Incidence Of Other Adverse Events Research Articles

Relationship Between Renal Function and the Incidence of Adverse Events in Patients With Colorectal Cancer Receiving Oxaliplatin.

To clarify whether renal dysfunction affects the incidence of adverse events associated with oxaliplatin, the present study was designed to investigate the relationship between creatinine clearance (Ccr) and the incidence of oxaliplatin-related adverse events. A total of 287 CRC patients who received the first cycle of oxaliplatin-based chemotherapy were eligible. Adverse events, including nausea, vomiting, neutropenia and thrombocytopenia, were graded, and the relationship between Ccr and the incidence of adverse events was examined using multivariable logistic regression analysis. A multivariable analysis indicated that the incidence of grade ≥2 nausea increased, while the incidence of other adverse events tended to be higher, as the Ccr decreased. Particularly, renal dysfunction (Ccr <60 ml/min) was a significant risk factor for grade ≥2 nausea (p=0.042). Care should be taken to avoid adverse events associated with oxaliplatin in patients with renal dysfunction.

Efficacy and safety of early administration of pegfilgrastim for esophageal cancer treated with DCF: A phase 2 study

Abstract Background It has been reported that docetaxel, cisplatin and 5-fluorouracil (DCF) regimen was effective for advanced esophageal cancer. However, the DCF regimen is associated with a high risk of severe neutropenia or febrile neutropenia (FN). In our retrospective study evaluating the efficacy of pegfilgrastim administration on day 7 (D7) in DCF regimen, the neutrophil count nadir was observed from D7. Thus, the timing of its administration could be too late. In this study, we assess the efficacy and safety of early administration (D3) of pegfilgrastim in DCF therapy for advanced esophageal cancer. Methods In this single-arm phase 2 study, patients with advanced esophageal cancer were recruited. They were treated with DCF therapy (DTX: 70mg/m2 on D1, CDDP: 70mg/m2 on D1, and 5-FU: 750mg/m2 on D1-5), and were administrated pegfilgrastim on D3. The primary endpoint was grade4 neutropenia. The secondary endpoints were the rate of FN and the incidence of other adverse events. This study was registered in UMIN system (UMI23393). Results Between July 2016 and Dec. 2018, we enrolled 23 patients (median age 62y ). The incidence of grade4 neutropenia was 8.7% (95%CI:4.7 - 22.1). The rate of FN was 0%. The rate of grade3 neutropenia was 17.4% (95%CI: 1.7 - 33.1), but no other serious adverse events related to pegfilgrastim were observed. Conclusion Primary prophylaxis with pegfilgrastim is recommended for the prevention of FN in patients receiving high-risk chemotherapy regimens such as DCF. According to the guidelines, G-CSF should be administered 24 h after the completion of chemotherapy. The optimal administration schedule remains unclear in regimens including IV continuous 5-FU administration like DCF. These results have shown that early administration (D3) of pegfilgrastim was safe and seemed to be more effective than D7 in DCF therapy. Further clinical studies with a larger sample size should be conducted to confirm our results.

363P - Maintenance chemotherapy is effective in patients with metastatic triple negative breast cancer after first-line platinum-based chemotherapy

BackgroundPlatinum-based chemotherapy (PBCT) has gained an important position as a first-line treatment for metastatic triple-negative breast cancer (mTNBC). We assessed whether maintenance chemotherapy is superior to observation after first-line PBCT in patients with mTNB. MethodsA total of 265 patients with mTNBC who exhibited disease control after 4-6 cycles of first-line PBCT at the Fudan University Shanghai Cancer Center from January 2008 to November 2016 were retrospectively analyzed. 107 patients who continued without additional treatment were defined as the control observation group, and the remaining 158 patients who continued to receive maintenance therapy were defined as the maintenance treatment group. ResultsThe median progression-free survival (PFS) time in the maintenance group was 9.63 months, which was significantly longer than the PFS time of 7.47 months in the observation group (HR 0.49, 95% CI 0.37-0.67, P<0.0001). The median overall survival (OS) of the observation group and the maintenance group was 25.37 months and 31.27 months, respectively (HR 0.65, 95% CI 0.44-0.95, P=0.019). Multivariate analyses suggested that maintenance chemotherapy is an independent predictive factor for PFS and OS. Interaction and stratified analyses showed no difference in the PFS between the single-drug maintenance group and the two-drug maintenance group. The most common adverse event in this study was hematologic toxicity. Except for hand-foot syndrome (0 vs. 7.6%, P=0.004), the incidence of other adverse events was not significantly different between the observation and maintenance groups. ConclusionsAfter achieving disease control with first-line PBCT in mTNBC patients, single-drug maintenance chemotherapy is recommended. Legal entity responsible for the studyFudan University Shanghai Cancer Center. FundingShanghai Municipal Science and Technology Commission Guidance Project, China (contract no. 18411967800); Shanghai Municipal Commission of Health and Family Planning (grant no. 201640069); Shanghai Natural Science Foundation (grant no. 17ZR1405700); and research grant from Shanghai Hospital Development Center (grant no. SHDC12018X03). DisclosureAll authors have declared no conflicts of interest.

