bluuebunny/crossref_metadata_2025 huggingface dataset:
Supplementary Tables 1-3 from A Phase I/Ib Study of Enzalutamide Alone and in Combination with Endocrine Therapies in Women with Advanced Breast Cancer
Authors: Schwartzberg Lee S. , Yardley Denise A. , Elias Anthony D. , Patel Manish , LoRusso Patricia , Burris Howard A. , Gucalp Ayca , Peterson Amy C. , Blaney Martha E. , Steinberg Joyce L. , Gibbons Jacqueline A. , Traina Tiffany A.
Published: April 2023

Supplementary Table S1. Pharmacokinetic parameters for enzalutamide administered as a single oral dose administered on day 1 to women with breast cancer and and on day 49 to men with prostate cancer; Supplementary Table S2. Pharmacokinetic parameters for enzalutamide and its active metabolite in patients taking enzalutamide 160 mg once daily to steady state; Supplementary Table S3. Most common grade â‰¥3 adverse events in more than one patient in the safety population.
Supplementary Data from miR-31-3p Expression and Benefit from Anti-EGFR Inhibitors in Metastatic Colorectal Cancer Patients Enrolled in the Prospective Phase II PROSPECT-C Trial
Authors: Anandappa Gayathri , Lampis Andrea , Cunningham David , Khan Khurum H. , Kouvelakis Kyriakos , Vlachogiannis Georgios , Hedayat Somaieh , Tunariu Nina , Rao Sheela , Watkins David , Starling Naureen , Braconi Chiara , Darvish-Damavandi Mahnaz , Lote Hazel , Thomas Janet , Peckitt Clare , Kalaitzaki Ria , Khan Nasir , Fotiadis Nicos , Rugge Massimo , Begum Ruwaida , Rana Isma , Bryant Annette , Hahne Jens C. , Chau Ian , Fassan Matteo , Valeri Nicola
Published: April 2023

Supplementary Figures and Tables
Table S7 from PDK1 Mediates NOTCH1-Mutated Head and Neck Squamous Carcinoma Vulnerability to Therapeutic PI3K/mTOR Inhibition
Authors: Sambandam Vaishnavi , Frederick Mitchell J. , Shen Li , Tong Pan , Rao Xiayu , Peng Shaohua , Singh Ratnakar , Mazumdar Tuhina , Huang Chenfei , Li Qiuli , Pickering Curtis R. , Myers Jeffery N. , Wang Jing , Johnson Faye M.
Published: April 2023

Table S7. Combination index (CI) values for the combination of MK2206 and GSK2334470 at the corresponding fraction affected (Fa) from the simulated values for four NOTCH1WT cell lines
Supplementary Data from PSMA Ligand PET/MRI for Primary Prostate Cancer: Staging Performance and Clinical Impact
Authors: Grubmüller Bernhard , Baltzer Pascal , Hartenbach Sabrina , D’Andrea David , Helbich Thomas H. , Haug Alexander R. , Goldner Gregor M. , Wadsak Wolfgang , Pfaff Sarah , Mitterhauser Markus , Balber Theresa , Berroteran-Infante Neydher , Grahovac Marko , Babich John , Seitz Christian , Kramer Gero , Susani Martin , Mazal Peter , Kenner Lukas , Shariat Shahrokh F. , Hacker Marcus , Hartenbach Markus
Published: April 2023

Supplemental methods and results
Supplementary Data from Role of Elevated PHIP Copy Number as a Prognostic and Progression Marker for Cutaneous Melanoma
Authors: Bezrookove Vladimir , Nosrati Mehdi , Miller James R. , De Semir David , Dar Altaf A. , Vosoughi Elham , Vaquero Edith , Sucker Antje , Lazar Alexander J. , Gershenwald Jeffrey E. , Davies Michael A. , Schadendorf Dirk , Kashani-Sabet Mohammed
Published: April 2023

Contains Supplementary Table 1, and Supplementary Figure 1 and 2
Supplementary Table S3. ALFA-0701 - Adverse Events in Consolidation 2 from FDA Approval: Gemtuzumab Ozogamicin for the Treatment of Adults with Newly Diagnosed CD33-Positive Acute Myeloid Leukemia
Authors: Jen Emily Y. , Ko Chia-Wen , Lee Jee Eun , Del Valle Pedro L. , Aydanian Antonina , Jewell Charles , Norsworthy Kelly J. , Przepiorka Donna , Nie Lei , Liu Jiang , Sheth Christopher M. , Shapiro Marjorie , Farrell Ann T. , Pazdur Richard
Published: April 2023

Supplemental Table 3 describes the adverse events with corresponding risk differences between treatment arms during consolidation 2 of pivotal trial ALFA-0701.
Supplementary Table S2. ALFA-0701 - Adverse Events in Consolidation 1 from FDA Approval: Gemtuzumab Ozogamicin for the Treatment of Adults with Newly Diagnosed CD33-Positive Acute Myeloid Leukemia
Authors: Jen Emily Y. , Ko Chia-Wen , Lee Jee Eun , Del Valle Pedro L. , Aydanian Antonina , Jewell Charles , Norsworthy Kelly J. , Przepiorka Donna , Nie Lei , Liu Jiang , Sheth Christopher M. , Shapiro Marjorie , Farrell Ann T. , Pazdur Richard
Published: April 2023

Supplemental Table 2 describes the adverse events with corresponding risk differences between treatment arms during consolidation 1 of pivotal trial ALFA-0701.
Supplementary Table S1 from Validation of the 16-Gene Recurrence Score in Patients with Locoregional, High-Risk Renal Cell Carcinoma from a Phase III Trial of Adjuvant Sunitinib
Authors: Rini Brian I. , Escudier Bernard , Martini Jean-Francois , Magheli Ahmed , Svedman Christer , Lopatin Margarita , Knezevic Dejan , Goddard Audrey D. , Febbo Phillip G. , Li Rachel , Lin Xun , Valota Olga , Staehler Michael , Motzer Robert J. , Ravaud Alain
Published: April 2023

