Preclinical Activity of JNJ-7957, a Novel BCMA×CD3 Bispecific Antibody for the Treatment of Multiple Myeloma, Is Potentiated by Daratumumab.

PURPOSE: Multiple myeloma (MM) patients with disease refractory to all available drugs have a poor outcome, indicating the need for new agents with novel mechanisms of action. EXPERIMENTAL DESIGN: We evaluated the anti-MM activity of the fully human BCMA×CD3 bispecific antibody JNJ-7957 in cell lines and bone marrow (BM) samples. The impact of several tumor- and host-related factors on sensitivity to JNJ-7957 therapy was also evaluated. RESULTS: We show that JNJ-7957 has potent activity against 4 MM cell lines, against tumor cells in 48 of 49 BM samples obtained from MM patients, and in 5 of 6 BM samples obtained from primary plasma cell leukemia patients. JNJ-7957 activity was significantly enhanced in patients with prior daratumumab treatment, which was partially due to enhanced killing capacity of daratumumab-exposed effector cells. BCMA expression did not affect activity of JNJ-7957. High T-cell frequencies and high effector:target ratios were associated with improved JNJ-7957-mediated lysis of MM cells. The PD-1/PD-L1 axis had a modest negative impact on JNJ-7957 activity against tumor cells from daratumumab-naïve MM patients. Soluble BCMA impaired the ability of JNJ-7957 to kill MM cells, although higher concentrations were able to overcome this negative effect. CONCLUSIONS: JNJ-7957 effectively kills MM cells ex vivo, including those from heavily pretreated MM patients, whereby several components of the immunosuppressive BM microenvironment had only modest effects on its killing capacity. Our findings support the ongoing trial with JNJ-7957 as single agent and provide the preclinical rationale for evaluating JNJ-7957 in combination with daratumumab in MM.

Effects of vitamin D supplementation on markers for cardiovascular disease and type 2 diabetes: an individual participant data meta-analysis of randomized controlled trials.

Background: Evidence from randomized controlled trials (RCTs) for the causal role of vitamin D on noncommunicable disease outcomes is inconclusive. Objective: The aim of this study was to investigate whether there are beneficial or harmful effects of cholecalciferol (vitamin D3) supplementation according to subgroups of remeasured serum 25-hydroxyvitamin D [25(OH)D] on cardiovascular and glucometabolic surrogate markers with the use of individual participant data (IPD) meta-analysis of RCTs. Design: Twelve RCTs (16 wk to 1 y of follow-up) were included. For standardization, 25(OH)D concentrations for all participants (n = 2994) at baseline and postintervention were re-measured in bio-banked serum samples with the use of a certified liquid chromatography-tandem mass spectrometry method traceable to a reference measurement procedure. IPD meta-analyses were performed according to subgroups of remeasured 25(OH)D. Main outcomes were blood pressure and glycated hemoglobin (HbA1c). Secondary outcomes were LDL, HDL, and total cholesterol and triglycerides; parathyroid hormone (PTH); fasting glucose, insulin, and C-peptide; and 2-h glucose. In secondary analyses, other potential effect modifiers were studied. Results: Remeasurement of 25(OH)D resulted in a lower mean 25(OH)D concentration in 10 of 12 RCTs. Vitamin D supplementation had no effect on the main outcomes of blood pressure and HbA1c. Supplementation resulted in 10-20% lower PTH concentrations, irrespective of the 25(OH)D subgroups. The subgroup analyses according to achieved 25(OH)D concentrations showed a significant decrease in LDL-cholesterol concentrations after vitamin D supplementation in 25(OH)D subgroups with <75, <100, and <125 nmol of -0.10 mmol/L (95% CI: -0.20, -0.00 mmol/L), -0.10 mmol/L (95% CI: -0.18, -0.02 mmol/L), and -0.07 mmol/L (95% CI: -0.14, -0.00 mmol/L), respectively. Patient features that modified the treatment effect could not be identified. Conclusions: For the main outcomes of blood pressure and HbA1c, the data support no benefit for vitamin D supplementation. For the secondary outcomes, in addition to its effect on PTH, we observed indications for a beneficial effect of vitamin D supplementation only on LDL cholesterol, which warrants further investigation. This trial was registered at www.clinicaltrials.gov as NCT02551835.

Reirradiation + hyperthermia for recurrent breast cancer en cuirasse.

