bluuebunny/crossref_metadata_2025 huggingface dataset:
Overexpression of the Low Molecular Weight Cyclin E in Transgenic Mice Induces Metastatic Mammary Carcinomas through the Disruption of the ARF-p53 Pathway
Authors: Akli Said , Van Pelt Carolyn S. , Bui Tuyen , Multani Asha S. , Chang Sandy , Johnson David , Tucker Susan , Keyomarsi Khandan
Published: August 2007

In tumor cells, cyclin E deregulation results in the appearance of five low molecular weight (LMW) isoforms. When overexpressed in breast cancer cells, these forms of cyclin E induce genomic instability, resistance to inhibition by p21 and p27, and resistance to antiestrogen therapy. Additionally, the LMW forms of cyclin E strongly correlate with decreased survival in patients with breast cancer. However, the oncologic role of the LMW forms of cyclin E in breast cancer tumorigenesis is yet to be determined. To this end, we generated transgenic mice expressing full-length cyclin E alone (M46A), full-length and the EL4 isoforms (EL1/EL4), or the EL2/3 isoforms of cyclin E (T1) under the control of the mouse mammary tumor virus promoter. Compared with full-length cyclin E, LMW cyclin E overexpression induces delayed mammary growth during the pubertal phase and abnormal cell morphology during lactation. Both primary mammary tumor formation and metastasis were markedly enhanced in LMW cyclin E transgenic mice. LMW cyclin E overexpression in mammary epithelial cells of mice is sufficient by itself to induce mammary adenocarcinomas in 34 of 124 (27%) animals compared with 7 of 67 (10.4%) mice expressing only the full-length cyclin E (P < 0.05). In addition, metastasis was seen in 25% of LMW cyclin E tumor–bearing animals compared with only 8.3% of tumors in the full-length cyclin E background (P < 0.05). Moreover, LMW cyclin E overexpression selects for inactivation of p53 by loss of heterozygosity and spontaneous and frequent inactivation of ARF. Therefore, LMW cyclin E overexpression strongly selects for spontaneous inactivation of the ARF-p53 pathway in vivo, canceling its protective checkpoint function and accelerating progression to malignancy. [Cancer Res 2007;67(15):7212–22]
Inhibition of Cysteine Cathepsin Protease Activity Enhances Chemotherapy Regimens by Decreasing Tumor Growth and Invasiveness in a Mouse Model of Multistage Cancer
Authors: Bell-McGuinn Katherine M. , Garfall Alfred L. , Bogyo Matthew , Hanahan Douglas , Joyce Johanna A.
Published: August 2007

Increases in protease expression and activity are associated with malignant progression and poor patient prognosis in a number of human cancers. Members of the papain family of cysteine cathepsins are among the protease classes that have been functionally implicated in cancer. Inhibition of the cysteine cathepsin family using a pan-cathepsin inhibitor, JPM-OEt, led to tumor regression in the RIP1-Tag2 (RT2) mouse model of pancreatic islet cell tumorigenesis. The present study was designed to determine whether this cathepsin inhibitor, when used in combination with chemotherapy, would increase antitumor efficacy. RT2 mice were treated in a late-stage regression trial with three different chemotherapy regimens, alone or in combination with the cathepsin inhibitor, JPM-OEt. Cyclophosphamide was administered in either a maximum tolerated dose (MTD) regimen, a “metronomic” continuous low-dose regimen, or a “chemo-switch” regimen consisting of MTD followed by metronomic dosing. Mice were sacrificed at a defined end point and tumor burden was assessed followed by a detailed analysis of cell proliferation, apoptosis, vascularization, and invasiveness in the treated and control lesions. An additional cohort of mice was followed for survival analysis. The cathepsin inhibitor plus the chemo-switch regimen of cyclophosphamide led to the most pronounced reduction in tumor burden and greatest increase in overall survival. Cysteine cathepsin inhibition resulted in a significant decrease in tumor invasiveness, which was further augmented in combination with each of the chemotherapy dosing regimens. These results encourage the development and continuing evaluation of cysteine cathepsin inhibitors as cancer therapeutics. [Cancer Res 2007;67(15):7378–85]
Mouse Models of Prostate Adenocarcinoma with the Capacity to Monitor Spontaneous Carcinogenesis by Bioluminescence or Fluorescence
Authors: Liao Chun-Peng , Zhong Chen , Saribekyan Gohar , Bading James , Park Ryan , Conti Peter S. , Moats Rex , Berns Anton , Shi Wei , Zhou Zongxiang , Nikitin Alexander Yu , Roy-Burman Pradip
Published: August 2007

The application of Cre/loxP technology has resulted in a new generation of conditional mouse models of prostate cancer. Here, we describe the improvement of the conditional Pten deletion model of prostate adenocarcinoma by combining it with either a conditional luciferase or enhanced green fluorescent protein reporter line. In these models, the recombination mechanism that inactivates the Pten alleles also activates the reporter gene. In the luciferase reporter model, the growth of the primary cancer can be followed noninvasively by bioluminescence imaging (BLI). Surgical castration of tumor-bearing animals leads to a reduced bioluminescence signal corresponding to tumor regression that is verified at necropsy. When castrated animals are maintained, the emergence of androgen depletion–independent cancer is detected using BLI at times varying from 7 to 28 weeks postcastration. The ability to monitor growth, regression, or relapse of the tumor with the use of BLI lead to the collection of tumors at different stages of development. By comparing the distribution of phenotypically distinct populations of epithelial cells in cancer tissues, we noted that the degree of hyperplasia of cells with neuroendocrine differentiation significantly increases in the recurrent cancer relative to the primary cancer, a characteristic which may parallel the appearance of a neuroendocrine phenotype in human androgen depletion–independent cancer. The enhanced green fluorescent protein model, at necropsy, can provide an opportunity to locate or assess tumor volume or to isolate enriched populations of cancer cells from tumor tissues via fluorescence-based technologies. These refined models should be useful in the elucidation of mechanisms of prostate cancer progression, and for the development of approaches to preclinical intervention. [Cancer Res 2007;67(15):7525–33]
Metastasis-Associated Protein 1 Transgenic Mice: A New Model of Spontaneous B-Cell Lymphomas
Authors: Bagheri-Yarmand Rozita , Balasenthil Seetharaman , Gururaj Anupama E. , Talukder Amjad H. , Wang Yui-Hsi , Lee Ju Han , Kim Young Sik , Zhang Xinaglan , Jones Daniel M. , Medeiros L. Jeffrey , Stephens L. Clifton , Liu Yong-Jun , Lee Norman , Kim Insun , Kumar Rakesh
Published: August 2007

