tbuckley/cabot-search huggingface dataset:
Outcomes of patients following dose-dense neoadjuvant chemotherapy for muscle-invasive bladder cancer: Implications for organ-sparing strategies.
Authors: Clement Dumont, Helene Gauthier, Pierre Mongiat-Artus, Alexandra Masson-Lecomte, Francois Desgrandchamps, Stephane Culine
Journal: Journal of Clinical Oncology (2019)

426 Background: Locoregional management of muscle-infiltrating bladder cancer (MIBC) after neoadjuvant chemotherapy (NAC) is controversial, because of both the morbidity of radical cystectomy (RC). Bladder preservation may be feasible after complete tumor response. Methods: This single-center retrospective study included 120 MIBC patients (stages ypT2-4aN0-3M0) treated between 2011 and 2017 with up to 6 cycles of neoadjuvant dose-dense Methotrexate, Vinblastin, Doxorubicin and Cisplatin (DD-MVAC). The primary outcome was relapse-free survival (RFS) depending on pathological findings on RC specimens, classified as either pathological complete response (pCR: ypT0N0/x), residual organ-confined disease (yOCD: ypTa/is/1/2N0/x), residual non-organ-confined disease (yNOCD: ypT≥3Nany or ypTanyN1-3). Secondary objectives included the rate of pCR in RC patients, the rate of ypT0 in the intention-to-treat population, and RFS in ypT0 patients according to locoregional management. Results: After a median number of 5 cycles of NAC, RC was performed in 75% of the patients, concurrent radiochemotherapy (CRC) in 11% and cystoscopic surveillance (CS) in 8%. In the intention-to-treat population, the ypT0 rate was 47%. Among 90 patients who underwent RC, 49% achieved pCR, 16% had yOCD and 34% yNOCD. Median follow-up in RC patients alive at last follow-up was 40 months. Three-year RFS was 86% in RC patients with pCR, 69% in patients with yOCD and 21% in patients with yNOCD (p &lt; 0.0001). Outcomes were similar between ypT0 patients treated with either RC or CRC/CS (3-year RFS: 81% vs 100%, p = 0.20). Limitations to this study included its restrospective design and the lower number of patients treated with CRC/CS. Conclusions: Patients reaching ypT0 after dose-dense NAC show improved prognosis regardless of locoregional treatment. Patients with yOCD are frequently cured by RC, as opposed to patients with yNOCD. Prospective trials are needed to compare upfront cystectomy and bladder-sparing management in patients with both pCR or yNOCD.
Predictive value of hypercholesterolemia on progression free survival in patients treated with everolimus for renal cell carcinoma.
Authors: Armelle Vinceneux, Aude Flechon, Helen Jane Boyle, Helene Vegas, Claude Linassier, Nawale Hajjaji
Journal: Journal of Clinical Oncology (2015)

e15598 Background: The mammalian target of rapamycin (mTOR) signalling pathway regulates major cellular fonctions including metabolism. Everolimus, a mTor inhibitor, is an effective treatment for metastatic renal cell carcinoma (RCC). Hypercholesterolemia and hypertriglyceridemia are well known side effets of everolimus which are reported in 70% of patients, and are supposed to be a surrogate markers for efficacy. We investigated the prognostic value of increased lipid serum levels. Methods: We retrospectively studied patients with RCC who received everolimus for > 1 month from 2006 to 2014 in two centers. Cholesterol levels at baseline and at 1 month were determined. Progression-free-survival (PFS) and overall survival (OS) were evaluated using the Log rank test and Cox proportional hazards model. Sex, ECOG status, lines of treatment, visceral metastasis, time from diagnosis to treatment < 1 year were studied. Results: 135 patients were analysed, 99 men (73.3%) and 36 women with a median age of 64 years [24-87]. 110 patients (81.5%) had clear cell carcinoma with a median of one prior treatment [0-4]. Median PFS was 7.5 months [IC95 6.1-8.9] and median OS was 14.9 months [IC95 13.2-16.6]. 55 patients (41%) had grade 0 hypercholesterolemia and 80 (59%) grade ≥1. Only 3 patients had grade 3/4. Median PFS of patients experiencing grade ≥ 1 hypercholesterolemia was statistically higher 8.2 months IC95[6.7-9.7] versus 6.1 months IC95[4.6-7.6] in grade 0 patients (p = 0.033). OS was also significatively better with a median of 17.2 months IC95[13-21.4] in patients with grade ≥ 1 hypercholesterolemia versus 9 months IC95[5.9-13.2] in grade 0 patients (p = 0.002). Blood cholesterol level value at one month or triglycerides serum levels were not significantly associated with PFS. In multivariate analysis, only time from diagnosis to treatment < 1 year (p = 0.003), visceral metastasis (p = 0.05), number of prior lines (p = 0.045) were associated with better PFS, Cholesterol grade was not correlated (p = 0.29) with PFS (p = 0.29) nor OS (p = 0.08). Conclusions: ≥ grade 1 cholesterol level increase was a potential predictor for everolimus efficacy in renal cell carcinoma in our retrospective series.
