tbuckley/cabot-search huggingface dataset:
The role of microRNAs (miRNAs) as predictive biomarker in advanced renal cell carcinoma (mRCC) patients (pts) with “extreme response” to tyrosine kinase inhibitors (TKIs) treatment.
Authors: Carmen Garrigos, Sonia Molina-Pinelo, Marta Espinosa Montano, Antonio Lerma, Ignacio Osman, Rainiero Ávila, Rafael Medina, Ricardo Melendez, Ana Salinas, Jesus Garcia-Donas, Cristina Rodriguez-Antona, Ignacio Duran
Journal: Journal of Clinical Oncology (2017)

470 Background: MiRNAs play an important role as modulators of gene expression in a multitude of biological processes, being closely linked to the regulation of development and cell differentiation. Promising results about their value as predictors of drug response have been published in lung, colorectal cancer [Molina-Pinelo] and RCC [García-Donas]. This study aims to determine whether miRNAs can predict TKIs “extreme responses” in mRCC pts. Methods: RNA from formalin fixed paraffin embedded tumor and non-tumor samples from 15 pts with mRCC was extracted with mirVana miRNA isolation kit (Ambion). We defined as TKI “extreme responders” those pts that either had a long-term response (LR) (PFS˃11 months, n=7) or that were primary refractory (PR) (progression as best response, n=8). The expression of 754 miRNAs was analyzed with TaqMan Low Density Array Human MicroRNA Panel (TLDA) (ThermoFisher). QPCR was carried out in the System of Gene Expression and Genotyping Arrays module ViiA7. A qPCR ThermoFisher software specifically designed was used to calculate the ΔCt, cluster analysis, comparison between groups and primary analysis of the results. MiRNAs differentially expressed were analyzed independently by individual qPCR assays in the same cohort. A validation in an external cohort is being currently conducted. Results: Four miRNAs were significantly associated with patient response and differentially expressed in PR vs. LR (up-regulated in PR: miR-425-5p, down-regulated in PR: miR-139-3p, let-7d, and let-7e). Validation in our cohort was successful with let-7d and let-7e (p&lt;0.05). Regarding differential expression in tumor vs non-tumor samples 14 miRNAs were identified by TLDA. Seven of those were validated in our series (tumor up-regulated: miR-146b, miR-21, miR-155, miR-122; tumor down-regulated: miR135a, miR-200c, miR-187) (p&lt;0.05). These miRNAs were located in genes related with apoptosis, proliferation, metastasis, migration, and oncogenic pathways. Conclusions: MiRNAs could represent a valid predictive biomarker in mRCC treatment. These results need further validation in an independent cohort [work in progress].
Use of dasatinib in patients (pts) with previously untreated chronic myelogenous leukemia (CML) in chronic phase (CML-CP)
Authors: E. L. Atallah, H. Kantarjian, S. O'Brien, D. Jones, G. Borthakur, C. Nicaise, J. Cortes
Journal: Journal of Clinical Oncology (2007)

7005 Background: Dasatinib (formerly BMS-354825) is a multi-targeted kinase inhibitor of BCR-ABL and SRC. Based on its high level of activity in pts with imatinib (im) resistant/intolerant CML-CP, the present phase II trial was designed to study previously untreated CML-CP pts treated with dasatinib. The primary objective was to estimate the proportion of pts attaining major molecular response (BCR-ABL/ABL ratio =0.05% by qPCR) at 12 months (mo). Methods: All pts received dasatinib orally 100 mg/day, and were randomized to either a 50 mg-twice-daily or a 100 mg-once-daily schedule. Dose escalation to 140 mg/day and 180 mg/day for poor response or dose reduction to 80 mg/day and 40 mg/day for toxicity, maintaining the same schedule, was allowed. Results: Of the 31 pts enrolled between 11/05 and 12/06; 52% were female; median age was 41 years (range 18–76). At 3 mo, complete hematologic response (CHR) and major cytogenetic response both occurred in 21 (81%) of 26 evaluable pts and complete cytogenetic response (CCyR) in 19 (73%) pts. After 6 mo of therapy, 20/21 (95%) evaluable pts had achieved CCyR. This compares favorably with a CCyR at 6 mo of 54% with im 400 mg/day and 85% with im 800 mg/day, in historical data of similar patients treated in studies at MD Anderson. At 9 mo, 4/15 (27%) evaluable pts had achieved a major molecular response. The most common non-hematologic adverse events (AE) included dyspnea (8 pts), fatigue (7 pts), muscle pain (6 pts), and headache (5 pts) and were predominantly