bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Longitudinal Investigation of Permeability and Distribution of Macromolecules in Mouse Malignant Transformation Using PET
Authors: Rygh Cecilie B. , Qin Shengping , Seo Jai W. , Mahakian Lisa M. , Zhang Hua , Adamson Roger , Chen Jane Q. , Borowsky Alexander D. , Cardiff Robert D. , Reed Rolf K. , Curry Fitz-Roy E. , Ferrara Katherine W.
Published: April 2023

Abstract
Purpose: We apply positron emission tomography (PET) to elucidate changes in nanocarrier extravasation during the transition from premalignant to malignant cancer, providing insight into the use of imaging to characterize early cancerous lesions and the utility of nanoparticles in early disease.

Experimental Design: Albumin and liposomes were labeled with 64Cu (half-life 12.7 hours), and longitudinal PET and CT imaging studies were conducted in a mouse model of ductal carcinoma in situ. A pharmacokinetic model was applied to estimate the tumor vascular volume and permeability.

Results: From early time points characterized by disseminated hyperproliferation, the enhanced vascular permeability facilitated lesion detection. During disease progression, the vascular volume fraction increased 1.6-fold and the apparent vascular permeability to albumin and liposomes increased ∼2.5-fold to 6.6 × 10−8 and 1.3 × 10−8 cm/s, respectively, with the accumulation of albumin increasing earlier in the disease process. In the malignant tumor, both tracers reached similar mean intratumoral concentrations of ∼6% ID/cc but the distribution of liposomes was more heterogeneous, ranging from 1% to 18% ID/cc compared with 1% to 9% ID/cc for albumin. The tumor-to-muscle ratio was 17.9 ± 8.1 and 7.1 ± 0.5 for liposomes and albumin, respectively, indicating a more specific delivery of liposomes than with albumin.

Conclusions: PET imaging of radiolabeled particles, validated by confocal imaging and histology, detected the transition from premalignant to malignant lesions and effectively quantified the associated changes in vascular permeability. Clin Cancer Res; 17(3); 550–9. ©2010 AACR.
Data from Early Tumor Progression Associated with Enhanced EGFR Signaling with Bortezomib, Cetuximab, and Radiotherapy for Head and Neck Cancer
Authors: Argiris Athanassios , Duffy Austin G. , Kummar Shivaani , Simone Nicole L. , Arai Yoshio , Kim Seungwon W. , Rudy Susan F. , Kannabiran Vishnu R. , Yang Xinping , Jang Minyoung , Chen Zhong , Suksta Nanette , Cooley-Zgela Theresa , Ramanand Susmita G. , Ahsan Aarif , Nyati Mukesh K. , Wright John J. , Van Waes Carter
Published: April 2023

Abstract
Purpose: A phase I clinical trial and molecular correlative studies were conducted to evaluate preclinical evidence for combinatorial activity of the proteasome inhibitor bortezomib, the epidermal growth factor receptor (EGFR) inhibitor cetuximab, and radiation therapy.

Experimental Design: Patients with radiotherapy-naive stage IV or recurrent squamous cell carcinoma of the head and neck (SCCHN) were studied. Escalating doses of bortezomib (0.7, 1.0, and 1.3 mg/m2) were given intravenously twice weekly on days 1, 4, 8, and 11, every 21 days, with weekly cetuximab beginning 1 week prior and concurrently with intensity-modulated radiotherapy, delivered in 2 Gy fractions to 70 to 74 Gy. Molecular effects were examined in serial serum and SCCHN tumor specimens and the cell line UMSCC-1.

Results: Seven patients were accrued before the study was terminated when five of six previously untreated patients with favorable prognosis oropharyngeal SCCHN progressed within 1 year (progression-free survival = 4.8 months; 95% CI, 2.6–6.9). Three patients each received bortezomib 0.7 or 1.0 mg/m2, without dose-limiting toxicities; one patient treated at 1.3 mg/m2 was taken off study due to recurring cetuximab infusion reaction and progressive disease (PD). Expected grade 3 toxicities included radiation mucositis (n = 4), dermatitis (n = 4), and rash (n = 1). SCCHN-related cytokines increased in serial serum specimens of patients developing PD (P = 0.029). Bortezomib antagonized cetuximab- and radiation-induced cytotoxicity, degradation of EGFR, and enhanced prosurvival signal pathway activation in SCCHN tumor biopsies and UMSCC-1.

Conclusions: Combining bortezomib with cetuximab and radiation therapy showed unexpected early progression, evidence for EGFR stabilization, increased prosurvival signaling, and SCCHN cytokine expression, warranting avoidance of this combination. Clin Cancer Res; 17(17); 5755–64. ©2011 AACR.
Data from Molecular Analysis of Colorectal Tumors within a Diverse Patient Cohort at a Single Institution
Authors: Sylvester Brooke E. , Huo Dezheng , Khramtsov Andrey , Zhang Jing , Smalling Rana V. , Olugbile Sope , Polite Blase N. , Olopade Olufunmilayo I.
Published: April 2023

Abstract
Purpose: African American colorectal cancer patients have worse survival outcomes than Caucasian patients. To determine whether differences exist in the molecular mechanisms driving colorectal cancer between African Americans and Caucasians, we characterized patient tumors from a single institution by assessing genetic alterations involved in colorectal cancer progression and response to treatment.

Experimental Design: We retrospectively examined 448 African Americans and Caucasians diagnosed with colorectal cancer at The University of Chicago Medical Center between 1992 and 2002. Microsatellite instability (MSI) status was determined by genotyping the BAT25, BAT26, BAT40, D5S346, and BAX loci. Mutations in KRAS codons 12 and 13 and BRAF codon 600 were identified by direct sequencing. MSI and detected mutations were correlated with clinicopathologic features.

