Large International Clinical Trial Research Articles

CNS Involvement in Pediatric Hodgkin Lymphoma: A Comprehensive Retrospective Analysis from the Staging, Evaluation and Response Criteria Harmonization (SEARCH) for Childhood, Adolescent and Young Adult Hodgkin Lymphoma (CAYAHL) Group

Introduction Hodgkin lymphoma (HL) accounts for approximately 7% of childhood cancer, most frequent in adolescents and young adults. In contrast to non-Hodgkin lymphoma (NHL), central nervous system (CNS) involvement at the time of diagnosis with HL is rare and poorly understood. Information regarding the clinical presentation, management, response to treatment and outcome of patients who exhibit this finding is limited to case reports or small series. We sought to describe CNS involvement at the time of diagnosis with pediatric HL by performing a retrospective analysis of 3 large international clinical trials. Methods Patients with CNS involvement were identified from the imaging databases of the COG trial AHOD1331 (NCT02166463) and EuroNet trials PHL-C1 (NCT00433459, EudraCT 2006-000995-33) and PHL-C2 (NCT02684708, EudraCT 2012-004053-88). Imaging was reviewed collaboratively by COG and Euronet radiologists and nuclear medicine physicians with expertise in HL, with input from radiation oncologists and pediatric oncologists. All identified cases of CNS involvement had morphologic (CT) and metabolic (FDG-PET) imaging prior to initiation of therapy, as well as disease response assessment after 2 cycles of therapy. Variables evaluated included: age, sex, Ann Arbor stage, histology, symptoms at the time of presentation (pain, neurologic symptoms), corticosteroid administration prior to FDG-PET scan, number and location of CNS lesions, tissue of origin of the CNS lesion, anatomic description of the involvement of the CNS lesion, number and location of E-lesions, whether emergency irradiation or an operative procedure were performed at diagnosis, FDG tracer uptake at the time of initial staging, response of the CNS lesions after 2 cycles of chemotherapy, whether relapse occurred and in which location. CNS involvement was defined in 2 ways: (1) lesions originating within the CNS parenchyma and (2) lesions extending into the CNS. Results 45 patients with 55 CNS lesions were identified from a combined cohort of 5569 patients with a new diagnosis of HL. 9 patients presented with pain and 4 with neurologic symptoms, however information regarding clinical symptoms was not available for 34/45 patients. Symptoms corresponded to the location of the CNS lesion. All identified lesions extended into the CNS from surrounding tissue, none originated within the CNS parenchyma. 82.2% of patients had a single lesion extending into the CNS, most commonly through the neural foramina into the thoracic spine (45.5%), sacrum (23.6%) or lumbar spine (21.8%). Lesions originated from adjacent bone (45%) or soft tissue (40%). 89% of patients with CNS lesions had stage IV HL, and 68.8% had extranodal (non-CNS) disease. 54.8% of lesions displaced the spinal cord, but none infiltrated the spinal cord itself. After 2 cycles of chemotherapy, 67.3% of CNS lesions had a >75% reduction in size or complete resolution, and 32.7% of CNS lesions decreased in volume by 50-75%. A residual mass was present for 74% of lesions involving the neural foramina after 2 cycles of chemotherapy. 89.1% of lesions were PET negative at interim response assessment (IRA). 2 CNS lesions were associated with relapse at the CNS site, these were PET negative at IRA. 13 lesions received irradiation, none of these were sites of subsequent relapse. Conclusions This large, combined cohort of intermediate- and high-risk pediatric patients enrolled on clinical trials from 2007 to 2021 confirms the rarity of CNS involvement at the time of diagnosis with HL, with an overall incidence of 0.8%. Importantly, CNS lesions extended from adjacent tissue and did not originate within the CNS itself. These lesions never directly infiltrated the brain parenchyma or spinal cord. They were highly metabolically active at diagnosis, and demonstrated an excellent metabolic and morphologic response to the first 2 cycles of chemotherapy. Patients with CNS involvement had a 2-fold greater incidence of extranodal disease than previously reported cohorts. In summary, this retrospective study provides key information about CNS involvement in pediatric HL at the time of diagnosis, contributing to our understanding of this rare, yet important, clinical presentation.

