bluuebunny/crossref_metadata_2025 huggingface dataset:
Development of a new HRD algorithm which was highly associated with anthracycline-containing neoadjuvant chemotherapy.
Authors: Cao Wen-Ming , Pan Jiani , Wang Xiaojia , Lou Feng , Li Mingwei , Wang Meng , Wang Rong , Ye Weiwu
Published: June 2022

e13575

Background: Homologous recombination deficiency (HRD) can be resulted from dysfunction of BRCA and is associated with sensitivity to platinum, PARP inhibitor and other DNA-damaging drugs. The results from a neoadjuvant trial showed that pathological complete response (pCR) was not significantly higher with cisplatin than with doxorubicin-cyclophosphamide in BRCA1/2-mutated breast cancers (BC). It suggests that BC with HRD might benefit from anthracycline-containing regiment. There are many commercial HRD detection assays, including the FoundationFocus CDx BRCA LOH and myChoice CDx, but there is still no uniform standard in China. Methods: A total of 96 in-house BC samples and 6 HRD positive standard cells (Cat No. CBP90023) were analyzed by whole-genome sequencing (WGS). Besides, 122 BCs from the TCGA database were down-sampled to ̃1X WGS. We constructed a new algorithm for HRD score based on WGS at low coverage as input data to estimate large-scale copy number alteration (LCNA) events on the genome. The sensitivity and specificity were compared between our algorithm and the ShallowHRD. A clinical cohort of 50 BCs (15 cases carrying BRCA mutation) was used to assess the association between HRD status and anthracyclines-containing neoadjuvant treatment outcomes. Results: A 100kb-window was defined as the optimal size by using 41 in-house cases and the TCGA dataset. The threshold of HRD was determined as the number of 10 LCNAs by using 55 in-house BCs with BRCA mutation, with the goal of achieving 95% sensitivity. The sensitivity and specificity of our algorithm were both 100%, while those of the ShallowHRD were 40% and 100%, respectively, by testing standard samples with positive HRD. Meanwhile, similar results were also observed that the sensitivity of our algorithm was far superior to ShallowHRD (87% vs 13%) in the clinical cohort. The association between HRD status and BRCA mutations was compared between our algorithm and the ShallowHRD by 120 BC WGS samples (20 cases carrying BRCA mutation) from the TCGA database. The results showed that BRCA status was significantly associated with HRD status by our algorithm and ShallowHRD (P = 0.00838 and P = 0.00284, respectively). However, our algorithm had a higher positive concordance rate than the ShallowHRD algorithm (70% vs 60%). In the clinical cohort of neoadjuvant treatment, HRD group was more likely to respond to anthracycline-containing chemotherapy than non-HRD group, with outcomes of pCR (OR = 9.5, 95% CI: 1.11–81.5, p = 0.04) and residual cancer burden score of 0 or 1 (RCB0/1) (OR = 10.29, 95% CI: 2.02–52.36, p = 0.005). Among 35 patients lacking BRCA mutations, HRD group tended to have RCB0/1 responses compared to non-HRD group (OR = 6.0, 95% CI: 1.00–35.91, p = 0.05). Conclusions: Here, we developed a new stable algorithm for HRD score. It’s a promising assay for clinical application to predict sensitivity of DNA-damaging drugs.
Electron flash-RT program in clinical setting for human translation.
Authors: Zhang Rongxiao , Rahman Mahbubur , Bruza Petr , Thomas Charles R. , Jarvis Lesley A. , Hoopes P. Jack , Gladstone David J. , Pogue Brian W.
Published: June 2022

e13596

Background: A FLASH-RT program was established at Dartmouth-Hitchcock Medical Center in minimally-modified clinical setting by joint efforts of biomedical engineering, radiation oncology, radiation biology and medical physics teams. Various projects on dosimetry, chemical sensing, molecular profiling, software/hardware development, and translational studies have been conducted. The aim is to share logistical considerations and experience on running a FLASH-RT program to support institution-wide academic activities with an ultimate goal of treating human patients with FLASH-RT in 2022. Methods: A linac was converted in the clinical setting by qualified engineers to deliver an ultra-high dose rate (UHDR) electron beam. Routine safety and dosimetry checks were done by physicists for every reversible conversion. Long-term record-keeping and retrospective surveys were carried out to demonstrate the feasibility, safety, stability and accuracy of this dual-purpose (FLASH and conventional RT) approach. Comprehensive failure mode and effects analysis (FMEA) has been completed to systematically evaluate safety related considerations. A treatment planning system (TPS) has been developed in Varian Eclipse to facilitated comparative studies. The FLASH-capable linac has been utilized as shared resource to support institution-wide academic activities as well as normal clinical treatments. Results: With its safety (no accident or FLASH-related malfunction), flexibility (> 100 conversions in 2 years), reliability (̃6000 hours in flash mode and ̃5x105 Gy accumulative dose delivered at isocenter) and accuracy (̃5% conversion-to-conversion variations) demonstrated by commissioning, long-term user experience and comprehensive FMEA analysis, the FLASH-RT platform has been actively utilized for researches in six major categories 1) FLASH beam dosimetry; 2) real-time beam delivery monitoring and control; 3) oximetry and chemical sensing; 4) preclinical/translational small/large animal treatment with tumor control and normal tissue complication endpoints, 5) treatment plan and delivery optimization; 6) the design of phase I/II trials. Key findings in each category will be reported. Conclusions: A FLASH-RT program in clinical setting is established at Dartmouth with joint efforts, promoting collaborative projects to advance FLASH-RT to clinical treatment. The system has been reliably utilized for over two years for mechanistic as well as translational studies and support a phase I/II trial treating cutaneous lymphoma with eFLASH-RT.
Association of enrollment duration on trial outcome in phase 3 randomized controlled trials: A pancancer analysis spanning 67 years.
Authors: Li Xuanyi , Warner Jeremy Lyle
Published: June 2022

