[Clinical and epidemiological cancer registration in Germany]. / Klinisch-epidemiologische Krebsregistrierung in Deutschland.

OBJECTIVE: Function and funding of detailed clinical cancer registries (CCRs) is defined by German Social Code Book V (SGB V) and shall be implemented by the end of 2017. CONTENT: Cancer registration according to regionally defined catchment areas, feedback of results and quality assurance are the basis which determines principles of operation and use of data. Each clinical department delivers only its own findings and therapy, while compilation by the clinical cancer registry describes the patients' way through the regional network of medical care. In this way, oncological centers are not burdened by troublesome documentation of data which originate from other clinics. CONCLUSION: After successful implementation of CCRs, interested physicians and clinics are able to spend time for analysis and use of meaningful data with the objective of improving quality of care within the region, implementing innovative therapies and presenting their results, and generating new hypotheses to stimulate research.

Effect of ranolazine on glycaemic control in patients with type 2 diabetes treated with either glimepiride or metformin.

AIM: To report the results of two phase III trials assessing the efficacy of ranolazine for glycaemic control in patients with type 2 diabetes on metformin or glimepiride background therapy. METHODS: In two double-blind trials we randomized 431 and 442 patients with type 2 diabetes to ranolazine 1000 mg twice daily versus placebo added to either glimepiride (glimepiride add-on study) or metformin background therapy (metformin add-on study). Patients receiving ranolazine added to metformin had their metformin dose halved (with the addition of a metformin-matched placebo) relative to the placebo group to correct for a metformin-ranolazine pharmacokinetic interaction. The primary endpoint of the trials was the change from baseline in glycated haemoglobin (HbA1c) at week 24. RESULTS: When added to glimepiride, ranolazine caused a 0.51% least squares mean [95% confidence interval (CI) 0.71, 0.32] decrease from baseline in HbA1c at 24 weeks relative to placebo and roughly doubled the proportion of patients achieving an HbA1c of <7% (27.1 vs 14.1%; p = 0.001). When added to metformin background therapy, there was no significant difference in the 24-week HbA1c change from baseline [placebo-corrected LS mean difference -0.11% (95% CI -0.31, 0.1)]. CONCLUSIONS: Compared with placebo, addition of ranolazine in patients with type 2 diabetes treated with glimepiride, but not metformin, significantly reduced HbA1c over 24 weeks. The decreased dose of metformin used in the metformin add-on study complicates the interpretation of this trial. Whether an effective regimen of ranolazine added to metformin for glycaemic control can be identified remains unclear.

Dietary triglycerides act on mesolimbic structures to regulate the rewarding and motivational aspects of feeding.

Circulating triglycerides (TGs) normally increase after a meal but are altered in pathophysiological conditions, such as obesity. Although TG metabolism in the brain remains poorly understood, several brain structures express enzymes that process TG-enriched particles, including mesolimbic structures. For this reason, and because consumption of high-fat diet alters dopamine signaling, we tested the hypothesis that TG might directly target mesolimbic reward circuits to control reward-seeking behaviors. We found that the delivery of small amounts of TG to the brain through the carotid artery rapidly reduced both spontaneous and amphetamine-induced locomotion, abolished preference for palatable food and reduced the motivation to engage in food-seeking behavior. Conversely, targeted disruption of the TG-hydrolyzing enzyme lipoprotein lipase specifically in the nucleus accumbens increased palatable food preference and food-seeking behavior. Finally, prolonged TG perfusion resulted in a return to normal palatable food preference despite continued locomotor suppression, suggesting that adaptive mechanisms occur. These findings reveal new mechanisms by which dietary fat may alter mesolimbic circuit function and reward seeking.

Obesity development in caspase-1-deficient mice.

