tbuckley/cabot-search huggingface dataset:
Effect of pneumocystis jirovecii pneumonia (PJP) on morbidity and mortality in oncology patients: A single centre experience.
Authors: Timothy Dudley Clay, Ciara Daly, Philip Craven, Nisha Sikotra, Sowmya Cheruvu, Eli Gabbay, Astrid Arellano
Journal: Journal of Clinical Oncology (2018)

e22088 Background: Patients with malignancy are at high risk for PJP due to profound immunosuppression from their treatment. Diagnosis may be delayed as many patients present with fevers, respiratory symptoms or pulmonary infiltrates on imaging. The mortality rate of PJP in cancer patients can be as high as 34%. Timely initiation of therapy is required to reduce significant morbidity and mortality. Methods: We conducted a retrospective cross sectional study of patients at our centre diagnosed with PJP from January 2015 to December 2017 in the setting of malignancy. Diagnosis of PJP was either definitive (PJP PCR positive in sputum, throat swab or BAL) or presumptive (appropriate clinical and radiographic findings and response to PJP directed therapy). Results: 18 patients were identified (6 haematological, 12 solid organ); median age 68 years (range 48-87); median time from diagnosis of malignancy to PJP infection 21 months (range 2-72); The median time from last chemotherapy to presentation 13 days (range 1 – 145). 10 patients (55%) had recent corticosteroids. No patients were receiving PJP prophylaxis. The features at admission were: tachypnoea n = 6 (33%); hypoxia n = 5 (28%); fever T > 38˚C/100.4˚F n = 8 (44%); and tachycardia 8 patients (44%). All patients had abnormal imaging (CT Chest n = 15; CXR n = 33). 11 cases (61%) had a sample sent for PJP PCR; 91% (10/11) were positive. On admission the median neutrophil was count 4.0 x 109/L (range 0.6-23.1, normal 2.0-7.5); lymphopenia was common [Median leucocyte count 0.5 x 109/L range (0.1-1.6, normal 1.5-4.0)]. The median length of stay (LOS) was 15.5 days (range 6-43). 4 patients (22%) required admission to ICU for non-invasive ventilation. The 30-day mortality was 44%. Conclusions: PJP led to significant morbidity and LOS in our cohort. Patients may not demonstrate typical signs of PJP at presentation. 30 day mortality was high, potentially reflecting the underlying burden of malignancy. PJP may become more frequent as cancer survival times improve and patients remain on immunosuppressive treatment for longer. Prompt initiation of diagnostic investigations and treatment may improve outcomes, together with increased use of PJP prophylaxis.
An easy-to-handle DPD deficiency test in saliva to identify patients at high-risk for life-threatening toxicity due to fluoropyrimidine therapy.
Authors: Gilberto Schwartsmann, Marina Venzon Antunes, Andres Galarza, Roberta Zilles Hahn, Suziane Raymundo, Anne Caroline Cezimbra da Silva, Rodrigo Staggemeier, Fernando R Spilki, Lidia B Longhinoti, Gabriel M Anjos, Maria Alice B Franzoi, Rafael Linden
Journal: Journal of Clinical Oncology (2017)

e14019 Background: Severe dihydropyrimidine dehydrogenase (DPD) deficiency can be lethal in 0.5-3.0% of patients receiving fluoropyrimidines. Unfortunately, there is no routine test in medical practice to identify high-risk patients. Here, we evaluated the use of plasma and saliva uracil (U) to dihydrouracil (UH2) metabolic ratio and DPYD genotyping, as a means to identify patients with DPD deficiency and fluoropyrimidine toxicity. In addition, we report on a functional test using UH2/U metabolic ratio in dried saliva spots (DSS). Methods: Prior to fluoropyrimidine therapy, plasma and saliva samples were obtained from 60 patients with GI cancer. U and UH2 levels were measured by LC-MS/MS in plasma and saliva. Patients were also genotyped for DPYD (*7/*2A/*13/Y186C). WHO grading were used to report treatment toxicity. Results: In 21 patients (35%) toxicity was documented. For those, no variant allele carrier for DPYD was identified. The UH2/U metabolic ratios were 0.1-26.7 in plasma and 0.1-24.0 in saliva, with a higher correlation with toxicity grade in saliva as compared to plasma (rs 0.52 vs 0.28). Median metabolic ratios were lower in patients with severe toxicity as compared to those with no toxicity (0.59 vs 2.83 saliva; 1.62 vs 6.75 plasma, P &lt; 0.01). A cut-off of 1.16 for the salivary UH2/U ratio was set (AUC 0.84) with 86% sensitivity and 77% specificity for the identification of grade 3-4 toxicity. A plasma cut-off of 4.0 (AUC 0.75) revealed a 71% sensitivity and 76% specificity. Moreover, saliva of 21 patients were applied to filter paper to obtain DSS and sent to the laboratory by regular mail. U and UH2 were stable in DSS stored at 45°C up to 7 days. In this set of patients, grade 3-4 toxicity was documented in 3/21 cases (14%), all three cases had metabolic ratios below 1.16 in DSS, confirming our prior results. Conclusions: DPYD genotyping failed to identify severe DPD deficiency, but the UH2/U metabolic ratios in saliva showed enough sensitivity and specificity to deserve further evaluation. DSS samples allowed medical oncologists working at distant sites to send us samples by post, with results available within a week. This test is being validated in a larger sample population.
