tbuckley/cabot-search huggingface dataset:
Association of single nucleotide polymorphisms in genes involved in autophagy with overall survival in patients with metastatic colorectal cancer.
Authors: Shinichi Yamauchi, Fotios Loupakis, Satoshi Matsusaka, Wu Zhang, Dongyun Yang, Yan Ning, Sebastian Stintzing, Yu Sunakawa, Stefan Stremitzer, Ana Sebio, Rita Elie El-Khoueiry, Giulia Pasquini, Federica Marmorino, Marta Schirripa, Yoshiya Fujimoto, Masashi Ueno, Nobuyuki Mizunuma, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2014)

e14506 Background: Autophagy is a lysosomal degradation process which is a key for the regulation of the turnover of long-lived or damaged proteins and organelles and which promotes cell survival during nutrient deprivation or other microenvironmental stresses. Recent studies report that it is a critical process in cancer initiation and progression. However, the association between genetic variants of genes involved in autophagy and clinical outcomes in colorectal cancer (CRC) is less well studied. The aim of this project was to examine whether polymorphisms in these genes are associated with outcomes in CRC. Methods: A total of 424 Italian patients (pts) with metastatic CRC (mCRC) treated with FOLFIRI/Bevacizumab as first line (male/female, n=252/172; median age, 62 years; median follow-up time, 2.8 years), and 215 Japanese pts with stage III CRC treated with adjuvant chemotherapy followed by curative surgery (male/female, n=177/176; median age, 65 years; median follow-up time, 4.7 years) were included in this study. Genomic DNA was extracted from the pts’ blood or tissue. Twelve putative functional single nucleotide polymorphisms in eight autophagy-related genes (ULK1, ATG13, FIP200, BECN1, ATG3, ATG5, ATG8, and UVRAG) were analyzed by polymerase chain reaction-based direct sequencing in CRCs. Results: Univariate analysis showed that pts with mCRC with any G (A/G or G/G) allele in rs1129660 (FIP200) had significantly longer overall survival (OS) compared to those with the A/A genotype [median survival A/A 25.4 months, A/G or G/G 31.6months, HR (95% CI) 0.71 (0.55-0.92), P=0.0089]. In multivariate analysis adjusted for baseline characteristics (age, ECOG performance status, primary tumor site, number of metastatic sites, liver involvement, synchronous or metachronous metastases), rs1129660 remained as a significant factor in OS [HR (95% CI) 0.76 (0.58-0.99), P=0.0387]. There was no significant difference in adjuvant pts with stage III with genotypes of rs1129660 in both relapse-free survival and OS (P=0.52, P=0.38, respectively). Conclusions: This study suggests for the first time that the autophagy-related gene polymorphism appeared to be a prognostic marker in pts with mCRC.
Modified isolated lung perfusion technique for allowance of prolonged perfusion without acute lung injury: A preclinical study with doxorubicin.
Authors: Pedro Augusto Reck dos Santos, Jin Sakamoto, Manyin Chen, Virginia Linacre, Chantel Arce, David Hwang, Marc de Perrot, Mingyao Liu, Natasha B. Leighl, Shaf Keshavjee, Thomas K. Waddell, Marcelo Cypel
Journal: Journal of Clinical Oncology (2014)

10597 Background: Isolated lung perfusion (ILP) can enhance the treatment of lung metastases, allowing the localized delivery of drugs to the lungs, without systemic exposure. Previously, short-term ILP (± 30 minutes) resulted in variable efficacy and frequent toxicity. We developed a technique that minimizes perfusion-related injury to the lung and allows an extended perfusion time. Using our strategy, our objective is to demonstrate the feasibility and safety of ILP with doxorubicin (Dox). Methods: In pigs, left pulmonary artery and veins (PVs) were cannulated and clamped. Left lung ILP with a protective mode of ventilation/perfusion was performed for 4h. Dox 75 mg/m2 alone or with ifosfamide (Ifos) 6 g/m2 is a standard regimen currently used systemically for patients with metastatic sarcomas. Based on this, Dox 75mg/m2 (group 1, n=4), 150 mg/m2 (group 2, n=2), 225 mg/m2 (group 3, n=2), and Dox 75mg/m2 + Ifos 6 g/m2(group 4, n=3) were administered