Summary Evidence suggests that platinum-based regimens confer a better survival in patients with non-small cell lung carcinoma (NSCLC). However, evidence is lacking regarding the specific effects of ...cisplatin or carboplatin when compared to non-platinum-based doublets. Methods Meta-analysis of all randomized trials comparing non-platinum-based with platinum-based doublet regimens given as first-line treatment for NSCLC. Relative risks were calculated for all outcomes ascertained. Sensitivity analysis, using methodological quality of the trials and different measures of effect, was undertaken. Results Seventeen trials, comprising 4920 patients were included. The use of platinum-based doublet regimens was associated with a slightly higher survival at 1 year (RR = 1.08, 95% CI 1.01–1.16, p = 0.03), better partial response (RR = 1.11, 95% CI 1.02–1.21, p = 0.02), with a higher risk of anemia, nausea, and neurotoxicity. Cisplatin-based doublet regimens improved survival at 1 year (RR = 1.16, 95% CI 1.06–1.27, p = 0.001), complete response (RR = 2.29, 95% CI 1.08–4.88, p = 0.03), partial response (RR = 1.19, 95% CI 1.07–1.32, p = 0.002) with an increased risk of anemia, neutropenia, neurotoxicity and nausea. Conversely, carboplatin-based doublet regimens did not increase survival rate at 1 year (RR = 0.95, 95% CI 0.85–1.07, p = 0.43). There was a statistically significant difference between the effect of cisplatin compared to carboplatin ( p = 0.05). Carboplatin-based doublet regimen included a higher risk of anemia and thrombocytopenia, but no increased nausea and/or vomiting, contrarily to cisplatin. Sensitivity analyses showed that the results were robust to the exclusion of lesser quality trials and the choice of the measure of effect. Conclusion We provide additional evidence that cisplatin, but not carboplatin-based doublet regimens are associated with a slightly better survival compared to non-platinum-based doublet regimens. Side effects of cisplatin- and carboplatin-based regimens differ between each other and when compared to non-platinum doublets. Although this analysis has limitations, it may provide valuable information to clinicians when choosing the appropriate regimen for patients with non-small cell lung cancer.
Atacicept is a soluble, fully human, recombinant fusion protein that inhibits B cell-stimulating factors APRIL (a proliferation-inducing ligand) and BLyS (B-lymphocyte stimulator). The APRIL- LN ...study aimed to evaluate the efficacy and safety of atacicept in patients with active lupus nephritis (LN), receiving newly initiated corticosteroids (CS) and mycophenolate mofetil (MMF).
This was a randomized, double-blind, placebo-controlled Phase II/III, 52-week study. At screening (Day -14), patients initiated high-dose CS (the lesser of 0.8 mg/kg/day or 60 mg/day prednisone) and MMF (1 g daily, increased by 1 g/day each week to 3 g daily). From Day 1, atacicept (150 mg, subcutaneously, twice weekly for 4 weeks, then weekly) was initiated with MMF along with a tapered dose of CS.
The trial was terminated after the enrollment of six patients, due to an unexpected decline in serum immunoglobulin G (IgG) and the occurrence of serious infections. Efficacy was thus not evaluated. By Day 1, serum IgG levels had declined substantially in patients then randomized to atacicept (n = 4) compared with placebo (n = 2). Patients receiving atacicept also had more severe proteinuria on Day -14 than those on placebo. Lymphocyte counts were low at screening in all patients. IgG decline continued following initiation (Day 1) of atacicept. Three atacicept-treated patients developed serum IgG below the protocol-defined discontinuation threshold of 3 g/l, two of whom developed serious pneumonia.
Future studies are needed to characterize the safety, efficacy, and pharmacodynamic response of atacicept in LN patients.
ClinicalTrials.gov: NCT00573157.
Maintaining therapeutic concentrations of drugs with a narrow therapeutic window is a complex task. Several computer systems have been designed to help doctors determine optimum drug dosage. ...Significant improvements in health care could be achieved if computer advice improved health outcomes and could be implemented in routine practice in a cost effective fashion. This is an updated version of an earlier Cochrane systematic review, by Walton et al, published in 2001.
To assess whether computerised advice on drug dosage has beneficial effects on the process or outcome of health care.
