bluuebunny/crossref_metadata_2025_split huggingface dataset:
Patient efficacy in telehealth is moderated by distress among patients with cancer: A cross-sectional survey study.
Authors: McCollom Joseph William , Drouin Michelle , Flanagan Mindy , Pfafman Rachel 
Published: June 2022

1590 Background: The COVID-19 pandemic increased the use of telehealth to reduce exposure, which was critical for patients with cancer. The extent to which patients with cancer view telehealth visits as meeting their medical needs was investigated using a cross-sectional survey. Methods: Patients currently receiving cancer treatment at a single cancer institute who had had at least one telehealth visit were emailed an online survey. Response rate was 5% (94/1944). The survey measured patients’: 1) Emotional Thermometer (i.e. distress, anger, depression, anxiety, and need for help on a 0-10 scale); 2) Telehealth usability questionnaire (TUQ; 21-items with various subscales, like interaction quality; α=0.98).); and 3) Perceived Efficacy in Patient-Physician Interactions (PEPPI-5) scale (five items, e.g., “How confident are you in your ability to make the most of your visits with your doctors?”). Respondents completed the PEPPI-5 for in-person visits and for telehealth visits. Descriptive statistics were calculated for all measures. A generalized linear model was estimated predicting PEPPI-5 for telehealth visits from emotional thermometer and TUQ scores. The interaction between emotional thermometer and TUQ scores was estimated to test the hypothesis that emotional distress moderated the relationship between TUQ and efficacy in patient-provider interactions during telehealth visits. Results: Across all five thermometers, 30.8% (28/91) reported a high score on at least one metric. The most frequently reported high score was for anxiety, 23.3% (21/90) and least frequently reported high score was for anger, 12.2% (11/90). The mean TUQ score was 5.5 (SD=1.5) and mean PEPPI-5 score for telehealth visits was 8.1 (SD=2.4). As shown in Table, emotional thermometer scores did moderate the relation between TUQ and patient self-efficacy during telehealth visits. For high emotional thermometer scores, self-efficacy decreased as TUQ scores decreased. Conclusions: For patients experiencing high emotional distress, low comfort and ability with telehealth usability resulted in low patient self-efficacy in communicating with providers and getting medical needs met. Telehealth is a convenient and effective modality; however, in times of emotional distress for patients who are not familiar with telehealth, in-person clinic visits may result in greater patient self-efficacy.[Table: see text]
Reproducibility of outcomes in sequential trials using CMV-targeted dendritic cell vaccination for glioblastoma.
Authors: Sampson John H. , Batich Kristen A , Mitchell Duane Anthony , Herndon James Emmett , Broadwater Gloria , Healy Patrick , Sanchez-Perez Luis , Nair Smita , Congdon Kendra , Norberg Pamela , Weinhold Kent J. , Archer Gerald E. , Reap Elizabeth A. , Xie Weihua , McLendon Roger E. , Reardon David A. , Vredenburgh James J. , Friedman Henry S. , Bigner Darell , Friedman Allan H. 
Published: June 2022

2005 Background: Vaccination with dendritic cells (DCs) fares poorly in primary and recurrent glioblastoma (GBM). Moreover, GBM vaccine trials are often underpowered due to limited sample size. Methods: To address these limitations, we conducted three sequential clinical trials utilizing Cytomegalovirus (CMV)-specific DC vaccines in patients with newly diagnosed GBM eligible to receive standard of care resection and adjuvant radiation therapy and temozolomide chemotherapy. Autologous DCs were generated and electroporated with mRNA encoding for the CMV protein pp65. Serial vaccination was given throughout adjuvant temozolomide cycles, and 111Indium radiolabeling was implemented to assess migration efficiency of DC vaccines. Patients were followed for median overall survival (mOS) and OS. Results: Our initial study was the phase II ATTAC study (NCT00639639; total n = 12) with 6 patients randomized to vaccine site preconditioning with tetanus-diphtheria (Td) toxoid. This led to an expanded cohort trial (ATTAC-GM; NCT00639639) of 11 patients receiving CMV DC vaccines containing granulocyte-macrophage colony-stimulating factor (GM-CSF). Follow-up data from ATTAC and ATTAC-GM revealed 5-year OS rates of 33.3% (mOS 38.3 months; CI95 17.5-undefined) and 36.4% (mOS 37.7 months; CI95 18.2-109.1), respectively. ATTAC additionally revealed a significant increase in DC migration to draining lymph nodes following Td preconditioning ( P = 0.049). Increased DC migration was associated with OS (Cox proportional hazards model, HR = 0.820, P = 0.023). Td-mediated increased migration has been recapitulated in our larger confirmatory trial ELEVATE (NCT02366728) of 43 patients randomized to preconditioning (Wilcoxon rank sum, Td n = 24, unpulsed DC n = 19; 24h, P = 0.031 and 48h, P = 0.0195). In ELEVATE, median follow-up of 42.2 months revealed significantly longer OS in patients randomized to Td ( P = 0.026). The 3-year OS for Td-treated patients in ELEVATE was 34% (CI95 19-63%) compared to 6% given unpulsed DCs (CI95 1-42%). Conclusions: We report reproducibility of our findings across three sequential clinical trials using CMV pp65 DCs. Despite their small numbers, these successive trials demonstrate consistent survival outcomes, thus supporting the efficacy of CMV DC vaccine therapy in GBM. Clinical trial information: NCT00639639, NCT02366728.
CSF proteomics for differentiation of brain malignancies.
Authors: Mikolajewicz Nicholas , Trifoi Mara , Khan Shahbaz , Glantz Michael J. , Moffat Jason , Zadeh Gelareh , Kislinger Thomas , Mansouri Alireza 
Published: June 2022

