tbuckley/cabot-search huggingface dataset:
Variation in the assessment of immune-related adverse event occurrence, grade, and timing.
Authors: David Hsieh, Mary Katherine Watters, Rong Lu, Yang Xie, David E. Gerber
Journal: Journal of Clinical Oncology (2019)

9047 Background: Accurate assessment of treatment toxicity is critical for patient safety, balancing clinical utility, and understanding treatment impact. Given their unpredictability and heterogeneity, immune-related adverse events (irAEs) may be particularly challenging to ascertain. Our objective was to evaluate the agreement between clinicians on the occurrence, grade, and timing of irAEs, and elucidate determinants of discordance. Methods: We performed a retrospective cohort study of 52 patients with cancer treated with immune checkpoint inhibitors at a National Cancer Institute-designated comprehensive cancer center. Two medical oncologist observers used algorithm-driven manual chart review to characterize eight well-described irAEs (adrenal insufficiency, colitis, hepatitis, hyperthyroidism, hypophysitis, hypothyroidism, pneumonitis, rash). Inter-rater agreement for incidence, severity, and timing of irAEs was determined using Cohen's kappa coefficient (κ) and weighted κ with linear weights. Results: The incidence of irAEs ranged from 4-35% for observer 1 and 6-27% for observer 2, while aggregate incidence rates ranged from 8% (hypophysitis) to 40% (pneumonitis). Inter-rater agreement was generally limited for irAE incidence (κ 0.37 [hypophysitis]-0.8 [hypothyroidism]). Weighted κ similarly showed limited or poor agreement for most irAE grades (κ 0.31-0.75). Differences in the assessment of irAE time of onset ranged from 5-188 days. Rates of discordance were greater for grade 1 (39%) and grade 2 (41%) irAEs than for grade 3-4 (20%) irAEs. Multivariable analyses showed that longer therapy duration (OR 4.8, P= 0.02) and a high Charlson Comorbidity Index (OR 4.09, P= 0.03) were significantly associated with discordant irAE assessment. Conclusions: Inter-rater reliability varied among irAEs and consistently showed poor agreement for the incidence, severity, and timing of irAEs. Agreement was greater for irAEs with distinct laboratory-based definitions (eg, hypothyroidism), higher-grade irAEs, and irAEs in patients with fewer comorbidities and shorter immunotherapy duration. These findings have implications in the clinical management of patients receiving immunotherapy and in the reporting of immunotherapy clinical trials.
Diagnostic utility of tele-cystoscopy for bladder cancer surveillance.
Authors: Haerin Lee Beller, James Mills, Jennifer Mason, Bethany J. Horton, Randy A. Jones, Thomas Corey, Terran Sims, Noah S. Schenkman, Tracey Lynn Krupski
Journal: Journal of Clinical Oncology (2019)

e18335 Background: Urology workforce shortage in rural areas limits access to surveillance cystoscopy for bladder cancer. Tele-cystoscopy is a novel solution whereby an advanced practice provider (APP) performs cystoscopy at a satellite location with real-time interpretation and guidance by an off-site urologist via transmitted video. We hypothesized that tele-cystoscopy videos would be comparable to traditional cystoscopy videos in diagnostic utility. Methods: Our IRB approved tele-cystoscopy protocol utilizes a dual-cystoscopy model. Two sequential cystoscopies are performed first by an APP with off-site urologist guidance (tele-cystoscopy) then by a urologist onsite (traditional cystoscopy) without removal of the cystoscope from the urethra. Both cystoscopies are video-captured. Twelve de-identified videos were reviewed via electronic survey (Qualtrics) by board-certified urologists who were blinded as to whom performed the cystoscopy. Survey questions centered on completeness of exam and diagnostic level of suspicion. A random effects logistic regression model was used to account for multiple reviews of the same video. Results: Diagnostic utility, defined as visibility sufficient for diagnosis, was 83% for both tele-cystoscopy and traditional cystoscopy. There were no statistically significant differences in completeness of exam between the two techniques (tele 83.3%, traditional 91.7%, p = 0.308). When asked about action taken based on cystoscopic findings, reviewers recommended action other than planned surveillance (i.e., biopsy, operative resection, etc.) for 58.3% of tele-cystoscopy videos vs. 66.7% for traditional cystoscopy videos (p = 0.300). Conclusions: Tele-cystoscopy provides high quality bladder surveillance with diagnostic capacity comparable to that of traditional cystoscopy. These results support continued expansion of the tele-cystoscopy platform as a means to amplify the care provided by a single urologist. [Table: see text]
Tumor copy number alteration (CNA) burden as a prognostic factor for overall survival in Chinese gastric cancers.
Authors: Bo Han, Dandan Ren, Beibei Mao, Xue Song, Wanning Yang, Henghui Zhang, Feng Gao
Journal: Journal of Clinical Oncology (2019)

