tbuckley/cabot-search huggingface dataset:
A randomized phase II study of paclitaxel (P) and carboplatin (C) ± bevacizumab (B) ± dulanermin (D) in non-small cell lung cancer (NSCLC).
Authors: F. H. Blackhall, Z. Márk, P. Zatloukal, B. Szima, I. Albert, E. Juhász, X. Yang, D. Smethurst, Y. Hei, J. Soria
Journal: Journal of Clinical Oncology (2010)

7534 Background: D is a pro-apoptotic agonist of death receptors 4 and 5. A randomized, open-label, 5-arm, phase II study evaluated the efficacy and safety of PC ± B ± D in patients (pts) with advanced NSCLC. Methods: Planned sample size = 200 (40/arm). Eligible pts: chemonaïve, advanced NSCLC, ECOG PS 0-1. A brain scan was mandatory. Pts received P (200 mg/m2) + C (AUC = 6 mg/mL min). Pts with squamous NSCLC and/or CNS metastases (met) received PC (Arm 1) vs. PC + D (8 mg/kg for 5 days; Arm 2). Pts with non-squamous NSCLC and no CNS met received PC + B (15 mg/kg; Arm 3) vs. PCB + D (8 mg/kg for 5 days; Arm 4) vs. PCB + D (20 mg/kg for 2 days; Arm 5). Pts received PC ± B ± D ≤ 6 cycles Q3W, then continued B and/or D until disease progression. Primary endpoint: objective response rate (ORR; central assessment of complete and partial responses by modified RECIST). Results: 213 pts were randomized (41, 42, 44, 43, 43 to arms 1-5); all were eligible; 41, 39, 42, 40, 41 received ≥ 1 dose of study drug. Median age was 60 (range 23-79) years, 63% were men, 42% were ECOG PS 0. As of 10/09, 194 pts (dosed; 96%) had discontinued treatment; median follow-up = 49 (range 0-91) wks. See Table for efficacy and safety. The most common serious adverse events (SAE) were pneumonia and pulmonary embolism (each = 4%). Conclusions: PC ± D ± B was well tolerated. In this study, the addition of D did not appear to improve efficacy compared with the standard treatment arms. Squamous NSCLC and/or CNS met Nonsquamous NSCLC and no CNS met 1: PC 2: PC + D 2 vs. 1 3: PCB 4: PCB + D 5: PCB + D 4 vs. 3 5 vs. 3 ORR 16(39%) 16 (38%) OR = 1.04 (0.39, 2.76), p = 1 22 (50%) 17 (40%) 17 (40%) OR = 1.53 (0.6, 3.91), p = 0.39 OR = 1.53 (0.6-3.91), p = 0.39 PFS events; KM median (95% CI), mo 85%; 6.1 (5.4-7.4) 76%; 5.5 (4.7-6.7) HR = 0.89 (0.54, 1.46), p = 0.65 68%; 7.3 (5.6, 8.5) 63%; 8.6 (6, 12.6) 63%; 9.5 (6.8, 13.7) HR = 0.83 (0.49, 1.40), p = 0.48 HR = 0.88 (0.52, 1.48), p = 0.62 OS events; KM median (95% CI), mo 61%; 10.1 (8.2, NE) 60%; 9.8 (5.9, 16.4) HR = 1.14 (0.66, 1.99) p = 0.64 52%; 15.1 (9, NE) 51%; 13.9 (11.4, 18.3) 56%; 14.3 (10, 16.1) HR = 1.03 (0.57, 1.86) p = 0.92 HR = 1.04 (0.59, 1.85) p = 0.89 AE 37 (90%) 36 (92%) 41 (98%) 40 (100%) 39 (95%) Grade ≥ 3 AE 17 (41%) 30 (77%) 29 (69%) 23 (58%) 30 (73%) SAE 11 (27%) 22 (56%) 19 (45%) 18 (45%) 18 (44%) Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen Amgen, Roche Amgen Amgen, Roche Amgen
Early detection of oxaliplatin-induced neurotoxicity: Getting it before it hurts
Authors: S. B. Park, C. S. Lin, A. V. Krishnan, D. Goldstein, M. Friedlander, M. C. Kiernan
Journal: Journal of Clinical Oncology (2008)