Real world treatment patterns and clinical outcomes associated with palbociclib combination therapy in Argentina: Results from the IRIS study.
Authors: Gavin Taylor-Stokes, John Waller, Debanjali Mitra, Katie Gibson, Gary Milligan, Shrividya Iyer
Journal: Journal of Clinical Oncology (2018)

e13026 Background: Palbociclib was the first CDK 4/6 inhibitor approved in Argentina for HR+/HER2- advanced/ metastatic breast cancer (ABC/ MBC) in combination with letrozole or fulvestrant. However, no data exists on real world outcomes associated with palbociclib in Argentina. Ibrance Real World Insights (IRIS) is a multi-country study aimed to describe treatment patterns and clinical outcomes of patients receiving palbociclib in real world clinical practices. Methods: Medical records of adult female patients with HR+/HER2- ABC/ MBC who received palbociclib + letrozole or fulvestrant were reviewed by their treating physicians. Data on demographic and clinical characteristics, treatment patterns, and clinical outcomes were extracted. Progression free rate and survival at 6 and 12 months were estimated via Kaplan-Meier analysis. Results: 162 patient records were abstracted by 41 physicians. Approximately, 44% of physicians were from public practices. The mean (SD) age of patients at palbociclib initiation was 63.6 (10.4) years (median, 64 years). Overall, 46.9% of patients were Hispanic/ Latino and 40.7% were White/ Caucasian. ECOG performance status at palbociclib initiation was mostly 0 (36.4%) or 1 (51.9%). Approximately, 39% of patients had visceral disease. Of the 162 patients, 105 (64.8%) received palbociclib + letrozole and 57 (35.2%) received palbociclib + fulvestrant. The 6 month progression free rate for palbociclib + letrozole was 94.3% and for palbociclib + fulvestrant was 95.0%. At 12 months, progression free rate for palbociclib + letrozole was 85.4%. The survival rate at 6 and 12 months for palbociclib + letrozole was 98.1% and 93.4% respectively and the survival rate at 6 months for palbociclib + fulvestrant was 98.2%. Patients in the fulvestrant combination group had insufficient follow-up to calculate 12 month progression free and survival rates. Conclusions: In this first real world evaluation of clinical outcomes in Argentina, palbociclib combined with letrozole or fulvestrant demonstrates high effectiveness in terms of progression free and survival rates. Funding: This study was funded by Pfizer, Inc.
