tbuckley/cabot-search huggingface dataset:
The outcomes of ‘8’suture suspension laparoscopic radical hysterectomy for early-stage cervical carcinoma.
Authors: Huaiwu Lu, Yuhao Zhang, Miaochun Xu, Chuying Huo, Zhongqiu Lin
Journal: Journal of Clinical Oncology (2021)

e17519 Background: The mainly causes may due to the use of uterine manipulator and unprotected vaginal incision. To avoid these disadvantages, we modified the procedures by using ‘8’ suture suspension of the uterine instead of the uterine manipulator and vagino-purse-string suture before cutting of the vaginal. The aim of this study is to evaluate surgical data and oncological outcome of LRH without uterine manipulator based‘8’suture suspension method for early-stage cervical cancer. Methods: Patients with cervical cancers who underwent‘8’ suture suspension LRH in our center between January 2018 to August 2020 were retrospective analyzed. Without the use of uterine manipulator, a 2-0 absorbable suture was used to make an‘8’suture at the fundus of the uterine, and then make a coil. Another suture was passed through the coil to manipulate the uterus towards suitable directions. When separating the rectovaginal space, a needle with suture was pierced into the abdominal cavity from the abdominal wall above the pubic symphysis and passed through the coil to pull the uterus upwards and forwards, which was remove when separating the vesicovaginal space. Before cutting of the vaginal, a vagino-purse-string suture was made to prevent the tumor exposure in the abdominal cavity. Surgical data, postoperative complications, relapse rate and disease-free survival rate were evaluated. All operations were performed by the same surgical team. Results: A total of 48 cervical cancer patients were included in this study. Eight patients were stage IA2, 37 patients were stage IB and 3 patients were stage IIA1. There were 37 patients with squamous carcinoma while 11 with adenocarcinomas. The mean operative time was 199min (ranged from 120 to 290min). The median time of hospital stay after surgery was 7 days (ranged from 4 to 17 days). The mean blood loss volume was 40ml (ranged from 5 to 200 ml). The mean of number of removed lymph nodes are 30. The median time of removing urinary tube was 18 days (ranged from 12 to 25 days). The median time of postoperative exhaust time was 3 days(ranged from 2 to 4 days). There were no intraoperative complications, while postoperative complications were observed in 4 patients with fever. The median follow- up times were 16 months. During the follow-up time, there were no recurrence. Conclusions: The‘8’suture suspension LRH is a feasible and safe surgical procedure for early stage cervical cancer, with acceptable surgical and oncological outcomes in the hands of well-trained and experienced laparoscopic surgeons.[Table: see text]
t(11;14)(q23;q24)を伴う新規白血病におけるMLLへのラットゲフィリンの遺伝子のヒトホモログ溶解
Authors: Kuwada N, Kimura F, Matsumura T, Yamashita T, Nakamura Y, Ikeda T, Sato K, Motoyoshi K
Journal: Blood (2000)
Latent atherosclerosis as a risk factor in chemotherapy-induced cardiomyopathy.