BACKGROUND AND PURPOSE: Patients with irresectable locoregional recurrent breast cancer en cuirasse (BCEC) do not have effective curative treatment options. Hyperthermia, the elevation of tumor temperature to 40-45 °C, is a well-established radio- and chemotherapy sensitizer. A total of 196 patients were treated with reirradiation and hyperthermia (reRT+HT) at two Dutch institutes from 1982-2005. The palliative effect was evaluated in terms of clinical outcome and toxicity. PATIENTS AND METHODS: All patients received previous irradiation to a median dose of 50 Gy. In all, 75% of patients received 1-6 treatment modalities for previous tumor recurrences. ReRT consisted of 8 × 4 Gy given twice a week or 12 × 3 Gy given four times a week. Superficial hyperthermia was added once or twice a week. Tumor area comprised ≥½ of the ipsilateral chest wall. RESULTS: Overall clinical response rate was 72% (complete response [CR] 30%, partial response [PR] 42%, stable disease [SD] 22%, progressive disease [PD] 6%). The local progression-free rate at 1 year was 24%. Median survival was 6.9 months. Forty-three percent of our patients with CR, PR, SD after treatment remained infield progression-free until death or last follow-up. Acute ≥grade 3 toxicity occurred in 33% of patients, while late ≥grade 3 toxicity was recorded in 14% of patients. Tumor ulceration prior to treatment had a negative impact on both clinical outcome and toxicity. CONCLUSION: ReRT+HT provides sustainable palliative tumor control, despite refractory, extensive tumor growth. Compared to currently available systemic treatment options, reRT+HT is more effective with less toxicity.

Health behaviour information provided to clients during midwife-led prenatal booking visits: Findings from video analyses.

OBJECTIVE: to quantify to what extent evidence-based health behaviour topics relevant for pregnancy are discussed with clients during midwife-led prenatal booking visits and to assess the association of client characteristics with the extent of information provided. DESIGN: quantitative video analyses. SETTING AND PARTICIPANTS: 173 video recordings of prenatal booking visits with primary care midwives and clients in the Netherlands taking place between August 2010 and April 2011. MEASUREMENTS: thirteen topics regarding toxic substances, nutrition, maternal weight, supplements, and health promoting activities were categorized as either 'never mentioned', 'briefly mentioned', 'basically explained' or 'extensively explained'. Rates on the extent of information provided were calculated for each topic and relationships between client characteristics and dichotomous outcomes of the extent of information provided were assessed using Generalized Linear Mixed Modelling. FINDINGS: our findings showed that women who did not take folic acid supplementation, who smoked, or had a partner who smoked, were usually provided basic and occasionally extensive explanations about these topics. The majority of clients were provided with no information on recommended weight gain (91.9%), fish promotion (90.8%), caffeine limitation (89.6%), vitamin D supplementation (87.3%), physical activity promotion (81.5%) and antenatal class attendance (75.7%) and only brief mention of alcohol (91.3%), smoking (81.5%), folic acid (58.4) and weight at the start of pregnancy (52.0%). The importance of a nutritious diet was generally either never mentioned (38.2%) or briefly mentioned (45.1%). Nulliparous women were typically given more information on most topics than multiparous women. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: although additional information was generally provided about folic acid and smoking, when relevant for their clients, the majority of women were provided with little or no information about the other health behaviours examined in this study. Midwives may be able to improve prenatal health promotion by providing more extensive health behaviour information to their clients during booking visits.

The Relationships of Health Behaviour and Psychological Characteristics with Spontaneous Preterm Birth in Nulliparous Women.

Objectives Preterm birth is the leading pregnancy outcome associated with perinatal morbidity and mortality and remains difficult to prevent. There is evidence that some modifiable maternal health characteristics may influence the risk of preterm birth. Our aim was to investigate the relationships of self-reported maternal health behaviour and psychological characteristics in nulliparous women with spontaneous preterm birth in prenatal primary care. Methods The data of our prospective study was obtained from the nationwide DELIVER multicentre cohort study (September 2009-March 2011), which was designed to examine perinatal primary care in the Netherlands. In our study, consisting of 2768 nulliparous women, we estimated the relationships of various self-reported health behaviours (smoking, alcohol consumption, folic acid supplementation, daily fruit, daily fresh vegetables, daily hot meal and daily breakfast consumption) and psychological characteristics (anxious/depressed mood and health control beliefs) with spontaneous preterm birth as a dichotomous outcome. Due to the clustering of clients within midwife practices, Generalized Estimating Equations was used for these analyses. Results Low health control beliefs was the sole characteristic significantly associated with spontaneous preterm birth (odds ratio 2.26; 95 % confidence interval 1.51, 3.39) after being adjusted for socio-demographics, anthropometrics and the remaining health behaviour and psychological characteristics. The other characteristics were not significantly associated with spontaneous preterm birth. Conclusions for Practice Maternal low health control beliefs need to be explored further as a possible marker for women at risk for preterm birth, and as a potentially modifiable characteristic to be used in interventions which are designed to reduce the risk of spontaneous preterm birth.

