Summary Background Necitumumab is a second-generation, recombinant, human immunoglobulin G1 EGFR antibody. In this study, we aimed to compare treatment with necitumumab plus gemcitabine and cisplatin ...versus gemcitabine and cisplatin alone in patients with previously untreated stage IV squamous non-small-cell lung cancer. Methods We did this open-label, randomised phase 3 study at 184 investigative sites in 26 countries. Patients aged 18 years or older with histologically or cytologically confirmed stage IV squamous non-small-cell lung cancer, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 and adequate organ function and who had not received previous chemotherapy for their disease were eligible for inclusion. Enrolled patients were randomly assigned centrally 1:1 to a maximum of six 3-week cycles of gemcitabine and cisplastin chemotherapy with or without necitumumab according to a block randomisation scheme (block size of four) by a telephone-based interactive voice response system or interactive web response system. Chemotherapy was gemcitabine 1250 mg/m2 administered intravenously over 30 min on days 1 and 8 of a 3-week cycle and cisplatin 75 mg/m2 administered intravenously over 120 min on day 1 of a 3-week cycle. Necitumumab 800 mg, administered intravenously over a minimum of 50 min on days 1 and 8, was continued after the end of chemotherapy until disease progression or intolerable toxic side-effects occurred. Randomisation was stratified by ECOG performance status and geographical region. Neither physicians nor patients were masked to group assignment because of the expected occurrence of acne-like rash—a class effect of EGFR antibodies—that would have unmasked most patients and investigators to treatment. The primary endpoint was overall survival, analysed by intention to treat. We report the final clinical analysis. This study is registered with ClinicalTrials.gov , number NCT00981058. Findings Between Jan 7, 2010, and Feb 22, 2012, we enrolled 1093 patients and randomly assigned them to receive necitumumab plus gemcitabine and cisplatin (n=545) or gemcitabine and cisplatin (n=548). Overall survival was significantly longer in the necitumumab plus gemcitabine and cisplatin group than in the gemcitabine and cisplatin alone group (median 11·5 months 95% CI 10·4–12·6) vs 9·9 months 8·9–11·1; stratified hazard ratio 0·84 95% CI 0·74–0·96; p=0·01). In the necitumumab plus gemcitabine and cisplatin group, the number of patients with at least one grade 3 or worse adverse event was higher (388 72% of 538 patients) than in the gemcitabine and cisplatin group (333 62% of 541), as was the incidence of serious adverse events (257 48% of 538 patients vs 203 38% of 541). More patients in the necitumumab plus gemcitabine and cisplatin group had grade 3–4 hypomagnesaemia (47 9% of 538 patients in the necitumumab plus gemcitabine and cisplatin group vs six 1% of 541 in the gemcitabine and cisplatin group) and grade 3 rash (20 4% vs one <1%). Including events related to disease progression, adverse events with an outcome of death were reported for 66 (12%) of 538 patients in the necitumumab plus gemcitabine and cisplatin group and 57 (11%) of 541 patients in the gemcitabine and cisplatin group; these were deemed to be related to study drugs in 15 (3%) and ten (2%) patients, respectively. Overall, we found that the safety profile of necitumumab plus gemcitabine and cisplatin was acceptable and in line with expectations. Interpretation Our findings show that the addition of necitumumab to gemcitabine and cisplatin chemotherapy improves overall survival in patients with advanced squamous non-small-cell lung cancer and represents a new first-line treatment option for this disease. Funding Eli Lilly and Company.
Animal models of exercise and Parkinson's disease (PD) have found that the physiologic use of exercise may interact with the neurodegenerative disease process, likely mediated by brain derived ...neurotrophic factor (BDNF). No reviews so far have assessed the methodologic quality of available intervention studies or have bundled the effect sizes of individual studies on exercise-induced effects on BDNF blood levels in human PD.
We searched MEDLINE, EMBASE, Cochrane Library, PsycINFO and PubMed from inception to June 2017.
Data aggregated from two randomized controlled trials and four pre-experimental studies with a total of 100 ambulatory patients with idiopathic PD (Hoehn/Yahr ≤3) found improvements in BDNF blood concentration levels in all 6 studies (two RCTs and 4 pre-experimental studies). Pooled BDNF level change scores from the 2 RCTs resulted in a significant homogeneous summary effect size (Standardized Mean Difference 2.06, 95% CI 1.36 to 2.76), and a significant heterogeneous SES for the motor part of the UPDRS-III examination (MD -5.53, 95% CI -10.42 to -0.64). Clinical improvements were noted in all studies using a variety of outcome measures.
The evidence-base consists primarily of small studies with low to moderate methodological quality.
This review provides preliminary evidence for the effectiveness of physical exercise treatments for persons with PD on BDNF blood levels. Further research is needed.
