bluuebunny/crossref_metadata_2025 huggingface dataset:
SYST-01 MULTI-INSTITUTIONAL RANDOMIZED TRIAL COMPARING CANCER STEM CELL-TARGETED VS PHYSICIAN-CHOICE TREATMENTS IN PATIENTS WITH RECURRENT HIGH-GRADE GLIOMAS (NCT03632135)
Authors: Sengupta Soma , Ranjan Tulika , Yu Alexander , Howard Candace , Chen Ricky , Chaudahary Rekha , Marko Nicholas , Aregawi Darit , Glantz Michael , Glass Jon , Green Richard , Lu-Hemerson Christine , Mammoser Aaaron , Moulding Hugh , Jubelirer Steven , Schoroeder Jason , Anderson Mark , Chow Frances , Lirette Seth , Denning Krista , Alberico Anthony , Valluri Jagan , Claudio Pier Paolo
Published: August 2022

BACKGROUND

Clinical outcomes in patients with recurrent high-grade glioma (HGG) remain poor. Cancer stem cells (CSCs) have been implicated in metastasis, treatment resistance and recurrence of HHGs. We have shown in several clinical studies that anti-CSC-directed therapy provides benefits in many cancer types; however, this is the first report of a randomized clinical trial evaluating it for recurrent HGGs.

OBJECTIVE

Determine whether CSC-targeted cytotoxic agents selected by ChemoID assay-guided therapy improves survival in patients with recurrent HGG.

DESIGN, SETTING, AND PARTICIPANTS

In this parallel-group, randomized, phase-3 clinical trial, patients at 13 clinical sites in the USA with grade-III/IV recurrent glioma (2016 WHO guidelines) were randomized 1:1 to either ChemoID assay-guided therapy or physician-choice therapy, and then treated and followed until unacceptable toxic effects, hospice, or death.

MAIN OUTCOMES AND MEASURES

The primary endpoint was overall survival (OS).

RESULTS

Combined median follow-up was 9 months. Median OS (mOS) was 12.5 months (95% CI, 10.2-14.7) in the ChemoID assay-guided group vs 9 months (95% CI, 4.2-13.8) in the physician-choice group (log-rank P = .010). Risk of death was significantly lower in the ChemoID assay group (HR = 0.44; 95% CI, 0.24-0.81; P = .008). Median progression free survival (PFS) was 10.1 vs 3.5 months (95% CI, 4.8-15.4 vs 1.9-5.1) (HR, 0.25; 95% CI, 0.14-0.44; P < .001).

CONCLUSIONS AND RELEVANCE

Primary endpoint was met in this randomized clinical trial. The mOS was 3.5 months longer in the ChemoID assay-guided group vs the physician-choice group.
SYST-03 INCIDENCE AND SURVIVAL OF PATIENTS WITH INTRACRANIAL METASTATIC DISEASE AND ERBB2-POSITIVE GASTROINTESTINAL CANCERS: A RETROSPECTIVE COHORT STUDY
Authors: Sherman Madison , Erickson Anders W , Das Sunit
Published: August 2022

BACKGROUND

Intracranial metastatic disease (IMD) is a mortality-driving complication of gastrointestinal (GI) cancers. In breast cancer, ERBB2 positivity is associated with shorter overall survival (OS) and increased risk of IMD, and while ERBB2 status is relevant in primary GI cancer, no study has directly assessed the relationship of ERBB2 status and IMD in these patients.

METHODS

Records for adult patients with GI cancer and IMD, treated with ERBB2-therapy between 2005 and 2018 were retrieved from ICES. Baseline characteristics were compared between subcohorts stratified by IMD and ERBB2 statuses. Kaplan-Meier and Cox regression analyses were performed to estimate survival.

RESULTS

Records for 99,256 patients with GI cancer were collected, and IMD was diagnosed in 2002 patients. The highest IMD incidence rate was among patients with esophageal cancer (5.5%). Among patients with ERBB2+ disease, 306 had gastric (9 IMD), 168 esophageal (15 IMD), and 17 colorectal cancer. Diagnosis of IMD was associated with shorter OS among patients with colorectal (HR 3.0; 95% CI 2.9–3.2), gastric (HR 1.7; 95% CI, 1.5–1.9), and esophageal cancers (HR 1.2; 95% CI, 1.1–1.4). Post-IMD ERBB2-targeted therapy was not associated with OS among patients with ERBB2+ esophageal (HR 0.5; 95% CI, 0.2–1.2; n = 15) or gastric cancer (HR 0; 95% CI 0–Inf; n = 9).

CONCLUSION

Our study assessed patients with ERBB2+ GI cancer and IMD. Diagnosis of IMD was associated with shorter survival in gastric, esophageal, and colorectal cancers. Post-IMD ERBB2 therapy was not associated with OS, and IMD diagnosis was associated with prolonged survival in patients with stage 4 ERBB2+ disease, although interpretation of these results is complicated by small sample size and selection bias. Our results motivate increased reporting and inclusion of patients with ERBB2+ GI cancers in clinical trials.
SYST-05 OPTIMIZING HER2-TARGETED THERAPIES (TT) FOR BREAST CANCER (BC) LEPTOMENINGEAL METASTASES (LM): A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Lazaratos Anna-Maria , Maritan Sarah , Quaiattini Andrea , Bouganim Nathaniel , Dankner Matthew
Published: August 2022

INTRODUCTION

LM is a debilitating condition associated with metastatic cancers, including BC. When oncogenic drivers are identified, TT represents an appealing therapeutic strategy. However, the efficacy of TT for LM is unknown as LM patients are routinely omitted from clinical trials.

METHODS

We conducted a systematic review and meta-analysis of individual patient data to evaluate the effectiveness of HER2-TT in HER2+ BCLM in accordance with PRISMA guidelines. TTs evaluated included trastuzumab (intrathecal (IT) or intravenous (IV)), trastuzumab-emtansine, trastuzumab-deruxtecan, and lapatinib. Primary outcome was overall survival (OS).

