tbuckley/cabot-search huggingface dataset:
High Survival Rate in Infant Acute Leukemia Treated With Early High-Dose Chemotherapy and Stem-Cell Support
Authors: Fernando Marco, Encarna Bureo, Juan J. Ortega, Isabel Badell, Amparo Verdaguer, Ana Martínez, Arturo Muñoz, Luis Madero, Teresa Olivé, Josep Cubells, Victoria Castel, Ana Sastre, M. Soledad Maldonado, Miguel A. Díaz
Journal: Journal of Clinical Oncology (2000)

PURPOSE: Infants with acute leukemia have a poor prognosis when treated with conventional chemotherapy. It is still unknown if stem-cell transplantation (SCT) can improve the outcome of these patients. In the present study, we review our experience with SCT in infant acute leukemia to clarify this issue. PATIENTS AND METHODS: We report the results of 26 infants who were submitted to a SCT for acute leukemia. There were 15 cases of acute myeloid leukemia and 10 cases of acute lymphoid leukemia. One patient had a bilineal leukemia. Twenty-two patients were in their first complete response (CR1), three were in their second CR, and one was in relapse. Eight patients were submitted to allogeneic SCT, and 18 underwent autologous SCT. RESULTS: With a median follow-up of 67 months, the 5-year overall survival and disease-free survival (DFS) are 64% (SE = 9%) and 63% (SE = 10%), respectively. Autologous and allogeneic SCT offered similar outcome. There was not any transplant-related mortality, and all deaths were caused by relapse in the first 6 months after SCT. In multivariate analysis, the single factor associated with better DFS was an interval between CR1 and SCT of less than 4 months (P &lt; .025). CONCLUSION: SCT is a valid option in the treatment of infant acute leukemia, and it may overcome the high risk of relapse with conventional chemotherapy showing very reduced toxicity. This study suggests that SCT should be performed in CR1 in the early phase of the disease.
Combined application of imatinib and standard chemotherapeutics results in additive cytotoxic effects in human prostate cancer cell lines
Authors: H. Kübler, H. Van Randenborgh, U. Treiber, A. Lehmer, S. Wagenpfeil, R. Hartung, R. Paul
Journal: Journal of Clinical Oncology (2004)

4737 Background: Hormone refractory prostate cancer (HRPC) has been a therapeutic challenge due to limited response to treatment. Prominent cell signaling pathways in tumor growth are mediated by tyrosinekinase (TK) receptors. Platelet-derived growth factor receptors (PDGF-R) are expressed in prostate cancer but not in benign prostate hyperplasia or normal prostatic epithelium. Imatinib (STI571, Gleevec®) is a selective inhibitor of the PDGF-R. The aim of this in vitro study was to evaluate cytotoxic effects of Imatinib in combination with commonly used chemotherapeutics for HRPC. Methods: The human prostate cancer cell lines LNCaP (androgen dependend), PC-3 and DU-145 (androgen refractory) were screened for TK receptors by immuncytochemical analysis. C-kit was expressed in none of these cell lines. The expression pattern of PDGF-R were different among these cell lines and will be presented. Variable cell growth was determined by XTT reduction assay. Cell lines were incubated 96 hours with rising concentrations of Imatinib alone and in combination with Etoposide, Doxetacel, and Estramustinphosphate (EMP). The cytotoxic interaction were evaluated by isobolograms as described by Steel & Peckham. Results: Imatinib showed dose-depended growth inhibition with nearly complete cell death in all three cell lines. The IC50-values of Imatinib for LNCaP, PC-3 and DU-145 were 12,48 μM, 11,68 μM and 16,24 μM respectively. Simultaneous exposure of Imatinib and Etoposide suggested additive to synergistic effects in DU-145. The combination of Imatinib and EMP showed additive effects in all three cell lines. Combination of Imatinib and Doxetacel resulted in additive to antagonistic effects in DU-145 and LNCaP, whereas in PC-3 antagonistic effects were observed. Conclusions: The simultaneous administration of Imatinib and Etposide resulted in additive to synergistic effects in DU-145. The combination with EMP produced additive effects in hormone refractory as well as hormone sensitive cell lines. Based on these encouraging in vitro data clinical trials of Imatinib with these promising combinations are planned in HRPC. No significant financial relationships to disclose.
TIMP-4 expression in breast cancer induces the Akt-pathway resulting in accelerated disease progression
Authors: R. Thirumaran, J. Sabol, N. Carp, V. Zemba-Palko, M. Wallon
Journal: Journal of Clinical Oncology (2008)

