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BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) deficiency is the main known cause of life-threatening fluoropyrimidine (FP)-induced toxicities. We conducted a meta-analysis on individual patient data to assess the contribution of deleterious DPYD variants *2A/D949V/*13/HapB3 (recommended by EMA) and clinical factors, for predicting G4-5 toxicity. METHODS: Study eligibility criteria included recruitment of Caucasian patients without DPD-based FP-dose adjustment. Main endpoint was 12-week haematological or digestive G4-5 toxicity. The value of DPYD variants *2A/p.D949V/*13 merged, HapB3, and MIR27A rs895819 was evaluated using multivariable logistic models (AUC). RESULTS: Among 25 eligible studies, complete clinical variables and primary endpoint were available in 15 studies (8733 patients). Twelve-week G4-5 toxicity prevalence was 7.3% (641 events). The clinical model included age, sex, body mass index, schedule of FP-administration, concomitant anticancer drugs. Adding *2A/p.D949V/*13 variants (at least one allele, prevalence 2.2%, OR 9.5 [95%CI 6.7-13.5]) significantly improved the model (p < 0.0001). The addition of HapB3 (prevalence 4.0%, 98.6% heterozygous), in spite of significant association with toxicity (OR 1.8 [95%CI 1.2-2.7]), did not improve the model. MIR27A rs895819 was not associated with toxicity, irrespective of DPYD variants. CONCLUSIONS: FUSAFE meta-analysis highlights the major relevance of DPYD *2A/p.D949V/*13 combined with clinical variables to identify patients at risk of very severe FP-related toxicity.
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Antineoplásicos , Deficiencia de Dihidropirimidina Deshidrogenasa , Humanos , Fluorouracilo/efectos adversos , Dihidrouracilo Deshidrogenasa (NADP)/genética , Heterocigoto , Genotipo , Capecitabina/efectos adversosRESUMEN
AIMS: The aim of this study was to identify risk variants and haplotypes that impair dihydropyrimidine dehydrogenase (DPD) activity and are, therefore, candidate risk variants for severe toxicity to 5-fluorouracil (5-FU) chemotherapy. METHODS: Plasma dihydrouracil/uracil (UH2 /U) ratios were measured as a population marker for DPD activity in a total of 1382 subjects from 4 independent studies. Genotype and haplotype correlations with UH2 /U ratios were assessed. RESULTS: Significantly lower UH2 /U ratios (panova < 2 × 10-16 ) were observed in carriers of the 4 well-studied 5-FU toxicity risk variants with mean differences (MD) of -43.7% for DPYD c.1905 + 1G > A (rs3918290), -46.0% for DPYD c.1679T > G (rs55886062), -37.1%, for DPYD c.2846A > T (rs67376798), and -13.2% for DPYD c.1129-5923C > G (rs75017182). An additional variant, DPYD c.496A > G (rs2297595), was also associated with lower UH2 /U ratios (P < .0001, MD: -12.6%). A haplotype analysis was performed for variants in linkage disequilibrium with c.496A > G, which consisted of the common variant c.85T > C (rs1801265) and the risk variant c.1129-5923C > G. Both haplotypes carrying c.496A > G were associated with decreased UH2 /U ratios (H3, P = .003, MD: -9.6%; H5, P = .002, MD: -16.9%). A haplotype carrying only the variant c.85T > C (H2) was associated with elevated ratios (P = .004, MD: +8.6%). CONCLUSIONS: Based on our data, DPYD-c.496A > G is a strong candidate risk allele for 5-FU toxicity. Our data suggest that DPYD-c.85T > C might be protective; however, the deleterious impacts of the linked alleles c.496A > G and c.1129-5923C > G likely limit this effect in patients. The possible protective effect of c.85T > C and linkage disequilibrium with c.496A > G and c.1129-5923C > G may have hampered prior association studies and should be considered in future clinical studies.
