bluuebunny/crossref_metadata_2025 huggingface dataset:
Preventing clinical deterioration in cancer outpatients: Human centered design of a predictive model and response system.
Authors: Salwei Megan Elizabeth , Anders Shilo , Novak Laurie , Reale Carrie , Slagle Jason , Harris Joyce , Unertl Kim , Nath Paromita , Mahadevan Sankaran , Agarwal Rajiv , Elliott Natalie , Lee Rachel , Weinger Matthew B. , France Daniel
Published: June 2022

e13567

Background: Patients (pts) with cancer in the outpatient setting are at a high-risk for adverse events, such as unplanned hospitalizations and ER visits. A recent study found that up to 30% of hospital admissions were preventable. Identifying pts at risk of avoidable clinical deterioration remains a challenge, as clinicians may not be aware of pts’ experiences at home. The growing use of health IT presents an opportunity to identify and respond to clinical deterioration in patients before an adverse event occurs. In this study, we describe a human-centered design (HCD) process used to develop a clinical deterioration risk prediction system to improve the detection of and response to deterioration in cancer outpatients. Methods: Predictive model: We enrolled eligible cancer pts and collected data from each one including: FitBit, geolocation, EHR, and weekly patient-reported outcome measures (PROMs). Pts and their family caregivers could also report non-routine events (NREs), defined as any deviation from expected optimal care. We also captured unplanned treatment events (UTEs), a clinically meaningful change in the pt’s treatment course or care pathway. We developed a predictive model that generates a pt’s 7-day risk of clinical deterioration. Response system: We are developing a risk communication system (RCS) to communicate predicted risk scores to clinical teams. Using a HCD process, we first conducted 36 observations across 100 patient encounters to understand the environment of use. Next, we conducted 18 clinician interviews to define user needs. We have conducted 7 multi-disciplinary design sessions to iteratively develop prototypes of the RCS. We are currently conducting formative usability testing to assess the prototype and gather clinician feedback. Results: Predictive model: We have enrolled 36 cancer outpatients (24 head & neck, 9 gastrointestinal, and 3 lung). Pts completed a total of 219 weekly PROM surveys, reported 107 NREs and experienced 18 UTEs (e.g., infection). So far, models using EHR and PROM data are the most sensitive and precise (AUC: 0.983; 0.999). More patient data are required to develop higher quality stable models. Response system: We identified key design elements to include in the RCS, such as the caregiver’s phone number and the pt’s weight over time. Preliminary findings demonstrate high usability of the prototype RCS. Oncologists identified opportunities for the system to better support team communication and coordination, and to improve the identification and response to clinical deterioration in cancer outpatients. Conclusions: We have developed and tested a clinical deterioration risk prediction system for cancer outpatients. Future studies will implement the response system and evaluate its impact on clinical care.
Prostate cancer prediction using classification algorithms.
Authors: Huo Xingyue , Finkelstein Joseph
Published: June 2022

e13590

Background: The object of this study was to evaluate the efficacy of machine learning classification algorithms for prostate cancer prediction using patients' age, CCI score, and medical procedures. Methods: We analyzed a dataset of 112,605 individuals from the IBM MarketScan database between 2016 and 2019, deviding them into two groups based on whether they diagnosis with prostate cancer in 2019. Then we retrospectively reviewed these subjects' medical records including the CCI, medical procedure records and ages. Machine learning classifiers consisting of support vector machine (SVM), decision tree (DT), random forest (RF), Extreme Gradient Boosting (XGBoost), and adaptive boosting (Adaboost) were used to analyze the prediction accuracy of prostate cancer. For all machine learning prediction models, 70% of the randomly chosen data samples were used for training, and 30% were used as a test set. The classifier with the highest accuracy were selected for prediction and identify feature importance. Results: The study included 112,605 subjects, of which 19,564 (17.4%) men who diagnosed with prostate cancer in 2019. Overall, The best prediction model for prostate cancer prediction was XGBoost, with the cancer prediction accuracy in the test set of 84%. The “Minor male genital procedures” was the highest scored feature importance, while age is not an important feature in prostate cancer prediction among elderly males. Conclusions: The more urethral/male genital examination procedures an individual has received in the past two years, the more attention should be paid to the risk of having prostate cancer. These results suggest that the analysis of individual medical records using machine learning classification algorithms can increase the prediction rate of prostate cancer.
The influence of blinded independent central review on subject eligibility in oncology studies.
Authors: Borys Larissa , Marini Matthew , Lu Edwin , Ford Robert
Published: June 2022