e15555 Background: Gastric cancer (GC) is associated with high morbidity and mortality rates in the world with poor prognosis and limited treatment options. The level of copy number alteration (CNA), termed CNA burden, is reported as a pan-cancer prognostic factor associated with recurrence and death. The current study aims to investigate association between CNA burden in primary tumor tissue and overall survival (OS) of Chinese patients with GC after surgical resection. Methods: The present study included 78 patients who had received surgical resection and adjuvant chemotherapy with poorly differentiated GC. The primary outcome was OS. Tumor specimens were obtained from surgery and submitted for next generation sequencing (NGS) with matched normal tissue samples. A 1408-gene panel was used to identify genome profiles. Data were analyzed using Cox proportional hazards models and Kaplan-Meier survival analysis. Results: The most frequently altered genes were TP53 (47%), PIK3CA (10%), PTEN (9%), NOTCH1 (8%) and RNF43 (6%), and copy numbers of TRPS1 (65%), COL1A2 (50%), CSMD3 (45%), ZFHX4 (45%), NAV3 (36%) varied most frequency in current cohort. Greater tumor CNA burden correlated with an increase in death from disease compared to a lower tumor CNA burden ( p= 0.0066). In addition, there were statistically significant differences in OS between different clinical staging ( p= 0.0011). Moreover, the Cox proportional hazard model showed that CNA burden was an independent prognosis factor in GC. Finally, we performed an independent signature that includes CNA burden and clinical staging to predict survival of GC. Conclusions: This study indicates that tumor CNA burden is an independent predictive survival biomarker for Chinese gastric cancers. CNA burden combined with clinical staging is a better predictor for postoperative survival prediction of gastric cancer.
Safe targeting of T cell acute lymphoblastic leukemia by pathology-specific NOTCH inhibition
Authors: Roger A. Habets, Charles E. de Bock, Lutgarde Serneels, Inge Lodewijckx, Delphine Verbeke, David Nittner, Rajeshwar Narlawar, Sofie Demeyer, James Dooley, Adrian Liston, Tom Taghon, Jan Cools, Bart de Strooper
Journal: Science Translational Medicine (2019)

Selective inhibition of γ-secretase complexes targets T-ALL without the dose-limiting side effects of complete γ-secretase inhibition.
Phase I study of DFP-11207, a novel oral 5-FU with enhanced PK and improved tolerability, in patients with solid tumors.
Authors: Jaffer A. Ajani, Milind M. Javle, Cathy Eng, David R. Fogelman, Barry Douglas Anderson, Chun Zhang, Kenzo Iizuka
Journal: Journal of Clinical Oncology (2019)

