Benmelstobart, anlotinib and chemotherapy in extensive-stage small-cell lung cancer: a randomized phase 3 trial.

Immunochemotherapy is the first-line standard for extensive-stage small-cell lung cancer (ES-SCLC). Combining the regimen with anti-angiogenesis may improve efficacy. ETER701 was a multicenter, double-blind, randomized, placebo-controlled phase 3 trial that investigated the efficacy and safety of benmelstobart (a novel programmed death-ligand 1 (PD-L1) inhibitor) with anlotinib (a multi-target anti-angiogenic small molecule) and standard chemotherapy in treatment-naive ES-SCLC. The ETER701 trial assessed two primary endpoints: Independent Review Committee-assessed progression-free survival per RECIST 1.1 and overall survival (OS). Here the prespecified final progression-free survival and interim OS analysis is reported. Patients randomly received benmelstobart and anlotinib plus etoposide/carboplatin (EC; n = 246), placebo and anlotinib plus EC (n = 245) or double placebo plus EC ('EC alone'; n = 247), followed by matching maintenance therapy. Compared with EC alone, median OS was prolonged with benmelstobart and anlotinib plus EC (19.3 versus 11.9 months; hazard ratio 0.61; P = 0.0002), while improvement of OS was not statistically significant with anlotinib plus EC (13.3 versus 11.9 months; hazard ratio 0.86; P = 0.1723). The incidence of grade 3 or higher treatment-related adverse events was 93.1%, 94.3% and 87.0% in the benmelstobart and anlotinib plus EC, anlotinib plus EC, and EC alone groups, respectively. This study of immunochemotherapy plus multi-target anti-angiogenesis as first-line treatment achieved a median OS greater than recorded in prior randomized studies in patients with ES-SCLC. The safety profile was assessed as tolerable and manageable. Our findings suggest that the addition of anti-angiogenesis therapy to immunochemotherapy may represent an efficacious and safe approach to the management of ES-SCLC. ClinicalTrials.gov identifier: NCT04234607 .

The Effects of Drug Exposure and Single Nucleotide Polymorphisms on Aaptinib-Induced Severe Toxicities in Solid Tumors.

To investigate the value of drug exposure and host germline genetic factors in predicting apatinib (APA)-related toxicities. METHOD: In this prospective study, plasma APA concentrations were quantified using liquid chromatography with tandem mass spectrometry, and 57 germline mutations were genotyped in 126 advanced solid tumor patients receiving 250 mg daily APA, a vascular endothelial growth factor receptor II inhibitor. The correlation between drug exposure, genetic factors, and the toxicity profile was analyzed. RESULTS: Non-small cell lung cancer (NSCLC) was more prone to APA-related toxicities and plasma concentrations of APA, and its main metabolite M1-1 could be associated with high-grade adverse events (AEs) (P < 0.01; M1-1, P < 0.01) and high-grade antiangiogenetic toxicities (APA, P = 0.034; P < 0.05), including hypertension, proteinuria, and hand-foot syndrome, in the subgroup of NSCLC. Besides, CYP2C9 rs34532201 TT carriers tended to have higher levels of APA (P < 0.001) and M1-1 (P < 0.01), whereas CYP2C9 rs1936968 GG carriers were predisposed to higher levels of M1-1 (P < 0.01). CONCLUSION: Plasma APA and M1-1 exposures were able to predict severe AEs in NSCLC patients. Dose optimization and drug exposure monitoring might need consideration in NSCLC patients with CYP2C9 rs34532201 TT and rs1936968 GG. SIGNIFICANCE STATEMENT: Apatinib is an anti-VEGFR2 inhibitor for the treatment of multiple cancers. Though substantial in response, apatinib-induced toxicity has been a critical issue that is worth clinical surveillance. Few data on the role of drug exposure and genetic factors in apatinib-induced toxicity are available. Our study demonstrated a distinct drug-exposure relationship in NSCLC but not other tumors and provided invaluable evidence of drug exposure levels and single nucleotide polymorphisms as predictive biomarkers in apatinib-induced severe toxicities.