Ankyrin-B Q1283H Variant Linked to Arrhythmias Via Loss of Local Protein Phosphatase 2A Activity Causes Ryanodine Receptor Hyperphosphorylation
Authors: Wengen Zhu, Cen Wang, Jinzhu Hu, Rong Wan, Jianhua Yu, Jinyan Xie, Jianyong Ma, Linjuan Guo, Jin Ge, Yumin Qiu, Leifeng Chen, Hualong Liu, Xia Yan, Xiuxia Liu, Jin Ye, Wenfeng He, Yang Shen, Chao Wang, Peter J. Mohler, Kui Hong
Journal: Circulation (2018)

Human loss-of-function variants of ANK2 (ankyrin-B) are linked to arrhythmias and sudden cardiac death. However, their in vivo effects and specific arrhythmogenic pathways have not been fully elucidated.We identified new ANK2 variants in 25 unrelated Han Chinese probands with ventricular tachycardia by whole-exome sequencing. The potential pathogenic variants were validated by Sanger sequencing. We performed functional and mechanistic experiments in ankyrin-B knockin (KI) mouse models and in single myocytes isolated from KI hearts.We detected a rare, heterozygous ANK2 variant (p.Q1283H) in a proband with recurrent ventricular tachycardia. This variant was localized to the ZU5C region of ANK2, where no variants have been previously reported. KI mice harboring the p.Q1283H variant exhibited an increased predisposition to ventricular arrhythmias after catecholaminergic stress in the absence of cardiac structural abnormalities. Functional studies illustrated an increased frequency of delayed afterdepolarizations and Ca2+ waves and sparks accompanied by decreased sarcoplasmic reticulum Ca2+ content in KI cardiomyocytes on isoproterenol stimulation. The immunoblotting results showed increased levels of phosphorylated ryanodine receptor Ser2814 in the KI hearts, which was further amplified on isoproterenol stimulation. Coimmunoprecipitation experiments demonstrated dissociation of protein phosphatase 2A from ryanodine receptor in the KI hearts, which was accompanied by a decreased binding of ankyrin-B to protein phosphatase 2A regulatory subunit B56α. Finally, the administration of metoprolol or flecainide decreased the incidence of stress-induced ventricular arrhythmias in the KI mice.ANK2 p.Q1283H is a disease-associated variant that confers susceptibility to stress-induced arrhythmias, which may be prevented by the administration of metoprolol or flecainide. This variant is associated with the loss of protein phosphatase 2A activity, increased phosphorylation of ryanodine receptor, exaggerated delayed afterdepolarization-mediated trigger activity, and arrhythmogenesis.
Characterization of tumor mutation load (TML) in solid tumors.
Authors: Mohamed E. Salem, Joanne Xiu, Heinz-Josef Lenz, Michael B. Atkins, Philip Agop Philip, Jimmy J. Hwang, Zoran Gatalica, Nianqing Xiao, Geoffrey Thomas Gibney, Wafik S. El-Deiry, Antoinette R. Tan, Edward S. Kim, Anthony Frank Shields, Derek Raghavan, John Marshall
Journal: Journal of Clinical Oncology (2017)

11517 Background: Rapid advances in immunotherapy have created a need for biomarkers to improve patient treatment selection. TML is proposed as a potential predictive biomarker due to its association with tumor immunogenicity. Methods: TML was assessed in 8020 tumors from 14 different cancers using somatic nonsynonymous missense mutations sequenced with a 592-gene panel. High TML was set at ≥ 17 mutations per megabase (mt/MB) based on an established concordance ( &gt; 99%) with MSI-High in colorectal cancer (CRC). Results: Mean TML was highest in melanoma (Mel; 21 mt/MB), NSCLC (11 mt/MB), and bladder cancer (BLC; 11 mt/MB), whereas prostate cancer (PC), pancreas adenocarcinoma (PA), and renal cell carcinoma (RCC) had the lowest levels (all 6 mt/MB). High TML was seen most frequently in Mel (36%), NSCLC (15%), BLC (15%), and anal cancer (SCCA; 9%); and least frequently in PA (1.6%) and RCC (0.5%). Primary NSCLC carried lower TML than its brain metastases (11 vs. 16 mt/MB, p &lt; 0.001). Older age was associated with higher TML in Mel (p = 0.001), CRC (p = 0.009), breast cancer (BC; p = 0.01), and NSCLC (p = 0.02). Higher TML was seen in males than in females for Mel (p = 0.002) and NSCLC (p &lt; 0.001). Presence of mutations in oncogenic driver genes such as EGFR, ALK, ROS1 RET fusions, cMET exon 14 skipping correlated with lower TML in NSCLC (6.9 vs. 12 mt/MB, p &lt; 0.001), as did BRAF and NRAS mutations in Mel (17 vs. 26, p = 0.003). Conversely, mutations in tumor suppressor genes such as ARID1A (CRC, NSCLC, and BLC) and NF1 (BC, CRC, Mel, BLC, and NSCLC) were associated with higher TML (p &lt; 0.05). MSI-high was correlated with high TML in CRC and gastric cancers (p &lt; 0.05). Conclusions: TML varied significantly among different cancers. High TML was associated with older age, absence of oncogenic mutations and presence of tumor suppressor gene mutations. Future studies will assess the impact of TML on clinical outcome and establish its role in selecting patients for immunotherapy. [Table: see text]
Pre-treatment hematological markers as a predictive biomarker for survival in patients with non-small cell lung cancer treated with nivolumab.
