tbuckley/cabot-search huggingface dataset:
Pre-clinical proof of principle of pharmacologically rational non-cytotoxic epigenetic-immunotherapy to treat lung cancer.
Authors: Kai Kang, Sagar Rakshit, Kurt Alex Schalper, Nathan A. Pennell, David S. Schrump, Yogen Saunthararajah, Vamsidhar Velcheti
Journal: Journal of Clinical Oncology (2016)

e14073 Background: Immune checkpoint inhibitor therapy (anti-PD1) has been approved to treat non-small cell lung cancer (NSCLC) in 2nd-line. Unfortunately, the response rate is only ~20%. Contributing to limited response is use by cancer cells of altered epigenetics to suppress neo-antigen expression and avoid immune-recognition. Epigenetic repression is mediated by DNA methyltransferase (DNMT1) that can be depleted by the cytidine analogue decitabine (Dec). Depleting DNMT1 with Dec is appealing also because it can cytoreduce NSLC directly by p53-independent, non-cytotoxic mechanisms that spare immune-effectors (increased epithelial-differentiation/p27 and decreased MYC). Unfortunately, pharmacologic limitations of Dec undermine translation: plasma t½ is < 15 minutes and solid tissue distribution/oral bioavailability is negligible, because of rapid inactivation by cytidine deaminase (CDA). Thus, we evaluated the combination of a CDA-inhibitor tetrahydrouridine (THU) with Dec in a syngeneic murine model of lung cancer. Methods: C57 mice were inoculated with KLN 205 (Lewis lung ca) cells in the flank. Mice (n = 12) randomized into 3 groups were treated with PBS, Dec (1mg/kg SC 2X/wk), or THU-Dec (10/1 mg/kg SC 2X/wk). At sacrifice, tumor samples were examined by weight, flow cytometry, H&E staining, Western blot (WB) and QRT-PCR. Results: Tumor weights significantly decreased with Dec and especially THU-Dec (means 3.1,1.3 and 0.6 g in PBS, Dec and THU-Dec groups respectively, p = 0.04). THU-Dec treatment significantly increased expression of immunotherapy antigenic target MAGE-A1 (1, 1.46 and 2.06 relative expression, QRT-PCR, p < 0.01). There was striking increase in CD8+ lymphocytes in tumor with THU-Dec (0.78) compared to Dec (0.22) or PBS (0.21)(%nucleated cells, flow cytometry, p = 0.01). Tumor DNMT1 and MYC protein decreased most prominently with THU-Dec, concurrent with substantial increase in p27/CDKN1B (WB). Conclusions: Addition of THU to Dec, to address pharmacologic limitations of Dec alone, improved immune-priming and induced p53-independent cell cycle exits in NSCLC in vivo. THU-Dec combination with nivolumab will be tested in clinical trial NCT02664181.
Inhibition of ATR in Combination with Nucleoside Analogues Eradicates Acute Myeloid Leukaemia in an Orthotopic Murine Xenograft Model
Authors: Sarah E Fordham, Helen J Blair, Claire J Elstob, Deepali Pal, Nicola Curtin, Paul Milne, Matthew Collin, Graham H Jackson, Helen J Marr, Olaf Heidenreich, Ruth Plummer, John Pollard, Tobias F. Menne, Gail L Jones, James M Allan
Journal: Blood (2016)
Evaluation of chemotherapy-induced nausea and vomiting (CINV) events and associated resource utilization for CINV in patients(pts) treated with highly emetogenic chemotherapy (HEC) and carboplatin (Carbo) and palonosetron (palo)-based anti-emetic regimens.
