tbuckley/cabot-search huggingface dataset:
PROPEL: A phase 1/2 trial of NKTR-214 (CD122-biased agonist) combined with anti-PD-1 (pembrolizumab) or anti-PD-L1 (atezolizumab) in patients (pts) with advanced solid tumors.
Authors: Daniel A. Vaena, Jorge Chaves, Nicholas J. Vogelzang, Marc Ryan Matrana, A. Eli Gabayan, Matthew John Riese, Daniel C. Cho, Mary Ann Tagliaferri, Jonathan Zalevsky, Sunny Xie, Ute Hoch, AHSAN NAQI RIZWAN, Sandra Aung, Michael Imperiale, James K. Schwarz
Journal: Journal of Clinical Oncology (2018)

TPS3115 Background: NKTR-214 is an investigational cytokine designed to target CD122 (IL-2Rβ) expressed on immune cells (CD8+ T cells and NK cells) in order to expand these tumor-killing cells. NKTR-214 monotherapy increases newly proliferative CD8+ T cells and NK cells in tumors and increases cell surface PD-1 and PD-L1 expression, demonstrating a potentially synergistic mechanism with anti-PD-1 therapy. NKTR-214 plus nivolumab resulted in rapid tumor responses in pts with metastatic melanoma (mM), non-small cell lung cancer (mNSCLC), and renal cell carcinoma. Given the early efficacy data and favorable safety profile of NKTR-214 plus nivolumab, PROPEL will evaluate the clinical benefit, safety and tolerability of NKTR-214 combined with pembrolizumab or atezolizumab. Methods: PROPEL (NCT03138889) will enroll approximately 60 pts in 2 separate arms concurrently. The first arm will evaluate NKTR-214 plus pembrolizumab in up to 30 select pts with locally advanced or mM, mNSCLC, or locally advanced or metastatic urothelial bladder cancer (UBC) within the FDA-approved pembrolizumab indications and dosage regimen. The second arm will evaluate NKTR-214 plus atezolizumab in up to 30 select pts with locally advanced or metastatic UBC or mNSCLC within the FDA-approved atezolizumab indications and dosage regimen. NKTR-214 is administered intravenously over 30 (±5) minutes every 3 weeks in an outpatient setting; the first studied dose of NKTR-214 will be 0.006 mg/kg. The primary objectives are to evaluate safety and tolerability and to define the maximum tolerated dose or recommended phase 2 dose of NKTR-214 combined with pembrolizumab or atezolizumab. The secondary objectives are to evaluate preliminary anti-tumor activity and efficacy by assessing overall survival and progression-free survival. In addition, the study will assess the immunological effects of treatment and the association between efficacy measures and PD-L1 expression in tumors. Treatment may continue beyond progression if there is clinical benefit as determined by the investigator. Enrollment is ongoing in the U.S. Clinical trial information: NCT03138889.
Risk of distant metastases in head and neck carcinoma patients and myeloperoxidase (MPO) expression.
Authors: Antonio Lopez-Pousa, Anna Sumarroca, Miquel Quer, Mercedes Camacho, Jacinto Garcia, Montserrat Lopez, Nuria Duenas Cid, Miguel Angel Pavon, Nuria Farre, Oscar Gallego Rubio, Ivana GABRIELA Sullivan, Agust Barnadas, Xavier Leon
Journal: Journal of Clinical Oncology (2016)

6067 Background: Tumor-associate neutrophils (TAN) represent a significant portion of the inflammatory cell infiltrate in head and neck carcinoma (HNSCC). Several studies have shown a significant association between TAN and poor clinical outcome in HNSCC patients. Myeloperoxidase (MPO) is a peroxidase enzyme expressed in TAN. MPO expression could be a biomarker for the identification and quantification of TAN. The objective of our study was to evaluate the transcriptional expression of MPO in HNSCC tumors, and to evaluate the relationship between MPO expression and the appearance of distant metastases Methods: RT-PCR was used to determine mRNA expression levels of MPO in 160 consecutive patients with HNSCC treated between 2004-2011. Continuous values of mRNA expression were analyzed using a classification and regression tree (CART) method considering the appearance of distant metastases as the dependent variable. During the followup period, 23 patients (14.4%) presented with distant metastases. Results: mRNA expression level of MPO for patients with distant metastases was significantly higher than for patients without (P = 0.007). The CART method classified patients in two categories: high (n = 60, 37.5%) or low (n = 100, 62.5%) expression level of MPO. The 5-year distant metastasis free survival was 66.7% for MPO high-expression level and 93.3% for MPO low-expression level (P < 0.001) patients. Considering patients with a low MPO expression as the reference group, patients with a high MPO expression had a 4.5 fold higher risk of appearance of distant metastases (CI 95%: 1.7-11.6). Patients with high risk of distant based on clinical and pathological variables, including patients with locally advanced tumors (cT3-T4), with advanced regional spread (cN2-N3), or with neck node metastases with extracapsular spread, who had a high MPO expression (n = 42) had a 5-year distant metastasis free survival of 59.2%. Conclusions: We found a significant relationship between mRNA MPO expression level and the appearance of distant metastases in HNSCC patients. The combination of clinical-pathological data with the MPO expression can be used to identify patients with a high risk of distant metastases
Treatment of Chronic Hepatitis B Infection—Reply
Authors: Lydia Tang, Shyam Kottilil
Journal: JAMA (2018)

