Survival, disease progression and prognostic factors in elderly patients with mycosis fungoides and Sézary syndrome: a retrospective analysis of 174 patients.

BACKGROUND: Advanced age at diagnosis is considered a poor prognostic factor in mycosis fungoides (MF) and Sézary syndrome (SS). OBJECTIVE: To evaluate the outcomes and prognostic factors in patients diagnosed at an advanced age (≥65 years) with MF/SS. METHODS: Survival, progression rates and various clinical and histopathological variables were studied in a group of 174 elderly patients diagnosed with MF/SS between 1992 and 2015 at a single referral cancer center in the United States. Kaplan-Meier estimates were used to determine survival and progression and Cox proportional hazards regression univariate and multivariate models were used to identify prognostic factors. RESULTS: Of 174 elderly patients, 76.4% were diagnosed with early-stage (clinical stages IA-IIA) and 23.6% with late-stage MF/SS (IIB-IV). Advanced age was associated with poor overall survival, but not with disease-specific survival (DSS) or progression-free survival (PFS). Gender, increasing clinical stage, T and B classifications, elevated lactate dehydrogenase (LDH) levels and development of large cell transformation (LCT) were significant predictors of poor survival or disease progression. Patients with early-stage MF and <10% total skin involvement (T1 classification) or patch-only disease (T1a/T2a) showed better PFS with no observed disease-specific mortality. Folliculotropic MF was associated with poor DSS in patients with early-stage disease. CONCLUSIONS: Older age at diagnosis of MF/SS does not predict worse disease-specific outcomes. Elderly patients with early-stage disease, specifically involving less than 10% of the skin surface with patches but without plaques or folliculotropism, have an excellent prognosis. However, the development of LCT is a strong prognostic indicator of poor survival in elderly patients with MF/SS.

Phase II study of idelalisib, a selective inhibitor of PI3Kδ, for relapsed/refractory classical Hodgkin lymphoma.

BACKGROUND: The phosphatidylinositol-3-kinase delta (PI3Kδ) inhibitor idelalisib has been shown to block downstream intracellular signaling, reduce the production of prosurvival chemokines and induce apoptosis in classical Hodgkin lymphoma (HL) cell lines. It has also been shown to inhibit regulatory T cells and myeloid-derived suppressor cells in other tumor models. We hypothesized that inhibiting PI3Kδ would have both direct and indirect antitumor effects by directly targeting the malignant cells as well as modulating the inflammatory microenvironment. We tested this hypothesis in a phase II study. PATIENTS AND METHODS: We enrolled 25 patients with relapsed/refractory HL with a median age of 42 years and who had previously received a median of five therapies including 18 (72%) with failed autologous stem cell transplant, 23 (92%) with failed brentuximab vedotin, and 11 (44%) with prior radiation therapy. Idelalisib was administered at 150 mg two times daily; an increase to 300 mg two times daily was permitted at the time of disease progression. RESULTS: The overall response rate to idelalisib therapy was 20% (95% confidence interval: 6.8%, 40.7%) with a median time to response of 2.0 months. Seventeen patients (68%) experienced reduction in target lesions with one complete remission and four partial remissions. The median duration of response was 8.4 months and median progression-free survival was 2.3 months. The most common grade ≥3 adverse event was elevation of alanine aminotransferase (two patients, 8%). Diarrhea/colitis was seen in three patients and was grade 1-2. There was one adverse event leading to death (hypoxia). CONCLUSIONS: Idelalisib was tolerable and had modest single-agent activity in heavily pretreated patients with HL. Rational combinations with other novel agents may improve response rate and duration of response. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov # NCT01393106.

A de novo splice site mutation in CASK causes FG syndrome-4 and congenital nystagmus.

