tbuckley/cabot-search huggingface dataset:
Molecular analysis of the Epstein-Barr virus LMP1 in Hodgkin lymphoma from Argentina and Brazil: Identification of a distinct LMP1 deleted variant
Authors: P. Chabay, R. Hassan, D. Guiretti, P. Valva, M. Barros, M. Lorenzetti, E. De Matteo, I. Zalcberg, G. Rey, M. V. Preciado
Journal: Journal of Clinical Oncology (2007)

21099 Background: Epstein Barr virus (EBV), a human oncogenic virus, has two types, EBV1 and 2, and several polymorphic markers allow individual variants to be distinguished. Variations in EBV latent membrane protein 1 (LMP1) gene could define a more oncogenic strain or reflect geographic EBV origin. By sequence analysis of C-ter, N-ter and promoter (prom) regions, 4 distinct EBV groups (A to D) have been defined. Aim: To analyze LMP1 molecular variability of two different groups of Hodgkin`s lymphoma (HL) from the same geographic area. Methods: EBV association by EBERs in situ hibridization and LMP1 immunohistochemistry was analyzed in 27 HL from Argentina (Arg) and 36 HL from Brazil (Br). EBV type was assessed by EBNA PCR. C-ter LMP1 PCR was done in all cases. Sequencing of C-ter, N-ter and prom regions was done in 16 patients. Results: 21/27 (78%) Arg HL and 31/36 (86%) Br HL were EBV1, while 6/27 (22%) and 4/36 (11%) were EBV2, respectively (p= 0.29). Coinfection was observed in 1 (3%) Br HL. LMP1 deleted (del) variant was observed in 20/27 (74%) Arg HL and 20/36 (55%) Br HL (p= 0.18), as well as in non-neoplastic controls, 4/11 and 3/10 (36 and 30%) from Arg and Br respectively. Most LMP1 del displayed high number (5–7) of 33bp repeats (86% LMP1 del Br HL and 77% LMP1 del Arg HL) compared with LMP1 wt that exhibited low number (3–4) 33bp repeats (68% LMP1 wt Br HL and 100% LMP1 wt Arg HL). Analysis of LMP1 sequences showed that: LMP1 wt C-ter regions had unmutated N-ter and prom as B95.8, A and B groups (31%), except for a case showing new mutations. LMP1 del C-ter regions showed molecular identity with C group, but they showed new, undescribed mutations in prom and N-ter (63%). Conclusions: We found high frequency of LMP1 del variants in HL from Argentina and Brazil, which was associated with high number of 33bp repeats in C-ter region. This suggests a role for this variant in lymphomagenesis. A new molecular variant with characteristic promoter and N-ter mutations was identified in LMP1 del cases, which could be proposed as a regional South American variant. No significant financial relationships to disclose.
COX-2 inhibition in combination with preoperative chemoradiation for CA esophagus
Authors: D. L. Kwong, S. Y. Law, D. K. Tong, K. H. Wong, J. Nicholls
Journal: Journal of Clinical Oncology (2009)

