tbuckley/cabot-search huggingface dataset:
Pretherapy predictive immunomodulation of NK cell activity and expression of activating and inhibitory receptors in stage IV melanoma patients
Authors: G. Konjevic, K. Mirjacic, A. Radovanovic, V. Jovic, N. Babovic, I. Spuzic
Journal: Journal of Clinical Oncology (2006)

12514 Background: As melanoma (MM) is an immunogenic tumor with poor response to chemotherapy immunomodulating agents are applied in order to potentiate cytotoxic effect of chemotherapy and enhance antitumor immune response. Beside therapeutic benefit of IFN-α and IL-2, 13-cis retinoic acid (RA), as an antiproliferative, differentiating and immunomodulating agent is also investigated. The effect of these agents on NK cells, as main innate immune system effectors, is being investigated. Methods: 35 patients with MM in stage IV prior to therapy and 20 controls were investigated. We evaluated NK activity and the expression of activating (NKG2D and CD161) and inhibitory (CD158a and CD158b) receptors on freshly isolated PBL. Predicitive immunomodulation was performed in 18 h in vitro treated PBL with rh IL-2 (200U/ml), IFN (250U/ml), RA (10 −6 M), and their combination. Results: Native NK cell cytotoxic activity and expression of NKG2D and CD161 activating receptors on fresh NK cells in MM patients is significantly decreased compared to controls. Predictive treatments with IL-2, IFN, IFN and RA, unlike RA alone, gave a significant increase in NK cell activity of MM patients. Singly, IFN also induced a significant increase in CD161 expression on NK cells in patients. The treatments gave no change in the expression of CD158b, while RA, alone, induced significant decrease in the expression of the inhibitory CD158a antigen. Evaluation of mRNA of transcription molecule IRF-1 shows that it is promptly up-regulated by IFNα, more by IFNα and RA, while single RA has no effect on mRNA induction. Conclusions: Considering that the mechanism of applied immunomodulating agents is continually investigated in order to optimize the dose and schedule of their administration and, also, considering controversial clinical results of RA application, alone, or with IFN, in this study we give novel results that show no significant effect of RA, whereas, IFN-induced increase in NK cell activity of MM patients is for the first time associated with the increase in the expression of NKG2D and CD161 receptors on CD16+NK cells, and not with the decrease in some inhibitory receptors, as the activity of NK cells is regulated by the balance of these two types of signals. No significant financial relationships to disclose.
Comparison of risk stratification of ER-positive, node-negative breast cancer patients by Oncotype DX versus molecular grade index and HOXB13/IL17BR ratio
Authors: D. Sgroi, O. Hameed, E. Hattab, B. Chang, S. Moulis, L. Steffel, R. Salunga, X. Ma, M. Erlander, P. Goss
Journal: Journal of Clinical Oncology (2008)

22061 Background: We have previously reported two complementary prognostic markers in breast cancer for predicting risk of recurrence: a molecular grade index (MGI) that recapitulates tumor grade and a gene expression ratio (HOXB13/IL17BR or H/I) that is a marker for estrogen signaling. MGI and H/I represent two distinct prognostic modules in breast cancer. Combined they are a strong predictor of recurrence (Ma et al., ASCO Breast Cancer Symposium, 2007). We conducted a study to compare risk stratification by MGI and H/I within samples for which a previous recurrence score (RS) by Oncotype Dx was reported. Methods: RNA was extracted from formalin-fixed paraffin-embedded sections from all obtainable samples from four institutions in which a RS was reported (78pts total; MGH, 43pts; IU, 19pts; UAB, 13pts; Scripps, 9pts). Real-time RT-PCR assays for MGI and H/I were completed and binary results of low and high for both were determined using pre-defined cutpoints. Three risk groups were categorized as follows: low (low MGI), intermediate (high MGI, low H/I) and high (high MGI, high H/I) as described (Ma et al., ASCO Breast Cancer Symposium, 2007). Risk stratification via MGI + H/I for each sample was compared to previously reported RS's (low, intermediate or high). Results: Overall, risk stratifications by RS versus MGI + H/I were significantly correlated (p = 0.00067). RS's from Oncotype DX were 47% low, 45% intermediate and 8% high. In contrast, risk groups according to MGI + H/I were 70% low, 17% intermediate and 13% high (see table). Conclusions: MGI + H/I produces a smaller group of patients with intermediate risk by re-stratifying a large number of patients with intermediate RS into low and high risk groups. This may allow for more informed treatment decisions by the treating oncologist. Further comparative studies with clinical outcome are required to establish the clinical significance of these different risk stratification methods. Comparison of Risk Stratification MGI + H/I Low MGI + H/I Inter. MGI + H/I High Total RS Low 31 6 0 37 RS Inter. 22 5 8 35 RS High 2 2 2 6 Total 55 13 10 78 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration AviaraDx AviaraDx AviaraDx
Expression and prognostic significance of differentiation markers in primary CNS lymphoma (PCNSL)
Authors: H. Momota, Y. Narita, Y. Miyakita, A. Shinomiya, A. Maeshima, T. Maruyama, Y. Muragaki, S. Shibui
Journal: Journal of Clinical Oncology (2009)