Back schools for acute and subacute non-specific low-back pain.

BACKGROUND: Since the introduction of the Swedish back school in 1969, back schools have frequently been used for treating people with low-back pain (LBP). However, the content of back schools has changed and appears to vary widely today. In this review we defined back school as a therapeutic programme given to groups of people, which includes both education and exercise. This is an update of a Cochrane review first published in 1999, and updated in 2004. For this review update, we split the review into two distinct reviews which separated acute from chronic LBP. OBJECTIVES: To assess the effectiveness of back schools on pain and disability for people with acute or subacute non-specific LBP. We also examined the effect on work status and adverse events. SEARCH METHODS: We searched CENTRAL, MEDLINE, EMBASE, CINAHL, PsycINFO, PubMed and two clinical trials registers up to 4 August 2015. We also checked the reference lists of articles and contacted experts in the field of research on LBP. SELECTION CRITERIA: We included randomised controlled trials (RCTs) or quasi-RCTs that reported on back school for acute or subacute non-specific LBP. The primary outcomes were pain and disability. The secondary outcomes were work status and adverse events. Back school had to be compared with another treatment, a placebo (or sham or attention control) or no treatment. DATA COLLECTION AND ANALYSIS: We used the 2009 updated method guidelines for this Cochrane review. Two review authors independently screened the references, assessed the quality of the trials and extracted the data. We set the threshold for low risk of bias, a priori, as six or more of 13 internal validity criteria and no serious flaws (e.g. large drop-out rate). We classified the quality of the evidence into one of four levels (high, moderate, low or very low) using the adapted Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. We contacted study authors for additional information. We collected adverse effects information from the trials. MAIN RESULTS: The search update identified 273 new references, of which none fulfilled our inclusion criteria. We included four studies (643 participants) in this updated review, which were all included in the previous (2004) update. The quality of the evidence was very low for all outcomes. As data were too clinically heterogeneous to be pooled, we described individual trial results. The results indicate that there is very low quality evidence that back schools are no more effective than a placebo (or sham or attention control) or another treatment (physical therapies, myofascial therapy, joint manipulations, advice) on pain, disability, work status and adverse events at short-term, intermediate-term and long-term follow-up. There is very low quality evidence that shows a statistically significant difference between back schools and a placebo (or sham or attention control) for return to work at short-term follow-up in favour of back school. Very low quality evidence suggests that back school added to a back care programme is more effective than a back care programme alone for disability at short-term follow-up. Very low quality evidence also indicates that there is no difference in terms of adverse events between back school and myofascial therapy, joint manipulation and combined myofascial therapy and joint manipulation. AUTHORS' CONCLUSIONS: It is uncertain if back schools are effective for acute and subacute non-specific LBP as there is only very low quality evidence available. While large well-conducted studies will likely provide more conclusive findings, back schools are not widely used interventions for acute and subacute LBP and further research into this area may not be a priority.

Reirradiation and hyperthermia for irresectable locoregional recurrent breast cancer in previously irradiated area: Size matters.

BACKGROUND/PURPOSE: Treatment options for irresectable locoregional recurrent breast cancer in previously irradiated area are limited. Hyperthermia, elevating tumor temperature to 40-45°C, sensitizes radio-and-chemotherapy. Four hundred and fourteen patients treated with reirradiation+hyperthermia (reRT+HT) in the AMC(n=301) and the BVI(n=113), from 1982 to 2005 were retrospectively analyzed for treatment response, locoregional control (LC) and prognostic factors for LC and toxicity. PATIENTS/METHODS: All patients received previous irradiation (median 50 Gy). reRT consisted of 8 × 4 Gy-2/week (AMC) or 12 × 3 Gy-4/week (BVI). Hyperthermia was added once (AMC)/twice (BVI) a week. RESULTS: Overall clinical response rate was 86%. The 3-year LC rate was 25%. The number of recurrence episodes, distant metastases (DM), tumor site, tumor size, time to recurrence and treatment year were significant for LC. Acute ⩾ grade 3 toxicity occurred in 24% of patients. Actuarial late ⩾ grade 3 toxicity was 23% at 3-years. In multivariable analysis reRT fraction dose was significantly related to late ⩾ grade 3 toxicity. CONCLUSION: reRT+HT is an effective curative and palliative treatment option for patients with irresectable locoregional recurrent breast cancer in previously irradiated area. Early referral, treatment of chest wall recurrences ⩽ 5 cm in the absence of distant metastases, provided the highest local control rates. The cumulative effects of past and present treatments should be accounted for by adjusting treatment protocol to minimize toxicity.