Authors: Robert B. Geller, Stanley M. Marks, Nashat Y. Gabrail, Lincy S. Lal, Urvi Mujumdar, Lee Steven Schwartzberg
Journal: Journal of Clinical Oncology (2016)

e21649 Background: This study assesses CINV events and resource utilization for CINV in pts treated with HEC and carbo with palo-based CINV regimens in a payer database. Methods: The cohort was randomly selected from Inovalon’s MORE2 Research Edition claims database of longitudinal data from US health plans. Pts received 1st line, either HEC (anthracycline plus cyclophosphamide (AC) or cisplatin) or carbo from 1/1/2010 to 3/30/2015. CINV event frequency (CINV events per ICD-9 for nausea and vomiting and CPT codes for hydration) and CINV-related resources were analyzed for the first four cycles. The use of rescue medications could not accurately be determined for this analysis. HEC pts received triple-drug anti-emetics (IV palo/NK-1/dex) and carbo pts received palo-based therapy. Results: HEC consisted of 1,299 pts receiving 4,503 cycles, 97% female, 96% with breast cancer, mean age 53.0 years. 96% pts treated AC, and 4% cisplatin. CINV triple regimens included IV NK-1 in 92% pts. CINV events were documented in 666 (51%) HEC pts, and 1781 (40%) cycles. CINV-related ER events were seen in 7% pts and 2% cycles. CINV-related hospitalizations were seen in 2% pts and 1% cycles. The length of stay averaged 2.82 days per pt (SD: 22.50). Carbo cohort consisted of 288 pts, total 774 cycles, 67% female, 31% ovarian cancer, with mean age 61.8 yrs. CINV regimens included 52% palo/dex (PD); 22% palo/dex/IV NK-1 (PDN); and 10% palo(P). CINV events for the P cohort were 31%, 48% for the PD group and 41% for the PDN group (NS). CINV-related ER events were in 6% pts and 3% cycles and CINV-related hospitalizations were in 4% pts and 1% cycles. Conclusions: For HEC, NCCN and ASCO recommend triple anti-emetic therapy; however CINV event frequencies for HEC pts with palo-based triple drugs are concerning. Carbo is considered moderately emetogenic chemotherapy. Despite the recommendations for either 2 drugs (5-HT3/dex) or 3 drugs, Carbo pts are still receiving monotherapy, and evidence is disappointing for all levels of prophylaxis, indicating need for better anti-emetic regimens.
Clinical characteristics associated with metastatic NSCLC harboring ALK rearrangements in Chinese patients.
Authors: Guangming Tian, Xinliang Zhao, Jun Nie, Ling Dai, Weiheng Hu, Jie Zhang, Xiaoling Chen, Jindi Han, Xiangjuan Ma, Di Wu, Sen Han, Yang Wang, Jieran Long, Jian Fang
Journal: Journal of Clinical Oncology (2016)

e20628 Background: In NSCLC patients harboring specific genetic changes, such as ALK rearrangement and EGFR mutations, targeted therapies have exhibited considerable therapeutic potential. As the genetic susceptibilities of tumors vary between populations, we conducted a retrospective study to investigate the populational difference between EGFR, ALK positive groups. Methods: Data were collected on patients with NSCLC who were admitted Peking University Cancer Hospital, during Nov 2011 - Dec 2015. The clinical data collected for each patient included age, gender, smoking history, histological tumor type, disease stage at the time of treatment, and results of detecting the ALK fusion gene and EGFR mutations. Results: 595 patients admitted to our institution with a pathological diagnosis of NSCLC, among which 357 were at the stage of IIIb - IV and tested for ALK translocation and EGFR mutation. A total of 37 patients (10.4%) were found to be ALK fusion gene-positive; 19 of the 223 male patients were positive (8.5%). Pearson Chi-square analysis of the gender data showed no statistical significance (χ2 = 2.174; P = 0.140). The median age of the ALK-positive patients was 50 (range, 21-70 years), and it was 58 for ALK negative (range from 15 to 81). Analyzed by the ANOVA test, this difference in age of occurrence was statistically significant (F = 23.81; P < 0.001). 25 of the ALK positive patients (67.6%) were non/light smokers. In ALK negative patients, the number of smokers and non/light smokers were 172 and 148. The difference of postive rate between two smoking groups was significant (χ2 = 5.21; P = 0.014) . EGFR muation were found in 118 patients (33.1%). Among the mutation group, median age of the patients was 57, 53 were male (44.9%), and 36 were smokers (30.5%). In the patients with ALK or EGFR muations, the distribution of age were different (F = 15.47, P < 0.001), and the distributions of smoking condition (χ2= 0, P = 0.823), gander (χ2= 0.25, P = 0.493) were not different. Conclusions: By perfoming the current study, we identified that the ALK translocation were more likely to be found in young and non/light smoking NSCLC patients in China, and the patients harboring ALK translocation were younger than those with EGFR mutations.