FLT3-ITD Activation Mediates Resistance to the BCL-2 Selective Antagonist, Venetoclax, in FLT3-ITD Mutant AML Models
Authors: Raghuveer Singh Mali, Elisabeth A. Lasater, Kelly Doyle, Ritu Malla, Erwin Boghaert, Andrew Souers, Joel D. Leverson, Deepak Sampath
Journal: Blood (2017)
PEAX: Men with metastatic castrate-resistant prostate cancer (mCRPC) treated with either sipuleucel-T (SIP-T), enzalutamide (ENZA) or abiraterone acetate (ABI) undergoing cardiopulmonary exercise testing (CPET).
Authors: Michael Roger Harrison, Michel Khouri, Andrew J. Armstrong, Tian Zhang, Megan Ann McNamara, Monika Anand, Ellen Bratt, Hillary Hood, Brian Coyne, Yuan Wu, Patrick Healy, Daniel J. George
Journal: Journal of Clinical Oncology (2019)

281 Background: Both ENZA and ABI are associated with significant toxicity to the cardiovascular-musculoskeletal system and physical side effects. However whether they cause a decline in cardiorespiratory fitness (CRF), as conventional ADT does, has not been studied. We hypothesized that men treated with ENZA or ABI would have a significant decline in CRF, whereas those treated with SIP-T would not. Methods: Men starting standard of care (SOC) ENZA or ABI for asymptomatic or minimally symptomatic mCRPC were treated per institutional standards. SIP-T (SOC) is the control arm. Primary endpoint is change in VO 2 peak from baseline to week 21 by CPET. Secondary endpoints include measurement of functional status by patient reported outcomes (FACT-P, FACIT-Fatigue) and physician reported outcomes (ECOG PS, AEs). Results: In this single-site, prospective, parallel group, observational study, 28 pts completed the baseline and week 21 CPET and secondary assessments. Median age was 68 years; 86% were white. Two-thirds of pts had ECOG PS 0; the rest had PS 1. 93% were nonsmokers. Intention to treat analyses for mean 21-week change from baseline with a 95% confidence interval (CI) for each assessment by arm are presented in the Table. Conclusions: Unexpectedly, there was great heterogeneity in 21-week ΔVO 2 peak within each therapy group. Reasons for heterogeneity will be explored and correlated with baseline variables, clinical status, and questionnaire data. A low percentage of patients exercised regularly. Larger trials of exercise training interventions in this setting are warranted. Clinical trial information: NCT02353715. [Table: see text]
Co-ordination of care at commencement of chemotherapy: How well do we communicate with PCPs?
