Association Between Brain Substructure Dose and Cognitive Outcomes in Children With Medulloblastoma Treated on SJMB03: A Step Toward Substructure-Informed Planning

2021 ◽  
Author(s):  
Sahaja Acharya ◽  
Yian Guo ◽  
Tushar Patni ◽  
Yimei Li ◽  
Chuang Wang ◽  
...  
Keyword(s):  
Associative Memory ◽  
Processing Speed ◽  
Cognitive Testing ◽  
Phase Iii ◽  
Reliable Change Index ◽  
Average Risk ◽  
Composite Processing ◽  
Dose Volume Histograms ◽  
Neurocognitive Outcomes ◽  
Risk Patients

PURPOSE To characterize the association between neurocognitive outcomes (memory and processing speed) and radiation (RT) dose to the hippocampus, corpus callosum (CC), and frontal white matter (WM) in children with medulloblastoma treated on a prospective study, SJMB03. PATIENTS AND METHODS Patients age 3-21 years with medulloblastoma were treated at a single institution on a phase III study. The craniospinal RT dose was 23.4 Gy for average-risk patients and 36-39.6 Gy for high-risk patients. The boost dose was 55.8 Gy to the tumor bed. Patients underwent cognitive testing at baseline and once yearly for 5 years. Performance on tests of memory (associative memory and working memory) and processing speed (composite processing speed and perceptual speed) was analyzed. Mixed-effects models were used to estimate longitudinal trends in neurocognitive outcomes. Reliable change index and logistic regression were used to define clinically meaningful neurocognitive decline and identify variables associated with decline. RESULTS One hundred and twenty-four patients were eligible for inclusion, with a median neurocognitive follow-up of 5 years. Mean right and left hippocampal doses were significantly associated with decline in associative memory in patients without posterior fossa syndrome (all P < .05). Mean CC and frontal WM doses were significantly associated with decline in both measures of processing speed (all P < .05). Median brain substructure dose–volume histograms were shifted to the right for patients with a decline in associative memory or processing speed. The odds of decline in associative memory and composite processing speed increased by 23%-26% and by 10%-15% for every 1-Gy increase in mean hippocampal dose and mean CC or frontal WM dose, respectively. CONCLUSION Increasing RT dose to the CC or frontal WM and hippocampus is associated with worse performance on tests of processing speed and associative memory, respectively. Brain substructure–informed RT planning may mitigate neurocognitive impairment.

scholarly journals Outcomes by Clinical and Molecular Features in Children With Medulloblastoma Treated With Risk-Adapted Therapy: Results of an International Phase III Trial (SJMB03)

2021 ◽  
pp. JCO.20.01372
Author(s):  
Amar Gajjar ◽  
Giles W. Robinson ◽  
Kyle S. Smith ◽  
Tong Lin ◽  
Thomas E. Merchant ◽  
...  
Keyword(s):  
High Risk ◽  
Risk Groups ◽  
Genetic Alterations ◽  
Low Risk ◽  
Phase Iii ◽  
Average Risk ◽  
Molecular Features ◽  
Group 4 ◽  
Risk Patients ◽  
Group 3