We searched the Cochrane Effective Practice and Organisation of Care Group specialized register (June 1996 to December 2006), MEDLINE (1966 to December 2006), EMBASE (1980 to December 2006), hand searched the journal Therapeutic Drug Monitoring (1979 to March 2007) and the Journal of the American Medical Informatics Association (1996 to March 2007) as well as reference lists from primary articles.
Randomized controlled trials, controlled trials, controlled before and after studies and interrupted time series analyses of computerized advice on drug dosage were included. The participants were health professionals responsible for patient care. The outcomes were: any objectively measured change in the behaviour of the health care provider (such as changes in the dose of drug used); any change in the health of patients resulting from computerized advice (such as adverse reactions to drugs).
Two reviewers independently extracted data and assessed study quality.
Twenty-six comparisons (23 articles) were included (as compared to fifteen comparisons in the original review) including a wide range of drugs in inpatient and outpatient settings. Interventions usually targeted doctors although some studies attempted to influence prescriptions by pharmacists and nurses. Although all studies used reliable outcome measures, their quality was generally low. Computerized advice for drug dosage gave significant benefits by:1.increasing the initial dose (standardised mean difference 1.12, 95% CI 0.33 to 1.92)2.increasing serum concentrations (standradised mean difference 1.12, 95% CI 0.43 to 1.82)3.reducing the time to therapeutic stabilisation (standardised mean difference -0.55, 95%CI -1.03 to -0.08)4.reducing the risk of toxic drug level (rate ratio 0.45, 95% CI 0.30 to 0.70)5.reducing the length of hospital stay (standardised mean difference -0.35, 95% CI -0.52 to -0.17).
This review suggests that computerized advice for drug dosage has some benefits: it increased the initial dose of drug, increased serum drug concentrations and led to a more rapid therapeutic control. It also reduced the risk of toxic drug levels and the length of time spent in the hospital. However, it had no effect on adverse reactions. In addition, there was no evidence to suggest that some decision support technical features (such as its integration into a computer physician order entry system) or aspects of organization of care (such as the setting) could optimise the effect of computerised advice.
To determine the diagnostic yield of a standardized sequential evaluation of patients with syncope in a primary care teaching hospital.
All consecutive patients who presented to the emergency ...department with syncope as a chief complaint were enrolled. Their evaluation included initial and routine clinical examination, including carotid sinus massage, as well as electrocardiography and basic laboratory testing. Targeted tests, such as echocardiography, were used when a specific entity was suspected clinically. Other cardiovascular tests (24-hour Holter monitoring, ambulatory loop recorder ECG, upright tilt test, and signal-averaged electrocardiography) were performed in patients with unexplained syncope after the initial steps. Electrophysiologic studies were performed in selected patients only as clinically appropriate. Follow-up information on recurrence and mortality were obtained every 6 months for as long as 18 months for 94% (n = 611) of the patients.
After the initial clinical evaluation, a suspected cause of syncope was found in 69% (n = 446) of the 650 patients, including neurocardiogenic syncope (n = 234, 36%), orthostatic hypotension (n = 156, 24%), arrhythmia (n = 24, 4%), and other diseases (n = 32, 5%). Of the 67 patients who underwent targeted tests, suspected diagnoses were confirmed in 49 (73%) patients: aortic stenosis (n = 8, 1%), pulmonary embolism (n = 8, 1%), seizures/stroke (n = 30, 5%), and other diseases (n = 3). Extensive cardiovascular workups, which were performed in 122 of the 155 patients in whom syncope remained unexplained after clinical assessment, provided a suspected cause of syncope in only 30 (25%) patients, including arrhythmias in 18 (60%), all of whom had abnormal baseline ECGs. The 18-month mortality was 9% (n = 55, including 8 patients with sudden death); syncope recurred in 15% (n = 95) of the patients.
The diagnostic yield of a standardized clinical evaluation of syncope was 76%, greater than reported previously in unselected patients. Electrocardiogram-based risk stratification was useful in guiding the use of specialized cardiovascular tests.
Introduction:
VEN is approved conditionally in the US in combination with HMA (azacitidine or decitabine) or low-dose cytarabine in newly-diagnosed AML patients (pts) ineligible for intensive ...chemotherapy due to age (≥75 years) or comorbidities. The Phase Ib clinical trial NCT02203773 (DiNardo et al. Blood 2019) and Phase III VIALE-A trial (NCT02993523; DiNardo et al. EHA 2020), demonstrated the clinical benefit of VEN+HMA, but frequent VEN dose modifications were observed due to the occurrence of cytopenias. This study aims to evaluate RW VEN+HMA response, treatment (Tx) duration, dose and schedule modifications in newly-diagnosed pts with AML treated predominantly in the community setting.
