bluuebunny/crossref_metadata_2025 huggingface dataset:
Demographic and laboratory determinants of humoral immune responses and impact of different anti-SARS-CoV-2 vaccine platforms in patients with cancer: A systematic review and meta-analysis.
Authors: Martins-Branco Diogo , Loizidou Angela , Nader Marta Guilherme , Tecic Vuger Ana , Debien Veronique , Ameye Lieveke , Brandão Mariana , Punie Kevin , Spilleboudt Chloe , Willard-Gallo Karen , Awada Ahmad , Piccart-Gebhart Martine J. , de Azambuja Evandro
Published: June 2022

1543

Background: Patients (pts) with cancer have increased mortality from COVID-19 and their vaccination is crucial to prevent severe infection. We aimed to identify demographic and laboratory determinants of humoral immune responses to COVID-19 vaccination in pts with cancer and investigate differences in responses based on the vaccine platform. Methods: We searched for records in PubMed, Embase, and CENTRAL up to 28/09/21, as well as conference proceedings from ASCO and ESMO 2021. We included studies of pts ≥16 yr with a cancer diagnosis, who were vaccinated against SARS-CoV-2. Studies were excluded if ≥10% of the participants had other causes of immunosuppression or baseline anti-SARS-CoV-2 spike protein antibodies (Ab)/previous COVID-19 (PROSPERO ID: CRD42021282338). For this subgroup analysis of studies that reported a proportion of pts with cancer and positive Ab titers at any timepoint following complete vaccination, a random-effects model was used to estimate the humoral response rate (HRR) with 95% confidence intervals (CI). Results: We included 64 records, reporting data from 10,511 cancer pts. The HRR in the overall population and by subgroup are shown in Table. Elder patients with hematologic cancers (59%, CI 47-70%, N = 667) and patients with lymphopenia (50%, CI 25-75%, N = 111) or hypogammaglobulinemia (36%, CI 19-57%, N=226) were the subgroups with lower HRR. Male (77%, CI 69-84%, N = 2,659) and Asian (84%, CI 54-96%, N = 37) pts showed a trend to lower HRR when compared with females and other races, respectively. Pts vaccinated with mRNA vaccine platforms (79%, CI 74-83%, N = 9,404) had numerically higher HRR than those receiving the adenovirus vaccines (28%, CI 19-40%, N = 74). Conclusions: This study highlights demographic and laboratory determinants of weaker immune responses to SARS-CoV-2 vaccination, permitting better identification of more vulnerable pts. Despite the small number of pts included receiving adenovirus vaccines, these data also suggest prioritizing mRNA platform vaccination in pts with cancer. [Table: see text]
Association between remotely-monitored activity, patient-reported outcomes, and physical function in patients with advanced pancreatic cancer.
Authors: Gresham Gillian , Liu Eileen , Diniz Marcio A. , Barnhill Katherine , Nikravesh Nima , Welborn Amelia , Shirazipour Celina , Asher Arash , Osipov Arsen , Hendifar Andrew Eugene
Published: June 2022

1572

Background: Patients with pancreatic ductal adenocarcinoma (PDAC) experience significant functional decline over the course of their treatment, which can negatively impact their quality of life (QOL) and clinical outcomes. There are currently no standardized methods to monitor physical function (PF) in PDAC patients outside the clinic setting. The use of wearable technology to obtain continuous and objective activity data combined with routine collection of patient-reported outcomes (PROs) provides an opportunity to monitor PF and intervene in a timely matter. Methods: We conducted a single-site, single-arm prospective study in advanced stage 3 and 4 PDAC patients between 2019 and 2/2022. Patients used a wrist-worn wearable activity monitor (Fitbit) continuously for 8 weeks and completed NIH PROMIS surveys (PF, pain, fatigue, sleep disturbance, and emotional distress) at baseline, week 4 and week 8. ECOG performance status (PS), hand grip strength, and timed 15-foot walk test were also assessed at each timepoint. Pearson correlation coefficients were calculated for activity data (step counts, distance, stairs, time spent sedentary and in light, moderate, or vigorous activity, sleep), PROs, and functional outcomes. Multivariable regression models, adjusted for age, sex, and cancer stage, were fit to evaluate associations between activity metrics, PROs, and functional outcomes. Multivariable cox proportional hazard models were fit to evaluate the impact of activity levels on survival. Results: A total of 40 patients consented onto study: 50% female, median age: 67 years (range 47-85), 92% ECOG 1. Baseline activity data are summarized in Table. Statistically significant correlations between step counts and PF T-scores (coeff: 0.6, p = 0.001) and lower pain scores (coeff: -0.53, p = 0.002) were observed. Increased stairs count and time spent in moderate and high physical activity were also positively correlated with increased PF (p<0.001). No statistically significant correlations were observed between hand grip strength, activity metrics or PROs. Fewer average step counts and worse PF scores were significantly associated with poor survival with hazard ratios (HR) of 1.44 per 1000 steps (95% CI 1.06, 1.97, p = 0.02) and 1.69 (95% CI 1.1-2.56, p = 0.017), respectively, after adjusting for age, sex, stage, and ECOG PS. Conclusions: Findings from this research suggest that the use of wearable technology for remote monitoring of daily activity is feasible and may be used to supplement functional assessment and predict outcomes in PDAC patients. Larger trials are needed to validate findings. [Table: see text]
Lack of price transparency for prostate-directed radiation therapy relative to radical prostatectomy.
Authors: Prasad Rahul Neal , Royce Trevor Joseph , Wang Shang-Jui
Published: June 2022