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Dihidrouracilo Deshidrogenasa (NADP) , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Dihidrouracilo Deshidrogenasa (NADP)/genética , Fluorouracilo/efectos adversos , Genotipo , Haplotipos , HumanosRESUMEN
BACKGROUND: The addition of bevacizumab to chemotherapy improved outcomes for patients with metastatic colon cancer. E5204 was designed to test whether the addition of bevacizumab to mFOLFOX6, following neoadjuvant chemoradiation and definitive surgery, could improve overall survival (OS) in patients with stage II/III adenocarcinoma of the rectum. SUBJECTS, MATERIALS, AND METHODS: Patients with stage II/III rectal cancer who had completed neoadjuvant 5-fluorouracil-based chemoradiation and had undergone complete resection were enrolled. Patients were randomized to mFOLFOX6 (Arm A) or mFOLFOX6 with bevacizumab (Arm B) administered every 2 weeks for 12 cycles. RESULTS: E5204 registered only 355 patients (17% of planned accrual goal) as it was terminated prematurely owing to poor accrual. At a median follow-up of 72 months, there was no difference in 5-year overall survival (88.3% vs. 83.7%) or 5-year disease-free survival (71.2% vs. 76.5%) between the two arms. The rate of treatment-related grade ≥ 3 adverse events (AEs) was 68.8% on Arm A and 70.7% on Arm B. Arm B had a higher proportion of patients who discontinued therapy early as a result of AEs and patient withdrawal than did Arm A (32.4% vs. 21.5%, p = .029).The most common grade 3-4 treatment-related AEs were neutropenia, leukopenia, neuropathy, diarrhea (without prior colostomy), and fatigue. CONCLUSION: At 17% of its planned accrual, E5204 did not meet its primary endpoint. The addition of bevacizumab to FOLFOX6 in the adjuvant setting did not significantly improve OS in patients with stage II/III rectal cancer. IMPLICATIONS FOR PRACTICE: At 17% of its planned accrual, E5204 was terminated early owing to poor accrual. At a median follow-up of 72 months, there was no significant difference in 5-year overall survival (88.3% vs. 83.7%) or in 5-year disease-free survival (71.2% vs. 76.5%) between the two arms. Despite significant advances in the treatment of rectal cancer, especially in improving local control rates, the risk of distant metastases and the need to further improve quality of life remain a challenge. Strategies combining novel agents with chemoradiation to improve both distant and local control are needed.
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Fluorouracilo , Neoplasias del Recto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab/uso terapéutico , Quimioterapia Adyuvante , Supervivencia sin Enfermedad , Fluorouracilo/uso terapéutico , Humanos , Leucovorina/uso terapéutico , Estadificación de Neoplasias , Compuestos Organoplatinos/uso terapéutico , Oxaliplatino/uso terapéutico , Calidad de Vida , Neoplasias del Recto/tratamiento farmacológico , Neoplasias del Recto/radioterapiaRESUMEN
We are in the midst of a technological revolution that is providing new insights into human biology and cancer. In this era of big data, we are amassing large amounts of information that is transforming how we approach cancer treatment and prevention. Enactment of the Cancer Moonshot within the 21st Century Cures Act in the USA arrived at a propitious moment in the advancement of knowledge, providing nearly US$2 billion of funding for cancer research and precision medicine. In 2016, the Blue Ribbon Panel (BRP) set out a roadmap of recommendations designed to exploit new advances in cancer diagnosis, prevention, and treatment. Those recommendations provided a high-level view of how to accelerate the conversion of new scientific discoveries into effective treatments and prevention for cancer. The US National Cancer Institute is already implementing some of those recommendations. As experts in the priority areas identified by the BRP, we bolster those recommendations to implement this important scientific roadmap. In this Commission, we examine the BRP recommendations in greater detail and expand the discussion to include additional priority areas, including surgical oncology, radiation oncology, imaging, health systems and health disparities, regulation and financing, population science, and oncopolicy. We prioritise areas of research in the USA that we believe would accelerate efforts to benefit patients with cancer. Finally, we hope the recommendations in this report will facilitate new international collaborations to further enhance global efforts in cancer control.
