tbuckley/cabot-search huggingface dataset:
Predicting Severe Infection and Effects of Hypogammaglobulinemia During Therapy With Rituximab in Rheumatic and Musculoskeletal Diseases
Authors: Md Yuzaiful Md Yusof, Edward M. Vital, Damien M. McElvenny, Elizabeth M. A. Hensor, Sudipto Das, Shouvik Dass, Andy C. Rawstron, Maya H. Buch, Paul Emery, Sinisa Savic
Journal: Arthritis & Rheumatology (2019)

To evaluate predictors of serious infection events (SIEs) during rituximab (RTX) therapy and effects of hypogammaglobulinemia on SIE rates, and humoral response and its persistence after discontinuation of RTX in the treatment of rheumatic and musculoskeletal diseases (RMDs).A retrospective longitudinal study of 700 RMD patients treated with RTX in a single center was conducted. Immunoglobulin levels were measured at baseline and at 4-6 months after each treatment cycle. Baseline predictors of SIEs were assessed using multivariable logistic regression; for RTX cycles 2-4, a mixed-effects logistic regression model was used.A total of 507 patients (72%) had rheumatoid arthritis, 94 (13%) had systemic lupus erythematosus, 49 (7%) had antineutrophil cytoplasmic antibody-associated vasculitis, and 50 (7%) had other RMDs. The number of SIEs recorded was 281 in 176 patients (9.8 per 100 person-years). Predictors of SIEs included non-RTX-specific comorbidities (previous history of SIE, cancer, chronic lung disease, diabetes mellitus, and heart failure), higher corticosteroid dose, and RTX-specific factors, including low IgG (<6 gm/liter) both at baseline and during treatment, RTX-associated neutropenia, higher IgM, and longer time to RTX re-treatment, but not B cell count or depletion status. Of 110 patients with low IgG, SIE rates were higher in those with low IgG at baseline (16.4 per 100 person-years) and in those who acquired low IgG during or after RTX treatment (21.3 per 100 person-years) versus those with normal IgG (9.7 per 100 person-years). Five of 8 patients (63%) had impaired humoral response to pneumococcus and hemophilus following vaccination challenge, and only 4 of 11 patients (36%) had IgG normalized after switching biologic disease-modifying antirheumatic drugs.Immunoglobulin levels should be monitored at baseline and before each RTX cycle to identify patients at risk of SIEs. Individualized risk-benefit assessment should be undertaken in those with lower IgG as this is a consistent SIE predictor and may increase infection profiles when RTX is switched to different therapies.
Long-term follow-up of pharmacokinetics (PK) and immunogenicity of the anti–PD-1 antibodies nivolumab (Nivo) and pembrolizumab (Pembro) in real-world practice.
Authors: Masahide Fukudo, Kazuto Mishima, Norihisa Kimura, Yuichiro Shinden, Takaaki Sasaki, Shunsuke Okumura, Yoshinobu Ohsaki, Jiro Uehara, Akemi Yamamoto, Gaku Tamaki, Hidehiro Kakizaki, Kan Kishibe, Miki Takahara, Tatsuya Hayashi, Yasuaki Harabuchi, Tatsuya Shonaka, Kimiharu Hasegawa, Takashi Ono, Yoshikazu Tasaki
Journal: Journal of Clinical Oncology (2019)

3120 Background: The PD-1 blockers Nivo and Pembro are widely used to treat patients (pts) with various types of cancer, but their PK and immunogenicity have not been adequately characterized in clinical practice. Here we report the first long-term follow-up of PK and anti-drug antibodies (ADAs) of Nivo and Pembro, correlated with efficacy and safety. Methods: We included 147 pts receiving Nivo (n = 98) or Pembro (n = 49) between May 2016 and Jan 2019. Plasma samples were longitudinally collected before each infusion and after discontinuation for as long as samples were obtainable. Drug concentrations were measured by ELISA (LLOQ: 0.0125 µg/mL), and ADAs were evaluated by bridging ELISA. Results: Median (range) follow-up was 6.0 (0.1-38.7) mo, and 1718 samples were analyzed. ADAs were confirmed at baseline or at last sample for both Nivo (2 [2.2%] and 4 [4.5%] pts, respectively) and Pembro (2 [4.2%] and 3 [6.7%] pts). Of the 4 baseline ADA-positive pts, 3 experienced drug-induced fever after initial infusion. Pts developing ADAs at last sample had earlier progression than ADA-negative pts (median PFS: 