Results: Overall, no difference existed in MSI or BRAF mutation frequencies between African Americans and Caucasians. However, African Americans with microsatellite stable (MSS)/MSI-low (MSI-L) tumors had a higher proportion of KRAS mutations than Caucasians (34% vs. 23%, P = 0.048) that was isolated to proximal colon cancers and primarily driven by mutations in codon 13. There was no racial difference in receipt of chemotherapy, but African Americans with MSS/MSI-L tumors had a 73% increased risk of death over Caucasians that could not be explained by known prognostic factors.

Conclusions: The significantly higher risk of death among African Americans with MSS/MSI-L tumors may be related to differences in the distribution of factors influencing response to standard therapies. These data underscore the need for further research into the molecular mechanisms driving colorectal cancer progression in underserved and understudied populations. Clin Cancer Res; 18(2); 350–9. ©2011 AACR.
Data from Analysis of Fcγ Receptor IIIa and IIa Polymorphisms: Lack of Correlation with Outcome in Trastuzumab-Treated Breast Cancer Patients
Authors: Hurvitz Sara A. , Betting David J. , Stern Howard M. , Quinaux Emmanuel , Stinson Jeremy , Seshagiri Somasekar , Zhao Ying , Buyse Marc , Mackey John , Driga Adrian , Damaraju Sambasivarao , Sliwkowski Mark X. , Robert Nicholas J. , Valero Vicente , Crown John , Falkson Carla , Brufsky Adam , Pienkowski Tadeusz , Eiermann Wolfgang , Martin Miguel , Bee Valerie , Marathe Omkar , Slamon Dennis J. , Timmerman John M.
Published: April 2023

Abstract
Purpose: The mechanisms by which trastuzumab imparts clinical benefit remain incompletely understood. Antibody-dependent cellular cytotoxicity via interactions with Fcγ receptors (FcγR) on leukocytes may contribute to its antitumor effects. Single-nucleotide polymorphisms (SNP) in FCGR3A and FCGR2A genes lead to amino acid substitutions at positions 158 and 131, respectively, and affect binding of antibodies to FcγR such that 158V/V and 131H/H bind with highest affinity. This study aimed to determine whether high-affinity SNPs are associated with disease-free survival (DFS) among patients with HER2-positive nonmetastatic breast cancer.

Experimental Design: Genomic DNA was isolated from 1,286 patients enrolled in a trial of adjuvant trastuzumab-based chemotherapy. Genotyping was conducted using Sanger sequencing and Sequenom mass spectrometry.

Results: Patient samples (N = 1,189) were successfully genotyped for FCGR3A and 1,218 for FCGR2A. Compared with the overall results of the BCIRG006 study, in the subset of patients genotyped in this analysis, a less robust improvement in DFS was observed for the trastuzumab arms than control arm (HR, 0.842; P = 0.1925). When stratified for prognostic features, the HR in favor of trastuzumab was consistent with that of the overall study (HR, 0.74; P = 0.036). No correlation between DFS and FCGR3A/2A genotypes was seen for trastuzumab-treated patients (158V/V vs. V/F vs. F/F, P = 0.98; 131H/H vs. H/R vs. R/R, P = 0.76; 158V/V and/or 131H/H vs. others, P = 0.67).

Conclusion: This analysis evaluating the association between FCGR3A/2A genotypes and trastuzumab efficacy in HER2-positive breast cancer did not show a correlation between FCGR3A-V/F and FCGR2A-H/R SNPs and DFS in patients treated with trastuzumab. Clin Cancer Res; 18(12); 3478–86. ©2012 AACR.
Data from Predictive Value of XRCC1 Gene Polymorphisms on Platinum-Based Chemotherapy in Advanced Non–Small Cell Lung Cancer Patients: A Systematic Review and Meta-analysis
Authors: Wu Junjie , Liu Jie , Zhou Yuhao , Ying Jun , Zou Houdong , Guo Shicheng , Wang Lei , Zhao Naiqing , Hu Jianjun , Lu Daru , Jin Li , Li Qiang , Wang Jiu-Cun
Published: April 2023

Abstract
Purpose: Published data have shown conflicting results about the relationship between X-ray repair cross-complementing group 1 (XRCC1) gene polymorphisms (Arg399Gln and Arg194Trp) and clinical outcome of platinum-based chemotherapy in patients with advanced non–small cell lung cancer (NSCLC). A meta-analysis is needed to provide a systematic review of the published findings.

Experimental Design: We conducted a systematic review and meta-analysis to evaluate the predictive value of XRCC1 gene polymorphisms on clinical outcome up to October 1, 2010. The quality of each study was scored on the basis of predefined criteria.

Results: A total of 13 eligible follow-up studies met all the inclusion criteria. The XRCC1194Trp allele was found to be significantly associated with a favorable response rate relative to 194Arg [Trp vs. Arg: OR, 1.88; 95% confidence interval (CI), 1.48–2.38]. XRCC1399Gln was less favorably associated with both response rate (Gln vs. Arg: OR, 0.67; 95% CI, 0.52–0.87) and overall survival (Gln vs. Arg: HR, 1.30; 95% CI, 1.04–1.63) than 399Arg in analyses using all available studies; but these associations became insignificant when only high-quality studies were used.

Conclusion: These findings suggest a predictive role for XRCC1 gene polymorphisms in clinical outcome. However, the role of 399Gln could be considered controversial because its impact on clinical outcome was insignificant in high-quality studies. These findings show the importance of establishing suitable criteria, including genetic epidemiologic, phenotypic, and clinical criteria, to improve quality control of study design and methods in pharmacogenomic studies related to XRCC1 gene polymorphism. Clin Cancer Res; 18(14); 3972–81. ©2012 AACR.
Data from Colorectal Cancers with Microsatellite Instability Display Unique miRNA Profiles
Authors: Balaguer Francesc , Moreira Leticia , Lozano Juan Jose , Link Alexander , Ramirez Georgina , Shen Yan , Cuatrecasas Miriam , Arnold Mildred , Meltzer Stephen J. , Syngal Sapna , Stoffel Elena , Jover Rodrigo , Llor Xavier , Castells Antoni , Boland C. Richard , Gironella Meritxell , Goel Ajay
Published: April 2023

Abstract
Purpose: microRNAs (miRNA) are small noncoding transcripts that play an important role in carcinogenesis. miRNA expression profiles have been shown to discriminate between different types of cancers. The aim of this study was to analyze global miRNA signatures in various groups of colorectal cancers (CRC) based on the presence of microsatellite instability (MSI).

