Direct modeling of the crude probability of cancer death and the number of life years lost due to cancer without the need of cause of death: a pseudo-observation approach in the relative survival setting.

In population-based cancer studies, net survival is a crucial measure for population comparison purposes. However, alternative measures, namely the crude probability of death (CPr) and the number of life years lost (LYL) due to death according to different causes, are useful as complementary measures for reflecting different dimensions in terms of prognosis, treatment choice, or development of a control strategy. When the cause of death (COD) information is available, both measures can be estimated in competing risks setting using either cause-specific or subdistribution hazard regression models or with the pseudo-observation approach through direct modeling. We extended the pseudo-observation approach in order to model the CPr and the LYL due to different causes when information on COD is unavailable or unreliable (i.e., in relative survival setting). In a simulation study, we assessed the performance of the proposed approach in estimating regression parameters and examined models with different link functions that can provide an easier interpretation of the parameters. We showed that the pseudo-observation approach performs well for both measures and we illustrated their use on cervical cancer data from the England population-based cancer registry. A tutorial showing how to implement the method in R software is also provided.

Confidence intervals for the Mann-Whitney test.

The Mann-Whitney test is a commonly used non-parametric alternative of the two-sample t-test. Despite its frequent use, it is only rarely accompanied with confidence intervals of an effect size. If reported, the effect size is usually measured with the difference of medians or the shift of the two distribution locations. Neither of these two measures directly coincides with the test statistic of the Mann-Whitney test, so the interpretation of the test results and the confidence intervals may be importantly different. In this paper, we focus on the probability that random variable X is lower than random variable Y. This measure is often referred to as the degree of overlap or the probabilistic index; it is in one-to-one relationship with the Mann-Whitney test statistic. The measure equals the area under the ROC curve. Several methods have been proposed for the construction of the confidence interval for this measure, and we review the most promising ones and explain their ideas. We study the properties of different variance estimators and small sample problems of confidence intervals construction. We identify scenarios in which the existing approaches yield inadequate coverage probabilities. We conclude that the DeLong variance estimator is a reliable option regardless of the scenario, but confidence intervals should be constructed using the logit scale to avoid values above 1 or below 0 and the poor coverage probability that follows. A correction is needed for the case when all values from one sample are smaller than the values of the other. We propose a method that improves the coverage probability also in these cases.

Comparison of the algorithms classifying the ABC and GCB subtypes in diffuse large B-cell lymphoma.

Different immunohistochemical algorithms for the classification of the activated B-cell (ABC) and germinal center B-cell (GCB) subtypes of diffuse large B-cell lymphoma (DLBCL) are applied in different laboratories. In the present study, 127 patients with DLCBL were investigated, all treated with rituximab and cyclophosphamide, hydroxydaunorubicin, oncovin and prednisone (CHOP) or CHOP-like regimens between April 2004 and December 2010. Multi-tumor tissue microarrays were prepared and were tested according to 4 algorithms: Hans; modified Hans; Choi; and modified Choi. For 39 patients, the flow cytometric quantification of CD19 and CD20 antigen expression was performed and the level of expression presented as molecules of equivalent soluble fluorochrome units. The Choi algorithm was demonstrated to be prognostic for OS and classified patients into the GCB subgroup with an HR of 0.91. No difference in the expression of the CD19 antigen between the ABC and GCB groups was observed, but the ABC subtype exhibited a decreased expression of the CD20 antigen compared with the GCB subtype.

Selection of Non-small Cell Lung Cancer Patients for Intercalated Chemotherapy and Tyrosine Kinase Inhibitors.

BACKGROUND: When treating patients with advanced non-small cell lung cancer (NSCLC) with tyrosine kinase inhibitors and chemotherapy, intercalated schedule with time separation between the two classes of drugs should avoid their mutual antagonism. In a survey of published trials, we focus on relation between eligibility criteria and effectiveness of intercalated treatment. METHODS: Published documents were identified using major medical databases, conference proceedings and references of published trials. Median progression-free survival (PFS) was taken as the basic parameter of treatment efficacy. Correlation between characteristics of patients and median PFS was assessed through the Pearson's correlation coefficient and the coefficient of determination, separately for first-line and second-line setting. RESULTS: The series includes 11 single-arm trials and 18 randomized phase II or phase III trials with a total of 2903 patients. Treatment-naive patients or those in progression after first-line treatment were included in 16 and 13 trials, respectively. In 14 trials, only patients with non-squamous histology were eligible. Proportion of patients with non-squamous carcinoma (in first-line setting), proportion of never-smokers (both in first- and second-line setting) and proportion of epidermal growth factor receptor (EGFR) mutant patients (both in first- and second-line setting) showed a moderate or strong correlation with median PFS. In six trials of intercalated treatment applied to treatment-naive EGFR-mutant patients, objective response was confirmed in 83.1% of cases and median PFS was 18.6 months. CONCLUSIONS: Most suitable candidates for intercalated treatment are treatment-naive patients with EGFR-mutant tumors, as determined from biopsy or liquid biopsy. For these patients, experience with intercalated treatment is most promising and randomized trials with comparison to the best standard treatment are warranted.

