tbuckley/cabot-search huggingface dataset:
Association between pesticides use and incidence of diffuse large B cell lymphoma (DLBCL).
Authors: Alaa Altahan, Michael Gary Martin
Journal: Journal of Clinical Oncology (2018)

1570 Background: Some studies have linked pesticide exposure to risk of developing cancers. However, these studies were limited to single or few pesticides. We analyze association between incidence of DLBCL and all chemicals reported by The United States Geological Survey (USGS). Methods: Using International Classification of Diseases for Oncology (ICDO-3) code 9680, patients (pts) diagnosed with DLBCL in 2012 were extracted from Lymphoma-leukemia dataset from The Surveillance, Epidemiology, and End Results (SEER) database. Pts were grouped by Federal Information Processing Standards (FIPS) code. United States Census data (www.census.gov) was used to obtain population estimates for each FIPS code in 2012. USGS data (www.usgs.gov) was used to extract quantitative pesticides use in the year of 1992 per FIPS code*. Incidence of DLBCL per FIPS code was calculated then matched to USGS data. SPSS software was used for statistical analysis. Association between level of pesticides use and incidence of DLBCL was analyzed using linear regression. Two tailed P value of < 0.05 on Pearson correlation was used for statistical significance. Results: A total of 2258 pts with DLBCL in 167 counties were identified. Of the 290 chemicals reported by USGS, 65 were excluded due to lack of data. Of the remaining 225, forty showed statistically significant correlation (30 positive and 10 negative) with incidence of DLBCL. Of these chemicals, 8 have moderate or strong correlation with R coefficient > 0.4 (table). Conclusions: Some agriculture chemicals have significant correlation with incidence of DLBCL. This warrants further evaluation of these chemicals as potential carcinogens or protective agents. Analysis of the underlying mechanisms may reveal some common mechanisms. Chemical R coeff P - value Median Range N** BARIUM POLYSULFIDE 0.997 0.049 8.3 3.1-12.2 3 PEBULATE 0.67 0.003 16.7 0.2-188.8 17 FERBAM 0.655 0.011 87.9 0.5-891.9 14 CHLORETHOXYFOS 0.478 0.038 201.4 114.2-451.1 19 MSMA 0.441 0.010 70.2 0.4-241.2 33 MONOCROTOPHOS -0.616 0.044 0.4 0.2-1.0 11 DICROTOPHOS -0.558 0.038 11.2 0.1-65.1 14 CHINOMETHIONAT -0.548 0.043 0.55 0.1-1.3 14 * Data reported by high use estimate ** N is number of counties included in analysis i.e. have data available
Utilization rates of enoxaparin and heparin in venous thromboembolism prophylaxis after education and electronic order change at a single institution: A quality improvement study.
Authors: Linda Phuong Hoang, Alexander A. Hindenburg
Journal: Journal of Clinical Oncology (2018)

e18836 Background: Despite data demonstrating an advantage of enoxaparin (LMWH) over heparin (UFH) for venous thromboembolism (VTE), an analysis of hospital prescribing trends showed use of each was about equal. In an attempt to increase LMWH over UFH use where it is not medically contraindicated, changes to the electronic medical record (EMR) for medical service patients and prescriber education was provided via multidisciplinary grand rounds conference in November 2016. This provided a unique opportunity to study trends in prescribing LMWH and UFH at our institution before and after aforementioned interventions. Methods: Patients were identified by Citrix Pharmacy. Data was extracted three months prior and after intervention (August 2016 to February 2017) excluding November 2016 when changes were made. Inclusion criteria were > 18 years of age and initiated on LMWH or UFH for VTE prophylaxis during hospitalization. Exclusion criteria were one time or duplicate orders and VTE treatment doses. The primary endpoint was to evaluate LMWH and UFH use among hospital services with focus in medical service which had both interventions compared to single intervention (grand rounds) among all other services. Results: 8921 patients were included in this study (4831 LMWH, 4090 UFH). In terms of utilization among all services prior to and after intervention for LMWH increased 51% to 57% and UFH decreased 49% to 43% respectively. Data was further divided into separate services (gynecology, medicine, neurology, obstetrics, orthopedics, surgery, thoracic and urology). Medicine comprised of 61% of patients and LMWH use was 52% to 60% and UFH was 48% to 40% respectively. Intervention with electronic order set and education with grand rounds for medicine patients resulted in 8% increase of LMWH use compared to all services 6%. Conclusions: Education through multidisciplinary grand rounds as well as changing the electronic order set to encourage LMWH as agent of choice over UFH for VTE prophylaxis in the medicine admission order set led to an increase in prescribing of LMWH in the medical services as well as all hospital services.
Phase 1b study of venetoclax in combination with azacitidine in patients with treatment-naïve higher-risk myelodysplastic syndromes.
Authors: Chun Yew Fong, Andrew H. Wei, Mark G. Frattini, Meagan Jacoby, Uma Borate, Katharina S. Gotze, Jacqueline Suen Garcia, Daniel Aaron Pollyea, Leanne Holes, Ying Zhou, Kaffa Mussumeh Fakouhi, Joel Leverson, Jason G Harb, Suresh K. Agarwal, Faraneh Attarchi, Mack H. Mabry, Wan-Jen Hong, Thomas Michael Jahn, Pierre Fenaux, Guillermo Garcia-Manero
Journal: Journal of Clinical Oncology (2018)