Authors: Pradnya Dinkar Patil, Monica Khunger, Sagar Rakshit, James Stevenson, Nathan A. Pennell, Paul Elson, Vamsidhar Velcheti
Journal: Journal of Clinical Oncology (2017)

11547 Background: The absolute neutrophil count (ANC), absolute monocyte count (AMC) and neutrophil to lymphocyte ratio (NLR) are known markers of inflammation. We evaluated whether ANC, AMC and NLR are prognostic for overall survival (OS) and evaluated change in NLR as a predictive marker of response per RECIST in non -small cell lung cancer (NSCLC) patients treated with nivolumab. Methods: A total of 115 patients with NSCLC treated with nivolumab were included. ANC, AMC and NLR were examined at initiation of nivolumab therapy and after two cycles. The prognostic role of ANC, AMC and NLR on OS and changes in NLR ratio in responders was assessed using Cox regression model. Results: ANC &gt; 6, AMC &gt; 0.5 and NLR &gt; 2.8 at baseline were independently associated with shorter OS (Hazard ratio (HR) 1.17 (1.08-1.27), p = .00001; HR 4.53 (1.99-10.31), p = 0.04 and HR 1.09 (1.04-1.13), p = 0.0002 . Responders had a decrease in NLR by (median (range) -0.93 (-14.7-52.95), p = 0.03) whereas non-responders had an increase in NLR by (median (range) 0.85 (-8.6-132.9), p = 0.03). Conclusions: ANC, AMC andNLR are independent prognostic factors in NSCLC patients treated with nivolumab. Changes in NLR can be an early biomarker for response with nivolumab in NSCLC patients. [Table: see text]
INDUCE-1: A phase I open-label study of GSK3359609, an ICOS agonist antibody, administered alone and in combination with pembrolizumab in patients with advanced solid tumors.
Authors: Eric Angevin, Mary S. Barnette, Todd Michael Bauer, Daniel C. Cho, Catherine Elizabeth Ellis, Hui Kong Gan, Aaron Richard Hansen, Axel Hoos, Roxanne C Jewell, Jessica Katz, Juan Martin-Liberal, Michele Maio, Patrick A. Mayes, Michael Millward, Victor Moreno, Anthony J. Olszanski, Danny Rischin, Jan H. M. Schellens, Sapna Yadavilli, Helen Zhou
Journal: Journal of Clinical Oncology (2017)

TPS3113 Background: Inducible T cell Co-Stimulator (ICOS), a member of the CD28/B7/CTLA-4 receptor superfamily expressed on T cells after engagement with cognate antigen and activation, provides a co-stimulatory signal augmenting T cell proliferation, survival and cytokine production. GSK3359609 is a humanized IgG4 antibody selected for its potent agonist activity against human ICOS. The unique mechanistic profile of an ICOS agonist antibody, such as GSK3359609, offers an opportunity to investigate the antitumor potential of targeting a T cell co-stimulator alone and in combination with other cancer immunotherapies such as pembrolizumab. Methods: INDUCE-1 is a first- in-human study evaluating safety, pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary antitumor activity of GSK3359609 administered as an intravenous (IV) infusion once every 3 weeks (Q3W) alone (Part 1) and in combination with 200 mg pembrolizumab (Q3W IV infusion) or other immunotherapy (Part 2) in approximately 304 adult patients. In dose escalation, eligible patients are required to have selected relapsed/refractory solid tumors. Primary objective is to determine safety, tolerability, and maximum tolerated or administered dose. Modified toxicity probability interval method will inform dose escalation decisions (minimum 3 patients per dose level [DL]). In expansion, cohorts may be defined by factors such as tumor histology, biomarker features, or prior treatment. More than one GSK3359609 DL may be evaluated in an expansion cohort by random assignment. Blood immunophenotyping is monitored in all patients; tumor biopsies (before and on-treatment) are optional in escalation and required in expansion to provide biomarker data that may inform on optimal dose selection as well as mechanistic understanding of GSK3359609. Efficacy measures are every 9 weeks and are according to immune-related RECIST. As of 7 Feb 2017, the first 3 monotherapy DL cohorts completed without dose limiting toxicities; DL 4 enrollment is ongoing. Study is funded by GlaxoSmithKline and is in collaboration with Merck &amp; Co., Inc. Clinical trial information: NCT02723955.
