Body-site distribution of skin cancer, pre-malignant and common benign pigmented lesions excised in general practice

Background Concern about skin cancer is a common reason for people from predominantly fair-skinned populations to present to primary care doctors. Objectives To examine the frequency and body-site distribution of malignant, pre-malignant and benign pigmented skin lesions excised in primary care. Methods This prospective study conducted in Queensland, Australia, included 154 primary care doctors. For all excised or biopsied lesions, doctors recorded the patient's age and sex, body site, level of patient pressure to excise, and the clinical diagnosis. Histological confirmation was obtained through pathology laboratories. Results Of 9650 skin lesions, 57·7% were excised in males and 75·0% excised in patients ≥50years. The most common diagnoses were basal cell carcinoma (BCC) (35·1%) and squamous cell carcinoma (SCC) (19·7%). Compared with the whole body, the highest densities for SCC, BCC and actinic keratoses were observed on chronically sun-exposed areas of the body including the face in males and females, the scalp and ears in males, and the hands in females. The density of BCC was also high on intermittently or rarely exposed body sites. Females, younger patients and patients with melanocytic naevi were significantly more likely to exert moderate/high levels of pressure on the doctor to excise. Conclusions More than half the excised lesions were skin cancer, which mostly occurred on the more chronically sun-exposed areas of the body. Information on the type and body-site distribution of skin lesions can aid in the diagnosis and planned management of skin cancer and other skin lesions commonly presented in primary care.

Molecular classification of cutaneous malignant melanoma by gene expression profiling

The most common human cancers are malignant neoplasms of the skin. Incidence of cutaneous melanoma is rising especially steeply, with minimal progress in non-surgical treatment of advanced disease. Despite significant effort to identify independent predictors of melanoma outcome, no accepted histopathological, molecular or immunohistochemical marker defines subsets of this neoplasm. Accordingly, though melanoma is thought to present with different 'taxonomic' forms, these are considered part of a continuous spectrum rather than discrete entities. Here we report the discovery of a subset of melanomas identified by mathematical analysis of gene expression in a series of samples. Remarkably, many genes underlying the classification of this subset are differentially regulated in invasive melanomas that form primitive tubular networks in vitro, a feature of some highly aggressive metastatic melanomas. Global transcript analysis can identify unrecognized subtypes of cutaneous melanoma and predict experimentally verifiable phenotypic characteristics that may be of importance to disease progression.

p53-independent NOXA induction overcomes apoptotic resistance of malignant melanomas

Once melanoma metastasizes, no effective treatment modalities prolong survival in most patients. This notorious refractoriness to therapy challenges investigators to identify agents that overcome melanoma resistance to apoptosis. Whereas many survival pathways contribute to the death-defying phenotype in melanoma, a defect in apoptotic machinery previously highlighted inactivation of Apaf-1, an apoptosome component engaged after mitochondrial damage. During studies involving Notch signaling in melanoma, we observed a gamma-secretase tripeptide inhibitor (GSI; z-Leu-Leu-Nle-CHO), selected from a group of compounds originally used in Alzheimer's disease, induced apoptosis in nine of nine melanoma lines. GSI only induced G2-M growth arrest (but not killing) in five of five normal melanocyte cultures tested. Effective killing of melanoma cells by GSI involved new protein synthesis and a mitochondrial-based pathway mediated by up-regulation of BH3-only members (Bim and NOXA). p53 activation was not necessary for up-regulation of NOXA in melanoma cells. Blocking GSI-induced NOXA using an antisense (but not control) oligonucleotide significantly reduced the apoptotic response. GSI also killed melanoma cell lines with low Apaf-1 levels. We conclude that GSI is highly effective in killing melanoma cells while sparing normal melanocytes. Direct enhancement of BH3-only proteins executes an apoptotic program overcoming resistance of this lethal tumor. Identification of a p53-independent apoptotic pathway in melanoma cells, including cells with low Apaf-1, bypasses an impediment to current cytotoxic therapy and provides new targets for future therapeutic trials involving chemoresistant tumors.