1579

Background: For patients with low to favorable-intermediate risk prostate cancer (PC), management with active surveillance, radical prostatectomy (RP), external beam radiation therapy (EBRT), and brachytherapy (BT) are all National Cancer Center Network-supported definitive monotherapy options. Because therapy is non-urgent and choosing therapy can be complex, patients routinely seek second opinions and cost can be an important consideration. Recent federal price transparency (PT) guidance requires hospitals to provide payer-negotiated prices for ≥300 common services in a “shoppable,” user-friendly, online format. 70 services, including RP, are specified, while the remainder are left to institutional discretion. Despite equipoise between radiation therapy (RT, inclusive of EBRT and BT) and RP in definitive treatment for PC, inclusion of prices for RT is optional. National Cancer Institute (NCI)-designated cancer centers (NCI-CC) are high volume referral centers who have the option to volunteer prices for RT; the rate at which NCI-CC choose to report payer-negotiated price estimates for prostate-directed RT is unknown. We hypothesize that reporting rates for BT and EBRT are significantly lower than for RP. Methods: Through online query, we identified “shoppable” price tools for NCI-CC in December 2021. Using billing codes and keyword searches, we queried these price tools for cost estimates for RP, EBRT (delivered using intensity modulated radiation therapy), and BT. Descriptive statistics, include frequency counts and proportions, were performed. The rate of reporting of “shoppable,” negotiated prices for each therapy was assessed. These rates were compared using the chi-squared test (significance level of α = 0.05). Results: Of the 63 NCI-CC offering clinical care, 58 (92%) published “shoppable” tools. 6 (10%), 7 (11%), and 51 (81%) published “shoppable” prices for EBRT, BT, and RP, respectively, demonstrating a significantly higher rate of publication of prices for RP than for EBRT or BT ( P < 0.001). All of the published prices for BT were for high dose rate BT. The 11 Medicare Prospective Payment System–exempt NCI-CC had the highest rates of reporting “shoppable” prices at 91%, with 64%, 27%, and 36% including prices for RP, EBRT, and BT, respectively. Conclusions: Under existing regulations, patients with PC can obtain payer-negotiated price estimates for EBRT and BT from just roughly 10% of NCI-CC, while price estimates for RP are offered by > 80% of these institutions. This represents a potential obstacle to informed decision making, undermines the stated goals of US PT health policy, and the impact on utilization rates (or patient choice of therapy) is unknown. Moving forward, mandating the inclusion of common RT services (EBRT and BT) in “shoppable” price tools is a straightforward intervention that may be highly beneficial in this common cancer population.
Pharmaceutical industry payments to physicians for the promotion of cancer drugs.
Authors: Mitchell Aaron Philip , Meza Akriti Mishra , Trivedi Niti U. , Bach Peter Brian , Gonen Mithat
Published: June 2022

1580

Background: Personal financial payments from the pharmaceutical industry to oncologists are common and increasing. A prevalent view is that the purpose of industry payments to physicians is to facilitate education on new drugs. However, little is known regarding the distribution and trends in industry payments related to cancer drugs. The goal of this study was to characterize current patterns in industry payments related to cancer drugs, and test whether these patterns are consistent with an educational purpose. Methods: We included on-patent cancer drugs without generic/biosimilar competitors, and used publicly-available federal data sources to measure Medicare spending (proxy for overall drug revenue), number of prescribers, and industry payments (Open Payments, which includes data regarding which the drug[s] was the subject of each payment) for each calendar year from 2014-2018. We analyzed General Payments to individual physicians, which encompasses payment types such as meals, travel, consulting, and speaking fees. We tested two hypotheses implied by the claim that industry payments serve educational purposes. First, payment amounts should not be associated with drug revenue. To test this hypothesis, we used generalized estimating equations (GEE) to model the association between mean per-physician industry payments and Medicare spending. Second, payments related to a given drug should decline over time as physicians become educated. To test this hypothesis, we determined the relative year-to-year change in industry payments for all cases wherein consecutive years were observed, and used GEE to estimate the year-to-year change with respect to duration of time since initial FDA approval. Results: The sample included 89 drugs and 361 drug-year observations. The total amount of industry payments for oncology drugs increased during the study period, from $53,333,854 in 2014 to $90,343,731 in 2018. There was no association between log-transformed mean, per-physician industry payments and per-physician Medicare spending (estimate -0.001, 95%CI: -0.005, 0.004). In aggregate, Industry payments for cancer drugs were greatest immediately after FDA approval and trended downward over time; the estimated industry payments in the subsequent year for a drug with mean payments of $1,000 per-physician in the index year was: $681* for drugs 0-4 years since approval, $825 for drugs 5-9 years, and $679* for drugs≥10 years (*p<0.05). Conclusions: The absence of association between industry payments and Medicare spending and the decline in industry payments for drug subsequent to approval are consistent with claims that these payments function to facilitate physician education.
Variation in telemedicine usage in gynecologic cancer: Are we widening or narrowing disparities?
Authors: Andriani Leslie , Smith Anna Jo Bodurtha , Alvarez Rafael , Heintz Jonathan , Ko Emily Meichun
Published: June 2022

1593

Background: Telemedicine rapidly increased with the COVID-19 pandemic and may be a way to reduce care disparities. Our aim was to evaluate sociodemographic (race, insurance), patient, health system, and cancer factors associated with use of telemedicine in gynecologic cancers. Methods: We conducted a retrospective cohort study of patients with documented endometrial or ovarian cancer using the nationwide de-identified electronic health record-derived Flatiron Health data. We used multi-level regression models to analyze the association of telemedicine usage during COVID-19 pandemic (2020-2021) with sociodemographic, patient, health system, and cancer factors overall. Results: Of 13,450 patients with endometrial or ovarian cancer, 14.4 % (95%CI 14.0-16.1) used telemedicine during COVID-19 for their cancer care within the Flatiron Health network. Insurance was not associated with likelihood of telemedicine in any model. Region was significantly associated with telemedicine usage across models with patients living in the Northeast more likely to use telemedicine. Conclusions: In this large cohort study, we found regional disparities across cancer types and oncology settings. Expanding access to telemedicine may improve racial and geographic disparities in gynecologic cancer. [Table: see text]
A targeted gene expression biomarker and association with meningioma outcomes and radiotherapy.
Authors: Chen William Cheng , Choudhury Abrar , Vasudevan Harish , Lucas Calixto-Hope C. , Nguyen Minh P. , Young Jacob S , Yu Theresa , Chan Jason , Oberheim Bush Nancy Ann , Schulte Jessica , Villanueva-Meyer Javier , Braunstein Steve E. , Butowski Nicholas A. , Sneed Penny , Berger Mitchell , Perry Arie , Solomon David , McDermott Michael W , Magill Stephen T. , Raleigh David R.
Published: June 2022