Risk group accurately predicts outcome in primary extremity non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) in patients &lt;30 years of age: Findings from Children’s Oncology Group study ARST0332.
Authors: Sara Regina Kreimer, Dixin Shen, Sheri L. Spunt, Simon C Kao, David Parham, Sarah S. Donaldson, Matthew Ladra, Michael J. Monument, Donald A. Barkauskas, Douglas S. Hawkins, R. Lor Randall
Journal: Journal of Clinical Oncology (2018)

10546 Background: Data are limited on primary extremity NRSTS in pediatric patients. Methods: This ARST0332 subset analysis evaluated the clinical features and outcomes of extremity (including shoulder/hip girdle) NRSTS in < 30 year old patients risk-stratified to receive surgery +/- radiotherapy +/- chemotherapy based on clinicopathologic characteristics including tumor size, grade, extent of surgery, and presence of metastases. Other variables analyzed included age, gender, race, tumor invasiveness, and depth. Results: Primary extremity tumors comprised 297/551 cases (100 upper and 197 lower extremity) treated with surgery only (n = 137), adjuvant radiotherapy (n = 9), adjuvant chemoradiotherapy (n = 38), or neoadjuvant chemoradiotherapy followed by surgery if feasible (n = 113). Extremity site correlated with older age (p = 0.0059), diameter < 5 cm (p = 0.0421), lower grade (p < 0.0001), superficial location (p = 0.0314), and non-invasiveness (p < 0.0001). However, among patients with extremity tumors, older patients more commonly had > 5 cm (p < 0.0001), deep (p = 0.0010), invasive (p = 0.0037) tumors, and distant metastases (p = 0.0003). Estimated 5-year cumulative incidence of local and distant recurrence was 5% and 20%, respectively. Five-year overall survival (OS) for low-, intermediate- and high-risk patients was 96.7%, 78%, and 25.4%, respectively, and was not statistically significantly different than for non-extremity tumors. Older age, size > 5 cm, invasiveness, and higher risk group predicted inferior event-free survival; only higher risk group predicted inferior OS. Conclusions: Although extremity NRSTS are more likely to have low-risk features (size < 5 cm, lower grade, superficial location, non-invasiveness) compared to non-extremity tumors, their outcomes are similar with risk-adapted therapy. Older patients had more high-risk features. Risk group was the most important predictor of overall survival. Clinical trial information: NCT00346164.
Prognostic value of genomic alterations of DNA repair genes in advanced bladder cancer (ABC).
