tbuckley/cabot-search huggingface dataset:
Does blood sugar impact on metastatic non-small cell lung cancer (NSCLC) outcome?
Authors: Mathieu Gravel, Normand Blais, Mustapha Ali Tehfe, Marie Florescu
Journal: Journal of Clinical Oncology (2017)

e20579 Background: Diabetes is a frequent diagnostic (9.3%) in general Western population, and because of its complications, becomes a comorbidity in NSCLC patients that could impact on prognostic. Impact of diabetes on NSCLC prognosis is unknown but the majority of patients fear eating desserts because feeding mostly the NSCLC tumor cells. Methods: Using our SARDO database and hospital files, we retrospectively reviewed 548 patients with metastatic NSCLC diagnosed and treated in our University hospital between 2006 and 2015. Uncontrolled diabetes was established when Hb1Ac &gt; 7% or with more than 2 hospital glycemia over 11 mmol/L. Results: Amongst 418 metastatic NSCLC patients, 294pts (70%) had synchronous metastasis at diagnostic and 117pts (30%) have metachronous metastasis. As expected metachronous metastasis patients had a better survival (mOS 25mo) than synchronous metastasis (mOS 6mo). Then, we divided our patients in 4 subgroups: 1) Patients with diagnosed and uncontrolled diabetes (n = 78); 2) Patients with high glycemia but not previously diabetes diagnostic (n = 19); 3) Patients with controlled diagnosed diabetes (n = 59); 4) Control patients with normal glycemias or HBA1c (n = 262). Some tumor stage and demographic disparities were seen between the 4 groups but we controlled for them. In upfront metastatic NSCLC patients, mOS was 4.0 months for group 1, 4.0 months for group 2, 4.0 months for group 3 and 7.0 months for our control group, not statistically different, which is lower than literature but expected for this unselected population treated before 2015. In metachronous patients, group 1 mOS was 21mo, group 2 was 58mo, group 3 was 30mo and mOS was 23mo for control patients, with no statistically difference between groups. Women had a better mOS 8 mo compared to 4 mo in men (p = 0,003) independently of diabetes or sugar status. Conclusions: This retrospective data is reassuring regarding patients blood glycemia during the metastatic lung cancer treatment. Even in a long term metachronous disease perspective, blood sugar or diabetes diagnostic did not seem to influence the outcome. However, these data should be validated in a prospective study that could acknowledge if blood sugar control could improve lung cancer outcome.
Impact of measuring quality of life in oncology practice: A prospective study.
Authors: Cecilia Castillo, Ana Laura Alfonzo, Natalia Camejo, Andrea Schiavone, Mariana Diaz, Ivanna Camano, Maria Eugenia Camblor, Lucia Beatriz Delgado, Juan Dapueto
Journal: Journal of Clinical Oncology (2017)

e21663 Background: To assess the impact of incorporating systematic quality of life measurements in oncology practice on the quality of care and well-being of patients; to assess physician's level of satisfaction with this instrument and detectable changes in clinical practice Methods: In a prospective study, 67 patients (pts) diagnosed with cancer, undergoing cancer-specific treatments, were randomized into a intervention and control group. In the intervention group , pts had regular completion of touch-screen health-related quality of life (HRQL) questionnaires (European Organization for Research and Treatment of Cancer–Core Quality of Life Questionnaire version 3.0, and Hospital Anxiety and Depression Scale) and feedback of results to physician and then were followed up with a phone call where HRQL was measured by the Functional Assessment of Cancer Therapy–General questionnaire (FACT-G). In the control group, pts were regular followed with a phone call to answer FACT-G questionnaire. Physicians completed a visit-specific questionnaire after each visit of pts from intervention group. Results: 58 pts were included, 36 in the intervention group and 22 in the control group. Median age was 59 years. The results of the patient-reported data were found to be very useful to quite useful by 87.5% of physicians (14/16), and 56.3% of them considered that there was no difference in the length of visits. Completing the HRQL questionnaires on a touch screen was easy to very easy for 97.1% of patients, and 97.1% found that important questions were asked and that they would be willing to complete the questionnaires. FACT-G scores and subscale scores were higher in the intervention group, but differences were not statistically significant (76.44 v 72.60; p 0.388). Conclusions: HRQL assessments had a positive impact on physician-patient communication. It made it possible to learn how cancer and its treatments affected pts not only physically, but also on functional and psychological states and social relationships. They helped us improve therapeutic interventions and specialist referrals, thus achieving positive changes in the well-being and satisfaction of pts.
Tuberous sclerosis complex 2 (TSC2) expression in hepatocellular carcinoma to predict responses to mTOR inhibitor.
Authors: Jinhyun Cho, Ji Yun Lee, Kwai Han Yoo, Cheol Keun Park, Seung Tae Kim, Su Jin Lee, Won Ki Kang, Jeeyun Lee, Ho Yeong Lim
Journal: Journal of Clinical Oncology (2016)