e13597

Background: Randomized controlled trials (RCTs) inform the standard of care in clinical oncology, yet a substantial proportion yield negative results. Difficulty with patient enrollment is a problem commonly encountered in the conduct of large multicenter RCTs, leading to slow enrollment. Slow enrollment can lead to increased financial costs, delayed reporting, and decreased relevance of trial results if standards of care shift. The effects of slow enrollment on trial success are understudied. We hypothesized that longer enrollment periods would be inversely correlated with trial success, after adjustment for year of study. Methods: Phase 3 RCTs studying malignant hematologic and solid tumor conditions available on the HemOnc.org website through December 31, 2021, were included in the analysis. HemOnc.org contains nearly all phase 3 RCTs of systemic anticancer therapy registered on ClinicalTrials.gov (with results) or with publications indexed in PubMed. Start year and end year of enrollment and comparative efficacy of control and experimental arms of RCTs were extracted. RCTs were deemed positive if the experimental arms were superior in superiority trials or non-inferior in non-inferiority trials, or if control arms were inferior in superiority trials. The remaining RCTs were deemed negative. Logistic regression was used to analyze the relationship between length of enrollment period and trial outcome, adjusted for year of study enrollment start. Results: The analysis included 3072 phase 3 RCTs spanning 99 different cancer types, enrolling from 1955-2019. Breast cancer was the most studied condition (n=554 trials) followed by non-small cell lung cancer (n=314 trials). 1513 (49.2%) of RCTs reported positive trial outcomes. The overall median enrollment period was 4 years (range 1-16 years). Negative trials took 1 year longer, on average, to complete enrollment (Table). The logistic regression model showed that shorter enrollment periods were associated with trial success. Later enrollment start year was also independently associated with trial success (Table). Conclusions: Our study showed that shorter enrollment period was significantly associated with positive trial outcomes. The success rate of trials has also increased over time; this could reflect both more efficacious drugs as well as more conservative enrollment criteria. Our main limitation is that we do not have data on early termination or closure for futility; these two issues might arise in both fast and slow accruing studies, which would bias results towards the null. The results of this analysis emphasize the importance of rapid phase 3 trial enrollment.[Table: see text]
Digital patient-reported outcomes and serological response to SARS-COV-2 vaccines in patients with cancer.
Authors: Sandoval Jose L. , Bugeia Sebastien , Mentu Santeri , Gutknecht Garance , Ekström Jussi , Battagin Anna , Friedlaender Alex , Metso-Lintula Mari , Kataja Vesa V , Dietrich Pierre-Yves , Mach Nicolas , Addeo Alfredo
Published: June 2022

e13606

Background: SARS-CoV-2 vaccines have changed the course of the current global pandemic. Cancer patients were identified as highrisk of adverse infection outcomes. We have previously characterised the serological response to SARS-CoV-2 vaccines in 220 cancer patients treated at our institution. In addition these patients were given the possibility to report their symptoms (patient-reported outcomes, PROs) weekly using a digital platform (ePROs). We sought to determine if, in cancer patients, the prospectively recorded post-vaccination ePROs could predict the serological response to SARS-CoV-2 vaccines. Methods: We used a pre-existing digital platform that allows monitoring of PROs using weekly questionnaires sent to patients and available on their desktop computers, tablets or smartphones. Serial serologies were performed at 28, 50 and 115 days after vaccination. Results: We observed that at day 50 after the first vaccination dose, coinciding with three weeks after the second dose, patients could be divided into two groups according to their serological response (low – below 1500 U/ml and high – above or equal 1500 U/ml). A peak in symptom burden could be observed after the second dose, as previously described. Omitting ePRO features decreased prediction performance of all models, whereas omitting baseline symptom scores had inconsistent effects. Among all models and feature constructions, the top performance metrics were given by the nearest centroid model7 with baseline symptoms omitted and 20 features chosen with the aforementioned procedure. The model achieved an accuracy of 0.704, an F1-score of 0.759 and an MCC of 0.398. Conclusions: we were able to identify the patients who achieved higher antibody levels against SARS-COV-2 based on the symptom burden reported through ePROs. This represents the first model showing that symptoms, assessed through ePRO can be predictive of response to vaccines. Our results could also be useful information for patients, as they could assuage their fears about adverse -effects, through the knowledge that toxicity could predict better protection against SARS-COV-2. The same toxicity-based prediction of efficacy has been identified with immunotherapy in cancer and is now a routine part of clinical discussions with patients.
Advancing digital health innovation in oncology to improve the lives of cancer patients.
Authors: Patel Smit , Van De Keere Isabel , Goldsack Jennifer , Rollison Dana Elise , Robinson Edmondo
Published: June 2022

