Outcomes following autologous hematopoietic stem cell transplant for patients with relapsed Wilms' tumor: a CIBMTR retrospective analysis.

Despite the marked improvement in the overall survival (OS) for patients diagnosed with Wilms' tumor (WT), the outcomes for those who experience relapse have remained disappointing. We describe the outcomes of 253 patients with relapsed WT who received high-dose chemotherapy (HDT) followed by autologous hematopoietic stem cell transplant (HCT) between 1990 and 2013, and were reported to the Center for International Blood and Marrow Transplantation Research. The 5-year estimates for event-free survival (EFS) and OS were 36% (95% confidence interval (CI); 29-43%) and 45% (95 CI; 38-51%), respectively. Relapse of primary disease was the cause of death in 81% of the population. EFS, OS, relapse and transplant-related mortality showed no significant differences when broken down by disease status at transplant, time from diagnosis to transplant, year of transplant or conditioning regimen. Our data suggest that HDT followed by autologous HCT for relapsed WT is well tolerated and outcomes are similar to those reported in the literature. As attempts to conduct a randomized trial comparing maintenance chemotherapy with consolidation versus HDT followed by stem cell transplant have failed, one should balance the potential benefits with the yet unknown long-term risks. As disease recurrence continues to be the most common cause of death, future research should focus on the development of consolidation therapies for those patients achieving complete response to therapy.

Detection of human papillomavirus in the oral cavities of persons with Fanconi anemia.

OBJECTIVE: We conducted a cross-sectional study to describe the prevalence and correlates of type-specific human papillomavirus (HPV) DNA in the oral cavities of persons with Fanconi anemia. MATERIALS AND METHODS: Oral swabs were collected from 67 participants with Fanconi anemia and tested for 27 HPV genotypes using polymerase chain reaction-based methods. RESULTS: Participants were a mean of 18.6 (standard deviation, 10.0) years of age (range 4-47 years). The prevalence of oral HPV infection was 7.5%, and the prevalence of high-risk HPV infection was 6.0%. HPV type 16 was not detected in any samples. Prevalence was higher in adults than in children (13.3% vs 2.7% in those ≥18 vs <18 years of age). Among adults, prevalence was higher in males than in females (25.0% vs 9.1%, respectively). CONCLUSIONS: Prevalence of oral HPV infection in persons with Fanconi anemia was comparable to estimates from other studies in the general population. However, in contrast to previous studies, we did not identify HPV type 16 (the type found in most HPV-related head and neck cancers) in any participants.

Newly diagnosed heart failure: change in quality of life, mood, and illness beliefs in the first 6 months after diagnosis.

OBJECTIVES: This study sought to examine how patients' mood and quality of life (QoL) change during the early high-risk period after a diagnosis of heart failure (HF) and to identify factors that may influence change. DESIGN: A within-subjects, repeated-measures design was used. Assessments took place within 4 weeks of diagnosis and 6 months later. METHODS: One hundred and sixty six patients with HF completed assessments of their mood, QoL, and beliefs about HF and its treatment. Correlation analysis was conducted between the variables and analysis of variance and t-tests were used to assess differences in categorical variables. To examine which variables predicted mood and QoL, hierarchical multiple regressions were conducted. RESULTS: At follow-up, patients' beliefs indicated a realization of the chronicity of their HF, however their beliefs about the consequences of having HF did not change and their satisfaction with their treatment remained high. QoL and anxiety improved significantly over time but there was no significant change in depressed mood. As would be expected, improvement in symptoms was a key factor in improved mood and QoL. Other significant explanatory variables included age, comorbid chronic obstructive pulmonary disease, depressed mood, patients' beliefs about the consequences of their HF and their concerns about treatment. CONCLUSIONS: This study suggests that addressing patients' mood and beliefs about their illness and its treatment may be additional ways of improving patient QoL in the early period after the diagnosis of HF.

Early clinical indicators of transplant-associated thrombotic microangiopathy in pediatric neuroblastoma patients undergoing auto-SCT.

Patients undergoing auto-SCT for neuroblastoma present a unique population to study transplant-associated thrombotic microangiopathy (TA-TMA), due to standardized chemotherapy and later exposure to radiation and cis-retinoic acid (cis-RA). We retrospectively analyzed 20 patients after auto-SCT to evaluate early clinical indicators of TA-TMA. A total of 6 patients developing TA-TMA (30% prevalence) were compared with 14 controls. Four of six patients were diagnosed with TA-TMA by 25 days after auto-SCT. Compared with controls, TA-TMA patients had higher average systolic and diastolic blood pressure levels during high-dose chemotherapy and developed hypertension by day 13 after auto-SCT. Proteinuria was a significant marker for TA-TMA, whereas blood and platelet transfusion requirements were not. Serum creatinine did not differ between groups post transplant. However, patients with TA-TMA had a 60% decrease in renal function from baseline by nuclear glomerular filtration rate, compared with a 25% decrease in those without TA-TMA (P=0.001). There was no TA-TMA-related mortality. Significant complications included end-stage renal disease (n=1) and polyserositis (n=3). Patients with TA-TMA were unable to complete cis-RA therapy after auto-SCT. We suggest that careful attention to blood pressure and urinalysis will assist in the early diagnosis of TA-TMA, whereas serum creatinine seems to be an insensitive marker for this condition.

