bluuebunny/crossref_metadata_2025_split huggingface dataset:
Survivin as a Prognostic Marker for Urothelial Carcinoma of the Bladder: A Multicenter External Validation Study
Authors: Shariat Shahrokh F. , Karakiewicz Pierre I. , Godoy Guilherme , Karam Jose A. , Ashfaq Raheela , Fradet Yves , Isbarn Hendrik , Montorsi Francesco , Jeldres Claudio , Bastian Patrick J. , Nielsen Matthew E. , Mller Stefan C. , Sagalowsky Arthur I. , Lotan Yair 
Published: November 2009

Abstract
Purpose: The aim of the current study was to externally validate the value of survivin as a prognostic marker for bladder cancer in a large multi-institutional cohort of patients treated with radical cystectomy.
Methods: The study comprised 726 patients treated with radical cystectomy and bilateral pelvic lymphadenectomy. Survivin staining and scoring were done with automated systems coupled with advanced color detection software. Specimens showing at least 10 reactivity were considered altered. Predictive accuracy was quantified using the concordance index and 200-bootstrap resamples were used to reduce overfit bias.
Results: Survivin was an independent predictor of disease recurrence and cancer-specific survival in multivariable analyses that controlled for the effects of standard clinicopathologic features (hazard ratios, 1.6; P values 0.002). In all patients (n = 726), addition of survivin to a model including standard clinicopathologic variables did not improve its predictive accuracy (P = 0.67 for disease recurrence and P = 0.27 for cancer-specific survival). In the subgroup of patients with pT1-3N0M0 disease (n = 398), addition of survivin improved the accuracy of standard clinicopathologic features for prediction of disease recurrence and cancer-specific survival (1.3, P &lt; 0.001 and 1.2, P &lt; 0.001, respectively).
Conclusions: Survivin expression improves our accuracy for prediction of cancer recurrence and survival in pT1-3N0M0 patients by a small but statistically significant margin. Our findings support the need for further evaluation of survivin and its signaling pathways as well as survivin-targeted therapies in bladder cancer. (Clin Cancer Res 2009;15(22):70129)
HIF-1α and HIF-2α Are Differentially Regulated In vivo in Neuroblastoma: High HIF-1α Correlates Negatively to Advanced Clinical Stage and Tumor Vascularization
Authors: Noguera Rosa , Fredlund Erik , Piqueras Marta , Pietras Alexander , Beckman Siv , Navarro Samuel , Påhlman Sven 
Published: November 2009

Abstract
Purpose: Hypoxia is considered to be a major driving force behind tumor angiogenesis. The stabilization and activation at hypoxia of the hypoxia-inducible factors HIF-1α and HIF-2α and the concomitant induction of expression of vascular endothelial growth factor (VEGF) and other proangiogenic factors provide a molecular frame for hypoxia-driven tumor angiogenesis. This study has investigated how HIF and VEGF protein levels relate to each other with regard to vascularization, tumor stage, and overall survival in neuroblastoma.
Experimental Design: Tissue cores taken from tumor specimens representing 93 children with neuroblastoma were arranged on a microarray and stained for HIF-1α, HIF-2α, VEGF, and CD31 proteins. Both fraction of positive cells and staining intensity were evaluated and protein levels were correlated with each other and with clinical variables.
Results: Although high levels of both HIF-1α (P &lt; 0.001) and HIF-2α (P &lt; 0.001) correlated positively to VEGF expression, they did not fully correlate with each other. Moreover, HIF-1α (P = 0.002) and VEGF (P &lt; 0.001), but not HIF-2α, correlated negatively to vascularization as determined by CD31 staining abundance. VEGF expression or degree of vascularization did not correlate with tumor stage or overall survival. High HIF-1α levels correlated with low tumor stage (P &lt; 0.001) and were associated with a favorable patient prognosis (P = 0.08).
Conclusions: The discordant results on expression of HIF-1α and HIF-2α suggest that these two proteins are differentially regulated in vivo, thus reflecting distinctive protein expression/stabilization mechanisms. The association between HIF-1α and favorable outcome stresses the importance of discriminating HIF-2α from HIF-1α expression and has implications for using HIFs as treatment targets. (Clin Cancer Res 2009;15(23):7130–6)
Subsets of Very Low Risk Wilms Tumor Show Distinctive Gene Expression, Histologic, and Clinical Features
Authors: Sredni Simone T. , Gadd Samantha , Huang Chiang-Ching , Breslow Norman , Grundy Paul , Green Daniel M. , Dome Jeffrey S. , Shamberger Robert C. , Beckwith J. Bruce , Perlman Elizabeth J. ,   for the Renal Tumor Committee of the Children's Oncology Group
Published: November 2009