e13609

Background: Oncology is renowned for leading innovation in research and in care. However, digital innovation in cancer care and research appears to be limited relative to other therapeutic areas. Methods: A multi-stakeholder roundtable, co-hosted by the Digital Medicine Society (DiMe) and Moffitt Cancer Center, convened experts from 35 leading organizations in life science R&D, regulators, payers, innovators, and with core representation from cancer patients and patient experts. Discussions addressed the current state of digital innovation in cancer care, root causes of digital health innovation challenges in oncology, and identifying action-oriented approaches to collaborative solutions needed to advance the safe, effective, ethical, and equitable use of digital innovations in oncology. Results: There was consensus among roundtable attendees that digital innovation lags behind in oncology relative to other therapeutic areas. Challenges identified as ‘low hanging fruit’ for digital innovation include reducing patient administrative burden, supporting care navigation, optimizing decision making in care and research, optimizing clinical pathways, and improving how we monitor both performance status and safety. Reducing financial toxicity and disparities in disease burden must be imperatives of digital innovation in oncology. Access to care and health outcomes for all patients must also be improved. Impediments to digital innovation in oncology include a proliferation of digital point solutions as opposed to system level innovations; transactional digital solutions that do not promote ongoing engagement and reengagement for the lifetime of the patient journey; lack of trust among patients and clinicians; the absence of data sharing incentives and infrastructure; and business and payer disincentives to digital transformation. Conclusions: Digital innovation frameworks can support more effective and equitable approaches to care that are accessible, scalable, and inclusive, thereby reducing the burden of cancer. To achieve this, clinical, technical, and operational best practices necessary to develop, design, and deploy high-quality digital interventions into cancer care must be established. There is no reason for the successful adoption of digital interventions in oncology to lag behind other therapeutic areas. Intentional action with urgency is required by the multi-stakeholder community through a collaborative effort to realize the full promise of digital innovation for patients and the systems that support those who care for them.
Physical activity levels in patients with melanoma during treatment with immune checkpoint inhibitors: Fitbit results from the CAMP-IT trial.
Authors: Kos Milan , Buffart Laurien M. , de Groot Jan Willem , Westgeest Hans M. , Boers-Sonderen Marye J. , Van Laarhoven Hanneke W.M. , van Oijen Martijn G.H.
Published: June 2022

e13610

Background: Wearable activity trackers offer possibilities to harness real-time patient data for predicting clinical outcomes in patients with cancer during treatment with immune checkpoint inhibitors (ICIs). As a first step towards this purpose, we aimed to assess the feasibility of using wearable activity trackers to objectively measure physical activity levels during the course of treatment. Methods: Patients with advanced melanoma, scheduled to receive treatment with ICIs were eligible to participate in the Comprehensive Ambulatory Monitoring Platform during ImmunoTherapy (CAMP-IT) trial. Participants were instructed to wear a Fitbit Versa 2.0 during waking hours for 12 weeks after start of immunotherapy. Feasibility of Fitbit use was assessed using predefined goals regarding compliance (> 75% participants with > 75% wear days) and acceptability (satisfaction score > 75%). Weekly averages of daily steps were calculated. A valid wear week was defined as a week with a minimum of 4 valid wear days (> 100 steps) including at least 1 weekend day. Linear mixed models were used to examine the changes in mean daily steps during 12 weeks after treatment initiation. We currently analyzed data of the first 30 of the 50 patients that will be included in the trial. Results: Of the 30 patients that were currently included 57% was female and mean age was 57,3 (SD 9,7). Forty percent had metastatic disease, and 30% received treatment with combination ICI therapy. Ninety-six percent of patients was compliant with Fitbit use. Moreover, Fitbit use was rated as satisfactory by 86% of patients. Mean steps per day in week 1 was 6728 (SD 3405). Mean daily steps per week did not change significantly over time during the observation period (b = -13,3 (95% CI: -85,7 - 59,1); p = 0.72). Conclusions: This is the first prospective study that reports on the use of consumer-grade wearable activity trackers to objectively measure physical activity in advanced melanoma patients during treatment with ICIs. Our results suggest that the use of wearable activity trackers in these patients is feasible and that treatment with ICI does not impact physical activity levels during the first 12 weeks. Future research should investigate whether our results hold true for specific subgroups (e.g., patients that receive combination ICI therapy). Clinical trial information: NL8827.
Immunogenicity of the vaccine against Sars-Cov-2 in cancer patients under active treatment.
Authors: Fernandez-Murga María Leonor , Serrano-Garcia Lucia , Garde-Noguera Javier , Portero Maria , García-Sánchez José , Regal Lorena , Dominguez-Martinez Victoria , Llombart-Cussac Antonio
Published: June 2022

