A pragmatic adaptive enrichment design for selecting the right target population for cancer immunotherapies

One of the challenges in the design of confirmatory trials is to deal with uncertainties regarding the optimal target population for a novel drug. Adaptive enrichment designs (AED) which allow for a data-driven selection of one or more prespecified biomarker subpopulations at an interim analysis have been proposed in this setting but practical case studies of AEDs are still relatively rare. We present the design of an AED with a binary endpoint in the highly dynamic setting of cancer immunotherapy. The trial was initiated as a conventional trial in early triple-negative breast cancer but amended to an AED based on emerging data external to the trial suggesting that PD-L1 status could be a predictive biomarker. Operating characteristics are discussed including the concept of a minimal detectable difference, that is, the smallest observed treatment effect that would lead to a statistically significant result in at least one of the target populations at the interim or the final analysis, respectively, in the setting of AED.     

不同化疗方案治疗晚期胃癌的疗效观察

目的比较FOLFOX、CF、DCFZ种化疗方案治疗晚期胃癌的效果。方法回顾分析173例分别采用FOLFOX、CF及DCF3种治疗方案的初治晚期胃癌患者：其中采用FOLFOX方案治疗71例,CF方案59例,DCF方案43例。每28天为1个疗程,至少完成2个周期的化疗后,评估患者的近期疗效和毒副反应。结果3种方案的近期疗效分别为：FOLFOX方案31．0％,CF方案27．1％,DCF方案55．8％,DCF方案疗效明显高于其他两个方案,差异有统计学意义（P〈0．01）。毒副反应主要为骨髓抑制和消化道反应,DCF方案发生几率较高,但患者均可耐受,差异无统计学意义（P〉0．05）。结论晚期胃癌患者应用DCF方案近期疗效较好,不良反应可以耐受,值得临床推广使用。     

A parallel analysis of individual and ecological data on residential radon and lung cancer in south-west England

Parallel individual and ecological analyses of data on residential radon have been performed using information on cases of lung cancer and population controls from a recent study in south-west England. For the individual analysis the overall results indicated that the relative risk of lung cancer at 100 Bq m⁻³ compared with at 0 Bq m⁻³ was 1.12 (95% confidence interval (0.99, 1.27)) after adjusting for age, sex, smoking, county of residence and social class. In the ecological analysis substantial bias in the estimated effect of radon was present for one of the two counties involved unless an additional variable, urban–rural status, was included in the model, although this variable was not an important confounder in the individual level analysis. Most of the methods that have been recommended for overcoming the limitations of ecological studies would not in practice have proved useful in identifying this variable as an appreciable source of bias.     

Ultraviolet radiation in urban ecosystems with consideration of effects on human health

Excess exposure to ultraviolet radiation (UV) from the sun, particularly the ultraviolet B (UVB), is cited as a cause or contributing factor for deleterious effects on human health, including skin cancers and cataracts. Rates of skin cancer have increased greatly in recent years, and increased UVB caused by reductions in stratospheric ozone may be responsible for some of the increase in rates, though quantified estimates of the effect of the UVB changes on health have low certainty. UVB exposure also affects the function of the immune system, and the potential resulting effects on infectious diseases and immunizations are a concern. Epidemiological considerations suggest that peoples' routine exposure to UV in urban areas can be significant in adverse health effects, particularly for young children. Projected trends of ozone indicate that agreements to limit ozone-depleting substances are slowing the UVB increase, but high levels will continue and apparently impact health to the middle of the current century. Urban trees greatly reduce ultraviolet irradiance in their shade when they obscure both the sun and sky. Where trees or other structures obscure only the sun, leaving much of the sky in view, UVB irradiance will be greater than suggested by the visible shade. Since air pollutants influence the UVB above the canopy, and the overlying atmosphere is usually more polluted in urban than rural areas, additional above-canopy monitoring of UV in urban areas is needed for comparison to existing rural monitoring sites. Such monitoring would facilitate the development of computer models of urban effects on UV, which are needed for epidemiological investigations, public education, and urban planning.     