e13028 Background: BCL-6 expression has been reported to be associated with a better prognosis in PCNSL. However, significant differences of B-cell lymphoma subtypes exist in different geographic regions. The objectives of this study were to characterize the immunophenotypes of PCNSL in Japan and to determine their utility in predicting clinical outcomes. Methods: Immunostaining for CD5, CD10, BCL-6, and MUM-1 was done to determine the profile of diffuse large B-cell lymphoma of PCNSL from 27 immunocompetent patients in Japan. Then, the authors evaluated whether clinical and immunophenotypic markers were associated with progression-free or overall survival. Results: Germinal center B-cell (GCB) marker CD10 was positive in 22% of PCNSL samples, while another GCB marker BCL-6 was positive in 48% of samples. Post-GCB marker MUM-1 was positive in 81% of samples. Poor prognostic marker of systemic B-cell lymphoma CD5 was expressed in 15% of samples. In univariate analyses, only BCL-6 expression had a significant effect on progression-free survival (median, 6.1 months in BCL-6-positive patients versus 15.6 months in BCL-6-negative patients; p = 0.037). Patients with BCL-6 expression had a trend towards longer overall survival but nonsignificant. GCB subgroup (CD10-positive or CD10-negative/BCL-6-positive/MUM-1-negative) was not significantly associated with favorable survival. Conclusions: BCL-6 expression is associated with a poor prognosis in patients with PCNSL. The discrepancy between the reports from other groups and our results is potentially due to the racial, geographic or immunophenotypic differences of PCNSL. No significant financial relationships to disclose.
A phase I study of ABT-751 in combination with docetaxel in patients with metastatic hormone-refractory prostate cancer
Authors: J. E. Michels, S. Ellard, L. Le, N. Murray, E. Guns, A. Hagey, K. N. Chi
Journal: Journal of Clinical Oncology (2006)

4651 Background: ABT-751 (A) is a novel oral sulfonamide anti-microtubule agent with broad-spectrum preclinical activity including paclitaxel-resistant tumors and additive effect with docetaxel (D). Dose-limiting toxicities (DLTs) with ABT-751 include peripheral neuropathy, ileus, and fatigue. The recommended phase II single-agent dose for a 21/28-day schedule is 200 mg/day. Methods: Patients (pts) with hormone-refractory prostate cancer (HRPC), ECOG performance status ≤ 2, and adequate organ function were eligible. D was administered intravenously on day 1 and A was administered orally once daily on days 1–14 of a 21-day cycle for a maximum of 10 cycles. Starting dose was 60 mg/m 2 D and 100 mg A; escalated in 4 dose levels (DLs) to 75 mg/m 2 D and 200 mg A. Pts received 10 mg oral prednisone daily. Plasma for PK analyses was obtained. Results: 18 pts have been enrolled (3 pts/DL1, 3 pts/DL2, 6 pts/DL3, 6 pts/DL4), 17 pts are currently evaluable: median age 66 years, median PSA 250 μg/L, metastatic sites to bone and/or lymph nodes (17), visceral (2), prior chemotherapy 5 pts. The median number of treatment cycles was 6 (range 2–10). 2 pts experienced DLT (1 febrile neutropenia/DL 3 and 1 diarrhea/grade 4 neutropenia at DL4); these dose levels were expanded to 6 pts with no further DLT. Hematologic toxicities include febrile neutropenia (2 pts), grade 3/4 neutropenia (7 pts). Additional non-hematologic toxicities were grade 1/2 beside 1 episode of grade 3 diarrhea and lethargy each. AUC and C max for A were similar to single-agent data. AUC and C max for D appeared independent of ABT-751 dosing. PSA decline of ≥50% occurred in 10/16 evaluable pts (63%), ≥30% in 14/16 pts (89%) and &lt;30% in 2/16 pts as best response thus far. Best response per RECIST in 12 pts with measurable disease was partial response in 4 pts (33%) and stable disease in 8 pts (67%). Conclusions: The combination of ABT-751 and docetaxel is well tolerated at the tested doses. PK results suggest no significant PK interaction. Early findings indicate encouraging clinical activity of the combination treatment. Extended accrual to the recommended phase II dose is ongoing to further define activity and toxicity. No significant financial relationships to disclose.
Meta-analysis of gender effect for first-line chronomodulated 5-fluorouracil-leucovorin-oxaliplatin (ChronoFLO) compared with FOLFOX or constant infusion (conventional delivery, CONV) against metastatic colorectal cancer (MCC) in three international controlled phase III randomized trials (RT)
Authors: F. Levi, P. Innominato, A. Poncet, T. Moreau, S. Iacobelli, C. Focan, C. Garufi, G. Bjarnason, R. Adam, S. Giacchetti
Journal: Journal of Clinical Oncology (2009)

