bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Pharmacokinetic Dose-Scheduling Study of Hedgehog Pathway Inhibitor Vismodegib (GDC-0449) in Patients with Locally Advanced or Metastatic Solid Tumors
Authors: LoRusso Patricia M. , Jimeno Antonio , Dy Grace , Adjei Alex , Berlin Jordan , Leichman Lawrence , Low Jennifer A. , Colburn Dawn , Chang Ilsung , Cheeti Sravanthi , Jin Jin Y. , Graham Richard A.
Published: April 2023

Abstract
Purpose: This study was designed to evaluate whether less frequent dosing [three times per week (TIW) or once weekly (QW)] of 150 mg vismodegib following a loading dose [150 mg once daily (QD) for 11 days] would result in similar safety, tolerability, and steady-state levels of total and unbound vismodegib as continuous QD dosing.

Experimental Design: Sixty-seven patients with advanced solid tumors were stratified by baseline plasma alpha 1-acid glycoprotein (AAG) levels and randomized to one of three vismodegib 150 mg regimens: QD (n = 23), TIW (n = 22), or QW (n = 22) for up to 42 days after an 11-day loading phase (150 mg QD). Total and unbound (dialyzed) plasma vismodegib concentrations were determined by LC-MS/MS.

Results: The most frequently reported adverse events were consistent with those in prior monotherapy trials, with similar incidence and severity regardless of dosing schedule. After the 150 mg QD loading phase, a concentration-dependent change in protein binding (3-fold increase in vismodegib fraction unbound) was observed at steady state compared with single dose. Mean total and unbound vismodegib steady-state concentrations were lower after TIW and QW than QD dosing, with an average intrasubject decrease of 50% and 80%, respectively, for unbound drug. Mechanism-based PK model simulations accurately and prospectively predicted the PK results.

Conclusions: Vismodegib 150 mg TIW or QW failed to achieve unbound plasma concentrations previously associated with efficacy in patients with advanced basal cell carcinoma and medulloblastoma, even after a QD loading dose period. The 150 mg QD regimen is appropriate for vismodegib based on its clinical activity, tolerability, and favorable unbound concentrations. Clin Cancer Res; 17(17); 5774–82. ©2011 AACR.
Data from Selective Tumor Hypoxia Targeting by Hypoxia-Activated Prodrug TH-302 Inhibits Tumor Growth in Preclinical Models of Cancer
Authors: Sun Jessica D. , Liu Qian , Wang Jingli , Ahluwalia Dharmendra , Ferraro Damien , Wang Yan , Duan Jian-Xin , Ammons W. Steve , Curd John G. , Matteucci Mark D. , Hart Charles P.
Published: April 2023

Abstract
Purpose: Tumor hypoxia underlies treatment failure and yields a more aggressive, invasive, and metastatic cancer phenotype. TH-302 is a 2-nitroimidazole triggered hypoxia-activated prodrug of the cytotoxin bromo-isophosphoramide mustard (Br-IPM). The purpose of this study is to characterize the antitumor activity of TH-302 and investigate its selective targeting of the hypoxic cells in human tumor xenograft models.

Experimental Design: Antitumor efficacy was assessed by tumor growth kinetics or by clonogenic survival of isolated cells after tumor excision. Hypoxic fractions (HF) were determined by immunohistochemistry and morphometrics of pimonidazole staining. Tumor hypoxia levels were manipulated by exposing animals to different oxygen concentration breathing conditions. The localization and kinetics of TH-302 induced DNA damage was determined by γH2AX immunohistochemistry.

Results: TH-302 antitumor activity was dose-dependent and correlated with total drug exposure. Correlation was found between antitumor activity and tumor HF across 11 xenograft models. Tumor-bearing animals breathing 95% O2 exhibited attenuated TH-302 efficacy, with whereas those breathing 10% O2 exhibited enhanced TH-302 efficacy, both compared with air (21% O2) breathing. TH-302 treatment resulted in a reduction in the volume of the HF 48 hours after dosing and a corresponding increase in the necrotic fraction. TH-302 induced DNA damage as measured by γH2AX was initially only present in the hypoxic regions and then radiated to the entire tumor in a time-dependent manner, consistent with TH-302 having a “bystander effect.”

Conclusions: The results show that TH-302 has broad antitumor activity and selectively targets hypoxic tumor tissues. Clin Cancer Res; 18(3); 758–70. ©2011 AACR.
Data from Prognostic Immune Markers in Non–Small Cell Lung Cancer
Authors: Suzuki Kei , Kachala Stefan S. , Kadota Kyuichi , Shen Ronglai , Mo Qianxing , Beer David G. , Rusch Valerie W. , Travis William D. , Adusumilli Prasad S.
Published: April 2023

Abstract
Tumor-associated immune responses have polarized effects in regulating tumor growth. Although a clear association has been shown between the tumor immune response and clinical outcome in colorectal and ovarian cancers, the role of immune markers for stratifying prognosis in non–small cell lung cancer (NSCLC) is less defined. Herein, we review the prognostic significance of published immune markers in the tumor microenvironment and peripheral blood of NSCLC patients. To identify prognostic immune genes, we reviewed all published gene-profiling studies in NSCLC and delineated the significance of immune genes by doing subanalysis on the microarray database of the NIH Director's Challenge study. This first comprehensive review of prognostic immune markers provides a foundation for further investigating immune responses in NSCLC. Clin Cancer Res; 17(16); 5247–56. ©2011 AACR.
Data from Modeling a Lethal Prostate Cancer Variant with Small-Cell Carcinoma Features
Authors: Tzelepi Vassiliki , Zhang Jiexin , Lu Jing-Fang , Kleb Brittany , Wu Guanglin , Wan Xinhai , Hoang Anh , Efstathiou Eleni , Sircar Kanishka , Navone Nora M. , Troncoso Patricia , Liang Shoudan , Logothetis Christopher J. , Maity Sankar N. , Aparicio Ana M.
Published: April 2023

Abstract
Purpose: Small-cell prostate carcinoma (SCPC) morphology predicts for a distinct clinical behavior, resistance to androgen ablation, and frequent but short responses to chemotherapy. We sought to develop model systems that reflect human SCPC and can improve our understanding of its biology.