Standardized Use of the Stanford Integrated Psychosocial Assessment for Transplantation in LVAD Patients

BackgroundIncreased psychosocial risk portends poor outcomes following heart transplantation. The Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT) is a validated, psychosocial risk assessment tool that helps stratify candidates for transplantation. We assessed the impact of psychosocial factors as measured by the SIPAT on clinical outcomes following left ventricular assist device (LVAD) implantation at our institution. Methods and ResultsA total of 115 individuals (mean age: 57 years, 75.6% men) who underwent LVAD implantation, for either bridge-to-transplant (63%) or destination therapy, from 2014 to 2016 were included for analysis. Correlations between SIPAT scores, baseline characteristics, and post-LVAD outcomes were assessed through a retrospective correlational design. At 1 year post-LVAD, the higher risk SIPAT group had more emergency department visits, urgent clinic visits, and readmissions in univariate analysis (rate ratio 1.7 [95% confidence interval (CI) 1.0–2.7, P = .035]). After multivariate analysis, this association retained near-statistical significance (rate ratio 1.6 [95% CI 1.0–2.8, P = .051]). There was also a trend toward more device-associated infections (rate ratio 2.1 [95% CI 0.96–4.4, P = .064]). There was no difference in incidence of other adverse events or 1-year mortality between the 2 groups. ConclusionsHigher psychosocial risk per SIPAT in patients undergoing LVAD implantation is associated with more emergency room visits, urgent visits and readmissions over 1 year, but not LVAD-related complications or mortality. Use of the SIPAT tool may help identify patients at higher risk for hospitalization and/or urgent care beyond traditional factors, but should not preclude LVAD implantation.

Severe Neutropenia is Associated with Better Clinical Outcomes in Patients with Advanced Pancreatic Cancer Who Receive Modified FOLFIRINOX Therapy.

While modified FOLFIRINOX therapy is effective for treating advanced pancreatic cancer, it frequently causes severe neutropenia. The present study investigated the effect of severe neutropenia on clinical outcomes in advanced pancreatic cancer patients who received modified FOLFIRINOX. The study subjects were 51 patients (30 males and 21 females) with advanced pancreatic cancer who received modified FOLFIRINOX (2h bolus injection of oxaliplatin at 85 mg/m2, 2 h bolus injection of L-leucovorin at 200 mg/m2, 90min bolus injection of irinotecan at 150 mg/m2, followed by continuous infusion of 5-fluorouracil for 46 h at 2400 mg/m2 without bolus 5-fluorouracil) during the period from January 2014 to May 2018. No patients had prior history of chemotherapy. Adverse events, including neutropenia, were graded according to the Common Terminology Criteria for Adverse Events, version 4.0. Median overall survival (OS) was the primary endpoint, while median time to treatment failure (TTF), overall response rate (ORR), and the incidence of other adverse events were secondary endpoints. Severe neutropenia (grade ≥3) occurred in 39 patients (76.4%), and Cox proportional hazard analysis identified high total bilirubin level as a significant risk factor. Median duration of OS was significantly longer in patients with severe neutropenia than in those without it (21.3 months versus 8.9 months, p = 0.020). Moreover, there was a significant correlation between OS and the grade of neutropenia (r = 0.306, p = 0.029). ORR tended to be higher, though not significantly, in patients with severe neutropenia. In contrast, the incidence rates of other adverse events were not different between the two groups. Severe neutropenia is an independent predictor of prognosis in advanced pancreatic cancer patients received modified FOLFIRINOX therapy.

2-year safety and efficacy results for benralizumab

The era of biological therapies for asthma started with approval in 2003 of a humanised anti-IgE antibody, omalizumab, for the treatment of patients with severe allergic asthma. Since then, IgG antibodies targeting interleukin (IL)-5 (mepolizumab and reslizumab) and IL-5 receptor α (benralizumab) have been approved for the treatment of patients with severe eosinophilic asthma characterised by recurrent exacerbations. In 2016, two phase 3 studies 1 Bleecker ER FitzGerald JM Chanez P et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet. 2016; 388: 2115-2127 Summary Full Text Full Text PDF PubMed Scopus (850) Google Scholar , 2 FitzGerald JM Bleecker ER Nair P et al. Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2016; 388: 2128-2141 Summary Full Text Full Text PDF PubMed Scopus (870) Google Scholar showed that benralizumab had good safety and efficacy when administered over 1 year in patients with severe uncontrolled asthma, reducing asthma exacerbations and improving lung function in patients with blood eosinophil counts of 300 cells per μL or greater at baseline. Although 1-year safety results for anti-IL-5 or anti-IL-5 receptor α antibodies have generally been acceptable, 3 He LL Zhang L Jiang L Xu F Fei DS Efficacy and safety of anti-interleukin-5 therapy in patients with asthma: a pairwise and Bayesian network meta-analysis. Int Immunopharmacol. 2018; 64: 223-231 Crossref PubMed Scopus (13) Google Scholar no study has assessed their long-term safety or efficacy. Long-term safety and efficacy of benralizumab in patients with severe, uncontrolled asthma: 1-year results from the BORA phase 3 extension trialThe 2 years of safety results validate that observations observed in the first year of benralizumab continued through a second year of treatment. No new consequences of long-term eosinophil depletion occurred, and the incidence of other adverse events, including opportunistic infections, were similar during the second year. Full-Text PDF