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MAVERICC, a Randomized, Biomarker-stratified, Phase II Study of mFOLFOX6-Bevacizumab versus FOLFIRI-Bevacizumab as First-line Chemotherapy in Metastatic Colorectal Cancer
Authors: Aparna R. Parikh, Fa-Chyi Lee, Linda Yau, Han Koh, James Knost, Edith P. Mitchell, Ivan Bosanac, Nicholas Choong, Frank Scappaticci, Christoph Mancao, Heinz-Josef Lenz
Journal: Clinical Cancer Research (2018)

Abstract Purpose: MAVERICC compared the efficacy and safety of modified leucovorin/5-fluorouracil/oxaliplatin plus bevacizumab (mFOLFOX6-BV) with leucovorin/5-fluorouracil/irinotecan plus bevacizumab (FOLFIRI-BV) in patients with previously untreated metastatic colorectal cancer (mCRC). Patients and Methods: MAVERICC was a global, randomized, open-label, phase II study. Primary objectives were to assess associations between (i) excision repair cross-complementing 1 (ERCC1) expression with progression-free survival (PFS), and (ii) plasma VEGF A (VEGF-A) with PFS in patients with previously untreated mCRC receiving mFOLFOX6-BV or FOLFIRI-BV. Before randomization, patients were stratified by tumoral ERCC1/β-actin mRNA expression level and region. Results: Of 376 enrolled patients, 188 each received mFOLFOX6-BV and FOLFIRI-BV. PFS and overall survival (OS) were comparable between FOLFIRI-BV and mFOLFOX6-BV, with numerically higher PFS [HR = 0.79; 95% CI (confidence interval): 0.61–1.01; P = 0.06] and OS (HR = 0.76; 95% CI: 0.56–1.04; P = 0.09) observed for FOLFIRI-BV. In the high ERCC1 subgroup, PFS and OS were comparable between treatment groups (PFS, HR = 0.84; 95% CI: 0.56–1.26; P = 0.40; OS, HR = 0.80; 95% CI: 0.51–1.26; P = 0.33). Across treatment groups, high plasma VEGF-A levels (&amp;gt;5.1 pg/mL) were observed with shorter PFS (HR = 1.19; 95% CI: 0.93–1.53; P = 0.17) and significantly shorter OS (HR = 1.64; 95% CI: 1.20–2.24; P &amp;lt; 0.01) versus low levels (≤5.1 pg/mL). Safety findings for FOLFIRI-BV or mFOLFOX6-BV were comparable with those reported previously. Conclusions: First-line FOLFIRI-BV and mFOLFOX6-BV had comparable PFS and OS, similar to results in patients with high baseline tumor ERCC1 levels. There were no new safety signals with these bevacizumab-containing regimens.
Long-Term Risk of Venous Thromboembolism in Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study
Authors: Arin L. Madenci, Brent R. Weil, Qi Liu, Andrew J. Murphy, Todd M. Gibson, Yutaka Yasui, Wendy M. Leisenring, Rebecca M. Howell, Christopher L. Tinkle, Larissa Nekhlyudov, Lisa R. Diller, Gregory T. Armstrong, Kevin C. Oeffinger, Christopher B. Weldon
Journal: Journal of Clinical Oncology (2018)