Patient baseline characteristics in the placebo versus sunitinib arm: all T3 patients in the gene signature cohort. aN0 or NX, any Fuhrman grade, ECOG PS 0 or Fuhrman grade 1 and ECOG PS ï,³1. bN0 or NX, Fuhrman grade {greater than or equal to}2, ECOG PS {greater than or equal to}1. cAny Fuhrman grade, any ECOG PS. Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; SD, standard deviation; RS, Recurrence Score.
Supplemental Table 12 from Acquired FGFR and FGF Alterations Confer Resistance to Estrogen Receptor (ER) Targeted Therapy in ER+ Metastatic Breast Cancer
Authors: Mao Pingping , Cohen Ofir , Kowalski Kailey J. , Kusiel Justin G. , Buendia-Buendia Jorge E. , Cuoco Michael S. , Exman Pedro , Wander Seth A. , Waks Adrienne G. , Nayar Utthara , Chung Jon , Freeman Samuel , Rozenblatt-Rosen Orit , Miller Vincent A. , Piccioni Federica , Root David E. , Regev Aviv , Winer Eric P. , Lin Nancy U. , Wagle Nikhil
Published: April 2023

Gene sets enrichment and associations
Supplementary Figure S1 from Capecitabine and Temozolomide versus FOLFIRI in RAS-Mutated, MGMT-Methylated Metastatic Colorectal Cancer
Authors: Pietrantonio Filippo , Lobefaro Riccardo , Antista Maria , Lonardi Sara , Raimondi Alessandra , Morano Federica , Mosconi Stefania , Rimassa Lorenza , Murgioni Sabina , Sartore-Bianchi Andrea , Tomasello Gianluca , Longarini Raffaella , Farina Gabriella , Petrelli Fausto , Gori Stefania , Randon Giovanni , Corallo Salvatore , Pagani Filippo , Guarini Vincenzo , Palermo Federica , Martinetti Antonia , Macagno Marco , Barault Ludovic , Perrone Federica , Tamborini Elena , Milione Massimo , Di Nicolantonio Federica , Di Maio Massimo , Fucà Giovanni , Di Bartolomeo Maria , de Braud Filippo
Published: April 2023

Supplementary Figure S1. Forest plots of progression-free survival by subgroups within the intention-to-treat population.
Figure S4 from A Somatostatin Receptor Subtype-3 (SST3) Peptide Agonist Shows Antitumor Effects in Experimental Models of Nonfunctioning Pituitary Tumors
Authors: Vázquez-Borrego Mari C. , Gupta Vandana , Ibáñez-Costa Alejandro , Gahete Manuel D. , Venegas-Moreno Eva , Toledano-Delgado Álvaro , Cano David A. , Blanco-Acevedo Cristóbal , Ortega-Salas Rosa , Japón Miguel A. , Barrera-Martín Ana , Vasiljevic Alexandre , Hill Jason , Zhang Shengwen , Halem Heather , Solivera Juan , Raverot Gérald , Gálvez María A. , Soto-Moreno Alfonso , Paez-Pereda Marcelo , Culler Michael D. , Castaño Justo P. , Luque Raúl M.
Published: April 2023

Cell viability in response to SST3-agonists and antagonists in NFPTs primary cell cultures, measured by Alamar-blue reduction.
Supplementary Figures from Deciphering Intratumoral Molecular Heterogeneity in Clear Cell Renal Cell Carcinoma with a Radiogenomics Platform
Authors: Udayakumar Durga , Zhang Ze , Xi Yin , Dwivedi Durgesh K. , Fulkerson Michael , Haldeman Sydney , McKenzie Tiffani , Yousuf Qurratulain , Joyce Allison , Hajibeigi Asghar , Notgrass Hollis , de Leon Alberto Diaz , Yuan Qing , Lewis Matthew A. , Madhuranthakam Ananth J. , Sibley Robert C. , Elias Roy , Guo Junyu , Christie Alana , McKay Renée M. , Cadeddu Jeffrey A. , Bagrodia Aditya , Margulis Vitaly , Brugarolas James , Wang Tao , Kapur Payal , Pedrosa Ivan
Published: April 2023

Supplementary Figures
Supplementary Figure 13 from PGC1α-Mediated Metabolic Reprogramming Drives the Stemness of Pancreatic Precursor Lesions
Authors: Nimmakayala Rama Krishna , Rauth Sanchita , Chirravuri Venkata Ramakanth , Marimuthu Saravanakumar , Nallasamy Palanisamy , Vengoji Raghupathy , Lele Subodh M. , Rachagani Satyanarayana , Mallya Kavita , Malafa Mokenge P. , Ponnusamy Moorthy P. , Batra Surinder K.
Published: April 2023

Analysis of ECAR in IPMN cells using Seahorse extracellular flux analyzer.
Figure S1 from Impact of Prior Treatment on the Efficacy of Adoptive Transfer of Tumor-Infiltrating Lymphocytes in Patients with Metastatic Melanoma
Authors: Seitter Samantha J. , Sherry Richard M. , Yang James C. , Robbins Paul F. , Shindorf Mackenzie L. , Copeland Amy R. , McGowan Christine T. , Epstein Monica , Shelton Thomas E. , Langhan Michelle M. , Franco Zulmarie , Danforth David N. , White Donald E. , Rosenberg Steven A. , Goff Stephanie L.
Published: April 2023

A CONSORT diagram of patients on trials not previously reported
Table S1 from Sex-Based Dimorphism of Anticancer Immune Response and Molecular Mechanisms of Immune Evasion
Authors: Conforti Fabio , Pala Laura , Pagan Eleonora , Bagnardi Vincenzo , De Pas Tommaso , Queirolo Paola , Pennacchioli Elisabetta , Catania Chiara , Cocorocchio Emilia , Ferrucci Pier Francesco , Saponara Maristella , Orsolini Gianmarco , Zagami Paola , Nicoló Eleonora , De Marinis Filippo , Tortora Giampaolo , Bria Emilio , Minucci Saverio , Joffe Hadine , Veronesi Paolo , Wargo Jennifer , Rosenthal Rachel , Swanton Charles , Mantovani Alberto , Gelber Richard D. , Viale Giuseppe , Goldhirsch Aron , Giaccone Giuseppe
Published: April 2023

Supplementary Table S1
Supplementary Table from Aberrant Activation of Cell-Cycle–Related Kinases and the Potential Therapeutic Impact of PLK1 or CHEK1 Inhibition in Uterine Leiomyosarcoma
Authors: Yoshida Kosuke , Yokoi Akira , Yamamoto Tomofumi , Hayashi Yusuke , Nakayama Jun , Yokoi Tsuyoshi , Yoshida Hiroshi , Kato Tomoyasu , Kajiyama Hiroaki , Yamamoto Yusuke
Published: April 2023

