RESUMO
PURPOSE: In a previous study of treatment for advanced colorectal cancer, the LV5FU2 regimen, comprising leucovorin (LV) plus bolus and infusional fluorouracil (5FU) every 2 weeks, was superior to the standard North Central Cancer Treatment Group/Mayo Clinic 5-day bolus 5FU/LV regimen. This phase III study investigated the effect of combining oxaliplatin with LV5FU2, with progression-free survival as the primary end point. PATIENTS AND METHODS: Four hundred twenty previously untreated patients with measurable disease were randomized to receive a 2-hour infusion of LV (200 mg/m2/d) followed by a 5FU bolus (400 mg/m2/d) and 22-hour infusion (600 mg/m2/d) for 2 consecutive days every 2 weeks, either alone or together with oxaliplatin 85 mg/m2 as a 2-hour infusion on day 1. RESULTS: Patients allocated to oxaliplatin plus LV5FU2 had significantly longer progression-free survival (median, 9.0 v 6.2 months; P = .0003) and better response rate (50.7% v 22.3%; P = .0001) when compared with the control arm. The improvement in overall survival did not reach significance (median, 16.2 v 14.7 months; P = .12). LV5FU2 plus oxaliplatin gave higher frequencies of National Cancer Institute common toxicity criteria grade 3/4 neutropenia (41.7% v 5.3% of patients), grade 3/4 diarrhea (11.9% v 5.3%), and grade 3 neurosensory toxicity (18.2% v 0%), but this did not result in impairment of quality of life (QoL). Survival without disease progression or deterioration in global health status was longer in patients allocated to oxaliplatin treatment (P = .004). CONCLUSION: The LV5FU2-oxaliplatin combination seems beneficial as first-line therapy in advanced colorectal cancer, demonstrating a prolonged progression-free survival with acceptable tolerability and maintenance of QoL.
RESUMO
BACKGROUND: We report updated overall survival (OS) data from study NO16966, which compared capecitabine plus oxaliplatin (XELOX) vs 5-fluorouracil/folinic acid plus oxaliplatin (FOLFOX4) as first-line therapy in metastatic colorectal cancer. METHODS: NO16966 was a randomised, two-arm, non-inferiority, phase III comparison of XELOX vs FOLFOX4, which was subsequently amended to a 2 × 2 factorial design with further randomisation to bevacizumab or placebo. A planned follow-up exploratory analysis of OS was performed. RESULTS: The intent-to-treat (ITT) population comprised 2034 patients (two-arm portion, n=634; 2 × 2 factorial portion, n=1400). For the whole NO16966 study population, median OS was 19.8 months in the pooled XELOX/XELOX-placebo/XELOX-bevacizumab arms vs 19.5 months in the pooled FOLFOX4/FOLFOX4-placebo/FOLFOX4-bevacizumab arms (hazard ratio 0.95 (97.5% CI 0.85-1.06)). In the pooled XELOX/XELOX-placebo arms, median OS was 19.0 vs 18.9 months in the pooled FOLFOX4/FOLFOX4-placebo arms (hazard ratio 0.95 (97.5% CI 0.83-1.09)). FOLFOX4 was associated with more grade 3/4 neutropenia/granulocytopenia and febrile neutropenia than XELOX, and XELOX with more grade 3 diarrhoea and grade 3 hand-foot syndrome than FOLFOX4. CONCLUSION: Updated survival data from study NO16966 show that XELOX is similar to FOLFOX4, confirming the primary analysis of progression-free survival. XELOX can be considered as a routine first-line treatment option for patients with metastatic colorectal cancer.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Capecitabina , Neoplasias Colorretais/patologia , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Feminino , Fluoruracila/análogos & derivados , Fluoruracila/uso terapêutico , Seguimentos , Humanos , Leucovorina/uso terapêutico , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Compostos Organoplatínicos/uso terapêutico , Oxaloacetatos , Taxa de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Alkaline phosphatase (ALP) is a strong prognostic factor in patients with metastatic colorectal cancer (MCRC). Patients with ALP more than three times the upper limit of normal (ULN) were excluded from our previous studies evaluating chemotherapy. An exploratory cohort of patients with ALP >3 ULN was included in the OPTIMOX1 study. PATIENTS AND METHODS: Previously untreated patients with MCRC were randomized to FOLFOX4 until progression (arm A) or FOLFOX7 for six cycles, maintenance without oxaliplatin for 12 cycles and reintroduction of FOLFOX7 (arm B). Patients were stratified according to ALP level Assuntos
Fosfatase Alcalina/metabolismo
, Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
, Neoplasias Colorretais/tratamento farmacológico
, Neoplasias Colorretais/enzimologia
, Adulto
, Idoso
, Idoso de 80 Anos ou mais
, Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem
, Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos
, Estudos de Coortes
, Neoplasias Colorretais/patologia
, Intervalo Livre de Doença
, Feminino
, Fluoruracila/administração & dosagem
, Fluoruracila/efeitos adversos
, Humanos
, Leucovorina/administração & dosagem
, Leucovorina/efeitos adversos
