Outcomes and relapse patterns following chemotherapy in advanced Hodgkin lymphoma in the positron emission tomography era.

BACKGROUND: This study evaluated relapse patterns and survival in advanced Hodgkin lymphoma (HL) patients treated with doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) with positron emission tomography (PET) used for staging and response assessment. PATIENTS AND METHODS: Patients aged 18 years or above with newly diagnosed histologically proven Stage III or IV HL treated with ABVD at Calvary Mater Newcastle from January 2005 to December 2012 were included in this study. All patients underwent pre-chemotherapy staging with 18F-fluorodeoxyglucose PET or PET/computed tomography and post-chemotherapy PET or PET/computed tomography for the assessment of response. RESULTS: Forty-three patients were included in the study. The 5-year disease-free survival, progression-free survival and overall survival were 88%, 74% and 86%, respectively. PET complete response was seen in 35 patients (81%), and the 5-year overall survival for this group was 94%. Relapse following a PET complete response was low (three patients) and occurred predominantly at the initial sites of disease. Four of five patients with bulky disease received consolidative radiotherapy and no in-field relapses were observed. CONCLUSION: Advanced stage HL with a PET complete response following ABVD is associated with an excellent prognosis.

Dosimetric comparison of optimization methods for multichannel intracavitary brachytherapy for superficial vaginal tumors.

PURPOSE: Multichannel vaginal applicators allow treatment of a more conformal volume compared with a single, central vaginal channel. There are several optimization methods available for use with multichannel applicators, but no previous comparison of these has been performed in the treatment of superficial vaginal tumors. Accordingly, a feasibility study was completed to compare inverse planning by simulated annealing (IPSA), dose point optimization (DPO), and graphical optimization for high-dose-rate brachytherapy using a multichannel, intracavitary vaginal cylinder. METHODS AND MATERIALS: This comparative study used CT data sets from five patients with superficial vaginal recurrences of endometrial cancer treated with multichannel intracavitary high-dose-rate brachytherapy. Treatment plans were generated using DPO, graphical optimization, surface optimization with IPSA (surf IPSA), and two plans using volume optimization with IPSA. The plans were evaluated for target coverage, conformal index, dose homogeneity index, and dose to organs at risk. RESULTS: Best target coverage was achieved by volume optimization with IPSA 2 and surf IPSA with mean V100 values of 93.89% and 91.87%, respectively. Doses for the most exposed 2-cm(3) of the bladder (bladder D2cc) was within tolerance for all optimization methods. Rectal D2cc was above tolerance for one DPO plan. All volume optimization with IPSA plans resulted in higher vaginal mucosa doses for all patients. Greatest homogeneity within the target volume was seen with surf IPSA and DPO. Highest conformal indices were seen with surf IPSA and graphical optimization. CONCLUSIONS: Optimization with surf IPSA was user friendly for the generation of treatment plans and achieved good target coverage, conformity, and homogeneity with acceptable doses to organs at risk.

Obstacles to participation in randomised cancer clinical trials: a systematic review of the literature.

Accrual to clinical trials continues to be a problem in many countries including Australia despite its fundamental importance to the progress of evidence-based medicine. This paper reviews the current literature addressing the obstacles to accrual excluding those related to protocol design. An electronic search of the literature identified publications in oncology specifically addressing the obstacles to participation in clinical trials. This search was supplemented by searches of key oncology journals. Obstacles fall into three main categories - clinician, patient and system; however, there are overlaps between categories. Clinician behaviour is the most important of these. Exclusion of patients for reasons other than defined eligibility criteria, concerns about increased time requirements, and suboptimal communication with patients all affect accrual. Risk management strategies for clinical trials need to be individualised to address the obstacles most likely to negatively impact on accrual. Communication between clinician and patient appears to be a greater issue than previously recognised. Time concerns need to be addressed as generational change affects the expectations of the medical workforce.

