bluuebunny/crossref_metadata_2025_split huggingface dataset:
Feasibility and patient perception of a web-based exercise program during COVID pandemic in breast and ovarian cancer patients.
Authors: Iglesias Campos Marcos , Pajares Bella , Roldán Jiménez Cristina , Jimenez Begona , Alba Emilio , Cuesta Vargas Antonio 
Published: June 2021

e13623 Background: Current literature shows us that therapeutic exercise has multiple benefits in oncology patients, such as improvement in quality of life or a reduction in cancer-related fatigue. Furthermore, given the risk of obesity, both exercise and diet play a key role in recovery from cancer. As a consequence of the COVID-19 pandemic, oncology patients present more difficulties to attend programs as they are considered a risk population, so new online exercise programs should be developed to ensure that patients take advantage of them in the post-COVID era. The main objective was to study patient´s perspectives and the feasibility of a web-based tailored and supervised therapeutic exercise program during COVID pandemic. Methods: A prospective study was performance on patients recruited from the Medical Oncology Unit of the Hospital Virgen de la Victoria, Malaga. Participants were between 18 and 65 years old and diagnosed of early resected breast cancer after finishing chemotherapy (CT) or metastatic ovarian (MOC) or breast cancer (MBC) with or without active treatment. Patients had had a good performance status (PS) with no prior cardiovascular history, and they were excluded if they were not used to online technologies. The duration of the program was 3 months, twice a week, delivered by a physiotherapist and a nutritionist. At the end of the program, women were asked 9 questions about their perspectives on the program. All of them signed informed consent. Results: 17 breast cancer survivor (BCS), 10 MBC and 3 MOC patients were initially recruited. From 30 patients recruited, 5 BCS did not started the program because of clinical contraindication and 5 patients left due to personal issues. 15 out of the remaining 20 completed the survey. All of patients reported that the program had contributed to improve their mood during the pandemic due to issues such functional ability, feeling better or less asthenia, and serving as improvement and encouragement in their lives. 86,7% reported having met their objectives and 100% reported going to continue doing some type of exercise or physical activity on a regular basis after the program is finished. Regarding advantages of online format compared to the face-to-face one, they reported avoiding displacement and lower risk of contagion. Lately, if they could participate again, 50% reported they would prefer online, while the remining 50% would prefer traditional modality. Conclusions: At the light of these results, the tele-exercise program contributed to improve the mood and fatigue of patients during the pandemic. The web-based program seems to be feasible and allow patients to meet their objectives after program completion and encourage them to keep doing some type of physical activity.
Ensuring the most effective strategy for cancer treatment of patients with brain tumors.
Authors: Sheiko Elena A. , Frantsiyants Elena M. , Rostorguev Eduard E. , Kaplieva Irina V. , Bandovkina Valeria A. , Neskubina Irina V. , Surikova Ekaterina I. , Kuznetsova Natalya S. , Kit Oleg I. , Kavitskiy Sergey E. , Pandova Olga V. , Khatyushin Vladislav E. 
Published: June 2021

e14000 Background: The purpose of the study was to analyze changes in the total activity of trypsin-like proteinases (TLPs) in the blood plasma in patients with brain tumors for the preoperative differential diagnosis of benign, primary and secondary malignant brain tumors. Methods: TLPs were measured in 164 patients with brain tumors. The blood had been collected from the patients in a standard plastic tube with 3.8% sodium citrate (9:1) 3 days prior to the surgery. Citrate blood was centrifuged; citrated plasma was obtained and used to determine the total TLP activity by the unified kinetic method. Results were compared with the data in donors. Results: TLP activity in 37 (22.6%) of 164 patients was within the normal range (258–402 IU/mL, on the average 333.0±27.1 IU/mL). Benign brain tumors (meningioma) were diagnosed in all 37 patients after the tumor removal and histological analysis. In 74 (45.1%) of 164 patients, TLP activity was within 1158–1626 IU/mL (on the average 1331.0±102.4 IU/mL, p < 0.05), i.e. 3.8-5.3 times higher than the norm in donors (malignancy coefficient on average 4.4±0.3 times). Primary malignant brain tumors (glioblastoma) were diagnosed in all 74 patients after the tumor removal and histological analysis. In 53 (32.3%) of 164 patients, TLP activity was within 1794–2868 IU/mL (on the average 2227.0±174.1 IU/mL, p < 0.05), i.e. 5.9-9.4 times higher than the norm in donors (malignancy coefficient on average 7.3±0.5 times). Secondary malignant brain tumors (metastases) were diagnosed in all 53 patients after the tumor removal and histological analysis. Conclusions: The specificity of the proposed method for the differential diagnosis of brain tumors was very high: for benign tumors - 97.2%, for primary malignant tumors - 98.6% and for secondary malignant tumors - 98.1%. So, TLP activity indices in the blood plasma are an informative auxiliary laboratory test that will help in clarifying and/or confirming the differential diagnosis of brain tumors.
