tbuckley/cabot-search huggingface dataset:
Tolerability of raltitrexed when it is used in monotherapy and in combination with oxaliplatin (TOMOX) as advanced colorectal cancer treatment in normal clinical practice.
Authors: Manuel Constenla, Jorge Aparicio, M.Auxiliadora Gomez, Cristina Gravalos Castro, Miriam Lopez-Gomez, Jose Luis Manzano, Maria Dolores Pineda, Juana Maria Cano, Isabel Sevilla, Jose Maria Vieitez de Prado, Antonio Viudez, Luis Lopez-Gomez, Juan Carlos Camara, Guillermo Lopez-Vivanco, Fuensanta Aranda, Paloma Isabel Palomo-Jimenez, Ana Barbon, Jaime Feliu Batlle
Journal: Journal of Clinical Oncology (2013)

e14648 Background: Fluoropyrimidines (FP) based chemotherapy continue to be the cornerstone of advanced colorectal cancer (aCRC) treatment. However, FP cannot be appropriated for some patients (FP intolerance, DPD deficit, history of ischemic heart disease, etc). In these cases, Raltitrexed (R) in monotherapy or in combination with oxaliplatin (TOMOX) could be an effective alternative to FP. Methods: We assessed in an observational retrospective study the patient profile and the tolerability of R when it is used in monotherapy or in combination with oxaliplatin (TOMOX) as aCRC treatment in the normal clinical practice setting. Data from patients treated between 2010 and 2012 were collected from 15 Spanish hospitals. Reason for choosing R as aCRC treatment, patient and disease characteristics, previous treatment and toxicity were gathered. Results: The data from 144 patients treated with R (72) and TOMOX (72) were included in the analysis (64% male, median age 68 years, ECOG PS 0/1/2 in 18%/62%/19%). The main reasons to choose R were: similar efficacy and safety to other treatments (19%), convenience of the administration (18%), cardiovascular disease (17%), resistance to FP (14%), previous FP inacceptable toxicity (10%) and old age (11%). R was mainly used as third or successive treatment line (64%) while TOMOX was equally used in all treatment lines (37%, 28% and 35%). The mean number of cycles was 5 (1-15). The dose was reduced in 26% of the patients and the treatment administration was delayed in 53%. The creatinine clearance was only calculated in 20% of the cycles. The most common grade 3-4 toxicities were neutropenia (8%), anaemia (5%), nausea (2%), vomiting (1%), diarrhoea (7%) and hepatic toxicity (4%). There were 2 toxic deaths (1.4%). Conclusions: R and TOMOX represent a safe alternative for aCRC patients in which FP are not appropriated. Despite R good tolerance in normal clinical practice, it is a must to assess creatinine clearance before each cycle.
Eros is a novel transmembrane protein that controls the phagocyte respiratory burst and is essential for innate immunity
Authors: David C. Thomas, Simon Clare, John M. Sowerby, Mercedes Pardo, Jatinder K. Juss, David A. Goulding, Louise van der Weyden, Daniel Storisteanu, Ananth Prakash, Marion Espéli, Shaun Flint, James C. Lee, Kim Hoenderdos, Leanne Kane, Katherine Harcourt, Subhankar Mukhopadhyay, Yagnesh Umrania, Robin Antrobus, James A. Nathan, David J. Adams, Alex Bateman, Jyoti S. Choudhary, Paul A. Lyons, Alison M. Condliffe, Edwin R. Chilvers, Gordon Dougan, Kenneth G.C. Smith
Journal: The Journal of Experimental Medicine (2017)

