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Diffusion-weighted imaging (DWI) has been at the forefront of cancer imaging since the early 2000s. Before its application in clinical oncology, this powerful technique had already achieved widespread recognition due to its utility in the diagnosis of cerebral infarction. Following this initial success, the ability of DWI to detect inherent tissue contrast began to be exploited in the field of oncology. Although the initial oncologic applications for tumor detection and characterization, assessing treatment response, and predicting survival were primarily in the field of neurooncology, the scope of DWI has since broadened to include oncologic imaging of the prostate gland, breast, and liver. Despite its growing success and application, misconceptions about the underlying physical basis of the DWI signal exist among researchers and clinicians alike. In this review, we provide a detailed explanation of the biophysical basis of diffusion contrast, emphasizing the difference between hindered and restricted diffusion, and elucidating how diffusion parameters in tissue are derived from the measurements via the diffusion model. We describe one advanced DWI modeling technique, called restriction spectrum imaging (RSI). This technique offers a more direct in vivo measure of tumor cells, due to its ability to distinguish separable pools of water within tissue based on their intrinsic diffusion characteristics. Using RSI as an example, we then highlight the ability of advanced DWI techniques to address key clinical challenges in neurooncology, including improved tumor conspicuity, distinguishing actual response to therapy from pseudoresponse, and delineation of white matter tracts in regions of peritumoral edema. We also discuss how RSI, combined with new methods for correction of spatial distortions inherent in diffusion MRI scans, may enable more precise spatial targeting of lesions, with implications for radiation oncology and surgical planning. See all articles in this Cancer Research section, "Physics in Cancer Research.", (©2014 American Association for Cancer Research.)

Background: Oxidative stress enhances lipid peroxidation (LPO), which both are implicated in the promotion and progression stages of carcinogenesis, in particular under conditions of chronic inflammation and infections. Exocyclic etheno-DNA adducts, which are formed by LPO-products such as 4-hydroxy -2-nonenal, are strongly pro-mutagenic DNA lesions., Methods: The development of ultra-sensitive detection methods for etheno-adducts in human tissues, white blood cells( WBC) and urine has provided evidence that these adducts are elevated in affected organs of cancer-prone patients, probably acting as a driving force to malignancy., Results: Two recent studies that yielded some new insights into disease causation are briefly reviewed: DNA-damage in WBC of mother-newborn child pairs, and lipid peroxidation derived DNA damage in patients with cancer-prone liver diseases. Our results indicate that biomonitoring of etheno-DNA adducts in humans are promising tools (i) to better understand disease aetiopathogenesis, allowing hazard identification(ii) to monitor disease progression and (iii) to verify the efficacy of chemopreventive and therapeutic interventions. Such clinical trials are warranted., (© 2011 Bartsch et al; licensee BioMed Central Ltd.)

Background: There are only few studies on cancer patients who are treated in complementary and alternative medicine clinics and comparing them with patients in conventional care. We will present the comparison of characteristics of two patient cohorts: one was treated in a homeopathic cancer care clinic and one was treated in a conventional oncology care (CC) outpatient clinic., Patients and Methods: Six-hundred and forty-seven patients were included in this cross-sectional cohort study and had to fill in questionnaires [health-related quality of life (QoL) (Functional Assessment of Cancer Therapy-General Scale), depression and anxiety (Hospital Anxiety and Depression Scale), fatigue (Multidimensional Fatigue Inventory) and expectancies toward treatment]. Clinical data were extracted from medical records. This study presents the comparison of both cohorts., Results: Patients in the homeopathy cohort are younger, better educated and more often employed than patients in the CC cohort. The most pronounced differences indicate longer disease histories and different diagnostic and clinical pretreatment variables. Despite the clinical differences, QoL as well as anxiety, depression and fatigue was similar in both the groups., Conclusions: Homeopathic treatment is sought by cancer patients at a different phase during the course of the disease, which has particular implications for research. However, expectancies toward the benefit of the treatment as well as QoL data are similar.

Neuropsychological deficits are potential side effects of hematopoietic stem cell therapy (HSCT). Systematic data on the long-term course of and therapeutic options for these consequences are limited. One hundred fifty-seven patients were screened for cognitive deficits following HSCT for malignant diseases at an in-patient oncologic rehabilitation clinic. Patients showing evidence of impairment were randomly assigned to one of two training groups: individualized PC-supported training or neuropsychological group therapy. The control group consisted of patients who received no specific training. During in-patient rehabilitation, the results of a comprehensive neuropsychological test battery improved significantly in all three groups, and no specific intervention effects were identified. Neuropsychological deficits were still evident in a subgroup of patients 6 months later. Correlation between neuropsychological testing and patients' self-evaluation of cognitive functioning in daily life was generally low. Sustained attention and verbal-semantic memory played the main role for self-appraisal and in the designation as 'neuropsychologically impaired'. In conclusion, a substantial number of patients revealed evidence of cognitive deficits a long time after HSCT. There is a need for more studies and for the development of differentiated rehabilitative measures for such therapeutic consequences.

Persistent oxidative stress and excess lipid peroxidation (LPO), induced by inflammatory processes, impaired metal storage, and/or dietary imbalance, cause accumulations and massive DNA damage. This massive DNA damage, along with deregulation of cell homeostasis, leads to malignant diseases. Reactive aldehydes produced by LPO, such as 4-hydroxy-2-nonenal, malondialdehyde, acrolein, and crotonaldehyde, react directly with DNA bases or generate bifunctional intermediates which form exocyclic DNA adducts. Modification of DNA bases by these electrophiles, yielding promutagenic exocyclic adducts, is thought to contribute to the mutagenic and carcinogenic effects associated with oxidative stress-induced LPO. Ultrasensitive detection methods have facilitated studies of the concentrations of promutagenic DNA adducts in human tissues, white blood cells, and urine, where they are excreted as modified nucleosides and bases. Thus, immunoaffinity-(32)P-postlabeling, high-performance liquid chromatography-electrochemical detection, gas chromatography-mass spectrometry, liquid chromatography-tandem mass spectrometry, immunoslotblot assay, and immunohistochemistry have made it possible to detect background concentrations of adducts arising from endogenous LPO products in vivo and studies of their role in carcinogenesis. These background adduct levels in asymptomatic human tissues occur in the order of 1 adduct/10(8) and in organs affected by cancer-prone inflammatory diseases these can be 1 or 2 orders of magnitude higher. In this review, we critically discuss the accuracy of the available methods and their validation and summarize studies in which measurement of exocyclic adducts suggested new mechanisms of cancer causation, providing potential biomarkers for cancer risk assessment in humans with cancer-prone diseases.

