tbuckley/cabot-search huggingface dataset:
Association of Killer cell immunoglobulin-like receptors (KIRs) polymorphisms and advanced cancer in a Caucasian population.
Authors: Cristina Morales-Estevez, Barbara Manzanares-Martin, Rafael Gonzalez-Fernandez, Ignacio Porras, M.Auxiliadora Gomez-España, Maria Teresa Cano, Maria Jose Ortiz, Alberto Moreno, Raquel Serrano, Juan de la Haba-Rodriguez, Enrique Aranda
Journal: Journal of Clinical Oncology (2015)

e12563 Background: Killer cell immunoglobulin-like receptors (KIRs) are a family of activating and inhibitory receptors expressed on natural killer (NK) cells and T cells, the genes of which show extreme polymorphism. Previous studies have shown associations between KIRs polymorphisms, their ligands and either protection or susceptibility to breast cancer. However, either the association to other solids tumor or advanced cancers remain unknown. Our aim was to investigate the prevalence of KIRs gene polymorphisms in 3 different advanced cancers: colorectal, breast and head and neck in a Caucasian population. Methods: 75 patients on monoclonal antibody treatment (Trastuzumab or Cetuximab) were selected (28 colorectal, 30 breast and 17 head and neck). KIR genotyping was performed using sequence-specific primers able to detect the presence of 16 different KIR genes (2DL1, 2DL2, 2DL3, 2DL4, 2DL5, 3DL1, 3DL2, 3DL3, 2DS1, 2DS2, 2DS3, 2DS4, 2DS5, 3DS1, 2DP1 and 3DP1). Results: Our results showed that the KIRs 2DL4, 3DL2, 3DL3, and 3DP1 polymorphisms were found in all patients and the KIRs 2DL1, 2DL3, 2DL1, 2DS4 y 2DP1 in more than 95%. In the group of breast cancer the rates of other activating and inhibitor polymorphisms were similar to previous cohorts. However the rate of activating 2DS1 and 2DS5 was much lower in patients with head and neck than in breast cancer (17% vs 53%, P = 0.016 and 11% vs 43%, P = 0.026, respectively). The rates of activating and inhibitor polymorphisms in advanced colorectal cancer were similar than breast cancer. Conclusions: We have described for the first time that the prevalence of KIRs polymorphisms in advanced breast and colorectal cancer is similar to those series including early-stage breast cancer. Nevertheless the rate of activating 2DS1 and 2DS5 was lower in patients with head and neck cancer. Future studies should explore how genetic diversity of KIRs can influence susceptibility to a variety of cancer and may be a function of disease morbidity and mortality.
Characterization of ipilimumab exposure-efficacy/safety response relationships in subjects with previously treated or untreated advanced melanoma.
Authors: Yan Feng, CJ Godfrey, Hui-May Chu, Eric Masson, Daphne Williams, David Mark Berman, Amit Roy
Journal: Journal of Clinical Oncology (2012)

8541 Background: Ipilimumab (IPI) is a fully human monoclonal antibody directed against CTLA-4 that is being developed as a novel immunotherapeutic agent against melanoma and other solid tumors. The objective of this analysis was to retrospectively characterize the exposure-response (E-R) relationships for efficacy (overall survival, OS) in subjects with previously untreated advanced melanoma (pu-MEL), and safety (immune related adverse-events, irAEs) in subjects with previously treated advanced melanoma (pt-MEL) or pu-MEL. Methods: The E-R analysis of OS included 498 pu-MEL from a phase III study (CA184024) of IPI administered at 10 mg/kg + dacarbazine (DTIC) or DTIC + placebo; and the E-R analyses of irAE included 1036 subjects from a phase I study (CA184078), 4 phase IIstudies (CA184004/007/008/022) and CA184024 of IPI administered at doses of 0.3, 3 or 10 mg/kg. The relationship between steady‑state IPI trough concentration (Cminss) and OS was described using a Cox proportional hazards model, and the relationships between Cminss and incidence of irAEs were described by ordinal logistic regression models (separate models for any irAE, as well as skin, liver and GI irAE). Results: The risk of death decreased with increasing Cminss, and is higher for subjects with elevated baseline LDH level. The risk of death was higher for subjects with baseline ECOG status &gt; 0 and was higher with increasing stage of disease (M1C&gt;M1B&gt;M1A&gt;M0). The hazard ratio for OS corresponding to the median Cminss of 49.99 µg/mL was 0.745 relative to subjects in DTIC + placebo group. The probability of Grade 2+ or Grade 3+ GI, skin, liver and any irAEs also increases with Cminss. Prior anti-cancer therapy (including prior DTIC) or concomitant DTIC were the only significant covariates in the E-R irAE models. Conclusions: These model-based analyses suggest that higher Cminss of IPI appears to be associated with improved survival in pu-MEL (based on data from CA184024) and higher Cminss also appears to be associated with increased probability of irAEs in pu-MEL or pt-MEL.
Everolimus treatment-associated interstitial lung disease (ILD) as a prognostic factor in Japanese patients with metastatic renal cell carcinoma.
Authors: Fumiya Hongo, Masakatsu Oishi, Takashi Ueda, Yasunori Kimura, Terukazu Nakamura, Yoshio Naya, Kazuya Mikami, Tsuneharu Miki
Journal: Journal of Clinical Oncology (2013)

