tbuckley/cabot-search huggingface dataset:
Addition of muramyl tripeptide to chemotherapy for patients with newly diagnosed metastatic osteosarcoma: A report from the Children’s Oncology Group
Authors: A. J. Chou, E. Kleinerman, M. D. Krailo, D. Betcher, J. Healey, H. Nadel, M. Nieder, M. Weiner, R. J. Wells, P. A. Meyers
Journal: Journal of Clinical Oncology (2008)

10018 Background: With longer followup, the addition of muramyl tripeptide (MTP) to chemotherapy has been shown to improve overall survival in patients with non-metastatic osteosarcoma (OS). We report the results of MTP addition to chemotherapy for patients with metastatic OS. Methods: Intergroup-0133 was a prospective randomized trial for the treatment of newly diagnosed patients with OS. We compared three drug chemotherapy with cisplatin, doxorubicin, and high-dose methotrexate (Regimen A) to the same three drugs with the addition of ifosfamide (Regimen B). We evaluated the addition of MTP to chemotherapy. We report herein the first analysis of 91 patients with metastatic OS at presentation. Outcome measures included event free survival (EFS) and survival. Results: Five-year EFS for patients who received MTP (n=46) was 42% versus 26% for those who did not (n=45), p=0.38. The 5-year overall survival for patients who received MTP versus no MTP was 53% and 40% respectively (p=0.36). The comparison of Regimen A with regimen B did not suggest a difference for EFS (35% v. 34% respectively, p=0.75) or overall survival (52% v. 43% respectively, p=0.95). While the small numbers of patients in the metastatic cohort preclude statistical significance, the pattern of outcome for the metastatic cohort was the same as the pattern of outcome for the non-metastatic cohort. Conclusions: When the metastatic cohort was considered in isolation, the addition of MTP to chemotherapy did not achieve a statistically significant improvement in outcome. The pattern of outcome is similar to the pattern in non-metastatic patients. Relative Risk of Death Metastatic Patients (n=91) Non-Metastatic Patients (n=662) MTP Assigned 1 1 No MTP Assigned 1.3 1.4 p-value 0.36 0.028 Regimen A 1 1 Regimen B 0.98 0.97 p-value 0.95 0.83 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration IDM IDM
Everolimus in patients with metastatic renal cell carcinoma (mRCC) who are intolerant of or have progressed after prior vascular endothelial growth factor receptor–tyrosine kinase inhibitor (VEGFr-TKI) therapy: An international expanded access program (EAP).
Authors: V. Grunwald, I. Bodrogi, K. Miller, J. H. Machiels, S. Lee, S. Chowdhury, R. Yuan, M. Rosamilia, J. L. Booth, P. I. Karakiewicz
Journal: Journal of Clinical Oncology (2011)

314 Background: The mammalian target of rapamycin (mTOR) inhibitor everolimus is the first agent to show efficacy in a randomized, controlled phase III trial in patients with mRCC after progression on VEGFr-TKIs (RECORD-1). Progression-free survival (PFS) was significantly improved (4.9 vs 1.9 months) and the risk of disease progression was reduced by 67% with everolimus compared with placebo. To fulfill an unmet medical need, everolimus was offered globally in this EAP. Presented here are preliminary results on 605 patients. Methods: The program began in July 2008 (ClinicalTrials.gov: NCT00655252 ; EudraCT: 2007-005460-28), and since then over 1,000 patients in 34 countries have been enrolled. Patients with clear cell and non–clear cell mRCC who failed or became intolerant of VEGFr-TKIs received daily oral doses of everolimus with investigator assessment every 3 months. Results: Data were collected for 605 patients who had discontinued treatment as of January 15, 2010. Evaluable patients had a mean age of 63 years, and most (94%) had progressed after prior VEGFr-TKI therapy. The adverse event (AE) profile did not differ significantly from that reported in the RECORD-1 trial. Most frequently reported grade 3–4 AEs were anemia (6.1%), stomatitis (4.6%), fatigue (4.6%), hyperglycemia (4.0%), and infection (3.6%). Grade 3–4 noninfectious pneumonitis was reported in 2.8%. Best overall response was stable disease, which was evident in 42% of patients. Conclusions: The EAP has allowed patients with mRCC access to everolimus before marketing approval. The rapid enrollment rate of this EAP confirms the unmet medical need after failure of VEGFr-TKIs. Everolimus has shown good tolerability, and no new safety issues have been identified. The investigator-assessed response rate is consistent with that reported in the RECORD-1 trial. The EAP provides an efficient framework for the development of other programs for innovative anticancer agents in patients without satisfactory therapeutic options. [Table: see text]
Prospective assessment of circulating endothelial cells (CECs) as early markers of clear cell renal cell carcinoma (CCRCC) progression in first line setting: The Circles study (SOGUG 2011-01).
