tbuckley/cabot-search huggingface dataset:
Results of the prospective, randomized, and customized NSCLC adjuvant phase II trial (IFCT-0801, TASTE trial) from the French Collaborative Intergroup.
Authors: Jean-Charles Soria, Fabrice Barlesi, Benjamin Besse, Julien Mazieres, Patrick Merle, Jacques Cadranel, Clarisse Audigier-Valette, Denis Moro-Sibilot, Laure Gautier-Felizot, Francois Goupil, Patrick Renault, Elisabeth A. Quoix, Pierre Jean Souquet, Anne Madroszyk, Romain Corre, David Pérol, Laurence Baudrin, Franck Morin, Gerard Zalcman, Marie Wislez
Journal: Journal of Clinical Oncology (2013)

7505 Background: Surgical resection followed by adjuvant platinum-based CT is the standard of care in stages II and III of NSCLC. ERCC1 is considered as a molecular determinant of benefit to platin-based CT and is an independent good prognostic marker in resected NSCLC. EGFR mutations predict for erlotinib efficacy. We included ERCC1 IHC status and EGFR mutational status in a prospective randomized multicentric phase II/III customized adjuvant CT trial. Methods: Completely resected patients (pts) with non-squamous tumors, mediastinal lymph node dissection and pathological stage IIA, IIB or IIIA (N2 excluded) (6 th TNM edition) were randomized either to a control arm (A) or a customized arm (B). Surgical blocks were centralized for biomarkers analyses. The control arm encompassed 4 cycles of standard dose cisplatin-pemetrexed (CP). In the experimental arm, EGFR mutated pts received erlotinib 150 mg for one year. ERCC1 negative pts received four cycles of CP. ERCC1 positive pts were closely monitored. The Fleming’s single stage phase II primary endpoint was feasibility (ie % of patients able to start therapy within 2 months of surgery and for which the biomarker’s status was readily available) (H 0 64%, H 1 80%, α 5% and β 95%). Results: 150 pts were randomized between May 2009 and July 2012, 74 in arm A and 76 in arm B. Most pts were male (61%), ≤ 60 years (51%), and smokers (91%). Pathological stage was IIA in 69 pt, IIB in 48 pt and IIIA in 32 pt. ERCC1 was positive in 38 pts (19 in each arm), EGFR mutation was identified in 10 pts (3 in arm A, 7 in arm B). In arm A, all pts received CP. In arm B, 7 pts received erlotinib, 53 pts received CP and 16 were followed-up. The median exposure time to erlotinib was 276 days (10-365). Out of 127 pts allocated to CP, 82% received the expected 4 cycles with a very good tolerability profile (no febrile neutropenia). The success rate was 80% (120 out of 150 pts). Conclusions: This adjuvant trial met its primary end point for its phase II component, demonstrating the feasibility of a national biology-driven trial in the adjuvant setting. Nevertheless the phase III was canceled due to the unexpected unreliability of the ERCC1 IHC read-out. Clinical trial information: NCT00775385.
Value of malignant pleural effusion supernatants (MPEs) in epidermal growth factor receptor (EGFR) mutation detection of patients with advanced lung adenocarcinoma (ADC).