Long-term safety and efficacy of benralizumab in patients with severe, uncontrolled asthma: 1-year results from the BORA phase 3 extension trial

Benralizumab is an interleukin-5 receptor α-directed cytolytic monoclonal antibody that has been shown to safely reduce exacerbations and improve lung function for patients with asthma. We assessed the long-term safety and efficacy of benralizumab for patients with severe, uncontrolled eosinophilic asthma. We conducted a randomised, double-blind, parallel-group, phase 3 extension study at 447 sites in 24 countries. Eligible patients had to have completed the SIROCCO or CALIMA trials and remained on subcutaneous benralizumab 30 mg every 4 weeks (Q4W) or every 8 weeks (Q8W). Patients who had received placebo in those trials were re-randomised in a 1:1 ratio, using an interactive web-based system, to benralizumab 30 mg either Q4W or Q8W (first three doses 4 weeks apart). Treatment lasted for 56 weeks for adult patients (age ≥18 years) and 108 weeks for adolescent patients (age 12-17 years). The primary endpoint was the safety and tolerability of the two dosing regimens of benralizumab up to 68 weeks for adult patients (including the follow-up visit post-treatment) and up to 56 weeks for adolescent patients. This endpoint was assessed in the full analysis set, which included all patients from the SIROCCO and CALIMA predecessor studies who received at least one dose of study treatment in BORA and did not continue into another trial. This study is registered with ClinicalTrials.gov (NCT02258542). Between Nov 19, 2014, and July 6, 2016, we enrolled 1926 patients, of whom 633 had received benralizumab Q4W and 639 had received benralizumab Q8W in SIROCCO or CALIMA. The remaining 654 patients had received placebo in those trials and were randomly re-assigned in this trial to receive benralizumab Q4W (n=320) or Q8W (n=334). 1576 patients, including 783 who received benralizumab Q4W (265 newly assigned) and 793 who received benralizumab Q8W (281 newly assigned), were included in the full analysis set. The most common adverse events in all groups were viral upper respiratory tract infection (14-16%) and worsening asthma (7-10%). The most common serious adverse events were worsening asthma (3-4%), pneumonia (<1% to 1%), and pneumonia caused by bacterial infection (0-1%). The percentages of patients who had any on-treatment adverse event, any serious adverse event, or any adverse event leading to treatment discontinuation during BORA were similar between patients originally assigned benralizumab and those originally assigned placebo and between benralizumab treatment regimens. The percentage of patients who had any adverse event was similar between SIROCCO or CALIMA (71-75%; benralizumab group only) and BORA (65-71%), as was the percentage of patients who had an adverse event that led to treatment discontinuation (2% in SIROCCO and CALIMA vs 2-3% in BORA). The 2 years of safety results validate that observations observed in the first year of benralizumab continued through a second year of treatment. No new consequences of long-term eosinophil depletion occurred, and the incidence of other adverse events, including opportunistic infections, were similar during the second year. AstraZeneca and Kyowa Hakko Kirin.

A Real-World Study of Maintenance Chemotherapy vs. Observation in Patients with Metastatic Triple Negative Breast Cancer after Achieving Disease Control with First-Line Platinum-Based Chemotherapy

Background: The platinum-based chemotherapy (PBCT) has gained its important position in the first-line treatment of metastatic triple-negative breast cancer (mTNBC). We accessed whether maintenance chemotherapy is superior to observation after first-line PBCT in patients with mTNBC. Patients and Methods: From January 2008 to November 2016, a total of 232 patients with mTNBC exhibited disease control with 4-6 cycles of first-line PBCT in the Fudan University Shanghai Cancer Center were retrospectively analyzed. 87 patients remained without any treatment were defined as a control observation group, and the remaining 145 patients continued to receive maintenance therapy were allocated into the maintenance treatment group. Findings: The median PFS time in the maintenance group was 9.6 months, which was significantly longer than the 7.7 months in the observation group (HR 0.47, 95% CI 0.34-0.65, P<0.0001). The median OS in the two groups was 23.9 months and 30.1 months, respectively (HR 0.67, 95% CI 0.45-0.98, P=0.029). Interaction and stratified analyses showed no difference in the PFS between the single drug maintenance group and the doublet drug maintenance group. The most common adverse event in this study was the hematologic toxicity. Except hand-foot syndrome (0 vs. 8.3%, P=0.003), the incidence of other adverse events was not significantly different between the two groups. Interpretation: After achieving disease control with first-line PBCT in mTNBC patients, maintenance chemotherapy is recommended. Funding Statement: This study was supported by the Shanghai Municipal Science and Technology Commission Guidance Project, P.R. China (contract no. 18411967800)；Shanghai Municipal Commission of Health and Family Planning (grant no. 201640069); Shanghai Natural Science Foundation (grant no. 17ZR1405700); and research grant from Shanghai Hospital Development Center (grant no. SHDC12018X03). Declaration of Interests: The Author(s) declare(s) that there is no conflict of interest. Ethics Approval Statement: This study was approved by the Regional Ethics Committee of our hospital and informed consent was obtained from all patients.

