Palbociclib in hormone receptor positive advanced breast cancer: A cost-utility analysis.

INTRODUCTION: The addition of palbociclib to letrozole improves progression-free survival in the first-line treatment of hormone receptor positive advanced breast cancer (ABC). This study assesses the cost-utility of palbociclib from the Canadian healthcare payer perspective. METHODS: A probabilistic discrete event simulation (DES) model was developed and parameterised with data from the PALOMA 1 and 2 trials and other sources. The incremental cost per quality-adjusted life-month (QALM) gained for palbociclib was calculated. A time horizon of 15 years was used in the base case with costs and effectiveness discounted at 5% annually. Time-to- progression and time-to-death were derived from a Weibull and exponential distribution. Expected costs were based on Ontario fees and other sources. Probabilistic sensitivity analyses were conducted to account for parameter uncertainty. RESULTS: Compared to letrozole, the addition of palbociclib provided an additional 14.7 QALM at an incremental cost of $161,508. The resulting incremental cost-effectiveness ratio was $10,999/QALM gained. Assuming a willingness-to-pay (WTP) of $4167/QALM, the probability of palbociclib to be cost-effective was 0%. Cost-effectiveness acceptability curves derived from a probabilistic sensitivity analysis showed that at a WTP of $11,000/QALM gained, the probability of palbociclib to be cost-effective was 50%. CONCLUSION: The addition of palbociclib to letrozole is unlikely to be cost-effective for the treatment of ABC from a Canadian healthcare perspective with its current price. While ABC patients derive a meaningful clinical benefit from palbociclib, considerations should be given to increase the WTP threshold and reduce the drug pricing, to render this strategy more affordable.

Patient and technique survival of diabetics on peritoneal dialysis: one-center's experience and review of the literature.

BACKGROUND: Diabetes is the leading cause of end-stage renal disease (ESRD). This retrospective study investigated the long-term patient and technique survival and sought to identify the predictors of mortality in diabetic patients receiving PD. METHODS: Patients, aged 17 years or more who commenced home PD between January 31, 1994, and December 31, 2001 were included. Clinical data were available for 358 patients out of 418 total patients who started PD during this period. They were followed until cessation of PD, death, or to January 31, 2003. Survival probabilities were generated according to the Kaplan-Meier method, and multivariate Cox proportional hazards models were used to assess predictors of survival. RESULTS: A total of 358 patients were enrolled in the study. Among them, 139 patients (38.8%) were diabetics. The 1-, 2-, 3- and 5-year patient survival rates were 91%, 76%, 66% and 47% in diabetics and 94%, 89%, 84% and 69% in non-diabetics, respectively. Median actuarial patient survival for diabetic patients (51.8 months; 95% CI 36.0 â 67.5 months) was significantly shorter than that of non-diabetic patients (log rank 14.117, p < 0.001). Death-censored technique survival rates at 1-, 2-, 3- and 5-year were 90%, 83%, 67% and 58% in diabetic, and 94%, 87%, 77% and 70% in non-diabetic patients, respectively. Similar to patient survival, the median technique survival time was significantly shorter for diabetic patients (63.9 months; 95% CI 35.7 - 92.2 months) than that of non-diabetic patients (log rank 4.884, p = 0.027). Multivariate Cox regression analysis showed that advancing age was the only independent predictor of death in the diabetic patients, whereas higher age and wider pulse pressure were associated with mortality in non-diabetic patients. CONCLUSION: Long-term patient and technique survival for diabetic patients on PD seem to be improved compared to our previous report and other studies. The mortality of diabetic patients was predicted predominantly by advancing age. PD remains a viable form of long-term renal replacement therapy for diabetic patients with ESRD.

Course of preeclamptic glomerular injury after delivery.