Bounds in Competing Risks Models and the War on Cancer

In 1971, President Nixon declared war on cancer. Thirty years later, many declared this war a failure: the age‐adjusted mortality rate from cancer in 2000 was essentially the same as in the early 1970s. Meanwhile the age‐adjusted mortality rate from cardiovascular disease fell dramatically. Since the causes that underlie cancer and cardiovascular disease are likely dependent, the decline in mortality rates from cardiovascular disease may partially explain the lack of progress in cancer mortality. Because competing risks models (used to model mortality from multiple causes) are fundamentally unidentified, it is difficult to estimate cancer trends. We derive bounds for aspects of the underlying distributions without assuming that the underlying risks are independent. We then estimate changes in cancer and cardiovascular mortality since 1970. The bounds for the change in duration until death for either cause are fairly tight and suggest much larger improvements in cancer than previously estimated.     

Nurturing Life with Dreams: Therapeutic Dream Work with Cancer Patients

This paper describes the use of dream work as a component of individual counseling for cancer patients. Motivated by the work of experts in the field, who use dream work with their clients facing life-threatening illness and corroborated by a review of the literature, this therapeutic modality was introduced with cancer patients at a social service agency. The clinical work seems to indicate that the use of dreams helps create a safe environment for therapy by encouraging clients to discuss the emotional aspects of their disease and introducing topics, like death and dying, which are normally difficult to discuss.     

Parameterization and inference for nonparametric regression problems

We consider local likelihood or local estimating equations, in which a multivariate function () is estimated but a derived function () of () is of interest. In many applications, when most naturally formulated the derived function is a non-linear function of (). In trying to understand whether the derived non-linear function is constant or linear, a problem arises with this approach: when the function is actually constant or linear, the expectation of the function estimate need not be constant or linear, at least to second order. In such circumstances, the simplest standard methods in nonparametric regression for testing whether a function is constant or linear cannot be applied. We develop a simple general solution which is applicable to nonparametric regression, varying-coefficient models, nonparametric generalized linear models, etc. We show that, in local linear kernel regression, inference about the derived function () is facilitated without a loss of power by reparameterization so that () is itself a component of (). Our approach is in contrast with the standard practice of choosing () for convenience and allowing ()> to be a non-linear function of (). The methods are applied to an important data set in nutritional epidemiology.     

Radon as a Tracer of Lung Changes Induced by Smoking

After smoking, exposure to radon and its progeny is the second leading cause of lung cancer. The probability of inducing lung carcinomas by inhaled radon progeny depends on the deposited radiation dose, and is significantly affected by physiological and morphometric changes induced by smoking. Due to irritation of the airways, the inhalation of cigarette smoke leads to the hyperproduction of mucus. Two concurrent processes occur: on one hand, increased production of mucus protects the target cells against radiation damage; on the other hand, in the case of long-term smokers, a chronic lung obstruction develops, causing an increase in the radiation dose to the lungs. Depending on the duration and intensity of smoking, these processes contribute to the final radiation dose with different weights. The primary objective of this study was to investigate to what extent these smoke-induced changes can modify the resulting absorbed dose of inhaled radon progeny relative to healthy nonsmokers. Since the bronchial dose depends on the degree of lung tissue damage, we have used this dose as a tool for detecting the effects of smoking on the lung epithelium. In other words, the biological effect of radon served as a tracer of changes induced by smoking.     

How Tautological Are Interspecies Correlations of Carcinogenic Potencies?

Crouch and Wilson demonstrated a strong correlation between carcinogenic potencies in rats and mice, supporting the extrapolation from mouse to man. Bernstein et al. , however, show that the observed correlation is mainly a statistical artifact of bioassay design. Crouch et al. have a comeback. This paper will review the arguments and present some new data. The correlation is largely (but not totally) tautological, confirming results in Bernstein et al.     

Biological Models of Carcinogenesis and Quantitative Cancer Risk Assessment

Biologically-based models of carcinogenesis were originally developed to explain certain quanti-tative phenomena associated with carcinogenesis, and to provide a framework within which questions regarding the process could be addressed. Some limitations in the use of these models for quantitative cancer risk assessment are discussed.