e13603

Background: Oncology clinical trials that use imaging based surrogate endpoints such as Progression Free Survival (PFS) and Overall Response Rate (ORR) generally have eligibility criteria based on imaging. Examples include but are not limited to the presence of a RECIST measurable lesion at baseline for studies where ORR is the primary endpoint, the absence of disease at baseline in recurrence studies, the absence of exclusionary brain metastases, and the presence or absence of a particular stage of disease at baseline, such as the absence of T4b, M1, and >N2 disease in studies of muscle invasive bladder cancer. Our experience suggested the percentage of subjects who did not meet those criteria during Blinded Independent Central Review (BICR) may be higher than expected and could have a significant effect on the statistical power of studies. We reviewed a large cohort of subjects (n = 8746) to determine the fraction of subjects who were considered for enrollment or enrolled in oncology clinical trials by investigators and were deemed ineligible during BICR. Methods: We analyzed 66 trials with a total of 8,746 total subjects. Trials were selected based on initiation between June 2020 and June 2021 and involvement of one (1) or more imaging eligibility criteria. Trials in this cohort fit into 2 categories: those that had prospective real time eligibility review where subjects could not be enrolled until the eligibility review was completed in real time (“eligibility review trials”) and those trials that did not have a prospective eligibility review however the data was available for retrospective analysis (“efficacy only trials”). Our analysis determined the fraction of subjects that were prospectively and retrospectively ineligible under each respective category. Results: In these categories, 56% of the subjects (n = 4934) were involved in efficacy only trials. Following BICR review, 12% (n = 614) of the subjects were found to be ineligible retrospectively. Conversely, 44% of the subjects (n = 3812) were enrolled in trials where Clario performed a prospective eligibility review. We found that only 89 of those subjects were deemed ineligible at the time of the prospective eligibility review (2%). This translates to 2% of the subjects were deemed eligible by the investigators, but ineligible by the Clario review. The 10% difference suggests that the eligibility review prevents inclusion of a significant number of subjects that are subsequently determined to have not met the initial imaging eligibility requirements. Conclusions: Eligibility review appears to improve standardization of subject eligibility. These data suggest that the omission of an eligibility review can cascade into censoring more than 10% of subjects. This could have significant impacts on the statistical power of a study and should be considered during study designs.
Real-world data on the clinical utility of a novel artificial intelligence-based computational method to support treatment decisions in gastrointestinal cancers.
Authors: Petak Istvan , Vodicska Barbara , Kispeter Eniko , Doczi Robert , Tihanyi Dora , Lakatos Dora , Dirner Anna , Vidermann Matyas , Szalkai-Denes Reka , Deri Julia , Kamal Maud , Schwab Richard , Le Tourneau Christophe
Published: June 2022

e13616

Background: Several molecularly targeted agents (MTA) are registered in the same indication, even in the same line, to treat gastrointestinal (GI) cancers. Comprehensive molecular profiling is readily available for many patients, but only a few biomarkers are used to make clinical decisions between on-label MTAs. Most tumors harbor a combination of driver alterations potentially affecting the sensitivity to MTAs according to hundreds or thousands of evidence items that can explain the heterogeneous clinical response of individual patients to these therapies. We have developed an AI-based computational method, an automated, evidence-based reasoning framework, called digital drug assignment (DDA) to provide decision support based on the complete molecular profile for each patient. DDA has been shown to potentially improve treatment decisions in case of complex molecular profiles acquired in the SHIVA01 trial. In the present study, we analyzed the clinical utility of DDA in on-label treatment decisions in GI cancers. Methods: We analyzed the next-generation sequencing (NGS) data obtained using 50-591-gene panels of 239 patients with GI tract cancers from our everyday practice. Molecular profiles were uploaded to a DDA-based software system to calculate the aggregated evidence level (AEL) values of associated MTAs registered in the same indication of selected GI cancers. Decision support rate (DSR) was calculated as the percentage of patients where DDA could support clinical decisions based on the presence of genetic alterations associated with any of the available MTAs. Results: Targeted treatment options registered in the same indications and the DDA-based decision support rates (DSR) are shown in the table. For example, DDA could support the decision between cetuximab and bevacizumab based on NGS results in 47% of RAS/RAF wild-type colorectal cancer cases. Larger NGS panels yielded higher rates of decision support (44% vs 52% with gene panels under and over 300 genes, respectively). Conclusions: DDA-based computational reasoning can support molecular profile-based treatment decisions among different on-label MTAs in a clinically meaningful fraction of GI cancers.[Table: see text]
Creating diversity, equity, inclusion, and access in cancer clinical research: Drive rank and Drive score.
Authors: Birhiray Maya Nicole , Birhiray Ruemu Ejedafeta
Published: June 2022

e13636

Background: The inequalities in improving cancer mortality rates in the United States can be ascribed to treatment disparities that are largely due to unequal access to clinical trials in cancer care, resulting in adverse clinical and economic effects. D.R.I.V.E is a five-step strategy for promoting and improving DEIA in clinical trials for minority patients based on the following steps. Methods: Appointing a clinical trial Diversity Officer, creating a RANK SCORE based on minority enrollment, Individual diversity plan, Verification of study diversity, and Elevate and Enhanced training of minority investigators and research team members. Results: Global Performance Indicators (GPIs), which rate and rank states relative to one another, shape decisions. Rankings should be reported by authors and required for publication in peer-reviewed journals and should be included in journal impact factor assessment. Conclusions: DRIVE aims to use these strategies to correct inequalities and promote the overall health of mankind, using proven principles and techniques to create meaningful improvements in cancer care and outcomes. DRIVE RANK), based on the achievement of minority participant representation relative to the epidemiology of disease, is an informational tool to evaluate DEIA efforts and provide a readily accessible measurement of the applicability of clinical data to all patient subgroups with the potential to force positive changes to promote DEIA and the health of mankind. We propose a ranking of 0-5 for diversity (Table). Establish a corporate ranking system (DRIVE SCORE) based on the diversity of clinical data from the totality of studies of the company to inform the choice of ethical investors. Studies will be ranked at the next lower rank if all criteria for next higher rank are not reached.[Table: see text]
Single institution assessment of compliance with guideline directed aspirin therapy in the prevention of colorectal cancer in Lynch syndrome.
Authors: Wu Kathie , Williams Heinric , Ramdin Nadia N.
Published: June 2022