Authors: Daniel E. Castellano, Emilio Esteban, Luis Leon, Laura Basterretxea, Arancha Gonzalez, Maria Jose Mendez, Paula Jimenez, Pablo Maroto, Xavier Garcia del Muro, Jose Angel Arranz, Miguel Angel Climent, Jesus Garcia-Donas
Journal: Journal of Clinical Oncology (2012)

TPS4685 Background: Since the identification of Von Hippel Lindau (VHL) gene mutations as a critical step in the development of most Clear Cell Renal Cell Carcinomas (CCRCC), neoangionesis inhibition has become a cornerstone in their treatment. Despite the proven efficacy of antiangiogenic drugs, most patients will not achieve partial response by RECIST criteria. Thus, to accurately determine tumor progression is a challenging question incompletely answered by traditional radiological assessment. In recent years CECs counts have been proposed as surrogate biomarkers of angiogenesis that could be used for monitoring tumor evolution while on targeted therapies. We aim to figure out if CECs elevations could anticipate radiological progression in CCRCC. Methods: An observational prospective study is being performed in 10 institutions members of the Spanish Oncology Genitourinary group (SOGUG). Patients older than 18 years with histologically proven CCRCC on first line treatment with any targeted drug who have not progressed after 3 months of therapy are considered elegible. Recruitment begun on August the 1st 2011 and 15 of the 75 scheduled patients have been included so far. CECs are periodically collected in peripheral blood every 6 weeks for 15 months or radiological tumor progression, whatever occurs first. Median CEC values will be calculated and stated by descriptive statistics (Cellsearch, VERIDEX). To explore the evolution of CECs counts along treatment a linear model will be constructed. An association among CECs counts changes and time to progression will be analyzed with Cox model.
Treatment (tx) patterns and drug (Rx) costs for patients (pts) with metastatic renal cell carcinoma (mRCC) in the United States.
