tbuckley/cabot-search huggingface dataset:
Risk factors associated with skeletal-related events following denosumab cessation among patients with bone metastases from solid tumors: A real-world machine learning approach.
Authors: Alison Stopeck, Celestia S. Higano, David H. Henry, Basia A. Bachmann, Marko Rehn, Dionna Jacobson, Benoit Cadieux
Journal: Journal of Clinical Oncology (2021)

1567 Background: The anti-RANKL monoclonal antibody denosumab has been shown to be superior to the bisphosphonate zoledronate for the prevention of skeletal-related events (SREs) in patients with incident bone metastases (BM) from solid tumors (ST). Clinical guidelines recommend the use of a bone-targeting agent for SRE prevention for ≥ 2 years. However, real-world treatment patterns in the U.S. suggest that the denosumab treatment duration is often &lt; 1 year. Applying a machine learning approach, we sought to identify risk factors associated with SRE incidence following cessation of denosumab to help inform optimal clinical SRE prevention strategies. Methods: Using the Optum PanTher Electronic Health Record repository, patients diagnosed with incident BM from a primary ST between 1 Jan 2007 and 1 Sep 2019 were evaluated for inclusion in the study. Eligible patients had to receive ≥ 2 consecutive 120 mg denosumab doses on an every 4-week (± 14 days) schedule and have a minimum follow-up ≥ 1 year after the last denosumab dose or an SRE occurring between days 84 and 365 after denosumab cessation. Extreme gradient boosting was used to develop an SRE risk prediction model evaluated on a test dataset. Impact and relative importance of available medical, clinical, and treatment factors on SRE risk following denosumab cessation were extracted from the model using Shapley additive explanations (SHAP). Univariate analyses on risk factors with the highest importance from pooled and tumor-specific models were also conducted. Results: A total of 1,414 patients (breast, n = 563 [40%]; prostate, 421 [30%]; lung, 180 [13%]; other cancers, 250 [17%]) met inclusion criteria, with a median of 253 (min, 88; max, 2726) days of denosumab treatment; 490 (35%) experienced ≥ 1 SRE following denosumab cessation. With a meaningful model performance based on an area under the receiver operating characteristic (AUROC) score of 77%, SHAP identified several significant factors that predicted an increased SRE risk following denosumab cessation, including prior SREs, shorter denosumab treatment duration, and a higher number of clinic visits as the top-ranked factors (Table). Conclusions: A machine learning approach to SRE risk factor identification may help clinicians better assess the individualized patient’s need for denosumab treatment persistence and improve patient outcomes. Results from tumor-specific groups will be presented at the meeting.[Table: see text]
Porous tantalum structure integrated on Ti6Al4V base by Laser Powder Bed Fusion for enhanced bony-ingrowth implants: In vitro and in vivo validation
Authors: Pengfei Lei, Hu Qian, Taomei Zhang, Ting Lei, Yihe Hu, Chao Chen, Kechao Zhou
Journal: Bioactive Materials (2021)

Despite the widespread application of Ti6Al4V and tantalum (Ta) in orthopedics, bioinertia and high cost limit their further applicability, respectively, and tremendous efforts have been made on the Ti6Al4V-Ta alloy and Ta coating to address these drawbacks. However, the scaffolds obtained are unsatisfactory. In this study, novel high-interface-strength Ti6Al4V-based porous Ta scaffolds were successfully manufactured using Laser Powder Bed Fusion for the first time, in which porous Ta was directly manufactured on a solid Ti6Al4V substrate. Mechanical testing revealed that the novel scaffolds were biomechanically compatible, and the interfacial bonding strength was as high as 447.5 MPa. In vitro biocompatibility assay, using rat bone marrow mesenchymal stem cells (r-BMSCs), indicated that the novel scaffolds were biocompatible. Alkaline phosphatase and mineralized nodule determination demonstrated that the scaffolds favored the osteogenic differentiation of r-BMSCs. Moreover, scaffolds were implanted into rabbits with femur bone defects, and imaging and histological evaluation identified considerable new bone formation and bone ingrowth, suggesting that the scaffolds were well integrated with the host bone. Overall, these results demonstrated good mechanical compatibility, biocompatibility, and osteointegration performance of the novel Ti6Al4V-based porous Ta scaffold, which possesses great potential for orthopedic clinical applications.
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: Mi Young Choi, Da Hye Moon, Jong-min Jo, Hae Ung Lee, Seri Park, Byung Hee Jeon, Chang Min Choi
Journal: Journal of Clinical Oncology (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.
Response to selpercatinib versus prior systemic therapy in patients (pts) with <i>RET</i> fusion+ non-small-cell lung cancer (NSCLC).
Authors: Alexander E. Drilon, Oliver Gautschi, Benjamin Besse, Vivek Subbiah, Daniel Shao-Weng Tan, Keunchil Park, Filippo G. De Braud, Guzman Alonso, Juergen Wolf, Victoria Soldatenkova, Pearl Plernjit French, Aimee K. Lin, Koichi Goto, Benjamin J. Solomon
Journal: Journal of Clinical Oncology (2021)