2007

Background: Improvements in risk stratification of meningioma are needed to guide post-operative management and application of adjuvant therapy. Although profiling of DNA methylation, copy number variants (CNVs), RNA sequencing, and exome sequencing have better elucidated meningioma biology, these approaches have not revealed clinically tractable biomarkers for radiotherapy responses. In this study, we develop and validate a targeted gene expression biomarker to predict meningioma outcomes and benefit from radiotherapy. Methods: Targeted gene expression profiling was performed on a development set of 173 meningiomas (median follow-up 8.1 years) and a validation set of 331 consecutive meningiomas (median follow-up 6.1 years) treated at independent institutions (70% WHO grade 1, 24% WHO grade 2, 6% WHO grade 3). All patients underwent surgery (n = 504) with or without postoperative radiotherapy (n = 73 with radiation). Regularized Cox regression within the development set resulted in a continuous gene expression risk score for local freedom from recurrence (LFFR). The model (34 genes and 7 housekeeping genes) and thresholds for low, intermediate, and high-risk scores were locked and applied to the validation set. Results: The gene expression risk score outperformed WHO grade (validation 5-year LFFR delta-AUC 0.15, 95% CI 0.076-0.229, p = 0.001) and DNA methylation grouping (delta-AUC 0.075, 95% CI 0.006-0.130, p = 0.01) for LFFR, disease-specific survival, and OS, achieving a negative predictive value for recurrence at 5-years of 93.2%. The biomarker reclassified 35.8% of WHO grade 1 tumors as intermediate or high risk (5-year LFFR/OS 62%/79%), and 18.3% of WHO grade 2-3 tumors as low risk (5-year LFFR/OS 78%/100%). The biomarker was independently prognostic after accounting for WHO grade, extent of resection, primary versus recurrent presentation, CNV status, DNA methylation group, and Ki67 labeling index, and was predictive for LFFR after postoperative radiotherapy, with a hazard ratio of 0.41 for intermediate to high risk propensity-matched meningiomas (95% CI 0.2-0.9, p = 0.0002) versus 0.79 for low risk meningiomas (95% CI 0.1-8.8, p = 0.5182). Conclusions: Targeted gene expression profiling of 504 meningiomas resulted in a biomarker which improved discrimination of meningioma local recurrence, disease-specific survival, and overall survival, and also predicted benefit from radiotherapy.
A controlled comparison of cerebral volume loss after brain irradiation with proton versus photon radiotherapy.
Authors: Gardner Melissa , Stahl Franziska , Dietrich Jorg , Gerstner Elizabeth R. , Sherman Janet , Shih Helen Alice , Parsons Michael
Published: June 2022

2017

Background: Previous work has demonstrated cerebral volume loss after glioma treatment with concurrent photon radiotherapy (PHT) and chemotherapy. Proton radiotherapy (PRT) minimizes exposure of normal brain tissue compared with PHT. The objective of this study was to compare neurotoxic effects of PRT vs PHT in a retrospective case-matched control series of WHO grade 2 and 3 gliomas. Methods: PRT subjects were selected from ongoing longitudinal single-arm outcome studies being conducted at our institution (NCT01358058, NCT03286335). PHT subjects were identified via medical record search and were individually matched to PRT subjects using an eleven-tiered criterion (i.e., age, sex, tumor type, tumor location, laterality, IDH mutation status, 1p19q deletion status, concurrent chemotherapy, adjuvant chemotherapy, total Gy dose, and number of fractions). When individual matching was not possible on all 11 variables, efforts were made to identify the closest possible match. Only those subjects with at least two years of progression free survival and available T1 and T2/FLAIR MRI at baseline, one year, and two years following RT were included. The resulting sample included 17 PRT and 17 PHT patients with grade 2 and 3 gliomas (19 male; mean age = 40.10y; SD = 11.27). Non-parametric analyses were used to compare groups on demographic and tumor/treatment-related variables. Diffuse cerebral volume loss was estimated by manually measuring lateral ventricular volume in the tumor-free hemisphere. Results: Mann-Whitney tests of independence showed no significant differences between groups on any of the demographic variables or clinical characteristics. One-way ANOVA demonstrated that ventricular volume increase after two years was significantly greater in patients treated with PHT than with PRT, (F(1, 32.00) = 5.90, p <.021, η2 =.156). Change in ventricular volume in the PHT group was 24.85% (SD = 14.45%) and in the PRT group was 12.03% (SD = 16.3%). Conclusions: The findings of this study suggest that 2 years post treatment for glioma, PRT is associated with less brain volume loss and ventricular expansion than PHT. The findings support the hypothesis that PRT can reduce neurotoxicity within the tumor-free hemisphere. This study is limited by the retrospective design and lack of randomization to treatment arms, though cohorts were well-matched following a rigorous set of criteria. The effects of PRT beyond 2 years after treatment remain unknown. Preservation of brain structure may be critically important for maintenance of brain function in this population of patients who have prolonged survival. Longitudinal cognitive assessment in brain tumor patients undergoing PHT vs PRT is needed and is currently being collected in NRG BN-005 (NCT03180502), which may provide important data regarding functional impact of the brain changes we have demonstrated.
Brain metastases in the setting of stable extracranial disease: A systematic review and meta-analysis.
Authors: Li Alyssa Y. , Gaebe Karolina , Zulfiqar Amna , Lee Grace , Jerzak Katarzyna Joanna , Sahgal Arjun , Erickson Anders W. , Das Sunit
Published: June 2022