46 vs. 119 days, log-rank P = 0.0827). Persistent drug exposure until ~1 y beyond discontinuation was observed for both drugs. In 1 Nivo-treated pt with delayed adrenal insufficiency 8.6 mo after discontinuation, Nivo was still detectable (0.2 µg/mL). In 71 and 41 efficacy-evaluable pts receiving Nivo and Pembro, respectively, mean trough levels in the early period (~cycle 6) were significantly higher in pts achieving response than in pts with progressive disease at first assessment (Nivo: 43.5 vs. 31.0 µg/mL, P = 0.0107; Pembro: 30.6 vs. 22.1 µg/mL, P = 0.0174). Conclusions: Our findings provide insight into the etiological mechanism of late-onset adverse events associated with PD-1 blockers. Moreover, ADA may potentially influence clinical outcomes, and it may be possible to optimize dose in certain pts with lower drug exposure for improved efficacy, warranting further investigation. Clinical trial information: UMIN000033036. [Table: see text]
Case 51-1985
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, Betty U. McNeely, Howard M. Pollack, Robert H. Young
Journal: New England Journal of Medicine (1985)

Presentation of CaseA 78-year-old woman was admitted to the hospital because of bilateral renal masses.She was in a stable state of health until three months earlier, when nausea, vomiting, and fever developed. She was examined by a physician, who found no abnormality. An x-ray film of the abdomen showed a large mass in the left kidney. An intravenous urographic examination, with nephrotomograms, revealed a mass, 11 by 16 cm, in the lower pole of the left kidney and another mass, 7 by 7 cm, in the lower pole of the right kidney. The masses appeared solid and hypervascular. . . .
Nab-paсlitaxel (Nab-P) in patients with metastatic breast cancer (mBC) with visceral crisis (VC): Efficacy and tolerability.
Authors: Kristina A. Novoselova, Liubov Yu Vladimirova, Natalia A Abramova, Anna E Storozhakova, Irina L. Popova, Natalia M. Tikhanovskaya, Ludmila A. Ryadinskaya, Aza A. Lyanova, Georgy Salamov, Maria Teplyakova, Ekaterina Prikhodko, Anna V. Tishina
Journal: Journal of Clinical Oncology (2019)

e12589 Background: Better efficiency and safety of Nab-P is known to be due to the advantages of pharmacokinetics and pharmacodynamics of the drug. The fraction of unbound paclitaxel in plasma is 2.6-fold higher with Nab-P than with P. The purpose of the study was to assess efficacy and safety of Nab-P in ≥2nd lines of chemotherapy (CT) in patients (pts) with mBC with VC. Methods: Inclusion criteria: mBC with VC, ≥ 2 line of CT, HR+, HER2neu+ or triple negative type (TN), normal liver and renal function. Pts received Nab-P 260 mg/m 2 q 21 days. Pts with Her2/Neu + received trastuzumab 6 mg/kg q 21 days. Results: 32 mBC pts, mean age 51.34 years (CI 35-76) were included. Among 32 pts Her2/Neu + had 5 (15.6%), TN – 9 (28.1%), HR+ 18(56.3%). 13(40.6%) pts received Nab-P as 2 line of CT, 13 (40.6%) pts, as 3-4 lines, 7(21.9%) as ≥5 lines. Pts were divided into 2 groups: group A - pts with VC 17(53.1%), group B - without VC 15(46.9%). Groups were comparable by age, number of previous CT lines, immunohistochemical types of BC. Group A had 2.47±0.32 CT lines (CV51.83%), including 8(47%) pts, who had received paclitaxel (P) in previous CT lines. Group B had on average 2±0.27 CT lines (CV53.03%). The objective response rate (ORR) was 37.5%(12 pts). In the group A ORR was 35.3% (6 pts). Out of 8 pts with VC, who had received P in previous lines, ORR was achieved in 3 pts (37.5%). In the group B ORR was 33.34%(5 pts). TTP was 6.8 mos (95% CI 6.1-13.7) for all pts, in the group A – 5.7 mos (95% CI 5.9-10.2), in the group B 6 mos (95% CI 6.5-13.7) (p = 0.046). Median 3-year OS of pts in group A was 18.9 mos (95% CI 4.3-22.4), in group B - 22.5 mos (95% CI 8.2-26.7) (p = 0.038). Toxicity did not differ significantly in pts in groups A and B and was manageable. Pts, who previously received P, had no new or severe toxicity. Conclusions: The data obtained confirms the possibility of Nab-P application in pts with VC. The use of Nab-P in pts treated with taxanes in previous lines is supposed for further study.
