bluuebunny/crossref_metadata_2025 huggingface dataset:
A radiomics model developed from pre-metastatic brain magnetic resonance imaging to predict brain metastasis in non–small-cell lung cancer: Evidence to the seed-and-soil theory.
Authors: Chu Xiao , Gong Jing , Zhu Zhengfei
Published: June 2023

2030

Background: Steven Paget’s “seed and soil” theory suggests that both the primary tumor and the target host organ play important roles in successful metastasis development. In this proof-of-concept study, we proposed that inter-individual differences exist in the brain’s congeniality for developing brain metastasis (BM), and validated the theory via developing a non-invasive radiomics BM prediction model. Methods: 256 non-small cell lung cancer (NSCLC) patients with no BM at baseline brain magnetic resonance imaging (MRI) were selected, 128 patients developed BM within three years after diagnosis and 128 remained BM-free. For radiomics analysis, both the BM and non-BM groups were randomly distributed into training and testing datasets at an 70%:30% ratio. Baseline brain MRI (representing the soil) and chest computed tomography (CT, representing the seed) radiomics features were extracted to develop the BM prediction models. We first developed radiomics models using the training dataset and subsequently validated the models in the testing dataset. A radiomics BM score (RadBM score) was generated and BM-free survival were compared between RadBM score-high and RadBM score-low groups. Results: The radiomics model developed from baseline brain MRI features alone can predict BM development in NSCLC patients. Furthermore, a fusion model integrating brain MRI features with primary tumor CT features (seed-and-soil model) provided synergetic effect and was more efficient in predicting BM (areas under the receiver operating characteristic curve 0.84[95% confidence interval: 0.80–0.89] and 0.80 [95% confidence interval: 0.71–0.88] in the training and testing datasets, respectively). BM-free survival was significantly shorter in the RadBM score-high group versus the RadBM score-low group (Log-rank P < 0.001). Cumulative BM rate at 3-year were 75.8% and 24.2% for RadBM score-high and RadBM score-low group, respectively. Conclusions: The results demonstrated that intrinsic features of a non-metastatic organ exert a significant impact on metastasis development, which is first-in-class in metastasis prediction studies and provided novel evidence for the "seed-and-soil" theory of tumor metastasis. Radiomics BM prediction model utilizing both pre-metastatic brain and primary tumor features might provide a useful tool for identifying NSCLC patients more prone to develop BM and providing individualized management for these patients.
HER2-low breast cancer brain metastases: Incidence and treatment implications.
Authors: Chehade Rania , Nofech-Mozes Sharon , Plotkin Anna , Moravan Veronika , Jerzak Katarzyna Joanna
Published: June 2023

2035

Background: Brain metastases (BrM) are a major cause of morbidity and mortality among women with breast cancer (BC). Central nervous system (CNS)-penetrating systemic therapies for patients with HER2-negative BrM are lacking; this is particularly problematic for patients with triple negative disease (TNBC) who have a high likelihood of developing BrM. Given CNS activity of trastuzumab deruxtecan, efficacy for patients with HER2-low BrM is of interest. Methods: A retrospective study of two cohorts of patients who underwent surgery for BC BrM at Sunnybrook Health Sciences Centre between 1999-2013 and 2008-2018 were identified. Estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2 (HER2) status were assessed based on 2018 ASCO/CAP guidelines. HER2-zero was defined as immunohistochemistry (IHC) 0; HER2-low was defined as IHC 1+ or IHC 2+ with fluorescence in situ hybridization (FISH) negative status. HER2-positive was defined as IHC 3+ or IHC 2+ with positive FISH. Clinicopathological features were recorded. We also assessed the prognostic association between extent of HER2 expression and i) brain-specific progression free survival (bsPFS), as well as ii) overall survival (OS). Results: Out of 137 patients with resected BrM, tissue for HER2 assessment was available in 74.5% (n=102) of cases. In this cohort, the median age at BrM diagnosis was 53.5 (range, 32-85). 18.6% (n=19) had leptomeningeal disease and 68.6% (n=70) had extracranial disease. 53% (n=54) of the BrM were HER2-positive; 29.4% (n=30) were HER2-low and 17.6% (n=18) had HER2-zero status. Among BrM that were triple negative based on ASCO/CAP guidelines, 14 out of 22 cases (63.6%) were re-classified as being HER2-low. 15/25 (60%) BrM that were hormone receptor positive/HER2 negative (HR+/HER2-) based on ASCO/CAP guidelines were re-classified as being HER2-low. In total, 51 patients had matched primary breast and BrM tissue available; results of HER2 status when categorized as HER2-zero, HER2-low and HER2-positive were concordant in 82.3% (n= 42/51) of cases (Cohen’s kappa 0.58, p=0.0719). In 7 cases, the primary breast tissue was HER2-zero whereas the BrM was either HER2-low (n=5) or HER2-positive (n=2). In only one case (2%), expression of HER2 was lower in the BrM (HER2-low) compared to the primary BC (HER2-positive). Median time from primary BC to the development of BrM was 35 months (IQR, 14-69) in the overall cohort; patients with HER2-zero BrM had a numerically longer time to development of BrM (45.8 months), compared to those with HER2-low (35 months) and HER2-positive (35 months) BrM (p=0.948). There was no significant association between HER2-zero, HER2-low and HER2-positive status in BrM and either bsPFS or OS. Conclusions: Among patients with surgically resected BrM, a high proportion of those with metastatic TNBC and HR+/HER2-negative disease have “HER2-low” BrM with potential to benefit from HER2-targeted therapy.
Assessment of electronic health record (EHR) –based machine learning (ML) in predicting risk of brain metastasis among patients with early-stage non–small-cell lung cancer (eNSCLC).
Authors: Honarvar Hossein , Hathi Deep K , Parikh Ravi Bharat , Das Rahul K
Published: June 2023