2022

Background: Intracranial metastatic disease (IMD) is a life-altering complication for many patients with cancer. Improvements in systemic therapies have transformed the epidemiology of IMD, with some patients presenting with IMD in the context of stable extracranial disease (IMD-SECD). Among patients with metastases in other sites with similarly stable systemic disease, surgical resection and targeted therapy can result in long-term disease control and extended overall survival (OS), yet little is known about the clinical outcomes for patients with IMD-SECD. Methods: We searched MEDLINE, EMBASE, CENTRAL, and grey literature sources up to June 21, 2021 for studies reporting brain metastasis (BrM) with controlled extracranial disease (ECD) as well as IMD-SECD secondary to any primary cancer (criteria: presence of BrM and ≤2 extracranial metastatic sites, with no prior second-line chemotherapy and second-line brain-directed therapy). In studies comparing IMD-SECD and IMD patients, hazard ratios (HR) for OS and intracranial progression-free survival (iPFS) were pooled using random-effects meta-analysis, while medians for OS were estimated from single-arm IMD-SECD studies based on distribution-free summary survival curves. Results: Of 1067 records identified, 68 studies involving 5325 patients with IMD-SECD were included. Patients with IMD-SECD had prolonged OS (HR 1.93; 95% CI, 1.44-2.59; n = 10 studies; n = 877 patients) and iPFS (HR 1.59; 95% CI 1.31-1.92; n = 4 studies; n = 673 patients) compared with IMD patients. Subgroup analysis of patients with BrM and controlled versus uncontrolled ECD found prolonged OS with controlled ECD (HR 2.46; 95% CI, 1.36-4.44; n = 4 studies; n = 135 patients). Pooled median OS for all IMD-SECD patients was 20.85 months (mo) (95% CI, 16.35-25.98; n = 27 studies; n = 2159 patients). Stratification by primary cancer type showed median OS 20.18 mo (95% CI, 10.43-38.20; n = 2 studies; n = 109 patients) and 27.46 mo (95% CI, 18.27-49.66; n = 13 studies; n = 497 patients) for patients with IMD-SECD secondary to breast cancer and non-small cell lung cancer, respectively. Conclusions: Patients with IMD-SECD demonstrate prolonged OS and iPFS compared with patients with IMD, who may have more extensive systemic disease. Our results suggest that patients with IMD-SECD may represent a distinct subpopulation of patients with IMD with a uniquely favourable prognosis. It is possible that aggressive and timely treatment may significantly prolong survival for these patients. Future prospective trials should aim to investigate the efficacy of current treatment regimens in patients with IMD-SECD to further clarify optimal treatment pathways in this unique population of patients.
Paxalisib in patients with newly diagnosed glioblastoma with unmethylated MGMT promoter status: Final phase 2 study results.
Authors: Wen Patrick Y. , de Groot John Frederick , Battiste James , Goldlust Samuel A. , Garner James Stuart , Friend John , Simpson Jeremy Andrew , Damek Denise , Olivero Alan , Cloughesy Timothy Francis
Published: June 2022

2047

Background: Paxalisib, a potent oral selective brain-penetrant small molecule PI3K/mTOR inhibitor, has shown activity in nonclinical brain cancer models and promising phase 1 data in progressive / recurrent high-grade gliomas (NCT01547546). This multicenter phase 2 progressive design trial (NCT03522298) aimed to establish the maximum tolerated dose (MTD) for once-daily (QD) dosing, and to evaluate safety, tolerability, pharmacokinetics (PK), and clinical activity of paxalisib in patients with newly diagnosed glioblastoma and unmethylated MGMT promotor status. Methods: Eligible patients were males or females, aged ≥18 years, who had undergone surgical resection and chemoradiotherapy (Stupp Regimen), and were considered to be progression free before starting adjuvant paxalisib. Stage 1 used a standard 3+3 dose-escalation design to determine the MTD in this population. Stage 2 was a two-arm, open-label, expansion cohort with patients randomized 1:1 to receive paxalisib at the MTD under fed or fasted conditions. In both stages, treatment comprised daily paxalisib administered in 28-day cycles, continuously until disease progression or unacceptable toxicity. Efficacy analyses are based on investigator review and from date of diagnosis. Results: Patients (n = 30; 70.0% males, 83.3% white, mean age 58.5 years) had a mean time since diagnosis of 3.75 months. The majority (n = 29) received between 1 and 6 treatment cycles and one received 29 cycles. In Stage 1 (n = 9), an MTD of 60mg was established on the dose-limiting toxicities of hyperglycemia (n = 1) and stomatitis (n = 1) at 75mg. Paxalisib at 60mg was well-tolerated and adverse events were consistent with other PI3K inhibitor medicines. At the MTD (60mg), the PK profile was linear and dose-proportional with no differences in Tmax and elimination half-life under fed and fasted conditions. For the overall ITT population, the median progression free survival was 8.4 months (RANO) and 8.6 months (mRANO) and the median overall survival was 15.7 months. In a mITT (n = 22 patients treated with 60mg daily and ≥1 post-baseline assessment), the median PFS was 9.6 months (mRANO). Conclusions: The primary study endpoints were met; PK and safety were consistent with prior clinical experience. The MTD showed encouraging clinical activity, prolonging PFS and improving OS. Further efficacy confirmation of paxalisib 60 mg QD in newly diagnosed glioblastoma in a pivotal trial is ongoing (GBM AGILE, NCT03970447). Clinical trial information: NCT03522298.
Prognostic value of hPG80 (circulating progastrin) in IDH-wild type glioblastoma treated with radio-chemotherapy.
Authors: Doucet Ludovic , Cailleteau Axel , Vaugier Loig , Gourmelon Carole , Bureau Mathilde , Salaud Celine , Roualdes Vincent , Samarut Edouard , Aumont Maud , Zenatri Morgan , Loussouarn Delphine , Quillien Veronique , Bocquet Francois , Payen-Gay Lea , Mahi Younes , Prieur Alexandre , Robert Marie , Frenel Jean-Sebastien
Published: June 2022