3034 Background: DFP-11207 combines a 5-fluorouracil (5-FU) pro-drug with a reversible dihydropyrimidine dehydrogenase inhibitor and a potent inhibitor of orotate phosphoribosyl transferase resulting in enhanced pharmacological activity of 5-FU with decreased gastrointestinal and myelosuppressive toxicity. Methods: Patients with advanced solid tumors were treated in this single arm, dose escalation study. Accelerated dose escalation using single pt cohorts was followed until drug-related Gr2 adverse events occurred; then a 3+3 design was followed to determine maximum tolerated dose (MTD). Pts were dosed daily in 28-day cycles until intolerable toxicity or disease progression. PK sampling was performed for DFP-11207 metabolites on all pts and a 6 pt cohort received DFP-11207 in fed and fasted states to determine drug bioavailability. Results: Primary tumors among the 23 enrolled pts included esophageal, colorectal, gastric, pancreatic and gallbladder. Seventeen pts were treated at 8 dose levels of oral DFP-11207 administered daily, ranging from 40 to 440 mg/m 2 /d. At 440 mg/m 2 /d one pt experienced drug-related Gr3 dehydration and mucosal inflammation, and Gr4 febrile neutropenia; a second pt experienced Gr4 febrile neutropenia. One DLT of Gr3 vomiting occurred among 6 pts treated at 330 mg/m 2 /d dosed q12hrs confirming the MTD. Six pts were administered 300 mg DFP-11207 q12 hrs in a fed or fasted state to determine drug bioavailability. Among all pts, the most frequently reported drug-related TEAEs were fatigue (47.8%), nausea (47.8%), decreased appetite (39.1%), diarrhea (26.1%), vomiting (21.7%), anemia (13.0%), dysgeusia (13.0%), mucosal inflammation (13.0%) and palmar-plantar erythrodysaesthesia syndrome (13.0%). PK analyses of pts treated at 330 and 440 mg/m 2 /d indicate 5-FU concentrations of ~20 ng/mL throughout the dose cycle. There was no substantial difference in DFP-11207 bioavailability among pts in a fed or fasted state. Out of 21 efficacy evaluable pts, 7 pts had stable disease (33.3%), of which 2 had prolonged stable disease of &gt; 6 months. No pts achieved CR or PR. Conclusions: DFP-11207 at the dose of 330 mg/m 2 /d q12hrs is well-tolerated in pts with solid tumors with mild myelosuppressive and gastrointestinal side effects, and results in circulating 5-FU levels conducive to an anti-tumor effect. DFP-11207 can be explored as monotherapy or substitute for 5-FU, capecitabine or S-1 in combination treatment regimens. Clinical trial information: NCT02171221.
Biofunctionalization of metallic implants by calcium phosphate coatings
Authors: Yingchao Su, Irsalan Cockerill, Yufeng Zheng, Liping Tang, Yi-Xian Qin, Donghui Zhu
Journal: Bioactive Materials (2019)

Metallic materials have been extensively applied in clinical practice due to their unique mechanical properties and durability. Recent years have witnessed broad interests and advances on surface functionalization of metallic implants for high-performance biofunctions. Calcium phosphates (CaPs) are the major inorganic component of bone tissues, and thus owning inherent biocompatibility and osseointegration properties. As such, they have been widely used in clinical orthopedics and dentistry. The new emergence of surface functionalization on metallic implants with CaP coatings shows promise for a combination of mechanical properties from metals and various biofunctions from CaPs. This review provides a brief summary of state-of-art of surface biofunctionalization on implantable metals by CaP coatings. We first glance over different types of CaPs with their coating methods and in vitro and in vivo performances, and then give insight into the representative biofunctions, i.e. osteointegration, corrosion resistance and biodegradation control, and antibacterial property, provided by CaP coatings for metallic implant materials.
Association of early bone metastases and outcomes of the bone predominant metastatic urothelial carcinoma (BP mUC) phenotype.
Authors: Ariel Ann Nelson, Matthew David Wright, Ali Raza Khaki, Leonidas Nikolaos Diamantopoulos, Ravi Kumar Kyasaram, Behtash Nezami, Scott Dawsey, Krupen Patel, Cheryl Eitman, Gregory MacLennan, Petros Grivas, Prateek Mendiratta, Lee Evan Ponsky, Christopher J. Hoimes
Journal: Journal of Clinical Oncology (2019)

e16016 Background: Prior analyses demonstrated worse outcomes with the BP mUC clinical phenotype. UC molecular subtypes that may correlate with the BP phenotype have been defined, however molecular subtyping is not a readily available standard practice. We hypothesized that BP mUC has worse prognosis vs. non-BP (NBP) mUC and evaluated patient (pt) characteristics associated with the mUC subtype, responses and outcomes. Methods: We searched the electronic medical record (EMR) to identify pts with mUC who received systemic therapy in the metastatic setting. Demographic, clinicopathologic, treatment (trt), response, progression-free survival (PFS), overall survival (OS ) from start of first line trt. Imaging was reviewed to identify NBP or BP disease. Logistic regression, Cox proportional-hazards and Kaplan-Meier analyses were performed. Results: 149 mUC pts were identified (64% male, 68% smokers ), median age at 1 st line trt was 68 years. 70% had de-novo mets, 46% to lung and 27% to liver. 22% of pts were BP, of these, 36% were de-novo metastatic. In non- de-novo metastatic pts (70% of pts), first progression of disease to bone was associated with development of the BP phenotype (OR = 30.46, 95% CI 6.37 to 145.61; p &lt; 0.0001). BP pts had higher rate of death (HR = 2.28, 95% CI 1.45 to 3.58, p = 0.0004), shorter PFS from 1 st line trt, (11.7 vs 14.9 weeks, p = 0.032) as well as shorter OS from 1 st line trt (24.6 vs 56.6 weeks, p = 0.002) compared to NBP pts. There was no difference in PFS between BP and NBP groups for pts treated with 1 st line platinum-based chemotherapy (11.8 vs 18.3 weeks, p = 0.091) or for BP pts treated with 1 st line immunotherapy vs platinum-based chemotherapy (11.71 vs 11.86 weeks, p = 0.135). Conclusions: Early bone metastases are associated with the development of the BP metastatic phenotype. BP pts have worse PFS and OS from 1st line trt compared to NBP pts. PFS remains poor when BP pts are treated with either platinum-based chemotherapy or immunotherapy in the first line setting. Imaging to determine the presence of bone metastases may routinely be pursued and careful attention paid on follow up imaging. Clinical trials and prospective registries focusing on efficacy endpoints for BP mUC are needed.
Cost-minimization analysis for biosimilar pegfilgrastim in the prophylaxis of chemotherapy induced (febrile) neutropenia and expanded access based on budget neutral basis.
Authors: Weijia Wang, Sanjeev Balu, Kim Campbell
Journal: Journal of Clinical Oncology (2019)