Downregulation of the circadian rhythm regulator HLF promotes multiple-organ distant metastases in non-small cell lung cancer through PPAR/NF-κb signaling.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death due to its early recurrence and widespread metastatic potential. Accumulating studies have reported that dysregulation of circadian rhythms-associated regulators is implicated in the recurrence and metastasis of NSCLC. Therefore, identification of metastasis-associated circadian rhythm genes is clinically necessary. Here we report that the circadian gene hepatic leukemia factor (HLF), which was dramatically reduced in early-relapsed NSCLC tissues, was significantly correlated with early progression and distant metastasis in NSCLC patients. Upregulating HLF inhibited, while silencing HLF promoted lung colonization, as well as metastasis of NSCLC cells to bone, liver and brain in vivo. Importantly, downexpression of HLF promoted anaerobic metabolism to support anchorage-independent growth of NSCLC cells under low nutritional condition by activating NF-κB/p65 signaling through disrupting translocation of PPARα and PPARγ. Further investigations revealed that both genetic deletion and methylation contribute to downexpression of HLF in NSCLC tissues. In conclusion, our results shed light on a plausible mechanism by which HLF inhibits distant metastasis in NSCLC, suggesting that HLF may serve as a novel target for clinical intervention in NSCLC.

Randomized, Multicenter Study of Gefitinib Dose-escalation in Advanced Non-small-cell Lung Cancer Patients Achieved Stable Disease after One-month Gefitinib Treatment.

There is no consensus on the optimal treatment for patients with advanced non-small-cell lung cancer (NSCLC) and stable disease (SD) after gefitinib therapy. This randomized, open-label, multicenter study aimed to explore whether dose-escalation of gefitinib would improve response and survival in NSCLC patients who achieved SD after one-month of standard gefitinib dosage. Between May 2009 and January 2012, 466 patients were enrolled and 100 eligible patients were randomized (1:1) to receive either a higher dose (500 mg/d; H group) or to continue standard dose (250 mg/d; S group) of gefitinib. Objective response rate (ORR) was similar between the two groups (12.5% vs 12.5%, p = 1.000). There were no significant differences regarding progression-free survival (PFS) and overall survival (OS) between both arms (H group vs S group: median PFS, 5.30 months vs 6.23 months, p = 0.167; median OS, 13.70 months vs 18.87 months, p = 0.156). Therefore, dose-escalation of gefitinib does not confer a response or survival advantage in patients who achieve SD with one month of standard-dose gefitinib treatment.

Common Diagnoses and Outcomes in Elderly Patients Who Present to the Emergency Department with Non-Specific Complaints.

OBJECTIVE: Elderly patients often present to the emergency department (ED) with non-specific complaints. Previous studies indicate that such patients are at greater risk for life-threatening illnesses than similarly aged patients with specific complaints. We evaluated the diagnoses and outcomes of elderly patients presenting with non-specific complaints. METHODS: Two trained data abstractors independently reviewed all records of patients over 70 years old presenting (to two academic EDs) with non-specific complaints, as defined by the Canadian Emergency Department Information System (CEDIS). Outcomes of interest were ED discharge diagnosis, hospital admission, length of stay, and ED revisit within 30 days. RESULTS: Of the 743 patients screened for the study, 265 were excluded because they had dizziness, vertigo, or a specific complaint recorded in the triage notes. 419 patients (87.7%) presented with weakness and 59 patients (12.3%) presented with general fatigue or unwellness. The most common diagnoses were urinary tract infection (UTI) (11.3%), transient ischemic attack (TIA) (10.0%), and dehydration (5.6%). There were 11 hospital admissions with median length of stay of five days. Eighty-one (16.9%) patients revisited the ED within 30 days of discharge. Regression analysis indicated that arrival to the ED by ambulance was independently associated with hospital admission. CONCLUSIONS: Our results suggest that elderly patients presenting to the ED with non-specific complaints are not at high risk for life-threatening illnesses. The most common diagnoses are UTI, TIA, and dehydration. Most patients can be discharged safely, although a relatively high proportion revisit the ED within 30 days.

Predictors of admission to hospital of patients triaged as nonurgent using the Canadian Triage and Acuity Scale.

