Analysis Of Individual Patient Data Research Articles

Effects of intensive blood pressure lowering in patients with diabetes: A pooled analysis of the STEP and ACCORD-BP randomized trials.

To determine whether intensive systolic blood pressure (SBP) lowering can benefit hypertensive patients with diabetes. We performed a pooled analysis of individual patient data from two randomized trials to compare intensive and standard SBP targets in hypertensive patients with diabetes (STEP diabetes subgroup and ACCORD-BP standard glycaemic group, n=1627 and n=2362, respectively). We defined a modified primary outcome as a composite of stroke, major coronary artery disease (myocardial infarction and unstable angina), heart failure, and cardiovascular death. The secondary outcomes were individual components of the primary outcome and death from any cause. A Cox proportional hazards regression model was used in the main analysis. We conducted one-stage mixed-effect models and two-stage analyses as sensitivity and supplementary analyses to verify the robustness of the findings. A total of 3989 patients were randomized to undergo intensive (n=1984) or standard SBP treatment (n=2005). After a median follow-up of 3.83 years, the primary outcome occurred in 193/1984 patients in the intensive group and in 247/2005 patients in the standard group (hazard ratio [HR] 0.77, 95% confidence interval [CI] 0.64-0.93). The incidence rates for secondary outcomes were lower in the intensive group than in the standard group, but were not significantly different, except for stroke (intensive vs. standard: 32/1984 vs. 58/2005; HR 0.56, 95% CI 0.36-0.86). These results remained consistent in the additional sensitivity and supplementary analyses. An intensive SBP-lowering target of 110 to <130 mmHg reduces the cardiovascular outcomes compared with a standard SBP-lowering target of 130 to <150 mmHg. The findings of this study support the favourable effects of intensive SBP lowering in hypertensive patients with diabetes.

Sex disparity in childhood cancer in India: a multi-centre, individual patient data analysis

Sex disparity and its determinants in childhood cancer in India remain unexplored, with scarce information available through summary statistics of cancer registries. This study analysed the degree of sex bias in childhood cancer in India and its clinical and demographical associations. In this retrospective, multicentre cohort study, we collected individual data of children (aged 0-19 years) with cancer extracted from the hospital-based records of three cancer centres in India between Jan 1, 2005, and Dec 31, 2019, and two population-based cancer registries (PBCRs; Delhi [between Jan 1, 2005, and Dec 31, 2014] and Madras Metropolitan Tumour Registry [between Jan 1, 2005, and Dec 31, 2017]). We extracted data on age, sex, and confirmed diagnosis of malignancy (according to the International Classification of Diseases-10 coding),and excluded participants if they were without a recorded diagnosis, had a benign diagnosis, had missing sex information, resided outside of India, or were a donor for haematopoietic stem cell transplantation (HSCT). The primary outcome was the male-to-female incidence rate ratio (MF-IRR) in the two PBCRs and the male-to-female ratios (MFR) from the hospital-based and the HSCT data. For PBCR data, MF-IRR was estimated by dividing the MFR by the total population at risk. MFR was analysed for patients seeking treatment at the cancer centres and for those undergoing HSCT. Logistic regression analyses were done to explore the association of clinical and demographical variables with sex of the patients seeking treatment and those undergoing HSCT in hospital-based data and multivariable analyses were done to determine independent sociodemographic predictors of sex bias. Annual time trends of MFR and MF-IRR during the 15-year study period were ascertained by time series regression analyses. We included 11 375 children from PBCRs in the study. 26 891 children from hospital-based records were screened, and data from 22 893 (85·1%) were included (including 514 who underwent HSCT). Residence details were missing for 257 (1·1%) of 22 893 patients from hospital-based records. The crude MFR of children at diagnosis was in favour of boys: 2·00 (95% CI 1·92-2·09) in the Delhi PBCR and 1·44 (1·32-1·57) in Madras Metropolitan Tumour Registry. The MF-IRRs for cancer diagnosis were also skewed in favour of boys in both PBCRs (Delhi 1·69 [95% CI 1·61-1·76]; Madras Metropolitan Tumour Registry 1·37 [1·26-1·49]). The MFR for children seeking treatment from hospital-based records was 2·06 (95% CI 2·00-2·12) in favour of boys. In subgroup analyses, the proportion of boys seeking treatment was higher in northern India than southern India (p<0·0001); in private centres than in centres providing subsidised treatment (p<0·0001); in patients with haematological malignancies than those with solid malignancies (p<0·0001); in those residing 100 km or further from the hospital than those within 100 km of a hospital (p<0·0001); and those living in rural areas than those living in urban areas (p=0·0006). The MFR of 514 children who underwent HSCT was 2·81 (95% CI 2·32-3·43) in favour of boys. Time trend analysis showed that MFR did not show any significant annual change in either the overall cohort or in any of the individual centres for hospital-based data; however, the analysis did show a declining MF-IRR in the Delhi PBCR from 2005 to 2014 (p=0·031). The sex ratio for childhood cancer in India has a bias towards boys at the level of diagnosis, which is more pronounced in northern India and in situations demanding greater financial commitment. Addressing societal sex bias and enhancing affordable health care for girls should be pursued simultaneously in India. None. For the Hindi translation of the abstract see Supplementary Materials section.

