tbuckley/cabot-search huggingface dataset:
Decrease of CA 19–9 in patients with advanced pancreatic cancer (APC) undergoing chemotherapy predicts survival time
Authors: K. Pohlank, A. Hilbig, U. Pelzer, J. Stieler, L. Roll, A. Goerke, M. Sinn, B. Dörken, H. Riess, H. Oettle
Journal: Journal of Clinical Oncology (2008)

15574 Background: Serum carbohydrate antigen 19–9 (CA 19–9), the sialylated Lewis a blood group antigen has been shown to be a very sensitive and specific serum marker for pancreatic cancer. The prognostic value for patients with pancreatic cancer undergoing resection or radiotherapy is well established. Few studies showed correlation between decrease of CA 19–9 level and median survival time, however the role of CA 19–9 in monitoring treatment efficacy remains unclear. Methods: The response of the tumor marker CA 19–9 to gemcitabine- based chemotherapy was retrospectively studied in 181 consecutive patients (pts) with APC treated in our outpatient department between 12/98 and 10/05 to find out whether it is related to survival time. 150 patients had elevated baseline CA 19–9 level at diagnosis and were separated in two groups. Group I (n=83) showed a decrease of at least 20 % of CA 19–9 level after 8 weeks of therapy, group II (n=67) showed a stabilization or an increase of CA 19–9 level after 8 weeks of therapy. Results: Median age was 64 years (range 33–101), median baseline level of CA 19–9 was 1498 U/ml (range 40–1043301). Median survival of 150 patients with APC and elevated baseline CA19–9 level treated with gemcitabine-based chemotherapy was 46 weeks (range 8–198). Patients of group I (n=83) had a median survival survival time of 50 weeks (range 13–198 weeks, 95% CI:38,1–61,8), patients of group II (n=67) 35 weeks (range 8–160 weeks, 95% CI:27,8–46,2; p=0.003). Conclusions: Patients with a decrease of CA 19–9 level of at least 20 % after 8 weeks of therapy showed a significant improvement in median survival in comparison to patients with a stabilization or an increase in CA 19–9 level. Measurements of CA 19–9 should be performed in patients with APC and increased baseline level after 8 weeks of treatment to assess prognosis together with further clinical parameters. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Amgen, Bayer, Hoffmann-La Roche, Lilly, Merck, Novartis, Pfizer, sanofi-aventis
A phase-I dose-escalation study of SR271425 administered intravenously in split doses (d1-d2-d3) in patients with refractory solid tumors
Authors: P. Fumoleau, M. Campone, N. Isambert, S. Maury, P. Monin-Baroille, E. Bourbouloux, G. Schackleton, F. de Braud, J. Berille, F. Dujardin
Journal: Journal of Clinical Oncology (2005)

3133
Impact of adjuvant therapy in lymph-node positive vulvar cancer: The AGO CARE 1 study.
Authors: Sven Mahner, Julia Kathrin Jueckstock, Felix Hilpert, Dirk Lubbe, Philipp Harter, Nikolaus De Gregorio, Severine Iborra, Frank Chen, Adela Stoenescu, Peter Hillemanns, Sophie Fuerst, Hans-Georg Strauss, Klaus H. Baumann, Falk Thiel, Alexander Mustea, Werner Meier, Andreas Du Bois, Pauline Wimberger, Lis-Femke Griebel, Linn Lena Woelber
Journal: Journal of Clinical Oncology (2012)

