Abstract Background & Aims MEDI2070 is a human monoclonal antibody that selectively inhibits interleukin 23 (IL23), a cytokine implicated in the pathogenesis of Crohn’s disease (CD). We analyzed its ...safety and efficacy in treatment of CD in a phase 2a study. Methods We conducted a double-blind, placebo-controlled, study of 119 adults with moderate to severe CD failed by treatment with tumor necrosis factor (TNF) antagonists. Patients were randomly assigned (1:1) to groups given MEDI2070 (700 mg) or placebo intravenously at weeks 0 and 4. Patients received open-label MEDI2070 (210 mg) subcutaneously every 4 weeks from weeks 12 to 112. The CD Activity Index (CDAI) was used to measure disease activity. Results The primary outcome, clinical response (either a 100-point decrease in CDAI score from baseline or clinical remission, defined as CDAI score below 150) at week 8 occurred in 49.2% of patients receiving MEDI2070 (n=59) compared with 26.7% receiving placebo (n=60; absolute difference, 22.5%; 95% CI, 5.6%–39.5%, P =.010). Clinical response at week 24 occurred in 53.8% of patients who continued to receive open-label MEDI2070 and in 57.7% of patients who had received placebo during the double-blind period and open-label MEDI2070 thereafter. The most common adverse events were headache and nasopharyngitis. Higher baseline serum concentrations of IL22, a cytokine whose expression is induced by IL23, were associated with greater likelihood of response to MEDI2070 compared to placebo. Conclusions In a phase 2a trial of patients with moderate to severe Crohn’s disease who had failed treatment with TNF antagonists, 8 and 24 weeks of treatment with MEDI2070 were associated with clinical improvement. Clinicaltrials.gov no: NCT01714726.
Summary Background Neurite outgrowth inhibitor A (Nogo-A) is thought to have a role in the pathophysiology of amyotrophic lateral sclerosis (ALS). A monoclonal antibody against Nogo-A showed a ...positive effect in the SOD1G93A mouse model of ALS, and a humanised form of this antibody (ozanezumab) was well tolerated in a first-in-human trial. Therefore, we aimed to assess the safety and efficacy of ozanezumab in patients with ALS. Methods This randomised, double-blind, placebo-controlled, phase 2 trial was done in 34 centres in 11 countries. Patients aged 18–80 years with a diagnosis of familial or sporadic ALS were randomly assigned (1:1), centrally according to a computer-generated allocation schedule, to receive ozanezumab (15 mg/kg) or placebo as intravenous infusions over 1 h every 2 weeks for 46 weeks, followed by assessments at week 48 and week 60. Patients and study personnel were masked to treatment assignment. The primary outcome was a joint-rank analysis of function (ALS Functional Rating Scale-Revised) and overall survival, analysed at 48 weeks in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov , number NCT01753076 , and with GSK-ClinicalStudyRegister.com , NOG112264, and is completed. Findings Between Dec 20, 2012, and Nov 1, 2013, we recruited 307 patients, of whom 303 were randomly assigned to receive placebo (n=151) or ozanezumab (n=152). The adjusted mean of the joint-rank score was −14·9 (SE 13·5) for the ozanezumab group and 15·0 (13·6) for the placebo group, with a least squares mean difference of −30·0 (95% CI −67·9 to 7·9; p=0·12). Overall, reported adverse events, serious adverse events, and adverse events leading to permanent discontinuation of study drug or withdrawal from study were similar between the treatment groups, except for dyspepsia (ten 7% in the ozanezumab group vs four 3% in the placebo group), depression (11 7% vs five 3%), and diarrhoea (25 16% vs 12 8%). Respiratory failure was the most common serious adverse event (12 8% vs seven 5%). At week 60, the number of deaths was higher in the ozanezumab group (20 13%) than in the placebo group (16 11%), mainly as a result of respiratory failure (ten 7% vs five 3%). Two deaths were considered related to the study drug (bladder transitional cell carcinoma in the ozanezumab group and cerebrovascular accident in the placebo group). Interpretation Ozanezumab did not show efficacy compared with placebo in patients with ALS. Therefore, Nogo-A does not seem to be an effective therapeutic target in ALS. Funding GlaxoSmithKline.
