bluuebunny/crossref_metadata_2025 huggingface dataset:
Extracting knowledge of NCI research directions from funding data using language processing.
Authors: Beidler Peter , Nguyen Mark , Kang John
Published: June 2021

e13547

Background: In fiscal year (FY) 2019, 42% of the $6 billion NCI budget went towards nearly 5,000 research project grants, of which about 60% are R01 type. Given the enormity of allocated resources, there is a need for the scientific community to have a more rigorous understanding of the cancer research landscape. While the NCI Budget Fact Book publishes statistics based on pre-designated codings, it is unclear if this method yields the best representation of fields within oncology. Open questions include: how many distinguishable areas of cancer research are being funded? Are there differences in growth rate, publication rate and geographic distribution among those areas? Addressing these questions in a systematic manner is a well-suited problem for unsupervised machine learning. Methods: We analyzed 55,362 R-type grants from FY 2010-2021 (up to 1/31/21) from NIH ExPORTER. Preprocessing was done on ‘Project Terms’ to weight their importance using TF*IDF vectorization and principal component analysis. We used minibatch K-means clustering repeated 100 times, with the best iteration chosen by Calinski-Harabasz clustering quality score. Over 100 repetitions, the Adjusted Rand Index was 0.9907±0.0037 (mean ±standard deviation), indicating robustness to initial conditions of K-means. For publication rate analysis, FY 2020 and 2021 grants were excluded, and 2021 grants were excluded for trajectory analysis. Optimal cluster number was determined based on a combination of inertia, Calinski-Halabasz, and silhouette scores. Results: We found the optimal number of 24 clusters to best represent separation of the R-type grant research directions. These 24 clusters clearly represent topics such as immunotherapy, cohort risk-factor studies, and imaging. Notable trends include increased funding of immunotherapy and targeted inhibitor clusters averaging +$9.9M and +$9.2M growth per year respectively over 10 years, and decreased funding of pathway regulation and genetics clusters averaging -$7.8M and -$5.7M per year. These examples suggest a broader trend that funding is shifting from basic to translational science. Further analysis shows that the targeted inhibitor cluster is most geographically skewed, with 30% of grants going to institutions in just three cities. The number of journal articles (per grant) also shows a bias, with development/training and genetics clusters having publication rates of 32.6 and 20.8 and randomized control trials having a publication rate of 6.3. The average publication rate of NCI was 14.8. Conclusions: Using a novel framework for unsupervised clustering of NCI grant key-phrases, we can organize research projects more holistically than keyword searching, and more efficiently than manual categorization. Our model identifies growing and shrinking areas of research and points out biases in location and publication rate across these areas.
To determine correlation of inter reader variability in sum of diameters using RECIST 1.1 with end point assessment in lung cancer.
Authors: Sharma Manish , Singareddy Anitha , Bajpai Surabhi , Narang Jayant , O'Connor Michael , Jarecha Rudresh
Published: June 2021

e13557

Background: Lung cancer is the leading cause of cancer death in the world including more than 160,000 deaths in the US. The purpose of the study was to determine whether inter reader variability in Sum of Diameters (SOD) of tumor burden has any correlation with variability in end point assessment in lung cancer progression. RECIST 1.1 is based on the SOD of target lesions seen on imaging studies. Response criteria for evaluation of target lesions include - Complete response (CR), Partial response (PR), Progressive disease (PD) and Stable disease (SD). The key determinant of patient response is based on Target Lesion response which in turn is determined by SOD. Inter reader variability study plays an important role in the development of reliable diagnostic tools and understanding of imaging outcomes given the confounding factors like effusion, atelectasis and consolidation in lung cancer that affect Target Lesion selection. Methods: Retrospective analysis of 470 patients was carried out using RECIST 1.1. Double read with adjudication is the preferred read model for submission studies where images are read by two independent reviewers blinded to treatment allocation. As per RECIST 1.1, lesions were measured in the longest diameter for non-nodal and short axis for nodal lesions. This was followed by the calculation of SOD for total tumor burden. If these two primary reviewers disagree, then a third radiologist, the “adjudicator”, reviews the assessments performed by the first two radiologists and selects between the more accurate one. For further analysis, patients were divided into 2 groups, the one with no adjudication i.e. agreement between both readers and the second group with adjudication i.e. disagreement between both readers and ANOVA was used to perform analysis of Variance. Results: Of 470 patients, 332 patients with disagreement were adjudicated, while there was agreement on 138 patients assessments between both readers. SOD of baseline visits for all patients was assessed using ANOVA - single factor with following results: F ratio of 4.76 for Disagreement group was more than F crit (3.86) with P-value 0.03, while for Agreement group F value was less than F crit. Conclusions: There is a direct relationship of variability in SOD at baseline between two readers to the possibility of disagreement in their end point assessment. Additional rules around selection and measurement of Target Lesions should be proposed in protocol to reduce variability and improve endpoint assessment outcomes.[Table: see text]
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.
Circulating tumor cell proportion scoring (CTPS) based PD-L1 assessment and clinical application of circulating tumor cells (CTCs) on stage IV non-small cell lung cancer (NSCLC) through liquid biopsy.
Authors: Choi Mi Young , Moon Da Hye , Jo Jong-min , Lee Hae Ung , Park Seri , Jeon Byung Hee , Choi Chang Min
Published: June 2021