Diabetic polyneuropathies: update on research definition, diagnostic criteria and estimation of severity.

Prior to a joint meeting of the Neurodiab Association and International Symposium on Diabetic Neuropathy held in Toronto, Ontario, Canada, 13-18 October 2009, Solomon Tesfaye, Sheffield, UK, convened a panel of neuromuscular experts to provide an update on polyneuropathies associated with diabetes (Toronto Consensus Panels on DPNs, 2009). Herein, we provide definitions of typical and atypical diabetic polyneuropathies (DPNs), diagnostic criteria, and approaches to diagnose sensorimotor polyneuropathy as well as to estimate severity. Diabetic sensorimotor polyneuropathy (DSPN), or typical DPN, usually develops on long-standing hyperglycaemia, consequent metabolic derangements and microvessel alterations. It is frequently associated with microvessel retinal and kidney disease-but other causes must be excluded. By contrast, atypical DPNs are intercurrent painful and autonomic small-fibre polyneuropathies. Recognizing that there is a need to detect and estimate severity of DSPN validly and reproducibly, we define subclinical DSPN using nerve conduction criteria and define possible, probable, and confirmed clinical levels of DSPN. For conduct of epidemiologic surveys and randomized controlled trials, it is necessary to pre-specify which attributes of nerve conduction are to be used, the criterion for diagnosis, reference values, correction for applicable variables, and the specific criterion for DSPN. Herein, we provide the performance characteristics of several criteria for the diagnosis of sensorimotor polyneuropathy in healthy subject- and diabetic subject cohorts. Also outlined here are staged and continuous approaches to estimate severity of DSPN.

Signs and symptoms versus nerve conduction studies to diagnose diabetic sensorimotor polyneuropathy: Cl vs. NPhys trial.

The purpose was to test whether physicians can validly and reproducibly diagnose diabetic sensorimotor polyneuropathy (DSPN). Twelve physicians assessed 24 patients with diabetes mellitus (DM) on consecutive days (576 examinations) with physical features and voice disguised. Results were compared to gold standard 75% group diagnosis (dx) and a nerve conduction score (Sigma5 NC nds). Masking of patients was achieved. Reproducibility measured by the kappa coefficient and compared to Sigma5 NC nd varied considerably among physicians: median and ranges: signs 0.8 (0.32-1.0); symptoms 0.79 (0.36-1.0), and diagnoses 0.47 (0.33-0.84), both low and high scores indicating poor performance. There was substantial agreement between 75% group dx and confirmed NC abnormality (abn). As compared to Sigma5 NC, individual physicians' clinical dx was excessively variable and frequently inaccurate. Study physician dx from signs and symptoms were excessively variable, often overestimating DSPN. Specific approaches to improving clinical proficiency should be tested.

Body fat distribution, adipocyte size, and metabolic characteristics of nondiabetic adults.

CONTEXT: It is unclear whether adipocyte size or body fat distribution is most strongly linked to the metabolic complications of obesity. OBJECTIVE: Our objective was to test whether adipocyte size better predicts metabolic characteristics of obesity than body composition. DESIGN, PARTICIPANTS, AND SETTING: We analyzed the relationship between metabolic and anthropometric data collected from 432 largely Caucasian research volunteers (264 women) participating in studies conducted in the Mayo General Clinical Research Center between 1995 and 2008. MAIN OUTCOME MEASURES: Metabolic variables included fasting plasma glucose, insulin, and triglyceride concentrations. Anthropometric variables included body composition, fat distribution, and sc abdominal and femoral adipocyte size. RESULTS: Using both univariate and multivariate regression analysis, fasting triglyceride in both men and women was best predicted by computed tomography of visceral fat area. Fasting insulin concentrations were best predicted by sc abdominal fat area in women (r(2) = 0.40; P < 0.01) and body mass index in men (r(2) = 0.53; P < 0.0001); adipocyte size did not contribute independently. In men, fasting glucose concentrations were predicted by femoral adipocyte size (partial r(2) = 0.07; P = 0.002), body mass index (partial r(2) = 0.03; P = 0.07), and age (partial r(2) = 0.02; P = 0.06). In women, fasting glucose was predicted by abdominal sc fat area (partial r(2) = 0.12; P < 0.0001) and age (partial r(2) = 0.03; P = 0.01). CONCLUSIONS: Our hypothesis that adipocyte size is the best predictor of metabolic characteristics was not supported in this population. The alternative explanation is that fat mass and body fat distribution have more influence on metabolic responses than adipocyte size.

