tbuckley/cabot-search huggingface dataset:
Targeting Y397 FAK scaffolding compared with FAK kinase inhibition: Efficacy and specificity for tumor cells.
Authors: Vita Golubovskaya, Baotran Ho, Adam Stright, Maria Zajac-Kaye, Steven N. Hochwald, William G. Cance
Journal: Journal of Clinical Oncology (2013)

e13547 Background: Focal Adhesion Kinase is a non-receptor kinase which is highly overexpressed and activated or autophosphorylated in many types of tumors and plays a major role in survival signaling and metastasis. Recently, our group developed a highly specific allosteric scaffolding FAK autophosphorylation inhibitor, Y15, that blocked FAK Y397 autophosphorylation, decreased cancer cell viability, and significantly decreased breast, neuroblastoma, pancreatic and glioblastoma tumor growth. In addition, Y15 was not toxic in mice. In this study, we compared side by side efficacy of Y15 with two other FAK inhibitors in clinical trials, Pfizer PF-04554878 and Glaxo GSK-2256098. Methods: MTT, clonogenicity and Western blotting assays were used to detect the effect of FAK inhibitors on different cancer and normal cells. Student’s t-test was used for statistical analysis and p&lt;0.05 was considered significant. Results: We tested different cancer cell lines: kidney 293T, colon SW620 and LoVo; lung A549; glioblastoma U251 and U87; breast: BT474, MDA-231, MDA-361, MDA-453, MDA-468 and T47D and pancreatic PANC-1 cancer cells with different doses of Y15, PF and GSK inhibitors by MTT assay and found that Y15 was the most effective at decreasing cancer cell viability in most cancer cell lines, with higher efficacy than PF and much higher efficacy than GSK inhibitor. The same was observed for clonogenicity assay. In addition, we found that Y15 did not significantly affect viability of normal colon (CCD-112) cells, while viability of these cells with PF and GSK decreased to 54% and 57% at a 2 microM dose, respectively, from 100% in untreated cells. In addition, Y15 significantly decreased Y397-FAK, Y418-Src, phospho- Ser 473-AKT and phospho-ERK1/2, while PF had less effect and GSK only a minimal effect in four different cancer cell lines: U251, A549, 293T and Lovo at 10 microM and 100 microM doses, showing high potency of the FAK Y397 scaffolding inhibitor. Conclusions: These data show that Y15, which inhibits the Y397 site of FAK, is more potent against cancer cells and less toxic to normal cells than FAK inhibitors that target the conserved ATP-binding site in the kinase domain.
Cetuximab (Cet) clearance and survival in patients (pts) with metastatic colorectal cancer (mCRC).
Authors: Di Maria Jiang, Hao-Wen Sim, Lillian L. Siu, Jeremy David Shapiro, Geoffrey Liu, Timothy Jay Price, Derek J. Jonker, Christos Stelios Karapetis, Andrew Strickland, Wenjiang Zhang, Mark Jeffery, Dongsheng Tu, Siobhan Ng, Sabe S. Sabesan, Jenny Shannon, Amanda Rose Townsend, Eric Morgen, Wei Xu, Christopher J. O'Callaghan, Eric Xueyu Chen
Journal: Journal of Clinical Oncology (2017)

