Expressão da p53 no tumor e no epitélio oral em pacientes com câncer de boca e faringe

INTRODUÇÃO: Expressiva porcentagem de pacientes com carcinomas de boca e faringe apresentam superexpressão da proteína p53 induzida por tabaco, álcool e radioterapia. OBJETIVO: Descrever a expressão da p53 em áreas de mucosa normal adjacente ao tumor e em carcinomas da boca e faringe. MÉTODO: Estudo prospectivo, com seguimento clínico por um ano, de 24 pacientes com câncer espinocelular de boca e faringe. Foram feitas biópsias na neoplasia e em áreas de mucosa normal adjacente ao tumor, antes e 9 meses após a radioterapia, e realizado estudo imunohistoquímico da expressão da p53. RESULTADOS: Antes da radioterapia, houve alteração da expressão da p53 em 20 das 24 biópsias feitas na neoplasia e em 14 nas de mucosa normal adjacente ao tumor. Onze paciente morreram antes de 1 ano de seguimento clínico. Dos 2 pacientes iniciais com aumento da p53 após a radioterapia continuava aumentada em 7 na área da neoplasia e em 6 nas áreas de mucosa normal. Observou-se associação da p53 com o tabagismo e estádio do tumor (p < 5%) mas não com o grau de diferenciação celular e alcoolismo. CONCLUSÃO: O aumento da expressão da p53 foi observado tanto na área da neoplasia como em mucosa normal na maioria dos pacientes com carcinoma de boca e faringe antes e após a radioterapia. Houve correlação estatisticamente significante da expressão da p53 com o tabagismo e estádio da neoplasia.

Body mass index, cigarette smoking, and alcohol consumption and cancers of the oral cavity, pharynx, and larynx: modeling odds ratios in pooled case-control data.

Odds ratios for head and neck cancer increase with greater cigarette and alcohol use and lower body mass index (BMI; weight (kg)/height(2) (m(2))). Using data from the International Head and Neck Cancer Epidemiology Consortium, the authors conducted a formal analysis of BMI as a modifier of smoking- and alcohol-related effects. Analysis of never and current smokers included 6,333 cases, while analysis of never drinkers and consumers of < or =10 drinks/day included 8,452 cases. There were 8,000 or more controls, depending on the analysis. Odds ratios for all sites increased with lower BMI, greater smoking, and greater drinking. In polytomous regression, odds ratios for BMI (P = 0.65), smoking (P = 0.52), and drinking (P = 0.73) were homogeneous for oral cavity and pharyngeal cancers. Odds ratios for BMI and drinking were greater for oral cavity/pharyngeal cancer (P < 0.01), while smoking odds ratios were greater for laryngeal cancer (P < 0.01). Lower BMI enhanced smoking- and drinking-related odds ratios for oral cavity/pharyngeal cancer (P < 0.01), while BMI did not modify smoking and drinking odds ratios for laryngeal cancer. The increased odds ratios for all sites with low BMI may suggest related carcinogenic mechanisms; however, BMI modification of smoking and drinking odds ratios for cancer of the oral cavity/pharynx but not larynx cancer suggests additional factors specific to oral cavity/pharynx cancer.

Risk of second cancer after lymphohematopoietic neoplasm

People living with lymphohematopoietic neoplasms (LHNs) are known to have increased risks of second cancer; however, the incidence of second cancers after LHNs has not been studied extensively in Australia. The Australian Cancer Database was used to analyze site-specific risk of second primary cancer after LHNs in 127,707 patients diagnosed between 1983 and 2005. Standardized incidence ratios (SIRs) were calculated using population rates. Overall, patients with an LHN had nearly twice the risk of developing a second cancer compared to the Australian population. Among 40,321 patients with non-Hodgkin's lymphoma (NHL), there was over a fourfold significant increase in melanoma, Kaposi sarcoma, cancer of the lip, connective tissue and peripheral nerves, eye, thyroid, Hodgkin's disease (HD) and myeloid leukemia. Among 6,396 patients with HD, there was over a fourfold significant increase in melanoma, Kaposi sarcoma, cancer of the lip, oral cavity and pharynx, female breast, uterine cervix, testis, thyroid, NHL and myeloid leukemia. Among the 33,025 patients with lymphoid and myeloid leukemia, significant excess were seen for cancers of the lip, eye, connective tissue and peripheral nerves, NHL and HD. Among the 13,856 patients with plasma cell tumors, there was over fourfold significant increase for melanoma, cancer of the connective tissue and peripheral nerves and myeloid leukemia. Our findings provide evidence of an increased risk of cancer, particularly ultraviolet radiation- and immunosuppression-related cancers, after an LHN in Australia. Copyright © 2010 UICC.