Nivolumab and stereotactic radiosurgery for patients with breast cancer brain metastases: A non-randomized, open-label phase Ib study.
Authors: Ahmed Kamran A. , Kim Youngchul , Arrington John , Kim Sungjune , DeJesus Michelle , Soyano Aixa , Armaghani Avan J. , Costa Ricardo L , Khong Hung T. , Rosa Marilin , Caudell Jimmy J. , Diaz Roberto , Robinson Timothy J. , Etame Arnold B. , Tran Nam D. , Sahebjam Solmaz , Soliman Hatem Hussein , Forsyth Peter A. J. , Yu Hsiang-Hsuan Michael , Han Hyo S. 
Published: June 2021

e14010 Background: There may be a potential synergy intracranially between stereotactic radiation and immune checkpoint inhibition in brain metastases management. We hypothesize treatment with nivolumab and stereotactic radiosurgery (SRS) will be feasible and well tolerated and may improve intracranial tumor control rates compared to SRS alone in the management of breast cancer brain metastases. Methods: The study was designed as a prospective, single-arm, nonrandomized, open-label, phase Ib trial of nivolumab and SRS among patients with metastatic breast cancer brain metastases. Key eligibility criteria included patients with breast cancer brain metastases of all subtypes, age ≥ 18, ECOG ≤ 2 with ≤ 10 brain metastases. The primary objective was to evaluate the safety and feasibility of study therapy. Secondary objectives included evaluation of local brain metastasis control, distant brain metastasis control, progression free survival (PFS), and overall survival following study therapy. Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) and immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) criteria were used to assess intracranial and extracranial disease, respectively. Treatment was initiated with a dose of nivolumab (480 mg IV) that was repeated every 4 weeks. The initial dose of nivolumab was followed 1 week later by SRS. This study is closed to accrual and is registered with ClinicalTrials.gov, NCT03807765. Results: Between February 2019 and July 2020, a total of 12 patients were treated to 17 lesions. Median follow-up from start of protocol therapy is currently 9.6 months (range: 2.8-18.7 months). No dose limiting toxicities (DLTs) were noted in our patient population. The most common neurologic adverse events included grade 1-2 headaches and dizziness occurring in 5 (42%) of patients. Median intracranial control was 6.2 months (95% CI 3.0 -14) with 6 and 12 month control rates of 55% and 22%, respectively. A total of 4 patients had systemic progression during the study. Median time to systemic PFS has not been reached with 6 and 12 month rates of 63% and 51%, respectively. Conclusions: Nivolumab and SRS is a safe and feasible treatment option in breast cancer brain metastases. Preliminary studies reveal activity in certain breast cancer patients to study therapy. Clinical trial information: NCT03807765.
Highly selective and potent p16-CDK-RB-E2F targeted oncolytic virus therapies.