Safety and efficacy of self-administered inhaled loxapine (ADASUVE) in agitated patients outside the hospital setting: protocol for a phase IV, single-arm, open-label trial

IntroductionThere is a need for fast-acting, non-injection antiagitation treatments that are well tolerated and can be used outside of healthcare facilities. In phase II/III trials, an inhaled formulation of loxapine...

Use of aspirin to reduce risk of initial vascular events in patients at moderate risk of cardiovascular disease (ARRIVE): a randomised, double-blind, placebo-controlled trial

The use of aspirin in the primary prevention of cardiovascular events remains controversial. We aimed to assess the efficacy and safety of aspirin versus placebo in patients with a moderate estimated risk of a first cardiovascular event. ARRIVE is a randomised, double-blind, placebo-controlled, multicentre study done in seven countries. Eligible patients were aged 55 years (men) or 60 years (women) and older and had an average cardiovascular risk, deemed to be moderate on the basis of the number of specific risk factors. We excluded patients at high risk of gastrointestinal bleeding or other bleeding, or diabetes. Patients were randomly assigned (1:1) with a computer-generated randomisation code to receive enteric-coated aspirin tablets (100 mg) or placebo tablets, once daily. Patients, investigators, and others involved in treatment or data analysis were masked to treatment allocation. The primary efficacy endpoint was a composite outcome of time to first occurrence of cardiovascular death, myocardial infarction, unstable angina, stroke, or transient ischaemic attack. Safety endpoints were haemorrhagic events and incidence of other adverse events, and were analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00501059. Between July 5, 2007, and Nov 15, 2016, 12 546 patients were enrolled and randomly assigned to receive aspirin (n=6270) or placebo (n=6276) at 501 study sites. Median follow-up was 60 months. In the intention-to-treat analysis, the primary endpoint occurred in 269 (4·29%) patients in the aspirin group versus 281 (4·48%) patients in the placebo group (hazard ratio [HR] 0·96; 95% CI 0·81-1·13; p=0·6038). Gastrointestinal bleeding events (mostly mild) occurred in 61 (0·97%) patients in the aspirin group versus 29 (0·46%) in the placebo group (HR 2·11; 95% CI 1·36-3·28; p=0·0007). The overall incidence rate of serious adverse events was similar in both treatment groups (n=1266 [20·19%] in the aspirin group vs n=1311 [20·89%] in the placebo group. The overall incidence of adverse events was similar in both treatment groups (n=5142 [82·01%] vs n=5129 [81·72%] in the placebo group). The overall incidence of treatment-related adverse events was low (n=1050 [16·75%] vs n=850 [13·54%] in the placebo group; p<0·0001). There were 321 documented deaths in the intention-to-treat population (n=160 [2·55%] vs n=161 [2·57%] of 6276 patients in the placebo group). The event rate was much lower than expected, which is probably reflective of contemporary risk management strategies, making the study more representative of a low-risk population. The role of aspirin in primary prevention among patients at moderate risk could therefore not be addressed. Nonetheless, the findings with respect to aspirin's effects are consistent with those observed in the previously published low-risk primary prevention studies. Bayer.

Prophylactic Effect of Polaprezinc, a Zinc-L-carnosine, Against Chemotherapy-induced Oral Mucositis in Pediatric Patients Undergoing Autologous Stem Cell Transplantation.

Polaprezinc suspension in sodium alginate (PZ-AG) reduces the incidence and severity of oral mucositis in adult patients receiving radiotherapy or high-dose chemotherapy. In the present study, the prophylactic effect of PZ-AG against oral mucositis was assessed in pediatric patients with hematological malignancies receiving high-dose chemotherapy followed by hematopoietic stem cell transplantation (HSCT). Data of 16 children who underwent HSCT during a period between January 2010 and December 2017 were obtained from medical records and they were retrospectively analyzed. Oral mucositis was evaluated by the WHO scale. Six (37.5%) of 16 children refused to take PZ-AG in a preliminary assessment and they were pretreated with azulene gargle. The remaining 10 (62.5%) patients were pretreated with PZ-AG for prevention of oral mucositis. Grade≥ 3 oral mucositis occurred in 5 (83.3%) of 6 patients receiving azulene gargle, but in 2 (20%) patients who took PZ-AG (p=0.035). The prevalence for the use of opioid analgesics was also significantly lower (30% vs. 100%, p=0.011), while the average duration of total parenteral nutrition use was significantly shorter (11.1 days vs. 24.3 days, p=0.016), in PZ-AG group than in azulene group. On the other hand, PZ-AG had no significant influence on the incidence of other adverse events, mean time to engraftment, or overall survival. PZ-AG was found to be highly effective in preventing oral mucositis in pediatric patients with hematological malignancies receiving high-dose chemotherapy followed by HSCT, as in adult patients.