Caspase-1 is a member of the intracellular cysteine protease family that mediates inflammation through the activation of the cytokines interleukin-1ß (IL-1ß) and interleukin-18 (IL-18). As mice lacking IL-18 become obese and insulin resistant, and both IL-18 and IL-1ß have a role in overall energy balance, we sought to determine whether caspase-1 deficiency also causes obesity. Male and female caspase-1-deficient (caspase-1-/-) and control (wild-type (WT)) mice were fed either a high-fat (HF, 45% of kcal) or a low-fat (LF, 10% of kcal) synthetic diet starting at 6 weeks of age. Caspase-1-/- mice maintained lower but detectable levels of IL-18 compared with WT mice. Plasma IL-1ß levels were below the detection limit for both KO and WT mice. Male caspase-1-/- mice gained extra fat mass by 16 weeks on the HF diet, but not until 40 weeks on the LF diet. Female capase-1-/- mice gained more fat by 28 weeks but only on the HF diet. These data indicate that caspase-1-/- mice develop obesity with an age and sex-dependent differences, and only male mice display obesity on LF diet. Overall, this study suggests that the lower level of IL-18 in caspase-1-/- mice might be causing obesity development similarly to IL-18-deficient mice.

Adults with type 1 diabetes eat a high-fat atherogenic diet that is associated with coronary artery calcium.

AIMS/HYPOTHESIS: Coronary heart disease is the leading cause of mortality among people with type 1 diabetes. Diet is an important lifestyle factor that relates to risk of CHD. The aim of this study was to examine how diet and adherence to dietary guidelines differ between adults with and without type 1 diabetes, and their correlation with CHD risk factors and coronary artery calcium (CAC). METHODS: The study involved 571 people with type 1 diabetes and 696 controls, aged 19 to 56 years, who were asymptomatic for CHD. CAC was measured by electron-beam computed tomography. RESULTS: Compared with the controls, adults with type 1 diabetes reported a diet higher in fat, saturated fat and protein but lower in carbohydrates. Fewer than half of those with type 1 diabetes met dietary guidelines for fat and carbohydrate intake, and only 16% restricted saturated fat to less than 10% of daily energy intake. Adults with type 1 diabetes were significantly less likely to meet dietary guidelines than controls. Fat and saturated fat intakes were positively correlated, but carbohydrate intake was negatively correlated with CHD risk factors and HbA(1c). A high-fat diet and higher intake of protein were associated with greater odds of CAC, while higher carbohydrate intake was associated with reduced odds of CAC. CONCLUSIONS/INTERPRETATION: Adults with type 1 diabetes reported consuming higher than recommended levels of fat and saturated fat. High fat intake was associated with increased CHD risk factors, worse glycaemic control and CAC. An atherogenic diet may contribute to the risk of CHD in adults with type 1 diabetes.

[Colorectal cancer metastasis. Frequency, prognosis, and consequences]. / Metastasierung beim kolorektalen Karzinom. Häufigkeiten, Prognose und Folgerungen.

BACKGROUND: In about 50% of colorectal cancer cases, metastases are responsible for tumour-specific death. This study examines influences on survival after diagnosis of metastases and conclusions that can be drawn from the time pattern of a progressive disease course. METHODS: The background was provided by Munich Cancer Registry database (Germany). Population-based, good follow-up, high quality of clinical data, and results comparable to those of other cancer registries stand for validity of these data. RESULTS: Number of positive lymph nodes is the best prognostic factor. However, since metastasis may be initiated before diagnosis of the primary tumour, growth of the primary tumour and the metastases may be two autonomous processes. Thus survival following metastasis is almost unrelated to prognostic factors from the primary tumour, and median survival time after diagnosis of metastases is therefore almost comparable with 17 months. From the distribution of survival time after diagnosis of the primary tumour, the time from initiation of metastases to their diagnosis can be estimated at about 6 years. This means that metastases diagnosed synchronously with the primary tumour (M1) were initiated 6 years before detection of the primary tumour and also that metastases diagnosed during follow-up had already started before therapy of the primary tumour. In consequence, positive lymph nodes are an indicator but not a cause of metastases. CONCLUSIONS: Specific time relations support the hypothesis that all metastases were initiated before diagnosis of the primary tumour. This hypothetic model has a high explanatory potential, also for evidence of the missing survival benefit from radical lymph node dissection.