Supplementary Table from Aberrant Activation of Cell-Cycle–Related Kinases and the Potential Therapeutic Impact of PLK1 or CHEK1 Inhibition in Uterine Leiomyosarcoma
Supplementary Data from Therapeutic Implications for Intrinsic Phenotype Classification of Metastatic Castration-Resistant Prostate Cancer
Authors: Coleman Ilsa M. , DeSarkar Navonil , Morrissey Colm , Xin Li , Roudier Martine P. , Sayar Erolcan , Li Dapei , Corey Eva , Haffner Michael C. , Nelson Peter S.
Published: April 2023

Supplementary Data from Therapeutic Implications for Intrinsic Phenotype Classification of Metastatic Castration-Resistant Prostate Cancer
Supplementary Table S1 from Favorable Activity and Safety Profile of Memory-Enriched CD19-Targeted Chimeric Antigen Receptor T-Cell Therapy in Adults with High-Risk Relapsed/Refractory ALL
Authors: Aldoss Ibrahim , Khaled Samer K. , Wang Xiuli , Palmer Joycelynne , Wang Yan , Wagner Jamie R. , Clark Mary C. , Simpson Jennifer , Paul Jinny , Vyas Vibhuti , Chien Sheng-Hsuan , Stein Anthony , Pullarkat Vinod , Salhotra Amandeep , Al Malki Monzr M. , Aribi Ahmed , Sandhu Karamjeet , Thomas Sandra H. , Budde Lihua E. , Marcucci Guido , Brown Christine E. , Forman Stephen J.
Published: April 2023

Extramedullary disease at time of lymphodepletion
Data from Enhanced Antitumor Therapy by Inhibition of p21waf1 in Human Malignant Mesothelioma
Authors: Lazzarini Raffaella , Moretti Simona , Orecchia Sara , Betta Pier-Giacomo , Procopio Antonio , Catalano Alfonso
Published: April 2023

Abstract
Purpose: The p21 cyclin-dependent kinase inhibitor was frequently expressed in human malignant pleural mesothelioma (MPM) tissues as well as cell lines. Recent data indicate that p21 keeps tumor cells alive after DNA damage, favoring a survival advantage. In this study, we assessed the possibility of p21 suppression as a therapeutic target for MPM.

Experimental Design: We established two different MPM-derived (from H28 and H2052 cells) subclones using vector-based short hairpin RNA (shRNA). Then, chemosensitivity against low doses of antineoplastic DNA-damaging agents was investigated by colony formation assays, and furthermore, the type of cell response induced by these drugs was analyzed. To examine the effect of p21 shRNA on chemosensitivity in vivo, tumor formation assays in nude mice were done.

Results: In colony formation assay, the IC50 of doxorubicin was 33 ± 3.0 nmol/L in p21 shRNA-transfected cells with respect to 125 ± 10 nmol/L of control vector–transfected cells. This enhancement of growth inhibition was achieved by converting a senescence-like growth arrest to apoptosis in response to doxorubicin, etoposide, and CPT11. In the in vivo assays, CPT11 and loss-of-expression of p21 in combination led to considerable suppression of tumor growth associated with a substantially enhanced apoptotic response, whereas CPT11 alone was ineffective at inducing these responses.

Conclusions: These results indicated that p21 might play an important role in chemosensitivity to anticancer agents, and the suppression of its expression might be a potential therapeutic target for MPM.
Data from Genomic Differences Between Pure Ductal Carcinoma In Situ of the Breast and that Associated with Invasive Disease: a Calibrated aCGH Study
Authors: Iakovlev Vladimir V. , Arneson Nona C.R. , Wong Vietty , Wang Chunjie , Leung Stephanie , Iakovleva Gaiane , Warren Keisha , Pintilie Melania , Done Susan J.
Published: April 2023

Abstract
Purpose: In the quest for new targets, genomes of ductal carcinoma in situ (DCIS) and infiltrating duct carcinoma (IDC) have been compared previously; however, genomic alterations associated with cancer progression were difficult to identify. We hypothesized that significant events can be detected by comparing lesions with a broader range of behavior: from pure DCIS to IDC associated with lymph node metastasis.

Experimental Design: Array comparative genomic hybridization, calibrated by self-self hybridization tests, was used to study 6 cases of pure DCIS and 17 cases of DCIS paired with IDC where 8 tumors had spread to the local lymph nodes.

Results: Pure DCIS exhibited a marginally higher degree of genomic complexity than DCIS and IDC components of invasive tumors. The latter two showed similarity between tumors and between components of the same tumor with several regions detected preferentially compared with pure DCIS. IDC associated with lymph node metastases showed similarity of genomic profiles as a group. Gain on 17q22-24.2 was associated with higher histologic grade, large IDC size, lymphatic/vascular invasion, and lymph node metastasis (P < 0.05).

Conclusions: Our findings suggest that DCIS and IDC are associated with specific genomic events. DCIS associated with IDC is genomically similar to the invasive component and therefore may represent either a clone with high invasive potential or invasive cancer spreading through the ducts. Specifically, gain on 17q22-24.2 is a candidate region for further testing as a predictor of invasion when detected in DCIS and predictor of nodal metastasis when detected in DCIS or IDC.
Data from Adiponectin Deficiency Limits Tumor Vascularization in the MMTV-PyV-mT Mouse Model of Mammary Cancer
Authors: Denzel Martin S. , Hebbard Lionel W. , Shostak Gregory , Shapiro Lawrence , Cardiff Robert D. , Ranscht Barbara
Published: April 2023

Abstract
Purpose: High levels of the fat-secreted cytokine adiponectin (APN) are present in the circulation of healthy people, whereas low levels correlate with an increased incidence of breast cancer in women. The current study experimentally probes the physiologic functions of APN in mammary cancer in a newly generated genetic mouse model.

Experimental Design: We established an APN null mouse model of mammary cancer by introducing the polyoma virus middle T (PyV-mT) oncogene expressed from mouse mammary tumor virus (MMTV) regulatory elements into APN null mice. MMTV-PyV-mT–induced tumors resemble ErbB2–amplified human breast cancers. We monitored tumor onset, kinetics, and animal survival, and analyzed vascular coverage, apoptosis, and hypoxia in sections from the primary tumors. Metastatic spreading was evaluated by analyses of the lungs.

