tbuckley/cabot-search huggingface dataset:
Circulating miR-371a-3p for the detection of low volume viable germ cell tumor: Expanded pilot data, clinical implications and future study.
Authors: Lucia Nappi, Brock O Neil, Siamak Daneshmand, Robert James Hamilton, Ricardo Romao Nazario Leao, Marisa Thi, Kim N. Chi, Martin Gleave, Bernhard J. Eigl, Peter C. Black, Alan I. So, Daniel Khalaf, Christian K. Kollmannsberger, Craig R. Nichols
Journal: Journal of Clinical Oncology (2018)

4549 Background: Determining the histology of borderline enlarged nodes in clinical stage I (CSI) or post-chemotherapy residual disease (PCRD) patients (pts) with germ cell tumor (GCT) is challenging, especially when classic tumor markers are negative. Currently, accurate assessment requires clinical follow-up with imaging to establish patterns of growth or pathological confirmation. A blood-based approach to reliably identify patients with non teratoma viable GCT (NTVGCT) would be valuable. Methods: miR-371a-3p (miR371) extracted from plasma of pts with GCT was analyzed by RT-PCR and relative expression calculated by the 2-ΔΔCt method with appropriate negative and positive controls. The sensitivity and specificity of miR371 were calculated correlating miR371 expression to the presence of relapsed/residual NTVGCT. Results: 74 samples were analyzed in 56 patients: 24 CSI; 32 metastatic, of whom 21 had PCRD. Among CSI patients, 8 relapses occurred and miR371 was positive in 6/8 relapses. Among the CSI patients that did not relapse, 7 had borderline enlarged nodes but negative miR371. For the metastatic pts, miR371 was positive in 16/18 pts pre-chemotherapy and became negative in all post-chemotherapy. 3 miR371 negative pts (1 CSI and 2 metastatic) had pathologically confirmed primary teratoma. miR371 was negative in all the pts with PCRD (n = 21) and no residual NTVGCT was detected in those pts by either pathology (n = 13) or clinical follow-up (n = 8). Sensitivity and specificity were 93.3% and 100%, respectively across the entire cohort of samples in detecting the presence of relapse or residual NTVGCT. Both internal and external validation studies have been performed with excellent concordance. Conclusions: Detectable plasma levels of miR371 have excellent correlation with the presence of NTVGCT. More rational selection of adjuvant therapy in CSI, reduction in imaging and more precise post-chemotherapy evaluations are among the more obvious settings in which biomarker-based decision making can improve GCT management. These and other data informed the development of two large US/Canadian intergroup studies to define the role of miRNA clusters in management of GCT.
Smad4 expression and chemosensitivity in non-small cell lung cancer.
Authors: Michael Ziemke, Tejas Patil, Kyle Nolan, Stephen Malkoski
Journal: Journal of Clinical Oncology (2017)

e20550 Background: Smad4 is a tumor suppressor that transduces transforming growth factor beta signaling and regulates genomic stability. We previously found that reduced Smad4 expression was associated with increased DNA damage in both human NSCLC and murine NSCLC models and that reduced Smad4 expression inhibits DNA repair and increases sensitivity to DNA topoisomerase inhibitors. In this study, we assessed the association between reduced Smad4 expression and DNA topoisomerase inhibitor sensitivity in human NSCLC as well as the relationship between Smad4 mutation and homozygous deletion and molecular alterations in other DNA repair molecules. Methods: After IRB approval, we retrospectively identified NSCLC patients who received etoposide or gemcitabine and had an evaluable tumor on CT scan at the University of Colorado Hospital between 2004 to 2014. Chemotherapeutic response was quantified by RECIST criteria, while Smad4 expression was assessed by immunohistochemistry (IHC) and quantified on a 0-300 scale. The relationship between Smad4 mutation and other DNA repair molecule alterations was assessed using TCGA data via cBioPortal. Results: Of the 21 evaluable patients, 19/21 received gemcitabine or etoposide for advanced (stage 3 or 4) disease and 10/21 received these agents with concurrent radiation therapy. Reduced Smad4 expression (IHC score &lt; 100) occurred in 8/21 patients and was associated with non-significant trend (p = 0.18, fisher exact test) toward responsiveness to gemcitabine or etoposide. TCGA data analysis revealed that while Smad4 mutation or homozygous loss was not associated with reduced survival, Smad4 alterations were mutually exclusive to defects in DNA repair molecules. Conclusions: Reduced Smad4 expression may be a biomarker for responsiveness to treatment with chemotherapeutic drugs that inhibit DNA topoisomerase, though this study was underpowered to detect this. That Smad4 signaling alterations are mutually exclusive with alterations in other DNA repair machinery is consistent with a role of Smad4 in regulating DNA repair.
Incidence of dermatological toxicities and fatigue in patients with cancer treated with regorafenib: A systematic review and meta- analysis of randomized controlled trials.
Authors: Miguel Quirch, Kyaw Zin Thein, Muhammad Saad Khan, Anita Sultan, Sriman Swarup, Lukman Aderoju Tijani, Fred L. Hardwicke, Catherine Jones
Journal: Journal of Clinical Oncology (2018)