Authors: Shuhang Wang, Hanxiao Chen, Jie Wang, Hua Bai
Journal: Journal of Clinical Oncology (2015)

e19093 Background: No study has compared MPEs with matching tumor tissues and plasma DNA and clinical value of MPEs for advanced ADC patients with pleural effusions is not confirmed. This study aims to evaluate MPEs as surrogate of tissue for EGFR mutation detection, and the correlation with efficacy of EGFR-TKI (tyrosine kinase inhibitor) treatment. Methods: 297 MPE samples from advanced lung ADC patients were collected, in which 92 have matched tissues and 248 have matched plasma samples. EGFR (exon 19 deletion and exon 21 L858R) mutation was detected by denaturing high performance liquid chromatography (DHPLC). Results: EGFR mutation rate in MPE is 39.1% (116/297). Consistency of MPE supernatant and tissue was 87.0% (Kappa = 0.71), sensitivity and specificity was 92.6%, 84.6% separately. For patients with EGFR mutant MPE treated with EGFR-TKI, the objective response rate (ORR) (54.5% VS. 18.9%, p < 0.001), progression free survival (PFS) (8.9m vs. 3.0m, P < 0.001) and overall survival (OS) (24.0m vs. 17.5m, P = 0.022) was significantly higher compared with EGFR wild MPEs patients. In subgroup patients of whom MPEs obtained before EGFR-TKI treatment, patients with EGFR-mutant MPEs (n = 78) had greater advantages in TKI therapy, compared with the EGFR-wild ones (n = 91) (ORR: 55.1% vs. 19.8% in EGFR-wild group; DCR: 92.3% vs. 65.9%; P < 0.001). Compared to chemotherapy, EGFR-TKI could benefit EGFR-mutant group with higher ORR (56.1% vs. 16.7%, P = 0.001) and longer PFS (8.8m vs. 3.5m, P < 0.001). Further analysis showed patients with exon 19 deletion mutation in MPE could benefit from first-line EGFR-TKI followed second-line chemotherapy with a median OS of 31.5m VS 20.7m (P = 0.036) compared with those treated with first-line chemotherapy followed EGFR-TKI, while patients with exon 21 L858R mutation showed the opposite result. Conclusions: MPEs could be used as surrogate for tumor tissue to detect EGFR mutation. Lung ADC patients with EGFR mutation in MPEs could benefit from EGFR-TKI treatment. Patients with EGFR exon 19-deletion mutation in MPE may prioritize first-line EGFR-TKI followed chemotherapy.
A preliminary study on the interaction between Asn-Gly-Arg (NGR)-modified multifunctional nanoparticles and vascular epithelial cells
Authors: Chunxi Liu, Tingxian Liu, Xiaoyue Yu, Yizhu Gu
Journal: Acta Pharmaceutica Sinica B (2017)

Previously developed Asn-Gly-Arg (NGR) peptide-modified multifunctional poly(ethyleneimine)–poly(ethylene glycol) (PEI–PEG)-based nanoparticles (TPIC) have been considered to be promising carriers for the co-delivery of DNA and doxorubicin (DOX). As a continued effort, the aim of the present study was to further evaluate the interaction between TPIC and human umbilical vein endothelial cells (HUVEC) to better understand the cellular entry mechanism. In the present investigation, experiments relevant to co-localization, endocytosis inhibitors and factors influencing the internalization were performed. Without any treatment, there was no co-localization between aminopeptidase N/CD13 (APN/CD13) and caveolin 1 (CAV1). However, co-localization between CD13 and CAV1 was observed when cells were incubated with an anti-CD13 antibody or TPIC. As compared with antibody treatment, TPIC accelerated the speed and enhanced the degree of co-localization. TPIC entered HUVEC not only together with CD13 but also together with CAV1. However, this internalization was not dependent on the enzyme activity of CD13 but could be inhibited by methyl-β-eyclodextfin (MβCD), further identifying the involvement of caveolae-mediated endocytosis (CvME). This conclusion was also verified by endocytosis inhibitor experiments.
A randomized trial of single versus multiple fractions (Fx) for re-irradiation (RE-RT) of painful bone metastases (PBM): NCIC CTG SC.20.