Experimental Design: We developed a set of castration-resistant prostate carcinomas xenografts and examined their fidelity to their human tumors of origin. We compared the expression and genomic profiles of SCPC and large-cell neuroendocrine carcinoma (LCNEC) xenografts to those of typical prostate adenocarcinoma xenografts. Results were validated immunohistochemically in a panel of 60 human tumors.

Results: The reported SCPC and LCNEC xenografts retain high fidelity to their human tumors of origin and are characterized by a marked upregulation of UBE2C and other mitotic genes in the absence of androgen receptor (AR), retinoblastoma (RB1), and cyclin D1 (CCND1) expression. We confirmed these findings in a panel of samples of CRPC patients. In addition, array comparative genomic hybridization of the xenografts showed that the SCPC/LCNEC tumors display more copy number variations than the adenocarcinoma counterparts. Amplification of the UBE2C locus and microdeletions of RB1 were present in a subset, but none displayed AR nor CCND1 deletions. The AR, RB1, and CCND1 promoters showed no CpG methylation in the SCPC xenografts.

Conclusion: Modeling human prostate carcinoma with xenografts allows in-depth and detailed studies of its underlying biology. The detailed clinical annotation of the donor tumors enables associations of anticipated relevance to be made. Future studies in the xenografts will address the functional significance of the findings. Clin Cancer Res; 18(3); 666–77. ©2011 AACR.
Data from Metformin Use Is Associated with Better Survival of Diabetic Patients with Pancreatic Cancer
Authors: Sadeghi Navid , Abbruzzese James L. , Yeung Sai-Ching J. , Hassan Manal , Li Donghui
Published: April 2023

Abstract
Purpose: Accumulating evidence suggests that metformin has antitumor activity. The aim of this study was to determine whether metformin use has a survival benefit in patients with pancreatic cancer.

Experimental Design: We conducted a retrospective study of patients with diabetes and pancreatic cancer treated at The University of Texas MD Anderson Cancer Center (Houston, TX). Information on diabetes history, including treatment modalities and clinical outcome of pancreatic cancer, was collected using personal interviews and medical record review. Survival analysis was carried out using a Kaplan–Meier plot, log-rank test, and Cox proportional hazards regression models.

Results: Among the 302 patients identified, there were no significant differences in demographic or major clinical characteristics between the patients who had received metformin (n = 117) and those who had not (n = 185). The 2-year survival rate was 30.1% for the metformin group and 15.4% for the non-metformin group (P = 0.004; χ2 test). The median overall survival time was 15.2 months for the metformin group, and 11.1 months for the non-metformin group (P = 0.004, log-rank test). Metformin users had a 32% lower risk of death; the HR (95% confidence interval) was 0.68 (0.52–0.89) in a univariate model (P = 0.004), 0.64 (0.48–0.86) after adjusting for other clinical predictors (P = 0.003), and 0.62 (0.44–0.87) after excluding insulin users (P = 0.006). Metformin use was significantly associated with longer survival in patients with nonmetastatic disease only.

Conclusions: Our finding that metformin use was associated with improved outcome of patients with diabetes and pancreatic cancer should be confirmed in independent studies. Future research should prospectively evaluate metformin as a supplemental therapy in this population. Clin Cancer Res; 18(10); 2905–12. ©2012 AACR.
Data from A Hypermethylated Phenotype Is a Better Predictor of Survival than MGMT Methylation in Anaplastic Oligodendroglial Brain Tumors: A Report from EORTC Study 26951
Authors: van den Bent Martin J. , Gravendeel Lonneke A. , Gorlia Thierry , Kros Johan M. , Lapre Lariesa , Wesseling Pieter , Teepen Johannes L. , Idbaih Ahmed , Sanson Marc , Smitt Peter A.E. Sillevis , French Pim J.
Published: April 2023

Abstract
Purpose: The MGMT promoter methylation status has been suggested to be predictive for outcome to temozolomide chemotherapy in patients with glioblastoma (GBM). Subsequent studies indicated that MGMT promoter methylation is a prognostic marker even in patients treated with radiotherapy alone, both in GBMs and in grade III gliomas.

Experimental Design: To help determine the molecular mechanism behind this prognostic effect, we have conducted genome-wide methylation profiling and determined the MGMT promoter methylation status, 1p19q LOH, IDH1 mutation status, and expression profile on a series of oligodendroglial tumors [anaplastic oligodendrogliomas (AOD) and anaplastic oligoastrocytomas (AOA)] within EORTC study 26951. The series was expanded with tumors of the same histology and treatment from our own archive.

Results: Methylation profiling identified two main subgroups of oligodendroglial brain tumors of which survival in the CpG island hypermethylation phenotype (CIMP+) subgroup was markedly better than the survival of the unmethylated (CIMP−) subgroup (5.62 vs. 1.24 years; P < 0.0001). CIMP status correlated with survival, MGMT promoter methylation, 1p19q LOH, and IDH1 mutation status. CIMP status strongly increases the predictive accuracy of survival in a model including known clinical prognostic factors such as age and performance score. We validated our results on an independent data set from the Cancer Genome Atlas (TCGA).

Conclusion: The strong association between CIMP status and MGMT promoter methylation suggests that the MGMT promoter methylation status is part of a more general, prognostically favorable genome-wide methylation profile. Methylation profiling therefore may help identify AODs and AOAs with improved prognosis. Clin Cancer Res; 17(22); 7148–55. ©2011 AACR.
Data from Circulating Cell-Free DNA in Plasma of Never Smokers with Advanced Lung Adenocarcinoma Receiving Gefitinib or Standard Chemotherapy as First-Line Therapy
Authors: Lee Young Joo , Yoon Kyong-Ah , Han Ji-Youn , Kim Heung Tae , Yun Tak , Lee Geon Kook , Kim Hyae Young , Lee Jin Soo
Published: April 2023

Abstract
Purpose: Circulating cell-free DNA (CFDNA) was investigated as potential screening or prognostic markers in a variety of cancers. This study investigated its clinical significance in a homogeneous group of lung cancer patients.