In the present review, we give a short introduction into the history, philosophy and traditional diagnosis and therapy of Kampo, which has its origins in traditional Chinese medicine. The main focus is on pharmacogenomics of natural products derived from Kampo medicinal plants, with special emphasis on cancer treatment. One of these natural products with profound cytotoxicity against tumor cell lines is shikonin from the medicinal plant Lithospermum erythrorhizon. This compound has been selected to demonstrate how molecular determinants of response of tumor cells to Kampo-derived natural products can be investigated by microarray-based approaches. Synthetic or semi-synthetic derivatives of natural products from Kampo medicine may lead to novel drugs with improved features for cancer treatment. Kampo-derived natural products represent a valuable reservoir for individual tumour treatment strategies in the future.

Cells in the body are permanently attacked by DNA-reactive species, both from intracellular and environmental sources. Inherited and acquired deficiencies in host defense mechanisms against DNA damage (metabolic and DNA repair enzymes) can modify cancer susceptibility as well as therapy response. Genetic profiles should help to identify high-risk individuals who subsequently can be enrolled in preventive measures or treated by tailored therapy regimens. Some of our attempts to define such risk profiles are presented. Cancer susceptibility: Single nucleotide polymorphisms (SNPs) in metabolic and repair genes were investigated in a hospital-based lung cancer case-control study. When evaluating the risk associated with different genotypes for N-acetyltransferases (Wikman et al. 2001) and glutathione-S-transferases (Risch et al. 2001), it is mandatory to distinguish between the three major histological subtypes of lung tumors. A promoter polymorphism of the myeloperoxidase gene MPO was shown to decrease lung cancer susceptibility mainly in small cell lung cancer (SCLC) (Dally et al. 2002). The CYP3A4*1B allele was also linked to an increased SCLC risk and in smoking women increased the risk of lung cancer eightfold (Dally et al. 2003b). Polymorphisms in DNA repair genes were shown to modulate lung cancer risk in smokers, and reduced DNA repair capacity elevated the disease risk (Rajaee-Behbahani et al. 2001). Investigations of several DNA repair gene variants revealed that lung cancer risk was only moderately affected by a single variant but was enhanced up to approximately threefold by specific risk allele combinations (Popanda et al. 2004). Therapy response: Inter-individual differences in therapy response are consistently observed with cancer chemotherapeutic agents. Initial results from ongoing studies showed that certain polymorphisms in drug transporter genes (ABCB1) differentially affect response outcome in histological subgroups of lung cancer. Stronger beneficial effects were seen in non-small cell lung cancer (NSCLC) patients following gemcitabine and in SCLC patients following etoposide-based treatment. Several DNA repair parameters (polymorphisms, RNA expression, and DNA repair capacity) were measured in vitro in lymphocytes of patients before radiotherapy and correlated with the occurrence of acute side effects (radio-hypersensitivity). Our initial analysis of several repair gene variants in breast cancer patients (n = 446) who received radiotherapy revealed no association of single polymorphisms and the development of side effects (moist desquamation of the irradiated normal skin). The risk for this side effect was, however, strongly reduced in normal weight women carrying a combination of XRCC1 399Gln and APE1 148Glu alleles, indicating that these variants afford some protection against radio-hypersensitivity (Chang-Claude et al. 2005). Based on these data we conclude that specific metabolic and DNA repair gene variants can affect cancer risk and therapy outcome. Predisposition to hereditary cancer syndromes is dominated by the strong effects of some high-penetrance tumor susceptibility genes, while predisposition to sporadic cancer is influenced by the combination of multiple low-penetrance genes, of which as a major challenge, many disease-relevant combinations remain to be identified. Before translating these findings into clinical use and application for public health measures, large population-based studies and validation of the results will be required.

Background and Aims: Chronic inflammation, induced by biological, chemical, and physical factors, was associated with increased risk of human cancer at various sites. Chronic inflammatory processes induce oxidative/nitrosative stress and lipid peroxidation (LPO), thereby generating excess reactive oxygen species (ROS), reactive nitrogen species (RNS), and DNA-reactive aldehydes. Miscoding etheno- and propano-modified DNA bases are generated inter alia by reaction of DNA with these major LPO products. Steady-state levels of LPO-derived (etheno-) DNA adducts in organs affected by persistent inflammatory processes were investigated as potential lead markers for assessing progression of inflammatory cancer-prone diseases., Results: Using ultrasensitive and specific detection methods for the analysis of human tissues, cells, and urine, etheno-DNA adduct levels were found to be significantly elevated in the affected organs of subjects with chronic pancreatitis, ulcerative colitis, and Crohn's disease. Patients with alcohol-related liver diseases showed excess hepatic DNA damage progressively increasing from hepatitis, fatty liver, to liver cirrhosis. Ethenodeoxyadenosine excreted after DNA repair in urine of hepatitis B virus-related chronic hepatitis and liver cirrhosis patients was increased up to 90-fold. Putative mechanisms that may control DNA damage in inflamed tissues including impaired or imbalanced DNA repair pathways are reviewed., Conclusion: Persistent oxidative/nitrosative stress and excess LPO are induced by inflammatory processes in a self-perpetuating process and cause progressive accumulation of DNA damage in target organs. Together with deregulation of cell homeostasis, the resulting genetic changes act as driving force in chronic inflammation-associated human disease pathogenesis. Thus steady-state levels of DNA damage caused by ROS, RNS, and LPO end products provide promising molecular signatures for risk prediction and potential targets and biomarkers for preventive measures.