Purpose To estimate the incidence of late-occurring venous thromboembolism (VTE) among survivors of childhood cancer and to identify risk factors for VTE to facilitate diagnosis and prevention. Methods The Childhood Cancer Survivor Study is a multi-institutional cohort of 24,355 5-year childhood cancer survivors (diagnosed between 1970 and 1999; median age at last follow-up, 28.7 years [range, 5.6 to 58.9 years]; median follow-up since diagnosis, 21.3 years [range, 5.0 to 39.2 years]) and 5,051 sibling participants. The primary end point was self-reported late (≥ 5 years after cancer diagnosis) VTE. Rate ratios (RRs) were estimated with multivariable piecewise exponential models. Results Late VTE incidence among survivors and siblings was 1.1 and 0.5 events per 1,000 person-years, respectively (RR, 2.2; 95% CI, 1.7 to 2.8), with 2.5 excess events per 100 survivors over 35 years. Among survivors, risk factors for VTE were female sex (RR, 1.3; 95% CI, 1.1 to 1.6), cisplatin (reference none; 1 to 199 mg/m
Enumeration of circulating tumor cells and assessment of immunotherapy biomarker PD-L1 in patients with colorectal cancer.
Authors: Ju-Yu Tseng, Chwen Cheng Chen, Chun-CHI Lin, Hung-Hsin Lin, Yen-Ru Chen, Chia-Ying Lee, Li-Fan Wu, Shin-Hang Wang, Hui-Min Yu, Wei-Feng Fang, Jeng-Kai Jiang
Journal: Journal of Clinical Oncology (2017)

e23029 Background: Circulating tumor cells (CTC) play a prognostic role in patients with metastatic colorectal cancer (mCRC). Studies investigating detection of CTC in peripheral blood (PB) showed limited clinical sensitivity. This study compares clinical sensitivity of CTC analysis in mesenteric venous blood (MVB) vs PB. PD-L1 expression on isolated CTCs was also characterized in various stages of CRC patients. Methods: 8mL PB and MVB samples were collected into K 2 EDTA-containing vacationer tubes and subsequently performed CTC enumeration and PD-L1 analysis by MiSelect R system. CTC is defined as EpCAM + , cytokeratin + and CD45 - with intact nuclei. CTC and PD-L1 + CTC number were counted and correlated to the patients’ clinical manifestations. Results: Blood samples were collected from 75 CRC patients with various stages. In MVB, CTC detection rate was 20%, 33%, 44% and 58% for stage I, II, III, and IV respectively, and the overall detection rate is 41%. In PB, CTC only detected in sporadic cases (7%). Also, the amount of CTC detected in MVB was more abundant than that in PB ( P &lt; 0.001) In addition, preoperative serum CEA levels were significantly associated with presence of CTC in MVB ( P= 0.011). PD-L1 expression was detected in 32% of the isolated CTCs, and was more abundant in those from late stage patients. The expression level of PD-L1 showed heterogeneity among CTCs. Conclusions: CTC enumeration in MVB could potentially increase the clinical sensitivity for CTC analysis in CRC. The CTC level in MVB significantly correlated with CEA levels which could serve as an important biomarker information for post-operative management. In additions, using MiSelect R System to determine PD-L1 expression on CTC could provide a promising approach for both patient selection or therapeutic monitoring of immunotherapies for CRC.
Primary tumor sidedness in colorectal cancer at VA hospitals: A nation-wide study.
Authors: Ibrahim Azar, Saghi Esfandiarifard, Gurjiwan Virk, Tariq Khreis, Syed Mehdi
Journal: Journal of Clinical Oncology (2018)

