tbuckley/cabot-search huggingface dataset:
Chemotherapy induced profound neutropenia (PN) in patients (pt) with breast cancer (BC) after chemotherapy and plinabulin (Plin) plus pegfilgrastim (Peg) combination versus (vs) peg alone: Final phase 3 results from protective-2 (BPI-2358-106).
Authors: Yuankai Shi, Douglas W. Blayney, Hryhorii Adamchuk, Qingyuan Zhang, Lihua Du, Lan Huang, Ramon Mohanlal
Journal: Journal of Clinical Oncology (2021)

546 Background: PN [absolute neutrophil count (ANC) of &lt;0.1 cells x 10E9/L)] is the most severe form of chemotherapy (Chemo)-induced neutropenia (CIN), and is associated with severe adverse clinical outcome. According to literature, PN leads to 80% death in first week of infection 1 , 48% FN and 50% Infection 2 . Peg is standard of care for the prevention of CIN. Peg has a slow onset of action with absolute neutrophil count (ANC) recovery occurring in week 2 of the cycle (C), leaving patients (pts) vulnerable in the first week of the Cycle (C), which &gt;75% of negative clinical consequences occur. Plin, which received breakthrough designation from FDA, is a novel, non-G-CSF small molecule agent for the prevention of CIN and has CIN protection in week 1 (Blayney JAMA Onc 2020), which is the rationale for adding Plin to Peg to achieve superior protection against CIN throughout the entire cycle vs Peg alone (Blayney, St Gallen 2019; ASCO 2019). Methods: Plin is given on Day (D)1 after the last Chemo, has a favorable safety profile, and also has anticancer activity. A phase 3 study evaluating Plin as an anticancer agent (DUBLIN-3; NCT02504489) in NSCLC pts, is fully enrolled, with anti-cancer OS results expected in 2021. In PROTECTIVE-2 (Study 106; NCT0329457), we compare the CIN preventive effects of Plin (on D1) added to Peg (on D2) vs Peg alone. Here we report on PN results. Study 106 is a global multicenter randomized (1:1) double-blind study to evaluate Plin 40 mg + Peg 6mg (Arm 1) versus Peg 6mg + Plac (Arm 2) in early-stage BC (node positive or node negative with a high risk of recurrence) pts (n=221) with ECOG status 0 or 1, receiving docetaxel (75 mg/m2), doxorubicin (50 mg/m2), and cyclophosphamide (500 mg/m2) (TAC). Primary objective was to compare the prevention of severe (Gr 4) neutropenia between Plin+Peg and Peg+Plac. As an exploratory objective in C1, we evaluated PN between the Plin/Peg and Peg/Plac. ANC (Covance Central Laboratory) was assessed in Cycle 1 (C1) on D 1, 2, 3, 6, 7, 8, 9, 10, 11, 12, 13, and 15. Results: Shown in the table below. Conclusions: In conclusion, Peg still cannot protect patients with the most severe form of neutropenia, PN, at 46.4% in this study. Adding Plin to Peg offers superior protection for the prevention of profound neutropenia by reducing &gt; 50% of PN, and its clinical sequelae in FN and hospitalization as compared to Peg alone. References: 1. Bodey et al. Ann Intern Med 64(2): 328 (1966); 2. Bodey et al. Cancer 41(4): 1610 (1978). Clinical trial information: NCT03531099. [Table: see text]
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Authors: Yongzhen Fan, Tao Guo, Zhibing Lu
Journal: JAMA Cardiology (2020)

Hence, we speculated that patients with COVID-19 might benefit from treatments specifically targeting the COVID-19associated inflammation storm.Indeed, in addition to antiviral medications, numerous immune-modulating medications to regulate inflammatory response are currently being investigated in patients with COVID-19.In clinical practice, glucocorticoid is generally used to inhibit severe inflammation in high-risk patients.Besides, chloroquine, which has been used as an antimalarial agent, blocks virus infection by increasing the endosomal pH required for virus/cell fusion and has been demonstrated in vitro to have inhibitory activity in SARS-CoV-2. 4 Yet, for patients with COVID-19 experiencing an inflammation storm, more evidence is needed to verify the effectiveness of glucocorticoid and immunosuppressive therapy.For us, it may be reasonable to triage patients with COVID-19 according to the presence of underlying CVD and evidence of myocardial injury for prioritized treatment and particularly for treatments specifically targeting on inflammation.