RESULTS

Of 7780 abstracts screened, 91 publications and a total of 109 patients were included in the final analysis. Patients receiving chemotherapy (either IT, IV, or as part of an antibody-drug conjugate) concurrently with HER2-TT (N=57) exhibited a median OS (mOS) of 44.0 months, compared to patients treated with targeted anti-HER2 therapies alone (N=52), which exhibited a mOS of 14.5 months (P=0.009, hazard ratio (HR): 0.538, 95% confidence interval (CI): 0.328-0.883). Patients receiving IT trastuzumab (N=83) exhibited a median progression-free survival (mPFS) and mOS of 6.0 and 21.0 months, respectively, while patients receiving IV trastuzumab (N=14) exhibited a mPFS and mOS of 6.5 and 27.0 months, respectively (PFS: P=0.31, HR: 0.712, 95% CI: 0.331-1.531; OS: P=0.68, HR: 1.154, 95% CI: 0.587-2.266). In the subgroup of patients receiving IT trastuzumab (N=58), those who concurrently received IT chemotherapy (N=48) exhibited mPFS and mOS of 5.7 and 14.0 months, respectively, while patients concurrently receiving IV chemotherapy (N=10) exhibited a mPFS and mOS of 6.0 and 27.0 months, respectively (PFS: P=0.45, HR: 1.360, 95% CI: 0.602-3.073; OS P=0.29, HR: 1.821, 95% CI: 0.630-5.260).

CONCLUSIONS

HER2-TT is an effective therapeutic strategy for BCLM. Patients with BCLM receiving concurrent cytotoxic chemotherapy alongside HER2-TT experience prolonged mOS. IV and IT trastuzumab are similarly effective. Univariate and multivariate analyses will be presented.
SYST-06 INTRACRANIAL ACTIVITY OF TEPOTINIB IN PATIENTS WITH MET EXON 14 (METEX14) SKIPPING NSCLC ENROLLED IN VISION
Authors: Leighl Natasha , Bestvina Christine , Patel Jyoti , Le Xiuning , Veillon Remi , Anderson Ian , Demedts Ingel , Garassino Marina Chiara , Mazières Julien , Morise Masahiro , Smit Egbert , Eggleton S Peter , O’Brate Aurora , Otto Gordon , Bruns Rolf , Schumacher Karl Maria , Paik Paul
Published: August 2022

BACKGROUND

Brain metastases (BMs) occur in 20–40% of patients with METex14 skipping NSCLC. Tepotinib, a highly selective MET inhibitor, demonstrated an objective response rate (ORR) of 49.1% and median duration of response (mDOR) of 13.8 months, in METex14 skipping NSCLC patients in the Phase II VISION study (Cohorts A+C; N=275). Here, we report the intracranial activity of tepotinib in VISION.

METHODS

Patients with METex14 skipping NSCLC received oral tepotinib 500 mg QD (450 mg active moiety). Patients with BM (asymptomatic and symptomatic/stable) were eligible. Primary endpoint was systemic ORR (RECIST v1.1); a subgroup analysis in patients with BM was predefined (data cut-off: February 1, 2021). An ad-hoc retrospective analysis of brain lesions was conducted by an IRC using RANO-BM criteria. Responses were determined in patients with ≥1 evaluable post-baseline tumor assessment. For those with only non-target lesions (NTLs) per RANO-BM (enhancing and non-enhancing NTLs), disease control was defined as non-complete response (CR)/nonprogressive disease (PD). Data cut-off: July 1, 2020.

RESULTS

Fifty-one patients had baseline BM (Cohorts A+C). Systemic efficacy was consistent with the overall population (ORR 52.9% [95% CI: 38.5, 67.1], mDOR 9.0 months [95% CI: 5.6, not estimable]). Fifteen patients were evaluable by RANO-BM (Cohort A); 12 received prior radiotherapy for BM (median 6.4 weeks before treatment). Systemic best objective responses (BORs) were partial response (PR, n=9), stable disease (SD, n=3), and PD (n=3). Seven patients had target CNS lesions per RANO-BM (all with prior radiotherapy); intracranial BORs were PR (n=5), SD (n=1), and PD (n=1). For patients with NTL only (n=8), one had PD, and seven achieved intracranial disease control with three patients achieving CR of the enhancing NTL. 13/15 patients achieved intracranial disease control.

CONCLUSIONS

Tepotinib demonstrated robust systemic activity in patients with METex14 skipping NSCLC with BM, complemented by intracranial activity in an ad-hoc analysis using RANO-BM.
SYST-08 SURVIVAL ANALYSIS OF METASTATIC MELANOMA PATIENTS WITH BRAIN METASTASIS USING SURVEILLANCE, EPIDEMIOLOGY, AND END RESULTS (SEER)
Authors: Stahl Caleb , Baroz Angel , Bhanja Debarati , Wilding Hannah , Mansouri Alireza
Published: August 2022