at the start of ILP. After 4h ILP, cannulas were removed and blood reperfusion was allowed for more 4h. Lung physiology (Lphys) was assessed with peak airway pressure (Pawp), dynamic compliance (Cdyn), pulmonary vascular resistance (PVR), and PVs oxygenation (P/F ratio). Lung biopsies were obtained before, after ILP and after reperfusion for histological assessment of acute lung injury (ALI). Lung tissue levels of Dox were measured at the end of reperfusion and systemic levels of Dox were analyzed hourly. Results: In groups 1 and 4, Lphys was stable during 4h ILP period and reperfusion, without histologic ALI (p=0.12 and p=0.36). In group 2, P/F ratio dropped at reperfusion, and in group 3, severe ALI happened during ILP (increase of Pawp and PVR, and drop in Cdyn). In groups 1 and 4, mean tissue levels of Dox were 70.3 ug/g, homogeneously distributed in the lung (p=0.12). No Dox was detected systemically during the experiment. Conclusions: ILP with standard doses of chemotherapy (groups 1 and 4) was well tolerated using our ILP strategy for an extended period of time and without measurable ALI. In these groups, comparing to previous large animal studies, we found 2-3 x higher tissue levels of Dox, demonstrating the protective effect of our ILP strategy.
Mutational status of ERBB-2 of an Argentinean population of lung adenocarcinoma patients.
Authors: Vanesa Gaido, Belen Zaffanella, Ruben Salanova, Asuncion Bena, Julio C Calderazzo Pereyra, Yanina Powazniak
Journal: Journal of Clinical Oncology (2014)

e18503 Background: The identification of receptor tyrosine-protein kinase erbB-2 somatic mutations defined a new molecularly classified subgroup of non-small-cell lung cancer (NSCLC). Activating mutations in the tyrosine kinase domain of erbB-2 are mutually exclusive with EGFR mutations and ALK rearrangements. The prevalence, clinicopathologic characteristics, prognostic implications, and molecular heterogeneity of erbB-2 mutated NSCLC are not well established in argentinean patients. The aim of this report is to present the mutational status of erbB-2 of an Argentinean population of NSCLC tumors. Methods: Tumor blocks were obtained from 163 consenting patients of various public and private hospitals. We analyzed the presence of erbB-2 insertion in a cohort of patients without an EGFR mutation and ALK rearrangements from formalin paraffin fixed sections with Polymerase Chain Reaction (PCR) amplification-Sanger sequencing. The median age of the population was 63 years (range, 34-93), being 35% F (females) and 65% males. Results: From a total of 163 patients, 97% (158) were found to be wild type, while the 3% (5) showed erbB-2 insertions: p.Ala775_Gly776insTyrValMetAla (n:3), p.Gly776>ValCys (n:1) and p.Pro780_Tyr781GlySerPro (n:1). The median age of the population that presents an erbB-2 insertion was 62 years (range, 35-85), being 25% F (females) and 75% males. Conclusions: erbB-2 mutations are identified in approximately 2% of NSCLC, in this study we identified 3% of insertion in the analyzed population. Our findings for p.Ala775_Gly776insTyrValMetAla insertion (60%) are associated with published results (76%). Given the high prevalence of lung cancer worldwide and the availability of standard and investigational therapies targeting erbB-2, routine clinical genotyping of NSCLC should include erbB-2 .
Tumor Mutational Burden and Other Immunotherapy Markers in Histiocytic Neoplasms Using Next Generation Sequencing
Authors: Gaurav Goyal, Robert Vassallo, Karen L Rech, Jay H Ryu, Caroline J Davidge-Pitts, W Oliver Tobin, Matthew J Koster, Nabila Nora Bennani, Mithun Vinod Shah, Minetta C Liu, Ronald S. Go
Journal: Blood (2018)
Induction of transforming growth factor-beta 1 (TGF-beta 1), receptor expression and TGF-beta 1 protein production in retinoic acid-treated HL-60 cells: possible TGF-beta 1-mediated autocrine inhibition
Authors: LA Falk, F De Benedetti, N Lohrey, MC Birchenall-Roberts, LW Ellingsworth, CR Faltynek, FW Ruscetti
Journal: Blood (1991)
Mobile applications in oncology: Need for assessing scientific contents more precisely.