Interventions for reducing sedentary behaviour in people with stroke

Background Stroke survivors are often physically inactive as well as sedentary,and may sit for long periods of time each day. This increases cardiometabolic risk and has impacts on physical and other functions. Interventions to reduce or interrupt periods of sedentary time, as well as to increase physical activity after stroke, could reduce the risk of secondary cardiovascular events and mortality during life after stroke. Objectives To determine whether interventions designed to reduce sedentary behaviour after stroke, or interventions with the potential to do so, can reduce the risk of death or secondary vascular events, modify cardiovascular risk, and reduce sedentary behaviour. Search methods In December 2019, we searched the Cochrane Stroke Trials Register, CENTRAL, MEDLINE, Embase, CINAHL, PsycINFO, Conference Proceedings Citation Index, and PEDro. We also searched registers of ongoing trials, screened reference lists, and contacted experts in the field. Selection criteria Randomised trials comparing interventions to reduce sedentary time with usual care, no intervention, or waiting-list control, attention control, sham intervention or adjunct intervention. We also included interventions intended to fragment or interrupt periods of sedentary behaviour. Data collection and analysis Two review authors independently selected studies and performed 'Risk of bias' assessments. We analyzed data using random-effects meta-analyses and assessed the certainty of the evidence with the GRADE approach. Main results We included 10 studies with 753 people with stroke. Five studies used physical activity interventions, four studies used a multicomponent lifestyle intervention, and one study used an intervention to reduce and interrupt sedentary behaviour. In all studies, the risk of bias was high or unclear in two or more domains. Nine studies had high risk of bias in at least one domain. The interventions did not increase or reduce deaths (risk difference (RD) 0.00, 95% confidence interval (CI) -0.02 to 0.03; 10 studies, 753 participants; low-certainty evidence), the incidence of recurrent cardiovascular or cerebrovascular events (RD -0.01, 95% CI -0.04 to 0.01; 10 studies, 753 participants; low-certainty evidence), the incidence of falls (and injuries) (RD 0.00, 95% CI -0.02 to 0.02; 10 studies, 753 participants; low-certainty evidence), or incidence of other adverse events (moderate-certainty evidence). Interventions did not increase or reduce the amount of sedentary behaviour time (mean difference (MD) +0.13 hours/day, 95% CI -0.42 to 0.68; 7 studies, 300 participants; very low-certainty evidence). There were too few data to examine effects on patterns of sedentary behaviour. The effect of interventions on cardiometabolic risk factors allowed very limited meta-analysis. Authors' conclusions Sedentary behaviour research in stroke seems important, yet the evidence is currently incomplete, and we found no evidence for beneficial effects. Current World Health Organization (WHO) guidelines recommend reducing the amount of sedentary time in people with disabilities, in general. The evidence is currently not strong enough to guide practice on how best to reduce sedentariness specifically in people with stroke. More high-quality randomised trials are needed, particularly involving participants with mobility limitations. Trials should include longer-term interventions specifically targeted at reducing time spent sedentary, risk factor outcomes, objective measures of sedentary behaviour (and physical activity), and long-term follow-up.

Application of seminal plasma to female genital tract prior to embryo transfer in assisted reproductive technology cycles (IVF, ICSI and frozen embryo transfer).

Application of seminal plasma to female genital tract prior to embryo transfer in assisted reproductive technology cycles (IVF, ICSI and frozen embryo transfer).

The efficacy and safety of linagliptin in elderly patients with type 2 diabetes: a pooled analysis of eight placebo-controlled clinical trials