Authors: Yuliya Paulenka, Maritza Cotto, Christine Rickette, Krystal Hunter
Journal: Journal of Clinical Oncology (2021)

e12525 Background: Anthracyclines and monoclonal antibodies targeting HER2/neu receptors are widely used antineoplastic agents in breast cancer treatment. Both therapies have been known to cause cardiovascular adverse effects, notably chemotherapy-induced congestive heart failure, especially if used in combination. Multiple factors have been postulated to increase the risk of doxorubicin and trastuzumab-associated cardiotoxicity, including a pre-existing coronary artery disease, but the role of latent atherosclerosis has not been widely studied. Methods: We retrospectively reviewed health records of female breast cancer patients at our institution treated with doxorubicin or trastuzumab between 2012 and 2017. Using echocardiography, we identified patients with underlying atherosclerotic lesions at the start of the treatment and those who subsequently developed cardiotoxicity. Chemotherapy-induced cardiomyopathy was defined as a drop in the ejection fraction (EF) to &lt; 50% from the normal EF of &gt; 53% pre-therapy. We used a χ 2 test to search for the relationship between atherosclerosis and subsequent cardiotoxicity. Results: A total of 518 patient records were reviewed. Of 518 patients with breast cancer, 93 (18%) received doxorubicin or trastuzumab-based chemotherapy. The median age for breast cancer diagnosis was 58. Sixty-one patients (66%) were identified to have atherosclerosis on echocardiography at the time of the first chemotherapy cycle. The most common location for atherosclerotic lesions was in the aortic arch and proximal upper abdominal aorta. Of 61 patients with atherosclerosis, ten (16.4%) subsequently developed chemotherapy-induced cardiomyopathy (p = 0.77). A post hoc analysis was performed to compare the two cohorts aged 40 to 50 (p = 0.49) and 51 to 75 (p = 1.00) as they represented the majority of breast cancer cases. Conclusions: The role of atherosclerosis in doxorubicin and trastuzumab-induced toxicity remains unclear. We did not observe any statistical correlation between atherosclerosis at the start of chemotherapy and increased rates of cardiac injury. A younger population may be more susceptible to cardiotoxicity, but further research is needed as the study has limitations. Although we identified patients with latent atherosclerosis, additional evaluation via carotid artery intima-media thickness measurements would yield more precision. Other methods such as the use of computed tomography and coronary artery calcium scores would also allow for assessing atherosclerotic plaque burden. Still, not all patients were subjected to these techniques. Furthermore, the study was challenged by the small sample size and its retrospective nature. Larger prospective studies are essential to explore this area further. Identifying the means of reducing cardiovascular complications remains a priority as heart disease is currently the leading cause of death among breast cancer survivors.
Research in Sickle Cell Disease: From Bedside to Bench to Bedside
Authors: Gabriel Salinas Cisneros, Swee Lay Thein
Journal: HemaSphere (2021)

Sickle cell disease (SCD) is an exemplar of bidirectional translational research, starting with a remarkable astute observation of the abnormally shaped red blood cells that motivated decades of bench research that have now translated into new drugs and genetic therapies. Introduction of hydroxyurea (HU) therapy, the only SCD-modifying treatment for >30 years and now standard care, was initiated through another clinical observation by a pediatrician. While the clinical efficacy of HU is primarily due to its fetal hemoglobin (HbF) induction, the exact mechanism of how it increases HbF remains not fully understood. Unraveling of the molecular mechanism of how HU increases HbF has provided insights on the development of new HbF-reactivating agents in the pipeline. HU has other salutary effects, reduction of cellular adhesion to the vascular endothelium and inflammation, and dissecting these mechanisms has informed bench-both cellular and animal-research for development of the 3 recently approved agents: endari, voxelotor, and crizanlizumab; truly, a bidirectional bench to bedside translation. Decades of research to understand the mechanisms of fetal to adult hemoglobin have also culminated in promising anti-sickling genetic therapies and the first-in-human studies of reactivating an endogenous (γ-globin) gene
Pre-clinical development of an anti-cancer drug ENZ302, a promising candidate for multiple cancer therapeutics.