Mutations in CASK cause X-linked intellectual disability, microcephaly with pontine and cerebellar hypoplasia, optic atrophy, nystagmus, feeding difficulties, GI hypomotility, and seizures. Here we present a patient with a de novo carboxyl-terminus splice site mutation in CASK (c.2521-2A>G) and clinical features of the rare FG syndrome-4 (FGS4). We provide further characterization of genotype-phenotype correlations in CASK mutations and the presentation of nystagmus and the FGS4 phenotype. There is considerable variability in clinical phenotype among patients with a CASK mutation, even among variants predicted to have similar functionality. Our patient presented with developmental delay, nystagmus, and severe gastrointestinal and gastroesophageal complications. From a cognitive and neuropsychological perspective, language skills and IQ are within normal range, although visual-motor, motor development, behavior, and working memory were impaired. The c.2521-2A>G splice mutation leads to skipping of exon 26 and a 9 base-pair deletion associated with a cryptic splice site, leading to a 28-AA and a 3-AA in-frame deletion, respectively (p.Ala841_Lys843del and p.Ala841_Glu868del). The predominant mutant transcripts contain an aberrant guanylate kinase domain and thus are predicted to degrade CASK's ability to interact with important neuronal and ocular development proteins, including FRMD7. Upregulation of CASK as well as dysregulation among a number of interactors is also evident by RNA-seq. This is the second CASK mutation known to us as cause of FGS4. © 2017 Wiley Periodicals, Inc.

Prognosis in HIV-infected patients with non-small cell lung cancer.

BACKGROUND: We conducted a population-based study to evaluate whether non-small cell lung cancer (NSCLC) prognosis was worse in HIV-infected compared with HIV-uninfected patients. METHODS: Using the Surveillance, Epidemiology and End Results (SEER) registry linked to Medicare claims, we identified 267 HIV-infected patients and 1428 similar controls with no evidence of HIV diagnosed with NSCLC between 1996 and 2007. We used conditional probability function (CPF) analyses to compare survival by HIV status accounting for an increased risk of non-lung cancer death (competing risks) in HIV-infected patients. We used multivariable CPF regression to evaluate lung cancer prognosis by HIV status adjusted for confounders. RESULTS: Stage at presentation and use of stage-appropriate lung cancer treatment did not differ by HIV status. Median survival was 6 months (95% confidence interval (CI): 5-8 months) among HIV-infected NSCLC patients compared with 20 months (95% CI: 17-23 months) in patients without evidence of HIV. Multivariable CPF regression showed that HIV was associated with a greater risk of lung cancer-specific death after controlling for confounders and competing risks. CONCLUSION: NSCLC patients with HIV have a poorer prognosis than patients without evidence of HIV. NSCLC may exhibit more aggressive behaviour in the setting of HIV.

The impact of gender on in-hospital outcomes after carotid endarterectomy or stenting.

AIM: We sought to better define the impact of sex on 'in-hospital outcomes' after carotid endarterectomy (CEA) or stenting (CAS). METHODS: Hospital discharge databases for all carotid interventions obtained from the New York State (NYS) Department of Health, Statewide Planning and Research Cooperative System between 2000 and 2009 (29,917 women, 39,771 men) were analysed. Mortality, stroke and composite event (stroke/death) were compared between procedures after matching of patients by propensity score. Acute myocardial infarction (AMI) was our secondary 'end' point. RESULTS: More than 90% of patients in both sexes were asymptomatic (27,439 women and 36,295 men). Compared to men, asymptomatic women experienced more strokes after CEA (women: 1.38%, men: 1.16%, P = 0.03) and higher AMI rates after both procedures (CEA; women: 0.75%, men: 0.51%, P = 0.0009, CAS; women: 0.96%, men: 0.28%, P = 0.01). Between procedures, symptomatic women undergoing CAS showed higher rates of mortality (CAS: 4.19%, CEA: 0.47%, P = 0.01) and combined (stroke/mortality) events (CAS: 12.09%, CEA: 6.05%, P = 0.02). In all other cohorts, no statistically significant difference was found between the procedures. CONCLUSIONS: Compared to CEA, CAS led to inferior in-hospital outcomes only in symptomatic women in the last decade in NYS. Men and asymptomatic women showed comparable outcomes after both procedures, whereas asymptomatic females were more prone to AMI after both interventions. These sex-associated differences should be taken into account for the treatment of carotid artery disease.