10123 Background: Fatigue and skin toxicities notably contributed to the quality of life of cancer patients undergoing chemotherapy. Regorafenib, an oral small molecule multi kinase inhibitor, targets signaling pathways implicated in tumor angiogenesis, oncogenesis and the tumor microenvironment and are utilized in many solid tumors. We performed a systematic review and meta-analysis of randomized controlled trials (RCT) to determine the risk of fatigue and dermatological toxicities among patients with cancer treated with regorafenib. Methods: We conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through August 2017. Phase 3 RCTs that mention hand foot syndrome (HFS), rash, fatigue and anorexia as adverse effects were incorporated in the analysis. Mantel-Haenszel method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Random effects model was applied. Results: A total of 1723 patients with hepatocellular, colorectal cancer and gastrointestinal stromal tumors from four phase 3 RCTs were eligible for analysis. Studies compared regorafenib versus placebo. All grade-HFS incidence was 603 (34.9%) in regorafenib arm vs 44 (2.55%) in control arm with a RR of 6.683 (95% CI: 4.392–10.169, P < 0.0001). High-grade HFS was reported in 178 (10.33%) in regorafenib group vs 2 (0.12%) in control group with a RR of 29.246 (95% CI: 9.381–91.176, P < 0.0001). The relative risks of all-grade rash was 6.435 (95% CI: 3.713–11.154, P < 0.0001); high-grade rash: 9.166 (95% CI: 1.753–47.927, P = 0.009); all- grade fatigue: 1.624 (95% CI: 1.376–1.917, P < 0.0001); high-grade fatigue: 2.209 (95% CI: 1.329 – 3.672, P = 0.002); all-grade anorexia: 2.425 (95% CI: 1.678–3.503, P < 0.0001); and high-grade anorexia: 1.704 (95% CI: 0.507–5.720, P = 0.389). Conclusions: Patients on regorafenib experienced a significant increase in all-grades of HFS with a relative risk of 29 for grade 3 and 4 HFS. They also contributed to significant toxicity of all-grade and high-grade rash and fatigue as well as all-grade anorexia.
A phase 3 randomized study of pembrolizumab (Pembro) plus pomalidomide (Pom) and dexamethasone (Dex) for relapsed/refractory multiple myeloma (RRMM): KEYNOTE-183.
Authors: Maria-Victoria Mateos, Hilary Blacklock, Fredrik Schjesvold, Albert Oriol Rocafiguera, David Simpson, Anupkumar George, Hartmut Goldschmidt, Alessandra Larocca, Daniel Wayne Sherbenou, Irit Avivi, Shinsuke Iida, Morio Matsumoto, Saad Zafar Usmani, Sundar Jagannath, Paula Rodriguez-Otero, Uma Kher, Mohammed Z.H. Farooqui, Jason Liao, Patricia Marinello, Sagar Lonial
Journal: Journal of Clinical Oncology (2018)