Survival outcomes of primary mediastinal germ cell malignancies based on clinicopathological characteristics: A SEER database analysis.
Authors: Trilok Shrivastava, Binav Baral, Garima Pudasaini, Prasanth Lingamaneni, Kunnal Batra, Shristi Upadhyay Upadhyay Banskota, Rohit Shrestha
Journal: Journal of Clinical Oncology (2021)

e17055 Background: Primary mediastinal germ cell malignancies (PMGCM) account for up to 5% of all germ cell tumors. Different clinical and epidemiological factors have been known to have important prognostic implications as they contribute to a wide range of long term survival in individuals with PMGCM. Methods: We obtained data from the Surveillance, Epidemiology and End Results (SEER) database from years 1975-2016 to include cases with confirmed primary mediastinal germ cell tumors. After complete gathering of selected data, a total of 1,328 number of cohorts were obtained which were stratified by age, sex, race, type of malignancy, size of primary tumor, site, grade etc. and were analyzed by Cox regression using proportional hazard model. Kaplan Meier curves were also obtained to visualize all cause survival and stratified survival according to the types of malignancy. Results: In our study, we found the incidence of PMGCM to be 0.18 per 1,000 people with malignant cancer with a median age at diagnosis of 28 years, the age range being 21-50 years. 92.9% patients were males and 7.1% were females with more common occurrence in White patients (54.5%). Most common type of PMGCM was found to be Seminoma (23.4%) and 56.32% were poorly differentiated (Grade III), excluding unknown cases. About half (52%) of all was found to arise from the anterior mediastinum. 36% of all cases died from primary cancer. 42.7% underwent surgery, however there was no data for chemotherapy or radiotherapy. Mean survival time among all PMGCM was 37.5 months (p &lt;0.05). A significant negative correlation was observed between survival time &amp; age at diagnosis with R p of 0.12 (p &lt; 0.001). On survival analysis, age was a significant factor for decreased survival time with patients more than 50 years having a HR of 2 (p&lt;0.001). Similarly, choriocarcinoma was associated with decreased survival time with HR 1.71 (p=0.03). Germinoma and seminoma were found to have higher survival time (HR 0.65 &amp; 0.18; p=0.03 and &lt;0.001 respectively). Patients with grade IV PMGCM had significantly lower survival time (HR 1.74, p&lt;0.001). Patients who had undergone surgery had a better survival time compared to those who didn’t get surgery. There was no significant association of sex, race, tumor size or site with the survival time. Conclusions: Our study concludes that among PMGCM, seminomatous tumors have a favorable prognosis compared to non-seminomatous tumors with higher survival time. Age was found to be a significant contributing factor with ages over 50 having lower survival time. Surgical intervention was found to be associated with increased survival time, although it is important to recognize the lack of chemo-radiotherapeutics data.
Association of pathological clinical characteristics, PD L 1 receptor expression (sp 142), with tumor lymphocytic infiltration cells (TILs) in patients (pts) with triple negative breast cancer (TNBC) in Tucumán, Argentina.