Process of care events in transplantation: effects on the cost of hospitalization.

Deviations in the processes of healthcare delivery that affect patient outcomes are recognized to have an impact on the cost of hospitalization. Whether deviations that do not affect patient outcome affects cost has not been studied. We have analyzed process of care (POC) events that were reported in a large transplantation service (n = 3,012) in 2005, delineating whether or not there was a health consequence of the event and assessing the impact on hospital resource utilization. Propensity score matching was used to adjust for patient differences. The rate of POC events varied by transplanted organ: from 10.8 per 1000 patient days (kidney) to 17.3 (liver). The probability of a POC event increased with severity of illness. The majority (81.5%) of the POC events had no apparent effect on patients' health (63.6% no effect and 17.9% unknown). POC events were associated with longer length of stay (LOS) and higher costs independent of whether there was a patient health impact. Multiple events during the same hospitalization were associated with the highest impact on LOS and cost. POC events in transplantation occur frequently, more often in sicker patients and, although the majority of POC events do not harm the patient, their effect on resource utilization is significant.

High vegetable and fruit diet intervention in premenopausal women with cervical intraepithelial neoplasia.

OBJECTIVE: To examine whether diet intervention can promote increased vegetable and fruit intake, as reflected in increased plasma carotenoid and decreased plasma total homocysteine concentrations, in premenopausal women with cervical intraepithelial neoplasia, a precancerous condition. DESIGN: Randomized controlled diet intervention study. SUBJECTS: Fifty-three free-living premenopausal women who had been diagnosed with cervical intraepithelial neoplasia, were randomly assigned to an intervention (n = 27) or a control (n = 26) group. INTERVENTION: Individualized dietary counseling to increase vegetable and fruit intake. MAIN OUTCOME MEASURES: Diet was assessed by food frequency questionnaire. Plasma carotenoids and total homocysteine were measured at enrollment and at 6 months follow up. ANALYSIS: Associations between baseline plasma concentrations of carotenoids and homocysteine and influencing factors were examined with multiple regression analysis. Repeated measures analysis of variance was used to test for group by time effects in these plasma concentrations. Plasma carotenoids at baseline and 6 months in the study groups, and differences in homocysteine concentrations from baseline to 6 months, were compared with independent sample t tests. RESULTS: Repeated measures analysis of variance showed significant group by time effects (P<.01) in plasma carotenoid and homocysteine concentrations. In the intervention group, total plasma carotenoids increased by an average of 91%, from 2.04+/-0.13 (mean+/-standard error of the mean) to 3.90+/-0.56 micromol/L and plasma total homocysteine was reduced by 11%, from 9.01+/-0.40 to 8.10+/-0.44 micromol/L (P<.003). Neither changed significantly in the control group. APPLICATIONS: Individualized dietary counseling can effectively promote increased vegetable and fruit intake in premenopausal women. This dietary pattern may reduce risk for cancer and other chronic diseases and also promote an improvement in folate status.

Assessment of quality of life in adolescent patients with orthopaedic problems: are adult measures appropriate?

New pressures of accountability brought on by a rapidly evolving system of health care financing have underscored the need for standardized, valid measures of patient outcome that reflect the effect of clinical intervention on all aspects of quality of life. In response, there has been a burgeoning interest in the area of outcomes assessment and measurement of quality of life after orthopaedic intervention in adults, but less attention has been focused on the assessment of broadly defined outcomes in children. In an effort to borrow from the broader adult experience in this area, the authors sought to examine whether the Medical Outcomes Study Short Form 36 (SF-36) or the EuroQol questionnaire, widely accepted adult health status measures, would be valid in this setting. These two measures were administered to 196 adolescent patients (10-18 years old) seeking orthopaedic evaluation. Tests of scale properties and construct validity show that these properties are maintained in this population, but neither instrument reflected known differences in health status among this cohort. Most importantly, both the SF-36 and the EuroQol exhibited serious ceiling effects (most respondents scored at the top of their scales), despite evidence indicating those patients often had suboptimal health status. Thus, neither the SF-36 nor the EuroQol is valid for use in this population. The assessment of pediatric health status demands outcomes measures specifically designed to reflect the unique needs of this population.