4112 Background: Gender predicted for the most effective schedule in a RT of ChronoFLO vs CONV against MCC: overall survival (OS) was significantly increased in men on chronoFLO vs FOLFOX, whereas the reverse was found in women (Giacchetti, JCO 2006). Methods: To assess the relevance of gender for patient (pt) outcome, meta-analysis was performed on individual pt data (IPD) from 3 RT in 845 MCC pts treated with chronoFLO vs CONV (346 F, 499 M at 36 centers in 1990–2002)(Lévi, JNCI 1994; Lancet 1997). Data bases were merged and updated at 9 y after inclusion of the 1 st pt. Main prognostic factors were comparable in each RT according to gender and treatment arm (median age: 61y; PS=0, 46% pts; liver M, 85% pts; liver involvement &gt;25%, 41% pts; lung M, 37% pts; CEA&gt;10, 56% pts). Results: No significant difference was found according to delivery schedule or gender in the whole population for Response Rate (RR), Progression-Free Survival (PFS) and OS. However, men on chronoFLO had highest RR, longest PFS and OS. PFS and OS were highest in women on CONV ( Table ). The rate of complete macroscopic resections of liver metastases (R0+R1) was 12.5% in men on chronoFLO vs 7.8–8.5% in men on CONV or in women on either schedule. A complete histologic response of liver metastases was documented in 2.1% of the men on chronoFLO vs 0–1.1% in the other groups. The relative risk of an earlier death in men vs women was 0.76 [95% CL, 0.91 to 0.94] on chronoFLO and 1.24 [0.99 to 1.56] on CONV. Conclusions: This IPD meta-analysis of 3 RT in MCC with a minimum follow up of 5 years confirms that men benefit from chronoFLO as compared to CONV delivery, with regard to long term outcome and medico-surgical strategy. ChronoFLO should be preferred to conventional oxaliplatin-5-FU-LV schedules in men with MCC. Support: ARTBC Internationale, P. Brousse Hospital, Villejuif, France. [Table: see text] No significant financial relationships to disclose.
Osteoarthritis Modular Measurement System (O2MS): Validity and responsiveness of Module 4 (Patient Global Assessment)
Authors: Nicholas Bellamy, Joan Hendrikz, C. Wilson
Journal: Annals of the Rheumatic Diseases (2011)

Background: The Osteoarthritis Modular Measurement System (O2MSt) contains 10 modules, of which Module 4 concerns Patient Global Assessment (PGA). There is currently no international agreement of the wording of the PGA question or a uniform response scale. However, PGA questioning is a key element of the OMERACT-OARSI Responder Criteria. Based on previous work conducted using the WOMBATt Index and the Osteoarthritis Global Index (OGIt), a battery of PGA questions was elaborated and incorporated as Module 4 of a multidimensional Patient Reported Outcome Measure (PRO) for OA clinical trials termed O2MSt.Objectives: The purpose of this study was to examine the validity and responsiveness of O2MSt Module 4 (Patient Global Assessment).Methods: During the validation of a mobile phone-based version of the WOMACr Index, 52 patients with hip and knee osteoarthritis (OA), about to undergo total joint replacement surgery completed the O2MSt (Module 4) pre-operatively and s12 weeks post-operatively. The study population was as follows (32 Females and 20 males, 18 hip OA and 34 Knee OA, Mean Age =68 (range 47-85), Mean disease duration 9.4 yrs (range 0.83 n 30 yrs).Results: Mean (SD) WOMACr NRS3.1 Index scores pre-op for the pain, stiffness and function subscales were as follows: Pain NRS =5.2 (2.00); Stiffness NRS =5.5 (2.21); Function NRS =5.6 (2.18). Median (Inter-quartile range) O2MSt Module 4 scores pre-op were as follows: PGA pain =6 (4-8); PGA Stiffness =6 (4-8); PGA function =7 (5-8). Pearson correlations between O2MSt and WOMACr scores pre-op were as follows: Pain =0.75; Stiffness =0.81; Function =0.84. For each subscale, the pattern of partial correlations between the WOMACr and O2MSt scores, controlling for the other two WOMACr subscales, supported the construct validity of the O2MSt subscales. Responsiveness to intervention was assessed by comparing the O2MSt scores post-operatively with those preoperatively. Statistically significant improvements in scores post-operatively were detected using Wilcoxon signed ranks test for matched pairs (all pl0.0001).Conclusions: These data are supportive of the validity and responsiveness of O2MSt (Module 4), and together with the demonstrable feasibility of asking short global assessment questions, are aligned with OMERACT Filter Criteria for Truth, Discrimination and Feasibility.
Abstract 12895: Factors Influencing the Higher In-Hospital Mortality of Female Patients with Acute Myocardial Infarction
Authors: Yoshitaka Ito, Jun Takahashi, Kiyotaka Hao, Yusuke Takagi, Ryuji Tsuburaya, Takashi Shiroto, Yasuharu Matsumoto, Masaharu Nakayama, Kenta Ito, Satoshi Yasuda, Hiroaki Shimokawa
Journal: Circulation (2012)