5007 Background: While the majority of patients with vulvar cancer can be cured by surgery alone, women with lymph-node metastases often show unfavorable outcome. Improved treatment strategies are therefore strongly needed. Methods: Patients with primary squamous-cell vulvar cancer treated at 29 gynecologic cancer centers in Germany between 1998 and 2008 were included in a centralized database and analyzed retrospectively. Results: A total of 1,637 patients were documented with a median follow-up of 121 months. UICC-Stage distribution was 597 (36.5 %) T1, 816 (49.8 %) T2, 160 (9.8 %) T3 and 31 (1.9 %) T4, 33 (2.0 %) were missing. 491 patients had lymph-node metastasis to the groins (N+). 214 N+ patients (43.6 %) developed recurrent disease within a median of 21.4 months. 190 N+ patients (38.7%) died, median overall survival (OS) was 43.4 months, compared to 212 months for node-negative patients. An increasing number of metastatic lymph-nodes was associated with shorter OS: 169 (34.4%) patients had 1, 101 (20.6%) patients 2, 62 (12.6%) patients 3 and 86 (17.5%) patients &gt;3 positive lymph-nodes, with a corresponding OS of 22.4, 17.2, 18.4 and 10.2 months, respectively (for 73 patients the number of nodes was not available). 240 N+ patients were treated with adjuvant radiotherapy (85.8%) or radiochemotherapy (14.2%). Median OS in these patients was significantly longer (66.9 months) compared to N+ patients without adjuvant treatment (35.7 months), the corresponding hazard ratio (HR) was 0.72 (95 % CI: 0.53 - 0.97 p = 0.029). This impact on OS remained consistent in multivariate analysis adjusted for age, ECOG, stage, grading, invasion depth and number of positive nodes (HR 0.68; 95% CI: 0.49 - 0.94 p = 0.020) and was observed irrespective of the number of affected nodes. Conclusions: To this day, this is the largest multicenter study on vulvar cancer. Our findings strongly suggest that the unfavorable prognosis of patients with node positive vulvar cancer can be improved by adjuvant therapy irrespective of the number of affected nodes. As adjuvant radiochemotherapy was shown to be superior to radiotherapy alone in many other squamous cell carcinomas, we are preparing a prospective phase III trial in node-positive vulvar cancer (AGO-CaRE 2 trial).
Targeted therapy to EGFR and HER2 combined with gemcitabine in a novel human pancreatic orthotopic model.
Authors: A. Vidal-Pla, S. Pérez-Torras, R. Miquel, S. Navarro, P. Gascon, J. Maurel, N. Carbo, A. Mazo
Journal: Journal of Clinical Oncology (2010)

e14601 Background: Treatment of pancreatic cancer remains challenging and mostly palliative. Gemcitabine and erlotinib has shown modest benefit compared with gemcitabine alone. The efficacy of anti-EGFR therapies has been probably hampered by the absence of biomarker selected strategies. Activation of compensatory pathways, such as Her-2 or IGF-IR signaling, should be considered. Methods: From eleven tumorgrafts only one shows moderate to high levels of both EGFR and HER2 and very low IGF-1R activity. The other models harbor null or very low EGFR and HER2 levels (n = 4) or were positive for EGFR or HER2 but also for IGF-IR activity (n = 6). Pancreatic tumors obtained at the time of surgery were implanted intrapancreatically in nude mice and expanded to develop cohorts of tumor bearing mice suitable for drug evaluation. Five groups of 8 mice each were treated for 7 weeks with vehicle, gemcitabine or gemcitabine combined with cetuximab, trastuzumab or both antibodies. To determine treatment effects, tumor size measurement, antibody array analysis, CD31 staining and TUNEL labeling were performed. Results: Combination of cetuximab and trastuzumab with gemcitabine potentiated tumor growth inhibition (p < 0.05, triple treatment vs. double treatments). In comparison to double treatments, this triple combination led to a 2.1-fold increase of cell death; the vascularization of the tumors determined by CD31 staining exhibited a 2.3-fold reduction. Moreover, significant decreases in the phosphorylation levels of EGFR, HER2 and several proteins implicated in angiogenesis, such as VEGFR2, VEGFR3 and PDGFRβ, were detected. Cell migration was also affected as shown by reduced levels of activation of Src, Fyn, Fak or Paxillin. Conclusions: Gemcitabine combined with cetuximab and trastuzumab is a promising strategy in pancreatic tumors with activated EGFR and HER2 but without activation of IGF-1R pathway. No significant financial relationships to disclose.
Efficacy of Chemotherapeutic Treatment of Guinea Pig Hepatoma Reflected in Host's Serum Lipid Composition&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;
Authors: S I Schlager
Journal: JNCI Journal of the National Cancer Institute (1983)