Capturing quality of life in pediatric orthopaedics: two recent measures compared.

There is a clear need for standardized measures to assess health status that are valid and appropriate to the needs of children with orthopaedic problems. The Child Health Questionnaire and the American Academy of Orthopaedic Surgeons Pediatric Outcomes Data Collection Instrument, two new pediatric health status measures, were assessed for their ability to detect differences in health states in a pediatric orthopaedic population. The instruments have a range of scales designed to measure various aspects of physical and psychosocial health. Two hundred forty-two patients with wide-ranging diagnoses were enrolled in this cross-sectional study. The instruments exhibited ceiling effects in some domains but generally performed as they were intended in this large cohort. Using secondary factor analysis, it was shown that the domains of the instruments appropriately distinguish physical and psychosocial health. Several domains from each instrument discriminated between diagnosis groups and patients with varying numbers of comorbidities. Both of these measures show significant promise and have an important role in helping define the outcomes of children with orthopaedic problems.

The cost of long-term LVAD implantation.

BACKGROUND: With increasing use of left ventricular assist devices (LVAD) worldwide, the economics of LVAD implantation have become an important focus of concern. Although these devices have high unit costs, they are the only hope for survival for a large group of terminally ill patients and are likely to have an expansion in indications for use. METHODS: We calculated the costs associated with long-term LVAD implantation. We used the ratio of cost-to-charges method to calculate hospital costs per resource category, market prices for drugs and device, and payments for physician services. RESULTS: Based on our experience with "bridge-to-transplantation" patients, we estimated average first-year costs to be $222,460 including professional fees and $192,154 excluding professional fees. The latter figure is comparable to average first-year costs for cardiac transplantation, which is $176,605 without professional fees at our institution. CONCLUSIONS: The costs of LVAD therapy will change after the first year of implantation, and device reliability and longevity will be important factors in determining these costs. Should the costs of LVAD therapy continue to track those of cardiac transplantation, devices will be cost-effective only if they offer similar efficacy to cardiac transplantation.

Long-term use of a left ventricular assist device for end-stage heart failure.

BACKGROUND: Implantable left ventricular assist devices have benefited patients with end-stage heart failure as a bridge to cardiac transplantation, but their long-term use for the purpose of enhancing survival and the quality of life has not been evaluated. METHODS: We randomly assigned 129 patients with end-stage heart failure who were ineligible for cardiac transplantation to receive a left ventricular assist device (68 patients) or optimal medical management (61). All patients had symptoms of New York Heart Association class IV heart failure. RESULTS: Kaplan-Meier survival analysis showed a reduction of 48 percent in the risk of death from any cause in the group that received left ventricular assist devices as compared with the medical-therapy group (relative risk, 0.52; 95 percent confidence interval, 0.34 to 0.78; P=0.001). The rates of survival at one year were 52 percent in the device group and 25 percent in the medical-therapy group (P=0.002), and the rates at two years were 23 percent and 8 percent (P=0.09), respectively. The frequency of serious adverse events in the device group was 2.35 (95 percent confidence interval, 1.86 to 2.95) times that in the medical-therapy group, with a predominance of infection, bleeding, and malfunction of the device. The quality of life was significantly improved at one year in the device group. CONCLUSIONS: The use of a left ventricular assist device in patients with advanced heart failure resulted in a clinically meaningful survival benefit and an improved quality of life. A left ventricular assist device is an acceptable alternative therapy in selected patients who are not candidates for cardiac transplantation.

The contribution of early traumatic events to schizophrenia in some patients: a traumagenic neurodevelopmental model.