2036

Background: Among patients (pts) with eNSCLC, development ofbrain metastasis (BM) is a poor prognostic sign, but routine surveillance for BM is not recommended post-therapy. EHR-based ML algorithms may identify pts who would benefit from active brain MRI surveillance and/or treatment intensification in the early-stage setting. Methods: ConcertAI Patient360 database, consisting of structured and curated EHR records from pts receiving care in ~900 US oncology clinics, was used to identify pts diagnosed with stage IB-IIIA NSCLC without prior evidence of BM between Jan 2010 – December 2021. Presence of BM was identified from human curation of patient documents. Gradient boosting (GB), random forest (RF), and logistic regression (LR) algorithms with 3-fold cross-validation were trained and compared to predict risk of BM at two landmarks: 18 and 24 months (mos) from initial diagnosis (index). Pts who did not develop BM and either died or were lost to follow-up prior to landmark times were removed. Feature importance was defined using Shapley Additive Explanation (SHAP)-derived marginal odds ratios (OR). Due to low prevalence of BM, AUPRC was used as performance metric. Pts in the 1st and 4th quartiles of predicted probabilities from GB model were flagged as low-risk vs. high-risk. Results: Among 7473 pts in 18 mos model, median age was 68.4 years (IQR 13.2), 50.5% were female, and 10.9% were black. Demographics were similar for 6863 pts in 24 mos model. 6.4% and 8.3% developed BM at 18 and 24 mos. Ability of GB, RF, and LR models to predict BM was similar with validation AUPRC of 0.109 at 18 mos and 0.137 at 24 mos. In the GB model, BM prevalence in high-risk vs. low-risk group was 10.3% vs. 3.1% at 18 mos and 13.4% vs. 4.4% at 24 mos. In both landmark models, N0 stage and surgery within 90 days after index diagnosis were protective against BM, while presence of EGFR targetable mutations, adenocarcinoma (AD) histology, higher platelets (PLT), and history of pneumonia were risk factors. A glucose-by-histology interaction was found: For pts with normal blood glucose (GLU), risk of BM was independent of histology, for pts with high GLU, AD conferred greater risk of BM. Conclusions: An EHR-based ML model identified risk factors for developing BM among pts with eNSCLC and may identify pts who would benefit from active brain MRI surveillance and treatment intensification. [Table: see text]
Surgically targeted radiation therapy (STaRT) for recurrent glioblastoma: Initial outcomes from a prospective multicenter registry.
Authors: Ozair Ahmad , Brachman David , Campbell Lisa , Chen Clark C , Patel Toral R. , Floyd John , Hayden Devon H , Nowlan Adam W , Wasilewski Andrea C , Wanebo John , Shah Mitesh , Richardson Angela , Hanft Simon , Choutka Ondrej , Shen Colette , Wardak Zabi , Lee Stuart , Ranjan Tulika , Khosla Atulya Aman , Ahluwalia Manmeet Singh ,   STaRT Investigators' Group
Published: June 2023

2038

Background: Surgically targeted radiation therapy (STaRT), using a novel bioresorbable collagen brachytherapy device containing 4 Cesium-131 sources, is FDA-cleared for use as adjuvant radiation therapy (RT) post-resection in both newly diagnosed and recurrent intracranial neoplasms. Intraoperative initiation of brachytherapy potentially minimizes post-resection tumor regrowth with a favorable dosimetric profile compared to external beam radiation. This work sought to determine early patterns of care and the safety of this approach in recurrent GBM. Methods: This prospective multi-institutional observational study (NCT04427384) included recurrent GBM patients who underwent maximum safe resection (MSR) and permanent implantation of the device(s) (GammaTile, GT Medical Technologies, Tempe, AZ, US). Descriptive and comparative analyses regarding patient characteristics and early clinical outcomes were performed. Toxicities were categorized using the CTCAE v5.0 adverse event (AE) criteria. Results: During 10/2020–01/2023, 14 participating sites enrolled 45 patients with recurrent GBM for STaRT; 2 patients had two sites treated for a total of 47 implants. 67% of patients were treated at the first recurrence, 24% at the second, and 13% at the third, respectively. The median age was 61 (range 28-75), 36% were female, and 23% were > 65 years. 85% of patients received prior same-site RT with the median time from last RT to implantation of 14.6 months (range 3.5-57). The median maximum preoperative size was 4.2 cm (range 1.6-7.0) and the median volume was 20.8 cm3 (range 0.8-130). 68% of resections were gross-total, 17% near-total, and 15% sub-total; the median time needed for device implantation was 5 minutes (range 1.0-13). Median follow-up was 5.2 months (range 0.6-23.2). Median Karnofsky performance status (KPS) at screening, at initial postoperative assessment, and 3 months were all 80 (range 40-100). 7 attributed AEs occurred in 13% (6/45) of patients, all grade 3 AEs: 2 CSF leaks, 2 seizures, 1 cerebral edema, 1 pseudomeningocele, and 1 left hemiparesis. All except one were coded as related to both radiation and surgery; the patient with pseudomeningocele experienced a seizure at 47 days that was considered related to radiation alone. Conclusions: Early data from this prospective registry demonstrate the feasibility and safety of STaRT in recurrent GBM. Data on 6-month progression-free survival will be presented at the conference. A prospective randomized trial of adjuvant systemic therapy (AST) +MSR+STaRT versus MSR+AST is planned for initiation in 2023.
Multi-cancer brain metastasis risk score development and validation using 220,246 whole transcriptomes and machine learning.
Authors: Abraham Jim , Anders Carey K. , Brufsky Adam , Glantz Michael J. , Brastianos Priscilla Kaliopi , Pike Luke Roy George , Heimberger Amy B. , Sledge George W. , Oberley Matthew James , Spetzler David
Published: June 2023