grade (gr) 1–2. Pleural effusion occurred in only 3 pts (gr 1–2 in all). Grade 3–4 hematologic toxicity (transient) included anemia in 4 pts, neutropenia in 7 pts, and thrombocytopenia in 4 pts. With a median duration of therapy of 10 mo, 13 pts required transient treatment interruption, 9 due to non-hematologic toxicities, 3 due to hematologic toxicities, and 1 due to both. The actual median daily dose for all pts was 100mg. No difference in AEs has been observed between dose schedules. Conclusions: Rapid, complete cytogenetic responses to dasatinib 100 mg/day have been observed in a high percentage of patients with previously untreated CML- CP. Accrual to this trial continues. No significant financial relationships to disclose.
Differentiation of germinal center B cells into plasma cells is initiated by high-affinity antigen and completed by Tfh cells
Authors: Nike J. Kräutler, Dan Suan, Danyal Butt, Katherine Bourne, Jana R. Hermes, Tyani D. Chan, Christopher Sundling, Warren Kaplan, Peter Schofield, Jennifer Jackson, Antony Basten, Daniel Christ, Robert Brink
Journal: The Journal of Experimental Medicine (2017)

Plasma cells (PCs) derived from germinal centers (GCs) secrete the high-affinity antibodies required for long-term serological immunity. Nevertheless, the process whereby GC B cells differentiate into PCs is uncharacterized, and the mechanism underlying the selective PC differentiation of only high-affinity GC B cells remains unknown. In this study, we show that differentiation into PCs is induced among a discrete subset of high-affinity B cells residing within the light zone of the GC. Initiation of differentiation required signals delivered upon engagement with intact antigen. Signals delivered by T follicular helper cells were not required to initiate differentiation but were essential to complete the differentiation process and drive migration of maturing PCs through the dark zone and out of the GC. This bipartite or two-signal mechanism has likely evolved to both sustain protective immunity and avoid autoantibody production.
Prognostic impact of tumor (T) and lymph node (N) status in metastatic colon cancer (MCC): A validation study using the National Cancer Database (NCDB).
Authors: Shiva Kumar Reddy Mukkamalla, Ponnandai Sadasivan Somasundar, Bharti Rathore
Journal: Journal of Clinical Oncology (2017)

786 Background: T and N status are not routinely utilized in prognosis of MCC. We had previously demonstrated that T and N serve as independent predictors for overall survival (OS) in MCC using SEER [Ann Oncol (2014) 25 (suppl 4): iv172-iv173]. The current study is undertaken to validate our findings using the NCDB. Methods: The NCDB was queried for patients diagnosed with MCC from 2004-2008 with survival information up to 2013. Pearson Chi-square test, Kaplan Meier survival curves and Cox proportional hazards model were used for statistical analysis. Results: A cohort of 5,788 patients was identified for analysis. Frequencies of T1, T2, T3 and T4 among the study population were 6.6%, 4.2%, 52.6% and 36.6% respectively, whereas N0, N1 and N2 were noted in 28.5%, 29.9% and 41.6% respectively. 5-year OS worsened with advancing T and N status, with the exception of T1 disease (Table). T1 disease was associated with poor prognosis compared to T2 and T3, but showed better survival outcome than T4 (p &lt; 0.05). Both T and N were identified as independent predictors of OS regardless of age, gender, race, comorbidity index, insurance status, income level, tumor sidedness, tumor grade, surgery, chemotherapy and academic level of treating institution. In multivariate analysis, we found left sided tumors to have better survival outcome compared to right (HR 0.85; p &lt; 0.0001). Conclusions: Similar to our previous findings, in MCC patients, a T1 status portends poor prognosis compared to T2 or T3 disease. It is possible that an overrepresentation of tumors, with a distinct biological subtype characterized by a tendency for early dissemination in T1 disease could be associated with poor outcomes observed in this patient subgroup. In future, we plan to validate this finding through T1 subgroup analysis. Our study also demonstrates poor OS in right sided tumors compared to left sided tumors, similar to prior studies by Schrag et al and Venook et al. [Table: see text]
Outcomes of patients ≥ 65 yrs with advanced cancer treated on phase I clinical trials.