Identification of early-stage colorectal cancer patients at risk of relapse post-resection by immunobead reverse transcription-PCR analysis of peritoneal lavage fluid for malignant cells

Purpose: Colorectal cancer patients diagnosed with stage I or II disease are not routinely offered adjuvant chemotherapy following resection of the primary tumor. However, up to 10% of stage I and 30% of stage II patients relapse within 5 years of surgery from recurrent or metastatic disease. The aim of this study was to determine if tumor-associated markers could detect disseminated malignant cells and so identify a subgroup of patients with early-stage colorectal cancer that were at risk of relapse. Experimental Design: We recruited consecutive patients undergoing curative resection for early-stage colorectal cancer. Immunobead reverse transcription-PCR of five tumor-associated markers (carcinoembryonic antigen, laminin γ2, ephrin B4, matrilysin, and cytokeratin 20) was used to detect the presence of colon tumor cells in peripheral blood and within the peritoneal cavity of colon cancer patients perioperatively. Clinicopathologic variables were tested for their effect on survival outcomes in univariate analyses using the Kaplan-Meier method. A multivariate Cox proportional hazards regression analysis was done to determine whether detection of tumor cells was an independent prognostic marker for disease relapse. Results: Overall, 41 of 125 (32.8%) early-stage patients were positive for disseminated tumor cells. Patients who were marker positive for disseminated cells in post-resection lavage samples showed a significantly poorer prognosis (hazard ratio, 6.2; 95% confidence interval, 1.9-19.6; P = 0.002), and this was independent of other risk factors. Conclusion: The markers used in this study identified a subgroup of early-stage patients at increased risk of relapse post-resection for primary colorectal cancer. This method may be considered as a new diagnostic tool to improve the staging and management of colorectal cancer. © 2006 American Association for Cancer Research.

Computer planning of stereotactic iodine-125 seed brachytherapy for recurrent malignant gliomas

At St Thomas' Hospital, we have developed a computer program on a Titan graphics supercomputer to plan the stereotactic implantation of iodine-125 seeds for the palliative treatment of recurrent malignant gliomas. Use of the Gill-Thomas-Cosman relocatable frame allows planning and surgery to be carried out at different hospitals on different days. Stereotactic computed tomography (CT) and positron emission tomography (PET) scans are performed and the images transferred to the planning computer. The head, tumour and frame fiducials are outlined on the relevant images, and a three-dimensional model generated. Structures which could interfere with the surgery or radiotherapy, such as major vessels, shunt tubing etc., can also be outlined and included in the display. Catheter target and entry points are set using a three-dimensional cursor controlled by a set of dials attached to the computer. The program calculates and displays the radiation dose distribution within the target volume for various catheter and seed arrangements. The CT co-ordinates of the fiducial rods are used to convert catheter co-ordinates from CT space to frame space and to calculate the catheter insertion angles and depths. The surgically implanted catheters are after-loaded the next day and the seeds left in place for between 4 and 6 days, giving a nominal dose of 50 Gy to the edge of the target volume. 25 patients have been treated so far.

Genetic polymorphisms in the human tissue kallikrein (KLK) locus and their implication in various malignant and non-malignant diseases

The Kallikrein (KLK) gene locus encodes a family of serine proteases and is the largest contiguous cluster of protease-encoding genes attributed an evolutionary age of 330 million years. The KLK locus has been implicated as a high susceptibility risk loci in numerous cancer studies through the last decade. The KLK3 gene already has established clinical relevance as a biomarker in prostate cancer prognosis through its encoded protein, prostate-specific antigen. Data mined through genome-wide association studies (GWAS) and next-generation sequencing point to many important candidate single nucleotide polymorphisms (SNPs) in KLK3 and other KLK genes. SNPs in the KLK locus have been found to be associated with several diseases including cancer, hypertension, cardiovascular disease and atopic dermatitis. Moreover, introducing a model incorporating SNPs to improve the efficiency of prostate-specific antigen in detecting malignant states of prostate cancer has been recently suggested. Establishing the functional relevance of these newly-discovered SNPs, and their interactions with each other, through in silico investigations followed by experimental validation, can accelerate the discovery of diagnostic and prognostic biomarkers. In this review, we discuss the various genetic association studies on the KLK loci identified either through candidate gene association studies or at the GWAS and post-GWAS front to aid researchers in streamlining their search for the most significant, relevant and therapeutically promising candidate KLK gene and/or SNP for future investigations.

