tbuckley/cabot-search huggingface dataset:
Association of immune checkpoint inhibitors (ICI) and venous thromboembolism (VTE): A single healthcare system experience.
Authors: Aneesha Ananthula, Andrew G Chapple, Shyam Mani, Anh Nguyen, Alejandra Matilde Del Toro, Brian C. Boulmay
Journal: Journal of Clinical Oncology (2021)

e14567 Background: Cancer and some anti-cancer therapies increase risk of VTE. ICIs cause immune activation and inflammation which are known to potentiate VTE formation. The risk of VTE associated with ICI is unclear, with conflicting evidence of association. Our study assessed the risk of VTE in patients treated with ICI compared to those receiving other cancer treatments. Methods: EPIC Slicer Dicer was used to collect data from three university-affiliated hospitals in New Orleans, LA. All patients &gt;17 years of age, with an oncology treatment plan (TP) between January 1 2012 – January 31 2021 were considered the base population (n=6,894) for the study. The base population was divided into two cohorts - those that received ICI (n=794) versus those who did not (n=6,100). ICIs included pembrolizumab, nivolumab, avelumab, atezolizumab, durvalumab, cemiplimab, ipilimumab. An encounter diagnosis of deep venous thrombosis (DVT) or pulmonary embolism (PE) which was preceded by a TP in the last 1 year was used to identify patients with VTE after initiation of a TP. Categorical covariates compared across VTE groups using Chi-squared tests of independence. Two sample t-tests were used to compare continuous covariates based on VTE status. Logistic regression used to predict VTE as a function of ICIs and other potential confounders including age, BMI, gender, race and cancer subtypes. Results: Patients who experienced VTE were significantly more likely to have received ICI (1.43 times odds of VTE (95% CI = 1.12-1.83; p &lt;0.005), be black or African American (p &lt; 0.05 compared with White and Asian races), and have GI cancer (1.82 times odds, 95% CI= 1.41 – 2.36, p&lt; 0.001), GU cancer (1.7 times odds, 95% CI = 1.3 – 2.23; p&lt;0.001). Patients with VTE were significantly less likely to have breast cancer or other cancer types. Males had a decreased odd of VTE (0.73 odds, 95% CI= 0.62 – 0.85, p&lt; 0.001). Conclusions: Based on the above results, there appears to be an increased likelihood of VTE in patients that receive ICI when compared to other types of cancer treatment. This study is a preliminary analysis and has limitations. At this time, it is unclear if prophylactic anticoagulation can reduce risk of VTE after ICI initiation. Further investigation is warranted in the form of individual chart review, or a prospective study.
Adjuvant chemotherapy with CAV/IE for malignant transformation of teratoma to primitive neuroectodermal tumor (PNET): An institutional analysis from Indiana University.
Authors: Cynthia Wei, Clint Cary, Timothy A. Masterson, Richard Foster, Ryan Ashkar, Nabil Adra, Nasser H. Hanna, Lawrence H. Einhorn
Journal: Journal of Clinical Oncology (2021)

5026 Background: Malignant transformation of teratoma to PNET has an aggressive disease biology and generally poor outcomes when metastasis occurs. The optimal management of patients (pts) with PNET who have complete surgical extirpation is unknown. Most pts who are monitored with surveillance will relapse. We report results from pts with metastatic PNET who had complete surgical resection to NED status followed by adjuvant chemotherapy, most commonly cyclophosphamide + doxorubicin + vincristine alternating with ifosfamide + etoposide (CAV/IE) for 4 cycles. Methods: We reviewed records for pts with histologically confirmed malignant transformation of teratoma at Indiana University from 1990 to 2020. We identified 13 pts with PNET who underwent resection of metastatic disease to NED status followed by treatment with adjuvant chemotherapy, most commonly CAV/IE comprising of cyclophosphamide (1200 mg/m2), doxorubicin (75 mg/m2), and vincristine (2 mg/m2) alternating with ifosfamide (1.8 g/m2) plus etoposide (100 mg/m2). Treatment was delivered every 3 weeks for 4 cycles or until unacceptable toxicity. Results: Thirteen pts with metastatic PNET resected to NED status and received adjuvant chemotherapy were identified. Median age at diagnosis was 29 (range, 20 to 55). Primary tumor site was testis in 11 pts, retroperitoneum in 1 pt, and mediastinum in 1 pt. Metastasis site was retroperitoneal lymph nodes in 11 pts, mediastinal lymph nodes in 1 pt, and local mediastinal recurrence in 1 pt. After resection to NED status, all 13 pts were treated with adjuvant chemotherapy: 11 pts were treated with CAV/IE and 2 received etoposide-ifosfamide-cisplatin (VIP) x 2. Among the 11 pts who received CAV/IE: 3 pts received &lt; 4 cycles due to toxicity and 8 completed 4 cycles. With a median follow-up of 16.3 months, 3 of 13 pts relapsed (23%) and 10 of 13 remained continuously disease free (77%). Of those who relapsed, median time to relapse was 9.3 months, 2 remained alive with disease at follow up and one patient died of disease progression. Conclusions: Adjuvant CAV/IE improves the outcomes of pts with malignant transformation of teratoma to PNET and who had resection of metastasis to NED status. Most pts who received adjuvant therapy remain continuously disease-free in comparison to historically high relapse rates in pts with resected PNET monitored with surveillance.
Treating the patient in front of you and the power of language: integrating research into effective clinical practice
Authors: Steve Aspinall
Journal: British Journal of Sports Medicine (2021)