Experimental Design: We analyzed genome-wide miRNA expression profiles in 54 CRC tissues [22 with Lynch syndrome, 13 with sporadic MSI due to MLH1 methylation, 19 without MSI (or microsatellite stable, MSS)] and 20 normal colonic tissues by miRNA microarrays. Using an independent set of MSI-positive samples (13 with Lynch syndrome and 20 with sporadic MSI), we developed a miRNA-based predictor to differentiate both types of MSI by quantitative reverse transcriptase PCR.

Results: We found that the expression of a subset of nine miRNAs significantly discriminated between tumor and normal colonic mucosa tissues (overall error rate = 0.04). More importantly, Lynch syndrome tumors displayed a unique miRNA profile compared with sporadic MSI tumors; miR-622, miR-1238, and miR-192 were the most differentially expressed miRNAs between these two groups. We developed a miRNA-based predictor capable of differentiating between types of MSI in an independent sample set.

Conclusions: CRC tissues show distinct miRNA expression profiles compared with normal colonic mucosa. The discovery of unique miRNA expression profiles that can successfully discriminate between Lynch syndrome, sporadic MSI, and sporadic MSS colorectal cancers provides novel insights into the role of miRNAs in colorectal carcinogenesis, which may contribute to the diagnosis, prognosis, and treatment of this disease. Clin Cancer Res; 17(19); 6239–49. ©2011 AACR.
Data from Omental Adipose Tissue–Derived Stromal Cells Promote Vascularization and Growth of Endometrial Tumors
Authors: Klopp Ann H. , Zhang Yan , Solley Travis , Amaya-Manzanares Felipe , Marini Frank , Andreeff Michael , Debeb Bisrat , Woodward Wendy , Schmandt Rosemarie , Broaddus Russell , Lu Karen , Kolonin Mikhail G.
Published: April 2023

Abstract
Purpose: Adipose tissue contains a population of tumor-tropic mesenchymal progenitors, termed adipose stromal cells (ASC), which engraft in neighboring tumors to form supportive tumor stroma. We hypothesized that intra-abdominal visceral adipose tissue may contain a uniquely tumor-promoting population of ASC to account for the relationship between excess visceral adipose tissue and mortality of intra-abdominal cancers.

Experimental Design: To investigate this, we isolated and characterized ASC from intra-abdominal omental adipose tissue (O-ASC) and characterized their effects on endometrial cancer progression as compared with subcutaneous adipose-derived mesenchymal stromal cells (SC-ASC), bone marrow–derived mesenchymal stromal cells (BM-MSC), and lung fibroblasts. To model chronic recruitment of ASC by tumors, cells were injected metronomically into mice bearing Hec1a xenografts.

Results: O-ASC expressed cell surface markers characteristic of BM-MSC and differentiated into mesenchymal lineages. Coculture with O-ASC increased endometrial cancer cell proliferation in vitro. Tumor tropism of O-ASC and SC-ASC for human Hec1a endometrial tumor xenografts was comparable, but O-ASC more potently promoted tumor growth. Compared with tumors in SC-ASC–injected mice, tumors in O-ASC–injected mice contained higher numbers of large tortuous desmin-positive blood vessels, which correlated with decreased central tumor necrosis and increased tumor cell proliferation. O-ASC exhibited enhanced motility as compared with SC-ASC in response to Hec1a-secreted factors.

Conclusions: Visceral adipose tissue contains a population of multipotent MSCs that promote endometrial tumor growth more potently than MSCs from subcutaneous adipose tissue. We propose that O-ASCs recruited to tumors express specific factors that enhance tumor vascularization, promoting survival and proliferation of tumor cells. Clin Cancer Res; 18(3); 771–82. ©2011 AACR.
Data from Detection of TIMP3 Promoter Hypermethylation in Salivary Rinse as an Independent Predictor of Local Recurrence-Free Survival in Head and Neck Cancer
Authors: Sun Wenyue , Zaboli David , Wang Hao , Liu Yan , Arnaoutakis Demetri , Khan Tanbir , Khan Zubair , Koch Wayne M. , Califano Joseph A.
Published: April 2023

Abstract
Purpose: To validate a panel of methylation-based salivary rinse biomarkers (P16, CCNA1, DCC, TIMP3, MGMT, DAPK, and MINT31) previously shown to be independently associated with poor overall survival and local recurrence in a larger, separate cohort of patients with head and neck squamous cell carcinoma (HNSCC).

Experimental Design: One hundred ninety-seven patients were included. All pretreatment saliva DNA samples were evaluated for the methylation status of the gene promoters by quantitative methylation-specific PCR. The main outcome measures were overall survival, local recurrence-free survival, and disease-free survival.

Results: In univariate analyses, the detection of hypermethylation of CCNA1, MGMT, and MINT31 was significantly associated with poor overall survival; the detection of hypermethylation of TIMP3 was significantly associated with local recurrence-free survival; and the detection of hypermethylation of MINT31 was significantly associated with poor disease-free survival. In multivariate analyses, detection of hypermethylation at any single marker was not predictive of overall survival in patients with HNSCC; detection of hypermethylation of TIMP3 in salivary rinse had an independent, significant association with local recurrence-free survival (HR = 2.51; 95% CI: 1.10–5.68); and none of the studied markers was significantly associated with disease-free survival.

