tbuckley/cabot-search huggingface dataset:
Mutations in hepatocellular carcinoma (hcc): related to geographical area but not an identified viral aetiology
Authors: S D Ryder, H Zentgraf, L M M B Pereira, D Luo, B Portmann, Sérgio Mies, R M L Muszkart, Q F Lui, J J Su, N Naoumov, R Williams
Journal: Journal of Hepatology (1993)
Preclinical evaluation of the ETS inhibitor TK216 against relapsed and refractory childhood leukemia.
Authors: Ritul Sharma, Satbir Thakur, Mohit Jain, Chunfen Zhang, Anne-Marie Langevin, Aru Narendran
Journal: Journal of Clinical Oncology (2021)

10033 Background: Although survival rates have improved in the recent past, relapse and refractory disease remain a significant cause of death in children with leukemia. This calls for an urgent need for the development of novel therapies that could effectively treat leukemias in children. The E26 transformation specific (ETS) family of transcription factors regulate various normal cellular functions but are abnormally expressed in various cancers, including leukemia. TK216 is an ETS inhibitor, that has shown pre-clinical activity and clinical efficacy in solid tumors. In this study, we explore the feasibility of using TK216 as a therapeutic agent for the treatment of high risk refractory pediatric leukemia. Methods: A panel of pediatric leukemia derived cell lines and primary blast cells representing a spectrum of molecular abnormalities seen in pediatric leukemia were treated in vitro with TK216 to determine cytotoxicity. Normal lymphocytes were used as controls and cell viability was determined 72 hours post-treatment by Alamar blue assay. The induction of tumor cell apoptosis and target modulation were detected by Western blotting. Alterations in the cell cycle were assessed by FACS analysis with PI staining. Drug combination studies were carried out with established anti-leukemic agents to identify synergy for greater therapeutic efficiency. Results: TK216 decreased cell viability in leukemia cells compared to normal lymphocyte controls in a dose-dependent manner with variations in sensitivity noted with inherent molecular abnormalities. The IC 50 values observed ranged from 0.22 µM for the most sensitive cell line, MV4-11 to 0.95 µM for least sensitive cell line, SUP-B15. Apoptosis induction upon TK216 treatment was confirmed by PARP cleavage and caspase 3 activation. Cell cycle analysis demonstrated increased sub-G1 population of cells after TK216 treatment. A strong correlation between sub-G1 population and sensitivity of the cell line towards TK216 (47% in MV4-11 vs 3.72% in SUP-B15) was observed. Screening of a panel of 200 FDA approved anti-cancer agents in drug combination studies identified potential agents for drug synergy. Significant drug synergy was noted with TK216 in combination with the epigenetic modifier 5-azacytidine and the Bcl-2 inhibitor, Venetoclax. [Combination Index for Venetoclax and TK216, mean = 0.65 for MV4-11 and 0.33 for SUP-B15]. Conclusions: Data from our study demonstrate that the ETS inhibitor TK216 induces apoptosis and cell cycle arrest in pediatric leukemia cells at physiologically relevant concentrations. Our combination studies identified distinct anti-cancer agents that could be used for developing effective drug combination regimens with TK216. Overall, our findings provide essential preclinical data for the consideration of TK216 in early phase clinical trials for the treatment of selected high-risk and refractory childhood leukemia.
Representation trends in radiation oncology training programs in the United States.
Authors: Emilie Garcia, Jacob Lang, Oluchi Ukaegbu Oke, Krishna Reddy, Obi Ekwenna
Journal: Journal of Clinical Oncology (2021)

11043 Background: The ASCO and American Society of Radiation Oncologists (ASTRO) have recently committed to initiatives on increasing URM representation in the radiation oncology workforce. This study aims to assess representation trends in radiation oncology training programs across five academic years in order to understand representation trends and better guide initiatives moving forward. Methods: Data on racial and ethnic representation from the ACGME Data Resource Books over a span of five academic years (2015-2020) was included. URM was defined as those who identified as Hispanic, Black, or Native American/Alaskan in concordance with AAMC definition. Chi square testing was used to compare the proportion of residency positions occupied by URM residents by self-identified race and ethnicity in radiation oncology to that of hematology and medical oncology, complex general surgical oncology, and all other specialties. Results: A total of 3,315 radiation oncology positions were identified over the study period, 2015 and 2020. 1,938 (58.5%) of radiation oncology residency positions were filled by residents who identified as White, 967 (29.2%) as Asian/ Pacific Islander, 126 (3.8%) as Hispanic, 120 (3.6%) as Black, 7 (0.2%) as Native American/ Alaskan, and 157 (4.7%) as Other. URM representation was 7.6% in total and was relatively stagnant, remaining between 7.3% and 8.0% across study years. Results of chi square comparative analysis demonstrated lower rates of representation in radiation oncology in comparison to hematology and medical oncology as well as all other specialties (Table). Conclusions: There is lack of racial and ethnic diversity in radiation-oncology residency training positions in the United States. Over the five-year study period, only 7.6% of trainees identified as URM. URMs have significantly lower rates of representation in radiation-oncology compared to hematology and medical oncology, and other specialties. Efforts to mitigate disparities require a multifaceted approach.[Table: see text]
Phase I study of liposomal irinotecan (LY01610) in patients with advanced esophageal squamous cell carcinoma.
Authors: Yun Liu, Bo Zhang, Jianping Xu, Xingyuan Wang, Jialin Tang, Jing Huang
Journal: Journal of Clinical Oncology (2021)