The phagocyte respiratory burst is crucial for innate immunity. The transfer of electrons to oxygen is mediated by a membrane-bound heterodimer, comprising gp91phox and p22phox subunits. Deficiency of either subunit leads to severe immunodeficiency. We describe Eros (essential for reactive oxygen species), a protein encoded by the previously undefined mouse gene bc017643, and show that it is essential for host defense via the phagocyte NAPDH oxidase. Eros is required for expression of the NADPH oxidase components, gp91phox and p22phox. Consequently, Eros-deficient mice quickly succumb to infection. Eros also contributes to the formation of neutrophil extracellular traps (NETS) and impacts on the immune response to melanoma metastases. Eros is an ortholog of the plant protein Ycf4, which is necessary for expression of proteins of the photosynthetic photosystem 1 complex, itself also an NADPH oxio-reductase. We thus describe the key role of the previously uncharacterized protein Eros in host defense.
Abstract A31: eIF4F links translation to energy stress response in cancer
Authors: Laura Hulea, Marie Cargnello, Simon-Pierre Gravel, Young Im, Shannon McLaughlan, Yunhua Zhao, Jenna Ching, Yutian Cai, Ola Larsson, Michael Ohh, Josie Ursini-Siegel, Julie St-Pierre, Michael Pollak, Ivan Topisirovic
Journal: Cancer Research (2017)

Abstract Protein synthesis is one of the most energy consuming process in the cell. Oncogenic kinases (e.g. EGFR/HER2, BCR/ABL and BRAF) play a central role in reprogramming translation and energy metabolism in neoplasia, whereby cancer cells must provide sufficient ATP to support increased levels of protein synthesis required for neoplastic growth. The downstream mechanisms that link translational machinery and energy homeostasis in cancer, however, remain largely unknown. We found that widely used anti-diabetics (biguanides) abrogate adaptations to EGFR/HER2 inhibitor-induced energetic stress, which results in synergistic anti-neoplastic effects both in vitro and in vivo. In turn, breast cancer cells in which 4E-BP1/2 expression was abrogated by CRISPR were partially resistant to the combination of EGFR/HER2 inhibitors and biguanides. This was paralleled by the inability of the drugs to inhibit the eIF4F complex assembly and translation of mRNAs encoding important metabolic regulators including those involved in serine biogenesis (PHGDH, PSAT1) and one carbon metabolism (MTHFD1L). Comparable results were observed when BRAF and BCR/ABL inhibitors were combined with biguanides, which suggests that translational regulation of metabolic genes via the mTORC1/4E-BE/eIF4E pathway plays a major role in energy stress response in cancer. Together our findings demonstrate that the eIF4F complex is an important mediator of metabolic adaptation in response to the combination of biguanides and clinically-used kinase inhibitors and suggest that the efficiency of such anti-cancer strategies are dependent on the integrity of the translation initiation machinery. Citation Format: Laura Hulea, Marie Cargnello, Simon-Pierre Gravel, Young Im, Shannon McLaughlan, Yunhua Zhao, Jenna Ching, Yutian Cai, Ola Larsson, Michael Ohh, Josie Ursini-Siegel, Julie St-Pierre, Michael Pollak, Ivan Topisirovic. eIF4F links translation to energy stress response in cancer. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr A31.
Racial and ethnic disparities among young patients with gastric cancer.
Authors: Ibrahim Nassour, Ali Mokdad, Madiha Khan, John C. Mansour, Adam Charles Yopp, Rebecca M Minter, Patricio Polanco, Mathew M Augustine, Michael A. Choti, Sam C. Wang, Matthew Porembka
Journal: Journal of Clinical Oncology (2017)