9032 Background: Selpercatinib, a first-in-class highly selective, potent, CNS-active RET kinase inhibitor, is approved in multiple countries for treatment of RET fusion+ lung or thyroid cancers. Selpercatinib demonstrated durable antitumor activity in previously treated pts with RET fusion+ NSCLC in an ongoing Phase 1/2 trial, LIBRETTO-001 (Besse et al., ASCO 2021). Methods: Pts with RET fusion+ NSCLC enrolled in the global, multicenter, LIBRETTO-001 trial (NCT03157128; 16 countries, 89 sites). Primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival, duration of response, and safety. This post-hoc intrapatient analysis was based on a 30 March 2020 data cutoff date. Historical physician-reported best overall response (BOR) from last systemic therapy received prior to enrollment was compared with selpercatinib BOR by independent review committee per RECIST v1.1, with each patient serving as his/her own control. Results: In efficacy-evaluable pts (N = 218) who previously received platinum-based chemotherapy (chemo), median pt age was 61 years, the majority with ECOG of 0/1 (37%/61%), with a median of 2 (range: 1-15) prior systemic therapies. Overall, 57% of patients responded to selpercatinib while 16% responded to the immediate prior therapy. ORR improvements with selpercatinib were observed regardless of prior therapy: chemotherapy + immune checkpoint inhibitor (ICI) (57% vs 14%), single-agent ICI (48% vs 3%), or chemotherapy (58% vs 15%). A total of 108 patients (49%) did not respond to immediate prior therapy but responded to selpercatinib. Fewer patients had progressive disease as their BOR with selpercatinib (2%) compared to the immediate prior therapy (28%). The median duration of therapy for selpercatinib was notably extended compared with that of the immediate prior therapy (11.8 vs. 3.4 months, respectively). Conclusions: In pts with RET fusion+ NSCLC treated on LIBRETTO-001, systemic therapies administered prior to enrollment achieved less meaningful clinical benefit than selpercatinib. Selpercatinib demonstrated consistent efficacy regardless of the type of prior therapy. Clinical trial information: NCT03157128.
National survey on access to new oncology drugs pending health technology assessment and financial arrangements.
Authors: Sahar Barjesteh van Waalwijk van Doorn-Khosrovani, Anke Pisters-van Roy, Haiko Bloemendal, Hans Gelderblom
Journal: Journal of Clinical Oncology (2021)

e13599 Background: In the Netherlands, the health insurance package usually covers cancer drugs after EMA approval and positive recommendation of the Dutch Society of Medical Oncology (NVMO). However, the government can temporarily exclude newly licensed indications with high budget impact from coverage until the national HTA-body advises on the clinical effectiveness and cost effectiveness. Based on the recommendations of the HTA-body, the government negotiates a financial arrangement with manufacturers. Because submitting value dossiers, assessments and negotiations takes time there have been concerns regarding patients’ access to these novel treatments, especially for life threatening conditions such as cancer. Due to a lack of transparency, it is not known to what extent patients are given access to ‘free of charge programmes’ (FCPs). Methods: A list of oncology drugs and indications which were temporarily excluded from reimbursement due to negotiations with the government (July 2015-Dec. 2020). We contacted all the pharmaceutical companies that were engaged in the process above, to inquire about access to their products during the HTA evaluation and negotiations. Results: In total 17 oncology drugs (46 EMA registered indications) of 11 companies were subjected to financial agreements by the government. In 41,3% (19/46) of cases, FCPs were available via individual prescriber requests in a selected number of hospitals. In all other cases such arrangements were not needed because alternative treatment options were available (15,2%; 7/46) or because treatment was not recommended by the NVMO (13,0%; 6/46). For one indication FCP was available but the treatment eventually received a negative recommendation. In 30,4% (14/46) of the cases there was immediate reimbursement in place following a positive NVMO recommendation through umbrella agreements. Such agreements cover existing indications but also all the indications that will be licensed in the future. Umbrella agreements were especially set up for immune checkpoint inhibitors that showed benefit across multiple indications. As anticipated, some patient-access programmes had already started prior to EMA approval. In 5 cases an official compassionate use programme was set up through the Dutch Medicines Evaluation Board prior to authorisation. Conclusions: Our survey indicates that all manufacturers are committed to enabling patients’ and clinicians’ early access to their products pending payers’ approval in a high income country such as the Netherlands. However, the lack of transparency regarding the hospitals offering these programmes may result in inequity in access. Besides, there is no structural data collection. Recently, the NVMO has established a platform (DRUG Access Protocol) to harmonise all compassionate use programmes and FCPs, generating real-world data and ensuring equal access for all patients.
Patient perceptions of palliative care in the process of allogeneic hematopoietic cell transplantation.
Authors: Megan Elizabeth Melody, Chimere Bruning, Rachel Mack, Kimberley Parrott, Richard Taylor, James M. Foran, Vivek Roy, Ernesto Ayala, Mohamed Kharfan-Dabaja, Hemant S. Murthy, Molly Kilpatrick, Maisha Robinson
Journal: Journal of Clinical Oncology (2021)