Summary Background In old age, reduction in physical function leads to loss of independence, the need for hospital and long-term nursing-home care, and premature death. We did a systematic review to ...assess the effectiveness of community-based complex interventions in preservation of physical function and independence in elderly people. Methods We searched systematically for randomised controlled trials assessing community-based multifactorial interventions in elderly people (mean age at least 65 years) living at home with at least 6 months of follow-up. Outcomes studied were living at home, death, nursing-home and hospital admissions, falls, and physical function. We did a meta-analysis of the extracted data. Findings We identified 89 trials including 97 984 people. Interventions reduced the risk of not living at home (relative risk RR 0·95, 95% CI 0·93–0·97). Interventions reduced nursing-home admissions (0·87, 0·83–0·90), but not death (1·00, 0·97–1·02). Risk of hospital admissions (0·94, 0·91–0·97) and falls (0·90, 0·86–0·95) were reduced, and physical function (standardised mean difference −0·08, −0·11 to −0·06) was better in the intervention groups than in other groups. Benefit for any specific type or intensity of intervention was not noted. In populations with increased death rates, interventions were associated with reduced nursing-home admission. Benefit in trials was particularly evident in studies started before 1993. Interpretation Complex interventions can help elderly people to live safely and independently, and could be tailored to meet individuals' needs and preferences.
Summary Background Proliferation markers and profiles have been recommended for guiding the choice of systemic treatments for breast cancer. However, the best molecular marker or test to use has not ...yet been identified. We did this study to identify factors that drive proliferation and its associated features in breast cancer and assess their association with clinical outcomes and response to chemotherapy. Methods We applied an artificial neural network-based integrative data mining approach to data from three cohorts of patients with breast cancer (the Nottingham discovery cohort (n=171), Uppsala cohort (n=249), and Molecular Taxonomy of Breast Cancer International Consortium METABRIC cohort; n=1980). We then identified the genes with the most effect on other genes in the resulting interactome map. Sperm-associated antigen 5 ( SPAG5 ) featured prominently in our interactome map of proliferation and we chose to take it forward in our analysis on the basis of its fundamental role in the function and dynamic regulation of mitotic spindles, mitotic progression, and chromosome segregation fidelity. We investigated the clinicopathological relevance of SPAG5 gene copy number aberrations, mRNA transcript expression, and protein expression and analysed the associations of SPAG5 copy number aberrations, transcript expression, and protein expression with breast cancer-specific survival, disease-free survival, distant relapse-free survival, pathological complete response, and residual cancer burden in the Nottingham discovery cohort, Uppsala cohort, METABRIC cohort, a pooled untreated lymph node-negative cohort (n=684), a multicentre combined cohort (n=5439), the Nottingham historical early stage breast cancer cohort (Nottingham-HES; n=1650), Nottingham early stage oestrogen receptor-negative breast cancer adjuvant chemotherapy cohort (Nottingham-oestrogen receptor-negative-ACT; n=697), the Nottingham anthracycline neoadjuvant chemotherapy cohort (Nottingham-NeoACT; n=200), the MD Anderson taxane plus anthracycline-based neoadjuvant chemotherapy cohort (MD Anderson-NeoACT; n=508), and the multicentre phase 2 neoadjuvant clinical trial cohort (phase 2 NeoACT; NCT00455533 ; n=253). Findings In the METABRIC cohort, we detected SPAG5 gene gain or amplification at the Ch17q11.2 locus in 206 (10%) of 1980 patients overall, 46 (19%) of 237 patients with a PAM50-HER2 phenotype, and 87 (18%) of 488 patients with PAM50-LumB phenotype. Copy number aberration leading to SPAG5 gain or amplification and high SPAG5 transcript and SPAG5 protein concentrations were associated with shorter overall breast cancer-specific survival (METABRIC cohort copy number aberration: hazard ratio HR 1·50, 95% CI 1·18–1·92, p=0·00010; METABRIC cohort transcript: 1·68, 1·40–2·01, p<0·0001; and Nottingham-HES-breast cancer cohort protein: 1·68, 1·32–2·12, p<0·0001). In multivariable analysis, high SPAG5 transcript and SPAG5 protein expression were associated with reduced breast cancer-specific survival at 10 years compared with lower concentrations (Uppsala: HR 1·62, 95% CI 1·03–2·53, p=0·036; METABRIC: 1·27, 1·02–1·58, p=0·034; untreated lymph node-negative cohort: 2·34, 1·24–4·42, p=0·0090; and Nottingham-HES: 1·73, 1·23–2·46, p=0·0020). In patients with oestrogen receptor-negative breast cancer with high SPAG5 protein expression, anthracycline-based adjuvant chemotherapy increased breast cancer-specific survival overall compared with that for patients who did not receive chemotherapy (Nottingham-oestrogen receptor-negative-ACT cohort: HR 0·37, 95% CI 0·20–0·60, p=0·0010). Multivariable analysis showed high SPAG5 transcript concentrations to be independently associated with longer distant relapse-free survival after receiving taxane plus anthracycline neoadjuvant chemotherapy (MD Anderson-NeoACT: HR 0·68, 95% CI 0·48–0·97, p=0·031). In multivariable analysis, both high SPAG5 transcript and high SPAG5 protein concentrations were independent predictors for a higher proportion of patients achieving a pathological complete response after combination cytotoxic chemotherapy (MD Anderson-NeoACT: OR 1·71, 95% CI, 1·07–2·74, p=0·024; Nottingham-ACT: 8·75, 2·42–31·62, p=0·0010). Interpretation SPAG5 is a novel amplified gene on Ch17q11.2 in breast cancer. The transcript and protein products of SPAG5 are independent prognostic and predictive biomarkers that might have clinical utility as biomarkers for combination cytotoxic chemotherapy sensitivity, especially in oestrogen receptor-negative breast cancer. Funding Nottingham Hospitals Charity and the John and Lucille van Geest Foundation.