2049

Background: hPG80 (circulating progastrin) is a protein secreted by many cancer types, playing a role in tumorigenesis by regulating cancer stem cells, angiogenesis, proliferation/differentiation and decreasing apoptosis. hPG80 is detectable in plasma of cancer patients and previous studies have shown its prognostic role in various cancers. Given the lack of circulating biomarker in glioblastoma, we evaluated the prognostic value of plasma hPG80 in patients with IDH wild type glioblastoma Methods: This multicentric retrospective study included IDHwt glioblastoma patients treated with standard radio-chemotherapy. The ELISA DxPG80.lab kit (Biodena Care, Lausanne, Switzerland) was used to measure hPG80 levels after surgery with a detection threshold of 1 pM in all plasma EDTA samples according to the manufacturer’s instruction. The prognostic impact of hPG80 was evaluated on patient’s progression-free survival (PFS) and overall survival (OS). Results: We included 70 patients (38 males /32 women) with a median age of 64 years (Range 19 - 84). Karnofsky index was > 70% in 52 (91%) of 57 evaluable patients. Tumor biopsy (B), partial resection (PR), complete resection (CR) were performed in 22, 25 and 23 patients respectively. MGMT promotor was methylated in 22 (40%) of the 55 evaluable patients. After surgery, hPG80 was detected in 48 (69%) patients (hPG80+) with a median concentration of 9.52 pM (IQR 5.21 - 21.20). Complete surgery was associated with undetectable levels of hPG80 (52% (CR) vs 28% (PR) vs 14% (B), p = 0.006) and lower concentration if hPG80+ (CR: 5.8 pM [IQR 1.92 - 11.38] vs PR: 12.84 pM [IQR 8.09 - 37.09]; p = 0.04 vs B: 9.86 pM [IQR 4.66 - 21.63]; p = 0.16). With a median follow-up of 39 months (22.4-NR), 86% of patients had progressed and 70% had died. In univariate analysis, hPG80 positivity was associated with PFS (5.6m vs 8.5m, p = 0.053) and OS (14.5 vs 22m, p = 0.04) in hPG80+ vs hPG80- patients respectively. hPG80+ patients with complete surgery had worse median OS than hPG80- patients (14.5 vs 22.0 m; p = 0.051 respectively. Cox proportional hazards model did not fit for covariate analysis. Conclusions: Our findings show that hPG80 could serve as a new circulating prognostic biomarker in IDHwt glioblastoma patients treated with radio-chemotherapy. Further explorations are ongoing in larger cohorts including longitudinal evaluation during the course of the disease.
Deep learning-based brain tumor segmentation on limited sequences of magnetic resonance imaging.
Authors: Huang Jacky , Molleti Powell , Iv Michael , Lee Richard , Itakura Haruka
Published: June 2022

2054

Background: Deep learning algorithms trained to segment brain tumors from magnetic resonance imaging (MRI) perform well in ideal conditions supplied by curated datasets. An example is the MICCAI BraTS 2018 dataset, which provides a set of four MRI sequences (T1, T1 post-gadolinium contrast-enhanced, T2, FLAIR) on 285 samples, along with ground truth segmentations annotated by experts. In real-world settings, however, it is not uncommon for patients to undergo MRI with a limited number of image sequence acquisitions. We examined the effect of restricting the imaging sequence set when training a deep learning model for brain tumor segmentation. Our goal was to identify a limited subset that still achieved acceptably high performance. Methods: In our experiments, we used the convolutional neural network-based U-Net architecture. Instead of the standard BraTS task, we focused on sub-segmenting specific areas of brain tumors: the active, enhancing tumor (AT) and the tumor core (TC; AT plus the cystic/necrotic core). We trained the architecture on 285 samples of the BraTS 2018 dataset using one or both of two sequences: T1 contrast-enhanced (T1CE) and FLAIR. Using each training model, we predicted segmentation masks given a volumetric MR image of a brain tumor on 66 samples in the held-out validation dataset. We submitted the predicted segmentations to the Center for Biomedical Image Computing and Analytics (CBICA) imaging portal for evaluation, which reports prediction accuracy by returning dice scores on each prediction. Results: As shown in the Table, the U-Net model using T1CE alone yielded high performances, with median dice scores of 0.84461 and 0.88267, when segmenting AT and TC, respectively. On the other hand, using FLAIR alone generated lower performances on the same tasks of segmenting the AT (0.25996) and the TC regions (0.51153). Combining T1CE and FLAIR provided no additional performance improvement compared with T1CE used as a standalone sequence. Conclusions: We achieved high performances in two brain tumor sub-segmentation tasks using a limited number of MRI sequences in training a deep-learning algorithm. T1CE alone produced high performances on both TC and AT segmentations. Given the ubiquity of the T1CE sequence, the ability to achieve high performance tumor segmentations in the face of limited image sequence availability is critical when applying our algorithm in real-world clinical or research settings. [Table: see text]
Prostate-specific membrane antigen expression in meningioma.
Authors: Elinzano Heinrich , Tubre Teddi , Hacking Sean , Alexander Abigail , Brickman Arlen , Delalle Ivana , Donahue John
Published: June 2022