Abstract
Purpose: Recent studies suggest that children &lt;24 months with stage I favorable histology Wilms tumors &lt;550 g [very low risk Wilms tumors (VLRWT)] have an excellent prognosis when treated with nephrectomy only, without adjuvant chemotherapy. The identification of risk categories within VLRWT may enable refinement of their definition and optimization of their therapy.
Experimental Design: To define biologically distinct subsets, global gene expression analysis was done on 39 VLRWT that passed all quality-control parameters and the clusters identified were validated in an independent set of 11 VLRWT. Validation of select differentially expressed genes was done with immunohistochemistry on a tissue microarray from 20 of 39 tumors. Loss of heterozygosity (LOH) for 11p15, 1p, and 16q was analyzed in 52 tumors using PCR.
Results: Two distinctive clusters were identified. One cluster included 9 tumors with epithelial differentiated tubular histology, paucity of nephrogenic rests, lack of LOH for 1p, 16q, and 11p, absence of relapse, and a unique gene expression profile consistent with arrest following mesenchymal-to-epithelial transition. The second cluster included 13 tumors with mixed histology, intralobar nephrogenic rests, and decreased expression of WT1. Three of 6 relapses occurred in this cluster. Of 43 informative tumors, 11p LOH was present in 5 of 5 relapses and 11 of 38 nonrelapses.
Conclusions: Two subsets comprising a total of 56 of VLRWT are identified that have pathogenetic and molecular differences and apparent differences in risk for relapse. If these predictors can be prospectively validated, this would enable the refinement of clinical stratification and less arbitrary definition of VLRWT. (Clin Cancer Res 2009;15(22):68009)
A Phase 1 Dose Escalation Study of the Safety and Pharmacokinetics of the Novel Proteasome Inhibitor Carfilzomib (PR-171) in Patients with Hematologic Malignancies
Authors: O'Connor Owen A. , Stewart A. Keith , Vallone Marcy , Molineaux Christopher J. , Kunkel Lori A. , Gerecitano John F. , Orlowski Robert Z. 
Published: November 2009

Abstract
Purpose: Carfilzomib (formerly PR-171) is a novel proteasome inhibitor of the epoxyketone class that is selective and structurally distinct from bortezomib. Proteasome inhibition by carfilzomib is mechanistically irreversible. Consequently, proteasome inhibition is more sustained with carfilzomib than with bortezomib.
Experimental Design: In a phase 1 trial evaluating the safety and efficacy of carfilzomib in relapsed or refractory hematologic malignancies, eight dose groups of three to six patients received 5 consecutive days of carfilzomib i.v. push at doses of 1.2, 2.4, 4, 6, 8.4, 11, 15, and 20 mg/m2 within 14-day cycles.
Results: Twenty-nine patients enrolled that were relapsed or refractory after at least two prior therapies. Nonhematologic toxicities included fatigue, nausea, and diarrhea in more than one third of patientsmostly grade 1 or 2 in severity. At 20 mg/m2, grade 3 febrile neutropenia and grade 4 thrombocytopenia were reported, establishing 15 mg/m2 as the maximum tolerated dose. No grade 3 or 4 peripheral neuropathies were reported. Antitumor activity was observed at doses 11 mg/m2: one unconfirmed complete response (mantle cell), one partial response (multiple myeloma), and two minimal responses (multiple myeloma and Waldenstrm's macroglobulinemia).
Conclusion: This is the first clinical use of carfilzomib that shows tolerability and clinical activity in multiple hematologic malignancies using consecutive-day dosing. (Clin Cancer Res 2009;15(22):708591)
Deregulated GSK3 Sustains Gastrointestinal Cancer Cells Survival by Modulating Human Telomerase Reverse Transcriptase and Telomerase
Authors: Mai Wei , Kawakami Kazuyuki , Shakoori Abbas , Kyo Satoru , Miyashita Katsuyoshi , Yokoi Kenji , Jin Mingji , Shimasaki Takeo , Motoo Yoshiharu , Minamoto Toshinari 
Published: November 2009

