Cancer constitutes an enormous burden on society in more and less economically developed countries alike. The occurrence of cancer is increasing because of the growth and aging of the population, as well as an increasing prevalence of established risk factors such as smoking, overweight, physical inactivity, and changing reproductive patterns associated with urbanization and economic development. Based on GLOBOCAN estimates, about 14.1 million new cancer cases and 8.2 million deaths occurred in 2012 worldwide. Over the years, the burden has shifted to less developed countries, which currently account for about 57% of cases and 65% of cancer deaths worldwide. Lung cancer is the leading cause of cancer death among males in both more and less developed countries, and has surpassed breast cancer as the leading cause of cancer death among females in more developed countries; breast cancer remains the leading cause of cancer death among females in less developed countries. Other leading causes of cancer death in more developed countries include colorectal cancer among males and females and prostate cancer among males. In less developed countries, liver and stomach cancer among males and cervical cancer among females are also leading causes of cancer death. Although incidence rates for all cancers combined are nearly twice as high in more developed than in less developed countries in both males and females, mortality rates are only 8% to 15% higher in more developed countries. This disparity reflects regional differences in the mix of cancers, which is affected by risk factors and detection practices, and/or the availability of treatment. Risk factors associated with the leading causes of cancer death include tobacco use (lung, colorectal, stomach, and liver cancer), overweight/obesity and physical inactivity (breast and colorectal cancer), and infection (liver, stomach, and cervical cancer). A substantial portion of cancer cases and deaths could be prevented by broadly applying effective prevention measures, such as tobacco control, vaccination, and the use of early detection tests.

DNA, mRNA and microRNA are released and circulate in the blood of cancer patients. Changes in the levels of circulating nucleic acids have been associated with tumour burden and malignant progression. In the past decade a wealth of information indicating the potential use of circulating nucleic acids for cancer screening, prognosis and monitoring of the efficacy of anticancer therapies has emerged. In this Review, we discuss these findings with a specific focus on the clinical utility of cell-free nucleic acids as blood biomarkers.

Recent estimates of global cancer incidence and survival were used to update previous figures of limited duration prevalence to the year 2008. The number of patients with cancer diagnosed between 2004 and 2008 who were still alive at the end of 2008 in the adult population is described by world region, country and the human development index. The 5-year global cancer prevalence is estimated to be 28.8 million in 2008. Close to half of the prevalence burden is in areas of very high human development that comprise only one-sixth of the world's population. Breast cancer continues to be the most prevalent cancer in the vast majority of countries globally; cervix cancer is the most prevalent cancer in much of Sub-Saharan Africa and Southern Asia and prostate cancer dominates in North America, Oceania and Northern and Western Europe. Stomach cancer is the most prevalent cancer in Eastern Asia (including China); oral cancer ranks as the most prevalent cancer in Indian men and Kaposi sarcoma has the highest 5-year prevalence among men in 11 countries in Sub-Saharan Africa. The methods used to estimate point prevalence appears to give reasonable results at the global level. The figures highlight the need for long-term care targeted at managing patients with certain very frequently diagnosed cancer forms. To be of greater relevance to cancer planning, the estimation of other time-based measures of global prevalence is warranted.

A radioimmunoassay for ng quantities of DNA was developed. [125l]lododeoxyuridine-labeled DNA was used as the antigen, and the serum of a lupus erythematosus patient served as the source of antibody. The level of free DNA in the serum of 173 patients with various types of cancer and in 55 healthy individuals was determined by this radioimmunoassay. DNA concentration in the normal controls had a range of 0 to 100 ng/ml with a mean of 13 +/- 3 ng/ml (S.E.). For comparison purposes, the range of 0 to 50 ng/ml was designated as normal, and 93% of controls were found in this range. In the cancer patients, the DNA concentration ranged from zero to mug levels with a mean of 180 +/- 38 ng/ml. Fifty % of the patients values were found in the range of 0 to 50 ng/ml; the other 50% were between 50 and 5000 ng/ml. No correlation could be seen between DNA levels and the size or location of the primary tumor. Significantly higher DNA levels, however, were found in the serum of patients with metastatic disease (mean of 209 +/- 39 ng/ml), as compared to nonmetastatic patients (mean 100 +/- 30, p less than 0.02). After radiation therapy in lymphoma, lung, ovary, uterus, and cervical tumors, the levels decreased in 66 to 90% of the patients, whereas in glioma, breast, colon, and rectal tumors, the DNA levels decreased only in 16 to 33% of the patients. Generally, the decrease in DNA concene of tumor size and reduction of pain. Conversely, when DNA levels either increased or remained unchanged, a lack of response to the treatment was noted. Of 17 patients who died within a year, 13 showed DNA levels that remained high or unchanged, whereas only 4 showed lower levels during treatment. Persistent high or increasing DNA levels in the circulation, therefore, may signal a relapse and are probably a poor prognostic sign. The relatively high percentage (50%) of cancer patients with apparently normal DNA levels would suggest that this test may have low diagnostic value. It should be pointed out, however, that all these patients represent a selected group considered for radiation therapy, usually after surgery and/or chemotherapy. It is possible that a better correlation between DNA levels and cancer will be obtained prior to the initiation of treatment. On the other hand, DNA in the serum may be an important tool for the evaluation of therapy or the comparison of different regimens.