15015 Background: Neurotoxicity is the major dose-limiting toxicity of oxaliplatin, presenting acutely and as a chronic sensory neuropathy at higher cumulative doses. We utilized a novel neurophysiological assessment tool to examine both the pathophysiology and development of oxaliplatin-induced neurotoxicity. Methods: Sensory excitability studies were undertaken in 25 patients with colorectal cancer receiving oxaliplatin, before and within 2–3 days after infusion (88 treatment cycles). A subset of 12 patients were followed longitudinally across all cycles. Conventional sensory nerve action potentials (SNAPs) were recorded from the second digit, stimulating the median nerve at the wrist. Multiple excitability parameters (threshold electrotonus (TE), refractoriness (RF) and superexcitability (SX)) were recorded as indices of axonal ion channel function. Neurotoxicity was graded using the National Cancer Institute scale. Results: Most patients developed acute neuropathic symptoms (92%). With a mean cumulative dose of 726 ± 57 mg/m2, 44% of patients developed neurotoxicity with a NCI rating of ≥ 2. Immediate changes occurred in nerve excitability after each infusion, particularly in measures related to Na+ channel activity (RF p<.05; SX p<.001). Lower single doses produced less change in nerve excitability (p<.05). Longitudinal assessment demonstrated progressive changes in nerve excitability with increasing cumulative doses (TE p<.05; RF p<.01; SX p≤.001). By the final dose, peak SNAP amplitude had decreased by 45% (p≤.005), confirming loss of sensory axons. Importantly, nerve excitability parameters changed by mid treatment (cycles 5 - 7), before changes in SNAP and clinical symptoms (cycles 8 -12) - predicting subsequent development of neuropathy (p<.05). Conclusions: These findings present a means of early identification of at-risk patients prior to the development of neuropathy, providing a significant advantage over conventional neurophysiological measures. The technique also yields insight into the pathophysiology of oxaliplatin-induced neurotoxicity, supporting previous in-vitro studies implicating Na+ channel dysfunction, and will aid development of future neuroprotective strategies. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration sanofi-aventis sanofi-aventis
Skin Cancer Risk Is Modified by KIR/HLA Interactions That Influence the Activation of Natural Killer Immune Cells
Authors: Karin A. Vineretsky, Margaret R. Karagas, Brock C. Christensen, Jacquelyn K. Kuriger-Laber, Ann E. Perry, Craig A. Storm, Heather H. Nelson
Journal: Cancer Research (2016)

Natural killer (NK)-cell phenotype is partially mediated through binding of killer-cell immunoglobulin-like receptors (KIR) with HLA class I ligands. The KIR gene family is highly polymorphic and not well captured by standard genome-wide association study approaches. Here, we tested the hypothesis that variations in KIR gene content combined with HLA class I ligand status is associated with keratinocyte skin cancers using a population-based study of basal cell carcinoma (BCC) and squamous cell carcinomas (SCC). We conducted an interaction analysis of KIR gene content variation and HLA-B (Bw4 vs. Bw6) and HLA-C (C1 vs. C2). KIR centromeric B haplotype was associated with significant risk of multiple BCC tumors (OR, 2.39; 95% confidence interval, 1.10-5.21), and there was a significant interaction between HLA-C and the activating gene KIR2DS3 for BCC (Pinteraction = 0.005). Furthermore, there was significant interaction between HLA-B and telomeric KIR B haplotype (containing the activating genes KIR3DS1 and KIR2DS1) as well as HLA-B and the activating KIR gene KIR2DS5 (Pinteraction 0.001 and 0.012, respectively). Similar but greatly attenuated associations were observed for SCC. Moreover, previous in vitro models demonstrated that p53 is required for upregulation of NK ligands, and accordingly, we observed there was a strong association between the KIR B haplotype and p53 alteration in BCC tumors, with a higher likelihood that KIR B carriers harbor abnormal p53 (P < 0.004). Taken together, our data suggest that functional interactions between KIR and HLA modify risks of BCC and SCC and that KIR encoded by the B genes provides selective pressure for altered p53 in BCC tumors.
EGFR mutations and response to gefitinib or erlotinib: A meta-analysis based on a comprehensive EGFR somatic mutation database (www.egfr-mutations.org)
Authors: I. J. Dahabreh, S. Murray, H. Linardou, P. Kosmidis
Journal: Journal of Clinical Oncology (2008)

