Personalizing treatment in end-stage kidney disease: deciding between haemodiafiltration and haemodialysis based on individualized treatment effect prediction.

Background: Previous studies suggest that haemodiafiltration reduces mortality compared with haemodialysis in patients with end-stage kidney disease (ESKD), but the controversy surrounding its benefits remains and it is unclear to what extent individual patients benefit from haemodiafiltration. This study is aimed to develop and validate a treatment effect prediction model to determine which patients would benefit most from haemodiafiltration compared with haemodialysis in terms of all-cause mortality. Methods: Individual participant data from four randomized controlled trials comparing haemodiafiltration with haemodialysis on mortality were used to derive a Royston-Parmar model for the prediction of absolute treatment effect of haemodiafiltration based on pre-specified patient and disease characteristics. Validation of the model was performed using internal-external cross validation. Results: The median predicted survival benefit was 44 (Q1-Q3: 44-46) days for every year of treatment with haemodiafiltration compared with haemodialysis. The median survival benefit with haemodiafiltration ranged from 2 to 48 months. Patients who benefitted most from haemodiafiltration were younger, less likely to have diabetes or a cardiovascular history and had higher serum creatinine and albumin levels. Internal-external cross validation showed adequate discrimination and calibration. Conclusion: Although overall mortality is reduced by haemodiafiltration compared with haemodialysis in ESKD patients, the absolute survival benefit can vary greatly between individuals. Our results indicate that the effects of haemodiafiltration on survival can be predicted using a combination of readily available patient and disease characteristics, which could guide shared decision-making.

Clone-directed therapy for proliferative glomerulonephritis with monoclonal immunoglobulin depositions: is it always necessary? : Two case reports and literature review.

Monoclonal gammopathy of renal significance (MGRS) encompasses a group of disorders in which a monoclonal immunoglobulin (M-protein) secreted by a B-cell or plasma cell clone causes renal disease. Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) is a form of MGRS where M-protein is deposited in the glomerulus. Although evidence is limited, the current consensus is that therapy for PGNMID should be directed against the underlying clone. However, it is conceivable that there is heterogeneity in the renal prognosis of PGNMID and that not all patients have need for clone-directed therapy. Here, we report two cases of PGNMID with IgM-kappa gammopathy. In one case of a 53-year-old woman the glomerulonephritis resolved without clone-directed therapy. In the other case of a 34-year-old woman clone-directed therapy was discontinued due to adverse effects. Although no hematological response was achieved, the PGNMID resolved. In both cases there are no signs of a recurrent glomerulonephritis in over 3 years of follow-up. Here, we review the literature and suggest that some PGNMID patients have a favorable renal prognosis in whom clone-directed therapy can be withheld or postponed. Further research is warranted to yield predictors to identify these patients and to better understand the disease course of PGNMID.

Choosing the right strategy based on individualized treatment effect predictions: combination versus sequential chemotherapy in patients with metastatic colorectal cancer.

BACKGROUND: Translating results from randomized trials to individual patients is challenging, since treatment effects may vary due to heterogeneous prognostic characteristics. We aimed to demonstrate model development for individualized treatment effect predictions in cancer patients. We used data from two randomized trials that investigated sequential versus combination chemotherapy in unresectable metastatic colorectal cancer (mCRC) patients. MATERIAL AND METHODS: We used data from 803 patients included in CAIRO for prediction model development and internal validation, and data from 1423 patients included in FOCUS for external validation. A Weibull model with pre-specified patient and tumour characteristics was developed for a prediction of gain in median overall survival (OS) by upfront combination versus sequential chemotherapy. Decision curve analysis with net benefit was used. A nomogram was built using logistic regression for estimating the probability of receiving second-line treatment after the first-line monochemotherapy. RESULTS: Median-predicted gain in OS for the combination versus sequential chemotherapy was 2.3 months (IQR: -1.1 to 3.7 months). A predicted gain in favour of sequential chemotherapy was found in 231 patients (29%) and a predicted gain of >3 months for combination chemotherapy in 294 patients (37%). Patients with benefit from sequential chemotherapy had metachronous metastatic disease and a left-sided primary tumour. Decision curve analyses showed improvement in a net benefit for treating all patients according to prediction-based treatment compared to treating all patients with combination chemotherapy. Multiple characteristics were identified as prognostic variables which identify patients at risk of never receiving second-line treatment if treated with initial monochemotherapy. External validation showed good calibration with moderate discrimination in both models (C-index 0.66 and 0.65, respectively). CONCLUSIONS: We successfully developed individualized prediction models including prognostic characteristics derived from randomized trials to estimate treatment effects in mCRC patients. In times where the heterogeneity of CRC becomes increasingly evident, such tools are an important step towards personalized treatment.