INTRODUCTION: Melanoma brain metastases (BM) are common and are historically associated with poor prognosis. In the early 2010s, the treatment paradigm for malignant metastatic melanoma shifted with the introduction of immunotherapy (IT). Recent studies suggest that IT provides survival benefits for patients with BM from melanoma primary. The goal of this study was to validate these findings in a large population cohort. METHODS: Data were collected from the Surveillance, Epidemiology and End Results (SEER) database, version 8.3.4 (22 March 2017). Three cohorts were created based on the FDA approval date of IT: ipilimumab (2011), nivolumab (2014), and nivolumab plus ipilimumab (2015) for use in metastatic melanomas. Respectively, the cohorts are defined as the pre-IT era cohort (2010), early-IT era cohort (2011-2015) and late-IT era cohort (2016-2018). One-year overall survival (OS), 2-year OS, and median OS were assessed using a Kaplan-Meier analysis and log rank tests. RESULTS: 1,893 patients were included in this analysis (190 in the pre-IT era, 1,021 in the early-IT era, and 682 in the late-IT era) that had histologically confirmed melanoma with secondary BM at diagnosis. Median OS was significantly increased across the pre-, early-, and late-IT era cohorts, respectively, with the largest increase occurring between the early-IT and late-IT eras (1-year OS: 20.6% vs. 17.0% vs. 38.2%, 2-year OS: 10.5% vs. 14.2% vs. 27.1%, and median OS: 5 vs. 6 vs. 8 months, p < 0.001 by log-rank test). CONCLUSION: The introduction of IT for malignant melanomas has significantly improved the survival outcomes of melanoma patients with brain metastasis. Novel treatment paradigms involving IT with other adjuvant therapies need to be explored to further improve intracranial activity in melanoma patients.
SYST-09 IMPACT OF END-STAGE RENAL DISEASE AND CONCOMITANT DIALYSIS ON THE EFFICACY OF IMMUNOTHERAPY IN BRAIN METASTASES PATIENTS: A PROPENSITY-MATCHED SURVIVAL ANALYSIS
Authors: Baroz Angel , Bhanja Debarati , Stahl Caleb , Wilding Hannah , Mansouri Alireza
Published: August 2022

INTRODUCTION

Mounting evidence demonstrates the therapeutic promise of immunotherapies (ITs) for brain metastases (BM). However, there is concern that stringent eligibility criteria in these clinical studies have selected against patients with comorbid conditions. As a result, it remains unclear if these results are truly applicable to the general population, particularly in individuals with end-stage renal disease (ESRD) on dialysis. Therefore, we sought to determine the impact of concomitant dialysis treatment and IT on overall survival (OS) of patients with BM.

METHODS

Data were collected from TriNetX (TriNetX, Inc., Cambridge, MA), a global research network that aggregates clinical data from 92 healthcare organizations. Independent variables included ‘secondary malignant neoplasm of brain’, ‘ipilimumab’, ‘pembrolizumab’, ‘ESRD’, ‘dependence on renal dialysis’, and ‘dialysis services and procedures’. Patients with BM receiving IT were dichotomized by dialysis use. Cohorts were propensity matched on age, gender, and race. Kaplan-Meier analyses and log rank tests were conducted to assess overall survival (OS) and survival probability over a five-year period.

RESULTS

Of the 14,368 confirmed BM patients treated with IT, 95 (0.6%) began dialysis within three months of IT initiation. Propensity matching established 95 patients in each cohort. The dialyzed cohort had a median OS of 277 days with a survival probability of 11.6%, compared to the non-dialyzed group with a median OS of 419 days and survival probability of 40.29% (p=0.109; hazard ratio 1.422, 95% confidence interval, 0.923-2.191, p=0.891). A separate comparison cohort was created to compare ESRD diagnosis with or without dialysis (n=56 and n=106 respectively). The comparison cohorts did not show a difference in median OS and survival probability (p=0.49).

CONCLUSION

Despite their health complexities, individuals with ESRD, with or without dependence on dialysis, may nonetheless derive a similar survival benefit from ITs. Therefore, we advocate for greater inclusion of patients with advanced comorbidities in clinical trials to assess for real-world safety and efficacy outcomes.
SYST-11 PHASE 2 STUDY OF VAL-083 AND RADIOTHERAPY IN NEWLY DIAGNOSED MGMT-UNMETHYLATED GBM
Authors: Chen Zhongping , Guo Chengcheng
Published: August 2022

VAL-083 is a novel bi-functional DNA targeting agent that induces inter-strand DNA cross-links at N7-guanine, leading to DNA double-strand breaks and cell death. In vitro and in vivo studies have demonstrated VAL-083 circumvents MGMT-mediated chemoresistance and differentiates it from other therapies used in the treatment of GBM, including temozolomide (TMZ). VAL-083 also acts as a radiosensitizer against GBM cancer stem cells in vitro. A Phase 2 study was conducted to evaluate the safety and tolerability of VAL-083 when administered concurrently with radiation therapy (RT) in newly diagnosed MGMT unmethylated GBM. Stage 1 was a dose-escalation phase to confirm the dose of VAL-083 in this setting. Patients received VAL-083 at 20, 30, or 40 mg/m2/day x 3 days every 21 days in combination with standard radiation treatment (RT) (2 Gy/day, 5 days/week for 6 weeks). Stage 2 was an expansion phase to enroll up to 20 additional patients at the 30 mg/m2/day of VAL-083 with RT. A total of 29 patients were enrolled in the study and completed treatment, with 25 patients receiving 30 mg/m2/day VAL-083. The median number of cycles completed by all patients was 9 (range 2-13). Consistent with our prior experience, myelosuppression was the most common adverse event. Pharmacokinetics (Cmax and AUC) of VAL-083 were broadly linear with respect to dose, and drug half-life was 0.8 hrs. In a sub-group of patients, levels of VAL-083 in CSF were found to be at least as high as those in plasma. The median progression free survival (PFS) for all patients enrolled was 9.3 (95%CI: 6.4-12.0) months. Eighteen (18/29; 62.1%) patients have died, and median overall survival for all patients enrolled was 19.6 (95%CI: 14.0-22.4) months. These results support the potential benefit of VAL-083 as a treatment alternative against GBM tumors with MGMT-mediated resistance to TMZ. Clinicaltrials.gov: NCT03050736.
SYST-12 D2C7 CAR: A NOVEL CAR T CELL THAT SIMULTANEOUSLY TARGETS WILDTYPE EGFR AND ITS MUTANT ISOFORM EGFRVIII FOR TREATMENT OF GLIOMA AND BRAIN METASTASES
Authors: Wilkinson Daniel , Ryan Katherine , Wilson Joseph , Chandramohan Vidyalakshmi , Bigner Darell , Fecci Peter
Published: August 2022

INTRODUCTION

Chimeric antigen receptor (CAR) T-cells represent a revolutionary class of immunotherapy, achieving considerable success in hematological cancers but generally failing to control solid tumors, including gliomas, partly due to the lack of a ubiquitously-expressed target antigen. In this study, we engineered a novel CAR T-cell consisting of the D2C7scfv targeting moiety that binds a shared epitope between EGFR and EGFRvIII. EGFR is the most homogeneous antigen on glial brain tumors, and the mutant EGFR variant, EGFRvIII, is present on a considerable subset of high grade gliomas. CAR T-cells targeting EGFRvIII alone fail to treat tumors possessing as few as 5-10% EGFRvIII-negative cell. Thus, D2C7 CAR is expected to be superior to the EGFRvIII CAR.