699 Background: Cet, a monoclonal antibody against EGFR, is a standard therapy for pts with RAS wild-type (WT) mCRC. Limited previous data suggest that Cet clearance correlates with progression-free survival (PFS). We performed a population pharmacokinetic (pop-pK) analysis of Cet in pts who participated in the randomized phase III NCIC CO.20 trial in KRAS WT mCRC patients. Methods: Standard Cet doses ± brivanib were administered. Using intermittent trough blood samples, pop-pK analysis was conducted to evaluate different models. Pts were divided into quartiles according to clearance parameters to assess the exposure-response relationship to response rate (RR), PFS and overall survival (OS). Clinical variables including demographic, laboratory, disease characteristics and co-administration of brivanib were evaluated as co-variates on Cet clearance. Results: In 701 pts, Cet elimination was best described as a one-compartment model with a non-linear saturable elimination process (defined by V max and K m ). Mean values (± standard deviation) for pop-pk parameters were 2.7 ± 0.5 L/m 2 for V, 2.5 ± 0.3 mg/h/m 2 for V max , and 101.0 ± 0.05 mg/L/m 2 for K m . Grouped into quartiles, V max and K m were significantly associated with OS, but not RR or PFS. The median OS for pts in the lowest quartile of V max was 12.0 ms versus (vs.) 6.9 ms for pts in the highest quartile ( p&lt; 0.001), while the median OS was 11.6 ms in the highest K m quartile vs. 6.9 ms in the lowest K m quartile ( p&lt; 0.001). When compared to the quartile with the combination of highest V max and lowest K m , pts in the quartile with the lowest V max and highest K m had longer PFS (5.0 vs. 3.7 ms, HR 0.75 (95% confidence interval (CI) 0.58-0.98, p= 0.032) and OS (11.7 vs. 6.6 ms, HR 0.59 (95% CI, 0.45-0.77, p&lt; 0.001). Pts in the lower V max and higher K m quartiles also experienced less grade 3 toxicity. Neither clinical variables nor brivanib administration were associated with Cet clearance parameters. Conclusions: For KRAS WT mCRC, standard Cet dosing is not optimal for all pts. Pts with slower Cet clearance have significantly improved PFS and OS. Further studies are needed to optimize Cet doses based on individual pK assessments, and to identify novel factors associated with clearance.
No Differences in Molecular Relapse-Free Survival after Stopping Imatinib Treatment of Chronic Myeloid Leukemia Between Patients with Prior 4.5 Log Reduction (MR4.5) but Detectable and Patients with Undetectable Disease in the EURO-SKI Trial
Authors: Markus Pfirrmann, Francois-Xavier Mahon, Joelle Guilhot, Johan Richter, Antonio Almeida, Jeroen J.W.M. Janssen, Jiri Mayer, Kimmo Porkka, Panayiotis Panayiotidis, Ulla Olsson-Stromberg, Marc G. Berger, Joana Diamond, Hans Ehrencrona, Veli Kairisto, Katerina Machova Polakova, Martin C. Müller, Satu Mustjoki, Andreas Hochhaus, Susanne Sauβele, Henrik Hjorth-Hansen
Journal: Blood (2016)
Treatment results of children with neuroblastoma in Hospital Infantil de Mexico Federico Gomez.
Authors: Luis Juarez Villegas, Marta Zapata-Tarres, Pablo Lezama del Valle
Journal: Journal of Clinical Oncology (2013)

10059 Background: Neuroblastoma (NB) is the main extracraneal cancer in children. Progress in survival has not been the same as in other neoplasms despite molecular markers research and new drugs. Our aim was to describe low and high risk patients at Hospital Infantil de México Federico Gómez (HIMFG) and their results. Methods: We included children from 0 to 18 years con NB diagnosed at HIMFG between january, 2002 and december 2011. We perform a retrospective, retrolective and descriptive study analyzing demographic variables and survival with Kaplan Meier. Results: 64 consecutive patients were included. 73.4% had metastasis at diagnosis (bone marrow 23.4%, liver 18.8%, bone 17.2%, 4.7% central nervous system, 9.4% other). 87.5% of patients received neoadyuvant chemotherapy. Patients were treated with POG 8104 y 8441. Global survival of patients with E4 stage was 50% at 120 months, with E3 of 76.5% at 110 months; stage 1, 2 patient´s survival was 4S 100% at120 months. Conclusions: At HIMFG, in Mexico City, 75% of patients with NB arrive with metastatic disease. Clinical prognosis factors are still current in development countries. Our results are similar as in developed countries suggesting that with low resources, we can obtain satisfactory results only with clinical evaluation.
Vemurafenib (VEM) in patients (pts) with BRAF-mutant melanoma and brain metastases (mets).
Authors: James J. Harding, Federica Catalanotti, Amin Yaqubie, Gregory C. McDermott, Romona Kersellius, Taha Merghoub, Richard D. Carvajal, Sandra P. D'Angelo, Mark Andrew Dickson, Gary K. Schwartz, Jedd D. Wolchok, Michael F. Berger, David B. Solit, Paul B. Chapman
Journal: Journal of Clinical Oncology (2013)