Results: APN prominently localized to the vasculature in human and mouse mammary tumors. In APN null mice, MMTV-PyV-mT–induced tumors appeared with delayed onset and exhibited reduced growth rates. Affected animals survived control tumor-bearing mice by an average of 21 days. Pathologic analyses revealed reduced vascularization of APN null tumors along with increased hypoxia and apoptosis. At the experimental end point, APN null transgenic mice showed increased frequency of pulmonary metastases.

Conclusion: The current work identifies a proangiogenic contribution of APN in mammary cancer that, in turn, affects tumor progression. APN interactions with vascular receptors may be useful targets for developing therapies aimed at controlling tumor vascularization in cancer patients.
Data from Gene Expression Profile and Angiogenic Markers Correlate with Response to Neoadjuvant Bevacizumab Followed by Bevacizumab plus Chemotherapy in Breast Cancer
Authors: Yang Sherry X. , Steinberg Seth M. , Nguyen Dat , Wu Thomas D. , Modrusan Zora , Swain Sandra M.
Published: April 2023

Abstract
Purpose: To identify biomarkers and gene expression profile signatures to distinguish patients with partial response (PR) from those with stable disease (SD) and progressive disease (PD).

Experimental Design: Twenty patients with inflammatory breast cancer and one patient with locally advanced breast cancer received one cycle of bevacizumab followed by six cycles of bevacizumab plus docetaxel-doxorubicin before surgery. Baseline angiogenic/tumor markers were examined by immunohistochemistry and gene expression profiles were measured by Agilent Whole Human Genome arrays. All were assessed for clinical response.

Results: Fourteen patients (67%, 95% confidence interval, 43-85.4%) had PR, five had SD, and two had PD. Expression of CD31 and platelet-derived growth factor receptor-β (PDGFR-β) in the tumor vasculature by immunohistochemistry was significantly associated with response (PR versus SD/PD; CD31 median, 33.5 versus 13.2; P = 0.0004; PDGFR-β median, 5.9 versus 0.6; P = 0.01). Tumor VEGF-A showed a trend towards association with response (2.65 versus 0.25; P = 0.04). pVEGFR2(Y996), pVEGFR2(Y951), MVD, Ki67, apoptosis, grade, ER, HER-2/neu, and p53 were not associated with response. Twenty-six of 1,339 Gene Ontology (GO) classes at the gene transcriptional level were differentially expressed between patients with PR and SD/PD (P < 0.005). Representative significant GO classes include spindle (11 genes; P = 0.001), vascular endothelial growth factor receptor activity including PDGFR-β (5 genes; P = 0.002), and cell motility including CD31 (80 genes; P = 0.005).

Conclusions: Baseline CD31, PDGFR-β, and GO classes for vascular endothelial growth factor receptor activity and mitosis were significantly associated with response to bevacizumab followed by bevacizumab plus chemotherapy.
Data from Targeting Aurora Kinase with MK-0457 Inhibits Ovarian Cancer Growth
Authors: Lin Yvonne G. , Immaneni Anand , Merritt William M. , Mangala Lingegowda S. , Kim Seung Wook , Shahzad Mian M.K. , Tsang Yvonne T.M. , Armaiz-Pena Guillermo N. , Lu Chunhua , Kamat Aparna A. , Han Liz Y. , Spannuth Whitney A. , Nick Alpa M. , Landen Charles N. , Wong Kwong K. , Gray Michael J. , Coleman Robert L. , Bodurka Diane C. , Brinkley William R. , Sood Anil K.
Published: April 2023

Abstract
Purpose: The Aurora kinase family plays pivotal roles in mitotic integrity and cell cycle. We sought to determine the effects of inhibiting Aurora kinase on ovarian cancer growth in an orthotopic mouse model using a small molecule pan-Aurora kinase inhibitor, MK-0457.

Experimental Design: We examined cell cycle regulatory effects and ascertained the therapeutic efficacy of Aurora kinase inhibition both alone and combined with docetaxel using both in vitro and in vivo ovarian cancer models.

Results:In vitro cytotoxicity assays with HeyA8 and SKOV3ip1 cells revealed >10-fold greater docetaxel cytotoxicity in combination with MK-0457. After in vivo dose kinetics were determined using phospho-histone H3 status, therapy experiments with the chemosensitive HeyA8 and SKOV3ip1 as well as the chemoresistant HeyA8-MDR and A2780-CP20 models showed that Aurora kinase inhibition alone significantly reduced tumor burden compared with controls (P values < 0.01). Combination treatment with docetaxel resulted in significantly improved reduction in tumor growth beyond that afforded by docetaxel alone (P ≤ 0.03). Proliferating cell nuclear antigen immunohistochemistry revealed that MK-0457 alone and in combination with docetaxel significantly reduced cellular proliferation (P values < 0.001). Compared with controls, treatment with MK-0457 alone and in combination with docetaxel also significantly increased tumor cell apoptosis by ∼3-fold (P < 0.01). Remarkably, compared with docetaxel monotherapy, MK-0457 combined with docetaxel resulted in significantly increased tumor cell apoptosis.

Conclusions: Aurora kinase inhibition significantly reduces tumor burden and cell proliferation and increases tumor cell apoptosis in this preclinical orthotopic model of ovarian cancer. The role of Aurora kinase inhibition in ovarian cancer merits further investigation in clinical trials.
Data from Bevacizumab Plus Irinotecan in Recurrent WHO Grade 3 Malignant Gliomas
Authors: Desjardins Annick , Reardon David A. , Herndon James E. , Marcello Jennifer , Quinn Jennifer A. , Rich Jeremy N. , Sathornsumetee Sith , Gururangan Sridharan , Sampson John , Bailey Leighann , Bigner Darell D. , Friedman Allan H. , Friedman Henry S. , Vredenburgh James J.
Published: April 2023

Abstract
Purpose: Although patients with newly diagnosed WHO grade 3 malignant glioma have a more favorable prognosis than those with WHO grade 4 malignant glioma, salvage therapies following recurrence offer essentially palliative benefit. We did a phase II trial of bevacizumab, a monoclonal antibody to vascular endothelial growth factor, in combination with irinotecan for patients with recurrent grade 3 malignant glioma.