Heterodimerization of human epidermal growth factor receptor 2 (HER2) with HER3 initiates aberrant downstream growth-signaling pathways in tumors. Our objective was to construct bispecific radioimmunoconjugates (bsRICs) that recognize HER2 and HER3 and evaluate their ability to image tumors in athymic mice that express one or both receptors using small-animal SPECT/CT. <b>Methods:</b> bsRICs were constructed by reacting the maleimide-derivatized trastuzumab Fab fragments that bind HER2 with a thiolated form of the HER3-binding peptide of heregulin-β1 (HRG) with or without a 12- or 24mer polyethylene glycol (PEG) spacer. bsRICs were derivatized with diethylenetriaminepentaacetic acid for labeling with <sup>111</sup>In. The ability of <sup>111</sup>In-bsRICs to bind HER2 or HER3 was determined in competition assays with unlabeled Fab or HRG on cells expressing one or both receptors. Tumor and normal-tissue uptake were examined in CD1 athymic mice bearing subcutaneous tumor xenografts that expressed HER2, HER3, or both receptors, with or without the preadministration of unlabeled Fab or HRG to determine the specificity of uptake. <b>Results:</b> Conjugation of Fab to HRG was confirmed by sodium dodecyl sulphate polyacrylamide gel electrophoresis–Western blot and size-exclusion high-performance liquid chromatography. Improved HER2 and HER3 binding and greater displacement of binding by competitors was found for <sup>111</sup>In-bsRICs that incorporated a PEG spacer, with the PEG<sub>24</sub> spacer being optimal. The highest uptake of <sup>111</sup>In-bsRICs (7.8% ± 2.1% injected dose per gram [%ID/g]) in BT-474 human breast cancer xenografts (HER2-positive/HER3-positive) occurred at 48 h after injection. The preadministration of trastuzumab Fab decreased uptake in SK-OV-3 (HER2-positive/HER3-negative) human ovarian cancer xenografts from 7.0 ± 1.2 to 2.6 ± 1.5 %ID/g (<i>P</i> &lt; 0.001). The preadministration of an excess of HRG decreased uptake in MDA-MB-468 (HER2-negative/HER3-positive) human breast cancer xenografts from 4.4 ± 0.9 to 2.6 ± 0.5 %ID/g (<i>P</i> &lt; 0.05). All tumors were imaged by small-animal SPECT/CT. <b>Conclusion:</b><sup>111</sup>In-bsRICs composed of trastuzumab Fab and HRG exhibited specific binding in vitro to tumor cells displaying HER2 or HER3 and were taken up specifically in vivo in tumors expressing one or both receptors, permitting tumor visualization by small-animal SPECT/CT. These agents could be useful for imaging heterodimerized HER2 and HER3 receptors because their bivalent properties may result in preferential binding to the heterodimerized forms. The approach may also be extended to constructing bsRICs for visualizing other peptide growth factor receptors.
Association between mammographic breast density and achievement of a pathologic complete remission (pCR) after neoadjuvant chemotherapy (NACT) for early breast cancer (EBC).
Authors: Cornelia Kolberg-Liedtke, Mohamed Shaheen, Oliver Hoffmann, Ann-Kathrin Bittner, Sarah Wetzig, Miltiades Stephanou, Hans-Christian Kolberg
Journal: Journal of Clinical Oncology (2021)