Methods:
This is a retrospective cohort study using the Flatiron Health electronic health record (EHR)-derived de-identified database; a nationwide database comprising patient-level structured (demographics, labs, visits and Tx administered in-network) and unstructured data (pathology reports, hospital discharges and physician notes, out-of-network and oral Tx), curated via technology-enabled abstraction (Flahavan et al. EHA 2020). Pts newly diagnosed with AML, age ≥18 years, and who initiated VEN+HMA within 30 days of diagnosis from June 1, 2018 to November 30, 2019 were evaluated. Additional variables related to VEN Tx were abstracted manually from EHR unstructured data: including Tx start/end dates, dose holds, schedule changes, dose changes (in mg) or discontinuation (d/c), and the reasons for these interruptions. Response to Tx was a measured “blast clearance” ≤5% from bone-marrow (BM) biopsy (unstructured) or peripheral blood (PB) (structured) data. RW complete response (CR)/CR with partial hematologic recovery (rwCR/CRh) was derived as ≤5% BM+PB blasts with partial hematologic count recovery within 14 days. Kaplan-Meier analyses were conducted to examine Tx duration of VEN+HMA Tx, with follow-up (f/u) to date of Tx d/c on VEN or censoring at the last EHR activity before data cut-off (February 29, 2020). VEN treatment cycles, derived based on the HMA dosing (28 days per cycle), were evaluated in a subset of pts with complete structured data on HMA administrations. Dosing intensity was calculated as dosed days as a percentage of total days from start to end of therapy or end of f/u.
Results:
Overall 145 VEN+HMA pts (n=89, 61.4% received azacitidine combination) were included, median age at diagnosis was 77 years; 6% had Eastern Cooperative Oncology Group (ECOG) performance status ≥3; 9% had therapy-related AML (t-AML) and 40% had AML secondary to antecedent hematologic disorder (s-AML). Of the 95 pts with evaluable response data during the f/u period, 67 (71%) had BM blast clearance, and 47 (49%) had rwCR/CRh. At a median f/u of 4.3 months (range 0.6-17.7), 65 pts (45%) had not d/c VEN Tx at data cut-off. Data were not mature for overall survival analyses.
The subset of 45 pts with complete structured HMA data that were examined for VEN Tx scheduling was similar to the overall cohort; however, median f/u was slightly lower at 3.0 months (range 0.6-16.7). VEN initiation was not always concurrent with HMA initiation; 50% started within 2 days and 75% within 9 days of HMA initiation. Twenty-six pts (58%) had not d/c VEN at end of f/u; a median of 3 cycles was observed for all-comers in this time (range 1-15). Dose and schedule modifications (not mutually exclusive) occurring in cycles 1-3 included VEN dose changes (67%), d/c (36%), in-cycle dose interruption (24%) and cycle delay (22%). The most commonly cited reason for dose and schedule modifications was toxicity. Mean VEN dosing intensity overall was 77%; 86% prior to dose and schedule modification and 90% prior to dose change.
Conclusions:
This study is the largest RW data analysis of pts with AML treated with VEN+HMA to date. This RW cohort treated predominantly in the community setting differed from the VEN+HMA clinical trial: pts were older, had worse ECOG performance status and a higher proportion had s-AML. Despite this, in the evaluable RW VEN+HMA pts, high response was observed. The RW Tx duration analyses were limited by short f/u and RW VEN initiation was not always concurrent with HMA. Dose modifications were common early in Tx course. Further characterization of this cohort will have additional f/u and analyses on the timing of VEN dose modifications in relation to cytopenia management and drug-drug interactions.