Authors: Ishwaria Mohan Subbiah, Jennifer J. Wheler, Kenneth R. Hess, David S. Hong, Siqing Fu, Robert A. Wolff, Razelle Kurzrock, Apostolia Maria Tsimberidou
Journal: Journal of Clinical Oncology (2013)

9544 Background: Older patients with cancer are underrepresented in clinical trials; their disease biology and comorbidities may impact the decision to consider a clinical trial. Here we systematically analyze outcomes of elderly pts treated on phase I clinical trials. Methods: The characteristics, toxicity, survival, and response of pts with advanced cancer treated on phase I clinical trials from 1/04 – 12/09 were studied. Results: Overall,347 of 1,182 pts (29%) were &gt;65 yrs old. The Table lists pt characteristics by treatment regimen. 251 pts received a targeted agent, of which 241 (96%) received an investigational, non-FDA approved drug. Of 347 pts, 3 (1%) had a CR, 15 (4%) a PR, 127 (37%) SD, of which 43 (12%) had SD ≥ 6mos. Of 347 pts, 194 (56%) had &gt;1 drug-related toxicity, of which 89 (26%) had a Grade 3-4 toxicity, most often hematologic; 72% of toxicities on targeted therapies were Grade 1-2. Six pts had a DLT; there was one death (&lt;0.01%) “possibly” attributed to the study drug. Median OS from 1st phase I Clinic visit was 8.8mos (95% CI, 7.8-10.6). Median TTF on 1st phase I trial was 1.9mos (95% CI, 1.8-2.1). Multivariate analyses demonstrated that ECOG PS 2-3 (vs. 01) (p &lt;0.001) and liver mets (vs. no liver mets) (p &lt;0.01) were independent factors predicting shorter TTF and OS. Conclusions: Our results suggest that phase I clinical trials are well tolerated and offer a reasonable therapeutic option for pts &gt; 65 yrs. [Table: see text]
Long-term follow-up of a phase Ib trial of idelalisib (IDELA) in combination with chemoimmunotherapy (CIT) in patients (pts) with relapsed/refractory (R/R) CLL including pts with del17p/<i>TP53</i> mutation.