2072

Background: Meningioma is the most common CNS tumor, yet there is no effective therapy for relapsed/refractory meningioma after surgery and radiation therapy. Although most meningiomas follow a relatively benign course, some have a more aggressive course with rapid tumor growth, brain invasion, higher recurrence rates or extracranial metastasis. Prostate-specific membrane antigen (PSMA) is a transmembrane peptidase upregulated on endothelial cells of malignant solid tumors including glioblastoma and metastatic brain tumors, but not in normal vasculature. PSMA has been investigated as a therapeutic target and as a molecular imaging marker to monitor response to treatment and evaluate disease activity in PSMA-avid tumors. PSMA expression however has not been studied in meningioma. Methods: Archival tumor specimens (96 tumor samples: 58 WHO grade 1, 35 WHO grade 2, 3 WHO grade 3) from 69 patients were stained for H&E, PSMA and CD31 and slides were scanned (Leica Aperio AT2 whole slide image scanner). 37 of these samples were recurrent tumors and 13 had prior radiation therapy (intensity-modulated, Gamma knife, craniospinal). 21 of the 69 patients had paired samples of initial and recurrent tumors. QuPath was utilized as open access solution to machine learning generating raw data for PSMA, CD31, PSMA/CD31 ratio and PSMA/vasculature ratio. Paired t-test, unpaired t-test and ROC curves were used for statistical analysis. Results: PSMA expression was seen in all of the study samples. PSMA expression (p = 0.0147) was lower in grade 1 compared to grade 2 and 3 tumors, but not different among histologic subtypes. PSMA/vasculature ratio (p = 0.0015) was lower in grade 1 compared to grade 2 and 3 tumors. PSMA expression (p = 0.002) and PSMA/vasculature ratio (p = 0.0015) were higher in recurrent compared to non-recurrent tumors. PSMA expression (p = 0.0442) was higher in recurrent compared to initial tumors among paired samples. When comparing initial tumors of paired samples to non-recurrent tumors, ROC curves demonstrated CD31 expression (AUC:0.7278; p = 0.0008), PSMA/CD31 ratio (AUC:0.7843; p = < 0.0001) and PSMA/vasculature ratio (AUC:0.6256; p = 0.0328) to be predictors of tumor recurrence. Tumors with prior radiation therapy had higher PSMA/vascular ratio (p = 0.0439) compared to those without. Conclusions: PSMA is expressed in tumor vasculature of meningioma of any grade, increases at recurrence and persists with prior radiation therapy. Since it is present in meningioma of different grades and throughout the course of the disease, it could potentially be utilized as consistent diagnostic biomarker, relevant factor for risk of recurrence stratification and novel therapeutic target for these tumors.
Single-cell profiling of human heart and blood in immune checkpoint inhibitor-associated myocarditis.
Authors: Blum Steven Michael , Zlotoff Daniel A. , Smith Neal , Ramesh Swetha , Kernin Isabela , Sen Pritha , Zubiri Leyre , Tirard Alice , Nasrallah Mazen , Tantivit Jessica , Barth Jaimie Lynn , Juric Dejan , Sullivan Ryan J. , Boland Genevieve Marie , Mino-Kenudson Mari , Stone James , Thomas Molly , Reynolds Kerry Lynn , Neilan Tomas G. , Villani Alexandra-Chloé
Published: June 2022

2507

Background: Myocarditis due to immune checkpoint inhibitors (ICIs) is uncommon; however, myocarditis due to ICIs leads to severe morbidity and even death in 20-40% of cases. The molecular underpinnings of ICI-associated myocarditis are poorly understood, and there is an unmet clinical need to identify therapeutic targets and biomarkers that can aid in disease management. Methods: Heart tissue was obtained through endomyocardial biopsy or autopsy of patients receiving ICIs and was profiled with paired single-cell RNA sequencing (scRNA-seq) and T cell receptor sequencing (TCR) using the 10x Genomics Chromium system. A control dataset was constructed using scRNAseq data of heart tissue from patients receiving ICIs but without myocarditis and a published dataset from healthy patients not receiving ICIs. Peripheral blood mononuclear cells (PBMCs) were collected at the time of myocarditis diagnosis in a larger cohort of patients and analyzed with ICI-treated controls. The CITE-Seq protocol was used to measure paired scRNA-seq, TCR, and surface proteomics in PBMCs, using serial timepoints where available. Results: Heart tissue from 13 patients with myocarditis, including three fatal cases, and seven controls yielded 77,712 single cells. Blood profiling from 27 patients with ICI myocarditis and ICI-treated controls across 54 samples yielded over 230,000 cells. ICI myocarditis tissue demonstrated an increased T cell infiltrate (OR 8.94, FDR = 0.0021). Expression of multiple inflammatory pathways, most notably interferon responses, was up-regulated across multiple immune and non-immune cell types in the setting of myocarditis, providing important pathophysiological insights. T cell clones were also found to be shared between blood and heart, enabling the identification of putative pathogenic T cell subsets. Conclusions: Increased intramyocardial T cells and the activation of interferon response gene networks were seen in the setting of ICI myocarditis. These preliminary findings highlight potential pathological pathways in ICI myocarditis that could serve as biomarkers or therapeutic targets.
External validation of the VIGex gene-expression signature (GES) as a novel predictive biomarker for immune checkpoint treatment (ICT).
Authors: Hernando-Calvo Alberto , Yang S Y Cindy , Vila-Casadesús Maria , Berman Hal K. , Spreafico Anna , Abdul Razak Albiruni Ryan , Lheureux Stephanie , Hansen Aaron Richard , Lo Giacco Deborah , Matito Judit , Pugh Trevor John , Bratman Scott Victor , Berché Roger , Saavedra Santa Gadea Omar , Garralda Elena , Elston Sawako , Siu Lillian L. , Ohashi Pamela S. , Vivancos Ana , Bedard Philippe L.
Published: June 2022