e15531 Background: Interstitial lung disease (ILD) is one of the adverse events during treatment with everolimus for metastatic renal cell carcinoma (mRCC). Japanese study of everolimus treatment-associated ILD as a prognostic factor is rare. Methods: We retrospectively assessed the incidence and outcome of ILD in mRCC patients treated with everolimus. Between April 2010 and August 2012, 25 cases were treated with everolimus after the failure of one or two TKIs in our institute. All adverse events were graded in accordance with NCI CTCAE, version 3.0. Results: A total of 25 patients received treatment with everolimus and included 18 male and 7 female patients ranging in age from 21 to 84 years (median 62). According to MSKCC risk criteria, 6 cases were at favorable risk, 16 cases were at intermediate risk, and 3 cases were at poor risk. The median treatment term was 4 months (range 2-17 months). SD was reported in 19 cases and PD in 6 cases. Progression free survival was 3.5 months and overall survival was 12 months. ILD was found in 7 cases (28%). One was G1, five were G2, and one was G3. Corticosteroid therapy was initiated in 3 cases. In 5 of 7 ILD cases, everolimus was re-challenged. In our series, patients with ILD showed significantly better progression free survival than those without ILD (PFS was 8 months vs 3 months. Log-rank, P&lt;0.001). There were no significant differences between the two groups in overall survival (12 months in patients with ILD vs 10 months in patients without ILD. Log-rank, NS). Conclusions: Everolimus appears to have been effective and well-tolerated in our institute. Re-challenge with everolimus was feasible after improving everolimus-induced ILD in cases of grade 1-2. To confirm these findings, the efficacy and AE profile of everolimus in Japanese patients should be investigated.
Aflibercept (Z) in combination with FOLFIRI for second-line treatment of patients (pts) with metastatic colorectal cancer (mCRC): Safety and quality of life (QoL) data from the Spanish subgroup of the Aflibercept Safety and Quality-of-Life Program (ASQoP).
Authors: Fernando Rivera, Eduardo Polo Marques, Enrique Aranda, Carlos Fernandez-Martos, Adelaida La Casta Munoa, Carmen Guillen, Rafael Lopez, Silvia Gil, Laura Lema, Jorge Aparicio, Mercedes Martinez Villacampa, Aleydis Pisa, Pablo Borrega, Guillermo Lopez-Vivanco, Pilar Garcia Alfonso
Journal: Journal of Clinical Oncology (2017)

751 Background: In the VELOUR trial, adding Z to FOLFIRI improves OS, PFS and RR in mCRC pts progressing after oxaliplatin ±biologic agents. The ASQoP trial (NCT01571284) was designed to gather safety and QoL data from mCRC in real-life setting. We report data collected by the Spanish investigators. Methods: ASQoP is single-arm, open-label trial evaluating safety and QoL of Z in mCRC pts as 2nd line. Eligible pts received Z (4mg/kg) q2wks on day 1/cycle, followed by FOLFIRI (dosing was at physician’s discretion) until disease progression, unacceptable toxicity, death, or investigator/pt decision. The EQ-5D was used for utility index (UI) measure and the EORTC QLQ-C30 as generic cancer instrument. QoL population consisted of pts completing the questionnaire at baseline and ≥1 assessment post-baseline and received ≥1 part of 1 dose of study treatment. Results: The safety population comprised 77 pts with ≥1 completed cycle of treatment. Grade (G)3/4 AEs were reported in 72.7% of pts (vs 83.5% in VELOUR), being G3 most commonly reported. There was no G4 hypertension, stomatitis, or proteinuria. G4 Diarrhea was found in 1.3% of pts. Mean baseline UI was 0.7 (95% CI, 0.63-0.78) in 51 pts, and remained relatively stable at cycles 3 (n=39) and 7 (n=24), with a mean (±SD) change from baseline of 0.03 (±0.26) and -0.06 (±0.35), respectively. Mean baseline global health status score was 63.1 (95% CI, 55.8-70.4) in 54 pts, and remained stable up to cycle 9 with a mean (±SD) change from baseline of 4.17 (±38). Conclusions: Thisanalysis has identified no new safety signals and suggests an acceptable toxicity profile with a relatively stable UI and QoL in Spanish mCRC pts in the real-life setting. [Table: see text]
The tyrosine kinase src plays a crucial role in leukemic cell proliferation in AML
Authors: G. Schuch, E. Schäfer, K. Eggert, S. Loges, M. Görn, E. Laack, C. Bokemeyer, W. Fiedler
Journal: Journal of Clinical Oncology (2007)