Sex differences in pain expressed by patients across diverse disease states: individual patient data meta-analysis of 33,957 participants in 10 randomized controlled trials.

The experience of pain is determined by many factors and has a significant impact on quality of life. This study aimed to determine sex differences in pain prevalence and intensity reported by participants with diverse disease states in several large international clinical trials. Individual participant data meta-analysis was conducted using EuroQol-5 Dimension (EQ-5D) questionnaire pain data from randomised controlled trials published between January 2000 and January 2020 and undertaken by investigators at the George Institute for Global Health. Proportional odds logistic regression models, comparing pain scores between females and males and fitted with adjustments for age and randomized treatment, were pooled in a random-effects meta-analysis. In 10 trials involving 33,957 participants (38% females) with EQ-5D pain score data, the mean age ranged between 50 and 74. Pain was reported more frequently by females than males (47% vs 37%; P < 0.001). Females also reported greater levels of pain than males (adjusted odds ratio 1.41, 95% CI 1.24-1.61; P < 0.001). In stratified analyses, there were differences in pain by disease group ( P for heterogeneity <0.001), but not by age group or region of recruitment. Females were more likely to report pain, and at a higher level, compared with males across diverse diseases, all ages, and geographical regions. This study reinforces the importance of reporting sex-disaggregated analysis to identify similarities and differences between females and males that reflect variable biology and may affect disease profiles and have implications for management.

JCS/JHRS 2021 guideline focused update on non-pharmacotherapy of cardiac arrhythmias.

JCS/JHRS 2021 guideline focused update on non-pharmacotherapy of cardiac arrhythmias.

Association of Apolipoprotein B–Containing Lipoproteins and Risk of Myocardial Infarction in Individuals With and Without Atherosclerosis

Lipid management typically focuses on levels of low-density lipoprotein cholesterol (LDL-C) and, to a lesser extent, triglycerides (TG). However, animal models and genetic studies suggest that the atherogenic particle subpopulations (LDL and very-low-density lipoprotein [VLDL]) are both important and that the number of particles is more predictive of cardiac events than their lipid content. To determine whether common measures of cholesterol concentration, TG concentration, or their ratio are associated with cardiovascular risk beyond the number of apolipoprotein B (apoB)-containing lipoproteins. This prospective cohort analysis included individuals from the population-based UK Biobank and from 2 large international clinical trials, FOURIER and IMPROVE-IT. The median (IQR) follow-up was 11.1 (10.4-11.8) years in UK Biobank and 2.5 (2.0-4.7) years in the clinical trials. Two populations were studied in this analysis: 389 529 individuals in the primary prevention group who were not taking lipid-lowering therapy and 40 430 patients with established atherosclerosis who were receiving statin treatment. ApoB, non-high-density lipoprotein cholesterol (HDL-C), LDL-C, and TG. The primary study outcome was incident myocardial infarction (MI). Of the 389 529 individuals in the primary prevention group, 224 097 (58%) were female, and the median (IQR) age was 56.0 (49.5-62.5) years. Of the 40 430 patients with established atherosclerosis, 9647 (24%) were female, and the median (IQR) age was 63 (56.2-69.0) years. In the primary prevention cohort, apoB, non-HDL-C, and TG each individually were associated with incident MI. However, when assessed together, only apoB was associated (adjusted hazard ratio [aHR] per 1 SD, 1.27; 95% CI, 1.15-1.40; P < .001). Similarly, only apoB was associated with MI in the secondary prevention cohort. Adjusting for apoB, there was no association between the ratio of TG to LDL-C (a surrogate for the ratio of TG-rich lipoproteins to LDL) and risk of MI, implying that for a given concentration of apoB-containing lipoproteins, the relative proportions of particle subpopulations may no longer be a predictor of risk. In this cohort study, risk of MI was best captured by the number of apoB-containing lipoproteins, independent from lipid content (cholesterol or TG) or type of lipoprotein (LDL or TG-rich). This suggests that apoB may be the primary driver of atherosclerosis and that lowering the concentration of all apoB-containing lipoproteins should be the focus of therapeutic strategies.