Authors: Edward Chow, Yvette van der Linden, Daniel Roos, William F. Hartsell, Peter Hoskin, Jackson S.Y. Wu, Michael Brundage, Abdenour Nabid, Carolyn F. Wilson, Ralph M. Meyer, Bingshu E Chen, Rebecca Wong
Journal: Journal of Clinical Oncology (2013)

9502 Background: The optimal RE-RT dose and fractionation schedule for PBM is uncertain. Methods: Patients (pts) with PBM after previous radiation (RT) to the same site were stratified by previous Fx schedule and pain response and randomized to 8 Gy in 1 Fx or 20 Gy in 5 Fx (8 Fx if previous RT was to spine/whole pelvis in multiple Fx). The primary endpoint was overall response rate (RR) at 2 months using the International Consensus schema (Chow 2002) which combines Brief Pain Inventory worst pain score and opioid analgesic use. We tested if 8Gy was non-inferior (NI), analyzed by intention to treat (ITT) and a per-protocol (PP) sensitivity analysis excluding those who were ineligible, inevaluable or received non-allocated therapy. Sample size was calculated using an expected RR of 70% with 20Gy and a NI margin of 10% (i.e. upper boundary of 1-sided 95% CI for the RR difference). Pts reported adverse events (AEs) by questionnaire on Day 14. Quality of life (QoL) was assessed using the EORTC QLQ C30. Results: Between 01/2004 and 06/2012, we enrolled 850 pts from 9 countries. Most common cancers were prostate (27%), breast (26%) and lung (22%). Before the 2 month assessment, 98 (11%) pts died. By ITT, the 2-month RR was available in 66% (557/850) and was 119/425 (28%) with 8Gy and 136/425 (32%) with 20Gy (P=0.2); the upper boundary of the 95% CI for RR difference = 9.2% and is less than the pre-specified NI margin. By PP analysis, 2-month RR was available in 521 and was 117/258 (45.3%) with 8Gy and 135/263 (51.3%) with 20Gy (P=0.17); the upper boundary of the 95% CI for RR difference = 13.2%, which exceeds 10% non-inferiority boundary. Day 14 AEs differing by treatment were: lack of appetite (P=0.01), vomiting (P= 0.001), diarrhea (P=0.02) and skin reddening (P=0.002); all were worse with 20Gy. There were 30 vs 20 pathological fractures and 7 vs 2 spinal cord compressions with 8Gy and 20Gy, respectively (P=NS). No difference in QoL existed between arms. Conclusions: In pts with PBM receiving RE-RT, the 2-month RR obtained with 8Gy is non-inferior to 20 Gy when assessed by ITT but findings were not robust to a PP sensitivity analysis. When choosing between options tested, trade-offs exist between pain response and acute toxicity. Clinical trial information: NCT00080912.
Incidence of neurotoxicity and ototoxicity with cisplatin vs. non-cisplatin regimens: A meta-analysis with subgroup analyses based on renal eligibility criteria.
Authors: Brandon Kyle Bellows, Arati Dahal, Matt D. Galsky, Guru Sonpavde, Neeraj Agarwal
Journal: Journal of Clinical Oncology (2013)

e15555 Background: Using glomerular filtration rate (GFR) to screen patients for trial eligibility may reduce the risk of cisplatin (CIS) associated nephrotoxicity compared to serum creatinine (SCr). The impact of using GFR or SCr on incidence of neurotoxicity and ototoxicity remains unknown. This meta-analysis compared incidence of neurotoxicity and ototoxicity among trials of solid tumors treated with CIS reporting nephrotoxicity when renal function was assessed using SCr or GFR. Methods: A PubMed literature search identified randomized trials comparing CIS to non-CIS containing chemotherapy regimens. Studies were included if performed from 1990-2010, used SCr or GFR as eligibility criteria, and reported incidence of WHO or NCI grade ≥3 nephrotoxic events. Separate analyses were performed on studies reporting grade ≥3 neurotoxic or ototoxic events. For neurotoxicity, studies comparing CIS to other neurotoxic drugs were excluded. Review articles, observational studies, phase 1 studies, non-randomized trials, studies without a comparator group, or studies not reported in English were excluded. Relative risk (RR) associated with CIS vs. non-CIS regimens was calculated and subgroup analyses were performed for studies using SCr, GFR, and either SCr or GFR for screening. Results: The literature search identified 2359 studies with 18 studies meeting all inclusion and exclusion criteria for neurotoxicity (N=3441 patients) and 9 for ototoxicity (N=2947). The RR for developing neurotoxicity was 1.27 (p=0.50) and ototoxicity was 2.32 (p=0.10) for CIS vs. non-CIS regimens. For neurotoxicity, the RR when SCr was used as eligibility criteria was 2.31 (p=0.11), 0.71 (p=0.54) when GFR was used, and 1.01 (p=0.99) when either was used. For ototoxicity, the RR for SCr was 2.33 (p=0.21) and 3.47 (p=0.20) for either. Studies using GFR reported zero ototoxic events. Conclusions: The risk of neurotoxicity and ototoxicity did not significantly change when SCr or GFR was used to screen patients. However, these analyses were performed on a subgroup of studies reporting nephrotoxicity and further research on all studies of neurotoxicity and ototoxicity is warranted.