e15607 Background: Squamous cell carcinoma of the thoracic esophagus (ESCC) is often diagnosed in advanced stage. Pre-operative chemoradiation is employed to downstage the disease before operation. Pathological complete response (pCR) was observed in around 20–40% of patients and was associated with improved survival. Cyclooxygenase 2 (COX-2) is overexpressed in ESCC and may contribute to chemo- and radio-resistance. This pilot study evaluates if COX-2 inhibition in combination with pre-operative chemoradiation will improve the response rate in ESCC. Methods: Patients with histologically confirmed ESCC undergo endoscopic ultrasound, ultrasound of neck and PET/ thoracic, abdominal CT for staging. Patients with disease which is considered potentially resectable are eligible. The primary and involved lymph nodes are irradiated to 40Gy in 20 fractions over 4 weeks with 2 cycles of concurrent cisplatin (100mg/sqm, D1, D22) and 5 fluorouracil (500mg/sqm, D1–5, D22–26). Celecoxib, a specific COX-2 inhibitor, 400mg bid, is started for 2 weeks before chemoradiation, continued throughout chemoradiation and for 4 more weeks after completion of chemoradiation. Patients are re-evaluated and esophagectomy is performed 6–8 weeks after completion of chemoradiation. Results: From 2004 to 2008, 32 patients were recruited. Pre-operative staging was stage II in 4, stage III in 25 and stage IVA in 3 patients. Celecoxib was well tolerated. 3 patients did not have full course of celecoxib: 1 complained of epigastric pain, 1 died early of disease, 1 had renal impairment after chemotherapy. 29 patients had esophagectomy performed after chemoradiation. Median follow-up after completion of chemoradiation was 11 months (range: 3 to 43 months). 23 patients (79.3%) had downstaging of the primary compared with pre-operative staging. The pCR rate in primary tumor was 51.7% (15/29 patients) and pCR rate in lymph nodes was 65.4% (17/26 patients). 3 years overall survival of patients who had esophagectomy was 79.3%. Conclusions: COX-2 inhibition in combination with pre-operative chemoradiation is well tolerated. Preliminary results of the pCR rates and survival are encouraging. Incorporation of COX-2 inhibition into multi-modality treatment of ESCC should be further investigated in a randomized trial. No significant financial relationships to disclose.
Phase III randomized, open-label, multicenter trial (BRIM3) comparing BRAF inhibitor RG7204 with dacarbazine in patients with V600E BRAF-mutated melanomas.
Authors: P. B. Chapman, A. Hauschild, C. Robert, J. M. G. Larkin, J. B. A. G. Haanen, A. Ribas, D. Hogg, S. O'Day, P. A. Ascierto, A. Testori, P. Lorigan, R. Dummer, J. A. Sosman, C. Garbe, R. J. Lee, K. B. Nolop, B. Nelson, J. Hou, K. T. Flaherty, G. A. McArthur
Journal: Journal of Clinical Oncology (2011)

LBA4 The full, final text of this abstract will be available in Part II of the 2011 Annual Meeting Proceedings, distributed onsite at the Meeting on June 4, 2011, and as a supplement to the June 20, 2011, issue of Journal of Clinical Oncology.
Increased frequency and suppressive function of CD4+ CD25<sup>high</sup> regulatory T-cells in acute myeloid leukemia patients
Authors: M. Boyiadzis, M. Szczepanski, L. Strauss, M. Czystowska, A. Welsh, K. Foon, T. L. Whiteside
Journal: Journal of Clinical Oncology (2007)

7054 Background: Regulatory CD4+CD25+ T cells (T reg) are critical regulators of immune tolerance. However, the functional role of T reg in human tumor immunity has been less well studied. The frequency of circulating Treg is increased in patients with solid malignancies. We evaluated the frequency, phenotype and suppressive function of T reg in patients with acute myeloid leukemia (AML). Methods: The frequency and phenotype of CD4+ CD25 high T cells were investigated in the peripheral blood of fifteen newly diagnosed AML patients prior to any treatment and fifteen healthy donors by multiparameter flow cytometry. The suppressive function of Treg was evaluated using CFSE-labeled fresh autologous CD4 + CD25 - T cells activated with an anti-CD3 antibody. Results: The percentage of circulating CD4+ CD25 high Treg was higher (p &lt;0.001) in the AML patients (5.2 ± 1.3%, range 0.4 −7%) compared to healthy donors (1.1 ± 0.2%, range 0.8–1.5%). T reg expressing Foxp3, CTLA-4, CD45 RO, CCR4 and Fas receptor (CD95) were significantly elevated in the circulation of AML patients, but GITR expression on Treg was low. Suppression mediated by T reg co-incubated with proliferating autologous responders was also significantly higher (p&lt;0.001) in AML than that mediated by control T reg (75 ± 6% vs 12%± 4%). Conclusions: These results indicate that T reg accumulate in the periphery of patients with AML and have vigorous suppressive functions. This high suppressive activity may impair the host anti-tumor responses and promote leukemogenesis. No significant financial relationships to disclose.
Vaccine for prevention of breast cancer
Authors: A. Deisseroth, Y. Tang, J. Maynard, H. Akbulut
Journal: Journal of Clinical Oncology (2006)