Central nervous system localisation of chronic lymphocytic leukaemia, description of two very distinct cases and a review of the literature.

Central nervous system (CNS) localisation of chronic lymphocytic leukaemia (CLL) can induce various neurological symptoms. Unfamiliarity with this manifestation causes diagnostic delay. We present two cases of leptomeningeal CLL. These cases and our literature review emphasise that CNS localisation of CLL should be considered in patients with any neurological symptom, irrespectively of the stage and systemic activity of CLL.

Individualised prediction of alternate-day aspirin treatment effects on the combined risk of cancer, cardiovascular disease and gastrointestinal bleeding in healthy women.

BACKGROUND: The value of aspirin in primary prevention of cancer and cardiovascular disease (CVD) remains unclear. The aim of this study was to identify women who benefit from alternate-day aspirin with regard to all relevant outcomes, including cancer, CVD and major gastrointestinal bleeding. METHODS: Long term follow-up data of 27 939 healthy women with baseline plasma samples in the Women's Health Study, a randomised trial of 100 mg alternate-day aspirin versus placebo, were used to develop competing risks models for individualised prediction of absolute risk reduction of the combination of CVD, cancer and major gastrointestinal bleeding by aspirin. RESULTS: Although aspirin was associated with a modestly decreased 15-year risk of colorectal cancer, CVD, and in some women non-colorectal cancer, aspirin treatment resulted in a negative treatment effect in the majority of women if gastrointestinal bleeding was also taken into account. The excess risk of major gastrointestinal bleeding by aspirin increased with age, but the benefits for colorectal cancer and CVD risk were also greater at higher age. Decision curves indicated that selective treatment of women ≥65 years may improve net benefit compared to treating all, none and prediction-based treatment. The observed 15-year number needed to treat to prevent one event among women ≥65 years was 29 (95% CI 12 to 102). CONCLUSIONS: Concurrent evaluation of the absolute effects on cancer, CVD and major gastrointestinal bleeding showed that alternate-day use of low-dose aspirin is ineffective or harmful in the majority of women in primary prevention. Selective treatment of women ≥65 years with aspirin may improve net benefit. TRIAL REGISTRATION NUMBER: NCT00000479.

The relation between resting heart rate and cancer incidence, cancer mortality and all-cause mortality in patients with manifest vascular disease.

BACKGROUND: Previous studies suggest that elevated resting heart rate (RHR) is related to an increased risk of cancer mortality. The aim of this study was to evaluate the relation between RHR and cancer incidence and mortality in patients with vascular disease. METHODS: Patients with manifest vascular disease (n=6007) were prospectively followed-up for cancer incidence and mortality. At baseline, RHR was obtained from an electrocardiogram. The relation between RHR and cancer incidence, cancer mortality and total mortality was assessed using competing risks models. RESULTS: During a median follow-up of 6.0 years (interquartile range: 3.1-9.3) 491 patients (8%) were diagnosed with cancer and 907 (15%) patients died, 248 (27%) died from cancer. After adjustment for potential confounders, the hazard ratio (HR) for incident cancer per 10 beats/min increase in RHR was 1.00 (95% confidence interval [CI]: 0.93-1.07). There was a trend toward an increased risk of colorectal cancer in patients with higher RHR (HR 1.15, 95% CI 0.97-1.36). The risk of all-cause mortality was increased in patients in the highest quartile of RHR compared to the lowest quartile (HR 1.86, 95% CI 1.53-2.27), but no effect of RHR on cancer mortality was observed (HR 1.01, 95% CI 0.70-1.46). CONCLUSIONS: In patients with manifest vascular disease, elevated RHR was related to a higher risk of premature all-cause mortality, but this was not due to increased cancer mortality. RHR was not related to risk of overall cancer incidence, although a relation between elevated RHR and incident colorectal cancer risk could not be ruled out.