10531 Background: Src-family tyrosine kinases are known to be involved in signal transduction pathways of growth factors and cytokines in hematopoetic cells. While the role of other src family members has been studied widely, only few data exist about c-src in leukemia. The actual study was performed to analyze src mutations in leukemic cells and to determine the role of pp60src in leukemic cell proliferation. Methods: AML cell lines and primary samples were analyzed for expression and activation of src by RT-PCR and Western blot analyses. Mutational analyses were performed by sequencing of C-terminal cDNA from 60 AML samples. The effects of src inhibition were studied by src-specific inhibitors PP1 and PP2 or by siRNA transfection. Effetcs of src inhibition were monitored in proliferation assays and analyzes of signalling through Erk1/2 and apoptosis by annexin V staining and DNA laddering. Results: In all 60 patients analyzed expression of c-src mRNA was detected by RT-PCR. Western blot analyses confirmed strong expression of src on the protein level and revealed a robust activation of the protein as determined by tyrosine phosphorylation. Incubation of leukemic cells with PP1 and PP2 caused significant inhibition of proliferation in a dose dependent manner. Similar results were observed after transfection with specific siRNAs. Src inhibition blocked phosphorylation of pp60src, Erk1/2 and induced apoptosis in leukemic cells. Mutational analyses as performed by SSCP/heteroduplex and bi-directionally sequencing revealed wildtype sequence in cell lines and 60 clinical samples. Conclusions: In summary, pp60src is highly expressed and activated in cell lines and clinical samples of human AML. Moreover, phosphorylation of src is essential for leukemic cell proliferation. Underlying mutations in the coding sequence of c-src causing constitutive activation could be excluded. These data suggest that pp60src plays a crucial role in AML and src inhibition by targeted therapy might offer a useful new approach in the treatment of AML. No significant financial relationships to disclose.
“Long extended” temozolomide in a selected population with not radically resected high-grade gliomas.
Authors: Gian Paolo Spinelli, Giuseppe Lo Russo, Evelina Miele, Antonio Maria Alberti, Martina Strudel, Valeria Stati, Federica Zoratto, Anselmo Papa, Luigi Rossi, Monica Verrico, Enrico Basso, Erika Giordani, Eleonora Zaccarelli, Marina Minozzi, Giovanni Codacci Pisanelli, Silverio Tomao
Journal: Journal of Clinical Oncology (2012)