e13637

Background: Patients with Lynch syndrome have up to 80% lifetime risk of developing colorectal cancer. Research shows chemoprevention with aspirin 600 mg for 25 months can reduce this risk for Lynch syndrome patients by 59%. In our study, we evaluated the compliance with aspirin therapy among Lynch patients at our institution. Methods: Our clinic identifies and follows all patients with a history of Lynch syndrome. Of our 125 patients, 62% were discovered after a family member was found to have a high-risk cancer, 29% were identified through MyCode, a DNA sequencing program which looks for gene mutations specific to Lynch. All patients in the clinic undergo discussion about starting aspirin therapy. Medication agreements and dosing are documented in the chart. Data was retrospectively reviewed to assess our patient compliance with recommendations. All data was based on subjective reports of compliance and reported doses. Results: 125 patients were included in the data analysis. Various risk factors were assessed including age, gender, history of cancer, and other comorbidities. Ages ranged from 20 to 78; 74% were female, 26% male. 90% of patients had a family cancer and of those, 47% had a personal history of cancer. Overall, 57% of patients agreed to take aspirin with doses ranging between 81 mg to 600 mg. 60.8% of patients took 81 mg of aspirin daily and 30.6% took 325 mg daily, citing concerns for bleeding and ulcer at higher doses. Only 8% of all patients agreeable to aspirin therapy took the recommended 600 mg dose. Of those who refused aspirin therapy, 5% reported allergy or prior intolerance, 13% had history of gastric ulcer or prior bleeding, 2% were taking medications which taken concomitantly with aspirin would increase risk of bleeding, and 80% provided no reason. Chi square test of independence was performed to examine the relationship between aspirin use and gender (χ² = 0.76, p = 0.38), age (χ² = 1.99, p = 0.37), and personal or family history of cancer (χ² = 9.89, p = .002). Results showed a patient with personal, or family history of cancer was more likely to take aspirin therapy, but there was no significant relationship among gender or age. Conclusions: Aspirin serves as an effective and affordable therapy for the prevention of colorectal cancer in patients with Lynch syndrome. Barriers to compliance should be identified and chemoprophylaxis should be initiated in all qualified patients. Future studies should be performed to establish more concrete recommendations about dosing and duration of aspirin therapy especially given the ease of access and cost effectiveness.[Table: see text]
Real-world practice patterns in the diagnosis of recurrent metastatic breast cancer in Washington state.
Authors: Manohar Poorni , Fedorenko Catherine R. , Sun Qin , Voutsinas Jenna M. , Wu Vicky , Roth Josh , Linden Hannah M. , Shankaran Veena
Published: June 2022

e13640

Background: Evidence-based, national guidelines for the diagnosis of recurrent metastatic breast cancer (MBC) recommend confirmation of recurrence with biopsy and reassessment of biomarker status. Real world practice patterns may demonstrate disparities in adherence to guidelines with implications for patients and health systems. Methods: We utilized the Hutchinson Institute for Cancer Outcomes Research (HICOR) data repository that links Washington State cancer registry data to enrollment and claims from the major insurance payers in the state. We identified women > 18 years old diagnosed with recurrent MBC between 2008 and 2017 with evidence of enrollment in a commercial plan (Premera or Regence), Medicare, or Medicaid. Recurrence in Stage I-III patients was detected through identification of ICD 9/10 codes for metastatic disease or resumption of breast cancer systemic therapy (after minimum of 4 months from completion of early breast cancer therapy). Using claims, we identified receipt of and factors associated with biopsy, biomarker re-assessment, and treatment administered at recurrence. Results: We identified 715 patients with recurrent MBC (any ER or HER2 status) with median age of 62 (range 52-73). The majority of the cohort were Caucasian (89%) with the rest comprising of Asian, Black, American Indian, and Hispanic patients. Based on the Rural Urban Commuting Area (RUCA) classification, patients predominantly lived in metropolitan neighborhoods (97%). Approximately 13% of patients lived in areas of high deprivation (area of deprivation index, ADI, 8-10). Patients had either Commercial (53.1%), Medicaid (4.2%), Medicare (29.7%) or multiple (13.0%) insurance. Patients were primarily treated at high volume centers (70.9%), though 23% of patients were seen at low volume centers (<25 breast cancer patients/year). Of the patients with recurrent MBC, 49.5% received a biopsy to confirm metastatic diagnosis. Similarly, 48.7% of recurrent MBC patients underwent biomarker reassessment. Patients with highest co-morbidity index (>2) were more likely to undergo biopsy confirmation (20.3% vs 13.0%, p = 0.02). Biopsy was more often performed in patients receiving care at a high-volume center compared to low-volume center (74.3% vs 18.6%, p = 0.03). First line treatment selection was directly associated with receipt of biopsy and biomarker testing. Hormone therapy only was more common in patients who did not undergo biopsy (62.3% vs 37.7%, p <0.001) or biomarker reassessment (62.7% vs 37.3%, p <0.001). Conclusions: Our study shows there is variation across Washington state in biopsy and biomarker assessment in the diagnosis of recurrent metastatic breast cancer. Nearly half of cases had metastatic biopsy omitted. Our findings demonstrate downstream implications for treatment selection and support the need for quality initiatives to improve adherence to guidelines.
The impact of virtual oncology care on chemotherapy continuity and clinical outcomes in patients treated for colorectal cancer: A pre-post analysis of the COVID-19 pandemic.
Authors: Phillips William James , Leung Macyn , Thavorn Kednapa , Asmis Timothy R.
Published: June 2022