Authors: Jacqueline Claudia Barrientos, Steven Coutre, Sven De Vos, Ian Flinn, Nina D. Wagner-Johnston, Marshall T. Schreeder, Jeff Porter Sharman, Thomas E. Boyd, Kanti Roop Rai, John Leonard, Bess Sorensen, Anthony Viggiano, Thomas Michael Jahn, Richard R. Furman
Journal: Journal of Clinical Oncology (2015)

7011 Background: IDELA is a first-in-class PI3Kδ inhibitor approved in combination with rituximab for pts with relapsed CLL. Methods: Pts with R/R CLL were treated continuously with 150 mg BID oral IDELA and a limited # of cycles (C) of CIT to evaluate safety and efficacy of combination regimens. Pts could enroll in extension study after 48 wks. Responses were evaluated by published criteria (Hallek 2008; Cheson 2012). Results: 114 pts (37F/77M) median (med) age 65 (range 41-87) yrs enrolled with: extensive prior therapies (med 3, range 1-9), refractory disease (51%), high risk Rai (60%), del17p/TP53 mutation (29%), del11q (13%), unmutated IGHV (79%). Med exposure was 14.6 (range 0-49) mos. 61 pts (54%) enrolled in extension study. 21 (34%) were continuing on study. Most common and select AEs independent of causality (any Grade/Gr ≥ 3): diarrhea/colitis (52%/19%), pyrexia (45%/4%), cough (37%/1%), nausea (29%/1%), fatigue (32%/4%), pneumonia (23%/15%), dyspnea (22%/3%), rash (21%/4%), pneumonitis (4%/4%). AST/ALT elevation Gr ≥ 3 was seen in 12%. Most common reasons for discontinuation were AEs (25%) or PD (25%). 2 pts discontinued due to AST/ALT elevation, 1 due to Richter’s transformation. 20 (18%) deaths were reported on study; 6 pts experienced PD before death. ORR was 82.5% in all pts, 70% in pts with del17p/TP53 mut, and 87% among pts without. SD/PD was reported in 10%/3%. Med overall PFS was 26.1 mos, 20.3 mos for pts with del17p/TP53 mut, and 36.8 mos for pts without. Med OS for all pts or pts with del17p/TP53 mut was not reached. Estimated OS at 36 mos was 73.1% for all pts, 57.3% for pts with del17p/TP53, and 78.3% for pts without. Conclusions: IDELA in combination with CIT shows a manageable safety profile without increased toxicities and has substantial clinical activity in heavily pretreated, refractory, and high-risk CLL including presence of del17p/TP53mutation. Phase 3 trials of IDELA with O or BR in pts with R/R CLL are ongoing (NCT01659021, NCT01732926). Clinical trial information: NCT01088048.Idelalisib +. Rituximab (R) N=19 Ofatumumab (O) N=21 Bendamustine (B) N=18 BR N=15 Fludarabine (F) (oral) N=12 Chlorambucil (Chl) N=15 ChlR N=14 8 wks up to 6 C up to 12 C
Safety and tolerability of clarithromycin in the treatment of multidrug-resistant tuberculosis
Authors: Anne-Fleur Louise Van der Paardt, Onno W. Akkerman, Gina Gualano, Fabrizio Palmieri, Lina Davies Forsman, Alena Aleksa, Simon Tiberi, Wiel C.M. de Lange, Mathieu S. Bolhuis, Alena Skrahina, Dick van Soolingen, Jos G.W. Kosterink, Giovanni Battista Migliori, Tjip S. van der Werf, Jan-Willem C. Alffenaar
Journal: European Respiratory Journal (2017)

Multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) are an emerging global threat. An estimated 3.3% of newly diagnosed TB patients and 20% of previously treated patients worldwide have MDR-TB [1]. Moreover, 9.7% of MDR-TB cases are suffering from XDR-TB. Treatment of TB is becoming more difficult since the resistance pattern of Mycobacterium tuberculosis is expanding and treatment success rate is decreasing, with newly emerging drug-resistant strains [2]. Therefore, evaluation of antimicrobial drugs active against M. tuberculosis is necessary. Clarithromycin (CLR) is a macrolide antibiotic previously listed as a World Health Organization (WHO) group 5 drug, but not included in the new WHO classification because it has only modest bacteriostatic effects against M. tuberculosis [3]. However, the in vitro synergy of CLR in combination with linezolid, ethambutol and spectinomycin, and its immunomodulatory effects, hold promise [4–6]. Despite the introduction of newer drugs such as bedaquiline and delamanid, clarithromycin may have added value for the treatment of TB patients in cases of extensive resistance but proven susceptibility to clarithromycin. Unfortunately, real-life data on the use of clarithromycin to guide physicians in the treatment of MDR-TB is scarce. Clarithromycin had a good tolerability and safety profile as assessed in MDR-TB patients receiving prolonged treatment <http://ow.ly/r8Jh306Ac0u>
Phase II study of low dose suramin as a sensitizer of paclitaxel/carboplatin (P/C) in non small cell lung cancer (NSCLC)
Authors: M. A. Villalona-Calero, G. A. Otterson, G. Wientjes, K. Kobayashi, R. Jensen, D. Young, T. Yeh, S. Song, M. Grever, J. Au
Journal: Journal of Clinical Oncology (2004)