BACKGROUND

In addition to cell lysis, apoptosis has been advanced as the origin of circulating DNA on the basis of several observations. Plasma or serum DNA often presents a ladder pattern reminiscent of that displayed by apoptotic cells when subjected to electrophoresis. However, the phenomenon of active release of DNA from cells might also be expected to result in a ladder pattern on electrophoresis. Non-dividing cells, such as lymphocytes, frog auricles and cultured cell lines including HL-60, spontaneously release a nucleoprotein complex within a homeostatic system in which newly synthesized DNA is preferentially released.

CONCLUSIONS

In relation to DNA synthesis, the phenomenon of extracellular DNA in different culture conditions favors apoptosis or spontaneous active DNA release.

BACKGROUND

In 1996, the International Association for the Study of Lung Cancer (IASLC) launched a worldwide TNM staging project to inform the next edition (seventh) of the TNM lung cancer staging system. In this article, we describe the methods and validation approaches used and discuss the internal and external validity of the recommended changes.

METHODS

The International Staging Committee agreed on a number of general principles that guided the decision-making process. Internal validity was addressed by visually assessing the consistency of Kaplan-Meier curves across database types, geographic regions and addressing external validity, by assessing the similarity of curves generated using the population-based Surveillance Epidemiology and End Results cancer registry data to those generated using the project database. Cox proportional hazards regression was used to calculate hazard ratios between the proposed stage groupings with adjustment for cell type, sex, age, and region.

RESULTS

Calls for data by the International Staging Committee resulted in the creation of an international database containing information on more than 100,000 cases. The present work is based on analyses of the 67,725 cases of non-small cell lung cancer. Validation checks were robust, demonstrating that the suggested staging changes are stable within the data sources used and externally. For example, suggested changes based on tumor size were well supported, with statistically significant hazard ratios ranging from 1.14 to 1.51 between adjacent pairs in the Surveillance Epidemiology and End Results data.

CONCLUSIONS

Lung cancer stage definitions have never been subjected to such an intense validation process. We do accept, however, that this work is limited in ways that can only be addressed by a prospective database, which we intend to develop. In the meantime, we think that this new system will greatly improve the usefulness of TNM lung staging across all of its purposes.

Detection of circulating tumor DNA (ctDNA) after resection of stage II colon cancer may identify patients at the highest risk of recurrence and help inform adjuvant treatment decisions. We used massively parallel sequencing-based assays to evaluate the ability of ctDNA to detect minimal residual disease in 1046 plasma samples from a prospective cohort of 230 patients with resected stage II colon cancer. In patients not treated with adjuvant chemotherapy, ctDNA was detected postoperatively in 14 of 178 (7.9%) patients, 11 (79%) of whom had recurred at a median follow-up of 27 months; recurrence occurred in only 16 (9.8 %) of 164 patients with negative ctDNA [hazard ratio (HR), 18; 95% confidence interval (CI), 7.9 to 40; P < 0.001]. In patients treated with chemotherapy, the presence of ctDNA after completion of chemotherapy was also associated with an inferior recurrence-free survival (HR, 11; 95% CI, 1.8 to 68; P = 0.001). ctDNA detection after stage II colon cancer resection provides direct evidence of residual disease and identifies patients at very high risk of recurrence.

OBJECTIVE

To assess the impact of cell type, age, and gender in addition to pathologic tumor, node, metastasis (TNM) stage in surgically managed stage I-IIIA non-small cell lung cancer (NSCLC) cases from the international staging database of the International Association for the Study of Lung Cancer.

METHODS

From the 67,725 cases of NSCLC submitted to the staging database, 9137 surgically managed cases were selected for which all the following variables were available: pathologic stage, age, gender, and specific histologic cell type. Performance status and smoking history were examined in subsets. Methods used were Cox proportional hazards regression and recursive partitioning and amalgamation (RPA) analyses.