This review discusses the potential role of the anti-tumor activity of pineal melatonin for the aetiology and prevention of cancers related to life-styles in industrialized societies, e.g. frequent long-distance flights as well as chronic night shift work leading to circadian disturbances of neuroendocrine parameters including melatonin. Experimental studies show that melatonin controls not only the growth of well-differentiated cancers, but also possesses anti-carcinogenic properties. Therefore, it is plausible that disturbances of circadian melatonin rhythmicity could be functionally involved in elevated cancer risks among aircrew members and nurses frequently working on night shifts. Due to the suppression of melatonin by light it can be assumed that too much artificial light at night could, at least in part, be responsible for generally increasing rates of e.g. breast cancer in industrialized countries. It is discussed under which conditions a transient substitutional therapy with melatonin could be justified or which forms of living could help to physiologically foster melatonin secretion to optimise control over cancerous growth and development.

Chronic inflammatory processes produce an excess of ROS and DNA-reactive aldehydes from lipid peroxidation (LPO), such as trans-4-hydroxy-2-nonenal (HNE) and malondialdehyde (MDA), which can modify cellular macromolecules and drive to malignancy. Etheno-modified DNA bases are generated inter alia by reaction of DNA with the major LPO product, HNE. We are investigating steady-state levels of etheno-DNA adducts in organs with diseases related to persistent inflammatory processes that can lead to malignancies. We have developed ultrasensitive and specific methods for the detection of etheno-DNA base adducts in human tissues and in urine. Etheno-DNA adduct levels were found to be significantly elevated in the affected organs of subjects with chronic pancreatitis, ulcerative colitis and Crohn's disease. When patients with alcohol abuse-related hepatitis, fatty liver, fibrosis and cirrhosis were compared with asymptomatic livers, excess hepatic DNA damage was seen in the three latter patient groups. Etheno-deoxyadenosine excreted in urine was measured in HBV-infected patients diagnosed with chronic hepatitis, cirrhosis and hepatocellular carcinoma. As compared to controls, these patients had up to 90-fold increased urinary levels. Impaired or imbalanced DNA-repair pathways may influence the steady-state levels of etheno-DNA adducts in inflamed tissues. In conclusion, etheno-DNA adducts may serve as potential lead markers for assessing progression of inflammatory cancer-prone diseases. If so, the efficacy of human chemopreventive interventions for malignant disease prevention could be verified.

Epidemiologic studies conducted in the latter part of the twentieth century demonstrate fairly conclusively that the people of the Mediterranean basin enjoy a healthy lifestyle with decreased incidence of degenerative diseases. The data show that populations within Europe that consume the so-called 'Mediterranean diet' have lower incidences of major illnesses such as cancer and cardiovascular disease. Studies have suggested that the health-conferring benefits of the Mediterranean diet are due mainly to a high consumption of fibre, fish, fruits and vegetables. More recent research has focused on other important factors such as olives and olive oil. Obviously fibre (especially wholegrain-derived products), fruits and vegetables supply an important source of dietary antioxidants. What is the contribution from olives and olive oil? Apparently the potential is extremely high but epidemiologic studies rarely investigate consumption of these very important products in-depth, perhaps due to a lack of exact information on the types and amounts of antioxidants present. Recent studies have shown that olives and olive oil contain antioxidants in abundance. Olives (especially those that have not been subjected to the Spanish brining process) contain up to 16 g/kg typified by acteosides, hydroxytyrosol, tyrosol and phenyl propionic acids. Olive oil, especially extra virgin, contains smaller amounts of hydroxytyrosol and tyrosol, but also contains secoiridoids and lignans in abundance. Both olives and olive oil contain substantial amounts of other compounds deemed to be anticancer agents (e.g. squalene and terpenoids) as well as the peroxidation-resistant lipid oleic acid. It seems probable that olive and olive oil consumption in southern Europe represents an important contribution to the beneficial effects on health of the Mediterranean diet.

Although the neurotoxicity of many anticancer therapies is well documented, the impact of cancer treatment on cognitive functioning has been studied less frequently. The present study examines deficits in cognitive functioning and their correlation with medical data as well as with psychosocial variables. A standardised neuropsychological test battery and several questionnaires were administered to a random sample of 119 patients. 24% of our patients fulfilled our criterion for cognitive impairment. There were no significant associations between the results of the neuropsychological testing and the current affective status or self-reports of attentional deficits in daily life. Cognitive impairment occurs in a clinically relevant percentage of cancer patients and cannot be explained exclusively due to depression or anxiety. Since subjective and objective cognitive impairment data showed little correlation, neuropsychological evaluation should not only be based on subjectively-reported complaints, but also on objective measurements.

Unlabelled: During chronic inflammatory processes an excess of free radicals and DNA-reactive aldehydes from lipid peroxidation (LPO) are produced, which deregulate cellular homeostasis and can drive normal cells to malignancy. Etheno (epsilon)-modified DNA bases are generated by reactions of DNA with a major LPO product, trans-4-hydroxy-2-nonenal. We investigated steady state levels of epsilon-DNA adducts in organs, blood or urine from patients with cancer prone diseases, especially when related to persistent inflammatory processes. We have developed sensitive and specific methods for adduct detection in vivo. Hepatic etheno-adduct levels were significantly elevated in patients with Wilson's disease and primary hemochromatosis. Excess storage of copper/iron causing oxidative stress and LPO-derived DNA-damage, are implicated in disease pathogenesis as confirmed by studies in LEC-rats, a model for Wilson's disease. When patients with alcohol related hepatitis, fatty liver, fibrosis and cirrhosis were compared with asymptomatic livers, excess hepatic DNA-damage was seen in all patients, except those with hepatitis. Etheno-deoxyadenosine excreted in urine was measured in HBV-infected patients diagnosed with chronic hepatitis, cirrhosis and hepatocellular carcinoma: as compared to controls, patients had 20-90-fold increased urinary levels., In Conclusion: epsilon-DNA adducts may serve as potential markers for assessing progression of inflammatory cancer-prone diseases. Also the efficacy of human chemopreventive interventions could be verified by using our non-invasive urine assay. Mechanisms and host-factors that influence the steady-state levels of epsilon-DNA adducts in cancer prone tissues are under investigation.