7108 Background: We described that elevated levels of acidic/basic fibroblastic growth factors in the extracellular medium of metastatic tumors result in tumor resistance to anticancer drugs and that low (10–15μM) suramin (S) concentrations (conc) produce reversal of resistance to paclitaxel in vivo (PNAS 2000; Cancer Res 2001). We also demonstrated that low dose S did not add to the toxicities of P/C in NSCLC pts and that pharmacokinetics (PK) were predictable and permitted the derivation of an equation for individualized dosing yielding the targeted range of S conc. Methods: P/C in combination with low dose S was evaluated in two arms: A-previously untreated patients and B- patients who had progression of disease while on P/C or within 3 months of treatment. Patients received i.v. P 200 mg/m2 and C AUC 6 on day 1, every 3 wks. S was administered i.v. in 2 divided doses; one preceding P/C (2/3rds of dose) and the other 24 hrs following (remaining 3rd), every 3 wks. The total dose of S was calculated based on the following: S Dose in mg = FACTOR x (absolute value of body surface area)2. First dose FACTOR was 125, whereas for subsequent cycles, FACTOR depended on the time lapsed since previous dose. Results: 54 pts were enrolled; 43 on Arm A and 11 on Arm B. 14 of 39 evaluable patients in Arm A experienced major antitumor responses (2 CR, 12 PR) (RR 37%, 95% CI 22–54%) and 15 additional patients (38%) had prolonged disease stabilization (≥4 months). The median time to tumor progression was 7 months. Although no responses were observed on Arm B (11 pts), prolonged disease stabilization (≥ 4 months) occurred in 4 pts. The most frequent moderate to severe toxicities were neutropenia (G4, 27 pts; febrile, 2 pts), peripheral neuropathy (G3, 3 pts), and fatigue (G3, 6 pts). S PK analysis in 41 pts revealed that the targeted minimal conc of 10μM was attained in >95% of treatments, and avoided >50μM conc in >99% of treatments. Conclusions: Suramin conc can be predicted based on clinical parameters. The tolerability and antitumor activity observed suggest a beneficial modulatory effect on standard NSCLC treatment. Further testing of this concept through randomization is warranted. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Optimum Therapeutics National Cancer Institute
Conditional survival (CS) in patients with stage II melanoma.
Authors: Victoria Gamerman, Giorgos Constantine Karakousis, DuPont Guerry, Phyllis A. Gimotty
Journal: Journal of Clinical Oncology (2012)

e19054 Background: While sentinel lymph node biopsy is recommended for those presenting with clinical stage II melanoma, it is not always performed. Future survival beyond the time already survived is captured by CS and is relevant to patient counseling and guiding follow up. We sought to investigate patterns of CS in patients with clinical (no nodal biopsy) or pathological stage II melanomas controlling for ulceration. Methods: The study included 5,370 patients diagnosed with primary cutaneous melanoma in 2004-2008 from the Surveillance, Epidemiology, and End Results (SEER) data. Three-year CS probabilities were estimated from the Kaplan-Meier survival curves (time to melanoma-specific death) at 6, 12, and 18 months from diagnosis. Newly developed biostatistical methods were used to evaluate the statistical significance of changes in CS as the time survived increased for four groups of patients: those clinically and pathologically staged with and without ulceration. Results: With increasing time survived up to 18 months, there was no significant change in the 3-year CS estimates for the cohort of pathologically-staged patients with non-ulcerated lesions (n=1702). For pathologically-staged patients with ulcerated lesions (n=1915), 3-year CS increased significantly only after having survived 1 year (86% to 87% p=0.001). A similar pattern was seen for the cohort of clinically-staged patients with non-ulcerated lesions (n=801), (85% to 87% p&lt;0.001). For clinically-staged patients with ulcerated lesions (n=952), the 3-year CS estimates for those who had survived 6, 12, or 18 months were 74%, 78%, and 82%. After the initial 6 months of survival, there was a significant change in 3-year CS having survived 6 versus 12 months (p=0.002), as well as having survived 12 versus 18 months (p&lt;0.001). Among patients with ulcerated lesions, CS for those clinically staged begins to change after 6 months whereas for those pathologically staged change occurs only after a year. Conclusions: CS provides up-to-date prognostic information to patients, their physicians and clinical trialists. Formal statistical methods, as illustrated here, identify when clinically meaningful CS estimates change in statistically significant ways.