OBJECTIVES: To identify factors known prior to triage that might have predicted hospital admission for patients triaged by the Canadian Triage Acuity Scale (CTAS) as level 5 (CTAS 5, nonurgent) and to determine whether inappropriate triage occurred in the admitted CTAS 5 patients. METHODS: We reviewed the triage records of patients triaged as CTAS 5 at the emergency departments (EDs) of three tertiary care hospitals between April 2002 and September 2009. Two triage nurses unaware of the study objective independently assigned the CTAS level in 20% of randomly selected CTAS 5 patients who were admitted. We used the kappa statistic (κ) to measure the agreement among the raters in CTAS level between the assessment of the research nurses and the original triage assessment and regression analysis to identify independent predictors of admission to hospital. RESULTS: Of the 37,416 CTAS 5 patients included in this study, 587 (1.6%) were admitted. Agreement on CTAS assignment in CTAS 5 patients who were admitted was κ -0.9, (95% confidence interval [CI] -0.96 to -0.84). Age over 65 (odds ratio [OR] 5.46, 95% CI 4.57 to 6.53) and arrival by ambulance (OR 7.42, 95% CI 6.15 to 8.96) predicted hospital admission in CTAS 5 patients. CONCLUSIONS: Most of the CTAS 5 patients who were subsequently admitted to hospital may have qualified for a higher triage category. Two potential modifiers, age over 65 and arrival by ambulance, may have improved the prediction of admission in CTAS 5 patients. However, the consistent application of existing CTAS criteria may also be important to prevent incorrect triage.

The SCRAP Rule: The derivation and internal validation of a clinical decision rule for computed tomography of the chest in blunt thoracic trauma.

OBJECTIVE: To derive and internally validate a clinical decision rule that will rule out major thoracic injury in adult blunt trauma patients, reducing the unnecessary use of chest computed tomographic (CT) scans. METHODS: Data were retrospectively obtained from a chart review of all trauma patients presenting to a Canadian tertiary trauma care centre from 2005 to 2008, with those from April 2006 to March 2007 being used for the validation phase. Patients were included if they had an Injury Severity Score > 12 and chest CT at admission or a documented major thoracic injury noted in the trauma database. Patients with penetrating injury, a Glasgow Coma Scale (GCS) score ≤ 8, paralysis, or age < 16 years were excluded. RESULTS: There were 434 patients in the derivation group and 180 in the validation group who met the inclusion criteria. Using recursive partitioning, five clinical variables were found to be particularly predictive of injury. When these variables were normal, no patients had a major thoracic injury (sensitivity 100% [95% CI 98.4-100], specificity 46.9% [95% CI 44.2-46.9], and negative likelihood ratio 0.00 [95% CI 0.00-0.04]). The five variables were oxygen saturation (< 95% on room air or < 98% on any supplemental oxygen), chest radiograph, respiratory rate ≥ 25, chest auscultation, and thoracic palpation (SCRAP). In the validation group, the same five variables had a sensitivity of 100% (95% CI 96.2-100%), a specificity of 44.7% (95% CI 39.5-44.7%), and negative likelihood ratio of 0.00 (95% CI 0.00-0.10). CONCLUSIONS: In major blunt trauma with a GCS score > 8, the SCRAP variables have a 100% sensitivity for major thoracic injury in this retrospective study. These findings need to be prospectively validated prior to use in a clinical setting.

Palatability, adherence and prescribing patterns of antiretroviral drugs for children with human immunodeficiency virus infection in Canada.

PURPOSE: To assess the impact of perceived palatability of antiretroviral drugs on adherence to therapy of children infected by human immunodeficiency virus and on prescribing patterns by their caring physicians. DESIGN: Two arms--retrospective chart review and a cross-sectional survey. SETTING: Tertiary-care pediatric human immunodeficiency virus clinic during a 17-year period. PARTICIPANTS: Children with human immunodeficiency virus infection and physicians actively caring for children with human immunodeficiency virus infection in seven provinces in Canada were surveyed regarding their perception of the palatability of 8-liquid and 15 non-liquid antiretroviral medications and its effect on drug selection. MAIN OUTCOME MEASURE: Effect of taste preferences of antiretroviral drugs on adherence to treatment by infected children and on drug selection by their caring physicians. RESULTS: Forty of 119 children (34%) refused at least once to an antiretroviral medication. In 5%, treatment was discontinued because of poor palatability. Ritonavir was the least palatable drug (50% of children; p = 0.01). Ritonavir use (OR 4.80 [95%CI 1.34-17.20]) and male gender (OR 7.25 [95%CI 2.30-22.90]) were independent predictors of drug discontinuation because of poor taste. Physicians also perceived liquid ritonavir as the least palatable (p = 0.01) and the most likely to be discontinued (p = 0.01). However, they commonly prescribed it as first-line therapy (p = 0.06). CONCLUSIONS: A third of children infected with human immunodeficiency virus fail to adhere to their treatment because of poor drug taste. Physicians are aware of that, but this does not prevent them from selecting the least palatable drugs as first-line therapy.

Improving diabetes management: structured clinic program for Canadian primary care.