8021 Background: KEYNOTE-183 (NCT02576977) evaluated pom + low-dose dex (SOC) ± pembro in patients (pts) with RRMM. Methods: Pts were randomized 1:1 to pembro (200 mg Q3W) + SOC (4 mg pom [d 1-21] + 40 mg dex [d 1, 8, 15, 22]) every 28 d vs SOC until progression (PD), unacceptable toxicity, withdrawal. Coprimary endpoints: PFS (2011 IMWG criteria), OS; secondary endpoints: safety, ORR. On July 3, 2017 based on interim data presented to the DMC, the FDA halted KEYNOTE-183. Results: 249/300 pts enrolled (125, pembro + SOC; 124, SOC) with median (range) age: 65 y (45-94) vs 67 y (22-90); 28 (22%) vs 17 (14%) pts had high-risk cytogenetics. Median (range) drug exposure was 123.5 d (2-477) vs 127 d (2-463); median 4.4 cycles. AEs with ≥5% difference between arms: neutropenia (38% vs 27%), nausea (17% vs 12%), pneumonia (23% vs 15%), ALT increase (10% vs 3%), headache (13% vs 4%). No SAEs had ≥5% difference between arms. In pembro + SOC arm, 21 (18%) pts had immune-mediated AEs: skin reaction (5%), pneumonitis (4%), hyperthyroidism (3%), infusion reaction (2%), myopathy (2%), myocarditis, iridocyclitis, hepatitis, Steven-Johnson syndrome (SJS; 1% each). 29 (23%) pts vs 21 (17%) died (16 from PD, 13 from AEs vs 18 from PD, 3 from AEs). 4 (3%) treatment related deaths occurred; 2 (1.5% [1 myocarditis, 1 SJS]) related to pembro. Median follow-up was 7.8 mo vs 8.6 mo. Median PFS: 5.6 mo vs 8.4 mo; HR, 1.53 (95% CI, 1.05-2.22); P= 0.98. Median TTP: 8.1 vs 8.7 mo. Median OS: not reached vs 15.2 mo; HR, 1.61 (95% CI, 0.91-2.85); P= 0.95. In a retrospective random forest analysis age, ECOG PS, disease stage, presence of plasmacytoma, double refractory status were more relevant contributors to death than treatment. A subsequent multivariable COX regression analysis showed age, ECOG, presence of plasmacytoma significantly contributed to risk of death. Age and presence of plasmacytoma were prognostic, while ECOG was prognostic and predictive of outcome with OS HR = 0.85 (ECOG 0) and OS HR = 2.3 (ECOG 1). Conclusions: The benefit-risk profile for combination of pembro, pom and dex is unfavorable for RRMM. Evaluation of T-cell subsets and cytokines along with long-term safety and survival follow-up is ongoing. Clinical trial information: NCT02576977.
ΔCT value of amplified refractory mutation system (ARMS) to predict efficacy of EGFR-TKIs in non-small cell lung cancer: A multicenter retrospective study.
Authors: Laiyu Liu, Min Chen, Gong Li, Dongyong Yang, Nanjie Xiao, Weijian Zhang, Libin Guo, Jian Guan
Journal: Journal of Clinical Oncology (2017)

e20573 Background: This multi-center retrospective study was to determine whether the ΔCt value of Amplified Refractory Mutation System (ARMS) in EGFR mutated detection in tumors predicts the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small-cell lung cancer (NSCLC). Methods: A total of 108 NSCLC patients harbored an exon 19 deletion (19Del) or exon 21 L858R mutation detected by ARMS were enrolled. We identified patients with ΔCt&lt;1(Group L) harbored a high proportion of EGFR mutation but the patients with ΔCt≥1 (Group H) harbored a low proportion of EGFR mutation in the tumor sample. The progression-free survival (PFS), objective response rates (ORRs) and overall survival (OS) between the groups were analyzed. Results: In the 108 patients we enrolled, 63 were in group L and 45 were in group H. Patients’ demographics and clinical characteristics including age, sex, smoking history, pathology, mutation sites, TNM stage, line of TKIs therapy were not significantly difference between group L and group H. The Median PFS was 331 days (95%CI: 311.8 to 350.2) in group L and 206 days (95%CI, 157.2 to 254.8) in group H and the difference showed statistically significant (P &lt; 0.001). Moreover, the ORRs in group L was significant higher than the group H (60.0% vs 34.9%, P = 0.011). The median OS was 744 days (95%CI, 635.5 to 852.5) in group L and 596 days in group H (95%CI, 491.7 to 700.0) but showed not statistically significant ( P = 0.098). Conclusions: ΔCt value of ARMS in EGFR mutated detection could be an efficacy predictor for EGFR-TKIs treatment in advanced EGFR-mutant NSCLC.
Discovery and characterization of novel, recurrent, targetable ALK fusions in leiomyosarcoma.
Authors: Lara Emily Davis, Kevin Nusser, Joanna Przybyl, Maria Debiec-Rychter, Janét Pittsenbarger, Nicolle Hofmann, Sushama Varma, Monika Davare
Journal: Journal of Clinical Oncology (2018)