e13632

Background: Coranavirus disease 2019 (COVID-19) has affected more than 220 millon people worldwide. The establishment of safe and effective vaccine coverage is crucial in these patients. We aim to investigate the safety, adverse effects and immune response (cellular and humoral) in cancer patients under active treatment and risk criteria. Methods: 56 samples from cancer patients under active treatment for cancer were collected before and after vaccination Demographic, clinical and biochemical data were collected and a post-vaccination symptomatology questionnaire was performed. For the determination of anti-SARS-Cov-2 antibodies (Immunoglobulin G and immunoglobulin M) we used the ELISA technique (LIASON SARS-CoV-2 S1/S2 IgG test and LIASON SARS-CoV-2 IgM test, DiaSorin, Saluggia, Italy). A study of the lymphocyte population was performed by flow cytometry. Results: We enrolled 52 patients with cancer who received mRNA vaccines (mRNA-1273 and BNT162b2), 2 patients with AZD1222vaccine and 2 with Ad26.COV2.S vaccine. All patients were SARS-COV-2 naive as determined by a negative anti-SARS-COVID-2 IgG test baseline. The median follow-up time was 50 days after receip of a second vaccine dosis. All subject received anti- cancer therapy. The most common anti-cancer treatment received by this cohort of patients was cytotoxic chemoterapy (44.6%), immunotherapy (25%), and monoclonal antibody therapy (14.3%). Overall, a high rate of seroconvertion(anti–IgG) (94,5%) was observed in our cohort, 1 patients with chemotherapy (1,8%) and 2 patients with immunotherapy (3,6%) were negatives. No significant differences in antibody titer were observed according to therapy. Thirty percent presented an antibody titer lower than 1000 U/ml, 27 (48%) patients developed an anti-SARS-CoV2 titer between 1000-4000 U/ml, and only 9 (16%) subjects presented a titer higher than 4000 U/ml. Studies of the lymphocyte profile of vaccinated patients showed no significant changes in the subtypes, except for peripheral memory CD3+ CD8+ lymphocytes which were significantly increased (p = 0.0001) after the second dose of anti-SARS-CoV-2 vaccine. Interestingly, cell apoptosis was significantly reduced in almost all T lymphocyte subtypes studied in vaccinated patients. Finally, analysis of blood cells showed a statistically significant increase (p = 0.0402) of eosinophils in vaccinated patients compared to baseline data. Conclusions: A personalized approach to vaccination can be proposed to cancer patients, especially depending on the type of tumor and the specific oncological treatments received. We are currently recruiting patients (n = 150) who have received the third dose of vaccine and plan to follow up at 6 months for humoral and cellular immune response. Final results will be reported at the ASCO meeting.
Factors associated with U.S. hospital payer-specific negotiated mammography charges.
Authors: Hsieh Kristin , Huang Hsin-Hui , Tarras Elizabeth Stieglitz , Weber Ellerie , Marshall Deborah Catherine
Published: June 2022

e13633

Background: The Hospital Price Transparency Rule, effective 1/1/2021, requires hospitals to publish payer-specific negotiated charges and cash prices. Given differences in insurance coverage for screening versus diagnostic mammography, we evaluate factors associated with these payer-negotiated charges. Methods: We conducted a cross-sectional study of U.S. acute care and critical access hospitals in CMS’ Care Compare linked to Turquoise Health (payer-negotiated charges), Healthcare Cost Report Information System (hospital characteristics) and Social Vulnerability Indices by county. Negotiated charges for mammography (CPT: screening 77067; diagnostic unilateral 77065, bilateral 77066) were estimated by payer type (self-pay, managed Medicare/Medicaid, or commercial). Adjusted models estimated commercial charges accounting for hospital factors. Results: Most hospitals (N=4212) were non-profits (61%) and acute care hospitals (69%). Median operating margin was .03 (IQR:-.03, .09), asset-to-liability ratio was 1.79 (1.06, 2.96), and social vulnerability index was .53 (.29, .74). 48-50% reported mammography charges. Charges were greater for commercial insurance compared to Medicare/Medicaid (+$55-$82 screening, +$122-$132 bilateral diagnostic; P<.001, all tests). Charges for commercial insurance were similar to self-pay for bilateral screening (p=.41) and diagnostic (p=.08) mammography. See Table for adjusted analysis of commercial charges. Conclusions: Our analysis showed U.S. negotiated mammography charges are similar for self-pay and commercial payers. Commercial charges are higher at private hospitals and those with higher operating margins for diagnostic exams, and lower in socially vulnerable areas. Price transparency may promote competition to lower healthcare prices and highlight any financial toxicity associated with self-pay charges. [Table: see text]
Analysis of a post covid multi-disciplinary meeting operating in a digitally supportive virtual platform.
Authors: van Loggerenberg Dominic , Benn Carol
Published: June 2022

e13645

Background: The BCCE is an NAPBC internationally accredited unit operating around a surgical oncology breast specialist surgeon, three reconstructive surgeons; four radiological units four pathology labs; 8 medical oncologists and 3 radiation oncologists. Whilst the centre was affected by the SARS Covid-19 pandemic, a rapid restructuring of the MDM procedure allowed for a return to -pre-pandemic service delivery and optimum time-to-treatment of 21days. Methods: Over the 2021 period the BCCE saw 778 newly diagnosed cancer patients, these are all reviewed at a 25 member MDM with 308 patients having full radiological review during the meetings and 609 full pathological reviews prior to treatment discussion amongst the members. These MDM discussions occurred within 6 days of clinical examination due to the integration of multiple specialists and facilities resulting in rapid appointments. Further pathological analysis of 203 patients occurred beyond initial presentation as well as over 350 OncotypeDx reviews. Five hundred and seventy-one individual patient treatment feedback discussions occurred directly postoperatively and 459 treatment plans were reviewed prior to secondary treatment pathways. Results: Digital MDM’s resulted in a full return to the centre’s optimum level of care, a 7 day MDM review with a 21-day treatment pathway plan proposal, whilst still under the effect of pandemic lockdown regulations. A 6-month comparison (during lockdown regulations) showed a 15% increase in patients seen whilst supported with virtual consultation platforms and digitally supported MDM decisions. Conclusions: Whilst the SARS Covid-19 pandemic affected service delivery. Medical IT transference to full digital MDM allowed for improved review and treatment planning. This improved service delivery to patients with physician and navigator knowledge transfer, resulting in growth of the unit.
Whole brain radiotherapy and association with rapid brain aging as determined by anatomic surface morphology.
Authors: Rammohan Nikhil , Ho Alexander , Kruser Tim J. , Besson Pierre , Bandt S Kathleen
Published: June 2022