2580 Background: Women with high risk breast cancer still succumb to their disease despite existing programs of adjuvant therapy. Thus, new approaches for adjuvant therapy are needed. Her-2-Neu overexpression on a breast cancer cells correlates with recurrence, metastasis and resistance to chemotherapy and radiation therapy. The immune response is tolerant of tumor associated antigens (TAA) like Her-2-Neu since they have been present on epithelial cells since birth. The immune response to vaccines in women with breast cancer is limited by the diminished number of CD4 and CD8 T cells and qualitative defects of CD4 cells in individuals above the age of 50. Methods: The following strains of mice were vaccinated: 6–8 week old hMUC-1.Tg mice, and rH2N.Tg mice, as well as 18 month and 2 month old C57BL/6J mice, by injecting subcutaneously the Ad-sig-TAA/ecdCD40L vector prime followed by sc injections of the TAA/ecdCD40L protein boost. Results: Vaccination of 18 month old mice with the Ad-sig-TAA/ecdCD40L vector prime protein boost produce regressions of TAA positive sc tumor and a 5 fold increase in antigen specific spleen cells, a 10X increase in subcutaneous tumor nodules of antigen specific effector CD8 T cells by tetramers, and a 2X decrease of CD4+CD25+FOXP3+ cells. Vaccination of rH2N.Tg mice starting at 6 weeks with the Ad-sig-rH2N/ecdCD40L vector prime/protein boost prevented the development of breast cancer in 50% of the mice. The Ad-sig-hMUC-1/ecdCD40L vector prime/ hMUC-1/ecdCD40L protein boost induced hMUC-1 specific antibodies in hMUC-1.Tg mice which bound to human breast cancer specimens. The rH2N/ecdCD40L vector prime/protein boost vaccine suppressed growth of rH2N positive tumor cells and this effect was potentiated by concomitant administration of chemotherapy. Conclusions: These results suggest that the Ad-sig-TAA/ecdCD40L platform can be used to suppress the growth of existing breast cancer even in old mice and prevent the development of breast cancer. We are preparing a phase I clinical trial of this approach in the setting of breast cancer patients who have failed first line adjuvant therapy. In this trial, the vaccine will be added to established salvage therapy and both in vivo evaluations of tumor response, in vitro assays of immune response and toxicity will be measured. No significant financial relationships to disclose.
EGFR, DCC, and K-RAS mutations as predictive factors for cetuximab sensitivity in metastatic colorectal cancer (mCRC)
Authors: A. Mancuso, A. Leone, L. Vigna, F. Calabrò, R. Giuliani, S. De Marco, A. D’Alessio, R. Gasbarra, R. Pisa, C. N. Sternberg
Journal: Journal of Clinical Oncology (2008)

4128 Background: Several studies suggest that increased gene copy number of the Epidermal Growth Factor Receptor (EGFR) or presence of mutations of the K-ras oncogene are associated with cetuximab response or resistance in patients (pts) with mCRC. In this setting data are not yet available regarding deleted in colorectal cancer (DCC), a tumor-suppressor gene located at chromosome 18q21, although DCC could theoretically modulate the EGFR/K-RAS pathway. This study aimed to identify biological predictors for sensitivity and resistance to cetuximab in pts with mCRC. Methods: Paraffin embedded tumor blocks from 31 mCRC pts treated with cetuximab-based regimens (Table 1) were retrospectively analyzed for EGFR (immunohistochemical staining - IHC and fluorescence in situ hybridization - FISH), DCC (Fragment analysis), and K-RAS (exon 12 mutation). Results: EGFR FISH positive patients (n=18), defined as ratio EGFR/nucleus =3, had a significantly higher time to progression -TTP (6.2 versus 3.2 months, p = 0.003) than EGFR FISH negative (n=13). The concordance rate of IHC-positive cases with cases positive for EGFR gene amplification by FISH was 55% (17/31) but EGFR expression assessed by IHC was not associated with any clinical end-point. Allelic losses (LOH) at the DCC locus were observed in 45% of pts. The median TTP was 6.6 months in pts without LOH and 2.7 months in pts with DCC-LOH (log-rank test, p =.04). Compared to pts with wild type K-RAS (n=21), K-RAS mutation carriers (n=10) had a significantly lower objective response rate (PR + SD, 3% versus 42%, p = 0.02), shorter TTP (2.3 versus 6.6 months, p = 0.06) and shorter survival which was not statistically significant (p = 0.2). Multivariate analysis showed that TTP was not correlated with treatment lines, sex, age and objective response rate. Conclusions: This study suggests that there is a significant benefit in TTP for EGFR FISH positive patients treated with cetuximab. DCC allelic losses could predict early resistance to cetuximab therapy and K-RAS mutation analysis identifies a group of pts with the lowest chance of benefiting from therapy. No significant financial relationships to disclose.
Role of protein kinase C in the adaptive increase in Na-H antiporter in respiratory acidosis.
Authors: P Pahlavan, L J Wang, E Sack, J A Arruda
Journal: Journal of the American Society of Nephrology (1993)