e15031

Background: Stage IV lung cancer is the most advanced lung cancer state accompanied by metastasized to the area around the lungs or distant major organs. The most common type of lung cancer is non-small cell lung cancer, which is more aggressive and may spread quickly due to organ-specific complex networks such as lymph and major blood vessels. Thus, only precise diagnostic strategy approaches will determine the effectiveness of the actual and successful clinical treatment. Until a recent date, Immunohistochemistry (IHC) for programmed death-ligand 1(PD-L1) test is the only available biomarker test that purpose diagnostics (CDx) and guide the treatment with immune checkpoint inhibitors in NSCLC. Methods: Given that CDx strategy, tissue biopsy has inevitable limitations, including patient risk, repetitive examination, sample preparation, sensitivity, and accuracy. For this reason, our research team contrived the best strategy for biomarker, PD-L1-specific CTCs in stage IV NSCLC group (N = 30) compared to pulmonary inflammatory patient groups (N = 30) CytoGen Smart biopsy platform. Herein, we removed false-positive cells for the first strategy of distinguishing between lymphoid/myeloid cells and the enriched-CTCs. And the second strategic approach is to calculate the pure CTCs (without false-positive cells) and then CTPS) as measured by the PD-L1 expression among pure-CTCs. That application is the percentage of viable CTCs showing partial or complete stained cells at the deducted cut-off value in each fluorescence, respectively. Results: Consequently, we demonstrated over 80% of the concordance rate between VENTANA PD-L1(SP263) and DAKO PD-L1(SP263) assay tested by the PD-L1 expression on stage IV NSCLC in tissue and pure-CTCs based CTPS from the blood. In contrast, pure-CTCs based CTPS in the pulmonary inflammatory group were all negative (recorded as zero). Conclusions: Conclusively, this study implicates that pure-CTCs based CTPS could be deployed for innovative diagnosis strategies as alternatives for tissue biopsy. Our clinical study's data suggested that the possibility for prompt decision for diagnosis and gain powerful insights to guide the personalized treatment in NSCLCs. Clinical trial information: 2020-0553.
PCSK9 inhibitor evolocumab to increase anticancer activities and reduce cardiotoxicity during doxorubicin and trastuzumab, as sequential treatment, through MyD88/NF-kB/mTORC1 pathways.
Authors: Quagliariello Vincenzo , Buccolo Simona , Iovine Martina , Paccone Andrea , Bonelli Annamaria , Cavalcanti Ernesta , Rea Domenica , De Laurentiis Michelino , Botti Gerardo , Maurea Nicola
Published: June 2021