25 Background: Although up to 15% of patients with gastric cancer present at young age, the characteristics of these patients are not well described. We sought to determine if there are different clinical and pathologic characteristics associated with race and ethnicity in young gastric cancer patients. Methods: We identified all gastric adenocarcinoma patients who were younger than 45 years in the National Cancer Data Base between 2006 and 2013. We analyzed patient, tumor, and treatment-related factors as well as overall survival using standard statistical methods. Results: 5,869 patients were identified with 40.6% being Non-Hispanic Whites (NHW), 27.7% Hispanics (HS), 16.9% African Americans (AA), and 9.0% Asians (AS). HS patients presented at a younger age compared to the other groups (p &lt; 0.01). HS presented most often with metastatic disease (59.2%) followed by AA (50.2%), NHW (49.6%), and AS (49.8%; p &lt; 0.01). NHW presented more often with tumors in the cardia (45.7%) compared to AA (12.7%), HS (12.5%), and AS (9.6%, p &lt; 0.01). HS (28.4%) and AA (14.2%) were more likely to be uninsured compared to AS (12.0%) and NHW (7.1%; p &lt; 0.01). AA (60.5%) and HS (49.1%) were more likely to have below median income compared to NHW (35.8%) and AS (24.2%, p &lt; 0.01). AS had better overall outcome, with median overall survival of 22.7 months compared to 15.2 months for NHW, 14.0 months for HS and 13.6 months for AA (p &lt; 0.01). Independent variables associated with favorable survival included being AS or HS, cardia tumor, treatment at an academic center, higher income, and low Charlson Comorbidity Index. Conclusions: There is racial/ethnic variability in disease presentation, treatment delivery, and outcomes in young gastric cancer patients. Further studies are warranted to determine whether these variations are due to disparity in health care access and/or inherent difference in biology.
Comparison of medical oncologists' approach to non-small cell lung cancer patients compared with breast cancer.
Authors: Shivani C. Patel, Heidi A Hamann, Prapti Arvind Patel, Joan H. Schiller
Journal: Journal of Clinical Oncology (2013)

6601 Background: Despite recent advances in the management of non-small cell lung cancer (NSCLC), treatment disparities persist. Evidence suggests that primary care physicians (PCPs) have less awareness of the benefit of adjuvant chemotherapy for lung cancer compared to breast cancer. They may also be less inclined to refer advanced stage NSCLC patients for further treatment and closely manage pain. This study’s goal was to refine this focus on treatment comparisons with a survey of medical oncologists. Methods: Online case scenarios were provided to medical oncologists identified through participating state and institutional organizations. Medical oncologists were randomized to receive one of four scenarios on the basis of cancer type (lung v. breast) and smoking status (30 pack/year smoker v. lifetime non-smoker). Medical oncologists’ treatment approaches were compared. Results: Two hundred seventy-one medical oncologists participated in the survey. The majority were male (71%) with a mean of 16.5 practice years; 28% worked within an academic setting. There were no significant differences in adjuvant chemotherapy use for early stage patients (98.3% lung v. 98.4% breast) or second-line chemotherapy for progressive disease (93.7% lung v. 95.9% breast). Almost all medical oncologists reported that they would offer an available clinical trial to a patient who had progressive disease but a good performance status (PS), regardless of cancer type. However, more medical oncologists were “very likely” to start third line chemotherapy for advanced stage breast cancer (33.6%) compared to advanced stage NSCLC (18.4%; p=.01). Conclusions: Medical oncologists report consistent first- and second-line adjuvant treatment patterns for NSCLC compared to breast cancer. However, they are less likely to consider third-line chemotherapy for advanced stage NSCLC, suggesting subtle treatment disparities. This study was supported by an award by GlaxoSmithKline (GSK) and by a grant from the National Lung Cancer Partnership and its North Carolina affiliate.
Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex.
Authors: Kendall D. Carey, Mathew C. Franklin, Abraham M. De Vos, Mark S. Sliwkowski
Journal: Cancer Research (2004)