Estimating the Burden of Malignant Neoplasm in Shandong Province [山东省恶性肿瘤疾病负担研究]

Objective To make a comprehensive estimation of the burden of malignant neoplasm in Shandong province by the means of disability- adjusted life year (DALY) for the first time. Methods DALYs were calculated following the procedures developed for the Global Burden of Disease (GBD) study to ensure comparability. We measured YLLs using the cancer mortality data of 19 Disease Surveillance Points (DSPs) in Shandong Province during 2000 and 2005. YLDs were estimated based on the cancer morbidity data of 6 Cancer Incidence Surveillance Points in Shandong Province in 2005. Results All cancers were responsible for 20.60 DALYs for every thousand population in Shandong Province (25.30 for men and 15.74 for women) . 94.3% of the losses were due to premature death and 5.7% to disability. 31.9% of the DALYs happened among 45~59 age group. The top 10 cancers for DALYs were lung cancer, liver cancer, stomach cancer, oesophagus cancer, colon/rectum cancer, breast cancer, leukemia, brain cancer, pancreas cancer and cervix uteri cancer in turn. The burden of major cancers such as lung cancer and liver cancer in Shandong were heavier than the global and national level. Conclusions he burden of disease of malignant neoplasm is mainly because of premature death. Lung cancer, liver cancer, stomach cancer and oesophagus cancer are the major cancers in Shandong Province and should be paid more attention to their prevention and control. Abstract in Chinese 目的 首次应用伤残调整寿命年(DALY)对山东省居民恶性肿瘤疾病负担进行综合评价. 方法 以2000-2005年山东省疾病监测系统的恶性肿瘤死亡资料和2005年山东省恶性肿瘤发病监测系统的发病资料为基础,利用世界卫生组织提供的专门公式,计算恶性肿瘤的YLLs、YLDs和DALYs,以此评价恶性肿瘤的疾病负担. 结果 山东省每千人每年因恶性肿瘤造成20.60个DALYs损失(男性25.30,女性15.74),其中,9413%为早死所致,5.7%因残疾所致:恶性肿瘤主要导致45～59岁人群的DALYs损失,占31.93%;恶性肿瘤疾病负担前10位依次为肺癌、肝癌、胃癌、食道癌、肠癌、乳腺癌、白血病、脑癌、胰腺癌和宫颈癌;山东省肺癌、肝癌等主要癌症疾病负担高于全球和全国水平. 结论 恶性肿瘤疾病负担主要由早死所致,肺癌、肝癌、胃癌和食道癌等主要癌症的防制地位十分突出.

Estimating the burden of malignant neoplasm on village residents in a mountainous area [山区农村居民恶性肿瘤疾病负担的估计]

Objective To make a comprehensive estimation of the burden of malignant neoplasm on village residents in Linqu County by the means of DALY (Disability-adjusted life year). Methods DALYs, YLLs and YLDs were calculated following the procedures developed for the Global Burden of Disease (GBD) study to ensure comparability, based on the cancer registration data of Linqu villages during 1998-2004, in order to measure the burden of various caners. Results All cancers were responsible for 20.00 DALYs for every thousand population in Linqu County (24.82 for men and 14.96 for women). 92.5% of the losses were due to premature death and 7.5% to disability. 31.5% of the DALYs happened among 45-59 age group. The top 10 cancers for DALYs were stomach cancer, lung cancer, liver cancer, oesophagus cancer, leukemia,colon/rectum cancer, brain cancer, pancreas cancer, breast cancer and bone cancer in turn. Only stomach cancer, lung cancer and liver cancer together account for 69.3% of total DALYs due to malignant neoplasm. The burden of malignant neoplasm was on rising recent years. Conclusions The burden of disease of malignant neoplasm is mainly because of premature death. Stomach cancer, lung cancer and liver cancer lead to heavier burden than the global and national levels. Abstract in Chinese 目的 应用伤残调整寿命年(DALY)对临朐县农村恶性肿瘤疾病负担进行评价. 方法 以1998～2004年临朐县农村肿瘤登记资料为基础,利用全球疾病负担研究中使用的专门公式计算恶性肿瘤的YLLs、YLDs和DALYs,以此评价各类恶性肿瘤的疾病负担. 结果 临朐农村每千人每年因恶性肿瘤造成20.0个DALYs损失(男性24.82,女性14.96),其中92.5%为早死所致,7.5%因残疾所致;恶性肿瘤主要导致45～59岁人群的DALYs损失,占31.5%;恶性肿瘤疾病负担前10位依次为胃癌、肺癌、肝癌、食道癌、白血病、肠癌、脑癌、胰腺癌、乳腺癌和骨癌,其中仅胃癌、肺癌和肝癌三大肿瘤DALYs就占全部肿瘤的69.3%;临朐县农村恶性肿瘤疾病负担有进一步上升的趋势. 结论 恶性肿瘤疾病负担主要由早死所致,胃癌、肺癌、肝癌等主要癌症疾病负担高于全球和中国区水平.

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.