Combined effect of obesity and comorbidity on toxicity of adjuvant chemotherapy for breast cancer (BC).
Authors: Ana Fernandez Sanchez, Alejandra Ivars Rubio, Pilar de la Morena, Elisa Garcia-Garre, Elena García-Martínez, Maria Angeles Vicente, Edgar Urrego, Enrique Gonzalez-Billalabeitia, Francisco Ayala
Journal: Journal of Clinical Oncology (2016)

1036 Background: Obesity is not clearly associated with toxicity of chemotherapy, and ASCO’s guidelines recommend full-weight based dosing. Appropriate consideration of comorbidity is also especially advised in obese patients. However, only limited data exist regarding the combined effects of obesity and comorbidity on toxicity of adjuvant chemotherapy for BC. Methods: We prospectively recruited patients with early BC receiving anthracyclines and/or taxanes-based adjuvant/neoadjuvant chemotherapy between 2012 and 2014 in a single center. Body mass index (BMI) and Charlson comorbidity index (CCI) were calculated before treatment. Acute toxicity of chemotherapy was scored according to NCI-CTCAE criteria. Dose modifications (delays or reductions), treatment discontinuation, toxicity-related hospital admissions and episodes of febrile neutropenia were registered. Comparisons of toxicity between groups were performed with Chi2 test. T-test was used for quantitative data. Results: A total of 217consecutive BC patients were included; median age: 50 (25-80); ECOG: 0, 79.2%, and 1, 20.4%; median BMI: 27.1 (14.9-27.2), with 60 obese patients (BMI > 30). Median CCI was 3.2 (0.6-7), with 28.6% showing CCI > 4. Chemotherapy regimens: FEC/AC, 17.1%; FEC/AC-wPaclitaxel, 24.9%; TAC, 34.6%; AC-Docetaxel, 19.8%; TC or wPaclitaxel, 3.7%. Obesity and comorbidity (CCI > 4) were significantly associated neither with grade 3-4 toxicity (hematologic or non-hematologic) nor with hospital admissions or dose modifications. The group of patients (12.5%) with both obesity and CCI > 4 had more frequent dose delays (40.7% vs 21.2%; p = 0.02) and treatment discontinuations (18.5% vs 6%; p = 0.038). Grade 2-3 neurotoxicity (44.4% vs 11.2%; p < 0.001) and thromboembolic events (18.5% vs 4.2%; p = 0.004) were also especially frequent in this group. Conclusions: Although obesity and comorbidity do not have a clear independent impact on BC adjuvant chemotherapy toxicity, a group of women with combined obesity and comorbidity (CCI > 4) show a higher risk of toxicities potentially leading to functional impairment. A higher frequency of chemotherapy delays and interruptions in this group might also compromise its efficacy.
Predictors of neck reoperation (NRO) in 35,538 Californians with differentiated thyroid cancer.