Angiotensin receptor blocker therapy for heart failure patients: is combination treatment a feasible prospect?

BACKGROUND: The addition of the angiotensin II type 1 receptor blocker (ARB) candesartan to a angiotensin-converting enzyme inhibitor (ACEI) has been associated with improved clinical outcomes in patients with heart failure. However many do not tolerate combination therapy and concerns have been raised regarding excessive neurohormonal inhibition. HYPOTHESIS: The majority of patients with chronic heart failure are not eligible or do not tolerate combination therapy with an ACEEI and ARB. METHODS: We prospectively evaluated 115 consecutive patients with heart failure (median age 74 y; 74% males; mean left ventricular ejection fraction 30%) within a district general hospital for eligibility and tolerance to combination therapy using candesartan in addition to recommended doses of an ACEI. RESULTS: Overall, 109 (95%) were ineligible to initiate candesartan. The most frequent reasons were that, despite best efforts at optimization, 77% of patients were unable to achieve recommended doses of an ACEI, 29% were relatively asymptomatic, 20% had symptomatic hypotension, and 35% were already taking an ARB due to previous ACEI "intolerance." Overall, 6 (5%) of patients satisfied the eligibility criteria of whom 3 (3% of total) were already taking "optimal" doses of an ARB in addition to an ACEI. The remaining 3 patients commenced the titration schedule with candesartan. All 3 patients failed the first titration phase (4 mg once daily) within 2 weeks of initiation, due to the development of hyperkalemia. CONCLUSIONS: The use of combination therapy with an ARB in addition to recommended doses of ACEI does not appear feasible in patients with heart failure in the general population, as the vast majority are not eligible.

Improving survival in the 6 months after diagnosis of heart failure in the past decade: population-based data from the UK.

OBJECTIVE: To investigate the secular trend in survival after a new diagnosis of heart failure in the UK population. DESIGN AND SETTING: Comparison of all-cause mortality in the 6 months after diagnosis of heart failure in population-based studies in the south east of England in 2004-5 (Hillingdon-Hastings Study) and 1995-7 (Hillingdon-Bromley Studies). PARTICIPANTS: 396 patients in the 2004-5 cohort and 552 patients in the 1995-7 cohort with incident (new) heart failure. MAIN OUTCOME MEASURES: All-cause mortality. RESULTS: All-cause mortality rates were 6% (95% CI 3% to 8%) at 1 month, 11% (8% to 14%) at 3 months and 14% (11% to 18%) at 6 months in the 2004-5 cohort compared with 16% (13% to 20%), 22% (19% to 25%) and 26% (22% to 29%), respectively, in the 1995-7 cohort (difference between the two cohorts, p<0.001). The difference in survival was not explained by any difference in the demographics or severity of heart failure at presentation. There was a difference at baseline and thereafter in the use of neurohormonal antagonists (beta-blockers and angiotensin-converting enzyme inhibitors). CONCLUSIONS: Although early mortality remains high among patients with newly diagnosed heart failure in the UK general population, there is strong evidence of a marked improvement in survival from 1995-7 to 2004-5, perhaps partly explained by an increased usage of neurohormonal antagonists.

High output heart failure.

The symptoms and signs of heart failure can occur in the setting of an increased cardiac output and has been termed 'high output heart failure'. An elevated cardiac output with clinical heart failure is associated with several diseases including chronic anaemia, systemic arterio-venous fistulae, sepsis, hypercapnia and hyperthyroidism. The underlying primary physiological problem is of reduced systemic vascular resistance either due to arterio-venous shunting or peripheral vasodilatation. Both scenarios can lead to a fall in systemic arterial blood pressure and neurohormonal activation leading to overt clinical heart failure. In contrast to low output heart failure, clinical trial data in this area are lacking. The use of conventional therapies for heart failure, such as angiotensin converting enzyme inhibitors, angiotensin receptor blockers and certain beta-blockers with vasodilatory properties, is likely to further reduce systemic vascular resistance resulting in deterioration. The condition, although uncommon, is often associated with a potentially correctable aetiology. In the absence of a remediable cause, therapeutic options are very limited but include dietary restriction of salt and water combined with judicious use of diuretics. Vasodilators and beta-adrenoceptor positive inotropes are not recommended.

