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.

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.

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.

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.

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.

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.

The effectiveness of preoperative erythropoietin in averting allogenic blood transfusion among children undergoing scoliosis surgery.

Concerns about the transmission of the human immunodeficiency virus (HIV) have driven the evolution of surgical transfusion practices including the use of preoperative erythropoietin (rhEPO). Although there is significant experience documenting the efficacy of preoperative rhEPO in reducing transfusion requirements for adult patients, there is little experience in the pediatric population. With 178 pediatric patients who underwent surgery for spinal deformity, a retrospective cohort study was performed using patient charts, administrative records, and blood bank computer data. Of these patients, 44% received erythropoietin and 55% did not. From the entire population, 17.5% were in the rhEPO treatment group that received homologous blood transfusion compared with 30.6% in the untreated group (p < 0.05). Among the children with idiopathic scoliosis, this effect was more pronounced, with 3.9% of rhEPO patients receiving blood transfusion compared with 23.5% of nontreated patients (p = 0.006). Additionally, rhEPO treatment was associated with a significantly decreased length of stay only for patients in the idiopathic group (9.3 vs. 6.7, p = 0.02). Use of preoperative erythropoietin in pediatric patients undergoing scoliosis surgery resulted in higher preoperative hematocrit levels. Significantly lower rates of transfusion were noted only in the idiopathic group, however. Although there is a possibility of erythropoietin "resistance" in the neuromuscular and congenital patients, alternative explanations for the lack of effect on transfusion rates may include underdosing and biases existent in this nonrandomized retrospective study.

Bioresorbable microporous stents deliver recombinant adenovirus gene transfer vectors to the arterial wall.

The use of intravascular stents as an adjunct for percutaneous transluminal revascularization is limited by two principal factors, acute thrombosis and neointimal proliferation, resulting in restenosis. To overcome these limitations, we have investigated the potential of microporous bioresorbable polymer stents formed from poly(L-lactic acid) (PLLA)/poly(epsilon-caprolactone) (PCL) blends to function both to provide mechanical support and as reservoirs for local delivery of therapeutic molecules and particles to the vessel wall. Tubular PLLA/PCL stents were fabricated by the flotation-precipitation method, and helical stents were produced by a casting/winding technique. Hybrid structures in which a tubular sheath is deposited on a helical skeleton were also generated. Using a two-stage solvent swelling technique, polyethylene oxide has been incorporated into these stents to improve hydrophilicity and water uptake, and to facilitate the ability of these devices to function as drug carriers. Stents modified in this manner retain axial and radial mechanical strength sufficient to stabilize the vessel wall against elastic recoil caused by vasoconstrictive and mechanical forces. Because of the potential of direct gene transfer into the vessel wall to ameliorate thrombosis and neointimal proliferation, we have investigated the capacity of these polymer stents to function in the delivery of recombinant adenovirus vectors to the vessel wall. In vitro, virus stock was observed to readily absorb into, and elute from these devices in an infectious form, with suitable kinetics. Successful gene transfer and expression has been demonstrated following implantation of polymer stents impregnated with a recombinant adenovirus carrying a nuclear-localizing betaGal reporter gene into rabbit carotid arteries. These studies suggest that surface-modified polymer stents may ultimately be useful adjunctive devices for both mechanical support and gene transfer during percutaneous transluminal revascularization.

Evolving costs of long-term left ventricular assist device implantation.

BACKGROUND: To examine the long-term costs of implanting a left ventricular assist device, we reviewed the initial hospitalization and outpatient costs for 12 patients who received a vented electric left ventricular assist device, and projected the first-year costs. METHODS: We used the ratio-of-cost-to-charges method to measure hospital costs and payments for physician time. We examined time trends in the resource use of 50 pneumatic left ventricular assist device recipients, using actuarial techniques and regression modeling. RESULTS: The average actual cost of left ventricular assist device support is $221,313 over an average of 9.5 months. If there had been no Food and Drug Administration regulatory policy precluding hospital discharge before 30 days, this value would have been $201,148. Based on this latter figure, the average predicted first-year cost is $219,139. The length of the intensive care unit stay, one of the most costly components of care, decreased significantly over time. CONCLUSIONS: The high costs of left ventricular assist device implantation are similar to those reported for cardiac transplantation. Given their success in supporting survival, we anticipate that these devices will be similarly cost-effective. However, further research is imperative to determine the cost-effectiveness of these devices beyond the introductory phase, when costs, benefits, and Food and Drug Administration requirements have stabilized.

An international comparison of cancer survival: Toronto, Ontario, and Detroit, Michigan, metropolitan areas.

OBJECTIVES: This study examined whether socioeconomic status has a differential effect on the survival of adults diagnosed with cancer in Canada and the United States. METHODS: The Ontario Cancer Registry and the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program provided a total of 58,202 and 76,055 population-based primary malignant cancer cases for Toronto, Ontario, and Detroit, Mich, respectively. Socioeconomic data for each person's residence at time of diagnosis were taken from population censuses. RESULTS: In the US cohort, there was a significant association between socioeconomic status and survival for 12 of the 15 most common cancer sites; in the Canadian cohort, there was no such association for 12 of the 15 sites. Among residents of low-income areas, persons in Toronto experienced a survival advantage for 13 of 15 cancer sites at 1- and 5-year follow-up. No such between-country differentials were observed in the middle- or high-income groups. CONCLUSIONS: The consistent pattern of a survival advantage in Canada observed across various cancer sites and follow-up periods suggests that Canada's more equitable access to preventive and therapeutic health care services is responsible for the difference.

