Relative effectiveness and adverse effects of cervical manipulation, mobilisation and the activator instrument in patients with sub-acute non-specific neck pain: results from a stopped randomised trial

<p>Abstract</p> <p>Background</p> <p>Neck pain of a mechanical nature is a common complaint seen by practitioners of manual medicine, who use a multitude of methods to treat the condition. It is not known, however, if any of these methods are superior in treatment effectiveness. This trial was stopped due to poor recruitment. The purposes of this report are (1) to describe the trial protocol, (2) to report on the data obtained from subjects who completed the study, (3) to discuss the problems we encountered in conducting this study.</p> <p>Methods</p> <p>A pragmatic randomised clinical trial was undertaken. Patients who met eligibility criteria were randomised into three groups. One group was treated using specific segmental high velocity low amplitude manipulation (diversified), another by specific segmental mobilisation, and a third group by the Activator instrument. All three groups were also treated for any myofascial distortions and given appropriate exercises and advice. Participants were treated six times over a three-week period or until they reported being pain free. The primary outcome measure for the study was Patient Global Impression of Change (PGIC); secondary outcome measures included the Short-Form Health Survey (SF-36v₂), the neck Bournemouth Questionnaire, and the numerical rating scale for pain intensity. Participants also kept a diary of any pain medication taken and noted any perceived adverse effects of treatment. Outcomes were measured at four points: end of treatment, and 3, 6, and 12 months thereafter.</p> <p>Results</p> <p>Between January 2007 and March 2008, 123 patients were assessed for eligibility, of these 47 were considered eligible, of which 16 were allocated to manipulation, 16 to the Activator instrument and 15 to the mobilisation group. Comparison between the groups on the PGIC adjusted for baseline covariants did not show a significant difference for any of the endpoints. Within group analyses for change from baseline to the 12-month follow up for secondary outcomes were significant for all groups on the Bournemouth Questionnaire and for pain, while the mobilisation group had a significant improvement on the PCS and MCS subscales of the SF-36_v2. Finally, there were no moderate, severe, or long-lasting adverse effects reported by any participant in any group.</p> <p>Conclusions</p> <p>Although the small sample size must be taken into consideration, it appears that all three methods of treating mechanical neck pain had a long-term benefit for subacute neck pain, without moderate or serious adverse events associated with any of the treatment methods. There were difficulties in recruiting subjects to this trial. This pragmatic trial should be repeated with a larger sample size.</p

Advances in our understanding of the pathogenesis of glomerular thrombotic microangiopathy

Glomerular thrombotic microangiopathy is a hallmark feature of haemolytic uraemic syndrome, the leading cause of acute renal failure in childhood. This paper is a review of the different mechanistic pathways that lead to this histological picture in the kidney. It will focus on atypical HUS and complement dysregulation, but will also highlight some other recent advances in our understanding of this condition, including the potential role of the molecule vascular endothelial growth factor- A (VEGF-A)

Therapy for metastatic melanoma: the past, present, and future

Metastatic melanoma is the most aggressive form of skin cancer with a median overall survival of less than one year. Advancements in our understanding of how melanoma evades the immune system as well as the recognition that melanoma is a molecularly heterogeneous disease have led to major improvements in the treatment of patients with metastatic melanoma. In 2011, the US Food and Drug Administration (FDA) approved two novel therapies for advanced melanoma: a BRAF inhibitor, vemurafenib, and an immune stimulatory agent, ipilimumab. The success of these agents has injected excitement and hope into patients and clinicians and, while these therapies have their limitations, they will likely provide excellent building blocks for the next generation of therapies. In this review we will discuss the advantages and limitations of the two new approved agents, current clinical trials designed to overcome these limitations, and future clinical trials that we feel hold the most promise

Encorafenib, Binimetinib, and Cetuximab in BRAF V600E-Mutated Colorectal Cancer.

BACKGROUND: Patients with metastatic colorectal cancer with the BRAF V600E mutation have a poor prognosis, with a median overall survival of 4 to 6 months after failure of initial therapy. Inhibition of BRAF alone has limited activity because of pathway reactivation through epidermal growth factor receptor signaling. METHODS: In this open-label, phase 3 trial, we enrolled 665 patients with BRAF V600E-mutated metastatic colorectal cancer who had had disease progression after one or two previous regimens. Patients were randomly assigned in a 1:1:1 ratio to receive encorafenib, binimetinib, and cetuximab (triplet-therapy group); encorafenib and cetuximab (doublet-therapy group); or the investigators' choice of either cetuximab and irinotecan or cetuximab and FOLFIRI (folinic acid, fluorouracil, and irinotecan) (control group). The primary end points were overall survival and objective response rate in the triplet-therapy group as compared with the control group. A secondary end point was overall survival in the doublet-therapy group as compared with the control group. We report here the results of a prespecified interim analysis. RESULTS: The median overall survival was 9.0 months in the triplet-therapy group and 5.4 months in the control group (hazard ratio for death, 0.52; 95% confidence interval [CI], 0.39 to 0.70; P<0.001). The confirmed response rate was 26% (95% CI, 18 to 35) in the triplet-therapy group and 2% (95% CI, 0 to 7) in the control group (P<0.001). The median overall survival in the doublet-therapy group was 8.4 months (hazard ratio for death vs. control, 0.60; 95% CI, 0.45 to 0.79; P<0.001). Adverse events of grade 3 or higher occurred in 58% of patients in the triplet-therapy group, in 50% in the doublet-therapy group, and in 61% in the control group. CONCLUSIONS: A combination of encorafenib, cetuximab, and binimetinib resulted in significantly longer overall survival and a higher response rate than standard therapy in patients with metastatic colorectal cancer with the BRAF V600E mutation. (Funded by Array BioPharma and others; BEACON CRC ClinicalTrials.gov number, NCT02928224; EudraCT number, 2015-005805-35.).status: publishe

Engineering CD19-specific T lymphocytes with interleukin-15 and a suicide gene to enhance their anti-lymphoma/leukemia effects and safety.

T lymphocytes expressing a chimeric antigen receptor (CAR) targeting the CD19 antigen (CAR.19) may be of value for the therapy of B-cell malignancies. Because the in vivo survival, expansion and anti-lymphoma activity of CAR.19(+) T cells remain suboptimal even when the CAR contains a CD28 costimulatory endodomain, we generated a novel construct that also incorporates the interleukin-15 (IL-15) gene and an inducible caspase-9-based suicide gene (iC9/CAR.19/IL-15). We found that compared with CAR.19(+) T cells, iC9/CAR.19/IL-15(+) T cells had: (1) greater numeric expansion upon antigen stimulation (10-fold greater expansion in vitro, and 3- to 15-fold greater expansion in vivo) and reduced cell death rate (Annexin-V(+)/7-AAD(+) cells 10+/-6% for iC9/CAR.19/IL-15(+) T cells and 32+/-19% for CAR.19(+) T cells); (2) reduced expression of the programmed death 1 (PD-1) receptor upon antigen stimulation (PD-1(+) cells 40% for CAR.19(+) T cells); and (3) improved antitumor effects in vivo (from 4.7- to 5.4-fold reduced tumor growth). In addition, iC9/CAR.19/IL-15(+) T cells were efficiently eliminated upon pharmacologic activation of the suicide gene. In summary, this strategy safely increases the anti-lymphoma/leukemia effects of CAR.19-redirected T lymphocytes and may be a useful approach for treatment of patients with B-cell malignancies