Experimental Design: Upon documentation of adequate safety among an initial cohort of nine patients treated with bevacizumab (10 mg/kg) and irinotecan every 14 days, a second cohort (n = 24) was treated with bevacizumab (15 mg/kg) every 3 weeks with irinotecan on days 1, 8, 22, and 29 of each 42-day cycle. For both cohorts, the dose of irinotecan was 340 mg/m2 for patients on enzyme-inducing antiepileptic drugs (EIAED) and 125 mg/m2 for patients not on EIAEDs. After each 6-week cycle, patients were evaluated with a physical examination and magnetic resonance imaging.

Results: The 6-month progression-free survival was 55% (95% confidence interval, 36-70%). The 6-month overall survival was 79% (95% confidence interval, 61-89%). Twenty patients (61%) had at least a partial response. Outcome did not differ between the two treatment cohorts. Significant adverse events were infrequent and included a central nervous system hemorrhage in one patient, and one patient who developed thrombotic thrombocytopenic purpura.

Conclusion: Bevacizumab and irinotecan is an active regimen with acceptable toxicity for patients with recurrent WHO grade 3 malignant glioma.
Data from Cannabinoid Receptor Activation Induces Apoptosis through Tumor Necrosis Factor α–Mediated Ceramide De novo Synthesis in Colon Cancer Cells
Authors: Cianchi Fabio , Papucci Laura , Schiavone Nicola , Lulli Matteo , Magnelli Lucia , Vinci Maria Cristina , Messerini Luca , Manera Clementina , Ronconi Elisa , Romagnani Paola , Donnini Martino , Perigli Giuliano , Trallori Giacomo , Tanganelli Elisabetta , Capaccioli Sergio , Masini Emanuela
Published: April 2023

Abstract
Purpose: Cannabinoids have been recently proposed as a new family of potential antitumor agents. The present study was undertaken to investigate the expression of the two cannabinoid receptors, CB1 and CB2, in colorectal cancer and to provide new insight into the molecular pathways underlying the apoptotic activity induced by their activation.

Experimental Design: Cannabinoid receptor expression was investigated in both human cancer specimens and in the DLD-1 and HT29 colon cancer cell lines. The effects of the CB1 agonist arachinodyl-2'-chloroethylamide and the CB2 agonist N-cyclopentyl-7-methyl-1-(2-morpholin-4-ylethyl)-1,8-naphthyridin-4(1H)-on-3-carboxamide (CB13) on tumor cell apoptosis and ceramide and tumor necrosis factor (TNF)-α production were evaluated. The knockdown of TNF-α mRNA was obtained with the use of selective small interfering RNA.

Results: We show that the CB1 receptor was mainly expressed in human normal colonic epithelium whereas tumor tissue was strongly positive for the CB2 receptor. The activation of the CB1 and, more efficiently, of the CB2 receptors induced apoptosis and increased ceramide levels in the DLD-1 and HT29 cells. Apoptosis was prevented by the pharmacologic inhibition of ceramide de novo synthesis. The CB2 agonist CB13 also reduced the growth of DLD-1 cells in a mouse model of colon cancer. The knockdown of TNF-α mRNA abrogated the ceramide increase and, therefore, the apoptotic effect induced by cannabinoid receptor activation.

Conclusions: The present study shows that either CB1 or CB2 receptor activation induces apoptosis through ceramide de novo synthesis in colon cancer cells. Our data unveiled, for the first time, that TNF-α acts as a link between cannabinoid receptor activation and ceramide production.
Data from Three-Gene Expression Signature Predicts Survival in Early-Stage Squamous Cell Carcinoma of the Lung
Authors: Skrzypski Marcin , Jassem Ewa , Taron Miquel , Sanchez Jose Javier , Mendez Pedro , Rzyman Witold , Gulida Grazyna , Raz Dan , Jablons David , Provencio Mariano , Massuti Bartomeu , Chaib Imane , Perez-Roca Laia , Jassem Jacek , Rosell Rafael
Published: April 2023

Abstract
Purpose: Adjuvant treatment may improve survival in early-stage squamous cell carcinoma (SCC) of the lung; however, the absolute gain is modest and mainly limited to stage II-IIIA. Current staging methods are imprecise indications of prognosis, but high-risk patients can be identified by gene expression profiling and considered for adjuvant therapy.

Experimental Design: The expression of 29 genes was assessed by reverse transcriptase quantitative PCR in frozen primary tumor specimens obtained from 66 SCC patients who had undergone surgical resection. Expression values were dichotomized using the median as a cutoff value. We used a risk score to develop a gene expression model for the prediction of survival.

Results: The univariate analysis of gene expression in the training cohort identified 10 genes with significant prognostic value: CSF1, EGFR, CA IX, PH4, KIAA0974, ANLN, VEGFC, NTRK1, FN1, and INR1. In the multivariate Cox model, CSF1 (hazard ratio, 3.5; P = 0.005), EGFR (hazard ratio, 2.7; P = 0.02), CA IX (hazard ratio, 0.2; P < 0.0001), and tumor size >4 cm (hazard ratio, 2.7; P = 0.02) emerged as significant markers for survival. The high prognostic value of a risk score based on the expression of the three genes (CSF1, EGFR, and CA IX) was positively validated in a separate cohort of 26 patients in an independent laboratory (P = 0.05).

Conclusions: The three-gene signature is strongly associated with prognosis in early-stage SCC. Positive independent validation suggests its suitability for selecting SCC patients with an increased risk of death who might benefit from adjuvant treatment.
Data from Prognostic Value of the Molecular Detection of Circulating Tumor Cells Using a Multimarker Reverse Transcription-PCR Assay for Cytokeratin 19, Mammaglobin A, and HER2 in Early Breast Cancer
Authors: Ignatiadis Michail , Kallergi Galatea , Ntoulia Maria , Perraki Maria , Apostolaki Stella , Kafousi Maria , Chlouverakis Grigorios , Stathopoulos Efstathios , Lianidou Evi , Georgoulias Vassilis , Mavroudis Dimitris
Published: April 2023

Abstract
Purpose: To investigate the prognostic value of the molecular detection of circulating tumor cells (CTCs) using three markers [cytokeratin 19 (CK19), mammaglobin A (MGB1), and HER2] in early breast cancer.

Experimental Design: CK19mRNA+, MGB1mRNA+, and HER2mRNA+ cells were detected using real-time (CK19) and nested (MGB1 and HER2) reverse transcription-PCR in the peripheral blood of 175 women with stage I to III breast cancer before the initiation of adjuvant chemotherapy. The detection of CTCs was correlated with clinical outcome. In 10 patients, immunofluorescence staining experiments were done to investigate the coexpression of cytokeratin, MGB1, and HER2 in CTCs.