Authors: Arindam Chakraborty, Abir Banerjee, Himanshu Gadgil
Journal: Journal of Clinical Oncology (2021)

e13053 Background: Vernonia cinerea extract has been known to be used for various haematological disorders including cancer. In the current study, using state-of-the-art extraction and bioanalytical tools we have identified an active compound having anti-tumor properties from the same plant Vernonia cinerea. The crude extract of Vernonia cinerea as well as the active molecule obtained through the chemical route (ENZ302) showed anti-tumor activity against various cancer models including CML, AML, ALL, HER2+ breast cancer, colon cancer, etc. Methods: Various methods including RP-HPLC, XRD, NMR, IR, cell based assay and LC-MS were used to elucidate the molecular structure of ENZ302. MTD, DRF, PK, and Xenograft study etc were carried out in murine model during the preclinical development of ENZ302. Results: ENZ302 resulted significant cytotoxic effect within 8 hrs of treatment in TNBC (Triple Negative Breast Cancer) model, MDA-MB-468 cells when compared with a known inhibitor Lapatinib. However, ENZ302 treatment in primary cells demonstrates no anti-proliferation activity, indicating the specificity of it’s mode of action. Interestingly, a dose-dependent decrease in tumor volumes was observed for ENZ302 in a xenograft model of TNBC while administered orally. ENZ302 did not cause any adverse changes even at 2gm/Kg dose, indicating the safety of the compound. Although a single-dose PK study showed that ENZ302 has a half-life of ̃40 mins, however, in vitro metabolism of the compound in mouse, rat, dog, and human hepatocytes/microsomes showed the molecule is stable in hepatocyte with very low clearance in microsomes (half-life &gt; 30 min), indicating most of the clearance occurring through the kidney. Conclusions: Our preliminary data suggest that ENZ302 is a specific tyrosine kinase (e.g. Src) inhibitor and a promising therapeutic agent against several cancers. A comprehensive proteomic analysis is ongoing to understand the mechanism of action of ENZ302 that makes it effective against several cancers. The discovery of ENZ302 holds ample opportunities to develop a safe and efficacious treatment regimen against several cancers including TNBC.
HGG-38. DE NOVO PYRIMIDINE SYNTHESIS INHIBITION INDUCES REPLICATION CATASTROPHE MEDIATED CELL DEATH IN DIFFUSE MIDLINE GLIOMA
Authors: Sharmistha Pal, Jakub Kaplan, Sylwia Stopka, Michael Regan, Benjamin Kann, Nathalie Agar, Charles Stiles, Tabitha Cooney, Sabine Mueller, Dipanjan Chowdhury, Daphne Haas-Kogan
Journal: Neuro-Oncology (2021)

Abstract Diffuse midline gliomas (DMG) are aggressive and lethal pediatric brain tumors that cannot be cured by conventional therapeutic modalities. Using a genome wide CRISPR screen we identified the de novo pyrimidine biosynthesis pathway as a metaboilic vulnerability in DMGs. BAY2402234 is a small molecule inhibitor of DHODH -a rate liminting enzyme in the de novo pyrimidine biosynthesis pathway. BAY2402234 induces cell death in DMG cells at low nanomolar concentrations while sparing adult glioblastoma cells and normal astrocytes. Further investigations revealed drammatic reduction in cellular UMP pools, the precursor for all pyrimidine nucleotides, after DHODH inhibition, specifically in DMG cells. Cytotoxicity of DHODH inhibition in DMG cells is rescued by exogenous uridine, supporting UMP depletion as the mechanism underlying DMG cell death and also showing that cell death is an “on target” response to BAY2402234. Cell death induced by BAY2402234 is a consequence of replication fork stalling as evident by accumulation of chromatin-bound RPA foci and g-H2AX. Stalled replication forks eventually collapse, resulting in replication catastrophy and apoptosis. Cytotoxic effects of DHODH inhibition are further exacerbated by inhibition of the intra-S checkpoint protein, ATR. Combined treatment of DMG cells with DHODH and ATR inhibitors resulted in enhanced accumulation of chromatin-bound RPA, g-H2AX, replication fork collapse and apoptosis. Importantly, in vivo studies verify that both BAY2402234 (DHODHi), and BAY1895344 (ATRi), cross the blood-brain barrier, accumulate in the brain at therapeutically relevant concentrations, and induce DNA damage in intracranial DMG xenografts in mice. Taken together, our studies have identified DHODH inhibition as a DMG-specific vulnerability resulting in cell death; the mechanism of DHODHi-induced cell death led us to identify combined inhibition of DHODH and ATR as a synergistic therapy against DMG tumors.