A correlation was found between the highly polar phospholipid (HPPL) content of serum lipids and the growth and metastasis of the line-10 hepatoma in strain 2 guinea pigs. Animals whose tumors were treated by intralesional injection of decarbazine (DTIC) or saline showed progressive tumor growth and metastasis resulting in death within 120 days of tumor implantation. The percent HPPL in the serum lipids of these animals rose to 40% by 80 days and remained elevated above 20–25% until death. Animals whose tumors were treated by intralesional injection of adriamycin were either cured of their tumors (67%) or showed little or no tumor growth. The percent HPPL in the serum lipids of these animals remained between 3 and 12% at all times. Adriamycin or DTIC injected into non-tumor-bearing animals resulted in an HPPL content of serum lipids that was not significantly different from that of control. saline-inoculated animals.
Suppression of tumor necrosis factor synthesis by n 3 fattyacids in end stage congestive heart failure
Authors: R.V. Milani, S. Endres, H.O. Ventura, C.B. Daul, P.C. Weber, F.W. Smart, D.D. Stapleton, C.J. Lavine, W. Barbee, J..P. Murgo
Journal: Journal of the American College of Cardiology (1994)
Continuous daily dosing (CDD) of sunitinib (SU) in patients with metastatic soft tissue sarcomas (STS) other than GIST: Results of a phase II trial
Authors: M. L. Keohan, J. A. Morgan, D. R. D’Adamo, D. Harmon, J. E. Butrynski, A. J. Wagner, G. K. Schwartz, R. G. Maki, G. D. Demetri, S. George
Journal: Journal of Clinical Oncology (2008)

10533 Background: SU is an oral multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, FLT3, CSF-1R and RET approved multinationally for treatment of imatinib-resistant/intolerant GIST. SU demonstrated early evidence of activity in sarcomas other than GIST during phase I testing. The current phase II study was designed to examine the clinical activity of CDD of SU in pts with advanced STS other than GIST. Methods: Pts with metastatic and/or locally advanced STS, measurable disease, ECOG PS 0–1 and ≤3 prior chemotherapy regimens were eligible. Pts are enrolled in 1/2 study arms: histologies that have shown responses to TKIs (Arm A) or histologies that have not (Arm B). Using a Simon 2-stage design, 21+20 patients will be recruited per arm based on ORR. The treatment regimen is administered as CDD of SU (37.5 mg) in 4-wk cycles. The primary endpoint is ORR per arm based on RECIST. Secondary endpoints include progression-free rate (CR+PR+SD) at 16 and 24 wks and OS. FDG-PET response before and after 2 wks of therapy was assessed in 21 pts and is reported in a separate abstract by Van den Abbeele et al (ASCO 2008). Results: As of Jan. 2008, 41 evaluable pts were enrolled, 20 in Arm A and 21 in Arm B (17 M, 24 F, ages 18 - 86). Results are available for 39 pts. In Arm A, there are no PRs or CRs; 11/20 pts had SD as best response (hemangiopericytoma 2, pulmonary intimal sarcoma 1, leiomyosarcoma 5, chordoma 2, angiosarcoma 1). 3/11 remain stable at wk 16 (range 16 - 32). In Arm B, 1 pt with desmoplastic small round-cell tumor (DSRCT) exhibited a PR at cycle 2 that continues at wk 32. There are no CRs. 6/19 pts had SD as best response (giant cell tumor 1, synovial 1, alveolar soft part sarcoma 1, DSRCT 1, well-/de-differentiated liposarcoma 2). 4 pts remain stable at wk 16. Grade 3 AEs include hematologic toxicities (19), diarrhea (5), mucositis (6), hand-foot syndrome (3), GI bleed (1) and seizure (1). One grade 4 event occurred: GI hemorrhage, duodenal ulcer. Conclusions: CDD of SU 37.5 mg has demonstrable activity in pts with certain subtypes of STS. Certain histologies such as DSRCT, giant cell tumor and solitary fibrous tumor/hemangiopericytoma may achieve prolonged disease control. Larger cohorts of these specific subtypes are needed to confirm this benefit. No significant financial relationships to disclose.
Phase II trial of extrapleural pneumonectomy followed by adjuvant radiotherapy in malignant pleural mesothelioma
Authors: C. Peigaud, L. Cellerin, J. Roussel, C. Sagan, S. Bordenave, S. Trogrlic, M. Mahé, J. Bennouna, J. Michaud, P. Despins
Journal: Journal of Clinical Oncology (2009)