The current diathesis-stress model of schizophrenia proposes that a genetic deficit creates a predisposing vulnerability in the form of oversenstivity to stress. This model positions all psychosocial events on the stress side of the diathesis-stress equation. As an example of hypotheses that emerge when consideration is given to repositioning adverse life events as potential contributors to the diathesis, this article examines one possible explanation for the high prevalence of child abuse found in adults diagnosed schizophrenic. A traumagenic neurodevelopmental (TN) model of schizophrenia is presented, documenting the similarities between the effects of traumatic events on the developing brain and the biological abnormalities found in persons diagnosed with schizophrenia, including overreactivity of the hypothalamic-pituitary-adrenal (HPA) axis; dopamine, norepinephrine, and serotonin abnormalities; and structural changes to the brain such as hippocampal damage, cerebral atrophy, ventricular enlargement, and reversed cerebral asymmetry. The TN model offers potential explanations for other findings in schizophrenia research beyond oversensitivity to stress, including cognitive impairment, pathways to positive and negative symptoms, and the relationship between psychotic and dissociative symptomatology. It is recommended that clinicians and researchers explore the presence of early adverse life events in adults with psychotic symptoms in order to ensure comprehensive formulations and appropriate treatment plans, and to further investigate the hypotheses generated by the TN model.

Hypoplastic left heart syndrome: valuing the survival.

OBJECTIVE: To examine the survival, developmental status, quality of life, and direct medical costs of children with hypoplastic left heart syndrome who have undergone stage I, II, and III reconstructive surgery. METHODS: A total of 106 children underwent staged repair for classic hypoplastic left heart syndrome between February 1990 and March 1999 (stage I: 106; stage II: 49; stage III: 25; 4 converted to heart transplantation). Survival was analyzed by the Kaplan-Meier method. In a cross-sectional study, parents assessed quality of life by completing the Infant/Toddler Child Health Questionnaire or Child Health Questionnaire Parent Format-28; they assessed developmental progress by completing the Ages and Stages Questionnaire. The ratio-of-costs-to-charges method was used to derive hospital costs, and payments were used to capture physician time and wholesale pricing for outpatient medications. RESULTS: Institutional 1-year and 5-year actuarial survivals were 58% and 54%. Birth weight, the need for preoperative inotropic drugs, and surgical experience were predictors of survival. Norwood I patients achieved fewer developmental benchmarks than those who survived to subsequent stages. Child Health Questionnaire Parent Format-28 mean summary scores for physical and psychosocial health were 48.5 +/- 6.3 and 42.8 +/- 9.9. The median inpatient costs for stage I, II, and III repairs were $51,000, $33,892, and $52,183, respectively. Monthly outpatient and readmission costs were less than 10% of total costs. CONCLUSION: A prospective, large-scale study of the comprehensive outcomes of staged repair and transplantation is needed. This study will need to address the longer-term developmental and quality-of-life outcomes, as well as the long-term cost effectiveness of these procedures.

Purine catabolism: links to mitochondrial respiration and antioxidant defenses?

Type I diabetes in rodents is associated with a spectrum of liver mitochondrial abnormalities ranging from evidence of oxidative stress and altered antioxidant defenses to frank defects in respiration rates and respiratory control ratios. To better address the myriad changes in redox metabolism in these mitochondria, we have applied new chromatographic techniques that enable simultaneous analysis of multiple components of pathways of interest (e.g., purine catabolites and oxidation by-products). We report here a portion of these results, which, in conjunction with other reported data, suggest that purine catabolism may contribute to mitochondrial antioxidant defenses by producing the antioxidant urate. In liver mitochondria from diabetic rats, increases in uric acid (threefold) and its direct precursor xanthine (sixfold) were observed in moderate diabetes, but levels fell essentially to normal in severe disease. Failure to maintain elevated xanthine and uric acid occurred contemporaneously with progressive mitochondrial dysfunction. Regression analysis revealed altered precursor-product relationships between xanthine, its precursors, and uric acid. An independent set of studies in isolated rat liver mitochondria showed that mitochondrial respiration was associated with essentially uniform decreases (approximately 30%) in all purine catabolites measured (urate, xanthine, hypoxanthine, guanine, guanosine, and xanthosine). That result suggests the potential for steady production of urate. Taken together, the two studies raise the possibility that purine catabolism may be a previously unappreciated component of the homeostatic response of mitochondria to oxidant stress and may play a critical role in slowing progressive mitochondrial dysfunction in certain disease states.

