, 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

Background: Heart failure with reduced ejection fraction (HFrEF) is characterized by blunting of the positive relationship between heart rate and left ventricular (LV) contractility known as the force-frequency relationship (FFR). We have previously described that tailoring the rate-response programming of cardiac implantable electronic devices in patients with HFrEF on the basis of individual noninvasive FFR data acutely improves exercise capacity. We aimed to examine whether using FFR data to tailor heart rate response in patients with HFrEF with cardiac implantable electronic devices favorably influences exercise capacity and LV function 6 months later. Methods: We conducted a single-center, double-blind, randomized, parallel-group trial in patients with stable symptomatic HFrEF taking optimal guideline-directed medical therapy and with a cardiac implantable electronic device (cardiac resynchronization therapy or implantable cardioverter-defibrillator). Participants were randomized on a 1:1 basis between tailored rate-response programming on the basis of individual FFR data and conventional age-guided rate-response programming. The primary outcome measure was change in walk time on a treadmill walk test. Secondary outcomes included changes in LV systolic function, peak oxygen consumption, and quality of life. Results: We randomized 83 patients with a mean±SD age 74.6±8.7 years and LV ejection fraction 35.2±10.5. Mean change in exercise time at 6 months was 75.4 (95% CI, 23.4 to 127.5) seconds for FFR-guided rate-adaptive pacing and 3.1 (95% CI, −44.1 to 50.3) seconds for conventional settings (analysis of covariance; P =0.044 between groups) despite lower peak mean±SD heart rates (98.6±19.4 versus 112.0±20.3 beats per minute). FFR-guided heart rate settings had no adverse effect on LV structure or function, whereas conventional settings were associated with a reduction in LV ejection fraction. Conclusions: In this phase II study, FFR-guided rate-response programming determined using a reproducible, noninvasive method appears to improve exercise time and limit changes to LV function in people with HFrEF and cardiac implantable electronic devices. Work is ongoing to confirm our findings in a multicenter setting and on longer-term clinical outcomes. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02964650.

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.

Aims Current guidelines recommend that disease-modifying pharmacological therapies may be considered for patients who have heart failure with mildly reduced ejection fraction (HFmrEF). We aimed to describe the characteristics, outcomes, provision of pharmacological therapies and dose-related associations with mortality risk in HFmrEF. Methods and results We explored data from two prospective observational studies, which permitted the examination of the effects of pharmacological therapies across a broad spectrum of left ventricular ejection fraction (LVEF). The combined dataset consisted of 2388 unique patients, with a mean age of 73.7 ± 13.2 years of whom 1525 (63.9%) were male. LVEF ranged from 5 to 71% (mean 37.2 ± 12.8%) and 1504 (63.0%) were categorised as having reduced ejection fraction (HFrEF), 421 (17.6%) as HFmrEF and 463 (19.4%) as preserved ejection fraction (HFpEF). Patients with HFmrEF more closely resembled HFrEF than HFpEF. Adjusted all-cause mortality risk was lower in HFmrEF (hazard ratio [HR] 0.86 (95% confidence interval [CI] 0.74–0.99); p = 0.040) and in HFpEF (HR 0.61 (95% CI 0.52–0.71); p < 0.001) compared to HFrEF. Adjusted all-cause mortality risk was lower in patients with HFrEF and HFmrEF who received the highest doses of beta-blockers or renin-angiotensin inhibitors. These associations were not evident in HFpEF. Once adjusted for relevant confounders, each mg equivalent of bisoprolol (HR 0.95 [95% CI 0.91–1.00]; p = 0.047) and ramipril (HR 0.95 [95%CI 0.90–1.00]; p = 0.044) was associated with incremental reductions in mortality risk in patients with HFmrEF. Conclusions Pharmacological therapies were associated with lower mortality risk in HFmrEF, supporting guideline recommendations which extend the indications of these agents to all patients with LVEF < 50%. Graphic abstract HFmrEF more closely resembles HFrEF in terms of clinical characteristics and outcomes. Pharmacological therapies are associated with lower mortality risk in HFmrEF and HFrEF, but not in HFpEF.