bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phase I Study of Estramustine, Weekly Docetaxel, and Carboplatin Chemotherapy in Patients with Hormone-Refractory Prostate Cancer
Authors: Oh William K. , Hagmann Elizabeth , Manola Judith , George Daniel J. , Gilligan Timothy D. , Jacobson Joseph O. , Smith Matthew R. , Kaufman Donald S. , Kantoff Philip W. 
Published: June 2022

Abstract
Purpose: To define the maximal tolerated dose, safety, and efficacy of docetaxel, carboplatin, and estramustine in patients with hormone-refractory prostate cancer (HRPC).
Methods: Patients with HRPC received docetaxel for 3 weeks, followed by a rest week. Docetaxel (20, 25, 30, 36, or 43 mg/m2) was given on days 2, 9, and 16 of a 28-day cycle. Patients also received estramustine (140 mg p.o. three times daily on days 1-5, 8-12, and 15-19) and carboplatin [area under the curve, AUC (5) or (6) on day 2].
Results: Thirty patients were treated. Five patients received carboplatin [AUC (6)] but experienced delayed thrombocytopenia. After a protocol amendment, 25 subsequent patients received carboplatin [AUC (5)]. Median age was 64 years. Median prostate-specific antigen (PSA) was 117 ng/mL. Fifty-three percent received prior ketoconazole and 10% had mitoxantrone. No dose-limiting toxicities were noted. Although maximal tolerated dose was not reached, docetaxel dose escalation was stopped at 43 mg/m2. Significant myelosuppression was not seen until the highest dose level, when seven and four patients experienced grade 3 and 4 toxicities, respectively. Among all patients, PSA declines of ≥50% occurred in 63%. At the recommended phase II dose, PSA declines of ≥50% occurred in 75% (95% confidence interval, 43-95). Four of 14 (29%) patients with measurable disease had partial responses. Median survival was 14.6 months.
Conclusions: Estramustine, docetaxel, and carboplatin are well tolerated and active in HRPC. Myelosuppression is the primary toxicity. The recommended phase II dose of docetaxel is 43 mg/m2 combined with estramustine and carboplatin. PSA declines were seen at every dose level.
Interstitial Diphtheria Toxin-Epidermal Growth Factor Fusion Protein Therapy Produces Regressions of Subcutaneous Human Glioblastoma Multiforme Tumors in Athymic Nude Mice
Authors: Liu Tie Fu , Hall Philip D. , Cohen Kimberley A. , Willingham Mark C. , Cai Jiaozhong , Thorburn Andrew , Frankel Arthur E. 
Published: June 2022

Abstract
Purpose: The novel fusion protein, DAB389EGF, composed of the catalytic and translocation domains of diphtheria toxin (DAB389) fused with a His-Ala linker to human epidermal growth factor (EGF) was tested for antiglioma efficacy in an in vivo model of human glioma.
Experimental Design: Female athymic nude mice (ages 4-6 weeks) were inoculated s.c. with 10 million U87MG human glioma cells in the right flank. When tumor volumes reached ∼100 mm3 (∼6-8 days), i.t. injections of saline, DAB389IL2, or DAB389EGF 1, 3, 5 or 10 μg in 50 μL were given every other day for three to six doses. Animals were monitored twice daily and tumor measurements were made by calipers.
Results: The maximal tolerated dose (MTD) of DAB389EGF was 3 μg every other day. Above the MTD, animals experienced loss of activity, reduced oral intake, and dehydration. Blood chemistries confirmed elevated blood urea nitrogen, creatinine, aspartate transaminase, and alanine transaminase. Histopathology revealed renal tubular necrosis. At the MTD, tumor regression was seen in all animals. Relapses occurred in 4 of 16 (25%) of animals after 1 month. These tumors contained EGF receptor, were sensitive in vitro to DAB389EGF, and responded to a second course of i.t. DAB389EGF.
Conclusions: DAB389EGF fusion protein shows in vivo antiglioma efficacy in a s.c. tumor model and warrants further preclinical testing in an i.c. tumor model for eventual treatment of patients with recurrent or refractory EGF receptor–positive glioblastoma multiforme.
Development of a Syngeneic Rat Brain Tumor Model Expressing EGFRvIII and Its Use for Molecular Targeting Studies with Monoclonal Antibody L8A4
Authors: Yang Weilian , Barth Rolf F. , Wu Gong , Ciesielski Michael J. , Fenstermaker Robert A. , Moffat Bradford A. , Ross Brian D. , Wikstrand Carol J. 
Published: June 2022

