Kevin C. Cain

Analysis of survival by tumor response.

The common practice of comparing the survival of responders and nonresponders when reporting the results of cancer chemotherapy treatment is investigated. The usual method of comparing responders and nonresponders is biased in favor of responders, and these results are frequently misinterpreted as providing evidence that response prolongs survival, or that the treatment under study is effective. Two valid methods for comparing responders and nonresponders are discussed and recommendations are made concerning the analysis of survival by response. A comparison of survival by response category may be useful descriptively, but such a comparison should not be used for inference concerning treatment effectiveness.

Cerebrospinal Fluid Biomarkers for Parkinson Disease Diagnosis and Progression

There is a clear need to develop biomarkers for Parkinson disease (PD) diagnosis, differential diagnosis of Parkinsonian disorders, and monitoring disease progression. We and others have demonstrated that a decrease in DJ‐1 and/or α‐synuclein in the cerebrospinal fluid (CSF) is a potential index for Parkinson disease diagnosis, but not for PD severity.

The effect of intensive endurance exercise training on body fat distribution in young and older men

Little is known about the effects of exercise interventions on the distribution of central and/or intra-abdominal (IA) fat, and until now there were no studies in the elderly. Therefore, in this study we investigated the effects of an intensive 6-month endurance training program on overall body composition (hydrostatic weighing), fat distribution (body circumferences), and specific fat depots (computed tomography [CT]), in healthy young (n = 13; age, 28.2 +/- 2.4 years) and older (n = 15; age, 67.5 +/- 5.8 years) men. At baseline, overall body composition was similar in the two groups, except for a 9% smaller fat free mass in the older men (P less than .05). The thigh and arm circumferences were smaller (P = .001 and P less than .05, respectively), while the waist to hip ratio (WHR) was slightly greater in the older men (0.92 +/- 0.04 v 0.97 +/- 0.04, P less than .01). Compared with the relatively small baseline differences in body composition and circumferences, CT showed the older men to have a twofold greater IA fat depot (P less than .001), 48% less thigh subcutaneous (SC) fat (P less than .01), and 21% less thigh muscle mass (P less than .001). Following endurance (jog/bike) training, both the young (+18%, P less than .001) and the older men (+22%, P less than .001) significantly increased their maximal aerobic power (VO2max). This was associated with small but significant decrements in weight, percent body fat, and fat mass (all P less than .001) only in the older men.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of physical conditioning on fibrinolytic variables and fibrinogen in young and old healthy adults.

BackgroundThe effects of 6 months of intensive endurance exercise training on resting tissue-type plasminogen activator (t-PA) activity, plasminogen activator inhibitor type 1 (PAI-1) activity, t-PA antigen, and fibrinogen were studied in 10 young (24–30 years) and in 13 old male subjects (60–82 years). Methods and ResultsAfter training, maximum oxygen consumption was increased in the young group by 18% (44.9±5.0 to 52.9±6.6 ml/kg/min, p <0.001), whereas it was increased in the old group by 22% (29.0±4.2 to 35.5±3.6 ml/kg/min, p < 0.001). The young group had no significant changes in any of the measured variables, whereas the old group had a 39% increase in t-PA activity (0.82 + 0.47 to 1.14 + 0.42 IU/ml, p < 0.03), a 141% increase in the percentage of t-PA in the active form (11.1+7.7 to 26.8 + 15.1%, p < 0.01), a 58% decrease in PAI-1 activity (8.4 + 4.9 to 3.5±1.7 AU/mI, p < 0.01), and a 13% decrease in fibrinogen (3.57±0.79 to 3.11±0.52 gIl, p < 0.01). ConclusionsWe conclude that intensive exercise training enhances resting t-PA activity and reduces fibrinogen and PAI-1 activity in older men. These effects are potential mechanisms by which habitual physical activity might reduce the risk of cardiovascular disease.

Bodies in motion: monitoring daily activity and exercise with motion sensors in people with chronic pulmonary disease.

A primary goal of pulmonary rehabilitation is to improve health and life quality by encouraging participants to engage in exercise and to increase daily physical activity. The recent advent of motion sensors, including digital pedometers and accelerometers that measure motion as a continuous variable, have added precision to the measurement of free-living daily activity. Daily activity and exercise are variables of keen interest to proponents of the national health agenda, epidemiologists, clinical researchers, and rehabilitation interventionists. This paper summarizes issues related to conceptualizing and monitoring activity in the rehabilitation setting; reviews motion sensor methodology; compares motion-sensing devices; presents analysis issues and current and potential applications to the pulmonary rehabilitation setting; and gives practical applications and limitations.

