tbuckley/cabot-search huggingface dataset:
Discovery and validation of a cross-platform 21-gene prognostic signature in neuroblastoma.
Authors: Mehul Gupta, Sunand Nageswaran Kannappan, Aru Narendran, Pinaki Bose
Journal: Journal of Clinical Oncology (2021)

10035 Background: Neuroblastoma (NB) is the most common extracranial solid tumor in children. Despite the development of risk stratification tools to improve prognostication, prediction of patient survival outcomes in NB remains poor. In this study we used an unbiased machine-learning algorithm to develop and validate a transcriptomic signature capable of predicting 5-year overall (OS) and event-free survival (EFS) in these patients. Methods: The TARGET-Neuroblastoma dataset (n = 243) was used as the training set. Two independent NB cohorts, E-MTAB-179 (n = 478) and GSE85047 (n = 266) were used as validation sets. Elastic net regression was employed to identify transcripts associated with EFS. Association of the developed signature with EFS and OS was evaluated using univariate Cox proportional hazards (CoxPH), Kaplan-Meier, and 5-year receiver-operator characteristic curves in validation cohorts. Further, the independent prognostic value of the signature was assessed using multivariate CoxPH models with relevant clinicopathologic variables including age, INSS stage, and N-Myc amplification status in both validation sets. Finally, a nomogram was developed to integrate the signature with prognostic clinicopathologic variables to evaluate their combined efficacy for prediction of 5-year EFS and OS. Results: We identified a 21-gene signature that demonstrates significant association with EFS and OS in both E-MTAB-178 and GSE49710 validation cohorts. Moreover, the signature is independent of clinicopathological variables and can be effectively incorporated into a risk model, improving the prognostic performance. Several genes within the signature have been previously implicated in NB, including ECEL1, HOXC9 and ARAF1. Conclusions: To the best of our knowledge, we are the first to use an unbiased machine learning approach to generate a transcriptomic gene signature for neuroblastoma prognosis externally validated in multiple cohorts across platforms. This 21-gene transcriptomic signature significantly associated with EFS and OS in this disease. Combining this signature with current prognostic clinicopathologic variables will improve risk stratification of affected patients and may inform effective clinical decision-making.[Table: see text]
Implementation of the Vinehealth application, a digital health tool, into the care of patients living with brain cancer.
Authors: Andrew Gvozdanovic, Riccardo Mangiapelo, Rayna Patel, Georgina Kirby, Neil Kitchen, Anna Miserocchi, Andy McEvoy, Patrick Grover, Lewis Thorne, Naomi Fersht, Norman R. Williams, Hani Marcus, Michael Kosmin
Journal: Journal of Clinical Oncology (2021)

e13582 Background: Cancers of the brain lead to significant neurocognitive, physical and psychological morbidities. Digital technologies provide a novel platform to capture and evaluate these needs. Mobile health (mHealth) applications typically focus on one aspect of care rather than addressing the multimodal needs of the demographic of these patients. The Vinehealth application aims to address this by tracking symptoms, delivering machine learning-based personalised educational content, and facilitating reminders for medications and appointments. Where mHealth interventions traditionally lack the evidence-based approach of pharmaceuticals, this study acts as an initial step in the rigorous assessment of a new digital health tool. Methods: A mixed methodology approach was applied to evaluate the Vinehealth application as a care delivery adjunct. Patients with brain cancer were recruited from the day of their procedure ± 7 days. Over a 12-week period, we collected real-world and ePRO data via the application. We assessed qualitative feedback from mixed-methodology surveys and semi-structured interviews at onboarding and after two weeks of application use. Results: Six participants enrolled of whom four downloaded the application; four completed all interviews. One patient set up their device incorrectly and so couldn't receive the questionnaires; excluding this patient, the EQ-5D-5L and EORTC QLQ-BN20 completion rates were 100% and 83% respectively. Average scores (±SD) at onboarding and offboarding were EQ-5D-5L: 2.07±1.28 and 1.73±1.22, and QLQ-BN20: 13.33 and 22.5. In total: 212 symptoms, 174 activity, and 47 medication data points were captured, and 113 educational articles were read. Participants were generally optimistic about application use. All users stated they would recommend Vinehealth and expressed subjective improvements in care. Accessibility issues in the ePRO delivery system which impacted completion rate were identified and have subsequently been fully addressed. Conclusions: This feasibility study showed acceptable patient use, led to a subjective improvement in care, and demonstrated effective collection of real-world and validated ePRO data. This provides a strong basis to further explore the integration of the Vinehealth application into brain cancer care. This study will inform the design of a larger, more comprehensive trial continuing to evaluate improvements in care delivery through data collection, educational support and patient empowerment.