e16097 Background: This phase I trial was performed to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), preliminary efficacy, and pharmacokinetics (PK) of LY01610, a novel liposome-encapsulated irinotecan, in patients with advanced esophageal squamous cell carcinoma (ESCC). Methods: This trial was conducted in two stages. In the dose-escalation stage, patients with advanced ESCC refractory or intolerant to previous chemotherapy received escalating doses of LY01610. A recommended dose based on patient tolerance was then expanded in the second stage. LY01610 was administered intravenously every 2 weeks, except that the first cycle in dose-escalation was three weeks to allow observation of DLTs. Results: Twenty-four patients were enrolled across four dose levels (30, 60, 90 and 120 mg/m 2 ). The DLTs included vomiting and febrile neutropenia, and the MTD was 90 mg/m 2 . The most common grade 3/4 adverse events were leukopenia in six patients (25.0 %), anemia in six patients (25.0 %) and neutropenia in five patients (20.8 %). One patient achieved complete response, and four had partial response, including one patient receiving LY01610 at the starting dose of 30 mg/m 2 . Compared with conventional irinotecan, the PK profile of LY01610 was characterized by increased and prolonged exposure of total irinotecan and the active metabolite SN-38 in plasma. Conclusions: LY01610 demonstrated manageable toxicity and promising antitumor activity in patients with advanced ESCC. Future clinical development of LY01610 as single agent or in combination with other anti-cancer agents in treating ESCC patients is warranted. Clinical trial information: NCT04088604.
Abstract 18116: Genetic Associations With Atherosclerotic Abdominal Aortic Calcification
Authors: Rajeev Malhotra, Andreas C Mauer, Jie Yao, Xiuqing Guo, Albert V Smith, Sonali Pechlivanis, Shih-Jen Hwang, Judy Wang, Lingyi Lu, Christian Lino-Cardenas, Georgia Shelton, Caitlin O’Rourke, Anjana Gupta, Catherine Y Campbell, Andrew D Johnson, Ci Song, Hagen Kälsch, Markus M Nöthen, Barry I Freedman, Donald W Bowden, George Thanassoulis, Mark E Lindsay, Donald B Bloch, Karl-Heinz Jöckel, Susanne Moebus, Raimund Erbel, Mary Feitosa, Vilmundur Gudnason, Wendy S Post, Christopher J O’Donnell
Journal: Circulation (2015)

Background: There is limited information regarding genetic contributions to atherosclerotic aortic calcification, an important predictor of cardiovascular disease. Methods: We conducted a genome-wide association study (GWAS) meta-analysis with subsequent replication analysis to define single nucleotide polymorphisms (SNPs) associated with abdominal (AAC) or thoracic aortic calcification (TAC). AAC and TAC were quantified using multi-detector computed tomography. SNPs were assayed by Illumina or Affymetrix arrays and imputation at the cohort level was performed using data from the 1000 Genomes project. Results: 9417 individuals of European descent from four cohorts of the Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) consortium were included in the AAC discovery analysis and 8422 individuals from five cohorts in the TAC discovery analysis. SNPs achieving genome-wide significance were tested for replication in four additional cohorts with Hispanic-American (HA) and African-American (AA) participants. Two regions contained SNPs associated at a genome-wide level for AAC (p&lt;5.0x10 -8 , Table), the HDAC9 (chromosome 7, 6 SNPs) and RAP1GAP (chromosome 1, 2 SNPs) genetic loci. All six HDAC9 SNPs were associated with AAC in HA. Among these, rs2107595 was associated with AAC both in HA (p=2.8x10 -6 ) and in AA (p=0.01). SNPs in RAP1GAP were not associated with AAC in the replication analysis. No SNPs were associated with TAC at the genome-wide threshold. SNPs in the HDAC9 locus were associated with other forms of calcification (coronary artery calcification) as well as clinically apparent coronary heart disease (p&lt;0.05). Conclusions: SNPs in the HDAC9 locus are associated with the presence of AAC in participants of European descent. This association was replicated in other ethnic groups in the United States. These findings suggest a novel role for HDAC9 in the development of abdominal aortic calcification.
Evaluation of dystrophin expression by immunohistochemistry as a prognostic factor in leiomyosarcomas (LMS).
Authors: Raul Terés, Paula Cerdà, Ana Sebio, Pablo Gallardo, Aida Bujosa, Maria Borrell, Berta Martin, Antonio Lopez-Pousa, Alberto Gallardo, Silvia Bague, Ruth Orellana
Journal: Journal of Clinical Oncology (2021)