Authors: O'Shea Clodagh , Miyake-Stoner Shigeki Joseph , Powers Colin J. , Partlo William 
Published: June 2021

e14543 Background: Growth factor and p16-CDK-RB-E2F pathway components are mutated in almost all cancers, resulting in oncogenic E2F transcriptional activity that drives uncontrolled proliferation. Chemotherapies indiscriminately kill all proliferating cells, resulting in limiting toxicities. CDK inhibitors are more targeted but cytostatic as opposed to tumoricidal. E2F was discovered as a factor that transcribes adenovirus (Ad) E2 and cellular genes to drive viral replication. Ad E1A binds to RB, which activates E2F. On this basis, viruses with E1A-RB binding mutations are being evaluated in the clinic as oncolytic viruses (OVs) that selectively replicate in and kill RB mutant tumor cells. However, E1A-RB mutations alone are not sufficient to prevent viral replication in normal cells. The addition of ‘tumor specific promoters’ improves tumor selectivity but drastically impacts replication and lytic activity. Therefore, a critical unmet need is the engineering of E2F addicted OVs that replicate like wildtype viruses in tumor cells, but leave normal cells unharmed. Methods: We have developed a proprietary platform that enables Ad therapeutics to be assembled from libraries of functional genomic parts that confer desirable properties. Here we describe E1 and E4 genomic modules that confer E2F dependent tumor selective replication. We assembled a panel of ̃50 viruses with combinations of mutations that ablate i) E1A interactions with RB/p107/p130 and/or EP300 ii) E4-ORF1 activation of PI3-Kinase and/or MYC iii) E4-ORF6/7 induced E2F1/DP1 dimerization. These viruses were screened in panels of primary, tumor, and CRISPR-engineered cells. Results: These studies reveal that E4-ORF6/7 functions independently of E1A to activate E2F transcriptional targets, S phase entry and viral replication. We show that viruses with both E1A and E4-ORF6/7 mutations (AdSyn-181) have the ideal tumor selectivity/efficacy profiles and outperform existing OVs. We also show that the deletion of p16 in primary cells rescues AdSyn-181 replication by ̃15 fold (̃20% wildtype virus), demonstrating the E2F dependence and tumor selectivity mechanism. Furthermore, we show that in tumor cells, which have multiple p16-CDK-RB pathway mutations, AdSyn-181 replication is rescued to 100% wildtype virus levels. ICVB-1042, which incorporates these selectivity mutations – together with other modules that enhance lytic cell death and spread, tumor tropisms and IV delivery – is in IND-enabling studies. Conclusions: Leveraging extensive research into the overlapping logic of viral and cancer pathways, we have engineered OVs, including ICVB-1042, that distinguish between tumor and normal cell proliferation. Furthermore, unlike therapies that target a single component, ICVB-1042 targets tumors with different p16-CDK-RB mutations, which all converge in activating oncogenic E2F transcription, driving exponential and tumoricidal viral replication.
Phase I study of BJ-001, a tumor-targeting interleukin-15 fusion protein, in patients with solid tumor.
Authors: Chung Ki Y. , Park Haeseong , Abdul-Karim Raghad Muhsin , Doroshow Deborah Blythe , Chaves Jorge , Coleman Teresa A. , Nakai Keiko , Patel Pankaj , Wang John , Zhang Haizhou , Hu Leijun 
Published: June 2021

e14545 Background: BJ-001 is the first tumor-targeting Interleukin-15 (IL-15) fusion protein, composed of an integrin-binding Arg-Gly-Asp (RGD)-4C motif, linked with a human IgG1 Fc, and then a modified sushi domain of human IL-15Rα unit and a human IL-15. Tumor-targeting is achieved with RGD-4C motif which binds to αvβ3, αvβ5, and αvβ6 integrins, commonly overexpressed in solid tumors. The molecule has shown an ability to activate Natural Killer (NK) and T cells in vitro and in pre-clinical in vivo studies. Methods: This first in-human (FIH) study has 2 phases: Phase 1a and Phase 1b. Phase 1a consists of 3 parts. In all 3 parts patients receive escalating doses of BJ-001 as a once weekly subcutaneous injection for 4 weeks in 6-week cycles. Part 1 utilizes an accelerated dose escalation design with single patient cohort for the first 3 dose levels. Part 2 uses a 3+3 dose escalation design. Part 3 uses a 3+3 dose escalation of BJ-001 but in combination with a fixed-dose PD-(L)1 inhibitor. Dose escalation will proceed based on clinical safety and tolerability data observed during the Dose Limiting Toxicity (DLT) period, i.e., Cycle 1 Days 1 through 28 for Part 1 and Cycle 1 Days 1 through 42 for Parts 2 and 3. Adult patients (ECOG PS ≤ 2) with locally advanced or metastatic solid tumors refractory to or intolerant of all existing therapies are eligible for Phase 1a. Phase 1b will enroll cohorts of adult patients with selected solid tumors known to have high levels of integrin expression at the Maximum Tolerated Dose or Recommended Phase 2 Dose of BJ-001 in combination with a PD-(L)1 inhibitor, as identified in Phase 1a, Part 3. Results: As of Jan 31, 2021, 9 patients have received BJ-001 dosing as a single agent at 0.21 µg/kg (n = 1), 0.9 µg/kg (n = 1), 3 µg/kg (n = 1), 6 µg/kg (n = 3), or 10 µg/kg (n = 3) in Phase 1a Parts 1 and 2, wherein 7 patients, including 1 patient in the 10 µg/kg cohort, have completed the DLT period. Among these 7 patients, 2 (1 in 3 µg/kg and 1 in 6 µg/kg cohorts) have stable disease and are still receiving BJ-001 treatment beyond Cycle 1. The longest duration in the study, to date, is approximately 4 cycles (over 5 months). Treatment Emergent Adverse Events (TRAEs) include injection site reactions (6/7, Grade 1-2), anorexia (2/7, Grade 1-2), cytokine release syndrome (1/7, Grade 1, resolved in 1 day), and temporal wasting (1/7, Grade 1). The AEs did not result in dose interruption or dose level adjustment. No DLTs observed to date. With escalating doses, a trend of increased post-dose NK cell counts observed, whereas Regulatory T cell (Treg) counts remained stable. Conclusions: To date, BJ-001 is well tolerated up to 6 µg/kg. The safety evaluation for 10 µg/kg is ongoing. The observed NK and Treg cell profiles are consistent with known IL-15 biology. Clinical trial information: NCT04294576.
