RNA-seq of newly diagnosed patients in the PADIMAC study leads to a bortezomib/lenalidomide decision signature.

Improving outcomes in multiple myeloma will involve not only development of new therapies but also better use of existing treatments. We performed RNA sequencing on samples from newly diagnosed patients enrolled in the phase 2 PADIMAC (Bortezomib, Adriamycin, and Dexamethasone Therapy for Previously Untreated Patients with Multiple Myeloma: Impact of Minimal Residual Disease in Patients with Deferred ASCT) study. Using synthetic annealing and the large margin nearest neighbor algorithm, we developed and trained a 7-gene signature to predict treatment outcome. We tested the signature in independent cohorts treated with bortezomib- and lenalidomide-based therapies. The signature was capable of distinguishing which patients would respond better to which regimen. In the CoMMpass data set, patients who were treated correctly according to the signature had a better progression-free survival (median, 20.1 months vs not reached; hazard ratio [HR], 0.40; confidence interval [CI], 0.23-0.72; P = .0012) and overall survival (median, 30.7 months vs not reached; HR, 0.41; CI, 0.21-0.80; P = .0049) than those who were not. Indeed, the outcome for these correctly treated patients was noninferior to that for those treated with combined bortezomib, lenalidomide, and dexamethasone, arguably the standard of care in the United States but not widely available elsewhere. The small size of the signature will facilitate clinical translation, thus enabling more targeted drug regimens to be delivered in myeloma.Wellcome Trust, Bloodwise, Cancer Research UK

Elevated protein concentrations in newborn blood and the risks of autism spectrum disorder, and of social impairment, at age 10 years among infants born before the 28th week of gestation

Among the 1 of 10 children who are born preterm annually in the United States, 6% are born before the third trimester. Among children who survive birth before the 28th week of gestation, the risks of autism spectrum disorder (ASD) and non-autistic social impairment are severalfold higher than in the general population. We examined the relationship between top quartile inflammation-related protein concentrations among children born extremely preterm and ASD or, separately, a high score on the Social Responsiveness Scale (SRS total score ≥65) among those who did not meet ASD criteria, using information only from the subset of children whose DAS-II verbal or non-verbal IQ was ≥70, who were assessed for ASD, and who had proteins measured in blood collected on ≥2 days (N = 763). ASD (N = 36) assessed at age 10 years is associated with recurrent top quartile concentrations of inflammation-related proteins during the first post-natal month (e.g., SAA odds ratio (OR); 95% confidence interval (CI): 2.5; 1.2–5.3) and IL-6 (OR; 95% CI: 2.6; 1.03–6.4)). Top quartile concentrations of neurotrophic proteins appear to moderate the increased risk of ASD associated with repeated top quartile concentrations of inflammation-related proteins. High (top quartile) concentrations of SAA are associated with elevated risk of ASD (2.8; 1.2–6.7) when Ang-1 concentrations are below the top quartile, but not when Ang-1 concentrations are high (1.3; 0.3–5.8). Similarly, high concentrations of TNF-α are associated with heightened risk of SRS-defined social impairment (N = 130) (2.0; 1.1–3.8) when ANG-1 concentrations are not high, but not when ANG-1 concentrations are elevated (0.5; 0.1–4.2)

Fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin with gemtuzumab ozogamicin improves event-free survival in younger patients with newly diagnosed aml and overall survival in patients with npm1 and flt3 mutations

Purpose To determine the optimal induction chemotherapy regimen for younger adults with newly diagnosed AML without known adverse risk cytogenetics. Patients and Methods One thousand thirty-three patients were randomly assigned to intensified (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin [FLAG-Ida]) or standard (daunorubicin and Ara-C [DA]) induction chemotherapy, with one or two doses of gemtuzumab ozogamicin (GO). The primary end point was overall survival (OS). Results There was no difference in remission rate after two courses between FLAG-Ida + GO and DA + GO (complete remission [CR] + CR with incomplete hematologic recovery 93% v 91%) or in day 60 mortality (4.3% v 4.6%). There was no difference in OS (66% v 63%; P = .41); however, the risk of relapse was lower with FLAG-Ida + GO (24% v 41%; P < .001) and 3-year event-free survival was higher (57% v 45%; P < .001). In patients with an NPM1 mutation (30%), 3-year OS was significantly higher with FLAG-Ida + GO (82% v 64%; P = .005). NPM1 measurable residual disease (MRD) clearance was also greater, with 88% versus 77% becoming MRD-negative in peripheral blood after cycle 2 (P = .02). Three-year OS was also higher in patients with a FLT3 mutation (64% v 54%; P = .047). Fewer transplants were performed in patients receiving FLAG-Ida + GO (238 v 278; P = .02). There was no difference in outcome according to the number of GO doses, although NPM1 MRD clearance was higher with two doses in the DA arm. Patients with core binding factor AML treated with DA and one dose of GO had a 3-year OS of 96% with no survival benefit from FLAG-Ida + GO. Conclusion Overall, FLAG-Ida + GO significantly reduced relapse without improving OS. However, exploratory analyses show that patients with NPM1 and FLT3 mutations had substantial improvements in OS. By contrast, in patients with core binding factor AML, outcomes were excellent with DA + GO with no FLAG-Ida benefit