e13649

Background: The coronavirus (COVID-19) pandemic has resulted in an abrupt transition to virtual oncology care at most cancer centres worldwide. A pillar of the American Medical Association’s proposed framework for digitally enabled care is assessing clinical quality, safety, and outcomes. This study’s objective is to evaluate chemotherapy quality and clinical outcomes in patients receiving intravenous chemotherapy for colorectal cancer before and during the COVID-19 pandemic. Methods: This is an observational study assessing patients treated with intravenous chemotherapy for colorectal cancer consecutively at the Ottawa Hospital Cancer Centre from June 2019 to September 2021. Patients with non-metastatic rectal cancer were excluded. Patient were stratified by whether they were started on chemotherapy pre-pandemic (June 2019 – Jan 2020) versus intra-pandemic (Feb 2020 – Sept 2021). Baseline characteristics and treatment data were collected from the electronic medical records. Outcomes of interest included chemotherapy delays, dose reductions, emergency department (ED) visits and hospitalizations. We used generalized linear and binary logistic regression modelling to compare outcomes between pre- and intra-pandemic periods. Results: There were 220 patients included in this study with 108 (49%) diagnosed with metastatic disease. In total, there were 66 (30%) patients treated in the pre-pandemic and 154 (70%) in the intra-pandemic period. As expected, virtual care consultations increased during the pandemic from 1.5% to 43.5% (p < 0.001). Likewise, the proportion of follow-up visits also increased from 37% to 84% (p < 0.001). There was no difference in the incidence of treatment delays (odds ratio [OR] = 1.01, p = 0.78), dose reductions (OR = 0.99, p = 0.69), ED visits (OR = 1.23, p = 0.37), hospitalizations (OR = 0.73, p = 0.43) or the total length of time off treatment (OR = 0.85, p = 0.17) between the pre- and intra-pandemic periods by multivariable analysis. A subgroup analysis was performed based on stage, which showed no difference in outcomes independent of the presence of metastases. Conclusions: This study demonstrates no significant difference in chemotherapy interruptions, dose intensity, or clinical outcomes in patients treated for colorectal cancer during the COVID-19 pandemic. These findings serve as an important quality-care indictor and demonstrate that virtual oncology care appears safe in a cohort of high-risk colorectal cancer patients. Future work dedicated to other tumor sites would allow for broader application of these findings.
Integration of traditional molecular diagnostic tools and targeted next generation sequencing for the precise diagnosis and management of adult gliomas.
Authors: Kanan Duaa , Safı Şebnem , Kanan Tarek , Celik Serkan , Öven Bala Başak , Yapicier Ozlem
Published: June 2022

e14011

Background: It is known that gliomas represent a wide variety of entities with varying biological features and clinical outcomes (Neuropathol Exp Neurol 2019, 78). Hence, optimal tumor classification that aids in the diagnosis and management of patients and which supports the use of specific treatment modalities is of critical importance in neuro-oncology. Targeted next-generation sequencing (NGS) has proven to be an efficient and reliable tool for identifying prognostic biomarkers for the diagnosis of CNS tumors (Neurooncol Adv 2020, 2). Here, an analysis of the impact of using NGS in addition to traditional molecular tools on tumor classification and therapy selection was analyzed; and the overall concordance was evaluated. Methods: Patients with glial tumors who were seen at our clinic between 2019-2020 and had an NGS analysis in addition to traditional molecular studies were included. All clinical data, histopathological findings and genetic reports were retrieved from the electronic medical record. We retrospectively studied each of the patients’ findings with regards to their clinical diagnosis, grade, anatomic localization; ki67 (%); TP53, IDH and ATRX mutations; as well as microsatellite instability (MSI) and additional mutational studies such as HER2 and BRAF for some patients. The concordance between the genetic and molecular data regarding TP53 and IDH mutations was also analyzed. Results: 9 patients (66.7% male) with grade 3-4 gliomas were identified at our single-center oncology institution. Most patients had a diagnosis of glioblastoma (55.6%), with a median age of 43 years at the time of diagnosis. 22.2% (2/9) had a genetic analysis through FoundationOneCDx. The concordance of the identification of mutations by NGS and immunohistochemistry (IHC) was 77.8% (7/9) for IDH mutations, and 55.6% (5/9) for TP53 mutations. NGS led to the identification of TP53 mutation in 1 patient (11%) which IHC failed to show. NGS also supported the use of targeted therapy [dabrafenib] in 1 patient (11.1%) with BRAF positivity. Conclusions: Traditional molecular diagnostic tools and targeted NGS are not perfectly concordant, but when integrated together can lead to a more comprehensive identification of genetic mutations and potential biomarkers. This can have significant implications on the precise diagnosis and potential use of targeted therapies of adult gliomas in the future.
Real-world analysis of outcomes of patients receiving bevacizumab for recurrent glioblastoma in British Columbia.
Authors: Chahal Manik , Harrison Rebecca A. , Thiessen Brian Arthur
Published: June 2022