We evaluated the early postpartum recovery of glomerular function over 4 wk in 57 women with preeclampsia. We used physiological techniques to measure glomerular filtration rate (GFR), renal plasma flow, and oncotic pressure (pi(A)) and computed a value for the two-kidney ultrafiltration coefficient (K(f)). Compared with healthy, postpartum controls, GFR was depressed by 40% on postpartum day 1, but by only 19% and 8% in the second and fourth postpartum weeks, respectively. Hypofiltration was attributable solely to depression, at corresponding postpartum times, of K(f) by 55%, 30%, and 18%, respectively. Improvement in glomerular filtration capacity was accompanied by recovery of hypertension to near-normal levels and significant improvement in albuminuria. We conclude that the functional manifestations of the glomerular endothelial injury of preeclampsia largely resolve within the first postpartum month.

Late renal transplant failure: an adverse prognostic factor at initiation of peritoneal dialysis.

BACKGROUND: Early renal transplant failure necessitating a return to dialysis has been shown to be a poor prognostic factor for survival. Little is known about the outcome of patients with late transplant failure returning to dialysis. It was our clinical impression that late transplant failure (>2 months) carries an increased morbidity and mortality risk in patients returning to dialysis. OBJECTIVE: To determine whether patients with a failed renal transplant have an outcome different to those on dialysis who have never received a kidney transplant. SETTING: Peritoneal dialysis (PD) unit in a teaching hospital. PATIENTS AND DESIGN: All failed renal transplant patients (fTx) in the Toronto Hospital Peritoneal Dialysis program between 1989 and 1996 were identified. This cohort of 42 fTx patients was compared with a cohort of randomly selected never-transplanted PD patients (non-Tx). The PD program was selected because of the availability of well-documented patient archival material. The non-Tx group was matched for age and presence of diabetes. Data were collected until retransplantation, change of dialysis modality or center, death, or until June 1998. RESULTS: There was no difference at initiation of PD between groups in serum albumin, residual renal function, or mean serum parathyroid hormone level. The mean low-density lipoprotein level was significantly higher in the fTx cohort. The duration of dialysis before Tx in fTx patients accounted for the increased total length of dialysis in fTx (mean 15 months). However, post-Tx the duration of PD was similar for both groups (30.7 months for fTx vs 31.6 months for non-Tx). The fTx group had a considerably worse outcome than the non-Tx group. The time to first peritonitis, subsequent episodes of peritonitis, catheter change, or transfer to hemodialysis occurred at a much faster rate in fTx patients. The most dramatic difference was in survival. There were 3 deaths in the non-Tx group and 12 in the fTx group (p < 0.01). The mean age at time of death in the fTx group was 47.5 years. Deaths were due mainly to gram-negative peritonitis and cardiovascular disease. CONCLUSIONS: We conclude that late failed renal transplant patients starting dialysis are at increased risk of complications and have strikingly higher mortality rates than non-Tx patients. A previously failed kidney transplant can be considered an adverse prognostic factor for patients commencing PD; these patients need to be closely monitored. Although this study was limited to PD patients, the same principles likely apply to fTx patients returning to any form of renal replacement therapy.

Long-term blood pressure control in a cohort of peritoneal dialysis patients and its association with residual renal function.

