Purpose
To determine the efficacy and toxicity of re-irradiation for patients with recurrent GBM.
Materials and methods
We searched various biomedical databases from 1998 to 2018, for eligible ...studies where patients were treated with re-irradiation for recurrent GBM. Outcomes of interest were 6 and 12-month overall survival (OS-6, OS-12), 6 and 12-month progression free survival (PFS-6, PFS-12) and serious (Grade 3 +) adverse events (AE). We used the random effects model to pool outcomes across studies and compared pre-defined subgroups using interaction test. Methodological quality of each study was assessed using the Newcastle-Ottawa scoring system.
Results
We found 50 eligible non-comparative studies including 2095 patients. Of these, 42% were of good or fair quality. The pooled results were as follows: OS-6 rate 73% (95% confidence interval (CI) 69–77%), OS-12 rate 36% (95% CI 32–40%), PFS-6 rate 43% (95% CI 35–50%), PFS-12 rate 17% (95% CI 13–20%), and Grade 3 + AE rate 7% (95% CI 4–10%). Subgroup analysis showed that prospective studies reported higher toxicity rates, and studies which utilized brachytherapy to have a longer OS-12. Within the external beam radiotherapy group, there was no dose–response above or below 36 Gy in 2 Gy equivalent doses (EQD2). However, a short fractionation regimen (≤ 5 fractions) seemed to provide superior PFS-6.
Conclusion
The available evidence, albeit mostly level III, suggests that re-irradiation provides encouraging disease control and survival rates. Toxicity was not uniformly reported, but seemed to be low from the included studies. Randomized controlled trials (RCT) are needed to establish the optimal management strategy for recurrent GBM.
To compare the efficacy of covid-19 vaccines between immunocompromised and immunocompetent people.
Systematic review and meta-analysis.
PubMed, Embase, Central Register of Controlled Trials, COVID-19 ...Open Research Dataset Challenge (CORD-19), and WHO covid-19 databases for studies published between 1 December 2020 and 5 November 2021. ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform were searched in November 2021 to identify registered but as yet unpublished or ongoing studies.
Prospective observational studies comparing the efficacy of covid-19 vaccination in immunocompromised and immunocompetent participants.
A frequentist random effects meta-analysis was used to separately pool relative and absolute risks of seroconversion after the first and second doses of a covid-19 vaccine. Systematic review without meta-analysis of SARS-CoV-2 antibody titre levels was performed after first, second, and third vaccine doses and the seroconversion rate after a third dose. Risk of bias and certainty of evidence were assessed.
82 studies were included in the meta-analysis. Of these studies, 77 (94%) used mRNA vaccines, 16 (20%) viral vector vaccines, and 4 (5%) inactivated whole virus vaccines. 63 studies were assessed to be at low risk of bias and 19 at moderate risk of bias. After one vaccine dose, seroconversion was about half as likely in patients with haematological cancers (risk ratio 0.40, 95% confidence interval 0.32 to 0.50, I
=80%; absolute risk 0.29, 95% confidence interval 0.20 to 0.40, I
=89%), immune mediated inflammatory disorders (0.53, 0.39 to 0.71, I
=89%; 0.29, 0.11 to 0.58, I
=97%), and solid cancers (0.55, 0.46 to 0.65, I
=78%; 0.44, 0.36 to 0.53, I
=84%) compared with immunocompetent controls, whereas organ transplant recipients were 16 times less likely to seroconvert (0.06, 0.04 to 0.09, I
=0%; 0.06, 0.04 to 0.08, I
=0%). After a second dose, seroconversion remained least likely in transplant recipients (0.39, 0.32 to 0.46, I
=92%; 0.35, 0.26 to 0.46), with only a third achieving seroconversion. Seroconversion was increasingly likely in patients with haematological cancers (0.63, 0.57 to 0.69, I
=88%; 0.62, 0.54 to 0.70, I
=90%), immune mediated inflammatory disorders (0.75, 0.69 to 0.82, I
=92%; 0.77, 0.66 to 0.85, I
=93%), and solid cancers (0.90, 0.88 to 0.93, I
=51%; 0.89, 0.86 to 0.91, I
=49%). Seroconversion was similar between people with HIV and immunocompetent controls (1.00, 0.98 to 1.01, I
=0%; 0.97, 0.83 to 1.00, I
=89%). Systematic review of 11 studies showed that a third dose of a covid-19 mRNA vaccine was associated with seroconversion among vaccine non-responders with solid cancers, haematological cancers, and immune mediated inflammatory disorders, although response was variable in transplant recipients and inadequately studied in people with HIV and those receiving non-mRNA vaccines.