Authors: Benoit Brouard, Pascale Bardo, Clément Bonnet, Caroline Even, Jean-Jacques Mazeron, Jean-Charles Soria, Stéphane Vignot
Journal: Journal of Clinical Oncology (2014)

e17611 Background: The emergence of eHealth enables patients (pts) and healthcare professionals to access to new ways of treatment monitoring. Mobile applications (apps) are software programs designed to be used on smartphones, tablets and other mobiles devices. They can be useful for information and optimization of follow up, potentially leading to cost savings. Development and use of healthcare related apps is growing rapidly and the volume of available apps can be confusing for pts and physicians. Moreover, no scientific validation process is required before publication on mobile stores. The purpose of this study is to analyze the profile of mobile apps dedicated to oncology and to estimate whether validation by a health professional is mentioned. Methods: The study was performed using
An estimation model for Oncotype DX recurrence score using routine histopathologic variables.
Authors: Hyunseok Kim, Christopher Umbricht, Peter B. Illei, Maria Cristina Figueroa Magalhaes, Catherine Pesce, Michele Maiko Gage, Charles Mylander, Martin Rosman, Lorraine Tafra, Kala Visvanathan, Leslie Cope, Antonio C. Wolff
Journal: Journal of Clinical Oncology (2014)

559 Background: The gene expression profile assayOncotypeDx (ODX) is frequently used to guide adjuvant chemotherapy decisions for patients with estrogen receptor (ER)-positive, lymph node (LN)-negative breast cancer. We hypothesized that in cases where ODX is being considered, the observed recurrence score (RS) category can be accurately estimated using routinely available, less costly histopathologic variables. Methods: We retrospectively reviewed pathology reports between June 2006 and August 2012 from Johns Hopkins (JH) patients (n=301) with early stage ER-positive, LN-negative breast cancer, for whom ODX was ordered. We developed a linear regression model using routine histopathologic markers (ER and progesterone receptor [PR] expression, HER2 status, tumor grade, and Ki67) to calculate an Estimated Recurrence Score (ERS), and correlated it with the observed ODX RS assay result. This model was internally cross-validated in the JH cohort, and externally validated in a separate 326-patient cohort from three Maryland community settings. Results: In the JH cohort, 244 patients had an observed RS ≤ 25 (80%) and 57 patients had an observed RS above 25 (20%). When the ERS was < 21 (n=200), we accurately classified 95% of them (191) who were found to have a low risk(observed RS ≤ 25). Similarly, 95% of those (18/19) with an ERS > 30 fell into a high risk category with observed RS > 25. An accuracy of 93% was observed in the external validation cohort (Table). Conclusions: We developed a clinical estimator of the ODX RS using cases in which the clinician chose to order ODX RS in routine clinical practice. For more than 80% of patients in the external validation cohort, ERS was estimated to be < 21 or > 30 and in this group, the Hopkins ERS model correctly predicted the observed RS category (≤ 25 or > 25) in 93% of cases. Although further validation of this model is warranted, preliminary evidence supports use of ERS to reliably identify those patients most likely to benefit from including ODX RS results in therapeutic decision-making. JH cohort ODX RS ≤ 25 ODX RS > 25 Total External cohort ODX RS ≤ 25 ODX RS > 25 Total ERS < 21 191 9 200 ERS<21 227 17 244 ERS(21-30) 52 30 82 ERS(21-30) 31 22 53 ERS(> 30) 1 18 19 ERS(>30) 2 27 29 Total 244 57 301 Total 260 66 326
Phase II randomized study of induction FOLFOXIRI plus bevacizumab (bev) followed by maintenance with bev alone or bev plus metronomic chemotherapy (metroCT) in metastatic colorectal cancer (mCRC): The MOMA trial.