Analysis of Survival by Tumor Response and Other Comparisons of Time-to-Event by Outcome Variables

Twenty-five years ago, in its first volume, the Journal of Clinical Oncology published our methodologic article, which highlighted an inappropriate analytic approach then in common use and suggested alternative unbiased techniques. Cited more than 380 times, this article and similar ones by other authors have had a large impact on how results from early-phase clinical trials are reported, almost completely eliminating so-called survival by tumor response analyses from the oncology literature. The success of treatments for patients with advanced cancers at diagnosis or recurrence is often assessed by computing overall response rates and survival from the start of treatment. Before 1983, analysis of survival by tumor response category was commonly included as part of the reports of these treatments. Patients were characterized as responders or nonresponders, estimates of survival from the start of treatment were calculated for each responder category, and differences in survival by these tumor response categories were compared using a significance test appropriate for time-to-event data. These analyses had been used to bolster the claim of benefit for the treatment, often as a surrogate for a randomized trial. Responders benefited from the therapy and thus constituted the treatment group. Nonresponders did not benefit, and thus their survival could be considered similar to that for untreated patients. Similarly, these analyses had also been used to argue that therapies that increase the response rate should necessarily result in increased survival. In March 1983, Weiss et al reported the results of a review of articles published in Cancer or Cancer Treatment Reports and found 228 articles presenting data on responders and nonresponders, with 61% containing formal statistical comparisons of survival by tumor response category. They identified problems in the interpretation of these comparisons. In November 1983, our article in the Journal of Clinical Oncology, “Analysis of Survival by Tumor Response,” was published. We showed that the usual methods of comparing responders with nonresponders were wrong, leading to biased estimates of the survival distributions, invalid statistical tests, and misleading conclusions. This bias results in part from the fact that responders must live long enough for response to be observed; there is no such requirement for nonresponders. We described several valid approaches to comparing survival by response category. One approach, the landmark method, determines each patient’s response at some fixed time point, with survival estimates calculated from that time point and associated statistical tests being conditional on patients’ landmark responses. Note that in this method, patients who die before the landmark time point are excluded from the analysis. An alternative approach treats response status as a timedependent covariate, where all patients begin in the nonresponse state and patients move to the response state at the time of their response. Shortly thereafter, Simon and Makuch proposed a method of obtaining estimates of survival probabilities for responders and nonresponders, combining ideas from the landmark and time-dependent covariate approaches. Even when these analyses were performed appropriately, we argued that longer survival for responders, as compared with nonresponders, could not be used to conclude that response caused longer survival. Response might act as a surrogate marker for prognostically favorable patients. Thus responders may survive longer than nonresponders, not because of an effect of response on survival, but because response identifies patients with pretreatment characteristics that favor longer survival. It is generally difficult to distinguish between cases where response prolongs survival and cases where it simply acts as a marker for favorable-prognosis patients. In 1985, Cancer Treatment Reports indicated it would not publish comparisons of survival by tumor response. Notwithstanding the reports by Weiss et al and us, Anderson and Davis showed that between July 1984 and June 1985, the Journal of Clinical Oncology published 18 articles that included analyses of survival by tumor response, 10 of which provided inappropriate statistical comparisons of survival of responders and nonresponders. They suggested that the Journal of Clinical Oncology follow the lead of Cancer Treatment Reports and no longer publish articles that include survival by tumor response. An editorial accompanying the letter by the then-editor of the Journal of Clinical Oncology, Joseph Bertino, MD, indicated that “authors should not compare survival of responders and nonresponders without discussing the limitations of such a comparison”. JOURNAL OF CLINICAL ONCOLOGY C E L E B R A T I N G 2 5 Y E A R S O F J C O VOLUME 26 NUMBER 24 AUGUST 2

Symptoms across the menstrual cycle in women with irritable bowel syndrome.