, Masculino
, Pessoa de Meia-Idade
, Metástase Neoplásica
, Compostos Organoplatínicos/administração & dosagem
, Compostos Organoplatínicos/efeitos adversos
, Oxaliplatina
, Resultado do Tratamento
RESUMO
BACKGROUND: Reports of the risk of colorectal neoplasia associated with a variant of the adenomatous polyposis coli (APC E1317Q) gene are conflicting. Using a case-control design, we investigated this relationship within a clinic-based cohort followed through the Integrated Cancer Prevention Center and the Tel-Aviv Sourasky Medical Center. MATERIALS AND METHODS: All study subjects were tested for the APC E1317Q variant at enrollment. Subjects underwent colonoscopic evaluation (+/-biopsy and/or polypectomy) and had cancer history and colorectal neoplasia risk factors assessed. The crude and adjusted risks of neoplasia associated with the E1317Q variant were calculated. RESULTS: The prevalence of the E1317Q variant was 1.4% in the entire study sample and 3.2% in Sephardic Jews. E1317Q was more prevalent among cases: 15 of 458 (3.3%) cases were carriers compared with 11 of 1431 (0.8%) controls [odds ratio (OR) 4.4, 95% CI 2.0-9.6]. When stratified by neoplasia type, adenoma risk was significantly elevated in carriers (OR 4.1, 95% CI 1.8-9.4) but colorectal cancer risk was not (OR 2.1, 95% CI 0.8-5.3). After adjustment, the E1317Q variant remained a significant predictor of colorectal adenoma (OR 4.6, 95% CI 2.0-10.8). CONCLUSIONS: The APC E1317Q variant is associated with colorectal neoplasia, particularly colorectal adenomas, but further studies are still needed. Variant prevalence is elevated in Sephardic Jews.
Assuntos
Proteína da Polipose Adenomatosa do Colo/genética , Neoplasias Colorretais/genética , Genes APC , Predisposição Genética para Doença , Adenoma/genética , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Judeus/genética , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de RiscoRESUMO
BACKGROUND: Second-line irinotecan-based chemotherapy is commonly used in metastatic colorectal cancers after first-line oxaliplatin-based chemotherapy. No standard schedule of irinotecan has been established in this situation. PATIENTS AND METHODS: Metastatic colorectal cancer patients included in the OPTIMOX1 phase III study received first-line oxaliplatin-based chemotherapy (FOLFOX). No second line was defined in the protocol, but data concerning second line were prospectively registered. Inclusion criterion was patients receiving an irinotecan-based second-line chemotherapy. Second-line progression-free survival (PFS) and tumor response were evaluated according to type of irinotecan-based regimen administered. RESULTS: A total of 342 patients received irinotecan-based chemotherapy as second-line chemotherapy: FOLFIRI-3 [n = 109, irinotecan 100 mg/m(2) days 1 and 3 combined with leucovorin (LV) 400 mg/m(2) day 1 and 46-h continuous 5-fluorouracil (5-FU) 2000 mg/m(2)], FOLFIRI-1 (n = 112, irinotecan 180 mg/m(2) day 1 combined with LV 400 mg/m(2) day 1, 5-FU bolus 400 mg/m(2) and 46-h continuous 5-FU 2400 mg/m(2)) and other various irinotecan-based regimens (n = 121). Median second-line PFS was 3.0 months (FOLFIRI-3: 3.7 months; FOLFIRI-1: 3.0 months; other regimens: 2.3 months). In multivariate analysis, FOLFIRI-3 regimen (relative risk 0.43, 95% confidence interval 0.28-0.68, P = 0.0003) and lactate deshydrogenase level at inclusion (P = 0.0006) in OPTIMOX1 were associated with a longer second-line PFS. CONCLUSION: In unselected patients pretreated with oxaliplatin, PFS in second line appeared to be improved by FOLFIRI-3 regimen.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Neoplasias Colorretais/secundário , Feminino , Fluoruracila/administração & dosagem , Humanos , Irinotecano , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Falha de Tratamento , Resultado do TratamentoRESUMO
Oral capecitabine (Xeloda) is an effective drug with favourable safety in adjuvant and metastatic colorectal cancer. Oxaliplatin-based therapy is becoming standard for Dukes' C colon cancer in patients suitable for combination therapy, but is not yet approved by the UK National Institute for Health and Clinical Excellence (NICE) in the adjuvant setting. Adjuvant capecitabine is at least as effective as 5-fluorouracil/leucovorin (5-FU/LV), with significant superiority in relapse-free survival and a trend towards improved disease-free and overall survival. We assessed the cost-effectiveness of adjuvant capecitabine from payer (UK National Health Service (NHS)) and societal perspectives. We used clinical trial data and published sources to estimate incremental direct and societal costs and gains in quality-adjusted life months (QALMs). Acquisition costs were higher for capecitabine than 5-FU/LV, but higher 5-FU/LV administration costs resulted in 57% lower chemotherapy costs for capecitabine. Capecitabine vs 5-FU/LV-associated adverse events required fewer medications and hospitalisations (cost savings pound3653). Societal costs, including patient travel/time costs, were reduced by >75% with capecitabine vs 5-FU/LV (cost savings pound1318), with lifetime gain in QALMs of 9 months. Medical resource utilisation is significantly decreased with capecitabine vs 5-FU/LV, with cost savings to the NHS and society. Capecitabine is also projected to increase life expectancy vs 5-FU/LV. Cost savings and better outcomes make capecitabine a preferred adjuvant therapy for Dukes' C colon cancer. This pharmacoeconomic analysis strongly supports replacing 5-FU/LV with capecitabine in the adjuvant treatment of colon cancer in the UK.