Publications by authors named "Mark Rosenthal"

152 Publications

Consensus core clinical data elements for meningiomas.

Neuro Oncol 2021 Nov 17. Epub 2021 Nov 17.

MacFeeters Hamilton Neuro-Oncology Program, Princess Margaret Cancer Centre, University Health Network and University of Toronto, ON, Canada.

Background: With increasing molecular analyses of meningiomas, there is a need to harmonize language used to capture clinical data across centers to ensure that molecular alterations are appropriately linked to clinical variables of interest. Here the International Consortium on Meningiomas presents a set of core and supplemental meningioma-specific Common Data Elements (CDEs) to facilitate comparative and pooled analyses.

Methods: The generation of CDEs followed the four-phase process similar to other National Institute of Neurological Disorders and Stroke (NINDS) CDE projects: discovery, internal validation, external validation, and distribution.

Results: The CDEs were organized into patient- and tumor-level modules. In total, 17 core CDEs (10 patient-level and 7-tumour-level) as well as 14 supplemental CDEs (7 patient-level and 7 tumour-level) were defined and described. These CDEs are now made publicly available for dissemination and adoption.

Conclusions: CDEs provide a framework for discussion in the neuro-oncology community that will facilitate data sharing for collaborative research projects and aid in developing a common language for comparative and pooled analyses. The meningioma-specific CDEs presented here are intended to be dynamic parameters that evolve with time and The Consortium welcomes international feedback for further refinement and implementation of these CDEs.
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http://dx.doi.org/10.1093/neuonc/noab259DOI Listing
November 2021

Palliative Care Clinical Trials: Building Capability and Capacity.

J Palliat Med 2021 Nov 17. Epub 2021 Nov 17.

Departments of Palliative Care and Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia.

Clinical trials are a key component of expanding the evidence base in palliative care. A key strategic objective of the Victorian Comprehensive Cancer Centre (VCCC), a multisite cancer center alliance, was to increase palliative care clinical trial expertise. The palliative care services within the VCCC alliance presented substantial trial development opportunities with large number of patients and established relationships, but few trial-active centers. To establish a multi-site "Building Capability in Palliative Care Clinical Trials" program as a service development, and to assess the strategies, activities, and the outcomes resulting from this program. A series of strategies and activities were developed linked to the key program objectives of increasing the number of clinical sites and skilled clinicians conducting clinical trials, increasing the number of trials available and patients participating, broadening research opportunities in palliative care, and establishing the program sustainability. In the two years of implementation, the program resulted in the establishment and conduct of several Phase 4 postmarketing pharmacovigilance studies, nine Phase 2 and 3 trials across five palliative care services, and a Phase 1 clinical trial. During the program, 150 patients were recruited to clinical trials, and 258 prospective pharmacovigilance monitoring cases were recorded. Five investigator-initiated trials were developed by clinical trial fellows and achieved competitive ( = 3) or commercial ( = 2) funding. Clinicians reported that undertaking clinical trials had increased attention to the evidence base of care provision, and increased service research activity more broadly. Long-term sustainability remains a challenge, particularly in the context of the COVID-19 pandemic. Clinical trials in palliative care services are feasible, acceptable, and result in increased attention to the evidence base of care. The strategies detailing the framework, activities, and outcomes have been collated to facilitate implementation of clinical trials in other sites and with other trial-naive disciplinary groups.
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http://dx.doi.org/10.1089/jpm.2021.0314DOI Listing
November 2021

Blood eosinophils in managing preschool wheeze: Lessons learnt from a proof-of-concept trial.

Pediatr Allergy Immunol 2021 Nov 16. Epub 2021 Nov 16.

Department of Respiratory Paediatrics, Royal Brompton Hospital, London, UK.

Background: Management of preschool wheeze is based predominantly on symptom patterns.

Objective: To determine whether personalizing therapy using blood eosinophils or airway bacterial infection results in fewer attacks compared with standard care.

Methods: A proof-of-concept, randomized trial to investigate whether the prescription of inhaled corticosteroids (ICS) guided by blood eosinophils, or targeted antibiotics for airway bacterial infection, results in fewer unscheduled healthcare visits (UHCVs) compared with standard care. Children aged 1-5 years with ≥2 wheeze attacks in the previous year were categorized as episodic viral wheeze (EVW) or multiple trigger wheeze (MTW). The intervention group was prescribed ICS if blood eosinophils ≥3%, or targeted antibiotics if there is positive culture on induced sputum/cough swab. The control group received standard care. The primary outcome was UHCV at 4 months.

Results: 60 children, with a median age of 36.5 (range 14-61) months, were randomized. Median blood eosinophils were 5.2 (range 0-21)%, 27 of 60 (45%) children were atopic, and 8 of 60 (13%) had airway bacterial infection. There was no relationship between EVW, MTW and either blood eosinophils, atopic status or infection. 67% in each group were prescribed ICS. 15 of 30 control subjects and 16 of 30 patients in the intervention group had UHCV over 4 months (p = .8). The time to first UHCV was similar. 50% returned adherence monitors; in those, median ICS adherence was 67%. There were no differences in any parameter between those who did and did not have an UHCV.

Conclusion: Clinical phenotype was unrelated to allergen sensitization or blood eosinophils. ICS treatment determined by blood eosinophils did not impact UHCV, but ICS adherence was poor.
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http://dx.doi.org/10.1111/pai.13697DOI Listing
November 2021

A pilot study investigating the efficacy of brief, phone-based, behavioral interventions for burnout in graduate students.

J Clin Psychol 2021 Sep 13. Epub 2021 Sep 13.

Department of Psychiatry and Behavioral Sciences, Cognitive-Behavioral Research and Therapy Program, Duke University Medical Center, Durham, North Carolina, USA.

Objective: This pilot study tested the efficacy of two brief, phone-administered, behavioral interventions derived from behavioral activation in reducing burnout among doctoral students.

Methods: Sixty-six doctoral students demonstrating current high burnout were randomly assigned to one of three intervention conditions: (1) Reward: increasing pleasant, rewarding behaviors, (2) Approach: approaching important goals that they have been avoiding, or (3) Control: monitoring only.