Background: Fatigue is one of the most frequent symptoms in cancer patients. It is the aim of medical and psychosocial rehabilitation programs to reduce physical impairments and psychosocial distress. There are no reliable data on the prevalence or the pattern of fatigue in patients attending such rehabilitation programs. We therefore initiated a cross-sectional study to evaluate this phenomenon., Patients and Methods: Using the EORTC QLQ-C30, HADS and MFI questionnaires in 144 patients with different malignant diseases the incidence, patterns and necessity of treatment of fatigue were evaluated., Results: One third of the patients were diagnosed with breast cancer, 27% with gastrointestinal cancers and 20% suffered from haematologic/lymphatic diseases. There was a good correlation between fatigue levels in the 3 instruments used. 22% of all patients showed significant symptoms of fatigue. The univariate analysis did not reflect any significant differences in severity of fatigue with respect to diagnosis, haemoglobin levels, medical and therapeutic history or sociodemographic data. However, using cluster analysis we could identify 3 groups of patients that differ significantly in fatigue and quality-of-life measurements., Conclusion: We conclude from our data that fatigue is an important phenomenon in cancer patients who attend medical and psychosocial rehabilitation programs. This has an impact on the ability and degree to reintegrate these patients into everyday life., (Copyright 2003 S. Karger GmbH, Freiburg)

The aim of this study was to evaluate the fatty acids, tocopherols, squalene, sterols and phenolic antioxidants in three types of argan oil (Moroccan food, Moroccan aesthetic and a French commercial variety) along with a basic comparison with extra virgin olive and sunflower oil. The fatty acid profiles in the argan oils were very similar, with oleic acid (43%) and linoleic acid (36%) and their respective monoacylglycerols predominating. The major vitamer identified was -tocopherol with a mean of 483+/-11 mg/kg, in contrast to -tocopherol, which is the major vitamer in olive (190+/-1 mg/kg) and sunflower oil (532+/-6 mg/kg). The squalene content of the argan oils was very similar with a mean of 313+/-4 mg/100 g, which is lower than that of the olive oil (499 mg/100 g) but significantly higher than in the sunflower oil (6 mg/100 g). In contrast to olive and sunflower oils in which -sitosterol is predominant, the major sterols detected in the argan oils were schottenol (mean 147+/-10 mg/kg) and spinasterol (mean 122+/-10 mg/kg). The only phenolic compounds other than the tocopherol vitamers which could be readily detected and quantitated were vanillic, syringic and ferulic (probably conjugated to glucose) acids along with tyrosol. In contrast to the extra virgin olive oil (793 mg/kg), the concentration of total phenolic compounds is extremely low (<5.0 mg/kg). Nevertheless, argan oil with its high content of the vitamer -tocopherol, squalene and oleic acid is likely to enhance the cancer prevention effects of the Moroccan diet.

Characterization and use of effective cancer chemopreventive agents have become important issues in public health-related research. Aiming to identify novel potential chemopreventive agents, we have established an interrelated series of bioassay systems targeting molecular mechanisms relevant for the prevention of tumor development. We report anticarcinogenic properties of Xanthohumol (XN), a prenylated chalcone from hop (Humulus Iupulus L.) with an exceptional broad spectrum of inhibitory mechanisms at the initiation, promotion, and progression stage of carcinogenesis. Consistent with anti-initiating potential, XN potently modulates the activity of enzymes involved in carcinogen metabolism and detoxification. Moreover, XN is able to scavenge reactive oxygen species, including hydroxyl- and peroxyl radicals, and to inhibit superoxide anion radical and nitric oxide production. As potential antitumor-promoting mechanisms, it demonstrates anti-inflammatory properties by inhibition of cyclooxygenase-1 and cyclooxygenase-2 activity and is antiestrogenic without possessing intrinsic estrogenic potential. Antiproliferative mechanisms of XN to prevent carcinogenesis in the progression phase include inhibition of DNA synthesis and induction of cell cycle arrest in S phase, apoptosis, and cell differentiation. Importantly, XN at nanomolar concentrations prevents carcinogen-induced preneoplastic lesions in mouse mammary gland organ culture. Because XN is easily cyclized to the flavanone isoxanthohumol, activities of both compounds were compared throughout the study. Together, our data provide evidence for the potential application of XN as a novel, readily available chemopreventive agent, and clinical investigations are warranted once efficacy and safety in animal models have been established.

The aim of this article is provide a survey of the current knowledge relating to the analysis of melatonin and its administration to cancer patients. On the basis of this compilation of data it can be discussed under which conditions melatonin may be used for diagnostic and/or therapeutic purposes in clinical oncology. Melatonin is depressed in patients with cancers of different origins during the phase of primary tumour growth whereas a normal or sometimes elevated pineal melatonin secretory activity is found during early stages of tumour development or when recidivations arise. The clinical studies of Lissoni show that melatonin, particularly if combined with interleukin-2, is able to favourably influence the course of advanced malignant disease leading to a prolonged survival as well as to an improved quality of life. These findings require to be verified by independent and controlled replication studies. If they can be confirmed it should be attempted to administer melatonin to patients with earlier stages of cancer parallel to standard oncological treatment regimens. In such trials it should be tested whether a substitutional therapy in patients with endogenously depressed melatonin may favourably affect the course of the disease both in quantitative (inhibitory effect on tumour growth and spread) and qualitative terms (improved performance status).