Chronic respiratory acidosis stimulates the Vmax of the renal brush border Na-H antiporter. The activation of protein kinase C (PKC) by phorbol esters stimulates the activity of the renal Na-H antiporter. In this study, the hypothesis that PKC plays a role in the adaptive increase of the renal brush border Na-H antiporter activity to respiratory acidosis was tested. In vivo respiratory acidosis was associated with an increase in in vitro Na-H antiporter activity and also with an increase in brush border membrane PKC activity, without changes in PKC activity in cytosol or basolateral membranes. Na-H antiporter activity, assessed as the amiloride-sensitive component of 22Na uptake, was measured in cultured proximal tubule cells exposed to 10% CO2 for 48 h. Na-H antiporter activity was significantly higher in cells exposed to 10% CO2 than in those exposed to 5% CO2. To evaluate the role of PKC, cultured cells were depleted of PKC by exposure to the active phorbol ester phorbol 12-myristate 13-acetate (PMA; 10(-7) or 10(-6) M) for 48 h before exposure to 10% CO2. In the presence of 10% CO2, Na-H antiporter activity was significantly lower in PKC-depleted cells than in control. In addition, sphingosine, an inhibitor of PKC, also prevented the adaptation of the Na-H antiporter to 10% CO2 as compared with 5% CO2. In cells treated with the inactive analog 4 alpha-PMA, 22Na uptake was not different than that in control. PMA-treated cells also had a decrease in Na-H antiporter activity during exposure to 5% CO2.(ABSTRACT TRUNCATED AT 250 WORDS)
Use of 99mTc-EC20 (a folate-targeted imaging agent) to predict response to therapy with EC145 (folate-targeted therapy) in advanced ovarian cancer.
Authors: J. T. Symanowski, A. H. Maurer, R. W. Naumann, N. P. Shah, D. Morgenstern, R. A. Messmann
Journal: Journal of Clinical Oncology (2010)

5034 Background: Use of targeted therapy requires identification of patients (pts) whose tumors express a specific molecular target. Several folate receptor (FR) molecular targeted drugs are in clinical development including the folate-vinca EC145. Before treatment with EC145, as part of study NCT00507741, pts underwent planar and SPECT scanning with the FR targeted, technetium-labeled imaging agent EC20 in order to evaluate whether scan results correlate with subsequent response to therapy with EC145. Methods: 45 pts with advanced ovarian cancer received 99 mTc labeled EC20. EC20 uptake for each tumor was classified as
Significance of elevated serum lactate dehydrogenase (LDH) in patients undergoing salvage autologous bone marrow/peripheral stem cell transplantation (BM/PSCT) for relapsed/refractory Hodgkin’s lymphoma (R/R-HL)
Authors: K. Kojouri, S. Pant, R. Kamble, N. Sylvester-Kohrt, G. B. Selby, H. Ozer, M. A. Kharfan-Dabaja
Journal: Journal of Clinical Oncology (2005)