2021 Background: Accurate diagnosis and prognostication of intra-axial brain tumors hinges on invasive brain sampling, which carries risk of morbidity. Minimally invasive sampling of proximal fluids, also known as liquid biopsy, can mitigate this risk. Although the cerebrospinal fluid (CSF) is the ideal liquid biopsy source, the traditionally high volumes required for impactful analyses have deterred progress. The objective of this study was to identify diagnostic and prognostic CSF proteomic signatures in glioblastoma (GBM), brain metastases (BM), and central nervous system lymphoma (CNSL). Methods: CSF samples were retrospectively retrieved from the Penn State Neuroscience Biorepository and profiled using shotgun proteomics with ultra-low sample volumes. Proteomic signatures were identified using machine learning classifiers and survival analyses. Results: Using 30µL CSF volumes, we recovered 800 unique peptides across 73 samples [20 normal pressure hydrocephalus (NPH, non-tumor control), 22 GBM, 17 BM, and 14 CNSL]. Externally-validated proteomic-based classifiers identified malignancy with AUROC of 0.94 and distinguished individual tumor entities from others with AUROC ≥0.96. More clinically relevant triplex classifiers, comprised of just 3 peptides, distinguished individual tumor entities with AUROC ≥0.90. Novel biomarkers were identified among the top classifiers, including TFF3 and CACNA2D2, and characterized using single-cell RNA sequencing data. Survival analyses validated previously implicated prognostic signatures, including blood brain barrier disruption. Conclusions: Reliable classification of intra-axial malignancies using ultra-low CSF volumes is feasible, which has ramifications for longitudinal tumor surveillance. Novel biomarkers identified here necessitate future validation. Based on emerging evidence, upfront implantation of CSF reservoirs in brain tumor patients warrants consideration.
Prospective validation of a new imaging scorecard to assess leptomeningeal metastasis: A joint EORTC BTG and RANO effort.
Authors: Le Rhun Emilie , Devos Patrick , Winklhofer Sebastian , Lmalem Hafida , Brandsma Dieta , Kumthekar Priya , Smits Marion , Tonn Joerg , Jaeckle Kurt A. , Preusser Matthias , Glantz Michael J. , Wen Patrick Y. , Bendszus Martin , Weller Michael ,   EORTC RANO LM scorecard task force, including 38 colleagues
Published: June 2022