A Quantitative Analysis Investigating the Prevalence of “Manels” in Major Urology Meetings
Authors: Jeremy Yuen-Chun Teoh, Daniele Castellani, Claudia Mercader, Alba Sierra, Flavio L. Heldwein, Erica On-Ting Chan, Marcelo L. Wroclawski, Fabio Sepulveda, Giovanni E. Cacciamani, Juan Gomez Rivas, Declan G. Murphy, Inge M. van Oort, Stacy Loeb, Maria J. Ribal
Journal: European Urology (2021)
Ultrasound‐Responsive Nanopeptisomes Enable Synchronous Spatial Imaging and Inhibition of Clot Growth in Deep Vein Thrombosis
Authors: Janna N. Sloand, Eric Rokni, Connor T. Watson, Michael A. Miller, Keefe B. Manning, Julianna C. Simon, Scott H. Medina
Journal: Advanced Healthcare Materials (2021)

Abstract Deep vein thrombosis (DVT) is a life‐threatening blood clotting condition that, if undetected, can cause deadly pulmonary embolisms. Critical to its clinical management is the ability to rapidly detect, monitor, and treat thrombosis. However, current diagnostic imaging modalities lack the resolution required to precisely localize vessel occlusions and enable clot monitoring in real time. Here, we rationally design fibrinogen‐mimicking fluoropeptide nanoemulsions, or nanopeptisomes (NPeps), that allow contrast‐enhanced ultrasound imaging of thrombi and synchronous inhibition of clot growth. The theranostic duality of NPeps is imparted via their intrinsic binding to integrins overexpressed on platelets activated during coagulation. The platelet‐bound nanoemulsions can be vaporized and oscillate in an applied acoustic field to enable contrast‐enhanced Doppler ultrasound detection of thrombi. Concurrently, nanoemulsions bound to platelets competitively inhibit secondary platelet–fibrinogen binding to disrupt further clot growth. Continued development of this synchronous theranostic platform may open new opportunities for image‐guided, non‐invasive, interventions for DVT and other vascular diseases.
TP53/NPM1-mutated acute myeloid leukemia as a molecularly distinct disease entity.
Authors: Frank J Scarpa, Madhuri Paul, Rachel Daringer, Wendy A. Wolfson, Fernando Lopez Diaz, Sally Agersborg, Vincent Anthony Funari, Lawrence Martin Weiss, Forrest Blocker
Journal: Journal of Clinical Oncology (2021)

7030 Background: TP53-mutated acute myeloid leukemia (AML) is a distinct disease entity associated with a dismal prognosis. This disease group is distinguishable by its low frequency of SNVs, unremarkable transcriptional signatures, and lower leukocyte and myeloblast counts compared to TP53 wildtype disease. Response to gold-standard hypomethylating agents is typically transient. NPM1 mutations in this disease subset are rare despite the fact that NPM1c has been shown to negatively regulate the tumor suppressive functions of p53 .Methods: Bone marrow, peripheral blood, or FFPE tissue samples from 10,118 patients with suspected myeloid disease were sequenced using a dual DNA/RNA 297 gene myeloid panel. Results were validated in a separate independent dataset using a 54 gene TruSight myeloid panel (N = 2463). FISH/cytogenetic data was analyzed across myeloid disease. Patients with confirmed AML (n = 460) were included in the NGS portion of this study. Statistics were performed using Fisher’s exact test for categorical variables and two-tailed T-test for continuous variables. Results: All TP53-mutated myeloid disease (n = 1282 / 10,118) was associated with fewer co-mutations except DNMT3A (13.4%; n = 172), and complex cytogenetics (36.4%; n = 134/381). TP53+/NPM1+ status across all myeloid disease was not associated with a complex karyotype (7.6% vs 38.5%; 1/13 vs. 133/368, p = 0.02). Among AML patients, NPM1+/TP53+ patients (n = 18) were more co-mutated with DNMT3A (33.3% vs. 10.3%, P = 0.01), FLT3 (33.33% vs. 2.5%, P &lt; 0.0001), IDH1 (27.8% vs. 4.4%, P = 0.002), IDH2 (22.2% vs. 6.4%, P = 0.03); and PTPN11 (22.2% vs. 2.5%, P = 0.003) when compared to TP53+/NPM1- patients. NPM1+/TP53+ AML had more mutations in recurrently mutated genes (4.5 vs 2.1; P &lt; 0.0001) than TP53+/NPM1- AML. Conclusions: TP53+/NPM1+ AML harbors molecular signatures which clearly distinguish it from ordinary TP53-mutated AML, and is more reflective of de novo and NPM1+ AML. Further clinical outcome studies are needed to determine the therapeutic and prognostic implications of this subset, and whether other TP53-mutated patients can be better risk stratified.[Table: see text]
The Discover Trial: Application of the Karius Plasma Next-Generation Sequencing Test for Pathogen Detection in Allogeneic Stem-Cell Transplant Patients
Authors: Monica Fung, Hon Seng, Desiree Hollemon, David Hong, Timothy Blauwkamp, Mickey Kertesz, Jamie Eng, Kathy Wong, Aaron C. Logan, Peter Chin-Hong
Journal: Blood (2017)
Association of acute graft versus host disease clinical outcomes and the Ann Arbor Biomarker Risk Probability Using the Commercial Assay.