Thrombin generation as a predictor of radiotherapy induced skin erythema.

BACKGROUND AND PURPOSE: Biological mechanisms underlying radiation induced erythema remain largely unknown, with no simple way to accurately predict or prevent extreme cases. Based on the recent findings in patients suffering from chronic urticaria, we sought to determine if similar mechanisms of hypercoagulation contributed to comparable skin reactions during radiotherapy. MATERIALS AND METHODS: Plasma levels of prothrombin factor 1+2 (F1+2), D-dimers and plasminogen activator inhibitor-1 (Pai-1) were tested in 32 women undergoing irradiation following breast conserving surgery for early breast cancer. Reflectance spectrophotometry was used to objectively assess erythema throughout the treatment by measuring the amount of light reflected from the skin surface as a function of wavelength. Correlations between peak levels of erythema and plasma biomarkers were then assessed. RESULTS: Individual peak reflectance readings generally occurred between day 29 of treatment and 2 weeks post radiotherapy, and represented a median increase of 66% (range: 11-146%; p<0.001) from baseline. Peak reflectance correlated with F1+2 and Pai-1 levels measured both at baseline and day 29 of treatment, and multivariate analysis indicated that these two baseline measurements were the best predictors of peak reflectance, accounting for 59% of the variability in erythema (p=0.000004). CONCLUSIONS: Patients with signs of intravascular thrombin generation are at higher risk of radiotherapy-induced skin reactions, providing a new therapeutic avenue for possibly predicting and preventing this side effect of cancer treatment.

A rank-based sample size method for multiple outcomes in clinical trials.

O'Brien (Biometrics 1984; 40:1079-1087) introduced a rank-sum-type global statistical test to summarize treatment's effect on multiple outcomes and to determine whether a treatment is better than others. This paper presents a sample size computation method for clinical trial design with multiple primary outcomes, and O'Brien's test or its modified test (Biometrics 2005; 61:532-539) is used for the primary analysis. A new measure, the global treatment effect (GTE), is introduced to summarize treatment's efficacy from multiple primary outcomes. Computation of the GTE under various settings is provided. Sample size methods are presented based on prespecified GTE both when pilot data are available and when no pilot data are available. The optimal randomization ratio is given for both cases. We compare our sample size method with the Bonferroni adjustment for multiple tests. Since ranks are used in our derivation, sample size formulas derived here are invariant to any monotone transformation of the data and are robust to outliers and skewed distributions. When all outcomes are binary, we show how sample size is affected by the success probabilities of outcomes. Simulation shows that these sample size formulas provide good control of type I error and statistical power. An application to a Parkinson's disease clinical trial design is demonstrated. Splus codes to compute sample size and the test statistic are provided.

Influence of glycemic variables on hemoglobin A1c.