Metastasis-associated protein 1 (MTA1), a component of the nuclear remodeling complex and the founding homologue of the MTA family, has been implicated in metastasis, but definitive causative evidence in an animal model system is currently lacking. Here, we show that MTA1 overexpression in transgenic mice is accompanied by a high incidence of spontaneous B cell lymphomas including diffuse large B cell lymphomas (DLBCL). Lymphocytes and lymphoma cells from MTA1-TG mice are hyperproliferative. Lymphomas were transplantable and of clonal origin and were characterized by down-regulation of p27Kip1 as well as up-regulation of Bcl2 and cyclin D1. The significance of these murine studies was established by evidence showing a widespread up-regulation of MTA1 in DLBCL from humans. These findings reveal a previously unrecognized role for the MTA1 pathway in the development of spontaneous B cell lymphomas, and offer a potential therapeutic target in B cell lymphomas. These observations suggest that MTA1-TG mice represent a new model of spontaneous DLBCL associated with high tumor incidence and could be used for therapeutic intervention studies. [Cancer Res 2007;67(15):7062–7]
Oncogenic NRAS, KRAS, and HRAS Exhibit Different Leukemogenic Potentials in Mice
Authors: Parikh Chaitali , Subrahmanyam Ramesh , Ren Ruibao
Published: August 2007

RAS proteins are small GTPases that play a central role in transducing signals that regulate cell proliferation, survival, and differentiation. The RAS proteins interact with a common set of activators and effectors; however, they associate with different microdomains of the plasma membrane as well as other endomembranes and are capable of generating distinct signal outputs. Mutations that result in constitutive activation of RAS proteins are associated with ∼30% of all human cancers; however, different RAS oncogenes are preferentially associated with different types of human cancer. In myeloid malignancies, NRAS mutations are more frequent than KRAS mutations, whereas HRAS mutations are rare. The mechanism underlying the different frequencies of RAS isoforms mutated in myeloid leukemia is not known. In this study, we compared the leukemogenic potential of activated NRAS, KRAS, and HRAS in the same bone marrow transduction/transplantation model system. We found that all three RAS oncogenes have the ability to induce myeloid leukemias, yet have distinct leukemogenic strengths and phenotypes. The models established here provide a system for further studying the molecular mechanisms in the pathogenesis of myeloid malignancies and for testing targeted therapies. [Cancer Res 2007;67(15):7139–46]
Epidermal Growth Factor Receptor Tyrosine Phosphorylation and Signaling Controlled by a Nuclear Receptor Coactivator, Amplified in Breast Cancer 1
Authors: Lahusen Tyler , Fereshteh Mark , Oh Annabell , Wellstein Anton , Riegel Anna T.
Published: August 2007

The steroid receptor coactivator amplified in breast cancer 1 (AIB1) as well as epidermal growth factor receptor (EGFR) family members are frequently overexpressed in epithelial tumors, and their expression is associated with poor prognosis. However, a direct role of AIB1 in EGF signaling has not been determined. To address this, we reduced endogenous AIB1 levels using RNA interference in lung, breast, and pancreatic cancer cell lines. We found that a knockdown of AIB1 levels resulted in a loss of the growth response of these cell lines to EGF. Further analysis revealed that the depletion of AIB1 reduced tyrosine phosphorylation of EGFR at multiple residues both at autophosphorylation and Src kinase phosphorylation sites. AIB1 knockdown did not affect tyrosine phosphorylation of the receptor tyrosine kinases, platelet-derived growth factor receptor and HER3, or overall tyrosine phosphorylation of cellular proteins. However, EGF-dependent phosphorylation of HER2 was decreased. EGFR levels and membrane trafficking were not changed by AIB1 depletion, but there was less recruitment of Src homology 2 domain-containing proteins to the EGFR. This led to a substantial reduction in EGF-induced phosphorylation of signal transducers and activators of transcription 5 and c-Jun NH2-terminal kinase but no significant change in the activation of AKT. Vanadate treatment of cells revealed that the reduction in EGFR tyrosine phosphorylation is dependent in part on changes in cellular phosphatase activity. We propose that a portion of the oncogenic effect of AIB1 could be through control of EGFR and HER2 activity and subsequent modulation of cellular signaling pathways. [Cancer Res 2007;67(15):7256–65]
Proteasome Function Is Required for DNA Damage Response and Fanconi Anemia Pathway Activation
Authors: Jacquemont Céline , Taniguchi Toshiyasu
Published: August 2007