e14007

Background: Brain metastases are the most common intracranial tumors in adults and are associated with significant morbidity and mortality. Whole brain radiotherapy (WBRT) is used frequently in patients for palliation, but can result in neurocognitive deficits. While dose-dependent injury to individual areas such as the hippocampus have been demonstrated, global structural changes after WBRT remain to be studied. Our group previously published a magnetic resonance imaging (MRI) deep learning model based on anatomic brain surface morphology to accurately predict brain age in healthy subjects. We now report the effect of WBRT on aging pace of the irradiated brain. Methods: We studied patients with brain metastases and examined MRI brain anatomic surface data before and after WBRT. We implemented a graph convolutional neural network model to estimate patient’s brain age. We further developed a mixed-effects linear model to compare age of whole brain and substructures before and after WBRT, written as follows: ΔAge = c + β(ΔScan) + 1|patient_ID; where for each patient, ΔAge = [(model_predicted_age_at_follow up – actual_age_at_follow up) – (model_predicted_age_pre_treatment – actual_age_pre_treatment)], ΔScan = time interval between pre-and post-treatment MRI scans, β = aging coefficient (β =0 corresponds to normal aging), and c = intercept (model_predicted_age_pre_treatment – actual_age_pre_treatment). Results: 56 patients were analyzed. The median age was 62 (range 32 – 85). Two-thirds of patients were female. Primary organ site was breast or lung in 87% of cases and 77% of patients had five or more metastases. Median radiation dose was 30Gy (range 25 – 37.5Gy). Results of aging analysis are presented in Table. Small c values demonstrate that model accurately predicted age pre-treatment. The whole brain and substructures underwent rapid aging compared to normal aging pace (β>>0). Based on median follow up of 6.3 months, the whole brain aged approximately 4.94 years, the cortex aged approximately 4.53 years, the subcortical structures aged approximately 5.94 years, and the hippocampus aged approximately 5.17 years. Conclusions: Our findings suggest that WBRT causes the brain and its substructures to age at a pace of 9-11x of the normal aging pace, mirroring deficits in long-term neurocognition seen post-treatment. Given post-treatment aging pace and increasing survival for many patients with brain metastases, WBRT needs to be used judiciously. [Table: see text]
Treatment patterns and outcomes of patients with high-grade glioma during the COVID-19 pandemic.
Authors: Chahal Manik , Aljawi Ghufran Abdulghaffar , Harrison Rebecca A. , Nichol Alan , Thiessen Brian Arthur
Published: June 2022

e14009

Background: During the first year of the COVID-19 pandemic there was global disruption in the provision of healthcare, causing significant pressure on hospital resources. High-grade gliomas (HGG) are rapidly progressive tumors, so patients with delays in diagnosis or treatment due to COVID-19-related disruptions might have poor outcomes. Therefore, we retrospectively evaluated the impact of the COVID-19 pandemic on treatment patterns and outcomes of patients with HGG in British Columbia (BC). Methods: A case cohort with a pathologic diagnosis of HGG (grade 4 astrocytoma and glioblastoma) treated at BC Cancer centers with radiotherapy between March 1, 2020 – March 1, 2021 (“COVID era”), and a control cohort treated between March 1, 2018 – March 1, 2019 (“pre-COVID era”) were identified. Patient demographics, tumor characteristics, treatment details, and dates of radiographic progression and death were included in the chart review. Analyses were performed with one-way ANOVA and Chi-squared tests for comparisons between eras. The Kaplan-Meier method was used to assess progression-free survival (PFS) and overall survival (OS) and differences in outcome between eras were investigated using the log-rank test. Results: 164 patients were identified: 85 in the pre-COVID era and 79 in the COVID era. There was no statistically significant baseline difference in age, sex, comorbidities, ECOG, tumor diameter, IDH mutation status, or MGMT methylation status between eras. There was also no statistically significant difference between time from symptom onset to first imaging, time from first imaging to surgery, time from surgery to oncologic consultation between eras, and time from surgery to radiotherapy. Significantly more patients were managed with biopsy relative to partial or gross total resection during the COVID era 22% (17/79) than the pre-COVID era 13% (11/85) (p = 0.04). However, radiation treatment (RT) did not differ between eras, with similar rates of conventionally fractionated RT in the pre-COVID era (87%, 74/85) and the COVID era (82%, 65/79) (p = 0.23). Use of concurrent and/or adjuvant temozolomide also was not significantly different between eras (p = 0.27 and p = 0.19, respectively). Median PFS was 7.0 months in both eras (CI95 = 5.5 – 8.5 months for pre-COVID era, CI95 = 5.8 – 8.2 months for COVID era, p = 0.3), and median OS was 13 months in the pre-COVID era (CI95 = 10.3 – 15.7 months) and 16 months in the COVID era (CI95 = 11.5 – 20.5 months), though this difference was not significant (p = 0.09). Conclusions: To our knowledge, this is the first study to assess outcomes of patients treated for HGG during the COVID-19 pandemic. We found that, despite less use of surgery in the COVID era, the outcomes of patients with HGG were not affected.
Impact of next-generation sequencing (NGS) on the diagnosis of gliomas according to the WHO-2016 and WHO-2021 classification in routine clinical practice.
Authors: Diaz-Santos Javier , Cantero-Gonzalez Alexandra , Muñoz-Ayllon Marta , Garrido-Almazan Lucia , Garcia-Gonzalez Cristina , Rueda Dominguez Antonio
Published: June 2022