e15039

Background: Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a novel therapy to treat hypercholesterolaemia and related cardiovascular diseases. Evolocumab, a PCSK9 inhibitor, reduced the risk of cardiovascular events in patients with atherosclerotic cardiovascular diseases when added to maximally tolerated statin therapy (± ezetimibe), and recent data from the ODYSSEY OUTCOMES trial indicate that alirocumab added to maximally tolerated statin therapy (± other lipid-lowering drugs) reduces the risk of cardiovascular events in patients with a recent acute coronary syndrome. Methods: Human fetal cardiomyocytes (HFC cell line), human HER2+ breast cancer cells were exposed to subclinical concentration of doxorubicin, trastuzumab, sequential treatment of both (all 100 nM), alone or in combination with evolocumab (50 nM) for 24 and 48h. After the incubation period, we performed the following tests: determination of cell viability, through analysis of mitochondrial dehydrogenase activity, study of lipid peroxidation (quantifying cellular Malondialdehyde and 4-hydroxynonenal), intracellular Ca2+ homeostasis. Moreover, pro-inflammatory studied were also performed (activation of NLRP3 inflammasome; expression of TLR4/MyD88; mTORC1 Fox01/3a; transcriptional activation of p65/NF-κB and secretion of cytokines involved in cardiotoxicity (Interleukins 1β, 8, 6). Results: Evolocumab co-incubated with doxorubicin alone or in sequence with trastuzumab exerts cardioprotective effects, enhancing cell viability of 35-43% compared to untreated cells (p < 0,05 for all); in cardiomyocytes Evolocumab reduced significantly the cardiotoxicity through MyD88/NF-KB/cytokines axis and mTORC1 Fox01/3α mediated mechanisms. In human HER2+ breast cancer cells, co-exposure of Evolocumab with doxorubicin and trastuzumab increased significantly cell apoptosis and necrosis through the involvement of key cytokines involved in chemoresistence. Conclusions: We demonstrated, for the first time, that the PCSK9 inhibitor evolocumab exerts direct effects in cardiomyocytes and human HER2+ breast cancer cells during doxorubicin and trastuzumab exposure turning on a new light on its possible use in the management of breast cancer therapies.
Discovery of HBW-3-10: A potent, orally active, reversible Bruton’s tyrosine kinase (BTK) inhibitor with antitumor activity in mice.
Authors: Lee Ning , Li Yingfu , Yuan Chester , Liu Guanfeng , Yue Chunchao
Published: June 2021

e15062

Background: The first generation irreversible BTK inhibitor ibrutinib has been approved for the treatment of B cell-related diseases, including chronic lymphocytic leukemia (CLL), for several years. However, CLL patients who used ibrutinib may develop drug resistance due to acquired mutations, in particular BTK C481S that directly impacts the binding of ibrutinib. In recent years, efforts have been made to develop the second generation reversible BTK inhibitors that are effective against both wild-type and C481S mutated B-cell malignancies. LOXO-305 and ARQ-531 are two examples of the second generation reversible BTK inhibitors in advanced clinical trials for ibrutinib-resistant CLL. Methods: New reversible BTK inhibitors were designed, synthesized and tested for enzymatic activities against wild-type and C481S-mutated BTK. Highly active compounds were confirmed for growth effects in diffuse large B-cell lymphoma derived TMD8 cells. Their microsomal stability and ADME properties were also assessed. Potent and bioavailable compounds were further evaluated in vivo efficacy using a TMD8 xenograft tumor model in mice. A 14-day toxicity study in rats was performed correspondingly. Results: As shown in the table, HBW-3-10 has greater potency and pharmacokinetic profile (rats, 10mg/kg PO) than ARQ-531. In a TMD8 mouse xenograft study, HBW-3-10, ARQ-531 and ibrutinib were compared directly, all dosed at 10mg/kg QD, and the resulting tumor growth inhibition rates (TGI) are 38.3%, 9.3% and 22.5%, respectively. Based on our data, HBW-3-10 is more efficacious than ARQ-531 and ibrutinib. In a 14-day preliminary toxicity experiment in rats, both HBW-3-10 and ARQ-531 were dosed 100mg/kg QD. Animals in ARQ531 group started showing signs of sickness on day 3, and all died on day 6 due toxicity; in contrast, no animal in HBW-3-10 group showed any sign of sickness or died during the entire course of study. Conclusions: We have discovered a novel second generation reversible BTK inhibitors HBW-3-10, that has a superior preclinical profile, efficacy and safety than other known ones. HBW-3-10 provides a valuable clinical candidate for treating Ibrutinib resistant CLL and beyond![Table: see text]
Deep learning to identify a gene signature associated with molecular subtypes that predicts prognosis in colorectal cancer.
Authors: Cai Du , Wang Wei , Zhong Min-Er , Fan Dejun , Liu Xuanhui , Li Cheng-Hang , Huang Ze-Ping , Zhu Qiqi , Lv Min-Yi , Hu Chuling , Duan Xin , Wu Xiaojian , Gao Feng
Published: June 2021