Authors: Javier Torres, Ilana Hournung, Sally Greenberg
Journal: Journal of Clinical Oncology (2015)

e17552 Background: Oncology patients develop symptoms due to disease and treatment. Knowledge of chemotherapy toxicity and its management remains the domain of oncologists. However majority of cancer patients receive chemotherapy in ambulatory setting, and Primary Care Practitioners (PCPs) may be consulted/ required to assess and manage toxicity. Adequate communication between Medical Oncology Teams and PCPs is vital and details of current practice is unknown. Methods: A retrospective audit of medical charts for 50 consecutive new patients receiving IV chemo/ biological targeted therapy from July 1, 2013 at 3 University-affiliated oncology departments in Victoria, Australia (suburban and rural) were conducted simultaneously. Details of timing, frequency, and quality of information communicated with PCPs were analysed. Results: 150 charts were analyzed. 132 (88%) had evidence of written communication with PCP. 52 (35%) patients were over 70 year old. The table summarizes details of communication. Conclusions: A multisite (rural and metropolitan) comprehensive review of current practice regarding communication with oncology and PCP at commencement of chemotherapy has highlighted deficiencies including details of potentially serious AE, indicators for urgent review and contact details from the hospital/oncology services. We are currently piloting an intervention to improve coordination of care for patients commencing chemotherapy. Information provided to PCP Number (%) Total 132 Details of treatment type 116(88%) Intent of treatment (curative vs palliative) 110 (84%) Planned timing of treatment 80 (61%) Potential adverse events (AE) 46 (35%) Advice on management of AE 11 (8%) Indicators for urgent review 7 (5%) Process for contacting hospitals/oncologist 13 (10%) Psycho-social issues mentioned 45 (34%)
Abstract P284: The Chemotherapeutic Agent Docetaxel Disrupts Mitochondrial Energetics in 3D Human Bioengineered Myobundles
Authors: Maria J Torres Alcalde, Xu Zang, Dorothy H Slentz, Timothy R Koves, George A Truskey, Deborah M Muoio
Journal: Circulation (2019)

Taxanes (i.e. docetaxel, (TAX)) comprise the first line-treatment for breast cancer (BC), mostly in combination with anthracyclines like doxorubicin (DOX). The efficacy of these drugs as antineoplastic agents has helped to boost 10-year survival rates to &gt; 90%, leading to a fast-growing population of over 3 million BC survivors in the US. However, epidemiological evidence shows that the highly abrasive nature of these therapies can give rise to a vicious cycle of metabolic decline and physical inactivity that compromises quality of life and increases risk of numerous musculoskeletal and cardio-metabolic disorders including arthritis, sarcopenic obesity, cardiovascular disease and type 2 diabetes. Major side effects of TAX include peripheral neuropathy, arthralgia, myalgia and muscle weakness. Taxanes act primarily by stabilizing microtubules (MTs), which causes cell cycle arrest. Importantly, MT dynamics can also impact mitochondrial function. For example, the MT protein unit, tubulin, can bind to the outer mitochondrial protein channel, VDAC, and thereby affect ATP transport to the cytosol. Herein, we sought to test the hypothesis that TAX exacerbates DOX-induced mitochondrial dysfunction, which is thought to underlie anthracyclines’ cardiotoxicity. To this end, we leveraged a newly developed 3-D bioengineered model of human muscle organoids (myobundles), derived from primary human skeletal muscle progenitor cells (HSkM), to study mechanisms of TAX-induced myotoxicity and its interactions with DOX. Preliminary findings in primary HSkM cells exposed to 3 daily x 3 h treatments with TAX (1 - 100 nM) +/- 10 nM DOX caused a robust ~10-fold acetylation of a-tubulin at lysine 40 (AcK40), reflecting marked stabilization of MTs. TAX treatment decreased basal and ATP-linked respiration (JO 2 ) up to 30 % (p&lt;0.05), in a dose-dependent manner. However, maximal uncoupled JO 2 (+FCCP) remained unchanged, suggesting TAX disrupts mitochondrial thermodynamics and energy transfer, rather than maximal oxidative phosphorylation capacity. Exposure of 3D myobundles to a TAX+/-DOX regimen that mimicked human pharmacokinetics post-infusion led to a 30-fold increase (p&lt;0.005) in AcK40 a-tubulin. TAX alone induced a biphasic JO 2 response to ADP (KM ADP 2- and 4-fold higher, p&lt;0.05), but when combined with DOX there was a 50 % loss in maximal JO 2 (p&lt;0.005) with no changes in KM ADP . We hypothesize that the TAX-driven stabilization of MTs leads to detrimental MT-mitochondria interactions that disrupt ATP/ADP transfer between cellular compartments, exacerbating DOX toxicity and ultimately impairing muscle function. The present findings provide novel insights into the mechanisms of TAX-induced myotoxicities, which is of paramount importance for developing therapeutic strategies to improve cardiovascular health and quality of life of long-term breast cancer survivors.