Proteasome inhibitors sensitize tumor cells to DNA-damaging agents, including ionizing radiation (IR), and DNA cross-linking agents (melphalan and cisplatin) through unknown mechanisms. The Fanconi anemia pathway is a DNA damage–activated signaling pathway, which regulates cellular resistance to DNA cross-linking agents. Monoubiquitination and nuclear foci formation of FANCD2 are critical steps of the Fanconi anemia pathway. Here, we show that proteasome function is required for the activation of the Fanconi anemia pathway and for DNA damage signaling. Proteasome inhibitors (bortezomib and MG132) and depletion of 19S and 20S proteasome subunits (PSMD4, PSMD14, and PSMB3) inhibited monoubiquitination and/or nuclear foci formation of FANCD2, whereas depletion of DSS1/SHFM1, a subunit of the 19S proteasome that also directly binds to BRCA2, did not inhibit FANCD2 monoubiquitination or foci formation. On the other hand, DNA damage–signaling processes, such as IR-induced foci formation of phosphorylated ATM (phospho-ATM), 53BP1, NBS1, BRCA1, FANCD2, and RAD51, were delayed in the presence of proteasome inhibitors, whereas ATM autophosphorylation and nuclear foci formation of γH2AX, MDC1, and RPA were not inhibited. Furthermore, persistence of DNA damage and abrogation of the IR-induced G1-S checkpoint resulted from proteasome inhibition. In summary, we showed that the proteasome function is required for monoubiquitination of FANCD2, foci formation of 53BP1, phospho-ATM, NBS1, BRCA1, FANCD2, and RAD51. The dependence of specific DNA damage–signaling steps on the proteasome may explain the sensitization of tumor cells to DNA-damaging chemotherapeutic agents by proteasome inhibitors. [Cancer Res 2007;67(15):7395–405]
Haploinsufficiency of Krüppel-Like Factor 4 Promotes Adenomatous Polyposis Coli–Dependent Intestinal Tumorigenesis
Authors: Ghaleb Amr M. , McConnell Beth B. , Nandan Mandayam O. , Katz Jonathan P. , Kaestner Klaus H. , Yang Vincent W.
Published: August 2007

The zinc finger transcription factor Krüppel-like factor 4 (KLF4) is frequently down-regulated in colorectal cancer. Previous studies showed that the expression of KLF4 was activated by the colorectal cancer tumor suppressor adenomatous polyposis coli (APC) and that KLF4 repressed the Wnt/β-catenin pathway. Here, we examined whether KLF4 plays a role in modulating intestinal tumorigenesis by comparing the tumor burdens in mice heterozygous for the ApcMin allele (ApcMin/+) and those heterozygous for both the ApcMin and Klf4 alleles (Klf4+/−/ApcMin/+). Between 10 and 20 weeks of age, Klf4+/−/ApcMin/+ mice developed, on average, 59% more intestinal adenomas than ApcMin/+ mice (P < 0.0001). Immunohistochemical staining showed that Klf4 protein levels were lower in the normal-appearing intestinal tissues of Klf4+/−/ApcMin/+ mice compared with wild-type, Klf4+/−, or ApcMin/+ mice. In contrast, the levels of β-catenin and cyclin D1 were higher in the normal-appearing intestinal tissues of Klf4+/−/ApcMin/+ mice compared with the other three genotypes. Klf4 levels were further decreased in adenomas from both ApcMin/+ and Klf4+/−/ApcMin/+ mice compared with their corresponding normal-appearing tissues. Reverse transcription-PCR showed an inverse correlation between adenoma size and Klf4 mRNA levels in both Klf4+/−/ApcMin/+ and ApcMin/+ mice. There was also a progressive loss of heterozygosity of the wild-type Apc allele in adenomas with increasing size from Klf4+/−/ApcMin/+ and ApcMin/+ mice. Results from this study show that KLF4 plays an important role in promoting the development of intestinal adenomas in the presence of ApcMin mutation. [Cancer Res 2007;67(15):7147–54]
Optical Markers in Duodenal Mucosa Predict the Presence of Pancreatic Cancer
Authors: Liu Yang , Brand Randall E. , Turzhitsky Vladimir , Kim Young L. , Roy Hemant K. , Hasabou Nahla , Sturgis Charles , Shah Dhiren , Hall Curtis , Backman Vadim
Published: August 2007

Purpose: Pancreatic cancer remains one of the most deadly cancers and carries a dismal 5-year survival rate of <5%. Therefore, there is urgent need to develop a highly accurate and minimally invasive (e.g., without instrumentation of the pancreatic duct given high rate of complications) method of detection. Our group has developed a collection of novel light-scattering technologies that provide unprecedented quantitative assessment of the nanoscale architecture of the epithelium. We propose a novel approach to predict pancreatic cancer through the assessment of the adjacent periampullary duodenal mucosa without any interrogation of the pancreatic duct or imaging of the pancreas.

Experimental Design: Endoscopically and histologically normal-appearing periampullary duodenal biopsies obtained from 19 pancreatic cancer patients were compared with those obtained at endoscopy from 32 controls. Biopsies were analyzed using our newly developed optical technologies, four-dimensional elastic light-scattering fingerprinting (4D-ELF) and low-coherence enhanced backscattering (LEBS) spectroscopy.

Results: 4D-ELF– and LEBS-derived optical markers from normal-appearing periampullary duodenal mucosa can discriminate between pancreatic cancer patients and normal controls with 95% sensitivity and 91% specificity. Moreover, the diagnostic performance of these optical markers was not compromised by confounding factors such as tumor location and stage.

Conclusions: Here, we showed, for the first time, that optical analysis of histologically normal duodenal mucosa can predict the presence of pancreatic cancer without direct visualization of the pancreas.
Mitochondrial Mutations Are a Late Event in the Progression of Head and Neck Squamous Cell Cancer
Authors: Mithani Suhail K. , Taube Janis M. , Zhou Shaoyu , Smith Ian M. , Koch Wayne M. , Westra William H. , Califano Joseph A.
Published: August 2007

Purpose: To determine the timing of mitochondrial mutations in the progression of head and neck squamous cell carcinoma.