Can radiomics combined with clinical data predict checkpoint inhibitor pneumonitis?
Authors: Montoya Christopher , Spieler Benjamin , Dal Pra Alan , Diwanji Tejan , Yechieli Raphael , Lopes Gilberto , Mihaylov Ivaylo 
Published: June 2021

e14555 Background: Immunotherapy (ImT) is increasingly utilized in patients with advanced non-small cell lung cancer (aNSCLC). Checkpoint-inhibitor pneumonitis (CIP) is an uncommon and potentially life-threatening adverse event (AE) associated with ImT. For patients with aNSCLC, CIP signs and symptoms can be misclassified in the setting of underlying lung disease and incidence may be underreported. The ability to identify patients at risk for CIP prior to ImT could prevent significant morbidity. Previously, we reported that radiomics, a datamining technique that extracts patterns from medical imaging, had identified texture features on pre-ImT CT that correlate with CIP. In this study, we hypothesized that such features combined with clinical data can predict CIP. Methods: In an IRB-approved database of 129 patients with aNSCLC treated with nivolumab, 9 controls were identified with clinical diagnosis of CIP. For all patients, uninvolved lung in the last pre-ImT CT was mined for textures associated with CIP. In the 9 controls, 3 features were identified that correlated with CIP. Imaging and patient charts were reviewed for signs and symptoms of CIP within the first 6 months after ImT administration. Non-controls with progressive clinical symptoms or radiographic findings consistent with CIP and unexplained by disease progression, infection or other medical interventions were treated as CIP-positives. Lastly, the area under the receiver operating curve (AUC) for predicting CIP was built progressively combining uncorrelated laboratory, imaging, and clinical data. Results: In all, 25 patients (19%) were identified with any-grade CIP. A model based on pre-ImT platelets (PLT) and neutrophil-to-lymphocyte ratio (NLR) had an AUC for predicting CIP of 0.648. The radiomics features associated with CIP were average gray value (p = .002), 3D normalized entropy (p = 0.022), and kurtosis (p = 0.011). When combined these 3 features had an AUC of 0.735. Combining both radiomics and laboratory data produced an AUC of 0.779. This increased to 0.793 with the addition of ECOG performance status and sex. Finally, incorporating smoking status yielded an AUC of 0.802. Paired sample difference in AUC between the final model and that including only PLT and NLR was significant (p = 0.003). Conclusions: In patients with aNSCLC treated with ImT, CIP is an uncommon but potentially serious AE. The ability to identify patients at higher risk for CIP could prevent significant morbidity. A model combining radiomics of pre-ImT imaging, laboratory, and clinical data showed better prediction for CIP than laboratory data alone. Future directions include validation of this model on an external cohort and with patients on different ImT regimens.
SYK gene mutations with TMB-H and MSI-H in solid tumors.