Different processing of the leaves of the tea plant Camellia sinensis yields green or black tea, the subject of numerous investigations on the preventive effects on chronic degenerative diseases. The tea polyphenols, in particular (-)-epigallocatechin gallate (EGCG) were found to account for most of the protective effects. Since the concentration of EGCG is 5 times higher in green than in black tea, it is assumed that green tea possesses a greater preventive potential. Protection against cancer and cardiovascular diseases are the most important biomedical effects. In experimental models the preventive activity of tea is well documented for tumors at many organ sites. In humans, tea was reported to be protective against tumors of the lung, the gastrointestinal tract and the liver. Tea polyphenols, especially EGCG, were shown to exert cancer-protective activity by the following mechanisms: they inhibit the metabolic activation of carcinogens and induce at the same time detoxifying enzymes. They inhibit signaling pathways controlling cell proliferation and tumor growth such as protein kinase C and the release of tumor necrose factor-alpha from cells. Tea polyphenols reactivate processes which are impaired in tumor cells, such as the programmed cell death and the tumorsuppressor gene p53. Finally, tea polyphenols can also block angiogenesis leading to a starvation of the tumor. By inactivation of proteolytic enzymes they inhibit the development of metastases. This short review summarizes relevant recent findings on the protective effects of green tea constituents.

Medical and psychosocial rehabilitation of cancer patients is deeply integrated into the German health system. In contrast to the majority of other European countries and the United States of America, rehabilitation is mainly done as inpatient care and only rarely in outpatient units. In curative treated cancer patients the main goals of rehabilitation include recovery from physical impairments, adaptation to functional disabilities and improvement of psychosocial functioning, including the ability to go back to work. In palliative cancer patients the improvement of health adjusted quality of life, the avoidance of permanent supportive care and the social integration are the major goals. Cancer rehabilitation needs an interdisciplinary strategy between medical, psychooncologic, physiotherapeutical and educational professionals. To attain a benefit for the individual cancer patient as well as for the medical system it is important to clearly define the rehabilitation needs and design a most individual rehabilitation program adjusted to the personal needs of the patient. A systematic quality management since 1995 of German rehabilitation clinics and rehabilitation programs did significantly improve this part of the professional health system. However it is necessary to add more outpatient units for cancer rehabilitation to reach more flexibility and satisfy the demand of patients for more home located support.

The article is concerned with the basic ideas of outcome quality within the field of oncological rehabilitation and expresses the position which is held by the Section for Rehabilitation, Aftercare and Social Medicine within the German Cancer Society. The authors explicitly express the necessity of rehabilitation-specific goals and corresponding outcome criteria as opposed to the goals and criteria of acute oncological treatment. In the formulation of goals and criteria, the medical-somatic, occupational-rehabilitative, social and psychological levels are considered. The consequences which arise from these outcome criteria with regard to the rehabilitative health care system for cancer patients are discussed.

The article concerns itself with the issue of process quality in inpatient institutions for oncological rehabilitation and expresses the viewpoint of the German Cancer Society's Section for Rehabilitation, Aftercare and Social Medicine (ARNS). Standards for the organization of patients' access to the rehabilitation clinic, for the design of oncological-rehabilitational diagnostics, for the formation of therapeutic strategies and the rehabilitative services offered will be described.

The article discusses the structural requirements on inpatient institutions for oncological rehabilitation and expresses the position of the German Cancer Society's Section for Rehabilitation, Aftercare and Social Medicine (ARNS). Standards are formulated concerning spatial conditions, technical equipment, personnel (number, professions, qualification) and networking conditions with regard to all cancer diagnoses. These standards are also discussed with regard to various specific cancer diagnoses such as, for example, breast cancer, gastrointestinal tumours, lung tumours and brain tumours, as well as with regard to patients in specific treatment measures such as bone marrow and stem cell transplantation.

Etheno (epsilon) modified DNA bases (epsilond A, epsilond C, epsilond G) are generated from the carcinogens vinyl chloride and urethane, but also by reactions of DNA with products derived from lipid peroxidation (LPO) and oxidative stress via endogenous pathways. Recently developed ultrasensitive methods allowed the detection of these epsilon-adducts in vivo and their role to be studied in experimental and human carcinogenesis. Highly variable background levels of epsilon-adducts were detected in DNA from different organs of unexposed humans and rodents. Several known cancer risk factors increased the level of these DNA lesions in target organs: elevated epsilon-adducts were found in hepatic DNA from patients with metal storage diseases, after overproduction of nitric oxide (NO) by inducible NO synthase (iNOS) in a mouse model, and in colonic polyps of familial adenomatous polyposis patients. A high omega-6-polyunsaturated fatty acid diet increased epsilon-DNA adducts in white blood cells of female subjects. In conclusion, epsilon-adducts were found to be elevated in cancer-prone tissues, suggesting that these promutagenic lesions could drive cells to malignancy. Therefore, exocyclic DNA adducts offer new tools in cancer aetiological research and in verifying the efficacy of chemopreventive agents.

Sensitive, specific methods have been developed that allow quantitative measurements of the metabolites of carcinogen metabolites and of DNA and protein adducts in humans exposed occupationally, environmentally and endogenously to genotoxic agents. The interrelationship between exposure to carcinogens, host risk factors and the responses of biomarkers has been examined in cross-sectional, ecological and case-control studies which provided new insights into the causes of cancer and the mechanisms of carcinogenesis. The identification of hitherto unknown DNA-reactive chemicals formed in the human body from dietary precursors and of carcinogenic components of complex mixtures has increased the possibility of establishing causal relationships in etiology. The identification of individuals and subgroups heavily exposed to carcinogens has led to the development of measures for avoiding or decreasing exposure to carcinogenic risk factors. New, ultrasensitive methods for measuring DNA adducts allow the quantification and structural elucidation of specific DNA damage in humans arising from oxidative stress and lipid peroxidation (LPO), which have been found to be the driving forces in several human malignancies. Background DNA damage in "unexposed" individuals has been shown unequivocally to be due to LPO products, and a significant interindividual variation in adduct levels has been shown in individuals with comparable exposure to carcinogens. Thus, pharmacogenetic variants with higher susceptibility to carcinogenic insults, due to genetic polymorphism in xenobiotic-metabolizing enzymes, have been characterized by a combination of genotyping and measurements of macromolecular adducts. Dosimetry has been used in human studies to evaluate the efficacy of interventions with chemopreventive agents like ascorbic acid, dietary phenols and green tea. Advances in the application of selected biomarkers in human studies are reviewed and illustrated by examples from the author's research conducted during the past two decades.