Experimental Design: Twenty-three mitochondrial mutations were identified in 12 tumors using a high-throughput mitochondrial sequencing array. Areas of adjacent dysplastic and normal epithelium adjacent to tumors were sequenced using conventional methods for the presence of mutations that occurred in the corresponding tumor.

Results: Two of 23 (8.7%) tumor mitochondrial mutations (2 of 12 tumors) were present in both the areas of adjacent dysplasia and normal epithelium. Five of 23 (21.7%) tumor mitochondrial mutations (4 of 12 tumors) were present in areas of adjacent dysplasia. Eleven of 12 tumors contained nonsynonymous mutations that resulted in protein coding alterations. A significant difference (P < 0.01, χ2) was found in the incidence of mitochondrial mutation that occurred after development of cancer compared with adjacent areas dysplasia and normal epithelium.

Conclusions: The majority of mitochondrial mutations occur during or after the transition of preneoplastic epithelium to cancer in head and neck squamous cell carcinoma, indicating that these are a late event in head and neck carcinogenesis.
Phase I Pharmacokinetic and Pharmacodynamic Study of the Oral Protein Kinase C β-Inhibitor Enzastaurin in Combination with Gemcitabine and Cisplatin in Patients with Advanced Cancer
Authors: Rademaker-Lakhai Jeany M. , Beerepoot Laurens V. , Mehra Niven , Radema Sandra A. , van Maanen Rianne , Vermaat Joost S. , Witteveen Els O. , Visseren-Grul Carla M. , Musib Luna , Enas Nathan , van Hal Gertjan , Beijnen Jos H. , Schellens Jan H.M. , Voest Emile E.
Published: August 2007

Purpose: Enzastaurin targets the protein kinase C and phosphatidylinositol 3-kinase/AKT pathways to reduce tumor angiogenesis and cell proliferation and to induce cell death. A phase I trial was conducted to evaluate the feasibility of combining enzastaurin with gemcitabine and cisplatin.

Experimental Design: Patients with advanced cancer received a 14-day lead-in treatment with oral enzastaurin followed by subsequent 21-day cycles of daily enzastaurin, gemcitabine on days 1 and 8, and cisplatin on day 1. Enzastaurin doses were escalated between 350 mg once daily to 500 mg twice daily, whereas gemcitabine doses were either 1,000 or 1,250 mg/m2 and cisplatin doses were either 60 or 75 mg/m2. Circulating endothelial cell numbers and CD146 and CD133 mRNA expression were evaluated as pharmacodynamic markers.

Results: Thirty-three patients (median age, 58 years) were enrolled in seven dose levels. The maximum tolerated dose was not identified. Two dose-limiting toxicities (grade 2 QT interval corrected for heart rate prolongation and grade 3 fatigue) were reported. Other toxicities included grade 3/4 neutropenia (3 of 6 patients), thrombocytopenia (1 of 6 patients), grade 3 leukopenia (2 patients), and fatigue (5 patients). Enzastaurin twice daily (≥250 mg) resulted in more discontinuations and low-grade toxicities. In the combination, enzastaurin exposures decreased slightly but remained above the target of 1,400 nmol/L, whereas gemcitabine/cisplatin exposures were unaltered. Three patients (9.1%) had partial responses and 13 (39.4%) had stable disease. Measurement of circulating endothelial cell numbers and CD146 and CD133 mRNA expression did not contribute to decision-making on dose escalation.

Conclusions: Recommended phase II dose is 500 mg enzastaurin once daily, 1,250 mg/m2 gemcitabine, and 75 mg/m2 cisplatin. This regimen is well tolerated with no significant alterations in the pharmacokinetic variables of any drug.
External Validation of Mathematical Models to Distinguish Between Benign and Malignant Adnexal Tumors: A Multicenter Study by the International Ovarian Tumor Analysis Group
Authors: Van Holsbeke Caroline , Van Calster Ben , Valentin Lil , Testa Antonia C. , Ferrazzi Enrico , Dimou Ioannis , Lu Chuan , Moerman Philippe , Van Huffel Sabine , Vergote Ignace , Timmerman Dirk
Published: August 2007

Purpose: Several scoring systems have been developed to distinguish between benign and malignant adnexal tumors. However, few of them have been externally validated in new populations. Our aim was to compare their performance on a prospectively collected large multicenter data set.

Experimental Design: In phase I of the International Ovarian Tumor Analysis multicenter study, patients with a persistent adnexal mass were examined with transvaginal ultrasound and color Doppler imaging. More than 50 end point variables were prospectively recorded for analysis. The outcome measure was the histologic classification of excised tissue as malignant or benign. We used the International Ovarian Tumor Analysis data to test the accuracy of previously published scoring systems. Receiver operating characteristic curves were constructed to compare the performance of the models.

Results: Data from 1,066 patients were included; 800 patients (75%) had benign tumors and 266 patients (25%) had malignant tumors. The morphologic scoring system used by Lerner gave an area under the receiver operating characteristic curve (AUC) of 0.68, whereas the multimodal risk of malignancy index used by Jacobs gave an AUC of 0.88. The corresponding values for logistic regression and artificial neural network models varied between 0.76 and 0.91 and between 0.87 and 0.90, respectively. Advanced kernel-based classifiers gave an AUC of up to 0.92.

Conclusion: The performance of the risk of malignancy index was similar to that of most logistic regression and artificial neural network models. The best result was obtained with a relevance vector machine with radial basis function kernel. Because the models were tested on a large multicenter data set, results are likely to be generally applicable.
Triple-Negative Breast Cancer: Clinical Features and Patterns of Recurrence
Authors: Dent Rebecca , Trudeau Maureen , Pritchard Kathleen I. , Hanna Wedad M. , Kahn Harriet K. , Sawka Carol A. , Lickley Lavina A. , Rawlinson Ellen , Sun Ping , Narod Steven A.
Published: August 2007

Purpose: To compare the clinical features, natural history, and outcomes for women with “triple-negative” breast cancer with women with other types of breast cancer.