Authors: Theresa H.M. Keegan, Ann Brunson, Alison Semrad, Gregory Farwell, Thomas John Semrad
Journal: Journal of Clinical Oncology (2016)

6093 Background: Our prior work documented variation in initial management patterns and survival for subgroups of patients (pts) with differentiated thyroid cancer (DTC) in California. Therefore, we hypothesized that patient, tumor, and hospital facility characteristics at initial thyroid surgery would predict NRO, an event associated with increased mortality. Methods: Using the California Cancer Registry linked to hospital records from the California Office of Statewide Health Planning and Development (OSHPD), we identified pts with initial thyroid surgery for papillary (PTC) or follicular thyroid cancer during 1991-2012. We defined NRO from OSHPD as a neck node surgery 91 days to 5 years from the initial thyroid surgery. In pts at least 5-years from initial total/near total thyroidectomy (1991-2008; N = 24,473), we performed multivariable logistic regression to identify demographic, tumor, and hospital characteristics associated with NRO. Results are presented as adjusted odds ratios (OR) and 95% confidence intervals (CI). Results: NRO was identified in 1,741 (4.9%) pts, in decreasing rates with time from diagnosis. Post-thyroidectomy radioiodine (RAI) was administered to 75.8% of those with NRO; whereas 56.6% of those without NRO received RAI. In multivariable models, NRO was associated with younger age (15-34: OR 1.41, CI 1.17-1.69; versus ≥ 55 years) male sex (OR 1.29, CI 1.13-1.47), and Asian/Pacific Islander (API: OR 1.19, CI 1.02-1.39) or Hispanic (OR 1.26, CI 1.07-1.49) race/ethnicity. Tumor characteristics were strongly associated with increased odds of NRO, including PTC (OR 1.59, 1.19-2.12), increasing T stage, extrathyroidal extension (OR 2.21, CI 1.94-2.52), and N stage (OR 3.42, CI 3.00-3.93). The odds of NRO increased from 1991-2008 and were higher in those initially treated with RAI. Hospital thyroid cancer surgery volume was not associated with NRO. Conclusions: NRO is becoming increasingly frequent, with tumor characteristics, younger age, API or Hispanic race/ethnicity, and male sex but not hospital volume associated with NRO. This study identifies subgroups of pts at higher risk for NRO and subsequent mortality due to persistent or more biologically aggressive disease.
Design and methodology of the COACH study: a multicenter randomised Coordinating study evaluating Outcomes of Advising and Counselling in Heart failure: a multicenter randomised Coordinating study evaluating Outcomes of Advising and Counselling in Heart failure
Authors: Trijntje (Tiny) Jaarsma, M.H.L. van der Wal, Jochem Hogenhuis, I. Lesman, Marie Louise Luttik, N.J.G.M. Veeger, D.J. Van Veldhuisen, Mla Luttik
Journal: European Journal of Heart Failure (2004)
Predictors of long-term smoking cessation in patients with COPD: results from a randomised controlled trial
Authors: Eva A.M. van Eerd, Onno C.P. van Schayck, Geertjan Wesseling, Daniel Kotz
Journal: European Respiratory Journal (2017)

In Western countries, cigarette smoking is the most important risk factor for the development of chronic obstructive pulmonary disease (COPD) [1]. Besides, patients with COPD who continue to smoke have a higher prevalence of respiratory symptoms, more accelerated decline in lung function and higher mortality rate than nonsmokers [1]. Therefore, smoking cessation is the single most effective way to prevent COPD and reduce its progression [1]. The Cochrane Review on smoking cessation interventions for people with COPD shows that evidence-based smoking cessation interventions exist, but the chances of successful quitting are still relatively low in this group of smokers [2]. The effectiveness of such interventions can depend on the characteristics of the patient [3]. Knowing which patient characteristics are associated with successful quitting might facilitate the design of more effective smoking cessation interventions for patients with COPD. Attention to patients' health perceptions and social environment is important for successful quitting <http://ow.ly/cPn630b3z1r>
PH-métrie oesophagienne sans fil: aspect technique chez 22 patients
Authors: JC Letard, M Happinono, P Georget
Journal: Endoscopy (2006)

Le nouveau dispositif de capsule télémétrique («Bravo», Medtronic, Paris) réfère à une technique de PH-métrie oesophagienne très récemment validée moyennant une adaptation de la valeur seuil discriminant pour le diagnostic de RGO acide à 3,1%. Il existe cependant peu d'études témoignant des aspects techniques de ce nouveau dispositif médical.
Phase 1b study of aldoxorubicin + gemcitabine in metastatic solid tumors.