Summary Background Cisplatin and gemcitabine is the standard first-line chemotherapy regimen for patients with advanced biliary tract cancer; expression of VEGF and its receptors is associated with ...adverse outcomes. We aimed to assess the effect of the addition of cediranib (an oral inhibitor of VEGF receptor 1, 2, and 3) to cisplatin and gemcitabine on progression-free survival. Methods In this multicentre, placebo-controlled, randomised phase 2 study, we recruited patients aged 18 years or older with histologically confirmed or cytologically confirmed advanced biliary tract cancer from hepatobiliary oncology referral centres in the UK. Patients were eligible if they had an ECOG performance status of 0–1 and an estimated life expectancy of longer than 3 months. Patients were given first-line cisplatin and gemcitabine chemotherapy (25 mg/m2 cisplatin and 1000 mg/m2 gemcitabine on days 1 and 8 every 21 days, for up to eight cycles) with either 20 mg oral cediranib or placebo once a day until disease progression. We randomly assigned patients (1:1) with a minimisation algorithm, incorporating the stratification factors: extent of disease, primary disease site, previous treatment, ECOG performance status, and centre. The primary endpoint was progression-free survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov , number NCT00939848 , and was closed on Sept 30, 2014; results of the final analysis for the primary endpoint are presented. Findings Between April 5, 2011, and Sept 28, 2012, we enrolled 124 patients (62 in each group). With a median follow-up of 12·2 months (IQR 7·3–18·5), median progression-free survival was 8·0 months (95% CI 6·5–9·3) in the cediranib group and 7·4 months (5·7–8·5) in the placebo group (HR 0·93, 80% CI 0·74–1·19, 95% CI 0·65–1·35; p=0·72). Patients who received cediranib had more grade 3–4 toxic effects than did patients who received placebo: hypertension (23 37% vs 13 21%; p=0·05), diarrhoea (eight 13% vs two 3%; p=0·05); platelet count decreased (ten 16% vs four 6%; p=0·09), white blood cell decreased (15 24% vs seven 11%; p=0·06) and fatigue (16 24% vs seven 11%; p=0·04). Interpretation Cediranib did not improve the progression-free survival of patients with advanced biliary tract cancer in combination with cisplatin and gemcitabine, which remains the standard of care. Although patients in the cediranib group had more adverse events, we recorded no unexpected toxic effects. The role of VEGF inhibition in addition to chemotherapy for patients with advanced biliary tract cancer remains investigational. Funding Cancer Research UK and AstraZeneca Pharmaceuticals.