Abstract
Purpose: Glycogen synthase kinase-3 (GSK3) regulates multiple cell signaling pathways and has been implicated in glucose intolerance, neurodegenerative disorders, and inflammation. We investigated the expression, activity, and putative pathologic role of GSK3 in gastrointestinal, pancreatic, and liver cancers.
Experimental Design: Colon, stomach, pancreatic, and liver cancer cell lines; nonneoplastic HEK293 cells; and matched pairs of normal and tumor tissues of stomach and colon cancer patients were examined for GSK3 expression and its phosphorylation at serine 9 (inactive form) and tyrosine 216 (active form) by Western immunoblotting and for GSK3 activity by in vitro kinase assay. The effects of small-molecule GSK3 inhibitors and of RNA interference on cell survival, proliferation, and apoptosis were examined in vitro and on human colon cancer cell xenografts in athymic mice. The effects of GSK3 inhibition on human telomerase reverse transcriptase (hTERT) expression and telomerase activity were compared between colon cancer and HEK293 cells.
Results: Cancer cell lines and most cancer tissues showed increased GSK3 expression and increased tyrosine 216 phosphorylation and activity but decreased serine 9 phosphorylation compared with HEK293 cells and nonneoplastic tissues. Inhibition of GSK3 resulted in attenuated cell survival and proliferation and increased apoptosis in most cancer cell lines and in HT-29 xenografts in rodents but not in HEK293 cells. GSK3 inhibition in colon cancer cells was associated with decreased hTERT expression and telomerase activity.
Conclusion: The results indicate that deregulated GSK3 sustains gastrointestinal cancer cells survival through modulation of hTERT and telomerase. (Clin Cancer Res 2009;15(22):68109)
Partial CD4 Depletion Reduces Regulatory T Cells Induced by Multiple Vaccinations and Restores Therapeutic Efficacy
Authors: LaCelle Michael G. , Jensen Shawn M. , Fox Bernard A. 
Published: November 2009

AbstractPurpose: A single vaccination of intact or reconstituted-lymphopenic mice (RLM) with a granulocyte macrophage colony-stimulating factorsecreting B16BL6-D5 melanoma cell line induces protective antitumor immunity and T cells that mediate the regression of established melanoma in adoptive immunotherapy studies. We wanted to study if multiple vaccinations during immune reconstitution of the lymphopenic host would maintain a potent antitumor immune response.Experimental Design: RLM were vaccinated multiple times over a 40-day period. Spleens were isolated from these mice, activated in vitro, and adoptively transferred into mice bearing 3-day experimental pulmonary metastases.Results: Multiple vaccinations, rather than boosting the immune response, significantly reduced therapeutic efficacy of adoptive immunotherapy and were associated with an increased frequency and absolute number of CD3+CD4+Foxp3+ T regulatory (Treg) cells. Anti-CD4 administration reduced the absolute number of Treg cells 9-fold. Effector T-cells generated from anti-CD4treated mice were significantly (P &lt; 0.0001) more therapeutic in adoptive transfer studies than T cells from multiply vaccinated animals with a full complement of CD4+ cells.Conclusion: These results suggest that CD4+ Treg cells limit the efficacy of multiple vaccinations and that timed partial depletion of CD4+ T cells may reduce suppression and tip-the-balance in favor of therapeutic antitumor immunity. The recent failure of large phase III cancer vaccine clinical trials, wherein patients received multiple vaccines, underscores the potential clinical relevance of these findings. (Clin Cancer Res 2009;15(22):688190)
PIK3CA Mutations Predict Local Recurrences in Rectal Cancer Patients
Authors: He Youji , Van't Veer Laura J. , Mikolajewska-Hanclich Izabela , van Velthuysen Marie-Louise F. , Zeestraten Eliane C.M. , Nagtegaal Iris D. , van de Velde Cornelis J.H. , Marijnen Corrie A.M. 
Published: November 2009