PURPOSE SJMB03 (ClinicalTrials.gov identifier: NCT00085202 ) was a phase III risk-adapted trial that aimed to determine the frequency and clinical significance of biological variants and genetic alterations in medulloblastoma. PATIENTS AND METHODS Patients 3-21 years old were stratified into average-risk and high-risk treatment groups based on metastatic status and extent of resection. Medulloblastomas were molecularly classified into subgroups (Wingless [WNT], Sonic Hedgehog [SHH], group 3, and group 4) and subtypes based on DNA methylation profiles and overlaid with gene mutations from next-generation sequencing. Coprimary study end points were (1) to assess the relationship between ERBB2 protein expression in tumors and progression-free survival (PFS), and (2) to estimate the frequency of mutations associated with WNT and SHH tumors. Clinical and molecular risk factors were evaluated, and the most robust were used to model new risk-classification categories. RESULTS Three hundred thirty eligible patients with medulloblastoma were enrolled. Five-year PFS was 83.2% (95% CI, 78.4 to 88.2) for average-risk patients (n = 227) and 58.7% (95% CI, 49.8 to 69.1) for high-risk patients (n = 103). No association was found between ERBB2 status and PFS in the overall cohort ( P = .74) or when patients were stratified by clinical risk ( P = .71). Mutations in CTNNB1 (96%), DDX3X (37%), and SMARCA4 (24%) were most common in WNT tumors and PTCH1 (38%), TP53 (21%), and DDX3X (19%) in SHH tumors. Methylome profiling classified 53 WNT (17.4%), 48 SHH (15.7%), 65 group 3 (21.3%), and 139 group 4 (45.6%) tumors. A comprehensive clinicomolecular risk factor analysis identified three low-risk groups (WNT, low-risk SHH, and low-risk combined groups 3 and 4) with excellent (5-year PFS > 90%) and two very high-risk groups (high-risk SHH and high-risk combined groups 3 and 4) with poor survival (5-year PFS < 60%). CONCLUSION These results establish a new risk stratification for future medulloblastoma trials.

scholarly journals The role of idecabtagene vicleucel in patients with heavily pretreated refractory multiple myeloma

2021 ◽  
Vol 12 ◽  
pp. 204062072110196
Author(s):  
Albert Oriol ◽  
Laura Abril ◽  
Anna Torrent ◽  
Gladys Ibarra ◽  
Josep-Maria Ribera
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Safety Profile ◽  
Proteasome Inhibitors ◽  
Clinical Development ◽  
Phase Iii ◽  
Acceptable Safety Profile ◽  
Refractory Multiple Myeloma ◽  
High Risk Patients ◽  
Risk Patients

The development of several treatment options over the last 2 decades has led to a notable improvement in the survival of patients with multiple myeloma. Despite these advances, the disease remains incurable for most patients. Moreover, standard combinations of alkylating agents, immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies targeting CD38 and corticoids are exhausted relatively fast in a proportion of high-risk patients. Such high-risk patients account for over 20% of cases and currently represent a major unmet medical need. The challenge of drug resistance requires the development of highly active new agents with a radically different mechanism of action. Several immunotherapeutic modalities, including antibody–drug conjugates and T-cell engagers, appear to be promising choices for patients who develop resistance to standard combinations. Chimeric antigen-receptor-modified T cells (CAR-Ts) targeting B-cell maturation antigen have demonstrated encouraging efficacy and an acceptable safety profile compared with alternative options. Multiple CAR-Ts are in early stages of clinical development, but the first phase III trials with CAR-Ts are ongoing for two of them. After the recent publication of the results of a phase II trial confirming a notable efficacy and acceptable safety profile, idecabtagene vicleucel is the first CAR-T to gain regulatory US Food and Drug Administration approval to treat refractory multiple myeloma patients who have already been exposed to antibodies against CD38, proteasome inhibitors, and immunomodulatory agents and who are refractory to the last therapy. Here, we will discuss the preclinical and clinical development of idecabtagene vicleucel and its future role in the changing treatment landscape of relapsed and refractory multiple myeloma.

scholarly journals 658 An Audit of Frequency of Cancer Genetics Referral in Patients with a Family History of Colorectal Cancer

2021 ◽  
Vol 108 (Supplement_2) ◽  
Author(s):  
M Abbakar ◽  
T James ◽  
P Boxall ◽  
M Lim
Keyword(s):  
Family History ◽  
High Risk ◽  
Hereditary Cancer ◽  
Risk Category ◽  
Average Risk ◽  
Insufficient Data ◽  
High Risk Patients ◽  
Amsterdam Criteria ◽  
Family History Questionnaire ◽  
Risk Patients