Seroconversion rates after covid-19 vaccination were significantly lower in immunocompromised patients, especially organ transplant recipients. A second dose was associated with consistently improved seroconversion across all patient groups, albeit at a lower magnitude for organ transplant recipients. Targeted interventions for immunocompromised patients, including a third (booster) dose, should be performed.
PROSPERO CRD42021272088.
To assess the quality of reporting of cranial irradiation (CR) techniques in randomized controlled trials (RCTs) of primary brain tumors.
We searched PubMed and EMBASE for RCTs of primary brain ...tumors, published from January 1999 to November 2019 which included CR as one of the intervention arms. We assessed the initial RCTs report on whether they reported the prespecified ten criteria for CR technique adequately. Multivariable logistic regression was performed to determine the factors that were predictive of adequate quality of reporting.
We found 85 eligible trial reports. There was significant variability in the quality of reporting among the included studies. Total radiotherapy (RT) dose and fractionation schedule were reported adequately in more than 90% of the included trials. The organs at risk dose constraints, treatment verification procedures and presence or absence of deviations in RT treatment planning and delivery were reported adequately in less than 30% of included trials. Twenty-three trials (27%) reported seven criteria or more adequately. Multivariable analysis showed that trials conducted by cooperative groups, published RT quality assurance results and having a low risk of bias in the methodological quality have higher odds of having adequate quality in reporting of CR technique (judged as adequate reporting in seven criteria or more).
The quality of reporting on CR techniques in the RCTs of primary brain tumors is variable and suboptimal. Guidelines should be introduced to improve clarity and ensure consistency in the quality of reporting.
To evaluate the rate of discordance of epidermal growth factor receptor (EGFR) mutation between primary lung tumor and paired distant metastases in non-small-cell lung cancer (NSCLC).
We performed a ...meta-analysis of 17 studies (518 cases) assessing discordance rates of EGFR mutation in primary tumors and paired distant metastases. We performed subgroup analyses based on EGFR mutation status in primary tumor (mutant or wildtype), site of distant metastasis (bone, central nervous system (CNS) or lung/ pleural), methods of testing (direct sequencing or allele-specific testing) and timing of metastasis (synchronous or metachronous).
The overall discordance rate in EGFR mutation was low at 10.36% (95% CI = 4.23% to 18.79%) and varied widely between studies (I2 = 83.18%). The EGFR discordance rate was statistically significantly higher in bone metastases (45.49%, 95% CI = 14.13 to 79.02) than CNS (17.26%, 95% CI = 7.64 to 29.74; P = 0.002) and lung/ pleural metastases (8.17%, 95% CI = 3.35 to 14.85; P < 0.001). Subgroup analyses did not demonstrate any significant effect modification on the discordance rates by the EGFR mutation status in primary lung tumor, methods of testing and timing of metastasis.
The overall discordance rate in EGFR mutation between primary lung tumor and paired distant metastases in NSCLC is low, although higher discordance rates were observed in bone metastases compared with CNS and lung/pleural metastases. Future studies assessing the impact of EGFR mutation discordance on treatment outcomes are required.
BackgroundThe COVID-19 has caused significant mortality and morbidity across the globe. Patients with cancer are especially vulnerable given their immunocompromised state. We aimed to determine the ...proportion of COVID-19 patients with cancer, their severity and mortality outcomes through a systematic review and meta-analysis (MA).MethodsSystematic review was performed through online databases, PubMed, Medline and Google Scholar, with keywords listed in the Methods section (1 November 2019–31 December 2020). Studies with clinical outcomes of at least 10 COVID-19 patients and at least one with a diagnosis of cancer were included. The studies for MA were assessed with PRISMA guidelines and appraised with Newcastle-Ottawa Scale. The data were pooled using a random-effects model using STATA software. The main outcomes were planned before data collection, including proportion of patients with cancer among COVID-19 populations, relative risk (RR) of severe outcomes and death of patients with cancer compared with general COVID-19 patients.ResultsWe identified 57 case series (63 413 patients), with 230 patients with cancer with individual patient data (IPD). We found that the pooled proportion of cancer among COVID-19 patients was 0.04 (95% CI 0.03 to 0.05, I2=97.69%, p<0.001). The pooled RR of death was 1.44 (95% CI 1.19 to 1.76) between patients with cancer and the general population with COVID-19 infection. The pooled RR of severe outcome was 1.49 (95% CI 1.18 to 1.87) between cancer and general COVID-19 patients. The presence of lung cancer and stage IV cancer did not result in significantly increased RR of severe outcome. Among the available IPD, only age and gender were associated with severe outcomes.ConclusionPatients with cancer were at a higher risk of severe and death outcomes from COVID-19 infection as compared with general COVID-19 populations. Limitations of this study include publication bias. A collaborative effort is required for a more complete database.