Results: Results indicated that doctoral students treated with the approach intervention reported significantly lower burnout compared to participants in the control condition immediately after the intervention and at a 1-week follow-up. Results also suggested that students in the approach intervention also reported higher well-being compared to students in the control condition.

Conclusion: These findings suggest that this approach intervention is an effective treatment for school burnout for doctoral students that can be delivered remotely through phone and web technology.
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http://dx.doi.org/10.1002/jclp.23245DOI Listing
September 2021

Acute Myocardial Infarction With Cardiogenic Shock Due to Pericardial Constriction and Multivessel Coronary Obstruction.

JACC Case Rep 2020 Sep 8;2(11):1708-1712. Epub 2020 Jul 8.

Department of Cardiovascular Medicine, Gagnon Cardiovascular Institute, Morristown Medical Center/Atlantic Health System, Morristown, New Jersey.

We present a rare case of cardiogenic shock and multivessel coronary compression due to focal pericardial inflammation and constriction. The patient was treated in the acute phase with coronary stenting and temporary mechanical support. Multimodality imaging was essential in elucidating the diagnosis. ().
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http://dx.doi.org/10.1016/j.jaccas.2020.05.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8312038PMC
September 2020

Systems-Level Change to Alleviate Barriers to Cancer Clinical Trial Access for Adolescents and Young Adults in Australia.

J Adolesc Young Adult Oncol 2021 Jul 22. Epub 2021 Jul 22.

ONTrac at PeterMac, Victorian Adolescent and Young Adult Cancer Service, Peter MacCallum Cancer Centre, Melbourne, Australia.

International data demonstrate association between clinical trial participation and reduced cancer mortality. Adolescents and young adults (AYA) have low clinical trial enrollment rates. We established a program to understand local barriers and develop targeted solutions that lead to greater AYA clinical trial participation. A steering committee (SC) with expertise in adult and pediatric oncology, research ethics, and consumer representation was formed. The SC mapped barriers related to AYA trial access and established working groups (WGs) around three themes. The Regulatory Awareness WG identified a lack of understanding of processes that support protocol approval for clinical trials across the AYA age range. A guideline to raise awareness was developed. The Access WG identified challenges for young adults (18-25 years) to access a pediatric hospital to enroll in a pediatric trial. A procedure was developed to streamline applications for access. The first six applications using this procedure have been successful. The Availability WG identified lack of pediatric-adult oncology reciprocal relationships as a barrier to awareness of open trials, and future collaboration. An AYA Craft Group Framework was established to grow relationships within tumor streams across institutions; two craft groups are now operating locally. An additional achievement was a successful request to the Therapeutic Goods Administration for Australian adoption of the Food and Drug Administration Guidance on Considerations for the Inclusion of Adolescent Patients in Adult Oncology Clinical Trials. This multipronged approach to improving AYA clinical trial access has relevance for other health environments. Our knowledge products are available as an online toolkit.
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http://dx.doi.org/10.1089/jayao.2021.0026DOI Listing
July 2021

A Short extension to multiple breath washout provides additional signal of distal airway disease in people with CF: A pilot study.

J Cyst Fibros 2021 Jul 15. Epub 2021 Jul 15.

Royal Brompton and Harefield NHS Foundation Trust, London, United Kingdom; National Heart and Lung Institute, Imperial College London, Manresa Rd, London, United Kingdom; European Cystic Fibrosis Society Lung Clearance Index Core Facility, London, United Kingdom.

Background: Adding a slow vital capacity (SVC) to multiple breath washout (MBW) allows quantification of otherwise overlooked signal from under/un-ventilated lung units (UVLU) and may provide a more comprehensive assessment of airway disease than conventional lung clearance index (LCI).

Methods: We conducted a pilot study on people undergoing MBW tests: 10 healthy controls (HC) and 43 cystic fibrosis (CF) subjects performed an SVC after the standard end of test. We term the new outcome LCI with Short extension (LCI). We assessed (i) CF/ HC differences, (ii) variability (iii) effect of pulmonary exacerbation (PEx)/treatment and (iv) relationship with CF computed tomography (CFCT) scores.

Results: HC/ CF group differences were larger with LCI than LCI (P<0.001). Within the CF group UVLU was highly variable and when abnormal it did not correlate with corresponding LCI. Signal showed little variability during clinical stability (n = 11 CF; 2 visits; median inter-test variability 2.6% LCI 2.5% LCI). PEx signal was significantly greater for LCI both for onset and resolution. Both MBW parameters correlated significantly with total lung CT scores and hyperinflation but only LCI correlated with mucus plugging.

Conclusions: UVLU captured within the LCI varies between individuals; the lack of relationship with LCI demonstrates that new, additional information is being captured. LCI repeatability during clinical stability combined with its larger signal around episodes of PEx may lend it superior sensitivity as an outcome measure. Further studies will build on this pilot data to fully establish its utility in monitoring disease status.
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http://dx.doi.org/10.1016/j.jcf.2021.06.013DOI Listing
July 2021

Perioperative clinical trials for glioma: Raising the bar.

J Clin Neurosci 2021 Jul 11;89:144-150. Epub 2021 May 11.

Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia. Electronic address:

Gliomas are a heterogeneous group of primary brain cancers with poor survival despite multimodality therapy that includes surgery, radiation and chemotherapy. Numerous clinical trials have investigated systemic therapies in glioma, but have largely been negative. Multiple factors have contributed to the lack of progress including tumour heterogeneity, the tumour micro-environment and presence of the blood-brain barrier, as well as extrinsic factors relating to trial design, such as the lack of a contemporaneous biopsy at the time of treatment. A number of strategies have been proposed to progress new agents into the clinic. Here, we review the progress of perioperative, including phase 0 and 'window of opportunity', studies and provide recommendations for trial design in the development of new agents for glioma. The incorporation of pre- and post-treatment biopsies in glioma early phase trials will provide valuable pharmacokinetic and pharmacodynamic data and also determine the target or biomarker effect, which will guide further development of new agents. Perioperative 'window of opportunity' studies must use drugs with a recommended-phase-2-dose, known safety profile and adequate blood-brain barrier penetration. Drugs shown to have on-target effects in perioperative trials can then be evaluated further in a larger cohort of patients in an adaptive trial to increase the efficiency of drug development.
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http://dx.doi.org/10.1016/j.jocn.2021.04.026DOI Listing
July 2021

A randomized phase II trial of veliparib, radiotherapy, and temozolomide in patients with unmethylated MGMT glioblastoma: the VERTU study.