Authors: Luke Mountjoy, Hannah McNally, Matthew Buras, Margaret McCallen, Jaime Rogers, Lisa Ostrosky Sproat, James L. Slack, Jeanne Palmer, Jose Francisco Leis, Nandita Khera
Journal: Journal of Clinical Oncology (2021)

e19023 Background: Acute GVHD (aGVHD) is a major cause of mortality and morbidity following stem cell transplantation (HCT). In effort to prognostic patients with aGVHD, the Mount Sinai Acute GVHD International Consortium (MAGIC) combined two biomarkers, ST2 and REG3α to generate an algorithm known as the Ann Arbor (AA) biomarker risk. This is now available as a commercial test to help predict risk for severe acute GVHD and non-relapse mortality when done at the onset of symptomatic aGVHD. Our institution began utilizing these lab values and here we report our “real world” experience. The primary aim was to correlate AA risk probabilities with recently defined endpoints including day 28 overall response rate (ORR) and 6 month freedom from treatment failure (6mFFTF) and overall survival (OS). Methods: 58 HCT patients who underwent HCT between October 2018 and November 2019 and had the biomarker assay at the onset of aGVHD were identified from the institutional database and clinical information about disease, transplant and outcomes was obtained from the medical records. Clinical staging of aGVHD was documented per standardized published guidelines. Day 28 ORR was defined as complete response by day 28. 6mFFTF was defined as a patient being alive, without relapse of underlying disease or addition of new systemic therapy for aGVHD, and prior to the development of cGVHD. Results: When comparing low (n = 39), intermediate (n = 11), and high (n = 8) AA risk, there was no difference in age ( p =0.254), primary disease ( p =0.10), DRI ( p =0.994), donor source ( p =0.193), conditioning regimen intent ( p =0.537), GVHD prophylaxis ( p =0.351) ATG use ( p =0.06). Low AA risk was associated with lower grades of aGVHD at onset (grade I = 15%, grade II = 80%, grade III = 5%, grade IV = 0%), whereas high AA risk was associated with higher grades of aGVHD at onset (grade I = 0%, grade II = 50%, grade III = 25%, grade IV = 25%) ( p =0.009). For low, intermediate, and high AA risk the day 28 ORR was 69%, 45% and 29% ( p = 0.083); the 6mFFTF was 82%, 82%, and 25% ( p = 0.0001); 6 month OS was 92%, 100%, and 50% ( p = 0.0006) respectively. Conclusions: Our study shows a high correlation between AA risk and outcomes. High risk AA risk was associated with inferior outcomes This study was limited by the retrospective single institutional experience with relatively small numbers. However, our findings using the commercial assay mirror that seen with the MAGIC studies. Our “real world data” can serve as a foundation and continued validation for institutional implementation of AA risk stratification for aGVHD.