OBJECTIVE: To assess the influences of a wide variety of glucose variables on hemoglobin A1c (A1C). METHODS: The Diabetes Control and Complications Trial database, restricted to volunteers whose 7-point daily capillary glucose profiles were complete in >or=80% of quarterly collections and who were in the study for >or=4 years, was used for analysis. Regression analyses were done to develop an equation for estimating A1C based on concurrent and prior mean blood glucose (MBG) values. The multivariate coefficient of determination (R2) was calculated for MBG, mean postprandial blood glucose, mean preprandial blood glucose, digestive glycemia, interdigestive glycemia, individual time points of the 7-point glucose profile, range of blood glucose, SD of blood glucose, M-value, and mean amplitude of glycemic excursions in relationship to A1C. By using regression analysis, the correlation between A1C and MBG within each study subject was determined. RESULTS: The most accurate prediction of A1C was obtained from the concurrent MBG. With use of univariate analysis, all glucose variables correlated significantly with concurrent A1C, the strongest correlation occurring with MBG. In multivariate analysis, the primary predictor of A1C was MBG; all other glucose variables added nothing to the models. Within-subject correlations between MBG and A1C showed considerable variation. CONCLUSION: A1C correlates best with MBG derived from 7-point-daily capillary glucose profiles. The influences of glucose measured at specific time points during the day or various measures of glucose variability on A1C are less than that of MBG. Within the limitations of the intermittent glucose determinations, wide variations in the relationship of MBG to A1C among and within patients with type 1 diabetes remain unexplained.

Challenges in design of multicenter trials: end points assessed longitudinally for change and monotonicity.

OBJECTIVE: Assessing clinimetric performance of diabetic sensorimotor polyneuropathy (DSPN) end points in single and multicenter trials. RESEARCH DESIGN AND METHODS: Assessed were placebo-treated patients with DSPN in the Viatris and Eli Lilly trials and an epidemiologic cohort. RESULTS: Test reproducibility in clinical trial cohorts (r(I) approximately 0.7-0.85) approached that in the epidemiologic cohort (r(I) approximately 0.85-0.95). Associations between pairs of end points explained <10% of the variability of data (sometimes 15-35%), being higher in the epidemiologic cohort and the Viatris trial than in the Lilly trial. Most end points did not show monotonic worsening over 4 years. However, sural nerve amplitude and peroneal motor conduction velocity did. A nerve conduction score (Sigma 5 NC nds [5 attributes of nerve conduction expressed as normal deviates]) did not show monotonic worsening in established DSPN. In the epidemiologic cohort followed for 9.5 years, monotonic worsening of small magnitude occurred for sural amplitude, vibration detection threshold, and especially for composite quantitative sensation. CONCLUSIONS: The main reason why it is difficult to demonstrate monotonic worsening of neuropathic end points appears to be a very slow worsening of DSPN, a placebo effect for symptoms and signs, and measurement noise. Demonstrating disease progression in controlled trials of DSPN is more likely when 1) patients with developing rather than established DSPN are selected, 2) type 1 diabetic patients are preferentially recruited, 3) patients are selected who cannot or will not achieve ideal glycemic control, 4) end points chosen are known to show monotonic worsening, and 5) a restricted number of centers and expert examiners (trained, certified, using standard approaches, and reference values and interactive surveillance of tests) are used.

Breast edema in patients undergoing breast-conserving treatment for breast cancer: assessment via high frequency ultrasound.

To identify factors that can influence breast edema in women undergoing breast-conserving therapy. Breast edema was assessed clinically and via high frequency ultrasound (HFUS) prior to, during and following radiotherapy. Fifty-four women were assessed. Breast edema was present prior to radiotherapy in patients who had undergone level 2 node dissection or had wound infection after sentinel node dissection. Edema increased during and after radiotherapy and peaked at 4-6 months. The time course of breast edema was related to the extent of nodal dissection, postoperative wound infection and regional radiotherapy. HFUS prior to irradiation was found to be no better than clinical assessment in predicting prolonged parenchymal breast edema but was significantly better at the end of irradiation. Breast edema levels are minimal in patients who do not undergo axillary node dissection or have an uncomplicated sentinel node dissection. Most edema is due to compromise of the draining lymphatics, which relates largely to the extent of axillary node dissection. HFUS appears to be a useful in the research setting in quantifying the effect of techniques that aim to reduce complications such as edema.

Intensive intraoperative insulin therapy versus conventional glucose management during cardiac surgery: a randomized trial.