Impaired hyperemic myocardial blood flow is associated with inducibility of ventricular arrhythmia in ischemic cardiomyopathy.

BACKGROUND: Risk stratification for ventricular arrhythmias (VAs) is important to refine selection criteria for primary prevention implantable cardioverter defibrillator therapy. Impaired hyperemic myocardial blood flow (MBF) is associated with increased mortality rate in ischemic and nonischemic cardiomyopathy, which may be attributed to electric instability inducing VAs. The aim of this pilot study was to assess whether hyperemic MBF impairment may be related with VA inducibility in patients with ischemic cardiomyopathy. METHODS AND RESULTS: Thirty patients with ischemic cardiomyopathy referred for primary prevention implantable cardioverter defibrillator implantation were prospectively included (26 men; 65±8 years old; left ventricular ejection fraction, 29±6%). [15O]H2O positron-emission tomography was performed to quantify resting MBF, hyperemic MBF, and coronary flow reserve. Left ventricular dimensions, function, and scar burden were assessed with cardiovascular magnetic resonance imaging. An electrophysiological study was performed to test VA inducibility. Positive electrophysiological study patients (n=12) showed reduced hyperemic MBF (1.25±0.30 versus 1.66±0.38 mL·min(-1)·g(-1); P<0.01) and coronary flow reserve (1.59±0.49 versus 2.12±0.48; P<0.01) compared with electrophysiological study negative patients (n=18). In electrophysiological study positive patients, the number of scar segments>75% transmurality was higher (P<0.05), although scar size and border zone did not differ. Receiver-operating characteristic curve analysis indicated that impaired hyperemic MBF (area under the curve, 0.84; 95% confidence intervals [0.69-0.99]) and coronary flow reserve (area under the curve, 0.77; 95% confidence intervals [0.57-0.96]) were associated with VA inducibility. CONCLUSIONS: In this pilot study, impaired hyperemic MBF and coronary flow reserve were associated with VA inducibility in patients with ischemic cardiomyopathy. These results are hypothesis generating for a potential role of quantitative positron-emission tomography perfusion imaging in risk stratification for VAs.

The working mechanism of manual therapy in participants with chronic tension-type headache.

STUDY DESIGN: Prospective longitudinal study. OBJECTIVE: To explore the working mechanism of manual therapy, we investigated whether 3 cervical spine variables were mediators of the effect of manual therapy on headache frequency. Background Manual therapy has been shown to reduce headache frequency in participants with chronic tension-type headache (CTTH). To what extent specific elements of treatment contribute to the effectiveness of manual therapy in CTTH is unknown. METHODS: One hundred eighty-two participants with CTTH participated in a prospective longitudinal study: 142 underwent manual therapy and 40 participants received usual care by their general practitioner. Regression analysis was performed according to the steps described by Baron and Kenny, and the proportion of mediated effect was estimated for 3 potential mediators: (1) cervical range of motion, (2) neck flexor endurance, and (3) forward head posture. Outcome was defined as a 50% or greater reduction in headache days. RESULTS: Neck flexor endurance mediated 24.5% of the effect of manual therapy. Cervical range of motion and forward head posture showed no mediated effect. CONCLUSIONS: Increased neck flexor endurance appears to be a working mechanism of manual therapy. This finding supports isometric training of neck flexors in participants with CTTH. Trial registered with Netherlands Trial Register (TR 1074).

Intraoperative cell salvage is associated with reduced postoperative blood loss and transfusion requirements in cardiac surgery: a cohort study.

BACKGROUND: This study investigated whether implementation of cell salvage of shed mediastinal and residual blood in all patients undergoing low-to-moderate-risk cardiac surgery reduces the need for allogeneic red blood cell (RBC) transfusion compared to patients not subjected to cell salvage. STUDY DESIGN AND METHODS: This retrospective cohort study included patients undergoing low-to-moderate-risk cardiac surgery with cardiopulmonary bypass without (control; n = 531) or with cell salvage (n = 433; Autolog, Medtronic). Study endpoints, including 24-hour blood loss and RBC requirements, were evaluated using adjusted logistic regression. RESULTS: Baseline characteristics were similar between groups. The cell saver group received 568 ± 267 mL of autologous blood. Median number of allogeneic RBC transfusions was higher in the control group (2 [1-5]) compared with the cell salvage group (1 [0-3]; p < 0.001). There were no clinically relevant differences in postoperative coagulation test results between groups. The relative risk (RR) for postoperative RBC transfusion was reduced to 0.76 (95% confidence interval [CI], 0.70-0.83; p < 0.0001) in the cell salvage group. Moreover, patients in the cell salvage group had a lower chance for myocardial infarction (RR, 0.26; 95% CI, 0.08-0.91; p = 0.035), whereas the cell salvage group was associated with a higher probability for intensive care discharge within 24 hours after surgery (RR, 1.08; 95% CI, 1.02-1.14; p = 0.009). CONCLUSION: The use of cell salvage throughout the entire procedure reduces postoperative blood loss and allogeneic RBC transfusion. These findings advocate implementation of cell salvage in all patients undergoing on-pump cardiac surgery, irrespective of anticipated surgery-related blood loss.