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Investigación Biomédica/tendencias , Planificación en Salud/tendencias , Prioridades en Salud , National Cancer Institute (U.S.)/tendencias , Neoplasias/terapia , Investigación Biomédica/métodos , Predicción , Humanos , Oncología Médica/tendencias , Neoplasias/diagnóstico , Medicina de Precisión/tendencias , Estados UnidosRESUMEN
Severe (grade≥3) adverse events (AEs) to 5-fluorouracil (5-FU)-based chemotherapy regimens can result in treatment delays or cessation, and, in extreme cases, life-threatening complications. Current genetic biomarkers for 5-FU toxicity prediction, however, account for only a small proportion of toxic cases. In the current study, we assessed DPYD variants suggested to correlate with 5-FU toxicity, a deep intronic variant (c.1129-5923 C>G), and four variants within a haplotype (hapB3) in 1953 stage III colon cancer patients who received adjuvant FOLFOX±cetuximab. Logistic regression was used to assess multivariable associations between DPYD variant status and AEs common to 5-FU (5FU-AEs). In our study cohort, 1228 patients (62.9%) reported any grade≥3 AE (overall AE), with 638 patients (32.7%) reporting any grade≥3 5FU-AE. Only 32 of 78 (41.0%) patients carrying DPYD c.1129-5923 C>G and the completely linked hapB3 variants c.1236 C>G and c.959-51 T>C showed at least one grade≥3 5FU-AE, resulting in no statistically significant association (adjusted odds ratio=1.47, 95% confidence interval=0.90-2.43, P=0.1267). No significant associations were identified between c.1129-5923 C>G/hapB3 and overall grade≥3 AE rate. Our results suggest that c.1129-5923 C>G/hapB3 have limited predictive value for severe toxicity to 5-FU-based combination chemotherapy.
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Antimetabolitos Antineoplásicos/efectos adversos , Neoplasias del Colon/tratamiento farmacológico , Dihidrouracilo Deshidrogenasa (NADP)/genética , Fluorouracilo/efectos adversos , Polimorfismo de Nucleótido Simple , Adulto , Anciano , Anciano de 80 o más Años , Antimetabolitos Antineoplásicos/uso terapéutico , Neoplasias del Colon/genética , Neoplasias del Colon/patología , Femenino , Fluorouracilo/uso terapéutico , Estudios de Asociación Genética , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Valor Predictivo de las PruebasRESUMEN
Key challenges facing the oncology community today include access to appropriate, high quality, patient-centered cancer care; defining and delivering high-value care; and rising costs. The National Comprehensive Cancer Network convened a Work Group composed of NCCN Member Institution cancer center directors and their delegates to examine the challenges of access, high costs, and defining and demonstrating value at the academic cancer centers. The group identified key challenges and possible solutions to addressing these issues. The findings and recommendations of the Work Group were then presented at the Value, Access, and Cost of Cancer Care Policy Summit in September 2015 and multi-stakeholder roundtable panel discussions explored these findings and recommendations along with additional items.
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Atención a la Salud/métodos , Oncología Médica/normas , Neoplasias/economía , HumanosRESUMEN
Percent mammographic density adjusted for age and body mass index (BMI) is one of the strongest risk factors for breast cancer and has a heritable component that remains largely unidentified. We performed a three-stage genome-wide association study (GWAS) of percent mammographic density to identify novel genetic loci associated with this trait. In stage 1, we combined three GWASs of percent density comprised of 1241 women from studies at the Mayo Clinic and identified the top 48 loci (99 single nucleotide polymorphisms). We attempted replication of these loci in 7018 women from seven additional studies (stage 2). The meta-analysis of stage 1 and 2 data identified a novel locus, rs1265507 on 12q24, associated with percent density, adjusting for age and BMI (P = 4.43 × 10(-8)). We refined the 12q24 locus with 459 additional variants (stage 3) in a combined analysis of all three stages (n = 10 377) and confirmed that rs1265507 has the strongest association in the 12q24 region (P = 1.03 × 10(-8)). Rs1265507 is located between the genes TBX5 and TBX3, which are members of the phylogenetically conserved T-box gene family and encode transcription factors involved in developmental regulation. Understanding the mechanism underlying this association will provide insight into the genetics of breast tissue composition.