e24082 Background: Allogeneic hematopoietic cell transplantation (allo-HCT) is associated with significant short- and long-term sequelae that affect patients’ overall quality of life (QoL) and their physical and psychological well-being. Studies have shown improvement in patient QoL and physician satisfaction with palliative care involvement in the allo-HCT process. However, patient and physician perceptions regarding palliative care often impact timely referral. We conducted a prospective study to examine patient perceptions of palliative care both before and after palliative care consultation during evaluation for allo-HCT. Methods: This is a prospective, single-center study, of patients &gt; 18 years of age, who were referred for a palliative care consultation as part of standard evaluation for allo-HCT. Patients were administered a pre- and post-visit internally derived questionnaire to assess their understanding and comfort level with palliative care. The primary objective of this study was to examine patient perceptions of palliative care consultation during evaluation for allo-HCT. Primary end point was the change in patient pre- and post- questionnaire responses. Secondary endpoint was the completion of advance care planning documentation pre- and post- consultation. Results: We enrolled 32 patients (male = 14) undergoing evaluation for allo-HCT with a primary diagnosis of AML (n = 8), NHL (n = 8), MDS (n = 7), ALL (n = 2), and other (n = 7). Following consultation with palliative care there was a statistically significant increase in patient understanding of the reason for the appointment, p = 0.0006. There was also a significant increase in patient’s knowledge of palliative care, with only 28% describing their knowledge as “good” or “excellent” prior to consultation and 79.3% after consultation, p &lt; 0.0001. There was an observed positive, non-statistically significant, trend in patient comfort level with palliative medicine with only 20.7% (n = 6) describing their comfort as “high” or “very high” prior to consultation and 51.7% (n = 15) after consultation, p = 0.60. There was a higher rate of completion of advance care planning documentation following consultation with palliative medicine 56.3% vs 71.4%, p = 0.042. Conclusions: Palliative care consultation prior to allo-HCT increases a patient’s understanding of the role of palliative medicine as part of their allo-HCT and improves advance care planning. These findings need to be validated in a larger, multicenter, patient cohort.
Efficacy of KD033, an anti-human-PD-L1-IL-15 bispecific protein, in human-PD-L1 positive and negative murine tumor models.
Authors: Stella Martomo, Dan Lu, Zhanna Polonskaya, Xenia Luna, Zhikai Zhang, Galit Regev, Olivier Schueller, Jeegar Patel
Journal: Journal of Clinical Oncology (2021)

e14556 Background: KD033 is a clinical-stage bispecific fusion molecule consisting of a high-affinity anti-human-PD-L1 antibody and human IL-15. Preclinical studies have demonstrated that targeting IL-15 with anti-PD-L1 antibody resulted in increased efficacy, safety and maximal tolerated dose of the fusion protein compared to administration of free IL-15, as well as reduction of tumor growth in both PD-L1 positive and negative tumor models (1). The goal of the current study is to directly compare KD033 efficacy when PD-L1 is present or absent on the surface of the same tumor. Methods: KD033 was administered in the human-PD-L1/PD-1 transgenic C57/Bl6 mice subcutaneously transplanted with human-PD-L1 positive and negative MC38 colon carcinoma cells. This animal model allowed the evaluation of the impact of the presence or absence of human-PD-L1 expression on the tumor cell surface without altering human-PD-L1 expression on immune cells. Results: KD033 treatment resulted in significant tumor growth reduction in both human-PD-L1 positive and negative MC38 tumors. Analysis of peripheral immune cell populations showed similar increases of CD8 T and NK cells between human-PD-L1 positive and negative MC38- bearing mice after KD033 administration. Immunohistochemistry demonstrated a significant increase in CD8 T-cell infiltration into the human-PD-L1 positive MC38 tumors, whereas NK cells infiltration was more pronounced in the human-PD-L1 negative MC38 tumors. Analysis of tumor gene transcription after KD033 treatment highlighted differences in gene signatures between human-PD-L1 positive and negative MC38 tumors following KD033 treatment. Conclusions: These results showed that the efficacy of anti-PD-L1-IL-15 fusion protein is not limited to PD-L1 tumor expression as KD033 was efficacious in both PD-L1 positive and negative tumors. Mol Cancer Ther February 1 2021 (20) (2) 347-356; DOI: 10.1158/1535-7163.MCT-20-0457
4,5 disubstituted acridones with high selectivity for telomeric G-quadruplex and low toxicity in normal cells
Authors: Francisco Cuenca, Michael Moore, Berengere Guyan, Karin Johnson, Shozeb Haider, Stephen Neidle
Journal: Cancer Research (2007)