Post-consultation acute respiratory tract infection recovery: a latent class-informed analysis of individual patient data.

There is a lack of evidence regarding post-consultation symptom trajectories for patients with respiratory tract infections (RTIs) and whether patient characteristics can be used to predict illness duration. To describe symptom trajectories in patients with RTIs, and assess baseline characteristics and adverse events associated with trajectories. The study included data about 9103 adults and children from 12 primary care studies. A latent class-informed regression analysis of individual patient data from randomised controlled trials and observational cohort studies was undertaken. Post-consultation symptom trajectory (severity and duration), re-consultation with same or worsening illness, and admission to hospital were assessed. In total, 90% of participants recovered from all symptoms by 28 days, regardless of antibiotic prescribing strategy (none, immediate, and delayed antibiotics). For studies of RTI with cough as a dominant symptom (n = 5314), four trajectories were identified: 'rapid (6 days)' (90% of participants recovered within 6 days) in 52.0%; 'intermediate (10 days)' (28.9%); 'slow progressive improvement (27 days)' (12.5%); and 'slow improvement with initial high symptom burden (27 days)' (6.6%). For cough, being aged 16-64 years (odds ratio [OR] 2.57, 95% confidence interval [CI] = 1.72 to 3.85 compared with <16 years), higher presenting illness baseline severity (OR 1.51, 95% CI = 1.12 to 2.03), presence of lung disease (OR 1.78, 95% CI = 1.44 to 2.21), and median and above illness duration before consultation (≥7 days) (OR 1.99, 95% CI = 1.68 to 2.37) were associated with slower recovery (>10 days) compared with faster recovery (≤10 days). Re-consultations and admissions to hospital for cough were higher in those with slower recovery (ORs: 2.15, 95% CI = 1.78 to 2.60 and 7.42, 95% CI = 3.49 to 15.78, respectively). Older patients presenting with more severe, longer pre-consultation symptoms and chronic lung disease should be advised they are more likely to experience longer post-consultation illness durations, and that recovery rates are similar with and without antibiotics.

Significance of Baseline Ischemic Core Volume on Stroke Outcome After Endovascular Therapy in Patients Age ≥75 Years: A Pooled Analysis of Individual Patient Data From 7 Trials.

Age and infarct volume are strong predictors of outcome in patients with ischemic stroke who underwent endovascular therapy (EVT). We aimed to investigate the impact of ischemic core volume (ICV) on stroke outcome after EVT in elderly. Using the HERMES (Highly Effective Reperfusion Using Multiple Endovascular Devices) collaboration, a patient-level meta-analysis of 7 randomized trials in which patients were enrolled from December 2010 to April 2015) dataset, we categorized patients into those aged <75 and ≥75 years. ICV was calculated on computed tomography perfusion or magnetic resonance diffusion-weighted imaging. The association between ICV and the benefit of EVT over best medical treatment on outcome (modified Rankin Scale [mRS] at 90 days) and an ICV threshold for high likelihood (≥90%) of very poor outcome (mRS score ≥5) after EVT were investigated. A total of 899 patients who had baseline ICV data, 247 patients aged ≥75 years, of which 118 were randomized in the EVT arm. Patients aged ≥75 years required smaller ICV to achieve mRS score ≤3 than those aged <75 years in the EVT arm (median 10.7 mL versus 23.9 mL, P<0.001). In patients aged ≥75 years, modeling of outcome in both treatment arms revealed potential loss of effect for EVT at ICV of ≥50 mL or ≥85 mL for achieving mRS score ≤3 or ≤4, respectively. Treatment effect of EVT was significant in ICV <50 mL for mRS ≤3 (odds ratio 2.38, 95% confidence interval 1.35-4.22). ICV ≥132 mL was a threshold for high likelihood of very poor outcome after EVT. However, EVT still predicted at least 30% rate of mRS ≤3 at 150 mL ICV if near-complete or complete reperfusion was achieved. Baseline ICV has an impact on stroke outcome after EVT in the elderly, but elderly patients with large ICV may still benefit from EVT if near-complete or complete reperfusion is achieved. Young patients seem to benefit from EVT regardless of ICV status.