Abstract
Purpose: The goals of the present study were 2-fold: (a) to develop and characterize a rat brain tumor model that could be used for studies of molecular targeting of EGFRvIII and (b) to study the tumor localizing properties of radiolabeled monoclonal antibody (mAb) L8A4, specifically directed against EGFRvIII, following systemic, i.t., and convection enhanced delivery to brain tumor–bearing rats.
Experimental Design and Results: F98 wild-type (F98WT) rat glioma cells were transfected with a gene encoding human EGFRvIII, and following selection and cloning, a cell line, designated F98npEGFRvIII, was identified, which expressed a nonconstitutively phosphorylated form of the receptor. As determined by a radioligand binding assay, there were 1.2×105 EGFRvIII sites per cell compared with an undetectable number on F98WT cells. The tumorigenicity of the F98npEGFRvIIIglioma was studied following i.c. implantation of 103, 104, or 105 cells into CD-Fischer rats. Mean survival times were 23, 17, and 13 days, respectively, which were equivalent to those obtained with F98EGFR and F98WT cells. As determined by magnetic resonance imaging, the mean doubling times for the F98WT and F98npEGFRvIII gliomas were similar (59.8 ± 4.8 versus 52 ± 3.3 hours). Following i.v. administration to glioma-bearing rats, mAb L8A4 specifically targeted the F98npEGFRvIII glioma, and at 24 hours, 7.7% of the injected dose per gram (ID/g) localized in the tumor. This increased 5-fold to 39.5% ID/g following i.t. injection and 7-fold to 59.8% ID/g at 24 hours following convection enhanced delivery.
Conclusions: Based on these data, we have concluded that the F98npEGFRvIII glioma should be a valuable animal model for therapy studies focusing on molecular targeting of EGFRvIII by receptor specific mAbs.
Targeting Toll-like Receptor 9 with CpG Oligodeoxynucleotides Enhances Tumor Response to Fractionated Radiotherapy
Authors: Mason Kathryn A. , Ariga Hisanori , Neal Robert , Valdecanas David , Hunter Nancy , Krieg Arthur M. , Whisnant John K. , Milas Luka 
Published: June 2022

Abstract
Synthetic oligodeoxynucleotides containing unmethylated CpG motifs detected by Toll-like receptor 9 of dendritic cells and B cells have potent immunomodulatory effects. CpG oligodeoxynucleotides induce cytokines, activate natural killer cells, and elicit T-cell responses leading to antitumor effects, including improved efficacy of chemotherapeutic agents and, as we reported recently, synergy between CpG oligodeoxynucleotide 1826 and single-dose radiotherapy of an immunogenic mouse fibrosarcoma. The present study extends this finding to the fractionated radiotherapy of the fibrosarcoma tumor and assesses the ability of CpG oligodeoxynucleotide 1826 to increase the radioresponse of a tumor (nonimmunogenic fibrosarcoma). The experiments used a murine immunogenic fibrosarcoma tumor, fibrosarcoma growing in the leg of mice, and response to radiotherapy was assessed by tumor growth delay and tumor cure rate (TCD50, radiation dose yielding 50% tumor cure). Multiple s.c. peritumoral or i.t. administrations of CpG oligodeoxynucleotide 1826 at a dose of 100 μg per mouse were given when established tumors were 6 mm in diameter. Local tumor irradiation was initiated when tumors grew to 8 mm in diameter; radiation was delivered in 1 to 9 Gy fractions given twice daily separated by 6 to 7 hours for 5 consecutive days to achieve a total dose of 10 to 90 Gy. CpG oligodeoxynucleotide 1826, given as a single agent, had only a small antitumor effect, but it dramatically enhanced fibrosarcoma response to radiotherapy. Although 83.1 (79.2-90.0) Gy total dose were needed to achieve tumor cures in 50% of mice treated with radiotherapy alone, only 23.0 (11.5-32.7) Gy total dose were needed in mice treated with both CpG oligodeoxynucleotide 1826 and radiotherapy. The magnitude of potentiation of tumor radioresponse at the TCD50 level was by a factor of 3.61, a much higher value than that (a factor of 1.93) that we reported for single-dose radiotherapy. Mice cured of their tumors by combined CpG oligodeoxynucleotide 1826 plus radiotherapy were highly resistant to s.c. tumor take or development of tumor nodules in the lung from i.v. injected tumor cells when rechallenged with fibrosarcoma cells 100 to 120 days after the treatment, suggesting the development of a memory response. CpG oligodeoxynucleotide 1826 also increased radioresponse of the nonimmunogenic fibrosarcoma tumor by a factor of 1.41 and 1.73 when CpG oligodeoxynucleotide 1826 was given s.c. and i.t., respectively. These findings show that CpG oligodeoxynucleotides are highly potent enhancers of tumor response to both single-dose and fractionated radiation and as such have potential to improve clinical radiotherapy.
CD8+ T-Cell–Dependent Immunity Following Xenogeneic DNA Immunization against CD20 in a Tumor Challenge Model of B-Cell Lymphoma
Authors: Palomba Maria Lia , Roberts Wendy K. , Dao Tao , Manukian Gregory , Guevara-Patiño Jose A. , Wolchok Jedd D. , Scheinberg David A. , Houghton Alan N. 
Published: June 2022