Objective: To evaluate the efficacy and safety of dipeptidyl peptidase-4 inhibitor, linagliptin, in subjects aged 60 years or older with type 2 diabetes mellitus (T2DM). Methods: Data from eight 24-week, multinational, multicenter, randomized, double-blind, placebo-controlled, parallel-group studies were analyzed. Patients aged 60 years or older with T2DM were received oral linagliptin (5 mg/d) or placebo in combination with metformin, or metformin plus sulfonylurea. Efficacy was assessed by the changes in glycosylated hemoglobin A1c (HbA1c) and fasting plasma glucose (FPG) from baseline to 24 weeks of treatment. Safety endpoint included the frequency and intensity of adverse events. Results: A total of 1 421 patients (placebo 429, linagliptin 992) were included in the full analysis set (FAS). Mean ages of the subjects were (67.4±5.6) years in the linagliptin group and (66.7±5.6) years in the placebo group. Baseline HbA1c was (8.0±0.8) % in the linagliptin group and (8.1±0.9) % in the placebo group. At the end of 24-week, placebo-adjusted reduction in HbA1c in subjects with linagliptin was (0.7±0.1)% (95%CI 0.6-0.8, P<0.000 1), and placebo-adjusted reduction in FPG in subjects with linagliptin was (0.88±0.12) mmol/L(95%CI 0.65-1.11, P<0.000 1). Overall safety and tolerability in the two groups were similar. Adverse events occurred in 57.1% of patients in the placebo group and 61.1% of patients in the linagliptin group, and the incidence of adverse events leading to discontinuation was 3.2% in the placebo group and 3.8% in the linagliptin group. Serious adverse events occurred in 1.6% of patients in the placebo group and 2.8% of patients in the linagliptin group. Investigator-defined hypoglycaemia occurred in 7.3% of patients in the placebo group and 11.9% of patients in the linagliptin group. Among them, most were mild or moderate hypoglycaemia, and severe hypoglycaemia only occurred in 0.2% of patients in the placebo and 0.5% in the linagliptin groups. Overall incidence of hypoglycaemia in linagliptin group was slightly higher than that in placebo group, which might be due to the fact that more patients were taking sulfonylureas in linagliptin group than in placebo group (26.8% linagliptin; 18.4% placebo). No difference could be viewed in hypoglycaemia between the two groups in patients without sulfonylureas (1.2% linagliptin, 1.1% placebo). Moreover, no severe hypoglycaemia was reported in subjects without sulfonylureas. The incidences of other adverse events were similar in both groups. Conclusion: Linagliptin was efficacious in lowering glucose with a safety profile similar to placebo in type 2 diabetic patients aged 60 years or older.

The efficacy and safety of sugammadex for reversing postoperative residual neuromuscular blockade in pediatric patients: A systematic review

The aim of this study is to evaluate the efficacy and safety of sugammadex for reversing neuromuscular blockade in pediatric patients. MEDLINE and other three Databases were searched. Randomized clinical trials were included if they compared sugammadex with neostigmine or placebo in pediatric patients undergoing surgery involving the use of rocuronium or vecuronium. The primary outcome was the time interval from administration of reversal agents to train-of-four ratio (TOFr, T4/T1) > 0.9. Incidences of any drug-related adverse events were secondary outcomes. Trial inclusion, data extraction, and risk of bias assessment were performed independently. Mean difference and relative risk were used as summary statistics with random effects models. Statistical heterogeneity was assessed by the I2 statistic. Funnel plot was used to detect publication bias. Ten studies with 580 participants were included. Although considerable heterogeneity (I2 = 98.5%) was detected in primary outcome, the results suggested that, compared with placebo or neostigmine, sugammadex can reverse rocuronium-induced neuromuscular blockade more rapidly with lower incidence of bradycardia. No significant differences were found in the incidences of other adverse events. Compared with neostigmine or placebo, sugammadex may reverse rocuronium-induced neuromuscular blockade in pediatric patients rapidly and safely.

Once-weekly dipeptidyl peptidase-4 inhibitors for type 2 diabetes: a systematic review and meta-analysis

ABSTRACTObjective: To assess the efficacy and safety of omarigliptin and trelagliptin, novel dipeptidyl peptidase-4 inhibitors administered once-weekly (DPP-4i QW).Methods: We systematically searched for placebo- and active-controlled randomized trials in adults with type 2 diabetes mellitus.Results: Fifteen primary studies with 5709 participants were included. DPP-4i QW were more effective than placebo in reducing hemoglobin A1c (HbA1c) (Weighted Mean Difference (WMD) −0.63%; 95% CI −0.80, −0.46; I2 = 84%) and had a similar glucose-lowering effect with daily DPP-4i (WMD 0.01%; −0.08, 0.11%; I2 = 34%). Omarigliptin was less effective compared with oral antidiabetic agents, other than daily DPP-4i, (WMD 0.24%; 0.10, 0.38; I2 = 12%). Omarigliptin did not affect body weight (WMD versus placebo 0.60 kg; 0.25, 0.96; I2 = 0%). Risk for any hypoglycemia was similar between DPP-4i QW and placebo (Odds Ratio 1.32; 0.78, 2.22; I2 = 0%). Incidence of other adverse events did not differ between DPP-4i QW and control.Conclusions: DPP-4i QW were superior to placebo and similar to daily DPP-4i in terms of glycemic control, and were not associated with any specific adverse events. There is limited comparative effectiveness evidence against other agents, while their effect on hard clinical safety outcomes is unknown.

The Efficacy and Safety of Iodine-125 Brachytherapy Combined with Chemotherapy in Treatment of Advanced Lung Cancer: A Meta-Analysis.