Background: We have previously demonstrated that in-hospital mortality after acute myocardial infarction (AMI) is higher in female patients than in male patients; however, the underlying cause(s) r...
Ifosfamide-doxorubicin combination in patients with locally recurrent or metastatic nasopharyngeal carcinoma pretreated with cisplatin based chemotherapy: Retrospective analysis of 21 patients
Authors: K. Altundag, S. Aksoy, I. H. Gullu, O. Altundag, E. Ozyar, S. Yalcin, M. Cengiz, F. Akyol
Journal: Journal of Clinical Oncology (2004)

5603 Background: We evaluated the efficacy and toxicity of ifosfamide and doxorubicin chemotherapy regimen retrospectively in Turkish patients with recurrent or metastatic nasopharyngeal carcinoma (NPC) previously treated with platinum-based chemotherapy Methods: A total of twenty-one patients with recurrent nasopharyngeal carcinoma who had received cisplatin based chemo-radiotherapy as a primary treatment were treated with ifosfamide 2500 mg/m2 days 1–3, mesna 2500 mg/m2 days 1–3, doxorubicin 60 mg/m2 day 1, repeated every 21 days. Eligible patients had measurable recurrent or metastatic disease, ECOG PS < 2, have adequate renal, hepatic and hematologic function. Results: Median age was 40 (range:17–54). Twenty of 21 patients were male; only one patient was female. Total 78 cycles of chemotherapy were introduced, and median cycles of chemotherapy for each patient is 3, (range:1–6). Sixteen patients were evaluable for toxicity and response. No patient achieved complete response and six partial response for a response rate of 37.5% in evaulable patients. Stable disease, and disease progression were observed in seven (43.8%) and three (18.7%) patients respectively. Clinical benefit was 68%. Median time to progression is 8.0 months Six patients had neutropenic fever as a result of chemotherapy and there were one treatment-related deaths due to tumor lysis syndrome at first cycle of the chemotherapy. There was no WHO grade 3 or 4 anemia, thrombocytopenia and cardiotoxicity. Treatments were generally well tolerated. Conclusions: Ifosfomide and doxorubicin combination is an effective regimen for the patients with recurrent and metastatic nasopharyngeal carcinoma. This combination may be considered as salvage therapy for NPC patients who failed to cisplatin based treatments No significant financial relationships to disclose.
Results from the first phase I clinical study of the novel Ii-Key/HER2/neu(776–790) hybrid peptide vaccine in patients with prostate cancer
Authors: S. A. Perez, S. Bisias, N. L. Kallinteris, A. Ardavanis, K. G. Georgakopoulou, N. Apostolikas, A. Thanos, M. Papamichail, E. von Hofe, C. N. Baxevanis
Journal: Journal of Clinical Oncology (2009)