Results: CK19mRNA+, MGB1mRNA+, and HER2mRNA+ cells were detected in 41.1%, 8%, and 28.6% of the 175 patients, respectively. Patients had one of the following molecular profiles: CK19mRNA+/MGB1mRNA+/HER2mRNA+ (n = 8), CK19mRNA+/MGB1mRNA+/HER2mRNA− (n = 1), CK19mRNA+/MGB1mRNA−/HER2mRNA+ (n = 42), CK19mRNA+/MGB1mRNA−/HER2mRNA− (n = 21), CK19mRNA−/MGB1mRNA+/HER2mRNA− (n = 5), and CK19mRNA−/MGB1mRNA−/HER2mRNA− (n = 98). Double-immunofluorescence experiments confirmed the following CTC phenotypes: CK+/MGB1+, CK+/MGB1−, CK−/MGB1+, CK+/HER2+, CK+/HER2−, MGB1+/HER2−, and MGB1+/HER2+. In univariate analysis, the detection of CK19mRNA+, MGB1mRNA+, and HER2mRNA+ cells was associated with shorter disease-free survival (DFS; P < 0.001, P = 0.001, and P < 0.001, respectively), whereas the detection of CK19mRNA+ and MGB1mRNA+ cells was associated with worse overall survival (P = 0.044 and 0.034, respectively). In multivariate analysis, estrogen receptor–negative tumors and the detection of CK19mRNA+ and MGB1mRNA+ cells were independently associated with worse DFS.

Conclusion: The detection of peripheral blood CK19mRNA+ and MGB1mRNA+ cells before adjuvant chemotherapy predicts poor DFS in women with early breast cancer.
Data from Gene Expression Profiles Associated with the Presence of a Fibrotic Focus and the Growth Pattern in Lymph Node–Negative Breast Cancer
Authors: Van den Eynden Gert G. , Smid Marcel , Van Laere Steven J. , Colpaert Cecile G. , Van der Auwera Ilse , Bich Trinh Xuan , van Dam Peter , den Bakker Michael A. , Dirix Luc Y. , Van Marck Eric A. , Vermeulen Peter B. , Foekens John A.
Published: April 2023

Abstract
Purpose: A fibrotic focus, the scar-like area found in the center of an invasive breast tumor, is a prognostic parameter associated with an expansive growth pattern, hypoxia, and (lymph)angiogenesis. Little is known about the molecular pathways involved.

Experimental Design: Sixty-five patients were selected of whom microarray data of the tumor and H&E slides for histologic analysis were available. The growth pattern and the presence and size of a fibrotic focus were assessed. Differences in biological pathways were identified with global testing. The correlations of growth pattern and fibrotic focus with common breast cancer signatures and with clinicopathologic variables and survival were investigated.

Results: Tumors with a large fibrotic focus showed activation of Ras signaling and of the hypoxia-inducible factor-1α pathway. Furthermore, unsupervised hierarchical cluster analysis with hypoxia- and (lymph)angiogenesis-related genes showed that hypoxia-inducible factor-1α, vascular endothelial growth factor A, and carbonic anhydrase 9 were overexpressed. The presence of a fibrotic focus, especially a large fibrotic focus, was associated with the basal-like subtype (P = 0.009), an activated wound-healing signature (P = 0.06), and a poor-prognosis 76-gene signature (P = 0.004). The presence of a fibrotic focus (P = 0.02) and especially of a large fibrotic focus (P = 0.004) was also associated with early development of distant metastasis.

Conclusions: Our results sustain the hypothesis that hypoxia-driven angiogenesis is essential in the biology of a fibrotic focus. Ras and Akt might play a role as downstream modulators. Our data furthermore suggest that vascular endothelial growth factor A does not only drive angiogenesis but also lymphangiogenesis in tumors with a fibrotic focus. Our data also show an association between the presence of a fibrotic focus and infaust molecular signatures.
Data from Predicting Clinical Outcome in Patients Diagnosed with Synchronous Ovarian and Endometrial Cancer
Authors: Ramus Susan J. , Elmasry Karim , Luo Zhiyuan , Gammerman Alex , Lu Karen , Ayhan Ayse , Singh Naveena , McCluggage W. Glenn , Jacobs Ian J. , Whittaker John C. , Gayther Simon A.
Published: April 2023

Abstract
Purpose: Patients with synchronous ovarian and endometrial cancers may represent cases of a single primary tumor with metastasis (SPM) or dual primary tumors (DP). The diagnosis given will influence the patient's treatment and prognosis. Currently, a diagnosis of SPM or DP is made using histologic criteria, which are frequently unable to make a definitive diagnosis.

Experimental Design: In this study, we used genetic profiling to make a genetic diagnosis of SPM or DP in 90 patients with synchronous ovarian/endometrial cancers. We compared genetic diagnoses in these patients with the original histologic diagnoses and evaluated the clinical outcome in this series of patients based on their diagnoses.

Results: Combining genetic and histologic approaches, we were able make a diagnosis in 88 of 90 cases, whereas histology alone was able to make a diagnosis in only 64 cases. Patients diagnosed with SPM had a significantly worse survival than patients with DP (P = 0.002). Patients in which both tumors were of endometrioid histology survived longer than patients of other histologic subtypes (P = 0.025), and patients diagnosed with SPM had a worse survival if the mode of spread was from ovary to endometrium rather than from endometrium to ovary (P = 0.019).

Conclusions: Genetic analysis may represent a powerful tool for use in clinical practice for distinguishing between SPM and DP in patients with synchronous ovarian/endometrial cancer and predicting disease outcome. The data also suggest a hitherto uncharacterized level of heterogeneity in these cases, which, if accurately defined, could lead to improved treatment and survival.
Data from Intertumor and Intratumor NY-ESO-1 Expression Heterogeneity Is Associated with Promoter-Specific and Global DNA Methylation Status in Ovarian Cancer
Authors: Woloszynska-Read Anna , Mhawech-Fauceglia Paulette , Yu Jihnhee , Odunsi Kunle , Karpf Adam R.
Published: April 2023

Abstract
Purpose: The cancer/germline antigen NY-ESO-1 is variably expressed in epithelial ovarian cancer (EOC), with most tumors showing low or heterogeneous expression, which limits patient responses to NY-ESO-1 vaccine therapy. We tested the hypothesis that promoter and global genomic DNA methylation status correlates with intertumor and intratumor NY-ESO-1 expression status in EOC.