PMON260 Cost-Effectiveness of Testosterone Treatment for Men with Hypogonadism

Abstract Background Testosterone replacement therapy is the standard treatment for male hypogonadism (MH). Prescribing rates of testosterone in the UK have risen between 2001 and 2010 without an observable increase in the prevalence of hypogonadism, which may reflect increasing media awareness among men about hypogonadism. Currently, there is uncertainty about the safety and efficacy of testosterone treatment for MH, especially regarding its impact on cardiovascular risk, which has led to mandatory safety labelling in some countries. Aim We conducted an economic evaluation of testosterone therapy in men with hypogonadism, using individual patient data (IPD) of safety and efficacy outcomes in over 3000 participants as part of an international collaboration of investigators of 17 existing placebo-controlled RCTs assessing the safety and efficacy of testosterone treatment for MH (TestES Consortium). Methods A cost-utility analysis of the use of testosterone treatment for MH was conducted using a cohort Markov model developed following best practice. The model care pathway was informed by existing clinical guidelines, the results of the TestES Consortium individual patient data (IPD) meta-analysis, and discussions with clinical and methodological experts. Five Markov states were included: no complications, post-Cardiac pathology, post-Peripheral Vascular System Pathology, post-Cerebrovascular System Pathology, and Death. All-cause mortality, cardiovascular and cerebrovascular complications, and utility weights were obtained from the TestES IPD analyses. The UK NHS and personal and social services perspective was adopted for costs. Ten-year and lifetime time horizons were considered with costs and effects discounted annually at 3.5% rate. The model was run probabilistically using 10,000 Monte Carlo simulations. Three starting ages were defined (40, 60, and 75 years). Mean total cost, mean QALYs and incremental cost-effectiveness ratios were calculated. Results Cost-effectiveness of testosterone treatment appears to be dependent on the relative risk (RR) of all-cause mortality - favouring TRT - and the methods used to derive health state utility scores (i.e., SF-6D or a mapping between Beck Depression Inventory -BDI- score and EQ-5D score) for testosterone treatment versus standard care. When the RR of mortality and the BDI utilities were used, ICERs remained below the £20,000 ($27,400) UK conventional threshold, irrespective of the cohort starting age. However, ICERs increased above the £20,000 threshold when the difference in all-cause mortality was dropped, and the SF-6D utility scores were used. Conclusions We report the most in-depth economic analysis of male hypogonadism treatment to date. There remains limited data for generating preference-based health-related quality of life (HRQoL) weights for economic evaluation. Further clarity on the long-term cardiovascular safety of testosterone treatment in men with hypogonadism, and more in-depth mapping of clinical outcomes to generic preference-based measures of HRQoL will be crucial to inform robust estimates of the cost-effectiveness of testosterone treatment for MH. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Finerenone efficacy in patients with chronic kidney disease, type 2 diabetes and atherosclerotic cardiovascular disease.

Finerenone, a selective, non-steroidal mineralocorticoid receptor antagonist, improves cardiovascular (CV) and kidney outcomes in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD). This subgroup analysis of FIDELITY, a pre-specified, pooled, individual patient-data analysis of FIDELIO-DKD (NCT02540993) and FIGARO-DKD (NCT02545049), compared finerenone vs. placebo in patients with and without baseline history of atherosclerotic CV disease (ASCVD). Outcomes included a composite CV outcome [CV death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for heart failure (HHF)]; CV death or HHF; a composite kidney outcome (kidney failure, sustained estimated glomerular filtration rate decrease≥57%, or kidney-related death); all-cause mortality; and safety by baseline history of ASCVD.Of 13 026 patients, 5935 (45.6%) had a history of ASCVD. The incidence of the composite CV outcome, CV death or HHF, and all-cause mortality was higher in patients with ASCVD vs. those without, with no difference between groups in the composite kidney outcome. Finerenone consistently reduced outcomes vs. placebo in patients with and without ASCVD (P-interaction for the composite CV outcome, CV death or HHF, the composite kidney outcome, and all-cause mortality 0.38, 0.68, 0.33, and 0.38, respectively). Investigator-reported treatment-emergent adverse events were consistent between treatment arms across ASCVD subgroups. Finerenone reduced the risk of CV and kidney outcomes consistently across the spectrum of CKD in patients with T2D, irrespective of prevalent ASCVD.

