Kaplan-Meier Survival Function Research Articles

Mutagen sensitivity predicts poor overall and disease specific survival in patients with stage III non-small cell lung cancer treated with chemo/radiotherapy

In light of the dismal outcome of current treatment and the significant treatment related toxicities in lung cancer, we urgently need markers to individualize our patient’s management. The mutagen sensitivity assay was developed to measure indirectly an individual’s DNA repair capacity to assess susceptibility to tobacco carcinogenesis. Since DNA repair capacity may also predict therapeutic effects and normal tissue repair after chemo/radiotherapy, we hypothesized that mutagen sensitivity may likewise serve as a biomarker for clinical outcome in lung cancer. Patients with lung cancer may have genetic instability unmasked by in vitro exposure of lymphocytes to a mutagen challenge such as bleomycin, a radiomimetic agent. In this study, we explored the role of bleomycin sensitivity in peripheral blood lymphocytes as a predictor of outcome in patients with inoperable stage III non-small cell lung cancer treated with definitive chemo/radiotherapy. 113 patients who were diagnosed with inoperable stage III non-small cell lung cancer at MD Anderson Cancer Center between 1995–2001 were included in this analysis. All patients received definitive radiotherapy with or without chemotherapy. Pre-treatment peripheral blood lymphocytes were collected and cultured for three days. Bleomycin was added for 5 hours and cells were arrested in mitosis using colcemid. Bleomycin sensitivity was measured by counting the mean number of chromatid breaks per cell in 50 metaphases. Patients with an average of more than 1.02 break/cell were considered to exhibit the bleomycin sensitivity phenotype. The data were analyzed using Kaplan-Meier survival function with S-plus 6.1 statistical software. The Log Rank test was used to compare different survivals. Spearman correlation test was used to analyze the correlation between bleomycin sensitivity and complications. High bleomycin sensitivity (mean chromatid break/cell >1.02, designated as bleomycin sensitive, BS) predicted poor disease specific survival (DSS) and overall survival (OS). The 6 years DSS was 27 % in patients with BS compared with 46 % in patients who didn’t exhibit the BS phenotype (p = 0.0094). The p value remained significant when adjusted (subgroup analysis) for smoking status, age (dichotomized at 60 years), radiation doses (50–55 GY, 55–65 GY, >65 GY). The 6 years OS was 19 % for patients with BS and 29 % for patients without BS (p = 0.0193). There was a trend toward worse local regional control and worse disease free survival among patients with BS (p = 0.0972 and 0.1813 respectively). There was no difference between two groups in distant metastasis free survival (p = 0.7695). To explore the predictive value of BS in treatment related complications, we analyzed the correlation between bleomycin sensitivity values with the toxicity grades of common treatment related complications including esophagitis, pneumonitis, and lung fibrosis. However, there was no significant correlation between BS and the treatment related complications when the side effects were analyzed individually or combined. BS correlated with poor overall survival and disease specific survival in these patients with stage III non-small cell lung carcinoma treated with chemo/radiotherapy. There was also a trend indicating poor local regional control and poor disease free survival with BS. There was no significant correlation between BS and treatment related complications. BS may function as a biomarker for poor clinical outcome for this group of patients. These data suggested the hypothesis that BS may indicate a genetic instability of cancer that contributes to high tumor grade, high genetic heterogeneity, and possible treatment resistance

Mutagen Sensitivity (MS) may predict lung protection by amifostine for patients with locally advanced non-small cell lung cancer (NSCLC) treated by chemoradiotherapy

7232 Background: Amifostine (AMF) has been shown to protect some normal tissues from acute effects of radiation therapy ± chemotherapy. We enrolled 62 pts in a randomized study investigating the efficacy of AMF: 31 had concurrent chemoradiation for NSCLC and 31 had the same treatment + AMF. AMF reduced the severity or frequency of esophagitis, pneumonitis and neutropenic fever. It was hypothesized that DNA repair capacity could predict outcome. Methods: Forty-six out of the 62 pts provided pretreatment blood for assessment of MS using a peripheral lymphocyte assay that infers DNA repair capacity from cellular damage remaining after in vitro mutagenic exposure and recovery. Bleomycin-induced chromosome breaks in 50 metaphases were counted and expressed as the mean number of breaks/cell. Pts with an average of >1 break/cell were deemed to exhibit the MS phenotype. Data analysis used Pearson's chi square and Kaplan-Meier survival function estimates with Strata 8.2 statistical software. The Log Rank test was ...