Experimental Design: We utilized 78 EOC tumors and 10 normal ovary controls for quantitative DNA methylation analyses and NY-ESO-1 expression analysis by immunohistochemistry (IHC) and quantitative reverse transcriptase PCR. A subset of EOC tumors were used to perform microdissections of NY-ESO-1 IHC-positive and NY-ESO-1 IHC-negative tissue regions, followed by DNA methylation analyses. EOC cell lines were treated in vitro with decitabine to determine the functional contribution of DNA methylation to NY-ESO-1 gene regulation in EOC.

Results: Compared with normal ovary, bulk EOC tissues display increased NY-ESO-1 expression, reduced NY-ESO-1 promoter methylation, and reduced LINE-1 DNA methylation. However, NY-ESO-1 expression is not significantly associated with NY-ESO-1 promoter methylation status in bulk tumors. We hypothesized that this resulted from heterogeneous intratumor NY-ESO-1 expression. Supporting this idea, experiments using microdissected material revealed that intertumor and intratumor NY-ESO-1 expression heterogeneity is significantly correlated with promoter and global DNA methylation status in EOC. Moreover, decitabine treatment functionally restored NY-ESO-1 expression in nonexpressing EOC cell lines.

Conclusion: DNA methylation status is associated with both intertumor and intratumor NY-ESO-1 expression status in EOC. These findings support a novel chemoimmunotherapy approach using decitabine to augment NY-ESO-1 vaccine therapy for treatment of recurrent EOC.
Data from C19orf48 Encodes a Minor Histocompatibility Antigen Recognized by CD8+ Cytotoxic T Cells from Renal Cell Carcinoma Patients
Authors: Tykodi Scott S. , Fujii Nobuharu , Vigneron Nathalie , Lu Sharon M. , Mito Jeffrey K. , Miranda Maureen X. , Chou Jeffrey , Voong Lilien N. , Thompson John A. , Sandmaier Brenda M. , Cresswell Peter , Van den Eynde Benoît , Riddell Stanley R. , Warren Edus H.
Published: April 2023

Abstract
Purpose: Tumor regression has been observed in some patients with metastatic renal cell carcinoma (RCC) after nonmyeloablative allogeneic hematopoietic cell transplantation (HCT). Cellular and molecular characterization of antigens recognized by tumor-reactive T cells isolated from responding patients could potentially provide insight into the mechanisms of tumor regression.

Experimental Design: CD8+ CTL clones that recognized a novel RCC-associated minor histocompatibility (H) antigen presented by HLA-A*0201 were isolated from two patients with metastatic RCC who experienced tumor regression or stable disease following nonmyeloablative allogeneic HCT. These clones were used to screen a cDNA library and isolate the unique cDNA encoding the antigen.

Results: An alternative open reading frame in the C19orf48 gene located on chromosome 19q13 encodes the HLA-A*0201–restricted minor H antigen recognized by the RCC-reactive T cells. The differential T-cell recognition of donor- and recipient-derived target cells is attributable to a nonsynonymous single-nucleotide polymorphism within the nucleotide interval that encodes the antigenic peptide. Assays for gene expression and CTL recognition showed that the C19orf48-encoded peptide is widely expressed in renal tumors and solid tumors of other histologies. The antigenic peptide can be processed for CTL recognition via both TAP-dependent and TAP-independent pathways.

Conclusions: Donor T-cell responses against the HLA-A*0201–restricted minor H antigen encoded by C19orf48 may contribute to RCC regression after MHC-matched allogeneic HCT.
Data from Phase I Study of Ipilimumab, an Anti–CTLA-4 Monoclonal Antibody, in Patients with Relapsed and Refractory B-Cell Non–Hodgkin Lymphoma
Authors: Ansell Stephen M. , Hurvitz Sara A. , Koenig Patricia A. , LaPlant Betsy R. , Kabat Brian F. , Fernando Donna , Habermann Thomas M. , Inwards David J. , Verma Meena , Yamada Reiko , Erlichman Charles , Lowy Israel , Timmerman John M.
Published: April 2023

Abstract
Purpose: The growth of non–Hodgkin lymphomas can be influenced by tumor–immune system interactions. Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a negative regulator of T-cell activation that serves to dampen antitumor immune responses. Blocking anti–CTLA-4 monoclonal antibodies improves host resistance to immunogenic tumors, and the anti–CTLA-4 antibody ipilimumab (MDX-010) has clinical activity against melanoma, prostate, and ovarian cancers.

Experimental Design: We did a phase I trial of ipilimumab in patients with relapsed/refractory B-cell lymphoma to evaluate safety, immunologic activity, and potential clinical efficacy. Treatment consisted of ipilimumab at 3 mg/kg and then monthly at 1 mg/kg × 3 months (dose level 1), with subsequent escalation to 3 mg/kg monthly × 4 months (dose level 2).

Results: Eighteen patients were treated, 12 at the lower dose level and 6 at the higher dose level. Ipilimumab was generally well tolerated, with common adverse events attributed to it, including diarrhea, headache, abdominal pain, anorexia, fatigue, neutropenia, and thrombocytopenia. Two patients had clinical responses; one patient with diffuse large B-cell lymphoma had an ongoing complete response (>31 months), and one with follicular lymphoma had a partial response lasting 19 months. In 5 of 16 cases tested (31%), T-cell proliferation to recall antigens was significantly increased (>2-fold) after ipilimumab therapy.

Conclusions: Blockade of CTLA-4 signaling with the use of ipilimumab is well tolerated at the doses used and has antitumor activity in patients with B-cell lymphoma. Further evaluation of ipilimumab alone or in combination with other agents in B-cell lymphoma patients is therefore warranted. (Clin Cancer Res 2009;15(20):6446–53)
Data from Activation of Placenta-Specific Transcription Factor Distal-less Homeobox 5 Predicts Clinical Outcome in Primary Lung Cancer Patients
Authors: Kato Tatsuya , Sato Nagato , Takano Atsushi , Miyamoto Masaki , Nishimura Hitoshi , Tsuchiya Eiju , Kondo Satoshi , Nakamura Yusuke , Daigo Yataro
Published: April 2023

Abstract
Purpose and Experimental Design: To identify novel biomarkers and therapeutic targets for lung cancers, we screened for genes that were highly transactivated in lung cancers using a cDNA microarray representing 27,648 genes. DLX5 gene, a member of the human distal-less homeobox transcriptional factor family that is expressed during early embryonic development, was found to be overexpressed in the great majority of lung cancers. Tissue microarray consisting of archival non–small cell lung cancer samples from 369 patients was applied to examine the clinicopathologic significance of DLX5 protein. A role of DLX5 in cancer cell growth and/or survival was investigated through small interfering RNA experiments.