Combined BRAF-Targeted Therapy with Immunotherapy in BRAF-Mutated Advanced Melanoma Patients.

To review evidence on the efficacy and safety of combined BRAF-targeted therapy and immune checkpoint inhibitors in patients with BRAF-mutated metastatic melanoma. Programmed death-1 pathway inhibitors administered with BRAF/MEK inhibitors showed promising anti-tumour activity in BRAF-mutated advanced melanoma and were investigated for safety and efficacy in three large international clinical trials. Although, in two out of those three randomized phase III studies, progression-free survival (PFS) did not reach statistical significance, results showed that duration of response (DOR) and overall survival (OS) were improved using combined therapy, sustaining the scientific rationale for its use at least in a subset of metastatic melanomas. However, the frequent occurrence of autoimmunity-induced toxicities should be considered since it is limiting the continuity and the wide application of these regimens. Novel treatment modalities combining targeted therapy with checkpoint inhibitors require further clinical investigation and elucidation of their effect on the immune system and cancer cell modulation.

Management of post-transplant lymphoproliferative disorders.

Management of post-transplant lymphoproliferative disorders.

Head Position in Stroke Trial (HeadPoST) – sitting-up vs lying-flat positioning of patients with acute stroke: study protocol for a cluster randomised controlled trial

BackgroundPositioning a patient lying-flat in the acute phase of ischaemic stroke may improve recovery and reduce disability, but such a possibility has not been formally tested in a randomised trial. We therefore initiated the Head Position in Stroke Trial (HeadPoST) to determine the effects of lying-flat (0°) compared with sitting-up (≥30°) head positioning in the first 24 hours of hospital admission for patients with acute stroke.Methods/DesignWe plan to conduct an international, cluster randomised, crossover, open, blinded outcome-assessed clinical trial involving 140 study hospitals (clusters) with established acute stroke care programs. Each hospital will be randomly assigned to sequential policies of lying-flat (0°) or sitting-up (≥30°) head position as a ‘business as usual’ stroke care policy during the first 24 hours of admittance. Each hospital is required to recruit 60 consecutive patients with acute ischaemic stroke (AIS), and all patients with acute intracerebral haemorrhage (ICH) (an estimated average of 10), in the first randomised head position policy before crossing over to the second head position policy with a similar recruitment target. After collection of in-hospital clinical and management data and 7-day outcomes, central trained blinded assessors will conduct a telephone disability assessment with the modified Rankin Scale at 90 days. The primary outcome for analysis is a shift (defined as improvement) in death or disability on this scale. For a cluster size of 60 patients with AIS per intervention and with various assumptions including an intracluster correlation coefficient of 0.03, a sample size of 16,800 patients at 140 centres will provide 90 % power (α 0.05) to detect at least a 16 % relative improvement (shift) in an ordinal logistic regression analysis of the primary outcome. The treatment effect will also be assessed in all patients with ICH who are recruited during each treatment study period.DiscussionHeadPoST is a large international clinical trial in which we will rigorously evaluate the effects of different head positioning in patients with acute stroke.Trial registrationClinicalTrials.gov identifier: NCT02162017 (date of registration: 27 April 2014); ANZCTR identifier: ACTRN12614000483651 (date of registration: 9 May 2014). Protocol version and date: version 2.2, 19 June 2014.Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-015-0767-1) contains supplementary material, which is available to authorized users.

Physical activity as a determinant of fasting and 2-h post-challenge glucose: a prospective cohort analysis of the NAVIGATOR trial.