Effect of CPAP therapy on blood pressure in patients with OSA: a worldwide individual patient data meta-analysis

Abstract Background Obstructive sleep apnoea (OSA) is a well-known cardiovascular risk factor and is frequently associated with hypertension. The treatment of OSA with continuous positive airway pressure (CPAP) can resolve apnoeas, hypoxia, and sympathetic hyperactivation. Meta-analyses of randomised controlled trials (RCTs) show that CPAP treatment modestly reduces blood pressure (BP) with a pronounced heterogeneity among different OSA patient subgroups. Purpose To study the effects of CPAP treatment on BP changes, and to identify predictors of BP response to CPAP through analysis of individual patient data from published RCTs. Methods Study groups who had published RCTs on the effect of CPAP therapy on BP in OSA were invited to share the individual patient data (i.e. BP values, history of hypertension and antihypertensive drugs use). The outcomes of interest were the group-difference (BP at follow-up – BP at baseline) in office and out-of-office BP. Data analysis was performed with a one-step approach using a linear regression model, with treatment as covariate, including a random effect. An additional analysis was performed by stratifying patients in three subgroups: normotension, controlled hypertension and uncontrolled hypertension, based on BP at baseline, history of hypertension or treatment with antihypertensive drugs. Lastly, we evaluated the determinants of CPAP associated BP changes. Results Individual patient data from 34 parallel-group RCTs (n=7,456, 72% males, body mass index, BMI 31.9±14.8 kg/m2, age 58.6±10.9 years, apnoea-hypopnoea index, AHI 35.5±20.6 /hour) were analysed. The overall CPAP effect was larger for 24-BP compared to office BP measurements (Table 1), the highest reductions being observed for nocturnal BP. The stratified analysis showed a consistent BP lowering effect in the group of patients with uncontrolled hypertension whereas there was no significant BP change in those with controlled hypertension or in normotensives (figure 1). Higher BP levels at baseline and history of hypertension were independent predictors of BP reduction by CPAP for office and 24-BP measurements. Younger age and more severe nocturnal oxygen desaturations predicted a larger treatment effect on office BP only. Conclusions BP response to CPAP in OSA patients varies in different patient groups as a function of baseline BP, the greatest reduction being observed in younger patients with uncontrolled BP. Thus, our individual patient data meta-analysis indicates that younger patients with uncontrolled hypertension and more severe nocturnal oxygen desaturations measured by minimum SpO2 are likely to benefit the most from CPAP treatment in terms of BP reduction. Funding Acknowledgement Type of funding sources: None.

P004: Advanced stage classical Hodgkin lymphoma (cHL) patients with a positive interim-PET (PET-2) Deauville score (DS) 5 after 2 ABVD cycles: A pooled analysis of individual patient data of three multicenter trials

Background: PET-2 is widely adopted to select patients (pt) with advanced-stage cHL, who might benefit from intensifying or de-escalating therapy. Improved PFS has been reported in PET-2 positive pt switched from ABVD to escalated BEACOPP (eBEACOPP) compared to historical controls continuing ABVD. Nevertheless, pt with a PET-2 Deauville score (DS) 5 have a dismal prognosis, with PFS from 35% to 50% at 3 years despite treatment intensification. Aim of Study: To refine outcome prediction, we conducted a pooled analysis of individual pt data from 3 multicenter trials: HD0607 GITIL/FIL, RATHL and SWOG S0816 focusing on pt with PET-2 DS 5 after ABVD who had intensified treatment with eBEACOPP or BEACOPP-14. Methods: The prognostic value of clinical characteristics, laboratory parameters, metabolic tumor volume (MTV) and total lesion glycolysis (TLG) at diagnosis was evaluated. MTV was calculated with an automatic software segmentation using SUV 4.0 threshold in each pt. Predictive factors of PFS measured from the date of PET-2 until progression, relapse, death from any cause or last follow-up, and overall survival (OS) were analyzed using Cox regression. Baseline characteristics and PET MTV/TLG of pt who failed vs those who achieved CR with intensified treatment were compared. Results: Among 2231 pt with available PET scans for review, 136 (6%) PET-2 DS 5 pt were included in the study: M 72, F 64, median age 34 yrs, Nodular Sclerosis 71%, stage IIB/III/IV 29%/ 22% /49%, B symptoms 72%, IPS >3: 31%; bulky 22%; neutrophil/lymphocyte ratio > 6: 61%. At baseline median MTV and TLG were 243 cm3 (range, 1.6–4266) and 1476cm3 (range, 7.3–29386). After a median follow-up of 41 months, 3-yr PFS and OS were 32% (95% CI, 25–42) and 82% (95% CI, 75–89), respectively. In univariate analysis no clinical or laboratory parameter nor MTV was significantly associated with PFS, whereas age ≥ 45 years, median numbers of leukocytes, lymphocytes and monocytes were significantly associated with OS. Using a threshold of 192 cm3 for MTV calculated by Youden index, 3-year PFS and OS were 35% and 87% vs 34% and 79% for pt with low vs high MTV (p=ns). Conclusions: Pt with PET-2 DS 5 after ABVD receiving intensified treatment have similar outcomes to refractory disease with only 32% 3-yr PFS. No factors measured at diagnosis were able to detect the later failures within the DS 5 cohort. Nevertheless, pt receiving PET-guided treatment intensification can benefit from a prolonged OS.