Nanoparticle incorporating Toll-like receptor 4 inhibitor attenuates myocardial ischaemia–reperfusion injury by inhibiting monocyte-mediated inflammation in mice
Authors: Masaki Fujiwara, Tetsuya Matoba, Jun-Ichiro Koga, Arihide Okahara, Daiki Funamoto, Kaku Nakano, Hiroyuki Tsutsui, Kensuke Egashira
Journal: Cardiovascular Research (2019)

Myocardial ischaemia-reperfusion (IR) injury hampers the therapeutic effect of revascularization in patients with acute myocardial infarction (AMI). Innate immunity for damage-associated protein patterns promotes the process of IR injury; however, the blockade of Toll-like receptor 4 (TLR4) in myocardial IR injury has not been translated into clinical practice. Therefore, we aimed to examine whether the nanoparticle-mediated administration of TAK-242, a chemical inhibitor of TLR4, attenuates myocardial IR injury in a clinically feasible protocol in a mouse model.We have prepared poly-(lactic-co-glycolic acid) nanoparticles containing TAK-242 (TAK-242-NP). TAK-242-NP significantly enhanced the drug delivery to monocytes/macrophages in the spleen, blood, and the heart in mice. Intravenous administration of TAK-242-NP (containing 1.0 or 3.0 mg/kg TAK-242) at the time of reperfusion decreased the infarct size, but the TAK-242 solution did not even when administered at a dosage of 10.0 mg/kg. TAK-242-NP inhibited the recruitment of Ly-6Chigh monocytes to the heart, which was accompanied by decreased circulating HMGB1, and NF-κB activation and cytokine expressions in the heart. TAK-242-NP did not decrease the infarct size further in TLR4-deficient mice, confirming the TLR4-specific mechanism in the effects of TAK-242-NP. Furthermore, TAK-242-NP did not decrease the infarct size further in CCR2-deficient mice, suggesting that monocyte/macrophage-mediated inflammation is the primary therapeutic target of TAK-242-NP.The nanoparticle-mediated delivery of TAK-242-NP represent a novel and clinical feasible strategy in patients undergone coronary revascularization for AMI by regulating TLR4-dependent monocytes/macrophages-mediated inflammation.
Predictors of attrition in the treatment of metastatic colorectal cancer (MCRC).