2510

Background: VIGex is a 12- gene GES classifier initially developed on the Nanostring platform and validated for RNA-seq. VIGex classifies samples into Hot, intermediate-Cold (I-Cold) and Cold subgroups. The Hot subgroup as defined by VIGex has been associated with better (PFS) in patients (pts) treated on phase 1 ICT trials at Vall D’Hebron Hospital (VH) (ESMO2020). We investigated the performance of VIGex in pts treated with Pembrolizumab (P) in the INSPIRE clinical trial (NCT02644369) at Princess Margaret Cancer Centre (PM) and compared VIGex with other predictive ICT biomarkers. Methods: Pts with advanced solid tumors were treated with P 200 mg IV Q3wks. RNA-seq from baseline biopsies was performed using the Illumina NextSeq550 platform. Tumor RNA-seq data were transferred from PM to VH and classified by the VIGex algorithm blinded to clinical data. Bespoke circulating tumor DNA (ctDNA) was assayed at baseline (B) and start of cycle 3 (C3) using a pt-specific amplicon-based NGS assay (Signatera). Tumor mutational burden (TMB) was defined as the number of non-synonymous mutations per megabase and PD-L1 was assessed by immunohistochemistry (22C3). Hot subgroup (HOT) was compared to I-Cold + Cold (COLD). We defined 4 groups based on the combination of VIGex subgroups and the change in ctDNA at cycle 3 from baseline (ΔctDNA). Survival times were calculated with the Kaplan–Meier method and Cox proportional-hazard models were constructed. Results: Out of 76 pts, median age was 55y (range 21-81y), M:F 31:45, all ECOG 0-1, 16 High-grade serous ovarian, 12 triple negative breast, 12 head and neck, 10 melanoma and 26 other. Median no. of P cycles was 3 (range 1–35); follow up was 14m (range 1-67); Median PFS 10.9m and median overall survival (OS) 14m. Overall response rate (RECIST 1.1) was 24% in HOT and 10% in COLD (p = 0.22 two-sided Fisher's exact test). The HOT subgroup was significantly associated with higher OS and PFS when included in a multivariate model adjusted by tumor histology, TMB and PD-L1 (HR 0.43; 95%CI 0.23-0.81; p = 0.009) and (HR: 0.48; 95%CI 0.25-0.95; p = 0.036) respectively. A total of 57 pts had both VIGex and ΔctDNA data. The addition of ΔctDNA further improved the predictive performance of VIGex for OS (Table). Conclusions: VIGex maintained its predictive power for ICT outcomes when applied to an independent external dataset using RNA-seq. The predictive information provided by VIGex was independent of PD-L1 and TMB. Our data indicates that the addition of ΔctDNA to baseline VIGex may refine prediction for ICT outcomes. [Table: see text]
Identifying mechanisms of acquired immune escape from sequential, paired biopsies.
Authors: Hodi F. Stephen , Spigel David R. , De Andrea Carlos E. , Sanmamed Miguel F. , Garralda Elena , Tabernero Josep , Gomez-Roca Carlos A. , Szabados Bernadett , Powles Thomas , Pachynski Russell Kent , Fong Lawrence , Rizvi Naiyer , Yoon Shinkyo , Kim Tae Won , Oh Do-Youn , Nicholas Alan , Tea Joy S. , Abbas Alexander R. , Price Richard
Published: June 2022

2519

Background: Resistance to immune checkpoint blockade (ICB) can manifest as disease progression either at the initiation of treatment (primary resistance) or after some initial response (acquired resistance). To better understand the mechanisms underlying acquired resistance, the imCORE Network is conducting a study (NCT03333655) to examine changes in tumor biology from pre-treatment to disease progression across cancer types. Methods: Eligible patients included those experiencing clinical benefit on ICB (defined as objective response or stable disease longer than 6 months) and had evaluable tissue samples from both pre-treatment and within 30 days of progression. Samples were subjected to whole exome sequencing (WES), RNA sequencing (RNA-Seq), and immunohistochemistry (IHC). Whole blood samples or adjacent normal tissue were used as a reference for tumor variant calling. Results: As of December 3rd, 2021, 24 enrolled patients have complete sample pairs. Of those, melanoma, bladder, and lung were most common (n = 7, 6 and 5 pairs, respectively), but our cohort also included patients with breast cancer, squamous head & neck, and renal cell carcinoma. IHC data unexpectedly showed a modest, but consistent increase in tumor infiltrating CD8+ T cells at progression. In addition, IHC evidence of a decrease in MHC-I proteins (HLA-A and B2M) suggest that in 5 out of 24 cases, key proteins needed for antigen presentation are lost. Global differential gene expression analysis showed that immune gene expression was significantly increased at progression, including numerous chemokines and significant enrichment in gene sets responsible for antigen presentation machinery. Protein-altering mutations at progression appeared in B2M in one patient, and CXCL9 in another. However, in most cases it is unclear what genetic alterations are responsible. We do not observe evidence of consistent IFNγ and Jak/stat signaling loss or antigen presentation loss. Conclusions: While ICB resistance is thought to be associated with a lack of immune response within the TME, we found that acquired resistance is usually associated with either maintenance or an increase in immune infiltration. Multiple alterations that are unique to individual patients also continue to emerge. Our data shows ICB resistance is multifactorial and associated with dynamic changes to markers amid immune activation and inhibition. Clinical trial information: NCT03333655.
The impact of COVID-19 infection on immune-related adverse events in patients with cancer receiving immune checkpoint inhibitors.
Authors: Guo Mengni , Liu Jieying , Ahmed Zohaib , Yu James , Miao Ruoyu , Guan Jian , Esmaeil Pour Mohammad Ali , Khayyat Azadeh , Grove Angela , Manoucheri Manoucher , Socinski Mark A. , Mekhail Tarek
Published: June 2022