Abstract Introduction Guidelines on the management of hereditary colorectal cancers were updated in 2019. In this study, data from patients within the colonoscopy surveillance programme for hereditary cancer at York Teaching Hospitals Trust were analysed to assess category of risk and appropriateness of referrals to regional geneticists. Method After examination of electronic records and clinical notes, patients were assigned a risk category of average, moderate or high according to the Amsterdam criteria and latest BSG/ACPGBI/UKCGG guidelines. Patients were then assessed to see if a concurrent referral had been made to the regional cancer genetic services. Results There were 228 patients. 72(31.6%) patients were in the average, 81(35.5%) in the moderate and 41(18%) were in the high-risk category. 34 (14.9%) patients with insufficient data and/or assessments were in the indeterminate category. 18 of 72 (25%) patients with average risk were unnecessarily referred to the regional genetics team, while 5/41(12%) of high-risk patients were not. A large proportion of patients with insufficient data (19/34, 55.8%) were rightly or wrongly, referred to the regional genetics team. Conclusions Assessment of hereditary cancer risk is difficult in the absence of good quality information. Risk assessment may be improved with use of a dedicated family history questionnaire/template - this facilitates identification of high-risk patients that benefit most from referral to geneticists.

Global tissue stiffness on breast MR elastography: High-risk dense breast patients have higher stiffness compared to average-risk dense breast patients.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 10541-10541
Author(s):  
Bhavika K. Patel ◽  
Kay Pepin ◽  
Kathy R Brandt ◽  
Gina L. Mazza ◽  
Barbara A. Pockaj ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Cancer Risk ◽  
Menopausal Status ◽  
Risk Groups ◽  
Average Risk ◽  
Tissue Stiffness ◽  
Tissue Properties ◽  
Dense Breasts ◽  
Risk Patients

10541 Background: Biomechanical tissue properties may vary in the breasts of patients at elevated risk for breast cancer. We aim to quantify in vivo biomechanical tissue properties in various breast densities and in both normal risk and high risk women using Magnetic Resonance Imaging (MRI)/MRE and examine the association of biomechanical properties of the breast with cancer risk. Methods: In this IRB–approved prospective single-institution study, we recruited two groups of women differing by breast cancer risk to undergo a 3.0 T dynamic contrast enhanced MRI/MRE of the breast. Low-average risk women were defined as having no personal or significant family history of breast cancer, no prior high risk breast biopsies and a negative mammography within 12 months. High-risk breast cancer patients were recruited from those patients who underwent standard of care breast MR. Within each breast density group (non-dense versus dense), two-sample t-tests were used to compare breast stiffness, elasticity, and viscosity across risk groups (low-average vs high). Results: There were 50 low-average risk and 86 high-risk patients recruited to the study. The risk groups were similar on age (mean age = 55.6 and 53.6 years), density (68% vs. 64% dense breasts) and menopausal status (66.0% vs. 69.8%). Among patients with dense breasts, mean stiffness, elasticity, and viscosity were significantly higher in high risk patients ( N = 55) compared to low-average risk patients ( N = 34; all p < 0.001). In the multivariate logistic regression model, breast stiffness remained a significant predictor of risk status (OR=4.26, 95% CI [1.96, 9.25]) even after controlling for breast density, MRI BPE, age, and menopausal status. Similar results were seen for breast elasticity (OR=4.88, 95% CI [2.08, 11.43]) and viscosity (OR=11.49, 95% CI [1.15, 114.89]). Conclusions: Structurally-based, quantitative biomarker of tissue stiffness obtained from global 3D breast MRE is associated with differences in breast cancer risk in dense breasts. As such, tissue stiffness could provide a novel prognostic marker to help identify the subset of high-risk women with dense breasts who would benefit from increased surveillance.[Table: see text]

scholarly journals Dyslipidaemias and Cardiovascular Disease: Focus on the Role of PCSK9 Inhibitors