Abstract
The CD20 B-cell differentiation antigen is an attractive target for immunotherapy of B-cell lymphomas. In an experimental lymphoma model, BALB/c mice were immunized with mouse or human CD20 cDNA (mCD20 and hCD20, respectively) or their extracellular domains (minigenes). IFNγ secretion by CD8+ T cells against CD20 was detected in mice vaccinated with hCD20 or human minigene, indicating that hCD20-primed CD8+ T cells recognize syngeneic CD20. Systemic challenge with syngeneic A20 cells, an aggressive lymphoma, resulted in long-term survival in a subset of immunized mice. Overall long-term survival was 14% in groups vaccinated with the human minigene versus 4% in control groups (P &lt; 0.001). CD8+ T-cell depletion during the effector phase completely abrogated this effect. Antibodies against a recombinant mouse CD20 protein produced in insect cells were detected in mice immunized with hCD20 DNA and human and mouse minigene, but not in mice receiving mCD20 DNA. These results show that active immunization with xenogeneic DNA vaccines can induce CD8+ T cell–dependent immunity against CD20.
New Frontiers in Translational Research in Neuro-oncology and the Blood-Brain Barrier: Report of the Tenth Annual Blood-Brain Barrier Disruption Consortium Meeting
Authors: Doolittle Nancy D. , Abrey Lauren E. , Bleyer W. Archie , Brem Steven , Davis Thomas P. , Dore-Duffy Paula , Drewes Lester R. , Hall Walter A. , Hoffman John M. , Korfel Agnieszka , Martuza Robert , Muldoon Leslie L. , Peereboom David , Peterson Darryl R. , Rabkin Samuel D. , Smith Quentin , Stevens Glen H.J. , Neuwelt Edward A. 
Published: June 2022

Abstract
The blood-brain barrier (BBB) presents a major obstacle to the treatment of malignant brain tumors and other central nervous system (CNS) diseases. For this reason, a meeting partially funded by an NIH R13 grant was convened to discuss recent advances and future directions in translational research in neuro-oncology and the BBB. Cell biology and transport across the BBB, delivery of agents to the CNS, neuroimaging, angiogenesis, immunotherapy, and gene therapy, as well as glioma, primary CNS lymphoma, and metastases to the CNS were discussed. Transport across the BBB relates to the neurovascular unit, which consists not only of endothelial cells but also of pericyte, glia, and neuronal elements.
Aberrant Expression of Human Achaete-Scute Homologue Gene 1 in the Gastrointestinal Neuroendocrine Carcinomas
Authors: Shida Takashi , Furuya Mitsuko , Nikaido Takashi , Kishimoto Takashi , Koda Keiji , Oda Kenji , Nakatani Yukio , Miyazaki Masaru , Ishikura Hiroshi 
Published: June 2022