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Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/genética , Cromosomas Humanos Par 12/genética , Glándulas Mamarias Humanas/química , Anciano , Neoplasias de la Mama/epidemiología , Estudios de Cohortes , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Glándulas Mamarias Humanas/efectos de la radiación , Mamografía , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Proteínas de Dominio T Box/genética , Estados Unidos/epidemiología , Población Blanca/genéticaRESUMEN
Genome-wide association studies (GWAS) of breast cancer defined by hormone receptor status have revealed loci contributing to susceptibility of estrogen receptor (ER)-negative subtypes. To identify additional genetic variants for ER-negative breast cancer, we conducted the largest meta-analysis of ER-negative disease to date, comprising 4754 ER-negative cases and 31 663 controls from three GWAS: NCI Breast and Prostate Cancer Cohort Consortium (BPC3) (2188 ER-negative cases; 25 519 controls of European ancestry), Triple Negative Breast Cancer Consortium (TNBCC) (1562 triple negative cases; 3399 controls of European ancestry) and African American Breast Cancer Consortium (AABC) (1004 ER-negative cases; 2745 controls). We performed in silico replication of 86 SNPs at P ≤ 1 × 10(-5) in an additional 11 209 breast cancer cases (946 with ER-negative disease) and 16 057 controls of Japanese, Latino and European ancestry. We identified two novel loci for breast cancer at 20q11 and 6q14. SNP rs2284378 at 20q11 was associated with ER-negative breast cancer (combined two-stage OR = 1.16; P = 1.1 × 10(-8)) but showed a weaker association with overall breast cancer (OR = 1.08, P = 1.3 × 10(-6)) based on 17 869 cases and 43 745 controls and no association with ER-positive disease (OR = 1.01, P = 0.67) based on 9965 cases and 22 902 controls. Similarly, rs17530068 at 6q14 was associated with breast cancer (OR = 1.12; P = 1.1 × 10(-9)), and with both ER-positive (OR = 1.09; P = 1.5 × 10(-5)) and ER-negative (OR = 1.16, P = 2.5 × 10(-7)) disease. We also confirmed three known loci associated with ER-negative (19p13) and both ER-negative and ER-positive breast cancer (6q25 and 12p11). Our results highlight the value of large-scale collaborative studies to identify novel breast cancer risk loci.