Acquired hypolipoproteinemia and hemophagocytic lymphohistiocytosis: A previously unexplored association?
Authors: Leo Edward Reap, Vincent T Ma, Radhika Takiar, Adam Matthew Forman
Journal: Journal of Clinical Oncology (2021)

e19041 Background: Hemophagocytic lymphohistiocytosis (HLH) is a rare disease that is the result of macrophage hyperactivation, leading to disordered cellular phagocytosis that is highly fatal if left untreated. The precise precipitating factor that leads to HLH is presently unknown. Secondary HLH is more common in adults and has numerous causes, including several autoimmune diseases, rheumatological disorders, cancers, and infections. These predisposing conditions are similar in that they are characterized by increased rates of cellular replication and often accompanied by significant oxidative stress. Lipoprotein changes in HLH have not been previously described. Methods: Between August 2018 and June 2020, three cases of secondary HLH were discovered to have profound hypolipoproteinemia with severely reduced total cholesterol, undetectable LDL-C, and extremely depressed HDL-C levels. As a result, a retrospective review of the University of Michigan HLH registry was performed, identifying cases of HLH where full lipid panels were performed as part of their diagnosis and/or treatment between 2012 and 2020. 18 total patients were identified with a confirmed diagnosis of HLH and who had a full lipid panel performed as a part of their diagnostic evaluation. Results: 100% of patients were found to have HDL-C less than 30 mg/dL, consistent with severe HDL-C deficiency, and 84% had HDL-C less than 20 mg/dL. Similarly, 74% of patients were found to have LDL-C &lt; 100 mg/dL, 47% with LDL-C &lt; 50 mg/dL, and 33% had undetectable LDL-C levels. Median total cholesterol was 124 mg/dL, median LDL-C was 35 mg/dL, and median HDL-C was 7 mg/dL. Notably, these reductions were not explained by the observed variability in hypertriglyceridemia, and marked hypertriglyceridemia &gt; 500 mg/dL was not seen in 88% of patients, with a median triglyceride value of 279. Interestingly, one patient displayed an opposite phenotype with extreme hyperlipidemia, with total cholesterol of 727 mg/dL and LDL-C of 658 md/dL. Conclusions: Severe derangements in circulating lipoproteins appear to be a common finding within sHLH.These findings have not been previously described within the context of the disease. Herein, we provide a framework for hypothesizing why HLH may potentially occur in the setting of hypolipidemia. Furthermore, we provide an additional hypothesis that serves to justify why these changes may occur in an evolutionary context.
Anti-tumor activity of SKLB-0322, a novel EZH2 covalent inhibitor, in ovarian cancer.
Authors: Yongxia Zhu, Xinyi Chen, Qiangsheng Zhang, Lihong Shi, Luoting Yu, Hongtao Xiao
Journal: Journal of Clinical Oncology (2021)

e15052 Background: Enhancer of Zeste Homolog 2 (EZH2) is the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2) that regulate downstream target genes expression, and then promotes tumor cell proliferation, metastasis and drug resistance. EZH2 also performs some functions in a PRC2-independent manner. Most of reported EZH2 inhibitors are S-adenosyle-methionine (SAM)-competitive inhibitor, and are less selective for EZH2 close homolog EZH1, which resulted in safety concerns and insufficient efficacy. To obtain irreversible EZH2 inhibitor, a novel covalent inhibitor was developed and characterized. Methods: SKLB-0322 and its derivatives were designed, synthesized and confirmed as EZH2 covalent inhibitor by us. The anti-tumor activities of SKLB-0322 were investigated by MTT assay, flow cytometry, and western blot assay. The reversible analog of SKLB-0322 (SKLB-0322’) was used as negative control. Results: SKLB-0322 inhibited EZH2 methyltransferase activity with nanomolar potency, while the inhibitory activities of SKLB-0322’ was reduced. The mass spectrometry (MS) analyses revealed that SKLB-0322 could efficiently forms a single modified covalent adduct. SKLB-0322 displayed noteworthy potency against ovarian cancer cell lines at low micromolar level and reduced the expression level of H3K27me3 in a concentration-dependent manner, which was about 5-fold more active than the reversible negative control SKLB-0322’. Besides, SKLB-0322 caused G2/M phase cell cycle arrest in A2780 and PA-1 cells. Furthermore, SKLB-0322 induced A2780 and PA-1 cell apoptosis in a time- and concentration- dependent manner. Conclusions: Our data clarified that SKLB-0322 is an EZH2 covalent inhibitor for ovarian cancer therapy which is worthy of further evaluation.
