Treatment with programmed death receptor-1 (PD-1) antibodies is associated with high response rates in patients with advanced melanoma. Reliable markers for early response and outcome are still ...sparse.
We evaluated 66 consecutive patients with advanced/metastatic melanoma treated with nivolumab or pembrolizumab between 2013 and 2014. The main objectives of this study were to investigate whether, first, serum lactate dehydrogenase (LDH) at baseline (normal vs above the upper limit of normal) correlates with overall survival (OS), and, second, whether the change of LDH during treatment predicts response before the first scan and OS in patients with an elevated baseline LDH.
After a median follow-up of 9 months, patients with an elevated baseline LDH (N=34) had a significantly shorter OS compared with patients with normal LDH (N=32; 6-month OS: 60.8% vs 81.6% and 12-month OS: 44.2% vs 71.5% (log-rank P=0.0292). In those 34 patients with elevated baseline LDH, the relative change during treatment was significantly associated with an objective response on the first scan: the 11 (32%) patients with partial remission had a mean reduction of -27.3% from elevated baseline LDH. In contrast, patients with progressive disease (N=15) had a mean increase of +39%. Patients with a relative increase over 10% from elevated baseline LDH had a significantly shorter OS compared with patients with ⩽ 10% change (4.3 vs 15.7 months, log-rank P<0.00623).
LDH could be a useful marker at baseline and during treatment to predict early response or progression in patients with advanced melanoma who receive anti-PD-1 therapy.
Summary
Context
Checkpoint inhibitors are emerging as important cancer therapies but are associated with a high rate of immune side effects, including endocrinopathy.
Objective
To determine the ...burden of thyroid dysfunction in patients with melanoma treated with immune checkpoint inhibitors and describe the clinical course.
Design and patients
Consecutive patients with melanoma treated with either ipilimumab, nivolumab, pembrolizumab or the combination of ipilimumab and nivolumab were identified. Baseline thyroid function tests were used to exclude those with pre‐existing thyroid abnormalities, and thyroid function tests during treatment used to identify those with thyroid dysfunction.
Results
Rates of overt thyroid dysfunction were in keeping with the published phase 3 trials. Hypothyroidism occurred in 13·0% treated with a programmed death receptor‐1 (PD‐1) inhibitor and 22·2% with a combination of PD‐1 inhibitor and ipilimumab. Transient subclinical hyperthyroidism was observed in 13·0% treated with a PD‐1 inhibitor, 15·9% following a PD‐1 inhibitor, and 22·2% following combination treatment with investigations suggesting a thyroiditic mechanism rather than Graves’ disease, and a high frequency of subsequent hypothyroidism. Any thyroid abnormality occurred in 23·0% following ipilimumab, 39·1% following a PD‐1 inhibitor and 50% following combination treatment. Abnormal thyroid function was more common in female patients.
Conclusion
Thyroid dysfunction occurs commonly in patients with melanoma treated with immune checkpoint inhibitors, with rates, including subclinical dysfunction, occurring in up to 50%.
The first observation of rf heating in a reversed field pinch (RFP) using the electron Bernstein wave (EBW) is demonstrated on the Madison Symmetric Torus. Propagation across and heating in a ...stochastic magnetic field is observed. Novel techniques are required to measure the suprathermal electron tail generated by EBW heating in the presence of intense Ohmic heating. rf-heated electrons directly probe the edge transport properties in the RFP; measured loss rates imply a large noncollisional radial diffusivity.
Recent phase III clinical trials have established the superiority of the anti-PD-1 antibodies pembrolizumab and nivolumab over the anti-CTLA-4 antibody ipilimumab in the first-line treatment of ...patients with advanced melanoma. Ipilimumab will be considered for second-line treatment after the failure of anti-PD-1 therapy.
We retrospectively identified a cohort of 40 patients with metastatic melanoma who received single-agent anti-PD-1 therapy with pembrolizumab or nivolumab and were treated on progression with ipilimumab at a dose of 3 mg kg(-1) for a maximum of four doses.
Ten percent of patients achieved an objective response to ipilimumab, and an additional 8% experienced prolonged (>6 months) stable disease. Thirty-five percent of patients developed grade 3-5 immune-related toxicity associated with ipilimumab therapy. The most common high-grade immune-related toxicity was diarrhoea. Three patients (7%) developed grade 3-5 pneumonitis leading to death in one patient.
Ipilimumab therapy can induce responses in patients who fail the anti-PD-1 therapy with response rates comparable to previous reports. There appears to be an increased frequency of high-grade immune-related adverse events including pneumonitis that warrants close surveillance.
Purpose
Prevalence data on the off-label use (OLU) of anticancer drugs are limited despite OLU being controversial for medical, pharmaco-economic, and ethical reasons. We therefore quantified and ...characterized the OLU of anticancer drugs and compared OLU based on the national drug label with international treatment recommendations.