e12611 Background: Neoadjuvant chemotherapy (NACT) is indicated in early breast cancer (EBC) with an unfavorable tumor biology. Achievement of pathologic complete remission (pCR) after NACT is indicating an improved prognosis. An association between pCR and mammographic breast density as defined by BIRADS (Breast Imaging Reporting and Data System) could be demonstrated. However, the definition of mammographic breast density by the American College of Radiology (ACR) is widely used worldwide and data regarding an association of breast density by this definition and pCR after NACT are missing. Methods: We conducted a retrospective analysis among patients who had received neoadjuvant chemotherapy (NACT) for EBC and had available data regarding mammographic breast density as defined by ACR before therapy, pCR, age, estrogen and progesterone receptor (ER, PR) status, HER2neu status and grading were included. An association between mammographic breast density (ACR) and pCR was analyzed. Results: 185 patients were included in this analysis, 35.7% of whom achieved a pCR. Mammographic breast density was ACR 1 in 15.1%, ACR 2 in 41.6%, ACR3 in 38.4% and ACR 4 in 4.9% of the patients. A negative correlation (Spearman-Rho) between mammographic breast density and pCR (correlation coefficient (CC) -0.240) was highly statistically significant (p = 0.001). The association of decreasing pCR rates with increasing mammographic breast density (pCR rates by ACR 1: 53.6%, ACR 2: 41.6, ACR 3: 25.4% and 11.1 %) was statistically significant (Chi-Square, p = 0.013). These results were independent of age, ER status, PR status, HER2neu status and grading. Conclusions: In our analysis higher mammographic breast density as defined by ACR was significantly correlated with a lower chance of achieving a pCR after NACT. Although this result has to be interpreted with caution due to the small sample size and the retrospective character of our investigation, it is completely in line with other investigations using other definitions of mammographic breast density. The pathophysiological cause of this association should be further elucidated to reveal potential mechanisms of treatment resistance.
<i><i>TP53</i></i> and <i><i>CHEK2</i></i> germline mutations in malignant solid tumors.
Authors: Zhiye Zhang, Yaqing Wu, Ningning Luo, Qin Zhang, Tiantian Han, Xuesong Bu, Qin Shuai, Yingxue Qi
Journal: Journal of Clinical Oncology (2021)

3119 Background: Li-Fraumeni syndrome (LFS, OMIM #151623) is an autosomal dominant cancer predisposition syndrome. Typical LFS tumors comprise adrenocortical carcinomas, sarcoma, breast cancer and central nervous system tumors. LFS is also associated with an increased risk of a multitude of other common types of cancer, such as prostate cancer, lung cancer, gastric cancer, colorectal cancer, ovarian cancer, melanoma, etc. TP53 germline mutations are the most common gene with LFS. Germline mutations of CHEK2 have been identified as another predisposing gene and associated with a range of cancer types. However, the pattern of TP53 and CHEK2 germline mutations in malignant tumors remains unknown. Methods: We identified 8535 malignant solid tumors patients without selecting age or family history in a retrospective cohort. Germline mutations were categorized based on ACMG (American College of Medical Genetics and Genomics) guidelines in pathogenicity. The patients were divided into three groups, P group (with pathogenic mutations), LP group (with likely-pathogenic mutations) and Non_P group (neither pathogenic nor likely-pathogenic mutation). Statistical significance was defined as P-value less than 0.05. Results: A total of 461 (461/8535) patients carried TP53 or CHEK2 germline mutations were identified, in which 15 patients with pathogenic mutations and 17 patients with likely-pathogenic mutations. One patient with lung cancer in LP group carried TP53 homozygous mutation ( p. Ser215Ile), and the remaining 31 patients all carried heterozygous mutations. Among these 31 carriers, 16 (51.6%) carried nonsense or missense mutations (10 for nonsense and 6 for missense mutations). 3 patients in the P group carried CHEK2 p. Y139* (one liver cancer patient and two lung cancer patients) were identified. The median age of group P, LP and Non_P was 55 (39 for TP53, 61 for CHEK2), 63 (52 for TP53, 66 for CHEK2) and 59, respectively. Somatic mutation analysis found no significant difference in tumor mutation burden (TMB) among three groups. The SNV/INDEL mutation frequency of LRP1B in the P or LP group was significantly lower than the Non_P group. Conclusions: Our data showed that 0.375% (32/8535) malignant solid tumor patients carried TP53 (16/8535) or CHEK2 (16/8535) germline pathogenic or likely-pathogenic mutations. The relationship between germline mutations and cancer susceptibility will be studied in the future.[Table: see text]
Minimum dataset for monitoring national human immunodeficiency virus pre-exposure prophylaxis (HIV PrEP) programmes: a five-nation consensus, 2019
Authors: John Saunders, O Noel Gill, Valerie Delpech, Claudia Estcourt
Journal: Eurosurveillance (2021)