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Neoplasias de la Mama/genética , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Femenino , Humanos , Polimorfismo de Nucleótido Simple/genética , Receptores de Estrógenos/genéticaRESUMEN
BACKGROUND: Human epidermal growth factor receptor 2 (HER2) is a therapeutic target in patients with esophageal adenocarcinoma (EAC), with gene amplification used as a selection criterion for treatment, although to the authors' knowledge the concordance between amplification and HER2 protein expression remains undefined in EAC. Furthermore, the association between HER2 and its interacting partner, human epidermal growth factor receptor 3 (HER3), is unknown yet appears to be of potential therapeutic relevance. METHODS: Patients with untreated EACs (N = 673) were analyzed for HER2 amplification and polysomy 17 by fluorescence in situ hybridization in parallel with immunohistochemistry (IHC) (IHC scores of 0-1+, 2+, and 3+). Amplification was defined as HER2/CEP17 ≥ 2. HER3 expression by IHC was analyzed in randomly selected cases (n = 224). IHC and fluorescence in situ hybridization results were compared using least squares linear regression. RESULTS: Overall, 17% of the EACs (116 of 673 EACs) were HER2-amplified with an amplification frequency that was highest among IHC3+ cases (89%) and declined among IHC2+ cases (13%) and IHC0 to IHC1+ cases (4%). Among HER2-amplified cases, the level of amplification increased linearly with HER2 membranous expression (HER2/CEP17 ratio: 7.9 in IHC3+ and 5.5 in IHC2+ vs 2.8 in IHC0 to IHC1+ [P < .0001]), with 14% of amplified tumors demonstrating absent/faint expression (IHC0 to IHC1+). Polysomy 17 was not found to be associated with HER2 expression. Cytoplasmic HER3 expression was detected in 87% of tumors (195 of 224 tumors) and was found to be significantly associated with better differentiation (P < .0001). Stepwise increases in HER3 expression were associated with higher HER2 expression levels (P = .0019). CONCLUSIONS: Levels of HER2 protein expression and amplification were found to be linearly associated and highly concordant. Among amplified tumors with absent/faint expression, the level of amplification was low. Frequent expression of HER3 suggests its relevance as a therapeutic target, and its significant association with HER2 supports ongoing efforts to inhibit HER2/HER3 in patients with EAC.
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Adenocarcinoma/genética , Neoplasias Esofágicas/genética , Amplificación de Genes , Receptor ErbB-2/genética , Receptor ErbB-3/análisis , Adenocarcinoma/química , Adenocarcinoma/patología , Anciano , Neoplasias Esofágicas/química , Neoplasias Esofágicas/patología , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos Proporcionales , Receptor ErbB-2/análisisRESUMEN
Enhancers are critical for regulating tissue-specific gene expression, and genetic variants within enhancer regions have been suggested to contribute to various cancer-related processes, including therapeutic resistance. However, the precise mechanisms remain elusive. Using a well-defined drug-gene pair, we identified an enhancer region for dihydropyrimidine dehydrogenase (DPD, DPYD gene) expression that is relevant to the metabolism of the anti-cancer drug 5-fluorouracil (5-FU). Using reporter systems, CRISPR genome edited cell models, and human liver specimens, we demonstrated in vitro and vivo that genotype status for the common germline variant (rs4294451; 27% global minor allele frequency) located within this novel enhancer controls DPYD transcription and alters resistance to 5-FU. The variant genotype increases recruitment of the transcription factor CEBPB to the enhancer and alters the level of direct interactions between the enhancer and DPYD promoter. Our data provide insight into the regulatory mechanisms controlling sensitivity and resistance to 5-FU.
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Enhancers are critical for regulating tissue-specific gene expression, and genetic variants within enhancer regions have been suggested to contribute to various cancer-related processes, including therapeutic resistance. However, the precise mechanisms remain elusive. Using a well-defined drug-gene pair, we identified an enhancer region for dihydropyrimidine dehydrogenase (DPD, DPYD gene) expression that is relevant to the metabolism of the anti-cancer drug 5-fluorouracil (5-FU). Using reporter systems, CRISPR genome-edited cell models, and human liver specimens, we demonstrated in vitro and vivo that genotype status for the common germline variant (rs4294451; 27% global minor allele frequency) located within this novel enhancer controls DPYD transcription and alters resistance to 5-FU. The variant genotype increases recruitment of the transcription factor CEBPB to the enhancer and alters the level of direct interactions between the enhancer and DPYD promoter. Our data provide insight into the regulatory mechanisms controlling sensitivity and resistance to 5-FU.