Authors: Daniel M. Geynisman, Ya-Chen T. Shih
Journal: Journal of Clinical Oncology (2014)

457 Background: The tx paradigm for mRCC has rapidly morphed from cytokine-based and cytotoxic tx to targeted therapy (TT). Five oral (O) and two intravenous (IV) TTs are approved for mRCC. No consensus exists on the sequence of TT use. This study aimed to examine the evolution of 1 st through 3 rd line tx patterns since 2004 and their associated costs. Methods: LifeLink Health Plan Claims Database (October 1, 2003-March 31, 2011), a commercial claims database, was used to create a cohort of age ≥ 18 yo, mRCC pts with at least 12 months of continuous enrollment. We examined tx patterns and sequences by year. When evaluating cost, we limited analysis to pts &lt;65 yo because the database does not have information on claims paid by Medicare. We described pt characteristics and tx patterns over time and applied a nonparametric bootstrapping method to compare costs. Results: 1,561 mRCC pts met the inclusion criteria with 71% men and a mean age of 62 yo (SD=11); 39% were from the South; 57% had a modified Charlson comorbidity score of zero. In 2010: 9 unique Rx regimens were used for 1 st line tx, 8 for 2 nd , 8 for 3 rd ; most common 1 st /2 nd /3 rd line tx was sunitinib (44%)/temsirolimus (24%)/everolimus=sunitinib (26%); most common sequence was VEGF-&gt;mTOR for the 1 st switch and VEGF-&gt;VEGF-&gt;VEGF for 2 nd switch. From 2004 to 2011, 1 st line cytotoxic tx decreased from 47% to 6%, IFN-α from 47% to 3%, bevacizumab from 33% to 9%. Over time, more pts were able to go from 1 st to 2 nd line tx (p=0.01) and 2 nd to 3 rd line tx (p=0.025). Median time to switch (TTS) from 1 st to 2 nd line was 175 days (SD 103) with a longer TTS if started on O vs. IV tx (188 vs. 143 days) (p&lt;0.001). For 959 pts &lt;65 yo, stratifying by whether the 1 st line tx was O or IV, mean total 1 st -yr tx cost/pt was $130,962 (IV) vs. $121,676 (O) (P=0.18) and total 1 st -yr Rx cost was $36,636 (IV) vs. $54,596 (O) (p&lt;0.001). Also, costs increased by the number of switches, from $108,428 for no switch to $190,976 for &gt; 1 switch. Conclusions: The results support a drastic shift in the tx of mRCC with wide heterogeneity in tx patterns, reflecting a lack of clear guidelines. Over the years, more pts are able to receive more lines of tx, TTS was longer with initial O tx, but 1 st -yr Rx costs were lower with initial IV tx.
Effect of lenalidomide on antileukemia activity in vitro against adult T-cell leukemia (ATL).
Authors: Y. Kitagawa, M. Matsuoka, S. Mitani
Journal: Journal of Clinical Oncology (2011)

6580 Background: Lenalidomide is an FDA approved agent for del 5q myelodysplastic syndromes and in combination with dexamethasone for previously treated multiple myeloma. Recently, phase II clinical trial has shown its anti-tumor activity against recurrent and refractory T-cell lymphomas. However, the mechanism underlining its effect is poorly understood. Adult T-cell leukemia (ATL) is a mature T cell malignancy caused by Human T-cell leukemia virus type I (HTLV-I) that is endemic in southwestern Japan, the Caribbean islands and Central Africa, and it still remains as one of the most difficult malignancies to be cured. We have evaluated the anti-ATL activity of lenalidomide in vitro using HTLV-I positive cell lines. Methods: The effect of lenalidomide (10-3-102µM) was assessed on the proliferation of seven HTLV-I positive cell lines by CellTiter-Glo Luminescent Cell Viability Assay. The effect of lenalidomide on CD56 positive cells from healthy volunteers was also studied. Their cytotoxic effect against HTLV-I positive cell lines was assessed using 51Cr releasing assay. Results: Lenalidomide alone did not inhibit cellular proliferation. Even 6 day incubation did not inhibit or stimulate proliferation of HTLV-1 positive cell lines. Lenalidomide slightly increased CD56 positive cells in peripheral blood mononuclear cells (PBMNCs) upon stimulation of interleukin-2 (IL-2). In addition, cytotoxic activity of IL-2 primed PBMNCs against HTLV-I positive cell lines was enhanced by lenalidomide. Conclusions: These results show that lenalidomide enhances cytotoxic effects against HTLV-I positive cells, without direct anti-proliferative effect on those cell lines. That effect might be mediated through CD56 positive cells stimulated by lenalidomide. Further study is now on-going to elucidate the mechanism of those actions.
Lymph node (LN) ratio (LNR) risk classification (RC) in stage III colon cancer (CC): A pooled analysis of 16,425 patients from the ACCENT database.