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/economia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Desoxicitidina/análogos & derivados , Fluoruracila/economia , Leucovorina/economia , Administração Oral , Capecitabina , Quimioterapia Adjuvante/economia , Análise Custo-Benefício , Desoxicitidina/administração & dosagem , Desoxicitidina/economia , Intervalo Livre de Doença , Esquema de Medicação , Custos de Medicamentos/estatística & dados numéricos , Fluoruracila/administração & dosagem , Custos de Cuidados de Saúde , Recursos em Saúde/estatística & dados numéricos , Humanos , Injeções Intravenosas , Leucovorina/administração & dosagem , Estadiamento de Neoplasias , Qualidade de Vida , Indução de Remissão , Sensibilidade e Especificidade , Taxa de Sobrevida , Fatores de Tempo , Resultado do Tratamento , Reino UnidoRESUMO
While the I1307K APC mutation clearly confers an increased lifetime risk for colorectal cancer, there is a paucity of data on the natural history of colonic neoplasia in symptomatic and asymptomatic mutation carriers. In this study, 51 Jewish I1307K APC mutation carriers were identified in a high-risk familial cancer clinic over a 4-year period, of whom 29 (56.8%) (four males and 25 females) were successfully telephone interviewed for 0.5-5 years (mean 2.4 +/- 1.4) after initial genetic testing. Of these 29 cases, one individual was diagnosed with colon cancer at the age of 45 years, five had adenomatous polyps (mean number of polyps = 1.8), 11 had breast cancer (mean age at diagnosis 49.5 +/- 10.5 years), and 12 were asymptomatic, at the time of the testing. During the follow-up period, new colonic polyps were diagnosed in three mutation carriers, two with previously diagnosed colon cancer and polyps and only one of the asymptomatic mutation carriers, and two additional previously affected patients had new cancer diagnoses: gastric cancer and melanoma. From this descriptive study, it seems that the short-term risk for colonic polyps in I1307K APC mutation is low, primarily affecting patients with previously diagnosed colon tumors.
Assuntos
Neoplasias Colorretais/genética , Genes APC , Mutação Puntual , Adulto , Idoso , Neoplasias da Mama/genética , Pólipos do Colo/genética , Feminino , Seguimentos , Heterozigoto , Humanos , Israel , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , RiscoRESUMO
BACKGROUND AND AIM: Adenocarcinoma of the Pancreas is a leading cause of cancer-related mortality, accounting for an estimated 30,000 deaths per year in the United States. Multiple studies have indicated that specific cyclooxygenase-2 (COX-2) inhibitors may serve in the prevention and treatment of a variety of malignancies including pancreatic adenocarcinoma. Recent studies had shown that the long-term use of high concentration of COX-2 inhibitors is not toxic free and may be limited due to serious gastrointestinal and cardiovascular side effects. The chemopreventive efficacy of the phytochemical, curcumin has been demonstrated in several in vitro and animal models. In this study we investigated whether curcumin potentiates the growth inhibition effect of a COX-2 inhibitor (celecoxib, Pfizer, NY, USA) in human pancreatic cancer cells. METHODS: P-34 (expressing high levels of COX-2), and MIAPaCa (expressing low levels of COX-2) and Panc-1 (no expression of COX-2) evaluated cell lines were exposed to different concentrations of celecoxib (0-40 microM), curcumin (0-20 microM) and their combination. Cell viability was by XTT assay. Apoptosis was assessed by flow cytometry and COX-2 expression was measured by Western blotting analysis. RESULTS: In P-34 cells, curcumin synergistically potentiated the inhibitory effect of celecoxib on cell growth. The growth inhibition was associated with inhibition of proliferation and induction of apoptosis. Western blot analysis showed that COX-2 expression was down-regulated by the combination therapy. CONCLUSION: Curcumin synergistically augments the growth inhibition inserted by celecoxib in pancreatic cancer cells expressing COX-2. The synergistic effect was mediated through inhibition of COX-2. This may enable the use of celecoxib at lower and safer concentrations and may pave the way for a more effective treatment in this devastating disease.
Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Curcumina/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Pirazóis/farmacologia , Sulfonamidas/farmacologia , Western Blotting , Celecoxib , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/biossíntese , Dieta , Sinergismo Farmacológico , Citometria de Fluxo , HumanosRESUMO
Hereditary nonpolyposis colorectal cancer (HNPCC) is caused by mutations in the mismatch-repair genes. We report here the identification and characterization of a founder mutation in MSH2 in the Ashkenazi Jewish population. We identified a nucleotide substitution, MSH2*1906G-->C, which results in a substitution of proline for alanine at codon 636 in the MSH2 protein. This allele was identified in 15 unrelated Ashkenazi Jewish families with HNPCC, most of which meet the Amsterdam criteria. Genotype analysis of 18 polymorphic loci within and flanking MSH2 suggested a single origin for the mutation. All colorectal cancers tested showed microsatellite instability and absence of MSH2 protein, by immunohistochemical analysis. In an analysis of a population-based incident series of 686 Ashkenazi Jews from Israel who have colorectal cancer, we identified 3 (0.44%) mutation carriers. Persons with a family history of colorectal or endometrial cancer were more likely to carry the mutation than were those without such a family history (P=.042), and those with colorectal cancer who carried the mutation were, on average, younger than affected individuals who did not carry it (P=.033). The mutation was not detected in either 566 unaffected Ashkenazi Jews from Israel or 1,022 control individuals from New York. In hospital-based series, the 1906C allele was identified in 5/463 Ashkenazi Jews with colorectal cancer, in 2/197 with endometrial cancer, and in 0/83 with ovarian cancer. When families identified by family history and in case series are included, 25 apparently unrelated Ashkenazi Jewish families have been found to harbor this mutation. Although this pathogenic mutation is not frequent in the Ashkenazi Jewish population (accounting for 2%-3% of colorectal cancer in those whose age at diagnosis is <60 years), it is highly penetrant and accounts for approximately one-third of HNPCC in Ashkenazi Jewish families that fulfill the Amsterdam criteria.
Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Proteínas de Ligação a DNA , Efeito Fundador , Predisposição Genética para Doença , Judeus/genética , Mutação Puntual/genética , Proteínas Proto-Oncogênicas/genética , Alanina/genética , Estudos de Casos e Controles , Cromossomos Humanos Par 2/genética , Cristalografia por Raios X , Feminino , Frequência do Gene/genética , Haplótipos/genética , Heterozigoto , Humanos , Israel , Masculino , Repetições de Microssatélites/genética , Proteína 2 Homóloga a MutS , Mutação de Sentido Incorreto/genética , Neoplasias/genética , Linhagem , Polimorfismo Genético/genética , Prolina/genética , Conformação Proteica , Proteínas Proto-Oncogênicas/análise , Proteínas Proto-Oncogênicas/químicaRESUMO
Germline mutations in BRCA1 or BRCA2 account for the majority of inherited breast cancer cases. Yet, in up to 40% of familial breast cancer cases, no mutations can be detected in either gene. Germline mutations in PTEN underlie two inherited syndromes: Cowden disease (CD) and Bannayan-Riley-Ruvalcaba syndrome (BRRS). The known association of CD with breast cancer risk made it plausible that germline mutations within PTEN may play a role in inherited predisposition to breast cancer. The nine coding exons of the PTEN gene were screened for harboring germline mutations using denaturing gradient gel electrophoresis (DGGE) complemented by sequencing, in two subsets of Israeli patients: 12 patients clinically diagnosed with BRRS, and 89 women with an apparent inherited predisposition to breast cancer, some with salient features of CD. Two of three familial BRRS patients exhibited novel germline mutations in PTEN: a missense mutation changing methionine to arginine at codon 134, and insertion of two nucleotides (CA) at cDNA position 1215 resulting in a frameshift at codon 61 and a premature stop at codon 99. Among 89 high-risk women, two missense mutations were detected in exon 4: A to C change at cDNA position 1279 resulting in a change of aspargine to threonine at codon 82 (N82T), and a G to an A alteration in 1269 which alters threonine to alanine at codon 78 (T78A), a non-conservative missense mutation. This study suggests that PTEN does not play a major role in predisposing to hereditary breast cancer in Israeli women, and that detection of PTEN mutations in BRRS patients is more likely in familial cases.