The effect of CD34+ cell telomere length and hTERT expression on the outcome of autologous CD34+ cell transplantation in patients with chronic heart failure.

Age-related telomere attrition in stem/progenitor cells may diminish their functional capacity and thereby impair the outcome of cell-based therapies. The aim of the present study was to investigate the effect of CD34+ cell telomere length and hTERT expression on the clinical outcome of autologous CD34+ cell transplantation. We studied 43 patients with cardiomyopathy. Their peripheral blood CD34+ cells were mobilized with granulocyte colony-stimulating factor, enriched by immunoselection and delivered transendocardially. Relative telomere length and expression levels of hTERT were measured using a real-time PCR assay. Immunoselected CD34+ cells had longer telomere length compared to leukocytes in leukapheresis products (p=0.001). In multivariate analysis, CD34+ cell telomere length was not associated with the clinical outcome (b=3.306, p=0.540). While hTERT expression was undetectable in all leukapheresis products, 94.4% of the CD34+ enriched cell products expressed hTERT. Higher CD34+hTERT expression was associated with a better clinical outcome on univariate analysis (b=87.911, p=0.047). Our findings demonstrate that CD34+ cell telomere length may not influence the clinical outcome in cardiomyopathy patients treated with autologous CD34+ cell transplantation. Larger studies are needed to validate the impact of the CD34+hTERT expression on the clinical outcome of autologous CD34+ cell transplantation.

On comparison of net survival curves.

BACKGROUND: Relative survival analysis is a subfield of survival analysis where competing risks data are observed, but the causes of death are unknown. A first step in the analysis of such data is usually the estimation of a net survival curve, possibly followed by regression modelling. Recently, a log-rank type test for comparison of net survival curves has been introduced and the goal of this paper is to explore its properties and put this methodological advance into the context of the field. METHODS: We build on the association between the log-rank test and the univariate or stratified Cox model and show the analogy in the relative survival setting. We study the properties of the methods using both the theoretical arguments as well as simulations. We provide an R function to enable practical usage of the log-rank type test. RESULTS: Both the log-rank type test and its model alternatives perform satisfactory under the null, even if the correlation between their p-values is rather low, implying that both approaches cannot be used simultaneously. The stratified version has a higher power in case of non-homogeneous hazards, but also carries a different interpretation. CONCLUSIONS: The log-rank type test and its stratified version can be interpreted in the same way as the results of an analogous semi-parametric additive regression model despite the fact that no direct theoretical link can be established between the test statistics.

Effect of repeated passive anterior loading on human knee anterior laxity.

BACKGROUND: Increased knee anterior laxity results when the anterior cruciate ligament is injured. This increased laxity can cause knee dysfunction. Until recently this laxity was believed to be only diminished through surgery. But recent findings indicate that knee anterior laxity may be decreased with repeated loading of the knee. OBJECTIVE: The purpose of this study was to test the hypothesis that regular passive anterior loading of the uninjured human knee would enhance its stiffness. STUDY DESIGN: Randomized controlled trial. METHODS: Knee anterior laxity was tested using an arthrometer in 22 young, uninjured females before, during and after a 3 month period during which passive anterior loading was applied by a trained physiotherapist over 5 sessions per week to a randomly assigned knee. RESULTS: Knee anterior laxity was not affected by the passive anterior loading of the knee. CONCLUSIONS: Given that in this study repeated passive loading of the knee did not change knee anterior laxity, it would be easy to conclude that this training is ineffective and no further research is required. We caution against this given the relatively short duration and possibly insufficient intensity of the training and the population studied; individuals with normal joint laxity. We recommend that future research be performed that consists of individuals with lax joints who receive training for prolonged periods.