e23525 Background: Leiomyosarcomas (LMS) are soft tissue sarcomas that derive from smooth muscle cells and can arise anywhere in the body (most frequently in extremities, uterus or retroperitoneum). The clinical prognostic factors are well established but molecular factors influencing prognostic are unknown. The DMD gene, which codifies for the dystrophin protein, has been proposed as tumour suppressor gene in LMS. The aim of our study is to evaluate dystrophin expression in LMS and its relation with the patient prognosis. Methods: A total of 103 patients (pts) with LMS were analysed. Clinical and pathological data were collected retrospectively from patients’ electronic board system. Dystrophin expression was analysed by immunohistochemistry (IHC) in paraffin embedded tissue LMS samples using the Novocastra NCL-DYS2 (Leica Biosystems). Semiquantitative assessment of the staining was classified from score 0 to 3 (0 = no dystrophin expression, 1 = low expression, 2 = moderate expression, 3 = high expression). Results: Of all 103 pts, 70 (68%) had localized disease and the majority of tumours were larger than 5 cm (75%). The most frequent locations of primary LMS were extremities (n = 31; 30.1%), uterus (n = 23; 23.2%) and retroperitoneum (n = 21; 20.4%). Most LMS were high grade (G): 7 pts G1 (6.8%), 35 pts G2 (34%) 2 and 53 pts G3 (51.5%). 50 of all grade LMS (48.6%) had loss of dystrophin expression (score 0), 17 (16.5%) had score 1, 23 (22.3%) score 2 and 10 (9.7%) score 3. Loss/low dystrophin expression measured as score 0 or 1, was more frequent in grade 3 LMS compared to grade 2 or grade 1 (77.4% vs. 57.1% vs. 16.7%; p = 0.005). There were no differences in dystrophin loss between localized or metastatic disease at diagnosis (64.2% vs. 72.2%; p &gt; 0.05). In our series, loss or reduced dystrophin expression did not correlate with the risk of relapse in localized patients or overall survival in metastatic patients. Conclusions: Loss of dystrophin expression is a common event in LMS. Loss/low dystrophin expression is more frequent in grade 3 LMS compared to grade 2 and grade 1 LMS. Loss of dystrophin expression did not correlate with risk of relapse or overall survival in our series. Additional genetic evaluations to study DMD in LMS are underway.
Clinical characteristics and outcomes of cancer patients with chronic kidney disease and coronavirus disease 2019.
Authors: Omar Mamlouk, Anastasia Turin, David D'Achiardi, Cesar Simbaqueba, Kodwo Dickson, Maria Franco-Vega, Josiah Halm, Sreedhar Mandayam
Journal: Journal of Clinical Oncology (2021)