2525

Background: Immune checkpoint inhibitors (ICIs) can cause a variety of inflammatory autoimmune tissue damage, referred to as immune-related adverse events (irAEs). COVID-19 is associated with increased amounts of proinflammatory cytokines, which may synergistically affect the outcome of irAEs. Data are limited regarding the impact of COVID-19 on irAEs in ICI-treated cancer patients. Methods: We retrospectively analyzed adult patients with malignant solid tumors treated with ICIs at AdventHealth Orlando between August 2020 and August 2021. All COVID-19 infections were confirmed by PCR. Patients who had the most recent ICI treatment over one month before or after the positive COVID-19 test were excluded from the study. For COVID-19 positive group, only the irAEs that developed after COVID-19 infection were considered as events. Results: A total of 579 patients were included in our study, with 46 (7.9%) in COVID-19 positive group, and 533 (92.1%) in COVID-19 negative group. The baseline characteristics of patients in the two groups were similar in terms of age, ethnicity, ECOG, cancer histology, and type of ICI. With a median follow-up of 10 months (1-73 months), no differences in the time from ICI initiation to irAE onset, corticosteroid use, or additional immunosuppressant use were seen. A trend in higher incidence of all-grade diarrhea/colitis (8.7% vs. 3.0%, p=0.07) and grade 3 and 4 hepatitis (4.3% vs. 0.8%, p=0.08) was noted in the COVID-19 positive group, however the difference was not statistically significant. No significant difference in the incidence of pneumonitis (2.2% vs. 1.1%, p=0.44), nephritis (2.2% vs. 0.8%, p=0.34) or dermatitis (6.5% vs. 6.4%, p=1.00) were noted between COVID-19 positive and negative groups. We noticed a higher incidence of all-grade irAEs in the COVID-19 positive group (30.4% vs. 19.9%, p=0.18), but the difference was not statistically significant. The incidence of grade 3 and 4 irAEs was significantly higher in the COVID-19 positive group (10.9% vs. 3.2%, p=0.02). Nine COVID-19 related death occurred while no irAE-related death was noted in the entire cohort. Conclusions: Our study suggested that COVID-19 may pose a risk of severe irAEs in cancer patients receiving ICIs. Close monitoring and possible delaying ICI administration could be considered when cancer patients were infected with COVID-19. [Table: see text]
FORTITUDE: Results of a phase 1a study of the novel transgene-armed and tumor-selective vector NG-350A with and without pembrolizumab (pembro).
Authors: Rosen Lee S. , Camidge D. Ross , Khalil Danny , Lillie Thomas , Carter Jo , Krige David , Davies Jessica , Miles David , Patel Minesh , Evilevitch Vladimir , Prieto González-Albo Isabel , Champion Brian , Naing Aung
Published: June 2022

2559

Background: Stimulating CD40 may support anti-cancer immune responses; however, on-target toxicity limits systemic dosing. NG-350A is a tumor-selective and blood stable adenoviral T-SIGn vector expressing a potent fully human IgG agonistic anti-CD40 antibody (mAb). NG-350A was designed to selectively deliver anti-CD40 to multiple tumor sites via IV delivery, driving immunological tumor re-engineering while avoiding systemic toxicity. We report results from a first-in-human trial after completion of enrollment. Methods: FORTITUDE (NCT03852511) is a phase 1 study of NG-350A ± pembro in patients (pts) with metastatic/advanced epithelial tumors. NG-350A monotherapy (mTx) was dose-escalated in separate intratumoral (IT; increasing numbers of doses) or IV (one cycle; three increasing dose levels) cohorts. IV NG-350A + pembro (200 mg Q3W for ≤8 cycles) was then assessed. Results: As of Jan 2022, 28 heavily pre-treated pts had received NG-350A, either as IT mTx (n=9; two dose levels), IV mTx (n=16; IV dose levels 1, 3 & 4) or IV + pembro (n=3; IV dose level 2). The MTD of NG-350A ± pembro was not reached, with no DLTs at the highest IT and IV dose levels. The safety profile of NG-350A was consistent with acute reactions to viral particles and asymptomatic aPTT prolongations (Table). No systemic CD40 transgene protein was detected at any dose level and the only SAE to occur in >1 pt was pneumonia. No objective responses were observed; however, 3/6 patients treated with NG-350A mTx at IV dose level 4 achieved stable disease (dose not yet tested with pembro). Dose-dependent specific increases in serum IL-12, IFNγ and IL-17a were detected in pts treated with IV NG-350A mTx from ̃Wk 2. Increases were sustained at ≥5x baseline levels 7 wks after dosing in the majority of evaluable pts treated at higher IV dose levels. These responses did not occur with IT dosing (or in prior studies with an unarmed vector); further follow-up is ongoing for NG-350A + pembro. IV NG-350A also led to the expansion of T cell clones in blood; most of these were newly detected. Conclusions: NG-350A ± pembro was well-tolerated, with no evidence of CD40-related toxicity. NG-350A IV mTx led to specific and sustained cytokine responses consistent with the MoA of the encoded anti-CD40 Ab. Peak cytokine elevations were typically higher than reported with systemic anti-CD40 Abs, suggesting NG-350A can drive local immunological tumor changes while avoiding systemic toxicity. A further trial (FORTIFY, NCT05165433) will continue dose-escalation of NG-350A + pembro to identify a dose level for efficacy assessments. Clinical trial information: NCT03852511. [Table: see text]