Virtual visits for children, adolescents, and young adults with cancer.
Authors: Peter Meade Anderson, Stacey Zahler, Lynn Harter, Rabi Hanna
Journal: Journal of Clinical Oncology (2019)

6622 Background: Children, adolescents, and young adults have rare cancers and standard-of-care treatment is commonly very aggressive. Virtual visits provide include many of the nuances of face-to face communication. These are much friendlier than phone calls or email and can be scheduled and structured to provide a large amount of information efficiently. Methods: Cleveland Clinic uses HIPPA-compliant software from American Well (Boston, MA) that allows the health care provider and patient to use a phone, tablet, or desktop computer for video visits. Our intake process involves obtaining a Medical Record Number (MRN), sending a brief summary, uploading or sending a CD with images in DICOM, and having an administrative assistant schedule the virtual visit. Telemedicine sessions typically last &lt;60 minutes. During the visit a summary is updated, images are reviewed, and this and other information shared via email after the visit. Results: In 2017+ 2018 we conducted 223 virtual visits; 85% were &lt;30 years old (table). The summary has been a key to efficient and effective organization and includes not only contact information and past medical history, but also an “Opportunities to Improve Health" section (problem list /action plan). Topics discussed in solid tumor patients include: 1) local control, 2) medical therapy (chemotherapy), 3) imaging and tumor markers, 4) control of side effects and nutrition, 5) social issues and goals of care (which can include palliative care and hospice), and 6) follow-up. A power point with key images and the updated summary and articles are emailed at the end of the visit to the patient &amp; caregivers and often referring physician, NP, or PA . Visit diagnoses have included osteosarcoma and Ewing sarcoma (73%), but also other rare cancers such as rhabdomyosarcoma, DSRCT, paraganglioma, and adrenal cortical carcinoma. Survivorship and cGVHD have also been discussed. Conclusions: A structured virtual visit to help young people and their caregivers understand complex multi-disciplinary cancer care is now possible for all regions of North America. A major source of satisfaction has been two-way sharing of information to improve not only cancer control, but also improved nutrition, communication, and proactive toxicity reduction. [Table: see text]
A polymorphism within the mismatch repair gene predicts prognosis and adjuvant chemotherapy benefit in gastric cancer patients.