Conclusion: The detection of promoter hypermethylation of the seven genes in salivary rinse as an independent prognostic indicator of overall survival in patients with HNSCC was not validated. Detection of promoter hypermethylation of TIMP3 in pretreatment salivary rinse is independently associated with local recurrence-free survival in patients with HNSCC and may be a valuable salivary rinse biomarker for HNSCC recurrence. Clin Cancer Res; 18(4); 1082–91. ©2012 AACR.
Data from A Pharmacodynamic Study of Docetaxel in Combination with the P-glycoprotein Antagonist Tariquidar (XR9576) in Patients with Lung, Ovarian, and Cervical Cancer
Authors: Kelly Ronan J. , Draper Deborah , Chen Clara C. , Robey Robert W. , Figg William D. , Piekarz Richard L. , Chen Xiaohong , Gardner Erin R. , Balis Frank M. , Venkatesan Aradhana M. , Steinberg Seth M. , Fojo Tito , Bates Susan E.
Published: April 2023

Abstract
Purpose: P-glycoprotein (Pgp) antagonists have been difficult to develop because of complex pharmacokinetic interactions and a failure to show meaningful results. Here we report the results of a pharmacokinetic and pharmacodynamic trial using a third-generation, potent, noncompetitive inhibitor of Pgp, tariquidar (XR9576), in combination with docetaxel.

Experimental Design: In the first treatment cycle, the pharmacokinetics of docetaxel (40 mg/m2) were evaluated after day 1 and day 8 doses, which were administered with or without tariquidar (150 mg). 99mTc-sestamibi scanning and CD56+ mononuclear cell rhodamine efflux assays were conducted to assess Pgp inhibition. In subsequent cycles, 75 mg/m2 docetaxel was administered with 150 mg tariquidar every 3 weeks.

Results: Forty-eight patients were enrolled onto the trial. Nonhematologic grade 3/4 toxicities in 235 cycles were minimal. Tariquidar inhibited Pgp-mediated rhodamine efflux from CD56+ cells and reduced 99mTc-sestamibi clearance from the liver. There was striking variability in basal sestamibi uptake; a 12% to 24% increase in visible lesions was noted in 8 of 10 patients with lung cancer. No significant difference in docetaxel disposition was observed in pairwise comparison with and without tariquidar. Four partial responses (PR) were seen (4/48); 3 in the non–small cell lung cancer (NSCLC) cohort, measuring 40%, 57%, and 67% by RECIST, and 1 PR in a patient with ovarian cancer.

Conclusions: Tariquidar is well tolerated, with less observed systemic pharmacokinetic interaction than previous Pgp antagonists. Variable effects of tariquidar on retention of sestamibi in imageable lung cancers suggest that follow-up studies assessing tumor drug uptake in this patient population would be worthwhile. Clin Cancer Res; 17(3); 569–80. ©2010 AACR.
Data from New Gene-Immunotherapy Combining TRAIL-Lymphocytes and EpCAMxCD3 Bispecific Antibody for Tumor Targeting
Authors: Groth Ariane , Salnikov Alexei V. , Ottinger Sabine , Gladkich Jury , Liu Li , Kallifatidis Georgios , Salnikova Olga , Ryschich Eduard , Giese Nathalia , Giese Thomas , Momburg Frank , Büchler Markus W. , Moldenhauer Gerhard , Herr Ingrid
Published: April 2023

Abstract
Purpose: To enhance T-cell responsiveness toward cancer cells, we overexpressed TRAIL in lymphocytes, as this death ligand induces tumor-specific apoptosis. To increase contact time of lymphocytes with tumor cells and thereby of TRAIL with its death receptors, lymphocytes were linked to the CD3 arm of bispecific antibody EpCAMxCD3, to guide the lymphocytes to tumor cells positive for the cancer stem cell marker EpCAM/ESA.

Experimental Design: Lymphocytes were transduced with TRAIL lentivirus and the antitumor effect in presence and absence of EpCAMxCD3 was evaluated in vitro and in xenograft studies using epithelial cell adhesion molecule (EpCAM)–positive pancreatic and prostate cancer cells.

Results: Compared with control lymphocytes, TRAIL-lymphocytes increased cytotoxicity and further induced expression of several apoptosis-related molecules. Cotransplantation of TRAIL-lymphocytes and tumor cells in mice or peritumoral injection of TRAIL-lymphocytes in larger xenografts retarded growth and induced apoptosis. Combination of TRAIL-lymphocytes with EpCAMxCD3 potentiated tumor eradication by enhancing antiapoptotic and antiproliferative signaling and by decreasing tumor vasculature. Intratumoral cyst formation was involved and associated with enhanced chemokine secretion and infiltration of mouse macrophages, suggesting contribution of an inflammatory host response. Most importantly, tumorigenicity of pancreatic cancer cells with cancer stem cell features resistant to conventional chemotherapy was strongly reduced.

Conclusions: This gene-immunotherapeutic approach may be a new tool to support endogenous immune responses toward cancer even in its advanced stages. Clin Cancer Res; 18(4); 1028–38. ©2012 AACR.
Data from RAF265 Inhibits the Growth of Advanced Human Melanoma Tumors
Authors: Su Yingjun , Vilgelm Anna E. , Kelley Mark C. , Hawkins Oriana E. , Liu Yan , Boyd Kelli L. , Kantrow Sara , Splittgerber Ryan C. , Short Sarah P. , Sobolik Tammy , Zaja-Milatovic Snjezana , Dahlman Kimberly Brown , Amiri Katayoun I. , Jiang Aixiang , Lu Pengcheng , Shyr Yu , Stuart Darrin D. , Levy Shawn , Sosman Jeffrey A. , Richmond Ann
Published: April 2023

Abstract
Purpose: The purpose of this preclinical study was to determine the effectiveness of RAF265, a multikinase inhibitor, for treatment of human metastatic melanoma and to characterize traits associated with drug response.

Experimental Design: Advanced metastatic melanoma tumors from 34 patients were orthotopically implanted to nude mice. Tumors that grew in mice (17 of 34) were evaluated for response to RAF265 (40 mg/kg, every day) over 30 days. The relation between patient characteristics, gene mutation profile, global gene expression profile, and RAF265 effects on tumor growth, mitogen-activated protein/extracellular signal-regulated kinase (MEK)/extracellular signal-regulated kinase (ERK) phosphorylation, proliferation, and apoptosis markers was evaluated.