Experimental Design: We analyzed the blood samples of 134 never smokers with advanced lung adenocarcinoma, who were enrolled in a prospective randomized phase III study (First-SIGNAL) comparing gefitinib with gemcitabine plus cisplatin (GP) as first-line therapy. The amount of plasma CFDNA was measured by real-time quantitative PCR targeting the human ACTB genomic sequence. The patients were divided into three groups according to the tertiles of baseline plasma CFDNA.

Results: Baseline plasma CFDNA did not correlate with primary tumor size (P = 0.961), whereas the number of metastatic sites correlated significantly with baseline plasma CFDNA (P = 0.015). In the GP arm, the low-CFDNA group showed a lower response rate than the middle- or high-CFDNA group (26.1%, 57.9%, and 60.9%, respectively; P = 0.035). However, in the gefitinib arm, there was no difference in response rate between the three CFDNA groups (57.1%, 47.4%, and 51.9%; respectively; P = 0.825). The high tertile CFDNA group showed a significantly shorter survival than the low tertile CFDNA group (median overall survival, 16.0 vs. 28.6 months, respectively; P = 0.030). The risk of death increased with increased baseline plasma CFDNA (HR = 1.23, 95% CI, 1.01–1.50; P = 0.045).

Conclusion: High plasma CFDNA is associated with aggressive tumor behavior and poor survival outcomes in these patients. Clin Cancer Res; 17(15); 5179–87. ©2011 AACR.
Data from Phase I Study of Rigosertib, an Inhibitor of the Phosphatidylinositol 3-Kinase and Polo-like Kinase 1 Pathways, Combined with Gemcitabine in Patients with Solid Tumors and Pancreatic Cancer
Authors: Ma Wen Wee , Messersmith Wells A. , Dy Grace K. , Weekes Colin D. , Whitworth Amy , Ren Chen , Maniar Manoj , Wilhelm Francois , Eckhardt S. Gail , Adjei Alex A. , Jimeno Antonio
Published: April 2023

Abstract
Purpose: Rigosertib, a dual non-ATP inhibitor of polo-like kinase 1 (Plk1) and phosphoinositide 3-kinase pathways (PI3K), and gemcitabine have synergistic antitumor activity when combined in preclinical studies. This phase I study aimed to determine the recommended phase II dose (RPTD) of the combination of rigosertib and gemcitabine in patients with cancer.

Experimental Design: Patients with solid tumors who failed standard therapy or were candidates for gemcitabine-based therapy were eligible. Gemcitabine was administered on days 1, 8, and 15 on a 28-day cycle and rigosertib on days 1, 4, 8, 11, 15, and 18. Pharmacokinetic studies were conducted during an expansion cohort of patients with advanced pancreatic ductal adenocarcinoma (PDA).

Results: Forty patients were treated, 19 in the dose-escalation phase and 21 in the expansion cohort. Dose levels evaluated were (gemcitabine/rigosertib mg/m2): 750/600 (n = 4), 750/1,200 (n = 3), 1,000/600 (n = 3), 1,000/1,200 (n = 3), and 1,000/1,800 (n = 6 + 21). One dose-limiting toxicity (death) occurred at the highest dose level (1,000/1,800) tested. Non–dose-limiting ≥grade II/III toxicities included neutropenia, lymphopenia, thrombocytopenia, fatigue, and nausea. Grade III/IV neutropenia, thrombocytopenia, and fatigue were seen in two, one, and two patients in the expansion cohort. Partial responses were observed in PDA, thymic cancer, and Hodgkin lymphoma, including gemcitabine-pretreated PDA. The pharmacokinetic profile of rigosertib was not affected by gemcitabine.

Conclusion: The RPTD established in this study is rigosertib 1,800 mg/m2 and gemcitabine 1,000 mg/m2. This regimen is well tolerated with a toxicity profile of the combination similar to the profile of gemcitabine alone. Antitumor efficacy was observed in patients who previously progressed on gemcitabine-based therapy. Clin Cancer Res; 18(7); 2048–55. ©2012 AACR.
Data from Tumor Engraftment in Nude Mice and Enrichment in Stroma- Related Gene Pathways Predict Poor Survival and Resistance to Gemcitabine in Patients with Pancreatic Cancer
Authors: Garrido-Laguna Ignacio , Uson Maria , Rajeshkumar N.V. , Tan Aik Choon , de Oliveira Elizabeth , Karikari Collins , Villaroel Maria C. , Salomon Ana , Taylor Gretchen , Sharma Rajni , Hruban Ralph H. , Maitra Anirban , Laheru Daniel , Rubio-Viqueira Belén , Jimeno Antonio , Hidalgo Manuel
Published: April 2023

Abstract
Purpose: The goal of this study was to evaluate prospectively the engraftment rate, factors influencing engraftment, and predictability of clinical outcome of low-passage xenografts from patients with resectable pancreatic ductal adenocarcinoma (PDA) and to establish a bank of PDA xenografts.

Experimental Design: Patients with resectable PDA scheduled for resection at the Johns Hopkins Hospital were eligible. Representative pieces of tumor were implanted in nude mice. The status of the SMAD4 gene and content of tumor-generating cells were determined by immunohistochemistry. Gene expression was carried out by using a U133 Plus 2.0 array. Patients were followed for progression and survival.

Results: A total of 94 patients with PDA were resected, 69 tumors implanted in nude mice, and 42 (61%) engrafted. Engrafted carcinomas were more often SMAD4 mutant, and had a metastatic gene expression signature and worse prognosis. Tumors from patients resistant to gemcitabine were enriched in stroma-related gene pathways. Tumors sensitive to gemcitabine were enriched in cell cycle and pyrimidine gene pathways. The time to progression for patients who received treatment with gemcitabine for metastatic disease (n = 7) was double in patients with xenografts sensitive to gemcitabine.