BACKGROUND: It is not known whether rigorous intraoperative glycemic control reduces death and morbidity in cardiac surgery patients. OBJECTIVE: To compare outcomes of intensive insulin therapy during cardiac surgery with those of conventional intraoperative glucose management. DESIGN: A randomized, open-label, controlled trial with blinded end point assessment. SETTING: Tertiary care center. PATIENTS: Adults with and without diabetes who were undergoing on-pump cardiac surgery. MEASUREMENTS: The primary outcome was a composite of death, sternal infections, prolonged ventilation, cardiac arrhythmias, stroke, and renal failure within 30 days after surgery. Secondary outcome measures were length of stay in the intensive care unit and hospital. INTERVENTION: Patients were randomly assigned to receive continuous insulin infusion to maintain intraoperative glucose levels between 4.4 (80 mg/dL) and 5.6 mmol/L (100 mg/dL) (n = 199) or conventional treatment (n = 201). Patients in the conventional treatment group were not given insulin during surgery unless glucose levels were greater than 11.1 mmol/L (>200 mg/dL). Both groups were treated with insulin infusion to maintain normoglycemia after surgery. RESULTS: Mean glucose concentrations were statistically significantly lower in the intensive treatment group at the end of surgery (6.3 mmol/L [SD, 1.6] [114 mg/dL {SD, 29}] in the intensive treatment group vs. 8.7 mmol/L [SD, 2.3] [157 mg/dL {SD, 42}] in the conventional treatment group; difference, -2.4 mmol/L [95% CI, -2.8 to -1.9 mmol/L] [-43 mg/dL {CI, -50 to -35 mg/dL}]). Eighty two of 185 patients (44%) in the intensive treatment group and 86 of 186 patients (46%) in the conventional treatment group had an event (risk ratio, 1.0 [CI, 0.8 to 1.2]). More deaths (4 deaths vs. 0 deaths; P = 0.061) and strokes (8 strokes vs. 1 strokes; P = 0.020) occurred in the intensive treatment group. Length of stay in the intensive care unit (mean, 2 days [SD, 2] vs. 2 days [SD, 3]; difference, 0 days [CI, -1 to 1 days]) and in the hospital (mean, 8 days [SD, 4] vs. 8 days [SD, 5]; difference, 0 days [CI, -1 to 0 days]) was similar for both groups. LIMITATIONS: This single-center study used a composite end point and could not examine whether outcomes differed by diabetes status. CONCLUSIONS: Intensive insulin therapy during cardiac surgery does not reduce perioperative death or morbidity. The increased incidence of death and stroke in the intensive treatment group raises concern about routine implementation of this intervention.

Longitudinal 1H MRS changes in mild cognitive impairment and Alzheimer's disease.

Magnetic resonance (MR)-based volume measurements of atrophy are potential markers of disease progression in patients with amnestic mild cognitive impairment (MCI) and Alzheimer's disease (AD). Longitudinal changes in (1)H MR spectroscopy ((1)H MRS) metabolite markers have not been characterized in MCI subjects. Our objective was to determine the longitudinal (1)H MRS metabolite changes in patients with MCI, and AD, and to compare (1)H MRS metabolite ratios and ventricular volumes in tracking clinical disease progression in AD. The neuronal integrity marker N-acetylaspartate/creatine ratio declined in MCI and AD patients compared to cognitively normal elderly. The change in (1)H MRS metabolite ratios correlated with clinical progression about as strongly as the rate of ventricular expansion, suggesting that (1)H MRS metabolite ratios may be useful markers for the progression of AD. Choline/creatine ratio declined in stable MCI, compared to converter MCI patients and cognitively normal elderly, which may be related to a compensatory mechanism in MCI patients who did not to progress to AD.

Direct medical costs associated with Parkinson's disease: a population-based study.