Obesity research in the next decade.

The obesity epidemic demands more insight into genetic predisposition, mechanisms, prevention and therapeutic interventions. Opinions about how to prioritize obesity research in the next decade are many and highly varied. However, in this article I have chosen three areas of focus that arguably should be at the top of the list. These include: (1) the physiologic basis of body weight and body fat regulation; (2) epigenetic mechanisms of energy balance; and (3) the prevention of obesity. The approach needs to be translational and bi-directional with a strong emphasis on basic science including studies of relevant gene expression and animal models of energy balance. Clinical research into mechanisms can challenge the existing paradigms that could direct research back to more basic understanding or to applications to populations at risk. Communication between scientists and physicians at the far end of the spectrum needs new and ongoing emphasis.

The apolipoprotein A-IV Gln360His polymorphism predicts progression of coronary artery calcification in patients with type 1 diabetes.

AIMS/HYPOTHESIS: Individuals with type 1 diabetes have an increased incidence of coronary artery disease (CAD) and a higher risk of cardiovascular death compared with individuals of the same age in the general population. While chronic hyperglycaemia and insulin resistance partially explain excess CAD, little is known about the potential genetic determinants of accelerated coronary atherosclerosis in type 1 diabetes. The aim of the present study was to evaluate the association of apolipoprotein A-IV (APOA4) polymorphisms with coronary artery calcification (CAC) progression, a marker of subclinical atherosclerosis. SUBJECTS AND METHODS: Two previously well-studied functional APOA4 polymorphisms resulting in the substitution of the amino acid Thr for Ser at codon 347 and Gln for His at codon 360 were genotyped in 634 subjects with type 1 diabetes and 739 non-diabetic control subjects, the participants of the prospective Coronary Artery Calcification in Type 1 Diabetes (CACTI) study. RESULTS: The His360 allele was associated with a significantly higher risk of CAC progression among patients with type 1 diabetes (33.7 vs 21.2%, p=0.014), but not in the control subjects (14.1 vs 11.1%, p=0.42). Logistic regression analysis confirmed that the presence of the APOA4 His360 allele predicts an increased risk of progression of coronary atherosclerosis in adults with type 1 diabetes of long duration (odds ratio = 3.3, p=0.003 after adjustment for covariates associated with CAD risk). CONCLUSIONS /INTERPRETATION: This is the first report suggesting an association between the APOA4 Gln360His polymorphism and risk of CAC progression in subjects with type 1 diabetes. Additional studies are needed to explore potential interactions between APOA4 genotypes and metabolic/oxidative stress components of the diabetic milieu leading to rapid progression of atherosclerosis.

Theoretical analysis of single-molecule force spectroscopy experiments: heterogeneity of chemical bonds.

We show that the standard theoretical framework in single-molecule force spectroscopy has to be extended to consistently describe the experimental findings. The basic amendment is to take into account heterogeneity of the chemical bonds via random variations of the force-dependent dissociation rates. This results in a very good agreement between theory and rupture data from several different experiments.

[Salivary gland carcinomas Part II. Diagnosis and therapy]. / Speicheldrüsenkarzinome. Teil II: Diagnostik und Therapie.

Salivary gland carcinomas comprise a rare group of malignant tumors which are difficult to diagnose and treat due to their histopathologic diversity, variable clinical course and anatomic location, particularly with respect to the facial nerve. The present paper summarizes important features of these tumors, including recent advances in their management, i.e., diagnosis, surgery of the primary tumor, neck dissection, radiation therapy, and updates risk factors, criteria of malignancy, and prognostic variables, taking into account the relevant literature. Additionally, the present paper highlights briefly the survival rates of patients suffering from salivary gland carcinomas. The present overview is divided into two parts: the first is focused on epidemiology, etiology, criteria of malignancy, prognostic factors, and tumor classification, while part II discusses the diagnosis and therapy of salivary gland carcinomas.