RESULTS

Pathologic TNM stage, age, and gender were all independently prognostic for survival. The bronchioloalveolar carcinoma (BAC) subtype had superior survival over other cell types despite the potential for heterogeneity in this group. Adjusted comparisons revealed a small survival advantage for squamous cell carcinomas over non-BAC adenocarcinoma histology and also over large cell, though the effect appeared to be limited to the male patients. RPA revealed the importance of TNM stage primarily, and age was prognostic within stage groups. Cell type was not found to add prognostic value in the RPA analysis. Prognostic groups were formed based on the RPA output, and the prognostic value of these groupings was validated using the North American Surveillance, Epidemiology, and End Results Registries. Performance status and smoking history were prognostic in the subsets where data were available. Effects of other variable were not influenced by the inclusion of smoking status in regression models.

CONCLUSIONS

Age and gender are confirmed as important prognostic factors in surgically resected NSCLC. Cell type is less important, although the small population of cases classified as BAC have a survival advantage over other histologies, and there may be a small survival advantage for squamous cell carcinomas over non-BAC adenocarcinomas. Imbalances between stage, gender, and cell type at presentation may lead to a misleading result with respect to cell type in unadjusted analyses. Pathologic TNM category is the most important prognostic factor in this analysis.

Circulating DNA is present in the blood of all individuals, but it has been found that cancer patients and patients with a variety of other conditions have increased amounts of these circulating DNA fragments in their blood. Even though more than 30 years of research have been done on this subject, the origin of these nucleic acid molecules is still not clear. We present evidence that does not support the general notion that apoptosis or necrosis is the major source of circulating free DNA. Active release of free circulating DNA by living cells may be a plausible mechanism. Disturbance of the equilibrium between the release of DNA by living cells and the mechanisms used for clearing this DNA may play the main role in the appearance of increased amounts of circulating DNA in the blood of individuals with different ailments. Elucidating the origin and the mechanism that cells use to release free circulating DNA into the blood may enhance the diagnostic and prognostic value of these nucleic acid molecules.

In the last decades the approach to cancer patient management has been deeply revolutionized. We are moving from a "one-fits-all" strategy to the "personalized medicine" based on the molecular characterization of the tumor. In this new era it is becoming more and more clear that the monitoring of the disease is fundamental for the success of the treatment, thus there is the need of new biomarker discovery. More precisely in the last years the scientific community has started to use the term "liquid biopsy". A liquid biopsy is a liquid biomarker that can be easily isolated from many body fluids (blood, saliva, urine, ascites, pleural effusion, etc.) and, as well as a tissue biopsy, a representative of the tissue from which it is spread. In this review we will focus our attention on circulating tumor cells, circulating tumor DNA, exosomes and secretomes with the aim to underlie their usefulness and potential application in a clinical setting for lung cancer patient management.

OBJECTIVE

Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive malignancies owing to the high frequency of tumor recurrence. The identification of markers for early ESCC diagnosis and prediction of recurrence is expected to improve the long-term prognosis. Therefore, we searched for associations between tumor recurrence and cell-free DNA (cfDNA) mutations in blood plasma, which contains genetic markers for various cancer types.

METHODS

Genomic DNA from tumors and cfDNA from plasma were obtained from 13 patients undergoing treatment for newly diagnosed ESCC. Next-generation sequencing of cfDNA in plasma was performed to identify mutations in 53 cancer-related genes, in which recurrent mutations were previously detected in ESCC. cfDNA mutational profiles were compared before and after tumor resection in four patients. Furthermore, somatic mutations in serial plasma samples were monitored after treatment in four patients.

RESULTS

We identified multiple concordant somatic mutations in cfDNA and primary tumor samples from 10 patients (83.3%) and in cfDNA and metastatic tumor samples from one patient (100%). Furthermore, the allele frequency of the concordant mutations in cfDNA changed concomitantly with tumor burden and increased approximately 6 months earlier than the detection of tumor recurrences by imaging tests in two patients. Conventional biomarkers, such as SCC and p53-Ab, did not reflect tumor recurrences.

CONCLUSIONS

The present multigene panel, which enabled the diagnosis of tumor recurrence with greater accuracy than did using standard tumor markers or imaging methods, is expected to greatly facilitate standard, postoperative follow-up monitoring in ESCC.

China is facing the challenges of an expanding ageing population and the impact of rapid urbanization, cancer rates are subsequently increasing. This study focuses on the changes of the ageing population and projects the incidence of common ageing-related cancers in the urban regions in China up to 2030.

Cancer incidence data and population statistics in China were extracted from the International Agency for Research on Cancer.

Due to improving longevity in China, continuous and remarkable increasing trends for the lung, colorectal and prostate cancers are expected.

The rate of expanding ageing population was taken into account when predicting the trend of cancer incidence; the estimations of ageing-related cancers were more factual and significant than using the conventional approach of age standardization.

The incidence rates of lung, colorectal and prostate cancers will continue to rise in the future decades due to the rise of ageing population. Lifestyle modification such as cutting tobacco smoking rates and promoting healthier diets as well as cancer screening programs should be a health system priority in order to decrease the growing burden of cancer-related mortality and morbidity.