Abstract
Purpose: Gastrointestinal neuroendocrine carcinoma (NEC) is extremely aggressive, but its pathophysiologic features remain poorly understood. There have been no biologically specific markers for this disease. In this study, distinctive up-regulation of human achaete-scute homologue 1 (hASH1) in gastrointestinal NECs was clarified.
Experimental Design: Expression of hASH1 in NECs (n=10), carcinoid tumors (n = 10), other tumors (10adenocarcinomas, 2 squamous cell carcinomas and 1 malignant lymphoma), and the corresponding normal mucosa were investigated by in situ hybridization, reverse transcription-PCR (RT-PCR), real-time RT-PCR, and immunohistochemistry.
Results: By in situ hybridization, mild to intense signals of hASH1 mRNA were detected in 9 of 10 NECs, but not in other tumors or normal mucosa, except for focally weak signals in one carcinoid tumor. RT-PCR showed strong expression of hASH1 in a small cell NEC, followed by a moderately differentiated NEC, and a carcinoid tumor, whereas it is undetectable in adenocarcinomas or normal mucosa. By real-time RT-PCR, the amounts of hASH1 mRNA in a small cell NEC were 16,600 times higher than those in adenocarcinomas and 110 times higher than those in a carcinoid tumor. Immunohistochemically, mammalian homologue of hASH1 was positive in 7 of 10 NECs but was negative in the other tumors. Pan-endocrine markers chromogranin A and synaptophysin were positive in almost all carcinoid tumors, in 4 and 7 of the 10 NECs, respectively.
Conclusions: These findings revealed that hASH1 is distinctly up-regulated in gastrointestinal NECs. hASH1 may be used as a more sensitive and specific marker than conventional pan-endocrine markers for clinical diagnosis of gastrointestinal NECs.
Fibroblast Growth Factor Receptor 3 Is Overexpressed in Urinary Tract Carcinomas and Modulates the Neoplastic Cell Growth
Authors: Gómez-Román J. Javier , Saenz Pilar , Cuevas González Jorge , Escuredo Kepa , Santa Cruz Simon , Junquera Corina , Simón Laureano , Martínez Antonio , Gutiérrez Baños J. Luis , López-Brea Marta , Esparza Clara , Val-Bernal J. Fernando 
Published: June 2022

Abstract
Purpose: Fibroblast growth factor receptor 3 (FGFR3) mutations have been associated with achondroplastic syndromes and urinary bladder carcinomas. Here we describe changes in FGFR3 mRNA and protein expression in transitional carcinomas and determine the effect of monoclonal antibodies against FGFR3 in RT-112 cell line proliferation.
Experimental Design: We used microarray tools to evaluate FGFR3 mRNA expression in 22 urinary bladder carcinomas at different stages (noninvasive pTa, lamina propria invasive pT1, and muscular invasive pT2) and 7 nonneoplastic tissue controls. FGFR3 protein expression was evaluated by Western blotting in 15 different carcinomas and 3 nonneoplastic controls. Two hundred thirty-seven urinary bladder and renal pelvis carcinomas and 21 negative controls were tested on tissue microarrays by immunohistochemistry. The effect on cell proliferation in the RT-112 bladder cancer cell line of monoclonal antibodies against FGFR3 was also evaluated.
Results: Overexpression of FGFR3 mRNA was found in pTa and pT1 stage carcinomas (fold change &gt;8) and in pT2 carcinomas (fold change &gt;4). Nonneoplastic urinary bladder samples do not express FGFR3 protein. However, 83% of pTa, 100% of pT1, and 50% of pT2 carcinomas expressed FGFR3 as determined by Western blotting. By immunohistochemistry, FGFR3 was positive in 71.4% of pTa, 72% of pT1, and 49.2% of pT2 cases as well as 61.5% of upper urinary tract carcinomas. Proliferation of the RT-112 cell line was inhibited with monoclonal antibodies against FGFR3.
Conclusions: FGFR3 seems to play an important role in transitional cell carcinoma development. Our results suggest that FGFR3 antagonists could be developed as possible therapeutics for treatment of urinary tract carcinoma.
Plasma Adiponectin and Gastric Cancer
Authors: Ishikawa Makoto , Kitayama Joji , Kazama Shinsuke , Hiramatsu Takeyuki , Hatano Kenji , Nagawa Hirokazu 
Published: June 2022