The objective was to provide population-based estimates of incremental medical costs associated with Parkinson's disease (PD) from onset forward. All Olmsted County, Minnesota, residents with confirmed PD onset from 1987 through 1995 (n = 92) and one age- and sex-matched non-PD referent subject per case were identified with retrospective record review and followed in provider-linked billing data for direct medical costs (excluding outpatient pharmaceutical costs) from 1 year before index (i.e., year of symptom onset) through 10 years after index. Costs for each referent subject were subtracted from those for his/her matched case. Tests for statistical significance used Wilcoxon signed ranks. Preindex costs were similar [median difference in annual costs (MD) = -3 dollars; P = 0.59]. One year post index, PD subjects exhibited borderline significantly higher costs compared to referent subjects (MD = 581 dollars; P = 0.052); the difference diminished over 5 years (MD = 118 dollars; P = 0.82). By 5 to 10 years, however, PD subjects exhibited significantly higher costs (MD = 1,146 dollars; P = 0.01). Over the full 10 years, excess costs were concentrated among PD subjects without rest tremor (MD = 2,261 dollars, P < 0.01, for those without tremor and -229 dollars, P = 0.99, for those with tremor). These population-based estimates of PD-associated direct medical costs from onset forward can uniquely inform policy decisions and cost-effectiveness research.

Modeling chronic glycemic exposure variables as correlates and predictors of microvascular complications of diabetes.

OBJECTIVE: The degree to which chronic glycemic exposure (CGE) (fasting plasma glucose [FPG], HbA1c [A1C], duration of diabetes, age at onset of diabetes, or combinations of these) is associated with or predicts the severity of microvessel complications is unsettled. Specifically, we test whether combinations of components correlate and predict complications better than individual components. RESEARCH DESIGN AND METHODS: Correlations and predictions of CGE and complications were assessed in the Rochester Diabetic Neuropathy Study, a population-based, cross-sectional, and longitudinal epidemiologic survey of 504 patients with diabetes followed for up to 20 years. RESULTS: In multivariate analysis, A1C and duration of diabetes (and to a lesser degree age at onset of diabetes but not FPG) were the main significant CGE risk covariates for complications. A derived glycemic exposure index (GE(i)) correlated with and predicted complications better than did individual components. Composite or staged measures of polyneuropathy provided higher correlations and better predictions than did dichotomous measures of whether polyneuropathy was present or not. Generally, the mean GE(i) was significantly higher with increasing stages of severity of complications. CONCLUSIONS: A combination of A1C, duration of diabetes, and age at onset of diabetes (a mathematical index, GE(i)) correlates significantly with complications and predicts later complications better than single components of CGE. Serial measures of A1C improved the correlations and predictions. For polyneuropathy, continuous or staged measurements performed better than dichotomous judgments. Even with intensive assessment of CGE and complications over long times, only about one-third of the variability of the severity of complications is explained, emphasizing the role of other putative risk covariates.

Pyridostigmine treatment trial in neurogenic orthostatic hypotension.

BACKGROUND: Midodrine hydrochloride is the only drug demonstrated in a placebo-controlled treatment trial to improve orthostatic hypotension (OH) but it significantly worsens supine hypertension. By enhancing ganglionic transmission, pyridostigmine bromide can potentially ameliorate OH without worsening supine hypertension. OBJECTIVE: To evaluate the efficacy of a single 60-mg dose of pyridostigmine bromide, alone or in combination with a subthreshold (2.5 mg) or suprathreshold (5 mg) dose of midodrine hydrochloride, compared with placebo. DESIGN: We report a double-blind, randomized, 4-way cross-over study of pyridostigmine in the treatment of neurogenic OH. A total of 58 patients with neurogenic OH were enrolled. After 1 day of baseline measurements, patients were given 4 treatments (3 active treatments [60 mg of pyridostigmine bromide; 60 mg of pyridostigmine bromide and 2.5 mg of midodrine hydrochloride; 60 mg of pyridostigmine bromide and 5 mg of midodrine hydrochloride] and a placebo) in random order on successive days. Blood pressure (BP) and heart rate were measured, both supine and standing, immediately before treatment and hourly for 6 hours after the treatment was given. RESULTS: No significant differences were seen in the supine BP, either systolic (P = .36) or diastolic (P = .85). In contrast, the primary end point of the fall in standing diastolic BP was significantly reduced (P = .02) with treatment. Pairwise comparison showed significant reduction by pyridostigmine alone (BP fall of 27.6 mm Hg vs 34.0 mm Hg with placebo; P = .04) and pyridostigmine and 5 mg of midodrine hydrochloride (BP fall of 27.2 mm Hg vs 34.0 mm Hg with placebo; P = .002). Standing BP improvement significantly regressed with improvement in OH symptoms. CONCLUSIONS: Pyridostigmine significantly improves standing BP in patients with OH without worsening supine hypertension. The greatest effect is on diastolic BP, suggesting that the improvement is due to increased total peripheral resistance.