2039

Background: Brain metastases occur in multiple cancer types with higher prevalence in lung, breast, melanoma, and GI cancers. The prognoses of patients who develop brain metastases are very poor and identification of brain metastasis risk could be useful for prognostication, monitoring, and therapy selection. Methods: Data from the whole transcriptome of 220,246 tumor profiles were analyzed and multiple machine learning models were trained on various molecular subtypes. The dataset was split 50% for training and the other 50% for testing, UMAP was employed for dimensionality reduction and the patterns learned across the entirety of the training dataset irrespective of brain metastasis were leveraged on the testing data set. Patients with brain metastasis were identified using the presence of ICD-10 code C79.31 (Secondary malignant neoplasm of the brain). As the absence of C79.31 could be due to the event not happening yet, patients without brain metastasis were stratified into groups based on 3, 4 or greater than 5 years without a C79.31 ICD-10 code. The brain metastasis risk score was defined by empirical evaluation of the positive predictive value in 7 groups of risk probabilities. The validation set contained 1,217 patients with brain metastasis and 4,631 without an observed brain metastasis within 3 years. Results: In the validation set, the prevalence of brain metastases within the risk scores across all cancer types ranged from 4% with the lowest risk score to 94% in the highest with 71% of cases receiving the lowest 2 risk scores, 15% the 2 intermediate risk scores, and 14% the 3 highest risk scores. For breast, lung and colon cancers, the prevalence of brain metastasis ranged from 4-10% in patients with the lowest risk scores to 92-100% in patients with the highest however the distribution of cases with each risk score was markedly different across cancer type. Breast cancer had 62% of cases receiving the lowest 2 risk scores versus 27% in lung, and 92% in colon. Breast cancer had 18% of cases receiving the 3 highest risk scores while lung had 42% and colon only 2% of cases with those 3 highest scores. Conclusions: Whole transcriptome data can be leveraged by a machine learning platform that employs dimensionality reduction techniques along with transfer learning to predict the risk of brain metastasis. This tool can be used to augment the clinical picture of cancer patients an unmet clinical opportunity to inform prognosis, monitoring, and therapeutic selection.
Cerebrospinal fluid immunological cytokines to predict intracranial tumor response to immunotherapy in non-small cell lung cancer patients with brain metastases: GASTO 1060.
Authors: Chen Likun , Li Meichen , Chen Jing , Yu Hui , Zhang Baishen , Hou Xue
Published: June 2023

2040

Background: Immunotherapy has been the standard first-line therapy in patients with advanced non-small cell lung cancer (NSCLC), and shown a certain efficacy for patients with brain metastases. however, the appropriate predictive biomarkers for intracranial tumor response to immunotherapy are unclear. We conducted this prospective study to explore the immunological cytokines in cerebrospinal fluid (CSF) to predict intracranial tumor response to immunotherapy in NSCLC patients with brain metastases. Methods: We prospectively enrolled treatment-naive, EGFR/ALK wild-type NSCLC patients with brain metastases in this study. Patients received chemotherapy plus camrelizumab (a humanized anti-PD-1 monoclonal antibody) as first-line treatment, and paired plasma and cerebrospinal fluid (CSF) samples were collected at baseline and first treatment evaluation (8-week). All samples were detected for 92 Immuno-Oncology cytokines using the Olink panels, and were explored for predictive biomarkers to immunotherapy. The Mann-Whitney U test was performed to compare the immunological cytokine expression between intracranial response and non-response groups. And logistic LASSO regression model was used to variate selection and develop a CSF immuno-cytokine model to predict intracranial tumor response. Results: Between April 2020 and May 2022, a total of 28 patients were enrolled this study.At baseline, most immunological cytokines were significantly lower in paired CSF than in plasma, whereas a subset including CD83, PTN, TNFRSF21, TWEAK, ICOSLG, DCN, IL-18 and MCP-1 were increasing expressed in CSF samples. For patients with objective intracranial tumor response compared to patients with non-response, the baseline CSF levels of LAMP3 were significantly higher, whereas the CXCL10, IL-12, CXCL11, IL-18, TIE2, HGF and PDCD1 levels were significantly lower. And patients with lower HGF, IL-18 or PDCD1 levels had significantly longer intracranial progression-free survival to immunotherapy. The above CSF immunological cytokines were significantly decreased at first treatment evaluation in patients with intracranial tumor response. Our logistic CSF immuno-cytokine model selected TIE2, IL-18, LAMP3, PDCD1 and IL-12 that were significantly associated with intracranial tumor response, and yielded a mean AUC of 0.91, compared to PD-L1 expression (mean AUC of 0.72). Conclusions: Immunological cytokines in CSF could predict intracranial tumor response to immunotherapy in NSCLC patients with brain metastases, and findings require validation in a larger prospective cohort.
Analysis of tumor progression among patients with glioma after COVID-19 infection.
Authors: Gregory Tim , Knight Stephanie , Aaroe Ashley , O'Brien Barbara Jane , Patel Chirag B , Weathers Shiao-Pei S. , Majd Nazanin , Puduvalli Vinay K. , Kamiya-Matsuoka Carlos
Published: June 2023