e18815 Background: Coronavirus disease 2019 (COVID-19) has been associated with higher risk of acute kidney injury (AKI) and mortality rate in cancer patients. The prevalence of CKD in cancer patients is close to 20-30% however there has been limited data about cancer patients with CKD and COVID-19 infection. The aim of this study is to evaluate the clinical characteristics and outcomes of this patient population at a tertiary cancer center. Methods: All patient data — demographics, labs, comorbidities and outcomes — were aggregated and analyzed in the Syntropy platform, Palantir Foundry (“Foundry”), as part of the Data-Driven Determinants of COVID-19 Oncology Discovery Effort (D3CODE) protocol at MD Anderson. The cohort was defined by the following: (1) positive COVID-19 test; (2) baseline eGFR 15-59 ml/min/1.73m2 calculated by chronic kidney disease epidemiology collaboration equation. The baseline GFR and creatinine values used the most temporally proximal lab results within 30 days prior to the patient’s infection. AKI was defined as an absolute change of creatinine ≥0.3 mg/dl above the baseline after the positive COVID-19 test. Results: Out of 790 patients with COVID-19,19.6% had underlying CKD. Among these, 86.5% and 46.5% had history of hypertension and diabetes mellitus, respectively. 77.3% had a solid malignancy and 87.3% of them had metastatic disease. 67.7% were asymptomatic, 14.2% required ICU admission, 10.3% required invasive ventilation support, and 11.6% died within 90 days of the COVID-19 test. AKI developed within the first 30 days in 61.3% and 8.4% required renal replacement therapy. AKI was more prevalent in patients who were hospitalized (84.2% vs. 31.7%, p&lt; 0.001), had concurrent pneumonia (63.3% vs. 36.8%, p&lt; 0.002), required critical care (68.3% vs. 15.8% , p&lt; 0.001), and were on ventilation support (16.8% vs. 0%, p=0.002). There was no significant statistical difference in rates of diabetes (52.6% vs. 36.7%, P of 0.076), tumor staging (metastasis; 95.1% vs. non metastatic 82.6%, p&lt; 0.2) , readmission rate (52.6% vs. 43.3%, p=0.336), and death rate at 30 days (9.5% vs. 3.3%, p=0.205) between the two groups. Conclusions: The overall mortality rate of cancer patients with CKD and positive COVID-19 test was relatively high and close to 1.7 times the rate of patients with no CKD at our tertiary cancer center. AKI is a common complication in CKD patients with concurrent pneumonia and requiring ventilation support, and was associated with increased morality at 90 days.
Germline testing in community oncology patients with somatic BRCA1/2 mutations.
Authors: Kate Principe, Trisha Nichols, Gayle Patel, Ann Bunnell, Camille Fisher, Katharine Lord, Steven Carlisle, Vanessa Torres, Lalan S. Wilfong, Dhatri Kodali
Journal: Journal of Clinical Oncology (2021)

1523 Background: The primary purpose of tumor mutation profiling (TMP) is to molecularly characterize tumors to identify targeted treatments and improve outcomes, but it may also uncover germline mutations with implications for patients and families. In September 2016, the National Comprehensive Cancer Network (NCCN) added “BRCA1/2 mutation detected by TMP” as a criterion for germline BRCA1/2 testing. This study aims to assess rates of germline testing, with and without genetic consultations, for individuals with a somatic BRCA1/2 finding in community oncology centers. Methods: Retrospective data was abstracted from an internal database of results from four TMP laboratories. Individuals with a somatic BRCA1/2 pathogenic/likely pathogenic (P/LP) variant reported from January 1, 2017 to December 31, 2019 were included. Clinical data was obtained from electronic medical records. The project was approved by the Texas Oncology Privacy Board. Results: 221 patients had a P/LP somatic BRCA1/2 result on TMP, 138 of which were BRCA1/2 spectrum tumors (breast, ovary, pancreas, prostate). 144/221 patients (65.2%) had BRCA1/2 germline testing. 133/221 (60.2%) met NCCN guidelines for germline BRCA1/2 testing independent of their somatic results; they were statistically more likely to undergo germline testing than patients who did not otherwise meet germline BRCA1/2 testing criteria (p=2.3e-16) (Table). 70/144 (48.6%) had a germline P/LP BRCA1/2 mutation identified. At locations with genetic providers versus those without, there was a significant difference in rates of genetic consultation (p=0.02) but not in the rate of germline testing (p=0.3). This indicates patients were more likely to receive pre- and post-test counseling at clinics offering in-house genetic consultations. Conclusions: Most individuals who had a P/LP somatic BRCA1/2 mutation identified on TMP underwent germline genetic testing. As 60.2% of our cohort qualified independently for germline testing, somatic BRCA1/2results may not have been the driving force behind germline testing. However, individuals who had a non- BRCA1/2-spectrum tumor were significantly less likely to have the recommended confirmatory germline testing. Quality improvement initiatives can focus on improving rates of counseling and germline testing for patients with somatic BRCA1/2 mutations, regardless of tumor type.[Table: see text]
NOTCH Activation at the Definitive Mesoderm Stage Facilitates Efficient Generation of T Cells with High Proliferation Potential from Human Pluripotent Stem Cells
Authors: Akhilesh Kumar, Kran Suknuntha, Saritha S D'souza, Jeong Hee Lee, Andres Grandea, Abhir S Thakur, David T Evans, Igor Slukvin
Journal: Blood (2017)
Low-dose metronomic topotecan and pazopanib in children with recurrent or refractory solid tumors: A C17 Canadian phase I trial (TOPAZ).
Authors: Arif Manji, Daniel A. Morgenstern, Yvan Samson, Rebecca Deyell, Donna Johnston, Victor Anthony Lewis, Alexandra Patricia Zorzi, Jason N. Berman, Kathy Brodeur-Robb, Ellen Morrison, Sylvain Baruchel, James A. Whitlock
Journal: Journal of Clinical Oncology (2021)