2020 ◽  
Vol 27 (27) ◽  
pp. 4494-4521 ◽  
Author(s):  
Olga Panagiotopoulou ◽  
Scott T. Chiesa ◽  
Dimitrios Tousoulis ◽  
Marietta Charakida
Keyword(s):  
Phase Iii ◽  
Short Term ◽  
Pcsk9 Inhibitors ◽  
Cardiovascular Risk Reduction ◽  
Pcsk9 Inhibitor ◽  
Phase Iii Clinical Trials ◽  
Risk Patients ◽  
Event Rates ◽  
Disease Focus

Genetic, experimental and clinical studies have consistently confirmed that inhibition of Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) can result in significant lowering of LDL-C and two fully human PCSK9 monoclonal antibodies have received regulatory approval for use in highrisk patients. Co-administration of PCSK9 with statins has resulted in extremely low LDL-C levels with excellent short-term safety profiles. While results from Phase III clinical trials provided significant evidence about the role of PCSK9 inhibitors in reducing cardiovascular event rates, their impact on mortality remains less clear. PCSK9 inhibitor therapy can be considered for high-risk patients who are likely to experience significant cardiovascular risk reduction.

Gastroenterologist-guided sedation with propofol for endoscopic ultrasonography in average-risk and high-risk patients

2012 ◽  
Vol 24 (5) ◽  
pp. 506-512 ◽  
Author(s):  
Eduardo Redondo-Cerezo ◽  
Antonio Sánchez-Robaina ◽  
Juan Gabriel Martínez Cara ◽  
Manuel Ojeda-Hinojosa ◽  
Ana Matas-Cobos ◽  
...  
Keyword(s):  
High Risk ◽  
Endoscopic Ultrasonography ◽  
Average Risk ◽  
High Risk Patients ◽  
Risk Patients

scholarly journals European Medicines Agency extension of indication to include the combination immunotherapy cancer drug treatment with nivolumab (Opdivo) and ipilimumab (Yervoy) for adults with intermediate/poor-risk advanced renal cell carcinoma

ESMO Open ◽  
2020 ◽  
Vol 5 (6) ◽  
pp. e000798
Author(s):  
Sahra Ali ◽  
Jorge Camarero ◽  
Paula van Hennik ◽  
Bjorg Bolstad ◽  
Maja Sommerfelt Grønvold ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Phase Iii ◽  
Advanced Renal Cell Carcinoma ◽  
Cancer Drug ◽  
European Medicines Agency ◽  
Poor Risk ◽  
Significant Difference ◽  
Risk Patients

On the 15 November 2018, the Committee for Medicinal Products for Human Use adopted an extension to an existing indication for the use of nivolumab (Opdivo) in combination with ipilimumab (Yervoy) for the first-line treatment of adult patients with intermediate/poor-risk advanced renal cell carcinoma (RCC). The approval was based on results from the Pivotal CA209214 study, a randomised, open-label, phase III study, comparing nivolumab +ipilimumab with sunitinib in subjects≥18 years of age with previously untreated advanced RCC (not amenable for surgery or radiotherapy) or metastatic RCC, with a clear-cell component. A total of 1096 patients were randomised in the trial, of which 847 patients had intermediate/poor-risk RCC and received either nivolumab (n=425) in combination with ipilimumab administered every 3 weeks for 4 doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks or sunitinib (n=422) administered orally for 4 weeks followed by 2 weeks off, every cycle. A statistically significant difference in overall survival (OS) was observed in the nivolumab + ipilimumab group compared with the sunitinib group in intermediate/poor-risk subjects (HR 0.63 (99.8% CI 0.44 to 0.89); stratified log-rank 2-sided p-value<0.0001). The median OS was not reached for the nivolumab + ipilimumab group and was 25.95 months for the sunitinib group. The OS rates were 89.5% and 86.2% at 6 months, and 80.1% and 72.1% at 12 months in the nivolumab +ipilimumab and the sunitinib groups, respectively. K-M curves separated after approximately 3 months, favouring nivolumab + ipilimumab. This was not mirrored in the favourable-risk patients where no statistically significant difference was observed between nivolumab + ipilimumab and sunitinib in favourable-risk patients (HR 1.45 (descriptive 99.8% CI 0.51 to 4.12), p =0.2715).

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