Experimental Design: We studied a cohort of 1,601 patients with breast cancer, diagnosed between January 1987 and December 1997 at Women's College Hospital in Toronto. Triple-negative breast cancers were defined as those that were estrogen receptor negative, progesterone receptor negative, and HER2neu negative. The prognostic significance of triple-negative breast cancer was explored.

Results: The median follow-up time of the 1,601 women was 8.1 years. One hundred and eighty of 1,601 patients (11.2%) had triple-negative breast cancer. Compared with other women with breast cancer, those with triple-negative breast cancer had an increased likelihood of distant recurrence (hazard ratio, 2.6; 95% confidence interval, 2.0-3.5; P < 0.0001) and death (hazard ratio, 3.2; 95% confidence interval, 2.3-4.5; P < 0.001) within 5 years of diagnosis but not thereafter. The pattern of recurrence was also qualitatively different; among the triple-negative group, the risk of distant recurrence peaked at ∼3 years and declined rapidly thereafter. Among the “other” group, the recurrence risk seemed to be constant over the period of follow-up.

Conclusions: Triple-negative breast cancers have a more aggressive clinical course than other forms of breast cancer, but the adverse effect is transient.
Her2 and Progesterone Receptor Status Are Not Predictive of Response to Fulvestrant Treatment
Authors: Bartsch Rupert , Wenzel Catharina , Altorjai Gabriela , Pluschnig Ursula , Mader Robert M. , Gnant Michael , Jakesz Raimund , Rudas Margaretha , Zielinski Christoph C. , Steger Guenther G.
Published: August 2007

Purpose: It has been hypothesized that response to endocrine therapy for breast cancer depends on Her2 and progesterone receptor status, grading, and tumor proliferation rate. In this study, we evaluated factors that are potentially predictive of response and time to progression in patients treated with fulvestrant.

Experimental Design: One hundred fifty-five patients were included and followed prospectively. Patients received fulvestrant at standard dose by i.m. injection. Response was evaluated every 3 months using International Union Against Cancer criteria. Time to progression and overall survival were estimated with the Kaplan-Meier product limit method. A multivariate analysis was done to evaluate factors potentially influencing response and time to progression.

Results: We observed a partial response in 19 patients (12.3%), stable disease ≥6 months in 56 patients (36.1%), stable disease >3 months but <6 months in 7 patients (4.5%), and progressive disease in 73 patients (47.1%). Median time to progression was 5 months, and median overall survival was 27 months. Probability of achieving clinical benefit was significantly associated with a low proliferation rate (P = 0.015), nonvisceral metastatic sites (P = 0.023), and first-line therapy (P = 0.023). First-line therapy was also associated with prolonged time to progression (P = 0.003).

Conclusions: Response rate and time to progression are shown to be independent of Her2 status, grading, and progesterone receptor status. This is probably caused by the unique mechanism of action associated with fulvestrant: Due to receptor down-regulation, it blocks nuclear, cytoplasmatic, and membrane-bound estrogen receptor. Therefore, it seems to inhibit the cross-talk between growth factor receptor signaling and estrogen receptor in a more effective manner.
Phase I Pharmacokinetic Study of the Safety and Tolerability of Lapatinib (GW572016) in Combination with Oxaliplatin/Fluorouracil/Leucovorin (FOLFOX4) in Patients with Solid Tumors
Authors: Siegel-Lakhai Wandena S. , Beijnen Jos H. , Vervenne Walter L. , Boot Henk , Keessen Marianne , Versola Melissa , Koch Kevin M. , Smith Deborah A. , Pandite Lini , Richel Dirk J. , Schellens Jan H.M.
Published: August 2007

Purpose: This phase I study was designed to determine the optimally tolerated regimen (OTR), safety, and clinical activity of lapatinib in combination with FOLFOX4 [oxaliplatin/leucovorin/5-fluorouracil (5-FU)] in patients with solid tumors. Furthermore, the pharmacokinetics of lapatinib, oxaliplatin, and 5-FU when given alone and in combination were evaluated.

Experimental Design: This study was conducted in two parts. Part 1 was designed to determine the OTR and part 2 was the pharmacokinetic part of the study. Lapatinib was administered once daily for the entire duration of the study. Leucovorin and oxaliplatin were given concurrently over 2 h as an i.v. infusion, after which 5-FU was given as a bolus followed by continuous infusion over 22 h on day 1. 5-FU and leucovorin administration were repeated in an identical manner on day 2. Cycles were repeated every 2 weeks. Once the OTR was determined, it was to become the dose level for patients included in the pharmacokinetic part of the study.

Results: A total of 34 patients was treated in this study. No dose-limiting toxicities were observed and the OTR was established at 1,500 mg/d lapatinib in combination with the standard FOLFOX4 regimen. Nonhematologic toxicities consisted mainly of nausea, diarrhea, vomiting, fatigue, neuropathy, and mucositis. The most important hematologic toxicity was neutropenia. No drug-drug interactions between lapatinib and the FOLFOX4 regimen were observed.

Conclusion: Lapatinib can be safely administered in combination with the standard FOLFOX4 regimen. Further studies are warranted to explore the potential additive antitumor effect of lapatinib in combination with the FOLFOX4 regimen.
Decreased DOC-2/DAB2 Expression in Urothelial Carcinoma of the Bladder
Authors: Karam Jose A. , Shariat Shahrokh F. , Huang Hong-Ying , Pong Rey-Chen , Ashfaq Raheela , Shapiro Ellen , Lotan Yair , Sagalowsky Arthur I. , Wu Xue-Ru , Hsieh Jer-Tsong
Published: August 2007

Purpose: DOC-2/DAB2 (differentially expressed in ovarian carcinoma-2/disabled-2), a potential tumor suppressor gene, is underexpressed in several cancers. Little is known about the expression of this gene in urothelial carcinoma of the bladder (UCB). We profiled DOC-2/DAB2 expression in mouse and human normal and neoplastic urothelia.