10020 Background: Low-dose metronomic topotecan (mTP) represents a novel approach to chemotherapy delivery which, in preclinical models, may work synergistically with pazopanib (PZ) in targeting angiogenesis. This study was designed to determine the recommended phase 2 dose (RP2D) of mTP/PZ in pediatric patients with solid tumors, while describing the safety and toxicity of this regimen. Methods: A phase I dose-escalation, pharmacokinetic (PK) and pharmacodynamic (PD) study of mTP/PZ was conducted at ten sites across Canada, enrolling pediatric patients aged 2-21 years with relapsed/refractory solid tumors. Patients were treated with oral mTP and PZ suspension daily without interruption in 28-day cycles, with dose escalation in accordance with the rolling-six design. Five dose levels (0.12/125, 0.16/125, 0.22/125, 0.22/160, and 0.3/160 mg/m 2 /day of mTP/PZ) were evaluated. PK studies were performed on day 1 and at steady state, and PD studies included circulating angiogenic factors VEGFR1, VEGFR2, VEGF, endoglin and placental growth factor. Results: Thirty patients (pts) were enrolled, of whom 26 were evaluable for dose-limiting toxicity (DLT), with median age 12 years (3-20). The most common diagnoses included osteosarcoma (8), neuroblastoma (NB, 7), Ewing sarcoma/PNET (4), and rhabdomyosarcoma (4). The most common grade 3/4 adverse events (AEs) related to protocol therapy were neutropenia (18%), thrombocytopenia (11%), lymphocytopenia (11%), AST elevation (11%), and lipase elevation (11%). Only 2 cycle-1 DLTs were observed on study, both at the 0.3/160 mg/m 2 mTP/PZ dose level (2/5 pts) comprising persistent grade 3 thrombocytopenia and grade 3 ALT elevation. No AEs experienced beyond cycle-1 required treatment discontinuation. Best response was stable disease in 10/25 pts (40%) for a median duration of 6.4 months (1.7-45.1). One patient with refractory NB achieved stable disease for 45 months and continued on mTP/PZ via compassionate access after study closure. PK and PD results are pending at this time. Conclusions: The combination of oral mTP and PZ is safe and tolerable in pediatric patients with solid tumors, with a RP2D of mTP 0.22 mg/m 2 /day and PZ suspension 160 mg/m 2 /day. Ten patients achieved stable disease for a median of 6 months. The lack of objective responses suggests that this combination is likely of limited benefit for relapsed disease, but may play a role as maintenance therapy. Clinical trial information: NCT02303028.
Developing and validating deep learning-based heterogeneous model to improve diagnostic performance of ultrasound elastography for axillary lymph node metastasis of early breast cancer.
Authors: Jian Li, Cai Nian, Xie Ze-Ming, Zhou Jingwen, Huang Kemin
Journal: Journal of Clinical Oncology (2021)

e12583 Background: To improve the performance of ultrasound (US) for diagnosing metastatic axillary lymph node (ALN), machine learning was used to reveal the inherently medical hints from ultrasonic images and assist pre-treatment evaluation of ALN for patients with early breast cancer. Methods: A total of 214 eligible patients with 220 breast lesions, from whom 220 target ALNs of ipsilateral axillae underwent ultrasound elastography (UE), were prospectively recruited. Based on feature extraction and fusion of B-mode and shear wave elastography (SWE) images of 140 target ALNs using radiomics and deep learning, with reference to the axillary pathological evaluation from training cohort, a proposed deep learning-based heterogeneous model (DLHM) was established and then validated by a collection of B-mode and SWE images of 80 target ALNs from testing cohort. Performance was compared between UE based on radiological criteria and DLHM in terms of areas under the receiver operating characteristics curve (AUC), sensitivity, specificity, accuracy, negative predictive value, and positive predictive value for diagnosing ALN metastasis. Results: DLHM achieved an excellent performance for both training and validation cohorts. In the prospectively testing cohort, DLHM demonstrated the best diagnostic performance with AUC of 0.911(95% confidence interval [CI]: 0.826, 0.963) in identifying metastatic ALN, which significantly outperformed UE in terms of AUC (0.707, 95% CI: 0.595, 0.804, P&lt;0.001). Conclusions: DLHM provides an effective, accurate and non-invasive preoperative method for assisting the diagnosis of ALN metastasis in patients with early breast cancer.[Table: see text]