e14022

Background: The WHO-2016 classification of central nervous system tumors introduced molecular data to perform the diagnosis, especially in gliomas. The cIMPACT-NOW updates and the WHO-2021 classification have consolidated this need, and today a comprehensive structured diagnosis is indicated. Therefore, we study the impact of the use of NGS in changing the diagnosis of gliomas in routine clinical practice. Methods: We have carried out a systematic search of glioma patients operated between January 2008 and September 2021 and diagnosed according to WHO-2016 and cIMPACT-NOW updated criteria at our academic medical center in Spain. All included patients were reclassified to WHO-2021 according to pathological data. Subsequently, we analyzed whether the application of NGS led to a change in the WHO-2016 or WHO-2021 diagnosis. We also analyzed the median of tumor mutation burden (TMB), variants of unknown significance (VUSs), potential enrollment eligible (PENs) and cancer-related alterations (CRAs). Results: Although our center serves a population of 1.8 million people, the scarcity of biopsied material and the difficulty of accessing NGS early enough limited the recruitable patients to 22. Of them 17 patients (77.27%) remained after NGS results with the same WHO-2016 and WHO-2021 diagnosis and in 5 (22.73%) it involved a change in diagnosis (Table). No PENs were detected for any patient. A median of 4 CRAs and 6 VUSs were detected per patient. The median TMB was 1.89 mutations per megabase. Conclusions: The scarce quality biopsied material and the limited access to NGS restrict its use in gliomas. Despite this, its impact in diagnosis cannot be ignored, in our study the diagnosis changed in 1 out of 3.18 patients regardless of the classification used. With these data we recommend increasing the effort to facilitate NGS to glioma patients early enough. Further studies remain essential to determine the impact of NGS results in treatment.[Table: see text]
Glioblastoma response to blood-brain-barrier permeable, MGMT-agnostic therapeutic LP-184 and sensitization by nucleotide-excision repair deficiency.
Authors: McDermott Joseph , Lal Bachchu , Lopez-Bertoni Hernando , Kulkarni Aditya , Zhou Jianli , Schimke Caleb , Kathad Umesh , Bhatia Kishor , Sharma Panna , Laterra John
Published: June 2022

e14023

Background: Glioblastoma (GBM), a WHO Grade IV cancer, is the most common and most aggressive primary malignant brain tumor. Prognosis following best standard-of-care surgical resection, radiation and temozolomide (TMZ) chemotherapy is poor, with median overall survival 15-18 months. TMZ, which acts primarily by methylating DNA at O6-guanine, has marginal efficacy in ̃70% of patients due to tumor expression of O-6-methylguanine-DNA methyltransferase (MGMT) and there is no effective therapy at tumor recurrence. New treatment options are therefore desperately needed for GBM patients. LP-184 is an acylfulvene-derived prodrug that is activated by the oxidoreductase PTGR1 and primarily alkylates adenine at the N3-position. Bioinformatic analysis showed that PTGR1 is elevated in clinical GBM tumor samples compared to normal brain. LP-184 response is influenced by tumor DNA repair status, and acylfulvene-induced damage is mainly repaired by the transcription-coupled nucleotide-excision repair (TC-NER) pathway. Spironolactone, an FDA approved, blood-brain-barrier permeable diuretic, induces degradation of ERCC3 protein, a key TC-NER component. Response of NER-deficient GBM was tested through co-administration of LP-184 and spironolactone. Methods: Cell viability assays with exposure to LP-184, with and without spironolactone, were used to determine IC50 values in vitro. Subcutaneous or intracranial tumor xenograft models were used to determine tumor volume or survival differences between control and LP-184 treated mice. Results: Nanomolar concentrations of LP-184 inhibited in vitro viability of multiple GBM cell models including 4 NCI-60 GBM cell lines (mean IC50= 286 nM), the TMZ-resistant LN-18 cell line (IC50= 46 nM), M1123 GBM neurosphere line (IC50= 151 nM), and a low passage GBM neurosphere isolate (IC50= 306 nM). Co-treatment with spironolactone resulted in a 3-6 fold decrease in LP-184 IC50 values in M1123, Mayo39, and U87 cultures. Pharmacokinetic analyses in SCID mice following a single LP-184 infusion (4 mg/kg, i.v.) showed favorable CNS bioavailability with brain/plasma ratio 0.11 (Cmax= 839 nM) and brain tumor/plasma ratio 0.2 (Cmax= 2.53 µM). LP-184 (4mg/kg i.v., q.o.d X 4) induced complete regression of all pre-established s.c. U87 xenografts (N = 5) and 3 of 6 M1123 s.c. xenografts (mean tumor volumes: 1456 ± 349 mm 3 controls vs 84 ± 39 LP-184, p < 0.001) and statistically significantly prolonged survival of mice bearing pre-established orthotopic U87 and M1123 xenografts (p < 0.0001). Conclusions: These preclinical results establish LP-184 as a promising new agent for future clinical testing in patients with GBM and suggest that LP-184 may be particularly efficacious in patients with intrinsic or spironolactone-induced NER deficient tumors.
Is IDO1 an adequate target for treatment in glioblastoma?
Authors: Mariño Siancas Christian Andre , Hernandez Gonzalez Ainhoa , Domenech Marta , Esteve-Codina Anna , Arpi Oriol , Alameda Francesc , Pineda Estela , Chekhun Sviatoslav , Lopez Paradis Assumpcio , Del Barco Sonia , de la Iglesia Nuria , Gallego Rubio Oscar , Mesia Carlos , Mallo Mar , Esteve Anna , Carrato Cristina , Balana Carmen , Martínez-García María
Published: June 2022