Authors: Deqiang Wang, Deyu Chen, Bo Shen, Xiaofeng Chen, Mingzhe Xiao, Xiaoqin Li, Yongqian Shu
Journal: Journal of Clinical Oncology (2019)

3025 Background: Radical surgery with subsequent adjuvant chemotherapy was effective treatment for early-stage gastric cancer (GC) patients. Unfortunately, after optimal multimodality therapy, up to 30% to 40% of patients undergoing resection will relapse within 5 years. There are no validated prognostic and predictive biomarkers for GC patients who receive adjuvant chemotherapy, and current patient selection is based mainly on postoperative pathological staging. Defective mismatch repair (MMR) or microsatellite instability (MSI) may affect GC outcome. Polymorphisms of MMR genes with a low-penetrant effect can cause heterogeneous MMR capability among individuals. It is not known about the impact of these polymorphisms on GC outcome. Methods: The polymorphisms rs1800734 in MLH1, rs2303428 and rs3732183 in MSH2, rs735943 in EXO1, and rs11797 in TREX1 were selected and analyzed in independent discovery and validation sets that included 167 and 593 patients, respectively. MSI was determined. Results: In the discovery set, both the rs2303428 TC+CC and the rs11797 GA+AA genotypes significantly correlated with poor overall survival (OS; P &lt; 0.05). In the validation set, we confirmed the prognostic association for the rs2303428 TC+CC genotype (P = 0.036) but not for the rs11797 GA+AA genotype (P = 0.737). Furthermore, the prognostic role of the rs2303428 TC+CC genotype was observed in non-cardia (P = 0.005) but not in cardia GC (P = 0.934). The multivariate model showed that the rs2303428 TC+CC genotype was an independent predictor for OS in non-cardia patients (HR = 1.54; 95% CI: 1.02-2.32; P = 0.040). Moreover, fluoropyrimidines-based adjuvant chemotherapy significantly improved OS (HR = 0.29; 95% CI: 0.15-0.58; P &lt; 0.001) for non-cardia patients with the rs2303428 TC+CC genotype but not for those with the rs2303428 TT genotype. The rs2303428 genotypes were not associated with MSI frequency. Conclusions: The rs2303428 TC+CC genotype may predict prognosis and adjuvant chemotherapy benefit in non-cardia GC patients independent of MSI. To our knowledge, our study is the first to report the prognostic and predictive roles of MMR genotype in GC. Although prospective validation is necessary, our findings have the potential to improve patient selection for adjuvant chemotherapy and spare large numbers of GC patients’ unnecessary therapy.
Re-evaluating the neutrophil-to-lymphocyte ratio: Machine learning-based variable selection for predicting survival at twelve months in late-stage cancer patients receiving immunotherapy.
Authors: Daniel Spakowicz, Mingjia Li, Rebecca Hoyd, Jarred Thomas Burkart, Sandip H. Patel, Marium Husain, Kai He, Carolyn J Presley, Erin Marie Bertino, Peter G. Shields, David Paul Carbone, Hiral A. Shah, Gabriel Tinoco, Edmund Folefac, Priyanka Bhateja, Claire F. Verschraegen, Gregory Alan Otterson, Lang Li, Kari Lynn Kendra, Dwight Hall Owen
Journal: Journal of Clinical Oncology (2019)

e18201 Background: Neutrophil to Lymphocyte Ratio (NLR) is prognostic for cancer patients treated with immune checkpoint inhibitors (ICI). We showed the change in NLR early during treatment to be a stronger, curvilinear predictor, i.e. patients with an intermediate change in NLR performed better than those with large decreases or increases. This led us to re-examine whether NLR is an optimal predictor of overall survival (OS). Methods: A retrospective review of 467 patients with advanced cancer who received ICIs from 2011 to 2017 at the Ohio State University was performed with IRB approval. NLR was collected at the initiation of ICI and on-treatment (median 21, IQR 8 days) and calculated as ratio of absolute neutrophil to lymphocyte counts. Variable selection machine-learning algorithms included fast and frugal decision trees and random forest, performed in R. Results: The machine-learning algorithm fast and frugal decision trees identified the ratio of NLR on treatment to baseline NLR, the NLR on treatment, the change in NLR and the cubic change in NLR to be the most informative predictors of survival at 12 months. A random forest algorithm identified the same four variables as the most important for prediction accuracy. Age, sex and cancer type were the least informative predictors in the model, suggesting the on-treatment NLR variables are of value across wide range of demographics. Conclusions: NLR measured during treatment, and its derivative values of the ratio to baseline, change from baseline, and the cubic change from baseline, hold more predictive value than NLR measured at baseline. Common control variables such as age, and sex showed little effect on the model, suggesting on-treatment NLR is useful across wide demographic space. [Table: see text]
A novel function for cyclin D1 as a transcriptional role in oncogenesis and tumor development by ChIP-Seq and RNA-Seq.