METHODS

We retrovirally transduced T-cells with a vector encoding the D2C7scFv in tandem with intracellular signaling domains of CD28, 4-1BB, and CD3ζ to generate D2C7 CAR. We co-cultured D2C7 CAR or control CAR with fluorescently-tagged tumor cells expressing either EGFRwt or EGFRvIII to validate efficacy and specificity by flow cytometry. To determine in vivo efficacy, EGFRwt or EGFRvIII-expressing tumors were implanted intracranially in immunodeficient NSG mice. 48 hours later, D2C7 CAR, VIII CAR, or Mock CAR were administered intracranially and mice were monitored for survival.

RESULTS

D2C7 CAR specifically killed tumor cells that expressed either EGFRwt or EGFRvIII, but not cells that lacked EGFR. Intracranial D2C7 CAR administration resulted in significantly prolonged survival of mice bearing EGFRwt or EGFRvIII tumors compared to Mock CAR controls. Importantly, D2C7 CAR significantly benefitted mice bearing a heterogeneous mix of EGFRwt and EGFRvIII tumor cells, a model of tumor heterogeneity.

CONCLUSIONS

D2C7 CAR is efficacious against EGFRwt/EGFRvIII heterogeneous tumors. Intracranial administration of D2C7 CAR is predicted to safely and effectively treat a large cohort of patients due to the relatively high prevalence of EGFR and/or EGFRvIII-expressing brain tumors.
SYST-13 PHASE II STUDY OF THE COMBINATION OF LIPOSOMAL IRINOTECAN AND PEMBROLIZUMAB FOR TRIPLE-NEGATIVE BREAST CANCER (TNBC) WITH BRAIN METASTASES (BM)
Authors: Xi Jing , Luo Jingqing , O’Sullivan Ciara , Chen Nan , Stringer-Reasor Erica , Ma Cynthia , Campian Jian
Published: August 2022

BACKGROUND

Breast cancer is one of the most common cancers associated with brain metastases (BM). Up to 50% of patients with metastatic triple-negative breast cancer (TNBC) develop BM which portends a poor prognosis, with a median survival of 4.4-7.3 months. There is a lack of effective systemic therapy. Irinotecan is a topoisomerase-1 inhibitor with a response rate of 5-23% in advanced breast cancer. Nal-IRI is an intravenous liposomal formulation of irinotecan, with greater efficacy in tumor growth inhibition and the ability to cross the blood brain barrier (BBB) than irinotecan, resulting in a prolonged survival in preclinical TNBC BM models. Additionally, Nal-IRI has demonstrated promising anti-tumor activity in patients with TNBC- BM in a phase-I trial (NCT01770353). Pembrolizumab is a humanized anti-PD-1 monoclonal antibody which has shown efficacy in TNBC. The purpose of this study is to evaluate whether the combination of Nal-IRI and pembrolizumab can provide a synergic effect to control the CNS disease and prolong survival in TNBC with progressive BM.

METHODS

This is a phase II, single arm trial with a safety lead-in to evaluate the efficacy of nal-IRI (50-70mg/m2 IV Q2W) in combination with pembrolizumab (400mg IV Q6W). Simon’s 2-stage design is used, with 18 patients in the 1st stage and additional 24 at 2nd stage for a total of 42. The first 6 patients will serve as a safety lead-in. Key eligibilities include: histologically/cytologically confirmed TNBC with new or progressive BM; prior immunotherapy is allowed but not prior nal-IRI/irinotecan; prior sacituzumab-govitecan is permitted if disease stable for ≥16-week while on therapy and ≥24-week washout prior to starting trial; measurable disease; and ≤4 prior lines of therapy in the metastatic setting. The primary endpoint is CNS disease control rate (DCR) at 6 months using RANO-BM criteria. Secondary endpoints include CNS and non-CNS ORR, PFS and OS.

(ClinicalTrials.gov: NCT05255666)
SYST-14 CLINICAL EFFICACY OF ONC201 IN RECURRENT H3 K27M-MUTANT DIFFUSE MIDLINE GLIOMA (DMG) PATIENTS
Authors: Arrillaga-Romany Isabel , Kurz Sylvia , Tarapore Rohinton , Lu Guangrong , Sumrall Ashley , Butowski Nicholas , Harrison Rebecca , DeGroot John , Chi Andrew , Shonka Nicole , Umemura Yoshie , Odia Yazmin , Mehta Minesh , Nghiemphu Phioanh , Cloughesy Timothy , Taylor Lynne , Graber Jerome , Kilburn Lindsay , Dixit Karan , Chen Clark , Gardner Sharon , Aguilera Dolly , MacDonald Tobey , Cluster Andrew , Mehta Kathan , Kheradpour Albert , Melemed Allen , Allen Joshua E , Batchelor Tracey , Lassman Andrew , Wen Patrick
Published: August 2022

BACKGROUND

H3 K27M-mutant DMG predominantly affects children and young adults; no effective therapy is known. ONC201 is a first-in-class, anti-cancer DRD2 antagonist and ClpP agonist.