To investigate whether previous physical activity levels are associated with blood glucose levels in individuals with impaired glucose tolerance in the context of an international pharmaceutical trial. Data were analysed from the NAVIGATOR trial, which involved 9306 individuals with impaired glucose tolerance and high cardiovascular risk from 40 different countries, recruited in the period 2002-2004. Fasting glucose, 2-h post-challenge glucose and physical activity (pedometer) were assessed annually. A longitudinal regression analysis was used to determine whether physical activity levels 2years (t-2 ) and 1year (t-1 ) previously were associated withlevels of glucose, after adjusting for previous glucose levels and other patient characteristics. Those participants with four consecutive annual measures of glucose and two consecutive measures of physical activity were included in the analysis. The analysis included 3964 individuals. Change in physical activity from t-2 to t-1 and activity levels at t-2 were both associated with 2-h glucose levels after adjustment for previous glucose levels and baseline characteristics; however, the associations were weak: a 100% increase in physical activity was associated with a 0.9% reduction in 2-h glucose levels. In addition, previous physical activity only explained an additional 0.05% of the variance in 2-h glucose over the variance explained by the history of 2-h glucose alone (R(2) =0.3473 vs. 0.3468). There was no association with fasting glucose. In the context of a large international clinical trial, previous physical activity levels did not meaningfully influence glucose levels in those with a high risk of chronic disease, after taking into account participants' previous trajectory of glucose control.

Resumption of HIV replication is associated with monocyte/macrophage derived cytokine and chemokine changes: results from a large international clinical trial

There is increasing interest in the role of immune activation and inflammation in HIV disease, but data on direct effects of HIV replication on immune cell activation are limited. High sensitivity multiplex bead array assays (MBAAs) were used to measure changes in plasma cytokines and chemokines [interleukin (IL)-1β, IL-2, IL-6, IL-7, IL-8, IL-12p70, IL-17, tumor necrosis factor-α (TNFα), interferon-γ, granulocyte macrophage colony-stimulating factor, IL-4, IL-5, IL-10, IL-13, CXCL10] from randomization (month 0) to month 2 in a random sample of 200 patients from both the drug conservation (DC) and viral suppression (VS) arms of the Strategies for Management of Antiretroviral Therapy (SMART) trial. IL-6 was also measured by ELISA. Data were evaluated using nonparametric correlation and censored parametric analysis of covariance and associations were declared as statistically significant when the Bonferroni-adjusted P-value was less than 0.003. Compared with the VS arm, significant increases were seen in the DC arm for TNFα (+0.34 log(e) pg/ml, P = 0.0001), IL-10 (+0.33 log(e) pg/ml, P = 0.00001) and CXCL10 (+0.66 log(e) pg/ml, P = 0.00001). IL-6 ELISA poorly correlated with IL-6 MBAA (Spearman's rho = 0.29, P = 0.0001). Resumption of HIV replication after ceasing antiretroviral therapy is associated predominantly with an increase of monocyte/macrophage-derived cytokines. Measurement of IL-6 levels may be affected by assay method and this should be considered in future studies of biomarkers.

Cost effectiveness of palivizumab in Spain: an analysis using observational data

ObjectivesTo assess the cost effectiveness of palivizumab for prevention of severe respiratory syncytial virus (RSV) disease in high-risk infants in Spain, incorporating country-specific observational hospitalisation data.MethodsAn existing decision tree model, designed using data from a large international clinical trial of palivizumab versus no prophylaxis, was updated to include Spanish observational hospitalisation data. The analysis was performed for preterm children born at or before 32 weeks gestational age, who are at high risk of developing severe RSV disease requiring hospitalisation. Data sources included published literature, official price/tariff lists and national population statistics. The primary perspective of the study was that of the Spanish National Health Service in 2006.ResultsThe base-case analysis included the direct medical costs associated with palivizumab prophylaxis and hospital care for RSV infections. Use of palivizumab produces an undiscounted incremental cost-effectiveness ratio (ICER) of €6,142 per quality-adjusted life-year (QALY), and a discounted ICER of €12,814/QALY.ConclusionPalivizumab provides a cost-effective method of prophylaxis against severe RSV disease requiring hospitalisation among preterm infants in Spain.