[Salivary gland carcinomas. 1. Epidemiology, etiology, malignancy criteria, prognostic parameters and classification]. / Speicheldrüsenkarzinome Teil I: Epidemiologie, Atiologie, Malignitätskriterien, Prognoseparameter und Klassifikation.

Salivary gland carcinomas comprise a rare group of malignant tumors which are difficult to diagnose and treat due to their histopathologic diversity, variable clinical course and anatomic location, particularly with respect to the facial nerve. The present paper summarizes important features of these tumors, including recent advances in their management, i.e., diagnosis, surgery of the primary tumor, neck dissection, radiation therapy, and updates risk factors, criteria of malignancy, and prognostic variables, taking into account the relevant literature. Additionally, the present paper highlights briefly the survival rates of patients suffering from salivary gland carcinomas. The present overview is divided into two parts: the first is focused on epidemiology, etiology, criteria of malignancy, prognostic factors, and tumor classification, while part II discusses the diagnosis and therapy of salivary gland carcinomas.

Influence of hospital volume on local recurrence and survival in a population sample of rectal cancer patients.

AIMS: To investigate the role of hospital volume and individual hospitals on long term outcomes (local recurrence and survival) of rectal cancer patients. METHODS: One thousand thirty-eight patients with rectal cancer were diagnosed between 1996 and 1998. From these, we analysed 884 patients with a resected invasive primary rectal cancer. Median follow-up was 5.7 years. The impact of hospital volume (<10, 10-30 and >30 rectal cancer patients annually) on local recurrence and survival was examined in a Cox model. Differences between the four largest clinics in the high volume group were also investigated. RESULTS: In the multivariate model predicting survival the following variables were significant: UICC stage, grade, age, local recurrence, and (neo-) adjuvant therapy treatment. In the multivariate model predicting local recurrence UICC stage, tumour localisation, and neoadjuvant therapy treatment were significant variables. Hospital volume was not a significant factor for survival or local recurrence. Within the high volume category one hospital showed significantly worse local recurrence rates than all other hospitals, but no survival difference could be seen between the four largest hospitals of the high volume group. CONCLUSIONS: This analysis of a rectal cancer population found that hospital volume did not determine survival or local recurrence. Detailed clinical data with long term follow-up from cancer registries are vital to demonstrate the quality of routine care.

Survival for rectal cancer patients and international comparisons.

BACKGROUND: Population-based cancer registry data are important because they reflect routine care, present long-term follow-up, can show differences in treatment, outcomes and health care over time, and can be used for comparisons between regions and countries. PATIENTS AND METHODS: Details of all cancer patients in the Munich region are recorded by the Munich Cancer Registry. Rectal cancer patients with an invasive primary tumor diagnosed between 1996 and 1998 were included in this analysis (n=936). Observed and relative survival are presented. Observed survival was also investigated with a Cox proportional hazards regression model. RESULTS: Median follow-up time of survivors was 5.7 years. Five-year relative survival for the whole sample was 62.2%. International Union Against Cancer (UICC) stage was the most important prognostic factor in the multivariate analysis. Compared with the 1992-1999 Surveillance Epidemiology and End Results (SEER) data (62.4%), relative survival for each disease stage and the whole sample were very similar. In comparison with other European registries, Munich patients had slightly higher survival rates per stage (for example, 5-year relative survival in UICC III was 58.3% in Munich, 54.6% in South East Netherlands, 33.3% in Modena and 47.4% in Cote d'Or); however, more patients in Munich were in higher disease stages with worse prognoses, indicating poorer early detection. CONCLUSIONS: These results indicate that treatment of rectal cancer in Munich is good, but early detection could be improved. Cancer registries should publish their population-based stage data to ensure quality of care and provide regular feedback to health-care workers and decision makers. Comparisons between countries without stage data should be conducted cautiously.