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Donnellan:PTC Therapeutics: Consultancy, Research Funding; Ryvu Therapeutics: Research Funding; Seattle Genetics: Consultancy, Research Funding; Takeda: Research Funding; TCR2 Therapeutics: Research Funding; AstraZeneca: Research Funding; Astex Pharmaceuticals: Research Funding; Amgen: Consultancy; Abbvie: Consultancy, Research Funding; Bellicum Pharmaceuticals: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Celularity: Research Funding; CTI Biopharma: Research Funding; Daiichi Sankyo: Research Funding; Forma Therapeutics: Research Funding; Forty Seven: Research Funding; Genentech: Research Funding; H3 Biomedicine: Research Funding; Incyte: Research Funding; Janssen: Research Funding; Karyopharm Therapeutics: Research Funding; Kite Pharma/Gilead: Research Funding; MedImmune: Research Funding; Pfizer: Research Funding. Xu:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Ma:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. Jin:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. Montez:F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Choi:AbbVie: Current Employment, Current equity holder in publicly-traded company. Ku:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Rajeswaran:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Ramsingh:NEKTAR: Current equity holder in publicly-traded company; F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Exelixis: Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months, Ended employment in the past 24 months; Genentech, Inc.: Current Employment. Flahavan:Roche Products Ltd.: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded company.
Objectives: To develop and validate a risk score predicting arrhythmias for patients with syncope remaining unexplained after emergency department (ED) noninvasive evaluation. Methods: One cohort of ...175 patients with unexplained syncope (Geneva, Switzerland) was used to develop and cross‐validate the risk score; a second cohort of 269 similar patients (Pittsburgh, PA) was used to validate the system. Arrhythmias as a cause of syncope were diagnosed by cardiac monitoring or electrophysiologic testing. Data from the patient's history and 12‐lead emergency electrocardiography (ECG) were used to identify predictors of arrhythmias. Logistic regression was used to identify predictors for the risk‐score system. Risk‐score performance was measured by comparing the proportions of patients with arrhythmias at various levels of the score and receiver operating characteristic (ROC) curves. Results: The prevalence of arrhythmic syncope was 17% in the derivation cohort and 18% in the validation cohort. Predictors of arrhythmias were abnormal ECG (odds ratio OR: 8.1, 95% confidence interval CI = 3.0 to 22.7), a history of congestive heart failure (OR: 5.3, 95% CI = 1.9 to 15.0), and age older than 65 (OR: 5.4, 95% CI = 1.1 to 26.0). In the derivation cohort, the risk of arrhythmias ranged from 0% (95% CI = 0 to 6) in patients with no risk factors to 6% (95% CI = 1 to 15) for patients with one risk factor, 41% (95% CI = 26 to 57) for patients with two risk factors, and 60% (95% CI = 32 to 84) for those with three risk factors. In the validation cohort, these proportions varied from 2% (95% CI = 0 to 7) with no risk factors to 17% (95% CI = 10 to 27) with one risk factor, 35% (95% CI = 24 to 46) with two risk factors, and 27% (95% CI = 6 to 61) with three risk factors. Areas under the ROC curves ranged from 0.88 (95% CI = 0.84 to 0.91) for the derivation cohort to 0.84 (95% CI = 0.77 to 0.91) after cross‐validation within the same cohort and 0.75 (95% CI = 0.68 to 0.81) for the external validation cohort. Conclusions: In patients with unexplained syncope, a risk score based on clinical and ECG factors available in the ED identifies patients at risk for arrhythmias.
Sickness certification is a routine task of primary care (PC) physicians which has an impact on patients' health, the health care system and the economy. As sickness certification is poorly studied, ...we quantified sickness certification and explored qualitatively the sickness certification process by Swiss PC physicians.
PC physicians participating in the Swiss Sentinel Surveillance Network (SSSN) recorded the frequency and duration of absence from work of each related consultation and certificate during 2005. Patients' age and gender, reason for sick leave, psychosocial cofactors, problems at the workplace, type of employment, type of occupation, duration of absence (weeks) and type of certificate were registered. Physicians' views on the procedure and their suggestions for change were gathered before and after the study by means of a questionnaire containing four open-ended questions.
Of the 223 SSSN physicians 73% participated. A total of 24,676 forms issued by 150 physicians were analysed. An average of four certificates was issued per 100 consultations; somewhat fewer by internists than by general practitioners and less in rural areas than urban areas. Psychosocial or work-related factors were mentioned in 20% of the certificates and were more often associated with longer absences from work. These factors were seen as inseparable from the somatic factors. Recommendations for change included the prolongation of self declaration time, a uniform declaration form, availability of an authority to which complex cases can be referred and the use of case management models.
Sickness certificates were issued in 4% of GP consultations. This task has been assessed by physicians as part of their function. The certification process should be improved through better coordination and communication between all parties involved: patients, employers, insurers, physicians and politicians.