Authors: Juan Jose Zarba, Ana Vinuales, Silvia Victoria Holgado, Erika Stagmeyer
Journal: Journal of Clinical Oncology (2021)

e13049 Background: Breast cancer (BC) is the most prevalent tumor in women and the leading cause of cancer death in women. TNBC has the worst prognosis among BC subtypes and limited treatment options, mainly including chemotherapy. The efficacy of immunotherapy is clear for immunogenic tumors, such as melanoma, kidney cancer, non-lung cancer small cell, among others. BC seems to be less immunogenic. Basal-type TNBC present a prominent infiltration of inflammatory cells, suggesting that an immune pathway plays a role in tumorogenesis. The development of immunotherapy (IO)has reached an important turning point in the history of cancer treatment based on the use of the immune system itself to fight tumor cells. PD-L1 overexpression is the only predictive response biomarker for anti-PD-1 / PD-L1 therapy that is accepted in TNBM. Methods: Retrospectively, 68 cases of TNBC from the Pathological Anatomy Service of the Ntra. Sra. De las Mercedes Maternity Institute, of Tucumán, between 2010 and 2016 were analyzed. VENTANA anti PDL1 sp142 assay platform was used. Tumor-infiltrating immune cells (IC) are scored as the proportion of tumor area that is occupied by PD-L1 staining IC of any intensity. A specimen should be considered to have PD-L1 expression if the specimen exhibits ≥ 1% IC. In addition, carcinomas with a proportion greater than 50% of lymphocytic infiltration and its association with the expression of PD L1 were studied according to the recommendations of the International TILs Working group. Results: The median age of the patients was 56 years (21-80). The predominant histological type was non-specific type ductal carcinoma, reported in 45/68 cases (66%), following the medullar 9 / 68 (13%) lobular in 8/68 (11%), metaplastic 3/68 (4%) and other 4%. The tumor grade (G), half of the cases were G 3 with 34/68 (50%), G 2 with 42%. The largest proportion of pts, 42%, had no lymph node (LN) involvement, 33% had between 1 to 3 positive LN and 25% showed 4 or more LN. Stage II 39/68 patients (58%) in stage III 20/68 (30%), I (9%, 6) and IV (3%, 2). 16% (11/68) of the patients were PD-L1 positive. Tumors with lymphocytic infiltration between 0% and 10% expressed 24% (2/37), no expression was observed in tumors with TIls between 10 and 50% and in cases with lymphocytic infiltration greater than 50% expression of PD L was observed 1 in 9/18 cases (50%) (Fisher's exact test, p &lt; 0.0001). Conclusions: It was demonstrated that there is an association between the stromal lymphocytic infiltrate (TILs) and the expression of PD-L1 in tumor cells, in this population of women from Tucumán, which would help to select patients as candidates for anti PD L1 therapies.
William Smith Mitchell
Authors: John J Keating, Fiona Wood, Alan Barton
Journal: BMJ (2021)

William Smith Mitchell (“Bill”) was a consultant general physician and rheumatologist at Furness General Hospital in Barrow for over 30 years. He did his initial medical training, including an intercalated BSc, in his home city of Glasgow. On completing his houseman posts in Glasgow and Stirling, he continued his medical senior house officer and registrar training, working with colleagues at the centre for rheumatic diseases at Glasgow Royal Infirmary. He left his native Scotland in 1984 and worked as a senior registrar in rheumatology …
Initial findings of the first-in-human phase I study of AGEN2373, a conditionally active CD137 agonist antibody, in patients (pts) with advanced solid tumors.