Results: Nine of the 17 tumors that successfully implanted (53%) were mutant BRAF (BRAFV600E/K), whereas eight of 17 (47%) tumors were BRAF wild type (BRAFWT). Tumor implants from 7 of 17 patients (41%) responded to RAF265 treatment with more than 50% reduction in tumor growth. Five of the 7 (71%) responders were BRAFWT, of which 1 carried c-KITL576P and another N-RASQ61R mutation, while only 2 (29%) of the responding tumors were BRAFV600E/K. Gene expression microarray data from nonimplanted tumors revealed that responders exhibited enriched expression of genes involved in cell growth, proliferation, development, cell signaling, gene expression, and cancer pathways. Although response to RAF265 did not correlate with pERK1/2 reduction, RAF265 responders did exhibit reduced pMEK1, reduced proliferation based upon reduced Ki-67, cyclin D1 and polo-like kinase1 levels, and induction of the apoptosis mediator BCL2-like 11.

Conclusions: Orthotopic implants of patient tumors in mice may predict prognosis and treatment response for melanoma patients. A subpopulation of human melanoma tumors responds to RAF265 and can be characterized by gene mutation and gene expression profiles. Clin Cancer Res; 18(8); 2184–98. ©2012 AACR.
Data from Mast Cells in Tumor Microenvironment Promotes the In Vivo Growth of Pancreatic Ductal Adenocarcinoma
Authors: Chang David Z. , Ma Ying , Ji Baoan , Wang Huamin , Deng Defeng , Liu Yan , Abbruzzese James L. , Liu Yong-jun , Logsdon Craig D. , Hwu Patrick
Published: April 2023

Abstract
Purpose: Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer death. No effective therapy is currently available for PDAC because of the lack of understanding of the mechanisms leading to its growth and development. Inflammatory cells, particularly mast cells, have been shown to play key roles in some cancers. We carried out this study to test the hypothesis that mast cells in the tumor microenvironment are essential for PDAC tumorigenesis.

Experimental Design: The presence of inflammatory cells at various stages of PDAC development was determined in a spontaneous mouse model of PDAC (K-rasG12V). The importance of mast cells was determined using orthotopically implanted PDAC cells in mast cell–deficient Kitw-sh/w-sh mice and further confirmed by reconstitution of wild-type bone marrow–derived mast cells. Clinical relevance was assessed by correlating the presence of mast cells with clinical outcome in patients with PDAC.

Results: In the spontaneous mouse model of PDAC (K-rasG12V), there was an early influx of mast cells to the tumor microenvironment. PDAC tumor growth was suppressed in mast cell–deficient Kitw-sh/w-sh mice, but aggressive PDAC growth was restored when PDAC cells were injected into mast cell–deficient mice reconstituted with wild-type bone marrow–derived mast cells. Mast cell infiltration into the tumor microenvironment was predictive of poor prognosis in patients with PDAC.

Conclusions: Mast cells play an important role in PDAC growth and development in mouse models and are indicative of poor prognosis in humans, which makes them a potential novel therapeutic target. Clin Cancer Res; 17(22); 7015–23. ©2011 AACR.
Data from XPF Expression Correlates with Clinical Outcome in Squamous Cell Carcinoma of the Head and Neck
Authors: Vaezi Alec , Wang XiaoZhe , Buch Shama , Gooding William , Wang Lin , Seethala Raja R. , Weaver David T. , D'Andrea Alan D. , Argiris Athanassios , Romkes Marjorie , Niedernhofer Laura J. , Grandis Jennifer R.
Published: April 2023

Abstract
Purpose: Tumor-specific biomarkers that predict resistance to DNA damaging agents may improve therapeutic outcomes by guiding the selection of effective therapies and limiting morbidity related to ineffective approaches. XPF (ERCC4) is an essential component of several DNA repair pathways and XPF-deficient cells are exquisitely sensitive to DNA damaging agents. The purpose of this study was to determine whether XPF expression levels predict clinical response to DNA damaging agents in head and neck squamous cell carcinoma (HNSCC).

Experimental Design: Quantitative immunohistochemistry was used to measure XPF expression in tumors from a cohort of 80 patients with newly diagnosed HNSCC treated with radiation therapy with or without platinum-based chemotherapy; samples were collected prospectively. Genomic DNA isolated from blood samples was analyzed for nine single nucleotide polymorphisms (SNP) in the XPF gene by using a custom array. The primary endpoint was progression-free survival (PFS).

Results: XPF expression was higher in tumors from the oral cavity than from the other sites (P < 0.01). High XPF expression correlated with early time to progression both by univariate (HR = 1.87, P = 0.03) and multivariate analysis (HR = 1.83, P = 0.05). The one year PFS for high expressers was 47% (95% CI = 31–62) compared with 72% (95% CI = 55–83) for low expressers. In addition, we identified four XPF SNPs that showed marginal association with treatment failure.

Conclusions: Expression level of XPF in HNSCC tumors correlates with clinical response to DNA damaging agents. XPF has potential to guide next generation personalized cancer therapy. Clin Cancer Res; 17(16); 5513–22. ©2011 AACR.
Data from Phase I Study of the Combination of Sorafenib and Temsirolimus in Patients with Metastatic Melanoma
Authors: Davies Michael A. , Fox Patricia S. , Papadopoulos Nicholas E. , Bedikian Agop Y. , Hwu Wen-Jen , Lazar Alexander J. , Prieto Victor G. , Culotta Kirk S. , Madden Timothy L. , Xu Quanyun , Huang Sha , Deng Wanleng , Ng Chaan S. , Gupta Sanjay , Liu Wenbin , Dancey Janet E. , Wright John J. , Bassett Roland L. , Hwu Patrick , Kim Kevin B.
Published: April 2023

Abstract
Purpose: This phase I clinical trial was conducted to determine the safety, efficacy, and molecular effects of sorafenib with temsirolimus in patients with advanced melanoma.