6734 Background: High-dose chemoRx→ BM/PSCT is an acceptable salvage for pts with R/R-HL. In a reported single institution(Bierman PJ.et al. Ann Oncol. 2002;13:1370), low albumin (<4g/dl), anemia (<10.5g/dl), age (≥45 y) and lymphocytopenia (<600/mm3 and/or<8% of WBC) were associated with inferior event-free and overall survival (OS) in pts with HL undergoing auto BM/PSCT. Elevated LDH levels, as in the IPI and age-adjusted index, adversely impact outcome in pts with aggressive NHL. The significance of elevated LDH in pts with R/R-HL s/p salvage auto BM/PSCT is less clearly defined and controversial. Objective: Evaluate a potential correlation between OS and elevated LDH levels (at transpl) in pts s/p salvage auto BM/PSCT for R/R-HL. Methods: Retrospective, single-institution of consecutive pts with R/R-HL who received salvage auto-BM/PSCT over 14 y (Nov 01,90-Nov 30,04). LDH level (U/L) at time of BM/PSCT (day 0±1) was noted. Pts were divided as normal (A) and high-LDH group (B), if LDH were <1x or ≥1x normal (institution normal:<190 U/L), respectively. OS was defined as the time-period in months from day of transpl to death, until last day of f/u, or until last day of study, for pts who died, were lost to f/u, or still alive, respectively. Survival curves were estimated according to the Kaplan-Meier method, and compared between the 2 groups with the log-rank test. One-sided P-value of <0.05 was significant. Results: 49 pts (33 men, 16 women) were identified, who were 13–69 yrs (median: 32 yrs) at time of transpl. 30 pts (61%) died during f/u, 12 pts (25%) were lost to f/u at 2 to 84 mos (median: 25 mos) after transpl, and 7 pts (14%) are alive at time of analysis, 7–75 mos (median: 40 mos) after transpl. LDH at transpl was not available in 5 pts. Median OS for A (n1=26, 15/26 [58%]died) was 15.6 mos (95% CI: 8.4–69.4 mos) and for B (n2=18, 13/18 [72%] died) was 33.7 mos (95% CI: 18.1–58.7 mos). The difference in OS curves was not significant (p=0.601,log-rank). Conclusion: Our results show that elevated serum LDH levels don’t correlate with inferior OS in pts with R/R-HL s/p salvage auto BM/PSCT. A prospective study is warranted. No significant financial relationships to disclose.
Phase Ib study of AMG 386 combined with either pegylated liposomal doxorubicin (PLD) or topotecan (T) in patients with advanced ovarian cancer.
Authors: R. M. Wenham, J. W. Leach, S. A. Scudder, B. R. Amin, C. H. Pippitt, A. N. Gordon, N. Nanayakkara, E. Hurh, D. E. Stepan, R. J. Schilder
Journal: Journal of Clinical Oncology (2010)