Treatment of asymptomatic carotid artery stenosis

There is much debate about the best approach for treating patients with tight (at least 70%) asymptomatic carotid artery stenosis. A pooled analysis of trials in recently symptomatic patients with carotid artery stenosis showed that successful, uncomplicated surgery or stenting had similar long-term outcomes for at least 8 years, but early post-procedural strokes were more common after stenting than surgery. 1 Brott TG Calvet D Howard G et al. Long-term outcomes of stenting and endarterectomy for symptomatic carotid stenosis: a preplanned pooled analysis of individual patient data. Lancet Neurol. 2019; 18: 348-356 Summary Full Text Full Text PDF PubMed Scopus (57) Google Scholar The ACST-2 trial reported that, for asymptomatic patients, both procedures had similar procedural and 5-year follow-up outcomes. 2 Halliday A Bulbulia R Bonati LH et al. Second asymptomatic carotid surgery trial (ACST-2): a randomised comparison of carotid artery stenting versus carotid endarterectomy. Lancet. 2021; 398: 1065-1073 Summary Full Text Full Text PDF PubMed Scopus (47) Google Scholar However, medical treatment for asymptomatic carotid artery stenosis has improved substantially in the past 20 years, when many clinical trials in this population were done, and best medical treatment could now be an option instead of more invasive approaches. Carotid endarterectomy or stenting or best medical treatment alone for moderate-to-severe asymptomatic carotid artery stenosis: 5-year results of a multicentre, randomised controlled trialCEA plus BMT or CAS plus BMT were not found to be superior to BMT alone regarding risk of any stroke or death within 30 days or ipsilateral stroke during the 5-year observation period. Because of the small sample size, results should be interpreted with caution. Full-Text PDF

P09.03.A Associations of levetiracetam use with the safety and tolerability of chemoradiotherapy for patients with newly diagnosed glioblastoma

Abstract Background Levetiracetam (LEV) is one of the most frequently used antiepileptic drugs (AED) for brain tumor patients with seizures. We hypothesized that toxicity of LEV and temozolomide-based chemoradiotherapy may overlap. Patients and Methods In a retrospective analysis of individual patient data using a pooled cohort of patients with newly diagnosed glioblastoma included in clinical trials prior to chemoradiotherapy (CENTRIC, CORE, AVAglio) or prior to maintenance therapy (ACT-IV), we tested associations of hematologic toxicity, nausea or emesis, fatigue, and psychiatric adverse events during concomitant and maintenance treatment with the use of LEV alone or with other AED versus other AED alone or in combination versus no AED use at the start of chemoradiotherapy and of maintenance treatment. Results Of 1681 and 2020 patients who started concomitant chemoradiotherapy and maintenance temozolomide, respectively, 473 and 714 patients (28.1% and 35.3%) were treated with a LEV-containing regimen, 538 and 475 patients (32.0% and 23.5%) with other AED, and 670 and 831 patients (39.9% and 41.1%) had no AED. LEV was associated with higher risk of psychiatric adverse events during concomitant treatment in univariable and multivariable analyses (RR 1.86 and 1.88, p&amp;lt;0.001) while there were no associations with hematologic toxicity, nausea or emesis, or fatigue. LEV was associated with reduced risk of nausea or emesis during maintenance treatment in multivariable analysis (HR=0.80, p=0.017) while there were no associations with hematologic toxicity, fatigue, or psychiatric adverse events. Conclusion Any association of psychiatric adverse events with LEV did not persist beyond the concomitant treatment phase. Antiemetic properties of LEV may be beneficial during the maintenance temozolomide.