e14017

Background: Bevacizumab (Bev) has been publicly funded in British Columbia (BC) since 2011 for treatment of recurrent glioblastoma (rGBM). We performed a retrospective outcomes assessment of patients with rGBM treated with Bev to evaluate treatment practices and outcomes. Methods: Patients with rGBM treated at BC Cancer centers with Bev between January 2011 and December 2017 were reviewed. Patient demographics, tumor characteristics, treatment regimens, and dates of radiographic progression and death were collected. Kaplan-Meier method was used to assess survival, and comparisons were made using the log-rank test. Results: 182 patients were reviewed. There were 180 reported deaths with median PFS 3 months (CI95 = 2.5 - 3.5) and OS 7 months (CI95 = 6.2-7.8) from Bev initiation. Higher corticosteroid dose prior to Bev initiation was associated with worse OS on univariate and multivariate analysis ( p = 0.40 and 0.01, respectively). 67% of patients on corticosteroids reduced their dose shortly after Bev initiation. Most patients (68%) were treated with multiple lines of therapy prior to Bev, with a median time from chemoradiation to Bev initiation of 8 months (range 1-67). Patients started on Bev < 6 months from completion of chemoradiation (prior to adjuvant temozolomide completion) had improved PFS ( p = 0.02) and OS compared to those who started Bev later ( p = 0.05), but there was no association between extent of treatment prior to Bev and outcomes ( p = 0.09). Addition of chemotherapy to Bev did not improve survival over Bev monotherapy ( p = 0.10). Conclusions: Bev combinations with chemotherapy did not confer survival advantage over Bev monotherapy. Furthermore, our results show that patients receiving Bev before completion of adjuvant chemotherapy have better outcomes, suggesting pseudoprogression may have prompted the therapeutic switch. Despite limited benefits to overall survival, Bev is associated with reduction in corticosteroid use and likely improvement in quality of life. Therefore, further research is required to optimize patient selection for and administration of Bev. Additional analysis of rGBM patients prescribed Bev until 2020 in BC is currently underway.
Seizures as treatment-emergent adverse events during glioblastoma clinical trials.
Authors: Dillman Robert O.
Published: June 2022

e14018

Background: Seizures are not an uncommon presenting symptom of glioblastoma (GBM), and may occur following surgery for GBM. Such seizures typically can be controlled with anti-epileptics, and the risk of seizures seems to decrease after concurrent radiation therapy and temozolomide chemotherapy (RT/TMZ). However, the risk of seizures theoretically might be increased in association with a therapeutic intervention designed to enhance local inflammation at the GBM site. 33% of patients experienced one or more seizures as a treatment-emergent-adverse-event (TEAE) during a phase II clinical trial of AV-GBM-1, patient-specific dendritic cell vaccines that consist of autologous dendritic cells loaded with autologous tumor associated antigens derived from a short-term culture of self-renewing tumor cells, that were injected subcutaneously for up to six months after recovery following concurrent RT/TMZ (Bota DA et al. 2021 Society for Immunotherapy of Cancer (SITC) late-breaking abstract #952, 2021 Society of Neuro-Oncology abstract #CTIM-33). A literature search was conducted to determine reported rates of seizures as TEAE in primary GBM patients in clinical trials. Methods: Phase III trials of systemic treatment of primary GBM, and published during 2005 to 2021, were identified by searches of clinicaltrials.gov and PubMed. Published reports were reviewed for data describing the frequency of seizures reported as TEAE in text and/or summary tables. Only trials that had at least 50 patients in a standard treatment arm of surgical resection, RT/TMZ and maintenance TMZ were included. Chi square test was used to compare proportions of patients experiencing seizures in these trials. Results: Eight such randomized trials were identified. Five trials did not mention seizures as TEAE. One trial provided data only for grade 3 and 4 events: 13/229 (5.7%). The other two trials reported all seizures regardless of grade, but were limited to patient populations with O6-methylguanine-DNA-methyltransferase promoter methylation in one, and epidermal growth factor receptor amplification in the other. The rates of seizures in those two trials were much lower than the 19/57 (33.0%) reported with AV-GBM-1: 28/258 (10.9%, p < 0.0001), and 69/372 (15.4%, p = 0.0136). Conclusions: The frequency of seizures that occur in GBM patients receiving standard RT/TMZ is not well-documented in publications of large, randomized trials. AV-GBM-1 may be associated with a higher rate of seizures because of treatment-induced inflammation at the tumor site, but a randomized trial would be needed to determine this.
Anlotinib plus radiotherapy-temozolomide for newly diagnosed glioblastoma: A prospective, multicenter phase II study.
Authors: Lai Shuzhen , Chen Yuan yuan Yuan , Li Peijing , Jiang Fagui , Liu Xiaohui , Tao Changjuan , Huang Jing , Tang Yiqiang , Liu Zhigang , Shen Guoping , Li Chaoming , Xie Tieming , Lu Fangxiao , Liu Guihong
Published: June 2022