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Dihidrouracilo Deshidrogenasa (NADP) , Elementos de Facilitación Genéticos , Epigénesis Genética , Fluorouracilo , Humanos , Antimetabolitos Antineoplásicos/farmacología , Antimetabolitos Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Línea Celular Tumoral , Dihidrouracilo Deshidrogenasa (NADP)/genética , Dihidrouracilo Deshidrogenasa (NADP)/metabolismo , Fluorouracilo/farmacología , Fluorouracilo/metabolismo , Mutación de Línea GerminalRESUMEN
Severe adverse events (toxicity) related to the use of the commonly used chemotherapeutic drug 5-fluorouracil (5-FU) affect one in three patients and are the primary reason cited for premature discontinuation of therapy. Deficiency of the 5-FU catabolic enzyme dihydropyrimidine dehydrogenase (DPD, encoded by DPYD) has been recognized for the past 3 decades as a pharmacogenetic syndrome associated with high risk of 5-FU toxicity. An appreciable fraction of patients with DPD deficiency that receive 5-FU-based chemotherapy die as a result of toxicity. In this manuscript, we review recent progress in identifying actionable markers of DPD deficiency and the current status of integrating those markers into the clinical decision-making process. The limitations of currently available tests, as well as the regulatory status of pre-therapeutic DPYD testing, are also discussed.
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Antimetabolitos Antineoplásicos/uso terapéutico , Deficiencia de Dihidropirimidina Deshidrogenasa/complicaciones , Fluorouracilo/uso terapéutico , Neoplasias/complicaciones , Neoplasias/tratamiento farmacológico , Antimetabolitos Antineoplásicos/farmacología , Dihidrouracilo Deshidrogenasa (NADP)/genética , Fluorouracilo/farmacología , Variación Genética , Humanos , Farmacogenética , Variantes Farmacogenómicas , Investigación , Resultado del TratamientoRESUMEN
Approximately 20 drugs have been shown to be effective for the treatment of colorectal cancer (CRC). These drugs are from several classes of agents and include cytotoxic drugs, therapeutics that target cell signaling pathways at the extracellular and/or intracellular levels, and combination therapies that contain multiple targeted agents and/or cytotoxic compounds. Targeted therapeutics can include monoclonal antibodies, fusion proteins, and small molecule drugs. The first introduced into clinical use was 5-fluorouracil in the early 1960s and remains the foundation for most CRC treatments in both adjuvant therapy and in advanced (metastatic) treatment regimens. As with other cancers, the consideration of biomarkers has the potential to improve CRC therapy through patient stratification. The biomarkers can include germline genetic markers, tumor-specific genetic markers, immune markers, and other biomarkers that can predict antitumor efficacy or the likelihood of toxicity prior to administration of a specific drug. Consistent with the benefit of considering biomarkers in treatment, many newer targeted therapies are developed and approved simultaneously with a companion diagnostic test to determine efficacy. This review will focus on biomarkers that have demonstrated clinical utility in CRC treatment; however, it is noted that many additional biomarkers have been theorized to contribute to drug response and/or toxicity based on known biological pathways but thus far have not attained widespread use in the clinic. The importance of pretreatment biomarker testing is expected to increase as future drug development will likely continue to focus on the concurrent development of companion diagnostics.
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Antineoplásicos/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Animales , Biomarcadores de Tumor/genética , Humanos , Farmacogenética/métodosRESUMEN
The long-term effectiveness of targeted cancer therapies is limited by the development of resistance. Although epigenetic reprogramming has been implicated in resistance, the mechanisms remain elusive. Herein, we demonstrate that increased chromatin accessibility is involved in adaptive BRAF inhibitor (BRAFi)-resistance in melanoma cells. We observed loss of chromatin assembly factor 1 (CAF-1) and its related histone H3 lysine 9 trimethylation (H3K9me3) with adaptive BRAFi resistance. We further showed that depletion of CAF-1 provides chromatin plasticity for effective reprogramming by AP1 components to promote BRAFi resistance. Our data suggest that therapeutic approaches to restore H3K9me3 levels may compensate for the loss of CAF-1 and, in turn, suppress resistance to BRAF inhibitors.