Factors affecting prognosis in patients treated with bevacizumab plus paclitaxel as first-line chemotherapy for HER2-negative metastatic breast cancer: an international pooled analysis of individual patient data from four prospective observational studies

BackgroundBevacizumab (BV) plus paclitaxel (PTX) is a treatment option in patients with HER2-negative metastatic breast cancer (mBC). We conducted an international pooled analysis with individual patient data to evaluate the effectiveness of BV + PTX as a first-line treatment for HER2-negative mBC patients under routine practice.MethodsA total of 2,474 mBC patients treated with BV + PTX from four prospective observational studies were analyzed. The primary endpoint was overall survival (OS). The other endpoints including identifying independent prognostic factors and validation of the modified Prognostic Factor Index (PFI) developed in the ATHENA trial.ResultsMedian follow-up time was 10.9 months (M). Median OS were 21.4 M (95% confidential interval 19.8–22.7 M). The seven independent prognostic factors (tumor subtype, age, ECOG performance status (PS), disease-free interval (DFI), liver metastases, number of metastatic organs, and prior anthracycline and/or taxane treatment) for OS found in this analysis included the five risk factors (RFs [DFI < 24 months, ECOG PS 2, liver metastases and/or > 3 metastasis organ sites, TNBC, prior anthracycline and/or taxane therapy]). High- (> 3 RFs [median OS 12.6 M]) and intermediate-risk groups (2 RFs [median OS 18.0 M]) had a significantly worse prognosis than the low-risk group (< 1 RF [median OS 27.4 M]), (p < 0.0001).ConclusionsThis international pooled analysis showed the effectiveness of first-line BV + PTX for HER2-negative mBC patients identifying seven independent prognostic factors as real-world evidence. The usefulness of the modified PFI developed in the ATHENA trial in predicting OS among patients receiving BV + PTX was also verified.

Maintenance therapy with a poly(ADP-ribose) polymerase inhibitor in patients with newly diagnosed advanced epithelial ovarian cancer: individual patient data and trial-level meta-analysis

BackgroundWe synthesize the efficacy and toxicity of poly(ADP-ribose) polymerase inhibitors (PARPis) in patients with newly diagnosed advanced ovarian cancer.Patients and methodsWe manually extracted individual patient data (IPD) for progression-free survival (PFS) from published survival curves of randomized controlled trials (RCTs) that compared PARPi versus placebo as maintenance therapy in first-line treatment, for whole study populations and subgroups, based on BRCA1/BRCA2 mutation (germline and/or somatic) and homologous recombination deficiency (HRD) status, using WebPlotDigitizer software. The respective PFS curves for each study and combined population were reconstructed from extracted IPD. The primary outcome was PFS in combined whole population and subgroups.ResultsIn IPD analysis of combined population from three RCTs, with 2296 patients and 1287 events, PFS was significantly longer in PARPi versus placebo [median 20.4 (95% confidence interval (CI) 18.6-21.9) versus 14.9 (95% CI 13.9-16.5) months, respectively; hazard ratio (HR) 0.67, 95% CI 0.60-0.75; P < 0.001]. In IPD subgroup analyses from four eligible RCTs (2687 patients and 1485 events), median PFS was significantly longer in PARPi versus placebo arm, in the BRCA-mutated (45.7 versus 17.7 months, respectively; HR 0.38, 95% CI 0.32-0.46; P < 0.001), HRD-positive including BRCA-mutated (34.7 versus 17.9 months, respectively; HR 0.45, 95% CI 0.38-0.54; P < 0.001), and HRD positive excluding BRCA-mutated (22.3 versus 13.1 months, respectively; HR 0.47, 95% CI 0.34-0.65; P < 0.001) subgroups, but not in the HRD-negative (15.0 versus 11.3 months, respectively; HR 0.90, 95% CI 0.76-1.05; P = 0.75) subgroup. Results of trial-level meta-analysis were concordant with IPD analysis in whole population and subgroups.ConclusionsAmong newly diagnosed ovarian cancer patients, PARPi maintenance therapy significantly improves PFS in those with germline and/or somatic BRCA mutation and/or HRD-positive tumor but not in those with HRD-negative tumor.

Acupuncture for hot flashes in hormone receptor-positive breast cancer, a coordinated multinational study: Rationale and design of the study protocol