Detection of novel HPV mutations and chromosomal number imbalance (CNI) in laryngeal cancer using next-generation sequencing (NGS).
Authors: Howard B. Urnovitz, Julia Beck, Kirsten Bornemann-Kolatzki, Brent E Richardson, John H Lee, William Marvin Mitchell, Ekkehard Schütz
Journal: Journal of Clinical Oncology (2014)

6072 Background: We selected HPV-associated laryngeal papillomas and squamous cell carcinomas for genomic analysis of viral induced benign and malignant neoplasms. The nearly universal presence of HPV in Recurrent Respiratory Papillomatosis (RRP) and in certain squamous cell carcinomas provides an important model for the study of biomarkers and clinical outcomes as well as the generation of robust panels of viral and genomic mutation biomarkers that can be used to follow disease progression. Methods: DNA was isolated from biopsies of three patients and sequenced on a NGS Illumina HiSeq platform. The sequences were compartmentalized in 250kbp bins, normalized, and compared to the mean (+/- 3SD) of Chronix controls to identify regions of chromosomal number imbalance (CNI). Sequences were also compared to databases with known viral genomes. Results: Sample 1: an exophytic, focally invasive, HPV positive (PCR), squamous cell carcinoma from a never-smoker. The full genome of HVP16 was detected in low amount (~ 500 sequences/10 million sequences, average coverage=42 fold). Mismatches to the closest reference HPV16 strain isolate were found in protein (number of mismatches) E7 (1), E1 (2), E2 (4), E4 (1), L2 (3) and L1 (4). Sample 2: from a RRP patient, contained the full genome of HPV6, also in low amount (~300 sequences/10 million sequences, average coverage = 24 fold). Interestingly, the HPV long control region was a variant as yet undescribed. Sample 3: from a RRP patient whose papillomas slowly and spontaneously regressed, did not contain any detectable viral DNA. Only the HPV16 squamous cell carcinoma contained CNI with gains at chromosomes 3q and 8p, and losses at chromosomes 3p, 11q, 12p, and 21q consistent with a malignant transformation. Conclusions: NGS reveals the identity and copy number of viral genes directly from clinical samples. This approach has revealed new HPV mutations not described by current viral analytical procedures. The detection of novel HPV mutations and CNI analysis in a single NGS run on HPV-related diseases provides important information into viral-host dynamics while generating biomarkers that can be correlated with treatment outcomes.
A phase I study of the safety, tolerability, pharmacokinetics, and immunoregulatory activity of urelumab (BMS-663513) in subjects with advanced and/or metastatic solid tumors and relapsed/refractory B-cell non-Hodgkin’s lymphoma (B-NHL).