TPS7082 Background: Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis leading to cytopenias and potentially transform to acute myeloid leukemia (AML). Treatment (tx) with hypomethylating agents (HMAs) is the standard of care for patients (pts) with tx-naïve higher-risk (HR) MDS who are not candidates for intensive chemotherapy/allogeneic stem cell transplant. Currently, azacitidine (AZA) is the only drug shown to prolong survival in tx-naïve HR MDS. However, ~50% of pts treated with HMA alone do not derive clinical benefit. Venetoclax (VEN) is a potent, orally bioavailable BCL-2-specific inhibitor, VEN plus AZA has demonstrated a tolerable safety profile and promising efficacy in elderly pts with tx-naïve AML (incl. secondary AML) ineligible for intensive chemotherapy. Preclinical data indicate activity of VEN in HR MDS (Jilg, 2016). Thus, the unmet medical need in HR MDS as well as relevant clinical data with VEN in AML provide a rationale for assessing VEN plus AZA in pts with tx-naïve HR MDS. Methods: This open-label, Phase 1b dose-escalation study evaluates VEN in combination with AZA for tx-naive HR MDS (NCT02942290) and consists of 2 portions, an initial dose-escalation (∼24 pts) and a safety expansion (∼20 pts) at the recommended Phase 2 dose (RPTD). Key eligibility criteria are no prior therapy for MDS, an overall International Prognostic Scoring System score of ≥1.5 (Int-2 and HR), bone marrow blasts ≥5% and < 20%, and ECOG score of ≤2. VEN will be administered at starting dose level of 100 mg daily for 14 days/cycle (28 days) and may be escalated up to 400 mg for subsequent dose-level cohorts. AZA will be administered at the standard dose (75 mg/m2) for 7 days/cycle. Primary study objectives are to assess safety and pharmacokinetics, and to determine the RPTD and dosing schedule of VEN plus AZA. Secondary objectives incl. rates of overall response, hematologic improvement, transfusion independence, and cytogenetic response, as well as duration of response, progression-free survival, overall survival, and time to transformation to AML. Exploratory objectives include patient-reported outcomes and translational biomarkers of response and resistance. Clinical trial information: NCT02942290.
History of PSA screening on prostate cancer aggressiveness.
Authors: Jennifer Cullen, Thomas Gerald, Allen Burke, Huai-Ching Kuo, Inger L. Rosner, Shiv Srivastava, Isabell Sesterhenn
Journal: Journal of Clinical Oncology (2017)