Abstract
Background: Recently, increased body weight has been associated with an increased risk of cancers at multiple specific sites, including gastric cancer. Adiponectin is a peptide hormone secreted by adipose tissue, affecting the proliferation and insulin sensitivity of various types of cells. Moreover, the circulating level of adiponectin has been reported to be inversely related to body mass index.
Methods: Fasting plasma levels of adiponectin were determined in 75 patients with gastric cancer and 52 healthy controls using an ELISA. In these patients, we analyzed the association between plasma adiponectin level and gastric cancer risk as well as various clinicopathologic characteristics.
Results: Plasma adiponectin level was significantly lower in patients with gastric cancer than in healthy controls (9.1 ± 6.2 versus 13.3 ± 9.4 ng/mL, P &lt; 0.01) and showed a significant modest inverse relation with the gastric cancer (odds ratio, 0.92; 95% confidence interval, 0.85-0.97; adjusted odds ratio, 0.89; 95% confidence interval, 0.84-0.95], although body mass index was not different. In addition, adiponectin level was extremely low in patients with upper gastric cancers (upper, 5.5 ± 4.1 ng/mL; middle, 9.7 ± 6.4 ng/mL; lower, 10.7 ± 4.1 ng/mL; P = 0.012). Furthermore, adiponectin level tended to decrease as the tumor stage increased (stage I, 9.9 ± 6.9 ng/mL; stage II, 8.7 ± 5.5 ng/mL; stage III, 8.6 ± 4.1 ng/mL; stage IV, 5.2 ± 6.2 ng/mL; P = 0.34). Interestingly, in 32 patients with undifferentiated cancer, serum adiponectin showed a negative correlation with pathologic findings such as tumor size, depth of invasion, as well as tumor stage (P &lt; 0.05), but no correlation in the remaining 43 patients with differentiated cancer.
Conclusions: Our results suggest that a low plasma adiponectin level is associated with an increased risk for gastric cancer and raise the possibility that adiponectin has a potential role in the progression of gastric cancer, especially in undifferentiated type cancers in the upper stomach.
Control of T-Cell–Mediated Immune Response by HLA Class I in Human Pancreatic Carcinoma
Authors: Ryschich Eduard , Nötzel Tanja , Hinz Ulf , Autschbach Frank , Ferguson James , Simon Ioan , Weitz Jürgen , Fröhlich Boris , Klar Ernst , Büchler Markus W. , Schmidt Jan 
Published: June 2022

Abstract
Purpose: Cell surface HLA class I molecules present peptides derived from human cellular proteins to T cells. In the present study, we investigated the expression of HLA class I in human pancreatic carcinoma.
Experimental Design: The expression of HLA class I antigen and the extent of tumor infiltration by T cells were investigated in 46 primary tumors and in 14 metastases of pancreatic cancer by standard immunohistochemistry.
Results: The locus-specific expression of HLA I was reduced in 61% of primary tumors and in 93% of metastases. The total loss of this molecule complex was detected in 6% of primary tumors and in 43% of metastases. Pancreatic carcinoma and peritumoral tissue showed a significantly higher infiltration by CD3+, CD4+, and CD8+ T-cells compared with the tumor-distant pancreatic tissue. The negative expression of HLA class I was uniformly accompanied by a low density of tumor-infiltrating cytotoxic T-cells whereas the HLA class I–positive tumors were characterized by a substantial lymphocyte accumulation. However, the infiltration by cytotoxic T-cells was not correlated with the density of tumor cells. Patients with a high accumulation of cytotoxic cells showed a longer median survival.
Conclusions: Pancreatic carcinoma frequently induces a cellular immune response that results in intratumoral and peritumoral T-cell infiltration. The expression of HLA class I is frequently lost in pancreatic carcinoma, which represents an effective mechanism to escape the tumor infiltration by cytotoxic T-cells. However, the infiltration by cytotoxic cells represents a favorable prognostic sign in pancreatic cancer patients.
CD34+CD7+ Leukemic Progenitor Cells May Be Involved in Maintenance and Clonal Evolution of Chronic Myeloid Leukemia
Authors: Kosugi Nobuharu , Ebihara Yasuhiro , Nakahata Tatsutoshi , Saisho Hiromitsu , Asano Shigetaka , Tojo Arinobu 
Published: June 2022