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OBJECTIVE: To highlight the current global trends in mortality for cardiovascular disease and cancer. METHODS: The World Health Organization and the World Bank DataBank databases were used to analyze mortality rates for cancer and cardiovascular disease by calculating age-standardized mortality rates (ASRs) from 2000 to 2015 for high-income, upper-middle-income, and lower-middle-income countries. Data for cancer mortality and population for 43 countries representing 5 of the 7 continents (except Australia and Antarctica) were analyzed. RESULTS: From 2000 to 2015, there was an increase in the ASR for cancer for both men and women irrespective of a country's income status, representing an overall 7% increase in cancer ASR (Pearson r, +0.99; P<.00001). We report a higher ASR for cancer in high-income countries than in upper-middle-income and lower-middle-income countries specifically; high-income countries saw a 3% increase in cancer ASR vs +31% for upper-middle-income and +19% for lower-middle-income countries (P<.01). There has been a decrease in the ASR for cardiovascular disease for the 15 years analyzed (P<.00001). In addition, high-income countries had a higher ASR for cardiovascular disease than upper-middle-income countries during the 15-year period (P<.05). CONCLUSION: We suspect that because of early detection and targeted interventions, cardiovascular disease mortality rates have decreased during the past decade. On the basis of our results, cancer mortality rates continue to rise, with the projection of surpassing cardiovascular disease mortality rates in the near future.
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Edotecarin (J-107088), a novel inhibitor of topoisomerase I has an additive effect on colon cell lines (HCT-116) when combined with 5-fluorouracil (5-FU). We conducted a phase I study to determine the maximum tolerated dose and recommended a phase II dose of edotecarin in combination with infusional 5-FU/leucovorin (LV) in patients with advanced solid tumors. Patients and cohorts of three to six patients were sequentially enrolled at progressively higher dose levels of edotecarin administered as a 1-h intravenous (IV) infusion every 2 weeks. The edotecarin starting dose was 6 mg/m, followed by 200 mg/m LV IV infusion administered over 2 h, then 400 mg/m bolus dose of 5-FU before the start of 2400 mg/m 5-FU continuous infusion for a further 46 h. Patients were evaluated for safety, pharmacokinetics, and tumor response according to the Response Evaluation Criteria in Solid Tumors criteria. Fourteen patients (10 male; four female) received a total of 90 cycles (range 3-18). Dose-limiting toxicities were observed in five of the 14 patients treated in the study. All dose-limiting toxicities were related to neutropenia. Only the 6 and 8 mg/m edotecarin dose levels were explored; however, no maximum tolerated dose was declared. One confirmed complete response in a patient with hepatocellular carcinoma and seven stable disease responses were achieved in the 14 treated patients. Pharmacokinetic analysis showed that edotecarin achieved and maintained apparent steady-state plasma concentrations during the IV administration in both the cycles. The administration of edotecarin in combination with infusional 5-FU/LV once every 14 days, even without the 5-FU bolus, did not permit adequate time for recovery from neutropenia.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carbazoles/administración & dosificación , Inhibidores Enzimáticos/administración & dosificación , Fluorouracilo/administración & dosificación , Leucovorina/administración & dosificación , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carbazoles/efectos adversos , Carbazoles/uso terapéutico , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/uso terapéutico , Femenino , Fluorouracilo/efectos adversos , Fluorouracilo/uso terapéutico , Humanos , Infusiones Intravenosas , Leucovorina/efectos adversos , Leucovorina/uso terapéutico , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Metástasis de la Neoplasia , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Inhibidores de Topoisomerasa IRESUMEN
Inhibition of thymidylate synthase (TS) is the primary mode of action for 5-fluorouracil (5FU) chemotherapy. TS expression is modulated by a variable number of tandem repeats in the TS enhancer region (TSER) located upstream of the TS gene (TYMS). Variability in the TSER has been suggested to contribute to 5FU-induced adverse events. However, the precise genetic associations remain largely undefined due to high polymorphism and ambiguity in defining genotypes. To assess toxicity associations, we sequenced the TSER in 629 cancer patients treated with 5FU. Of the 13 alleles identified, few could be unambiguously named using current TSER-nomenclature. We devised a concise and unambiguous systematic naming approach for TSER-alleles that encompasses all known variants. After applying this comprehensive naming system to our data, we demonstrated that the number of upstream stimulatory factor (USF1-)binding sites in the TSER was significantly associated with gastrointestinal toxicity in 5FU treatment.