Intense artificial selection over the last 100 years has produced elite maize (Zea mays) inbred lines that combine to produce high-yielding hybrids. To further our understanding of how genome and ...transcriptome variation contribute to the production of high-yielding hybrids, we generated a draft genome assembly of the inbred line PH207 to complement and compare with the existing B73 reference sequence. B73 is a founder of the Stiff Stalk germplasm pool, while PH207 is a founder of Iodent germplasm, both of which have contributed substantially to the production of temperate commercial maize and are combined to make heterotic hybrids. Comparison of these two assemblies revealed over 2500 genes present in only one of the two genotypes and 136 gene families that have undergone extensive expansion or contraction. Transcriptome profiling revealed extensive expression variation, with as many as 10,564 differentially expressed transcripts and 7128 transcripts expressed in only one of the two genotypes in a single tissue. Genotype-specific genes were more likely to have tissue/condition-specific expression and lower transcript abundance. The availability of a high-quality genome assembly for the elite maize inbred PH207 expands our knowledge of the breadth of natural genome and transcriptome variation in elite maize inbred lines across heterotic pools.
Exercise training may affect the blood levels of brain-derived neurotrophic factor (BDNF), but meta-analyses have not yet been performed comparing pre- and post-intervention BDNF concentrations in ...patients with multiple sclerosis (PwMS).
To perform a meta-analysis to study the influence of exercise on BDNF levels and define components that modulate them across clinical trials of exercise training in adults living with multiple sclerosis (MS).
Five databases (PubMed, EMBASE, Cochrane Library, PEDro database, CINAHL) were searched up to June 2021. According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses, we included 13 articles in the meta-analysis, including 271 subjects. To investigate sources of heterogeneity, subgroup analysis, meta-regression, and sensitivity analysis were conducted. We performed the meta-analysis to compare pre- and post-exercise peripheral levels of BDNF in PwMS.
Post-exercise concentrations of serum BDNF were significantly higher than pre-intervention levels (Standardized Mean Difference (SMD): 0.33, 95% CI: 0.04; 0.61, p-value = 0.02). Meta-regression indicated that the quality of the included studies based on the PEDro assessment tool might be a source of heterogeneity, while no significant effect was found for chronological age and disease severity according to the expanded disability status scale.
This systematic review and meta-analysis shows that physical activity increases peripheral levels of BDNF in PwMS. More research on the effect of different modes of exercise on BDNF levels in PwMS is warranted.
Abstract Introduction While animal models of exercise and PD have pushed the field forward, few studies have addressed exercise-induced neuroplasticity in human PD. Method As a first step toward ...promoting greater international collaboration on exercise-induced neuroplasticity in human PD, we present data on 8 human PD studies (published between 2008 and 2015) with 144 adults with PD of varying disease severity (Hoehn and Yahr stage 1 to stage 3), using various experimental (e.g., randomized controlled trial) and quasi-experimental designs on the effects of cognitive and physical activity on brain structure or function in PD. We focus on plasticity mechanisms of intervention-induced increases in maximal corticomotor excitability, exercise-induced changes in voxel-based gray matter volume changes and increases in exercise-induced serum levels of brain derived neurotrophic factor (BDNF). Finally, we provide a future perspective for promoting international, collaborative research on exercise-induced neuroplasticity in human PD. Conclusion An emerging body of evidence suggests exercise triggers several plasticity related events in the human PD brain including corticomotor excitation, increases and decreases in gray matter volume and changes in BDNF levels.
Lung cancer remains the leading cause of cancer-related death worldwide. NSCLC accounts for more than 85% of all lung cancers, and the prognosis for advanced-stage disease is typically poor. In ...recent years, the importance of histologic subtypes of NSCLC has been recognized, and the distinction between squamous and other NSCLC histologic subtypes is now critical to patient management. Squamous cell lung cancer (sqCLC) represents approximately 25% to 30% of NSCLC. The prognosis for patients with advanced NSCLC is poorer for those with sqCLC than for those with adenocarcinoma. This is partly due to a number of clinical characteristics that distinguish sqCLC from other NSCLC histologic subtypes, such as smoking history, comorbid diseases, age, and molecular profile. Together, these factors make sqCLC an especially challenging disease to manage. Herein, we review some of the key clinicopathologic features of sqCLC. Understanding these features to optimally address many of the unique therapeutic challenges of this disease is likely to be central to ultimately improving outcomes for patients with squamous NSCLC.