22111 Background: Tissue inhibitor of metalloproteinase-4 (TIMP-4) has been shown to be expressed among early stage breast cancer patients with poor prognosis. The TIMP-4 staining of clinical specimens from breast cancer patients indicated that TIMP-4 is localized to the nucleus. We undertook this study in order to identify a mechanism for the observed effect of TIMP-4 in breast cancer cells. Methods: We tested the breast cancer cell-line MDA-MB-435S, which does not express TIMP-4, for changes in expression using array analysis. Total RNA was isolated from cells that had been incubated with or without recombinant TIMP-4 for 24 hours. The total RNA was then used to label probes according to the manufacturer's recommendation and hybridized over night at 60°C to the Pathway Finder array (SuperArray, Inc). This array contains 128 genes involved in signal transduction, apoptosis, angiogenesis and cell cycle control. Results: Of the 128 genes, 12 showed more than 20-fold increase in expression after exposure to TIMP-4. Interestingly, among the genes with increased expression were several genes in the Akt-signaling pathway such Akt, PI3K and PTEN. We have tested and found that Akt protein is also increased after TIMP-4 exposure and that the TIMP-4 induced increase in Akt is stronger than EGF-induced Akt expression. The principal role of phosphorylated Akt is to facilitate cell survival and to block apoptotic cell death. We also have preliminary data showing that the levels of phosphorylated Akt are elevated in the TIMP-4 exposed cells. This indicates that TIMP-4 when taken up by cells that normally should not be exposed to TIMP-4 induces a cell survival environment. With the advantage of increased survival signaling, the breast cancer cells might gain a more aggressive phenotype and therefore have an accelerated disease progression. No significant financial relationships to disclose.
Costs of care and outcomes for high-dose therapy and autologous transplantation for lymphoid malignancies: results from the University of Nebraska 1987 through 1991.
Authors: C L Bennett, J L Armitage, G O Armitage, J M Vose, P J Bierman, J O Armitage, J R Anderson
Journal: Journal of Clinical Oncology (1995)

High-dose therapy with autologous stem-cell support has become common treatment for relapsed or refractory lymphomas. We conducted a study of 178 patients with Hodgkin's disease and 149 patients with non-Hodgkin's lymphoma who received high-dose therapy with stem-cell support. We evaluated the following: (1) whether improvements in outcomes over time found for surgical procedures were also true for a new nonsurgical procedure, autologous bone marrow and peripheral stem-cell transplantation; and (2) whether such a relationship, if it existed, applied to both clinical and economic outcomes.Mortality rates for patients with Hodgkin's disease decreased from 20% in 1987 to 0% in 1991. For non-Hodgkin's lymphoma, the mortality rate decreased from 29% in 1987 to 4% in 1991. Multivariate analyses indicated that the number of previous transplants was the most important factor associated with survival and low-cost care. After controlling for differences in clinical factors, a logistic regression model predicted that patients with Hodgkin's disease had a 20% chance of dying after 30 cases and a 5% chance after 178 cases; patients with non-Hodgkin's disease had a 33% chance of dying after 14 cases and a 5% chance after 149 cases. For patients with Hodgkin's disease, the cost decreased at a rate of 10% per year from 1987 to 1991 (P = .001), while for patients with non-Hodgkin's lymphoma, the cost of transplants decreased at a rate of 8% per year.Survival rates improved and costs of care decreased over time for patients who received high-dose therapy with stem-cell support. These changes are most likely related to improvements in supportive care technologies, better patient selection, and experience of the transplant team.
Preliminary tolerability and anti-tumor activity of intravenous recombinant human Interleukin-21 (IL-21) in patients with metastatic melanoma and metastatic renal cell carcinoma
Authors: B. D. Curti, B. G. Redman, J. A. Thompson, E. L. Sievers
Journal: Journal of Clinical Oncology (2005)