The aim of this study was to systematically review the efficacy and safety of iodine-125 brachytherapy combined with chemotherapy in patients with advanced lung cancer. PubMed, MEDLINE, EBSCO, FMJS and Web of Science were searched to obtain randomized controlled trials (RCTs), published in English and Chinese, until February 2016. The evaluating indicators were complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), overall response rate (ORR), disease control rate (DCR), one-year overall survival, two-year overall survival and adverse events. Revman 5.2 software was used for data syntheses and analyses. A total of 296 patients enrolled in 5 RCTs were ultimately included in this study based on our selection criteria, and 150 patients received chemotherapy alone, while another 146 patients received the combination therapy of iodine-125 brachytherapy and chemotherapy. The results showed that iodine-125 brachytherapy combined with chemotherapy was superior to chemotherapy alone in CR (risk ratio [RR] = 3.66, 95% confidence interval [CI]: 2.08 to 6.44, p<0.001), PR (RR = 1.47, 95% CI: 1.16 to 1.86, p=0.001), ORR (RR = 1.85, 95% CI: 1.54 to 2.22, p<0.001), DCR (RR = 1.19, 95% CI: 1.10 to 1.29, p<0.001), one-year overall survival (RR = 1.46, 95% CI: 1.12 to 1.92, p=0.006) and PD (RR = 0.20, 95% CI: 0.09 to 0.43, p<0.001); meanwhile, there was no significant difference in two-year overall survival (RR = 1.30, 95% CI: 0.72 to 2.37, p=0.39). In terms of adverse events, the combination therapy significantly increased the incidence of neumothorax (RR = 4.93, 95% CI: 1.94 to 12.55, p=<0.001); however, no significant differences were found in the incidence of other adverse events. This study indicated that the combination therapy of iodine-125 brachytherapy and chemotherapy could improve the therapeutic efficacy of advanced lung cancer without increasing the incidence of adverse events, except pneumothorax.

TG02, an Oral CDK9-Inhibitor, in Combination with Carfilzomib Demonstrated Objective Responses in Carfilzomib Refractory Multiple Myeloma Patients

Introduction: TG02 is an orally-bioavailable, multikinase inhibitor where the primary mechanism of action is through CDK9-dependent depletion of oncoproteins such as Mcl-1 and MYC. Safety and efficacy results for multiple myeloma (MM) patients (pts) enrolled in this ongoing phase 1b study are presented. CDK9 inhibition potently suppresses Mcl-1 to induce durable apoptotic responses in lymphoma (Gregory GP, Leukemia, 2015). CDK9 dependence may represent a druggable vulnerability in lymphomas and myelomas with dysregulated MYC expression, although inhibition of both CDK9 and MYC/BRD4 may be required for apoptosis (Lu H et al, Elife, 2015).Methods: This open-label Phase 1b study enrolled MM pts that previously received ≥2 lines of therapy. The primary objective was to determine the maximum tolerated dose (MTD) of TG02 in combination with carfilzomib (TG02/CFZ); key secondary objectives were anti-tumor activity and safety. TG02 was administered once daily on days 1, 4, 8, 11, 15, 18 of a 28-day schedule (BIW). The TG02 starting dose was 150 mg; TG02 dosing was escalated in 50 mg increments up to 300 mg. CFZ was dosed according to the Prescribing Information. Responses were assessed using standard criteria.Results: Fourteen pts were enrolled for dose escalation and 10 pts were enrolled for the MTD cohort expansion. Patients were heavily pretreated: median 6 previous treatments [min 3; max 15] and 92% pts received CFZ in a prior regimen. Best response to previous therapy was progressive disease in 46% pts. The MTD was 250 mg TG02 combined with CFZ. Two dose-limiting toxicities were observed (including Grade (Gr) 4 sepsis and Gr 4 neutropenia), both on the 300 mg cohort. The most common drug-related adverse events (AEs) were diarrhea (Gr 1-2: 71% Gr 3: 17%), nausea (Gr 1-2: 79%), vomiting (Gr 1-2: 50%), fatigue (Gr 1-2: 38%, Gr 3: 4%), anorexia (Gr 1: 21%), anemia (Gr 1-2: 4%, Gr 3: 17%) and thrombocytopenia (Gr 3: 8%, Gr 4: 13%). Six patients (25%) discontinued treatment due to an AE. Serious AEs occurred in 50% pts; only acute renal failure and febrile neutropenia occurred in >1 pt (8% each). The severity of AEs was similar to single agent TG02. The incidence of diarrhea was increased in the TG02/CFZ administration (88% vs 67%) but the incidence of other AEs was similar to single agent TG02. Fourteen pts administered TG02 at the MTD were evaluable for response. The overall response rate (≥PR) was 27%; the clinical benefit rate (≥MR) was 45% (1 very good partial response, 2 partial response and 2 minimal response). All responders (MR or better) were CFZ-refractory in a previous treatment regimen. Durable stable disease was observed in 27% pts.Conclusions: The safety profile of TG02 BIW/CFZ was similar to that of TG02 alone. The most common drug-related AEs were diarrhea, nausea, and vomiting; grade 4 AEs were infrequent. Additional measures will be taken to improve gastrointestinal tolerability. Objective responses were observed in CFZ-refractory pts. Enrollment of CFZ-refractory pts administered TG02 on a once-weekly schedule in combination with CFZ is continuing. Based on promising preclinical data, analysis of Mcl-1 and MYC expression and correlation to clinical outcome will be performed. DisclosuresBerdeja:MEI: Research Funding; Curis: Research Funding; BMS: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Janssen: Research Funding; Onyx: Research Funding; Takeda: Research Funding; Acetylon: Research Funding; Celgene: Research Funding; Array: Research Funding. Abonour:Celgene: Research Funding, Speakers Bureau.