Abstract
Purpose: Identifying rectal cancer patients at risk for local recurrence would allow for refinement in the selection of patients who would benefit from preoperative radiotherapy. PIK3CA, KRAS, and BRAF mutations are commonly found in colon cancers, but their prevalence has not been clearly assessed in rectal cancer. In this study, we aim to determine the mutation frequencies of PIK3CA, KRAS, and BRAF and to investigate whether a mutation may be used as a prognostic parameter in rectal cancer patients.
Experimental Design: We evaluated DNA mutations in PIK3CA, KRAS, and BRAF in 240 stage I to III rectal tumors obtained from nonirradiated patients from the Dutch Total Mesorectal Excision trial.
Results: PIK3CA, KRAS, and BRAF mutations were identified in 19 (7.9), 81 (33.9), and 5 (2.1) rectal cancers. Patients with PIK3CA mutations developed more local recurrences (5-year risks, 27.8 versus 9.4; P = 0.006) and tended to develop these recurrences more rapidly after surgery (median local recurrence-free interval since surgery: 7.9 versus 19.6 months; P = 0.07) than patients without PIK3CA mutations. In multivariate analysis, PIK3CA mutations remained as an independent predictor for the development of local recurrences (hazard ratio, 3.4; 95 confidence interval, 1.2-9.2; P = 0.017), next to tumor-node-metastasis stage.
Conclusion: PIK3CA mutations can be used as a biomarker in identifying rectal cancer patients with an increased risk for local recurrences. Currently, our findings suggest that prospective evaluation of PIK3CA mutation status could reduce overtreatment by preoperative radiotherapy for the low-risk patients who might otherwise only experience the side effects. (Clin Cancer Res 2009;15(22):695662)
Phase I Trial of a Combination of the Multikinase Inhibitor Sorafenib and the Farnesyltransferase Inhibitor Tipifarnib in Advanced Malignancies
Authors: Hong David S. , Sebti Said M. , Newman Robert A. , Blaskovich Michelle A. , Ye Lei , Gagel Robert F. , Moulder Stacy , Wheler Jennifer J. , Naing Aung , Tannir Nizar M. , Ng Chaan S. , Sherman Steven I. , El Naggar Adel K. , Khan Rabia , Trent Jon , Wright John J. , Kurzrock Razelle 
Published: November 2009

Abstract
Purpose: We evaluated the safety, maximum tolerated dose, pharmacokinetics, and biological effects of the combination of the Raf-1, RET, KIT, platelet-derived growth factor receptor, and vascular endothelial growth factor receptor 2 kinase inhibitor sorafenib and the farnesyltransferase inhibitor tipifarnib.
Experimental Design: A standard 3 + 3 phase I dose-escalation design was used with a 28-day cycle (sorafenib daily and tipifarnib for 21 days, by mouth).
Results: Fifty patients were treated; 43 reached restaging evaluation after cycle 2. The most common side effects were grade 1 to 2 rash, hyperglycemia, and diarrhea. Dose-limiting toxicity was rash, and the recommended phase II dose is sorafenib 400 mg p.o. qam/200 mg p.o. qpm and tipifarnib p.o. 100 mg bd. Despite the low doses of tipifarnib, one quarter of patients had 50 reduction in farnesyltransferase levels. Interestingly, six of eight patients with medullary thyroid cancer had durable stable disease (n = 3) or partial remissions (n = 3), lasting 12 to 26+ months. Five of the six responders had available tissue, and RET gene mutations were identified in them. Prolonged (6 months) stable disease was also seen in nine patients as follows: papillary thyroid cancer (n = 4; 18+ to 27+ months), adrenocortical cancer (n = 2; 7 and 11 months), and one each of melanoma (platelet-derived growth factor receptor mutation positive; 14 months), renal (6 months), and pancreatic cancer (6 months).
Conclusions: Our study shows that the combination of tipifarnib and sorafenib is well tolerated. Activity was seen, especially in patients with medullary thyroid cancer, a tumor characterized by RET mutations. (Clin Cancer Res 2009;15(22):70618)
Electrocardiographic Characterization of the QTc Interval in Patients with Advanced Solid Tumors: Pharmacokinetic- Pharmacodynamic Evaluation of Sunitinib
Authors: Bello Carlo L. , Mulay Marilyn , Huang Xin , Patyna Shem , Dinolfo Melissa , Levine Steven , Van Vugt Andrew , Toh Melvin , Baum Charles , Rosen Lee 
Published: November 2009

Abstract
Purpose: To evaluate the effects of sunitinib, a multitargeted tyrosine kinase inhibitor, on the QT interval in patients with cancer.
Experimental Design: Patients received sunitinib loading doses (150-200 mg) on days 3 and 9 and maintenance doses (50 mg/d) on days 4 to 8. Moxifloxacin (day 1), placebo (day 2), and granisetron [with placebo (day 2) or sunitinib (days 3 and 9)] were also administered. Treatment effects were evaluated by time-matched, serial electrocardiograms, and manually overread.
Results: Twenty-four of 48 patients were QT/PK evaluable. Moxifloxacin produced a time-matched, maximum mean placebo-adjusted corrected QT interval (QTcF) of 5.6 ms [90 confidence interval (CI), 1.9-9.3]. Sunitinib QTcF changes correlated with exposure, but not Tmax. Maximum mean time-matched, placebo-adjusted QTcF was 9.6 ms (90 CI, 4.1-15.1) at steady state/therapeutic concentrations (day 3) and 15.4 ms (90 CI, 8.4-22.4) at supratherapeutic concentrations (day 9). No patient had a QTcF &gt;500 ms. Concomitant granisetron produced no significant QTcF prolongation. Sunitinib-related adverse events were as previously described.
Conclusions: Sunitinib has a dose-dependent effect on QT interval. The increased risk of ventricular arrhythmias must be weighed against the therapeutic benefit sunitinib provides to patients with advanced cancer. (Clin Cancer Res 2009;15(22):704552)
Effect of Granulocyte/Macrophage Colony-Stimulating Factor on Vaccination with an Allogeneic Whole-Cell Melanoma Vaccine
Authors: Faries Mark B. , Hsueh Eddy C. , Ye Xing , Hoban Mary , Morton Donald L. 
Published: November 2009