Mutagen Sensitivity (MS) may predict lung protection by amifostine for patients with locally advanced non-small cell lung cancer (NSCLC) treated by chemoradiotherapy

7232 Background: Amifostine (AMF) has been shown to protect some normal tissues from acute effects of radiation therapy ± chemotherapy. We enrolled 62 pts in a randomized study investigating the efficacy of AMF: 31 had concurrent chemoradiation for NSCLC and 31 had the same treatment + AMF. AMF reduced the severity or frequency of esophagitis, pneumonitis and neutropenic fever. It was hypothesized that DNA repair capacity could predict outcome. Methods: Forty-six out of the 62 pts provided pretreatment blood for assessment of MS using a peripheral lymphocyte assay that infers DNA repair capacity from cellular damage remaining after in vitro mutagenic exposure and recovery. Bleomycin-induced chromosome breaks in 50 metaphases were counted and expressed as the mean number of breaks/cell. Pts with an average of >1 break/cell were deemed to exhibit the MS phenotype. Data analysis used Pearson's chi square and Kaplan-Meier survival function estimates with Strata 8.2 statistical software. The Log Rank test was used to assess the equality of survival function using a p-value of 0.05. Results: Twelve patients (10 AMF, 2 control) exhibited the MS phenotype. The remaining 34 pts (13 AMF, 21 control) were considered to have normal DNA repair. There were no significant differences in overall survival, disease specific survival, or local control by MS. Those with MS had shorter distant metastasis-free survival (DMFS) compared to nonsensitive pts (p=0.029). There were no differences in severe esophagitis or neutropenic fever by MS. Both MS pts from the control group developed severe lung fibrosis compared with 5 of 21 who did not have MS (p=0.025). The incidence of grade 3–4 lung fibrosis was 2/10 with AMF compared with 2/2 in the control group (p=0.025) with MS. Conclusions: MS was associated with shorter DMFS and more frequent Gr 3–4 lung fibrosis. AMF reduced the incidence of Gr 3–4 lung fibrosis. These data suggest that MS might help identify subgroups of pts who could derive benefit from AMF with respect to lung damage. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration MedImmune

The high risk of stroke immediately after transient ischemic attack: a population-based study.

The risk of stroke is elevated in the first 48 hours after TIA. Previous prognostic models suggest that diabetes mellitus, age, and clinical symptomatology predict stroke. The authors evaluated the magnitude of risk of stroke and predictors of stroke after TIA in an entire population over time. Administrative data from four different databases were used to define TIA and stroke for the entire province of Alberta for the fiscal year (April 1999-March 2000). The age-adjusted incidence of TIA was estimated using direct standardization to the 1996 Canadian population. The risk of stroke after a diagnosis of TIA in an Alberta emergency room was defined using a Kaplan-Meier survival function. Cox proportional hazards modeling was used to develop adjusted risk estimates. Risk assessment began 24 hours after presentation and therefore the risk of stroke in the first few hours after TIA is not captured by our approach. TIA was reported among 2,285 patients for an emergency room diagnosed, age-adjusted incidence of 68.2 per 100,000 population (95% CI 65.3 to 70.9). The risk of stroke after TIA was 9.5% (95% CI 8.3 to 10.7) at 90 days and 14.5% (95% CI 12.8 to 16.2) at 1 year. The risk of combined stroke, myocardial infarction, or death was 21.8% (95% CI 20.0 to 23.6) at 1 year. Hypertension, diabetes mellitus, and older age predicted stroke at 1 year but not earlier. Although stroke is common after TIA, the early risk is not predicted by clinical and demographic factors. Validated models to identify which patients require urgent intervention are needed.

Transcobalamin Polymorphism and Serum Holo-Transcobalamin in Relation to Alzheimer’s Disease

Isoforms of the vitamin B₁₂ carrier protein transcobalamin (TC) might influence its cellular availability and contribute to the association between disrupted single-carbon metabolism and Alzheimer’s disease (AD). We therefore investigated the relationships between the TC 776C>G (Pro259Arg) genetic polymorphism, total serum cobalamin and holo-TC levels, and disease onset in 70 patients with clinically diagnosed AD and 74 healthy elderly controls. TC 776C>G polymorphism was also determined for 94 histopathologically confirmed AD patients and 107 controls. Serum holo-TC levels were significantly higher in TC 776C homozygotes (p = 0.04). Kaplan-Meier survival functions differed between homozygous genotypes (Cox’s F-Test F(42, 46) = 2.1; p = 0.008) and between 776C homozygotes and heterozygotes (Cox’s F test F(46, 108) = 1.7; p = 0.02). Proportionately fewer TC 776C homozygotes appear to develop AD at any given age, but this will require confirmation in a longitudinal study.