e15628 Background: Hepatocellular carcinoma (HCC) is the third cause of cancer-related deaths and the 16th absolute cause of deaths globally. Mechanistic target of rapamycin (mTOR) is frequently up-regulated in HCC and plays an important role in HCC tumorigenesis. Recent study demonstrated that loss of tuberous sclerosis complex 2 (TSC2), a negative regulator of mTOR signaling, tended to respond better to mTOR inhibitor. We aimed to analysis TSC2 expression status in Asian HCC patients and evaluate the correlation between TSC2 loss and the response of mTOR inhibitor, everolimus. Methods: We retrospectively assessed 36 patients with advanced HCC who had received sorafenib and had available tumor specimens for TSC2 immunohistochemical(IHC) analysis between 2008 and 2014 at single center in Korea. Three patient-derived tumor cells (PDC), which were isolated and cultured from HCC tissue, were analyzed by western blot in terms of TSC2 expression and drug sensitivity to mTOR inhibitor or AKT inhibitor. Results: We identified eleven of 36 patients (30.6%) with low to undetectable levels of TSC2 IHC expression. Hepatitis B virus is most common disease etiology in TSC2 null or low patients (10 of 11 patients, 90.9%). There were no significant difference in progression free survival (PFS) and overall survival with sorafenib treatment based on TSC2 expression status. Among 36 patients, two patients had treated with everolimus after sorafenib failure. One of them whose tumor expressed low level of TSC2 experienced a stable disease with a PFS of 5.8 months, while the other with high level of TSC2 expression experienced rapid progression. PDC models demonstrated that TSC2-null HCC PDC line was significantly sensitive to everolimus or AKT inhibitor as compared with TSC2-high HCC PDC lines. Conclusions: Loss of TSC2 may predict better response to everolimus in HCC patients, but further studies are needed to confirm the predictive role of TSC2 expression for everolimus treatment.
OS1.5 Harnessing soluble LRIG1 for pan-RTK targeting in glioblastoma
Authors: V Neirinckx, A Schuster, A Chevigné, M H H Schmidt, S P Niclou
Journal: Neuro-Oncology (2018)

The role of receptor tyrosine kinases (RTKs) in glioblastoma is widely acknowledged. However, therapies based on RTK targeting have been continuously unsuccessful in GBM patients, highlighting the complexity of RTK signaling and biology. LRIG1 (Leucine-rich Repeats and ImmunoGlobulin domains protein 1) was identified as an endogenous inhibitor of epidermal growth factor receptor (EGFR) and other RTKs, and was confirmed as a tumor suppressor in various cancer types. We previously identified the soluble form of LRIG1 as a potent inhibitor of GBM growth in vivo, irrespective of EGFR status. Here, we aim to shed light on the molecular mechanisms underlying its anti-cancer activity. We used GBM cells overexpressing EGFRvIII, with or without soluble LRIG1 overexpression. In parallel, we generated a recombinant human soluble LRIG1 protein (rh-sLRIG1) by expressing LRIG1 ectodomain in insect cells via baculovirus infection and subsequent His-tag purification. rh-sLRIG1 was applied in the medium of classical GBM cell lines and patient-derived GBM stem-like cells. Applying a variety of cell-based assays, cell proliferation, migration, cell morphology, as well as protein expression and protein-protein interactions were investigated. We confirmed that sLRIG1 efficiently reduced proliferation and invasion capacities of GBM cells, and modulated cytoskeleton proteins and cell shape. Inhibition of cell proliferation by sLRIG1 was independent of EGFR expression levels in GBM cells and interestingly, rh-sLRIG1 treatment was associated with downregulation of AXL, which constitutes a newly-identified regulatory function of LRIG1. We are currently addressing the impact of the LRIG1-AXL signaling axis on GBM invasion and resistance to EGFR inhibition. We identified AXL as a novel LRIG1 target and provide evidence for the potential therapeutic application of recombinant sLRIG1 in the inhibition of growth factor signaling in GBM.
A phase 1 multicenter study evaluating KITE-585, an autologous anti-BCMA CAR T-cell therapy, in patients with relapsed/refractory multiple myeloma.
Authors: Robert F. Cornell, Frederick Lundry Locke, Michael Russell Bishop, Robert Z. Orlowski, Sarah Marie Larson, Ivan Borrello, Sergio Giralt, Shaji Kumar, Ajay K. Nooka, Noopur S. Raje, John M. Rossi, Lisa Thomrongsith, Allen Xue, Zachary Roberts
Journal: Journal of Clinical Oncology (2018)