Patients and Methods: Patients with stage IV or unresectable or recurrent stage III melanoma and Eastern Cooperative Oncology Group performance status of 0 to 1 were eligible. Sorafenib was given orally once or twice daily and temsirolimus was given i.v. weekly, both starting on day 1, with a 4-week cycle. Responses were assessed every 2 cycles per Response Evaluation Criteria in Solid Tumors criteria. Consenting patients with accessible tumors underwent optional tumor biopsies before treatment and after the second infusion of temsirolimus. Tumor biopsies were analyzed for activating mutations in BRAF and NRAS, and for expression of P-extracellular signal-regulated kinase (P-ERK) and P-S6 proteins.

Results: A total of 25 patients were accrued to the study. The maximum tolerated doses were sorafenib 400 mg every morning and 200 mg every evening and temsirolimus 25 mg i.v. weekly. Dose-limiting toxicities included thrombocytopenia, hand-foot syndrome, serum transaminase elevation, and hypertriglyceridemia. There were no complete or partial responses with the combination; 10 patients achieved stabilization of disease as their best response. The median progression-free survival was 2.1 months. Matching pretreatment and day 15 tumor biopsies showed marked inhibition of P-S6 with treatment in 3 of 4 evaluable patients, but minimal inhibition of P-ERK.

Conclusions: Combination therapy with sorafenib and temsirolimus resulted in significant toxicity at higher dose levels, failed to achieve any clinical responses in genetically unselected patient population, and did not inhibit P-ERK. Clin Cancer Res; 18(4); 1120–8. ©2012 AACR.
Data from Serum Galectin-2, -4, and -8 Are Greatly Increased in Colon and Breast Cancer Patients and Promote Cancer Cell Adhesion to Blood Vascular Endothelium
Authors: Barrow Hannah , Guo Xiuli , Wandall Hans H. , Pedersen Johannes W. , Fu Bo , Zhao Qicheng , Chen Chen , Rhodes Jonathan M. , Yu Lu-Gang
Published: April 2023

Abstract
Purpose: Adhesion of disseminating tumor cells to the blood vascular endothelium is a pivotal step in metastasis. Previous investigations have shown that galectin-3 concentrations are increased in the bloodstream of patients with cancer and that galectin-3 promotes adhesion of disseminating tumor cells to vascular endothelium in vitro and experimental metastasis in vivo. This study determined the levels of galectin-1, -2, -3, -4, -8, and -9 in the sera of healthy people and patients with colon and breast cancer and assessed the influence of these galectins on cancer-endothelium adhesion.

Experimental Design: Serum galectins and auto–anti-MUC1 antibodies were assessed using ELISA and mucin protein (MUC1) glycan microarrays, and cancer-endothelium adhesion was determined using monolayers of human microvascular lung endothelial cells.

Results: The levels of serum galectin-2, -3, -4, and -8 were significantly increased up to 31-fold in patients with cancer and, in particular, those with metastases. As previously shown for galectin-3, the presence of these galectins enhances cancer-endothelium adhesion by interaction with the Thomsen-Friedenreich (TF; Galβ1,3GalNAcα-) disaccharide on cancer-associated MUC1. This causes MUC1 cell surface polarization, thus exposing underlying adhesion molecules that promote cancer-endothelium adhesion. Elevated circulating galectin-2 levels were associated with increased mortality in patients with colorectal cancer, but this association was suppressed when anti-MUC1 antibodies with specificity for the TF epitope of MUC1 were also present in the circulation.

Conclusions: Increased circulation of several members of the galectin family is common in patients with cancer and these may, like circulating galectin-3, also be involved in metastasis promotion. Clin Cancer Res; 17(22); 7035–46. ©2011 AACR.
Data from Loss of 18q22.3 Involving the Carboxypeptidase of Glutamate-like Gene Is Associated with Poor Prognosis in Resected Pancreatic Cancer
Authors: Lee Jih-Hsiang , Giovannetti Elisa , Hwang Jin-Hyeok , Petrini Iacopo , Wang Qiuyan , Voortman Johannes , Wang Yonghong , Steinberg Seth M. , Funel Niccola , Meltzer Paul S. , Wang Yisong , Giaccone Giuseppe
Published: April 2023

Abstract
Purposes: Pancreatic cancer is the fourth leading cause of cancer-related death, and studies on the clinical relevance of its genomic imbalances are warranted.

Experimental Design: Recurrent copy number alterations of cytobands and genes were analyzed by array comparative genomic hybridization (aCGH) in 44 resected pancreatic cancer specimens. Prognostic markers identified by aCGH were validated by PCR gene copy number assay in an independent validation cohort of 61 resected pancreatic cancers. The functions of gene identified were evaluated by proliferation, cell cycle, and migration assays in pancreatic cancer cells.

Results: We showed recurrent copy number gains and losses in the first cohort. Loss of 18q22.3 was significantly associated with short-term overall survival in the first cohort (P = 0.019). This cytoband includes the carboxypeptidase of glutamate-like (CPGL) gene. CPGL gene deletion was associated with shorter overall survival in the validation cohort (P = 0.003). CPGL deletion and mutations of TP53 or Kras seem to be independent events. A Cox model analysis of the two cohorts combined showed that loss of 18q22.3/deletion of the CPGL gene was an independent poor prognostic factor for overall survival (HR = 2.72, P = 0.0007). Reconstitution of CPGL or its splicing variant CPGL-B into CPGL-negative pancreatic cancer cells attenuated cell growth, migration, and induced G1 accumulation.

Conclusion: Loss of 18q22.3/deletion of the CPGL gene is a poor prognostic marker in resected pancreatic cancer, and functional studies suggest the CPGL gene as growth suppressor gene in pancreatic cancer. Clin Cancer Res; 18(2); 524–33. ©2011 AACR.
Data from Tumor Epidermal Growth Factor Receptor and EGFR PY1068 Are Independent Prognostic Indicators for Head and Neck Squamous Cell Carcinoma
Authors: Wheeler Sarah , Siwak Doris R. , Chai Raymond , LaValle Courtney , Seethala Raja R. , Wang Lin , Cieply Kathleen , Sherer Carol , Joy Corwin , Mills Gordon B. , Argiris Athanassios , Siegfried Jill M. , Grandis Jennifer R. , Egloff Ann Marie
Published: April 2023

Abstract
Purpose: To assess the prognostic value of epidermal growth factor receptor (EGFR) molecular characteristics of head and neck squamous cell carcinoma (HNSCC).