Abemaciclib, a CDK4 and 6 inhibitor with unique pharmacological properties for breast cancer therapy.
Authors: Raquel Torres-Guzmán, Maria Patricia Ganado, Cecila Mur Pérez, Carlos Marugán, Carmen Baquero, Yanzhu Yang, Jian Du, Alfonso de Dios, Oscar Puig, Maria Jose Lallena
Journal: Journal of Clinical Oncology (2021)

e12506 Background: Breast cancer is the second most common cancer worldwide. Pharmacologically targeting cyclin-dependent kinases 4 and 6 (CDK4 &amp; 6) has proven to be a successful therapeutic approach in patients with estrogen receptor positive (ER+) breast cancer. Differences in both efficacy and toxicity among the available CDK4 &amp; 6 inhibitors has generated interest in a biological explanation. Abemaciclib is an adenosine triphosphate-competitive, reversible, selective inhibitor of CDK4 &amp; 6 that has shown antitumor activity as a single agent and in combination with standard endocrine therapy (ET), in hormone receptor positive (HR+) metastatic breast cancer patients including those with ET resistance, and in combination with ET in high-risk early breast cancer patients. This study examines attributes of abemaciclib and other CDK4 &amp; 6 inhibitors. Methods: The potency of abemaciclib for CDK4 was evaluated using biochemicals and breast cancer cell-based assays. Additionally, different combinations with an anti-estrogen therapy (e.g., tamoxifen, fulvestrant) were analyzed in an in vitro palbociclib (CDK4 &amp; 6 inhibitor)-resistant breast cancer cell model, as well as in a set of CDK4 &amp; 6 sensitive breast cancer cell models. Using cell-free assays, high content imaging and flow cytometry approaches, a subset of markers were monitored to characterize the phenotype of sensitive cell lines in a continuous dose schedule. Results: In in vitro, cell-free assays, abemaciclib shows selectivity for CDK4 over CDK6, and in cell-based assays, abemaciclib preferentially inhibits the proliferation of cells dependent on the presence of CDK4, not CDK6. Abemaciclib inhibits cell proliferation in a wide range of breast cancer cell lines, showing activity regardless of human epidermal growth factor receptor 2 (HER2) and PI3KCA gene mutation status. Furthermore, in a cell line resistant to palbociclib, abemaciclib in combination with fulvestrant (ET) restores CDK4 &amp; 6 sensitivity, leading to cell senescence and cell death. Finally, in human bone marrow progenitor cells, abemaciclib shows a lesser impact on myeloid maturation than other CDK4 &amp; 6 inhibitors, palbociclib and ribociclib, allowing for continuous dosing. Conclusions: In pre-clinical experiments, abemaciclib is a potent cell growth inhibitor, inhibiting preferentially the CDK4/CyclinD1 complex, leading to cell senescence and cell death. These pre-clinical results support the differentiated safety and efficacy profile of abemaciclib observed in clinical trials.
A phase 1b study of avelumab plus DCC-3014, a potent and selective inhibitor of colony stimulating factor 1 receptor (CSF1R), in patients with advanced high-grade sarcoma.