Conclusion: A successful xenograft was generated in 61% of patients attempted, generating a pool of 42 PDA xenografts with significant biological information and annotated clinical data. Patients with PDA and SMAD4 inactivation have a better engraftment rate. Engraftment is a poor prognosis factor, and engrafted tumors have a metastatic gene expression signature. Tumors from gemcitabine-resistant patients were enriched in stromal pathways. Clin Cancer Res; 17(17); 5793–800. ©2011 AACR.
Data from Vandetanib Improves Anti-Tumor Effects of L19mTNFα in Xenograft Models of Esophageal Cancer
Authors: Crescenzi Marika , Persano Luca , Esposito Giovanni , Zulato Elisabetta , Borsi Laura , Balza Enrica , Ruol Alberto , Ancona Ermanno , Indraccolo Stefano , Amadori Alberto
Published: April 2023

Abstract
Purpose: Targeting the tumor vasculature by vascular disrupting agents (VDAs) has shown therapeutic activity in mouse models. In most cases, however, VDA efficacy is substantially compromised by the inability of these drugs to completely kill tumor cells located at the periphery of the tumor mass. In this study, we investigated anti-tumor effects of L19mTNFα, a fusion protein composed of L19 (scFv), specific for the angiogenesis-associated ED-B containing fibronectin isoform, and murine TNFα, in xenograft models of esophageal cancer.

Experimental design: We evaluated ED-B expression in esophageal cancer samples. Subsequently, we generated subcutaneous xenografts from primary tumors, treated them with the L19mTNFα scFv, and determined effects on tumor vasculature, viability and proliferation, and VEGF expression and infiltration by hematopoietic cells. To overcome tumor resistance, L19mTNFα scFv was combined with vandetanib, a tyrosine kinase inhibitor of VEGF receptor, epidermal growth factor receptor, and RET signaling.

Results: ED-B was broadly expressed by esophageal cancer cell lines, as well as xenografts and primary surgical samples of esophageal cancer. Administration of L19mTNFα acutely damaged tumor vasculature and increased necrosis, indicating a VDA-like activity of this immunoconjugate. This event was followed, however, by rapid tumor growth recovery associated with increased expression of VEGF and recruitment of CD11b+Gr1+ myeloid cells into tumors. Combination of L19mTNFα with vandetanib severely impaired vascular functions in tumors, leading to a reduction of cell proliferation and increased necrosis, without apparent signs of toxicity.

Conclusion: These findings indicate that a combination of vascular damaging agents with anti-angiogenic drugs could represent a promising therapeutic strategy for esophageal cancer. Clin Cancer Res; 17(3); 447–58. ©2010 AACR.
Data from CDKN2A/B Alterations Impair Prognosis in Adult BCR-ABL1–Positive Acute Lymphoblastic Leukemia Patients
Authors: Iacobucci Ilaria , Ferrari Anna , Lonetti Annalisa , Papayannidis Cristina , Paoloni Francesca , Trino Stefania , Storlazzi Clelia Tiziana , Ottaviani Emanuela , Cattina Federica , Impera Luciana , Abbenante Maria Chiara , Vignetti Marco , Vitale Antonella , Potenza Leonardo , Paolini Stefania , Soverini Simona , Pane Fabrizio , Luppi Mario , Foà Robin , Baccarani Michele , Martinelli Giovanni
Published: April 2023

Abstract
Purpose: The 9p21 locus, encoding three important tumor suppressors (p16/CDKN2A, p14/ARF, and p15/CDKN2B), is a major target of inactivation in the pathogenesis of many human tumors.

Patients and Methods: To explore, at high resolution, the frequency and size of alterations affecting this locus in adult BCR-ABL1–positive acute lymphoblastic leukemia (ALL) and to investigate their prognostic value, 112 patients (101 de novo and 11 relapsed cases) were analyzed by genome-wide single-nucleotide polymorphism arrays and gene candidate deep exon sequencing. Paired diagnosis–relapse samples were further available and analyzed for 19 (19%) cases.

Results:CDKN2A/ARF and CDKN2B genomic alterations were identified in 29% and 25% of newly diagnosed patients, respectively. Deletions were monoallelic in 72% of cases, and in 43% of them, the minimal overlapping region of the lost area spanned only the CDKN2A/B gene locus. An analysis conducted at relapse showed an increase in the detection rate of CDKN2A/ARF loss (47%) compared with the time of diagnosis (P = 0.06). Point mutations within the 9p21 locus were found at very low levels, with only a nonsynonymous substitution in the exon 2 of CDKN2A. Of note, deletions of CDKN2A/B were significantly associated with poor outcomes in terms of overall survival (P = 0.0206), disease free-survival (P = 0.0010), and cumulative incidence of relapse (P = 0.0014).

Conclusions: Inactivation of the 9p21 locus by genomic deletion is a frequent event in BCR-ABL1–positive ALL. Deletions are frequently acquired during leukemia progression and are a poor prognostic marker of long-term outcomes. Clin Cancer Res; 17(23); 7413–23. ©2011 AACR.
Data from Differential Gene Expression Profile Associated to Apoptosis Induced by Dexamethasone in CLL Cells According to IGHV/ZAP-70 Status
Authors: Baptista Maria Joao , Muntañola Ana , Calpe Eva , Abrisqueta Pau , Salamero Olga , Fernández Eva , Codony Carles , Giné Eva , Kalko Susana G. , Crespo Marta , Bosch Francesc
Published: April 2023

Abstract
Purpose: Glucocorticoids are part of the therapeutic armamentarium of chronic lymphocytic leukemia (CLL) where it has been suggested that cells with unmutated IGHV genes exhibit higher sensitivity. The mechanisms by which glucorticoids are active in CLL are not well elucidated. We aimed to ascertain the activity of dexamethasone in CLL cells according to prognosis and to identify the molecular mechanisms that are influencing the response to this drug.