Neuro Oncol 2021 10;23(10):1736-1749

NHMRC Clinical Trials Centre, University of Sydney, Sydney, Australia.

Background: Temozolomide offers minimal benefit in patients with glioblastoma with unmethylated O6-methylguanine-DNA methyltransferase (MGMT) promoter status, hence, the need for novel therapies. This study evaluated whether veliparib, a brain-penetrant poly(ADP-ribose) polymerase (PARP) inhibitor, acts synergistically with radiation and temozolomide.

Methods: VERTU was a multicenter 2:1 randomized phase II trial in patients with newly diagnosed glioblastoma and MGMT-unmethylated promotor status. The experimental arm consisted of veliparib and radiotherapy, followed by adjuvant veliparib and temozolomide. The standard arm consisted of concurrent temozolomide and radiotherapy, followed by adjuvant temozolomide. The primary objective was to extend the progression-free survival rate at six months (PFS-6m) in the experimental arm.

Results: A total of 125 participants were enrolled, with 84 in the experimental arm and 41 in the standard arm. The median age was 61 years, 70% were male, 59% had Eastern Cooperative Oncology Group (ECOG) performance status of 0, and 87% underwent macroscopic resection. PFS-6m was 46% (95% confidence interval [CI]: 36%-57%) in the experimental arm and 31% (95% CI: 18%-46%) in the standard arm. Median overall survival was 12.7 months (95% CI: 11.4-14.5 months) in the experimental arm and 12.8 months (95% CI: 9.5-15.8 months) in the standard arm. The most common grade 3-4 adverse events were thrombocytopenia and neutropenia, with no new safety signals.

Conclusion: The veliparib-containing regimen was feasible and well tolerated. However, there was insufficient evidence of clinical benefit in this population. Further information from correlative translational work and other trials of PARP inhibitors in glioblastoma are still awaited.
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http://dx.doi.org/10.1093/neuonc/noab111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8485443PMC
October 2021

in the Cystic Fibrosis Airway: Does It Deserve Its Reputation as a Predatory "Bully"?

Am J Respir Crit Care Med 2021 04;203(8):1027-1030

Royal Brompton and Harefield NHS Foundation Trust London, United Kingdom and.

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http://dx.doi.org/10.1164/rccm.202009-3639LEDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048747PMC
April 2021

Buparlisib plus carboplatin or lomustine in patients with recurrent glioblastoma: a phase Ib/II, open-label, multicentre, randomised study.

ESMO Open 2020 07;5(4)

Department of Oncology, Princess Margaret Hospital Cancer Centre, Toronto, Ontario, Canada.

Background: Glioblastoma relapse is associated with activation of phosphatidylinositol 3-kinase (PI3K) signalling pathway. In preclinical studies, the pan-PI3K inhibitor buparlisib showed antitumour activity in glioma models.

Methods: This was a two-part, multicentre, phase Ib/II study in patients with recurrent glioblastoma pretreated with radiotherapy and temozolomide standard of care. Patients received buparlisib (80 mg or 100 mg once daily) plus carboplatin (area under the curve (AUC)=5 every 3 weeks), or buparlisib (60 mg once daily) plus lomustine (100 mg/m every 6 weeks). The primary endpoint was to determine the maximum tolerable dose (MTD) and/or recommended phase II dose of buparlisib plus carboplatin or lomustine.

Results: Between 28 February 2014 and 7 July 2016, 35 patients were enrolled and treated with buparlisib plus carboplatin (n=17; buparlisib (80 mg) plus carboplatin, n=3; and buparlisib (100 mg) plus carboplatin, n=14), or buparlisib (60 mg) plus lomustine (n=18). The MTD of buparlisib was determined to be 100 mg per day in combination with carboplatin at an AUC of 5 every 3 weeks. The MTD of buparlisib in combination with lomustine could not be determined as it did not satisfy the MTD criteria per the Bayesian logistic regression model.

Conclusion: The overall safety profile of buparlisib remained unchanged, and no new or unexpected safety findings were reported in this study. Preliminary assessment for both combinations did not demonstrate sufficient antitumour activity compared with historical data on single-agent carboplatin or lomustine.

Trial Registration Number: NCT01934361.
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http://dx.doi.org/10.1136/esmoopen-2020-000672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359195PMC
July 2020

Phase I, open-label, multicentre study of buparlisib in combination with temozolomide or with concomitant radiation therapy and temozolomide in patients with newly diagnosed glioblastoma.

ESMO Open 2020 07;5(4)

Medical Oncology, Royal Melbourne Hospital, Melbourne, Victoria, Australia.

Background: Most glioblastoma tumours exhibit intrinsic phosphatidylinositol 3-kinase (PI3K) pathway activation. Preclinical in vitro and in vivo models suggest that buparlisib (an oral pan-PI3K inhibitor) can have an effect on glioblastoma directly and by enhancing the activity of radiation and of temozolomide.

Methods: This was a phase I, two-stage, multicentre, open-label, dose-escalation study of buparlisib in combination with temozolomide and radiotherapy in patients with newly diagnosed glioblastoma. In stage I, patients who completed the concomitant phase of combination of temozolomide and radiation prior to study entry received buparlisib in combination with temozolomide. In stage II, patients received buparlisib in combination with temozolomide and radiotherapy in the concomitant phase and temozolomide in the adjuvant treatment phase. The primary objective was to estimate the maximum tolerated dose (MTD) of buparlisib when combined with the approved first-line treatment of temozolomide and radiotherapy.

Results: The MTD of buparlisib in combination with temozolomide at stage I (adjuvant phase only) was 80 mg/day, which was used as the starting dose in stage II. The MTD of buparlisib in combination with temozolomide and radiotherapy in stage II (concomitant + adjuvant phase) was not determined due to the observed dose-limiting toxicities and treatment discontinuations due to adverse events (AEs). In stage I, the most commonly reported AEs were nausea (72.7%) and fatigue (59.1%). In stage II, the most commonly reported AEs were fatigue and nausea (56.3% each). No on-treatment deaths were reported during the study.