2475  The inappropriate activation or overexpression of members of the epidermal growth factor family of receptors (ErbB) is associated with the development and severity of many cancers, particularly breast cancer, where overexpression correlates strongly with a more aggressive disease and poor survival rate. Antibodies against ErbB1 and ErbB2 have proven to be effective therapeutically for the treatment of several cancers. The anti-ErbB2 monoclonal antibody trastuzumab (Herceptin) is indicated for patients whose metastatic tumors overexpress ErbB2. In contrast, pertuzumab (Omnitarg) is currently being evaluated in Phase II clinical trials in patients whose breast, non-small cell lung, prostate, or oviarian tumors do not contain the amplified ErbB2 gene. In order to provide a molecular basis for understanding the mechanism of action of pertuzumab, we have determined the X-ray crystal structure at 3.2 angstrom resolution of the soluble extracellular domain of ErbB2 in a complex with the antigen binding fragment of pertuzumab. Pertuzumab binds near the center of the second cysteine-rich domain, a region of the ErbB receptor family that is highly conserved and previously shown to be necessary for ErbB1 receptor homodimerization. Alanine substitutions of ErbB2 residues that contact pertuzumab, while effecting pertuzumab binding affinity for ErbB2, do not detectably influence ErbB2 heterodimerization with ErbB3, indicating a steric mechanism for the ability of pertuzumab to inhibit ErbB2 receptor dimerization and signaling. Additional mutagenesis of this region of ErbB2 suggests that residues that have previously been shown to be required for ErbB1 homodimerization are dispensable for ErbB2 heterodimerization. These findings suggest that certain aspects of ErbB2 heterodimerization with other ErbB family members may be fundamentally different than ErbB1 homodimerization. In conclusion, Pertuzumab inhibits the ability of ErbB2 to function as a co-receptor in ligand-mediated ErbB signaling by sterically blocking a binding pocket necessary for receptor dimerization.
Phase I study of MEDI0639 in patients with advanced solid tumors.
Authors: Gerald Steven Falchook, Afshin Dowlati, Aung Naing, Matthew Joseph Gribbin, David William Jenkins, Linda L Chang, Dominic W Lai, David C. Smith
Journal: Journal of Clinical Oncology (2015)

3024 Background: MEDI0639 is an investigational monoclonal antibody that selectively binds to Delta-like ligand 4 (DLL4) and blocks its ability to bind to and activate signaling through the Notch receptors, potentially inhibiting tumor growth by multiple mechanisms. Methods: This study (NCT01577745) included patients (pts) with advanced solid tumors who had ECOG performance status 0–1 and adequate organ function. MEDI0639 10–200 mg was given every 21 days with a 3+3 dose-escalation design. Primary objective was to determine maximum tolerated dose (MTD) and safety. Other objectives included pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity (IG), and antitumor activity. Results: As of Jan 7, 2015, 20 pts were enrolled (median age 61y [range 40–83y]; median number of prior therapies: 5). The most common tumors were colorectal (n = 5), small cell lung cancer (n = 4), and melanoma (n = 4). No dose-limiting toxicities were identified through the 150 mg dose; the 200 mg dose is currently being evaluated. Of 20 safety-evaluable pts, the most common treatment-related adverse events (trAEs) were increased aspartate aminotransferase, increased brain natriuretic peptide (BNP), and fatigue (n = 3 each). Grade 3/4 trAEs were observed in 3 pts (acute myocardial infarction [AMI], atrial fibrillation [AF], ventricular dilatation [VD], and ventricular hypokinesia [VH] in 1 pt; lower abdominal pain in 1 pt, and hypertension in 1 pt), and 3 pts had serious trAEs (AMI, AF, VD, VH in 1 pt; diplopia in 1 pt; hemorrhagic diarrhea (HD), chest discomfort, and back pain in 1 pt). One pt discontinued due to a trAE (AMI). The trAEs of interest consistent with the mechanism of action included AMI (n = 1), hypertension (n = 2), increased BNP (n = 3), and HD (n = 1). No treatment-related deaths occurred. Of 19 efficacy evaluable pts, partial response was observed in 1 pt with melanoma; 7 pts had stable disease lasting ≥ 12 weeks. Preliminary PK was nonlinear at doses < 100 mg, and PD showed target engagement at the doses tested. IG has not been observed. Conclusions: MEDI0639 150 mg did not exceed the MTD. Enrollment at the 200 mg dose level is ongoing. The safety profile is consistent with the mechanism of action and appears to be manageable. Preliminary evidence of antitumor activity was observed. Clinical trial information: NCT01577745.
Phase II study of the AKT inhibitor MK-2206 plus erlotinib (E) in patients (pts) with advanced non-small cell lung cancer (NSCLC) who progressed on prior erlotinib: A California Cancer Consortium Phase II trial (NCI 8698).
Authors: Primo Lara, Jeff Longmate, Philip C. Mack, Karen Kelly, Mark A. Socinski, Ravi Salgia, Barbara Jennifer Gitlitz, Tianhong Li, Marianna Koczywas, Karen L. Reckamp, David R. Gandara
Journal: Journal of Clinical Oncology (2014)