Authors: Lisa Salvatore, Fotios Loupakis, Chiara Cremolini, Gianluca Masi, Francesca Bergamo, Antonella Galiano, Vittorina Zagonel, Laura Ferrari, Elena Ongaro, Giovanni Cardellino, Lorenzo Marcucci, Sara Lucchesi, Maria Banzi, Andrea Ciarlo, Emanuela Miraglio, Sara Delfanti, Domenico C. Corsi, Alberto Zaniboni, Giuseppe Tonini, Alfredo Falcone
Journal: Journal of Clinical Oncology (2014)

TPS3664 Background: FOLFOXIRI plus bevacizumab (bev) followed by 5-FU plus bev is an efficacious option for first line tx of metastatic colorectal cancer (mCRC) patients (pts) (TRIBE study). CAIRO-3 trial demonstrated that maintenance with standard doses of capecitabine plus bev provides a significant second progression (PFS2) advantage, as compared to observation alone, although at the cost of some toxicities that limited the rate of reintroduction of CAPOX. Metronomic chemotherapy (metroCT) may represent an alternative and better tolerated strategy for targeting tumor angiogenesis and preclinical evidences show that it may synergize with bev in order to maximize the antiangiogenic effect. On the basis of such premises we are conducting the MOMA study to explore maintenance tx with bev alone or bev plus metroCT following a four-months induction phase with FOLFOXIRI plus bev. Methods: This is a multi-center, phase II randomized study. Pts with unresectable mCRC, untreated for the metastatic disease, are randomized to receive 8 cycles of induction FOLFOXIRI plus bv, followed by bev (7.5 mg/Kg every three weeks) until the evidence of disease progression (PD), or the same induction regimen followed by bev in combination with metronomic capecitabine and oral cyclophosphamide (Cape: 500 mg/tid, CTX: 50 mg/die) continuously, until PD. The primary end-point is first-line PFS. FOLFOXIRI plus bev is reintroduced in pts undergoing PD during maintenance. Secondary end-points are response rate, resection rate, duration of response, time to strategy failure, time to second PD, overall survival, safety profile and the evaluation of potential surrogate markers of bev and metroCT efficacy (including pharmacodynamic, pharmacokinetic, and pharmacogenetic parameters). According to Rubinstein and Korn’s design, estimating a first-line PFS with CT plus bev of 11 months, to detect a hazard ratio of 0.75 in favour of the experimental arm, with a power of 80% and a type-I error of 15%, 173 events are required. From May 2012 to Jan 2014, 117 pts have been so far enrolled in 13 Italian centers and the study is still recruiting. Supported by ARCO Foundation. Clinical trial information: 2011-006332-23.
Gemcitabine plus cisplatin versus vinorelbine plus cisplatin in patients with anthracycline- and taxane-pretreated HER2-negative metastatic breast cancer.
Authors: Huiqiang Zhang, Tao Wang, Li Bian, Jinmei Zhou, Shaohua Zhang, Shikai Wu, Santai Song, Hong Zhang, Zefei Jiang
Journal: Journal of Clinical Oncology (2014)

e12006 Background: The percentage of breast cancer patients exposed to anthracyclines and taxanes in the adjuvant or neoadjuvant chemotherapy is increasing, in metastatic stage using again is limited by drug resistance. In the targeted therapy era, the treatment of HER2-negative metastatic breast cancer (MBC) still need combination chemotherapy.Gemcitabine plus cisplatin and vinorelbine plus cisplatin have been used as salvage therapy. It is necessary to evaluate the efficacy and toxicity of the two treatments. Methods: We conducted this study. 186 patients with metastatic breast cancer pretreated with anthracyclines and taxanes received gemcitabine-cisplatin (GP) (n=76) and ,vinorelbine-cisplatin (NP) (n=110), at The Department of Breast Cancer between 2005.04 and 2013.05. Chemotherapy was given every 3 weeks as follows: vinorelbine (25 mg/m2) or gemcitabine (1000mg/m2) all on day 1–day 8; and cisplatin (75 mg/m2) on day 1 every 3 weeks. Results: The objective response rate (ORR) to GP was 26.3% and to NP 31.8% (P=0.419). Disease stabilized is 55.2% and 54.5% of patients treated with GP and NP respectively. Median progression-free survival (PFS) for the GP and NP groups was 5 months (95% CI: 3.8∼6.2 months) and 6 months (95% CI: 5.0∼6.9 months) (log-rank, P=0.797). We observed no difference of PFS and ORR. The main adverse events of grade 3~4 were hematological toxicities without statistical significance. The incidence rate of vomiting was similar in GP and NP groups. Conclusions: We had observed the similar results in this study, the efficacy of two cisplatin-based regimens had no difference. And toxicity was acceptable. Longer observation and further analysis are warranted. Patient characteristics. GP NP Characteristics Total (N) n (%) P Total No. of patients 186 76 110 Age (years) 45 (25-69) 44 (25-69) 46 (27-63) Hormone receptor status 0.716 0.022 Positive 119 56 (73.7) 63 (57.3) Negative 67 20 (26.3) 47 (42.7) Metastatic sites Visceral 131 56 (73.7) 75 (68.2) Therapy line 0.419 0.066 1-3 99 51 (67.1) 87 (79.1) >3 87 25 (32.9) 23 (20.9) DFS (months) 0.087 ≤12 56 18 (23.7) 39 (35.5) >12 130 58 (76.3) 71 (64.5)
An Internet-based registry for the documentation of neoplastic meningitis.