2026 Background: Validation of the 2016 RANO MRI scorecard for leptomeningeal metastasis failed for multiple reasons. Accordingly, this joint EORTC Brain Tumor Group and RANO effort sought to prospectively validate a revised MRI scorecard for response assessment in leptomeningeal metastasis. Methods: Coded paired cerebrospinal MRI of 20 patients with leptomeningeal metastases from solid cancers at baseline and follow-up after treatment and instructions for assessment were provided via the EORTC imaging platform. The Kappa coefficient was used to evaluate the inter-observer pairwise agreement. Results: Thirty-five raters participated, including 9 neuroradiologists, 17 neurologists, 4 radiation oncologists, 3 neurosurgeons and 2 medical oncologists. Among single leptomeningeal metastases-related imaging findings at baseline, the best median concordance was noted for hydrocephalus (Kappa = 0.63), and the worst median concordance for spinal linear enhancing disease (Kappa = 0.46). The median concordance of raters for the overall response assessment was moderate (Kappa = 0.44). Notably, the interobserver agreement for the presence of parenchymal brain metastases at baseline was fair (Kappa = 0.29) and virtually absent for their response to treatment. 394 of 700 ratings (20 patients x 35 raters, 56%) were fully completed. In 308 of 394 fully completed ratings (78%), the overall response assessment perfectly matched the summary interpretation of the single ratings as proposed in the scorecard instructions. Conclusions: This study confirms the principle utility of the new scorecard, but also indicates the need for training of MRI assessment with a dedicated reviewer panel in clinical trials. Electronic case report forms with “blocking options” may be required to enforce completeness and quality of scoring.
Final data from the phase 2a single-arm trial of SurVaxM for newly diagnosed glioblastoma.
Authors: Ciesielski Michael J , Ahluwalia Manmeet Singh , Reardon David A. , Abad Ajay P. , Curry William T. , Wong Eric T. , Peereboom David M. , Figel Sheila A. , Hutson Alan , Groman Adrienne , Withers Henry G. , Liu Song , Belal Ahmed , Qiu Jing-Xin , Mogensen Kathleen , Schilero Cathy , Casucci Danielle M. , Mechtler Laszlo , Fenstermaker Robert Alan 
Published: June 2022

2037 Background: Newly diagnosed glioblastoma (nGBM) routinely treated with surgery, radiation, and temozolomide (TMZ), still result in early progression and near-universal lethality within 5 years. Tumor associated “survivin” is expressed in >95% of nGBM and targetable by SurVaxM immunotherapy. Results from the recently completed multi-center phase 2a trial of SurVaxM in nGBM are presented. Methods: nGBM patients (pts) were enrolled at 5 trial sites. Eligibility criteria included: age ≥ 18, Karnofsky performance status ≥70, IHC confirmation of survivin expression, expression of HLA-A*02, A*03, A*11 or A*24 MHC-I alleles and residual contrast enhancement of ≤1 cm3 by MRI within 72h post-resection. Pts received standard TMZ chemoradiation followed by initiation of 4 priming doses of SurVaxM (500 mcg in emulsion with Montanide ISA 51, every 2 weeks) with 100 mcg sargramostim. Maintenance doses of SurVaxM-Montanide plus sargramostim were thereafter administered every 12 weeks. Adjuvant TMZ was administered for at least 6 cycles, after at least the first dose of SurVaxM and beginning no sooner than 28 days after completion of chemoradiation. Pts were monitored by MRI every 8 weeks, and progression was assessed using modified RANO criteria. The primary endpoint was 70% progression free survival (PFS) at 6 mos. Primary analyses of median PFS (mPFS) and median overall survival (OS) were measured from first immunization. Safety, tolerability, and immune responsiveness were also determined. Results: 63 pts with nGBM were enrolled, comprised of 38 males and 25 females with a median age of 60 years. The cohort was consistent with the 4 commonly observed primary molecular GBM subtypes (classical, mesenchymal, neural and proneural). SurVaxM was well tolerated, with no serious adverse events. A strong positive correlation, accounting for censoring, was observed between PFS and OS of all pts (r = 0.79; 95% CI (0.66,0.87)). SurVaxM was immunogenic and produced survivin-specific CD8+ T-cells and antibody (IgG) titers in both methylated and unmethylated MGMT pts and both groups showed clinical benefit. Conclusions: SurVaxM appeared to be safe and well-tolerated in pts with nGBM. SurVaxM was effective at stimulating survivin-specific immune responses and the primary endpoint was met. SurVaxM represents a promising therapy for nGBM, including for those pts with unmethylated MGMT genes. For pts treated with SurVaxM, PFS may be an acceptable surrogate for OS. Clinical trial information: NCT02455557. [Table: see text]
Phase I study of drug-resistant immunotherapy (DRI) with gene-modified autologous γδ T cells in patients with newly diagnosed glioblastoma multiforme (GBM) receiving maintenance temozolomide (TMZ).
Authors: Nabors Louis B. , Lobbous Mina , Lamb Lawrence S. , Rochlin Kate , Pillay Thriumaine , Youngblood Samantha , ter Haak Mariska , Goswami Trishna 
Published: June 2022