Conclusion: Considering that the primary objective of estimating the MTD was not achieved in addition to the observed challenging safety profile of buparlisib in combination with radiotherapy and temozolomide, Novartis decided not to pursue the development of buparlisib in newly diagnosed glioblastoma.ClinicalTrials.gov identifier: NCT01473901.
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http://dx.doi.org/10.1136/esmoopen-2020-000673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359189PMC
July 2020

Comparative Survival of Asian and White Metastatic Castration-Resistant Prostate Cancer Men Treated With Docetaxel.

JNCI Cancer Spectr 2020 Apr 29;4(2):pkaa003. Epub 2020 Jan 29.

Medical Oncology and Urology, Sidney Kimmel Cancer Center at Thomas Jefferson University, Philadelphia, PA, USA.

There are few data regarding disparities in overall survival (OS) between Asian and white men with metastatic castration-resistant prostate cancer (mCRPC). We compared OS of Asian and white mCRPC men treated in phase III clinical trials with docetaxel and prednisone (DP) or a DP-containing regimen. Individual participant data from 8820 men with mCRPC randomly assigned on nine phase III trials to receive DP or a DP-containing regimen were combined. Men enrolled in these trials had a diagnosis of prostate adenocarcinoma. The median overall survival was 18.8 months (95% confidence interval [CI] = 17.4 to 22.1 months) and 21.2 months (95% CI = 20.8 to 21.7 months) for Asian and white men, respectively. The pooled hazard ratio for death for Asian men compared with white men, adjusted for baseline prognostic factors, was 0.95 (95% CI = 0.84 to 1.09), indicating that Asian men were not at increased risk of death. This large analysis showed that Asian men did not have shorter OS duration than white men treated with docetaxel.
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http://dx.doi.org/10.1093/jncics/pkaa003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190204PMC
April 2020

Carboplatin dosing in the era of IDMS-creatinine; the Cockroft-Gault formula no longer provides a sufficiently accurate estimate of glomerular filtration rate for routine use in clinical care.

Gynecol Oncol 2020 06 24;157(3):793-798. Epub 2020 Mar 24.

Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia 3000; Royal Womens Hospital, Parkville, Victoria, Australia 3052; Royal Melbourne Hospital, Parkville, Victoria 3050, Australia; The University of Melbourne, Parkville, Victoria 3010, Australia. Electronic address:

Background: Glomerular filtration rate (GFR) measured by Chromium-51-EDTA excretion (Cr-GFR) is considered the gold standard of renal function assessment, but serum creatinine in the Cockcroft-Gault (CG) formula is routinely used to estimate GFR for carboplatin dosing. Serum creatinine measured by isotope-dilution-mass-spectrometry (IDMS) can generate spuriously high GFR estimates when used in the CG formula. We hypothesized that GFR calculated using IDMS-creatinine in the CG formula (CG-GFR) exposes patients to inaccurate carboplatin dosing.

Methods: This is a multicenter retrospective study of patients who had a Cr-GFR assessment for malignant or non-malignant indications, with a matched CG-GFR. Carboplatin dose based on Cr-GFR at AUC5 was used as the reference.

Results: 550 patients were analyzed, median age 62 (19-90), 64% female. Indication for GFR evaluation: malignancy (85%), assessment for live kidney donation (12%), other (3%). Median ratio of CG-GFR: Cr-GFR 1.04 (0.43-3.38); <0.8 in 72 patients (13%), >1.2 in 180 patients (33%). Despite capping of CG-GFR at 125 mL/min, dosing according to AUC6 would have resulted in 18% of patients being underdosed and 23% overdosed by >100 mg compared to Cr-GFR. Subgroup analysis identified BMI (>35, MPE 39%), gender (female MPE 15%), GFR indication (malignancy MPE 11%) as risk factors for overestimate of CG-GFR, and BMI < 20 for underestimate (MPE -3.5%).

Conclusions: The convention of considering AUC5 carboplatin based on Cr-GFR, and AUC6 carboplatin based on CG-GFR as equivalent is invalid and should be abandoned. When Cr-GFR is unavailable, capping CG-GFR at 125 mL/min is recommended.
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http://dx.doi.org/10.1016/j.ygyno.2020.03.017DOI Listing
June 2020

The McGill score as a screening test for obstructive sleep disordered breathing in children with co-morbidities.

Sleep Med 2020 04 28;68:173-176. Epub 2019 Dec 28.

Department of Pediatric Respiratory Medicine, Royal Brompton Hospital, London, UK.

Background: The McGill score is used to stratify severity of oximetry in children referred for investigation of obstructive sleep apnoea (OSA) to identify those with more severe disease and prioritize treatment. We hypothesized that its positive predictive value (PPV) and negative predictive value (NPV) in detecting OSA differs significantly between children with medical conditions and otherwise healthy children.

Methods: We performed a two-year retrospective analysis of children referred for investigation of OSA who underwent a cardiorespiratory (CR) polygraphy study. McGill score was calculated from the oximetry trace blinded to polygraphy results. We looked at two definitions of OSA: Obstructive Apnoea Hypopnoea Index (oAHI) ≥1 and ≥ 5. McGill sensitivity, specificity, PPV and NPV were calculated. McGill score = 1 was considered normal or inconclusive, >1 abnormal.

Results: We studied 312 children, 190 males (61%), median age 4.5 (2.4-7.9) years. 129 were otherwise healthy and 183 had associated medical conditions. The PPV of the McGill score was significantly lower in children with medical conditions than otherwise healthy children. The NPV was similar in both groups of children.

Conclusions: The higher number of false positives in children with medical conditions may be due to non-obstructive causes such as central apnoeas. Children with underlying lung disease are also more likely to desaturate following a brief apnoea or hypopnoea. Children with co-morbidities who have an abnormal McGill score should not be assumed to have OSA and need more detailed sleep studies to determine the reason for the oxygen desaturations.
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http://dx.doi.org/10.1016/j.sleep.2019.12.010DOI Listing
April 2020

Syphilis among adult males with a history of male-to-male sexual contact living with diagnosed HIV in New York State (excluding New York City): The challenge of intersecting epidemics.