22049 Background: Somatic EGFR mutations have been evaluated in numerous studies as potential predictive factors of response to tyrosine kinase inhibitors, such as gefitinib and erlotinib, for patients with non-small cell lung cancer (NSCLC). Methods: We used information from a comprehensive free-access online analytical database of somatic EGFR mutations in NSCLC (www.egfr-mutations.org) to identify studies reporting on the association between mutations and response to EGFR tyrosine kinase inhibitors. Studies were eligible if they reported on the treatment of unselected patients with advanced NSCLC. Between-study heterogeneity was assessed with the I2 statistic; small study effects were assessed using Begg's and Egger's tests. In the absence of large between-study inconsistency (I2 >50%), RRs were pooled using the Mantel-Haenszel method. Results: Out of a total 202 studies reporting on somatic EGFR mutations in NSCLC patients, 30 studies (1,437 patients) were considered eligible for this analysis; 28 (1,365 patients) assessed the association of mutational status with response to gefitinib and 2 (72 patients) with response to erlotinib. Overall, 482 somatic mutations were detected (33.5%). There was no evidence of large between-study inconsistency (I2 = 30.5%), but there was strong evidence of differential small study effects (p- values for Begg's and Egger's tests <0.01). The presence of any EGFR somatic mutation was highly correlated with response, RR= 6.4 (5.17–7.91). Patient ethnicity did not alter this association: non-Asians, RR= 7.92 (5.31–11.82); Asians, RR = 6.00 (4.68–7.70); interaction p-value = 0.25. Mutational status was a predictor of response both to gefitinib, RR = 6.38 (5.14–7.91) and erlotinib, RR= 7.29 (2.12–25.09); interaction p-value = 0.84. Conclusions: Our analysis provides large-scale empirical evidence that EGFR mutations are predictive of response to gefitinib and erlotinib for patients with advanced NSCLC. The effect of the mutations appears to be independent of ethnicity. A meta-analysis of patient-level data would allow more thorough evaluation of the interaction of clinico-pathological characteristics, mutational status and treatment efficacy. No significant financial relationships to disclose.
Reversal of Deamination-Related Cytotoxicity of 5-Methyl-2′-deoxycytidine by Tetrahydrouridine in Human Leukemia Cells&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: A Jekunen, J A Vilpo
Journal: JNCI Journal of the National Cancer Institute (1984)

The present experiments were conducted to test the effects of the potent cytidine deaminase inhibitor tetrahydrouridine (THU) on the metabolism and cytotoxicity of 5-methyl-2′-deoxycytidine (5-Med-Cyd) in several human leukemia cell lines in vitro. It was observed that 5-Med-Cyd exerts its effects via deamination to thymidine, which is particularly toxic to human promyelocytic (HL-60) and T-cell (JM) leukemia cell lines in vitro. The deamination and the cytotoxicity of 5-Med-Cyd were effectively hindered by 10-3M THU in 3-day cultures of HL-60 cells. Although the catabolism of [14C]5-Med-Cyd in the HL-60 cell cultures was blocked by THU, no radioactive 5-Med-Cyd was incorporated into DNA. The cytotoxicity and DNA incorporation of fluorodeoxycytidine are enhanced by THU. Unlike that compound 5-Med-Cyd resembled more bromodeoxycytidine and iododeoxycytidine; THU decreases the toxicity of both of these deoxycytidine analogues.
Patient-oriented psychotherapy can objectively improve the quality of life (QOL) of oncological patients: From empiricism to science
Authors: D. Gercovich, E. Gil Deza, P. Lopez, F. Torrente, P. Margiolakis, H. Hirsch, D. Bortolato, M. Morgenfeld, E. J. Rivarola, E. Morgenfeld, F. G. Gercovich
Journal: Journal of Clinical Oncology (2008)