Authors: Anthony W. Tolcher, Richard D. Carvajal, Anthony B. El-Khoueiry, Waldo Ortuzar Feliu, Hong Zang, Marek Ancukiewicz, Irina Shapiro, James Fredric Strauss
Journal: Journal of Clinical Oncology (2021)

2634 Background: CD137 is a member of the tumor necrosis factor receptor superfamily that functions as a potent co-stimulator of both adaptive and innate immune cells, thus making it an attractive target for cancer immunotherapy. The development of first-generation anti-CD137 antibodies has been hampered by limited clinical activity or dose-limiting hepatotoxicity. AGEN2373 is a novel, conditionally active CD137 agonist antibody designed to selectively enhance tumor immunity while mitigating side effects associated with systemic activation of CD137. Here we report the initial findings from the first-in-human evaluation of AGEN2373 in pts with advanced solid cancers. Methods: Pts received AGEN2373 on day 1 of a 28-day cycle (Q4W dosing), with cycles repeated until progression, intolerable toxicity or investigator/patient decision. Dose-escalation followed a standard 3+3 scheme, with planned dosing of 0.03, 0.06, 0.3, 1.0, 2.0, and 3.0 mg/kg. The primary objective was to determine the safety, tolerability, and dose-limiting toxicity (DLT) of AGEN2373 as monotherapy. Secondary objectives included pharmacokinetics (PK) and preliminary clinical activity. Adverse events (AEs) were reported per CTCAE v5.0 and DLTs evaluated within a 28-day window. For PK analyses, serum AGEN2373 concentrations determined using a validated bioanalytical assay and simultaneously analyzed by an NLME model. Antitumor activity was assessed using RECIST v1.1. Results: As of January 21 2021, 19 pts (median age 54.4 years, range 33-74; 11 men, 8 women; 7 with prior immunotherapy) have been treated with AGEN2373 Q4W at escalating doses from 0.03 – 2.0 mg/kg across 5 cohorts. Eleven pts (57.9%) experienced treatment-related AEs; none were grade 3 or higher. The most common events were fatigue (4 pts, 21.1%) and nausea (2 pts, 10.6%). No DLTs have been observed. Importantly, no drug-related elevations in liver transaminases (ALT, AST) or bilirubin beyond 1 grade have been seen. AGEN2373 PK were consistent with linear elimination. Prolonged disease stabilization as best response occurred in 5 pts (26.3%; range, 6-41 weeks); three of which were seen in heavily pretreated pts with metastatic leiomyosarcoma, including one who had progressed on prior combination checkpoint immunotherapy. Enrollment into the 3.0 mg/kg cohort is continuing. Conclusions: AGEN2373 demonstrates good tolerability in pts with advanced solid tumors, with a safety profile characterized by a lack of hepatotoxicity frequently observed with CD137-targeting antibodies. These findings underscore the suitability of AGEN2373 as a potential partnering agent for other immunomodulatory agents, including planned expansion as combination therapy with balstilimab (anti-PD-1). Clinical trial information: NCT04121676.
Phase 1b/2a study of PLX2853, a small molecule BET inhibitor, in subjects with advanced solid tumors and lymphoma.
Authors: Michael S. Gordon, Richard D. Carvajal, Alexander I. Spira, Marilyn Huang, Paul Watkins, Ben Powell, Kerry Inokuchi, Michael Sterba, Bernice Matusow, Chelsea Hope, Jason Halladay, Chao Zhang, Jacqueline M. Walling, Athanasios C. Tsiatis, Amita Patnaik
Journal: Journal of Clinical Oncology (2021)

3018 Background: PLX2853 is a potent, orally active small molecule BET inhibitor. Its unique pharmacokinetic (PK) profile is associated with less thrombocytopenia and improved tolerability by allowing transient target engagement with a prolonged pharmacodynamic (PD) response and time for recovery after dosing. Methods: We conducted a first-in-human 3+3 Ph1b/2a study of PLX2853 in adults with relapsed or refractory solid tumors and lymphoma to determine the safety, PK and recommended phase II dose (RP2D) (NCT03297424). Secondary endpoints included efficacy and PD. Results: As of 2 February 2021, 44 subjects (median age 65, range 39 - 84) received PLX2853 in escalating doses from 5mg to 120mg QD and 40mg to 60mg BID. Ovarian cancer (n = 11), uveal melanoma, colorectal, and prostate (n = 5 each) were the most represented tumor types. Adverse events (AE) occurring in ≥15% of subjects included nausea (41%), decrease appetite (39%), fatigue (27%), vomiting (25%), diarrhea (25%), dysgeusia (25%), dehydration (23%), anemia (20%), dry