BACKGROUND: Hypertension is the prime contributor for cardiovascular mortality in the dialysis population. Peritoneal dialysis (PD) has been thought to improve blood pressure (BP) control in the short term, but the long-term benefits are not conclusively proven. We aimed to evaluate the degree of BP control in PD patients in the long term and analyse the factors associated with poor control. METHODS: Data of all patients who were initiated on PD at one centre between July 1994 and July 1998 and completed at least 1 year of PD were analysed retrospectively at initiation of PD, at 6 months, and annually thereafter until 5 years or until discontinuation of therapy. Hypertension was defined as per WHO/ISH criteria. A 'Blood Pressure Control Index' was empirically defined to account for the effect of antihypertensives on measured BP. Factors associated with poor BP control were analysed. RESULTS: Out of 207 patients (age 57.0+/-16.0 years, 103 male, 104 female) 91.3% were hypertensive at the start of PD. About 33.8% had diabetic nephropathy. Systolic and mean arterial pressure index improved in early phase reaching a nadir between 6 months and 1 year followed by steady progressive worsening through out the rest of follow up. On multiple linear regression analysis age (P<0.001), duration of hypertension prior to dialysis (P<0.001), and declining residual renal function, expressed as both average of urea and creatinine clearance (P=0.002) and residual urine output (P<0.001) were independently associated with poor BP control. Diabetes (P=0.836), peritoneal transport (D/P 4 of creatinine at start) (P=0.218), peripheral oedema (P=0.479) and dose of erythropoetin (P=0.488) were not associated. CONCLUSIONS: Initiation of PD results in early improvement of hypertension in end-stage renal disease (ESRD). BP control thereafter deteriorates steadily with time and this is associated with age, duration of hypertension, and declining residual renal function. This suggests that hypertension in ESRD patients is a progressive disease primarily related to falling glomerular filtration rate, the preservation of which might improve BP control and possibly modify cardiovascular risk.

A comparison of four treatment strategies for ductal carcinoma in situ using decision analysis.

BACKGROUND: The goals of the current study were to compare four treatment approaches in the management of ductal carcinoma in situ (DCIS), to determine the conditions where mastectomy may be preferred to breast-conserving therapy (BCT), and to determine conditions where the addition of tamoxifen produces better results than BCT alone. METHODS: A decision analysis model was used to compare four treatment approaches after local excision for DCIS: mastectomy, irradiation, irradiation plus adjuvant tamoxifen, or observation. The model weighed the potential benefits of each treatment approach (reduction of ipsilateral and/or contralateral breast carcinoma) against the potential risks of treatment-related toxicities. In addition, the model adjusted for the potential detrimental impact of local recurrence or treatment-related toxicity on health-related quality of life (HRQOL). Base-case estimates were obtained from published randomized trial data. One-way and two-way sensitivity analyses were performed. RESULTS: According to the model, the optimal treatment for DCIS was strongly dependent on the individual's risk of local recurrence and the patient's attitudes toward mastectomy. Mastectomy was preferred in patients whose estimated 10-year risk of local recurrence was > 15%, provided that mastectomy resulted in a very low reduction in quality of life (i.e., utility estimate > 0.97). Conditions where the addition of tamoxifen was preferred to breast-conserving therapy alone included the following: estimated 10-year risk of local recurrence > 38%, estimated 10-year risk of developing a contralateral breast carcinoma > 6%, or a significant decrement in HRQOL associated with the development of an invasive local recurrence or salvage mastectomy (utility estimates < 0.85). CONCLUSION: Based on this quality-adjusted model, BCT appeared to be the preferred treatment for DCIS. The most important determinants of optimal management for DCIS included the risk of local recurrence and the utility of mastectomy. Formal evaluation of utilities in the context of DCIS and more accurate determination of the risk of recurrence are required.

A replication study of obsessional followers and offenders with mental disorders.

The purpose of this study was to compare certain demographic, clinical, and criminal variables within subgroups of obsessional followers, and compare them to a group of offenders with mental disorders to attempt to replicate earlier findings. A static group archival design utilized a non-random group of convenience and a randomly selected comparison group. Sixty-five obsessional followers and 65 offenders with mental disorders were evaluated by psychiatrists and psychologists for court ordered reasons during their criminal proceedings. Both groups were evaluated during the same period, in the same court diagnostic clinic, and generally for sentencing determinations. The obsessional followers were measured on demographic, diagnostic, pursuit, victim, threat, violence, emotional, motivational, and defense variables. Inferential comparisons that used parametric and nonparametric statistics were done within and between groups on select variables. The obsessional followers had significantly greater estimated IQ than the offenders with mental disorders, but were neither older nor better educated. There were no significant differences in the high prevalence of both DSM-IV Axis I and II diagnoses. Obsessional followers who stalked prior sexual intimates were significantly more likely to have a substance abuse or dependence diagnosis. Obsessional followers who stalked strangers or acquaintances were more likely to be delusional. The majority of the obsessional followers, primarily motivated by anger, both threatened and were violent toward person or property. The modal obsessional follower is an average or above IQ, unemployed, unmarried male in his fourth decade of life. chronically pursuing a prior sexually intimate female. He is diagnosed with substance abuse or dependence and a personality disorder NOS, and has a prior psychiatric, criminal and substance abuse history. He is angry, likely to threaten her, and assault her person or property without causing serious injury.