Authors: Q. Shi, J. M. Hubbard, G. A. Yothers, T. Andre, L. Saltz, G. Francini, B. M. Bot, C. Twelves, M. E. Buyse, A. Grothey, D. J. Sargent
Journal: Journal of Clinical Oncology (2011)

3556 Background: The degree of LN involvement is one of the most important prognostic factors in CC. Current staging does not consider the number of total LN examined (TLN) and its predictive ability of nodal associated disease RC. Our aim was to develop a RC model based on LNR with internal and external validation. Methods: Individual patient (pt) data from 18 randomized clinical trials were used. LNR is defined as number of positive LNs divided by number of TLN. The primary endpoint was disease-free survival (DFS). The development dataset consisted of pts receiving 5FU based chemotherapy only. This dataset was randomly split into a training set (6848 pt) and an internal validation set (4952 pt). Pts receiving surgery alone (951 pt) and 5FU plus other agents (oxaliplatin, irinotecan, or oral-based) (3674 pt) comprised two external validation populations. Optimal cutoffs were selected based on Cox model goodness of fit. Validation was based on two key aspects of a predication model - discrimination (c statistics, accurately distinguishes those at high risk from those at low risk), and calibration (calibration slope, measures the reliability of the predictive effect, which is important if a predictive model is used in decision-making). All analyses were stratified by study. Results: Overall 54% of pts were male with median age of 61. Median follow-up was 8 yrs. 7320 pts had recurrence or died, with 5 yr DFS of 58.6% (95% CI: 57.8%, 59.4%). Two new RCs were identified with the same discrimination but improved calibration over AJCC N staging (Table). The hazard ratios comparing higher risk subgroups to reference group for both LNR based RCs range from 1.5 to 3.0 (all p < .0001). Conclusions: LN ratio and number of total LN examined can aid prognostic calibration of DFS in stage III CC. External validation. Nodal risk category External validation C statistic Calibration Slope AJCC N stage N1a [32%], N1b [34%], N2a [21%], N2b [13%] 1 0.58 0.76 2 0.59 0.78 LNR <0.18 [40%], 0.18≤ LNR <0.36 [27%], 0.36≤ LNR <0.67 [22%], ≥0.67 [11%] 1 0.59 0.87 2 0.60 0.94 LNR and total LNs exam TLN<15 <0.36 [37%], 0.36≤ LNR <0.67 [17%], ≥0.67 [9%] 1 0.59 0.94 TLN≥15 <0.18 [22%], 0.18≤ LNR <0.36 [8%], ≥0.36 [7%] 2 0.60 0.90
Regional differences in patient (pt) characteristics of AVAGAST: An exploratory comparison in chemotherapy plus placebo (PL) arm between Japanese (JPN) and the rest of the world (ROW) pts.
Authors: Tomohira Nishina, Akira Sawaki, Kensei Yamaguchi, Toshihiko Doi, Yasuhide Yamada, Keisho Chin, Taroh Satoh, Narikazu Boku, Yasushi Omuro, Yoshito Komatsu, Hiroya Takiuchi, Yasuo Hamamoto, Wasaburo Koizumi, Shigehira Saji, Manish A. Shah, Eric Van Cutsem, Yoon-Koo Kang, Atsushi Ohtsu
Journal: Journal of Clinical Oncology (2012)

100 Background: AVAGAST study showed regional differences in efficacy, including notable differences in progression free survival (PFS) and overall survival in the PL arm. In Japan, there is a certain number of pts with minimal peritoneal metastasis (PM) diagnosed only by laparoscopy or open surgery, which seems unusual in Western as well as in other Asian countries, and it might have led the differences. Therefore, an exploratory analysis was conducted among the PL arm to examine pt characteristics including PM associated with differences in outcome between JPN and ROW. Methods: We compared PFS of PL arm between pts enrolled from JPN and those from ROW. Hazard ratio (HR) and its 95% confidence interval (95%CI) between JPN and ROW were calculated using Cox’s proportional hazard model for each major covariates (disease status, performance status, prior gastrectomy, prior (neo)adjuvant chemotherapy, age, sex, primary site, liver metastasis (mets), number of metastatic sites, disease measurability, histologic type, maximum of tumor size, sum of tumor size, bone mets, PM and only PM) Results: 188 pts from 14 sites were enrolled from JPN, of which 94 pts were randomized to PL arm. Compared with 293 pts from ROW in PL arm, PFS tend to be favorable in JPN. Subgroups of JPN without liver mets, with diffuse or mixed type gastric cancer (GC), with PM and with only PM were clearly favorable than that of ROW. The difference in subgroup with PM was especially large with lower confidence limit of 1.21. When the pts with only PM were excluded, the difference of PFS in PL arm between JPN and ROW became smaller ( Table ). Conclusions: In this exploratory analysis, pts with PM in JPN had a better prognosis than ROW pts. Understanding this unique pt population may provide insight to the regional differences in outcome noted on this study. [Table: see text]
Association of the apoptotic effect of the coffee deterpene kahweol on human colon cancer cell with the expression of heat shock proteins (HSPs).