Reduced-intensity conditioning is effective and safe for transplantation of patients with Shwachman-Diamond syndrome.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only potentially curative treatment for the BM dysfunction seen in patients with Shwachman-Diamond syndrome (SDS). Historically, these patients have fared poorly with intensive conditioning regimens with increased regimen-related toxicity especially involving the heart and lungs. We report our institutional experience with a reduced-intensity-conditioning protocol in seven patients with SDS and BM aplasia or myelodysplastic syndrome/AML. The preparative regimen consisted of Campath-1H, fludarabine and melphalan. Four patients received matched related marrow and three received unrelated stem cells (two PBSCs and one marrow). All but one was 8 of 8 allele HLA matched. All patients established 100% donor-derived hematopoiesis. No patient in this cohort developed grades III-IV GVHD. One patient had grade II skin GVHD that responded to systemic corticosteroids and one had grade I skin GVHD, treated with topical corticosteroids. Two out of seven patients developed bacterial infections in the early post transplant period. Viral infections were seen in four out of seven patients and were successfully treated with appropriate antiviral therapy. All patients are currently alive. These data indicate that HSCT with reduced-intensity conditioning is feasible in patients with SDS and associated with excellent donor cell engraftment and modest morbidity.

DNA repair polymorphisms and outcome of chemotherapy for acute myelogenous leukemia: a report from the Children's Oncology Group.

Polymorphisms of DNA repair genes RAD51 and XRCC3 increase susceptibility to acute myeloid leukemia (AML) in adults, an effect enhanced by deletion of the glutathione-S-transferase M1 (GSTM1) gene. In this study, we genotyped 452 children with de novo AML treated on CCG protocols 2941 and 2961 and compared genotype frequencies with those of normal blood donors, and analyzed the impact of genotype on outcome of therapy. XRCC3 Thr241Met, RAD51 G135C and GSTM1 genotypes did not increase susceptibility to AML when assessed singly. In contrast, when XRCC3 and RAD51 genotypes were examined together a significant increase in susceptibility to AML was seen in children with variant alleles. Analysis of outcome of therapy showed that patients heterozygous for the XRCC3 Thr241Met allele had improved post-induction disease-free survival compared to children homozygous for the major or minor allele, each of whom had similar outcomes. Improved survival was due to reduced relapse in the heterozygous children, and this effect was most marked in children randomized to therapy likely to generate DNA double-strand breaks (etoposide, daunomycin), compared with anti-metabolite (fludarabine, cytarabine) based therapy. In contrast, RAD51 G135C and the GSTM1 deletion polymorphism did not influence outcome of AML therapy in our study population.

Allogeneic transplantation for childhood ALL.

More than 80% of children with ALL are now cured with chemotherapy without need for transplantation. This remarkable progress is the result of serial large-scale randomized clinical trials incorporating improvements in risk group assignment, administration of risk-adjusted therapy and intensified therapy for children with high-risk disease. Despite these advances, significant numbers of children still die of relapsed or refractory ALL, as ALL is the most frequent malignancy of childhood. This review focuses on the appropriate use of transplantation for children with ALL and optimization of transplant procedures to improve survival and reduce late consequences of therapy.

Perforin polymorphism A91V and susceptibility to B-precursor childhood acute lymphoblastic leukemia: a report from the Children's Oncology Group.

Perforin plays a key role in the cytotoxicity of natural killer and cytotoxic T cells. Genetic mutations in the perforin gene (PRF1) give rise to approximately 30% cases of familial hemophagocytic lymphohistiocytosis. A frequent polymorphism, A91V (C to T transition at position 272), may impair processing of perforin protein to the active form, and has been suggested to increase susceptibility to childhood acute lymphoblastic leukemia (ALL). To investigate the role of A91V in ALL, we genotyped 2272 children with de novo ALL registered on the Pediatric Oncology Group ALL Classification study P9900 and 655 normal controls. Allele frequencies in the controls showed a very low frequency of the variant allele in blacks, 0.7% compared to 4% in white controls. In light of this, analysis was restricted to a comparison of white cases and controls only. Overall genotype frequencies were similar in white ALL cases and normal white controls (P=0.58), indicating that in contrast to the previous report, A91V polymorphism is not associated with increased risk of childhood ALL. PRF1 A91V frequency was significantly increased in children with BCR-ABL positive ALL (24 vs 8.5%; P=0.0048); however, this observation includes a relatively small number of cases and needs further exploration.

Heart failure in a district general hospital: are target doses of beta-blockers realistic?