6645 Background: Pegfilgrastim (pegfil) injection is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. Assuming biosimilarity of biosim-pegfil and pegfil in the prevention of febrile neutropenia, we estimated cost minimization of conversion from pegfil to biosim-pegfil and subsequent potential expanded access due to cost savings. Methods: A cost minimization model was conducted based on a hypothetical panel of 20,000 patients using average selling price (ASP) for one chemotherapy cycle. ASP was obtained from 1Q 2019 payment allowance limits. The simulation included two steps: 1) cost minimization was calculated per cycle (biosim-pegfil and pegfil is administered 1 dose per cycle) when patients were converted to biosim-pegfil from pegfil on ratio of 10% to 100% at 10% intervals and at a discount from 15% to 35% at 5% intervals, and 2) expanded access to biosim-pegfil was calculated based on budget neutrality. Since pegfil has two forms of availability (Neulasta and Neulasta-Onpro) with the same price, results were to either conversion scenario. Results: Per-cycle per-patient cost minimization from converting pegfil to biosim-pegfil ranged from $702.27 (15% discount) to $1,638.63 (35% discount). For 20,000 patients, this yields savings of over $14 million (15% discount) to $32 million (35% discount) at 100% conversion rate. When half the patients were converted to biosim-pegfil, savings could range from &gt; $7 million (15% discount) to &gt; $16 million (35% discount). With 100% conversion rate and 15% discount, 3,529 additional patients could be treated with the savings generated. At 50% conversion rate, cost savings could be applied to another 1,765 patients with 15% discount, 3,333 patients with 25% discount, and 5,385 patients with 35% discount, respectively. Conclusions: Conversion from pegfil to biosim-pegfil can lead to potential cost savings and these savings can be applied to offer increased access to supportive care with biosim-pegfil for patients receiving chemotherapy on a budget-neutral basis. For payers with larger populations, savings can be substantial. More studies are warranted to evaluate such potential cost savings due to use of biosim-pegfil over reference pegfil.
Pathway analysis of hypoxia-related factors in early colorectal cancer patients with poor prognosis.
Authors: Yingxin Tan, Yuming Rong, Zhaoliang Yu, Feng Gao, Yufeng Chen, Xutao Lin, Yifeng Zou, Xi Chen
Journal: Journal of Clinical Oncology (2019)