PLoS One 2019 18;14(12):e0226614. Epub 2019 Dec 18.

Division of HIV/STD Epidemiology, Evaluation, and Partner Services, AIDS Institute, New York State Department of Health, Albany, New York, United States of America.

Since 2009, syphilis has been increasing in New York State (NYS) excluding New York City (NYC) among men with a history of male-to-male sexual contact (MSM). Because MSM make up a disproportionate number of new HIV infections, this study aims to: 1) establish yearly rates of early syphilis diagnosis, 2) assess factors associated with early syphilis diagnosis, and 3) describe missed opportunities for earlier diagnosis of syphilis among MSM living with diagnosed HIV(MSMLWDH) in NYS, excluding NYC. A cohort of adult MSMLWDH alive in 2013 were followed through 2016 to identify individuals with at least one early syphilis diagnosis between July 2014 and December 2016. Early syphilis diagnosis rates were calculated for 2015 and 2016. Crude relative risks and 95% confidence intervals were calculated to determine associations between available covariates and both syphilis diagnosis and missed opportunities. Missed opportunities were defined as reports of an HIV-related laboratory test within a given window corresponding to syphilis staging where syphilis testing was not performed at the same time. Of 7,512 MSMLWDH, 50.0% were non-Hispanic white, 85.4% aged ≥35, and 320(4.3%) had an early syphilis diagnosis. Yearly rates were: 1,838/100,000, and 1,681/100,000 in 2015 and 2016, respectively. Persons who were non-Hispanic black, living with diagnosed HIV for less than three years, aged <45, and were always virally suppressed or always in HIV care were significantly more likely to have a syphilis diagnosis. Over half of individuals had evidence of a missed opportunity for earlier syphilis diagnosis. Syphilis stage at diagnosis, older age, and syphilis diagnosis not concurrent with an HIV-related laboratory test were associated with a higher likelihood of having a missed opportunity. This study supports high interrelatedness of the syphilis and HIV epidemics among MSM. Since syphilis can impact HIV viral load suppression status, efforts to end the HIV epidemic need to be coupled with syphilis elimination efforts.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0226614PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6919591PMC
April 2020

Whole genome and biomarker analysis of patients with recurrent glioblastoma on bevacizumab: A subset analysis of the CABARET trial.

J Clin Neurosci 2019 Dec 30;70:157-163. Epub 2019 Sep 30.

Prince of Wales Clinical School, Cure Brain Cancer Biomarkers and Translational Research Group, University of New South Wales, Sydney, NSW, Australia.

The CABARET trial (ACTRN12610000915055) reported no difference in overall survival (OS) between patients with recurrent glioblastoma (GBM) randomized to either bevacizumab monotherapy or bevacizumab plus carboplatin. However, a subset of patients showed durable responses and prolonged survival, with recorded survival times of over 30 months in five of 122 patients (4%). Patient selection for bevacizumab therapy would be enhanced if a predictive biomarker of response or survival could be identified; this biomarker sub-study attempted to identify novel biomarkers. Patients who opted to participate in this sub-study and who had adequate biospecimens for analysis (n = 54) were retrospectively evaluated for the expression of a series of tumor proteins. Immunohistochemistry (IHC) was used to measure the expression of 19 proteins previously implicated in cancer treatment response to bevacizumab. MGMT promoter methylation was also assessed. Tumor DNA from five patients with outlying survival duration ('poor' and 'exceptional' survivors) was subjected to whole genome sequencing (WGS). No single protein expression level, including VEGF-A, predicted OS in the cohort. WGS of poor and exceptional survivors identified a gain in Chromosome 19 that was exclusive to the exceptional survivors. Validation of this finding requires examination of a larger independent cohort.
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http://dx.doi.org/10.1016/j.jocn.2019.08.044DOI Listing
December 2019

Emotion regulation difficulties and borderline personality disorder: The moderating role of race.

Personal Disord 2020 07 23;11(4):280-289. Epub 2019 Sep 23.

Department of Psychology.

Borderline personality disorder (BPD) is a disorder characterized by emotion regulation (ER) difficulties. Although research indicates that patterns of ER differ across racial groups, few studies have examined the role of race in the ER-BPD association. This study sought to address this gap. Participants in this study identified as either East Asian, White, or Black, and were recruited from sites in Western Canada and the Southern United States. Two samples were included in this study: (a) 194 university students who self-reported BPD features and (b) 88 adults from the community who underwent diagnostic interviews and had a BPD diagnosis. All participants self-reported ER difficulties. Results revealed that race moderated the link between some aspects of ER difficulties and BPD. For instance, relations between (a) nonacceptance of emotions and BPD affect instability, (b) limited access to ER strategies and BPD identity disturbance, and (c) low emotional awareness and BPD diagnosis were stronger among White (vs. Black or East Asian) participants. Implications of these findings for the diagnosis and treatment of BPD across racial groups are discussed. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
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http://dx.doi.org/10.1037/per0000355DOI Listing
July 2020

Safety, tolerability, and pharmacokinetics of anti-EGFRvIII antibody-drug conjugate AMG 595 in patients with recurrent malignant glioma expressing EGFRvIII.

Cancer Chemother Pharmacol 2019 08 1;84(2):327-336. Epub 2019 Jun 1.

The Ronald Reagan UCLA Medical Center, Los Angeles, CA, USA.

Purpose: Epidermal growth factor receptor variant III (EGFRvIII) is expressed in a significant percentage of primary and recurrent glioblastoma (GBM), a common malignant primary brain tumor in adults. AMG 595 is an antibody-drug conjugate comprising a fully human, anti-EGFRvIII monoclonal antibody linked to DM1. The study goals were to assess safety, tolerability, and pharmacokinetics of AMG 595 in GBM.

Methods: In this phase 1, first-in-human, open-label, sequential-dose, exploration study, adults with recurrent GBM received AMG 595 once every 3 weeks (Q3W) according to incremental dosing cohorts (0.5-3.0 mg/kg). Primary endpoints were to assess safety, the incidence of dose-limiting toxicities (DLTs), objective response (per Macdonald criteria), evaluate pharmacokinetics, and estimate the maximum tolerated dose (MTD).