20569 Background: Although there has been an important development of psycho-oncology during the past few years, there is little objective evidence regarding the usefulness of psychotherapy in terms of QOL. The aim of this study was to evaluate the focalized psychotherapy with psychometric instruments that might allow us to document objectively the pt´s response. Material and Methods: Between January 2006 and December 2007, 114 oncological pt which had been referred for psychotherapy were studied. We identified two groups: Group A: 40 pt were treated exclusively with psychotherapy and Group B: 74 pt were treated with psychotherapy plus pharmacological treatment. Both groups were comparable in terms of age, diagnosis and stage of disease. The pt were evaluated with the Hospital Anxiety and Depression Scale (HADS; Zigmond and Snaith, 1983) and the EORTC QLQ-C30 scale (Aaronson et al., 1993). The scores that were obtained in the admission interview and those obtained at the final session (mean time 8 weeks) were analyzed by the sign test. Results: Significant statistical differences in the HADS and in the QLQ-C30 between admission and the final session were found in both groups as we can see in the table below. Conclusion: The results obtained in this study suggest that 1) the pt have shown a significant decrease in the symptoms of anxiety and depression in Group A and anxiety in Group B 2) there has been an objective increase in the QOL in both groups. 3) the psychological support is -to our understanding- a relevant and scientifically proved tool for the wellbeing of the cancer pt. Group A (n=40) Group B (n=74) HADS total p=0.0001 p=0.0001 HADS anxiety p=0.0001 p=0.0001 HDAS depression p=0.0001 p=0.104 QLQ-C30 Global p=0.007 p=0.001 No significant financial relationships to disclose.
Long-term results of a combination of paclitaxel, oxaliplatin and gemcitabine as far rescue in heavily pre-treated male germ-cell tumors (GCT)
Authors: A. Necchi, N. Nicolai, L. Piva, D. Biasoni, T. Torelli, A. Milani, S. Stagni, G. Pizzocaro, R. Salvioni
Journal: Journal of Clinical Oncology (2008)

16036 Background: Patients (pts) who fail to be cured following 2 lines at least of cisplatin-based chemotherapy (CT), high-dose CT (HD-CT) or both fare badly. Nonetheless a combination with paclitaxel, cisplatin and gemcitabine showed good efficacy in a previous phase II study of ours. We replaced cisplatin with oxaliplatin aiming at achieving greater efficacy due to possible cisplatin resistance overcoming and even lower toxicity. Methods: Between 01/01 and 02/04, 19 pts have been submitted to the 3rd or further line combination of paclitaxel 80 mg/m2, oxaliplatin 85 mg/m2 and gemcitabine 800 mg/m2 on day 1 every 2 weeks until disease progression with a minimum of 2 and a maximum of 8 administrations. Results: Thirteen pts were cisplatin refractory or absolutely refractory, 3 had mediastinal primary, 2 had experienced relapse after HDCT. Pts were pre-treated with a median of 7 cisplatin-based cycles. Median number of administrations was 5 (range, 1–8). Two pts (10.5%) achieved a complete remission (CR) and 5 (26%) a partial remission (PR). Two further pts had stable disease (SD). One PR and 1 SD could be rendered disease-free (NED) with radical surgery of viable cancer. So far, a total of 4 pts (21.1%) were NED at the end of treatment. Median response duration was 6 months in the whole series (1–60+). Median overall survival (OS) was 10 months (4–73+). After a median follow-up of 70 months (42–78+), 2 pts are still alive and disease-free. Grade 3–4 hematologic toxicity occurred as neutropenia in 21%, anemia as well as thrombocytopenia in 10.5%. Grade 3–4 neurotoxicity occurred in 2 patients, one of them needed treatment discontinuation. All the 102 administrations have been at full-dose and with no delay. Conclusions: This 3-drug combination associated with poorer results than those we achieved with cisplatin. Nonetheless 2 CRs could be achieved and 2 further pts could be rendered free of disease with radical surgery. Two of these 4 had been pre-treated with paclitaxel, cisplatin and gemcitabine. Two pts are long-term survivors. This regimen needs to be furtherly evaluated considering dose intensification and a possible role in pts not amenable for further cisplatin as those who failed previous third or more CT lines. No significant financial relationships to disclose.
COX-2 expression in post-mastectomy chest wall relapse
Authors: J. H. Kim, V. Bossuyt, D. Lannin, B. G. Haffty
Journal: Journal of Clinical Oncology (2005)

