Mendelian randomization analysis with survival outcomes

Mendelian randomization (MR) is an established approach for assessing the causal effects of heritable exposures on outcomes. Outcomes of interest often include binary clinical endpoints, but may also include censored survival times. We explore the implications of both the Cox proportional hazard model and the additive hazard model in the context of MR, with a specific emphasis on two‐stage methods. We show that naive application of standard MR approaches to censored survival times may induce significant bias. Through simulations and analysis of data from the Women's Health Initiative, we provide practical advice on modeling survival outcomes in MRs.     

Cancer patients who refuse treatment

The value of cancer treatment was assessed using a natural experiment where patients who refused treatment served as no-treatment controls in a situation where withholding treatment to form a control group is unethical. Each cancer patient who refused treatment in Alberta, Canada between 1975 and 1988 was compared with five subjects who accepted treatment, matched on cancer site, age, number of cancers, and time period. Variables associated with treatment-refusal were included in Cox's proportional hazards model of survival, with death from cancer as the endpoint and deaths from other causes as censored observations. Treatment was refused at a rate of 7.5 per 1,000. One-third of patients who refused treatment had lung cancer and most had unstaged disease. Treatment refusal was associated with a difference in median survival of approximately nine months. Site-specific analyses showed a range of effects. Case fatality among the treated patients fell by approximately 10 percent during the 14-year study period. Even in advanced disease, treatment can result in improved survival. However, the results of this study must be interpreted with caution and cannot be generalized to all cancer patients.Dr Huchcroft and Mr Snodgrass are with the Alberta Cancer Board, Calgary, Alberta, Canada. Address correspondence to Dr Shirley Huchcroft, Senior Scientist, Division of Epidemiology and Preventive Oncology, Alberta Cancer Board, Calgary, Alberta, Canada T2N 4N2.     

Autologous peripheral blood stem cell transplantation in the patients with hematologic malignancies and solid tumors

Objective To evaluate the long-term therapeutic effects of autologous peripheral blood st em cell transplantation (auto-PBSCT) on the treatment of hematological and soli d tumors. Methods Fifty-one patients were recruited in this auto-PBSCT study, in which several p otentially important parameters were studied including the optimal time for stem cell co llection, the dose of stem cell reinfusion, the time of hematopoietic reconsti tution, the disease free survival (DFS) and overall survival (OS), complication s related to transplantation, and maintenance chemotherapy after auto-PBSCT. Results After APBSCT, 3-year and 5-year survival rates of NHL were 83.3%; those of AM L were 74.7%; those of MM were 37.9% and 19%; those of ALL were 40% and 0% res pectively. Hematopoietic reconstitution was greatly promoted by granulocyte col ony stimulating factor (G-CSF). The mean time for patients’ neutrophil to reco ver up to >0.5×10(9) /L after APBSCT was 11.14 days in the group of the patien ts receiving G-CSF in contrast to 17.6 days in the group receiving no G-CSF. The most common complications of transplantation were fever, liver dysfunction and hypokalaemia, which were curable. No death was due to transplantation related complications.Conclusion Comparing with conventional chemotherapy, our study suggests that auto-PBSCT i s a very important therapeutic option that can significantly improve the prognos is in the patients with hematological and solid tumors, especially in the patien ts with AML and NHL.     

喉大部切除联合双蒂肌皮瓣声门整复术的疗效

目的 探讨喉癌手术的疗效,提高喉癌病人的生存质量。方法 ５３例男性声门型鳞状细胞癌采用垂直前侧位喉大部切除颈前皮瓣和肌筋膜双蒂整复术。术后辅以放疗。结果 ５３例病人术后吞咽及发音功能基本恢复,拔管率９２．５％,３年生存率为８２．５％,５年生存率为７６．８％。结论 对一侧声带癌向前至声带前联合并累及对侧声带前１／３的病人,采用垂直前侧位喉大部切除颈前皮瓣和肌筋膜双蒂整复是一种有效的术式,在切除肿瘤的     