2041

Background: As of January 2023, there have been 6.7 million worldwide deaths attributed to SARS-CoV-2 COVID-19, which has impacted outcomes and medical care for all patients. Relatively little is known about the direct effects mediated by the virus on CNS tumor biology, despite the fact that viral neurotropism is well described, various coronavirus receptors have been observed in glioblastoma (GBM) tissues, and differential monocytic infiltration has been proposed to dysregulate the immune microenvironment. We detected a trend of rapid progression following COVID-19 infection among several patients with primary brain tumor patients and sought to systematically evaluate the pace of progression among infected patients in our institution. Methods: A single-institutional database of COVID-19 patients and an electronic medical record (EMR) search tool were used to identify a total cohort of 67 patients with glioma for retrospective analysis. This included 38 GBMs, 18 IDH-mutant gliomas, 5 ependymomas, 2 pilocytic astrocytomas, 1 diffuse midline glioma, 1 diffuse hemispheric glioma, and 1 ganglioglioma patients, each of whom had a documented COVID-19 infection between June 2020-December 2022. Hyperprogression was defined as tumor increase ≥40% compared to previous scan using RECIST size criteria. Results: Thirty-nine (58%) patients experienced tumor progression following COVID-19 infection at a median of 34 days (range=1-734 days) after testing positive for COVID-19. Twenty-two (56%) had received COVID-19 vaccine before their infection and 5 (13%) had asymptomatic infections. Twenty-two patients had measurably increased tumor area by a median of 63% (range=10-2,900%), 18 of which constituted hyperprogression;16 patients developed multifocal disease, 8 developed new nodular enhancement, 3 developed leptomeningeal disease (LMD), and 2 experienced increased infiltrative disease alone. Ten patients’ presentation with new glioma was preceded by COVID-19 infection by a median of 31 days. GBM patients represented the majority of progression events, among whom 59% progressed within 60 days of documented infection (median 25 days). This subgroup of GBM with rapid progression within 60 days had a mOS from infection of 5.2 months; 89% had TERT promotor mutations and 42% had MGMT promoter methylation. Conclusions: Glioma patients appear to have disease progression at an accelerated pace in the first two months after COVID-19 infection. This suggests that glioma patients should continue observing strict precautions to prevent infection and should be clinically monitored vigilantly after infection, with consideration for short interval imaging during treatment. These preliminary data warrant further investigation exploring changes of immune cell infiltration in the tumor microenvironment and the possible correlation between tumor progression and COVID-19.
A phase 0 pharmacokinetic trigger trial of infigratinib in patients with recurrent high-grade glioma.
Authors: Sanai Nader , Margaryan Tigran , Molloy Jennifer , DeSantis Anita , Harmon Jocelyn , Hong Amy , Braun Kelly , Wanebo John , Yoo Wonsuk , Tien An-Chi , Tovmasyan Artak , Mehta Shwetal
Published: June 2023

2051

Background: This Phase 0 trial evaluates tumor pharmacokinetic (PK) and pharmacodynamic (PD) responses of fibroblast growth factor receptor (FGFR) inhibitor, infigratinib, in participants with recurrent high-grade glioma carrying FGFR1 K656E or FGFR3 K650E mutation or FGFR3-TACC3 translocation. Patients with high unbound drug concentrations in the gadolinium-nonenhancing tumor region were graduated to a therapeutic regimen of infigratinib. Methods: Recurrent high-grade glioma patients received 7 days of infigratinib (125 mg QD) prior to planned resection at 7-9 hours following the last dose. Tumor tissue (enhancing and nonenhancing regions), cerebrospinal fluid (CSF), and plasma were collected. Total and unbound infigratinib concentrations were measured using validated LC-MS/MS methods. A PK ‘trigger’ determined eligibility for the therapeutic expansion phase and was defined as unbound [infigratinib] > 5-fold biochemical IC50 (i.e., 5 nM) in non-enhancing tumor. PD response was assessed by quantification of percentage of positive pERK, MIB-1, and Cleaved Caspase 3 cells in the surgical tissue compared to baseline archival/biopsy tissue. Patients with tumors exceeding the PK threshold for unbound drug concentration were eligible for expansion phase therapeutic dosing of infigratinib. Results: Seven patients were enrolled into the Phase 0 study with 3 patients who met the PK threshold continued to the expansion phase. In non-enhancing tumor region, the mean unbound concentration of infigratinib was 3.5 nM (n=7). The mean non-enhancing tumor-to-plasma coefficient for unbound drug (Kp,uu) was calculated to be 1.4. The suppression of pERK levels and MIB-1 levels was observed in 17% (1/6) and 67% (4/6) of the patients, respectively. At a median follow-up of 16.3 months [range: 2.8-18.7 months], the median progression-free survival (PFS) was 2.8 months (n=3). One patient remains on treatment. No grade 3+ toxicities were observed, and no adverse events resulted in discontinuation of therapy. Conclusions: Despite relatively high unbound tumor-to-plasma (Kp,uu) value, infigratinib achieves sub-optimal unbound drug concentration in the non-enhancing brain tumor tissue. Pharmacodynamic response with archival tissue as comparator did not reveal inhibition of pERK. Clinical trial information: NCT04424966 .
H3.3-K27M neoantigen vaccine elicits anti-tumor T cell immunity against diffuse intrinsic pontine glioma: The phase I ENACTING trial.
Authors: Zhang Yang , Ji Nan , Chen Gang , Wu Haiyang , Wang Yi , Li Xiao’ou , Peng Ling , Xu Wei , Li Tian , Wang Yi , Zhang Li-Feng , Sun Shengjun , Zhao Xiaobin , Li Si , Su Frank , Li Qi-Jing , Zhang Liwei
Published: June 2023