5066 Background: In 2012, PSA screening for prostate cancer (CaP) detection was given a “Grade D” recommendation for all men by the USPSTF. Recent U.S. studies report declines in PSA screening with concomitant increases in advanced CaP at diagnosis. This study examined the association between PSA screening history and CaP aggressiveness in a racially diverse, military cohort with equal health care access. Methods: This retrospective cohort study evaluated CaP patients undergoing radical prostatectomy (RP) from 1994-2015 at Walter Reed National Military Medical Center. Whole-mounted prostatectomy specimens were classified using 2014 ISUP Gleason grading system. Excluding the diagnostic PSA, screening history was categorized as: ≥ 6 PSA’s prior to CaP diagnosis (uppermost quartile), 1-5 (lower 3 quartiles), vs. no screening history. Multivariable logistic regression (MLR) was used to examine NCCN risk stratum (intermediate-high vs. low) and Gleason upgrade (GU) from biopsy to RP. Multivariable Cox proportional hazards (Cox PH) analyses were used to model time to biochemical recurrence (BCR). Multivariable models controlled for age at RP, race, family history and obesity (BMI &gt; 30 vs. ≤ 30 kg/m 2 ). The GU and BCR models also controlled for NCCN risk classification. Results: There were 1,772 eligible patients with a median follow-up and age at RP of 7.0 and 59.8 years, respectively. Prior to CaP diagnosis, 42% and 19% of men had 1-5 and ≥ 6 PSA’s screenings, respectively. MLR showed greater odds of intermediate or high vs. low risk disease for PSA screening history of none vs. 1-5 (OR = 1.33, CI = 1.03-1.70, p = 0.028) but not for none vs. ≥ 6 (p = 0.44). MLR showed increased odds of GU for none vs. ≥ 6 (OR = 1.81, CI = 1.23-2.7, p &lt; 0.001). Multivariable Cox PH models showed incrementally poorer BCR-free survival as screening history decreased (HR None vs. ≥6 = 2.27, CI = 1.54-3.33, p &lt; 0.001; HR None vs. 1-5 = 1.49, CI = 1.15-1.92, p = 0.002). Conclusions: In this RP cohort, higher risk stratum, increased GU, and poorer BCR-free survival were associated with no PSA screening history. BCR-free survival was incrementally worsened by less PSA screening. A complete absence of PSA screening may lead to more aggressive disease at presentation and poorer clinical outcomes.
A phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of PLX9486 alone and in combination (combo) with the KIT inhibitors pexidartinib (pexi) or sunitinib (su) in patients (Pts) with advanced solid tumors and gastrointestinal stromal tumor (GIST).
Authors: Andrew J. Wagner, William D. Tap, Anthony Frank Shields, Amita Patnaik, Rashmi Chugh, Gabriel Tinoco, Glenn Michelson, Oscar Alcantar, Michael Pelayo, Chao Zhang, Paul Severson, Eric Martin, Jonathan C. Trent
Journal: Journal of Clinical Oncology (2018)

11509 Background: Most metastatic GISTs have primary (10) mut in KIT exons (ex) 9 or 11, which confer sensitivity to imatinib and other agents. Tumors develop clonal secondary (2y) resistance mut, typically in ex 13, 14, 17, and 18. PLX9486 inhibits KIT 10 mut and ex 17 and 18 2y mut. Pexi (PLX3397) and su inhibit 10 mut and ex 13 and 14 2y mut. Combo of PLX9486 with pexi or su may have activity against a broader spectrum of mutations. Methods: 3 + 3 dose escalation study in pts with solid tumors and GIST who had progressed on imatinib and other TKI. Safety, efficacy per RECIST, and PK were assessed. Ct DNA was assessed as a biomarker. Part (P) 1: single agent PLX9486 dose escalation once (QD) and twice daily (BID). P2: combos of PLX9486 500 mg QD with pexi 600 mg QD fed and fasted or su 25 mg QD with food. Results: As of January 8, 2018, 36 pts (31 GIST; Part 1-20 pts, part 2-11 pts) were enrolled; median age was 63 years (range 49-82). GIST pts had a median of 4 prior therapies (range 1-7), and all progressed on imatinib. Most pts had tumors with ex 11 and 17 mut. QD dosing of PLX9486 had saturable absorption at steady state with a half-life of 71.4 hrs. No PK advantage to BID dosing and no food effect. One DLT of Grade (G) 3 anemia was reported at the 1000 mg dose level. Escalation stopped due to PK plateau; the RP2D was 1000 mg QD. In P2, no DLTs were observed at the doses studied. PK of PLX9486 was not affected by pexi. Pexi food effect was observed. Adverse events (AEs) in P1 in ≥ 20% pts (N = 24) were diarrhea, nausea, increased AST (29% each) and fatigue (21%). AEs in P2 in ≥ 20% pts (N = 12) were hair color changes (42%), anemia (25%), nausea (25%), and anorexia (25%). Majority were G1-2. No ≥ G3 LFT changes in P1 or P2. In P1, 2 partial responses (PR) were seen with PLX9486 1000 mg and PFS was > 24 weeks. In P2, 1 pt had a PR in the pexi/PLX9486 combo, and the median PFS has not been reached. Conclusions: PLX9486 alone and in combo with pexi was generally well tolerated with evidence of activity against resistant GIST. Combos with su and pexi, agents with complementary activity against KIT 2y resistance mut in GIST, are accruing. Clinical trial information: NCT02401815.
A phase 3, randomized, open-label, multicenter study to compare the efficacy and safety of tislelizumab, an anti-PD-1 antibody, versus sorafenib as first-line treatment in patients with advanced hepatocellular carcinoma.
Authors: Shukui Qin, Richard S. Finn, Masatoshi Kudo, Tim Meyer, Arndt Vogel, Michel Ducreux, Teresa Macarulla Mercade, Gianluca Tomasello, Frederic Boisserie, Jeannie Hou, Cindy Li, James Song, Andrew X. Zhu
Journal: Journal of Clinical Oncology (2018)