Experimental Design: Sensitivity to dexamethasone was analyzed ex vivo in 50 CLL and compared according to IGHV mutational status and/or ZAP-70 expression. The response was further compared by gene expression profiling (GEP) of selected cases. Expression of genes of interest was validated by quantitative reverse transcriptase PCR.

Results: Response to dexamethasone was higher in cases with unmutated IGHV/high ZAP-70 expression, and the levels of induction of the pro-apoptotic Bim protein correlated with the degree of cell death. GEP analysis showed few genes differentially expressed after dexamethasone treatment between mutated and unmutated cases. However, functional annotation analysis showed that unmutated cases had significant enrichment in terms related to apoptosis. Specific analysis of genes of interest conducted in a large series disclosed that in unmutated IGHV cells, FKBP5 expression was higher at baseline and after dexamethasone exposure and that GILZ was more induced by dexamethasone treatment in these cases.

Conclusions: Unmutated IGHV/high ZAP-70 CLL cells exhibit better response to dexamethasone treatment, which is accompanied by a differential expression of genes involved in the glucocorticoid receptor pathway and by an increased induction of genes related to apoptosis. Clin Cancer Res; 18(21); 5924–33. ©2012 AACR.
Data from Immunochemotherapy with Intensive Consolidation for Primary CNS Lymphoma: A Pilot Study and Prognostic Assessment by Diffusion-Weighted MRI
Authors: Wieduwilt Matthew J. , Valles Francisco , Issa Samar , Behler Caroline M. , Hwang James , McDermott Michael , Treseler Patrick , O'Brien Joan , Shuman Marc A. , Cha Soonmee , Damon Lloyd E. , Rubenstein James L.
Published: April 2023

Abstract
Purpose: We evaluated a novel therapy for primary central nervous system lymphoma (PCNSL) with induction immunochemotherapy with high-dose methotrexate, temozolomide, and rituximab (MT-R) followed by intensive consolidation with infusional etoposide and high-dose cytarabine (EA). In addition, we evaluated the prognostic value of the minimum apparent diffusion coefficient (ADCmin) derived from diffusion-weighted MRI (DW-MRI) in patients treated with this regimen.

Experimental Design: Thirty-one patients (median age, 61 years; median Karnofsky performance score, 60) received induction with methotrexate every 14 days for 8 planned cycles. Rituximab was administered the first 6 cycles and temozolomide administered on odd-numbered cycles. Patients with responsive or stable central nervous system (CNS) disease received EA consolidation. Pretreatment DW-MRI was used to calculate the ADCmin of contrast-enhancing lesions.

Results: The complete response rate for MT-R induction was 52%. At a median follow-up of 79 months, the 2-year progression-free and overall survival were 45% and 58%, respectively. For patients receiving EA consolidation, the 2-year progression-free and overall survival were 78% and 93%, respectively. EA consolidation was also effective in an additional 3 patients who presented with synchronous CNS and systemic lymphoma. Tumor ADCmin less than 384 × 10–6 mm2/s was significantly associated with shorter progression-free and overall survival.

Conclusions: MT-R induction was effective and well tolerated. MT-R followed by EA consolidation yielded progression-free and overall survival outcomes comparable to regimens with chemotherapy followed by whole-brain radiotherapy consolidation but without evidence of neurotoxicity. Tumor ADCmin derived from DW-MRI provided better prognostic information for PCNSL patients treated with the MTR-EA regimen than established clinical risk scores. Clin Cancer Res; 18(4); 1146–55. ©2012 AACR.
Data from The HDAC Inhibitor LBH589 Enhances the Antimyeloma Effects of the IGF-1RTK Inhibitor Picropodophyllin
Authors: Lemaire Miguel , Fristedt Charlotte , Agarwal Prasoon , Menu Eline , Van Valckenborgh Els , De Bruyne Elke , Österborg Anders , Atadja Peter , Larsson Olle , Axelson Magnus , Van Camp Ben , Jernberg-Wiklund Helena , Vanderkerken Karin
Published: April 2023

Abstract
Purpose: We have previously shown the use of the insulin-like growth factor type 1 receptor tyrosine kinase (IGF-1RTK) inhibitor picropodophyllin (PPP) as an attractive strategy to combat multiple myeloma (MM) in vitro and in vivo. After a combinatorial drug screening, the histone deacetylase inhibitor LBH589 was shown to act in synergy with PPP reducing survival of MM cells. In this study, we tried to elucidate the molecular mechanisms underlying this combinatorial effect.

Experimental Design: The in vitro anti-MM effects of PPP and LBH589 alone and in combination were evaluated by studying apoptosis, cell cycle distribution, and downstream transcriptome using both human MM cell lines and cells from the murine 5T3MM model. In vivo the effect on survival of 5T33MM-inoculated mice was evaluated.

Results: In the human MM cell line RPMI8226, treatment with PPP and LBH589 in combination resulted in a five-fold increase of apoptosis, and an additive effect on the cleavage of the active forms of caspase-8 was observed as compared with the single drug treatments. Cell cycle analysis revealed an accumulation of cells in the G2–M phase and subsequent downregulation of cell cycle regulating proteins. These data were also confirmed in the 5T33MM cells in vitro. Also, the transcriptome was analyzed by Affymetrix arrays showing gene expression alterations mainly in categories of genes regulating apoptosis and cell adhesion. Combined treatment in vivo resulted in a significantly prolonged survival of 5T33MM-inoculated mice.

Conclusions: The results indicate an improved MM treatment opportunity in using a combination of PPP and LBH589. Clin Cancer Res; 18(8); 2230–9. ©2012 AACR.
Data from Engrailed-2 (EN2): A Tumor Specific Urinary Biomarker for the Early Diagnosis of Prostate Cancer
Authors: Morgan Richard , Boxall Angela , Bhatt Aagna , Bailey Michael , Hindley Richard , Langley Stephen , Whitaker Hayley C. , Neal David E. , Ismail Mohammed , Whitaker Hamish , Annels Nicola , Michael Agnieszka , Pandha Hardev
Published: April 2023

Abstract
Purpose: Prostate cancer (PC) is the second most common cause of cancer related death in men. A number of key limitations with prostate specific antigen (PSA), currently the standard detection test, has justified evaluation of new biomarkers. We have assessed the diagnostic potential of Engrailed-2 (EN2) protein, a homeodomain-containing transcription factor expressed in PC cell lines and secreted into the urine by PC in men.