There are limited studies on the association between systemic autoimmune rheumatic diseases (SARDs) and leptospirosis. Therefore, this study aims to identify the effects of leptospirosis on the risks ...of developing SARDs with a nationwide retrospective cohort study. Patients with leptospirosis who did not have a diagnosis of SARDs before the index date were enrolled from the Taiwan National Health Insurance Research Database between 2000 and 2010, as the leptospirosis cohort. For each patient with leptospirosis, one control without a history of leptospirosis and SARDs was randomly selected (non-leptospirosis cohort). Cox proportional hazards regression models were used to analyze the risk of SARDs according to sex, age, and comorbidities. Among the 23 million people in the cohort, 3,393 patients with leptospirosis (68.91% men, mean age 52.65 years) and 33,930 controls were followed for 18,778 and 232,999 person-years, respectively. The incidence of SARDs was higher in the leptospirosis cohort than in the non-leptospirosis cohort (1.38 vs 0.33 per 1000 person-years), with a hazard ratio (HR) of 4.42 (95% confidence interval CI = 2.82-6.92). The risk of developing SARDs was highest for leptospirosis patients aged ≥65 years (HR = 2.81% CI = 1.07-7.36) compared with patients aged ≤39 years. Patients with leptospirosis have a 4.42-fold higher risk of SARDs than that in the general population. Further research is warranted to investigate the mechanism underlying this association.
Immune‐related adverse events (IrAEs) of immune checkpoint inhibitors (ICIs) can be serious and unpredictable. We examine the incidence rate and risk factors for IrAEs in an Asian cohort of nonsmall ...cell lung cancer (NSCLC) patients treated with immunotherapy. Between June 2014 and August 2020, we retrospectively analysed IrAEs in NSCLC patients treated with anti‐PD‐1 or anti‐PD‐L1 inhibitors at the National University Cancer Institute, Singapore. A Poisson regression model was used to estimate the effect of risk factors on incidence rate of any grade IrAEs. One hundred and forty‐one patients were enrolled. Median age was 63. Majority were male (67%) with Eastern Cooperative Oncology Group (ECOG) PS 0‐1 (77%). More than half (56%) received pembrolizumab. Eleven percent harboured epidermal growth factor receptor (EGFR) mutation. Eighteen percent received concomitant chemotherapy. Median number of cycles was 4, and median duration of treatment was 2.1 months. IrAEs were seen in 71 (50.4%) patients, with an incidence rate of 99 events per 1000 person‐months. Fatigue (25%), rash (10.5%) and pneumonitis (7.9%) were the most common IrAEs. Twenty out of 152 IrAEs (13.2%) were Grade 3 or higher in severity: most common being pneumonitis (5.3%), fatigue (3.3%) and transaminitis (1.3%). Multivariable analysis demonstrated that concomitant chemotherapy use, higher BMI and presence of EGFR mutation are significant predictors for IrAEs (P < .0001; P = .016; P = .007). Our findings can help guide risk stratification and monitoring of IrAEs among NSCLC patients on immunotherapy.
What's new?
Immunotherapy is the mainstay of treatment for nonsmall cell lung cancers that lack oncogenic drivers. However, few studies have examined the risk factors for the potential immune‐related adverse events associated with immunotherapy. This retrospective study in an Asian cohort found that lung cancer patients who had concomitant chemotherapy use, a higher body mass index, and sensitising EGFR mutations were at higher risk of developing immune‐related adverse events with anti‐PD1 or anti‐PDL1 treatment. The findings can help guide risk stratification and the monitoring of immune‐related adverse events among patients receiving immunotherapy.