Assuntos
Neoplasias da Mama/genética , Mutação em Linhagem Germinativa , Síndrome do Hamartoma Múltiplo/genética , Síndromes Neoplásicas Hereditárias/genética , Monoéster Fosfórico Hidrolases/genética , Proteínas Supressoras de Tumor/genética , Neoplasias da Mama/complicações , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Testes Genéticos , Síndrome do Hamartoma Múltiplo/complicações , Humanos , Israel , Mutação de Sentido Incorreto , Síndromes Neoplásicas Hereditárias/complicações , PTEN Fosfo-Hidrolase , Fenótipo , Transtornos da Pigmentação/etiologia , Transtornos da Pigmentação/genética , Saúde da MulherRESUMO
The I1307K APC germline mutation is associated with an increased risk to colo-rectal cancer (CRC). Whether and to what extent the phenotype of CRC in mutation carriers differs from sporadic cases, remains unknown. To gain insight into this issue, we analysed 307 unselected Israeli patients with CRC, who were treated in a single medical centre, for harbouring the I1307K mutation. Twenty-eight mutation carriers (9.1%) were detected. Two of 28 mutation carriers (7.1%) and 93/277 (33.6%) of non-carriers, were of non-Ashkenazi origin (P < 0.01). In 74/278 (26.6%) of the sporadic cases, and only 1/28 (3.6%) of mutation carriers (3.6%) the tumour was located in the right colon (P < 0.01). Mutation carriers had a more advanced disease stage (14/28 - 50% Dukes C), as compared with 60 (19.5%) of non-carriers (P = 0.02). The mean age at diagnosis was similar: 65 (+/- 9.7) years and 66.3 (+/- 11.6) years, for mutation carriers and non-carriers, respectively. No statistical differences were noted between the two groups in sex distribution, tumour grade, and family history of cancer. We conclude that early age at diagnosis and family history of cancer cannot be used to predict who is likely to harbour the I1307K APC germline mutation carriers. However, the tumours in patients with this mutation appear different than those without, are less likely to be proximal and more likely to be advanced than tumours in non-carriers.
Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Genes APC , Mutação em Linhagem Germinativa/genética , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA , DNA de Neoplasias , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Linhagem , Fenótipo , Reação em Cadeia da Polimerase , Fatores SexuaisRESUMO
A missense mutation within the APC gene, I1307K, was described in Ashkenazi individuals at risk for colorectal cancer (CRC) and in the general population. The anecdotal reporting of the occurrence of this mutation in some non-Ashkenazi individuals led us to hypothesize that within the Jewish people, the I1307K polymorphism may reflect a founder mutation, and that the mutation is not restricted to ethnic Ashkenazis. To test that notion, and to establish the occurrence rate of the I1307K polymorphism in non-Ashkenazi Jewish populations, we screened Iraqi and Moroccan Jews and consecutive Jewish CRC patients and performed haplotype analysis with APC-linked markers in two I1307K carrier families. We analyzed Jewish individuals: 210 Moroccans, 160 Iraqis, 148 Ashkenazi, and 349 CRC patients (227 Ashkenazi and 122 non-Ashkenazi). The mutation detection scheme included PCR followed by denaturing gradient gel electrophoresis (DGGE) or modified restriction analysis (MRA). Haplotypes were assessed using three intragenic and three flanking markers. The I1307K polymorphism was detected in 29/227 Ashkenazi (12.8%), 2/122 (1.6%) non-Ashkenazi CRC patients, and in 2 individuals each (approximately 1%) within the Moroccan and Iraqi populations. Allelic pattern analysis in all our I1307K carriers, revealed a common haplotype for the three intragenic markers tested, in all mutation carriers, regardless of ethnic origin. The I1307K polymorphism, therefore, exists in all ethnic Jewish populations: Ashkenazi and non-Ashkenazi, with or without colon cancer. Jewish I1307K mutation carriers share a common allelic pattern with APC-linked markers. This strongly supports the notion of a founder mutation for I1307K.