TPS3103 Background: In the United States there are > 30,000 new cases of multiple myeloma (MM) and an estimated > 12,000 deaths annually (Howlader et al. SEER Cancer Statistics Review. 2017). Despite an increasing number of treatment options, the disease remains incurable. KITE-585, an autologous, fully-human anti-B cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cell therapy, potently and specifically targets MM cells in preclinical studies (Adams et al. AACR. 2017 #2135, #4979). This Phase 1, open-label, multicenter, first-in-human study evaluates the safety and efficacy of KITE-585 in patients (pts) with relapsed/refractory MM (RRMM; NCT03318861). Methods: Planned enrollment is ≤ 64 pts. After leukapheresis and manufacturing, pts undergo lymphodepleting chemotherapy with fludarabine (30 mg/m2/d) and cyclophosphamide (300 mg/m2/d) for 3 d followed by a single infusion of KITE-585. The study follows a standard 3 + 3 cell-dose-escalation design with an option to expand enrollment at doses that have passed dose-limiting toxicity (DLT) criteria. Pts in the first dose cohort will receive 3 × 107 CAR T cells. Pts may receive optional bridging chemotherapy after leukapheresis and before conditioning. The primary endpoint is incidence of adverse events (AEs) defined as DLTs. Secondary endpoints include overall response rate per International Myeloma Working Group criteria, duration of response, progression-free survival, time to next treatment, overall survival, incidence of AEs, and clinically significant changes in laboratory values. Eligible pts (≥ 18 y) must have RRMM (defined as ≥ 3 prior lines of therapy including both a proteasome inhibitor [PI] and an immunomodulatory drug [IMiD] or MM that is refractory to a regimen containing both a PI and an IMiD), an ECOG performance status of ≤ 1, and adequate bone marrow and organ function. BCMA expression is not required for eligibility. Key exclusion criteria include plasma cell leukemia, nonsecretory MM, active infection, a history of central nervous system involvement, active autoimmune disease, or prior allogeneic stem cell transplant. The study opened to accrual in October 2017. Clinical trial information: NCT03318861.
Hypercapnia increases airway smooth muscle contractility via caspase-7–mediated miR-133a–RhoA signaling
Authors: Masahiko Shigemura, Emilia Lecuona, Martín Angulo, Tetsuya Homma, Diego A. Rodríguez, Francisco J. Gonzalez-Gonzalez, Lynn C. Welch, Luciano Amarelle, Seok-Jo Kim, Naftali Kaminski, G. R. Scott Budinger, Julian Solway, Jacob I. Sznajder
Journal: Science Translational Medicine (2018)

The elevation of carbon dioxide (CO2) in tissues and the bloodstream (hypercapnia) occurs in patients with severe lung diseases, including chronic obstructive pulmonary disease (COPD). Whereas hypercapnia has been recognized as a marker of COPD severity, a role for hypercapnia in disease pathogenesis remains unclear. We provide evidence that CO2 acts as a signaling molecule in mouse and human airway smooth muscle cells. High CO2 activated calcium-calpain signaling and consequent smooth muscle cell contraction in mouse airway smooth muscle cells. The signaling was mediated by caspase-7-induced down-regulation of the microRNA-133a (miR-133a) and consequent up-regulation of Ras homolog family member A and myosin light-chain phosphorylation. Exposure of wild-type, but not caspase-7-null, mice to hypercapnia increased airway contraction and resistance. Deletion of the Caspase-7 gene prevented hypercapnia-induced airway contractility, which was restored by lentiviral transfection of a miR-133a antagonist. In a cohort of patients with severe COPD, hypercapnic patients had higher airway resistance, which improved after correction of hypercapnia. Our data suggest a specific molecular mechanism by which the development of hypercapnia may drive COPD pathogenesis and progression.
The 4q25 variant rs13143308T links risk of atrial fibrillation to defective calcium homoeostasis
Authors: Adela Herraiz-Martínez, Anna Llach, Carmen Tarifa, Jorge Gandía, Verónica Jiménez-Sabado, Estefanía Lozano-Velasco, Selma A Serra, Alexander Vallmitjana, Eduardo Vázquez Ruiz de Castroviejo, Raúl Benítez, Amelia Aranega, Christian Muñoz-Guijosa, Diego Franco, Juan Cinca, Leif Hove-Madsen
Journal: Cardiovascular Research (2018)