Authors: Sung Chul Park, Dong Wook Choi, Jin Myung Park, Dae Hee Choi, Chang Don Kang, Sung Joon Lee, Wan Joo Chun
Journal: Journal of Clinical Oncology (2015)

622 Background: It has been reported that coffee has a preventative effect in several cancers because of its anti-oxidant, anti-inflammatory, and anti-tumor properties. However, there have been few reports about the effect and mechanism of coffee compounds in colorectal cancer. Heat shock proteins (HSPs) are molecular chaperones that prevent cell death. Their expression is significantly elevated in many tumors and is accompanied by increased cell proliferation, metastasis, and poor response to chemotherapy. Methods: We investigated the apoptotic effect of major components of coffee in the HT-29 human colon adenocarcinoma cells and evaluated the antitumor mechanism via the regulation of HSPs expression. HT-29 cells were cultured with bioactive compounds of coffee such as caffeine, chlorogenic acid, caffeic acid, and kahweol. Cell viability was determined by MTT and LDH assay according to the concentration of each component. Western blot assay was taken for evaluation of the apoptosis-related signals such as cleaved caspase-3, cleaved PAPR, Bcl-2, phospho-AKT(p-AKT), and HSPs including HSP40, HSP70, and HSP90. Results: Among the various coffee compounds, only kahweol showed significant anti-tumor cell activity, and cell death was observed in a concentration-dependent manner on MTT and LDH assay. Kahweol induced an increase in expression of cleaved caspase-3 and PAPR. In contrast, the reduction of anti-apoptotic proteins such as Bcl-2 and p-AKT was derived. HSPs including HSP40, HSP70, and HSP90 were decreased by kahweol treatment. HSP70 inhibitor such as quercetin and triptolide showed the significantly decreased viability of HT-29 cells. Conclusions: Kahweol had a cytotoxic effect on HT-29 cells via the apoptotic signal pathway in a concentration-dependent manner and inhibited the expressions of HSPs. HSP70 inhibitors showed tumor cell cytotoxicity, suggesting that HSP might play a significant role in the proliferation of cancer cells.