Assuntos
Polipose Adenomatosa do Colo/genética , Efeito Fundador , Genes APC , Judeus/genética , Mutação de Sentido Incorreto , Polimorfismo Genético , Adenocarcinoma/etnologia , Adenocarcinoma/genética , Polipose Adenomatosa do Colo/etnologia , Substituição de Aminoácidos , Neoplasias Colorretais/etnologia , Neoplasias Colorretais/genética , Europa Oriental/etnologia , Feminino , Frequência do Gene , Predisposição Genética para Doença , Haplótipos/genética , Humanos , Iraque/etnologia , Israel/epidemiologia , Judeus/classificação , Masculino , Marrocos/etnologia , Linhagem , PrevalênciaRESUMO
The genetic basis for the majority of early onset or non-syndromic "familial" colorectal cancer (CRC) is unknown. Attenuated APC phenotype is characterized by relatively few colonic polyps, early age at onset of colon cancer compared with the general population, and inactivating germline mutations within specific regions of the APC gene. We hypothesized that germline mutations within these APC gene regions, might contribute to early onset or familial CRC susceptibility. To test this notion, we analysed 85 Israeli patients with either early onset (< 50 years at diagnosis) or familial CRC for harbouring mutations within the relevant APC gene regions: exons 1-5, exon 9 and a region within exon 15 (spanning nucleotides c.3900 to c.4034; codons 1294 to 1338) using denaturing gradient gel electrophoresis (DGGE), and all of exon 15 employing protein truncation test (PTT). No inactivating, disease-associated mutations were detected in any patient. A novel polymorphism in intron 5 was detected in 16 individuals, 8 patients were carriers of the 11307K variant, a mutation prevalent among Jewish individuals with colorectal cancer, and 4 displayed the E1317Q variant. We conclude that in Israeli individuals with early onset or familial CRC, truncating mutations in the APC gene regions associated with attenuated APC phenotype probably contribute little to disease pathogenesis.
Assuntos
Pólipos do Colo/genética , Neoplasias Colorretais/genética , Genes APC/genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Pólipos do Colo/patologia , Neoplasias Colorretais/patologia , Feminino , Humanos , Israel , Judeus/genética , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo GenéticoRESUMO
It is presently unclear whether carriers of BRCA1 mutations have an increased risk for colorectal cancer (CRC). To gain insight into this issue, 225 unselected Ashkenazi Jewish CRC patients were tested for the presence of the three common Jewish BRCA1/2 germline mutations: 185delAG and 5382insC (BRCA1) and 6174delT (BRCA2). A total of four carriers was found (4/225, 1.78%). This frequency is similar to the estimated normal Ashkenazi population frequency, thus suggesting that these specific mutations do not contribute to CRC predisposition.
Assuntos
Proteína BRCA1/genética , Neoplasias Colorretais/genética , Predisposição Genética para Doença , Judeus/genética , Proteínas de Neoplasias/genética , Fatores de Transcrição/genética , Idoso , Idoso de 80 Anos ou mais , Proteína BRCA2 , Neoplasias Colorretais/etnologia , Análise Mutacional de DNA , Feminino , Genética Populacional , Mutação em Linhagem Germinativa , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da PolimeraseRESUMO
Inherited predisposition occurs in 5-10% of all gastrointestinal (GI) cancer patients, but with the exception of colorectal cancer (CRC), the genes involved in conferring genetic susceptibility remain largely unknown. Indirect evidence indicates that germline mutations in BRCA2 might be associated with an increased risk for various GI malignancies. A single mutation (6174delT) occurs in the BRCA2 gene in high-risk breast ovarian cancer families of Jewish Ashkenazi origin, in about 1% of the general Ashkenazi population, and rarely in non-Ashkenazi Jews. In order to assess the contribution of this germline mutation to non-CRC GI cancer in Jewish Israeli patients, we tested 70 unselected, consecutive Jewish Ashkenazi patients with gastrointestinal malignancies for this mutation by PCR amplification and modified restriction enzyme digests. Patients' age range was 38-90 years (mean 65.8+/-11.8 years). The most common malignancies were gastric cancer (n = 35) and exocrine pancreatic cancer (n = 23). Overall, 6 mutation carriers were detected: 3/23 (13%) of the patients with pancreatic cancer, 2/35 (5.7%) of patients with gastric cancer and 1/4 (25%) of patients with bile duct cancer. The 8.6% mutation carrier rate among patients is a rate significantly higher than that of the general Ashkenazi population (1.16%, P = 0.0002). We conclude that the rate of the predominant Jewish BRCA2 mutation in patients with gastric and pancreatic cancer significantly differ from that of the general population of the same ethnic origin. Thus, BRCA2 mutations probably contribute to gastrointestinal tumorigenesis other then colon cancer, and the surveillance scheme for mutation carriers should incorporate this information.