Oncological quality and preliminary long-term results in laparoscopic colorectal surgery

Our aim here was interpret data on the perioperative course, oncological quality, and preliminary long-term results of laparoscopic colorectal surgery carried out with a curative intent. The data were collected within the framework of a prospective multicenter observational study that has been ongoing since 1 Aug 1995 and includes 46 hospitals. Of a total of 3133 patients, 826 (26.4%) underwent a curative resection for colorectal carcinoma. The average age of the patients was 67.9 years; the sex distribution was almost 1:1. UICC staging of tumors (stages I, II, and III) showed the following figures: 301/36.4%, 265/32.1%, and 260/31.5%. In the majority of cases, an oncologically radical resection with high transection of the supplying vessels was performed. Intraoperative seeding of tumor cells was reported in 1.8% of the patients. In eight cases, the seeding was due to spontaneous rupture of the tumor. A mean of 13.5 lymph nodes in the resected specimen were investigated histopathologically (10.9 lymph nodes in stage I, 15 each in stages II and III). Depending on the individual hospital, we found a remarkable variation in the number of lymph nodes investigated. With a mean follow-up period of 2.1 years, Kaplan-Meier survival function showed acceptable results, both for rectal and colonic carcinoma, in comparison with conventional colorectal surgery. A stage-related consideration of the survival data yielded similar results. All in all, the results show that a laparoscopic colorectal procedure can meet oncological radicality criteria, even though certain reservations-in particular, in the case of procedures done with a curative intent-have not been completely eliminated.

Vasculocentricity Versus Cerebrocentricity: What Stroke-Related Baroreceptor Reflex Sensitivity Changes Might Be Telling Us

Vasculocentricity Versus Cerebrocentricity: What Stroke-Related Baroreceptor Reflex Sensitivity Changes Might Be Telling Us

Approaches to Analysis of Length of Hospital Stay Related to Antibiotic Therapy in a Randomized Clinical Trial: Linezolid versus Vancomycin for Treatment of Known or Suspected Methicillin‐Resistant Staphylococcus Species Infections

As length of hospital stay (LOS) represents about 70-90% of the total cost of treating serious infections, it represents a key variable in analyzing the health economic differences between treatments for hospitalized patients. In a retrospective analysis using LOS data from a multinational, randomized, phase III clinical trial, we examined two methods (the log-logistic model and Kaplan-Meier survival function) and three approaches (unadjusted total LOS, total LOS adjusted for nontreatment factors, and adjusted LOS based on antibiotic treatment [the antibiotic treatment LOS]) for estimating antibiotic treatment effect on LOS and determined if these approaches could reduce the variation in LOS and control for the imbalance between treatment groups. The trial enrolled patients who were hospitalized with known or suspected Staphylococcus species infections who received at least one dose of linezolid or vancomycin (intent-to-treat sample) and who continued taking the study drug for at least 7 days (clinically evaluable sample). In the intent-to-treat sample, the linezolid group had a 2- (unadjusted) or 4-day (adjusted for nontreatment factors) shorter LOS at the 25th percentile; a 1- or 2-day advantage, respectively, at the 50th percentile (median); and a 0.6- or 1.6-day mean LOS advantage, compared with the vancomycin group. With the antibiotic treatment LOS approach, the linezolid group had mean and median LOS reductions comparable to or greater than those seen in the nontreatment-factor-adjusted results. Results for the clinically evaluable sample were similar to those of the intent-to-treat sample, but the differences between the treatment groups were greater. Linezolid-treated patients had significant LOS reductions that otherwise would be masked without the use of more appropriate, but less commonly used, methods.