11563 Background: Leiomyosarcoma (LMS), a type of soft tissue tumor that originates from smooth muscle, is the second most common type of sarcoma. Despite multimodal treatment including surgery, chemotherapy and radiation, locally advanced or metastatic LMS portends poor prognosis. We hypothesize that discovery and validation of oncogenic drivers and cognate targeted therapies holds the potential to dramatically impact LMS patient outcomes. Methods: To discover putative kinase fusions, we analyzed existing genomic or transcriptomic data from LMS clinical samples. We functionally validated the oncogenic potential and targetability of discovered kinase fusions through biochemical, cell-based and in vivo tumor modelling approaches. Multiple independent cell-based (Ba/F3, NIH3T3 and murine smooth muscle cell) model systems were utilized. Results: We identified ALK rearrangements in 7 of 280 (2.5%) LMS patients, including a novel KANK2-ALK fusion and a recurrent ACTG2-ALK fusion. KANK2-ALK and ACTG2-ALK operate as dominant oncogenes in Ba/F3 or NIH3T3 model systems, and KANK2-ALK is tumorigenic when introduced in smooth muscle cells, the cell of origin for leiomyosarcoma. Oral monotherapy with the targeted ALK kinase inhibitor lorlatinib significantly inhibited tumor growth and prolonged survival in a murine model of KANK2-ALK leiomyosarcoma. Conclusions: These results provide the first validation of a targetable oncogenic kinase fusion as a driver in a subset of leiomyosarcomas. Overall, these findings suggest that some soft tissue sarcomas may harbor previously unknown kinase gene translocations, and their discovery may propel new therapeutic strategies in this treatment-refractory cancer.
New NHS app will let patients book GP appointments on mobiles
Authors: Susan Mayor
Journal: BMJ (2018)

The NHS is piloting an app that will enable patients in England to book GP appointments, order repeat prescriptions, and view their medical records on their mobile phone or tablet, the health and social care secretary, Matt Hancock, announced this week.

A test version of the new NHS App will be piloted in general practices and among patients in five areas in England from October: Liverpool, …
Taxane-based or platinum-based combination chemotherapy given concurrently with radiation followed by surgery resulting in high cure rates in esophageal cancer patients.
Authors: Anthony Lopez, Hsiang-Chun Chen, Kazuto Harada, Manoop S. Bhutani, Brian Weston, Jeffrey H Lee, Dipen M. Maru, Wai Chin Foo, Jane Elizabeth Rogers, Irene Thomas, Fatemeh Ghazanfari Amlashi, Mariela A. Blum Murphy, David C. Rice, Wayne Lewis Hofstetter, Quynh Nguyen, Jaffer A. Ajani
Journal: Journal of Clinical Oncology (2018)