Direct microscopic monitoring of initial and dynamic clot lysis using plasmin or rt-PA in an in vitro flow system.

INTRODUCTION: Plasmin is a direct-acting thrombolytic agent with a favorable safety profile upon intra-arterial delivery in pre-clinical and phase I studies. However, the thrombolytic efficacy of plasmin, relative to that of rt-PA, remains to be established. We have compared the dynamics of clot lysis with plasmin or rt-PA in an in vitro perfusion system, in which thrombolytic agent is administered locally, allowed to induce lysis for short intervals, then washed with plasma in a re-circulation circuit. MATERIALS AND METHODS: Whole blood human clots were prepared in observation chambers, exposed to plasmin or rt-PA at equimolar concentrations (1.2/1.0, 1.8/1.5 and 2.4/2.0 mg/ml) for measured intervals of time, followed by perfusion with human plasma. Clot size was monitored by digital analysis of sequential photographs obtained through an optical microscope. RESULTS: Plasma perfusion after incubation with thrombolytic agent rapidly removed superficial clot fragments. This initial decrease in clot size was greater with plasmin than with rt-PA when tested at the highest concentrations of agent (0.63 ± 0.11 vs. 0.30 ± 0.11, p=0.001 for clots with non-cross-linked fibrin and 0.53 ± 0.15 vs. 0.14 ± 0.15, p=0.02, for clots with cross-linked-fibrin). Subsequent clot lysis during plasma flow was greater after prior incubation with rt-PA. Longer incubation times of plasmin resulted in larger portions of the clot being washed free. Repeated plasmin incubations and plasma perfusions of a clot successfully induced stepwise reductions in clot size. CONCLUSIONS: Initial clot lysis is greater with direct exposure using plasmin than rt-PA. During washout and circulation with plasma, rt-PA induced continued clot lysis, while plasmin lysis was curtailed, presumably because of plasmin inhibition.

Outcomes of peritoneal dialysis patients and switching to hemodialysis: a competing risks analysis.

BACKGROUND: We performed a review of a large incident peritoneal dialysis cohort to establish the impact of current practice and that of switching to hemodialysis. METHODS: Patients starting peritoneal dialysis between 2004 and 2010 were included and clinical data at start of dialysis recorded. Competing risk analysis and Cox proportional hazards model with time-varying covariate (technique failure) were used. RESULTS: Of 286 patients (median age 57 years) followed for a median of 24.2 months, 76 were transplanted and 102 died. Outcome probabilities at 3 and 5 years respectively were 0.69 and 0.53 for patient survival (or transplantation) and 0.33 and 0.42 for technique failure. Peritonitis caused technique failure in 42%, but ultrafiltration failure accounted only for 6.3%. Davies comorbidity grade, creatinine and obesity (but not residual renal function or age) predicted technique failure. Due to peritonitis deaths, technique failure was an independent predictor of death hazard. When successful switch to hemodialysis (surviving more than 60 days after technique failure) and its timing were analyzed, no adverse impact on survival in adjusted analysis was found. However, hemodialysis via central venous line was associated with an elevated death hazard as compared to staying on peritoneal dialysis, or hemodialysis through a fistula (adjusted analysis hazard ratio 1.97 (1.02 - 3.80)). CONCLUSIONS: Once the patients survive the first 60 days after technique failure, the switch to hemodialysis does not adversely affect patient outcomes. The nature of vascular access has a significant impact on outcome after peritoneal dialysis failure.

Inter-rater reliability of the GNRB® knee arthrometer.

BACKGROUND: In clinical settings, where arthrometers are mainly used by different clinicians, knowing the inter-rater reliability of the instrument is crucial in order for the results from different examiners to be accurately interpreted and limitations fully understood. The aim of this study was to evaluate the inter-rater reliability of the GNRB® knee arthrometer. METHODS: Knee anterior laxity in both knees was tested in a group of young, uninjured subjects (N=27, 13 females) by two examiners. Knee anterior laxity was calculated at test forces of 134 N and 250 N with values presented for the unstandardised and standardised conditions (relative to patellar stabilisation force). RESULTS: The ICCs ranged from 0.220 to 0.424. CONCLUSIONS: The inter-rater reliability of the GNRB® knee arthrometer is low.

Robotic knee laxity testing: reliability and normative data.