mouth (18%), dizziness (16%), abdominal pain (16%), and pyrexia (16%). Thrombocytopenia occurred in 11% of subjects. Most AEs ( &gt; 85%) were grades (G) 1-2. Of all AEs, 40% were related. There were 5 treatment-related serious AEs in 2 subjects (n = 1 G4 thrombocytopenia, G4 ischemic stroke, G3 subarachnoid hemorrhage [SAH], and G3 thromboembolic event; n = 1 G3 vomiting). Dose-limiting toxicities were observed at 120mg QD (G4 thrombocytopenia, G4 ischemic stroke, G3 thromboembolic event, and G3 SAH; asymptomatic G4 thrombocytopenia), 60mg BID (G3 thrombocytopenia with recovery &gt; 7 days), and 40mg BID (dose reduction for transient G3 fatigue). PLX2853 systemic exposure was dose-proportional up to 120mg with a short terminal half-life ( &lt; 3.5 hr). Plasma concentrations were above the IC 90 in the MYC-responsive reporter assay for 9 hr at 80mg or higher doses. RNA-seq analyses of peripheral blood mononuclear cells showed a dose-dependent modulation of BET target gene expression. One complete response (ongoing 9+ months) was seen in a patient with DLBCL, two patients had partial responses (1 uveal melanoma, 1 primary peritoneal cancer), and 14 patients had stable disease. The median PFS was 82.5 days (range: 51 – 209 days). Conclusions: PLX2853 shows encouraging signs of clinical activity and is well tolerated at the anticipated RP2D of 80 mg/day. PLX2853 is being evaluated as monotherapy and in combination. Clinical trial information: NCT03297424.
Leveraging machine learning technology to efficiently identify and match patients for precision oncology clinical trials.
Authors: Laura Sachse, Smriti Dasari, Marc Ackermann, Emily Patnaude, Stephanie OLeary, Hussein Al-Olimat, Alexander Grigorenko, Andrew Stewart, AnnaJane Ward, Annie Darmofal, Sowmya Ballakur, William Bennett, Amy Franzen, Sibel Blau, Abhinav Binod Chandra, Petros Nikolinakos, James Michael Orsini, Julio Antonio Peguero, Kimberly L. Blackwell, Matthew M. Cooney
Journal: Journal of Clinical Oncology (2021)

e13588 Background: Pre-screening for clinical trials is becoming more challenging as inclusion/exclusion criteria becomes increasingly complex. Oncology precision medicine provides an exciting opportunity to simplify this process and quickly match patients with trials by leveraging machine learning technology. The Tempus TIME Trial site network matches patients to relevant, open, and recruiting clinical trials, personalized to each patient’s clinical and molecular biology. Methods: Tempus screens patients at sites within the TIME Trial Network to find high-fidelity matches to clinical trials. The patient records include documentation submitted alongside NGS orders as well as electronic medical records (EMR) ingested through EMR Integrations. While Tempus-sequenced patients were automatically matched to trials using a Tempus-built matching application, EMR records were run through a natural language processing (NLP) data abstraction model to identify patients with an actionable gene of interest. Structured data were analyzed to filter to patients that lack a deceased date and have an encounter date within a predefined time period. Tempus abstractors manually validated the resulting unstructured records to ensure each patient was matched to a TIME Trial at a site capable of running the trial. For all high-level patient matches, a Tempus Clinical Navigator manually evaluated other clinical criteria to confirm trial matches and communicated with the site about trial options. Results: Patient matching was accelerated by implementing NLP gene and report detection (which isolated 17% of records) and manual screening. As a result, Tempus facilitated screening of over 190,000 patients efficiently using proprietary NLP technology to match 332 patients to 21 unique interventional clinical trials since program launch. Tempus continues to optimize its NLP models to increase high-fidelity trial matching at scale. Conclusions: The TIME Trial Network is an evolving, dynamic program that efficiently matches patients with clinical trial sites using both EMR and Tempus sequencing data. Here, we show how machine learning technology can be utilized to efficiently identify and recruit patients to clinical trials, thereby personalizing trial enrollment for each patient.[Table: see text]
The role of PP2A variants to predict outcome in patients (pts) with metastatic colorectal cancer (mCRC): Data from FIRE-3 and TRIBE trials.