Tobacco use is causally associated with cancers of the lung, larynx, mouth, esophagus, kidneys, urinary tract, and possibly, breast. Major classes of carcinogens present in tobacco and tobacco smoke are converted into DNA-reactive metabolites by cytochrome P450 (CYP)-related enzymes, several of which display genetic polymorphism. Individual susceptibility to cancer is likely to be modified by the genotype for enzymes involved in the activation or detoxification of carcinogens in tobacco and repair of DNA damage. We summarize here the results of case-control studies published since 1990 on the effects of genetic variants of CYP1A1, 1A2, 1B1, 2A6, 2D6, 2E1, 2C9, 2C19, 17, and 19 alone or in combination with detoxifying enzymes as modifiers of the risk for tobacco-related cancers. The results of studies on gene-gene interactions and the dependence of smoking-related DNA adducts on genotype were also analyzed. Some CYP variants were associated with increased risks for cancers of the lung, esophagus, and head and neck. The risk was often increased in individuals who also had GSTM1 deficiency. For breast cancer in women, a few studies suggested an association with CYPs related to metabolism of tobacco carcinogens and steroidal hormones. The overall effects of common CYP polymorphisms were found to be moderate in terms of penetrance and relative risk, with odds ratios ranging from 2 to 10. Some CYP1A1/GSTM1 0/0 genotype combinations seem to predispose the lung, esophagus, and oral cavity of smokers to an even higher risk for cancer or DNA damage, requiring, however, confirmation. Future strategies in molecular cancer epidemiology for identifying such susceptible individuals are discussed with emphasis on well-designed larger studies.

The first p53 gene mutation arising in a human tumor was described a decade ago by Baker et al. [S.J. Baker, E.R. Fearon, J.M. Nigro, S.R. Hamilton, A.C. Preisinger, J.M. Jessup, P. van Tuinen, D.H. Ledbetter, D.F. Barker, Y. Nakamura, R. White, B. Vogelstein, Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas, Science 244 (1989) 217-221]. There are now over 10,000 mutations extracted from the published literature in the IARC database of human p53 tumor mutations [P. Hainaut, T. Hernandez, A. Robinson, P. Rodriguez-Tome, T. Flores, M. Hollstein, C.C. Harris, R. Montesano, IARC database of p53 gene mutations in human tumors and cell lines: updated compilation, revised formats and new visualization tools, Nucleic Acids Res. 26 (1998) 205-213; Version R3, January 1999]. A large and diverse collection of tumor mutations in cancer patients provides important information on the nature of environmental factors or biological processes that are important causes of human gene mutation, since xenobiotic mutagens as well as endogenous mechanisms of genetic change produce characteristic types of patterns in target DNA [J.H. Miller, Mutational specificity in bacteria, Annu. Rev. Genet. 17 (1983) 215-238; T. Lindahl, Instability and decay of the primary structure of DNA, Nature 362 (1993) 709-715; S.P. Hussain, C.C. Harris, Molecular epidemiology of human cancer: contribution of mutation spectra studies of tumor suppressor genes, Cancer Res. 58 (1998) 4023-4037; P. Hainaut, M. Hollstein, p53 and human cancer: the first ten thousand mutations, Adv. Cancer Res. 2000]. P53 gene mutations in cancers can be compared to point mutation spectra at the HPRT locus of human lymphocytes from patients or healthy individuals with known exposure histories, and accumulated data indicate that mutation patterns at the two loci share certain general features. Hypotheses regarding specific cancer risk factors can be tested by comparing p53 tumor mutations typical of a defined patient group against mutations generated experimentally in rodents or in prokaryotic and eukaryotic cells in vitro. Refinements of this approach to hypothesis testing are being explored that employ human p53 sequences introduced artificially into experimental organisms used in laboratory mutagenesis assays. P53-specific laboratory models, combined with DNA microchips designed for high through-put mutation screening promise to unmask information currently hidden in the compilation of human tumor p53 mutations.

A review of findings is given which relate to the levels of circulating melatonin as well as the urinary excretion of its main peripheral metabolite 6-sulphatoxymelatonin (aMT6s) in patients with different types of cancer as well as in tumor-bearing animals. Clinical results show that circulating melatonin tends to be depressed in patients with primary tumors of different histological types including both endocrine-dependent (mammary, endometrial, prostate cancer) and endocrine-independent tumors (lung, gastric, colorectal cancer). Reduction of melatonin is most pronounced in patients with advanced localized primary tumors, such as mammary and prostate cancer where a clear negative correlation with tumor-size exists. The phenomenon of a reduction of circulating melatonin appears to be a transient one since patients with recidives show a normalization of melatonin. Surgical removal of the primary tumor does, however, not lead to normalization indicating that complex systemic changes appear to be involved in the down-regulation of melatonin. It is unclear at present, whether circulating melatonin is depleted in cancer patients due to a reduced production by the pineal gland or due to certain peripheral metabolic processes, although no evidence for an enhanced hepatic degradation to aMT6s, the main peripheral metabolite of melatonin, was found. The reduction of circulating melatonin is accompanied by neuroendocrine changes affecting the circadian secretion of the adenohypophyseal hormones prolactin, somatotropin and thyroid-stimulating hormone. In contrast to the above-described types of tumors many patients with ovarian cancer show highly elevated levels of melatonin perhaps due to the production of tissue-specific growth factors that could affect pineal melatonin secretion. Experiments with tumor-bearing animals clearly demonstrate that nocturnal circulating melatonin is modulated due to malignant growth. Detailed investigations with chemically induced mammary tumors in rats and serial transplants derived thereof show that slow-growing and well-differentiated tumors containing epithelial cell elements (adenocarcinomas and carcinosarcomas) lead to an enhanced production of melatonin involving activation of the rate-limiting enzyme of pineal melatonin biosynthesis (serotonin N-acetyltransferase) probably due to elevation of the sympathetic tone in response to a stimulation of the cellular immune system by malignant growth. As opposed to that nocturnal melatonin is depleted in animals with fast-growing mammary tumor transplants when myoepithelial-mesenchymal conversion leads to pure sarcomas. The reduction of melatonin appears to be due to either a reduced availability of the precursor amino acid tryptophan because of a glucocorticoid-induced activation of the hepatic enzyme tryptophan 2,3-dioxygenase or a direct peripheral degradation of melatonin via indoleamine 2,3-dioxygenase expressed in tumor and/or other tissues. The significance of these clinical and experimental findings relating to melatonin is discussed both in terms of their practical application as a possible tumor marker and from a theoretical point of view to understand better the mechanisms involved in complex host-tumor interactions involving the neuroimmunoendocrine network.