PURPOSE: To evaluate the reliability of the GeNouRoB knee arthrometer and present normative values of knee anterior laxity using this device on young females. METHODS: Anterior laxity in both knees was tested in two groups of young, uninjured females using the hamstrings electromyography biofeedback feature of the device. There were 13 participants in the group tested for reliability and 23 for the normative study. Laxity (mm of movement of the proximal tibia in the anterior direction relative to the femur) was calculated at test forces of 134 N and 250 N with values presented for the unstandardised and standardised (relative to stabilisation force) conditions. RESULTS: The relative reliability (95% limits of agreement) of the device for laxity at a test force of 134 N was 2 to 3mm. Left knee anterior laxity was almost 1mm greater than the right. CONCLUSIONS: The relative reliability of the GeNouRoB arthrometer is comparable to the KT device. In agreement with previous work on the nonrobotic KT arthrometer, the knee anterior laxity values found with the GeNouRoB are greater in the left as compared to the right knee.

On estimation in relative survival.

Estimation of relative survival has become the first and the most basic step when reporting cancer survival statistics. Standard estimators are in routine use by all cancer registries. However, it has been recently noted that these estimators do not provide information on cancer mortality that is independent of the national general population mortality. Thus they are not suitable for comparison between countries. Furthermore, the commonly used interpretation of the relative survival curve is vague and misleading. The present article attempts to remedy these basic problems. The population quantities of the traditional estimators are carefully described and their interpretation discussed. We then propose a new estimator of net survival probability that enables the desired comparability between countries. The new estimator requires no modeling and is accompanied with a straightforward variance estimate. The methods are described on real as well as simulated data.

Has equity in relative survival improved over time in Finland - a methodological exercise.

BACKGROUND: Population-based relative survival is widely used as a method of monitoring the success of cancer control. This success may not be relevant only for an entire country but also regional developments over time are of interest. It would not only be important that the relative survival improved but also that the differences between regions decreased over time. METHODS: In this paper the authors show how relative survival methods can be used to study such differences. In addition to standard methods, some more recently introduced approaches are used, most notably a method for checking the goodness of fit of the relative survival model. This gives confidence in the obtained results and provides additional insight when assumptions are not met. RESULTS: An analysis of cancers of the colon and ovary by cancer control region in Finland in 1953-2003 shows an overall improvement in relative survival, accompanied in colon cancer also by a decrease of differences in relative survival between the regions. Thus, the desired course was observed in colon cancer but not in cancer of the ovary. CONCLUSIONS: These results, applied to further sites, should lead to investigation of differences in cancer control policies between regions.

Rate and risk of anterior cruciate ligament injury among sportswomen in Slovenia.

CONTEXT: Anterior cruciate ligament (ACL)-injury rate is greater among female athletes than among male athletes. OBJECTIVE: To investigate the rate and risk of ACL injury among Slovenian sportswomen playing professional basketball, team handball, or volleyball. DESIGN: Prospective cohort study. SETTING: The Slovenian National Organizations of basketball, team handball, and volleyball. PATIENTS OR OTHER PARTICIPANTS: During the 2003-2004 season, we prospectively followed 585 Slovenian sportswomen registered in the Slovenian National Organizations of basketball, team handball, and volleyball. MAIN OUTCOME MEASURE(S): We asked sportswomen and coaches to document the occurrence of every significant traumatic knee injury requiring medical attention. Injury rate and injury risk were calculated for sportswomen in each sport group. To calculate injury rate, we estimated the average exposure of each sportswoman during the research period. RESULTS: During the 2003-2004 season, 585 Slovenian sportswomen sustained 12 ACL injuries. The ACL-injury risk was different in athletes participating in the various sports, with basketball players having the greatest ACL-injury risk and volleyball players having the lowest ACL-injury risk (P  =  .04). The risk of ACL injury among Slovenian sportswomen was 2.1 per 100 athletes (95% confidence interval  =  0.9, 3.2), whereas the rate of ACL injury was 0.037 per 1000 exposure hours (95% confidence interval  =  0.016, 0.06). CONCLUSIONS: Overall differences in injury risk were found among sports, but no differences were noted among divisions within sports. No differences for injury rate were observed between or within sports. The rate and risk of ACL injury among Slovenian sportswomen are high, with basketball players having the greatest ACL-injury risk.

A measure of explained variation for event history data.