Quality of life with an implanted left ventricular assist device.

BACKGROUND: With the increasing use of left ventricular assist devices (LVADs) for longer-term support of patients awaiting cardiac transplantation, we must now consider whether to use these devices as alternatives to medical therapy when biologic hearts are needed but not forthcoming. This expansion of use depends as much on quality of life as it does on survival. To draw an inference about long-term quality of life with implanted LVADs, we studied "bridged" patients at our institution. METHODS: We elicited, by standard gamble, the utilities (preferences) of bridged patients at three points in their care: before LVAD implantation, during LVAD support, and after cardiac transplantation. RESULTS: Utility was 0.548 (+/-0.276) before implantation, 0.809 (+/-0.136) during LVAD support, and 0.964 (+/-0.089) after transplantation. For patients interviewed during all three states of health, the utilities were significantly different (p = 0.0009 by analysis of variance). CONCLUSIONS: The quality of life with an LVAD was substantially better than with medical therapy, on par with renal transplantation (as established by others), and not as good as after cardiac transplantation. These results portend an acceptable quality of life for long-term use of LVADs for patients with end-stage heart failure and contribute to the growing body of evidence supporting a clinical trial to test this new use.

Improved bioresorbable microporous intravascular stents for gene therapy.

Drug imbibing microporous stents are under development at a number of centers to enhance healing of the arterial wall after balloon coronary angioplasty procedures. The authors improved the mechanical strength and reservoir properties of a biodegradable microporous stent reported to this Society in 1994. A combined tubular/helical coil stent is readily fabricated by flotation/precipitation and casting/ winding techniques. A two stage solvent swelling technique allows precise adjustment of the surface hydrophilic/hydrophobic balance. These developments permit seven-fold improvement in drug capacity without significantly altering mechanical properties. Stents modified in this manner retain tensile and compressive strength and are suitable for remote deployment. Elution kinetics of these modified stents suggest they are suitable for gene delivery. Successful gene transfer and transmural expression have been demonstrated after implantation of stents impregnated with a recombinant adenovirus carrying a nuclear localizing beta-galactosidase reporter gene into rabbit carotid arteries. These studies suggest that surface modified, bioresorbable polymer stents ultimately may be useful adjunctive devices for gene transfer during percutaneous transluminal revascularization.

Expression of quinone reductase activity in embryonal and adult porcine tissues.

Quinone reductase (QR; EC 1.6.99.2) is recognized as a major antimutagenic/anticarcinogenic enzyme in the organism. Our recent studies demonstrated the presence of significant QR activity in the early human placenta; whether this enzyme is expressed by the mammalian embryo is not known at present. In the investigation reported here, we sought to determine whether or not QR activity is detected in porcine embryonal tissues and if so, how early this expression takes place. In addition, the enzyme activity in the embryo was compared to that present in adult porcine tissue. Enzyme activity was determined by a colorimetric method with menadione as substrate in the presence of tetrazolium salt (MTT). NADH was a preferable cofactor in the embryo, whereas in the adult tissues NADPH was a better cofactor. Results show that the enzyme is present in all the embryonal organs tested from a very early age (30 days of gestation). Among the organs tested, activity was highest in the porcine embryo liver, and the specific activity remained unchanged until Day 70. Activity in the embryonal kidney increased with advancing gestation. The enzyme activity in embryonal tissues was much lower than that measured in the adult liver (30-40-fold). These findings suggest that the embryo has the potential for inactivating carcinogens/mutagens that will subsequently be eliminated by the maternal organism, thus protecting against adverse environmental impacts during the most critical period of development.

Surgical and clinical results of scoliosis surgery using Zielke instrumentation.

All patients with idiopathic thoracolumbar or lumbar scoliosis treated by a single surgeon with a single-stage fusion with Zielke instrumentation and a minimum 2-year follow-up were reviewed. Thirty-two patients were reviewed (94% follow-up), 13 adolescents and 19 adults. All patients were evaluated clinically and radiographically, as well as psychosocially. There were no major complications. The average curve correction was 73%. The instrumentation was kyphogenic, but this did not affect the overall sagittal contour or the clinical results. Back pain was significantly improved, as was cosmesis. The Zielke device was found to be an effective device for the correction of thoracolumbar and lumbar curves in selected adolescents and adults.

A patient with new Q waves: methods for decision making in the individual patient.

Decision analysis, an analytic approach to making decisions when uncertainty is present, has its foundation in probability and utility theory. It provides insights into the trade-offs that are involved when a selection must be made among patient management strategies. In general, several broad steps are involved. The process begins by formulating the clinical problem as a well focused choice among a limited set of clinical etiologies. These strategies are then structured explicitly in a model that depicts the clinical events that may ensue from each option. By assigning probability values to each outcome, the weighted average outcome or expected utility can be calculated for each alternative strategy. The strategy with the highest expected utility is the optimal one. The methods of decision analysis offer a number of distinct advantages. These include: 1) providing a structure with which to simplify and focus clinical dilemmas; 2) providing a forum for discussing clinical reasoning; and 3) developing a consensus among groups of decision makers.