e14039

Background: Glioblastoma (GB) is the most prevalent primary brain tumor in adults. The first-line treatment is based on standard brain surgery and adjuvant radio-chemotherapy. Indoleamine 2,3-dioxygenase 1 (IDO1) is a catabolic enzyme that plays a role in the metabolism of tryptophan (Trp), thereby promoting a state of immunosuppression. New treatments inhibiting this pathway are being tested in GB. This study aims to assess the expression of IDO in GB patients to determine whether this enzyme may be an actionable target for the treatment of GB. Methods: This is a retrospective transversal study whose database comes from the GLIOCAT project. Expression of IDO protein and mRNA was evaluated in tumor specimens of newly diagnosed GB patients by immunohistochemistry (IHC) (percentage of positive tumor cells) with an antibody anti-IDO1 (Sigma-Aldrich Cat#HPA027772) and by RNA sequencing (RNA-seq). RNA-seq (IIlumina HiSeq2000) in paired-end mode with a read length of 2x76bp using TruSeq SBS Kit v4). Reads were mapped to the human reference genome version hg38 with STAR. Genes were quantified with RSEM using gencode annotation version 24. Normalization of gene expression was performed with the trimmed-mean of M values (TMM) method. IDO gene expression values of -6 logCPM were considered as not expressed. Results: From the 255 samples assessed by IHC, 199 patients (78%) did not express IDO1 protein (mean 0.8±2.73, range 0-21%). From the 139 samples assessed by RNA-seq, TMM values, were negative for 49.6%, while low expression was detected for the other samples (mean -3.36 +/- 3.15 logCPM, range -6.12-4.32). Conclusions: Although IDO1 is barely expressed in normal brain tissue, certain studies show that its expression is upregulated in GB, either by tumor cells or indirectly induced in host antigen presenting cells, leading to immune evasion. Therefore, the metabolism of Trp is an attractive pathway to be targeted for the treatment of GB; however, our results show that IDO may not be the main target to be inhibited due to its undetectable or very low levels of expression.
Modelling treatment benefit for bexmarilimab (an anti-Clever-1 antibody and a novel macrophage reprogrammer) using phase I/II first-in-man trial data.
Authors: Bono Petri , Ekström Jussi , Fjällskog Marie-Louise , Jalkanen Juho , Huttunen Teppo , Koivunen Jussi
Published: June 2022

e14500

Background: Bexmarilimab, an investigational immunotherapeutic antibody targeting Clever-1, is currently investigated in phase I/II MATINS study (NCT03733990) for advanced solid tumors. Machine learning (ML) based models combining extensive data could be generated to predict treatment responses to this first-in-class macrophage checkpoint inhibitor. Methods: 52 baseline features from 138 patients included in the part 1/2 of phase I/II MATINS trial were included in ML modelling. 19 patients were classified as benefitting from the therapy by RECIST 1.1 defined clinical benefit rate (DCR) at cycle 4. Initial feature selection was done using both domain knowledge and removal of features with several missing values resulting in 44 features from 102 patients. The remaining data was standardized and feature selection using variance analysis (ANOVA) based on F-values between response and features was performed. With this approach, and by removing features with high multicollinearity, the number of features could be further reduced, and used sample size increased by removing features with missing values, until only the most important features were included in the data. Feature selection resulted in nine baseline features from 127 patients, of which 18 with DCR, to be used for ML model selection and training Several ML models were trained, and prediction performance evaluated using leave-one-out cross-validation (LOOCV). In LOOCV a ML model is trained as many times as there are samples in the data (127 times in this case), each time leaving one sample out from the training set as a test set. Finally, the out-of-sample test results are aggregated to form an overall view of the model performance with unseen data. Regularized Extreme gradient boosting (XGBoost) was found out to be the best performing prediction model. Results: Nine baseline features were associated with bexmarilimab treatment benefit, and the best ML prediction performance was obtained with five features. CBR was associated with low TNFalpha and neutrophils, and high Eotaxin, CK, and T-regs. ML model trained with these five features performed well in LOOCV as 15/18 (83%) DCR and 101/109 (93%) non-DCR were classified correctly, and all considered classification performance metrics were excellent. In feature importance analysis, high baseline T-regs and Eotaxin, and low TNFalpha were characterized as the most important predictors for treatment benefit with relative importances of 0.34, 0.25, and 0.24 (out of 1). Conclusions: This study highlights possibility of using ML models in predicting treatment benefit for novel cancer drugs such as bexmarilimab and boost the clinical development. The findings are in line with expected novel immune activating mode-of-action of bexmarilimab. Clinical trial information: NCT03733990.
A next generation inducible armored CAR to overcome the immunosuppressive tumor microenvironment and enhances cytotoxicity of CAR-T and TILs.
Authors: Granger David , Harrasser Micaela , Evans Rachel , Muczynski Vincent , Chester Kerry , Nathwani Amit C.
Published: June 2022