Application of probabilistic neural network analysis to a disease with complex inheritance: the GAW11 simulated data.

A probabilistic neural network analysis was applied to the simulated GAW11 data. Six replicates drawn at random from one of the simulated populations were used to generate training and test vectors for pairs of siblings. The vectors incorporated two environmental indicators as well as identical-by-descent allele sharing scores from each of 300 genetic markers. The performance of a 'naïve' probabilistic neural network (PNN) was fair. However, by combining a traditional linkage analysis with a PNN which incorporated gene x environment interaction, the performance was considerably enhanced.

Genetic anticipation and breast cancer: a prospective follow-up study.

Genetic anticipation is characterized by an earlier age of disease onset, increased severity, and a greater proportion of affected individuals in succeeding generations. The discovery of trinucleotide repeat expansion (TRE) mutations as the molecular correlate of anticipation in a number of rare Mendelian neurodegenerative disorders has led to a resurgence of interest in this phenomenon. Because of the difficulties presented to traditional genetics by complex diseases, the testing for genetic anticipation coupled with TRE detection has been proposed as a strategy for expediting the identification of susceptibility genes for complex disorders. In the case of breast cancer, a number of previous studies found evidence consistent with genetic anticipation. It is known that a proportion of such families are linked to either BRCA1 or BRCA2, but no TRE mutations have been identified. It has been shown that the typical ascertainment employed in studies purporting to demonstrate genetic anticipation combined with unadjusted statistical analysis can dramatically elevate the type I error. We re-examine the evidence for anticipation in breast cancer by applying a new statistical approach that appears to have validity in the analysis of anticipation to data ascertained from a recent follow-up of a large prospective cohort family study of breast cancer. Using this approach, we find no statistically significant evidence for genetic anticipation in familial breast cancer. We discuss the limitations of our analysis, including the problem of adequate sample size for this new statistical test.

The analysis of parental origin of alleles may detect susceptibility loci for complex disorders.

The phenomenon of genomic imprinting describes the differential behavior of genes depending on their parental origin, and has been demonstrated in a few rare genetic disorders. In complex diseases, parent-of-origin effects have not been systematically studied, although there may be heuristic value in such an approach. Data from a genome scan performed using 356 affected sibling pair families with type 1 diabetes were examined looking for evidence of excess sharing of either maternal or paternal alleles. At the insulin gene (IDDM2), evidence for excess sharing of alleles transmitted from mothers was detected, which is consistent with transmission disequilibrium results published elsewhere. We also identified additional loci that demonstrate allele sharing predominantly from one parent: IDDM8 shows a paternal origin effect, IDDM10 shows a maternal effect, and a locus on chromosome 16q demonstrates a paternal effect. We have also evaluated these loci for confounding by differences in sex-specific meiotic recombination by performing linkage analysis using sex-specific genetic maps. The analysis of the parental origin of shared alleles from genome scans of complex disorders may provide additional evidence for linkage for known loci, help identify regions containing additional susceptibility loci, and assist the cloning of the genes involved.

Decision analysis as an aid to determining the management of early low rectal cancer for the individual patient.