7579 Background: This phase II clinical study was conducted to evaluate the effectiveness of the association of extrapleural pneumonectomy followed by radiation therapy in patients with potentially resectable malignant pleural mesothelioma (MPM). Methods: Eligible patients had histologically proven epithelial or mixed MPM with clinical stage T1–3, N0–2, M0 disease considered to be completely resectable and a WHO performance status of 0 or 1. Surgery had to consist of a complete extrapleural pneumonectomy including resection of pericardium and diaphragm. Postoperative radiotherapy (40 Gy) was delivered through anterior and posterior fields, with a 10 to 20 Gy boost dose if necessary. Results: Thirty seven patients were included in this study. Extrapleural pneumonectomy was completed in 35 patients. Overall hospital mortality was 5,7 %. Major post operative complications were: 3 acute lung injury, 1 bronchopleural fistula, 1 stroke, 1 chylothorax and one diaphragmatic patch dehiscence. IMIG post-operative staging was: stage II = 5 patients; stage III = 25 patients; stage IV = 5 patients. Adjuvant radiation was administered to 29 patients. Survival for the 35 patients with complete resection was 47 ± 8 % at 2 years. Median overall survival time was 22 months. Survival without recurrence was 37 ± 8 % at 2 years. Median time to progression was 15 months. Locoregional recurrence is the most common form of relapse. Conclusions: In the era of surgical neoadjuvant therapy in MPM treatment, extrapleural pneumonectomy followed by radiation therapy in patients with resectable epithelial or mixed MPM can achieve acceptable results. No significant financial relationships to disclose.
Phase I trial of bevacizumab plus sunitinib in patients (pts) with metastatic renal cell carcinoma (mRCC)
Authors: D. R. Feldman, G. V. Kondagunta, E. A. Ronnen, P. Fischer, R. Chang, M. Baum, M. S. Ginsberg, N. Ishill, S. Patil, R. J. Motzer
Journal: Journal of Clinical Oncology (2007)

5099 Background: Bevacizumab, an intravenous monoclonal antibody against VEGF, and sunitinib, an oral multi-targeted tyrosine kinase inhibitor of VEGF and PDGF receptors, both have activity in mRCC [NEJM 349:427–434; JAMA 295:2516–2524]. Combining bevacizumab and sunitinib may increase antitumor efficacy by maximizing inhibition of the VEGF pathway. The safety and maximum tolerated dose (MTD) of sunitinib in combination with bevacizumab was assessed in this Phase I trial. Methods: Cohorts of 3–6 pts with mRCC received escalating doses of sunitinib (dose levels: 25, 37.5, and 50 mg po) daily for 4 weeks (wks) followed by 2 wks off with fixed- dose bevacizumab (10 mg/kg iv) every 2 wks continuously. Pre-determined dose-limiting toxicities (DLTs) in the first 6-wk cycle included Grade (Gr) 4 neutropenia, ≥Gr 3 thrombocytopenia of ≥7 days, Gr 4 hypertension or proteinuria, and other Gr 3 non-hematologic toxicity of ≥7 days. Pts who came off study prior to completion of cycle 1 for any reason other than a DLT were replaced. Serum VEGF levels were measured before and during cycles 1 and 2. Results: 16 pts (11 male, 5 female, median age 57) were enrolled. Of 8 patients entered at the first dose level (sunitinib 25 mg, bevacizumab 10 mg/kg), 2 were replaced; 1 never received treatment and 1 did not complete cycle 1 due to rapid progression of disease (PD). No DLTs occurred in the remaining 6 evaluable pts in this cohort. At the 2 nd dose level (n =6, sunitinib 37.5 mg, bevacizumab 10 mg/kg), 1 pt receiving low molecular weight heparin had a DLT of Gr 4 hemorrhage. 2 pts have enrolled in the 3 rd dose level (sunitinib 50 mg, bevacizumab 10 mg/kg) but are not yet evaluable for toxicity or response. Gr 3/4 toxicities over all cycles included Gr 3 hypertension (n=4), Gr 3 proteinuria (n=2), Gr 3 abdominal pain (n=2), Gr 4 hemorrhage (n=1), and Gr 3 hand/foot syndrome (n=1). 13 pts were evaluated for best response–4 had partial responses, 7 had stable disease, and 2 had PD. Serum VEGF levels decreased during cycle 1 in all pts. Conclusions: The combination of sunitinib and bevacizumab in mRCC pts was tolerable at the first 2 dose levels. Once the MTD is identified, further testing of this combination in phase II trials may be indicated for mRCC as well as other malignancies. [Table: see text]
Biomarkers of early operable primary breast cancer in elderly (≥70 years) women (EPC) and their correlation with breast cancer-specific survival (BCSS).
Authors: B. M. Syed, A. R. Green, E. C. Paish, D. A. Morgan, I. O. Ellis, K. Cheung
Journal: Journal of Clinical Oncology (2010)