The methodology applied for DNA adducts in humans has become more reliable in recent years, allowing to detect even background carcinogenic adduct levels in environmentally exposed persons. Particularly, combinations of the various methods now allow the elucidation of specific adduct structures with detection limits of 1 adduct in 108 unmodified nucleotides or even lower. The quantification of polycyclic aromatic hydrocarbon-DNA (PAH-DNA) adducts in human tissues and cells has been achieved with a number of highly sensitive techniques: immunoassays and immunocytochemistry using polyclonal or monoclonal antisera specific for DNA adducts or modified DNA, the assay, and adduct identification using physicochemical instrumentation. The results summarized in this review show that PAH-DNA adducts have been detected in a variety of human tissues, including target organs of PAH- and tobacco-associated cancers. Although dosimetry has not always been precise, a large number of data now clearly show that lowering exposure to carcinogenic PAH results in decreasing PAH-DNA adduct levels. In most studies, however, bulk DNA of a certain tissue or cell type has been examined, and there were relatively few studies in which mutations as a consequence of DNA damage at specific genes have been investigated. Promising as these biomarker studies seem for epidemiology and health surveillance, future biomonitoring and molecular epidemiological studies should be directed to combine several endpoint measurements: i.e., adduct formation (preferably at specific sites), mutational spectra in cancer-relevant genes, and genetic markers of (cancer) susceptibility in a number of cancer-predisposing genes., (Copyright 1998 Elsevier Science B.V. All rights reserved.)

The review summarizes experimental and preliminary clinical findings relating to the application of melatonin in malignancy to allow a differential discussion concerning its potential therapeutic use in cancer patients. In vivo experiments show that melatonin inhibits chemically induced, as well as spontaneous rodent tumors, but is mostly ineffective in controlling the growth of undifferentiated transplantable tumors. Some human and murine in vitro cancer cell lines are inhibited by physiological concentrations of melatonin, but the majority of the tested cell lines is resistant to melatonin or can be inhibited at pharmacological doses only. In individual cases melatonin was reported to stimulate cell growth. The molecular mechanisms of how melatonin affects the proliferation of cancer cells under in vivo and in vitro conditions are mostly unknown and their elucidation will require further basic research to determine the therapeutic potential of melatonin. From a theoretical point of view substitution therapy with melatonin might be worthwhile since a progressive decline of pineal melatonin secretion is observed parallel to the growth of the primary tumor in breast and prostate cancer. The mechanisms involved in this depression are at present poorly understood but do not appear to be identical among species so that similar results in animal experiments are of limited applicability to humans. First clinical experience with melatonin in the treatment of cancer patients has been confined to adjuvant therapies at advanced and terminal stages of malignancy and have yielded certain encouraging results. It is imperative to verify these preliminary data applying double-blind protocols and future therapeutic trials of melatonin in patients with early-stage malignant disease should be contemplated. Evidence exists that the role of the pineal gland in malignancy may not be confined to melatonin since potent antineoplastic fractions of yet unknown chemical structure have been detected which are capable of inhibiting in vitro cell lines resistant to melatonin.

Lipid peroxidation generates reactive aldehydes such as trans-4-hydroxy-2-nonenal and malonaldehyde, which form promutagenic exocyclic DNA adducts in human cells and may contribute to diet-related cancers. Using ultrasensitive detection methods, analysis of WBC DNA from volunteers in a dietary study revealed that high intake of omega-6 polyunsaturated fatty acids increased malonaldehyde-derived adducts in male and female subjects. In contrast, etheno adducts (1,N6-ethenodeoxyadenosine; 3,N4-ethenodeoxycytidine) were not elevated in males but were, on average, 40 times higher in females, displaying a huge intersubject variation in lipid peroxidation-derived DNA damage. Exocyclic DNA adducts are promising biomarkers for examining the hypothesis of possible links between increased intake of dietary omega-6 polyunsaturated fatty acids, DNA damage, and elevated cancer risk for breast, colon, and prostate.