2044 Background: γδ T cells, MHC unrestricted immune cells, target NKG2D ligands differentially expressed on tumor cells. DeltEx drug resistant immunotherapy (DRI), a novel ex vivo expanded, activated γδ T cell expresses MGMT, conveying TMZ resistance. NCT04165941 , a phase 1 trial assessing the safety of single and multiple infusions of autologous DeltEx DRI cells presents updated safety and efficacy data. Methods: Adult newly diagnosed GBM patients with adequate organ function and KPS≥70% are enrolled. Cells engineered from apheresis after tumor resection were infused through a Rickham catheter placed during surgery. Cohort (C) 1, 2 and 3 receive 1, 3 and 6 doses of cells respectively on day (D) 1 of each 28-day maintenance cycle. Patients receive 1 x 107 γδ T cells intratumorally on D1 with 150 mg/m2 of TMZ intravenously with the Stupp regimen. Primary endpoint is safety; secondary endpoints include progression free and overall survival. Immunologic and genomic correlative analyses are being conducted. Dose limiting toxicities (DLTs) are defined as treatment related ≥ grade 3 cardiopulmonary or hepatic toxicity, grade 4 toxicity exceeding 72 hours or neurologic deterioration that exceeds 2 weeks. Results: 12 patients (58% male; median age 66.5 (range: 21-76); 66.7% IDH-WT, 66.7% MGMT unmethylated) were enrolled with 6 dosed (3 in C1, 3 in C2). No patients had DLTs, cytokine release syndrome (CRS), or neurotoxicity. The most common adverse events (AEs) were Grade 1/2 events including fever, leukopenia, nausea, and vomiting attributable to TMZ or radiotherapy. One subject had Grade 3 treatment related AEs of UTI, dehydration, and thrombocytopenia. Three evaluable C1 patients have PFS of 8.3, 11.9, 7.4 months and OS of 15.6, 17.7 and 9.6 months respectively. In C2, three patients have been dosed, with one patient with stable disease at 8.2 months after receiving all three doses and no DLTs. Patient recruitment continues with anticipated completion in 2022. Conclusions: Data demonstrates that single, repeat doses of DRI T cells have manageable toxicity with encouraging trend in PFS.
Predicting CNS penetration of precision medicine therapies in oncology: A comparison of the CNS TAP tool and the BOILED-Egg computational model.
Authors: Walker Gianni , Franson Andrea Flynn , Pai Manjunath , Ravi Karthik , Roberts Holly , Schepers Allison , Koschmann Carl Johannes , Marini Bernard L. 
Published: June 2022

2062 Background: The number of available targeted therapies has vastly expanded in recent years; however, only a selection of such therapies achieve adequate central nervous system (CNS) penetration. The CNS Targeted Agent Prediction (CNS TAP) Tool was developed to aid in the selection of precision medicine therapies based on preclinical data, clinical data, patient-specific genomic data, and importantly, optimal blood brain barrier penetration. Using a standardized murine pharmacokinetic (PK) model, we sought to determine the concordance of CNS penetration prediction by the CNS TAP Tool compared to the SwissADME BOILED-Egg computational model. Methods: Eleven drugs were chosen based on the most commonly altered and targeted pathways by our CNS tumor board. Mice were injected individually with the compounds of interest and sacrificed at four different time points to quantify drug concentration via LC-MS in brain tissue and blood samples for PK analyses (1,2,4,7 hours). The percent brain penetration (AUCbrain/plasma) was compared to published human phase I PK data and pathway IC-50 to determine if agents were adequately CNS penetrant. These results were compared against the CNS TAP Tool and BOILED-Egg prediction of CNS penetrance. Results: All 11 drugs chosen (Table) demonstrated adequate CNS penetration, suggesting likely CNS efficacy. The CNS TAP Tool correctly predicted 10/11 agents (91% concordance), the lone exception being panobinostat. In contrast, the BOILED-Egg model only successfully predicted 3/11 agents (27%). When restricting the analysis to drugs with >50% CNS penetration (ponatinib, panobinostat, and ONC-201), the BOILED-Egg model successfully predicted CNS penetration of all agents. Conclusions: The clinician-curated CNS TAP Tool more accurately predicted CNS penetration of precision medicine therapies than the BOILED-Egg computational model, which performed best for drugs that achieve extremely high CNS penetration. The resulting PK and CNS penetration data for all agents was utilized to update and refine the CNS TAP tool for future patient use. [Table: see text]
Risk factors for cranial irradiation-related late neurocognitive toxicity: A prospective cohort study.
Authors: Bhanja Debarati , Tuohy Kyle J. , Wilding Hannah E. , Aregawi Dawit , Glantz Michael J. 
Published: June 2022