2052

Background: Diffuse intrinsic pontine glioma (DIPG) harboring H3.3-K27M mutation is a malignant pediatric brain tumor with a >90% mortality rate within two-year of diagnosis. Current therapeutic options for DIPG are limited. Aiming to improve therapeutic outcomes, we herein report the preliminary findings of a phase I trial studying a neoantigen peptide vaccine targeting H3.3-K27M. Methods: ENACTING is an open-label, single center, two-armed phase 1 trial to assess the safety and T cell immunity of a neoantigen peptide vaccine against H3.3-K27M. Patients aged ≥ 5 years old with newly diagnosed DIPG were consented and screened. HLA-A*02+/H3.3-K27M+ patients were enrolled to a two-arm study: Arm A consists of subjects receiving open debulking surgery, and Arm B consists of subjects without surgery eligibilities who received stereotactic biopsy. All patients subsequently received conformal radiotherapy and neoantigen vaccine treatment designed to elicit both CD4+ and CD8+ T cell immune response. Vaccine was administered intramuscularly in combination with polyinosinic-polycytidylic acid-poly-L-Iysine carboxymethylcellulose (Poly-ICLC). The primary objective is to evaluate the safety (AEs graded by CTCAE v4.03) and survival outcomes. Secondary objectives include maximum tolerated dose (MTD) and immunological responses. Results: As of Jan 2023, 11 patients have been treated, with 7 in Arm A and 4 in Arm B. No grade 3-4 treatment-related adverse events have been observed, with fever (81.9%) and injection site pain (54.5%) being the most common AEs. Among 10 efficacy-assessable patients, median progression-free survival (mPFS) and median overall survival (mOS) were 11.4 months (95% CI: 5.8~14.7) and 15.4 months (95% CI: 7.53~not reached), respectively. One-year OS rate was 66.7% (95% CI: 42~100%). One patient was assessed as complete response (CR). T cell responses against neoantigen were detected and H3.3-K27M mutation-specific CD4+ and CD8+ TCR clones were validated. Conclusions: The H3.3-K27M neoantigen vaccine was well tolerated. Initial results from this ongoing study suggest that, compared with other current therapies against DIPG, H3.3-K27M peptide vaccination may provide superior patient survival outcomes. Clinical trial information: NCT04749641 . [Table: see text]
New ESMO scale for clinical actionability of molecular targets (ESCAT) for gliomas based on a multicentric real world data cohort using next-generation sequencing (NGS).
Authors: Mirallas Oriol , Velilla Gabriel , Ruiz-Pace Fiorella , Yaringaño Jesús , Hernandez Gonzalez Ainhoa , Lopez Valbuena Daniel , Gómez-Puerto Diego , Gorria Teresa , Vaz Maria Ángeles , Doménech Marta , Martinez-Monino Alvaro , González Macarena , Castro Maria , Martínez-García María , Pineda Estela , Carles Joan , Dienstmann Rodrigo , Balana Carmen , Sepulveda Sanchez Juan Manuel , Vieito Maria
Published: June 2023

2055

Background: The ESMO ESCAT scale rank molecular alterations (MA) based on the published evidence supporting their clinical use. Building on our proposal for the first ESCAT classification for primary brain tumors (pBT) [Mirallas et al. ESMO 2022], we aim to describe the clinical actionability of NGS in a multicentric glioma cohort and gather clinical factors that enrich patients with MA to justify performing NGS. Methods: A multicentric retrospective study included pts with molecular profiling using NGS methods (Foundation Medicine, local NGS, Caris, Oncomine, and fusion panels). Clinical actionability was classified using the ESCAT scale; Tier 1 (ready for clinical implementation), Tier 2 (alteration-drug match with antitumor activity), Tier 3 (supported in other tumor types), and Tier 4 (preclinical evidence). Clinical factors considered for enrichment were diagnosis of glioblastoma (GBM), sex, and age ≤40 years, differences between groups were determined using Chi-squared test. The overall survival (OS) was calculated through Kaplan-Meier method and cox hazard ratio were fitted. Results: A total of 361 pts with NGS performed between Feb 2018 and Dec 2022 at 4 hospitals in Spain. Median age was 51.5 (range, 3.3-83.8), 77% had ECOG ≥1, 39.2% were women, 23.4% were 40 or younger, 20.8% had IDH1mut, and 73.5% had a diagnosis of GBM. The distribution of MA according to ESCAT was: 10 pts ESCAT 1 (5 BRAFV600E mut, 5 NTRK 1-3 fusions); 75 pts ESCAT 2 (67 IDH1 mut, 6 FGFR-TACC rearrangement, 4 FGFR 1-3 mut, 3 IDH2 mut); 105 pts ESCAT 3 (98 PIK3CA/PTEN mut, 12 PTEN loss, 11 H3K27M mut, 6 BRAF fusion, 2 MET mut, 1 FGFR3 amplification); 93 pts ESCAT 4 (119 TERT mut, 77 EGFR gain, 67 CDKN2A loss, 58 CDKN2B loss, 48 EGFRvIII rearrangement, 46 ATRX mut, 40 EGFR mut, 8 ATM mut). Prevalence of Tier 1-2 MA was 23.6%. In relation to enrichment factors: 12% >40y pts had ESCAT1-2 vs 61% in ≤40y (p<0.001), pts with GBM had a 11% prevalence vs 61% non-GBM (p<0.001), and non-gender differences were seen. The median OS for Tier 1-2 was 135 months (95% CI 166-99) vs Tier 3-4 of 24 months (95% CI 21.5-29.6). Significantly worse OS was observed for Tier 3-4 gliomas (HR: 4.11; 2.84-5.95, p<0.001), and remained significant after adjusting for histology and hospital center (p<0.01). Conclusions: The prevalence of ESCAT Tier 1-2 alterations is high in gliomas suggesting that molecular profiling should be offered, at least, in tertiary centers where these techniques are available. Potential enrichment factors to offer NGS were age and non-GBM pBT, but not gender.
Depth of radiographic response (DpR) and time to tumor regrowth (TTG) to predict overall survival following anti-VEGF therapy in recurrent glioblastoma.
Authors: Ellingson Benjamin M. , Hagiwara Akifumi , Morris Connor , Cho Nicholas , Oshima Sonoko , Sanvito Francesco , Oughourlian Talia , Raymond Catalina , Abrey Lauren E. , Garcia Josep , Aftab Dana T. , Hessel Colin , Rachmilewitz Minei Tamar , Fain Shmueli Shifra , Nathanson David , Wen Patrick Y. , Cloughesy Timothy Francis
Published: June 2023