Economic burden of malignant neoplasms in Shandong province [山东省恶性肿瘤经济负担分析]

Objective: To evaluate the economic burden of malignant neoplasms in Shandong province in order to provide scientific evidence for policy-making. Methods: The main sources for this study were the data from the third sampling survey of death cause in 2006 and cancer prevalence survey in 2007 in Shandong province. The direct medical cost was calculated based on the survey data. The indirect cost due to mortality and morbidity were estimated with human capital approach based on the data of disability-adjusted life years derived from the two surveys and gross domestic product (GDP) data. The total economic burden was the sum of direct medical cost and indirect cost. The uncertainty analysis was conducted according to the methodology in global burden of disease study. Results: The total cost of cancer in Shandong province in 2006 estimated was 18 057 million Yuan RMB (95% confidence interval:16 817 － 19 393 million), which accounted for 0. 83% of the total GDP. The direct medical cost，indirect mortality cost and indirect morbidity cost accounted for 17.28%, 78.53%, and 4.20% of total economic burden of malignant neoplasms, respectively. Liver，lung and stomach cancer were the top three tumors with heavier economic burden, with accounted for more than one half (57. 83%) of the total economic burden of all cancers. The uncertainty of total burden estimated was around ± 7%, which mainly derived from the uncertainty of indirect economic burden. Conclusion: The influence of cancers on social economy is dominated by the loss of productivity, especially by the productivity loss due to premature death. Liver, lung and stomach cancer are the major cancers for disease control and prevention in Shandong province. Abstract in Chinese 目的 评价山东省恶性肿瘤经济负担,为卫生决策提供科学依据. 方法 以2006年山东省第3次死因回顾抽样凋查资料和2007年山东省恶性肿瘤现患状况抽样调查资料为基础,测算全省直接医疗成本;采用人力资本法测算死亡间接负担和伤残间接负担;参考全球疾病负担研究的方法对测算结果的不确定性进行分析. 结果 2006年山东省因恶性肿瘤导致的总经济负担为180.57亿元(95%CI=16 817～19 393),占全省GDP总量的0.83%,其中直接医疗成本占总负担的17.28%,死亡造成的间接经济负担占78.53%,伤残所致间接经济负担占4.20%;肝癌、肺癌和胃癌为山东省经济负担最重的3种恶性肿瘤,总经济负担合计占全部恶性肿瘤的57.83%;总经济负担估计结果的不确定性范围在±7%左右,主要取决于间接经济负担的不确定性. 结论 恶性肿瘤对社会经济的影响主要通过生产力的损失产生作用,并以死亡所致生产力损失为主;肝癌、肺癌和胃癌应是山东省恶性肿瘤预防控制的重点.