e14020

Background: Concurrent radiotherapy and temozolomide (TMZ) followed by adjuvant TMZ (STUPP regimen) is the standard therapy for newly diagnosed glioblastoma after resection, however, the progression-free survival (PFS) was only about 7 months (m) and the overall survival (OS) was less than 17m. This study aims to assess the efficacy and safety of adding anlotinib, a multitarget tyrosine kinase inhibitor, to the STUPP regimen for newly diagnosed glioblastoma. Methods: This was a prospective, sing-arm, multicenter, phase II study (NCT04119674). Eligible patients (pts) were diagnosed with newly diagnosed GBM and had undergone surgery within 6 weeks before enrollment. Previous exposure to other therapies was not permitted. Other key inclusion criteria included 18 to 75 years old, Karnofsky performance status ≥ 60 %, had at least one measurable lesion according to RANO criteria, and adequate bone marrow, hepatic, and renal functions. All pts received radiotherapy (54̃60 Gy administered as 1.8-2.0 Gy fractions, 5 days per week) for 6 weeks, with concurrent oral TMZ (75 mg/m2 QD) and anlotinib (8 mg QD, d1̃d14 per 3 weeks). After a 28-day treatment break, adjuvant therapy was started with six cycles of TMZ (150–200mg/m2, d1–5/4wks) and eight cycles of anlotinib (10 mg QD, d1–14/3wks) ，and followed by anlotinib monotherapy until disease progression or intolerable toxicities. The primary endpoint was progression-free survival (PFS). The adverse events (AEs) were recorded according to CTCAE 5.0. Results: From January 2019 to February 2021, 33 pts (17 males and 16 females) were enrolled from 7 hospitals in China. The median age was 52 (range: 32, 69). At the data cutoff date on January 25th, 2022, all pts had completed the concurrent treatment and 30 pts (90.0%) completed the 6 cycles of adjuvant treatment. The median treatment duration of anlotinib was 16 cycles. At the data cutoff date, 21 patients experienced disease progression and 17 pts were dead. The median PFS was 10.9m (95% CI, 6.6-15.2) and the median OS reached 18.7m (95% CI, 15.0-22.4). The PFS at 1 year was 45.5% and OS at 1 year was 72.7%. No grade 3 or worse AEs were observed during the concurrent phase and anlotinb maintenance phase. Three pts (9.1%) had grade 3 or 4 thrombocytopenia and 1 pts (3.0%) had grade 3 vomiting during the course of adjuvant therapy. Conclusions: This is the first study to explore the feasibility of adding anlotinib to the standard treatment for newly diagnosed GBM. The efficacy was impressive in that the median OS had exceeded 18m and the safety profile was favorable. The positive-controlled study was ongoing. Clinical trial information: NCT04119674.
Using variant allelic fraction of driver mutations to determine the reliability of MGMT promoter methylation testing in adult-type diffuse gliomas.
Authors: McCord Matthew , Jamshidi Pouya , Bell Burdett Kirsten Bell , Jennings Lawrence , Horbinski Craig M.
Published: June 2022

e14034

Background: Methylation of the O6-methylguanine-DNA methyltransferase ( MGMT) promoter predicts response to temozolomide (TMZ) in adult-type diffuse gliomas. MGMT testing is thus standard practice. However, accurate results depend on adequate tumor cellularity in the analyzed sample. If the sample contains too many admixed nonneoplastic cells (which are consistently MGMT unmethylated), a false-negative result may be generated. Currently, ̃70% tumor cells are considered the minimum for reliable testing, but that is based on visual estimation by light microscopy; such estimation varies between observers and is often inaccurate. Since next-generation sequencing (NGS) is also frequently done on adult-type diffuse gliomas, and such tumors usually have heterozygous driver mutations known to be present in nearly 100% of tumor cells (IDH mutations in astrocytomas and oligodendrogliomas; TERT promoter mutations in ̃85% of IDH wild-type GBM), we sought to determine whether the variant allelic fraction (VAF) of these mutations could improve quality assurance in MGMT promoter methylation testing. Methods: We used an in-house cohort of 175 WHO gliomas (112 IDHwt, TERTmut GBM, 34 WHO grade 2-4 IDHmut astrocytomas, 29 WHO grade 2-3 IDHmut oligodendrogliomas), all with MGMT pyrosequencing and NGS data obtained from the same tissue blocks. Gliomas with average 10% methylation across all four CpG sites in the MGMT promoter were considered positive, as per standard cutoffs for that assay. Results: Overall, there was a positive correlation between driver VAF and amount of MGMT promoter methylation (slope = 0.25, R2= 0.33, P = 0.016). The largest dropoff in average methylation was when VAF was below 13% (7.4% average CpG methylation when VAF < 13% vs. 19.0% when VAF≥13%, P= 0.029). Based on our prior published study (PMID: 33830235), 36.5% of IDHwt GBMs, 86.7% of IDHmut astrocytomas, and 98.6% of IDHmut oligodendrogliomas should have MGMT promoter methylation. Among our GBMs, only 1/7 (14.0%) below a TERT mutant VAF of 13% reached the cutoff for MGMT promoter methylation, whereas 39/105 (37.0%) of GBMs VAF≥13% did. However, this did not reach statistical significance, likely because our cohort was underpowered for GBMs with TERTmut VAF < 13%. Among 34 IDHmut astrocytomas, only 1 had a VAF below 13%, and was reported as MGMT promoter unmethylated; all others had VAF between 21-56%, and showed consistent rates of MGMT methylation positivity across that entire range. All 29 oligodendrogliomas had VAFs of at least 26%; 2/29 were MGMT-negative, and both had VAFs at or above 36%. Conclusions: Additional cases are being prospectively collected to boost statistical power. Still, our existing data suggest that, when driver mutation VAF falls below ̃13% (i.e., tumor cellularity ̃26%), the risk of false-negative MGMT methylation results increases, and caution is warranted in such cases.
Efficacy of Gemcitabine in recurrent meningioma: A phase II study.
Authors: Shah Devanshee , Menon Nandini Sharrel , Puranik Ameya , Choudhary Amit , Patil Vijay Maruti , Pathak Shruti , Peelay Zoya
Published: June 2022