579 Background: Cyclooxygenase 2 (COX-2) expression has been shown to be associated with radiation resistance, which theoretically could be overcome with the use of COX-2 inhibitors. The purpose of this study was to assess the prognostic significance and clinical correlations of COX-2 expression (COX) in a cohort of patients treated with radiation (RT) for post-mastectomy chest wall relapse (PMCWR). Methods: Between 1975 and 1999, 113 patients were treated for isolated PMCWR. All patients were treated with biopsy and/or excision of the CWR followed by RT. Median follow-up was 10 years. All clinical data including demographics, pathology, staging, receptor status, HER-2/neu status, and adjuvant therapy were entered into a computerized database. Paraffin-embedded CWR specimens were retrieved from 42 patients, created into a tissue microarray, stained by immunohistochemical methods for COX, and graded 0–3+. A score of 2–3+ was considered positive. Results: Survival from original diagnosis for entire cohort was 47% at 10 years. Survival rate after chest wall recurrence was 30% at 10 years. The distant metastasis-free survival rate was 53% at 10 years. Local-regional control of disease was achieved in 79% at 10 years. COX was inversely correlated with ER (p= .07) and PR (p = .054), and positively correlated with HER-2/neu (p =.003). COX was also associated with a shorter time to PMCWR. The distant metastasis-free rate for COX negative patients was 69% at 10 years, compared with 37% at 10 years for COX-2 positive patients (P = .14). COX positive had a poorer local-regional progression-free rate of 55% at 10 years, compared with 82% at 10 years for COX negative. This was of borderline statistical significance with a p-value of 0.059. Conclusions: Outcome following RT for PMCWR is relatively poor. Positive COX correlated with other markers of poor outcome including a shorter time to local relapse, negative ER/PR and positive Her-2/neu status. Positive COX correlated with higher distant metastasis and lower local-regional control of disease. If confirmed with larger studies, these data have implications with respect to the concurrent use of COX-2 inhibitors and radiation for PMCWR. No significant financial relationships to disclose.
Phase I/II personalized therapy trial for metastatic colorectal cancer using functional pathway mapping: Stratification to imatinib therapy.
Authors: M. Pierobon, S. Banks, A. Silvestri, G. Gambara, J. Wiedemann, L. A. Liotta, E. Petricoin, K. H. Edmiston, A. I. Spira
Journal: Journal of Clinical Oncology (2010)