e16051 Background: Preoperative chemoradiotherapy (CRT) is one standard option for localized esophageal or gastroesophageal junction (GEJ) cancer patients but an optimal concurrent chemotherapy combination is not established. Our objective was to compare the efficacy of the addition of docetaxel (DF) or oxaliplatin (FOX) to fluoropyrimidine with radiation. Methods: We retrospectively analyzed 412 patients with resectable (cT1N1M0 or cT2-4N0-3M0) esophageal or GEJ cancer treated with CRT followed by surgery (trimodality; TMT) at the MDACC between October 2002 and June 2016. Primary endpoints were overall survival (OS) and disease-free survival (DFS). Univariate and multivariate Cox analyses were performed. Results: Of the 412 patients analyzed, 264 (64%) received DF and 148 (36%) FOX. The median age was 60 years, and 95% had adenocarcinoma. The clinical complete response, positron emission tomography response, and pathological complete response rates were 73%, 73% and 30%, respectively. Median follow-up was 60.4 months. Median OS for the entire cohort was 81.6 months (95% CI, 56.3-122.0); 81.6 months (95% CI, 55.9–not estimable) for the DF group and 67.7 months (95% CI, 41.6–not estimable) for the FOX group (P = .24). The median DFS was 45.6 months (95% CI, 33.1-61.7) for the entire cohort; 49.5 months (95% CI, 38.6-70.3) for DF and 33.0 months (95% CI, 18.1-70.4; P = .38) for FOX. Higher tumor location (unfavorable) and clinical complete response (favorable) were prognostic for both OS and DFS in the multivariate analysis. Conclusions: At our high-volume center, the outcome of 412 TMT esophageal cancer patients was excellent. The class of agent (taxane or platinum) added to fluoropyrimidine with radiation had no influence on the outcome.
Abstract 16090: Inappropriate Transmissions With Reveal LinQ Wireless Implantable Loop Recorder
Authors: Sandia Iskandar, Madhav Lavu, Moustapha Atoui, Mamatha Vodapally, Ravali Neerumalla, Maruthsakhi Molugu, RajaRajeswari Swarna, Quratulain Javed, Karthik Gangu, Anirudh Gone, Donita Atkins, Sudharani Bommana, Raghuveer Dendi, Rhea Pimentel, Loren Berenbom, Martin Emert, Madhu Reddy, Dhanunjaya Lakkireddy
Journal: Circulation (2016)

Introduction: Reveal LinQ is a novel, wireless implantable monitor which has revolutionized arrhythmia monitoring. There is no data on the rate of inappropriate detections with transmissions and subsequent clinical and work flow impact in real world. Hypothesis: Inappropriate transmissions from implantable loop recorder are common in daily practice. Methods: We retrospectively reviewed all the wireless transmissions of all consecutive patients who underwent a Reveal LINQ implantation at our center. Results: A total of 233 patients were included in the study with a mean age of 60 ±16.5 years. 102 (44%) were males. The primary indications were syncope (37.3%), palpitations (24%) and AF management (18%). Patient’s detections and transmissions were tailored to their indications using a standard, rigorously designed protocol. A total of 3440 CareLink transmissions occurred during the 8 ±4 months of follow up (mean of 15 transmissions per patient) which consisted of routine, symptoms triggered, and device activ...
Renal function after treatment for childhood cancer.
Authors: Daniel M. Green, Liang Zhu, Noel M Delos Santos, John J Bissler, Daniel A. Mulrooney, Kirsten K. Ness, Rohit P. Ojha, Sheri L. Spunt, Fariba Navid, Deo Kumar Srivastava, Andrew M. Davidoff, Leslie L. Robison, Melissa M. Hudson
Journal: Journal of Clinical Oncology (2016)