10558 Background: Biological features of breast cancer seem to change with age. Most studies have small sample size or data collected from multiple centres with different laboratory protocols, limiting their importance. This study was conducted in a single centre with a dedicated service for EPC and breast histopathology team, all following the same clinical and laboratory guidelines at any time point, with long-term follow-up. Methods: Over 36 years, 2,000+ EPC were diagnosed. Of these, 831 underwent surgery as primary therapy and 575 had good quality tumour samples available for tissue microarray (TMA) analysis. A total of 306 patients from this group did not receive adjuvant systemic therapy. Conventional histological features (size, grade and axillary stage) were available as part of standard reporting. For this study, immunohistochemistry analysis of 18 biomarkers using TMA of surgical specimens was performed. Positivity was defined using standard cut-offs: ≥1% cells stained considered positive in ER, PR, HER4, CD44 and E-Cadherin, ≥5% in p53, ≥10% in CK (5, 5/6, 7/8, 14, 17, 18 and 19), BRCA1, Ki67, MUC1 and bcl2; HER2 with 3+ score was considered positive. The results were correlated with BCSS. Results: At median follow-up of 66 months (maximum=261), tumour size <3 cm, low grade (1-2), involvement of 0-3 axillary node(s), positive ER, PR, and bcl2 were found to be associated with better 5-year BCSS, while positive HER2 and Ki67 correlated with worse BCSS. On multivariate analysis, only tumour size (85 vs 75%, p=0.042, HR=3.270), grade (99 vs 73%, p=0.046, HR=12.141), axillary stage (90 vs 40%, p=0.000, HR=12.072) and PR (90 vs 80%, p=<0.017, HR=0.190) were found to show significant differences in 5-year BCSS. Conclusions: In a selected group of EPC treated by primary surgery, tumour size, grade, axillary stage, and PR status have been found to be independent prognostic factors. They need to be considered alongside contexts relevant to elderly population (including patients treated by non-operative therapy (eg primary endocrine therapy) and the impact of co-morbidities on overall survival), when long-term clinical outcome is assessed. No significant financial relationships to disclose.
Improved Detection of Chromosomal Abnormalities in CLL by Conventional Cytogenetics Using CpG Oligonucleotide and Interleukin-2 Stimulation. A Belgian Multicentric Study
Authors: Natalie Put, Katrina Rack, Nadine Van Roy, Jeanne-Marie Libouton, Pascal Vannuffel, Daniel Sartenaer, Geneviève Ameye, Frank Speleman, Hélène A Poirel, Peter Vandenberghe, Lucienne Michaux
Journal: Blood (2008)
A phase I study of daily oral TRC102 (methoxyamine) to enhance the therapeutic effects of pemetrexed in patients with advanced refractory cancer
Authors: S. P. Anthony, L. S. Rosen, G. J. Weiss, M. S. Gordon, B. J. Adams, S. L. Gerson, D. Alvarez, C. P. Theuer, B. R. Leigh
Journal: Journal of Clinical Oncology (2009)