There is no shortage of proposed measures of prognostic value of survival models in the statistical literature. They come under different names, including explained variation, correlation, explained randomness, and information gain, but their goal is common: to define something analogous to the coefficient of determination R(2) in linear regression. None however have been uniformly accepted, none have been extended to general event history data, including recurrent events, and many cannot incorporate time-varying effects or covariates. We present here a measure specifically tailored for use with general dynamic event history regression models. The measure is applicable and interpretable in discrete or continuous time; with tied data or otherwise; with time-varying, time-fixed, or dynamic covariates; with time-varying or time-constant effects; with single or multiple event times; with parametric or semiparametric models; and under general independent censoring/observation. For single-event survival data with neither censoring nor time dependency it reduces to the concordance index. We give expressions for its population value and the variance of the estimator and explore its use in simulations and applications. A web link to R software is provided.

Melanoma metastases to the neck nodes: role of adjuvant irradiation.

PURPOSE: To review experiences in the treatment of regionally advanced melanoma to the neck and/or parotid with emphasis on the role of adjuvant radiotherapy. PATIENTS AND METHODS: Clinical and histopathologic data, treatment details, and outcomes in patients treated during the period 2000-2006 at the Institute of Oncology, Ljubljana, Slovenia, were reviewed. RESULTS: A total of 40 patients with 42 dissections underwent surgery, and 43 patients with 45 dissections received irradiation postoperatively to a median equivalent dose (eqTD(2): 2 Gy/fraction, 1 fraction/day, 5 fractions/week) of 60 Gy (range, 47.8-78.8). Regional control 2 years after surgery was 56% (95% confidence interval [CI] 40-72%) and after postoperative radiotherapy 78% (CI 63-92%) (p = 0.015). On multivariate analysis, postoperative radiotherapy (yes vs. no: hazard ratio [HR] 6.3, CI 2.0-20.6) and sum of the risk factors present (i.e., risk factor score; HR 1.7 per score point, CI 1.2-2.6) were predictive for regional control. On logistic regression testing, the number of involved nodes was associated with the probability of distant metastases (p = 0.021). The incidence of late toxicity did not correlate with the mode of therapy, eqTD(2), or fractionation pattern. CONCLUSIONS: Adjuvant radiotherapy has the potential to compensate effectively for the negative impact of adverse histopatologic features to disease control in a dissected nodal basin. More conventionally fractionated radiotherapy regimens using fraction doses of 2-2.5 Gy, with cumulative eqTD(2)> or =60 Gy, are recommended. The number of involved lymph nodes is proposed as an additional criterion for limiting the implementation of adjuvant irradiation.

Pseudo-observations in survival analysis.

We review recent work on the application of pseudo-observations in survival and event history analysis. This includes regression models for parameters like the survival function in a single point, the restricted mean survival time and transition or state occupation probabilities in multi-state models, e.g. the competing risks cumulative incidence function. Graphical and numerical methods for assessing goodness-of-fit for hazard regression models and for the Fine-Gray model in competing risks studies based on pseudo-observations are also reviewed. Sensitivity to covariate-dependent censoring is studied. The methods are illustrated using a data set from bone marrow transplantation.

Ljubljana nomograms for predicting the likelihood of non-sentinel lymph node metastases in breast cancer patients with a positive sentinel lymph node.

Several tools for predicting the likelihood of non-sentinel lymph node (non-SLN) involvement in SLN positive breast cancer patients have been created so far.The aim of our study was to create and validate different nomograms for predicting the likelihood of non-SLN involvement that would be applicable in different institutions and that would also include the results of the preoperative US examination of the axilla. From January 2000 to January 2009, 534 breast cancer patients underwent axillary lymph node dissection (ALND) due to metastatic SLN at our institution. Using logistic regression results three nomograms differing in the inclusion of the results of intraoperative examination of SLN were created. The nomograms were validated using bootstrap methods. In all three nomograms, US examination of the axilla was a powerful independent variable. Other variables included(different in different nomograms) were tumor size, lymphovascular invasion, metastasis size in SLN, number of negative and number of positive SLNs. Mean absolute error and mean area under the ROC curve equals to 0.016 and 0.77 for the first, 0.023 and 0.75 for the second and 0.014 and 0.79 for the third nomogram. Three nomograms for predicting the likelihood of non-SLN metastases including the results of the preoperative US examination of the axilla were created at our institution. They differ in the inclusion of the results of intraoperative examination of SLNs and are thus applicable in different institutions. The validation results seem promising and omission of completion ALND might be considered in patients with the probability of having non-SLN metastases of 10% or less.