Bayesian estimation of cost-effectiveness ratios from clinical trials.

Estimation of the incremental cost-effectiveness ratio (ICER) is difficult for several reasons: treatments that decrease both cost and effectiveness and treatments that increase both cost and effectiveness can yield identical values of the ICER; the ICER is a discontinuous function of the mean difference in effectiveness; and the standard estimate of the ICER is a ratio. To address these difficulties, we have developed a Bayesian methodology that involves computing posterior probabilities for the four quadrants and separate interval estimates of ICER for the quadrants of interest. We compute these quantities by simulating draws from the posterior distribution of the cost and effectiveness parameters and tabulating the appropriate posterior probabilities and quantiles. We demonstrate the method by re-analysing three previously published clinical trials.

The REMATCH trial: rationale, design, and end points. Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure.

BACKGROUND: Because left ventricular assist devices have recently been approved by the Food and Drug Administration to support the circulation of patients with end-stage heart failure awaiting cardiac transplantation, these devices are increasingly being considered as a potential alternative to biologic cardiac replacement. The Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial is a multicenter study supported by the National Heart, Lung, and Blood Institute to compare long-term implantation of left ventricular assist devices with optimal medical management for patients with end-stage heart failure who require, but do not qualify to receive cardiac transplantation. METHODS: We discuss the rationale for conducting REMATCH, the obstacles to designing this and other randomized surgical trials, the lessons learned in conducting the multicenter pilot study, and the features of the REMATCH study design (objectives, target population, treatments, end points, analysis, and trial organization). CONCLUSIONS: We consider what will be learned from REMATCH, expectations for expanding the use of left ventricular assist devices, and future directions for assessing clinical procedures.

Volume-outcome relationships in cardiovascular operations: New York State, 1990-1995.

BACKGROUND: It has been known for nearly 20 years that, in cardiovascular operations, a significant inverse relationship exists between clinical outcomes and the volume of procedures performed. Interestingly, this relationship persists 2 decades after it was recognized. OBJECTIVE: The purpose of this study was to examine the relationship between hospital volume and in-hospital deaths in 3 cardiovascular procedures: coronary artery bypass grafting, elective repair of abdominal aortic aneurysms, and repair of congenital cardiac defects. METHODS: The database includes all patients who were hospitalized in New York State during the years 1990 to 1995. Using standard logistic regression techniques, we analyzed the relationship between hospital volume and outcome. RESULTS: No correlation exists between hospital volume and in-hospital deaths in coronary artery bypass grafting. Statewide, 31 hospitals performed 97,137 operations over the 6-year period (overall mortality rate, 2. 75%). By contrast, most of the hospitals statewide (195 of 230 hospitals) performed 9847 elective abdominal aortic aneurysm repairs with an overall mortality rate of 5.5%. In abdominal aortic aneurysm operations, a significant inverse relationship between hospital volume and in-hospital deaths was determined. Sixteen hospitals performed 7199 repairs for congenital cardiac defects. A significant inverse relationship (which was most pronounced for neonates) was found between volume and death. CONCLUSIONS: The importance of these findings lies in the rather striking difference between the volume-outcome relationship found for operations for abdominal aortic aneurysms and congenital cardiac defects and the lack of such a relationship for coronary artery bypass grafting. This observation may be largely explained by the quality improvement program in New York State for bypass operations since 1989. If so, these results have important implications for expanding the scope of quality improvement efforts in New York State.

Problems with interval estimates of the incremental cost-effectiveness ratio.

The defining feature of a confidence interval is that it has a fixed minimum probability of covering the true value of the parameter being estimated, whatever the value of the parameter. The authors demonstrate by simulation that some recently proposed methods for interval estimation of the incremental cost-effectiveness ratio (ICER) either do not satisfy this definition or have other problems that limit their usefulness in applications. The problems are most prominent when the ICER is large and the true effectiveness difference is small relative to its standard error. A modification of the percentile bootstrap confidence interval that involves a reordering of the sample space provides a partial solution of the problem.