3613 Background: Colorectal cancer is one of the most common malignancies with a high mortality rate. Patients with stage I and stage II colorectal cancer have limited options for treatment. Hypoxia affects the activation and regulation of colorectal cancer cells and participates in its invasion and migration. However, there is lack of an accurate and non-invasive method for assessing tumor hypoxia. The aim of this study was developing and validating a hypoxia gene signature for predicting the outcome in stage I/II colorectal cancer patients. At the same time , we hypothesized that analysis of database of CIT microarray dataset could identify important biomarkers for stage I/II colorectal cancer patients. Methods: A total of 309 colorectal cancer patients of early stage with complete clinical information were enrolled for construction generation of hypoxia-related gene signature (HRGS) based on the CIT microarray dataset. 1877 colorectal cancer patients with complete prognostic information in 5 independent datasets were divided into a training cohort and two validation cohort (TCGA and meta-validation). Prognostic analysis was assessed in these cohort to evaluate the predictive value of HRGS. Results: A model of prognostic HRGS containing 14 hypoxia-related genes was developed. In training cohort and two validation cohorts, patients in hypoxia high-risk group satisfied by our HRGS had significant poor disease free survival compared with those in the in the low risk group (HR=4.35, 95% CI=2.30-8.23, P&lt;0.001 in training cohort, HR=2.14, 95% CI=1.09-4.21, P=0.024 in TCGA cohort, HR=1.91, 95% CI=1.08-3.39, P=0.024 in meta-validation cohort). When compared with Oncotype DX, HRGS achieved an improved survival correlation in the training cohort (mean C-index, 0.80 vs 0.65, P&lt;0.05) and the validation cohort (mean C-index, 0.70 vs 0.61 in the TCGA cohort, mean C-index, 0.68 vs 0.73 in the meta-validation cohort). Analysis of the data found that patients with low survival rates have significant relationships with genes regulated by the cell cycle pathway, such as mTROC1, E2F, G2-M, mitotic, oxidative phosphorylation, MYC, PI3K-AKT-mTOR (P&lt;0.005). Conclusions: HRGS was a satisfactory prognostic prediction model for early stage colorectal patients. Hypoxia-related genes that regulate the cell cycle pathway were associated with prognosis in patients with stage I and stage II colorectal cancer. Further researches are needed to assess the clinical effectiveness of the system and the treatment options for biological targets.
FRI0713-HPR COMPARISON OF BIOPSYCHOSOCIAL STATUS OF PATIENTS WITH ANKYLOSING SPONDYLITIS WITH AND WITHOUT ANTI-TNF TREATMENT
Authors: nur banu karaca, Edibe Ünal, Sedat Kiraz
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> It is known that anti-TNF therapy is given to patients with persistently high disease activity despite conventional treatments according to the ASAS recommendations (1). Although biopsychosocial symptoms were well known, biopsychosocial assessments are insufficient in the literature. <h3>Objectives</h3> The aim of this study was to compare the biopsychosocial status between patients with AS who were decided to be treated with anti-TNF treatment and patients with AS who did not receive any anti-TNF treatment. Also, it was aimed to investigate the effectiveness of 3 months anti-TNF treatment on biopsychosocial status. <h3>Methods</h3> 74 AS patients who are decided to receive anti-TNF treatment and 38 AS patients, who didn't, were included in the study. Socio-demographic informations of patients were collected. The mean age of the patients (n = 112) was 41,9±19,8 years. Health Assessment Questionnaire (HAQ) was used to assess functional status and daily living activities. The Hospital Anxiety and Depression Scale (HADS) was used to assess anxiety and depression levels. Biopsychosocial status of the patients was evaluated by the BETY-Biopsychosocial Questionnaire (BETY-BQ) (2,3). The same evaluations were repeated after 3 months in 36 patients using anti-TNF. <h3>Results</h3> A statistically significant difference was observed in BETY-BQ, HADS anxiety and HAQ scores, when the groups were compared. There was no statistically significant difference in HADS depression scores (Table 1). The difference after 3 months of anti-TNF treatment was significant in all parameters (Table 2). <h3>Conclusion</h3> It was observed that the patients who were decided to be received anti-TNF treatment had worse functionality, anxiety, and biopsychosocial status than the patients who did not receive anti-TNF treatment. Anti-TNF treatment was found to be effective in three months period in terms of these biopsychosocial symptoms that the patients had. <h3>References</h3> [1] Braun Jv, Van Den Berg R, Baraliakos X, Boehm H, Burgos-Vargas R, Collantes-Estevez E, et al. 2010 update of the ASAS/EULAR recommendations for the management of ankylosing spondylitis. Annals of the rheumatic diseases. 2011;70(6):896-904. [2] Ünal E, Arin G, Karaca Nb, Kiraz S, Akdoğan A, Kalyoncu U, et al. Romatizmalı hastalar için bir yaşam kalitesi ölçeğinin geliştirilmesi: madde havuzunun oluşturulması. Journal of Exercise Therapy and Rehabilitation. 2017;4(2):67-75. [3] Kisacik P, Unal E, Akman U, Yapali G, Karabulut E, Akdogan A. Investigating the effects of a multidimensional exercise program on symptoms and antiinflammatory status in female patients with ankylosing spondylitis. Complementary therapies in clinical practice. 2016;22:38-43. <h3>Disclosure of Interests</h3> None declared