METHODS

Fifty pediatric and adult patients with recurrent H3 K27M DMG who received oral ONC201 monotherapy in clinical trials and expanded access were selected for a planned efficacy analysis. Eligibility criteria included measurable contrast-enhancing disease by RANO-HGG criteria (excluding pontine and spinal cord tumors), KPS/LPS≥60, ≥90 days from prior radiation, and adequate washout from prior anti-cancer therapy. The primary endpoint was overall response rate (ORR) by RANO-HGG criteria. Secondary endpoints included duration of response, time to response, progression-free survival (PFS), overall survival (OS), corticosteroid response rate, performance status response rate, and ORR by RANO-LGG criteria. Radiographic endpoints were assessed by dual-reader blinded independent central review. Data cutoff was May 31, 2021.

RESULTS

ORR was 20.0% (95%CI, 10.0–33.7) by RANO-HGG criteria. Median duration of response was 11.2 months (95%CI, 3.8–not reached) and median time to response was 8.3 months (range, 1.9–15.9). PFS at 6 months was 35.1% (95%CI, 21.2–49.3). The ORR was 26.0% (95%CI, 14.6–40.3) by RANO-LGG criteria. Fifteen patients (30.0%; 95%CI, 17.9–44.6) achieved an objective response by RANO-HGG and/or RANO-LGG criteria. Of 15 patients receiving ≥4 mg daily dexamethasone at baseline, 7 (46.7%; 95%CI, 21.3–73.4) achieved ≥50% confirmed reduction in dose. Of 34 patients with baseline KPS/LPS <80, 7 (20.6%; 95%CI, 8.7–37.9) achieved a confirmed performance status improvement. With a median follow-up of 18.8 months, median OS was 13.7 months (95%CI, 8.0–20.3) and OS at 24 months was 34.7% (95%CI, 20.7–49.2). Twenty-five patients had serious adverse events with one possibly related to ONC201 by investigator assessment.

CONCLUSIONS

ONC201 monotherapy exhibits durable and clinically meaningful efficacy in recurrent H3 K27M-mutant DMG.
SYST-15 TARGETING AXONAL GUIDANCE WITH ANTI-ROBO1 CAR T CELLS: A NEW THERAPEUTIC STRATEGY FOR MALIGNANT BRAIN CANCER
Authors: Brakel Benjamin , Chokshi Chirayu , Rossotti Martin , Venugopal Chitra , Salim Sabra , Mobilio Daniel , Chafe Shawn , Henry Kevin , Singh Sheila
Published: August 2022

No standardized treatments exist for patients with treatment-refractory brain metastasis, glioblastoma and other recurrent brain tumours. Given the aggressive nature of these diseases and difficulty in modelling tumour recurrence, minimal efforts have been made to design rational therapies against them. Neurodevelopmental pathways are often highjacked and go awry in the progression of these cancers. The roundabout guidance receptor 1 (ROBO1) protein is involved in axonal guidance during neurodevelopment, and we have shown that aberrant ROBO signalling promotes invasiveness and tumour growth in glioblastoma. Likewise, this signalling may contribute to the metastasis and growth of metastatic brain tumours, making the ROBO1-expressing tumour cell population an attractive and functionally relevant therapeutic target. Here, we present that ROBO1 is highly expressed on the surface of malignant and treatment-refractory brain tumour initiating cells (BTICs), prompting the development of an anti-ROBO1 CAR-T cell therapy. Using the binding region of a single-domain antibody targeting ROBO1, we developed second-generation anti-ROBO1 CAR-T cells specific and effective against malignant brain cancers, upregulating markers of activation and degranulation upon exposure to ROBO1-expressing BTICs. Additionally, orthotopic patient-derived xenograft models of malignant brain tumours treated with anti-ROBO1 CAR-T cells had a reduced tumour burden and prolonged survival, demonstrating therapeutic potential for treating brain malignancies.
SYST-16 PROPENSITY-MATCHED SURVIVAL ANALYSIS OF SECOND AND THIRD GENERATION TYROSINE KINASE INHIBITORS IN THE TREATMENT OF BRAIN METASTASES FROM LUNG CANCER PRIMARY
Authors: Bhanja Debarati , Baroz Angel , Stahl Caleb , Wilding Hannah , Mansouri Alireza
Published: August 2022

INTRODUCTION

Brain metastases from lung cancer (BMLC) are common and represent an aggressive form of disease. Numerous ongoing clinical trials are investigating targeted molecular therapies against epidermal growth factor receptor (EGFR), which have demonstrated blood-brain-barrier permeability and intracranial activity. However, there is limited real-world efficacy data on second and third-generation EGFR tyrosine kinase inhibitors (TKI), Afatinib and Osimertinib, for the treatment of BMLC. This study provides a real-world assessment to evaluate the impact of these agents on overall survival (OS) at the population-level.

METHODS

This retrospective cohort study queried data from TriNetX, a multi-institutional de-identified database, aggregating data from 90 U.S. healthcare organizations. Three cohorts were established, consisting of patients with BMLC treated with 1) Osimertinib, 2) Afatinib, or 3) Neither Osimertinib nor Afatinib. Cohorts 1 and 3, as well as cohorts 2 and 3, were propensity matched on demographics and comorbidities. Median overall survival (OS) was compared via Kaplan Meier analyses, using log-rank tests and Cox proportional hazards ratios (HR).

RESULTS

After matching, we identified 1,990 BMLC patients treated with Osimertinib (cohort 1) and 1,990 treated without Afatinib and Osimertinib (cohort 3). Median OS was 21.2 months and 13.5 months for the two cohorts, respectively (p < 0.0001; HR [95% CI], 0.69 [0.63-0.77]). Furthermore, we identified 685 BMLC patients treated with Afatinib (cohort 2) and 685 treated without Afatinib and Osimertinib (cohort 3) after matching. Median OS was 19.0 months and 11.5 months, respectively (p < 0.0185; HR [95% CI], 0.83 [0.71-0.97]).