4-硒硫酸酯多糖的体内抗瘤作用

目的　观察 4-硒硫酸酯多糖 (Se-carra)的体内抗瘤作用。方法　于小鼠右腋皮下接种瘤细胞 2 4h后开始给药 ,连续 10天 ,观察其抑瘤率 ;小鼠腹腔接种肿瘤细胞前或接种后连续给药 10天 ,观察动物的生存时间。结果　 4-硒硫酸酯多糖能明显抑制肿瘤细胞的生长 ,延长小鼠的生存期。结论　 4-硒硫酸酯多糖体内给药有良好的抗瘤效果 ,值得进一步研究。     

Decrease of Interleukin-2 secretion is a new independent prognostic factor associated with poor survival in patients with small-cell lung cancer

Background: We have previously shown that suppression of Interleukin-2(IL-2) secretion was mediated by transforming growth factor (TGF) 1secreted by small-cell lung cancer (SCLC) tumor cells. We have also shown thatIL-2 secretion was significantly impaired in patients with SCLC at the timeof diagnosis. Reconstitution of cytokine secretion correlated with reductionof tumor load. These data suggested that the immune system was suppressed bythe tumor. To address the clinical relevance of cytokine suppression in SCLC,we investigated the correlation of the level of IL-2 secretion with survival.Patients and methods: The significance of correlations between singleparameters in the test groups was calculated by using the linear regressionanalysis, the Wilcoxon rank sum test and the exact test according to Fisher.Using the Kaplan–Meier method, the log-rank test and the Cox-regressionmodel, we analysed the relation of IL-2 secretion in whole blood cell culturesfrom 52 patients with SCLC at the time of diagnosis to established prognosticfactors relevant for survival in SCLC.Results: Impairment of IL-2 secretion significantly correlates to survivalin SCLC (P = 0.004). Further univariate and multivariate analysis showed thatthis prognostic factor is independent from other factors of prognosticrelevance in SCLC, namely stage of disease, neurone specific enolase (NSE),lactate dehydrogenase (LDH), age, and sex. More important, the prognosticvalue of IL-2 secretion is comparable to the most predominant prognosticfactors for survival in SCLC identified so far. In the final model of the coxregression analysis, the P-value for IL-2 secretion in relation to stage ofdisease was 0.012 and 0.019, respectively.Conclusions: IL-2 secretion at the time of diagnosis represents anindependent prognostic factor for survival in SCLC. Although its prognosticvalue has to be confirmed in a larger group of patients, our resultsdemonstrate that IL-2 secretion may play an important role in diagnosis andtreatment of SCLC. Moreover, in contrast to other prognostic factors,impairment of IL-2 secretion may help to understand immunosuppression in SCLCand, thus, important elements of the pathogenesis of this disease.     

Pretreatment prognostic factors for survival in small-cell lung cancer: A new prognostic index and validation of three known prognostic indices on 341 patients

Aims: a) To identify which pretreatment clinical or blood parameters werepredictive of patient survival in small-cell lung cancer (SCLC) in aretrospective analysis. b) To validate three known prognostic indices: RoyalMarsden Model (index 1), London Group (index 2) and Manchester Score (index3).Patients and methods: From 1981 to 1993, 341 SCLC patients were treatedwith chemotherapy with or without surgery or radiotherapy. Univariate andmultiple regression analyses of survival were performed and the feasibilityof these models was explored, index 1: Karnofsky index, albumin, sodium andalkaline phosphatase; index 2: ECOG performance status (PS), albumin andalanine transaminase; and index 3: lactate dehydrogenase (LDH), diseaseextent, sodium, Karnofsky index, alkaline phosphatase and bicarbonate.Results: Significant prognostic factors for survival after univariate andmultiple regression analysis were: disease extent, PS, creatine kinase,neutrophilia, LDH, hypoalbuminemia, hyperglycemia and bicarbonate. A newprognostic index was performed that included LDH, hypoalbuminemia,neutrophilia, disease extent and PS. It defined three prognostic groups (PG).Median survival and two-year survival for these PG were 12.3, 8 and 3.4 monthsand 16.5%, 2.3% and 0%, respectively. The following PGwere identified after application of the three models proposed: Index 1identified two PG with 0% and 16.6% two-year survival (P <0.001); index 2 detected three PG with 0%, 5% and 15.7%two-year survival (P < 0.001) and index 3 detected three PG with 0%,2.5% and 16.2% two-year survivals, respectively (P < 0.001).Conclusion: A new prognostic index is proposed allowing identification ofthree different PG. The feasibility of three known prognostic models wasvalidated and demonstrated. Variables other than disease extent or PS (albuminor LDH) should be taken into account in designing future clinical trials.     