Lipid metabolism and nutrient partitioning strategies.

The increasing prevalence of overweight and obesity worldwide is daunting and requires prompt attention by the affected, health care profession, government and the pharmaceutical industry. Because overweight/obesity are defined as an excess of adipose tissue mass, all approaches in prevention and treatment must consider redirecting lipid storage in adipose tissue to oxidative metabolism. Lipid partitioning is a complex process that involves interaction between fat and other macronutrients, particularly carbohydrate. In an isocaloric environment, when fat is stored carbohydrate is oxidized and vice versa. Processes that influence fat partitioning in a manner in which weight is maintained must be modified by changes in organ-specific fat transport and metabolism. When therapy is considered, however, changes in lipid partitioning alone will be ineffective unless a negative energy balance is also achieved, i.e. energy expenditure exceeds energy intake. The intent of this review is to focus on molecules including hormones, enzymes, cytokines, membrane transport proteins, and transcription factors directly involved in fat trafficking and partitioning that could be potential drug targets. Some examples of favorably altering body composition by systemic and/or tissue specific modification of these molecules have already been provided with gene knockout and/or transgenic approaches in mice. The translation of this science to humans remains a challenging task.

Measurement of abdominal fat by CT compared to waist circumference and BMI in explaining the presence of coronary calcium.

OBJECTIVE: To evaluate the association between standard and computed tomography (CT)-based measures of obesity and subclinical atherosclerosis, defined as coronary artery calcium (CAC) by Electron Beam Computed Tomography (EBCT). DESIGN: Cross-sectional, observational study of anthropometric and CT obesity measures and presence of CAC. SUBJECTS: Participants were 383 men and 379 women, aged 20-58 y and asymptomatic for coronary artery disease (CAD). MEASUREMENTS: Intra-abdominal fat (IAF) and subcutaneous fat (SQF) were measured at the level of lumbar 2-3 and 4-5 spaces, using EBCT. Body mass index (BMI) was calculated from height and weight, and minimum waist circumference and maximum hip circumference were measured. CAC was measured by EBCT. RESULTS: In both men and women, BMI, waist circumference, IAF, and SQF were significantly related to CAC. However, BMI or waist circumference explained variation in the presence of CAC as well as IAF or SQF, univariately and after adjustment for additional cardiovascular risk factors. CONCLUSION: CT-based obesity exposure measures are not superior to BMI or waist circumference in association studies of subclinical CAD.

Comparison of breast and rectal cancer patients' quality of life: results of a four year prospective field study.

This paper compares quality of life in breast and rectal cancer patients. The Munich Cancer Registry records clinical details of all cancer patients in the region. Over a 2-year period, cooperating clinicians recruited patients who were sent quality of life questionnaires, including the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - C30 over 4 years. Breast cancer patients were compared to both male and female rectal cancer patients. A total of 1315 patients returned questionnaires (988 breast cancer, 327 rectal cancer). More breast cancer patients were under 70 years old, received adjuvant therapy, had a good prognosis, took medication and rated psychological support as important. Breast cancer patients reported poorer quality of life than rectal cancer patients in more than half the variables. In particular, they suffered significantly worse emotional functioning, fatigue, pain and sleeplessness. Female rectal cancer patients did not suffer the same problems. Both age groups and those with or without adjuvant therapy indicated the same trend, with breast cancer patients reporting lower scores. Breast cancer patients, despite better prognoses, appear to suffer more psychological problems than rectal cancer patients. Gender, age and therapy did not seem to explain these differences. The negative public perception of breast cancer may play a role.

Fat distribution is altered in HIV-infected men without clinical evidence of the HIV lipodystrophy syndrome.

