, CM Vajdic 5 and CAST study group 6 Population-based evidence on second cancer risk following autologous haematopoietic SCT (HCT) is lacking. We quantified second cancer risk for a national, population-based cohort of adult Australians receiving autologous HCT for cancer and notified to the Australasian Bone Marrow Transplant Recipient Registry 1992Registry -2007. Cancer diagnoses and deaths were ascertained by linkage with the Australian Cancer Database and National Death Index. Standardized incidence ratios (SIRs) were calculated and Cox regression models were used to estimate within-cohort risk factors treating death as a competing risk. During a median 2.5 years follow-up, second cancer risk was modestly increased compared with the general population (SIR 1.4, 95% confidence interval 1.2-1.6); significantly elevated risk was also observed for AML/myelodysplastic syndrome (SIR ¼ 20.6), melanoma (SIR ¼ 2.6) and non-Hodgkin lymphoma (SIR ¼ 3.3). Recipients at elevated risk of any second cancer included males, and those transplanted at a younger age, in an earlier HCT era, or for lymphoma or testicular cancer. Male sex, older age (445 years) and history of relapse after HCT predicted melanoma risk. Transplantation for Hodgkin lymphoma and older age were associated with lung cancer risk. Second malignancies are an important late effect and these results inform and emphasize the need for cancer surveillance in autologous HCT survivors.Bone Marrow Transplantation (2014) 49, 691-698; doi:10.1038/bmt.2014.13; published online 17 February 2014Keywords: autologous transplantation; outcomes; risk; surveillance INTRODUCTION Autologous haematopoietic SCT (HCT) is increasingly being used in Australia and elsewhere as a therapy for several haematopoietic and solid organ malignancies. 1,2 Life expectancy following HCT has also improved, 3 increasing the number of HCT survivors globally. Characterizing late effects and identifying those at risk will maximize the long-term health of HCT recipients.Second cancers are a recognized late effect of chemo-radiation therapy in general, and in the HCT setting specifically. 4-11 The cumulative incidence of second cancer after autologous HCT may be as high as 29% after 15 years, 11 with the greatest excess risk observed for AML and myelodysplastic syndromes (MDSs). 10,[12][13][14][15] Most prior studies have examined second cancer risk in recipients of allogeneic and autologous HCT, with the largest based on international transplant registry cohorts. 9 Furthermore, most studies ascertained second cancers from hospital records or by self-report, potentially under-estimating risk. There are no population-based estimates of the risk of secondary cancer in adult recipients of autologous HCT. We examined the incidence and risk factors for second cancer in a national, population-based cohort of 7765 adult Australian autologous HCT recipients, 1992HCT recipients, -2007
IMPORTANCEIn children undergoing heart surgery, nitric oxide administered into the gas flow of the cardiopulmonary bypass oxygenator may reduce postoperative low cardiac output syndrome, leading to improved recovery and shorter duration of respiratory support. It remains uncertain whether nitric oxide administered into the cardiopulmonary bypass oxygenator improves ventilator-free days (days alive and free from mechanical ventilation).OBJECTIVE To determine the effect of nitric oxide applied into the cardiopulmonary bypass oxygenator vs standard care on ventilator-free days in children undergoing surgery for congenital heart disease.DESIGN, SETTING, AND PARTICIPANTS Double-blind, multicenter, randomized clinical trial in 6 pediatric cardiac surgical centers in Australia, New Zealand, and the Netherlands. A total of 1371 children younger than 2 years undergoing congenital heart surgery were randomized between July 2017 and April 2021, with 28-day follow-up of the last participant completed on May 24, 2021. INTERVENTIONS Patients were assigned to receive nitric oxide at 20 ppm delivered into the cardiopulmonary bypass oxygenator (n = 679) or standard care cardiopulmonary bypass without nitric oxide (n = 685). MAIN OUTCOMES AND MEASURESThe primary end point was the number of ventilator-free days from commencement of bypass until day 28. There were 4 secondary end points including a composite of low cardiac output syndrome, extracorporeal life support, or death; length of stay in the intensive care unit; length of stay in the hospital; and postoperative troponin levels. RESULTS Among 1371 patients who were randomized (mean [SD] age, 21.2 [23.5] weeks; 587 girls [42.8%]), 1364 (99.5%) completed the trial. The number of ventilator-free days did not differ significantly between the nitric oxide and standard care groups, with a median of 26.6 days (IQR, 24.4 to 27.4) vs 26.4 days (IQR, 24.0 to 27.2), respectively, for an absolute difference of −0.01 days (95% CI, −0.25 to 0.22; P = .92). A total of 22.5% of the nitric oxide group and 20.9% of the standard care group developed low cardiac output syndrome within 48 hours, needed extracorporeal support within 48 hours, or died by day 28, for an adjusted odds ratio of 1.12 (95% CI, 0.85 to 1.47). Other secondary outcomes were not significantly different between the groups. CONCLUSIONS AND RELEVANCEIn children younger than 2 years undergoing cardiopulmonary bypass surgery for congenital heart disease, the use of nitric oxide via cardiopulmonary bypass did not significantly affect the number of ventilator-free days. These findings do not support the use of nitric oxide delivered into the cardiopulmonary bypass oxygenator during heart surgery.
We quantified the risk of second cancer and late mortality in a population-based Australian cohort of 3273 adult (≥15 years) allogeneic hematopoietic stem cell transplant recipients (1992 to 2007). Most recipients received nonradiation-based conditioning and a peripheral blood graft from a matched related donor. Using record linkage with death and cancer registries, 79 second cancers were identified a median of 3.5 years after transplantation. The competing-risk adjusted cumulative incidence of second cancers was 3.35% (95% CI, 2.59 to 4.24) at 10 years, and the cancer risk relative to the matched general population was 2.10 (95% CI, 1.65 to 2.56). We observed an excess risk of melanoma and lip, tongue, esophagus, and soft tissue cancers. Cancer risk relative to the general population was elevated for those transplanted for lymphoma, some leukemia subtypes, and severe aplastic anemia, recipients who developed chronic graft-versus-host disease (cGVHD) and irrespective of radiation-based conditioning or stem cell source. In those alive 2 years after transplantation (n = 1463), the cumulative incidence of late mortality was 22.2% (95% CI, 19.7 to 24.9) at 10 years, and the risk of death relative to the matched general population was 13.8 (95% CI, 12.2 to 15.6). In multivariable modeling, risk of late death was reduced for females compared with males and those transplanted for chronic myeloid leukemia compared with acute myeloid leukemia; risk was increased for recipients with discordant sex donors, cGVHD, those undergoing second transplants, and disease relapse. Adults undergoing allogeneic transplantation have unique cancer and mortality risk profiles that continue to warrant prevention and surveillance activities targeted at high-risk subgroups.
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