Allogeneic gastric cancer cell-dendritic cell hybrids induce tumor antigen (carcinoembryonic antigen) specific CD8+ T cells
Authors: H. Saito, S. Matsumoto, S. Tsujitani, M. Ikeguchi
Journal: Journal of Clinical Oncology (2005)

2545 Background: The development of protocols for the ex vivo generation of dendritic cells (DCs) has led to intensive research of their potential use in immunotherapy. Accumulating results show the efficacy of this treatment on melanomas, which are highly immunogenic. However, its efficacy remains unclear in other tumors. In this study, allogeneic gastric cancer cell-DC hybrids were used to determine the efficacy of this type of immunotherapy in gastric cancer. Methods: Fusion cells of DC and allogeneic gastric cancer cells were generated by polyethylene glycol (PEG) and electrofusion. These hybrids were used to induce tumor associated antigen (TAA) specific cytotoxic T lymphocytes (CTLs). Results: The DCs were successfully fused with the allogeneic gastric cancer cells resulting in hybrid cells. These hybrid cells were functional as antigen presenting cell because they induced allogeneic CD4+ T cells proliferation. A gastric cancer cell line, MKN-45, and DC hybrid cell induced autologous CD4+ and CD8+ T cell proliferation, indicating that MKN-45-DC hybrids present some antigens from the MKN-45 cells to the CD4+ and CD8+ T cells. CD8+ T cells stimulated by the MKN-45-DC hybrid cells were able to kill MKN-45 when used for immunization. The CTLs killed another gastric cancer cell line, MKN-1, as well as a melanoma cell line, 888mel, suggesting the recognition of a shared tumor antigen. Moreover, the CTLs killed TAP-deficient T2-A24 cells expressing HLA-A24 loaded with HLA-A24 restricted carcinoembryonic antigen (CEA) peptides (CEA652 or CEA 268), indicating that the killing is due to tumor antigens as well as alloantigens. The tetramer staining showed that the MKN-45-DC hybrids induced more CEA-specific CD8+ T cell expansion than the MKN-45 lysate-pulsed DCs. Conclusions: This approach suggests the possible use of allogeneic gastric cancer cell-DC hybrids in DC based immunotherapy for gastric cancer treatment. No significant financial relationships to disclose.
Phase II study of preoperative bevacizumab, capecitabine, and radiotherapy for resectable locally advanced rectal cancer.
Authors: M. Martinez Villacampa, C. Santos, M. García, V. Navarro, A. Teule, F. Losa, A. Pisa, L. Lema, S. Biondo, R. Salazar
Journal: Journal of Clinical Oncology (2011)

516 Background: Bevacizumab into chemoradiotherapy appears safe and active in locally advanced rectal cancer (LARC).This study evaluates whether the addition of bevacizumab to capecitabine-based chemoradiotherapy in the preoperative treatment of LARC improves pathological complete response rate (pCR). Methods: Open-label, unicentric, phase II study in patients with resectable LARC (stage II or III), with or without nodal involvement and no evidence of distant metastases. Treatment schedule of 4-cycles: bevacizumab administered iv on day 1 (10 mg/kg in the first cycle and 5 mg/kg in the following 3 cycles) and capecitabine (900mg/m 2 /bid) in the 2nd cycle (5 d/wk) concomitantly with radiotherapy 45Gy (25 fractions of 1.8Gy/day) over 5 weeks. Surgical resection was scheduled 6-8 weeks after therapy completion. Preliminary results from ITT analysis are presented. Results: Of the 43 patients included, 41 comprised ITT population. Baseline characteristics: median age 63 (55-67) years; male 76%; ECOG 0/1 49%/51%; stage T3/N1 80.5%/58.5%; nodal metastases 85%. 39 patients underwent surgery, 9 abdominoperineal and 30 anterior resection. No evidence of metastasis after surgery in 97%. Total mesorectal excision was performed in 69% of patients and 85% underwent R0 resection. Sphincter-preservation was achieved in 79.5%. Downstaging occurred in 82%. Among 39 patients evaluable for pathological response, 7.7% experienced pCR, 69.2% partial response and 20.5% stable disease. Grade 3/4 toxicities: 9.8% lymphopenia (all related to capecitabine and 4.9% to bevacizumab), 2.4% neutropenia (capecitabine-related), 2.4% radiodermatitis (related to RT and capecitabine) and 2.4% vasospastic angina (bevacizumab and capecitabine-related). 13 patients had postoperative complications not treatment-related. The most common were wound infection (6), intra-abdominal collection (3), wound dehiscence (2) and paralytic ileus (2). Conclusions: Preoperative regimen with bevacizumab, capecitabine and RT is active for LARC with promising results of R0 resection, sphincter- preservation and tumour downstaging as well as manageable toxicity. Further studies are ongoing to confirm these data. No significant financial relationships to disclose.