2066 Background: Neurocognitive dysfunction is a common complication of cranial irradiation, occurring in up to 50% of irradiated brain tumor patients. Symptoms often severely compromise quality of life long before patients succumb to their tumor; however, risk factors are poorly understood, and consequently, prognostication and prevention have not been possible. The objective of this study was to evaluate the prognostic value of vascular risk factors for the development of irradiation-related brain injury. Methods: This single-institution prospective cohort study included patients with malignant primary brain tumors who received cranial irradiation as part of their initial tumor-directed therapy. Three putative vascular risk factors – homocysteine, total cholesterol, apoprotein E genotype (ApOE) – were measured and dichotomized (above vs. below the laboratory normal). Univariate analyses compared each risk factor with four measures of neurocognitive dysfunction: mini-mental status exam (MMSE), MRI white matter changes at 6 months (MRI), physician (Phys) assessment, and patient (Pat) assessment. Decision analysis was used to construct a prediction algorithm. Results: 80 patients were included in this analysis. Elevated homocysteine was the most powerful and consistent predictor of neurocognitive toxicity, followed by elevated triglycerides and the ApOE genotype (Table). Logistic regression revealed a highly significant (p<0.01) association between homocysteine level and each of the four outcome variables. Decision tree analysis using homocysteine level (high vs. low) and ApoE genotype (yes vs. no) provided the most efficient predictive algorithm. Conclusions: Two putative vascular risk factors (homocysteine level > 14 and ApOE genotype) provide moderate ability to predict post-radiation neurocognitive dysfunction using a variety of simple but clinically meaningful definitions of dysfunction. This predictive algorithm should be validated in prospective trials. If these findings are corroborated, studies examining additional risk factors as well as studies looking at risk factor mitigation will be appropriate. [Table: see text]
Changes in circulating tumor DNA (ctDNA) and outcomes in solid tumors treated with immune checkpoint inhibitors (ICIs).
Authors: Al-Showbaki Laith , Iafolla Marco , Tamimi Faris , Molto Consolacion , Mittal Abhenil , Cescon David W. , Amir Eitan 
Published: June 2022

2544 Background: Quantification of ctDNA levels can be a reliable prognostic tool in several malignancies. More recently, detection of genomic alterations in ctDNA have been validated as a predictive biomarker to guide treatment planning. Dynamic changes in ctDNA levels over time and in response to treatment may also provide prognostic information. However, less is known about the value of changes to ctDNA levels in response to immune checkpoint inhibitors (ICIs). Methods: We searched MEDLINE (host:PubMed) and reviewed trials exploring outcomes of patients with advanced solid tumors receiving ICIs in which outcomes were reported based on changes to ctDNA levels. ctDNA clearance was defined as reported in individual trials. Typically, this was defined as either >50% reduction or a reduction to undetectable levels. We extracted progression free survival (PFS) and/or overall survival (OS) values, related 95% Confidence intervals (CI) and/or p-values. Data were then included in a meta-analysis utilizing the generic inverse variance and random effects model. Variation in effect size was examined using random effects meta-regression analysis. Results: A total of 17 trials were included in the meta-analysis; ctDNA levels were detectable in all participants in all studies prior to initiation of ICIs. Method of detection included next generation sequencing and/or droplet digital polymerase chain reaction assays. Overall, low to undetectable ctDNA levels, measured 6-16 weeks after starting treatment was associated with significantly better PFS, (HR 0.20 95% CI, 0.14-0.28; p<0.001). Similarly, OS was superior in patients with substantially reduced or undetectable ctDNA levels after receiving ICIs, (HR 0.18, 95% CI, 0.12-0.26; p<0.001. The results were consistent across all disease sites, lines of treatment, level of change (undetectable vs. >50% reduction) and whether treatment exposure comprised single or multiple ICIs (see Table). Conclusions: In unselected advanced solid tumors, a substantial fall in ctDNA levels in response to ICIs is associated with substantial improvements in both PFS and OS. ctDNA change is an early response biomarker which may allow for de-escalation of cross-sectional imaging in patients receiving ICIs, or support treatment de-escalation strategies. Further research is needed to quantify variations in sensitivity between the available NGS assays, as well as differences discovery range between assay platforms. [Table: see text]