bluuebunny/crossref_metadata_2025 huggingface dataset:
Maintenance Therapy to Suppress Micrometastasis: The New Challenge for Adjuvant Cancer Treatment
Authors: Epstein Richard J.
Published: September 2005

The palliative efficacy of cytotoxic drugs is routinely assessed using tumor shrinkage (response) rates shown in clinical trials. Although adjuvant drug therapy has a goal distinct from that of palliative therapy (i.e., to prolong survival by inhibiting progression of micrometastatic disease), it is widely assumed that the adjuvant efficacy of a drug will parallel its response rate (“activity”) in advanced stages of the disease. Reconsideration of this assumption seems timely in view of recent developments: the realization that many predictors of short-term tumor response correlate inversely with long-term survival outcomes; the characterization of tumor progression as a discontinuous process that may include dormant phases; the understanding that micrometastasis is therapeutically suppressible by a variety of mechanisms including direct tumor cell kill, cytotoxic disruption of paracrine growth signals from normal tissues, and targeted inhibition of prometastatic pathways; the recognition that tumor dormancy not only blocks the antimetastatic efficacy of cytotoxic drugs but also represents a therapeutic end point for metastasis-suppressive noncytotoxic drugs such as hormone inhibitors; and the insight that optimal adjuvant drug therapy is likely to include both induction and maintenance components. The traditional view of cytoreductive response as a prerequisite for adjuvant drug efficacy thus merits reappraisal, with a view to accelerating incorporation of novel noncytotoxic maintenance therapies into controlled studies.
Immunomodulatory Drug CC-5013 or CC-4047 and Rituximab Enhance Antitumor Activity in a Severe Combined Immunodeficient Mouse Lymphoma Model
Authors: Hernandez-Ilizaliturri Francisco J. , Reddy Nishitha , Holkova Beata , Ottman Edris , Czuczman Myron S.
Published: September 2005

New thalidomide derivatives CC-5013 and CC-4047 (immunomodulatory drugs, IMiD) are up to 10,000 times more potent than Thalidomide. The biological effects of IMiDs are presumed to be mediated by (a) activation of some components of the innate [natural killer (NK) cells] or adoptive immune system (T cells), (b) modification of cytokine microenvironment in the tumor bed, or by (c) inhibition of angiogenesis. In this article, we tested an innovative combination strategy involving rituximab and IMiDs in aggressive lymphoma cell lines and human lymphoma xenografts. Treatment of non-Hodgkin's lymphoma cells with CC-5013 resulted in a 40% to 70% growth inhibition when compared with controls (P < 0.05). Exposure of lymphoma cells to CC-4047 resulted in a lesser degree of growth inhibition. Induction of apoptosis was shown in 10% to 26% of lymphoma cells 24 hours following exposure to either IMiD. In vivo studies in severe combined immunodeficient mice showed synergistic activity between CC-4047 (and to a lesser degree, CC-5013) plus rituximab. Animals treated with the CC-4047/rituximab combination had a median survival of 74 days (P = 0.0012) compared with 58 days (P = 0.167) in CC-5013/rituximab-treated animals compared with 45 days in rituximab monotherapy–treated animals. The synergistic effect between IMiDs and rituximab in our mouse model was attributed to NK cell expansion. The enhancement of rituximab activity by IMiDs was abrogated by in vivo depletion of NK cells. Augmenting NK cell function by CC-4047 or CC-5013 exposure may increase the antitumor effects of rituximab against B-cell lymphomas and warrants further exploration in the context of a clinical trial.
Effects of Ketoconazole on Glucuronidation by UDP-Glucuronosyltransferase Enzymes
Authors: Yong Wei Peng , Ramirez Jacqueline , Innocenti Federico , Ratain Mark J.
Published: September 2005

Purpose: Ketoconazole has been shown to inhibit the glucuronidation of the UGT2B7 substrates zidovudine and lorazepam. Its effect on UGT1A substrates is unclear. A recent study found that coadministration of irinotecan and ketoconazole led to a significant increase in the formation of SN-38 (7-ethyl-10-hydroxycamptothecine), an UGT1A substrate. This study investigates whether ketoconazole contributes to the increase in SN-38 formation by inhibiting SN-38 glucuronidation.