Assuntos
Neoplasias Gastrointestinais/genética , Predisposição Genética para Doença , Judeus/genética , Proteínas de Neoplasias/genética , Fatores de Transcrição/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteína BRCA2 , Transformação Celular Neoplásica , Análise Mutacional de DNA , Feminino , Neoplasias Gastrointestinais/etnologia , Genética Populacional , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Fatores de RiscoRESUMO
OBJECTIVES: Infection with Helicobacter pylori, particularly with strains positive for CagA protein, increases the risk of gastric adenocarcinoma. Few studies have explored the possible association between H. pylori infection and colorectal cancer. This study evaluated whether the seroprevalence of CagA in H. pylori-infected patients affected risk for colorectal cancer independently of H. pylori status. METHODS: In this study, we tested serum IgG antibodies against H. pylori (ELISA) and CagA protein (Western blot assay) in 67 patients with colorectal adenocarcinoma, 36 with gastric adenocarcinoma, 47 with other malignancies (cancer controls), and 45 hospitalized for transesophageal echocardiography (TEE controls). Colonic cancer and gastric cancer patients with H. pylori infection were compared to each control group and to the pooled controls using simple and adjusted analyses. RESULTS: H. pylori infection was noted in 50 colon cancer patients, 31 gastric cancer patients, 31 cancer controls, and 32 TEE controls. In all, 41 (82%), 29 (94%), 11 (35%), and 13 (41%), respectively, of these H. pylori-positive sera expressed CagA reactivity (p < 0.001 for all pairwise comparisons between cases and controls). In the adjusted analysis, infection with H. pylori CagA+ compared to H. pylori CagA- was associated with increased risk for colorectal adenocarcinoma (odds ratio = 10.6; 95% CI = 2.7-41.3; p = 0.001) and gastric adenocarcinoma (odds ratio = 88.1; 95% CI = 6.3-1229.2; p = 0.001). CONCLUSIONS: Among patients infected with H. pylori, CagA+ seropositivity is associated with increased risk for both gastric and colonic cancer. This finding should stimulate additional research into the role of cagA+ H. pylori infection in the development of colorectal cancer.
Assuntos
Antígenos de Bactérias , Proteínas de Bactérias/metabolismo , Neoplasias Colorretais/microbiologia , Infecções por Helicobacter/complicações , Infecções por Helicobacter/metabolismo , Anticorpos Antibacterianos/análise , Proteínas de Bactérias/imunologia , Neoplasias Colorretais/imunologia , Humanos , Imunoglobulina G/análise , Masculino , Pessoa de Meia-Idade , Valores de Referência , Fatores de Risco , Estudos Soroepidemiológicos , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/microbiologiaRESUMO
Forty-seven patients with pancreatic cancer were treated with two different schedules of 5-fluorouracil (5FU) and leucovorin (LCV): standard and dose-intense schedules. The standard regimen was monthly and the dose intense was biweekly. Partial response was observed in one patient (4%), no change in 12 (48%) and progression of disease in another 12 patients. Clinical benefit, measured by symptomatic improvement, was observed in 19% of all the patients, in 12% of those treated with the standard regimen and in 27% of the intense group. Median survival was 8 months for all the patients. The 1-year survival rate was 32%. Toxicity was mild. There was no survival benefit for the dose intense regimen. These results indicate that clinical benefit can be obtained with 5FU and LCV regimens despite the lack of objective response and that a dose-intense schedule is of little benefit in treating pancreatic cancer.
Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fluoruracila/administração & dosagem , Leucovorina/administração & dosagem , Neoplasias Pancreáticas/tratamento farmacológico , Adulto , Idoso , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/uso terapêutico , Fluoruracila/efeitos adversos , Fluoruracila/uso terapêutico , Humanos , Leucovorina/uso terapêutico , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Pancreáticas/mortalidade , Taxa de Sobrevida , Resultado do TratamentoRESUMO
OBJECTIVE: To assess whether there is a decrease in endometrial thickness following discontinuation of tamoxifen treatment as measured by ultrasound. DESIGN: Prospective study. SETTING: Department of Obstetrics and Gynaecology, Sapir Medical Centre, Kfar-Saba, Israel. POPULATION: Fifty-eight postmenopausal women with breast cancer who were treated with tamoxifen. METHODS: Transvaginal ultrasonographic measurements of endometrial thickness. MAIN OUTCOME MEASURES: Evaluation of the changes of endometrial thickness and the frequency the endometrium reached a thickness of < or = 5 mm at different time intervals after stopping tamoxifen treatment. RESULTS: There was a significant decrease in median thickness of the endometrium, within six months after stopping tamoxifen, from 7.75 mm measured at the last ultrasonographic study performed before tamoxifen discontinuation down to 5.2 mm (P = 0.002). There were no further reductions in endometrial thickness, and it remained constantly low in subsequent ultrasonographic studies which were performed at various times up to 30 months following the discontinuation of tamoxifen treatment. While taking tamoxifen, only 25-9% of the women had an endometrial thickness of < or = 5 mm. This proportion doubled in their first six months after stopping. CONCLUSIONS: Median thickness of endometrial thickness significantly reduced within six months following tamoxifen discontinuation, and remained constantly low thereafter. This finding may support use of ultrasonographic imaging for the measurement of tamoxifen's effect on the endometrium of postmenopausal breast cancer patients.