Empirical comparisons between Kaplan-Meier and Nelson-Aalen survival function estimators

The Kaplan-Meier is the most commonly used estimator of the survival function, while the Nelson-Aalen is an alternative estimator for the same function. There are many asymptotic results for these estimators in the literature. In particular, it is known that they are asymptotically equivalent. On the other hand empirical results comparing these estimators are difficult to obtain and they are necessary to guide applied statisticians. This paper addresses small-sample properties of these survival function estimators. Monte Carlo simulations are performed in order to compare both estimators. Percentile and survival fraction estimates of the survival function are used to attain this goal. The results show a slight superiority in favor of the Nelson-Aalen estimator in survival fraction estimation. However for percentile estimation the Kaplan-Meier estimator presents a better performance for decreasing failure rates while the Nelson-Aalen estimator provides better results for increasing failure rates.

Survival of Dicor glass-ceramic dental restorations over 16 years. Part III: Effect of luting agent and tooth or tooth-substitute core structure

Statement of Problem. The influence of different types of restorative design features on the long-term survival of Dicor glass-ceramic restorations is only partially understood. Purpose. This study examined the effect of different types of luting agents and preparation core structures on the survival of Dicor glass-ceramic restorations functioning in vivo. Material and Methods. A total of 1444 Dicor glass-ceramic restorations were placed on the teeth of 417 adults. Failure was defined as a restoration that required remake because of material fracture. The survival of restorations of different types, with different luting agents and preparation core structures, was described with Kaplan-Meier survival functions. The significance of differences in survival between different tooth or tooth-substitute preparation core structures and different luting agents was determined with the log-rank test. Results. The probability of survival of a typical acid-etched Dicor restoration luted to gold preparation core structures was 91% at 16 years compared with 75% for dentin preparation core structures (P<.01). The survival of acid-etched Dicor restorations luted to dentin preparations was significantly better than nonacid-etched restorations luted to dentin. Acid-etched Dicor restorations luted with resin composite exhibited a more favorable survival function than those luted with glass ionomer (P<.01) and zinc phosphate (P<.05). Differences between restorations luted with glass ionomer or zinc phosphate agents were not significant. Conclusion. Acid-etched Dicor restorations luted to gold preparation core structures exhibited significantly better intraoral survival than restorations luted to dentin. Acid-etched Dicor restorations survived better than nonacid-etched restorations when luted to dentin preparations. Acid-etched Dicor restorations luted with resin composite exhibited more favorable survivor functions than restorations luted with glass ionomer or zinc phosphate agents. (J Prosthet Dent 2001;86:511-19.)

Phase specific analysis of herpes zoster associated pain data: a new statistical approach

Herpes zoster or shingles is a frequent occurrence in both elderly individuals and immunocompromised hosts. The pain associated with herpes zoster is the most debilitating complication of the disease. It can be described as acute pain and post-herpetic neuralgia or zoster associated pain (ZAP). The latter definition encompasses pain from the onset of disease through its resolution and provides a convenient analytic tool for evaluation of antiviral therapy. A heuristic examination of ZAP historical data suggests the existence of three phases of pain resolution: the acute, subacute and chronic phases. The subacute and chronic phases comprise the post-herpetic neuralgia (PHN) stage. Common analytic methods, such as a Kaplan-Meier survival function or a Cox's model, have been used to assess the pain. However, such approaches do not adequately allow for phase comparison. Notably, in the clinical trial setting the comparison of specific treatment effects on the latter stages of pain are of the greatest medical relevance since this is the most debilitating phase of the illness. In order to incorporate the phase-specific information in the modelling of time to cessation of ZAP, we assumed the hazard function was a stepwise constant. Utilizing the full likelihood function, we obtained the maximum likelihood estimate for the transition times (that is, change-points), and other parameters of medical importance. The standard error of the change-point estimates were obtained through a bootstrapping method. The asymptotic properties of the parameter estimates are also discussed. Hence, the rates of pain resolution across all phases can be examined in order to precisely define the existence of multiple phases. In addition, the covariates effect can be examined across phases and populations, thereby allowing us to translate potential efficacy of a standard therapy to different populations. These results can be utilized in the design of clinical trials or in targeting the outcome for a specific phase while controlling for the effect of other variables.