Authors: Jingyuan Wang, Joshua Millstein, Fotios Loupakis, Sebastian Stintzing, Hiroyuki Arai, Francesca Battaglin, Natsuko Kawanishi, Priya Jayachandran, Shivani Soni, Wu Zhang, Christoph Mancao, Chiara Cremolini, Volker Heinemann, Alfredo Falcone, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2021)

3581 Background: Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase with functions that counter-balance kinase-mediated phosphorylation throughout cell signaling networks. PP2A was reported to upregulate the angiogenesis, while negatively regulate the pathways downstream of receptor tyrosine kinases at multiple nodes. Previous studies showed PP2A variants were associated with the increased risk of cancer. Therefore, we hypothesized that PP2A variants may predict first-line treatment outcome in mCRC pts treated with bevacizumab (bev)/cetuximab (cet)-based chemotherapy. Methods: Genomic DNA from blood samples of pts enrolled in two independent randomized trials, TRIBE (bev arm, n=215, as discovery cohort) and FIRE-3 (bev arm, n=107, as validation cohort; cet arm, n=129, as control cohort), was genotyped through the OncoArray, a customized array manufactured by Illumina including approximately 530K SNP markers. The impact on outcome of 17 selected SNPs in 3 main PP2A core subunits (PPP2CA, PPP2R1B, PPP2R1A), one phosphatase activator (PPP2R4) and 2 endogenous inhibitors (TIPRL, CIP2A) was analyzed. Results: In the discovery cohort, pts with PPP2R4 rs2541164 A/A (N=16) showed significantly shorter overall survival (15.3 vs 27.3 months) compared to carriers of any G allele (N=198) in both univariate (hazard ratio [HR]=1.8; 95% confidence interval [CI]: 1.1-3.1; p=0.02) and multivariate (HR=2.4; 95%CI: 1.4-4.4; p=0.006) analysis. These data were validated in the FIRE-3 bev cohort in both univariate (A/A vs. Any G: 17.3 vs 39.9 months, HR=2.8, 95%CI: 1.4-5.9, p=0.004) and multivariate (HR=4.3, 95%CI: 1.5-12.2, p=0.0095) analysis. Conversely, pts carrying CIP2A rs13069780 C/C (N=24) only showed significantly longer progression-free survival (17.7 vs 12.3 months) than carriers of any T allele (n=105) in the FIRE-3 cet cohort in both univariate (HR=0.6; 95%CI 0.4-0.99; p=0.04) and multivariate (HR=0.5; 95%CI 0.3-0.94; p=0.02) analysis, but no association were observed in the bev cohort of TRIBE and FIRE-3. Conclusions: Our study demonstrated for the first time that PPP2R4 polymorphisms could predict outcomes of bev-based treatment in mCRC patients; Meanwhile CIP2A polymorphism could predict outcomes of cet-based treatment in mCRC patients. These findings support a possible role of the PP2A variants in contributing to resistance to anti-VEGF/EGFR treatment.
Typical Kidney Tumor With Atypical Presentation
Authors: Elizabeth A. Hedges, Chuong D. Hoang
Journal: JAMA Oncology (2021)

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全てのゲノムの8%の配列多様性による遺伝子型FのB型肝炎ウイルス隔離集団の2つのサブグループ(F1およびF2)への分類
Authors: Kato H, Orito E, Sugauchi F, Suzuki S, Ueda R, Gish Rg, Tanaka Y, Miyakawa Y, Mizokami M
Journal: Hepatology (2002)