OBJECTIVE: To determine if fat distribution is altered in HIV-infected men without clinical evidence of lipodystrophy. METHODS: In a cross-sectional design, 14 protease inhibitor (PI)-treated men with lipodystrophy and 12 PI-treated and five PI-naive men without clinical evidence of lipodystrophy underwent body composition and fat distribution analysis by dual-energy X-ray absorptiometry and computed tomography. Their fat distribution was compared to 43 uninfected male controls matched for age and BMI. RESULTS: The percent of body fat in the trunk of men with HIV lipodystrophy was significantly greater compared to both HIV-infected and healthy controls. The percentage of body fat in the extremities was significantly lower in men with HIV lipodystrophy compared to both HIV-infected and healthy controls. HIV-infected men without clinical evidence of lipodystrophy also had a significantly greater percentage of total body fat in the trunk and a significantly lower percent of body fat in the extremities compared to healthy controls. Among the HIV-infected men, age was an independent predictor of truncal and extremity adiposity. CONCLUSION: This study suggests that a continuum of change is present in the adipose organ of HIV-infected men on antiretroviral therapy. Physical examination alone can miss significant changes in body fat distribution in HIV-infected patients.

The process of metastasisation for breast cancer.

To investigate the process of metastasis, primary clinical data and disease events such as metastases, local recurrence and survival (median follow-up 9.4 years) from the Munich Cancer Registry from 1978 to 1996 were analysed. Since metastases, even from small tumours, may be initiated before the diagnosis of the primary tumour, the growth of the primary tumour and metastasisation may be two autonomous processes. In our data, survival following metastases was almost unrelated to primary tumour size. However, the number of M1 cases and the time to metastasisation depended on the tumour diameter at diagnosis. The time from initiation of metastases to its diagnosis was estimated as 5.8 years. The growth of metastases was almost homogeneous. However, the growth time following metastasisation-depending on the metastases-free time, receptor status and histological grade-only varied by approximately a factor of 2. Local recurrence, above all, was an indicator of metastases. Furthermore, local recurrence may also have the potential to metastasise. Excess mortality due to local recurrence was estimated up to 9.3 years after diagnosis. Our hypothesised metastases model illustrates the importance of early detection, the concept of breast-conserving therapy and additional metastases from local recurrence. It highlights the benefits of optimal local therapy of the primary tumour and the limitations of systemic therapy. It also questions the use of axilla dissection and lymph node irradiation. Its generalisation to solid tumours may help to clarify many of the current controversial debates.

Moderate progress for ovarian cancer in the last 20 years: prolongation of survival, but no improvement in the cure rate.

Although ovarian cancer treatment has advanced in the last 20 years, long-term survival remains stable. The purpose of this study was to determine whether survival has improved in line with treatment advances in a population-based prospective cohort of ovarian cancer patients (1978-1997, with a follow-up through to 2000). The 10-year overall survival rate for cancer patients was similar before and after 1988: 32.2% (n=1661) and 34.4% (n=2089). For patients after 1988, a 12-month prolongation of median survival was observed. In terms of stage according to the International Federation of Gynecology and Obstetrics (FIGO), only FIGO I and FIGO II patients showed, in addition to a prolongation in survival, an absolute improvement of 12.9 and 12.6% after 5 years and of 13.2 and 8.6% after 10 years. This hardly affected the survival of the total sample. For the most frequent stage FIGO III patients and for FIGO IV patients, a prolongation in survival time, but no improvement in survival rate, was seen after five or 10 years. The progress in FIGO I and II patients may be due to more accurate staging. More effective chemotherapy may also explain some of the improvement. The prolongation in FIGO-stages III-IV may be due to more radical surgery. Patient selection criteria, not only the treatment modalities, may be responsible for the superior results reported in clinical trials. Cancer registries are important for evaluating the quality of healthcare delivery.