Highlights of Swedish ophthalmology in the 20th century

Highlights of Swedish ophthalmology in the 20th century

A detailed analysis of the risk factors influencing local and distant breast cancer recurrence during adjuvant endocrine therapy

562 Background: The ‘Arimidex’, Tamoxifen, Alone or in Combination (ATAC; ISRCTN18233230 ) trial compared the efficacy and safety of 5 years’ anastrozole, tamoxifen, or combination as adjuvant therapy for 9366 postmenopausal women with early invasive breast cancer. Here, risk factors influencing local and distant recurrences during the trial, independent of trial treatment, are assessed. Methods: The influence of standard baseline factors such as hormone receptor status, nodal involvement, tumor size, grade and age were evaluated on both local and distant recurrence rates. The use of other treatments (adjuvant chemotherapy, radiotherapy) and surgical status (mastectomy and axillary surgery) were also included. In addition, weight, body mass index, hysterectomy and prior hormone- replacement therapy were added. Cox models were used to analyze events by prognostic factors, and subsequently adjusted by country, before the production of confirmatory models. Results: For both local and distant recurrence, the highest risk correlated with poorer tumor differentiation, larger tumor size, increased nodal involvement and a negative hormone receptor status (see table ). While surgical status also affected the risk of developing a recurrence, previous treatments were less important, but residence in the USA showed a significant advantage. No association was seen with hysterectomy or weight for any recurrence. Conclusions: Although the pattern of risk varied for local and distant recurrence, tumor grade, size, and nodal involvement were the strongest risk factors for both. In comparison, the impact of previous treatments on hazard risk was lower. These data from a large international clinical trial confirm that women with less differentiated or larger tumors, and those with involved nodes, are at an increased risk of recurrence. [Table: see text] [Table: see text]

Entecavir is a potent anti-HBV drug superior to lamivudine: experience from clinical trials in China

Infection with the hepatitis B virus (HBV) can result in chronic hepatitis B (CHB) in many patients. Patients with CHB require regular screening and monitoring to facilitate disease surveillance and to determine if/when treatment is indicated. The current goal of CHB treatment is sustained viral suppression with the aim of reducing or preventing hepatic injury and disease progression. Effective anti-HBV therapy is now available that can suppress, but not eradicate, HBV replication. Among the currently licensed and approved anti-HBV nucleos(t)ides, entecavir demonstrates a potent anti-HBV activity and a low rate of emergence of drug resistance, with good safety and tolerability profiles. These excellent pharmacological characteristics were assessed both in large international clinical trials and in separate studies in China. This article presents results from Phase II and Phase III trials involving 876 Chinese patients with CHB. The results of these studies suggest that entecavir should be recommended as a first-line choice among the currently available anti-HBV nucleos(t)ides.

Quality of life assessment and research in the EORTC (European Organisation for Research and Treatment of Cancer)

Quality of Life (QOL) assessment and research within the European Organisation for Research and Treatment of Cancer (EORTC) has become increasingly important over the past 25 years, starting already in 1979 with the founding of the EORTC Quality of Life Group (EORTC QLG), and QOL has become part of many cancer clinical trial protocols in different ways. This paper briefly presents an overview of QOL within the EORTC, the development of the QLQ-C30 instrument, the construction of specific modules, issues of cross-cultural validation and translation, and the various other activities of the QLG and the Data Centre Quality of Life Unit (QLU). The article also includes key findings from selected QOL studies published by the EORTC, highlighting this large international clinical trial organisation’s contribution to this field of oncology.

A disturbed glucose metabolic state (dysglycaemia) is a key risk factor for cardiovascular events

Diabetes is a well-established, independent risk factor for future cardiovascular events. A growing literature is now showing that cardiovascular risk is not restricted to glucose levels above the thresholds that differentiate diabetes from nondiabetes. Rather, the relationship between glucose and cardiovascular events extends from normal glucose levels right into the diabetic range. Indeed, cardiovascular risk is predicted by the degree of glucose elevation and not by the presence or absence of diabetes per se. Whether or not strategies that lower glucose will reduce the risk of cardiovascular events is now being tested in several large international clinical trials.