2552 Background: TRC102 (methoxyamine) is a small molecule inhibitor of base-excision repair (BER) that enhances the cytotoxicity of alkylator and antimetabolite chemotherapy and reverses chemotherapy resistance. TRC102 inhibits BER by stabilizing abasic sites produced by glycosylase removal of damaged DNA bases. Methods: A phase 1 trial evaluated the safety, PK, and PD of oral TRC102 combined with intravenous pemetrexed in patients with advanced refractory cancer. Patients were required to have ECOG PS ≤ 1 and adequate organ function. TRC102 was escalated in cohorts of 3–6 patients in combination with standard dose pemetrexed. All patients received TRC102 alone on Days 1–4 of a 2 week cycle followed by the combination of pemetrexed and TRC102 every 3 weeks thereafter. Results: Eight patients were treated with a total of 22 cycles of TRC102 at 15 mg/m 2 (n=3) and 30 mg/m 2 (n=5). No adverse events were attributed to TRC102 alone, and grade 3–4 neutropenia without fever, grade 3 thrombocytopenia, and grade 1–2 fatigue and asthenia were considered possibly related to the combination of TRC102 and pemetrexed. One patient at 30 mg/kg TRC102 experienced grade 3 anemia during Cycle 2 that was considered a dose-limiting toxicity. He recovered after 2 units PRBCs and a 50% dose-reduction of TRC102, and remained on study through Cycle 5. Clinical PK analyses indicate that TRC102 plasma concentrations required for in vivo activity are achievable with daily oral administration (Cmax = 49–62 ng/mL, half-life = 29–40 hr), and PD studies confirm that TRC102 stabilizes pemetrexed-induced abasic sites in these patients. Conclusions: Daily oral TRC102 is tolerated at doses that potentiate the clinical activity of pemetrexed in patients with advanced refractory cancer. Phase 2 studies are planned in multiple indications. [Table: see text]
Abstract #669: Development of new tumor targeting 10B-carrier: Boron cluster-cyclic RGD pentapeptide conjugates for boron neutron capture therapy
Authors: sadaaki Kimura, Yusuke Inaba, Yasuo Kawamura, Satoshi Ueda, Kensuke Okuda, Shin-ichiro Masunaga, Hideko Nagasawa
Journal: Cancer Research (2009)

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

A neutron capture reaction in boron [10B(n, \#945;)7Li] is, in principle, very effective in destroying tumors, providing that sufficient amount of 10B can be accumulated in the target tumor. However one of the major limitations in boron neutron capture therapy (BNCT) is insufficient and heterogeneous delivery of 10B from currently used 10B carriers, such as sodium mercaptoundecahydrododecaborate-10B (BSH) and L-4-boronophenylalanine-10B (BPA), into the target tumors. To augment the efficiency of BNCT, we developed new 10B carriers containing the Arg-Gly-Asp (RGD) motif which is the minimum recognition element for the \#945;v\#946;3 integrin. The \#945;v\#946;3 integrin is expressed on proliferating endothelial cells such as those present in growing tumors, as well as on tumor cells of various origins. In this report, various boron cluster-cyclic RGD pentapeptide conjugates were synthesized and we analyzed their biodistribution and cytocidal effects of neutron irradiation to evaluate their usefulness in BNCT. The cyclo(-Arg-Gly-Asp-D-Phe-Lys-) and N -methyl analog, cyclo(-Arg-Gly-Asp-D-Phe-MeLys-) were synthesized as a tumor targeting moiety by Fmoc solid-phase method and conjugated to various boron clusters, such as carboranes and BSH, through alkyl amide linker chain. They were purified by RP-LC and identified by ESI-MS. We estimated their hydrophobicity by RP-TLC experiments and cytotoxicity of these compounds by MTT assay using HCT116 cells. All of the boron cluster-cyclic RGD pentapeptide conjugates are more hydrophobic than BSH. The IC50 values of BSH derivatives on HCT116 cells are less than those of carborane derivatives because of higher hydrophilicity. Biodistribution studies were carried out using C3H/He female mice bearing SCCVII tumors on both hind legs. At various time points after administration, mice were sacrificed and tumors and some organs were collected. The boron concentrations in these tissues were measured by ICP-AES. Based on these findings in the biodistribution study, we have a plan to select a suitable dosage and a time point for starting thermal neutron irradiation for BNCT. And then, we will examine the effects of the new 10B-carrier on tumor cells in vivo in comparison with BSH. Further, we are also going to evaluate some other new derivatives for improving effects in BNCT.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 669.