Patients and Methods: HNSCC tumors from patients prospectively enrolled in either an Early Detection Research Network (EDRN) study and treated with surgery without an EGFR-targeted agent (N = 154) or enrolled in a chemoradiation trial involving the EGFR-targeted antibody cetuximab (N = 39) were evaluated for EGFR gene amplification by FISH and EGFR protein by immunohistochemical staining. Fresh-frozen tumors (EDRN) were also evaluated for EGFR protein and site-specific phosphorylation at Y992 and Y1068 using reverse-phase protein array (n = 67). Tumor (n = 50) EGFR and EGFRvIII mRNA levels were quantified using real-time PCR.

Results: EGFR expression by immunohistochemistry (IHC) was significantly higher in the EDRN tumors with EGFR gene amplification (P < 0.001), and a similar trend was noted in the cetuximab-treated cohort. In the EDRN and cetuximab-treated cohorts elevated EGFR by IHC was associated with reduced survival (P = 0.019 and P = 0.06, respectively). Elevated expression of total EGFR and EGFR PY1068 were independently significantly associated with reduced progression-free survival in the EDRN cohort [HR = 2.75; 95% confidence interval (CI) = 1.26–6.00 and HR = 3.29; 95% CI = 1.34–8.14, respectively].

Conclusions: In two independent HNSCC cohorts treated with or without cetuximab, tumor EGFR levels were indicative of survival. Tumor EGFR PY1068 levels provided prognostic information independent of total EGFR. Clin Cancer Res; 18(8); 2278–89. ©2012 AACR.
Data from Robust Gene Expression Signature from Formalin-Fixed Paraffin-Embedded Samples Predicts Prognosis of Non–Small-Cell Lung Cancer Patients
Authors: Xie Yang , Xiao Guanghua , Coombes Kevin R. , Behrens Carmen , Solis Luisa M. , Raso Gabriela , Girard Luc , Erickson Heidi S. , Roth Jack , Heymach John V. , Moran Cesar , Danenberg Kathy , Minna John D. , Wistuba Ignacio I.
Published: April 2023

Abstract
Purpose: The requirement of frozen tissues for microarray experiments limits the clinical usage of genome-wide expression profiling by using microarray technology. The goal of this study is to test the feasibility of developing lung cancer prognosis gene signatures by using genome-wide expression profiling of formalin-fixed paraffin-embedded (FFPE) samples, which are widely available and provide a valuable rich source for studying the association of molecular changes in cancer and associated clinical outcomes.

Experimental Design: We randomly selected 100 Non–Small-Cell lung cancer (NSCLC) FFPE samples with annotated clinical information from the UT-Lung SPORE Tissue Bank. We microdissected tumor area from FFPE specimens and used Affymetrix U133 plus 2.0 arrays to attain gene expression data. After strict quality control and analysis procedures, a supervised principal component analysis was used to develop a robust prognosis signature for NSCLC. Three independent published microarray datasets were used to validate the prognosis model.

Results: This study showed that the robust gene signature derived from genome-wide expression profiling of FFPE samples is strongly associated with lung cancer clinical outcomes and can be used to refine the prognosis for stage I lung cancer patients, and the prognostic signature is independent of clinical variables. This signature was validated in several independent studies and was refined to a 59-gene lung cancer prognosis signature.

Conclusions: We conclude that genome-wide profiling of FFPE lung cancer samples can identify a set of genes whose expression level provides prognostic information across different platforms and studies, which will allow its application in clinical settings. Clin Cancer Res; 17(17); 5705–14. ©2011 AACR.
Data from Notch1 Expression, Which Is Related to p65 Status, Is an Independent Predictor of Prognosis in Colorectal Cancer
Authors: Chu Dake , Zhou Yi , Zhang Zixi , Li Yuming , Li Jipeng , Zheng Jianyong , Zhang Hongwei , Zhao Qingchuan , Wang Weizhong , Wang Rui'an , Ji Gang
Published: April 2023

Abstract
Purpose: Notch1 has been proven to be aberrantly expressed in colorectal cancer and related to tumor differentiation status. However, few previous studies concentrated on the predictive role of Notch1 expression on the overall survival of patients with colorectal cancer. This study explored expression of Notch1 and its relationship with p65 and prognosis in colorectal cancer.

Experimental Design: Two independent study cohorts were involved in the present study. Clinical specimens from 941 eligible patients were constructed into tissue microarrays. The expression of Notch1 and p65 protein was investigated by immunohistochemistry.

Results: Statistically significant positive correlations were found between protein expression of Notch1 and p65 in both retrospective and prospective study cohorts. Patients with higher Notch1 expression showed a trend of having shorter survival time, whereas patients with lower Notch1 expression had better survival in both study cohorts. In multivariate analysis, Notch1 expression was proven to be an independent predictor of prognosis. Moreover, the prognostic value of Notch1 might differ according to p65 status.