Results: Of 382 patients screened, 32 were enrolled and received ≥ 1 dose of AMG 595. Ten patients experienced 18 DLTs (all grade 4 thrombocytopenia), and the MTD was 2.0 mg/kg. Twenty-eight patients (88%) experienced ≥ 1 treatment-related adverse event (AE); the most common AEs were thrombocytopenia (50%) and fatigue (25%). Grade ≥ 3 treatment-related AEs occurred in 17 patients (53%); 11 (34%) had serious treatment-emergent AEs, and none were considered treatment related. Pharmacokinetic profiles indicated low levels of circulating unconjugated antibody and cytotoxin, dose-proportional increases in plasma exposures for the conjugated antibody over the studied range, and less than twofold accumulation following multiple Q3W dosing. Two patients (6%) had partial responses; 15 (47%) had stable disease.

Conclusions: AMG 595 exhibited favorable pharmacokinetics and is a unique therapy with possible benefit for some patients with EGFRvIII-mutated GBM with limited therapeutic options.
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http://dx.doi.org/10.1007/s00280-019-03879-2DOI Listing
August 2019

Biallelic human ITCH variants causing a multisystem disease with dysmorphic features: A second report.

Am J Med Genet A 2019 07 15;179(7):1346-1350. Epub 2019 May 15.

Department of Clinical Genetics, North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.

We report a 23 year old female with biallelic truncating variants in the ITCH (Itchy E3 Ubiquitin protein ligase, mouse homolog of; OMIM60649) gene associated with marked short stature, severe early onset chronic lung disease resembling asthma, dysmorphic facial features, and symmetrical camptodactyly of the fingers but normal intellect. The condition has only been reported once previously (Lohr et al., American Journal of Human Genetics, 2010, 86, 447-453) in 10 children from an Old Order Amish family found to have a homozygous frameshift truncating variant in association with failure to thrive, chronic lung disease, motor and cognitive delay, and variable autoimmune diseases including autoimmune hepatitis, enteropathy, hypothyroidism, and diabetes. The condition is listed in OMIM as Autoimmune disease, Multisystem with Facial Dysmorphism (OMIM613385). The clinical course as well as the dysmorphic facial and limb features overlap closely with our patient. We believe the triad of marked syndromic short stature, chronic lung disease, and dysmorphism (with or without cognitive impairment and wider autoimmune involvement) is distinctive.
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http://dx.doi.org/10.1002/ajmg.a.61169DOI Listing
July 2019

The Effect of Systolic Variation of Mitral Regurgitation on Discordance Between Noninvasive Imaging Modalities.

JACC Cardiovasc Imaging 2019 12 17;12(12):2431-2442. Epub 2019 Apr 17.

Carnegie Hill Radiology, New York, New York.

Objectives: This study sought to assess the impact of systolic variation of mitral regurgitation (MR) has on discordance between echocardiography and magnetic resonance imaging (MRI).

Background: Studies have shown discordance between echocardiography and MRI when assessing the severity of MR. Contributing factors to this discordance may include the systolic variation of MR and the use of the color Doppler jet at a single point in time as the basis of many echocardiographic methods.

Methods: This analysis included 117 patients (62 ± 14 years of age; 58% male) with MR who underwent echocardiographic and MRI evaluation. Discordance was defined as the difference between the grades of MR (mild, moderate, or severe) by MRI and echocardiography. For each patient, 2 echocardiographic methods, the continuous wave time index and the color Doppler time index, and 1 MRI method, the systolic variation score (SVS), were measured to quantify systolic variation of MR.

Results: There was absolute agreement between echocardiography and MRI in 47 (40%) patients, a 1-grade difference in 54 (46%) patients, and a 2-grade difference in 16 (14%) patients. Only the SVS significantly differed between patients with and without discordance (0.60 ± 0.23 vs. 0.47 ± 0.21; p = 0.003). On receiver-operating characteristic analysis SVS had moderate predictive power of discordance (area under the curve: 0.67; p = 0.003), with an SVS of 53 having a sensitivity of 61% and a specificity of 65% to predict discordance.

Conclusions: Discordance between MRI and echocardiographic assessment of MR severity is associated with systolic variation of MR as quantified by MRI using the SVS. Continuous wave Doppler and the presence of color Doppler were not correlated with discordance. This study highlights an advantage of MRI. Namely, it does not rely on a single point in time to determine MR severity. Because systolic variation had only moderate sensitivity and specificity for predicting discordance, other factors are also responsible for the discordance between the 2 techniques.
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http://dx.doi.org/10.1016/j.jcmg.2019.02.014DOI Listing
December 2019

Impact of access to novel therapies on the initial management of castrate-resistant prostate cancer: an Australian multicentre study.

Intern Med J 2019 11;49(11):1378-1385

Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.

Background: The impact of regulatory approvals of new therapies for castration-resistant prostate cancer (CRPC) in Australia is unclear.

Aims: To determine if changes in novel therapy access in Australia affected how clinicians initially managed men with newly diagnosed CRPC.

Methods: Data from patients diagnosed with CRPC from 2013 to 2016 across three Australian hospitals were retrospectively collected. Baseline clinicopathological factors and initial management decision at the time of CRPC development (early treatment (ET) vs deferred treatment (DT)) were recorded. Categorical variables between cohorts were compared by Chi-squared analysis. Cox regression analysis was performed to assess the impact of CRPC diagnosis year on time to commencing life-prolonging systemic treatment (TTT).

Results: Our study identified 137 CRPC patients, with 126 (92%) patients receiving life-prolonging systemic treatment. The median age was 73 years. The initial management decision was DT in 71 (52%) patients and ET in 66 (48%) patients. There was a significant shift from DT to ET during the study period (2013-2014: DT 61% vs ET 33%; 2015-2016: DT 39% vs ET 67%; P = 0.004), with a rise in novel androgen receptor signalling inhibitor use and simultaneous reduction in first-generation antiandrogen use at CRPC development. Each successive CRPC diagnosis year was associated with shorter TTT on univariate analysis (HR: 1.5, 95% CI: 1.3-1.7, P < 0.001).