Results: Northern blot and immunohistochemical analyses detected expression of DLX5 only in placenta among 23 normal tissues examined. Immunohistochemical analysis showed that positive immunostaining of DLX5 was correlated with tumor size (pT classification; P = 0.0053) and poorer prognosis of non–small cell lung cancer patients (P = 0.0045). It was also shown to be an independent prognostic factor (P = 0.0415). Treatment of lung cancer cells with small interfering RNAs for DLX5 effectively knocked down its expression and suppressed cell growth.

Conclusions: These data implied that DLX5 is useful as a target for the development of anticancer drugs and cancer vaccines as well as for a prognostic biomarker in clinic.
Data from An Embryonic Stem Cell–Like Signature Identifies Poorly Differentiated Lung Adenocarcinoma but not Squamous Cell Carcinoma
Authors: Hassan Khaled A. , Chen Guoan , Kalemkerian Gregory P. , Wicha Max S. , Beer David G.
Published: April 2023

Abstract
Purpose: An embryonic stem cell (ESC) profile correlates with poorly differentiated breast, bladder, and glioma cancers. In this article, we assess the correlation between the ESC profile and clinical variables in lung cancer.

Experimental Design: Microarray gene expression analysis was done using Affymetrix Human Genome U133A on 443 samples of human lung adenocarcinoma and 130 samples of squamous cell carcinoma (SCC). To identify gene set enrichment patterns, we used the Genomica software.

Results: Our analysis showed that an increased expression of the ESC gene set and a decreased expression of the Polycomb target gene set identified poorly differentiated lung adenocarcinoma. In addition, this gene expression signature was associated with markers of poor prognosis and worse overall survival in lung adenocarcinoma. However, there was no correlation between this ESC gene signature and any histologic or clinical variable assessed in lung SCC.

Conclusions: This work suggests that not all poorly differentiated non–small cell lung cancers exhibit a gene expression profile similar to that of ESC, and that other characteristics may play a more important role in the determination of differentiation and survival in SCC of the lung. (Clin Cancer Res 2009;15(20):6386–90)
Data from γH2AX Expression in Tumors Exposed to Cisplatin and Fractionated Irradiation
Authors: Bañuelos C. Adriana , Banáth Judit P. , Kim Joo-Young , Aquino-Parsons Christina , Olive Peggy L.
Published: April 2023

Abstract
Purpose: Is retention of γH2AX foci useful as a biomarker for predicting the response of xenograft tumors to cisplatin with X-ray? Is a similar approach feasible using biopsies from patients with cervical cancer?

Experimental Design: Mice bearing SiHa, WiDr, or HCT116 xenograft tumors were exposed to cisplatin and/or three daily doses of 2 Gy. Tumors were excised 24 h after treatment and single cells were analyzed for clonogenic fraction and retention of γH2AX foci. Tumor biopsies were examined using 47 paraffin-embedded sections from untreated tumors and 24 sections from 8 patients undergoing radiochemotherapy for advanced cancer of the cervix.

Results: Residual γH2AX measured 24 h after cisplatin injection accurately predicted surviving fraction in SiHa and WiDr xenografts. When a clinically equivalent protocol using cisplatin and fractionated irradiation was employed, the fraction of xenograft cells lacking γH2AX ranked survival accurately but underestimated tumor cell kill. Residual γH2AX foci were detected in clinical samples; on average, only 25% of tumor nuclei exhibited one or more γH2AX foci before treatment and 74% after the start of treatment.

Conclusion: γH2AX can provide useful information on the response of human tumors to the combination of cisplatin and radiation, but prediction becomes less accurate as more time elapses between treatment and tumor biopsy. Use of residual γH2AX as a biomarker for response is feasible when cell survival exceeds ∼20%, but heterogeneity in endogenous and treatment-induced γH2AX must be considered.
Data from Targeted Inhibition of Cyclic AMP Phosphodiesterase-4 Promotes Brain Tumor Regression
Authors: Goldhoff Patricia , Warrington Nicole M. , Limbrick David D. , Hope Andrew , Woerner B. Mark , Jackson Erin , Perry Arie , Piwnica-Worms David , Rubin Joshua B.
Published: April 2023

Abstract
Purpose: As favorable outcomes from malignant brain tumors remain limited by poor survival and treatment-related toxicity, novel approaches to cure are essential. Previously, we identified the cyclic AMP phosphodiesterase-4 (PDE4) inhibitor Rolipram as a potent antitumor agent. Here, we investigate the role of PDE4 in brain tumors and examine the utility of PDE4 as a therapeutic target.

Experimental Design: Immunohistochemistry was used to evaluate the expression pattern of a subfamily of PDE4, PDE4A, in multiple brain tumor types. To evaluate the effect of PDE4A on growth, a brain-specific isoform, PDE4A1 was overexpressed in xenografts of Daoy medulloblastoma and U87 glioblastoma cells. To determine therapeutic potential of PDE4 inhibition, Rolipram, temozolomide, and radiation were tested alone and in combination on mice bearing intracranial U87 xenografts.

Results: We found that PDE4A is expressed in medulloblastoma, glioblastoma, oligodendroglioma, ependymoma, and meningioma. Moreover, when PDE4A1 was overexpressed in Daoy medulloblastoma and U87 glioblastoma cells, in vivo doubling times were significantly shorter for PDE4A1-overexpressing xenografts compared with controls. In long-term survival and bioluminescence studies, Rolipram in combination with first-line therapy for malignant gliomas (temozolomide and conformal radiation therapy) enhanced the survival of mice bearing intracranial xenografts of U87 glioblastoma cells. Bioluminescence imaging indicated that whereas temozolomide and radiation therapy arrested intracranial tumor growth, the addition of Rolipram to this regimen resulted in tumor regression.

Conclusions: This study shows that PDE4 is widely expressed in brain tumors and promotes their growth and that inhibition with Rolipram overcomes tumor resistance and mediates tumor regression.