Authors: Evan Rosenbaum, Sujana Movva, Ciara Marie Kelly, Mark Andrew Dickson, Mary Louise Keohan, Mrinal M. Gounder, Katherine Anne Thornton, Ping Chi, Jason Earl Chan, Benjamin Nacev, Viswatej Avutu, Matthew Biniakewitz, Olivia Robin McKennan, Haley Phelan, Silvia Perez, Sinchun Hwang, Samuel Singer, Li-Xuan Qin, William D. Tap, Sandra P. D'Angelo
Journal: Journal of Clinical Oncology (2021)

11549 Background: Select sarcomas are infiltrated with immunosuppressive myeloid cells. DCC-3014 is an inhibitor of the CSF1R kinase that decreases tumor infiltrating myeloid cells in preclinical models. We hypothesized that DCC-3014 combined with the anti-PDL1 inhibitor avelumab would be safe and tolerable, decrease immunosuppressive myeloid cells, and increase cytotoxic T cells. Methods: This investigator initiated, open label, single center, phase I study of DCC-3014 plus avelumab in patients (pts) with unresectable or metastatic sarcoma utilized a standard 3+3 dose escalation design. DCC-3014 was administered on days 1-3 (loading dose of 20, 30, or 50 mg) followed by oral daily maintenance (10, 14, or 20 mg) in 28-day cycles; 800 mg of IV avelumab was administered q2weeks. The primary endpoint was to determine the recommended phase 2 dose (RP2D). Secondary endpoints defined the adverse event (AE) profile and assessed clinical efficacy. Peripheral blood CD14 + Lin - HLA-DR lo myeloid-derived suppressor cells (MDSCs) were measured by flow cytometry. Results: 13 pts were treated; median age was 61 (range 32 – 71), 8 were female, and median prior lines of therapy was 5 (range 2 – 10). Histologic subtypes included leiomyosarcoma (LMS, n = 7), undifferentiated pleomorphic sarcoma (2), dedifferentiated liposarcoma (LPS, 2), synovial sarcoma (1), and pleomorphic LPS (1). The Table lists treatment-related AEs (TRAEs) of any grade (G) occurring in ≥ 10% of pts and all G ≥ 3 TRAEs, sorted by frequency. All pts had at least 1 TRAE. Seven pts (54%) had a G ≥ 3 TRAE. Most TRAEs were either G ≤ 2 or expected on-target effects of CSF1R inhibition. 1 of 6 pts on the highest dose level had a dose limiting toxicity (G4 elevated AST with abdominal pain) that resolved with treatment cessation. The highest dose level was declared the RP2D. Best objective response by RECIST 1.1 was stable disease in 3 pts; 2 had LMS and were treated at the highest dose level. At baseline, the mean proportion of monocytes in peripheral blood samples with an MDSC phenotype was 12.2% (range 7.1 – 19.9). 5 of 7 pts with serial blood samples had decreased circulating MDSCs (mean decrease of 26.9% from baseline to last time point). Conclusions: DCC-3014 combined with avelumab was safe and tolerable. Study therapy decreased circulating MDSCs in select patients; T cell analyses will be reported. Study expansion at the RP2D is ongoing. Clinical trial information: NCT04242238. [Table: see text]
An integrative scoring system for survival prediction following gefitinib therapy in non-small cell lung cancer: From a long-term real-world study.
Authors: Shaoxing Guan, Xi Chen, Youhao Chen, Min Huang, Li Zhang, Xueding Wang
Journal: Journal of Clinical Oncology (2021)

e21041 Background: Gefitinib is first-line therapy for patients with EGFR-activating mutation in non-small cell lung cancer (NSCLC). Meanwhile, ̃30% patients were progression within 12 months even harboring EGFR-activating mutation. Furthermore, integrative scoring models for prediction of gefitinib outcomes are still lacking. Variations in genes of DNA repair and cell cycle pathway may have potential impacts on proliferation, migration and invasion of tumor cells. Therefore, we investigated a series of single nucleotide polymorphisms (SNP) in DNA repair and cell cycle genes based on an efficient algorithm machine learning algorithm for establishing an integrative scoring system for survival prediction following gefitinib therapy in NSCLC patients. Methods: A total of 282 patients with activating EGFR mutations were enrolled and divided into train cohort and test cohort, randomly. 