9060 Background: Emerging data suggest that RAF inhibitors are an effective therapy for pts with BRAF-mutant melanoma and brain mets. Although reported efficacy is encouraging, these data are derived from case reports or early stage trials enriched with physiologically fit pts. It is therefore of interest to assess the “real world” experience of VEM in this population. Methods: Records of all BRAF-mutant melanoma pts treated with RAF inhibitors at our center from 2007 to 2012 were reviewed retrospectively. We determined the best overall response rate (BORR) and, when applicable, the overrall intracranial response rate (OIRR) by RECIST v1.1, progression-free survival (PFS), and overall survival (OS) to RAF inhibition. Pretreatment formalin-fixed, paraffin-embedded tumor was assessed using an exon capture assay able to sequence coding exons of 279 cancer-associated genes. Results: 21 (18%) of 119 pts with BRAF-mutant melanoma treated with VEM had active brain mets (age range: 25-86, sex: 52% men, median ECOG PS: 1, proportion with extracranial mets: 90%, BRAF mutation: 86% V600E and 14% V600K). 10/21 pts had no prior intracranial (IC) therapy; 11/21 pts received whole brain radiotherapy (WBRT, 7/21), stereotactic radiosurgery (1/21), metastasectomy (2/21) or multimodality therapy (1/21) prior to VEM. 12/21 pts received ipilimumab sometime during their disease course. For radiographically evaluable pts (N=17), the BORR was 65% (95% CI: 43-88) and the OIRR was 40% (95% CI: 15-65). For 4 pts, the BORR and OIRR were discordant−3 pts had IC progression but visceral tumor shrinkage, 1 pt had IC disease control but visceral progression. VEM was effective in pts whether or not they had received prior local brain therapy. The estimated median PFS and OS for all brain mets pts (N=21) were 4 and 8 months, respectively. Pretreatment tumor is available for exon sequencing in approximately half of these patients. This analysis is ongoing. Conclusions: In routine clinical practice, the OIRR to VEM was 40% which is higher than historical response rates to WBRT. VEM may be preferable to WBRT as a first-line therapy for pts with BRAF-mutant melanoma and brain mets. Whether RAF inhibitor treatment improves OS in this population will require further study.
Acute toxicity profile of patients with low-grade gliomas and meningiomas receiving proton therapy.
Authors: Genevieve Maquilan, Surbhi Grover, Michelle Alonso-Basanta, Robert A. Lustig
Journal: Journal of Clinical Oncology (2012)

e12508 Background: Quality of life is not often studied but is an important outcome to measure when evaluating types of radiation treatment. This study attempts to provide data on the treatment effects of proton beam therapy on patients with low grade gliomas and meningiomas, using the National Cancer Institute Common Terminology Criteria (CTCAE) version 4.0 to analyze the severity and frequency of symptoms experienced acutely during and after radiotherapy. Methods: 23 patients diagnosed with low grade gliomas or meningiomas were enrolled in a prospective proton beam radiation treatment protocol (NCT01024907) and were treated and followed between April 2010 and August 2011 in the University of Pennsylvania Radiation Oncology Department. Patients received 54 Gy [relative biologic effectiveness (RBE)] in 1.8 Gy (RBE) per fraction and were assessed at the time of consult, weekly during treatment, and followed up at 1, 3, 6, and 9 months after treatment. Symptoms were graded based on the CTCAE version 4.0. Results: At week 1 of treatment, 4/23 patients experienced Grade 1 anorexia. At week 3, 5/23 patients had Grade 1 nausea, 10/23 patients had Grade 1 headaches, and 1/23 patients had a Grade 3 headache. At the end of treatment at week 6, 13/23 patients had Grade 1 fatigue, 6/23 patients had Grade 2 fatigue, 3/23 patients had Grade 1 nausea, 4/23 patients had Grade 1 headaches, 7/23 patients had Grade 1 insomnia, and 1/23 patients had Grade 2 insomnia. At the 1-month follow-up, 3/23 patients had Grade 1 fatigue, 1/23 patients had Grade 2 fatigue, 2/23 patients had Grade 1 anorexia, 1/23 patients had a Grade 1 headache, and 2/23 patients had Grade 1 insomnia. No patients were reported to have experienced vomiting at any of the 4 time points. Conclusions: Proton therapy has a favorable side effect profile--most patients experienced mild fatigue, headaches, and insomnia that largely resolved by one month after treatment. This study provides a useful starting point for larger-scale studies which could directly compare the acute side effects of proton and conventional radiotherapy.
Reduced folate carrier (RFC) as a predictive marker for response to pemetrexed in advanced non-small cell lung cancer (NSCLC).
Authors: Carlos Alvarez Fernandez, Quionia Pérez Arnillas, Ana Lucrecia Ruiz, David Jose Rodriguez Rubi, Luisa Sánchez Lorenzo, Walter Antonio Li Torres, Marta Izquierdo Manuel, Jose Pablo Berros Fombella, Maria Luque Cabal, Paula Jiménez, Noemi Villanueva Palicio, Emilio Esteban
Journal: Journal of Clinical Oncology (2013)