Experimental Design: Immunohistochemical staining for DOC-2/DAB2 was carried out on tissue specimens from two transgenic mouse models with urothelium-specific molecular alterations and on a tissue microarray containing cores from 9 normal controls, 44 patients who underwent transurethral resection of the bladder tumor (TURBT), 195 patients who underwent radical cystectomy for UCB, and 39 lymph nodes with metastatic UCB.

Results: Normal mouse urothelium stained uniformly with DOC-2/DAB2. Weaker staining was observed in low-grade, superficial papillary bladder tumors from transgenic mice harboring constitutively active Ha-Ras, whereas carcinoma in situ–like lesions and high-grade bladder tumors from transgenic mice expressing a SV40 T antigen completely lacked DOC-2/DAB2 expression. In human tissues, DOC-2/DAB2 expression was decreased in 11% of normal bladder specimens, 59% of TURBT specimens, 65% of radical cystectomy specimens, and 77% of the metastatic lymph node specimens. Decreased DOC-2/DAB2 expression was associated with advanced pathologic stage (P = 0.023), lymph node metastases (P = 0.050), and lymphovascular invasion (P < 0.001). In univariable, but not in multivariable analysis, decreased DOC-2/DAB2 was associated with an increased probability of bladder cancer recurrence (log-rank test, P = 0.020) and bladder cancer–specific mortality (log-rank test, P = 0.023).

Conclusions: Decreased DOC-2/DAB2 expression seems to occur early in bladder tumorigenesis and becomes more prominent in advanced stages of UCB.
Antibodies to the Epidermal Growth Factor Receptor in Non–Small Cell Lung Cancer: Current Status of Matuzumab and Panitumumab
Authors: Socinski Mark A.
Published: August 2007

Matuzumab and panitumumab are antibodies against the epidermal growth factor receptor (EGFR) that are being evaluated in several malignancies including non–small cell lung cancer (NSCLC). In phase I trials of single-agent matuzumab in patients with EGFR-positive cancer, three tumor responses were documented in esophageal squamous cell carcinoma as well as colorectal carcinoma. A phase I trial of matuzumab in combination with paclitaxel has been reported in 18 patients with EGFR-positive advanced NSCLC. Objective responses were seen in 4 of 18 (23%) patients. A randomized phase II trial is currently ongoing in second-line NSCLC with matuzumab in combination with pemetrexed. A large dose/schedule trial of single-agent panitumumab enrolled 96 patients with EGFR-positive solid tumors. No responses were seen in the 14 lung cancer patients evaluated; 5 of 39 patients with colorectal cancers had objective responses. A randomized phase II trial of carboplatin/paclitaxel with or without panitumumab in 166 patients with previously untreated advanced stage IIIB/IV NSCLC did not find any benefit for the panitumumab arm compared with the chemotherapy alone arm with regard to response rates, time to disease progression, or median survival time. The lack of a biomarker to identify a subset of NSCLC patients who may derive benefit from this agent limits any potential enthusiasm for further trials of panitumumab at this time in NSCLC.
A Phase I Clinical Trial of Single-Dose Intrapleural IFN-β Gene Transfer for Malignant Pleural Mesothelioma and Metastatic Pleural Effusions: High Rate of Antitumor Immune Responses
Authors: Sterman Daniel H. , Recio Adri , Carroll Richard G. , Gillespie Colin T. , Haas Andrew , Vachani Anil , Kapoor Veena , Sun Jing , Hodinka Richard , Brown Jennifer L. , Corbley Michael J. , Parr Michael , Ho Mitchell , Pastan Ira , Machuzak Michael , Benedict William , Zhang Xin-qiao , Lord Elaina M. , Litzky Leslie A. , Heitjan Daniel F. , June Carl H. , Kaiser Larry R. , Vonderheide Robert H. , Albelda Steven M.
Published: August 2007

Purpose: This phase 1 dose escalation study evaluated the safety and feasibility of single-dose intrapleural IFN-β gene transfer using an adenoviral vector (Ad.IFN-β) in patients with malignant pleural mesothelioma (MPM) and metastatic pleural effusions (MPE).

Experimental Design: Ad.IFN-β was administered through an indwelling pleural catheter in doses ranging from 9 × 1011 to 3 × 1012 viral particles (vp) in two cohorts of patients with MPM (7 patients) and MPE (3 patients). Subjects were evaluated for (a) toxicity, (b) gene transfer, (c) humoral, cellular, and cytokine-mediated immune responses, and (d) tumor responses via 18-fluorodeoxyglucose-positron emission tomography scans and chest computed tomography scans.

Results: Intrapleural Ad.IFN-β was generally well tolerated with transient lymphopenia as the most common side effect. The maximally tolerated dose achieved was 9 × 1011 vp secondary to idiosyncratic dose-limiting toxicities (hypoxia and liver function abnormalities) in two patients treated at 3 × 1012 vp. The presence of the vector did not elicit a marked cellular infiltrate in the pleural space. Intrapleural levels of cytokines were highly variable at baseline and after response to gene transfer. Gene transfer was documented in 7 of the 10 patients by demonstration of IFN-β message or protein. Antitumor immune responses were elicited in 7 of the 10 patients and included the detection of cytotoxic T cells (1 patient), activation of circulating natural killer cells (2 patients), and humoral responses to known (Simian virus 40 large T antigen and mesothelin) and unknown tumor antigens (7 patients). Four of 10 patients showed meaningful clinical responses defined as disease stability and/or regression on 18-fluorodeoxyglucose-positron emission tomography and computed tomography scans at day 60 after vector infusion.