Experimental Design: SN-38 glucuronidation activities were determined by measuring the rate of SN-38 glucuronide (SN-38G) formation using pooled human liver microsomes and cDNA-expressed UGT1A isoforms (1A1, 1A7 and 1A9) in the presence of ketoconazole. Indinavir, a known UGT1A1 inhibitor, was used as a positive control. SN-38G formation was measured by high-performance liquid chromatograph.

Results: Ketoconazole competitively inhibited SN-38 glucuronidation. Among the UGT1A isoforms screened, ketoconazole showed the highest inhibitory effect on UGT1A1 and UGT1A9. The Ki values were 3.3 ± 0.8 μmol/L for UGT1A1 and 31.9 ± 3.3 μmol/L for UGT1A9.

Conclusions: These results show that ketoconazole is a potent UGT1A1 inhibitor, which seems the basis for increased exposure to SN-38 when coadministered with irinotecan.
Molecular Alterations in Tumors and Response to Combination Chemotherapy with Gefitinib for Advanced Colorectal Cancer
Authors: Ogino Shuji , Meyerhardt Jeffrey A. , Cantor Mami , Brahmandam Mohan , Clark Jeffrey W. , Namgyal Chungdak , Kawasaki Takako , Kinsella Kate , Michelini Ann L. , Enzinger Peter C. , Kulke Matthew H. , Ryan David P. , Loda Massimo , Fuchs Charles S.
Published: September 2005

Purpose: Recently, activating mutations of the epidermal growth factor receptor (EGFR) gene were discovered in non–small cell lung cancers sensitive to gefitinib (ZD1839, an EGFR tyrosine kinase inhibitor) but not in gefitinib-resistant cancers. Abnormalities of EGFR and related pathways may have an effect on responsiveness of advanced colorectal cancer to combination chemotherapy with gefitinib.

Experimental Design: We examined patients with previously untreated metastatic colorectal cancer, who were enrolled into two phase I/II trials of combination chemotherapy (irinotecan, leucovorin, and 5-fluorouracil) and daily oral gefitinib. We obtained paraffin tissue blocks of primary tumors from 31 patients, sequenced the EGFR, KRAS, and BRAF genes, and did immunohistochemistry for EGFR, phosphorylated AKT1, p53, p21, and p27.

Results: Twelve (39%) of the 31 patients experienced a partial objective response to the therapy. A novel EGFR mutation in exon 18 (c.2170G>A, p.Gly724Ser) was identified in only one patient who did not experience an objective tumor response. EGFR immunohistochemistry was not predictive of responsiveness. In contrast, loss of p21 was associated with a higher response rate to therapy (P = 0.05). Moreover, the response rate among patients whose tumors maintained p21 expression and possessed a mutation in p53 was only 9% (1 of 11, P = 0.005). Overexpression of phosphorylated AKT1 also seemed to predict a trend towards resistance to the therapy.

Conclusions: p21 expression in colorectal cancer, especially in combination with p53 mutation, is a predictor of resistance to the combination chemotherapy with gefitinib. Activating EGFR mutations are rare in colorectal cancer and do not seem to confer sensitivity to gefitinib and chemotherapy.
Identification of NicotinamideN-Methyltransferase as a Novel Serum Tumor Marker for Colorectal Cancer
Authors: Roeßler Markus , Rollinger Wolfgang , Palme Stefan , Hagmann Marie-Luise , Berndt Peter , Engel Alfred M. , Schneidinger Bernd , Pfeffer Michael , Andres Herbert , Karl Johann , Bodenmüller Heinz , Rüschoff Josef , Henkel Thomas , Rohr Gerhard , Rossol Siegbert , Rösch Wolfgang , Langen Hanno , Zolg Werner , Tacke Michael
Published: September 2005

Purpose: The goal of this study was to identify and validate novel serum markers of human colorectal cancer as potential candidates for noninvasive detection of early colorectal neoplasm.

Experimental Design: Employing two-dimensional gel electrophoresis and mass spectrometry, we analyzed 16 matched colorectal cancer and adjacent normal tissue samples. Proteins found to be elevated in cancer tissue were further validated by generating antibodies which were used for immunoblotting of tissue samples and for the development of highly sensitive immunoassays for assessment of serum samples.