e12510 Background: Despite the important progress in the treatment of solid tumors, high grade gliomas (HGGs) remain neoplasm with poor prognosis, especially when are not radically resected. Here we report the results of a selected population treated with standard schedule of Radiotherapy (RT) + Temozolomide (TMZ) followed by TMZ until progression. Methods: From January 2008 to January 2010, 14 newly diagnosed HGG patients, with median age of 50.6 years (range 27-75 yrs), were enrolled at Oncology Unit of S. Maria Goretti Hospital in Latina (University of Rome “Sapienza”). All patients were not radically resected and with ECOG PS=O. Furthermore patients were selected according to O6 Methyl-Guanine-DNA-Methyl Transferase (MGMT) promoter methylation status. Only methylated patients were included in our study. After surgery, patients received standard treatment with TMZ (75 mg/m2) concomitant with RT (60 Gy total dose). After a break of six weeks, Magnetic Resonance Imaging (MRI) was performed and all patients with stable or responsive disease received TMZ (150mg/200mg/m2/d x 5dq 28d) until progression. The response to treatment was evaluated according to RANO criteria Results: In our study the results showed one year overall survival (OS) and progression free survival (PFS) rates of 85,7% and 71,4% respectively. Moreover we observed two years OS rate of 70% and two years PFS rate of 10%. A total of 108 cycles of adjuvant TMZ were administered with average number of 9 per patient (range 1-16). The most frequent side effects observed were haematological toxicity and fatigue. Thrombocytopenia (G2-G3) was observed in 42% of patients, neutropenia (G2-G3), fatigue (G2-G3) and nausea (G2-G3) in 30%, 32% and 25% of patients respectively. Conclusions: Despite the small number of patients, our experience suggests a manageable safety profile and a good efficacy of TMZ until progression in a selected population of patients (HGGs not radically resected, with a good ECOG PS). These data also confirms the literature knowledge, underlining the prognostic positive impact of MGMT promoter methylation in patients with HGG.
Complete Hematologic and Molecular Response in Adult Patients With Relapsed/Refractory Philadelphia Chromosome–Positive B-Precursor Acute Lymphoblastic Leukemia Following Treatment With Blinatumomab: Results From a Phase II, Single-Arm, Multicenter Study
Authors: Giovanni Martinelli, Nicolas Boissel, Patrice Chevallier, Oliver Ottmann, Nicola Gökbuget, Max S. Topp, Adele K. Fielding, Alessandro Rambaldi, Ellen K. Ritchie, Cristina Papayannidis, Lulu Ren Sterling, Jonathan Benjamin, Anthony Stein
Journal: Journal of Clinical Oncology (2017)

Purpose Few therapeutic options are available for patients with Philadelphia chromosome-positive (Ph+) B-precursor acute lymphoblastic leukemia (ALL) who progress after failure of tyrosine kinase inhibitor (TKI) -based therapy. Here, we evaluated the efficacy and tolerability of blinatumomab in patients with relapsed or refractory Ph+ ALL. Patients and Methods This open-label phase II study enrolled adults with Ph+ ALL who had relapsed after or were refractory to at least one second-generation or later TKI or were intolerant to second-generation or later TKIs and intolerant or refractory to imatinib. Blinatumomab was administered in 28-day cycles by continuous intravenous infusion. The primary end point was complete remission (CR) or CR with partial hematologic recovery (CRh) during the first two cycles. Major secondary end points included minimal residual disease response, rate of allogeneic hematopoietic stem-cell transplantation, relapse-free survival, overall survival, and adverse events (AEs). Results Of 45 patients, 16 (36%; 95% CI, 22% to 51%) achieved CR/CRh during the first two cycles, including four of 10 patients with the T315I mutation; 88% of CR/CRh responders achieved a complete minimal residual disease response. Seven responders (44%) proceeded to allogeneic hematopoietic stem-cell transplantation, including 55% (six of 11) of transplantation-naïve responders. Median relapse-free survival and overall survival were 6.7 and 7.1 months, respectively. The most frequent AEs were pyrexia (58%), febrile neutropenia (40%), and headache (31%). Three patients had cytokine release syndrome (all grade 1 or 2), and three patients had grade 3 neurologic events, one of which (aphasia) required temporary treatment interruption. There were no grade 4 or 5 neurologic events. Conclusion Single-agent blinatumomab showed antileukemia activity in high-risk patients with Ph+ ALL who had relapsed or were refractory to TKIs. AEs were consistent with previous experience in Ph- ALL.
Combinatorial optimization of PEG architecture and hydrophobic content improves ternary siRNA polyplex stability, pharmacokinetics, and potency in vivo
Authors: Thomas A. Werfel, Meredith A. Jackson, Taylor E. Kavanaugh, Kellye C. Kirkbride, Martina Miteva, Todd D. Giorgio, Craig Duvall
Journal: Journal of Controlled Release (2017)
Phase I/II study of concurrent erlotinib and chemoradiation for post-resected locally advanced squamous head and neck cancer (HNSCC): A GICOR study
Authors: F. Arias de la Vega, I. Herruzo, M. de las Heras, A. de la Torre, L. del Rio, J. Contreras, I. Prieto, J. A. Garcia, M. L. Amador, F. A. Calvo
Journal: Journal of Clinical Oncology (2007)