e15520

Background: Identifying robust prognostic risk groups of colorectal cancer (CRC) will significantly improve patients’ outcomes. However, CRC has been demonstrated to be molecularly heterogeneous which affected clinical decision-making. Recently, a comprehensive study proposed four consensus molecular subtypes (CMSs) of CRC with a comprehensive biological and clinical characterization, but a cost-effective clinical assay for prognosis is lacking. To fill this gap, we present a supervised framework using deep learning to identify CMS associated gene signature for prognosis. Methods: A total of 1,729 CRC patients with complete follow-up data were included in this study. We first applied a supervised deep learning-based framework in the training cohort ( n = 624) to extract the CMS-associated deep features and then identified a gene panel highly correlated to these deep features. Subsequently, the prognostic power of this gene signature was evaluated on 6 independent CRC datasets. Results: We identified a 21-gene signature associated CMS subtypes and a trained risk model significantly predicted patients’ disease-free survival (DFS) on six independent CRC datasets ( n = 1,729): Training cohort ( n = 624, HR = 2.53, 95% CI: 1.53-4.18, P < 0.001), Validation 1 cohort ( n = 557, HR = 1.77, 95%CI: 1.27 – 2.47, P < 0.001) and Validation 2 cohort merged by other four datasets ( n = 548, HR = 2.10, 95%CI: 1.50 – 2.93, P < 0.001). Especially, this 21-gene signature can also stratify stage 2 and 3 patients into distinct survival groups: Training cohort ( n = 338, HR = 2.14, 95%CI: 1.18-3.85, P < 0.01), Validation 1 cohort ( n = 457, HR = 1.63, 95%CI: 1.12 – 2.37, P < 0.01) and Validation 2 cohort ( n = 437, HR = 1.73, 95%CI: 1.37 – 2.82, P < 0.001), outperformed Oncotype DX on the same cohorts. Conclusions: To summarize, using our DL-based framework, we successfully developed a CMS-associated gene signature for robust prognostic prediction in CRC. Compared with genome-wide expression profile-based CMS classification system, the 21-gene panel can be easily deployed in clinical practice to facilitate decision making.
Landscape of homologous recombination-related (HRR) genes mutations in colon cancer.
Authors: Zhao Tuanjie , Ren Chuncheng , Zhang Zhiliang , Liu Huanhuan , Wang Huina , Zhang Yanrui , Zhang Yun , Liang Xiayuan , Lou Feng , Cao Shanbo , Zhang Yuru
Published: June 2021

e15525

Background: Homologous recombination deficiency (HRD) might serve as a biomarker of immunotherapy and chemotherapy response. In addtion, HRD is associated with sensitivity to PARP inhibitor (PARPi) therapy. The HRD phenotype has been defined as the presence of a non-silent somatic mutation in homologous recombination-related (HRR) genes. Here, we focused on mutational landscape of HRR genes and the relationship between HRR-related genes and clinical outcomes in colon cancer. Methods: We prospectively sequenced 784 Chinese patients with colon cancer using next-generation sequencing techniques with 808 cancer-related genes. 290 patients with somatic mutation from the TCGA project were included. The 15 HRR genes were selected on clinical evidence of sensitivity to PARP inhibitors and immunotherapy. TCGA datasets were performed to identify the correlations between HRR gene mutations and clinical outcomes. Results: In the Chinese cohort, 11.5% (90/784) patients exhibited deleterious somatic mutation in HRR genes, including ATM (3.3%), BRCA2 (2.4%), CDK12 (2.4%), BRCA1 (1.0%), BRIP1 (1.0%), CHEK2 (0.5%), BARD1 (0.4%), RAD54L (0.4%), PALB2 (0.3%), and RAD51B (0.3%). In TCGA cohort, 28.6% (83/290) patients had at least one deleterious somatic mutation in HRR genes, including ATM (14.8%), BRCA2 (9.0%), CDK12 (7.9%), BRIP1 (3.8%), BRCA1 (3.4%), FANCL (3.1%), CHEK2 (2.4%), PALB2 (2.1%), PPP2R2A (2.1%), RAD54L (2.1%), CHEK1 (1.7%), BARD1 (1.4%), RAD51C (1.4%), RAD51B (1.0%), and RAD51D (0.3%). Overall, the mutational frequency of HRR genes in the Chinese cohort was lower than that in the TCGA cohort (p < 0.001). In the TCGA cohort, colon patients with HRR-mut had significantly higher tumor mutational burden and incidence of microsatellite instability high and enhanced immune activity than patients with HRR-wt. Furthermore, In the MSK-IMPACT cohort treated by immune checkpoint inhibitor, patients with HRR-mut had significantly better OS (p = 0.009) and increased immune activities, such as infiltration of cytotoxic cells (p < 0.05) and exhausted CD8+ T cells (p < 0.01), and increased the IFN-γ scores (p < 0.05) than patients with HRR-wt. Conclusions: Our data suggest that detection of somatic mutations in HRR genes might contribute to identify patients who might benefit from immune checkpoint blockade therapy and PARP inhibitors. In addition, the molecular features of HRR provide new opportunities to predict the tumor response to multiple treatments. Exploring other biomarkers of HRD to predict the response to PARPi and immunotherapeutic in colon cancer is necessary.
Prognostic role of apolipoprotein and lactate dehydrogenase levels in resectable colorectal cancer.
Authors: Ma Yifei , Lu Ping , Liang Xinjun , Wei Shaozhong
Published: June 2021