Authors: Ignacio Melero, Tara C. Gangadhar, Holbrook Edwin Kohrt, Neil Howard Segal, Theodore Logan, Walter John Urba, F. Stephen Hodi, Patrick Alexander Ott, Jose Luis Perez-Gracia, Jedd D. Wolchok, Aadhar Shah, John F. Kurland, Lewis J. Cohen, Ronald Levy, Jon M. Wigginton, Stacie M. Goldberg
Journal: Journal of Clinical Oncology (2013)

TPS3107 Background: CD137 (4-1BB) is a costimulatory molecule that belongs to the TNF superfamily. It is upregulated on activated lymphocytes, NK cells and dendritic cells and plays an important role in the potentiation of antigen-specific immune responses in T-cell directed therapy as well as in antibody-dependent cell-mediated cytotoxicity. Urelumab is an agonistic antibody targeting CD137 which has demonstrated antitumor activity against a variety of cancers in pre-clinical and clinical studies. We describe a phase I study to investigate the clinical and biologic effects of treatment with urelumab in patients with advanced solid tumors and B-cell non-Hodgkin’s lymphoma (B-NHL). Methods: This phase I study (n=70) will include dose escalation (Part 1) using a 6+9 design, cohort expansion (Part 2), and tumor-specific cohort expansion (Part 3). In Part 1, successive cohorts of pts with advanced solid tumors will be treated as follows: Cohort 1 (0.1 mg/kg q3weeks) and Cohort 2 (0.3 mg/kg q3weeks). In Part 2, both cohorts (1 +2) will expand to 20 patients with advanced solid tumors. In Part 3, additional tumor-specific cohorts with B-NHL, colorectal cancer, and head and neck cancer (10 subjects each) will be enrolled at the highest tolerated dose. The primary objective of this study is to evaluate the safety and to define the MTD of the respective doses of 0.1 and 0.3 mg/kg administered every 3 weeks with special attention to hepatic toxicity. Secondary objectives include assessment of the preliminary antitumor activity, pharmacokinetics, and immunogenicity. Exploratory objectives include investigation of the immunoregulatory activity in peripheral blood and paired tumor biopsy specimens and associations with clinical outcome. Part 1 (dose escalation) has been completed without any DLTs. Clinical trial information: NCT01471210.
Tandem high-dose therapy with autologous stem cell support for small-cell lung cancer (SCLC)
Authors: J. N. Machatschek, G. Kobbe, R. Haas, U. P. Rohr
Journal: Journal of Clinical Oncology (2006)

17033 Background: We evaluated the therapeutic efficacy of tandem high-dose chemotherapy followed by autologous peripheral stem-cell transplantation (PBSCT) in patients with newly diagnosed SCLC in complete remission or very good partial response after induction chemotherapy. Methods: Between 1996 and 2000, 19 patients with newly diagnosed SCLC in CR or very good PR after two cycles of induction chemotherapy (cisplatin 90 mg/m 2 day 1, etoposide 120 mg/m 2 day 1–3, ifosfamide 1500 mg/m 2 day 1–4) received a tandem high-dose chemotherapy (cyclophosfamide 2000 mg/m 2 day 1 and 2, etoposide 700 mg/m 2 day 1–3, carboplatin 1200 mg/m 2 day 1) followed by PBSCT. Following transplantation, patients received concurrent chest and cranial radiotherapy to a total dose of 45 Gy and 30 Gy, respectively. Results: Of 19 patients with SCLC, 18 had stage III and one stage IV disease. The median age was 50.7 years. Median time to leukocyte-recovery above 1000/μl and platelet-recovery above 20.000/μl was 12 days and 9 days, respectively. The median follow-up was 6.38 years (range 5.11–7.23) for surviving patients. There were no transplant-related deaths and toxicity was moderate. Using the Kaplan-Meier method, the 2- and 5-year survival rates after high-dose therapy were 42% and 32% respectively. Median time to relapse was 0.7 years (range 0.2–4.6). The mean survival was 36.8 months. This outcome compared favourably to a group of 77 patients who did not receive high-dose therapy but responded to conventional chemotherapy (mean survival 11.4 months). Using the Cox regression model, among all patients response to induction, normal LDH and PBSCT were associated with favourable outcome. Conclusions: Our findings suggest that patients with or near complete response after conventional therapy might benefit from tandem high-dose therapy with PBSCT with tolerable toxicicity. No significant financial relationships to disclose.
Expression and function of TIM-3, a potential therapeutic target in acute myeloid leukemia.