Summary Background A detailed description of viral kinetics, duration of virus shedding, and intraviral evolution in different body sites is warranted to understand Ebola virus pathogenesis. Patients ...with Ebola virus infections admitted to university hospitals provide a unique opportunity to do such in-depth virological investigations. We describe the clinical, biological, and virological follow-up of a case of Ebola virus disease. Methods A 43-year-old medical doctor who contracted an Ebola virus infection in Sierra Leone on Nov 16, 2014 (day 1), was airlifted to Geneva University Hospitals, Geneva, Switzerland, on day 5 after disease onset. The patient received an experimental antiviral treatment of monoclonal antibodies (ZMAb) and favipiravir. We monitored daily viral load kinetics, estimated viral clearance, calculated the half-life of the virus in plasma, and analysed the viral genome via high-throughput sequencing, in addition to clinical and biological signs. Findings The patient recovered rapidly, despite an initial high viral load (about 1 × 107 RNA copies per mL 24 h after onset of fever). We noted a two-phase viral decay. The virus half-life decreased from about 26 h to 9·5 h after the experimental antiviral treatment. Compared with a consensus sequence of June 18, 2014, the isolate that infected this patient displayed only five synonymous nucleotide substitutions on the full genome (4901A→C, 7837C→T, 8712A→G, 9947T→C, 16201T→C) despite 5 months of human-to-human transmission. Interpretation This study emphasises the importance of virological investigations to fully understand the course of Ebola virus disease and adaptation of the virus. Whether the viral decay was caused by the effects of the immune response alone, an additional benefit from the antiviral treatment, or a combination of both is unclear. In-depth virological analysis and randomised controlled trials are needed before any conclusion on the potential effect of antiviral treatment can be drawn. Funding Geneva University Hospitals, Swiss Office of Public Health, Swiss Agency for Development and Cooperation, and Swiss National Science Foundation.
Summary Background Outcome of low-grade glioma (WHO grade II) is highly variable, reflecting molecular heterogeneity of the disease. We compared two different, single-modality treatment strategies of ...standard radiotherapy versus primary temozolomide chemotherapy in patients with low-grade glioma, and assessed progression-free survival outcomes and identified predictive molecular factors. Methods For this randomised, open-label, phase 3 intergroup study (EORTC 22033-26033), undertaken in 78 clinical centres in 19 countries, we included patients aged 18 years or older who had a low-grade (WHO grade II) glioma (astrocytoma, oligoastrocytoma, or oligodendroglioma) with at least one high-risk feature (aged >40 years, progressive disease, tumour size >5 cm, tumour crossing the midline, or neurological symptoms), and without known HIV infection, chronic hepatitis B or C virus infection, or any condition that could interfere with oral drug administration. Eligible patients were randomly assigned (1:1) to receive either conformal radiotherapy (up to 50·4 Gy; 28 doses of 1·8 Gy once daily, 5 days per week for up to 6·5 weeks) or dose-dense oral temozolomide (75 mg/m2 once daily for 21 days, repeated every 28 days one cycle, for a maximum of 12 cycles). Random treatment allocation was done online by a minimisation technique with prospective stratification by institution, 1p deletion (absent vs present vs undetermined), contrast enhancement (yes vs no), age (<40 vs ≥40 years), and WHO performance status (0 vs ≥1). Patients, treating physicians, and researchers were aware of the assigned intervention. A planned analysis was done after 216 progression events occurred. Our primary clinical endpoint was progression-free survival, analysed by intention-to-treat; secondary outcomes were overall survival, adverse events, neurocognitive function (will be reported separately), health-related quality of life and neurological function (reported separately), and correlative analyses of progression-free survival by molecular markers (1p/19q co-deletion, MGMT promoter methylation status, and IDH1/IDH2 mutations). This trial is closed to accrual but continuing for follow-up, and is registered at the European Trials Registry, EudraCT 2004-002714-11, and at ClinicalTrials.gov , NCT00182819. Findings Between Sept 23, 2005, and March 26, 2010, 707 patients were registered for the study. Between Dec 6, 2005, and Dec 21, 2012, we randomly assigned 477 patients to receive either radiotherapy (n=240) or temozolomide chemotherapy (n=237). At a median follow-up of 48 months (IQR 31–56), median progression-free survival was 39 months (95% CI 35–44) in the temozolomide group and 46 months (40–56) in the radiotherapy group (unadjusted hazard ratio HR 1·16, 95% CI 0·9–1·5, p=0·22). Median overall survival has not been reached. Exploratory analyses in 318 molecularly-defined patients confirmed the significantly different prognosis for progression-free survival in the three recently defined molecular low-grade glioma subgroups ( IDH mt, with or without 1p/19q co-deletion IDH mt/codel, or IDH wild type IDH wt; p=0·013). Patients with IDH mt/non-codel tumours treated with radiotherapy had a longer progression-free survival than those treated with temozolomide (HR 1·86 95% CI 1·21–2·87, log-rank p=0·0043), whereas there were no significant treatment-dependent differences in progression-free survival for patients with IDH mt/codel and IDH wt tumours. Grade 3–4 haematological adverse events occurred in 32 (14%) of 236 patients treated with temozolomide and in one (<1%) of 228 patients treated with radiotherapy, and grade 3–4 infections occurred in eight (3%) of 236 patients treated with temozolomide and in two (1%) of 228 patients treated with radiotherapy. Moderate to severe fatigue was recorded in eight (3%) patients in the radiotherapy group (grade 2) and 16 (7%) in the temozolomide group. 119 (25%) of all 477 patients had died at database lock. Four patients died due to treatment-related causes: two in the temozolomide group and two in the radiotherapy group. Interpretation Overall, there was no significant difference in progression-free survival in patients with low-grade glioma when treated with either radiotherapy alone or temozolomide chemotherapy alone. Further data maturation is needed for overall survival analyses and evaluation of the full predictive effects of different molecular subtypes for future individualised treatment choices. Funding Merck Sharpe & Dohme-Merck & Co, Canadian Cancer Society, Swiss Cancer League, UK National Institutes of Health, Australian National Health and Medical Research Council, US National Cancer Institute, European Organisation for Research and Treatment of Cancer Cancer Research Fund.