Summary Background Necitumumab is a second-generation recombinant human immunoglobulin G1 EGFR monoclonal antibody that competitively inhibits ligand binding. We aimed to compare necitumumab plus ...pemetrexed and cisplatin with pemetrexed and cisplatin alone in patients with previously untreated, stage IV, non-squamous non-small-cell lung cancer (NSCLC). Methods We did this randomised, open-label, controlled phase 3 study at 103 sites in 20 countries. Patients aged 18 years or older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 and adequate organ function, were randomly assigned 1:1 to treatment with a block randomisation scheme (block size of four) via a telephone-based interactive voice-response system or interactive web-response system. Patients received either cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 on day 1 of a 3-week cycle for a maximum of six cycles alone, or with necitumumab 800 mg on days 1 and 8. Necitumumab was continued after the end of chemotherapy until disease progression or unacceptable toxic effects. Randomisation was stratified by smoking history, ECOG performance status, disease histology, and geographical region. Patients and study investigators were not masked to group assignment. The primary endpoint was overall survival. Efficacy analyses were by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT00982111. Findings Between Nov 11, 2009, and Feb 2, 2011, we randomly assigned 633 patients to receive either necitumumab plus pemetrexed and cisplatin (n=315) or pemetrexed and cisplatin alone (n=318). Enrolment was stopped on Feb 2, 2011, after a recommendation from the independent data monitoring committee. There was no significant difference in overall survival between treatment groups, with a median overall survival of 11·3 months (95% CI 9·5–13·4) in the necitumumab plus pemetrexed and cisplatin group versus 11·5 months (10·1–13·1) in the pemetrexed and cisplatin group (hazard ratio 1·01 95% CI 0·84–1·21; p=0·96). The incidence of grade 3 or worse adverse events, including deaths, was higher in the necitumumab plus pemetrexed and cisplatin group than in the pemetrexed and cisplatin group; in particular, deaths regarded as related to study drug were reported in 15 (5%) of 304 patients in the necitumumab group versus nine (3%) of 312 patients in the pemetrexed and cisplatin group. Serious adverse events were likewise more frequent in the necitumumab plus pemetrexed and cisplatin group than in the pemetrexed and cisplatin group (155 51% of 304 vs 127 41% of 312 patients). Patients in the necitumumab plus pemetrexed and cisplatin group had more grade 3–4 rash (45 15% of 304 vs one <1% of 312 patients in the pemetrexed and cisplatin alone group), hypomagnesaemia (23 8% vs seven 2% patients), and grade 3 or higher venous thromboembolic events (23 8% vs 11 4% patients) than did those in the pemetrexed and cisplatin alone group. Interpretation Our findings show no evidence to suggest that the addition of necitumumab to pemetrexed and cisplatin increases survival of previously untreated patients with stage IV non-squamous NSCLC. Unless future studies identify potentially useful predictive biomarkers, necitumumab is unlikely to provide benefit in this patient population when combined with pemetrexed and cisplatin. Funding Eli Lilly and Company.
Squamous cell lung cancer (SqCLC) is a distinct histologic subtype of NSCLC that is challenging to treat because of specific clinicopathologic characteristics, which include older age, advanced ...disease at diagnosis, comorbid diseases, and the central location of tumors. These characteristics have a bearing on treatment outcomes in advanced SqCLC, resulting in a median survival approximately 30% shorter than for patients with other NSCLC subtypes. In the context of the specific features of SqCLC, we review challenges of treating SqCLC and the current guideline-recommended treatments for advanced (metastatic) SqCLC in different patient subpopulations. We also evaluate recently approved treatment options, including necitumumab, afatinib, nivolumab, pembrolizumab, and atezolizumab; discuss the survival benefits associated with each agent in the advanced SqCLC population; and propose a treatment algorithm incorporating these agents for this challenging-to-treat disease. Lastly, we review the preliminary clinical evidence for immunotherapy agents in development for advanced NSCLC.
To examine sociodemographic and clinical characteristics independently associated with discharge home compared with discharge to a skilled nursing facility (SNF) after acute inpatient rehabilitation.
...Retrospective cohort study.
Three tertiary accredited acute care rehabilitation facilities.
Adult patients with stroke (N=2085).
Not applicable.
Not applicable.
Of 2085 patients with stroke treated at 3 centers over a 4-year period, 78.2% (n=1631) were discharged home and 21.8% (n=454) discharged to an SNF. Findings from a multivariable logistic regression analysis indicated that patients were less likely to be discharged home if they were older (odds ratio OR, .98; 95% confidence interval CI, .96-.99), separated or divorced (compared with married; OR, .61; 95% CI, .48-.79), or with Medicare health insurance (compared with private insurance; OR, .69; 95% CI, .55-.88), or had dysphagia (OR, .83; 95% CI, .71-.98) or cognitive deficits (OR, .79; 95% CI, .77-.81). The odds of being discharged home were higher for those admitted with a higher motor FIM score (OR, 1.10; 95% CI, 1.09-1.11). The following were not associated with discharge disposition: sex, race, prestroke vocational status, availability of secondary health insurance, number of days from stroke onset to rehabilitation facility admission, stroke type, impairment group, cognitive FIM on admission, other stroke deficits (aphasia, ataxia, neglect, or speech disturbance), stroke complications of hyponatremia or urinary tract infection, or comorbid conditions.
One in 5 patients with stroke were discharged to an SNF after inpatient rehabilitation. On admission, several sociodemographic and clinical characteristics were identified that could be considered as important factors in early discussions for discharge planning.
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