2063

Background: Anti-angiogenic therapies, anti-VEGF agents, cause high radiographic response rates due to reduction in vascular permeability. However, we theorized the degree of tumor shrinkage combined with the duration of response might be a more meaningful measure of tumor control and may better reflect real patient benefit. In the current study, we investigate the association between model-derived parameters describing enhancing tumor volumetric dynamics and overall survival (OS) in recurrent glioblastoma treated with anti-VEGF therapy from multiple clinical trials. Methods: N=134 patients treated with bevacizumab +/- irinotecan (BRAIN Trial; NCT00345163) and N=121 patients treated with cabozantinib (XL184-201; NCT00704288) were used to identify potential imaging biomarkers, and N=63 patients in the bevacizumab control arm in a phase III trial (GLOBE Trial; NCT02511405) were used as a validation dataset. Enhancing tumor volumes were estimated using T1 subtraction maps, and a biexponential model was used to model tumor response ( d) and regrowth ( g) rates, as well as time to tumor regrowth ( TTG), the inflection point where the tumor stops shrinking and starts to regrow, and the depth of response ( DpR) after initiation of anti-VEGF therapy for each patient. Log-rank, univariate, and multivariable Cox regression were used to quantify the relationship of these parameters and OS. Results: Optimized thresholds based on maximum hazard ratio occurred at d =0.11 months-1 ( P=5x10-9 training; P=0.0082 validation); g=0.07 months-1 ( P=5x10-20 training; P<0.0001 validation); TTG of 3.8 months ( P=6x10-17training; P<0.0001 validation); and DpR of 11.3% ( P=0.0026 training; P=0.0177 validation). Univariate and multivariable Cox regression using these thresholds and controlling for age and baseline tumor volume confirmed that d, g, TTG, and DpR were all significant and independent predictors of OS in both phase II training and phase III validation datasets ( P<0.01). Additionally, patients exhibiting combinations of a high DpR and/or long TTG showed differential median OS, while patients with favorable diffusion MR phenotypes exhibited a longer OS and significantly longer TTG. Conclusions: Volumetric response and regrowth rates, TTG, and DpR using a biexponential model are significant and independent predictors of OS in recurrent glioblastoma treated with anti-VEGF therapy. Clinical trial information: NCT00345163 ; NCT00704288 ; NCT02511405 .
Immune checkpoint inhibitor (ICI) therapy in glioblastoma: Institutional experience at the Massachusetts General Hospital (MGH).
Authors: Rhee John Yohan , Song Kun Wei , Arrillaga-Romany Isabel , Forst Deborah Anne , Jordan Justin T. , Ly Ina , Plotkin Scott Randall , Wang Nancy , Parsons Michael , Gerstner Elizabeth R , Dietrich Jorg
Published: June 2023

2065

Background: Immune checkpoint inhibitors (ICI) have resulted in promising outcomes in systemic cancer but response in glioblastoma (GBM) has not met early expectations based on early clinical trial results. Conflicting data exists regarding the incidence of pseudoprogression after ICI in brain tumors. Here, we present our institutional experience of the radiographic response following ICI therapy in GBM both at initial diagnosis and recurrence. Methods: We retrospectively identified IDH-wildtype GBM (per 2021 WHO criteria) patients treated either at time of initial diagnosis or at recurrence with nivolumab, pembrolizumab, or durvalumab between 2015 and 2022 at MGH. Overall radiographic and clinical responses after initiation of ICI were assessed in both groups. Results: 56 pts (18 female, 38 male) were identified (average age 58.6). Eight (14.3%) patients had ICI-related non-hematological toxicities, including granulomatosis folliculitis, arthritis and myositis, headache, acneiform rash, transaminitis, and gastritis). Four (7.1%) of the eight patients had to discontinue treatment due to ICI-related severe toxicity (hepatitis and/or gastritis) and were not included in the final response assessment. Of the remaining 52 patients, none had evidence of pseudoprogression related to ICI. We did not identify any complete response (CR) or partial response (PR) secondary to ICI monotherapy. In the 13 patients treated at initial diagnosis, the following radiographic responses were seen: CR=0, PR=0, stable disease (SD)=5 (38.5%), and progressive disease (PD)=8 (61.5%). In the 39 patients treated at disease recurrence, the responses were: CR=0, PR=4 (10.3%), SD=10 (33.3%), PD= 22 (56.4%). Noteworthy, all patients with PR were concurrently treated with bevacizumab. Conclusions: 0/52 patients showed radiographic response after ICI monotherapy. While treatment was overall tolerated, ICI therapy was discontinued due to toxicity in 7% of patients. Pseudoprogression attributable to ICI was not seen in any of the patients treated.
Intraoperative glioma characterization using time-resolved fluorescence spectroscopy.
Authors: Menaker Simon , Patil Chirag , Krawczyk Kamil , Chu Ray M. , Mamelak Adam N. , Bannykh Serguei I. , Hu Jethro Lisien , Black Keith L. , Butte Pramod V.
Published: June 2023