Cancer risk in patients with manifest vascular disease: effects of smoking, obesity, and metabolic syndrome.

BACKGROUND: Patients with vascular disease may be at increased risk of cancer because of shared risk factors and common pathogenesis. METHODS: Patients with vascular disease (n = 6,172) were prospectively followed for cancer incidence. Standardized incidence ratios (SIRs) were calculated to compare the cancer incidence of the study population with that of the general population. Multivariable-adjusted hazard ratio's (HRs) of cancer were estimated for smoking status, pack-years, body mass index, waist circumference and visceral adipose tissue (VAT), and metabolic syndrome (MetS). RESULTS: During a median follow-up of 5.5 years, 563 patients were diagnosed with cancer. Patients with vascular disease were at increased risk of cancer [SIR = 1.19; 95% confidence interval (CI), 1.10-1.29]. Specifically, risk of lung cancer (SIR = 1.56; 95% CI, 1.31-1.83), as well as bladder cancer (SIR = 1.60; 95% CI, 1.11-2.24) and cancer of the lip, oral cavity, or pharynx in men (SIR = 1.51; 95% CI, 0.89-2.39), and colorectal (SIR = 1.71; 95% CI, 1.11-2.53) and kidney cancer (SIR = 2.92; 95% CI, 1.05-6.38) in women was increased. A relation between smoking and cancer risk was observed (HR for current smokers = 1.37; 95% CI, 1.05-1.73), whereas an increase in VAT was associated with higher breast cancer risk in women (HR = 1.42; 95% CI, 1.03-1.96). No relation between MetS and cancer risk was found. CONCLUSIONS: Patients with vascular disease have a 19% higher cancer risk compared to the general population. Smoking increased cancer risk and abdominal obesity is a risk factor for breast cancer in female patients with vascular disease. IMPACT: These results call for awareness of the increased cancer risk in patients with vascular disease among physicians and underline the necessity of lifestyle improvement not only for reducing cardiovascular risk.

[Competing risks in clinical research]. / Concurrerende risico's in klinisch onderzoek.

In clinical research, study populations are often followed up until the occurrence of a certain outcome, such as breast cancer or death. Survival analysis, used to analyse the time-to-event data, is usually focused on one particular event; however, study participants may experience other events that prevent the event of interest from occurring. This is a situation of competing risks. An example is the risk of death in a study investigating breast cancer recurrence, as women who have died without having recurrent disease are no longer at risk of this recurrent disease. Competing risks can lead to biased results if not taken into account. Competing risks are important in studies including patients with a high risk of varying clinical outcomes, and in those studies with a long follow-up period. If competing risks are present, the competing outcomes can be combined into one outcome measure or should be taken into account in adapted survival analysis.

Obesity and cancer: the role of dysfunctional adipose tissue.

Overweight and obesity are health problems of epidemic proportions, increasing the risk not only of cardiovascular disease and type 2 diabetes mellitus but also of various types of cancer. Obesity is strongly associated with changes in the physiological function of adipose tissue, leading to insulin resistance, chronic inflammation, and altered secretion of adipokines. Several of these factors, such as insulin resistance, increased levels of leptin, plasminogen activator inhibitor-1, and endogenous sex steroids, decreased levels of adiponectin, and chronic inflammation, are involved in carcinogenesis and cancer progression. This article reviews these mechanisms, focusing on adipose tissue dysfunction as a unifying causal factor. Although understanding of the link between obesity and cancer might provide therapeutic targets, preventing overweight and obesity still remains number one priority.