Conclusions: Notch1 is an independent predictor of prognosis for patients with colorectal cancer. In addition, the predictive role of Notch1 on clinical outcome might be modified by p65 status, suggesting that targeting Notch1 and nuclear factor κB (NF-κB) might be a promising strategy for colorectal cancer treatment. Clin Cancer Res; 17(17); 5686–94. ©2011 AACR.
Data from Targeting ALDHbright Human Carcinoma–Initiating Cells with ALDH1A1-Specific CD8+ T Cells
Authors: Visus Carmen , Wang Yangyang , Lozano-Leon Antonio , Ferris Robert L. , Silver Susan , Szczepanski Miroslaw J. , Brand Randall E. , Ferrone Cristina R. , Whiteside Theresa L. , Ferrone Soldano , DeLeo Albert B. , Wang Xinhui
Published: April 2023

Abstract
Purpose: Cancer-initiating cells (CIC) are considered to represent the subpopulation of tumor cells that is resistant to conventional cancer treatments, highly tumorigenic in immunodeficient mice, and responsible for tumor recurrence and metastasis. Based on an elevated aldehyde dehydrogenase (ALDH) activity attributable to ALDH1/3 isoforms, ALDHbright cells have been identified and isolated from tumors and shown to have characteristics of CIC. The ALDH1A1 isoform was previously identified as a tumor antigen recognized by CD8+ T cells. This study examines the ability of ALDH1A1-specific CD8+ T cells to eliminate ALDHbright cells and control tumor growth and metastases.

Experimental Design: ALDHbright cells were isolated by flow cytometry using ALDEFLUOR from HLA-A2+ human head and neck, breast, and pancreas carcinoma cell lines and tested for their tumorigenicity in immunodeficient mice. ALDH1A1-specific CD8+ T cells were generated in vitro and tested for their ability to eliminate CICs in vitro and in vivo by adoptive transfer to immunodeficient mice bearing human tumor xenografts.

Results: ALDHbright cells isolated by flow cytometry from HLA-A2+ breast, head and neck, and pancreas carcinoma cell lines at low numbers (500 cells) were tumorigenic in immunodeficient mice. ALDHbright cells present in these cell lines, xenografts, or surgically removed lesions were recognized by ALDH1A1-specific CD8+ T cells in vitro. Adoptive therapy with ALDH1A1-specific CD8+ T cells eliminated ALDHbright cells, inhibited tumor growth and metastases, or prolonged survival of xenograft-bearing immunodeficient mice.

Conclusions: The results of this translational study strongly support the potential of ALDH1A1-based immunotherapy to selectively target CICs in human cancer. Clin Cancer Res; 17(19); 6174–84. ©2011 AACR.
Data from Significant Biological Role of Sp1 Transactivation in Multiple Myeloma
Authors: Fulciniti Mariateresa , Amin Samir , Nanjappa Puru , Rodig Scott , Prabhala Rao , Li Cheng , Minvielle Stephane , Tai Yu-tzu , Tassone Pierfrancesco , Avet-Loiseau Herve , Hideshima Teru , Anderson Kenneth C. , Munshi Nikhil C.
Published: April 2023

Abstract
Purpose: The transcription factor specificity protein 1 (Sp1) controls number of cellular processes by regulating the expression of critical cell cycle, differentiation, and apoptosis-related genes containing proximal GC/GT-rich promoter elements. We here provide experimental and clinical evidence that Sp1 plays an important regulatory role in multiple myeloma (MM) cell growth and survival.

Experimental Design: We have investigated the functional Sp1 activity in MM cells using a plasmid with Firefly luciferase reporter gene driven by Sp1-responsive promoter. We have also used both siRNA- and short hairpin RNA–mediated Sp1 knockdown to investigate the growth and survival effects of Sp1 on MM cells and further investigated the anti-MM activity of terameprocol (TMP), a small molecule that specifically competes with Sp1-DNA binding in vitro and in vivo.

Results: We have confirmed high Sp1 activity in MM cells that is further induced by adhesion to bone marrow stromal cells (BMSC). Sp1 knockdown decreases MM cell proliferation and induces apoptosis. Sp1-DNA binding inhibition by TMP inhibits MM cell growth both in vitro and in vivo, inducing caspase-9–dependent apoptosis and overcoming the protective effects of BMSCs.

Conclusions: Our results show Sp1 as an important transcription factor in myeloma that can be therapeutically targeted for clinical application by TMP. Clin Cancer Res; 17(20); 6500–9. ©2011 AACR.
Data from Prognostic and Predictive Role of JWA and XRCC1 Expressions in Gastric Cancer
Authors: Wang Shouyu , Wu Xuming , Chen Yansu , Zhang Jianbing , Ding Jingjing , Zhou Yan , He Song , Tan Yongfei , Qiang Fulin , Bai Jin , Zeng Jinyan , Gong Zhenghua , Li Aiping , Li Gang , Røe Oluf Dimitri , Zhou Jianwei
Published: April 2023

Abstract
Purpose: To investigate the expression pattern and significance of DNA repair genes JWA and X-ray repair cross complement group 1 (XRCC1) in gastric cancer.

Experimental Design: Expressions of JWA and XRCC1 were assessed by immunohistochemistry in a training cohort and they went into a second testing cohort and finally to a validating cohort. Prognostic and predictive role of JWA and XRCC1 expression status in cases treated with surgery alone or combined with adjuvant chemotherapy was evaluated, respectively.

Results: JWA and XRCC1 protein levels were significantly downregulated in gastric cancer lesions compared with adjacent noncancerous tissues. Low tumoral JWA or XRCC1 expression significantly correlated with shorter overall survival (OS), as well as with clinicopathologic characteristics in patients without adjuvant treatment. Multivariate regression analysis showed that low JWA and XRCC1 expressions, separately and together, were independent negative markers of OS. Adjuvant fluorouracil-leucovorin-oxaliplatin (FLO) significantly improved OS compared with surgery alone (log-rank test, P = 0.01). However, this effect was evident only in the JWA or XRCC1 low expression group (HR = 0.44; 95% CI: 0.26–0.73; P = 0.002, and HR = 0.44, 95% CI: 0.26–0.75; P = 0.002, respectively); Adjuvant fluorouracil-leucovorin-platinol (FLP) did not improve OS, except in the patients with low JWA and XRCC1 expressions (P = 0.010 for JWA and 0.024 for XRCC1, respectively).

Conclusions: JWA and XRCC1 protein expressions in tumor are novel candidate prognostic markers and predictive factors for benefit from adjuvant platinum-based chemotherapy (FLO or FLP) in resectable human gastric carcinoma. Clin Cancer Res; 18(10); 2987–96. ©2012 AACR.