8015 Background: Preclinical modeling in NSCLC cell lines shows that in some E-sensitive cells (whether epidermal growth factor receptor [EGFR] mutated or wild type), stimulation with HGF reverses the cytostatic and cytotoxic effects of E. Inhibitors of AKT signaling mitigated this HGF-mediated resistance, partially restoring E activity. We conducted a phase II trial of E plus MK2206, a highly selective inhibitor of AKT, in NSCLC pts previously benefiting from E. Methods: Eligible pts must have had progression (PD) following prior benefit from E [response or stable disease > 12 weeks]. Treatment consisted of E 150 mg po QD + MK-2206 45 mg po QOD on a 28-day cycle. Pts were accrued into 2 strata: 1) presence of EGFR activating mutation; and 2) EGFR wild type. Primary endpoints: RECIST response rate (RR) > 30% (stratum 1) and disease control rate (DCR) > 20% at 12 weeks (stratum 2). Up to 41 pts per stratum were planned in a two-stage design. Results: Eighty pts were enrolled with median age 64 years (range 40-86); tumor EGFR status: mutant – 46, wild type-34; females - 51 (64%); performance status 90-100% - 53 (66%); and median time from diagnosis – 2.3 years (range 0.2-11.1). Most common attributable adverse events (all grade 3) were rash (12), diarrhea (11), fatigue (7), and mucositis (5). There was one treatment-related death (pneumonia). Efficacy results are shown in the Table. Conclusions: Combination MK2206 and E met its primary endpoint (DCR 47%) in E-pretreated pts with EGFR wild type NSCLC while its activity in EGFR mutants appears modest (RR 9%). Treatment was generally tolerable and toxicities manageable. AKT pathway inhibition merits further clinical evaluation in pts with E-refractory EGFR wild type NSCLC (N01-00038). Clinical trial information: NCT01294306. Stratum RR, N (%) DCR at 12 weeks, N (%) Median progression-free survival, months (95% CI) 1: EGFR mutant (N=46) 4 (9%) 18 (39%) 4.4 (2.7,6.6) 2: EGFR wild-type (N=34) 1 (3%) 16 (47%) 4.6 (2.9, 8.5)
Two CD14 promoter polymorphisms and atopic phenotypes in Czechpatients with IgE-mediated allergy
Authors: Dana Bučková, Lydie Izakovičová Hollá, Marcel Schüller, Vladimír Znojil, Jiří Vácha
Journal: Allergy (2003)

Our study supports the idea that CD14 gene variants [C(-159)T
and G(-1359)T polymorphisms] may act as disease modifiers of
IgE-mediated allergic diseases.
Direct cost-survival analysis of therapies for metastatic colorectal cancer
Authors: Y. Wong, N. J. Meropol, D. Sargent, R. Goldberg, J. R. Beck
Journal: Journal of Clinical Oncology (2006)