PURPOSE: Because there are no data available from randomized controlled trials (RCT), a decision analysis was performed to aid in the decision of which option, a local excision with or without radiotherapy or an abdominal perineal resection (APR), should be offered to medically fit patients with early (suspected T1/T2) low (< 5 cm) rectal cancer. METHODS: All clinically relevant outcomes, including complications of surgery and radiotherapy, cure, salvageability after local recurrence, distant disease, and death, were modeled for both options. The probabilities of complications and outcomes after radiotherapy and/or local excision were derived from weighted averages of results from studies conducted between 1969 and 1997. The probabilities for the APR option were extracted from relevant RCTs. Long- and short-term patient-centered utilities for each complication and outcome were extracted from the literature and from expert opinion. RESULTS: The expected utility of local excision (EU = 0.81) for the base case was higher than the expected utility for APR (EU = 0.78). Although the result was sensitive to all variables, local excision was always favored over APR within the plausible ranges of the variables taken one, two, or three at a time. The model illustrated the tension between the patient's perception of a colostomy and the higher recurrence rates with local excision. CONCLUSION: The results of this decision analysis suggest that local therapy for early low rectal cancer is the preferred method of treatment. However, there must be careful preoperative assessment, patient selection, and consideration of patient concerns. In addition, decision analysis may be useful in providing patient information and assisting in decision making.

Psychoses in Parkinson's Disease.

Psychotic symptoms occur in up to 40% of patients with Parkinson's disease (PD) and other degenerative parkinsonian disorders, usually but not exclusively in the context of their pharmacologic treatment. We describe the following six psychotic syndromes in PD based on existing literature: (1) hallucinations with preserved insight; (2) medication-induced psychotic disorders (in clear consciousness); (3) delirium; (4) schizophrenia-like psychotic disorders (in clear consciousness and in the absence of medication treatment); (5) schizophrenia with subsequent development of PD; and (6) other psychotic disorders. Psychosis in PD has been noted to be a marker for illness deterioration. Psychotic symptoms can profoundly affect the quality of life for PD patients and their families and may increase the economic burden of this illness. Various approaches have been used to treat psychotic symptoms in PD. We critically review this literature, which is limited, but includes studies indicating promise for "atypical" antipsychotics in these patients. Further elucidation of the phenomenology, course, pathophysiology, and treatment of the different psychotic disorders in PD is urgently needed.

Primer on medical decision analysis: Part 3--Estimating probabilities and utilities.

This paper describes how to estimate probabilities and outcome values for decision trees. Probabilities are usually derived from published studies, but occasionally are derived from existing databases, primary data collection, or expert judgment. Outcome values represent quantitative estimates of the desirability of the outcome states, and are often expressed as utility values between 0 and 1. Utility values for different health states can be derived from the published literature, from direct measurement in appropriate subjects, or from expert opinion. Methods for assigning utilities to complex outcome states are described, and the concept of quality-adjusted life years is introduced.

Primer on medical decision analysis: Part 5--Working with Markov processes.

Clinical decisions often have long-term implications. Analysis encounter difficulties when employing conventional decision-analytic methods to model these scenarios. This occurs because probability and utility variables often change with time and conventional decision trees do not easily capture this dynamic quality. A Markov analysis performed with current computer software programs provides a flexible and convenient means of modeling long-term scenarios. However, novices should be aware of several potential pitfalls when attempting to use these programs. When deciding how to model a given clinical problem, the analyst must weigh the simplicity and clarity of a conventional tree against the fidelity of a Markov analysis. In direct comparisons, both approaches gave the same qualitative answers.

Primer on medical decision analysis: Part 1--Getting started.

This paper is Part 1 of a five-part series covering practical issues in the performance of decision analysis. The intended audience is individuals who are learning how to perform decision analyses, not just read them. The series assumes familiarity with the basic concepts of decision analysis. It imparts many of the recommendations the authors have learned in teaching a one-semester course in decision analysis to graduate students. Part 1 introduces the topic and covers questions such as choosing an appropriate question, determining the tradeoff between accuracy and simplicity, and deciding on a time frame.