Comparative meta-analysis of balloon-expandable and self-expandable valves for transcatheter aortic valve replacement

BackgroundBalloon-expandable valves (BEVs) and self-expandable valves (SEVs) are two major types of valves utilized for transcatheter aortic valve replacement (TAVR). We conducted a meta-analysis of available studies to compare the safety and efficacy of these two valve types. MethodsMedline search was conducted using standard search terms to determine eligible studies. Primary outcomes of the meta-analysis included death and stroke at 30days and 1year. Pooled estimates of procedural outcomes were also compared between the valve types. Analysis was performed for entire cohort and separately for patients undergoing transfemoral TAVR (TF-TAVR). ResultsAnalysis of entire cohort revealed similar 30-day mortality in the SEV and BEV cohorts. There was no significant difference in the incidence of stroke at 30days between the two study groups. Both pooled comparisons demonstrated a significant heterogeneity with I2>50%, necessitating the use of random effect modeling. We observed a significantly higher incidence of new pacemaker implantation, aortic regurgitation≥2+ at 30days, valve embolization, and need for >1 valve following SEV implantation compared with BEV implantation. Analysis of TF-TAVR cohort showed higher 30day [IRR (95% CI): 1.34 (1.19–1.52)] but a similar 1-year mortality [IRR (95% CI): 1.07 (0.96–1.19)] for SEV compared to BEV implantation. ConclusionCompared to BEV implantation, SEV implantation was associated with a similar risk of mortality and stroke at 30-day and 1-year follow-up duration. Analysis of the TF-TAVR cohort revealed a significantly higher mortality at 30days among patients undergoing SEV implantation, compared with BEV implantation. In addition, there was a significantly higher incidence of other adverse events noted above, following SEV implantation, compared with BEV implantation.

Patient controlled opioid analgesia versus non-patient controlled opioid analgesia for postoperative pain.

This is an updated version of the original Cochrane review published in Issue 4, 2006. Patients may control postoperative pain by self administration of intravenous opioids using devices designed for this purpose (patient controlled analgesia or PCA). A 1992 meta-analysis by Ballantyne et al found a strong patient preference for PCA over non-patient controlled analgesia, but disclosed no differences in analgesic consumption or length of postoperative hospital stay. Although Ballantyne's meta-analysis found that PCA did have a small but statistically significant benefit upon pain intensity, a 2001 review by Walder et al did not find statistically significant differences in pain intensity or pain relief between PCA and groups treated with non-patient controlled analgesia. To evaluate the efficacy and safety of patient controlled intravenous opioid analgesia (termed PCA in this review) versus non-patient controlled opioid analgesia of as-needed opioid analgesia for postoperative pain relief. We ran the search for the previous review in November 2004. For this update, we searched the Cochrane Central Register of Controlled Trials (CENTRAL 2014, Issue 12), MEDLINE (1966 to 28 January 2015), and EMBASE (1980 to 28 January 2015) for randomized controlled trials (RCTs) in any language, and reference lists of reviews and retrieved articles. We selected RCTs that assessed pain intensity as a primary or secondary outcome. These studies compared PCA without a continuous background infusion with non-patient controlled opioid analgesic regimens. We excluded studies that explicitly stated they involved patients with chronic pain. Two review authors independently extracted data, which included demographic variables, type of surgery, interventions, efficacy, and adverse events. We graded each included study for methodological quality by assessing risk of bias and employed the GRADE approach to assess the overall quality of the evidence. We performed meta-analysis of outcomes that included pain intensity assessed by a 0 to 100 visual analog scale (VAS), opioid consumption, patient satisfaction, length of stay, and adverse events. Forty-nine studies with 1725 participants receiving PCA and 1687 participants assigned to a control group met the inclusion criteria. The original review included 55 studies with 2023 patients receiving PCA and 1838 patients assigned to a control group. There were fewer included studies in our updated review due to the revised exclusion criteria. For the primary outcome, participants receiving PCA had lower VAS pain intensity scores versus non-patient controlled analgesia over most time intervals, e.g., scores over 0 to 24 hours were nine points lower (95% confidence interval (CI) -13 to -5, moderate quality evidence) and over 0 to 48 hours were 10 points lower (95% CI -12 to -7, low quality evidence). Among the secondary outcomes, participants were more satisfied with PCA (81% versus 61%, P value = 0.002) and consumed higher amounts of opioids than controls (0 to 24 hours, 7 mg more of intravenous morphine equivalents, 95% CI 1 mg to 13 mg). Those receiving PCA had a higher incidence of pruritus (15% versus 8%, P value = 0.01) but had a similar incidence of other adverse events. There was no difference in the length of hospital stay. Since the last version of this review, we have found new studies providing additional information. We reanalyzed the data but the results did not substantially alter any of our previously published conclusions. This review provides moderate to low quality evidence that PCA is an efficacious alternative to non-patient controlled systemic analgesia for postoperative pain control.