OBJECTIVE:The purpose of this study was to describe the patterns of GI, somatic, and psychological symptoms across the menstrual cycle in women with irritable bowel syndrome, and to determine whether symptoms differed by oral contraceptive use or predominant bowel pattern.METHODS:A daily diary was used to assess symptoms across one menstrual cycle. Repeated-measures analysis of covariance, controlling for age and body mass index, was used to compare patterns of symptoms across the menstrual cycle by oral contraceptive use and predominant bowel pattern (diarrhea, constipation, alternating). Data from control women are presented for comparison.RESULTS:For somatic and psychological as well as GI symptoms, women with irritable bowel syndrome had higher symptom severity than did controls. Women with irritable bowel syndrome using oral contraceptives had lower cognitive, anxiety, and depression symptoms (p < 0.05, but not significant after multiple comparison adjustment), but no differences were seen for most symptoms of irritable bowel syndrome. All symptoms except diarrhea were highest in the alternating group and lowest in the diarrhea group, with the constipation group either intermediate or close to the alternating group. This pattern was significant after multiple comparisons adjustment for GI symptoms, and trending toward significance (p < 0.05, but not significant after multiple comparison adjustment) for menstrual, sleep, and cognitive symptoms. The strongest menstrual cycle effect was seen in somatic and menstrual symptoms. The pattern of symptoms over the menstrual cycle did not differ by predominant bowel pattern or by oral contraceptive use.CONCLUSIONSMany of the symptoms examined differed by predominant bowel pattern and menstrual cycle phase, not just the GI symptoms. The menstrual cycle variation was similar regardless of oral contraceptive use or predominant bowel pattern.

Sleep disturbance influences gastrointestinal symptoms in women with irritable bowel syndrome

This analysis evaluated the association between sleep disturbance and gastrointestinal symptoms in women with and without irritable bowel syndrome (IBS), and examined the role of psychological distress in this relationship. Women with IBS (N = 82) reported considerably higher levels of sleep disturbance compared to controls (N = 35), using both retrospective seven-day recall and daily diary recall for two menstrual cycles (P < 0.05 on 8 of 10 measures). We used daily diary data to estimate the association between sleep disturbance and gastrointestinal symptoms, both across women (ie, whether women with high average sleep disturbance have higher average gastrointestinal symptoms) and within woman (ie, whether poorer than average sleep on one night is associated with higher than average gastrointestinal symptoms the following day). The regression coefficients for the across-women effect are large and highly significant in both groups (IBS, β ± se = 0.46 ± 0.08, P < 0.001; controls, 0.57 ± 0.13, P < 0.001). The regression coefficients for the within-woman effect are considerably smaller and statistically significant only in the IBS group (IBS, 0.06 ± 0.02, P = 0.006; control, 0.01 ± 0.03, P = 0.691). These regression coefficients showed little change when daily psychological distress or stress was controlled for, the one exception being the coefficient for the across-women effect in the IBS group, which decreased substantially but still remained highly significant. Because it is possible that gastrointestinal symptoms could, in fact, cause poor sleep, we also fitted the temporally reversed model to evaluate the association between gastrointestinal symptoms on one day and sleep disturbance that night. The within-woman regression coefficients were nonsignificant in both the IBS and control groups. In conclusion, these results are consistent with the hypothesis that poor sleep leads to higher gastrointestinal symptoms on the following day among women with IBS.

The relationship between daily life stress and gastrointestinal symptoms in women with irritable bowel syndrome.

Research on irritable bowel syndrome (IBS), a functional disorder of the gastrointestinal (GI) system, has linked GI symptoms to stress. This study examined the relationship between daily stress and GI symptoms across women and within woman in IBS patients (n = 26), IBS nonpatients (IBS-NP; n = 23), and controls (n = 26), controlling for menstrual cycle phase. Women (ages 20–45) completed daily health diaries for two cycles in which they monitored daily GI symptoms and stress levels. The Life Event Survey (LES) was used as a retrospective measure of self-reported stress. The across-women analyses showed higher mean GI symptoms and stress in the IBS and IBS-NP groups relative to controls but no group differences in LES scores. The within-woman analyses found a significant and positive relationship between daily stress and daily symptoms in both the IBS-NP and the IBS groups. Controlling for menstrual cycle had no substantial impact on the results.

Autonomic Nervous System Function in Women with Irritable Bowel Syndrome

Autonomic nervous system (ANS) balance was assessed in women with and without irritable bowel syndrome (IBS) using laboratory tests of function (ie, expiratory/inspiratory ratio, Valsalva, posture changes, and cold pressor) and spectral and nonspectral measures of heart rate variability (HRV). Women with (N = 103) and without IBS (N = 49) were recruited, interviewed, then completed a laboratory assessment and wore a 24-hr Holter monitor Analysis using the entire sample showed little difference between IBS and control women and between subgroups with IBS on either laboratory measures or 24-hr HRV measures. However, analysis restricted to those women with severe IBS symptoms showed quite pronounced differences between two IBS subgroups on 24-hr HRV measures. Parasympathetic tone was significantly lower and ANS balance was significantly higher in the constipation-predominant compared to the diarrhea-predominant group. Subgroups of women with IBS do differ in ANS function as measured by 24-hr HRV; however, these differences are only apparent among women with severe symptoms. These findings point out the importance of considering symptom severity when interpreting studies of IBS.