Authors: Herwig Matthias Strik, Hans Rock
Journal: Journal of Clinical Oncology (2014)

TPS2105^ Background: Cerebrospinal fluid (CSF) and meningeal neoplastic involvement is rare, but severe and often limits patient survival. Only few randomized studies investigated different treatment strategies and achieved no conclusive results. New prospective studies with homogeneous entities are difficult to establish and some initiatives failed recently. An open, multicentric registry may be an adequate alternative for a prospective documentation of a large number of cases of neoplastic meningitis from different primary neoplasms. Methods: To enable an easy multicentric access, an internet-based database was chosen. Secutrial is a professional database which enables pseudonymized registration of clinical courses and meets all requirements for the protection of personal data. Predefined routines allow for a immediate calculation of parameters like survival or toxicity also with newly documented data. The configuration of the database allows for a separate documentation of treatment responses of primary neoplasm, systemic and solid central nervous system metastases as well as of neoplastic meningitis. Also, complications of the disease and toxicity of treatment can be documented. By such, the database is able to discriminate between different causes of clinical deterioration and death.
Metformin use and allogeneic stem cell transplant (ASCT) outcomes.
Authors: Farhad Khimani, Chandler H. Park, Manish Monga, Gerald Hobbs, Sonia Leadmon, Soumit K. Basu
Journal: Journal of Clinical Oncology (2014)

e18001 Background: Metformin is used to treat diabetes mellitus (DM) but its cellular mechanism of action is not completely understood. A potential role of metformin to treat inflammation related disorders has been described. Kim et al have shown that metformin suppresses MHC restricted antigen presentation by inhibiting co stimulatory factors and MHC molecules in APCs. T cell response-regulating activity of metformin in relation to its actions on APCs may have a role in modulating graft vs host disease (GVHD) in ASCT patients. Our study is the first to explore the potential role of metformin in this setting. Methods: At West Virginia University an IRB approved retrospective review of patients who underwent ASCT from 2003-2012 was performed. Patients with DM were stratified based on metformin use. Statistical analysis was performed with JMP V11- SAS. Results: 247 patients underwent ASCT. 40.4% (100) were females and 59.5% (147) were males. Mean age at transplant was 47.8±13.6yrs. 59.5 %(147) were unrelated donor transplants. 47.3%(117) received myeloablative and 43.3%(107) reduced intensity conditioning. GVHD prophylaxes consist of tacrolimus, mycophenolate, cyclosporine, ATG, alemtuzumab and atorvastatin in various combinations. 39.6%(98) developed aGVHD and 40.4%(100) developed chronic cGVHD. 16.2%(40) had diabetes mellitus(DM). 30%(12) were on metformin at the time of transplant and 15%(6) were on metformin therapy at last follow up. Stratified analysis and survival plots were obtained. No significant associations were found between DM and aGVHD(p=0.98), cGVHD(p=0.34) and overall survival(p=0.7). Similar analysis comparing diabetics on metformin vs not on metformin did not show significant associations between metformin use and aGVHD (p=0.43), cGVHD(p= 0.6) or survival (p=0.4) Conclusions: Our study is limited due to smaller sample size and though we did not show any significant associations between metformin use and ASCT outcomes, the role of metformin based on its immunomodulatory and anti tumor mechanism of action, deserves further exploration. Larger transplant registry and animal model studies are required to investigate the potential role of metformin in transplant outcomes including GVHD, disease relapse and diabetes.