125 SNPs in 47 candidate genes were selected by Heploview 4.2 and sequenced by Agena MassARRAY System. Predictive features were selected by randomForestSRC, an efficient algorithm machine learning algorithm to analyze survival data, for PFS following gefitinib therapy. The top candidate variables were presented into COX regression models with hazard ratio as weight for each predictor (HR = 1-1.49 = 1; HR = 1.5-2.49 = 2; HR = 2.5-3.49 = 3), providing p &lt; 0.1. This study was approved by the ethical committee of Sun Yat-Sen University Cancer Center. Results: The progression risk predictive model was established by random forest survival and validated by COX regression analysis, included XRCC1 rs3213263(CT vs CC, RR = 1.997, 95%CI = 1.314-3.036, p = 0.001), FOXO3 rs75544369(GA vs GG, RR = 1.942, 95%CI = 1.139-3.309, p = 0.012), FOXM1 rs2302257(CC vs GG, RR = 2.889, 95%CI = 1.477-5.691, p = 0.002) and ERCC1 rs10408989(TT vs GT, RR = 1.735, 95%CI = 1.152-2.613, p = 0.008; GG vs GT, RR = 3.788, 95%CI = 1.625-8.832, p = 0.002). The progression risk score ranged from 0-10. 49 patients (25.52%) and 20 patients (22.22%) were scored 0, 18(9.38%) and 10(11.11%) patients were scored more than 5 in train cohort and test cohort, respectively. According to the risk score of patients, we divided the patients into four groups, the median PFS were 26.23(95%CI:14.23-35.37), 16.80(95%CI:12.87-23.60), 11.13(95%CI:8.87-16.70) and 6.25 (95% CI:4.43-11.67) months for 0, 2, 3&amp;4 and ≥5 group (p &lt; 0.0001) in the train cohort. Meanwhile, the median PFS were 18.80(95%CI:11.80-64.53),13.60(95%CI:9.17-27.33), 13.47(95%CI:9.83-18.40), 13.47(95%CI:9.83-18.40) and 7.40(95%CI:3.33- NA) months for 0, 2, 3&amp;4 and ≥5 group in validation cohort (p = 0.0017). Conclusions: The risk score system is a simple tool for risk stratification in patients undergoing gefitinib. Widespread application of the score system will require further independent validation.
Weight management following endometrial cancer treatment: A pilot trial to evaluate the efficacy of the profile by Sanford program.
Authors: Maria Bell, Valerie Reed, Jan Wernisch, Natalie Papini, Steve Herrmann
Journal: Journal of Clinical Oncology (2021)

12056 Background: Excess weight and weight gain are risk factors for endometrial cancer and cancer recurrence following treatment for women with endometrial cancer. Conversely, weight loss among women with obesity has been shown to reduce endometrial cancer risk. Intensive behavioral weight management programs may be an effective method to improve health and reduce weight following treatment. Methods: Twenty-two women following endometrial cancer treatment (age = 59.4 ± 11.5; weight = 241.3 ± 46.3; BMI = 40.5 ± 7.8; time since last treatment 19 ± 17.4 months) were enrolled in a behavioral weight management program and followed for 12 months and 28 matched controls (age = 58.4 ± 11.5; weight = 246.9 ± 60.3; BMI = 41.6 ± 8.6) were assessed over 12 months. The program consists of weekly health coaching meetings to discuss nutrition, activity, and behavior change topics. The nutrition plan targets ≥4 cups of vegetables per day, a ‘lean and green’ grocery meal, complimented with meal replacement foods to provide a nutritionally complete meal plan. Cost of participant membership, coaching, and meal replacements were covered for 6 months and available to purchase for months 7-12. Results: The treatment group completed 28.3 ± 14.1 appointments throughout 12 months resulting in an average weight change of -31.2 ± 17.3 pounds (-13.3 ± 7.4%) at 6 months and -36.1 ± 27.6 pounds (-15.3 ± 11.4%) at 12 months (all p&lt;0.001). Controls had a weight change of -3.9 ± 18.4 pounds (-2.3 ± 7.6%) at 12 months which was significantly different than the treatment group (p&lt;0.001). BMI was significantly reduced in the treatment group at 6 months (-4.8 ± 4.5, p&lt;0.001) and 12 months (-5.2 ± 5.9, p&lt;0.001) and significantly different than in the control group at 12 months (-0.9 ± 3.2, p=0.007). Conclusions: This behavioral weight management program with health coaching and structured nutrition provided clinically significant weight loss that was sustained to 12 months. Future research should examine long-term enrollment in the Profile by Sanford program with reduction in endometrial cancer recurrence.[Table: see text]
Safety and efficacy of an anti-claudin-5 monoclonal antibody to increase blood–brain barrier permeability for drug delivery to the brain in a non-human primate
Authors: Keisuke Tachibana, Yosuke Hashimoto, Keisuke Shirakura, Yoshiaki Okada, Ryuichi Hirayama, Yumi Iwashita, Itsuki Nishino, Yukio Ago, Hiroyuki Takeda, Hiroki Kuniyasu, Masuo Kondoh
Journal: Journal of Controlled Release (2021)