Experimental Design: EN2 expression in PC cell lines and prostate cancer tissue was determined by semi-quantative RT-PCR and immunohistochemistry. First pass urine [without prior digital rectal examination (DRE)] was collected from men presenting with urinary symptoms (referred to exclude/confirm the presence of prostate cancer) and from controls. EN2 protein was measured by ELISA in urine from men with PC (n = 82) and controls (n = 102).

Results: EN2 was expressed and secreted by PC cell lines and PC tissue but not by normal prostate tissue or stroma. The presence of EN2 in urine was highly predictive of PC, with a sensitivity of 66% and a specificity of 88.2%, without requirement for DRE. There was no correlation with PSA levels. These results were confirmed independently by a second academic center.

Conclusions: Urinary EN2 is a highly specific and sensitive candidate biomarker of prostate cancer. A larger multicenter study to further evaluate the diagnostic potential of EN2 is justified. Clin Cancer Res; 17(5); 1090–8. ©2011 AACR.
Data from High ALK Receptor Tyrosine Kinase Expression Supersedes ALK Mutation as a Determining Factor of an Unfavorable Phenotype in Primary Neuroblastoma
Authors: Schulte Johannes H. , Bachmann Hagen S. , Brockmeyer Bent , DePreter Katleen , Oberthür André , Ackermann Sandra , Kahlert Yvonne , Pajtler Kristian , Theissen Jessica , Westermann Frank , Vandesompele Jo , Speleman Frank , Berthold Frank , Eggert Angelika , Brors Benedikt , Hero Barbara , Schramm Alexander , Fischer Matthias
Published: April 2023

Abstract
Purpose: Genomic alterations of the anaplastic lymphoma kinase (ALK) gene have been postulated to contribute to neuroblastoma pathogenesis. This study aimed to determine the interrelation of ALK mutations, ALK expression levels, and clinical phenotype in primary neuroblastoma.

Experimental Design: The genomic ALK status and global gene expression patterns were examined in 263 primary neuroblastomas. Allele-specific ALK expression was determined by cDNA cloning and sequencing. Associations of genomic ALK alterations and ALK expression levels with clinical phenotypes and transcriptomic profiles were compared.

Results: Nonsynonymous point mutations of ALK were detected in 21 of 263 neuroblastomas (8%). Tumors with ALK mutations exhibited about 2-fold elevated median ALK mRNA levels in comparison with tumors with wild-type (WT) ALK. Unexpectedly, the WT allele was preferentially expressed in 12 of 21 mutated tumors. Whereas survival of patients with ALK mutated tumors was significantly worse as compared with the entire cohort of WT ALK patients, it was similarly poor in patients with WT ALK tumors in which ALK expression was as high as in ALK mutated neuroblastomas. Global gene expression patterns of tumors with ALK mutations or with high-level WT ALK expression were highly similar, and suggested that ALK may be involved in cellular proliferation in primary neuroblastoma.

Conclusions: Primary neuroblastomas with mutated ALK exhibit high ALK expression levels and strongly resemble neuroblastomas with elevated WT ALK expression levels in both their clinical and molecular phenotypes. These data suggest that high levels of mutated and WT ALK mediate similar molecular functions that may contribute to a malignant phenotype in primary neuroblastoma. Clin Cancer Res; 17(15); 5082–92. ©2011 AACR.
Data from Copy Number Losses Define Subgroups of Dedifferentiated Liposarcoma with Poor Prognosis and Genomic Instability
Authors: Crago Aimee M. , Socci Nicholas D. , DeCarolis Penelope , O'Connor Rachael , Taylor Barry S. , Qin Li-Xuan , Antonescu Cristina R. , Singer Samuel
Published: April 2023

Abstract
Purpose: Molecular events underlying progression of well-differentiated liposarcoma (WDLS) to dedifferentiated liposarcoma (DDLS) are poorly defined. This study sought to identify copy number alterations (CNA) associated with dedifferentiation of WDLS, with DDLS morphology, and with patient outcomes.

Experimental Design: Fifty-five WDLS and 52 DDLS were analyzed using Agilent 244K comparative genomic hybridization and Affymetrix U133A expression arrays. CNAs were identified by RAE analysis. Thirty-nine of the DDLS specimens were categorized morphologically by a single pathologist.

Results: Nine regions of CNA were identified as recurrent in DDLS but not WDLS; 79% of DDLS had at least one of these CNAs. Loss of the chromosome segment 11q23–24, the most common event, was observed only in DDLS that morphologically resembled the genomically complex sarcomas, undifferentiated pleomorphic sarcoma and myxofibrosarcoma. 11q23–24 loss was itself associated with increased genomic complexity in DDLS. Loss of 19q13, but not 11q23–24, was associated with poor prognosis. Median disease-specific survival was shorter for patients with19q13 loss (27 months) than for patients with diploid 19q13 (>90 months; P < 0.0025), and 19q13 loss was associated with local recurrence (HR, 2.86; P = 0.013). Common copy number losses were associated with transcriptional downregulation of potential tumor suppressors and adipogenesis-related genes (e.g., EI24 and CEBPA).