Efficacy of automated auditory brainstem response hearing screening in very preterm newborns

Objective: To investigate the efficacy of an automated auditory brainstem response (AABR) hearing screening method in very preterm newborns in the neonatal intensive care setting. Study design: In this prospective cohort study, 90 consecutive preterm newborns (<32 weeks’ gestational age) had AABR hearing screening weekly from birth until a bilateral pass result was obtained. If the newborn had a unilateral pass result, AABR screening was repeated in the same week. Data were analyzed by using the Kaplan-Meier survival function technique, resulting in a cumulative pass rate curve for postmenstrual age. Cox’s regression method was used to analyze the effect of co-variables, such as sex and growth restriction, on pass rates. Results: Median gestational age was 29.5 weeks (range, 25.3-31.9 weeks), and median birth weight was 1115 g (range, 600-1960 g). Mean age was 6.2 days (SD 4.3) at first test, 15.7 (SD 8.1) at second test, and 21.4 (SD 8.6) at third test. Eighty percent (CI: 70.2%-89.8%) of the newborns passed at 30.3 weeks’ postmenstrual age, 90% (CI: 83.6%-96.4%) passed at 31.2 weeks, and 100% passed at 34 weeks’ postmenstrual age. The attainment of these pass rates correlated to postmenstrual age was not significantly influenced by sex, growth restriction, or gestational age at birth. Postnatal pass rates (in days) were strongly influenced by gestational age. Conclusion: AABR pass rates of >80% can be obtained from 30 weeks’ postmenstrual age. Therefore AABR neonatal hearing screening can be used before discharge from a neonatal intensive care unit. (J Pediatr 2001;138:674-8)

Cyclophosphamide therapy for lupus nephritis: Poor renal survival in black Americans

Intravenous cyclophosphamide is widely used to treat severe lupus nephritis. Yet interpretation of the literature is limited by the small number of patients evaluated with varied renal histology. We analyzed the renal outcome of cyclophosphamide therapy for diffuse proliferative lupus glomerulonephritis in a cohort of 89 patients from the Glomerular Disease Collaborative Network. Statistical analysis included Wilcoxon rank sum tests or continuity-adjusted chi-square for comparisons between groups. Kaplan-Meier survival function estimates were calculated for renal survival curves. Cox's proportional hazards models were employed for multivariate evaluation. The renal survival rate declined yearly from 89%, to 86%, 81%, 75%, and 71% at year 5. Renal survival was significantly worse in blacks compared with white patients. Among white patients 95% retained renal function at year 5 whereas black patients showed a progressive yearly decline from 85% at year 1, to 79%, 72%, 62%, and 58% at year 5. Racial differences in renal outcome were independent of age, duration of lupus, history of hypertension, hypertension control during therapy, and activity or chronicity indices on renal biopsy. The factors that predispose black patients to more aggressive and treatment-resistant lupus nephritis are not apparent.

Temporal influences on the prediction of postinfarction mortality by heart rate variability: a comparison with the left ventricular ejection fraction.

To examine the influence of the duration of follow up on the values of heart rate variability (HRV) and the left ventricular ejection fraction (LVEF) for predicting mortality after infarction. HRV is an index of autonomic balance that identifies patients at a high risk of arrhythmic events. The index is most depressed during the first few weeks after myocardial infarction whereas left ventricular function tends to deteriorate with time. The value of depressed HRV measured before discharge from hospital for predicting mortality after infarction should decline with time. The HRV and the LVEF were assessed in 433 survivors of a first acute myocardial infarction: HRV < 20 units and LVEF < 40% were taken as cut off points. Kaplan-Meier survival functions for total cardiac mortality and sudden cardiac death were calculated for the whole five year follow up period and for different intervening periods. During follow up of four weeks to five years there were 46 (10.6%) deaths and 15 (3.5%) patients died suddenly. Within the whole follow up period, HRV < 20 units and LVEF < 40% were both strongly associated with total cardiac mortality (p < 0.0001), but HRV was an independent predictor of total cardiac mortality only during the first six months of follow up. There were no deaths predicted by HRV < 20 units after the first year of follow up whereas LVEF < 40% had a sensitivity of 43% and a positive predictive accuracy of 9% for predicting death during this period. HRV < 20 units was better than LVEF < 40% in predicting sudden deaths during the first year of follow up but was an independent predictor only of those sudden deaths occurring within six months of infarction. The duration of follow up affects the prediction of sudden death and total cardiac mortality from HRV. Reduced HRV as measured before discharge from hospital does not seem to retain independent prognostic value after six months of follow up. These findings have potential implications for the serial evaluation of HRV and for the prevention of sudden death after myocardial infarction.