Assuntos
Antineoplásicos Hormonais/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Endométrio/diagnóstico por imagem , Tamoxifeno/efeitos adversos , Doenças Uterinas/diagnóstico por imagem , Endométrio/efeitos dos fármacos , Feminino , Humanos , Pessoa de Meia-Idade , Pós-Menopausa , Estudos Prospectivos , Síndrome de Abstinência a Substâncias/complicações , UltrassonografiaRESUMO
PURPOSE: In a previous study of treatment for advanced colorectal cancer, the LV5FU2 regimen, comprising leucovorin (LV) plus bolus and infusional fluorouracil (5FU) every 2 weeks, was superior to the standard North Central Cancer Treatment Group/Mayo Clinic 5-day bolus 5FU/LV regimen. This phase III study investigated the effect of combining oxaliplatin with LV5FU2, with progression-free survival as the primary end point. PATIENTS AND METHODS: Four hundred twenty previously untreated patients with measurable disease were randomized to receive a 2-hour infusion of LV (200 mg/m(2)/d) followed by a 5FU bolus (400 mg/m(2)/d) and 22-hour infusion (600 mg/m(2)/d) for 2 consecutive days every 2 weeks, either alone or together with oxaliplatin 85 mg/m(2) as a 2-hour infusion on day 1. RESULTS: Patients allocated to oxaliplatin plus LV5FU2 had significantly longer progression-free survival (median, 9.0 v 6.2 months; P =.0003) and better response rate (50.7% v 22.3%; P =.0001) when compared with the control arm. The improvement in overall survival did not reach significance (median, 16.2 v 14.7 months; P =. 12). LV5FU2 plus oxaliplatin gave higher frequencies of National Cancer Institute common toxicity criteria grade 3/4 neutropenia (41. 7% v 5.3% of patients), grade 3/4 diarrhea (11.9% v 5.3%), and grade 3 neurosensory toxicity (18.2% v 0%), but this did not result in impairment of quality of life (QoL). Survival without disease progression or deterioration in global health status was longer in patients allocated to oxaliplatin treatment (P =.004). CONCLUSION: The LV5FU2-oxaliplatin combination seems beneficial as first-line therapy in advanced colorectal cancer, demonstrating a prolonged progression-free survival with acceptable tolerability and maintenance of QoL.
Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Compostos Organoplatínicos/uso terapêutico , Adenocarcinoma/mortalidade , Adenocarcinoma/secundário , Adolescente , Adulto , Idoso , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/secundário , Diarreia/induzido quimicamente , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Humanos , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Neutropenia/induzido quimicamente , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Estudos Prospectivos , Qualidade de Vida , Transtornos de Sensação/induzido quimicamente , Estatísticas não Paramétricas , Resultado do TratamentoRESUMO
The frequency of the APC I1307K mutation and its association with disease pattern was examined in 996 Ashkenazi women consisting of individuals with either sporadic (n = 382) or hereditary (n = 143) breast and/or ovarian cancer; asymptomatic BRCA1/2 mutation carriers (185delAG, 5382insC and 6174delT) (n= 53) and healthy controls (n= 418). The I1307K allele was equally distributed among women with sporadic (17/382; 4.6%) and inherited (10/143; 7%) breast and/or ovarian cancer irrespective of their being diagnosed before or after 42 years of age and among asymptomatic (7/53; 13.2%) and cancer manifesting BRCA1/2 carriers (10/143; 7%). Taken together, the prevalence of the I1307K allele was significantly higher in BRCA1/2 carriers compared to non-BRCA1/2 carriers (17/196; 8.7% and 40/800, 5%; respectively). The high prevalence of the I1307K allele among BRCA1/2 carriers is not associated with increased cancer risk but seems to be genetically connected because of Jewish ancestry.