Conclusion: Over time, clinicians are favouring earlier introduction of life-prolonging systemic treatment at the development of CRPC. This trend is largely driven by substantial uptake of novel androgen receptor signalling inhibitors as the preferred initial treatment for CRPC patients.
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http://dx.doi.org/10.1111/imj.14262DOI Listing
November 2019

Overall Survival of Black and White Men With Metastatic Castration-Resistant Prostate Cancer Treated With Docetaxel.

J Clin Oncol 2019 02 21;37(5):403-410. Epub 2018 Dec 21.

15 Sidney Kimmel Cancer Center at Thomas Jefferson University, Philadelphia, PA.

Purpose: Several studies have reported that among patients with localized prostate cancer, black men have a shorter overall survival (OS) time than white men, but few data exist for men with advanced prostate cancer. The primary goal of this analysis was to compare the OS in black and white men with metastatic castration-resistant prostate cancer (mCRPC) who were treated in phase III clinical trials with docetaxel plus prednisone (DP) or a DP-containing regimen.

Methods: Individual participant data from 8,820 men with mCRPC randomly assigned in nine phase III trials to DP or a DP-containing regimen were combined. Race was based on self-report. The primary end point was OS. The Cox proportional hazards regression model was used to assess the prognostic importance of race (black v white) adjusted for established risk factors common across the trials (age, prostate-specific antigen, performance status, alkaline phosphatase, hemoglobin, and sites of metastases).

Results: Of 8,820 men, 7,528 (85%) were white, 500 (6%) were black, 424 (5%) were Asian, and 368 (4%) were of unknown race. Black men were younger and had worse performance status, higher testosterone and prostate-specific antigen, and lower hemoglobin than white men. Despite these differences, the median OS was 21.0 months (95% CI, 19.4 to 22.5 months) versus 21.2 months (95% CI, 20.8 to 21.7 months) in black and white men, respectively. The pooled multivariable hazard ratio of 0.81 (95% CI, 0.72 to 0.91) demonstrates that overall, black men have a statistically significant decreased risk of death compared with white men ( P < .001).

Conclusion: When adjusted for known prognostic factors, we observed a statistically significant increased OS in black versus white men with mCRPC who were enrolled in these clinical trials. The mechanism for these differences is not known.
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http://dx.doi.org/10.1200/JCO.18.01279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804881PMC
February 2019

A Phase Ib Dose-Escalation and Expansion Study of the BCL2 Inhibitor Venetoclax Combined with Tamoxifen in ER and BCL2-Positive Metastatic Breast Cancer.

Cancer Discov 2019 03 5;9(3):354-369. Epub 2018 Dec 5.

The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.

Venetoclax, a potent and selective BCL2 inhibitor, synergizes with endocrine therapy in preclinical models of ER-positive breast cancer. Using a phase Ib 3 + 3 dose-escalation and expansion study design, 33 patients with ER and BCL2-positive metastatic disease (mean prior regimens, 2; range, 0-8) were treated with daily tamoxifen (20 mg) and venetoclax (200-800 mg). Apart from uncomplicated "on-target" lymphopenia, no dose-limiting toxicities or high-grade adverse events were observed in the escalation phase (15 patients), and 800 mg was selected as the recommended phase II dose (RP2D). In the expansion phase (18 patients), few high-grade treatment-related adverse events were observed. For 24 patients treated at the RP2D, the confirmed radiologic response rate was 54% and the clinical benefit rate was 75%. Treatment responses were preempted by metabolic responses (FDG-PET) at 4 weeks and correlated with serial changes in circulating tumor DNA. Radiologic responses (40%) and clinical benefit (70%) were observed in 10 patients with plasma-detected mutations. SIGNIFICANCE: In the first clinical study to evaluate venetoclax in a solid tumor, we demonstrate that combining venetoclax with endocrine therapy has a tolerable safety profile and elicits notable activity in ER and BCL2-positive metastatic breast cancer. These findings support further investigation of combination therapy for patients with BCL2-positive tumors...
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http://dx.doi.org/10.1158/2159-8290.CD-18-1151DOI Listing
March 2019

Never mind the biologics, just take the inhalers.

Authors:
Mark Rosenthal

Breathe (Sheff) 2018 Sep;14(3):176-179

Dept of Paediatric Respiratory Medicine, Royal Brompton Hospital, London, UK.

http://ow.ly/OaGK30kFtsD.
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http://dx.doi.org/10.1183/20734735.021118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6118888PMC
September 2018

Sleep disordered breathing and ventilatory support in children with Down syndrome.

Pediatr Pulmonol 2018 10 10;53(10):1414-1421. Epub 2018 Jul 10.

Department of Pediatric Respiratory Medicine, Royal Brompton Hospital, London, United Kingdom.

Study Objectives: Obstructive sleep apnoea (OSAS) in children with Down syndrome (DS) is now well recognized, but other forms of sleep disordered breathing (SDB) in this population are less well described. Anecdotally, respiratory support for SDB treatment in this population is not easily tolerated. We aimed to characterize the types of SDB in children with DS referred to a tertiary respiratory center and to assess the effectiveness and adherence to respiratory support.

Methods: Retrospective study of DS patients <18 years old under follow-up at a tertiary respiratory center. Anthropometrics, comorbidities, sleep study results, and details of respiratory support were collected. Satisfactory adherence to oxygen (O ), Continuous Positive Airway Pressure (CPAP), or bilevel noninvasive ventilation (NIV) was defined as use >4 h/night for >50% nights.

Results: Sixty patients were included, median age 1.5 (0.7-5.3) years; 49 (82%) had congenital heart disease, 16 (27%) pulmonary hypertension, 28 (47%) gastroesophageal reflux, 38 (63%) swallowing impairment; 16/17 who underwent CT scanning had evidence of aspiration. Forty-two had SDB: 27 (61%) OSAS (10 mild, 5 moderate, 12 severe), 11 (25%) central apnoeas, 19 (32%) nocturnal hypoventilation. Twenty-six had baseline saturations <95%. Lower SpO correlated with pulmonary hypertension (r  = 0.1, P = 0.04). Thirty-nine (65%) patients started respiratory support (14 O , 18 CPAP, 7 NIV) and 22 (56%) have regularly used it. After a 1.9 years follow up 11/24 had satisfactory adherence to CPAP/NIV (average use 8 h/night).