Authors: Kamalesh Kumar Sankhala, Shanta Chawla, Victoria S. Chua, Jasgit C. Sachdev, Erkut Hasan Borazanci, Kelli Sung, Monica M. Mita, Alain C. Mita, Brenda Laabs, Scott Wieland, Daniel J. Levitt, Sant P. Chawla
Journal: Journal of Clinical Oncology (2016)

2523 Background: Aldoxorubicin (A) is a novel prodrug of doxorubicin (D) that binds covalently to albumin, accumulates in tumors and releases D under acidic conditions. It has demonstrated significant efficacy against soft tissue sarcomas in a phase 2b study versus D. Gemcitabine (G), when combined with various chemotherapies (albumin/paclitaxel nanoparticles, liposomal D) has demonstrated efficacy in patients with pancreatic, ovarian and lung cancers. It was hypothesized that A+G might possess synergistic activity against solid tumors. This study was designed to identifiy the major toxicities of this combination and establish its MTD. Methods: Adults who had relapsed or not responded to prior chemotherapies were eligible. Initial cohorts were (i) A 170 mg/m2+ G 900 mg/m2 ); (ii) A 250 mg/m2 + G 900 mg/m2; and (iii) A 200 mg/m2 + G 750 mg/m2. A was administered on Day 1 and G on Days 1 and 8 of each 21 day cycle. Safety was monitored continuously, cardiac function was assessed every 2 months by echocardiogram, and tumor response every 6 weeks by CT scan. The MTD was defined as the dose level where < 3 of 6 subjects experienced a dose limiting toxicity. Results: 22 subjects have been entered with a median age of 60 years (20-71) with 5 males and 17 females entered. Tumor types included 10 sarcomas (soft tissue and skeletal) and 4 ovarian cancers. 2 PRs (uterine leiomyosarcoma and ovarian cancer), 11 SDs and 2 PDs as best responses were documented. Major grades 3 and 4 adverse events included neutropenia in 7 subjects, thrombocytopenia in 13 subjects and anemia in 8 subjects. Febrile neutropenia occurred in 2 subjects and pneumoinia in 1 subject. 11 SAEs have been observed that include Klebsiella infection, sepsis, fever, increased anemia, small bowel obstruction, stomatitis, pneumonia, pleural effusion, thrombocytopenia, febrile neutropenia and UTI. No subjects exhibited an LVEF < 50% of normal at any evaluation; no treatment-related deaths occurred. The study is completing dosing of A 200 mg/m2 + G 500 mg/m2, considered the phase 2 doses. Conclusions: A + G can be administered safely at a recommended dose of 200 mg/m2 of A on Day 1 and 500 mg/m2 of G on Days 1 and 8 of a 21 day cycle. Thrombocytopenia is the major grade 3 or 4 AE that limits dosing. Clinical trial information: NCT02235688.
For Patients with Sustained MR4-MR4.5, Less Frequent Molecular Monitoring during the First 12 Months after Tyrosine Kinase Inhibitor Cessation Is Viable for Timely Detection of Loss of MMR
Authors: Naranie Shanmuganathan, Susan Branford, Jodi Braley, Devendra Hiwase, David T. Yeung, David M. Ross, Timothy P. Hughes
Journal: Blood (2016)
Glucose Catabolism in Liver Tumors Induced by c-MYC Can Be Sustained by Various PKM1/PKM2 Ratios and Pyruvate Kinase Activities
Authors: Andrés Méndez-Lucas, Xiaolei Li, Junjie Hu, Li Che, Xinhua Song, Jiaoyuan Jia, Jingxiao Wang, Chencheng Xie, Paul C. Driscoll, Darjus F. Tschaharganeh, Diego F. Calvisi, Mariia Yuneva, Xin Chen
Journal: Cancer Research (2017)

Abstract Different pyruvate kinase isoforms are expressed in a tissue-specific manner, with pyruvate kinase M2 (PKM2) suggested to be the predominant isoform in proliferating cells and cancer cells. Because of differential regulation of enzymatic activities, PKM2, but not PKM1, has been thought to favor cell proliferation. However, the role of PKM2 in tumorigenesis has been recently challenged. Here we report that increased glucose catabolism through glycolysis and increased pyruvate kinase activity in c-MYC-driven liver tumors are associated with increased expression of both PKM1 and PKM2 isoforms and decreased expression of the liver-specific isoform of pyruvate kinase, PKL. Depletion of PKM2 at the time of c-MYC overexpression in murine livers did not affect c-MYC–induced tumorigenesis and resulted in liver tumor formation with decreased pyruvate kinase activity and decreased catabolism of glucose into alanine and the Krebs cycle. An increased PKM1/PKM2 ratio by ectopic PKM1 expression further decreased glucose flux into serine biosynthesis and increased flux into lactate and the Krebs cycle, resulting in reduced total levels of serine. However, these changes also did not affect c-MYC–induced liver tumor development. These results suggest that increased expression of PKM2 is not required to support c-MYC–induced tumorigenesis in the liver and that various PKM1/PKM2 ratios and pyruvate kinase activities can sustain glucose catabolism required for this process. Cancer Res; 77(16); 4355–64. ©2017 AACR.