Ex-Vivo Stimulation with DC/AML Fusion Vaccine in the Presence of Cytokines Leads to an Activated T Cell Memory Phenotype and Enhanced Cytotoxicity with Potential for Use As an Adoptive Cellular Therapy
Authors: Jessica Liegel, Dina Stroopinsky, Lourdes M. Mendez, Malgorzata McMasters, Haider Ghiasuddin, Maryam Rahimian, Myrna Nahas, Matthew Weinstock, Salvia Jain, Marzia Capelletti, Lina Bisharat, Adam Morin, Shira Orr, Jacalyn Rosenblatt, Donald Kufe, David E. Avigan
Journal: Blood (2018)
A phase I and pharmacokinetic study of a weekly dosing schedule of paclitaxel injection concentrate for nano-dispersion (PICN) in patients with advanced solid tumors.
Authors: Wen Wee Ma, Jennifer Robinson Diamond, Grace K. Dy, Wells A. Messersmith, Yujie Zhao, Lynne A. Bui, Gerald J. Fetterly, Ronald Harning, Henry Raphael Wolfe, Pepi Pencheva, Shravanti Bhowmik, Ganesh Divekar, Narendra B. Lakkad, Ajay J. Khopade, Ann Marie DiRaddo, S. Gail Eckhardt, Alex A. Adjei, Antonio Jimeno
Journal: Journal of Clinical Oncology (2014)

2566 Background: PICN is a novel Cremaphor-free composite of paclitaxel nano-particles stabilized with polymer and lipid using NanotectonTechnology. PICN started development with every-3-week schedule of PICN +/- carboplatin (ASCO 2013; #2557). This study aimed to determine the maximum tolerated dose (MTD) and pharmacokinetic (PK) profile of PICN dosed using a weekly schedule. Methods: Patients (pt) with solid malignancies and ECOG PS 0-1 were eligible, and the dose escalation was conducted per a ‘3+3’ design. PICN was administered i.v. weekly for 3 weeks then1 week rest (28 days per cycle) at planned dose levels 80, 100, 125 and 150 mg/m2. The 125 mg/m2level was intolerable in pts who previously received multiple lines of chemotherapy (Arm A), and the study was amended to continue dose escalation in pts who previously received 2 or less lines of treatment (Arm B). Only standard anti-emetic pre-medications were used. Adverse events (AEs) were graded using CTCAE 4.0 and tumor response by RECIST 1.1 Results: A total of 22 pts were enrolled from 2 US academic centers and 15 evaluable for dose limiting toxicity (DLT). Number of pts at each level were n=3 at 80, n=6 at 100, n=3 at 125 (Arm A) and n=3 at 125 mg/m2 (Arm B). The DLTs observed were: dose delay for > 7 days for Gr1 ANC at 100 mg/m2; Gr3 fatigue and Gr3 weakness at 125 mg/m2 (Arm A). Anti-tumor efficacy was observed in breast (PR, 80 mg/m2), ovarian (SD for > 12 months; 100 mg/m2), and urothelial (PR; 125 mg/m2) cancers. Previous treatments received in the ovarian pt included platinum(P)/paclitaxel, P/docetaxel and P/gemcitabine; and, P/gemcitabine in the urothelial pt. The dose level of 125 mg/m2(Arm B) was tolerable and enrollment to higher dose levels are underway. PK analysis showed dose-proportional increase in total plasma paclitaxel level. Conclusions: When administered on a weekly schedule (3-weeks-on/1-week-off), 100 mg/m2 was the MTD in heavily pretreated pts. 125 mg/m2 was tolerable in pts who received 2 or less previous lines of chemotherapy. Anti-tumor efficacy was observed in breast, ovarian and urothelial cancers. Final PK, toxicity and efficacy data will be reported at the conference. Clinical trial information: NCT01305512.