BACKGROUND: Carvedilol therapy reduces mortality in patients with chronic heart failure. Multi-centre studies suggest a low first dose failure rate and high levels of tolerability to carvedilol. Little is known, however, concerning the eligibility and tolerance to treatment with carvedilol within a district general hospital setting. AIM: To evaluate the eligibility and tolerance of patients with heart failure to carvedilol within a district general hospital. DESIGN: Prospective clinical audit analysis. METHODS: We assessed 100 heart failure patients eligibility to commence carvedilol therapy. In those who satisfied clinical criteria, we evaluated first dose failure rate, target dose achievement, reasons for intolerance, heart rate and blood pressure reduction and resource requirements over a six-month period. RESULTS: Of 100 patients, 16% had contra-indications to commence carvedilol and 22% were receiving a beta-blocker as part of their existing heart failure therapy. Although 62% satisfied eligibility criteria, 1% refused therapy, thus 61% were initiated on carvedilol. The first dose failure rate was 11.5% and 6.6% of patients achieved 'target dose'. Mean heart rate and systolic blood pressure reductions were 15 (SE 1.2)bpm and 17 (SE 1.7) mmHg, respectively. Resource requirements included 155 hours of work-time for a trained heart failure specialist nurse and doctor. CONCLUSIONS: In the general setting, eligible patients appear to display a high first dose failure rate, poor tolerance to higher doses and achievement of a 'target dose' of carvedilol. Responses to adrenergic blockade were similar to previously published data, irrespective of the final tolerated dose, suggesting that the concept of achieving a 'target dose' may not be clinically useful. Guidelines and treatment protocols for heart failure should reflect not only what is considered gold standard, but also what is practical in general hospitals.

Epithelial cells infected with respiratory syncytial virus are resistant to the anti-inflammatory effects of hydrocortisone.

In this work we continue our study of the biochemical responses of respiratory epithelial cells to infection with human paramyxovirus pathogens. In our earlier studies, we detected elevated concentrations of the proinflammatory chemokines MIP-1alpha and IL-8 in upper and lower respiratory tract secretions from patients infected with respiratory syncytial virus (RSV). Here we demonstrate the same trend for individuals infected with parainfluenza virus (PIV), with elevated concentrations of MIP-1alpha and IL-8 (means of 309 +/- 51 and 2280 +/- 440 pg/ml/mg protein, respectively) detected in nasal wash samples from 17 patients with culture-positive PIV. Similar to our findings with RSV, cells of the HEp-2 epithelial line and primary cultures of human bronchial epithelial cells respond to PIV infection with production and release of both MIP-1alpha and IL-8. Addition of the glucocorticoid anti-inflammatory agent hydrocortisone (200-1000 ng/ml) attenuated the production of MIP-1alpha and IL-8 in PIV-infected cells while having minimal to no effect on the production of these mediators from cells infected with RSV. Neither virus infection resulted in a change in the total cellular concentration of glucocorticoid receptors, nor did hydrocortisone exert any differential effect on viral replication. As repression of chemokine production by epithelial cells is likely to result in diminished recruitment of proinflammatory leukocytes, these results may explain in part why glucocorticoid therapy reduces the symptoms associated with acute PIV infection, but have little to no effect in the overall outcome in the case of RSV.

Risk factors for sternal wound and other infections in pediatric cardiac surgery patients.

BACKGROUND: This study was undertaken to determine the incidence, pathogens and risk factors associated with development of sternal wound and other infections in children undergoing cardiac surgery. METHODS: Retrospective chart review was performed for all cardiac surgeries performed on children <18 years of age at Upstate Medical University at Syracuse between January, 1996, and June, 1998. For evaluation of risk factors for sternal wound infection, only patients undergoing sternotomy are included in the analysis: those with infection are compared with those without for preoperative, intraoperative and postoperative risk factors. RESULTS: Sternal wound infection developed in 10 of 202 (5%) children after median sternotomy. Superficial sternal wound infection developed in 6 (3%) children, and 4 (2%) had deep infection. Children with sternal wound infection had lower age, higher American Society of Anesthesiologist score, longer preoperative stay, longer period of ventilation and inotropic support, longer intensive care unit and total postoperative hospital stays and increased leukocyte band cell counts preoperatively and on Postoperative Day 1 than those without sternal infection. Causative agents for sternal wound infection were Staphylococcus aureus (6), Pseudomonas aeruginosa (1) and Haemophilus influenzae non-type b (1). In addition 32 bacterial infections occurred at nonsurgical sites after 28 procedures. Infections included pneumonia, urinary tract infection and bacteremia. Longer bypass time and longer operation time were two additional risk factors for nonwound infection. CONCLUSION: Infections continue to be a significant cause of morbidity in cardiac surgery patients. Knowledge of risk factors for infection could be useful in preventive and treatment strategies for these high-risk groups.