TPS3110 Background: Advanced hepatocellular carcinoma (HCC) accounts for 70% of diagnosed HCC. Tislelizumab (also known as BGB-A317) is a humanized, IgG4 monoclonal antibody with high affinity and binding specificity for programmed cell death receptor-1 (PD-1). Furthermore, tislelizumab was specifically engineered to minimize FcgR binding on macrophages, thereby abrogating antibody-dependent phagocytosis, a potential mechanism of T-cell clearance. A first-in-human, phase 1A/1B study (NCT02407990) demonstrated that single-agent tislelizumab was generally well tolerated and showed evidence of antitumor activity in patients with advanced solid tumors, including HCC. A recommended phase 3 dose of 200 mg administered intravenously (IV) every 3 weeks (Q3W) has been established for tislelizumab. Methods: This global, phase 3, randomized, multicenter, non-inferiority study (NCT03412773) was designed to evaluate the efficacy and safety of tislelizumab compared with sorafenib as a first-line treatment of advanced HCC. Adult patients, aged ≥18 years, with unresectable, histologically confirmed HCC, an ECOG score ≤1, Child-Pugh A classification, BCLC Stage C disease or BCLC Stage B disease that has relapsed after loco-regional therapy, and who have not received prior systemic therapy, are being enrolled. Approximately 640 patients from 100 international centers will be randomized (1:1) to receive tislelizumab 200 mg IV Q3W or sorafenib 400 mg orally BID. The primary outcome of this non-inferiority study is overall survival (OS) of patients treated with tislelizumab compared with OS of patients treated with sorafenib; secondary outcomes include objective response rate, progression-free survival, duration of response, time to progression, and quality-of-life outcomes. Safety/tolerability assessments include monitoring adverse events (AEs), including immune-related AEs, as well as physical examinations, vital signs, and electrocardiograms. Clinical trial information: NCT03412773.
Impact of incoming phone calls on oncology departments in oral therapies era: a large national prospective survey.
Authors: Florence Joly, Rachid El Amarti MD, Aline Guillot, Ali Hasbini, Bachar EL Sayadi MD, Dominique Spaeth, Delphine Topart, Yann Alexandre Vano, Aude Flechon
Journal: Journal of Clinical Oncology (2016)

e18210 Background: Oral therapies, and an increase of patient involvement have shifted the follow-up of patients with cancer from hospital to home. As a consequence, the number of incoming phone calls (IPC) has increased. To understand the source, reasons, management and burden of IPC, we underwent a French national survey. The objective was to describe IPC and to understand the way they are managed in oncology departments. Methods: The study was a prospective survey in a representative sample of 51 French oncology specialists (Sp) treating patients with oral therapies. Data on all IPC was collected during a one-week period in 2014. Characteristics of centers were also registered. Results: Among 51 participating onco/radiotherapy departments, 86% of Sp were oncologists or hematologists and 14% radiation oncologists. 80% were from public centers and 20% from private ones. 41%, 39% and 20% treated less than 250, 251 to 1000 and more than 1000 new metastatic patients per year, respectively. The number of IPC/week was 17 to 64, 65 to 130 and over 130 for respectively 33%, 35% and 31% of centers (mean = 119/week). 66% of IPC were from patients and families and 23% from general practitioners. Upon IPC reception by the secretaries, half of them correspond to a medical question. A majority (65%) of centers did not have an established specific procedure and 70% of responders did not specifically train their teams (secretaries and nurses) to address the management of IPC. 65% of the sp spent more than 30 min/day. Most of them considered it disturbing medical activities. 66% of patients IPC were related to adverse effects (AE) of treatments. 22% of Sp declared at least one severe AE linked to some misinterpretation of an IPC. Centers with IPC procedures and outgoing systematic phone calls had much less IPC. Conclusions: With the increase of oral therapies, incoming phone calls in French oncology centers (mainly patient calls who need exchanging information on AE) represent an important burden of work. To improve IPC management, recommendations are produced including dedicated procedures, trained telephone triage personnel (secretaries and dedicated nurses), standardized management of AE and documentation of answers.
Postmarketing safety review of everolimus and cardiac failure or left ventricular dysfunction.
Authors: Afrouz Nayernama, Peter Waldron, Tracy Salaam, Scott Proestel
Journal: Journal of Clinical Oncology (2016)