Obesity and subcutaneous fat patterning in relation to survival of postmenopausal breast cancer patients participating in the DOM-project

Summary The effect of obesity and fat distribution on survival of breast cancer patients was studied prospectively in 241 women with a natural menopause who participated in a breast cancer screening project, the DOM-project in Utrecht, The Netherlands. Mean follow-up time was 9.1 years and endpoint of interest was death from breast cancer. Fat distribution was assessed by contrasting groups of subscapular and triceps skinfold thickness.No significant differences in survival time between more obese (Quetelet's index 26 kg/m²) and leaner (Quetelet's index < 26 kg/m²) patients or between patients with central fat distribution and patients with peripheral fat distribution were observed. Analyses were stratified by axillary node status, estrogen receptor status, and way of detection (by first screening or afterwards). Results of the stratified analyses were suggestive of a modifying effect of these factors.The absence of an association between obesity and survival time might be explained by two counteracting mechanisms. On the one hand obesity might be related to impaired survival, due to a tumor growth promoting effect of extra-ovarian estrogens. On the other hand obesity might be related to improved survival in a screened population, because obese patients profit more from screening by earlier detection of tumors than leaner counterparts.     

Gender and Ethnic Differences in Survival in a Cohort of HIV Positive Clients

Objectives: The purpose of this study was to examine gender and ethnic differences in survival of persons receiving treatment for HIV infection to determine if differences existed, and if they did, to assess the possibility of explaining these differences by examining other factors, such as age, disease severity when beginning treatment, alcohol, illicit drugs, tobacco, educational level, living arrangements, antiretroviral treatment, PCP prophylaxis, sexually transmitted diseases, mode of transmission and opportunistic infections.

Design: A retrospective cohort study of all clients receiving treatment at an HIV only clinic from its opening in early 1988 until the end of May 1993. Statistical methods used to examine the data included incidence density ratios, Kaplan‐Meier survival curves, Breslow (generalized Wilcoxon) tests of equality of survival curves and Cox proportional hazards models both with and without time dependent covariates.

Results: In the cohort (37% African American, 7% Hispanic American and 25% female), 220 deaths occurred during 1223 person years of follow‐up. Compared to European American males, the following incidence density ratios were observed: European American females: 0.50, Hispanic American females: 0.70, Hispanic American males: 0.96, African American females: 1.28 and African American males: 2.38. The differences were noted above for gender/ethnicity groups were significant at the p < 0.0001 level. After adjusting for disease stage (as measured by laboratory testing of CD4 positive T‐lymphocytes), educational level, and age, no differences in survival by gender or ethnicity remained. Disease stage and educational level had the greatest prognostic significance.

Conclusions: European Americans entered treatment at a much earlier disease stage (as measured by CD4 positive T‐lymphocyte counts) and had higher educational levels (a surrogate for socioeconomic status) than African Americans. These factors may explain the longer survival in European Americans as compared to African Americans in this cohort.     

The case for liver transplantation in end-stage alcoholic liver disease

Liver transplantation is now a routine procedure and is seen as a valid treatment option for end-stage liver disease. Alcoholism has been regarded as a relative or absolute contraindication to liver transplantation in many transplant units. Recent data document a success rate for transplantation in alcoholic patients that equals that in other patient groups. Issues relating to the ethical and scientific arguments surrounding this complex area of treatment are discussed. It is concluded that individual patients should be assessed in their own right for this treatment option. It is argued that patient groups should not be denied access to specific life-saving treatments.