e14517

Background: The full potential of CAR-T cells in clinic is limited by the immunosuppressive tumour microenvironment (TME), which induces expression of exhaustion markers and limits the activity of tumour infiltrating lymphocytes (TILs) including CAR-T cells. We developed a next generation inducible Armored CAR platform (aCAR) that releases an anti-PD-1 checkpoint inhibitor upon CAR-T cell activation, limiting payload release exclusively to the TME, thereby reducing the risk of systemic exposure. This differentiated strategy facilitates activation of CAR-T cells and TILs within the TME and has the potential for lower toxicity. Methods: A ROR1-targeting second-generation CAR containing a 41BB-CD3ζ intracellular domain was cloned into a lentivirus transfer vector alongside a prototypic anti-PD1 antibody. The CAR was under the control of a constitutively active promoter, and the PD1 targeting payload was controlled by an inducible promoter that was activated upon engagement of CAR with ROR1 on tumour cells. CAR-T cells were subject to in vitro co-culture assays with target ROR1+ tumour cells and their cytotoxic responses evaluated by flow cytometry. Levels and binding functionality of released payload were analyzed by ELISA and flow cytometry. In vivo xenograft models were performed in NSG mice with tumor growth assessed by bioluminescent imaging (BLI) and caliper measurement of the tumour volume. Results: Non-Armored CAR cells displayed potent and specific cytotoxic responses directed towards ROR1+ TNBC and NSCLC cells lines at different effector to target (E:T) ratios. The results were equivalent or superior to CARs generated with comparator anti-ROR1 antibodies, which may be due to the ROR1 CAR targeting a membrane proximal epitope within the ROR1 frizzled domain. The aCAR cells released measurable levels of anti-PD1 payload within 5 hours of binding to ROR1 on tumors and enhanced the cytotoxic effects at challenging 1:10 E:T ratios. Established PDL1+ TNBC xenograft models using the aCAR cells and comparing with non-Armored CAR cells displayed a qualitative abrogation in tumor growth by BLI, which was confirmed and shown to be significant by caliper measurement of the tumor volume. Continuing the experiment out to 3 months showed a significant survival advantage for the animals receiving aCAR. All other cohorts were terminated by day 70, however 20% of the aCAR cohort survived at day 95. Conclusions: Our next generation inducible aCAR platform enables the release of an immune stimulating payload only in the presence of target tumor cells, enhancing the therapeutic activity of the CAR-T cells and limiting payload exposure to the site of action. This technology provided a significant survival advantage in challenging in vivo xenograft models. This coupled with its potential safety attributes merits further clinical evaluation of this approach.
Tumour ERO1A instigates T cell dysfunction by transmission of endoplasmic reticulum stress.
Authors: Liu Lihui , Li Sini , Qu Yan , Wang Jian , Fei Kailun , Wang Chao , Zhang Xue , Ma Zixiao , Bai Hua , Wang Jie
Published: June 2022

e14533

Background: Infiltrated-excluded tumor microenvironment (TME) predicts poor prognoses in multiple malignancies. T cell dysfunction is a hallmark of immune exclusion in patients and correlates with response to immune checkpoint inhibitors (ICIs). However, strategies to classify TME based on T cell dysfunction for predicting response to ICIs are lacking. Methods: MC-38, LLC, and 4T1 tumours knocked out and restored for endoplasmic reticulum oxidoreductin-1α ( Ero1a) were engrafted subcutaneously into immunocompetent hosts. Anti-PD-1 antibody was injected intraperitoneally every three days. We used immunofluorescence staining and flow cytometry to characterize the intratumoral infiltrates. Coculturing of tumour cells with T cells, single-cell RNA-seq, and western blotting were utilized to unveil the underlying mechanisms. Multi-color immunohistochemistry was used to identify the expression of ERO1A and define TME in patient samples. Results: Here, we show that ERO1A, an oxidoreductase involved in endoplasmic reticulum stress (ER stress)-induced apoptosis, instigates an immune-exclusive TME by transmitting ER stress to T cells. In mouse models, knocking out of Ero1a in Ero1a-expressed tumours promotes the infiltration of CD8+ T cells and enhances responses to anti-PD-1 treatment. By contrast, ectopic expression of Ero1a enhances tolerance to ER stress in tumour cells by activating IRE1α-signaling. Additionally, ero1a promotes the transmission of ER stress to T cells and triggers CHOP-dependent apoptosis, resulting in an immune-exclusive TME. Elimination of ER stress status suppresses tumour growth in immunocompetent mice and promotes response to ICIs. In 37 patients with non-small cell lung cancer treated with neoadjuvant immunotherapy, the expression of ERO1A is negatively correlated with the abundance of tumour infiltrated lymphocytes ( P< 0.001) and responses to ICIs ( P< 0.001). Patients with low expression of ERO1A also exhibit a superior recurrence-free survival compared to those with high expression of ERO1A ( P= 0.039). Conclusions: Together, our findings identify a mechanism for immune-exclusive TME and suggest a potential immunotherapeutic target for terminating T cell dysfunction and apoptosis through eliminating transmissible ER stress.[Table: see text]