RARE-11. PRIMARY INTRACRANIAL LEIOMYOSARCOMA IN A PATIENT WITH NEUROFIBROMATOSIS TYPE 1
Authors: Aaron Goldberg, Clay Hoerig, Jordan Xu, Jody Pathare, Chenue Abongwa, Joffre Olaya, Ashley Plant
Journal: Neuro-Oncology (2021)

Abstract Primary intracranial leiomyosarcoma (LMS) is very rare, with only a few reported cases. Only one prior case report of intracranial LMS in a patient with neurofibromatosis type 1 (NF1) was identified. We report a case of primary intracranial LMS in a patient with known history of NF1. Our patient is a 17-years-old female without history of immunocompromise presenting with severe headaches representative of right frontal hemorrhagic tumor found to be primary intracranial LMS. In prior reported cases, most primary intracranial LMS were treated with sarcoma-based chemotherapy and radiation therapy. Our patient underwent multiple resections, as well as focal radiation. Her chemotherapy initially included ifosfamide, carboplatin, and etoposide, but when she failed etoposide twice due to severe allergic reactions, she completed treatment successfully with the combination of ifosfamide and doxorubicin. She continues to be doing well with no evidence of disease at 41 months post-treatment.
The impact of COVID-19 pandemic on access to new patient cancer care as evaluated in the Integra Connect Database (ICD).
Authors: Mike Gart, Prateesh Varughese, Lucio N. Gordan, Trevor Heritage, Greg Brown, Elizabeth Botts, Dakshesh Keni, Simon Blanc, Jeffrey A. Scott, Robert E. Smith
Journal: Journal of Clinical Oncology (2021)

e18792 Background: The Covid-19 pandemic has affected all aspects of life. Integra Connect sought to assess its impact on new visits for cancer care by querying its Electronic Medical Record and Claims database as a surrogate for understanding Covid’s impact on cancer care in the larger United States population. Methods: Using Real World Data (RWD) from over 1200 oncology providers in 14 large practice settings, comprising 250 plus care sites in the ICD, we measured new patient (Pt) and established Pt visits from 2018 through 2020. Centers for Medicare &amp; Medicaid Services (CMS) codes for new and established Pt’s were applied to define cohorts. Disease states were defined using CMS Oncology Care Model (OCM) mapping to diagnosis codes. Because the ICD is heavily based in the Eastern US, we conducted a geographic analysis by segmenting providers by Northeast (NE) with 506 providers from NY, NJ, PA, and VA and Southeast (SE) with 578 providers from FL, GA, SC, and AL. We looked at visits across all tumor types and identified breast cancer (BC) and colorectal cancer (CC) as likely to be most affected by decreased screening, and multiple myeloma (MM) and advanced prostate cancer (APC) as likely to be vulnerable to delay in initiation of first treatment since treatment often trails diagnosis. Results: We found a decline in new patient volume (NPV) in ‘20 of -1% compared to ‘19; this compared to an anticipated increase of +7% based on growth in NPV in the ICD from ‘18 to ‘19. In the NE we saw NPV decrease in ‘20 by -7% vs. ‘19 but increase by +6% in the SE compared to ‘19. In comparing NPV ‘20 to ’19 and ’19 to ‘18, we saw a smaller increase for BC of +4% vs. +6% and for CC of +5% vs. +7%, respectively. Whereas in MM it was -7% vs. +3% and APC -6% vs. +8%. (See Table). Conclusions: Covid-19 has negatively impacted cancer care access. This RWD shows the number of both newly diagnosed Pts and those with initial oncologic intervention in established Pts, where symptoms traditionally have determined initiation of treatment, has declined year-over-year. The American Cancer Society projected new Pt cases to increase +2% in ‘20 to 1.806 million ( ACS, Cancer Facts and Figures 2020), whereas in the ICD, that figure was projected +7% but resulted in -1%. This suggests a major expected reduction of new Pt cases in the US at large. The drop in cases during Covid-19 in our data was greater in the NE compared to the SE. In addition, the drop in the NE in our data was earlier and more prolonged than SE. While recovery occurred in both regions, after an initial overshoot following lockdowns, volumes plateaued at levels lower than pre-pandemic.[Table: see text]