Adverse event reporting and developments in radiation biology after normal tissue injury: International Atomic Energy Agency consultation.

PURPOSE: Recent research has enhanced our understanding of radiation injury at the molecular-cellular and tissue levels; significant strides have occurred in standardization of adverse event reporting in clinical trials. In response, the International Atomic Energy Agency, through its Division of Human Health and its section for Applied Radiation Biology and Radiotherapy, organized a consultation meeting in Atlanta (October 2, 2004) to discuss developments in radiobiology, normal tissue reactions, and adverse event reporting. METHODS AND MATERIALS: Representatives from cooperative groups of African Radiation Oncology Group, Curriculo Radioterapeutica Ibero Latino Americana, European Organization for Research and Treatment of Cancer, National Cancer Institute of Canada Clinical Trials Group, Radiation Therapy Oncology Group, and Trans-Tasman Radiation Oncology Group held the meeting discussion. RESULTS: Representatives of major radiotherapy groups/organizations and prominent leaders in radiotherapy discussed current understanding of normal tissue radiobiologic effects, the design and implementation of future clinical and translational projects for normal tissue injury, and the standardization of adverse-event reporting worldwide. CONCLUSIONS: The consensus was to adopt NCI comprehensive adverse event reporting terminology and grading system (CTCAE v3.0) as the new standard for all cooperative group trials. Future plans included the implementation of coordinated research projects focusing on normal tissue biomarkers and data collection methods.

Comorbid conditions associated with Parkinson's disease: a population-based study.

The burden of comorbidity in Parkinson's disease (PD) remains unclear. All Olmsted County, Minnesota, residents with incident PD in 1976-1995 (n = 197) plus one age- and sex-matched non-PD referent subject per case were followed for all clinical diagnoses from 5 years before through 15 years after index (i.e., year of PD onset for each case and same year for the referent subject). Both members of a case-referent pair were censored at death or emigration of either member to ensure equivalent follow-up. Cases and referent subjects were compared for summary comorbidity (Charlson index) and for the likelihood of having one or more diagnoses within each International Classification of Diseases chapter/subchapter. Before index, the groups were similar for all comparisons. After index, cases had a higher likelihood of diagnoses within the chapters "Mental Disorders" and "Diseases of the Genitourinary System," and within the subchapters "Organic Psychotic Conditions," "Other Psychoses," "Neurotic/Personality/Other Nonpsychotic Disorders," "Hereditary/Degenerative Diseases of Central Nervous System," "Symptoms," "Other Diseases of Digestive System," "Other Diseases of Urinary System," "Diseases of Veins/Lymphatics/Other Circulatory System Diseases," "Fractures of Lower Limb," "Other Diseases of Skin/Subcutaneous Tissue," "Osteopathies/Chrondropathies/Acquired Musculoskeletal Deformities," and "Pneumonia and Influenza." The excess morbidity and mortality observed for persons with PD are consistent with recognized PD sequelae.