e15638 Background: Right-sided Colon Cancer (RC) is derived from the mid-gut, while left-sided Colon Cancer (LC) originates from the hindgut. LC has been associated with better survival compared to RC. The effect of Primary Tumor Sidedness on Colorectal Cancer (CRC) survival rates has not been studied in VA hospitals. Methods: Data from the National VA Cancer Cube Registry was studied. 65,940 cases of CRC were diagnosed between 2001 and 2015. ICD codes C18 to C20 were used to delineate patients with RC vs. LC. RC was defined as cancer from the cecum to the hepatic flexure, LC from the splenic flexure to the rectum with transverse cancer in between flexures. Local IRB approval was obtained. Results: Of the total number of CRC, 30.3% were RC & 58.8% LC. RC constituted 36.3% of cases in women and 30.1% of cases in men. RC was diagnosed after the age of 70 years in 51.8% of cases, compared to 38.5% of LC. LC constituted 56.0% of CRC in blacks, and 59.4% in whites. RC was more likely to be diagnosed at more advanced stage, with 60.84% of cases diagnosed at stage II-IV, compared to 51.82 % of LC. Stage IV RC has worse one-year survival as compared to LC (50.5% vs 42.2% surviving less than 1 years, respectively) Conclusions: RC is associated with female gender, older age, poorer functional status, and more advanced stage at diagnosis. LC was associated with white race. Stage IV RC had worse one-year survival than LC colon cancer. RC (%) LC (%) p-value Incidence 19969 (30.3) 38754 (58.8) - Gender - - - Male 19386 (30.1) 37913 (58.9) <0.0001 Female 582 (36.3) 838 (52.3) Age - - - 50-60 2685 (13.5) 8163 (21.1) <0.0001 60-70 6439 (32.2) 14273 (36.8) <0.0001 >70 10339 (51.8) 14905 (38.5) Race - - - Black 3580 (31.9) 6286 (56.0) <0.0001 White 13684 (30.2) 26928 (59.4) ECOG-PS - - - 0 2903 (30.6) 5719 (60.3) <0.0001 1 1890 (32.0) 3437 (58.1) (χ2trend test) 2 420 (33.2) 673 (53.1) 3 220 (34.2) 327 (50.8) 4 52 (36.4) 62 (43.4) Stage - - - 0 1659 (8.3) 3723 (9.6) <0.0001 I 4556 (22.8) 10801 (27.9) (χ2trend test) II 4606 (23.1) 7102 (18.3) III 4081 (20.4) 6922 (17.9) IV 3461 (17.3) 6058 (15.6) Stage IV Survival (yrs) - - - <1 1748 (50.5) 2557 (42.2) <0.0001 1-5 1378 (39.8) 2829 (46.7) (χ2trend test) 5-10 202 (5.8) 445 (7.4)
Multidimensional spatial characterization of the tumor microenvironment (TME) in synchronous melanoma metastases (SMM) to yield insights into mixed responses to therapy in metastatic melanoma (MM) patients (pts).
Authors: Alexandre Reuben, Michael T. Tetzlaff, Christine Spencer, Giang Ong, Kristi Barker, Peter A. Prieto, Christopher Vellano, Jinho Lee, Courtney Hudgens, Meredith Ann McKean, Vancheswaran Gopalakrishnan, Robert Szczepaniak Sloane, Sangeetha Reddy, Chris Merritt, Sarah Warren, Joseph M Beechem, Michael A. Davies, Patrick Hwu, Gordon B. Mills, Jennifer Ann Wargo
Journal: Journal of Clinical Oncology (2017)

9575 Background: Although both targeted and immune therapies have significantly improved outcomes for mm pts, only a minority of pts experience durable responses with many pts with multiple SMM demonstrating differential responses to therapy. We performed multidimensional spatial characterization of immune markers in SMM from mm patients treated with targeted and immune therapies to improve our understanding of correlations and determinants of response. Methods: NanoString's Digital Spatial Profiling research platform was used on 6 SMM from 3 pts (treatment-naïve; BRAF + MEK targeted therapy treated; anti-PD-1 immunotherapy treated) for 30 immune and signaling proteins. For analysis, we selected and compared immune-rich (CD45+) and tumor-rich (S100B+) regions across SMM. Results were compared to lesion-specific clinical responses. Results: Striking differences in patterns of expression across SMM from individual pts were detected, including in Ki67, CD68 myeloid cells, and the potent immunosuppressor B7-H3. SMM progressing after targeted therapy demonstrated higher pAKT and PD-L1 expression, consistent with described resistance mechanisms. Large differences in expression of PD-L1 were noted following anti-PD-1 therapy, which could contribute to heterogeneous responses. Differential expression patterns in the TME associated with response were also detected, including in increases in CD4 and CD14 cells in progressing lesions. Conclusions: Striking differences in responding and non-responding SMM were observed, providing potential explanations for the heterogeneous clinical responses frequently observed in mm pts. Studies are ongoing to further characterize interactions and spatial distribution of cell types, as well as integrate these findings with previous molecular and immune profiling data (whole exome sequencing, gene expression profiling, flow cytometry, IHC, TCR sequencing) in these and additional SMM to identify actionable strategies to homogenize responses across metastases in mm pts.
Health intelligence: how artificial intelligence transforms population and personalized health
Authors: Arash Shaban-Nejad, Martin Michalowski, David L. Buckeridge
Journal: npj Digital Medicine (2018)

Advances in computational and data sciences for data management, integration, mining, classification, filtering, visualization along with engineering innovations in medical devices have prompted demands for more comprehensive and coherent strategies to address the most fundamental questions in health care and medicine. Theory, methods, and models from artificial intelligence (AI) are changing the health care landscape in clinical and community settings and have already shown promising results in multiple applications in healthcare including, integrated health information systems, patient education, geocoding health data, social media analytics, epidemic and syndromic surveillance, predictive modeling and decision support, mobile health, and medical imaging (e.g. radiology and retinal image analyses). Health intelligence uses tools and methods from artificial intelligence and data science to provide better insights, reduce waste and wait time, and increase speed, service efficiencies, level of accuracy, and productivity in health care and medicine.
Abstract 13898: Simvastatin Inhibited Myocardial Apoptosis Undergoing Noncoronary Artery Cardiac Surgery
Authors: Jingsong Ou, Li Zhou, Xiang Liu, Zhen-Qing Wang, Zhi-Jun Ou, Yin-Qi Xu, Zhi-Ping Wang
Journal: Circulation (2016)