5049 Background: AMG 386 is an investigational peptide-Fc fusion protein that inhibits angiogenesis by preventing angiopoietin 1/2 interaction with the Tie2 receptor. We report on an ongoing, open-label study of AMG 386 combined with PLD or T in advanced ovarian cancer. Methods: In part 1 of this 2-part dose de-escalation study, adult patients (pts) with recurrent, epithelial ovarian, fallopian tube, or primary peritoneal cancer and GOG performance 0 or 1, and ≤ 3 prior chemotherapy regimens received, IV, AMG 386 at 10 mg/kg QW plus PLD at 50 mg/m2 Q4W (Arm A, n = 6 planned) or T at 4 mg/m2 QW (3 on/1 off; Arm B, n = 6 planned) until progression or unacceptable toxicity. Dose-limiting toxicities (DLTs) in ≥ 3 pts in either arm triggers dose de-escalation of AMG 386 to 3 mg/kg; 6 pts to be enrolled at lower dose. Cohort expansion with 19 pts is planned for part 2 of the study if ≤ 1 pt in either arm has a DLT at either AMG 386 dose. The primary endpoint is DLT incidence; secondary endpoints are safety, PK and response per RECIST (ORR) or CA-125 (GCIG criteria). Results: 12 pts have been enrolled and received ≥ 1 dose of AMG 386 (Arm A/B, n = 6/6). With ≥ 4 weeks follow-up for each pt, there have been no DLTs and no AMG 386 dose de-escalations. 11 pts (Arm A/B, n = 6/5) had AMG 386-related adverse events (AEs): 5 had grade 3 AEs (n = 4/1). There were no grade 4 or 5 AEs. The most common AMG 386-related AEs were nausea (Arm A/B, n = 3/2; no grade 3), fatigue (n = 3/2; grade 3, n = 2/0), rash (n = 3/0; grade 3, n = 2/0), and anemia (n = 0/2; no grade 3). Other key AMG 386-related AEs included hypertension (n = 5/4, no grade 3) and peripheral edema (n = 0/1, grade 3). With median follow-up of 13/21 weeks (Arm A/B), 8 pts were progression-free (n = 5/3); 3 pts had progressed (n = 1/2) and 1 pt (Arm B) died from disease progression. ORR data are not mature. 6 pts had CA-125 responses (Arm A/B, n = 3/3); 1 pt in Arm A had CA-125 progression. Combining AMG 386 with PLD or T did not appear to affect the PK parameters of either agent. Planned cohort expansion to part 2 is underway. Conclusions: Based on these interim results with short follow-up, AMG 386 combined with PLD or T appears tolerable in pts with advanced ovarian cancer. Updated safety and efficacy data will be presented. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen, Nuwan Nanayakkara via Quintiles Amgen, CTI Amgen Amgen, GlaxoSmithKline, Ortho Biotech Amgen
Treatment of high-risk, nonseminomatous testicular cancer with cisplatin, ifosfamide and bleomycin: Long-term results
Authors: U.B. Wandl, K. Günzel, R. Kath, M.E. Scheulen, J. Hayungs, K. Höffken, S. Seeber, N. Niederle
Journal: Annals of Oncology (1992)
Do the treatment outcome priorities of head and neck cancer patients change after undergoing radiation treatment?
Authors: H. Badr, D. I. Rosenthal, K. Milbury, A. S. Garden, S. J. Frank, G. B. Gunn, C. S. Cleeland, E. R. Gritz
Journal: Journal of Clinical Oncology (2010)

5599 Background: Although head and neck cancer (HNC) patients have access to a broad range of treatment options that may differ in toxicities and late effects, little is known about how patients prioritize such outcomes. The purpose of this study was to determine whether patient preferences for different treatment outcomes prior to initiating radiotherapy change after completing treatment and to explore whether preferences are related to patients' experience of physical symptoms. Methods: Twenty-four patients were asked to rank a series of 12 HNC treatment effects prior to initiating radiotherapy (baseline) and at a 4 month post-treatment follow-up. Lower ranks indicated greater priority. They also completed the M. D. Anderson Symptom Inventory Head and Neck Module (MDASI-HN) at each time point. Results: Being cured was ranked as the top priority by 83% of patients at baseline and 88% at 4-months. Wilcoxon sign rank tests indicated this change was marginally significant (Z=− 1.83; p=.08). A significant change was found for returning to a normal activity level (Z=−2.19, p<.05); 29% of patients ranked this as one of their top 3 concerns at baseline compared to 38% at follow-up. Excluding the top ranked item, there was considerable variability in rankings. Although rankings for cure were not associated with either of the MDASI symptom severity or HN-specific subscales at baseline, patients with more physical symptoms were more likely to prioritize being able to swallow all foods/liquids (Spearman's rho = −.43, p<.05), being able to chew normally (rho=−.49, p<.05), and having a comfortably moist mouth (rho = −.39) at the 4-month follow-up. Conclusions: Results of this ongoing study highlight the complexity of patient-centered care for HNC. Although most patients prioritized cure regardless of symptom severity and there was a trend toward patients valuing cure even more after treatment, other treatment outcomes increased in importance at follow-up, after patients experienced symptoms. Further study is needed to understand how elucidation of patient preferences should guide decisions regarding medical treatment. No significant financial relationships to disclose.