Estimation of disability weights on malignant neoplasms in Shandong province [山东省现患恶性肿瘤残疾权重的测量]

Objective To determine stage-specific and average disability weights (DWs) of malignant neoplasm and provide support and evidence for study on burden of cancer and policy development in Shandong province. Methods Health status of each cancer patient identified during the cancer prevalence survey in Shandong, 2007 was investigated. In line with the GBD methodology in estimating DWs, the disability extent of every case was classified and evaluated according to the Six-class Disability Classification version and then the stage-specific weights and average DWs with their 95 % confidence intervals were calculated, using SAS software. Results A total of 11 757 cancer cases were investigated and evaluated. DWs of specific stage of therapy, remission, metastasis and terminal of all cancers were 0.310, 0.218, 0.450 and 0.653 respectively. The average DW of all cancers was 0.317(95 % CI:0.312-0.321). Weights of different stage and different cancer varied significantly, while no significant differences were found between males and females. DWs were found higher (>0.4) for liver cancer, bone cancer, lymphoma and pancreas cancer. Lower DWs (<0.3) were found for breast cancer, cervix uteri, corpus uteri, ovarian cancer, larynx cancer, mouth and oropharynx cancer. Conclusion Stage-specific and average DWs for various cancers were estimated based on a large sample size survey. The average DWs of 0.317 for all cancers indicated that 1/3 healthy year lost for each survived life year of them. The difference of DWs between different cancer and stage provide scientific evidence for cancer prevention strategy development. Abstract in Chinese 目的 测算各种恶性肿瘤的分病程残疾权重和平均残疾权重,为山东省恶性肿瘤疾病负担研究及肿瘤防治对策制定提供参考依据. 方法 在山东省2007年恶性肿瘤现患调查中对所有恶性肿瘤患者的健康状况进行调查,参考全球疾病负担研究的方法 ,利用六级社会功能分级标准对患者残疾状况进行分级和赋值,分别计算20种恶性肿瘤的分病程残疾权重和平均残疾权重及其95%CI. 结果 共调查恶性肿瘤患者11757例,所有恶性肿瘤治疗期、恢复期、转移期和晚期的残疾权重分别为0.310、0.218、0.450和0.653,平均残疾权重为0.317(95%CI:0.312～0.321).不同恶性肿瘤和不同病程阶段的残疾权重差别显著,性别间差异无统计学意义.肝癌、骨癌、淋巴瘤和胰腺癌平均残疾权重较高(>0.4),乳腺癌、子宫体癌、子宫颈癌、卵巢癌、喉癌和口咽部癌症相对较低(<0.3). 结论 山东省恶性肿瘤平均残疾权重为0.317,即恶性肿瘤患者每存活1年平均损失近1/3个健康生命年;不同恶性肿瘤和不同病程阶段的残疾权重差别为肿瘤防治对策的制定具有重要意义.

Platinum-based chemotherapy in metastatic breast cancer : current status

Cisplatin and carboplatin are active in previously untreated patients with metastatic breast cancer (MBC) with mean response rates (RRs) of 50 and 32%, respectively. In pretreated patients the RR to cisplatin/carboplatin monotherapy declines markedly to <10%. Cisplatin and carboplatin have been combined with many other cytotoxics. In first-line setting high activity has been observed in combination with taxanes or vinorelbine (RRs consistently ∼60%). It appears that these newer combinations are superior to older regimens with etoposide (RRs 30 to 50%) or 5-fluorouracil (RRs 40 to 60%). Cisplatin-/carboplatin-based regimens with infusional 5-FU and epirubicin/paclitaxel/vinorelbine achieve high RRs of around 60 to 80%. However these regimens are difficult to administer in all patients because they require central venous access for continuous 5-FU infusion. In pretreated MBC the combinations of cisplatin-taxane/vinorelbine/gemcitabine or carboplatin-docetaxel/vinorelbine yield RRs of 40 to 50%, which are higher than those achieved with platinum-etoposide/5-FU. In locally advanced disease cisplatin-based regimens achieve very high RRs (>80%). This would suggest that in chemotherapy-naïve patients platinum-based therapy might have an important role to play. Additionally the synergy demonstrated between platinum compounds, taxanes and herceptin, in preclinical and clinical studies is of immense importance and the results of the two ongoing Breast Cancer International Research Group randomized phase III studies are eagerly awaited. These studies may help clarify the role of platinum compounds in the treatment of metastatic and possibly early breast cancer. © 2003 Elsevier Ltd. All rights reserved.

