación de Biotecnología y Salud del CITBM por su contribución en biología molecular y al personal del Laboratorio de Epidemiología Molecular y Genética de la Universidad Nacional Mayor de San Marcos por su continuo apoyo Fuentes de financiamiento: Estudio financiado por FONDECYT para los Círculos de Investigación en Ciencia y Tecnología (RD N.o 142-2015-FONDECYT-DE) y el Centro de Investigaciones Tecnológicas, Biomédicas y Medioambientales (CITBM)