CONCLUSION

Afatinib and Osimertinib demonstrated a significant survival benefit for patients with BMLC, with comparable, if not better, results to other therapeutic options. These findings suggest strong intracranial efficacy of these agents, while indicating a greater generalizability of the results. Further prospective studies are warranted to better understand their potential role in the BMLC treatment paradigm.
Clinical and molecular features of disseminated pediatric low-grade glioma and glioneuronal tumors: a systematic review and survival analysis
Authors: Haizel-Cobbina Joseline , Thakkar Rut , Richard Kelsey , Du Liping , Levine Adrian , Bennett Julie , Hawkins Cynthia , Tabori Uri , Dewan Michael C
Published: August 2022

Background

Disseminated pediatric low-grade gliomas and glioneuronal tumors (dpLGG/GNTs) are associated with a poorer prognosis than nondisseminated pLGG/GNTs. To date there is no comprehensive report characterizing the genome profile of dpLGG/GNTs and their relative survival. This systematic review aims to identify the pattern of genetic alterations and long-term outcomes described for dpLGG/GNT.

Methods

A systematic review of the literature was performed to identify relevant articles. A quality and risk of bias assessment of articles was done using the GRADE framework and ROBINS-I tool, respectively.

Results

Fifty studies published from 1994 to 2020 were included in this review with 366 cases reported. There was sporadic reporting of genetic alterations. The most common molecular alterations observed among subjects were 1p deletion (75%) and BRAF-KIAA1549 fusion (55%). BRAF p.V600E mutation was found in 7% of subjects. A higher proportion of subjects demonstrated primary dissemination compared to secondary dissemination (65% vs 25%). First-line chemotherapy consisted of an alkylation-based regimen and vinca alkaloids. Surgical intervention ranged from biopsy alone (59%) to surgical resection (41%) and CSF diversion (28%). Overall, 73% of cases were alive at last follow-up. Survival did not vary by tumor type or timing of dissemination. All studies reviewed either ranked low or moderate for both quality and risk of bias assessments.

Conclusions

Chromosome 1p deletion and BRAF-KIAA1549 fusion were the most common alterations identified in dpLGG/GNT cases reviewed. The relative molecular heterogeneity between DLGG and DLGNT, however, deserves further exploration and ultimately correlation with their biologic behavior to better understand the pathogenesis of dpLGG/GNT.
Long COVID Symptomatology After 12 Months and Its Impact on Quality of Life According to Initial Coronavirus Disease 2019 Disease Severity
Authors: Fischer Aurélie , Zhang Lu , Elbéji Abir , Wilmes Paul , Oustric Pauline , Staub Therese , Nazarov Petr V , Ollert Markus , Fagherazzi Guy
Published: August 2022

Background

“Long COVID” is characterized by a variety of symptoms and an important burden for affected people. Our objective was to describe long COVID symptomatology according to initial coronavirus disease 2019 (COVID-19) severity.

Methods

Predi-COVID cohort study participants, recruited at the time of acute COVID-19 infection, completed a detailed 12-month symptom and quality of life questionnaire. Frequencies and co-occurrences of symptoms were assessed.

Results

Among the 289 participants who fully completed the 12-month questionnaire, 59.5% reported at least 1 symptom, with a median of 6 symptoms. Participants with an initial moderate or severe acute illness declared more frequently 1 or more symptoms (82.6% vs 38.6%, P < .001) and had on average 6.8 more symptoms (95% confidence interval, 4.18–9.38) than initially asymptomatic participants who developed symptoms after the acute infection. Overall, 12.5% of the participants could not envisage coping with their symptoms in the long term. Frequently reported symptoms, such as neurological and cardiovascular symptoms, but also less frequent ones such as gastrointestinal symptoms, tended to cluster.

Conclusions

Frequencies and burden of symptoms present 12 months after acute COVID-19 infection increased with the severity of the acute illness. Long COVID likely consists of multiple subcategories rather than a single entity. This work will contribute to the better understanding of long COVID and to the definition of precision health strategies.

Clinical Trials Registration

NCT04380987.
The Intersection of Antimicrobial Stewardship, the Pharmaceutical Industry, and the Federal Legislature
Authors: Gregory Eric , Martin Craig
Published: August 2022

To mitigate the dangers of inappropriate antimicrobial use leading to increased multidrug-resistant organisms and mortality, antimicrobial stewardship programs have become a mainstay in many health systems. Unfortunately, some pharmaceutical manufacturers simultaneously have ended antimicrobial research and development efforts altogether due to suboptimal return on investments. An optimal and sustainable antimicrobial armamentarium requires a broad alliance between antimicrobial stewardship programs, the pharmaceutical industry, the legislature, and federal and state agencies. Public–private relationships such as the Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator (CARB-X) and legislative policies creating push and pull incentives, including the Generating Antibiotic Incentives Now (GAIN), Developing an Innovative Strategy for Antimicrobial-Resistant Microorganisms (DISARM), and Pioneering Antimicrobial Subscriptions to End Upsurging Resistance (PASTEUR) Acts, are each a step in the right direction, but more work remains. Understanding these legislative actions is imperative for all clinicians, as is teamwork from those involved in the antimicrobial field to develop and maintain the life cycle of each drug that harbors societal value.
Within-retailer price dispersion in e-commerce: Prevalence, magnitude, and determinants
Authors: Fedoseeva Svetlana , Irek Judith
Published: August 2022

Whereas between-retailer price discrepancies are well documented, less is known about price differentiations within a single chain. This article investigates the prevalence and the magnitude of online within-retailer price dispersion over time. Amazon is the US largest online food retailer (and the second largest retailer in the entire US grocery market), and we use the rich daily price data on food and beverages sold by Amazon Fresh in New York City and Los Angeles to shed light on the prevalence, magnitude, and determinants of the within-retailer price dispersion over time. We show that differences in economic indicators, competitive pressure, and COVID-19 exposure across locations contribute to price dispersion. Once those factors are controlled for, we observe a negative linear time trend in the share and magnitude of non-identical prices confirming an increasing market integration as e-commerce matures.
Sounding the Archival Silence: Searching for Music in the Nineteenth-Century English Asylum
Authors: Golding Rosemary
Published: August 2022