AbstractPurpose: The availability of a variety of immune response modifiers creates an opportunity for improved efficacy of immunotherapy, but it also leads to uncertainty in how to combine agents and how to assess those combinations. We sought to assess the effect of the addition of granulocyte/macrophage colony-stimulating factor (GM-CSF) to vaccination with a melanoma vaccine.Experimental Design: Ninety-seven patients with resected melanoma (stage II-IV) were enrolled, stratified by stage, and randomized to receive a cellular melanoma vaccine with or without GM-CSF. The primary endpoint was delayed-type hypersensitivity (DTH) response to melanoma cells. Antibody responses, peripheral leukocyte counts, and survival were also examined.Results: The GM-CSF arm showed enhanced antibody responses with an increase in IgM titer against the TA90 antigen and increased TA90 immune complexes. This arm also had diminished antimelanoma cell delayed-type hypersensitivity response. Peripheral blood leukocyte profiles showed increases in eosinophils and basophils with decreased monocytes in the GM-CSF arm. These immune changes were accompanied by an increase in early melanoma deaths and a trend toward worse survival with GM-CSF.Conclusion: These data suggest that GM-CSF is not helpful as an immune adjuvant in this dose and schedule and raise concern that it may be harmful. Based on the discordant findings of an immune endpoint and clinical outcome, the use of such surrogate endpoints in selecting treatments for further evaluation must be done with a great deal of caution. (Clin Cancer Res 2009;15(22):702935)
Effect of Granulocyte/Macrophage Colony-Stimulating Factor on Circulating CD8+ and CD4+ T-Cell Responses to a Multipeptide Melanoma Vaccine: Outcome of a Multicenter Randomized Trial
Authors: Slingluff Craig L. , Petroni Gina R. , Olson Walter C. , Smolkin Mark E. , Ross Merrick I. , Haas Naomi B. , Grosh William W. , Boisvert Marc E. , Kirkwood John M. , Chianese-Bullock Kimberly A. 
Published: November 2009

AbstractPurpose: Granulocyte/macrophage colony-stimulating factor (GM-CSF) administered locally together with vaccines can augment T-cell responses in animal models. Human experience has been limited to small and uncontrolled trials. Thus, a multicenter randomized phase II trial was done to determine whether local administration of GM-CSF augments immunogenicity of a multipeptide vaccine. It also assessed immunogenicity of administration in one versus two vaccine sites.Experimental Design: One hundred twenty-one eligible patients with resected stage IIB to IV melanoma were vaccinated with 12 MHC class Irestricted melanoma peptides to stimulate CD8+ T cells plus a HLA-DRrestricted tetanus helper peptide to stimulate CD4+ T cells, emulsified in incomplete Freund's adjuvant, with or without 110 g GM-CSF. Among 119 evaluable patients, T-cell responses were assessed by IFN- ELIspot assay and tetramer analysis. Clinical outcomes were recorded.Results: CD8+ T-cell response rates to the 12 MHC class Irestricted melanoma peptides (by day 50) with or without GM-CSF were 34 and 73, respectively (P &lt; 0.001), by direct ELIspot assay. Tetramer analyses corroborated the functional data. CD4+ T-cell responses to tetanus helper peptide were higher without GM-CSF (95 versus 77; P = 0.005). There was no significant difference by number of vaccine sites. Three-year overall and disease-free survival estimates (95 confidence interval) were 76 (67-83) and 52 (43-61), respectively, with too few events to assess differences by study group.Conclusions: High immune response rates for this multipeptide vaccine were achieved, but CD8+ and CD4+ T-cell responses were lower when administered with GM-CSF. These data challenge the value of local GM-CSF as a vaccine adjuvant in humans. (Clin Cancer Res 2009;15(22):703644)