2502 Background: IL-21, a cytokine with homology to IL-2, has demonstrated anti-tumor activity in multiple preclinical tumor models. Methods: In an ongoing phase I dose-escalation study, IL-21 was administered by intravenous push to patients (pts) with AJCC stage 4 metastatic melanoma and renal cell carcinoma. Doses ranging from 3–1000 μg/kg/day x 5 days are planned. Study objectives are to determine a maximally tolerated dose, and to assess pharmacokinetics, immunogenicity, immunomodulatory and anti-tumor activity of IL-21. Results: Patients have been sequentially enrolled in groups of three at dose levels of 3 and 10 μg/kg/day for two 5-day cycles separated by a 9 or 16 day rest interval. All patients experienced one or more adverse events, but no drug-related serious adverse events or CTCAE grade 3 or 4 events have been observed among 6 pts treated {metastatic melanoma (5) and metastatic renal cell carcinoma (1)}. A disease-related grade 3 hemoptysis was observed. Grade 2 adverse events of any relationship to IL-21 include arthralgia, fatigue, headache, increased sweating, pruritus, neutropenia, lymphopenia, increased INR, hypophosphatemia, and hypoalbuminemia. Increases in NK, CD8+, and CD4+ cells and levels of soluble IL-2 receptor were observed in most pts. By RECIST criteria, one patient with metastatic renal cell carcinoma achieved a partial response and two patients with metastatic melanoma had stable disease. Conclusions: IL-21 administered at doses up to 10 μg/kg/day x 5 days for 2 cycles has been well tolerated and preliminary evidence of immunomodulatory and clinical activity has been observed. Enrollment at higher dose levels is ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration ZymoGenetics ZymoGenetics
Sorafenib and radiation: A promising combination in colorectal and pancreas cancer
Authors: G. D. Wilson, A. Suen, J. Robertson, S. Galoforo, B. Marples
Journal: Journal of Clinical Oncology (2009)

e14622 Background: Sorafenib inhibits both RAF kinase, a critical component of the RAS/RAF/MEK/ERK signaling pathway that controls cell proliferation, and VEGFR-2/PDGFR-beta signaling cascade, blocking tumor angiogenesis; this dual activity has great potential for radiosensitization. This study examines the effectiveness of radiation and sorafenib in a series of human colorectal and pancreatic cell lines and xenografts with differing ras mutational status. Methods: Three colorectal cell lines were selected. HT29 and SW48 are wild-type ras whilst SW480 has a mutation in codon 12 . Two pancreatic cancer cell lines were selected, Panc 03.27 is wild-type ras whilst Panc 02.03 has a mutation in codon 12. MTT assays were used to find the best drug concentration and timing to combine with radiation. Radiosensitization was assayed using clonogenic assays with either 5 or 10μg/ml sorafenib. Xenografts were established and randomized to control, sorafenib at 20mg/kg daily (5 days/week) for 3 weeks, radiation given as 2.5 Gy daily fractions (5 days/week) for 3 weeks or a combination of the two with sorafenib administered immediately after radiation Results: The MTT data suggested that sorafenib given immediately after or at least within 2 hours of radiation appeared to give the greatest growth inhibition. Sorafenib had no effect on cell survival in the colorectal cell lines but showed a modest radiosensitization, the surviving fractions at 2 Gy alone or with 5 or 10 μg/ml sorafenib were 34%, 26% and 23% (p=0.0018) in SW48 cells. In pancreatic cells, sorafenib was toxic at 10 μg/ml and reduced survival by 30% at 5 μg/ml without sensitization The endpoint in the xenograft studies was tumor growth to 2000mm 3 within a period of 120 days. In SW48 tumors, the number of days to grow to 2,000 mm 3 was 13.6 ± 2.2 in the control arm, 37.0 ± 21.2 in the radiation alone arm, 17.0 ± 8.2 in the sorafenib arm and100.8 ± 28.0 in the combined arm (2 of the 5 animals were ‘cured‘). The respective data in the HT29 xenografts was13.2 ± 2.1, 62.6 ± 9.8, 38.2 ± 26.5 and106.2 ± 36.2 days (3 of 5 animals were ‘cured‘. Conclusions: Sorafenib and radiation are a promising combination. Phase I studies are under development in both pancreatic and colorectal cancer at our Instittution. No significant financial relationships to disclose.
Carboplatin-based sequential chemotherapy for aged patients with advanced bladder cancer.
Authors: Takahiro Yoneyama, Yuki Tobisawa, Tohru Yoneyama, Hayato Yamamoto, Atsushi Imai, Kazuyuki Mori, Shingo Hatakeyama, Yasuhiro Hashimoto, Takuya Koie, Chikara Ohyama
Journal: Journal of Clinical Oncology (2015)