Effects of opioids and sedatives on survival in an Australian inpatient palliative care population

Aims: To assess whether opioid and sedative medication use affects survival (from hospice admission to death) of patients in an Australian inpatient palliative care unit. Background: Retrospective audit. Newcastle Mercy Hospice - a tertiary referral palliative care unit. All patients who died in the hospice between 1 February and 31 December 2000. Methods: Length of survival from hospice admission to death, and the median and mean doses of opioids and sedatives used in the last 24 h of life. Comparison of these with published studies outside of Australia. Results: In this study, the use of opioids, benzodiazepines and haloperidol did not have an association with shortened survival and the only statistical significant finding was an increased survival in patients who were on 300 mg/day or more of oral morphine equivalent (OME). The proportion of patients requiring greater than or equal to 300 mg OME/day (at 28%) was higher than published studies, but the mean dose of 371 mg OME/day was within the range of other studies. The proportion of patients receiving sedatives (94%) was higher than other studies, but the median dose of parenteral midazolam equivalent of 12.5 mg per 24 h was lower than other studies from outside Australia. Conclusions: There was no association between the doses of opioids and sedatives on the last day of life and survival (from hospice admission to death) in this population of palliative care patients

Survey of bereavement support provided by Australian palliative care services

Objective: To determine the prevalence, staffing, methods, timing and allocation of bereavement programs in Australian palliative care services. Design: Questionnaire-based postal survey. Setting and participants: The questionnaire was mailed in January 2007 to all 324 palliative care centres identified from the Australian Palliative care national directory 2004. Results: 236 of the 324 centres responded (73%), and 95% of these undertook bereavement follow-up, with similar prevalence in metropolitan and regional areas. Staff from a range of disciplines were involved in coordinating and delivering these services, with nurses taking on these roles in most regional centres. Common types of bereavement follow-up included individual sessions and visits, telephone contact, letters, anniversary cards and memorial services. Most centres (74%) approached the bereaved within 2 weeks of the death, and 83% of centres offered bereavement suppor to families or “significant others” of all patients who died under their care. Some form of risk assessment for complicated grief was performed by 69% of participating centres. Conclusion: Bereavement care is an integral part of Australian palliative care services. Given the multidisciplinary staffing demonstrated, it is important that those coordinating for further research to guide the development of bereavement support practice and delivering these programs are adequately trained and supported. There is a need for further research to guide the development of bereavement support practice

A retrospective study of risk factors of akathisia in terminally ill patients

Akathisia is a distressing disorder that manifests as a state of restlessness and motor agitation. We aim to highlight the problem of akathisia to the palliative care physician by identifying and quantifying risk factors in the terminally ill. A retrospective case-control study was utilized to investigate risk factors for akathisia. Medical records of cases (N = 100) and controls (N = 365) archived in a computerized database were downloaded and risk factors determined using conditional logistic regression analyses. Exposure to pharmacologically similar drugs, such as haloperidol [odds ratio (OR), 18.4; 95% confidence interval (CI), 8.2-41.4], prochlorperazine (OR, 8.1; 95% CI, 3.0-21.8), and promethazine (OR, 3.3; 95% CI, 1.3-8.0), conferred an increased risk. Other significant variables were exposure to morphine (OR, 5.3; 95% CI, 1.9-14.2), sodium valproate (OR, 2.5; 95% CI, 1.0-6.4), and sodium bicarbonate/tartrate (Ural) (OR, 4.2; 95% CI, 1.2-15.3). Highlighting factors that predispose patients to akathisia emphasizes that this syndrome should not be forgotten when treating the terminally ill. It is recommended that those drugs identified should be judicially used and carefully monitored

What are the essential medications in pallative care? - a survey of Australian palliative care doctors

BACKGROUND: There is a disparity of availability and cost of drugs in the community for palliative care patients through the Pharmaceutical Benefits Scheme (PBS) compared to those available to inpatients in public hospitals. METHODS: The Joint Therapeutics Committee of the Australian and New Zealand Society of Palliative Medicine, Palliative Care Australia and the Clinical Oncological Society of Australia surveyed palliative care practitioners in Australia to compile a list of drugs they considered essential. RESULTS: Drugs nominated generally had good levels of evidence for use in palliative care, although many practitioners still used some without evidence of benefit. DISCUSSION: We are now working with the Commonwealth Department of Health and Ageing to agree on a list of drugs for specific palliative care indications. As a result, the first ever section in the PBS for a specific patient population has been created. There is a need for high quality studies in palliative care to determine the best drugs to add to the list