3515 Background: Patients with metastatic colorectal cancer (mCRC) treated with 5Fluorouracil plus leucovorin (5FU/LV) have a median life expectancy (LE) of approximately12 months. The addition of irinotecan, oxaliplatin, bevacizumab and cetuximab has increased LE significantly. Although they have been widely adopted, little is known about the financial impact of these new drugs. Methods: Using published reports and aggregate data from NCCTG 9741, we developed a Markov Model which assumes forward progression through up to three lines of therapy compared to 5FU/LV alone. Patients who do not die of toxicity (tox) transition through supportive care prior to death. State changes are based on progression and dose-limiting toxicity. Drug costs are based on Average Sales Price. No other direct or indirect costs are included. Dose modifications for toxicity are defined as 80% of standard doses. Sensitivity analyses (SA) were performed on key variables. Results: LE, total drug costs, and cost-effectiveness (CE) ratios compared to single line-5FU/LV and FOLFOX for 9 commonly used treatement sequences are presented below. SA show that results are sensitive to progression rates,drug costs and length of time on supportive care. Changes in 1st line tox rates have a greater impact on final results than changes in 2nd or 3rd line therapy tox rates. Conclusions: Using drug costs alone, this model shows sequential combination therapy including all available agents to cost $2000-$2800K/week life gained ($100-$145K/year) compared to both 5FU/LV and FOLFOX. For clarity only 9 strategies are presented, but the model presented will contain multiple sequences consisting of 1–3 lines of therapy. Refined tox data, associated costs and quality of life adjustments are needed for realistic comparisons among specific combinations. Combination therapy may have CE ratios similar to other currently accepted intensive medical interventions. These data can help inform discussions of how the cost of care impacts patients, providers, and societies. [Table: see text] [Table: see text]
Patient derived xenografts of upper tract urothelial carcinoma: A potential tool for personalized medicine.
Authors: Kwanghee Kim, Katie S Murray, Aditya Bagrodia, Francois Audenet, Sylvia Jebiwott, Benjamin Gordon, Alex Somma, Stephen LaRosa, Yiyu Dong, Ricardo Alvim, A. Ari Hakimi, James Hsieh, Hikmat Al-Ahmadie, Jonathan E. Rosenberg, David B. Solit, Jonathan Coleman
Journal: Journal of Clinical Oncology (2017)

344 Background: Historically, upper tract urothelial carcinomas (UTUC) are treated similarly to urothelial carcinoma of the bladder (UCB). However, compared to UCB, UTUC demonstrates a more aggressive clinical course which may be explained by significant differences in mutational frequencies between UTUC and UCB that were reported using a customized exon capture sequencing assay (the MSK-IMPACT assay). A major limitation in the advancement of the UTUC field is the lack of appropriate models specific to the disease. The objective of this study was to develop and evaluate preclinical models that would recapitulate treatment responses observed in patients. Methods: 35 surgical specimens from nephroureterectomy of patients with UTUC were implanted into immunocompromised NOD-SCID IL2Rg−/− (NSG) mice. The histological and the genomic characterization of patient tumors and PDXs were examined by a board certified pathologist and MSK-IMPACT assay, respectively. Cell lines were also established to assess histologic and genetic fidelity. Chemosensitivity of PDX models was assessed using a 4 week cycle of gemcitabine/cisplatin (or carboplatin) administration and analysis of tumor growth was performed using a Two-way ANOVA test. Results: 12 patient-derived xenograft (PDX) models were established with a success rate of 34% (12/35) and a 14% (3/21) success in developing cell lines. Both models were highly reflective of their original tumors in terms of histology and genomic characteristics in mutation status and copy number alterations. For a representative PDX, chemosensitivity experiments identified gemcitabine/carboplatin as a potentially effective combination, which was also used in the clinical scenario with a therapeutic response. Chemosensitivity of additional PDXs is continuing to be investigated to potentially guide post-operative decision making for treatment of the patient’s clinically. Conclusions: We developed a cohort of stable PDX models and cell lines for UTUC that maintains the genetic characteristics of the patient’s initial tumor. The continued development of these models may facilitate personalized medicine strategies in the treatment of UTUC.