4740  Telomerase is an enzyme expressed in around 90% of cancer cells. We are studying approaches to telomerase inhibition as an anticancer strategy that targets its substrate, 3’-end single-stranded telomeric DNA. Telomerase does not recognise the substrate when it is folded into a G-quadruplex structure. The formation in vivo and ligand-mediated stabilisation of these structures would effectively inhibit telomerase.  We have designed and synthesised a diverse library of 4,5-disubstituted compounds based on the acridone core and evaluated them as G-quadruplex stabilising agents (by fluorescence resonance energy transfer assay, FRET), telomerase inhibitors (with the telomeric repeat amplification protocol assay, TRAP) and as anticancer agents (by cell culture studies). Furthermore, we have also carried out molecular modelling studies in order to identify the mode of binding to the quadruplex and also calculated their binding energies using MM-PBSA method.  A particular group of features confers to these molecules potency and selectivity towards the G-quadruplex DNA. The results from the biophysical assays and cell culture studies support this hypothesis. The DNA melting experiments showed a degree of stabilisation for the G-quadruplex DNA comparable to the most potent existing ligands but only very low affinity for duplex DNA. The values of telomerase inhibition correlated well with the DNA melting experiments and the most potent compounds were in the low micromolar range. In the short term cell culture experiments most compounds showed selective toxicity towards the cancer cell lines (MCF7 and A549) when compared with a somatic one (IMR90). The long-term studies for a number of compounds showed effects on cell proliferation at concentrations below those required for short-term cell kill and no sign of resistance.
EPCT-13. SINGLE INSTITUTION RETROSPECTIVE ANALYSIS OF TUMOR MUTATIONAL BURDEN AND SURVIVAL IN PEDIATRIC BRAIN TUMORS
Authors: Rose Parisi, Roshal Patel, Lauren Weintraub
Journal: Neuro-Oncology (2021)

Abstract Tumor mutational burden (TMB) has been studied across numerous cancer types as a means of risk stratification. To examine the prognostic relevance of TMB to pediatric central nervous system (CNS) tumors, we conducted a retrospective analysis of patients at Albany Medical Center diagnosed from 2012 to present. Patients were &amp;lt;21 at diagnosis, had a primary CNS tumor and available genomic data. Forty-seven patients were included – 22 low-grade gliomas, 10 high-grade gliomas, 5 medulloblastomas, 3 ependymomas, 2 choroid plexus carcinomas, and 5 other CNS tumors, with a median follow up of 36 months, median age at diagnosis 10 (1–19), and 47% female. Median TMB was 1 mutation per megabase (mut/mb); range 0–6. Nine patients did not have available TMB data. Twenty-seven patients had driver mutations and other alterations implicated in cancer development including, including BRAF-KIAA1549 fusion (n=6), NF1 loss (n=5), FGFR1 amplification (n=4), TP53 inactivation (n=4), BRAF V600E mutation (n=3), and H3F3A K28M mutation (n=3). Patients with low TMB (&amp;lt;3 muts/mb; n=24) versus high TMB (≥3 muts/mb; n=14) had a survival of 87% versus 71%, respectively, at last follow-up. Of note, all but one patient in the low TMB cohort had localized disease at diagnosis versus three in the high TMB cohort. High TMB was more prevalent in high- (45%, 9/20) versus low-grade histologies (22%, 4/18). Patients with BRAF alterations had LGGs and low TMB (0–1 muts/mb) with all patients surviving at last follow up. Of the eight deaths observed (median 18 months from diagnosis) TMB was high in 4, low in 3, and unknown in 1; all had high-grade histology. Although limited, our data suggests higher TMB may be associated with worse outcome. This analysis will be expanded via a multi-institutional review of TMB and genomic alterations in pediatric CNS patients to better identify high-risk patients requiring alternative treatment strategies.