2072

Background: Extent of surgical resection significantly improves progression-free and overall survival in glioma patients. Due to the infiltrative nature of gliomas, tumor margin detection is often difficult, and current intraoperative visualization methods are limited. Time-resolved fluorescence spectroscopy (TRFS) has the potential of differentiating glioma from normal brain tissue, thereby maximizing extent and safety of resection. Methods: Twenty-seven preoperative patients diagnosed with glioma met inclusion criteria for an IRB-approved study aimed to assess the accuracy of TRFS relative to tissue histopathology for differentiating glioma from normal cortex (NC), normal white matter (NWM), and white matter with edema (WME). A multi-channel TRFS system was developed for in vivo brain tissue and tumor characterization during glioma surgery. A custom-designed fiber optic probe was used to deliver ultrafast laser pulses to tissue regions of interest and collect fluorescence signals, with simultaneous registration to intraoperative neuronavigation. The fluorescence light was collected using a photomultiplier tube and digitized across six wavelength bands. Biopsies were taken at each measurement site for evaluation by a blinded neuropathologist to determine the accuracy of TRFS, which was calculated using parameters derived from the recorded fluorescence pulse and used to characterize tissue signatures. Results: During surgical resection of 27 patients, 162TRFS measurements were collected in vivo followed by biopsy of the same tissue. Samples from brain tumors (39 low grade gliomas (LGG, WHO grade I to III), 35 high grade gliomas (HGG, WHO grade IV)) were compared with 47 samples of normal brain tissue (NC and NWM). The time-resolved system was able to differentiate LGG from normal tissue with 97% sensitivity and 93% specificity (93% PPV and 98% NPV). When all tumor grades were tested, the sensitivity dropped to 91% (96% PPV and 86% NPV), which we believe reflects the heterogeneity of HGG. HGG alone showed a sensitivity of 83% and specificity of 93% (91% PPV and 88% NPV). Normal cortex had the fastest decays across all wavelength bands among different tissue types, WME had longer decays compared to other tissue types at all wavelengths, and HGG had a variable but predictably different fluorescence decay pattern. Conclusions: TRFS is an intraoperative tool that can distinguish glioma from normal brain tissue and has the potential to maximize safe surgical resection.
The ketogenic diet plus standard of care for adults with recently diagnosed glioblastoma: Results from a phase 1 trial.
Authors: Amaral Lj , Gresham Gillian , Kim Sungjin , Tighiouart Mourad , Nelson Thomas , Welborn Amelia , Lockshon Laura , Noorvash Brandon , Rudnick Jeremy David , Irwin Scott A , Freedland Stephen J. , Hu Jethro Lisien
Published: June 2023

2076

Background: Facing limited treatment options, brain tumor patients are often highly motivated to use complementary therapies, including diet, to help themselves. There is now an abundance of preclinical evidence suggesting possible benefit with a ketogenic diet (KD) for brain tumor patients, but clinical evidence is still limited. Thus, we conducted a single-arm, phase 1 safety and feasibility trial of a KD among patients with recently diagnosed glioblastoma (GBM) during standard- of-care (SOC) treatment. Methods: Adults with GBM within 3 months of diagnosis followed a supervised 16-week diet intervention of a standard 3:1 KD (Fat(g):Carbohydrate+Protein(g)) plus SOC chemoradiation. Primary outcome was safety, evaluated by weekly assessments of weight and body mass index (BMI). Secondary outcomes included feasibility (pre-specified as > 50% of patients maintaining blood ketone levels > 0.3 mM over 50% of study days), progression-free survival (PFS), overall survival (OS), health-related quality-of-life (QOL), and cognitive function. Twice daily blood glucose and ketone levels, weight/BMI, physical activity, and sleep were assessed by remote monitoring. Results: Seventeen patients were evaluable: 53% women, median age 55, median Karnofsky Performance Status 85. All participants met the primary safety objective with no instances of excessive weight loss or related serious adverse events. Adherence to KD was high: all 17 patients maintained nutritional ketosis (≥0.3 mM/dL) >50% of study days, where 14 patients maintained nutritional ketosis >85% of study days. Median time to ketosis from diet initiation was 3 days. Diet-related AEs were mild and manageable; no patients came off study due to inability to tolerate KD. Median progression-free survival (PFS) and overall survival (OS) were 12.5 months and 28.6 months from KD initiation respectively. QOL, symptom control, and cognitive function remained stable or improved, although these did not reach statistical significance. Conclusions: This phase 1 trial demonstrates that KD is safe and feasible for GBM patients receiving SOC, may improve outcomes, and provides a foundation for future randomized trials to assess efficacy. Clinical trial information: NCT03451799 .
Osmotic blood-brain barrier disruption with mannitol followed by methotrexate, rituximab, and carboplatin in treating patients with newly diagnosed primary central nervous system lymphoma.
Authors: Ambady Prakash , Doolittle Nancy Diane , Neuwelt Edward A. , Fu Rongwei (Rochelle) , Teglassy Gerda , Vo Anh Huan
Published: June 2023

2077

Background: Osmotic blood-brain barrier disruption (BBBD) uses intra-arterial (IA) mannitol to open the neuro-vascular unit to enhance delivery of therapeutic agents to the brain. We report the results of a multi-institutional, single arm, phase 2 study evaluating the efficacy and safety of BBBD-enhanced chemotherapy in combination with immunotherapy in patients with newly diagnosed primary central nervous system lymphoma (PCNSL). PCNSL is a rare non-Hodgkin’s lymphoma that is limited to the brain, cerebrospinal fluid, spinal cord and/or the vitreoretinal compartment. Methods: Non-immunocompromised subjects with newly diagnosed PCNSL received rituximab IV over 5 hours on day 1. On days 2 and 3, under general anesthesia in the angiography suite, subjects received IA mannitol immediately followed by IA methotrexate over 10 minutes, and then IA carboplatin over 10 minutes. Subjects received sodium thiosulfate IV for hearing protection at 4 and 8 hours after each carboplatin dose. Treatment was repeated every month for up to 12 courses in the absence of disease progression or unacceptable toxicity. Per institutional recommendations, further accrual was terminated during the COVID-19 pandemic. Contrast MRI was used for response assessment based on IPCG criteria. Results: Twenty subjects (10 F, 10 M, Median KPS = 80; range 40-100) received a median of 8 cycles at 3 US institutions. Sixteen radiographic complete responses (80%) and 1 partial response were documented, 3 subjects were not evaluable (2 withdrew consent and 1 unrelated death). Median PFS was 55.2 months (95% CI :10.3 – not reached) and Median Overall survival was 82.8 months (95% CI :19.8-145.8). Fourteen patients (82% of evaluable patients) had grade 3 or 4 adverse events (AE). Grade 4 AEs (n = 14 in n = 7 patients) included neurologic toxicities (ischemia, cervical cord inflammation, neuropathy) and blood/bone marrow toxicities (lymphopenia, neutropenia, granulocytopenia). There were no treatment-related deaths. Conclusions: We demonstrate the feasibility of performing BBBD in a multi-institutional setting with excellent PFS and OS in patients without whole brain radiation or autologous transplant. Our CR rates, PFS and OS are comparable to other IV high-dose MTX regimens, with acceptable toxicity profile and no documented treatment-related deaths. Clinical trial information: NCT00293475 .
Belzutifan treatment of Von Hippel-Lindau (VHL) related central nervous system (CNS) hemangioblastomas (HBs): A single institution experience.
Authors: Iliopoulos Othon , Rapalino Otto , Barker Frederick G. , Coumans Jean-Valery , Jones Pamela , Bear Lauren , Konstantakou Eumorphia , Orr Christina , Mahar Maura , Nahed Brian
Published: June 2023