Doxorubicin plus evofosfamide versus doxorubicin alone in locally advanced, unresectable or metastatic soft-tissue sarcoma (TH CR-406/SARC021): an international, multicentre, open-label, randomised phase 3 trial
Authors: William D Tap, Zsuzsanna Papai, Brian A Van Tine, Steven Attia, Kristen N Ganjoo, Robin L Jones, Scott Schuetze, Damon Reed, Sant P Chawla, Richard F Riedel, Anders Krarup-Hansen, Maud Toulmonde, Isabelle Ray-Coquard, Peter Hohenberger, Giovanni Grignani, Lee D Cranmer, Scott Okuno, Mark Agulnik, William Read, Christopher W Ryan, Thierry Alcindor, Xavier F Garcia del Muro, G Thomas Budd, Hussein Tawbi, Tillman Pearce, Stew Kroll, Denise K Reinke, Patrick Schöffski
Journal: The Lancet Oncology (2017)
Efficacy and prognosis of adjuvant trastuzumab therapy in T1 HER2-overexpressing early primary breast cancer: A single-center restrospective analysis.
Authors: SUN Gang, Yang LE, LI FAN Zhou, MA Bin, MA BIN Lin
Journal: Journal of Clinical Oncology (2016)

e12080 Background: Although the prognosis of patients with small、HER2-over expressing breast cancer is generally good, it is controversial how to make personalize adjuvant trastuzumab therapy strategies. We compared efficacy and prognosis of adjuvant therapy with or without trastuzumab in T1 HER2-overexpressing breast cancer patients. Methods: A single-center, restrospective analysis was conducted using data from 218 patients classified as having T1 HER2-over expressing breast cancer and treated in the affiliated cancer hospital of Xinjiang medical university from June 2009 to December 2014. We defined 2 cohorts based on tumor size:T1ab( ≤ 1.0cm) and T1c(1.0~2.0cm). Subground analysis based on Factors including status of axillary lymph nodes, LVI(Lymphatic vessel infiltration), HR(hormonal receptor) and adjuvant trasuzumab therapy. The primary outcomes were RFS (recurrence-free survival) and OS (overall survival). Univariate and multivariate analysis were used to determine associations with potential risk factors on RFS and OS. Results: In total, there were 73.4% patients in T1c，which differed significantly from T1ab（26.6%）with the following characteristics: advanced TNM stage, higher histological grade and Ki-67 expression, frequently occurred vascular invasion and axillary lymph node metastasis, easier to accept adjuvant trasuzumab therapy. Of these, 47 cases (21.56%) received adjuvant chemotherapy with trasuzumab, and 6 patients were in T1ab, 41 patients were in T1c. With median follow-up of 42 months, 3-RFS was 100% and 88.2% for patients treated with/withnot adjuvant trasuzumab therapy，respectively. There were 16 recurrence events and 2 deaths which all occurred in the absence of adjuvant trasuzumab therapy group. Univariate Cox regression showed that trasuzumab, LVI and axillary lymph node metastasis were associated with better RFS, but neighter of these factors was significant in the multivariate Cox regression. Conclusions: Adjuvant trasuzumab therapy was associated with a significantly reduced risk of recurrence in T1 HER2-overexpressing breast cancer, and was more beneficial in HR negitive and/or LVI+ subgroup.