Conclusions: Intrapleural instillation of Ad.IFN-β is a potentially useful approach for the generation of antitumor immune responses in MPM and MPE patients and should be investigated further for overall clinical efficacy.
Genetic Alterations of the ATBF1 Gene in Gastric Cancer
Authors: Cho Yong Gu , Song Jae Hwi , Kim Chang Jae , Lee Youn Soo , Kim Su Young , Nam Suk Woo , Lee Jung Young , Park Won Sang
Published: August 2007

Purpose: α-Fetoprotein (AFP)–producing gastric cancers are aggressive tumors with venous and lymphatic invasion and hepatic metastasis. The goal of the present study was to investigate whether somatic changes of the AFP-negative regulator AT motif binding factor-1 (ATBF1) gene are involved in the development or progression of gastric cancers and the production of AFP in gastric cancer cells.

Experimental Design: We searched for genetic alterations of the ATBF1 gene by single-strand conformational polymorphism and sequencing methods as well as allelic loss analysis with the microsatellite markers D16S3066 and D16S3139. Immunochemistry for AFP expression in gastric cancer cells was also done.

Results: In 81 sporadic gastric cancers, four mutations were detected in seven cases: one was a missense mutation and three were deletions; loss of heterozygosity at the ATBF1 locus was detected in 52.9% of informative samples. Five of the eight cancers with AFP expression showed ATBF1 genetic alterations.

Conclusions: These results suggest that genetic alteration of the ATBF1 gene may contribute to the aggressive nature of gastric cancers and the production of AFP in gastric cancer cells.
The Role of Phosphoinositide 3-Kinase Pathway Inhibitors in the Treatment of Lung Cancer
Authors: Engelman Jeffrey A.
Published: August 2007

The phosphoinositide 3-kinase signaling network is widely implicated in the pathogenesis of human cancer. This pathway is commandeered by cancer cells to promote unrestrained cellular growth and survival. In this brief review, we speculate about the uses of inhibitors of phosphoinositide 3-kinase signaling as treatments for human cancers, with an emphasis on non–small cell lung cancer.
Vaccination of Colorectal Cancer Patients with Modified Vaccinia Ankara Encoding the Tumor Antigen 5T4 (TroVax) Given Alongside Chemotherapy Induces Potent Immune Responses
Authors: Harrop Richard , Drury Noel , Shingler William , Chikoti Priscilla , Redchenko Irina , Carroll Miles W. , Kingsman Susan M. , Naylor Stuart , Melcher Alan , Nicholls Joanna , Wassan Harpreet , Habib Nagy , Anthoney Alan
Published: August 2007

Purpose: The attenuated strain of vaccinia virus, modified vaccinia Ankara (MVA) encoding the tumor antigen 5T4 (TroVax), has been evaluated in an open-label phase II study in metastatic colorectal cancer patients. The primary objective was to assess the safety and immunogenicity of TroVax injected before, during, and after treatment with cycles of 5-fluorouracil, folinic acid, and oxaliplatin.

Experimental Design: TroVax was administered to 17 patients with metastatic colorectal cancer. In total, 11 patients were considered to be evaluable for assessment of immunologic responses having received a total of six injections of TroVax, administered before, during, and following completion of chemotherapy. Antibody and cellular responses specific for 5T4 and MVA were monitored throughout the study.

Results: Administration of TroVax alongside 5-fluorouracil, folinic acid, and oxaliplatin was safe and well tolerated with no serious adverse events attributed to TroVax. Ten of the 11 evaluable patients mounted 5T4-specific antibody responses with titers ranging from 10 to >1,000. IFNγ enzyme-linked immunospot responses specific for 5T4 were detected in 10 patients with precursor frequencies exceeding 1 in 1,000 peripheral blood mononuclear cells in 4 patients. Of the 11 evaluable patients, 6 had complete or partial responses. 5T4-specific immune responses, but not MVA-specific immune responses, correlated with clinical benefit.

Conclusions: Potent 5T4-specific cellular and/or antibody responses were induced in all evaluable patients and were still detectable during the period in which chemotherapy was administered. These results suggest that TroVax can be added to chemotherapy regimens without any evidence of enhanced toxicity or reduced immunologic efficacy and may provide additional clinical benefit.
Novel Agents in the Treatment of Lung Cancer: Fourth Cambridge Conference
Authors: Lynch Thomas J. , Bonomi Philip D. , Butts Charles , Davies Angela M. , Engelman Jeffrey , Govindan Ramaswamy , Herbst Roy S. , Heymach John V. , Johnson Bruce E. , Martins Renato G. , Perez-Soler Roman , Riely Gregory J. , Sandler Alan B. , Sequist Lecia V. , Socinski Mark A. , Wong Kwok-Kin , Hart Carol S.
Published: August 2007

The Fourth Cambridge Conference on Novel Agents in the Treatment of Lung Cancer was held in Cambridge, Massachusetts on September 29 to 30, 2006, to discuss ongoing clinical research of novel targeted agents for the treatment of non–small cell lung cancer, along with supportive basic and translational research into the molecular pathways implicated in cancer growth and resistance. New information, conclusions, and recommendations considered significant for the field by the program faculty are summarized below and presented at greater length in the individual articles and accompanying discussions that comprise the full conference proceedings.
Monthly Changes in Atmospheric Carbon Dioxide at Mauna Loa: Possible Asymmetric Effects of Warming
Authors: Kaufmann Robert K.
Published: August 2007