Conclusions: Dedifferentiation of WDLS is associated with recurrent CNAs in 79% of tumors. In DDLS, loss of 11q23–24 is associated with genomic complexity and distinct morphology whereas loss of 19q13 predicts poor prognosis. CNAs in liposarcoma improve risk stratification for patients and will help identify potential tumor suppressors driving liposarcoma progression. Clin Cancer Res; 18(5); 1334–40. ©2012 AACR.
Data from PRAME-Induced Inhibition of Retinoic Acid Receptor Signaling-Mediated Differentiation—A Possible Target for ATRA Response in AML without t(15;17)
Authors: Bullinger Lars , Schlenk Richard F. , Götz Marlies , Botzenhardt Ursula , Hofmann Susanne , Russ Annika C. , Babiak Anna , Zhang Lu , Schneider Vanessa , Döhner Konstanze , Schmitt Michael , Döhner Hartmut , Greiner Jochen
Published: April 2023

Abstract
Purpose: In acute myeloid leukemia (AML) without retinoic acid receptor (RAR) rearrangement, the effect of all-trans-retinoic acid (ATRA) is still poorly understood despite an association of NPM1 mutation and ATRA response. Recently, preferentially expressed antigen in melanoma (PRAME) has been shown to be a dominant repressor of RAR signaling.

Experimental Design: Thus, we further investigated ATRA response mechanisms, especially the impact of PRAME expression on ATRA responsiveness. We profiled gene expression in diagnostic samples derived from our AML HD98B trial, in which ATRA was administered in addition to intensive chemotherapy.

Results: Our data revealed a PRAME expression-associated gene pattern to be significantly enriched for genes involved in the retinoic acid metabolic process. In leukemia cell line models, we could show that retinoic acid-regulated cell proliferation and differentiation are impacted by PRAME expression. In patients with primary AML, repressor activity of high-PRAME levels might be overcome by the addition of ATRA as indicated by better outcome in 2 independent studies (P = 0.029).

Conclusions: PRAME seems to impair differentiation and to increase proliferation likely via blocking RAR signaling, which might be reversed by ATRA. PRAME therefore represents a promising target for both ATRA treatment and possibly future immunotherapeutic approaches in AML. Clin Cancer Res; 19(9); 2562–71. ©2013 AACR.
Data from Clinical Outcomes in Non–Small Cell Lung Cancers Harboring Different Exon 19 Deletions in EGFR
Authors: Chung Kuei-Pin , Wu Shang-Gin , Wu Jenn-Yu , Yang James Chih-Hsin , Yu Chong-Jen , Wei Pin-Fei , Shih Jin-Yuan , Yang Pan-Chyr
Published: April 2023

Abstract
Purpose: Several deletions in exon 19 of epidermal growth factor receptor (EGFR) gene have been reported in non–small cell lung cancer (NSCLC). It is unknown if deletions occurring at different amino acid positions or of different sizes are associated with different clinical outcome to EGFR tyrosine kinase inhibitors (TKI).

Experimental Design: This study enrolled NSCLC patients with deletions in EGFR exon 19. Patients who had received EGFR TKIs for advanced NSCLC were further evaluated for response rate (RR), progression-free survival (PFS), and overall survival (OS).

Results: In 308 patients with deletions in EGFR exon 19, 298 had deletions encompassing the entire amino acid string from L747 through E749 (LRE deletions). EGFR TKIs were used in 204 patients with advanced NSCLC. Patients with non-LRE deletions had the least RR, compared with those with deletions from E746 or L747 (42.9%, 68.2%, and 79.6%, respectively; P = 0.022). Patients with non-LRE deletions had relatively short median PFS, though not significantly different from those with deletions from E746 or L747 (5.9, 9.8, and 10.5 months, respectively; P = 0.665). The OS was not different among patients with deletions occurring at different amino acid positions (P = 0.776). Deletions in exon 19 of different sizes were not associated with different RR, PFS, or OS.

Conclusions: Non-LRE deletions in exon 19 were associated with worse response to EGFR TKIs, compared with LRE deletions. Therefore, the expected clinical outcome under EGFR TKIs depends on not only the existence but also the types of deletions in exon 19. Clin Cancer Res; 18(12); 3470–7. ©2012 AACR.
Data from Cyclin-Dependent Kinase 5 Is Amplified and Overexpressed in Pancreatic Cancer and Activated by Mutant K-Ras
Authors: Eggers John P. , Grandgenett Paul M. , Collisson Eric C. , Lewallen Michelle E. , Tremayne Jarrod , Singh Pankaj K. , Swanson Benjamin J. , Andersen Judy M. , Caffrey Thomas C. , High Robin R. , Ouellette Michel , Hollingsworth Michael A.
Published: April 2023

Abstract
Purpose: To evaluate the nature of cyclin-dependent kinase 5 (CDK5) hyperactivity in pancreatic cancer progression.

Experimental Design: We used genetic, biochemical, and molecular biology methods to investigate the nature and function of overexpression of CDK5 and its activators p35 and p39 during the progression of pancreatic cancer.

Results: Amplification of the CDK5 gene or either of its main activators, p35 and p39, was observed in 67% of human pancreatic ductal adenocarcinoma (PDAC). CDK5, p35, and p39 were rarely expressed in pancreatic ducts whereas more than 90% of PDACs had increased levels of CDK5 and p35. Increased levels of CDK5, p35, and p39 protein were observed in several pancreatic cancer cell lines. Inhibition of CDK5 kinase activity using a CDK5 dominant-negative mutant or the drug roscovitine significantly decreased the migration and invasion of pancreatic cancer cells in vitro. Increased CDK5 kinase activity was also observed in immortalized human pancreatic nestin-expressing (HPNE) cells expressing a mutant form of K-Ras (G12D) compared with HPNE cells expressing native K-Ras. G12D K-Ras increased cleavage of p35 to p25, a stable and greater activator of CDK5, thus implicating a role for CDK5 in early progression of PDAC. Inhibition of the signaling cascade downstream of mutant K-Ras (G12D) that involves mitogen-activated protein/extracellular signal–regulated kinase, phosphoinositide 3-kinase, or CDK5 decreased p25 protein levels.