2078

Background: Patients with inactivating germline mutations in the VHL gene develop CNS (brain and/or spine) HBs and/or renal cancers, pheochromocytomas and pancreatic neuroendocrine tumors. The oral HIF2a inhibitor belzutifan has been approved by FDA for the treatment of VHL-related HBs. We present here data on a cohort of VHL patients with CNS HBs treated with belzutifan in a single institution. Methods: Adult VHL patients, with radiologically documented CNS (brain and/or spine) HBs that displayed documented growth within the last 6 months prior to therapy, were treated with an initial dose of 120 mg belzutifan orally per day. Target lesions included HBs > 0.4cm long in one maximal cross-sectional diameter. Lesions were imaged by MRI at 1.5, 3, 6 months after initiation of treatment and at 6-month intervals thereafter. Solid enhancing lesions, associated cysts and peritumoral edema were recorded and quantified. Tumor sizes were evaluated by RECIST 1.1 criteria and volumetric analysis. All patients were evaluated and treated in the Hemangioblastoma Center and the VHL Clinic of the Massachusetts General Hospital Cancer Center. Results: At the time of analysis, 9 females and ten 10 male VHL patients (n=19) have been treated. Median age at treatment initiation was 36 yo (range 19-59). Median follow up is 12 months (range 1-19.5 months). Two patients were not yet evaluable for response. Of 17 evaluable patients, 8 had a PR (ORR 47%; 95% CI, 34-60), 8 had SD and 1 patient had progression (PD, 5.8%). Two patients had dose reduction to 80 mg/d because of anemia. No patient had grade 3 or greater toxicity and no patient experienced a CNS related toxicity during treatment. Volumetric analysis of solid and cystic components of the lesions, VHL germline mutations and other correlates of response to belzutifan will be presented. Conclusions: Real world data collected at a single institution confirm the high response rate of both solid and cystic components of CNS HBs to the FDA approved HIF2a inhibitor, belzutifan. Belzutifan was well tolerated. Further prospective controlled studies addressing the optimal dose, schedule and duration of treatment of HBs with belzutifan are required.
Phase I study of the bifunctional anti-PD-L1/TGF-βRII agent SHR-1701 combined with SHR2554, an EZH2 inhibitor, in patients with previously treated advanced lymphoma and solid tumors.
Authors: Feng Kaichao , Liu Yang , Wang Chunmeng , Nie Jing , Xia Yan , Jiang Jingting , Han Weidong
Published: June 2023

2507

Background: Despite the remarkable successes of cancer immunotherapies, the majority of patients (pts) experience only partial response and most pts will progress. Enhancer of zeste homolog 2 (EZH2) as an epigenetic target for cancer therapy has been shown to enhanced antigen presentation and synergize with immunotherapy in preclinical studies. This study investigates the safety and efficacy of SHR-1701 (anti-PD-L1/TGF-βRII) plus SHR2554 (EZH2i) in pts with pretreated advanced lymphoma and solid tumors. Methods: This open-label, single-arm, phase 1 study enrolled pts with pretreated advanced lymphoma and solid tumors. Escalating doses of SHR2554 (300–350mg bid) plus fixed-dose SHR-1701 (30mg/kg q3w) were evaluated in the dose-escalation phase. SHR2554 at the recommended phase 2 dose (RP2D) plus SHR-1701 were administered in the dose-expansion phase. The primary end point was determination of the RP2D of SHR2554 plus SHR-1701. Secondary end points included safety and preliminary activity. Results: By January 6, 2023, 33 patients were enrolled (dose-escalation: n=7; dose-expansion, n=26). No dose-limiting toxicities were observed, and RP2D was established as SHR2554 350mg bid plus SHR-1701 30mg/kg q3w. Treatment-related adverse events (TRAEs) occurred in 13 of 32 patients (40.6%), mainly including platelet count decreased (21.9%), anemia (15.6%) and vomiting (15.6%). The most common Grade ≥3 TRAEs were anemia (3.1%) and fever (3.1%). In the efficacy-evaluable population (n = 26), objective response rate (ORR) was 57.7%, including 2 complete response (CR) achieved by patients with Metastatic Renal Cell Carcinoma and classical Hodgkin lymphoma (cHL). 16 patients with relapsed/refractory classical Hodgkin lymphoma (cHL) after a median of 10 prior lines of therapy have been enrolled. 16 (100%) cHL pts had received prior anti-PD1/PD-L1 antibody therapy, and 15 ( 93.8%) prior epigenetic therapies, such as decitabine or chidamide. Out of 14 cHL-evaluable patients, ORR was 100% and the CR rate was 7.1%. Conclusions: SHR-1701 combined with SHR2554 showed acceptable safety profile and encouraging antitumor activity in immunotherapy-pretreated cHL, establishing the foundation for further exploration. Clinical trial information: NCT04407741 .