To determine if it is preferable to extend chemotherapy beyond a standard number of cycles in patients receiving first-line chemotherapy for advanced non-small-cell lung cancer.
We searched ...biomedical literature databases and conference proceedings for randomized controlled trials (RCTs) comparing a defined number of cycles with continuation of the same chemotherapy until disease progression, a larger defined number of cycles of identical chemotherapy, and a defined number of cycles of identical initial chemotherapy followed by additional cycles of an alternative chemotherapy. Meta-analysis was performed using the fixed effect model. The primary outcome was overall survival (OS); secondary outcomes included progression-free survival (PFS), adverse events (AE), and health-related quality of life (HRQL).
We found 13 RCTs including 3,027 patients. Extending chemotherapy improved PFS substantially (hazard ratio HR, 0.75; 95% CI, 0.69 to 0.81; P < .00001) and OS modestly (HR, 0.92; 95% CI, 0.86 to 0.99; P = .03). Subgroup analysis revealed that effects on PFS were greater for trials extending chemotherapy with third-generation regimens rather than older regimens (HR, 0.70 interaction v 0.92 interaction; P = .003). Extending chemotherapy was associated with more frequent AE in all trials where it was reported and impaired HRQL in two of seven trials.
Extending chemotherapy, particularly with a third-generation regimen, improved PFS substantially, but OS less so. Future trials should test extending treatment with more effective and/or better-tolerated agents.
Cohesive sediments exhibit complex rheological behaviors that are non-Newtonian and time-dependent when subjected to external loading. This paper presents the results of an investigation on the ...theological properties of three types of dense cohesive sediments, collected from the mouth of the Yangtze River, the shoal of the ttangzhou Bay, and the Yangcheng Lake in China. A set of rheological parameters （including viscosity, yield stress, etc.） was studied based on experiments that were conducted with a RheolabQC rheometer. Measurements of the flow curves, shear stress-time responses, and yield stresses were made. The solid-liquid transition of the dense cohesive sediments occurred both in the shear rate ramp tests and the shear stress ramp tests. This transition was not direct, but it was mediated by a transitional deformation regime or stress plateau. Both the Herschel-Bulkley model and Carreau model were able to describe the theological behavior of dense cohesive sediments, and the empirical expressions for calculating the parameters in these models were obtained by a dimensional and regression analysis. The yield stresses determined by the shear stress ramp test and by the vane method were compared and discussed. The influence of the water content on the rheological properties of dense cohesive sediments was considered.
The primary objective was to quantify changes in vascular micro-environment in spinal metastases (SM) patients treated with stereotactic body radiotherapy (SBRT) with multi-parametric dynamic ...contrast enhanced (DCE) magnetic resonance imaging (MRI). The secondary objective was to study plasma biomarkers related to endothelial apoptosis.
Patients were imaged with DCE-MRI at baseline/1-week/12-weeks post-SBRT. Metrics including normalised time-dependent leakage (Ktrans), permeability surface product (PS), fractional plasma volume (Vp), extracellular volume (Ve) and perfusion (F) were estimated using distributed parameter model. Serum acid sphingomyelinase (ASM) and sphingosine-1-phosphate (S1P) were quantified using ELISA. Clinical outcomes including physician-scored and patient-reported toxicity were collected.
Twelve patients (with varying primary histology) were recruited, of whom 10 underwent SBRT. Nine patients (with 10 lesions) completed all 3 imaging assessment timepoints. One patient died due to pneumonia (unrelated) before follow-up scans were performed. Median SBRT dose was 27 Gy (range: 24-27) over 3 fractions (range: 2-3). Median follow-up for alive patients was 42-months (range: 22.3-54.3), with local control rate of 90% and one grade 2 or higher toxicity (vertebral compression fracture). In general, we found an overall trend of reduction at 12-weeks in all parameters (Ktrans/PS/Vp/Ve/F). Ktrans and PS showed a reduction as early as 1-week. Ve/Vp/F exhibited a slight rise 1-week post-SBRT before reducing below the baseline value. There were no significant changes, post-SBRT, in plasma biomarkers (ASM/S1P).
Tumour vascular micro-environment (measured by various metrics) showed a general trend towards downregulation post-SBRT. It is likely that vascular-mediated cell killing contributes to excellent local control rates seen with SBRT. Future studies should evaluate the effect of SBRT on primary-specific spinal metastases (e.g., renal cell carcinoma).
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