Human immunodeficiency virus (HIV) pre-exposure prophylaxis (PrEP), the use of antiretroviral medication to prevent HIV acquisition, is a highly effective biomedical prevention tool. The World Health Organization (WHO) recommends PrEP for people at substantial risk of HIV infection, as part of combination prevention, and highlights the need for robust evaluation of PrEP programmes. Based on suggested WHO core indicators, we created a concise set of HIV PrEP-related dataset variables, to harmonise the monitoring and evaluation of PrEP programmes across five closely related nations (England, Northern Ireland, Ireland, Scotland and Wales). The dataset is based on the PrEP cascade and is intended to represent the minimum variables needed for reporting and comparison of meaningful data at national and multinational level. The dataset can be modified for settings with different health and surveillance systems. It is intended for public health, academic, clinical and health planning, and public audiences. Here we describe the dataset and illustrate its use with data from the first year of the Scottish National PrEP programme.
Updated overall survival of eltanexor for the treatment of patients with hypomethylating agent refractory myelodysplastic syndrome.
Authors: Sangmin Lee, Sanjay Mohan, Jessica Knupp, Kamal Chamoun, Xiang BAI, Xiwen Ma, Jatin J. Shah, Michael Kauffman, Sharon Shacham, Bhavana Bhatnagar
Journal: Journal of Clinical Oncology (2021)

e19037 Background: Patients (pts) with myelodysplastic syndrome (MDS) refractory to hypomethylating agents (HMAs) have limited therapeutic options and a dismal prognosis with a median overall survival (mOS) of 4-6 months. Eltanexor (ELTA) is a second-generation, oral, selective inhibitor of nuclear export (SINE) compound that showed anti-tumor activity and lower brain penetration compared to selinexor (SEL) in nonclinical models. It was hypothesized that ELTA could be dosed more frequently than SEL with a lower incidence of centrally mediated nausea. Early results from a phase 1/2 study of ELTA in pts with HMA refractory MDS showed anti-tumor activity with marrow complete response (mCR) and stable disease (SD); side effects were primarily low-grade, dose-dependent, and reversible (Lee et al. ASH 2019). In this abstract, we provide a subgroup analysis of the efficacy evaluable population with an update on mOS in the same population. Methods: This phase 1/2 study (NCT02649790) evaluated single-agent ELTA in pts with higher-risk MDS, ie, high-risk or intermediate-2 MDS by International Prognostic Scoring System (IPSS) and 5%-19% myeloblasts. Out of 20 pts enrolled, 15 pts were evaluable for efficacy and constitute the population studied in this analysis. Two doses of ELTA were evaluated: 10 mg (n=5) or 20 mg (n=15) every day for 5 days per week of a 28-day cycle. Results: As of 1 Feb 2021, the 15 pts evaluable for efficacy (median age 76 years; range 62-89) had a median of 2 prior treatment regimens (range 1-4); 93% had high/int-2 risk per IPSS. Of the 20 enrolled patients, 7 (35%) had mCR, and 5 (25%) had SD for a total disease control (mCR+SD) rate of 60%. Of the 15 pts evaluable for efficacy, 7 (47%) had mCR and 5 (33%) had SD. In the 10-mg cohort (n=5), all pts derived clinical benefit with 3 pts (60%) reaching mCR and 2 pts (40%) SD. In the 20-mg cohort (n=10), 4 pts (40%) had mCR and 3 (30%) had SD. Four pts had hematologic improvement (HI) and became transfusion independent for at least 8 weeks including 2 pts with tri-lineage HI. OS for pts who reached mCR (n=7) was significantly longer than for pts who did not reach mCR (n=8): median 11.86 vs 8.67 months (mo) (hazard ratio [HR]=0.27, p=0.05), and significantly longer than OS for pts with PD (n=3, mOS=3.15 mo, HR=0.23, p=0.04). Pts with disease control (n=12) had numerically longer mOS than pts with PD (9.86 vs 3.15 mo, HR=0.38, p=0.09). Pts with HI had a mOS of 10.58 months. Conclusions: Single-agent oral ELTA was active in pts with high-risk, HMA refractory MDS. Pts with mCR had significantly longer mOS than pts without mCR or with PD. Further evaluation of ELTA in MDS as a single agent and in combination with other agents is ongoing. Clinical trial information: NCT02649790.
Results from a global survey of clinical cancer researchers on clinical trial design and conduct during the COVID-19 pandemic and beyond.
Authors: Bruno Henrique Rala De Paula, Gary Doherty
Journal: Journal of Clinical Oncology (2021)