PROBLEM BEING ADDRESSED: Adherence to diabetes treatment guidelines is often poor in primary care. OBJECTIVE OF PROGRAM: To introduce simple accessible interventions in our clinic to improve both physicians' adherence to diabetes treatment guidelines and patient outcomes. PROGRAM DESCRIPTION: A physician and a nurse practitioner used 3 interventions for diabetes care: 30-minute appointments, reminder telephone calls to patients, and standardized flow sheets. Evaluation of this structured program found that, after 3 years, these interventions had improved primary caregivers' adherence to diabetes care guidelines and several physiologic parameters in patients with diabetes (compared with outcomes of patients managed with the usual less structured approach). CONCLUSION: This program improved delivery of diabetes care in our clinic. We believe a similar approach could help other physicians and nurse practitioners in primary care practices increase their adherence to guidelines and improve the clinical outcomes of their patients.

Increased adverse drug reactions to antimicrobials and anticonvulsants in patients with HIV infection.

OBJECTIVE: To review the incidence, signs, symptoms, and mechanisms of adverse drug reactions (ADRs) to sulfonamides, anticonvulsants, and antimycobacterial medications among people with HIV. DATA SOURCES: Searches of MEDLINE/PubMed (1980-November 2005) and National Library of Medicine Meeting Abstracts (1989-November 2005), as well as hand searches of journals and abstracts, were conducted to identify primary literature. Reference lists were reviewed to identify additional relevant reports. STUDY SELECTION AND DATA EXTRACTION: Relevant articles and abstracts, particularly of in vitro experiments and clinical studies, were compiled and reviewed. DATA SYNTHESIS: ADRs, especially in HIV-infected patients, are a cause for concern. Sulfonamides, anticonvulsants, and antimycobacterial drugs are commonly used to prevent and treat complications of HIV, including seizures and opportunistic infections. Patients with HIV have a much greater rate of ADRs to these drug classes, including severe and life-threatening hypersensitivity reactions. Several mechanisms of these ADRs have been postulated. Sulfamethoxazole and anticonvulsant hypersensitivity may involve the increased formation and decreased detoxification of reactive metabolites. The mechanisms for the marked increase in hypersensitivity ADRs to antimycobacterial drugs may be related to an altered immune profile in patients infected with both tuberculosis and HIV. CONCLUSIONS: ADRs to antimicrobial and anticonvulsant therapy cause markedly increased morbidity and mortality in HIV-positive patients. Further research involving the interaction between HIV and the increased ADRs to these drugs is required.

[A randomized clinical trial on taxol plus oxaliplatin versus taxol plus cisplatin as first-line treatment in advanced non-small cell lung cancer].

BACKGROUND: Paclitaxel plus cisplatin is an effective regimen in the treatment of non-small cell lung cancer (NSCLC), but it has severe adverse toxicities. The aim of this clinical trial is to evaluate the effect and safety of paclitaxel plus oxaliplatin compared with paclitaxel plus cisplatin in the treatment of advanced NSCLC. METHODS: From January, 2002 to October, 2004, 83 initially treated patients with advanced NSCLC were randomized into two groups: the trial group was treated with paclitaxel 175mg/m², and oxaliplatin 130mg/m² on day 1;and the control group was treated with paclitaxel 175mg/m² and cisplatin 80mg/m² on day 1. Both of them were repeated every 21 days and 2-6 cycles were given to patients. The evaluation of efficacy and safety was performed after chemotherapy regularly. RESULTS: All patients were evaluable and received 2 cycles chemotherapy at least. The response rate of the trial group and control group was 34.1% (14/41) and 33.3% (14/42) respectively, median time to progression of them was 6.0 months and 5.5 months, median survival time was 10.7 months and 10.5 months, 1-year survival was 39.0% (16/41) and 40.5% (17/42) respectively. The following adverse effects of the two groups were different: the incidence rate of III+IV leukopenia was 4.9% and 28.6% in the trial group and the control group respectively, III+IV thrombocytopemia was 0 and 14.3%, III+IV nausea and vomiting was 7.3% and 26.2%. The difference of the incidence rate of III+IV nerve abnormality (9.8% and 9.5%), imparied renal function (0 and 7.1%), myalgia and anthralgia (0 and 2.4%) was insignificant. CONCLUSIONS: The regimen of paclitaxel plus oxaliplatin have the similar efficacy and less adverse toxicities as compared to Paclitaxel plus Cisplatin in treatment of advanced NSCLC.