Authors: Arvin Bahrabadi, Jenny Ruan, Gillian Gresham, Winson Y. Cheung
Journal: Journal of Clinical Oncology (2015)

e17734 Background: The treatment landscape for many cancers has evolved significantly with the introduction of novel and more efficacious agents. However, the positive impact of these new therapies on outcomes may be limited by patient attrition if individuals are not exposed to later lines of treatment. Using a population-based cohort of MCRC, our aims were to characterize rates of attrition and determine factors associated with failure to receive each line of treatment. Methods: Medical records of patients who were diagnosed with MCRC from 2008 to 2009 and referred to any 1 of the 5 regional cancer centers in British Columbia were merged with systemic therapy data from the provincial pharmacy database. We classified patients into mutually exclusive treatment categories: a) receipt of all available lines of MCRC treatments; b) attrition directly attributable to disease, such as cancer progression or death; and c) attrition secondary to other clinical factors, including toxicities. Multivariate logistic regression models with all-cause attrition as the main outcome were constructed to identify predictors, while adjusting for potential confounders. Results: We identified 302 eligible MCRC patients with complete records: median age was 65 years, 55% were men, 40% were White, 53% were ECOG 0/1, and 41% and 59% were never and ever smokers, respectively. In the entire cohort, only 60 (19%) patients received all lines of MCRC therapies. While worsening disease and death represented the most common cause (40%), other frequent causes of attrition included severe toxicities from prior or ongoing therapies (22%), patient preference (10%), decline in functional status (12%), and presence of significant comorbidities. In multivariate analyses, never smokers (p = 0.01) and individuals with baseline ECOG 2+ (p = 0.01) were significantly more likely to experience treatment attrition. Conclusions: Treatment attrition is a prevalent problem in MCRC and can hinder the benefit of treatment algorithms that rely on a temporal sequence of effective therapies. Some causes of attrition are potentially modifiable and may reflect opportunities for patients to maximize exposure to all lines of therapies.
Outcome, costs and dollar value of docetaxel and abiraterone in prostate cancer.
Authors: Helmy M. Guirgis
Journal: Journal of Clinical Oncology (2019)

155 Background: Questions have emerged on the role of diet, cost and value of Abiraterone (Abi) in prostate cancer. Abi improved the quality of life (QoL), in contrast to docetaxel (Doc) used &gt; 6 cycles. We analyzed the data of 5 major clinical studies. Our objective was to weigh outcome, costs and dollar value of Abi and Doc in prostate cancer. Methods: Hazard ratios (HR) and company-posted prices were quoted. In hormone sensitive (HS), Doc costs x 6 cycles and Abi x 18-24 months were compared. Tests, follow-up and adverse events treatment costs (AEsTC) were computed separately. The probability of survival (PoS) was calculated as (1.0-HR) and dollar value as cost/PoS. Results: Doc costs x 6 cycles were $27,408 and AEsTC $1,450. In HS, at HR of 0.61 (Sweeney, 2015) and 0.73 (updated CHAARTED), Doc dollar value was $70,277 and $101,511 respectively. Abi costs x 2-years were $250,704, AEsTC $2,010, HR 0.73 (STAMPEDE) and value $928,533. In high risk HS (LATTITUDE), HR was 0.62 and value $659,747. At 18 months, Abi costs were $188,028. At an average HR of 0.73, value was $696,400. In comparison, in castrate-resistant (CR) chemo-naïve patients, Doc costs x 12 cycles were $54,816, AEsTC $4,840, HR 0.76 (Tannock, 2004) and value $228,400. Abi costs x one-year were $125,352 and AEsTC $1,050, HR 0.80 (COU-AA-302) and value $626,760. Conclusions: In HS, the results tend to suggest superior dollar value of Doc over Abi. In CR, the negative impact of Doc on QoL would undermine its dollar value.
The relationship between autophagy and the immune system and its applications for tumor immunotherapy
Authors: Guan-Min Jiang, Yuan Tan, Hao Wang, Liang Peng, Hong-Tao Chen, Xiao-Jun Meng, Ling-Ling Li, Yan Liu, Wen-Fang Li, Hong Shan
Journal: Molecular Cancer (2019)

Autophagy is a genetically well-controlled cellular process that is tightly controlled by a set of core genes, including the family of autophagy-related genes (ATG). Autophagy is a "double-edged sword" in tumors. It can promote or suppress tumor development, which depends on the cell and tissue types and the stages of tumor. At present, tumor immunotherapy is a promising treatment strategy against tumors. Recent studies have shown that autophagy significantly controls immune responses by modulating the functions of immune cells and the production of cytokines. Conversely, some cytokines and immune cells have a great effect on the function of autophagy. Therapies aiming at autophagy to enhance the immune responses and anti-tumor effects of immunotherapy have become the prospective strategy, with enhanced antigen presentation and higher sensitivity to CTLs. However, the induction of autophagy may also benefit tumor cells escape from immune surveillance and result in intrinsic resistance against anti-tumor immunotherapy. Increasing studies have proven the optimal use of either ATG inducers or inhibitors can restrain tumor growth and progression by enhancing anti-tumor immune responses and overcoming the anti-tumor immune resistance in combination with several immunotherapeutic strategies, indicating that induction or inhibition of autophagy might show us a prospective therapeutic strategy when combined with immunotherapy. In this article, the possible mechanisms of autophagy regulating immune system, and the potential applications of autophagy in tumor immunotherapy will be discussed.