Estimation of the burden of malignant neoplasms by DALYs in Shandong Province [应用伤残调整寿命年测量山东省恶性肿瘤疾病负担的研究]

Objective: To evaluate the burden of malignant neoplasms in Shandong Province in order to provide scientific evidence for policy-making. Methods: The main data for this study were from Shandong third cause of death sampling survey in 2006 and Shandong 2007 cancer prevalence survey. YLLs, YLDs, DALYs and disability weights of each type of cancers were calculated according to the global burdens of disease （GBD） methodology. The direct method was used to estimate YLDs. The uncertainty analysis was conducted following the methodology in GBD study. Results: The total cancers burden in Shandong population was 1 383 thousands DALYs. Lung cancer, liver cancer, stomach cancer and esophagus cancer were the top four cancers with the highest health burden. The burden of the four major cancers together accounted for 71.45% of the total burden of all cancers. 95% of the total burden of malignant tumors was caused by premature death, and only 5.26% of the total cancer burden was due to disability. The uncertainty of total burden estimate was around±11%， the uncertainty of YLDs was bigger than that of YLLs. Conclusion: The health burden due to cancers in Shandong population is heavier than that of the national average level. Liver cancer, lung cancer and stomach cancer should be the major cancers for disease control and prevention in Shandong.

Genomic alterations in Myeloproliferative Neoplasms and Myelodysplastic Syndromes

Myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic disorders whose etiology and molecular pathogenesis are poorly understood. During the past decade, enormous developments in microarray technology and bioinformatics methods have made it possible to mine novel molecular alterations in a large number of malignancies, including MPN and MDS, which has facilitated the detection of new prognostic, predictive and therapeutic biomarkers for disease stratification. By applying novel microarray techniques, we profiled copy number alterations and microRNA (miRNA) expression changes in bone marrow aspirate and blood samples. In addition, we set up and validated an miRNA expression test for bone marrow core biopsies in order to utilize the large archive material available in many laboratories. We also tested JAK2 mutation status and compare it with the in vitro growth pattern of hematologic progenitors cells. In the study focusing on 100 MPN cases, we detected a Janus kinase 2 (JAK2) mutation in 71 cases. We observed spontaneous erythroid colony growth in all mutation-positive cases in addition to nine mutation negative cases. Interestingly, seven JAK2V167F negative ET cases showed spontaneous megakaryocyte colony formation, one case of which also harbored a myeloproliferative leukemia virus oncogene (MPL) mutation. We studied copy number alterations in 35 MPN and 37 MDS cases by using oligonucleotide-based array comparative hybridization (array CGH). Only one essential thrombocythemia (ET) case presented copy number alterations in chromosomes 1q and 13q. In contrast, MDS cases were characterized by numerous novel cryptic chromosomal aberrations with the most common copy number losses at 5q21.3q33.1 and 7q22.1q33, while the most common copy number gain was trisomy 8. As for the study of the bone marrow core biopsy samples, we showed that even though these samples were embedded in paraffin and underwent decalcification, they were reliable sources of miRNA and suitable for array expression analysis. Further, when studying the miRNA expression profiles of the 19 MDS cases, we found that, compared to controls, two miRNAs (one human Epstein-Barr virus (miR-BART13) miRNA and one human (has-miR-671-5p) miRNA) were downregulated, whereas two other miRNAs (hsa-miR-720 and hsa-miR-21) were upregulated. However, we could find no correlation between copy number alterations and microRNA expression when integrating these two data. This thesis brings to light new information about genomic changes implicated in the development of MPN and MDS, and also underlines the power of applying genome-wide array screening techniques in neoplasias. Rapid advances in molecular techniques and the integration of different genomic data will enable the discovery of the biological contexts of many complex disorders, including myeloid neoplasias.