Sex differences in clinical response to olanzapine compared with haloperidol

There is current disagreement over whether men and women respond differently to typical or atypical antipsychotic medications. This study reanalyzed a large international clinical trial of olanzapine (Olz) compared with haloperidol (Hal) to test for sex differences in treatment response, controlling for illness chronicity and menopausal status. We hypothesized that women would show a greater response to either medication than men, particularly among first admission, premenopausal women. DSM-III-R schizophrenia inpatients (700 women and 1295 men) were randomly assigned to a 6-week trial of Olz vs. Hal. Longitudinal random effect models were used to test for interactions of sex with medication, chronicity and menopausal status on treatment response. Findings showed that women on olanzapine had a greater drop in overall symptomatology by week 4 than any other group, and their level of symptomatology remained lower throughout the 6-week trial. The sex differences in treatment response in olanzapine compared with haloperidol were, in part, dependent on chronicity and, in women, menopausal status. That is, first episode women on haloperidol exhibited an increase in symptomatology over the 6-week trial compared to their male counterparts, while multiply hospitalized women had a better treatment response on haloperidol than their male counterparts. Women on olanzapine had a significantly better treatment response than men, regardless of chronicity. Finally, premenopausal women had a significantly better treatment response than postmenopausal women, regardless of treatment and chronicity.

Familial Combined Hyperlipidemia and Insulin Resistance

Familial Combined Hyperlipidemia and Insulin Resistance

Laboratory standardization of a large international clinical trial: the DAIS experience

Objective: To implement a quality control program for the standardization and harmonization of lipid and lipoprotein analyses as performed at two core laboratories (St. Paul’s Hospital, UBC [Vancouver], and NPHI [Helsinki]) for the Diabetes Atherosclerosis Intervention Study (DAIS). Design and methods: A DAISSOFT computer program was designed to minimize the occurrence of data and sample management errors during the course of the study. Fresh human serum was used for the provision of an accuracy based external quality control program that monitored the analytical performance of lipid testing at these two laboratories. A separate program was designed for monitoring hemoglobin A 1c (HbA 1c). At the outset of the study, allowable total error goals were established for each analyte. Ongoing performance was monitored using bimonthly blinded challenges of fresh human serum. The two EQA programs routinely monitored the analysis of total cholesterol, calculated LDL-cholesterol, HDL-cholesterol, net triglycerides, apoprotein A-1, apoprotein B, and HbA 1c. Results: The EQA precision and accuracy data for the measurement of total cholesterol at the two core laboratories over the last 5 years indicated both laboratories operated with good precision, approximately 1% CV over the time period. The accuracy at both laboratories was similar initially. Part way through the study, the accuracy of the cholesterol method at NHPI tended to drift upward with an operating positive bias (+3%) relative to the Abell Kendall reference method. Triglyceride measurements were the most problematic for the study. By EQA cycle 8, the accuracy of the method at UBC had stabilized and was meeting the accuracy goals of the study. NPHI’s method was negatively biased relative to the accuracy base of the DAIS study. In spite of recalibrating their method, NPHI found it difficult to maintain consistent accuracy for the measurement of triglycerides during the study. Both laboratories operated their HDL methods with excellent precision. Accuracy at NHPI was well maintained over the course of the study whereas the accuracy of HDL measurements at UBC was more problematic. There was an inconsistent variation in the accuracy of apoprotein A-1 measurements at both laboratories. In most cases, the bias would be corrected by the time of the next EQA challenge. In the case of apo B, one laboratory was standardized to the CDC while the other laboratory was standardized to IFCC/WHO. The discrepancy between these two accuracy bases was > 20%. Recalibration to a common accuracy base rectified the problem. Only minor problems were encountered with the precision and accuracy of the DIAMAT assay for hemoglobin A-1c. The two DAIS core laboratories consistently operated within the 9% total error goals of the study for HbA 1c. Conclusions: Through the use of this program, the two DAIS core laboratories were able to maintain their lipid analyses within the limits of allowable total error that had been established for the study.

Current Contraceptive Research

No contraceptive panacea is near or likely. The most exciting prospect, man-made analogs of LHRH (a brain hormone) for both male and female use, could not be available before the late 1980s. Other potential methods in human trials face serious obstacles.