Methods
We prospectively collected data on patients receiving systemic anticancer therapy between October and December 2012 at hospitals affiliated with the Eastern Switzerland Oncology Network. Individual data on patient characteristics, tumor disease, and systemic treatment were collected, and each individual treatment was compared with the national drug label and international treatment guidelines.
Results
A total of 985 consecutive patients receiving 1,737 anticancer drug treatments were included in the study. Overall, 32.4 % of all patients received at least one off-label drug, corresponding to 27.2 % of all anticancer drugs administered. Major reasons for OLU were the lack of approval for the specific disease entity (15.7 %) and modified application of the anticancer drug (10 %). OLU that was unsupported by the current European Society for Medical Oncology (ESMO) treatment recommendations was rare (6.6 %) but higher for bevacizumab (29.6 %) due to its use in treating advanced ovarian cancer beyond the second-line setting and advanced breast cancer beyond the first-line setting and for lenalidomide (22.6 %) due to its use in treating Non-Hodgkin lymphoma.
Conclusions
Based on data collected on our patient cohort, OLU of anticancer drugs in a European clinical setting applies to one-third of all cancer patients. ESMO-unsupported use of chemotherapies or molecularly-targeted drugs is rare, opposing concerns that the off-label use of newer anticancer drugs is a substantial clinical problem.
Summary
In this prospective cohort study, depressive symptoms were associated with higher rates of bone loss in older men. Poorer performance on physical function tests partly explained the ...association between depressive symptoms and bone loss, suggesting that efforts to increase exercise and improve physical performance in depressed men may be beneficial.
Introduction
The aim of this study was to ascertain whether depressive symptoms are associated with increased rates of bone loss at the hip in older men.
Methods
A population-based prospective cohort study of 2,464 community-dwelling men, aged 68 and older, enrolled in the Osteoporosis in Men Sleep Ancillary Study had depressive symptoms assessed by the Geriatric Depression Scale (GDS). Subjects were categorized as depressed if GDS ≥6 at the initial examination. Bone mineral density (BMD) at the hip was measured using dual-energy X-ray absorptiometry at the initial and follow-up examination (average 3.4 years between exams). Use of antidepressant medications was assessed by interview and verified from medication containers at the two examinations. A computerized dictionary was used to categorize type of medication.
Results
In a base model adjusted for age, race/ethnicity, and clinic site, the mean total hip BMD decreased 0.70 %/year in 136 men with a GDS score of ≥6 compared to 0.39 %/year in 2,328 men with a GDS score of <6 (
p
= 0.001). Walking speed and timed chair stand partly explained the association between depressive symptoms and rates of bone loss.
Conclusion
Depression, as defined by a score of 6 or greater on the Geriatric Depression Scale, is associated with an increased rate of bone loss at the hip in this cohort of older men. Adjustment for walking speed and timed chair stand attenuated the strength of the association, suggesting that differences in physical functioning do partially explain the observed association.
For the design and the assessment of river restoration projects, it is important to know to what extent the elimination of reactive nitrogen (N) can be improved in the riparian groundwater. We ...investigated the effectiveness of different riparian zones, characterized by a riparian vegetation succession, for nitrate (NO3−) removal from infiltrating river water in a restored and a still channelized section of the river Thur, Switzerland. Functional genes of denitrification (nirS and nosZ) were relatively abundant in groundwater from willow bush and mixed forest dominated zones, where oxygen concentrations remained low compared to the main channel and other riparian zones. After flood events, a substantial decline in NO3− concentration (> 50%) was observed in the willow bush zone but not in the other riparian zones closer to the river. In addition, the characteristic enrichment of 15N and 18O in the residual NO3− pool (by up to 22‰ for δ15N and up to 12‰ for δ18O) provides qualitative evidence that the willow bush and forest zones were sites of active denitrification and, to a lesser extent, NO3− removal by plant uptake. Particularly in the willow bush zone during a period of water table elevation after a flooding event, substantial input of organic carbon into the groundwater occurred, thereby fostering post-flood denitrification activity that reduced NO3− concentration with a rate of ~21 μmol N l−1 d−1. Nitrogen removal in the forest zone was not sensitive to flood pulses, and overall NO3− removal rates were lower (~6 μmol l−1 d−1). Hence, discharge-modulated vegetation–soil–groundwater coupling was found to be a key driver for riparian NO3− removal. We estimated that, despite higher rates in the fairly constrained willow bush hot spot, total NO3− removal from the groundwater is lower than in the extended forest area. Overall, the aquifer in the restored section was more effective and removed ~20% more NO3− than the channelized section.
In critical care units and hospital wards across the country, patients and physicians struggle with decisions about whether or not to undertake cardiopulmonary resuscitation (CPR) and other ...potentially life-sustaining treatment. Often, these decisions are not made on a sound basis. Doctors are frequently unaware of their patients' wishes concerning treatment.
1
Even when physicians are aware, they may find the patients' requests problematic. Ideally, decisions about the prospective use of CPR should be made jointly by the patients and physicians,
2
but for patients to participate in medical decisions, they must be informed about the risks and benefits of a procedure and . . .
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