Single nucleotide polymorphisms on chromosome 4q25 have been associated with risk of atrial fibrillation (AF) but the exiguous knowledge of the mechanistic links between these risk variants and underlying electrophysiological alterations hampers their clinical utility. Here, we tested the hypothesis that 4q25 risk variants cause alterations in the intracellular calcium homoeostasis that predispose to spontaneous electrical activity.Western blotting, confocal calcium imaging, and patch-clamp techniques were used to identify mechanisms linking the 4q25 risk variants rs2200733T and rs13143308T to defects in the calcium homoeostasis in human atrial myocytes. Our findings revealed that the rs13143308T variant was more frequent in patients with AF and that myocytes from carriers of this variant had a significantly higher density of calcium sparks (14.1 ± 4.5 vs. 3.1 ± 1.3 events/min, P = 0.02), frequency of transient inward currents (ITI) (1.33 ± 0.24 vs. 0.26 ± 0.09 events/min, P < 0.001) and incidence of spontaneous membrane depolarizations (1.22 ± 0.26 vs. 0.56 ± 0.17 events/min, P = 0.001) than myocytes from patients with the normal rs13143308G variant. These alterations were linked to higher sarcoplasmic reticulum calcium loading (10.2 ± 1.4 vs. 7.3 ± 0.5 amol/pF, P = 0.01), SERCA2 expression (1.37 ± 0.13 fold, P = 0.03), and RyR2 phosphorylation at ser2808 (0.67 ± 0.08 vs. 0.47 ± 0.03, P = 0.01) but not at ser2814 (0.28 ± 0.14 vs. 0.31 ± 0.14, P = 0.61) in patients carrying the rs13143308T risk variant. Furthermore, the presence of a risk variant or AF independently increased the ITI frequency and the increase in the ITI frequency observed in carriers of the risk variants was exacerbated in those with AF. By contrast, the presence of a risk variant did not affect the amplitude or properties of the L-type calcium current in patients with or without AF.Here, we identify the 4q25 variant rs13143308T as a genetic risk marker for AF, specifically associated with excessive calcium release and spontaneous electrical activity linked to increased SERCA2 expression and RyR2 phosphorylation.
Revised 2017 international consensus on ANCA testing in small vessel vasculitis: support from an external quality assessment
Authors: Sylvia Broeders, Sylvie Goletti, Jean-Paul Tomasi, Carolien Bonroy, René-Louis Humbel, Laurence Lutteri, Sofie Schouwers, Lieve Van Hoovels, Martine Vercammen, Xavier Bossuyt
Journal: Annals of the Rheumatic Diseases (2018)

We read with great interest the multicentre study of Damoiseaux et al 1–3 on the detection of antineutrophil cytoplasmic antibodies (ANCA). ANCAs are important laboratory markers to support the diagnosis of ANCA-associated small vessel vasculitis (AAV), including granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). Traditionally, laboratories screen for ANCA by indirect immunofluorescence (IIF) and IIF positive samples are further evaluated for antibodies to proteinase 3 (PR3) or myeloperoxidase (MPO) by specific immunoassays. Such diagnostic algorithm is based on an international consensus statement on ANCA testing issued in 1999.4 Over the last two decades, the diagnostic performance of immunoassays has significantly improved. The recent multicentre study showed a …
A phase I study of a novel IAP inhibitor APG-1387 in patients with advanced solid tumors.
Authors: Ruihua Xu, Yuhong Li, Jiao Ji, Miaozhen Qiu, Yang Zhang, Wenqin Liu, Xiaohong Tian, Su Li, Hengbang Wang, Fenghua Wang, Dongsheng Zhang, Feng Wang, Zhiqiang Wang, Huiyan Luo, Benyan Zou, De shen Wang, Chao Ren, Ying Jin, Yifan Zhai, Dajun Yang
Journal: Journal of Clinical Oncology (2018)