Authors: Shi Jian , Liu Rongfeng , Huang Guanglei , Wang Lixing , Shan Baoen , Luo Ningning , Zhang Qin , Wu Yaqing , Qi Yingxue , Qi Chuang 
Published: June 2021

e14572 Background: Spleen tyrosine kinase ( SYK) gene encodes a cytoplasmic non-receptor tyrosine kinase (NRTK) and mediates signal transduction downstream of multiple transmembrane receptors, which plays an important role in a variety of signaling pathways. The change of SYK gene expression and gene mutations may lead to the formation and metastasis of multiple solid tumors. Previous studies on SYK mostly focus on the protein isomers and the methylation of SYK gene promoter. We previously used next generation sequencing (NGS) to explore SYK gene mutations on DNA level and found novel mutation types of SYK gene. Herein, NGS were performed to explore the relationship of SYK gene mutations with TMB and MSI in solid tumors for further clinical research. Methods: We retrospectively collected NGS detection data by 539-gene panel in 5648 patients with pan-cancer, of which 3931 patients by tumor tissue and 1717 patients by blood ctDNA, and screened out somatic SYK gene mutations. 539-gene panel contained all exon regions of SYK gene. Then we divided 5648 patients into four groups depending on whether SYK gene mutations: tumor tissue mutant group (T-mut) / non-mutant group (T-non-mut), and ctDNA mutant group (ctDNA-mut) / non-mutant group (ctDNA-non-mut). The difference in TMB between T-mut and T-non-mut groups; between ctDNA-mut and ctDNA-non-mut groups were analyzed via the Wilcoxon sign test respectively. The difference in MSI between T-mut and T-non-mut groups were analyzed via Fisher test. Results: In 5648 patients with solid tumors, 64 patients (48/3931 in tumor tissue and 16/1717 in blood ctDNA) were found harboring SYK gene mutations and the mutation frequency was 1.13%. TMB in T-mut group was higher than in T-non-mut group and significant difference of TMB was found via the Wilcoxon sign test (p = 5.3e-12) between the two groups. TMB in ctDNA-mut group was higher than in ctDNA-non-mut group and significant difference of TMB was found too (p = 4.6e-05). 12 patients were found MSI-H in T-mut group (12/48) and 53 patients were found MSI-H in T-non-mut group (35/3875). We found significant difference in the probability of MSI-H occurrence between the two groups by Fisher test (p = 6.531e-12, HR: 23.933, 95%CI: 10.734-50.415). Conclusions: This is the first report on the relationship between SYK gene mutations with TMB and MSI in solid tumors and we found that SYK gene mutations are associated with TMB-H and MSI-H in solid tumors. As a retrospective study in solid tumors, the conclusion and the mechanism need to be studied in the future.
Pretreatment 18F-FDG uptake heterogeneity predicts response to pyrotinib in patients with metastatic HER2-positive breast cancer.
Authors: Gong Cc , Liu Cheng , Tao Zhonghua , Zhang Jian , Wang Leiping , Cao Jun , Zhao Yannan , Li Yi , Xie Yizhao , Wang Biyun , Yang Zhongyi , Hu Xichun 
Published: June 2021

e15026 Background: Heterogeneity of 18F-fluorodeoxyglucose (FDG) uptake is a promising marker for predicting response to treatment. This study aimed to evaluate the ability of pretreatment positron emission tomography/computed tomography (PET/CT) 18F-FDG-based heterogeneity to predict the response to pyrotinib in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). Methods: Patients with MBC in the Fudan University Shanghai Cancer Center who underwent whole-body 18F-FDG PET/CT before the initiation of pyrotinib was included. The intertumoral and intratumoral heterogeneity indexes (HI-inter and HI-intra, respectively), maximum standardized uptake value (SUVmax), total lesion glycolysis (TLG), and metabolic tumor volume (MTV) on the baseline PET/CT were assessed. Progression-free survival (PFS) was estimated by the Kaplan-Meier method and compared by log-rank test. Time-dependent receiver operating characteristic (ROC) curve analysis was performed, and the predictive accuracies of all markers were evaluated by plotting the cumulative area under the ROC curve (AUC) over time. Results: A total of 22 patients were included in this study. The median PFS of patients with a high HI-intra (> 1.9) was 6.6 months, whereas that of patients with a low HI-intra was 13.4 months (p = 0.044). The HI-inter was able to discriminate patients as well as the coefficient of variance. Univariate analysis showed that patients with a higher HI-inter tended to have worse PFS (10.6 months vs. 13.4 months, p = 0.067). Higher SUVmax and TLG were also associated with worse PFS. ROC curve analysis confirmed the predictive value of the HI-inter and HI-intra. TLG had the highest accuracy in predicting PFS (AUC = 0.87), followed by HI-inter (AUC = 0.86), SUVmax (AUC = 0.85), HI-intra (AUC = 0.80), mean standardized uptake value (AUC = 0.63), and MTV (AUC = 0.60). Conclusions: Intratumoral and intertumoral heterogeneities in metastatic lesions on pretreatment 18F-FDG PET/CT could predict response to pyrotinib treatment in patients with HER2-positive breast cancer, which could provide information to guide treatment decisions.