e18226 Background: Everolimus is a mammalian target of rapamycin (mTOR) kinase inhibitor approved for treatment of several human cancers including renal cell carcinoma, pancreatic neuroendocrine tumor, and breast cancer. As a routine pharmacovigilance activity, we performed a postmarketing safety review of everolimus and cardiac dysfunction (CD), including cardiac failure (CF) or left ventricular (LV) dysfunction. Methods: We searched the FDA Adverse Event Reporting System (FAERS) and the literature for reports of oncological everolimus use and CD submitted to the FDA from product approval to April 6, 2015. We adapted a case definition for cardiac dysfunction developed by the Cardiac Review and Evaluation Committee supervising trastuzumab clinical trials, and evaluated cases for time to onset, response to stopping and resuming therapy, comorbidity, and concomitant or prior use of other antineoplastic therapy. Results: A total of 148 FAERS and literature cases met the case definition. The review and analysis revealed that everolimus-associated CD has a spectrum of clinical presentations that range from fatal cases, to reversibly decreased LV ejection fraction (EF). Among the cases that provided an echo measurement of decreased LVEF, 68% (30/44) reported a CTCAE grade 3-4 decreased LVEF. An association of everolimus with CD is supported by a temporal relationship (median time to onset = 86 days, range = 3-1143 days), improvement or resolution of cardiac failure, decreased LVEF, or both in 49% after discontinuation of everolimus, and biologic plausibility due to dysregulation of the PI3K-AKT-mTOR pathway. The majority of the cases were confounded by concomitant or prior use of cytotoxic or targeted therapies, or cardiac comorbidities. However, many cases with prior exposure to other antineoplastic drugs and pre-existing cardiac risk factors reported a documented normal baseline ejection fraction (EF), prior to everolimus exposure. Hypertension was the most common cardiovascular risk factor reported in the case series. Conclusions: The use of everolimus in cancer therapy is associated with cardiac dysfunction. Clinicians should be aware of this potential safety issue.
Characterization of LASEP3 as a serological and prognostic biomarker and a therapeutic target for lung cancer.
Authors: Atsushi Takano, Phung Manh Thang, Yusuke Nakamura, Yataro Daigo
Journal: Journal of Clinical Oncology (2016)

e23278 Background: The improved understanding of cancer-specific oncoproteins could lead to the development of novel diagnostic/prognostic biomarkers or therapeutic targets. Methods: i) Identification of up-regulated genes in non-small cell lung cancers (NSCLCs) by means of cDNA microarray, ii) Validation of clinicopathological significance of their protein expression by tissue microarray, iv) Examination of the growth/invasion on cancer cells by siRNA/Matrigel invasion assays, and v) Measurement of their serum protein levels by ELISA. Results: We identified a secreted protein, LASEP3 (lung cancer-associated serum protein 3) as a candidate. Immunohistochemical staining of LASEP3 showed that LASEP3 expression was observed in 198 (54.8%) of 361 NSCLCs (non-small cell lung cancer) that had undergone curative surgery. High level of LASEP3 expression was associated with poor prognosis for NSCLC patients. (P = 0.0183 by log-rank test). Serum LASEP3 levels were higher in NSCLC patients than in healthy volunteers. The proportion of serum LASEP3-positive cases was 160 (61.8%) of 259 NSCLCs (49.4% for stage I-II, 67.4% for stage III-IV), while 6 (5.5%) of 109 healthy volunteers were falsely diagnosed. Furthermore, reduction of LASEP3 by siRNA suppressed lung cancer cell proliferation and invasion. Transfection of siRNAs for LASEP3 into lung cancer cells revealed induction of caspase-dependent apoptosis. Furthermore, we found its 50-kDa receptor (LASEPR) which interacts with LASEP3 on lung cancer cell surface. Suppression of LASEPR expression by siRNAs inhibited the growth of lung cancer cells. Conclusions: LASEP3 is a possible diagnostic and prognostic biomarker and therapeutic target for lung cancer.