BackgroundAcupuncture has been reported to reduce hot flashes in patients with breast cancer undergoing adjuvant hormonal therapy. Although hot flashes are common, the prevalence varies among cultures, races, and ethnicities; the efficacy of acupuncture across cultures has not been investigated. MethodsThis is a coordinated multinational study, including three parallel randomized trials with a planned analysis of individual patient data, to test the effectiveness of acupuncture on hot flash-related symptoms in hormone receptor-positive breast cancer patients on adjuvant endocrine therapy. Using a standardized acupuncture protocol (total across all three studies of n = 80) versus usual care (total n = 80), symptoms are assessed using changes in the Endocrine Symptom Subscale of Functional Assessment of Cancer Therapy-Endocrine Symptoms. Secondary outcomes include hot flash severity, quality of life, and sleep quality. Differences in response to acupuncture between participants in the three countries will also be explored. DiscussionHere we describe the design of a protocol for a coordinated multinational study, with attention to the complex considerations in developing a multinational research effort testing a non-pharmacologic intervention. This protocol and approach provide guidance for future efforts to evaluate and test non-pharmacologic interventions across multinational populations. Trial registrationclinicaltrials.gov (Identifier: NCT00797732, registered on December 21, 2018), Chinese Clinical Trial Registry (ChiCTR2100045888), and The Clinical Research Information Service (CRIS) of Korea (Registration number: KCT0003618).

Intrahepatic cholestasis of pregnancy: Green-top Guideline No. 43 June 2022.

Intrahepatic cholestasis of pregnancy: Green-top Guideline No. 43 June 2022.

Association of Pathologic Complete Response and Long-Term Survival Outcomes Among Patients Treated With Neoadjuvant Chemotherapy or Chemoradiotherapy for NSCLC: A Meta-Analysis

IntroductionIncreased efforts to optimize outcomes for early stage NSCLC through the investigation of novel perioperative treatment strategies are ongoing. An emerging question is the role of pathologic response and its association with long-term clinical outcomes after neoadjuvant therapy. MethodsTo investigate the association of pathologic complete response (pCR) and event-free survival (EFS) and overall survival (OS), we performed a systematic review and meta-analysis identifying studies reporting on the prognostic impact of pCR after neoadjuvant chemotherapy or chemoradiotherapy. To evaluate this prognostic value, an aggregated data (AD) meta-analyses was conducted to estimate the pooled hazard ratios (HRs) of EFS and OS for pCR. Using reconstructed individual patient data (IPD), pooled Kaplan-Meier curves were obtained to estimate this association in a more granular fashion. Subgroup analyses were conducted to further explore the impacts of study-level characteristics. ResultsA total of 28 studies comprising 7011 patients were included in the AD meta-analysis, of which, IPD was available for 6274 patients from 24 studies. Results from our AD meta-analysis revealed a pooled pCR rate of 18% (95% confidence interval [CI]: 15%–21%), including significant improvements in OS (HR = 0.50, 95% CI: 0.45–0.56) and EFS (HR = 0.46, 95% CI: 0.37–0.57) on the basis of pCR status. Our IPD analysis revealed a 5-year OS rate of 63% (95% CI: 59.6–67.4) for patients with a pCR compared with 39% (95% CI: 34.5–44.5) for those without a pCR. ConclusionspCR after neoadjuvant chemotherapy plus or minus radiotherapy is associated with significant improvements in EFS and survival for patients with resectable NSCLC.

CT findings of COVID-19-associated pulmonary aspergillosis: a systematic review and individual patient data analysis

PurposeCommon CT abnormalities of pulmonary aspergillosis represent a cavity with air-meniscus sign, nodule, mass, and consolidation having an angio-invasive pattern. This study aims to conduct a systematic review and an individual patient-level image analysis of CT findings of COVID-19-associated pulmonary aspergillosis (CAPA). MethodsA systematic literature search was conducted to identify studies reporting CT findings of CAPA as of January 7, 2021. We summarized study-level clinical and CT findings of CAPA and collected individual patient CT images by inviting corresponding authors. The CT findings were categorized into four groups: group 1, typical appearance of COVID-19; group 2, indeterminate appearance of COVID-19; group 3, atypical for COVID-19 without cavities; and group 4, atypical for COVID-19 with cavities. In group 2, cases had only minor discrepant findings including solid nodules, isolated airspace consolidation with negligible ground-glass opacities, centrilobular micronodules, bronchial abnormalities, and cavities. ResultsThe literature search identified 89 patients from 25 studies, and we collected CT images from 35 CAPA patients (mean age 62.4 ± 14.6 years; 21 men): group 1, thirteen patients (37.1%); group 2, eight patients (22.9%); group 3, six patients (17.1%); and group 4, eight patients (22.9%). Eight of the 14 patients (57.1%) with an atypical appearance had bronchial abnormalities, whereas only one (7.1%) had an angio-invasive fungal pattern. In the study-level analysis, cavities were reported in 12 of 54 patients (22.2%). ConclusionCAPA can frequently manifest as COVID-19 pneumonia without common CT abnormalities of pulmonary aspergillosis. If abnormalities exist on CT images, CAPA may frequently accompany bronchial abnormalities.