Introduction: We previously demonstrated that simvastatin was cardioprotective in patients undergoing noncoronary artery cardiac surgery. However, the mechanisms by which simvastatin protected myocardium were not fully understood. Hypothesis: Simvastatin protects myocardium is related to the inhibition of apoptosis Methods: 35 patients undergoing noncoronary cardiac surgery such as valvular surgery, congenital heart diseases surgery, 19 from simvastatin group and 16 from untreated control group, were selected from a previous clinical trial. Simvastatin (20mg) was administered preoperatively for 5-7 days. Myocardial tissues biopsies were taken in the right atrial appendage before cross-clamping the aorta and heart beating 10 minutes after removing the aorta cross-clamp. The apoptosis in myocardium was detected by transmission electron microscope and TUNEL staining. The expression of Bcl-2 and Bak were detected by Western blot. Results: In the untreated controls, electron microscopic analyses revealed evidence for ischemic injury in cardiomyocytes characterized by swollen mitochondria with vacuoles, and shortened and disrupted cristae. Simvastatin significantly reduced these changes compared to the control group. TUNEL staining showed that myocardial apoptosis in simvastatin group was much less than that in the control group. Simvastatin significantly upregulated the expression of Bcl-2 and downregulated the expression of Bak after surgery. Conclusions: The mechanisms by which simvastatin protected myocardium undergoing noncoronary cardiac surgery is, at least in part, related to the inhibition of apoptosis, which may be related to the preservation of mitochondrial structure and function.
Neurologic morbidities, psychological distress, and functional independence in adult survivors of childhood cancer treated with CNS-directed therapies: A report from the Childhood Cancer Survivor Study.
Authors: Stefanie C. Vuotto, Kevin R. Krull, Chenghong Li, Mehmet Fatih Okcu, Daniel C. Bowers, Nicole J. Ullrich, Deokumar Srivastava, Rebecca M. Howell, Todd M. Gibson, Wendy M. Leisenring, Kevin C. Oeffinger, Leslie L. Robison, Gregory T. Armstrong, Tara M. Brinkman
Journal: Journal of Clinical Oncology (2018)

10570 Background: Survivors of childhood cancer who received CNS-directed therapies are at risk for neurologic sequelae, which may adversely impact psychological functioning and independence in adulthood. Methods: Participants included 7,942 survivors of childhood cancer treated from 1970-99 with cranial radiation, intrathecal methotrexate or cytarabine (59% leukemia; 27% CNS tumor; 11% non-Hodgkin; 3% other; mean[SD] age = 25.5[5.8] yrs, time since diagnosis = 17.7[4.6] yrs). Self-reported neurologic conditions included stroke, seizure, sensory deficits, focal neurologic dysfunction, and severe headaches. Emotional distress symptoms (BSI-18) included anxiety, depression, and suicide ideation (SI). Functional independence was assessed using latent class analysis with six indicators (independent living, assistance with routine needs, assistance with personal care needs, ability to attend work/school, driver’s license, marital status). Multivariable regression models, adjusted for age, sex, race, pain, and health status, estimated relative risks (RR) and odds ratios (OR) for associations of neurologic morbidity with emotional distress and functional independence. Results: Prevalence of neurologic conditions was: 3% stroke; 11% seizure; 25% sensory deficits; 29% focal neurologic dysfunction; 31% severe headaches. In multivariable models, risk of emotional distress was associated with focal neurologic dysfunction (anxiety: RR 1.6; 95% CI 1.3-2.1; depression: RR 1.4; CI 1.2-1.7), sensory deficits (anxiety: RR 1.3; CI 1.0-1.6; depression: RR 1.3; CI 1.1-1.5; SI: RR 1.3; CI 1.0-1.6), and severe headaches (anxiety: RR 1.5; CI 1.2-1.9; depression: RR 1.6; CI 1.4-2.0; SI: RR 1.5; CI 1.2-1.8). Stroke (OR 0.3, CI 0.2-0.5), seizure (OR 0.2, CI 0.2-0.3), and focal neurologic deficits (OR 0.26, CI 0.2-0.3) were associated with decreased likelihood of functional independence. Conclusions: Childhood cancer survivors who develop neurologic morbidities are at-risk of emotional distress symptoms, including suicide ideation, and failure to attain independence in adulthood.