342 Background: We retrospectively evaluated the feasibility and effectiveness of carboplatin based chemotherapy for the patients 65 years or older with advanced bladder cancer. Methods: We treated 86 patients with advanced bladder cancer at our clinic between August 2004 and June 2014. 56 patients (40 men and 16 women) with the age of 65 years or older were enrolled. Their average age was 75.8 years old (65–86), average Ccr was 54.4 ml/min (14.5–113.0), and an average follow-up period was 21.7 months (2–81). There were 18 recurrent cases after radical surgery and 38 inoperable cases. The therapeutic regimen consisted of 2 lines: gemcitabine/carboplatin (GCarbo) therapy as the first line, with two courses as a set; GCarbo/docetaxel (GCarboD) therapy as the second line if the response in the first line was insufficient. GCarbo consisted of 800mg/m 2 gemcitabine on days 1, 8, and 15 and carboplatin (AUC 4) on day 2. If this regimen was effective, another 2 courses of GCarbo was performed. If this regimen did not induce any tumor size reduction, we switched to GCarboD, which consisted of 800mg/m 2 gemcitabine on days 1 and 8, 70mg/m 2 docetaxel on day 1, and carboplatin(AUC 3) on day 2. Treatment efficacy was checked every 2 course. Results: Of the 56 subjects who had undergone the GCarbo therapy, the response rate was 37.5% (CR+PR) with 4 and 17 subjects exhibiting CR and a PR, respectively; the average response duration was 10.0 months (2–78). The response rates of 12 instances of GCardoD was25.0 %; the overall median survival was 14.0 months throughout the carboplatin-based sequential chemotherapy. Adverse events (AE) of grade 3 or higher occurred in 33 of those who had undergone the GCarbo therapy (58.9%). In GCarboD regimen, there were 11 (91.7 %) of G3/4 AEs. Conclusions: Although the present study is small and preliminary, the present carboplatin-based sequential chemotherapy is safe and active for advanced bladder cancer of the patients 65 years or older. GCarbo regimen achieved acceptable response rate (37.5%) in advanced bladder cancer. The median overall survival of 14.0 months is acceptable when average age of 75.8 year for the subjects is took into consideration. However, GCardoD had limited effectiveness for non-responder of GCarbo.
Phase I trial of oxaliplatin and doxorubicin in children and adolescents with recurrent solid tumors.
Authors: L. Mascarenhas, S. Armenian, J. L. Harrington, H. Mahmoud, R. Sposto, M. H. Malogolowkin
Journal: Journal of Clinical Oncology (2010)

9543 Background: The combination of a platinum agent and anthracycline has activity in pediatric solid tumors. This trial evaluated the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of oxaliplatin combined with doxorubicin given with dexrazoxane intravenously in pediatric patients with recurrent solid tumors and evaluated the pharmacokinetics (PK) of oxaliplatin when administered with doxorubicin. Methods: Patients with prior exposure to anthracyclines were eligible. Oxaliplatin was administered on day 1 and Doxorubicin on days 1-3 of each 21-day course. Three dose levels were evaluated: 1) oxaliplatin 105 mg/m2 and doxorubicin 20 mg/m2, 2) oxaliplatin 130 mg/m2 and doxorubicin 20 mg/m2 and 3) oxaliplatin 130 mg/m2 and doxorubicin 25 mg/m2. Dexrazoxane was administered at 10 times the doxorubicin dose prior to doxorubicin infusion. A cumulative anthracycline exposure up to 750 mg/m2 was allowed. Filgrastim support was provided. DLT was evaluated during the first course and defined as >Grade (gr) 1 cardiac, >gr 1 neuro, gr 4 hematologic lasting > 7days, all other >gr 2 excluding gr 3 infection and any toxicity delaying planned therapy > 14 days. Responding patients were treated for a maximum of 8 courses. Results: Seventeen patients were enrolled and 16 were evaluable for toxicity on 3 dose levels. Dose level 1 was the determined MTD. Gr 2 cardiac DLT was seen in 1 of 6 patients on dose level 1, gr 4 platelets in 2 of 5 patients on dose level 2 and 1 each of gr 2 cardiac and gr 4 platelets in 5 patients on dose level 3. Cardiac DLT was noted in patients with prior exposure to both anthracyclines and chest radiation. Two of 3 patients with platelet DLT had prior stem cell transplant. No significant neurotoxicity was seen. Oxaliplatin PK is being evaluated. Objective (≥partial) responses were noted in 3 neuroblastomas and 1 each of osteosarcoma, mixed germ cell tumor, neurofibrosarcoma, thymic neuroendocrine carcinoma and nasopharyngeal carcinoma. Four patients completed all 8 courses of protocol therapy. Conclusions: Oxaliplatin 105 mg/m2 on day 1 combined with doxorubicin 20 mg/m2 days 1-3 was the MTD. Dexrazoxane administration may have contributed to hematologic toxicity. Significant anti-tumor activity was noted. No significant financial relationships to disclose.
Abnormal Lymphatic Channels Detected by T2-Weighted MR Imaging as a Substrate for Ventricular Arrhythmia in HCM
Authors: Louis Kolman, Donald G. Welsh, Edward Vigmond, Sebastien X. Joncas, John Stirrat, David Scholl, Martin Rajchl, Edward Tweedie, Yoko Mikami, Carmen Lydell, Andrew Howarth, Raymond Yee, James A. White
Journal: JACC. Cardiovascular imaging (2016)
Non-seminomatous retroperitoneal histology in patients with a pure testicular seminoma and an elevated serum alpha feto-protein
Authors: N. T. Karanikolas, F. P. Secin, J. Stasi, B. S. Carver, Z. Dotan, J. Sheinfeld
Journal: Journal of Clinical Oncology (2006)