e13576 Background: The COVID-19 pandemic has had profound detrimental consequences on cancer patient outcomes and clinical cancer research, with considerable adaptations made to both standard care and clinical research to optimise patient safety. Detailed perspectives of clinical researchers on such risk mitigation, and granular insight into which adaptions should persist long term, are required to inform future clinical trial design. Methods: We designed and performed an in depth, global survey (open between 04/22/20 and 06/10/2020) of cancer research professionals to assess the impact of the pandemic on clinical care and research, and how researchers prioritise and view clinical research methodologies. Results: 162 valid responses were received (58.7% oncologists, 14.8% research nurses; 69.1% working in academic centers) from six continents. There was significant heterogeneity in how the pandemic has affected healthcare workers, patients on standard of care or investigational trial treatments, and clinical trial recruitment. Our results detail how trial and non-trial patient care has altered in respondents’ centres and how respondents would prioritise specific trial designs while the pandemic continues. We show marked variance in the perceived value of specific trial protocol features and assessments (regardless of the pandemic). More respondents agreed than disagreed that trial eligibility criteria are too restrictive (48% agreed versus 28% disagreed), that screening assessments generally have unnecessary tests (51% versus 23%), that physical examination should only be performed when clinically indicated (43% versus 30%), that electronic patient outcomes/questionnaires are better at detecting adverse events that a consultation with a study doctor (33% versus 29%), that wearable technology/validated tools for patients to perform self-examination would provide more useful information than vital sign assessment in the study center (48% versus 13%), and that replacing routine in person visits with virtual visits would not significantly compromise patient safety (36% versus 28%). However, 65% of respondents indicated that fully virtual clinical trials (in the absence of reported clinically significant toxicities) would not be sufficiently safe (versus 15% who indicated that they would be). Conclusions: These detailed data provide further evidence of a significant adverse impact of the pandemic on cancer patient care and drug development, may help inform risk mitigation for studies in times of heightened infection risk, and aid with future clinical trial design.
E2A Modulates Stemness, Metastasis, and Therapeutic Resistance of Breast Cancer
Authors: Celia López-Menéndez, Alberto Vázquez-Naharro, Vanesa Santos, Pierre Dubus, Patricia G. Santamaría, Ángel Martínez-Ramírez, Francisco Portillo, Gema Moreno-Bueno, Marisa M. Faraldo, Amparo Cano
Journal: Cancer Research (2021)

Abstract Cancer stem cells (CSC) are considered responsible for tumor initiation, therapeutic resistance, and metastasis. A comprehensive knowledge of the mechanisms governing the acquisition and maintenance of cancer stemness is crucial for the development of new therapeutic approaches in oncology. E2A basic helix–loop–helix (bHLH) transcription factors are associated with epithelial–mesenchymal transition (EMT) and tumor progression, but knowledge of their functional contributions to cancer biology is still limited. Using a combination of in vivo and in vitro analyses in a novel PyMT-E2A conditional knockout mouse model and derived primary tumor cell lines, we report here an essential role of E2A in stemness, metastasis, and therapeutic resistance in breast cancer. Targeted deletion of E2A in the mammary gland impaired tumor-initiating ability and dedifferentiation potential and severely compromised metastatic competence of PyMT-driven mammary tumors. Mechanistic studies in PyMT-derived cell lines indicated that E2A actions are mediated by the upregulation of Snai1 transcription. Importantly, high E2A and SNAIL1 expression occurred in aggressive human basal-like breast carcinomas, highlighting the relevance of the E2A–Snail1 axis in metastatic breast cancer. In addition, E2A factors contributed to the maintenance of genomic integrity and resistance to PARP inhibitors in PyMT and human triple-negative breast cancer cells. Collectively, these results support the potential for E2A transcription factors as novel targets worthy of translational consideration in breast cancer. Significance: These findings identify key functions of E2A factors in breast cancer cell stemness, metastasis, and drug resistance, supporting a therapeutic vulnerability to targeting E2A proteins in breast cancer.