2593 Background: APG-1387 is a bivalent small molecule Smac mimetic that antagonizes the IAPs. Preclinical studies have shown its dose- and schedule-dependent, strong antitumor activities in multiple human cancer xenograft models. In addition, the preclinical results strongly support the notion that APG-1387 in combination with anti-PD1 antibody would be a very attractive approach for cancer therapy. Methods: Phase I dose-escalation study enrolled 28 patients with advanced solid tumors in China (#CTR20150161). During dose escalation, the patients received APG-1387 (0.3–45 mg) intravenous infusion for 30 minutes once every week for 3 out of 4 weeks in a 28-day cycle until disease progression. Endpoints included safety (primary), pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity assessed every 8 weeks per RECIST v1.1. Results: Till Jan 15, 2018, 28 patients had been treated in 8 cohorts of APG-1387(0.3mg, 0.6mg, 4mg, 7mg, 12mg, 20mg, 30mg, 45mg). Twenty-eight patients received at least 1 cycle of treatment. The MTD was not reached yet. No DLT was observed during Cycle 1 across dose levels. Twenty-five of 28 patients experienced at least 1 TEAE. The most common TEAEs were vomiting, abdominal pain, anemia, cough, headache, AST increased and ventricular arrhythmia. Of these, 4 grade 3/4 clinical TEAEs including blood bilirubin increased, ALT increased, hypokalemia , pain and soft tissue infection were documented across dose levels. A total of 12 definitively or possibly drug-related AE occurred to date. Human PK data of APG-1387 showed a dose proportionality in exposure, elimination appeared to be linear, no significant accumulation was observed in plasma. Preliminary results from the Human Cytokine 30-Ple analyses indicated that IL-12, IP-10 and MCP-1 were significantly increased in the patient plasma after treatment with APG-1387, indicating potential effects of APG-1387 on the host immune responses. Conclusions: APG-1387 was well tolerated and had manageable adverse events.Further evaluation of APG-1387 in combination with immunotherapy agents in patients with advanced solid tumors or hematologic malignancies is recruiting. Clinical trial information: NCT03386526. Clinical trial information: 20150161.
P01.147 Recurrent glioblastoma or therapy-related changes: The diagnostic accuracy of O-(2-[18F]-fluoroethyl)-L-tyrosine PET imaging
Authors: A Bashir, S Jacobsen, T Urup, H Broholm, K Grunnet, S Møller, O Henriksen, V Larsen, J Skjøth-Rasmussen, H Skovgaard Poulsen, I Law
Journal: Neuro-Oncology (2018)

Discrimination between recurrent glioblastoma and therapy-related changes with conventional magnetic resonance imaging (MRI) is challenging. There is increasing evidence for the clinical value of positron emission tomography (PET) with O-(2-18F-fluoroethyl)-L-tyrosine (FET) in addition to MRI in cases of ambiguous findings in the setting of posttreatment care. The diagnostic accuracy, however, varies among the published studies and is influenced by the composition of the population with different glioma subtypes/grades, lack of histological confirmation, and differences in data processing. Herein, we evaluated the diagnostic accuracy of FET PET scans in glioblastoma patients. One hundred thirty-seven consecutive patients who had undergone 150 FET PET were reviewed retrospectively. Inclusion criteria were 1) histologically-proven glioblastoma; 2) previous surgery followed by oncological treatment consisting of standard radiochemotherapy or - if at second recurrence - chemotherapy; 3) unexplained constant or increasing contrast-enhancing (CE) lesions on T1, or non-CE lesions on T2 FLAIR MRI later than 6 months after radiotherapy, where the differentiation between disease recurrence or therapy-related changes was uncertain; 4) FET PET for supplementary evaluation; 5) a histological evaluation following surgery less than 3 months after FET PET, or MRI follow-up. FET PET scans were performed as 20-minute static PET/CT acquisitions and evaluated co-registered to T1 post-contrast MRI with measurement of maximum and mean tumor-to-brain ratios (TBRmax, TBRmean). Receiver operating characteristics (ROC) analysis was used to determine the optimal threshold of FET parameters. The prognostic influence of FET parameters on overall survival (OS) was investigated with the Cox proportional hazards model. The median time interval from radiotherapy until the radiological progression was 13 months. One hundred twenty-six PET scans demonstrated FET uptake of varying intensity. Surgical interventions were performed following 88 PET scans, while 62 PET scans were evaluated by clinical or MRI follow-up, resulting in 131 glioblastoma recurrences and 19 therapy-related changes. ROC analysis yielded the thresholds of 2.0 for TBRmax and 1.8 for TBRmean for differentiation between recurrent disease and therapy-related changes with the best performance of TBRmax with a sensitivity of 96% and a specificity of 100% (p < 0.0001). Using this threshold, 145 of 150 PET scans of glioblastoma recurrence or therapy-related changes were accurately classified. Multivariate survival analysis showed that TBRmax > 2.0 predicted independently a shorter OS in patients, who did not undergo subsequent therapy following PET (p = 0.002). FET PET is a powerful noninvasive tool to distinguish recurrent glioblastoma from therapy-related changes.