Transcranial direct current stimulation enhances theory of mind in Parkinson’s disease patients with mild cognitive impairment: a randomized, double-blind, sham-controlled study
Authors: Mauro Adenzato, Rosa Manenti, Ivan Enrici, Elena Gobbi, Michela Brambilla, Antonella Alberici, Maria Sofia Cotelli, Alessandro Padovani, Barbara Borroni, Maria Cotelli
Journal: Translational Neurodegeneration (2019)

Parkinson's Disease (PD) with mild cognitive impairment (MCI) (PD-MCI) represents one of the most dreaded complications for patients with PD and is associated with a higher risk of developing dementia. Although transcranial direct current stimulation (tDCS) has been demonstrated to improve motor and non-motor symptoms in PD, to date, no study has investigated the effects of tDCS on Theory of Mind (ToM), i.e., the ability to understand and predict other people's behaviours, in PD-MCI.In this randomized, double-blind, sham-controlled study, we applied active tDCS over the medial frontal cortex (MFC) to modulate ToM performance in twenty patients with PD-MCI. Twenty matched healthy controls (HC) were also enrolled and were asked to perform the ToM task without receiving tDCS.In the patients with PD-MCI, i) ToM performance was worse than that in the HC, ii) ToM abilities were poorer in those with fronto-executive difficulties, and iii) tDCS over the MFC led to significant shortening of latency for ToM tasks.We show for the first time that active tDCS over the MFC enhances ToM in patients with PD-MCI, and suggest that non-invasive brain stimulation could be used to ameliorate ToM deficits observed in these patients.
OA02.01 Efficacy and Safety of Entrectinib in Locally Advanced or Metastatic ROS1 Fusion-Positive Non-Small Cell Lung Cancer (NSCLC)
Authors: R. Doebele, M. Ahn, S. Siena, A. Drilon, M. Krebs, C. Lin, F. De Braud, T. John, D. Tan, T. Seto, R. Dziadziuszko, H. Arkenau, F. Barlesi, C. Rolfo, J. Wolf, E. Chow-Maneval, P. Multani, N. Cui, T. Riehl, B.C. Cho
Journal: Journal of Thoracic Oncology (2018)
Plasma Cell Disorders in Patients with Age-Related Transthyretin (ATTRwt) Amyloidosis
Authors: M Hasib Sidiqi, Shaji K. Kumar, Surendra Dasari, Ellen D. McPhail, Francis K. Buadi, Rahma Warsame, Martha Q. Lacy, David Dingli, Wilson I Gonsalves, Prashant Kapoor, Taxiarchis Kourelis, Nelson Leung, Eli Muchtar, John A. Lust, Robert A. Kyle, S. Vincent Rajkumar, Morie A. Gertz, Angela Dispenzieri
Journal: Blood (2018)
Cell Derived Microparticles (MP) in Different Phases of Thrombotic Thrombocytopenic Purpura (TTP) and Effect of Exchange Plasmapheresis (EPP) on Their Profiles
Authors: Robert A Ali, Yonette Paul, Robert Forestal McCauley, Miriam Yaniz, Martha Q. Gonzalez, Lawrence L. Horstman, Wenche Jy, Yeon S. Ahn
Journal: Blood (2018)