e19034 Background: RFC is the major transport system in mammalian cells for folate cofactors and antifolate therapeutics. The aim of this study was to assess the predictive value of RFC expression in patients receiving pemetrexed for advanced NSCLC. Methods: The study was carried out in a population of 48 patients with advanced NSCLC which have received pemetrexed monotherapy in second and third line. RFC expression was assessed using a two-step model of immunohistochemical staining in paraffin-embedded tissue samples. Results: RFC expression was detected in 16 (33%) patients. In the global population, the median progression free survival (PFS) and the median overall survival (OS) were 3.3 and 6.5 months respectively. The subgroup of patients with expression of RFC had a tendency to better median PFS (4.5 vs 2.8 months; p=0.926) and median OS (11.7 vs 4.8; p=0.150). In patients with adenocarcinoma histology and RFC expression median OS after treatment with pemetrexed was 14.4 months versus 5.0 in those with adenocarcinoma but without RFC expression (p=0.039). Conclusions: These results suggest the possible relation between RFC expression and response to treatment with antifolates (pemetrexed) independently of the tumor histology. Further studies are required to confirm these results.
Epidemiology of Extranodal Diffuse Large B Cell Lymphomas in Algeria: A Study of the Algerian Group of Extranodal Lymphomas (GALEG)
Authors: S Hamdi, I Bentahar, H Harbadji, F Grifi, S Bougherira, T Filali, F Smaili, A Djabellah, H Ait Ali, M Allouda, N Mesli, B Berber, K Bouzid, R Sai, RM Hamladji, R Ahmed Nacer, N Ait Ameur, F Belhadri, MA Bekadja, L Charef, H Touhami, L Zatla, M Belhani, N Boudjerra, S Nekkal, L Louanchi, M Saidi, S Bougoufa, M Bitam, N Mehalhal, MT Abad, S Oukid, Fz Ardjoun, SE Belakehal, L Sahraoui, M Oukal, Z Zouaoui, N Si Ali, A Bachiri, L Belkesmaoui, B Bendjabellah, D Lamara, N Lakhdari, L Touati, N Sidi Mansour, Y Ouarhlent, S Bouaoud, L Kara, M Benakli
Journal: Blood (2016)
Clinical features and tumor mutational profile of younger versus older patients with cholangiocarcinoma (CCA).
Authors: Lipika Goyal, Stephanie Reyes, Apurva Jain, Rachna T. Shroff, Tri Minh Le, Osama E. Rahma, Robin Kate Kelley, Andrea Grace Bocobo, Advaita Kanakamedala, Kylie Boyhen, Christine VanCott, Stacie Lindsey, Hui Zheng, Andrew X. Zhu, Milind M. Javle
Journal: Journal of Clinical Oncology (2017)

240 Background: As seen in lung cancer, young patients with cancer can have different risk factors, presentation, and tumor genotype than older patients with the same disease. The clinical and molecular features of young patients with CCA have yet to be well characterized. Methods: Retrospective chart review was performed on patients with intrahepatic (ICC) or extrahepatic cholangiocarcinoma (ECC) across 5 institutions. Data on demographics, risk factors, treatments, pathology, and overall survival (OS) were collected. Tumor genotyping results from MGH SNaPShot and Foundation Medicine were analyzed. Log-rank tests and Kaplan-Meier survival curves were used for statistical analysis. Results: Of 567 patients analyzed, 134 (23.6%) were &lt; 50 years old (yo) and 455 (80.2%) had ICC. When assessed for risk factors, younger patients ( &lt; 50yo) were more likely to have primary sclerosing cholangitis (PSC) (p &lt; 0.001) and less likely to have diabetes (p = 0.05), compared to older patients ( ≥ 50yo). Surgical resection rates were similar in younger vs older patients (41.9 vs 42.6%, p = 0.890), but younger patients had larger tumors (median size 7.1 vs 5.3cm p = 0.012). Younger patients were also more likely to receive palliative systemic chemotherapy (p &lt; 0.001) and more lines of therapy (median, 2 vs 1 line, p &lt; 0.001). Frequency of treatment with liver directed therapy did not differ between the two groups. Molecular testing was performed on 222/567 (39.1%) patients of which 84/134 (62.7%) were younger patients and 138/433 (31.9%) were older patients. FGFR aberrations were more common in younger patients versus older patients (17.6 vs. 5.7%, p = 0.002). Targeted therapy was given to 15/84 (17.9%) younger and 28/138 (20.3%) older patients based on results of mutational profiling. Finally, no significant difference was seen in OS between younger and older patients (22.9 vs 22.7 months, p = 0.89). Conclusions: Younger patients with CCA may have different risk factors, tumor biology, and tolerance of systemic therapy compared to older patients. Further study is needed as referral patterns to tertiary care centers and motivation of younger patients to seek tertiary care may impact these results.
Weekly <i>nab</i>-paclitaxel in combination with carboplatin as first-line therapy in patients (pts) with advanced non-small cell lung cancer (NSCLC): Analysis of patient-reported neuropathy and taxane-associated symptoms.
Authors: Vera Hirsh, Isamu Okamoto, Jeremy K. Hon, Shaker R. Dakhil, Ray D. Page, James Orsini, Hui Zhang, Markus Frederic Renschler, Mark A. Socinski
Journal: Journal of Clinical Oncology (2012)