Authors: Yudi Xiong, Yunfeng Zhou
Journal: Journal of Clinical Oncology (2019)

e14628 Background: Cancer is a major public health problem and remains one of the most leading causes of death worldwide. Aberrations in cell cycle control is defined as one of the hallmarks of cancer.While cyclin D1 is an essential protein to cell cycle which promote G1 phase into S phase, and frequently overexpressed in many human cancers.Although the participation in cell cycle and tumorigenesis has not been well characterized,new functions have been identified in transgenic mice models, including the transcription of genome,the development of chromosome instability and DNA repair.However,it remains unclear that the function of cyclin D1 indenpend of involving cell cycle.In this research,our aim is to find the function of cyclin D1 in transcription in human cancers. Methods: We chose the human cervical cancer cell line,C33A as our main research object.Using chromatin immunoprecipitation sequencing (ChIP-seq) coupled with RNA sequencing (RNA-seq),to find out the genes differentially expressed in C33A,cyclin D1 knock-in C33A and cyclin D1 knock-down C33A. Results: We detected 5590 genes involved in binding with cyclin D1 by ChIP-seq,screened 2811 genes up-regulation,2727 genes down-regulation in cyclin D1 knock-in cells,2244 genes up-regulation,1738 genes down-regulation in cyclin D1 knock-down cells by RNA-seq.Through analysis of the results of ChIP-seq and RNA-seq,we finally identified 422 genes differentially expressed at the RNA level.These genes are highly enriched in Gene Ontology categories and involve in diverse cellular functions via KEGG classification , including translation,replication and repair,signal transduction,cell growth and death. Conclusions: These findings suggested that cyclin D1 can serve both to activate and downregulate gene expression as a transcriptional role directly binding with genome DNA,which means that cyclin D1 may be a key protein during oncogenesis and tumor development.
Gemcitabine plus carboplatin versus gemcitabine plus oxaliplatin in cisplatin unfit patients with advanced urothelial carcinoma: A randomized phase II study (COACH, KCSG GU10-16).
Authors: Jae-Lyun Lee, Bong-Seog Kim, Ho Yeong Lim, Hee Jun Kim, Inkeun Park, Yoon Ji Choi, Kyong Hwa Park, Kyung Hee Lee, Shinkyo Yoon, Bumsik Hong, Jun Hyuck Hong, Hanjong Ahn
Journal: Journal of Clinical Oncology (2019)

4534 Background: We investigated the activity and safety of first-line gemcitabine-oxaliplatin (GemOx) compared with gemcitabine-carboplatin (GCb) in cisplatin-ineligible patients with advanced UCCC. Methods: Treatment naïve, cisplatin-ineligible patients with advanced UCCC were randomly assigned to GemOx [gemcitabine 1,000 mg/m 2 , oxliplatin 100 mg/m 2 on day 1 (D1) every 2 weeks] or GCb (gemcitabine 1,000 mg/m 2 on D1 and D8, carboplatin AUCC 4.5 on D1 every 3 weeks) stratified by ECOG performance status (PS) and visceral metastases. The primary endpoint was objective response rate (ORR), and secondary endpoints were progression-free survival (PFS) and overall survival (OS). Results: Between January 2011 and Mar 2017, 80 patients were enrolled; 39 patients and 40 patients were allocated to GCb and GemOx arm, respectively. Median age was 72 years (range 46-84) in GCb arm and 72.5 (55-85) in GemOx arm. ECOG PS was 2 in 41% (GCb arm) and 43% (GemOx arm), and median GFR was 45 ml/min (interquartile range 36-56) in GCb and 47 ml/min (37-56) in GemOx arm. ORR were 48.7% and 55.0% in GCb and GemOx, respectively. With a median follow-up duration of 37.8 months, median PFS and OS in GCb and GemOx arm were 5.5 months (95% CI, 4.8-6.2) vs. 4.4 months (95% CI, 2.7-6.1) and 9.1 months (95% CI, 5.2-13.0) vs. 11.0 months (95% CI, 6.9-15.0), respectively. Grade 3 leukopenia, neutropenia and fatigue were significantly more common in GCb arm (26% vs. 3%, p=0.003; 33% vs. 10%, p=0.014; 15% vs. 3%, p=0.057) while any grade neuropathy was more common in GemOx (8% vs. 60%, p&lt;0.001). Conclusions: GemOx has showed comparable efficacy with GCb and favorable hematologic toxicity profile. GemOx may be used as a new option for UCCC patients who are not suitable for platinum-containing chemotherapy. Clinical trial information: NCT01487915.