Assessment of surgical skill is a critical component of surgical training. Approaches to assessment remain predominantly subjective, although more objective measures such as Global Rating Scales are ...in use. This study aimed to validate the use of elbow-worn, wireless, miniaturized motion sensors to assess the technical skill of trainees performing arthroscopic procedures in a simulated environment.
Thirty participants were divided into three groups on the basis of their surgical experience: novices (n = 15), intermediates (n = 10), and experts (n = 5). All participants performed three standardized tasks on an arthroscopic virtual reality simulator while wearing wireless wrist and elbow motion sensors. Video output was recorded and a validated Global Rating Scale was used to assess performance; dexterity metrics were recorded from the simulator. Finally, live motion data were recorded via Bluetooth from the wireless wrist and elbow motion sensors and custom algorithms produced an arthroscopic performance score.
Construct validity was demonstrated for all tasks, with Global Rating Scale scores and virtual reality output metrics showing significant differences between novices, intermediates, and experts (p < 0.001). The correlation of the virtual reality path length to the number of hand movements calculated from the wireless sensors was very high (p < 0.001). A comparison of the arthroscopic performance score levels with virtual reality output metrics also showed highly significant differences (p < 0.01). Comparisons of the arthroscopic performance score levels with the Global Rating Scale scores showed strong and highly significant correlations (p < 0.001) for both sensor locations, but those of the elbow-worn sensors were stronger and more significant (p < 0.001) than those of the wrist-worn sensors.
A new wireless assessment of surgical performance system for objective assessment of surgical skills has proven valid for assessing arthroscopic skills. The elbow-worn sensors were shown to achieve an accurate assessment of surgical dexterity and performance.
The validation of an entirely objective assessment of arthroscopic skill with wireless elbow-worn motion sensors introduces, for the first time, a feasible assessment system for the live operating theater with the added potential to be applied to other surgical and interventional specialties.
Genetically determined hypoparathyroidism can lead to life-threatening episodes of hypocalcemia and, more rarely, to end-stage kidney disease at a young age. Parathyroid allotransplantation is the ...only curative treatment, and in patients already receiving immunosuppression for kidney transplantation, there may be little additional risk involved. We report the first such case in a child.
An 11-y-old girl, known to have hypoparathyroidism secondary to an activating pathogenic variant in the calcium-sensing receptor, developed end-stage kidney disease and was started on intermittent hemodialysis. Since the age of 2.5 y, she had been receiving treatment with exogenous synthetic parathyroid hormone (PTH). In June 2019, at the age of 11.8 y, she received a living-donor kidney and simultaneous parathyroid gland transplant from her father. The kidney was implanted into the right iliac fossa, followed by implantation of the parathyroid gland into the exposed rectus muscle.
The kidney graft showed immediate function while the intrinsic serum PTH level remained low at 3 ng/L. Exogenous PTH infusion was reduced on day 6 posttransplantation to stimulate PTH production by the new gland, which resulted in improving intrinsic PTH concentrations of 28 ng/L by day 9. Twelve months after transplantation, PTH levels remain in normal range and the kidney graft function is stable with a serum creatinine of 110 μmol/L.
Simultaneous living donation and transplantation of a kidney and a parathyroid gland into a child is safe and feasible and has the potential to cure primary hypoparathyroidism as well as kidney failure.
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