TPS7618 Background: Neuropathy and its associated symptoms are dose-limiting toxicities of taxane-based regimens. Measuring disease symptoms has utility for maintaining a balance between the benefits and costs of treatment. In a phase III trial nab-paclitaxel (nab-P, 130 nm albumin-bound paclitaxel particles) + carboplatin (C) vs solvent-based paclitaxel (sb-P) + C significantly improved the primary endpoint of overall response rate (ORR) (25% vs 33%, P = 0.005), with a 1-month improvement in median overall survival (OS; P = NS), and an improved tolerability profile in pts with advanced NSCLC. Here we report on patient-assessed neuropathy and taxane-associated symptoms, important factors in a palliative patient setting. Methods: Pts with untreated stage IIIB/IV NSCLC were randomized 1:1 to C AUC 6 day 1 and either nab-P 100 mg/m 2 on days 1, 8, 15 (n = 521) or sb-P 200 mg/m 2 day 1 (n = 531) q 21 days. Treatment was continued until disease progression. Safety was assessed per the Common Terminology Criteria for Adverse Events (CTCAE) v3.0. The mean change from baseline to day 1 of each cycle for the neuropathy, pain, and hearing subscales of Functional Assessment of Cancer Therapy (FACT)‑Taxane v 4.0 were assessed. Results: 1031 (98%) pts completed FACT-Taxane at baseline, and 987 (94%) during follow-up or at completion of treatment. Baseline scores for neuropathy and pain were well balanced. Significant treatment effects favoring nab-P/C were noted for patient-reported neuropathy (P &lt; 0.001), neuropathic pain hands/feet (P &lt; 0.001), and hearing loss (P = 0.002). Physician-assessed rates of neuropathy were significantly lower in the nab-P/C arm vs the sb-P/C arm: 47% vs 63%, P &lt; 0.001, all grades; 3% vs 12%, P &lt; 0.001, grade 3/4, respectively. More pts treated with nab-P/C vs sb-P/C had no neuropathy (53% vs 47%, P &lt; 0.001). Conclusions: nab-P/C was associated with statistically and clinically significant reductions in patient-reported neuropathy, neuropathic pain in the hands and feet, and hearing loss compared with sb-P/C. Patient-reported outcomes for neuropathy were consistent with physician assessment.
Evaluation with DCE-US of antiangiogenic treatments in 539 patients allowing the selection of one surrogate marker correlated to overall survival.
Authors: Nathalie Lassau, Valérie Vilgrain, Sophie Taieb, Joëlle Lacroix, Richard Aziza, Marie Cuinet, Jean-Charles Soria, Louis Chapotot, Serge Koscielny
Journal: Journal of Clinical Oncology (2012)

4618 Background: A prospective study of dynamic contrast-enhanced ultrasound (DCE-US) with quantification for the evaluation of antiangiogenic treatments was launched (19 centers), supported by the French National Cancer Institute. The objectives were the diffusion of the standardized method, a cost evaluation and the identification of perfusion parameters predicting tumor response. Methods: All patients had DCE-US at baseline, D7, D14, D30, D60 and every two months. Each examination included a bolus injection of sonovue (Bracco) and 3 minutes of raw linear data with an Aplio (Toshiba). Raw data were analyzed with a mathematical model (patent PCT/IB2006/003742) to evaluate 7 parameters characterizing the tumor perfusion curve. Response to treatment was evaluated every 2 months with RECIST criteria. In order to have sufficient follow-up data, the statistical analysis has to be performed more than 6 months after the inclusion of the last analyzed patient. Inclusions were closed in March 2010. Results: A total of 539 patients have been included (mainly RCC (157) and HCC (107)); more than 2 000 DCE-US and 1700 CT-scan were performed. A follow-up more than 12 months showed that 3 parameters have a strong significant difference (p&lt;0.0003) according to the response at 6 months. The decrease of more than 40% of AUC at one month is correlated to the TTP (p&lt; 001) and OS (p&lt; 0.04). Conclusions: Final results confirm the usefulness of this tool to monitor anti-angiogenic treatments. The criteria: the decrease of more than 40% of AUC at one month is predictive of response.