AbstractPurpose: We analyzed CD34+ cells coexpressing CD7 in chronic myeloid leukemia (CML) in chronic phase (CP) or accelerated phase (AP) to clarify their role in progression or regression of the disease during treatment.Experimental Design: Enumeration of CD34+CD7+ cells was done on bone marrow nucleated cells from normal donors and CML patients. Fluorescence in situ hybridization analysis was done on sorted CD34+CD7+ and CD34+CD7− cells to examine the occupancy rate of each fraction by BCR-ABL+ cells with or without additional cytogenetic abnormalities.Results: The proportion of CD34+CD7+ cells was significantly affected by the treatment outcome and/or the disease status as follows: 20.5 ± 10.4% in normal donors (n = 22), 18.1 ± 10.2% in CP with major cytogenetic response (n = 14), 53.0 ± 12.9% in CP at diagnosis (n = 18), 55.0 ± 15.8% in CP with minor or no cytogenetic response (n = 28), and 70.2 ± 18.1% in AP (n = 6). The proportion of CD34+CD7+ cells decreased in parallel with cytogenetic improvement in individual patients. In six untreated CP patients, the ratio of BCR-ABL+ cells was comparable between each fraction. In three patients with major cytogenetic response, the ratio of BCR-ABL+ cells was remarkably lower in CD34+CD7− cells than in CD34+CD7+ cells. In three AP patients with additional cytogenetic abnormalities, extra signals were detected at a much higher rate in CD34+CD7+ cells than in CD34+CD7− cells.Conclusions: Our results suggest that CD34+CD7+ cells may be involved in maintenance and clonal evolution of BCR-ABL+ cells in CML.
Expression and Signaling Activity of Wnt-5a/Discoidin Domain Receptor-1 and Syk Plays Distinct but Decisive Roles in Breast Cancer Patient Survival
Authors: Dejmek Janna , Leandersson Karin , Manjer Jonas , Bjartell Anders , Emdin Stefan O. , Vogel Wolfgang F. , Landberg Göran , Andersson Tommy 
Published: June 2022

AbstractPurpose: The loss of Wnt-5a, a G-protein-coupled receptor ligand, or Syk, an intracellular kinase, has in separate studies been associated with poor prognosis of breast cancer patients. Both proteins are involved in cell adhesion, a key event in epithelial cancer metastasis. Here, we have investigated whether Syk is part of the Wnt-5a/discoidin domain receptor-1 (DDR1) signaling pathway and if a signaling interaction of these proteins is important for breast cancer–specific survival.Experimental Design: The signaling interactions between Wnt-5a/DDR1 and Syk were addressed in mammary cell lines. Their mRNA and protein levels and the respective clinical correlates were investigated in 94 cases of primary breast cancer.Results: The expression of Wnt-5a and Syk correlated in four of five tumor cell lines. However, despite a constitutive association between Syk and the Wnt-5a-dependent adhesion receptor DDR1, we found no evidence of a Wnt-5a/DDR1-mediated activation of Syk. Instead, β1 integrins initiate the adhesion-induced activation of Syk. In tumors from breast cancer patients, the protein expression of Wnt-5a and Syk were differently regulated at the translational and transcriptional level, respectively. Analysis of breast cancer–specific survival revealed that the presence of Wnt-5a and Syk in primary tumors has good predictive value for a favorable outcome. Intriguingly, a simultaneous loss of both proteins did not reduce survival more than loss of either.Conclusions: Despite the difference in regulation of Wnt-5a and Syk protein expression and their lack of signaling interaction, our clinical data indicate that a favorable prognosis in breast cancer requires the expression and signaling activity of both.