Authors: Catherine Joy Lee, Lawrence Patrick Kane
Journal: Journal of Clinical Oncology (2014)

7095 Background: Transmembrane immunoglobulin mucin-3 (TIM-3) is a cell-surface protein that has been identified as a novel acute myeloid leukemia stem cell (AML-LSC) surface marker and a potential candidate for targeted therapy with monoclonal antibodies. However, the function of TIM-3 on LSCs and blasts, and in the pathogenesis of AML, is currently unclear. We have shown in T cells that TIM-3 regulates the growth and survival of normal and transformed cells by activation of kinase Akt (pAkt) and phosphorylation of ribosomal S6 protein (pS6). We hypothesize that TIM-3 may similarly contribute to the survival of AML through activation of pAkt and pS6 in LSCs and leukemic blasts. Methods: Established human AML cell lines NB4, U-937, and HL-60 were assessed for surface TIM-3 expression by flow cytometry and western blot when at rest and when stimulated with phorbol 12-myristate 13- acetate (PMA; 5 ng/ml, 10 ng/ml, 50 ng/ml) for 24-72 hrs. Cell surface CD11b was used as a marker for PMA-induced monocytic differentiation. Primary human AML peripheral blood samples were analyzed for TIM-3 and intracellular pS6 expression in the CD34+population by flow cytometry. Results: 1) Basal levels of TIM-3 expression were minimal in NB4, U-937, and HL-60 cells; however, TIM-3 expression was up-regulated at least two-fold in all cell lines during PMA-induced differentiation along the monocytic/macrophage lineage by 24 hrs. 2) In a 24-hour kinetics assay, TIM-3 up-regulation occurred at 6 hrs versus 10 hrs for CD11b in NB4 cells. 3) Four primary human AML samples were obtained thus far. We identified a TIM-3+CD34+pS6+population from at least two of these patients. Conclusions: We have evaluated the expression and possible function of TIM-3 in AML cell lines and primary human AML samples. In NB4 cells, TIM-3 may be involved in the differentiation pathway of AML cells by PMA as up-regulation of TIM-3 preceded that of CD11b. We have also identified human AML samples that express TIM-3 and pS6 in the CD34+ population. Ongoing studies include the use of TIM-3 modulating antibodies on AML cell lines and on CD34+CD38-TIM3+ primary AML samples to determine the role of TIM-3 on downstream signaling activation, and on viability, proliferation, and differentiation.
Effect of tumor-infiltrating T-lymphocytes on the aggressiveness of epithelial ovarian tumors.
Authors: Ines Vasconcelos, Sven Olek, Katharina Gellhaus, Tim Schwachula, Ioana Braicu, Christina Fotopoulou, Radoslav Chekerov, Desislava Dimitrova, Jalid Sehouli
Journal: Journal of Clinical Oncology (2012)

5053 Background: Borderline ovarian tumors (BOT) are a low-grade form of ovarian malignancy with significantly less aggressive behavior than epithelial ovarian cancer (EOC). Since there is neither convincing scientific evidence nor a marker capable of predicting BOT’s behavior, we analyzed the role of immune tolerance in differential disease outcome. EOC and BOT were chosen due to similar disease etiology, despite different disease courses. Increased numbers of T-cell subpopulations infiltrate malignant tumors, so we used epigenetic tests to determine the prevalence of regulatory T-cells (Treg) and overall-T-Lymphocytes (oTL) in EOC and BOT. Methods: The ovarian cancer samples were provided by the European multicentric OVCAD study. The BOT samples were obtained from Tumor Bank Ovarian Cancer at Charité Campus Virchow (Germany). Samples and clinical data were prospectively collected and documented using validated SOPs. DNA was bisulphite-converted and forwarded to methylation-specific RT-PCR for CD3 and FOXP3 loci. Results: We evaluated 90 high-grade EOC, 12 BOT with invasive implants and 25 non-invasive BOT samples. Higher oTL-values correlate with mortality (p=0.008) and recurrence (p&lt;0.001), while higher Treg levels correlate with recurrence (p=0.028). Patients with non-invasive BOT have lower oTL (p=0.019) and Treg (p=0.0005) levels than patients with invasive BOT and EOC, while BOT (both invasive and non-invasive) patients have lower Treg-to-oTL ratios than EOC patients (p=0.0005). Finally, oTL levels associate with overall survival in EOC (p=0.042). Conclusions: We observed a strict correlation between tumor-type, Treg and oTL levels, as well as Treg-to-oTL ratio. This is in agreement with our hypothesis that disease aggressiveness is associated with the amount tumor-infiltrating lymphocytes and may provide the explanation for differing disease courses in EOC and BOT.