10571 Background: Childhood cancer survivors (CCS) are exposed to nephrotoxic treatments. We assessed renal function (RF), and factors associated with chronic kidney disease (CKD) in a large cohort of long-term CCS unexposed to abdominal irradiation. Methods: We evaluated 2,314 SJLIFE participants ( > 10 years (yrs) post-diagnosis, age ≥ 18 yrs) measuring serum sodium, potassium, magnesium, urinalysis (hematuria ≥ 5 RBC/hpf; proteinuria ≥ 1+ protein), and estimated glomerular filtration rate (eGFR) using the CKD Epidemiology Collaboration (CKD-EPI) equation. CKD was defined according to the National Kidney Foundation Kidney Disease Outcome Quality Initiative. Logistic regression, adjusting for length of follow-up, was used to estimate odds ratios (ORs) and 95% confidence intervals (CI) for the association between demographic and clinical factors, and CKD. Results: 1110(48%) survivors were female. 1920(83%) were non-Hispanic white. Median age at diagnosis-6.9 yrs (interquartile range [IQR] = 3.2-12.6), median age at RF evaluation-31 yrs (IQR = 25.3-37.0), and median elapsed time from diagnosis to evaluation-23 yrs (IQR = 17.3-29.4). 70(3.0%) were hypokalemic ( < 3.4 mmol/L or taking supplement), 39(1.7%) hypomagnesemic ( < 1.3 meq/dL or taking supplement) and 12(0.5%) hyponatremic ( < 134 mmol/L or taking supplement). Survivors with No CKD or CKD Grades 1-5 were 93.6%, 4.1%, 0.9%, 1.2%, 0.1%, and 0.1%, respectively. In multivariable analyses, non-Hispanic black race (OR = 2.19, 1.43-3.34), history of nephrectomy (OR = 2.74, (1.39- 5.41)), increased body mass index (BMI) (BMI 35-40 vs ≤ 25, OR = 2.36 (1.38-4.05), BMI ≥ 40 vs > 0-25 (OR = 2.15 (1.21-3.82)), history of treatment with ifosfamide (IFOS) (OR = 2.24 (1.23-4.06)), or cis-platinum (DDP) (OR = 1.89 (1.10-3.23)) were associated with CKD Grade 1-5 vs No CKD. age at RF evaluation ≥ 50 yrs vs ≥ 18-30 yrs (OR = 6.72 (1.06-42.79)), history of treatment with IFOS (OR = 7.23 (2.47-21.12)), or DDP (OR = 5.25 (2.14-12.85)) exposure were risk factors for CKD = Grade 3-5 vs No CKD. High-dose cyclophosphamide ( ≥ 1000 mg/m2/course) was not associated with CKD. Conclusions: CKD and abnormalities of electrolyte concentrations are infrequent among CCS. BMI, race/ethnicity, and treatment may be associated with CKD.
Phase 2 study of nivolumab in metastatic leiomyosarcoma of the uterus.
Authors: Suzanne George, Constance M Barysauskas, Sarah Solomon, Kadija Tahlil, Rita Malley, Melissa Hohos, Kathleen Polson, Margaret Loucks, Andrew J. Wagner, Priscilla Merriam, Jeffrey A. Morgan, Scott J. Rodig, F. Stephen Hodi, Geoffrey Shapiro, George D. Demetri
Journal: Journal of Clinical Oncology (2016)

11007 Background: Immune checkpoint inhibition (ICI) with monoclonal antibodies such as nivolumab has induced dramatic results in several types of cancers, although sarcoma subtypes have not been extensively studied. Predictive biomarkers for response, either related to tumor histology and/or immunologic characteristics of the tumor and host remain poorly defined. This trial aimed to assess the impact of PD1-targeted ICI with nivolumab among patients (pts) with metastatic uterine leiomyosarcoma (ULMS) with associated tumor immunoprofiling Methods: Phase II, Simon 2-stage, single arm trial of nivolumab was conducted among pts with metastatic ULMS who received at least one prior systemic chemotherapy. Nivolumab (3 mg/kg IV every 2 weeks) was dosed until disease progression or unacceptable toxicity. Tumor assessment per RECIST 1.1 was performed at baseline and every 12 weeks, with continuous toxicity assessment. Archival tumor samples were assayed by immunohistochemistry (IHC) for PD1, PDL-1 and PDL-2 expression. Results: 12 women were enrolled from May to October 2015 within the first stage and all received study drug. Median age 54.5 (29-73) yrs, median number of prior therapies 3.5 (1-10), 75% of participants had ECOG 0. The median PFS is 1.8 months (95% CI: 0.8 - not defined). No objective responses were observed. Three patients experienced grade 3 or higher toxicities at least possibly related to study drug including: abdominal pain, increased serum amylase and lipase, and fatigue. IHC expression of archival tumor material and analysis of changes in circulating immunophentypes are ongoing. Conclusions: Nivolumab as a single agent failed to demonstrate antitumor activity among ULMS pts without any biomarker selection. The study is currently being amended to explore combination treatment with nivolumab among pts with metastatic ULMS. Clinical trial information: NCT02428192.
The Inhibitory Innate Immune Sensor NLRP12 Maintains a Threshold against Obesity by Regulating Gut Microbiota Homeostasis
Authors: Agnieszka D. Truax, Liang Chen, Jason W. Tam, Ning Cheng, Hao Guo, A. Alicia Koblansky, Wei-Chun Chou, Justin E. Wilson, W. June Brickey, Alex Petrucelli, Rongrong Liu, Daniel E. Cooper, Mark J. Koenigsknecht, Vincent B. Young, Mihai G. Netea, Rinke Stienstra, R. Balfour Sartor, Stephanie A. Montgomery, Rosalind A. Coleman, Jenny P.-Y. Ting
Journal: Cell Host & Microbe (2018)