Microsatellite instability and sex differences in resectable gastric cancer – A pooled analysis of three European cohorts

ObjectiveBiological sex differences in cancer are increasingly acknowledged. Here, we examined these differences in clinicopathological characteristics and survival in microsatellite instability (MSI)-high and microsatellite stable (MSS) gastric cancer (GC). DesignWe analysed MSI status by polymerase chain reaction (PCR) and/or mismatch repair (MMR) status by immunohistochemistry in a pooled analysis of individual patient data from one retrospective cohort from Cologne, and the randomised phase III clinical trials D1/D2 and CRITICS. All patients had resectable adenocarcinoma of the stomach and/or gastro-oesophageal junction. Patients were treated with either surgery only or perioperative chemo(radio)therapy. ResultsMSI and/or MMR analyses on 1307 tumours resulted in 1192 (91.2%) MSS and/or MMR proficient (MMRP) [median age, 65 years; 759 males (63.7%); 619 treated with surgery only (51.9%)], and 115 (8.8%) MSI-high [median age, 69 years; 67 males (58.3%); 76 treated with surgery only (66.1%)] GC cases. Males had shorter overall survival (OS) than female MSI-high GC (5-year OS 34.7% vs. 69.7%; hazard ratio (HR) 2.68, 95%CI 1.60 to 4.49; p < 0.001). Females with MSI-high had longer OS than those with MSS/MMRP GC (HR 0.61, 95%CI 0.41 to 0.92; p = 0.02). Males with MSI-high did not have longer OS than those with MSS/MMRP GC (HR 1.26, 95%CI 0.94 to 1.69; p = 0.12). ConclusionsMSI-high GC males had a significantly worse prognosis compared to their female counterparts in three independent cohorts. In addition, the favourable prognostic value of MSI was only seen in females and not in males. These observations emphasise the need to consider sex differences in prognosis and treatment effects in oncology. Clinical trial registrationThe CRITICS trial is registered at ClinicalTrials.gov, number NCT00407186; EudraCT, number 2006-004130-32; and CKTO, 2006-02.

Comparison of recommended daily energy intakes in people with cirrhosis, based on current guidelines, and their directly measured energy requirements: an individual patient data analysis

Comparison of recommended daily energy intakes in people with cirrhosis, based on current guidelines, and their directly measured energy requirements: an individual patient data analysis

Infertility, recurrent pregnancy loss, and risk of stroke: pooled analysis of individual patient data of 618 851 women

ObjectiveTo examine the associations of infertility, recurrent miscarriage, and stillbirth with the risk of first non-fatal and fatal stroke, further stratified by stroke subtypes.DesignIndividual participant pooled analysis of eight prospective...

Developing and implementing a self-monitoring toolkit for a coordinated multinational randomized acupuncture trial

BackgroundIn 2019, investigators from China, South Korea and the United States of America initiated a coordinated multinational trial. The trial included three parallel randomized studies with a planned pooled analysis of individual patient data, to test the effectiveness of acupuncture on hot flash-related symptoms in hormone receptor-positive breast cancer patients prescribed adjuvant endocrine therapy. Given the study's approach, there was no central coordinating center or data monitoring committee for the study, so a site performance self-monitoring toolkit was developed and implemented to support study teams in collecting and maintaining high-quality regulatory information, and consistent review of study data and documentation.MethodsThe site performance self-monitoring toolkit was created based on best practices related to post-approval quality assurance/quality improvement (QA/QI) procedures that support data quality. The toolkit included: (1) a binder of essential study management documents and related monitoring logs for sites to complete and maintain (herein called regulator binder), (2) a study start-up checklist, (3) a self-assessment study conduct and oversight checklist to be completed regularly, and (4) a study close-out checklist. In addition, a process of regular virtual meetings to discuss documentation progress coupled with periodic external remote review of completed logs and checklists provided accountability checks.ResultsOver the course of the study, the sites in China and South Korea completed the entirety of the site performance self-monitoring toolkit, and successfully submitted their completed materials for review. The process of implementing a self-monitoring toolkit in a multinational integrative medicine study is described qualitatively. Periodic external review of the completed toolkit materials revealed categories of findings. Written follow-up reports were provided to sites and discussion of the documents occurred via separate virtual meetings.ConclusionsSite study team self-monitoring provides a feasible, consistent, and effective way to review the collection and maintenance of data and regulatory documentation for quality assessment in minimal risk clinical research studies and can augment formal study monitoring activities in higher risk studies. Iterative feedback and support appeared to drive a disciplined approach to maintaining regulatory document compliance and helped sustain investigator and study team engagement in the process.Trial registrationClinicalTrials.gov Identifier NCT03783546 (21/12/2018).