TPS194 Background: Profiling protein signaling pathways in human cancer is critical because proteins represent the targets for new molecular guided therapeutics. Pathway mapping of liver metastasis from patients with stage IV colorectal cancer (CRC) revealed the unexpected activation of the drug targets of imatinib: PDGFR, c-kit and c-abl. Based on these results, we are conducting a trial whereby patients with advanced CRC with WT kras are stratified for imatinib therapy in conjunction with panitumimab, based on the pathway activation status obtained from metastatic tumor biopsies using Reverse Phase Protein Microarray (RPMA) technology. This trial represents the first personalized therapy trial for stage IV CRC patients stratifying patients to targeted therapy based upon functional protein pathway activation of a metastatic lesion. The ability to perform pathway- based stratification in a clinical setting represents an important milestone for future personalized therapy trials. Further patient enrollment will be required to determine the clinical utility of this particular combination therapy for patients with stage IV CRC. Methods: Stage IV CRC patients with WT kras who progressed on prior therapy are eligible. A liver biopsy is taken for functional pathway activation analysis of PDGFR, c-kit and c-abl by RPMA analysis of the laser capture microdissected (LCM) tumor epithelium. A predefined cut-point, based on the activation of these proteins of an independent cohort of colorectal metastases, is used to stratify patients to: Arm 1: 28-day run-in with imatinib monotherapy (300-600 mg/kg/day) followed by a second biopsy and addition of panitumumab (6 mg/kg) or Arm 2: panitumimab alone. Evaluation is per RECIST. Further, comparisons are made with sequential biopsies of the liver metastasis obtained pre and post treatment with imatinib and downstream pathway activation of AKT, ERK and EGFR pathways is analyzed. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Theranostics Health Theranostics Health Theranostics Health
Comparison of progression-free survival (PFS) and tumor response as endpoints for predicting overall survival (OS) in untreated extensive-stage small cell lung cancer (ED-SCLC): Findings based on North Central Cancer Treatment Group (NCCTG) trials
Authors: N. R. Foster, Y. Qi, J. E. Krook, J. W. Kugler, S. A. Kuross, J. R. Jett, J. R. Molina, S. E. Schild, A. A. Adjei, S. J. Mandrekar
Journal: Journal of Clinical Oncology (2009)

8085 Background: Historically, tumor response has been the primary endpoint in phase II (P2) trials in ED-SCLC. We investigated the suitability of alternate PFS based endpoints to predict OS as early evidence of efficacy in the P2 setting. Methods: Individual patient (pt) data from 942 pts from 11 previously untreated ED-SCLC P2 and phase III (P3) platinum- or paclitaxel-based treatment trials were pooled. Best response (BR), response confirmed (RC), objective status at 16 weeks (RR16), and PFS rate at 5 and 6 months were considered. Percent agreement (PA) and kappa (k) for PFS5, PFS6, BR, RC, and RR16 with OS at 12 months (OS12) was calculated on a per-pt basis and predictive utility was assessed using the area under the receiver operating characteristic (A- ROC) curve in logistic models. Cox models were used to assess the prognostic impact of the endpoints on subsequent survival, using landmark analysis. Results: The median OS and PFS were 9.6 m and 5.5 m, respectively. PFS5 and PFS6 had the highest PA, k, and A-ROC values, and were predictive of subsequent survival in the landmark analysis (p &lt;0.0001; c-statistics ≥ 0.60). While RR16 and BR were significantly associated with subsequent survival (p&lt;0.0001, c-statistics of 0.61 and 0.57, respectively) the PA, k, and A-ROC values were lower. Conclusions: PFS rate at 5 and 6 months is more predictive of 12-month OS and subsequent survival than tumor response in untreated ED-SCLC. PFS based endpoints should be routinely used as primary endpoints in P2 trials within ED-SCLC. [Table: see text] No significant financial relationships to disclose.
“The Guard Dies, It Does Not Surrender!” Progress in the Management of Small-Cell Lung Cancer?
Authors: David H. Johnson
Journal: Journal of Clinical Oncology (2002)

Article Tools EDITORIALS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2002.20.24.4618 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 12488404 “The Guard Dies, It Does Not Surrender!” Progress in the Management of Small-Cell Lung Cancer? David H. JohnsonxDavid H. JohnsonSearch for articles by this author Show More Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical School, Nashville, TN https://doi.org/10.1200/JCO.2002.20.24.4618 First Page Full Text PDF Figures and Tables © 2002 by American Society of Clinical Oncology
In Vivo Disruption Of The Hepcidin−Ferroportin Regulatory Circuitry Causes Fatal Systemic and Exocrine Pancreatic Iron Overload
Authors: Sandro Altamura, Hermann Josef Gröne, Regina Kessler, Bruno Galy, Matthias W. Hentze, Martina U. Muckenthaler
Journal: Blood (2013)