Changes in the intra-annual cycle of atmospheric CO2 at Mauna Loa, Hawaii, are investigated by comparing monthly observations to the mean value of each year’s waxing and waning phase of the cycle. Results identify a previously unnoticed change between 1965 and 2004 during October in which October concentrations declined relative to the cycle’s mean value. Results confirm a previously noted change in spring (April), but unlike previous analyses, this result indicates that between 1965 and 2004 April concentrations rose relative to the cycle’s mean value. The timing of these changes is not caused by commonly recognized patterns of atmospheric circulation, such as ENSO events. Instead, these changes may be generated by asymmetric effects of warming. Warming in early spring may increase heterotrophic respiration relative to net primary production while warming in late summer/early fall may enhance net primary production relative to heterotrophic respiration.
Extreme Value Statistics of the Total Energy in an Intermediate-Complexity Model of the Midlatitude Atmospheric Jet. Part I: Stationary Case
Authors: Felici Mara , Lucarini Valerio , Speranza Antonio , Vitolo Renato
Published: August 2007

A baroclinic model of intermediate complexity for the atmospheric jet at middle latitudes is used as a stochastic generator of atmosphere-like time series. In this case, time series of the total energy of the system are considered. Statistical inference of extreme values is applied to sequences of yearly maxima extracted from the time series in the rigorous setting provided by extreme value theory. The generalized extreme value (GEV) family of distributions is used here as a basic model, both for its qualities of simplicity and its generality. Several physically plausible values of the parameter TE, which represents the forced equator-to-pole temperature gradient and is responsible for setting the average baroclinicity in the atmospheric model, are used to generate stationary time series of the total energy. Estimates of the three GEV parameters—location, scale, and shape—are inferred by maximum likelihood methods. Standard statistical diagnostics, such as return level and quantile–quantile plots, are systematically applied to assess goodness-of-fit. The GEV parameters of location and scale are found to have a piecewise smooth, monotonically increasing dependence on TE. The shape parameter also increases with TE but is always negative, as is required a priori by the boundedness of the total energy. The sensitivity of the statistical inferences is studied with respect to the selection procedure of the maxima: the roles occupied by the length of the sequences of maxima and by the length of data blocks over which the maxima are computed are critically analyzed. Issues related to model sensitivity are also explored by varying the resolution of the system. The method used in this paper is put forward as a rigorous framework for the statistical analysis of extremes of observed data, to study the past and present climate and to characterize its variations.
Tropical Stationary Waves in a Nonlinear Shallow-Water Model with Realistic Basic States
Authors: Kraucunas Ian , Hartmann Dennis L.
Published: August 2007

The nonlinear shallow-water equations are used to study the tropical stationary wave response to steady thermal forcing near the equator in earthlike zonally symmetric basic states. A thin (200 m) fluid layer is superimposed over a large (1500 m) zonally symmetric topography distribution that decreases smoothly from the Tropics to the Poles, thus providing the large meridional height gradients required to maintain realistic zonal-mean zonal winds without introducing unrealistically large tropical wave speeds. A mean meridional circulation is maintained by relaxing the fluid toward its initial, global-mean depth. Both hemispherically symmetric (equinoctial) and hemispherically asymmetric (solstitial) basic states are considered. Stationary waves are generated by adding a fixed mass source/sink distribution near the equator.

The presence of westerly zonal-mean winds in the subtropics amplifies the steady eddy response to the tropical mass forcing and shifts the Rossby gyres poleward and eastward, relative to their position in a resting basic state. When either the mass forcing or the center of the topography distribution is moved off the equator, the eddy response develops considerable hemispheric asymmetry. When the eddy forcing is centered in the “summer” hemisphere of the solstitial basic state, the eddy response exhibits a similar amplitude in both hemispheres, which suggests that the considerable hemispheric symmetry of the observed seasonally varying eddy circulations in the tropical upper troposphere may be attributed to the tendency for the maximum zonal-mean and eddy diabatic heating to occur in the same latitude band throughout the seasonal cycle. Hemispheric asymmetry in either the basic state or the eddy forcing also leads to cross-equatorial eddy momentum fluxes. Experiments performed using a balanced basic state with zero-mean meridional flow indicate that the cross-equatorial mean meridional winds play a significant role in promoting the propagation of wave activity across the equator under solstitial conditions.
Sources and Sinks of Available Potential Energy in a Moist Atmosphere
Authors: Pauluis Olivier
Published: August 2007

Available potential energy (APE) is defined as the difference between the total static energy of the atmosphere and that of a reference state that minimizes the total static energy after a sequence of reversible adiabatic transformations. Determining the rate at which APE is generated in the atmosphere allows one to estimate the amount of kinetic energy that can be generated by atmosphere flows. Previous expressions for the sources and sinks of APE rely on a dry framework and are limited by the fact that they require prior knowledge of the distribution of latent heat release by atmospheric motion. In contrast, this paper uses a moist APE framework to derive a general formula for the sources and sinks of APE that can be equally applied to dry and moist circulations.

Two key problems are addressed here. First, it is shown that any reorganization of the reference state due to diabatic heating or addition of water does not change its total static energy. This property makes it possible to determine the rate of change in APE even in the absence of an analytic formula for the reference state, as is the case in a moist atmosphere. Second, the effects of changing the total water content of an air parcel are also considered in order to evaluate the changes of APE due to precipitation, evaporation, and diffusion of water vapor. Based on these new findings, one can obtain the rate of change of APE from that of atmospheric entropy, water content, and pressure.

This result is used to determine the sources and sinks of APE due to different processes such as external energy sources, frictional dissipation, diffusion of sensible heat and water vapor, surface evaporation, precipitation, and reevaporation. These sources and sinks are then discussed in the context of an idealized atmosphere in radiative–convective equilibrium. For a moist atmosphere, the production of APE by the surface energy flux is much larger than any observational or theoretical estimates of frictional dissipation, and, as is argued here, must be balanced by a comparable sink of APE due to the diffusion of water vapor from unstable to stable air parcels.