Missing data and imputation: a practical illustration in a prognostic study on low back pain.

OBJECTIVE: When designing prediction models by complete case analysis (CCA), missing information in either baseline (predictors) or outcomes may lead to biased results. Multiple imputation (MI) has been shown to be suitable for obtaining unbiased results. This study provides researchers with an empirical illustration of the use of MI in a data set on low back pain, by comparing MI with the more commonly used CCA. Effects will be shown of imputing missing information on the composition and performance of prognostic models, distinguishing imputation of missing values in baseline characteristics and outcome data. METHODS: Data came from the Beliefs about Backpain cohort, a study of psychologic obstacles to recovery in primary care back pain patients in the United Kingdom. Candidate predictors included demographics, back pain characteristics, and psychologic variables. Complete case analysis was compared with MI within patients with complete outcome but missing baseline data (n=809) and patients with missing baseline or outcome data (n=1591). Multiple imputation was performed by a Multiple Imputation by Chained Equations procedure. RESULTS: Cases with missing outcome data (n=782, 49.1%) or with missing baseline data (n=116, 8%) both differed from complete cases regarding the distribution of some predictors and more often had a poor outcome. When comparing CCA with MI, model composition showed to be affected. CONCLUSIONS: Complete case analysis can give biased results, even when only small amounts of data are missing. Now that MI is available in standard statistical software, we recommend that it be used to handle missing data.

Clinical variables associated with recovery in patients with chronic tension-type headache after treatment with manual therapy.

The aims of this study were to describe the course of chronic tension-type headache (CTTH) in participants receiving manual therapy (MT), and to develop a prognostic model for predicting recovery in participants receiving MT. Outcomes in 145 adults with CTTH who received MT as participants in a previously published randomised clinical trial (n=41) or in a prospective cohort study (n=104) were evaluated. Assessments were made at baseline and at 8 and 26 weeks of follow-up. Recovery was defined as a 50% reduction in headache days in combination with a score of 'much improved' or 'very much improved' for global perceived improvement. Potential prognostic factors were analyzed by univariable and multivariable regression analysis. After 8 weeks 78% of the participants reported recovery after MT, and after 26 weeks the frequency of recovered participants was 73%. Prognostic factors related to recovery were co-existing migraine, absence of multiple-site pain, greater cervical range of motion and higher headache intensity. In participants classified as being likely to be recovered, the posterior probability for recovery at 8 weeks was 92%, whereas for those being classified at low probability of recovery this posterior probability was 61%. It is concluded that the course of CTTH is favourable in primary care patients receiving MT. The prognostic models provide additional information to improve prediction of outcome.

Back schools in occupational health care: design of a randomized controlled trial and cost-effectiveness study.

OBJECTIVE: To describe the design of a randomized controlled trial (RCT), including a cost-effectiveness analysis, comparing high-intensity and low-intensity back schools with usual care in occupational health care. DESIGN: RCT and cost-effectiveness analysis. STUDY POPULATION: Employees sick-listed for a period of 3 to 6 weeks because of nonspecific low back pain. Interventions High-intensity back school treatment consists of a training program based on the principles of cognitive-behavioral therapy. Low-intensity back school treatment is comparable to the original Swedish Back School. Usual care is provided by the occupational physician according to the Dutch guidelines for the occupational health treatment of patients with low back pain. OUTCOME MEASURES: Primary outcome measures are return to work, pain intensity, functional status, and general improvement. Secondary outcome measures are kinesiophobia and pain coping. The cost-effectiveness analysis includes the direct and indirect costs. The outcome measures are assessed before randomization and 3, 6, and 12 months after randomization. CONCLUSION: RCTs of different methodological quality have been conducted to examine the effectiveness of back schools in occupational health care. The large variation in type, content, and intensity of back schools has led to conflicting evidence. Therefore, 2 different forms of back schools are compared. Moreover, this is the first RCT to include a cost-effectiveness analysis comparing low-intensity and high-intensity back schools with usual care in occupational health care.