Lung cancer is the leading cause of cancer-associated deaths worldwide. Surgery is the standard treatment for early-stage non-small cell lung cancer (NSCLC). However, 30% to 80% of these patients will die within 5 yearS of diagnosis. Circulating cell-free DNA (cfDNA) harbors pathologic characteristics of the original tumor, such as gene mutations or epigenetic alterations. Analysis of cfDNA has revolutionized the clinical care of advanced lung cancer patients undergoing targeted therapies. However, the low concentration of cfDNA in the blood of early-stage NSCLC patients has hampered its use for management of early disease. Continuing development of more specific and sensitive techniques for detection and analysis of cfDNA will soon enable its leverage in early stage and, perhaps, even screening settings. Therefore, cfDNA analysis may become a tool used for routine NSCLC diagnosis and for monitoring tumor burden, as well as for identifying hidden residual disease. In this review, we will focus on the current evidence of cfDNA in patients with early-stage NSCLC, new and upcoming approaches to identify circulating-tumor biomarkers, their clinical applications and future directions.

Although studies have examined the associations between fine particles (PM2.5) and lung cancer mortality in US and European countries, the evidence is still limited for China. In addition, no study has provided estimates of spatial variation in lung cancer mortality attributable to PM2.5 in China. In this study, we quantified the associations between lung cancer mortality and PM2.5, using a spatiotemporal model with observed data of lung cancer mortality from 75 communities from the National Cancer Registration of China from 1990 to 2009 and the annual concentrations of PM2.5 at 0.5°×0.5° spatial resolution. We also estimated lung cancer mortality burden attributable to PM2.5 in China, with predicted county level lung cancer deaths in 2005. We found that the PM2.5-lung cancer mortality associations were non-linear, with thresholds of 40μg/m3 overall, 45μg/m3 for male, 42μg/m3 for female, 45μg/m3 for those aged 30-64years, 48μg/m3 for those aged 65-74years, and 40μg/m3 for those aged 75years and more, above which the relative risks were 1.08 (95% CI: 1.07, 1.09), 1.07 (95% CI: 1.05, 1.08), 1.12 (95% CI: 1.1, 1.14), 1.05 (95% CI: 1.04, 1.07), 1.07 (95% CI: 1.06, 1.09), and 1.14 (95% CI: 1.12, 1.16) respectively. There were 51,219 (95% CI: 45,745-56,512) lung cancer deaths attributed to PM2.5 in 2005, with attributable fractions of 13.7% (95% CI: 12.23-15.11%) overall, 10.01% (95% CI: 8.37-11.58%) for men, 18.06% (95% CI: 15.81-20.18%) for women, 8.35% (95% CI: 6.07-10.51%) for those aged 65-74years, 9.73% (95% CI: 7.6-11.75%) for those aged 65-74years, 21.7% (95% CI: 19.27-23.99%) for those aged 75years or more. In conclusion, assuming a causal relation a reduction in exposure levels of PM2.5 below thresholds would avert a substantial number of deaths from lung cancer in China.

The first Chinese-German Lung Cancer Expert Panel was held in November 2015 one day after the 7th Chinese-German Lung Cancer Forum, Shanghai. The intention of the meeting was to discuss strategies for the diagnosis and treatment of lung cancer within the context of lung cancer screening. Improved risk classification criteria and novel imaging approaches for screening populations are highly required as more than half of lung cancer cases are false positive during the initial screening round if the National Lung Screening Trial (NLST) demographic criteria [≥30 pack years (PY) of cigarettes, age ≥55 years] are applied. Moreover, if the NLST criteria are applied to the Chinese population a high number of lung cancer patients are not diagnosed due to non-smoking related risk factors in China. The primary goal in the evaluation of pulmonary nodules (PN) is to determine whether they are malignant or benign. Volumetric based screening concepts such as investigated in the Dutch-Belgian randomized lung cancer screening trial (NELSON) seem to achieve higher specificity. Chest CT is the best imaging technique to identify the origin and location of the nodule since 20% of suspected PN found on chest X-ray turn out to be non-pulmonary lesions. Moreover, novel state-of-the-art CT systems can reduce the radiation dose for lung cancer screening acquisitions down to a level of 0.1 mSv with improved image quality to novel reconstruction techniques and thus reduce concerns related to chest CT as the primary screening technology. The aim of the first part of this manuscript was to summarize the current status of novel diagnostic techniques used for lung cancer screening and minimally invasive treatment techniques for progressive PNs that were discussed during the first Chinese-German Lung Cancer. This part should serve as an educational part for the readership of the techniques that were discussed during the Expert Panel. The second part summarizes the consensus recommendations that were interdisciplinary discussed by the Expert Panel.