The music of the nineteenth-century English asylum provides a rare insight into the place of music within the structure of a medical institution during this period. Yet with archives literally ‘silent’, how far can the sound and experience of music be retrieved and reconstructed? Drawing on critical archive theory and the idea of the soundscape as well as musicological and historical practice, this article questions how we can investigate asylum soundscapes through the silences of the archive, and how we can use the resulting processes to deepen our relationship with the archive and enrichen other aspects of historical and archive studies. I argue that in drawing attention to new forms of evidence in order to address the literal ‘silence’ of the nineteenth-century asylum, new approaches to metaphorical ‘silences’ can be found.
Immunomodulatory and Regenerative Effects of MSC-Derived Extracellular Vesicles to Treat Acute GVHD
Authors: Fujii Sumie , Miura Yasuo
Published: August 2022

The development of human mesenchymal stromal/stem cell (MSC)-based therapy has focused on exploring biological nanoparticles secreted from MSCs. There is emerging evidence that the immunomodulatory and regenerative effects of MSCs can be recapitulated by extracellular vesicles released from MSCs (MSC-EVs). Off-the-shelf allogeneic human MSC products are clinically available to treat acute graft-versus-host disease (GVHD), but real-world data have revealed the limitations of these products as well as their feasibility, safety, and efficacy. MSC-EVs may have advantages over parental MSCs as drugs because of their distinguished biodistribution and importantly dose-dependent therapeutic effects. Recent research has shed light on the role of microRNAs in the mode-of-action of MSC-EVs. A group of specific microRNAs alone or in combination with membrane proteins, membrane lipids, and soluble factors present in MSC-EVs play key roles in the regulation of GVHD. In this concise review, we review the regulation of T-cell-mediated adaptive immunity and antigen-presenting cell-mediated innate immunity by MSC-EVs and the direct regenerative effects on damaged cells in association with the immunopathology of GVHD.
DCBLD2 regulates vascular hyperplasia by modulating the platelet derived growth factor receptor‐β endocytosis through Caveolin‐1 in vascular smooth muscle cells
Authors: Wang Shuai , Liu Xiaoning , Meng Zeqi , Feng Qi , Lin Yanling , Niu Honglin , Yu Chao , Zong Yanhong , Guo Lingling , Yang Weiwei , Ma Yuehua , Zhang Wenjun , Li Chenyang , Yang Yunran , Wang Wenjuan , Gao Xurui , Hu Yaxin , Liu Chao , Nie Lei
Published: August 2022

DCBLD2 is a neuropilin‐like transmembrane protein that is up‐regulated during arterial remodeling in humans, rats, and mice. Activation of PDGFR‐β via PDGF triggers receptor phosphorylation and endocytosis. Subsequent activation of downstream signals leads to the stimulation of phenotypic conversion of VSMCs and arterial wall proliferation, which are common pathological changes in vascular remodeling diseases such as atherosclerosis, hypertension, and restenosis after angioplasty. In this study, we hypothesized that DCBLD2 regulates neointimal hyperplasia through the regulation of PDGFR‐β endocytosis of vascular smooth muscle cells (VSMCs) through Caveolin‐1 (Cav‐1). Compared with wild‐type (WT) mice or control littermate mice, the germline or VSMC conditional deletion of the Dcbld2 gene resulted in a significant increase in the thickness of the tunica media in the carotid artery ligation. To elucidate the underlying molecular mechanisms, VSMCs were isolated from the aorta of WT or Dcbld2−/− mice and were stimulated with PDGF. Western blotting assays demonstrated that Dcbld2 deletion increased the PDGF signaling pathway. Biotin labeling test and membrane‐cytosol separation test showed that after DCBLD2 was knocked down or knocked out, the level of PDGFR‐β on the cell membrane was significantly reduced, while the amount of PDGFR‐β in the cytoplasm increased. Co‐immunoprecipitation experiments showed that after DCBLD2 gene knock‐out, the binding of PDGFR‐β and Cav‐1 in the cytoplasm significantly increased. Double immunofluorescence staining showed that PDGFR‐β accumulated Cav‐1/lysosomes earlier than for control cells, which indicated that DCBLD2 gene knock‐down or deletion accelerated the endocytosis of PDGF‐induced PDGFR‐β in VSMCs. In order to confirm that DCBLD2 affects the relationship between Cav‐1 and PDGFR‐β, proteins extracted from VSMCs cultured in vitro were derived from WT and Dcbld2−/− mice, whereas co‐immunoprecipitation suggested that the combination of DCBLD2 and Cav‐1 reduced the bond between Cav‐1 and PDGFR‐β, and DCBLD2 knock‐out was able to enhance the interaction between Cav‐1 and PDGFR‐β. Therefore, the current results suggest that DCBLD2 may inhibit the caveolae‐dependent endocytosis of PDGFR‐β by anchoring the receptor on the cell membrane. Based on its ability to regulate the activity of PDGFR‐β, DCBLD2 may be a novel therapeutic target for the treatment of cardiovascular diseases.
Culinary Medicine as Innovative Nutrition Education for Medical Students: A Scoping Review
Authors: Newman Courtney , Yan Justin , Messiah Sarah E. , Albin Jaclyn
Published: August 2022

Purpose

Lifestyle-related disease substantially impacts health, but physicians lack adequate nutrition education to discuss behavioral change with patients. Many medical schools have developed culinary medicine programs as a nutrition education strategy, but common elements of success have not been defined.

Method

The authors conducted a scoping review of the literature on culinary medicine programs for medical students. They searched PubMed, Ovid MEDLINE, and MedEdPORTAL databases to identify English-language studies published between January 1, 2012, and October 15, 2021. Multiple search terms were used to identify medical student–focused culinary medicine programs. The authors focused inclusion criteria on medical student learners, curricular description, hands-on cooking components, reflection or application to patient care, and assessment. Additionally, the authors reviewed 2 online databases which list programs delivering culinary medicine education for U.S. medical students.