3011 Background: HER-2/neu(776–790) represents an immunogenic epitope from the HER-2/neu oncoprotein whose immunogenicity is highly potentiated upon linkage with the Ii-Key moiety (LRMK) from the MHC class II invariant chain. Herein, we present the results of the first phase I clinical trial of the Ii-Key/HER-2/neu(776–790) (AE37) vaccine in patients (pts) with prostate cancer. Methods: Androgen-dependent (AD) and androgen-independent (AI) pts with HER-2/neu+ (IHC: 1–3) prostate adenocarcinomas were eligible. Concomitant medication with bicatulamide and LHRH or docitaxel was allowed. All pts received 6 monthly vaccinations with the AE37 vaccine (500 μg of AE37 plus 125 μg of GM-CSF) administered in two doses intradermally 5cm apart in the same extremity for each vaccination cycle. Immunologic responses were measured monthly in vitro by the IFNγ-based ELISPOT assay using pts’ PBMC and in vivo at the beginning and end of immunizations using DTH. Local dermal reactions were also measured after each vaccination. Results: Eligible pts [AD (n=18), AI (n=10)] were at stages T1–3N0M0, GS: 3–7 (n=18); T1–3N+M0, GS: 6–7 (n=2); T1–3N0M+, GS: 6–9 (n=4) and T1–3N+M+, GS: 6–9 (n=4). All pts had standard treatment prior to vaccinations, including surgery (S) (n=9); hormonal treatment (HT) (n=4); S+HT (n=6); S+HT+radiotherapy (RT); (n=2); S+chemotherapy (CH) (n=2); HT+RT (n=2); CH (n=3) and S+HT+CH (n=2). During vaccinations, 11 pts were free of any treatment, while 5 pts who had progressive disease received additional chemotherapy; the remainder received HT alone or combined with RT. 25 pts completed all vaccinations. Toxicity and side effects beyond grade-2 were not observed. GM-CSF was reduced by 50% for subsequent vaccinations when a local reaction of 100mm or greater was observed. DTH reactions to the parent HER-2/neu(776–790) peptide were increased (compared to pre-vaccination) for all pts, while approximately half the pts responded with significantly increased IFNγ responses to AE37 and/or parent HER-2/neu(776–790) peptide in at least 2 sequential vaccination cycles. Conclusions: The AE37 vaccine is safe and well tolerated. AE37 is also capable of eliciting potent and specific immunologic responses in prostate cancer pts. [Table: see text]
Phase III study of oxaliplatin plus 5-fluorouracil/leucovorin (FOLFOX4) versus doxorubicin as palliative systemic chemotherapy in advanced HCC in Asian patients.
Authors: S. Qin, Y. Bai, S. Ye, J. Fan, H. Lim, J. Y. Cho, S. Thongprasert, Y. Chao, K. Rau, Y. Sun
Journal: Journal of Clinical Oncology (2010)

4008 Background: In Asia, where hepatitis B is very common, hepatocellular carcinoma (HCC) is the third most common cancer. Asian patients often present with locally advanced or metastatic HCC, which are not eligible for surgery or localized treatments – median survival is only 3 months with supportive care. Systemic chemotherapies are commonly used but there is no evidence of a survival benefit. Oxaliplatin-containing regimens have shown efficacy against advanced HCC in several phase II trials. Methods: This open-label, randomized, multicenter phase III study was conducted in patients from mainland China, Taiwan, Korea and Thailand, who had locally advanced or metastatic HCC and were ineligible for complete resection or local treatment. Patients were randomized 1:1 to receive either FOLFOX4 (oxaliplatin 85 mg/m2 i.v. d1; LV 200 mg/m2 i.v. h0–h2 d1 and d2; 5FU 400 mg/m2 i.v. bolus h2, then 600 mg/m2 over 22 hours d1 and d2 q2w) or doxorubicin (50 mg/m2 i.v. q3w). Treatment was continued until disease progression, intolerable toxicity, or eligibility for surgical resection. The primary objective was to determine whether FOLFOX4 improves overall survival (OS) compared with doxorubicin; secondary objectives included time to tumour progression (TTP), response rate (RR) by RECIST 1.0, and safety. Results: Median OS with FOLFOX4 (N = 184) was 6.4 months vs. 4.9 months with doxorubicin (n = 187) (p = 0.0859 using a stratified log-rank test; HR 0.797 [0.625, 1.017]). Median TTP with FOLFOX4 was 2.9 months vs. 1.8 months with doxorubicin (p < 0.0001; HR 0.620 [0.489, 0.787]). With FOLFOX4 and doxorubicin, respectively, the RR was 8.2% vs. 2. 7% (p = 0.0233) and the disease control rate (DCR) was 52.2% vs. 31.6% of patients (p < 0.0001). Toxicity was consistent with previous experience of FOLFOX4. The proportions of adverse events reported at grade 4 severity were similar between the two study arms. Conclusions: In this large international Phase III study in Asian patients with unresectable HCC, FOLFOX4 treatment significantly increased RR and TTP vs. doxorubicin, and led to a prolonged median OS. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration sanofi-aventis sanofi-aventis sanofi-aventis