Sensitive methods for quantifying DNA adducts from (i) benzo[a]pyrene (BP), (ii) alkylation exposure, and (iii) etheno(epsilon)-DNA adduct-forming chemicals were developed and applied to humans and animal models. The aims were to identify hitherto unknown sources and mechanisms of exogenous and endogenous DNA damage, to examine the effect of drug polymorphism on BP adduct levels, and to develop QSAR between tumorigenic potency, heritable genetic damage and structural elements of alkylating carcinogens (Vogel and Nivard (1994) Mutation Res., 395, 13-32). (i) BP-DNA adducts: An HPLC/fluorimetry assay suitable for measuring (+)-anti-BP-diol-epoxide (BPDE) adducts in human tissues and white blood cells (WBC) was developed (Alexandrov et al. (1992) Cancer Res., 52, 6248-6253). In smokers, a positive correlation was found between pulmonary CYP1A1-related catalytic activity (AHH) and the level of lung BPDE-DNA adducts. In coke oven workers, an enhancing effect of smoking on BPDE-adduct levels in WBC was demonstrated (Rojas et al. (1995) Carcinogenesis, 16, 1373-1376). (ii) 3-Alkyladenines (3-alkAde): Alkylating carcinogens form 3-alkAde adducts in DNA which depurinate to yield 3-alkAde in urine, for which a detection method was developed (Friesen et al. (1991) Chem. Res. Toxicol., 4, 102-106; Prevost et al. (1990) Carcinogenesis, 11, 1747-1751), using immunoaffinity purification and GC-MS analysis. The usefulness of 3-alkAde analysis for the determination of the whole-body dose of alkylating agents derived from exogenous and endogenous sources was demonstrated. (iii) Etheno-DNA adduct-forming agents: Etheno(epsilon)-DNA base adducts (epsilon A, epsilon dC, epsilon dG) are promutagenic DNA lesions that are formed by occupational (vinyl halides) and environmental (urethane) carcinogens. An ultrasensitive detection method was developed (Nair et al. (1995) Carcinogenesis, 16, 613-617), based on immunoaffinity purification and 32P-postlabelling of epsilon-nucleoside 3'-monophosphates. Liver DNA from unexposed rats, mice and from human samples contained background levels of epsilon dA and epsilon dC (Bartsch et al. (1994) Drug. Metab. Rev., 26, 349-371). As formation of epsilon dA and epsilon dC adducts by lipid peroxidation products was demonstrated (El Ghissassi et al. (1995) Chem. Res. Toxicol., 8, 278-283), they may serve as markers for oxidative stress. Results from testing this hypothesis are presented.

Individual susceptibility to cancer may result from host factors including differences n metabolism, DNA repair, altered expression of protooncogenes and tumor suppressor genes, and nutritional status. Since most carcinogens require metabolic activation before binding to DNA, variations in an individual's metabolic phenotype that have detected in enzymes involved in activation and detoxification should play an essential role in the development of environmental cancer. This phenotypic metabolic variation has now been related to genetic polymorphisms, and many genes encoding carcinogen-metabolizing enzymes have been identified and cloned. Consequently, allelic variants or genetic defects that give rise to the observed variation and new polymorphisms have been recognized. Development of simple polymerase chain reaction (PCR)-based assays has enabled identification of an individual's genotype for a variety of metabolic polymorphisms. Thus, recent knowledge of the genetic basis for individual metabolic variation has opened new possibilities of studies focusing on increased individual susceptibility to environmentally induced cancer, which are reviewed with special reference to smoking-induced lung cancer. Cancer susceptibility due to chemical exposure is likely to be determined by an individual's phenotype for a number of enzymes (both activating and detoxifying) relevant to that of a single carcinogen or mixtures of carcinogens. Given the number and variability in expression of carcinogen-metabolizing enzymes and the complexity of chemical exposures, assessment of a single polymorphic enzyme (genotype) may not be sufficient. Mutations in the p53 gene are among the most common genetic changes in human cancer. The frequency and type p53 mutations can act as a fingerprint of carcinogen exposure and may therefore provide information about external etiological agents, intensity of exposure, and host factors affecting the tumorigenesis process. In human lung cancer, p53 mutations (both the mutation pattern and frequency) have been linked with tobacco smoking; the type of mutation most frequently observed is G:C to T:A transversion, a mutation preferentially induced by benzo[a]pyrene diol epoxide. An association between the presence of this transversion and the genotype deficient in glutathione S-transferase M1-mediated detoxification has been observed in lung cancer. Taken together, these findings suggest that determination of metabolic at risk genotypes in combination with levels of DNA adducts in target (surrogate) tissues and the p53 mutation pattern should allow the identification of susceptible individuals and subgroups in carcinogen-exposed populations.

The protective function of the pineal hormone melatonin in the etiology of cancer and carcinogenic activation is increasingly well-established. Low melatonin levels seem to parallel cancer growth. The question arises as to which factors cause the depression of melatonin levels and what the direct effects are. Melatonin is known to be metabolized in the liver by hydroxylation and subsequent conjugation yielding 6-sulfatoxymelatonin as a main product. Nevertheless, the microsomal monoxygenases catalyzing the first step have been poorly investigated. To further characterize these enzymes, typical inducers of three different sub-classes, namely phenobarbital, 7,12-dimethylbenz[a]anthracene, and 17 beta-estradiol, were administered to female Fischer rats. Circadian urinary excretion patterns of melatonin and 6-sulfatoxymelatonin were determined over a 24-hour period on the third (second) day of induction. Liver homogenates were used to monitor the in vitro conversion of melatonin or 6-hydroxymelatonin to 6-sulfatoxymelatonin. Results of both approaches showed the microsomal monoxygenases catalyzing the 6-hydroxylation of melatonin to be strongly inducible by phenobarbital and to a lesser degree by the polyaromatic hydrocarbon 7,12-dimethylbenz[a]anthracene. The dramatic depletion of circulating melatonin as a result of these induction patterns and its possible implications for oncogenesis are discussed.

Infection by bacteria, parasites or viruses and tissue inflammation such as gastritis, hepatitis and colitis are recognized risk factors for human cancers at various sites. Nitric oxide (NO) and other oxygen radicals produced in infected and inflamed tissues could contribute to the process of carcinogenesis by different mechanisms, which are discussed on the basis of authors' studies on liver fluke infection and cholangiocarcinoma development. A similar mechanism could apply to other suspected and known cancer-causing agents including Helicobacter pylori infection (stomach cancer) or asbestos exposure (lung mesothelioma). Studies on the type of tissue and DNA damage produced by NO and by other reactive oxygen species are shedding new light on the molecular mechanisms by which chronic inflammatory processes may initiate or enhance carcinogenesis in humans.