Authors: Ming Yin, Petros Grivas, Siraj Mahamed Ali, Joann Hsu, Monali K. Vasekar, Hamid Emamekhoo, Sumanta K. Pal, Monika Joshi
Journal: Journal of Clinical Oncology (2018)

4536 Background: DNA repair defect plays an important role in tumorigenesis, progression, treatment response and outcomes of BC. There is conflicting data on the prognostic & predictive role of DDR gene alterations in ABC patients (pts) treated with platinum-based chemotherapy (Teo et al. ASCO 2017; Mendiratta et al. GU ASCO 2018). Thus, further validation is needed to understand prognostic implications of DDR genomic alterations in ABC. Methods: Exome sequencing data were obtained from 81 ABC pts who received comprehensive genomic sequencing using FoundationOne (315 cancer-related genes). Overall survival (OS) was measured from time of initial diagnosis and metastasis-related survival (MRS) was measured from time of metastatic diagnosis to death or last follow-up. Cox proportional hazard regression analysis was performed to calculate the hazard ratio (HR) and 95% confidence interval (CI). Results: In a panel of 28 DDR genes, mutations were present in 74.1% pts (60/81) with18.5% pts carrying mutations in ≥3 DDR genes. Overall, mutations of DDR genes were not significantly associated with OS (HR = 0.76, 95% CI 0.41–1.43, p = 0.397) or MRS (HR = 0.57, 95% CI 0.30–1.08, p = 0.084). Further evaluation showed that most DDR mutations (excluding ATM/RB1) were associated with longer OS (HR = 0.49, 95% CI 0.27–0.87, p = 0.015) and longer MRS (HR = 0.39, 95% CI 0.21–0.70, p = 0.002), while mutations of ATM/RB1 genes were associated with shorter OS (HR 1.87, 95% CI 0.97–3.59, p = 0.06) but not MRS. There was a trend for longer OS and MRS with increased number of DDR mutations in individual pts. Pts carrying ≥3 DDR mutations (excluding ATM/RB1) seemed to have the best prognosis in our cohort (OS: HR 0.36, 95% CI 0.14–0.92, p = 0.03; MRS: HR 0.20, 95% CI 0.07–0.56, p = 0.002). Conclusions: Most DDR mutations correlated with improved clinical outcomes in ABC pts. However, ATM/RB1 mutations correlated with poor prognosis. Pts carrying ≥3 DDR (excluding ATM/RB1) mutations had the best prognosis. Further exploration of the deleterious nature and impact of alterations as well as further external validation are critical. Clinical trials evaluating synthetic lethality with DDR inhibitors are ongoing.
New generation of cancer stem cells inhibitors in non-small cell lung cancer.
Authors: Héctor Amado Labrador, Cristóbal Aguilar-Gallardo, Alejandro Herreros-Pomares, Ester Munera-Maravilla, Silvia Calabuig-Fariñas, Eva Escorihuela, Juan Murga, Eloisa Jantus-Lewintre, Carlos Camps
Journal: Journal of Clinical Oncology (2018)

e20545 Background: Lung cancer is the commonest tumor worldwide of which the most frequent type is non-small cell lung cancer (NSCLC) that represents a large proportion of cancer deaths and is characterized by low response treatment rates and poor overall prognosis. Cancer Stem Cells (CSCs) model proposes that drug resistance, tumor progression, metastasis and recurrence might be driven by this subset of cells, with increased expression of stemness-associated markers and the ability to self-renew and differentiate. Methods: Drug screening was performed by comparing tumorspheres and monolayer cells from 4 resected NSCLC patients and 12 NSCLC cell lines, which were plated at the desired density in 200 μl of medium in 96-well plates. High-throughput screening was performed with two chemical libraries (Prestwick and Myria). Experiments were done in triplicate. Cell viability was measured after 48 h (MTS Assay) and was normalized to the respective mock-treated control cells. Based on this study 3 novel compounds were identified, namely A, B and C. Statistical analyses were considered significant at p < 0.05. EC50 was calculated with GraphPad. Relative gene expression analysis was run by RT-qPCR in the tumorspheres treated with the three compounds. Results: CSC-markers, pluripotency genes and signaling pathways were characterized from the resected NSCLC patients’ tumor-tissue and cell lines-like tumor spheres to use them as an in vitro drug screening platform. The screening assay showed selective reduced cellular viability specifically in lung tumorspheres when the three chemically-related compounds were tested (p < 0.05). This anti-proliferative effect correlated with an earlier decrease in the expression of the CSC markers critical in lung tumorspheres, such as ALDH1A1, KLF4 and SOX2. Conclusions: These compounds could be a serious promising targeted therapy for lung CSCs as major CSC-markers inhibitors, including pluripotency genes and signaling pathways. Our findings suggest that these compounds can inhibit CSCs-like properties, as evidenced by the lung sphere assays and reveal a potential use for developing novel therapeutic approaches. Supported by grants CIBERONC, PI12-02838, PI15-00753 from ISCIII, Arnal Planelles Foundation.