Conclusion: These results suggest that mutant K-Ras acts in concert with CDK5 and its activators to increase malignant progression, migration, and invasion of pancreatic cancer cells. Clin Cancer Res; 17(19); 6140–50. ©2011 AACR.
Data from Adoptive Transfer of Autologous Natural Killer Cells Leads to High Levels of Circulating Natural Killer Cells but Does Not Mediate Tumor Regression
Authors: Parkhurst Maria R. , Riley John P. , Dudley Mark E. , Rosenberg Steven A.
Published: April 2023

Abstract
Purpose: Adoptive transfer of tumor-infiltrating lymphocytes (TIL) can mediate regression of metastatic melanoma. However, many patients with cancer are ineligible for such treatment because their TIL do not expand sufficiently or because their tumors have lost expression of antigens and/or MHC molecules. Natural killer (NK) cells are large granular lymphocytes that lyse tumor cells in a non–MHC-restricted manner. Therefore, we initiated in a clinical trial to evaluate the efficacy of adoptively transferred autologous NK cells to treat patients with cancers who were ineligible for treatment with TIL.

Experimental Design: Patients with metastatic melanoma or renal cell carcinoma were treated with adoptively transferred in vitro activated autologous NK cells after the patients received a lymphodepleting but nonmyeloablative chemotherapy regimen. Clinical responses and persistence of the adoptively transferred cells were evaluated.

Results: Eight patients were treated with an average of 4.7 × 1010 (± 2.1 × 1010) NK cells. The infused cells exhibited high levels of lytic activity in vitro. Although no clinical responses were observed, the adoptively transferred NK cells seemed to persist in the peripheral circulation of patients for at least one week posttransfer and, in some patients, for several months. However, the persistent NK cells in the circulation expressed significantly lower levels of the key activating receptor NKG2D and could not lyse tumor cell targets in vitro unless reactivated with IL-2.

Conclusions: The persistent NK cells could mediate antibody-dependent cell-mediated cytotoxicity without cytokine reactivation in vitro, which suggests that coupling adoptive NK cell transfer with monoclonal antibody administration deserves evaluation. Clin Cancer Res; 17(19); 6287–97. ©2011 AACR.
Data from MiR-1 Downregulation Cooperates with MACC1 in Promoting MET Overexpression in Human Colon Cancer
Authors: Migliore Cristina , Martin Valentina , Leoni Vera P. , Restivo Angelo , Atzori Luigi , Petrelli Annalisa , Isella Claudio , Zorcolo Luigi , Sarotto Ivana , Casula Giuseppe , Comoglio Paolo M. , Columbano Amedeo , Giordano Silvia
Published: April 2023

Abstract
Purpose: MET, the tyrosine kinase receptor for hepatocyte growth factor, is frequently overexpressed in colon cancers with high metastatic tendency. We aimed to evaluate the role of its negative regulators, miR-1 and miR-199a*, and its transcriptional activator, the metastasis-associated in colon cancer 1 (MACC1), in controlling MET expression in human colon cancer samples.

Experimental Design: The expression of MET, miR-1, miR-199a*, and MACC1 was evaluated by real-time PCR in 52 matched pairs of colorectal cancers and nontumoral surrounding tissues. The biological role of miR-1 in controlling MET expression and biological activity was assessed in colon cancer cells either by its forced expression or by AntagomiR-mediated inhibition.

Results: MiR-1 was downregulated in 84.6% of the tumors and its decrease significantly correlated with MET overexpression, particularly in metastatic tumors. We found that concurrent MACC1 upregulation and miR-1 downregulation are required to elicit the highest increase of MET expression. Consistent with a suppressive role of miR-1, its forced in vitro expression in colon cancer cells reduced MET levels and impaired MET-induced invasive growth. Finally, we identified a feedback loop between miR-1 and MET, resulting in their mutual regulation.

Conclusions: This study identifies an oncosuppressive role of miR-1 in colorectal cancer in which it acts by controlling MET expression through a feedback loop. Concomitant downregulation of miR-1 and increase of MACC1 can thus contribute to MET overexpression and to the metastatic behavior of colon cancer cells. Clin Cancer Res; 18(3); 737–47. ©2011 AACR.
Data from Genome-Wide CpG Island Profiling of Intraductal Papillary Mucinous Neoplasms of the Pancreas
Authors: Hong Seung-Mo , Omura Noriyuki , Vincent Audrey , Li Ang , Knight Spencer , Yu Jun , Hruban Ralph H. , Goggins Michael
Published: April 2023

Abstract
Purpose: Intraductal papillary mucinous neoplasms (IPMN) are precursors to infiltrating pancreatic ductal adenocarcinomas. Widespread epigenetic alterations are characteristic of many cancers, yet few studies have systematically analyzed epigenetic alterations of neoplastic precursors. Our goal was to conduct genome-wide CpG island methylation profiling to identify aberrantly methylated loci in IPMNs.

Experimental Design: We compared the CpG island methylation profiles of six IPMNs to normal primary pancreatic duct samples using methylation CpG island amplification (MCA) and Agilent CpG island microarray (MCAM) analysis. When selected 13 genes identified as differentially methylated by MCAM for methylation-specific PCR (MSP) analysis in an independent set of IPMNs and normal pancreas samples and conducted expression analysis of selected genes.

Results: We identified 2,259 loci as differentially methylated in at least one of six IPMNs including 245 genes hypermethylated in IPMNs with high-grade dysplasia compared with normal pancreatic duct samples. Eleven of 13 genes evaluated by MSP were more commonly methylated in 61 IPMNs than in 43 normal pancreas samples. Several genes (BNIP3, PTCHD2, SOX17, NXPH1, EBF3) were significantly more likely to be methylated in IPMNs with high-grade than with low-grade dysplasia. One gene, SOX17, showed loss of protein expression by immunohistochemistry in 22% (19 of 88) of IPMNs. The most specific marker, BNIP3, was not methylated in any IPMNs with low-grade dysplasia or in normal pancreas samples.

Conclusions: IPMNs undergo extensive aberrant CpG island hypermethylation. The detection of genes selectively methylated in high-grade IPMNs such as BNIP3 may have use in the clinical evaluation of IPMNs. Clin Cancer Res; 18(3); 700–12. ©2011 AACR.