Conclusions: Our results confirm the high prevalence of OSAS in children with DS. A significant number also have low baseline saturations, central apnoeas, and nocturnal hypoventilation. Contrary to popular belief, more than half of children with DS had satisfactory adherence to respiratory support.
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http://dx.doi.org/10.1002/ppul.24122DOI Listing
October 2018

Should oral corticosteroids be prescribed for preschool viral wheeze?

Lancet Respir Med 2018 06;6(6):e21

National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK; Department of Respiratory Paediatrics, Royal Brompton Hospital, London, UK.

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http://dx.doi.org/10.1016/S2213-2600(18)30146-2DOI Listing
June 2018

Children with cystic fibrosis demonstrate no respiratory immunological, infective or physiological, consequences of vitamin D deficiency.

J Cyst Fibros 2018 09 7;17(5):657-665. Epub 2018 Apr 7.

National Heart and Lung Institute, Imperial College, London, United kingdom; Department of Paediatric Respiratory Medicine, Royal Brompton & Harefield NHS Foundation Trust, London, United Kingdom.

Background: Vitamin D has health benefits in many respiratory diseases but the evidence in CF is unclear. Induction of the antimicrobial peptides cathelicidin (LL37) and human-beta-defensin-2 (HBD-2) may be the mechanism of any benefit. We hypothesised that antimicrobial peptide levels would be decreased, and airway infection and inflammation greater, in CF children with vitamin D deficiency. The objective of the study was to explore relationships between vitamin D, LL37 and HBD-2, and airway infection, inflammation and physiology in children with CF.

Methods: Bronchoalveolar lavage (BALF) and blood were obtained from children undergoing fibreoptic bronchoscopy. Serum vitamin D, BALF HBD-2 and LL37, cultured bacteria and inflammatory markers were measured. Clinical parameters were recorded.

Results: 113 patients with CF, 23 with non-CF chronic suppurative lung disease (CSLD) and 6 healthy controls were included. We found no relationship between serum vitamin D and BALF HBD-2 or LL-37. There were no differences in infective or inflammatory markers between vitamin D sufficient and deficient groups. Vitamin D deficient patients (<50 nmol/L) did not have a worse FEV (CF: 66 (58-71)% vs. 71.5 (61-76)%, ns; non-CF CSLD: 69 (36-88)% vs. 70 (62-95)%, ns).

Conclusions: In the first bronchoscopic study exploring this question, we demonstrate that vitamin D deficiency is not associated with immunological, infective or clinical markers of disease severity in patients with CF or CSLD.
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http://dx.doi.org/10.1016/j.jcf.2018.02.011DOI Listing
September 2018

The evolutionary pattern of mutations in glioblastoma reveals therapy-mediated selection.

Oncotarget 2018 Jan 15;9(8):7844-7858. Epub 2017 Dec 15.

School of Medicine, Deakin University, Geelong, Victoria, Australia.

Glioblastoma presents as a heterogeneous disease with poor prognosis despite the use of multimodal therapy. Analysis of genomic DNA changes between initial diagnosis and recurrence in response to standard treatment protocols would enhance understanding of disease progression and better inform new treatment strategies. A cohort of 21 patients with primary glioblastoma were examined between diagnosis and first recurrence. This study presented a rare opportunity to characterize molecular alterations in tumors observed in three patients who received no therapeutic intervention, other than surgery, offering a unique control. We focused this study by comparing the dynamic mutation profiles between the primary tumors and their matched recurrent counterparts. Molecular profiling of tumors was performed using multiplexed targeted deep sequencing of 409 well characterized cancer-associated genes, achieving a mean read depth of 1272 x. Three levels of evidence suggested an evolutionary pattern consistent with a response to therapy-mediated selection pressures exists in treated patients: 1) variant burden was reduced in recurrent tumors, 2) neutral evolutionary dynamics apparent in untreated tumors shifted toward a non-neutral mode of evolution in treated patients at recurrence, and 3) the recurrent tumor of one patient displayed an increased mutation rate attributable to a temozolomide-associated hypermutator phenotype. Our observations suggest that current treatment modalities are likely to fail in achieving long term remission with the majority of relapse samples containing distinct mutations when compared to primary diagnostic samples.
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http://dx.doi.org/10.18632/oncotarget.23541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5814263PMC
January 2018

Comparison between site and central radiological assessments for patients with recurrent glioblastoma on a clinical trial.

Asia Pac J Clin Oncol 2018 Oct 8;14(5):e359-e365. Epub 2017 Nov 8.

Royal Melbourne Hospital, Melbourne, Victoria, Australia.

Aim: Assessment of magnetic resonance imaging (MRI) in glioblastoma can be challenging. For patients with recurrent glioblastoma managed on the CABARET trial, we compared disease status assessed at hospitals and subsequent blinded central expert radiological review.

Methods: MRI results and clinical status at specified time points were used for site and central assessment of disease status. Clinical status was determined by the site. Response Assessment in Neuro-Oncology (RANO) criteria were used for both assessments. Site and central assessments of progression-free survival (PFS) and response rates were compared. Inter-rater variability for central review progression dates was assessed.

Results: Central review resulted in shorter PFS in 45% of 89 evaluable patients (n = 40). Median PFS was 3.6 (central) versus 3.9 months (site) (hazard ratio 1.5, 95% confidence interval 1.3-1.8, P < 0.001). Responses were documented more frequently by sites (n = 16, 18%) than centrally (n = 11, 12%). Seven of 120 patients continued on trial without site-determined progression for more than 6 months beyond the central review determination of progression. Of scans reviewed by all three central reviewers, 33% were fully concordant for progression date.

Conclusion: While the difference between site and central PFS dates was statistically significant, the 0.3-month median difference is small. The variability within central review is consistent with previous studies, highlighting the challenges in MRI interpretation in this context. A small proportion of patients benefited from treatment well beyond the centrally determined progression date, reinforcing that clinical status together with radiology results are important determinants of whether a therapy is effective for an individual.
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http://dx.doi.org/10.1111/ajco.12806DOI Listing
October 2018
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