14561 Background: There is controversy regarding the management of patients with pure testicular seminoma (PTS) and elevated alpha-fetoprotein (AFP) level (Nazeer, Oncol Rep 1998;5:1425). Our objective was to determine the retroperitoneal histology and clinical outcome of patients with pure testicular seminoma and elevated serum AFP level. Methods: Between 1989 and 2004, 15 patients with PTS and elevated AFP level underwent post chemotherapy retroperitoneal lymph node dissection (PC-RPLND) at MSKCC. All diagnoses of PTS were confirmed by a MSKCC uropathologist. Clinical and pathologic data were obtained from our prospective surgical database and subsequently analyzed. Results: The median pretreatment AFP level was 339 ng/ml (interquartile range [IQR]: 42, 1,006). Clinical stage at initial presentation was IIa in 1, IIb in 1, IIc in 9, and III in 4. According to the International Germ Cell Cancer Collaborative Group (IGCCCG) risk classification, 6 patients had good, 6 had intermediate, and 3 had poor risk for disease. The histology at PC-RPLND demonstrated teratoma in 6 patients (40%), fibrosis/necrosis in 6 patients (40%), and viable germ cell tumor in 3 patients (20%; 1 embryonal, 1 yolk sac, and 1 seminoma). Overall, 8 of 15 (53%) had persistent nonseminomatous retroperitoneal histology after chemotherapy. At a median follow-up of 4.2 years (IQR: 2.3, 7.1), 10 patients were alive without disease, 2 were alive with disease, and 3 died of disease. Cancer-specific survival rate was 83% at 5 years (95% confidence interval: 47, 96). Conclusion: Contrary to prior reports (Nazeer, Oncol Rep 1998;5:1425), patients with pure seminoma and an elevated AFP level should be managed as having nonseminomatous germ cell tumor (GCT), including post chemotherapy RPLND because more than half will harbor either teratoma or viable GCT. No significant financial relationships to disclose.
The proteasome inhibitor bortezomib induces rapid alterations of cell cycle regulators and augments sensitivity to cytostatic drugs in mantle cell lymphoma
Authors: O. Weigert, M. Rieken, Y. Zimmermann, G. Hutter, M. Weinkauf, W. Hiddemann, M. Dreyling
Journal: Journal of Clinical Oncology (2005)

6609 Background: Mantle cell Lymphoma (MCL) is a distinct subtype of malignant lymphoma with an especially poor clinical outcome and only transient response to chemotherapy. In various phase II studies the proteasome inhibitor bortezomib (Velcade) achieved remarkable response rates of up to 60% in relapsed MCL. However, besides NF-κB, little is known about the critical target molecules mainly affected by proteasome inhibition. Methods: Four MCL cell lines (HBL2, Granta 519, Jeko-1, NCEB-1) and two hematological control cell lines (Jurkat, Karpas 422) were exposed to bortezomib at a previously defined cytotoxic concentration (25 nmol). Real-time RQ-PCR and Western Blot analysis of cyclin D1, various cdk inhibitors (INK4s, KIPs), and other regulators of cell cycle and apoptosis were performed at various time points during bortezomib treatment (0,5 - 12 hours). In addition, cell cycle phase and apoptosis (Annexin V PE/7-AAD staining) were directly determined by flow cytometry. All cells lines were also simultaneously exposed to different doses of bortezomib and various cytostatic drugs (WST1 assay). Results: Analysis of relative RNA expression levels revealed that downregulation of cdk4 inhibitors was observed already after a few hours of bortezomib treatment and thus represents an early effect of proteasome inhibition in MCL cell lines. In contrast, cyclin D1 expression temporarily increased especially in cell lines with only moderate sensitivity to bortezomib. Interestingly, efficacy of proteosome inhibition varied widely between the MCL cell lines. Simultaneous exposure of bortezomib and various cytostatic drugs (especially cytarabine) resulted in a significant inhibition of proliferation and enhanced apoptosis. Conclusions: In summary, alteration of cell cycle regulators represents an early effect of proteasome inhibition in MCL. In addition, a superadditive efficacy of bortezomib and distinct cytostatic agents was observed in the cell line model. Currently, confirmatory analyses of primary patient samples are being performed representing the rationale of a future randomized phase II/III study of the European MCL Network. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Ortho-Biotech