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OBJECTIVES: T4N0-1 non-small-cell lung cancer (NSCLC) was historically considered curable but now includes tumours of size >7 cm according to the 8th edition tumour, node and metastasis (TNM) staging. This study was set out to evaluate the role of surgery and predictors of long-term survival after surgery in this renewed group of patients. METHODS: Patients, with clinical T4N0-2M0 NSCLC diagnosed in 2010-2013, in the National Cancer Database were queried. A Cox regression analysis was applied to investigate independent predictors of survival in 1588 N0-1 surgical cases. For previous T3 cases, the efficacy of treatment including and not including surgery was compared after propensity score matching by age, gender, race, facility type, comorbidity, laterality, clinical N stage, histology and tumour grade. RESULTS: In newly defined T4N0-1 NSCLC patients undergoing surgery, age, gender, comorbidity, nodal status, resection margin, tumour grade, chemotherapy and extension-size group were shown to be independent predictors of survival. In particular, patients with only T4 extension showed better survival than patients with tumour size >7 cm only [hazard ratio (HR) 0.75, 95% confidence interval (CI) 0.62-0.92, P = 0.016]. In the latter group, surgical treatment was associated with better survival than non-surgical treatment after matching (HR 0.45, 95% CI 0.42-0.48, P < 0.001). CONCLUSIONS: In the newly defined T4 NSCLC, tumour size >7 cm is a descriptor that is more predictive of worse survival than local extension alone for patients whose treatment included surgery. For T4-extended, N0-1 NSCLC with a tumour size ≤7 cm, surgery might be associated with favourable long-term outcomes and should be further encouraged as a treatment option.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Neoplasias Pulmonares/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Femenino , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/cirugía , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Pronóstico , Puntaje de Propensión , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Análisis de SupervivenciaRESUMEN
OBJECTIVE: To determine the optimal number of lymph nodes (LNs) examined and the role of adjuvant chemotherapy in stage I lung cancer. METHODS: The National Cancer Database was queried for surgically treated patients with pathologic stage I lung cancer between 2006 and 2014 (N = 65,438). The optimal LN numbers were determined in the multivariate Cox model and were further validated in the cohort with clinical stage I disease (N = 117,112) in terms of nodal upstaging and prognostic stratification. The role of adjuvant chemotherapy in patients with suboptimal staging (number of LNs examined was less than than the optimum) was evaluated in each T stage. RESULTS: The number of LNs examined correlated with tumor size (p < 0.001). There were increasing survival benefits with each additional LN examined-up to eight, nine, 10, and 11 nodes for patients with T1a, T1b, T1c, and T2a, respectively. Validation from the cohort with clinically staged disease showed that the threshold of eight to 11 LNs was an independent predictor of nodal upstaging (OR = 1.706, 95% confidence interval [CI] 1.608-1.779) and survival outcome (hazard ratio = 0.890, 95% CI: 0.865-0.916). After propensity matching, adjuvant chemotherapy was associated with improved survival in patients with stage T2a disease having suboptimal staging (hazard ratio = 0.841, 95% CI: 0.714-0.990), but not in patients with stage T1a to T1c disease. CONCLUSION: LN evaluation was important for accurate staging and adequate treatment, and examinations of an increasing number of nodes for progressively higher T components (i.e., eight, nine, 10, and 11 nodes for T1a, T1b, T1c, and T2a tumors, respectively) seemed crucial to predict upstaging and survival outcomes. Adjuvant chemotherapy might be beneficial to patients with stage T2a disease who have suboptimal nodal staging.