TBCRC 018: Phase II study of iniparib plus chemotherapy to treat triple-negative breast cancer (TNBC) central nervous system (CNS) metastases (mets).
Authors: Carey K. Anders, Allison Mary Deal, Vandana Gupta Abramson, Minetta C. Liu, Anna Maria Storniolo, John T. Carpenter, Shannon Puhalla, Rita Nanda, Amal Melhem-Bertrandt, Nancy U. Lin, Paul K. Marcom, Catherine H. Van Poznak, Vered Stearns, Michelle E. Melisko, J. Keith Smith, Olga Karginova, Eric P. Winer, Charles M. Perou, Antonio C. Wolff, Lisa A. Carey
Journal: Journal of Clinical Oncology (2013)

515 Background: Nearly half of women with advanced TNBC develop CNS mets. This study evaluated the safety and efficacy of iniparib, a small molecule anti-cancer agent that penetrates the blood brain barrier (BBB), and the topoisomerase I inhibitor, irinotecan, in patients (pts) with TNBC CNS mets. Methods: Eligible pts had TNBC with new or progressive CNS mets with at least 1 measurable (&gt; 5mm) lesion. Pts received irinotecan 125mg/m 2 IV days (d) 1, 8 and iniparib (initial dose 5.6mg/kg, later changed to 8mg/kg) IV d 1, 4, 8, 11 every 21d. Tumor response rate (RR) was assessed by brain MRI and body CT every 9 weeks. The Kaplan Meier method estimated the primary endpoint of time to progression (TTP, intracranial [modified RECIST] or extracranial [RECIST 1.1]). Secondary endpoints were RR, PFS, OS, quality of life (QOL) and correlative endpoints. Results: Of 37 pts who began treatment, 34 were evaluable for efficacy. Mean age was 48 yrs (34 – 80 yrs). BRCA status was known for 16 patients of whom 5 had a mutation (4 BRCA1, 1 BRCA2). 88% received prior (neo)adjuvant and 68% prior metastatic chemotherapy (median 2 [1–14] lines). While 15% were CNS radiation (RT) naïve, 32% had received whole brain RT, 21% stereotactic RT, and 32% both. The most common grade (gr) 3/4 adverse events were neutropenia (14%), fatigue (5%), leukopenia (5%), hypokalemia (5%). Diarrhea was common (54%), but gr 3/4 was rare (3%). Median TTP (CNS and non-CNS) was 2.1 months (mos) (95% CI 1.7–4.3) and OS was 7.6 mos (95% CI 5.1-10.2). First progression site was CNS in 39%, non-CNS in 29% or both in 32%. CNS best RR was (12%; 0 CRs, 4 PRs); CNS clinical benefit rate (CBR, CR + PR + SD ≥ 6 mos) was 30%. Non-CNS RR was 5% (0 CRs, 1 PR) and CBR was 11%. Conclusions: Iniparib and irinotecan was well-tolerated among pts with TNBC CNS mets. While TTP was shorter than expected and contribution of iniparib to irinotecan remains uncertain, 30% of pts demonstrated CNS clinical benefit raising the question of whether predictive biomarkers could be identified. QOL, volumetric analysis of CNS lesions and translational studies evaluating molecular subtype, germline BRCA1/2, and DNA repair gene expression/methylation are ongoing. Clinical trial information: NCT01173497.