e14044

Background: Systemic therapy has a limited role in meningiomas. There is in-vivo and in-vitro data that gemcitabine can potentially be useful in meningiomas. We did a phase II study with the primary objective of studying the 6-month progression-free survival (PFS) of gemcitabine in meningiomas. Methods: This was a single-arm prospective phase II study. Adult patients with recurrent meningiomas who were not eligible for local therapies with Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1 with normal organ and marrow function were included in this study. Patients who had received any chemotherapy within the last three weeks or on any other investigational agents were excluded. All patients received gemcitabine 1000 mg/m2 administered intravenously over 30 minutes on day 1, day 8 and day 15 every 4 weeks until disease progression or development of intolerable side effects. The response was assessed as per Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1. The adverse events were recorded as per the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. The primary objective of this study was to assess the 6-months progression-free survival (PFS). The 6-months progression-free survival (PFS) of 50% or more was considered sufficient to warrant further studies. Results: Nine patients were recruited in this study. The median age of the patient was 56 years(24-73). The m: f ratio was 2:3. All patients had undergone previous surgeries and 8 patients had undergone previous radiotherapy. The median number of cycles of gemcitabine was 3. Any grade toxicity was observed in all patients. Grade 3 and above adverse events were not observed. The two commonest adverse events noted were anaemia in 7 (77.8%) patients and vomiting in 2 (22.2) patients. The best response was stable disease (SD) in 3 patients (33.4%) and progressive disease (PD) in 6 (66.6%) patients. At a median follow up of 18.8 months, the 6-months progression-free survival (PFS) was 33.3% (95%CI 7.8-62.3). The 1-year overall survival (OS) was 66.7 % (95%CI 28.2-87.8). Conclusions: Gemcitabine failed to meet the prespecified endpoint of 6-month PFS and does not warrant any further investigation in this setting. Clinical trial information: CTRI/2019/02/017499.
A novel humanized antibody targeting CD39 that enhances anti-tumor immunity and the efficacy of cancer immunotherapy.
Authors: Ban Haruka , Obonai Toshifumi , Mishima Yuji , Matsumoto Noriko , Mie Motoya , Nakamura Norihiro
Published: June 2022

e14508

Background: Immunotherapy using immune-checkpoint inhibitors (ICIs) has shown remarkable clinical efficacy in patients with cancer. However, it is crucial to utilize appropriate combination of immunotherapy for patient condition, as most patients do not benefit or sustain responses of immunotherapy. We focused on CD39 that is highly expressed in some tumors and tumor infiltrating immune cells (e.g. exhausted T cells and Tregs) as a target for cancer immunotherapy. CD39 is an ectoenzyme that converts extracellular ATP to immunosuppressive adenosine. Since the ATP-adenosine pathway is a key modulator of innate and adaptive immunity within the tumor microenvironment (TME), we presume that anti-CD39 antibodies suppress the production of adenosine and limit the immunosuppressive state in TMEs. Methods: Anti-human CD39 antibodies were screened by sorting B cells of mice immunized with human CD39 protein. The obtained clones that inhibit enzyme activity of CD39 were humanized on IgG1 and IgG4. PBMC were used in proliferation and functional assays. The anti-tumor effect was investigated with mouse xenograft model. Results: Analyzing gene expression profiles from TCGA data, high CD39 expression is associated with a poor prognosis in several cancers. There was a strong correlation between them in multiple myeloma treated with chemotherapies. The expression of CD39 was upregulated in some cancer cell lines treated with chemotherapeutic agents. A novel humanized anti-CD39 antibody, BP1202, which has a high affinity for the recombinant CD39 protein (KD: 481 pM) and inhibits the enzyme activity of CD39 expressed on a cancer cell line (IC50: 1 nM) and human Tregs. The antibody showed a high potency to enhance T cell activity including their proliferation, cytokine production, and cytotoxicity against a cancer cell line. We examined the anti-tumor effect of BP1202 in vivo using tumor-bearing mice and found that the combination treatment of BP1202 with chemotherapeutic agents significantly reduced tumor volume. Conclusions: We developed a new humanized antibody that enhances anti-tumor immunity by inhibiting CD39 expressed on exhausted T cells and intra-tumor T cells. These data suggest the scientific rationale for the clinical development of BP1202 and their use in combination with ICIs, with ATP-adenosine pathway inhibitors, and with chemotherapies. BP1202 is currently being developed as a new antibody agent for cancer immunotherapy.
Engineered, fully human nanobody-based CAR T cells have enhanced antitumor activity against hepatocellular carcinoma in preclinical models.
Authors: Kolluri Aarti , Li Dan , Li Nan , Ho Mitchell
Published: June 2022