Primer on medical decision analysis: Part 2--Building a tree.

This part of a five-part series covering practical issues in the performance of decision analysis outlines the basic strategies for building decision trees. The authors offer six recommendations for building and programming decision trees. Following these six recommendations will facilitate performance of the sensitivity analyses required to achieve two goals. The first is to find modeling or programming errors, a process known as "debugging" the tree. The second is to determine the robustness of the qualitative conclusions drawn from the analysis.

Primer on medical decision analysis: Part 4--Analyzing the model and interpreting the results.

This paper is the fourth of a five-part series that describes the principles of construction and evaluation of valid decision models. In this review, the authors describe the key principles of detecting and eliminating structural and programming errors in decision trees (debugging). In addition, they offer guidelines to facilitate the interpretation of analytic results of decision models.

Guidelines for verbal presentations of medical decision analyses.

Individuals new to decision analysis often have difficulty with oral presentations of original research projects. This article provides general guidelines on how to present effectively. Points include: 1) articulating the research issue, 2) reviewing current beliefs, 3) portraying the study question, 4) listing the main assumptions, 5) presenting the base-case analysis, 6) showing sensitivity analyses, and 7) discussing the implications. The guidelines comment on what to exclude from presentation and how best to handle audience questions. The guidelines do not replace general instruction in public speaking (or rigorous training in decision analysis), but may help students present research projects effectively.

Psychotic symptoms in Parkinson's disease patients with dementia.

OBJECTIVE: To assess the prevalence of psychotic symptoms in a group of patients with Parkinson's disease (PD) and dementia and examine the association of psychotic symptoms with neuropsychiatric problems, the level of distress reported by caregivers, and cognitive and functional impairment. DESIGN: The psychotic and nonpsychotic patients with PD dementia were compared on a series of demographic, neuropsychiatric, behavioral, caregiver complaint, and cognitive measures. SETTING: The database from nine university-based State of California Alzheimer's Disease Diagnostic and Treatment Centers (ADDTCs). PARTICIPANTS: 101 patients diagnosed with PD. RESULTS: A total of 36 of the 101 patients (35.6%) had either hallucinations, delusions, or both. The psychotic patients had significantly more insomnia, confusion, agitation, personality changes, and self-care problems and were noted by their caregivers to be significantly more unmanageable at home than their nonpsychotic counterparts. On cognitive scales, psychotic patients were significantly more impaired. CONCLUSION: Many patients with PD and dementia experience psychosis. Psychotic symptoms in PD dementia patients are associated with major behavioral, cognitive, and functional problems.

An analysis of predictors of long-term cadaveric renal allograft survival.

To determine factors predictive of long-term graft function in patients treated prophylactically with an antilymphocyte antibody, 670 first cadaveric adult renal transplant procedures performed between 1985 and 1991 were reviewed. The actuarial 1- and 5-year patient survival in this group was 95% and 87% respectively, and graft survival was 84% and 70% respectively. The final analysis was based on a study group of 635 patients which excluded 28 patients who lost grafts to early technical failures and 8 patients who were not induced with an antilymphocyte preparation. Multivariate analysis showed that 5-year graft survival was lower in patients with delayed graft function (p = 0.0001), in those who had an acute rejection episode in the first 6 months post-transplant (p = 0.0001), recipients greater than 55 years of age at the time of transplant (p = 0.0001), in patients who were highly sensitized at the time of transplant (p = 0.0331) and, finally, in those who received a graft from an older donor (p = 0.044). The 209 patients with delayed graft function had a 16% lower long-term graft survival than 425 patients with early graft function (62% vs. 78% respectively at 5 years). One or more rejection episodes in the first 6 months post-transplant (329 patients) reduced long-term graft survival by 13% compared to those who did not have a rejection episode (67% vs. 80% respectively at 5 years).(ABSTRACT TRUNCATED AT 250 WORDS)