To develop and validate a risk score predicting arrhythmias for patients with syncope remaining unexplained after emergency department (ED) noninvasive evaluation.
One cohort of 175 patients with ...unexplained syncope (Geneva, Switzerland) was used to develop and cross-validate the risk score; a second cohort of 269 similar patients (Pittsburgh, PA) was used to validate the system. Arrhythmias as a cause of syncope were diagnosed by cardiac monitoring or electrophysiologic testing. Data from the patient's history and 12-lead emergency electrocardiography (ECG) were used to identify predictors of arrhythmias. Logistic regression was used to identify predictors for the risk-score system. Risk-score performance was measured by comparing the proportions of patients with arrhythmias at various levels of the score and receiver operating characteristic (ROC) curves.
The prevalence of arrhythmic syncope was 17% in the derivation cohort and 18% in the validation cohort. Predictors of arrhythmias were abnormal ECG (odds ratio OR: 8.1, 95% confidence interval CI=3.0 to 22.7), a history of congestive heart failure (OR: 5.3, 95% CI=1.9 to 15.0), and age older than 65 (OR: 5.4, 95% CI=1.1 to 26.0). In the derivation cohort, the risk of arrhythmias ranged from 0% (95% CI=0 to 6) in patients with no risk factors to 6% (95% CI=1 to 15) for patients with one risk factor, 41% (95% CI=26 to 57) for patients with two risk factors, and 60% (95% CI = 32 to 84) for those with three risk factors. In the validation cohort, these proportions varied from 2% (95% CI=0 to 7) with no risk factors to 17% (95% CI=10 to 27) with one risk factor, 35% (95% CI=24 to 46) with two risk factors, and 27% (95% CI=6 to 61) with three risk factors. Areas under the ROC curves ranged from 0.88 (95% CI=0.84 to 0.91) for the derivation cohort to 0.84 (95% CI=0.77 to 0.91) after cross-validation within the same cohort and 0.75 (95% CI=0.68 to 0.81) for the external validation cohort.
In patients with unexplained syncope, a risk score based on clinical and ECG factors available in the ED identifies patients at risk for arrhythmias.
Abstract
Background
Sexual dysfunction after Inflammatory Bowel Disease (IBD), pelvic and perineal surgery is common but poorly discussed, investigated and treated in the peri-operative period. There ...remains no standardised measurement tool to assess sexual function in routine use for patients undergoing benign pelvic colorectal surgery.
The necessity for open dialogue regarding sexual dysfunction was evidenced in a patient-led study conducted by Dames et al. Our primary objective was to undertake a systematic review of sexual function measurement instruments, to identify the need for a novel sexual function patient-reported outcome measure (sex-PROM) that may be used in the context of pelvic and perineal surgery for IBD e.g. fistula surgery, defunctioning ostomy formation, ileo-anal pouch formation and proctectomy.
Methods
We performed a systematic review according to Consensus-based Standards for the selection of health Measurement Instruments (COSMIN) criteria (Prospero registration: CRD42023403396). Embase, Medline and PubMed Databases were searched for previously validated patient-reported outcome measures that could be used in the assessment of sexual function. These instruments were evaluated for their psychometric properties, in addition to their overall quality, utility and suitability in the context of IBD and other benign surgery. A global rating was attained according to COSMIN criteria. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) checklist was applied to evaluate the quality of evidence. In addition, patient involvement in instrument development was assessed.
Results
Some 2331 articles were screened, 305 full-text studies were assessed for eligibility and 56 measurement instruments were identified and evaluated. All studies showed limited psychometric validation. The Female Sexual Function Index and the International Index of Erectile Function were among the highest-scoring instruments, however conveyed significant limitations, including an anatomical focus, limited exploration of quality of life and relationship satisfaction, and a lack of significant patient involvement in their development. All identified measurement instruments carried limited specific clinical utility for patients after IBD surgery.
Conclusion
Sexual dysfunction after pelvic surgery for inflammatory bowel pathology is multi-factorial. It can result from anatomical nerve damage but can also occur secondary to the psychological impact of altered body image, sexual self-esteem, and relationships and intimacy. We recommend the development of a novel patient-centred sexual function measurement instrument that may be used after benign pelvic/perineal colorectal surgery to be used in the clinical and research settings.
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