Quantitative radiographic analysis of phase II and III trials in recurrent glioblastoma treated with VB-111 with or without bevacizumab or bevacizumab monotherapy.
Authors: Benjamin M. Ellingson, Catalina Raymond, Jingwen Yao, Ararat Chakhoyan, Dallas Turley, Joseph Tsung, Jodi Goldman, Jacob Schlossman, Caleb Tan, Andrew Jacob Brenner, Nicholas A. Butowski, Patrick Y. Wen, Tamar Rachmilewitz Minei, Yael Chava Cohen, Dror Harats, Timothy Francis Cloughesy
Journal: Journal of Clinical Oncology (2019)

2018 Background: VB-111 is a non-replicating adenovirus carrying a pro-apoptotic transgene for TNFR1/Fas under the control of a modified murine promoter to pre-proendothelin 1. The transgene is expressed only in angiogenic endothelial cells, and therefore VB-111 results in targeted apoptosis of neovascular vessels. The current study characterizes the quantitative radiographic results and impact on OS in phase 2 and 3 trials of recurrent glioblastoma (GBM) patients treated with VB-111 with or without bevacizumab (BV) or BV monotherapy. Methods: MRI data from a phase 2 (NCT01260506) and randomized, double arm, controlled phase 3 (GLOBE; NCT02511405) trial of VB-111 in recurrent GBM were used in current study: Arm A) VB-111 monotherapy until progression followed by combination VB-111 and bevacizumab (BV) (“Primed Combination”; Phase 2; N = 24); Arm B) VB-111 in combination with BV (“Unprimed Combination”; Phase 3; N = 124) and Arm C) BV monotherapy (“Control”; Phase 3; N = 120). Contrast enhanced T1-weighted digital subtraction was used to quantify tumor volume at all time points. Results: Baseline tumor volume was not significantly different between patient cohorts (Kruskal-Wallis; P = 0.1482; median~20mL). Continuous measures of baseline tumor volume were prognostic for OS in all treatment groups when controlling for therapy and age (Cox, P &lt; 0.001, HR = 1.02). In patients with small tumors ( &lt; 25mL), the “primed combination” cohort (Arm A) from the phase 2 trial had a significant OS advantage compared to both upfront combination of VB-111 and BV (Arm B; P = 0.0094, HR = 0.5328; median OS = 7mo vs. 15mo) as well as BV alone (Arm C; P = 0.0248, HR = 0.5776; median OS = 8.5mo vs. 15mo). Patients with a radiographic response ( &gt; 65% reduction) had a significant survival difference from non-responders when controlling for age, baseline tumor volume, and treatment arm ( P = 0.0014, HR = 0.5822). Notably, in responders to VB-111 monotherapy or combination therapy after priming with VB-111 exhibited characteristic, expansive areas of necrosis in areas of initial disease. Conclusions: Small recurrent tumors have a significant OS advantage when “priming” with VB-111 monotherapy prior to combination VB-111 and BV at recurrence. Patients responding to VB-111 exhibit specific imaging characteristics related to the drug mechanism of action. Clinical trial information: NCT02511405; NCT01260506.