Altered glutamyl-aminopeptidase activity and expression in renal neoplasms

Background: Advances in the knowledge of renal neoplasms have demonstrated the implication of several proteases in their genesis, growth and dissemination. Glutamyl-aminopeptidase (GAP) (EC. 3.4.11.7) is a zinc metallopeptidase with angiotensinase activity highly expressed in kidney tissues and its expression and activity have been associated wtih tumour development. Methods: In this prospective study, GAP spectrofluorometric activity and immunohistochemical expression were analysed in clear-cell (CCRCC), papillary (PRCC) and chromophobe (ChRCC) renal cell carcinomas, and in renal oncocytoma (RO). Data obtained in tumour tissue were compared with those from the surrounding uninvolved kidney tissue. In CCRCC, classic pathological parameters such as grade, stage and tumour size were stratified following GAP data and analyzed for 5-year survival. Results: GAP activity in both the membrane-bound and soluble fractions was sharply decreased and its immunohistochemical expression showed mild staining in the four histological types of renal tumours. Soluble and membrane-bound GAP activities correlated with tumour grade and size in CCRCCs. Conclusions: This study suggests a role for GAP in the neoplastic development of renal tumours and provides additional data for considering the activity and expression of this enzyme of interest in the diagnosis and prognosis of renal neoplasms.

Glycemic index, glycemic load, and risk of digestive tract neoplasms: a systematic review and meta-analysis

Background: Habitual consumption of diets with a high glycemic index (GI) and a high glycemic load (GL) may influence cancer risk via hyperinsulinemia and the insulin-like growth factor axis.
Objective: The objective was to conduct a systematic review to assess the association between GI, GL, and risk of digestive tract cancers.
Design: Medline and Embase were searched for relevant publications from inception to July 2008. When possible, adjusted results from a comparison of cancer risk of the highest compared with the lowest category of GI and GL intake were combined by using random-effects meta-analyses.
Results: Cohort and case-control studies that examined the risk between GI or GL intake and colorectal cancer (n = 12) and adenomas (n = 2), pancreatic cancer (n = 6), gastric cancer (n = 2), and squamous-cell esophageal carcinoma (n = 1) were retrieved. Most case-control studies observed positive associations between GI and GL intake and these cancers. However, pooled cohort study results showed no associations between colorectal cancer risk and GI intake [relative risk (RR): 1.04; 95% CI: 0.92, 1.12; n = 7 studies] or GL intake (RR: 1.06; 95% CI: 0.95, 1.17; n = 8 studies). Furthermore, no significant associations were observed in meta-analyses of cohort study results of colorectal cancer subsites and GI and GL intake. Similarly, no significant associations emerged between pancreatic cancer risk and GI intake (RR: 0.99; 95% CI: 0.83, 1.19; n = 5 studies) or GL intake (RR: 1.01; 95% CI: 0.86, 1.19; n = 6 studies) in combined cohort studies.
Conclusions: The findings from our meta-analyses indicate that GI and GL intakes are not associated with risk of colorectal or pancreatic cancers. There were insufficient data available regarding other digestive tract cancers to make any conclusions about GI or GL intake and risk.

SOCS3 tyrosine phosphorylation as a potential bio-marker for myeloproliferative neoplasms associated with mutant JAK2 kinases

JAK2 V617F, identified in the majority of patients with myeloproliferative neoplasms, tyrosine phosphorylates SOCS3 and escapes its inhibition. Here, we demonstrate that the JAK2 exon 12 mutants described in a subset of V617F-negative MPN cases, also stabilize tyrosine phosphorylated SOCS3. SOCS3 tyrosine phosphorylation was also observed in peripheral blood mononuclear cells and granulocytes isolated from patients with JAK2 H538QK539L or JAY2 F537-K539delinsL mutations. JAK kinase inhibitors, which effectively inhibited the proliferation of cells expressing V617F or K539L, also caused a dose-dependent reduction in both mutant JAK2 and SOCS3 tyrosine phosphorylation. We propose, therefore, that SOCS3 tyrosine phosphorylation may be a novel bio-marker of myeloproliferative neoplasms resulting from a JAK2 mutation and a potential reporter of effective JAK2 inhibitor therapy currently in clinical development.