e14512

Background: Glypican 3 (GPC3), a cell surface protein associated with early development, is an established biomarker of hepatocellular carcinoma (HCC). In a vast compendium of work, HN3, a human GPC3 nanobody (VH) isolated from a phage library, was shown to abrogate HCC tumors and block the distally located Wnt binding domain of GPC3. To date, it remains challenging how to precisely engineer CAR T cells for improved efficacy in solid tumors. In the context of hepatocellular carcinoma, we determined how hinges and transmembrane portions of varying structures and sizes affect CAR T cell function. Here, we show how rationally designed, engineered Chimeric Antigen Receptor (CAR) T cells containing HN3, demonstrate enhanced CAR T activity in HCC. Methods: We generated and compared multiple permutations of GPC3 targeted CAR T cells containing HN3, CD8, CD28, IgG4 and Fc domains. Incorporation of HN3, into multiple CAR formats yielded nine constructs, which were screened for antigen-specific and antigen-independent signaling using a luciferase reporter system in Hep3B, Huh7 and HepG2 cell lines. For in vivo assessment, immunodeficient NSG mice were intraperitonially injected with Hep3B or Huh7 cells and treated with a single dose (5 or 15 million) of engineered HN3 CAR T cells. Blood was collected at 2, 4 and 5 weeks to assess proliferation, T cell subtypes and exhaustion. Results: In vitro, the HN3-IgG4H-CD28TM CAR T cells induced high specificity and cytotoxic activity. HN3-IgG4H-CD28TM CAR T cells markedly improved HN3 cell killing activity by 30-40% in low (1.6:1) and high (25:1) effector to target ratios. Similarly, in vivo, in a high antigen environment, two determinative changes in the hinge region and transmembrane domains led to complete tumor eradication in immunodeficient mice bearing HCC tumors within 7-10 days. Moreover, HN3-IgG4H-CD28TM CAR T cells maintained specific tumor killing and averted exhaustion by producing a clear T cell response signature of enriched cytotoxic-memory (Temra) CD8+ along with a subset of naïve T cells. Conclusions: Engineered nanobody based CAR T cells containing the appropriate hinge and transmembrane domains can lead to determinative T cell signaling capable of inducing swift and durable eradication of HCC tumors. Altogether, we show that engineered HN3 CAR T cell therapy demonstrates strong potential for treatment of aggressive HCCs enabled by Wnt dysregulation.
Baseline endogenous corticosteroid as a biomarker for predicting response to immune checkpoint blockade in patients with metastatic cancer.
Authors: Wang Jun , Cui Yu , Guan Yaping , Yin Beibei , Xie Qi
Published: June 2022

e14588

Background: Previous studies indicate that exogenous use of corticosteroids affects immune checkpoint inhibitor (ICI) efficacy comparing patients receiving corticosteroids versus no corticosteroids. However, there is a paucity of clinical data evaluating the direct effect of endogenous corticosteroids on ICI efficacy for cancer patients with immune checkpoint blockade. Methods: We retrospectively reviewed patients with advanced cancer who were treated with PD-1 inhibitor alone or combination therapy in a single center between December 2019 and January 2022. Serum corticosteroid levels (8:00 AM) were routinely measured before ICI treatment. The effects of serum corticosteroids on objective response rate (ORR), progression‐free survival (PFS), and overall survival (OS) were analyzed. Propensity score matching (PSM) analysis was performed to match the characteristics of the high and low serum corticosteroid groups. Results: A total of 144 patients were included in this retrospective cohort study. The median age was 62.5 years and 71.5% was male. Overall, ORR was 20.1%, and median OS and PFS were 22.2 and 4.9 months, respectively. Patients with low corticosteroid levels (n = 64) had a significantly improved ORR compared to those with high corticosteroid levels (n = 80) (34.4% vs 8.8%; p < 0.001). The increased corticosteroid level was significantly associated with reduced OS ( p < 0.001) and PFS ( p = 0.025) for all patients and those with non-small cell lung cancer regarding OS ( p = 0.004). Moreover, statistically significant differences regarding OS ( p = 0.017) were also detected after PSM. In a multivariable model, the corticosteroid level was identified as an independent indicator for predicting OS ( p = 0.001) and PFS ( p = 0.006). Conclusions: Endogenous corticosteroid can predict efficacy and prognosis for advanced cancer patients with immune checkpoint blockade. Baseline evaluation of baseline corticosteroids should be considered before ICI initiation. Further prospective clinical trials designed to validate the predictive role of endogenous corticosteroid are warranted.