16544 Background: Concurrent chemoradiation is considered the optimal treatment for advanced HNSCC, including post-resected status. Erlotinib is an oral EGFR TKI, with activity in recurrent and metastatic HNSCC.The Spanish Group of Clinical Research in Radiation Oncology (GICOR) leads a phase I/II study to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of adding erlotinib (e) to chemoradiation to patients (p) with surgically resected locally advanced HNSCC Methods: p had surgically resected advanced HNSCC, with a least one of the following criteria: T3 or T4 primary lesion (except T3N0 with negative resection margins), pathologic N2-N3 disease, and poor prognostic findings (i.e. extranodal spread, positive resection margins, perineural or perivascular involvement). Additional eligibility criteria included: age 18–70 y; life expectancy = 12 w; PS 0–1; no evidence of metastasis; adequate organic function; and written informed consent. Dose-escalating phase I study consisted on 3 cohorts of 3–6 p each, with increasing doses of erlotinib (100–150 mg po qd) and cisplatin (30–40 mg/m 2 , iv, d 1) for 7 w. Radiotherapy was delivered as a fixed standard regimen of daily 1.8 Gy (5 fractions/w) to a total dose of 63 Gy in high risk areas along 7 w. Results: By the time of this analysis, 7 p have entered the phase I component of the study. Median age: 52 y; male 100%. Complete data for 4 pats included in cohort 1 (e 100 mg/d, c 30 mg/m 2 ) are available. One p withdrew prematurely the study due to a grade 2 toxicity (not considered DLT) and was considered unevaluable by the Scientific Committee. Among evaluable p, 2 developed mucositis (1g.3), vomiting (g.1) and nausea (g.1). All p developed skin rash (mild in all the cases). Haematological toxicities were single cases of anaemia, leukopenia and thrombocytopenia (g.1). All 3 p completed 7 weeks of treatment and no dose reduction was required. No DLT as per protocol has been described and study went subsequently further to cohort 2. Conclusions: This study demonstrates the safe addition of erlotinib to chemoradiotherapy in the treatment of this p population. Full data from the phase I study will be presented. No significant financial relationships to disclose.
The FNTB-609G&gt;C polymorphism as a possible predictive factor for efficacy of lonafarnib-treatment? Exploratory analysis of a randomized phase II clinical trial in stage IIb-IV ovarian cancer, treated with first-line platinum-based chemotherapy with or without lonafarnib.
Authors: Pauline Wimberger, Hagen Sjard Bachmann, Andreas Du Bois, Rainer Kimmig, Jan Dominik Kuhlmann, Winfried Siffert, Jalid Sehouli, Kerstin Wollschlaeger, Jens Bodo Huober, Peter Hillemanns, Alexander Burges, Barbara Schmalfeldt, Behnaz Aminossadati, Werner Meier
Journal: Journal of Clinical Oncology (2014)

e16534 Background: Despite promising preclinical findings regarding clinical utility of farnesyltransferase inhibitors (FTI), such as lonafarnib, success of clinical studies is limited. In some studies, response to FTI was observed in 20-30% of patients, whereas other studies failed to resolve a benefit of lonafarnib, or even showed a negative effect of lonafarnib on the outcome of suboptimally debulked ovarian cancer patients (AGO-OVAR 15 phase II). In this regard, aim of the present study was to investigate clinical utility of a -609G>C polymorphism, located within the promoter core region of the farnesyltransferase ß-subunit gene (FNTB), in terms of a molecular biomarker for lonafarnib response. Methods: Influence of -609G>C on FNTB-promoter activity was investigated in vitro by electrophoretic mobility shift assay, luciferase reporter assay and RT-qPCR. Subsequently, 57 out of 105 patients from the prospective, randomized AGO-OVAR 15 phase II trial, treated with carboplatin and paclitaxel ± lonafarnib, were genotyped for -609G>C by pyrosequencing. Progression-free survival (PFS) and overall survival (OS) was analyzed by Kaplan-Meier analysis with regard to the underlying genotype. Results: The presence of the -609G allele was associated with increased FNTB promoter activity in vitro, compared to the -609C allele. However, the main effect of lonafarnib treatment in terms of PFS and OS was exclusively limited to patients, bearing a -609GG genotype (HRPFS 4.9, p<0.001; HROS 9.0, p=0.001). Median PFS for patients with -609GG genotype in the FTI treated arm was 10 months, whereas median PFS for placebo treated patients was 40 months. Median OS in the FTI treated group was 19 months, whereas median OS was not reached in the non-treated group. Conclusions: Observed discrepancies between preclinical and clinical results might be related to higher inter-individual variability of the FNTB locus in patients. Nevertheless, our results encourage to re-evaluate FNTB polymorphisms in other FTI studies, especially those including patients with FTI response.