Results

Authors identified 251 studies, of which 12 met inclusion criteria. These studies described programs that used a kitchen or similar space adaptable for food preparation to enable hands-on learning, and some programs provided opportunities for practical application. Most programs administered surveys to assess course impact, but the type of survey and cohort size varied. Culinary medicine programs for medical students varied in learner level, number of participants, course length and structure, and instructor background but consistently improved student knowledge in key areas of nutrition application and changed knowledge and attitudes about food and nutrition. Funding was often noted as a barrier to program sustainability. When funding source was provided, it derived from philanthropic or academic sources. When the authors reviewed the 2 online databases, they identified 34 programs offering medical student-focused culinary medicine courses.

Conclusions

As culinary education programs emerge across academic centers, standardizing programmatic and curricular elements, best practices, and assessment strategies will be vital for quality control, sustainability, and optimal population health impact.
Orthopaedic surgery residency match trends during COVID-19 pandemic: A cross-sectional study
Authors: Hayward Dan , Dowdle Travis S. , Steadman Jesse , Froerer Devin , Perry Cody , Zumwalt Mimi
Published: August 2022

Background:

Orthopaedic surgery is one of the more competitive specialties for medical students to pursue. Students often complete subinternship rotations to demonstrate skill, work ethic, and fit within a program. Away rotations were suspended during the COVID-19 pandemic.

Methods:

This investigation compared home and regional match rates before the pandemic to the match cycle of 2020-2021.

Results:

There was a statistically significant increase in students matching to their home program, and insignificant increase in regional matches.

Conclusion:

This increase is likely due in part to the familiarity of students to programs where they could still rotate during the pandemic.

Level of Evidence:

Level IV.
Gender and outcomes in total joint arthroplasty: a systematic review on healthcare disparities in the United States
Authors: McKeon John F. , Alvarez Paul M. , Spitzer Andrew I. , Krueger Chad A. , Pigott Matthew , Li Mengnai , Vajapey Sravya P.
Published: August 2022

Background:

The authors evaluated the currently available evidence regarding the effect gender has, if any, on utilization of and outcomes after total knee (TKA) and hip (THA) arthroplasty. Recent studies have shown that TKA and THA are not utilized equally across different demographic cohorts. A comprehensive search of MEDLINE database was performed using keywords “disparities,” “arthroplasty,” “joint replacement,” “hip,” “knee,” “gender,” and “outcomes” in all possible combinations.

Methods:

All English studies with levels of evidence I to IV published over the last 20 yr were included in the review. Quantitative and qualitative analysis was performed on the data collected where applicable.

Results:

A total of 33 articles that met inclusion and quality criteria were analyzed. Overall, men and women have similar utilization rates of THA and TKA. Men and women have similar expectations regarding outcomes after total joint arthroplasty (TJA). Female gender has been shown to be protective against mortality, major complications, and revisions after TJA. However, women are at higher risk of being discharged to a facility after TJA compared with men (P<0.05). Functional outcomes are similar for men and women.

Conclusions:

This systematic review showed that there are no significant differences in utilization of and outcomes after TJA between men and women. Female gender was shown to be protective against complications but remained a risk factor for nonhome discharge after TJA.

Level of Evidence: IV
Safety of intra-articular platelet rich plasma injections for large joint osteoarthritis: a review article
Authors: Chiu Yu M. , Wang Daniel , McCormick Zachary , Diwan Sudhir , Candido Kenneth D. , Chang Chien George C.
Published: August 2022

Platelet-rich plasma (PRP) use in intraarticular injections is thought to be potentially efficacious in the treatment of osteoarthritis (OA) and as an alternative to corticosteroid injections. However, little is known about the safety of PRP usage in the treatment of large joint osteoarthritis. In the 21 identified studies, there were primarily minor adverse effects include pain, redness, swelling, nausea, and dizziness. The limitations of this review include the relative paucity of well-designed studies that describe detailed adverse effects using safety as an outcome measure. Intraarticular injection of platelet-rich plasma has low risk of morbidity. This review describes the evidence for the short-term safety of intraarticular PRP injections and its derivations in the treatment of large joint OA (knee, hip, shoulder). Further investigation is needed to determine the short-term safety of PRP for use in the management of OA in the hip and shoulder, as well as the documentation of long-term safety in the shoulder, hip and knee.
Temporary hemiepiphysiodesis for correction of genu valgum due to cystinosis: a preliminary interventional study in children
Authors: Ghaznavi Alireza , Mohammadpour Mehdi , Taheri Nima , Cheraghiloohesara Sahand , Aslani Masoud
Published: August 2022

Background:

Few studies have assessed the efficacy of temporary hemiepiphysiodesis in the treatment of genu valgum in patients with cystinosis. In the present study, the authors aimed to assess the postsurgical outcome of temporary hemiepiphysiodesis for genu valgum in patients with cystinosis.

Methods:

In this case series study, the inclusion criterion was the occurrence of genu valgum due to definitive diagnosis of cystinosis that was treated with temporary hemiepiphysiodesis technique. The lateral distal femoral angle (LDFA) and medial proximal tibial angle (MPTA) were measured before and 6 to 12 mo after the operation. Surgical complications also were assessed within the mean follow-up time of 40.21±19.86 mo.

Results:

Overall, 14 patients undergoing temporary hemiepiphysiodesis due to genu valgum after cystinosis were assessed. The mean age was 10.00±2.41 yr (male 35.7%, female 64.3%). Hemiepiphysiodesis led to significantly increased LDFA in both left side (from 79.64±3.89 to 88.28±1.26, P=0.001) and right side (from 79.42±2.59 to 89.57±1.69, P=0.001). The change in MPTA in left side (from 88.21±1.36 to 86.07±1.32, P=0.001) and right side (from 88.35±2.49 to 86.42±1.74, P=0.016) also was significant.

Conclusions:

Temporary hemiepiphysiodesis is a reproducible, efficient, and safe approach for correction of genu valgum in patients with cystinosis with low and amendable complications in a short stature patient.

Level of Evidence:

Level III.