e15541

Background: Apolipoprotein b (apob), apolipoprotein a1 (apoa1), and lactate dehydrogenase (LDH) levels are circulating biomarkers that relate to tumor inflammation. This study aimed to evaluate the prognostic role of apob/apoa1 and LDH in resectable colorectal cancer (CRC). Methods: 513 patients of colorectal cancer (CRC) from Hubei cancer hospital were included finally, and we collected the pre-operative laboratory results within a week before surgery. We combined the two indicators and divided them into three groups (group 1: apob/apoa1-LDH low; group 2: apob/apoa1 or LDH high; group 3: apob/apoa1-LDH high). Kaplan-Meier survival analysis, univariate COX regression and multivariate COX regression were used to assess the prognoses of colorectal cancer patients. Results: The median follow-up was 35 months. Our study found that the prognosis of group 1 was better than group 2 in both overall survival (88.2% vs. 75.4% vs. 61.9%) (P≤0.001) and diseases-free survival (77.4% vs. 64.7% vs. 42.8%) (P≤0.001), and group 3 was the worst. By multivariate analysis, the new predictive marker obtained by combining apob/apoa1 and LDH could independently predict outcomes in CRC [overall survival: (HR: 1.487; 95% CI, 1.074-2.061); diseases-free survival (HR: 1.381; 95% CI, 1.045-1.827)]. Conclusions: New marker based on apob/apoa1 and LDH is useful for predicting the prognosis of patients with CRC. However, more research is needed in the future.
Functional precision medicine in colorectal cancer based on patient-derived tumoroids and in-vitro sensitivity drug testing.
Authors: Jensen Lars Henrik , Jakobsen Anders Kristian Moeller , Havelund Birgitte Mayland , Abildgaard Cecilie , Vagn-Hansen Chris , Dam Claus , Lindebjerg Jan , Canto Luisa M , Rogatto Silvia Regina , Rafaelsen Soeren Rafael , Hansen Torben
Published: June 2021

e15567

Background: Precision oncology based on in-vitro, functional assays has potential advantages compared to the much more common molecular approach, but the clinical benefit is unknown. We here report the results from the largest prospective interventional clinical trial testing the clinical outcome in colorectal cancer patients treated with drugs showing cytotoxic effect in matched patient-derived tumoroids. Methods: This single-center, phase II trial included patients with metastatic colorectal cancer previously exposed to all standard therapies. Specimens from one to three 18-16 G core needle biopsies were manually dissected, enzymatically treated, cultivated, and incubated to form 3D spherical microtumors, i.e. tumoroids. In the assay for in-vitro sensitivity testing, the tumoroids were challenged with single drugs and combinations thereof to determine patient-specific responses. Using tumoroid screening technology (IndiTreat, 2cureX, Copenhagen, Denmark), results were generated by comparing the sensitivity of the individual patient’s tumoroids with a reference panel from other patients. The testing included standard cytostatics and drugs with proven effect in previous early-phase clinical trials, a total of 15 drugs. The primary endpoint was the fraction of patients with progression-free survival (PFS) at two months. Based on placebo arms in randomized last-line trials, a minimal relevant difference of 20% (20% to 40%) was stated. Using Simon's two-stage design, a sample size of 45 patients was calculated with at least 14 PFS at two months (significance 5%, power 90%). Results: Ninety patients were enrolled from 9/2017 to 9/2020. Biopsies from 82 patients were obtained and sent for tumoroid formation of which 44 (54%, 95% CI 42-65) were successful and at least one treatment was suggested. Thirty-four patients initiated treatment according to the response obtained in the drug assays within a median of 51 days from inclusion (IQR 39-63). The primary endpoint, PFS at two months, was met in 17 of 34 patients (50%, 95%CI 32-68). There were no radiological responses. Median PFS was 81 days (95% CI 51-112) and median OS was 189 days (95% CI 103-277). Conclusions: Precision oncology using a functional approach with patient-derived tumoroids and in-vitro drug sensitivity testing seems feasible. The approach is limited by the fraction of patients with successful tumoroid development. The primary endpoint was met, as half of the patients were without progression at two months. Further clinical studies are justified. Clinical trial information: NCT03251612.