Results: In total, 735 different proteins were identified in colon tissue. Strong elevation in colorectal cancer for five proteins was confirmed by immunoblot analysis: transforming growth factor-β induced protein ig-h3 (βIG-H3), nicotinamide N-methyltransferase (NNMT), nucleoside diphosphate kinase A (nm23-H1), purine nucleoside phosphorylase (PNPH), and mannose-6-phosphate receptor binding protein 1 (M6P1). Elevated levels of NNMT, which is not predicted to be secreted but is known as a cytoplasmic protein, were found in serum from patients with colorectal cancer. Employing a receiver-operating characteristic curve based on the measurement of 109 patients with colorectal cancer and 317 healthy controls, we obtained an area under the curve of 0.84 for NNMT, which was superior to the established tumor marker carcinoembryogenic antigen with an area under the curve of 0.78.

Conclusions: It is proposed that NNMT serum levels may have significance in the early detection and in the management of patients with colorectal cancer.
Patient Subsets Benefiting from Adjuvant Therapy Following Surgical Resection of Non–Small Cell Lung Cancer
Authors: Johnson Bruce E. , Rabin Michael S.
Published: September 2005

Adjuvant chemotherapy is the standard of therapy for some patients with stages I, II, and III breast and colon cancer. The therapeutic efficacy of adjuvant chemotherapy following surgical resection of early stage non–small cell lung cancer (NSCLC) has been less clear. A meta-analysis was reported in 1995 of patients who underwent surgical resection for early stage NSCLC and were then randomized to either observation or chemotherapy. This meta-analysis showed a 13% reduction in the hazard ratio of death, leading to a 5% absolute improvement in survival 5 years after the start of adjuvant cisplatin-based chemotherapy treatment compared with observation only. Multiple prospective randomized trials for patients with NSCLC were planned and undertaken to attempt to validate the observations of the meta-analysis. Six trials with ≥150 patients with early stage NSCLC (stages I-IIIA) on each arm have been reported in the last 2 years. Four of the six trials show a survival advantage for the patients with early stage NSCLC treated with adjuvant chemotherapy compared with those who underwent observation. The survival benefit in these four studies varies from a 4% to a 16% survival advantage at 4 to 5 years after the start of chemotherapy. The hazard ratio of death for the patients treated with chemotherapy ranged from 0.61 to 0.86 compared with patients on observation. Thus, the information available at the current time supports the administration of chemotherapy for patients with stages IB and II NSCLC. Further research will be needed to define the role of adjuvant chemotherapy and its use in conjunction with chest radiotherapy for the treatment of patients with resected stages IA and IIIA NSCLC.
Surgical Management of T3 and T4 Lung Cancer
Authors: DiPerna Costanzo A. , Wood Douglas E.
Published: September 2005

Locally advanced lung cancer (T3 or T4) has a significantly worse prognosis than lower stage disease. However, this diagnosis is usually made radiologically, and experienced thoracic surgeons are familiar with the low radiologic to pathologic correlation in tumors that abut the great vessels, mediastinum, or chest wall. Commonly these tumors do not directly invade adjacent structures and are, in fact, T1 or T2 tumors that are resectable through standard techniques. Where there is no clearly evident invasion of unresectable structures, the patient should be given the benefit of the doubt and considered at a lower (resectable) stage until proven otherwise. The curability of T3 tumors varies according to the involved site. A T3N0 tumor involving the chest wall provides the most favorable prognosis among the resected T3 lesions, with a 5-year survival of >50% in lymph node–negative patients if resection is complete. Palliative incomplete resections of T4 disease, in which tumor has invaded mediastinal structures, have not shown any survival benefit and are associated with very high morbidity and mortality. However, patients with limited invasion of the carina, left atrium, superior vena cava, or pulmonary artery may be able to be completely resected despite their T4 classification. Surgical resection remains an important part of the therapy for patients with locally advanced lung cancer. Modern techniques of chest wall resection and reconstruction and bronchoplastic procedures allow complete resection of locally advanced tumors with favorable 5-year survival rates and low morbidity and mortality.
The Role of Surgery in N2 Non–Small Cell Lung Cancer
Authors: DeCamp Malcolm M. , Ashiku Simon , Thurer Robert
Published: September 2005

Historical series document the poor survival (7-16% at 5 years) for patients with N2-positive, stage IIIA non–small cell lung cancer (NSCLC) treated with primary surgery. In 1994, two small randomized trials showed the superiority of induction chemotherapy followed by surgery over surgery alone for stage IIIA NSCLC. These findings, as well as subsequent studies showing the superiority of chemoradiotherapy over chemotherapy alone in nonoperable stage III disease, prompted investigations of preoperative chemoradiotherapy for N2-positve patients. As induction therapy improved, the use of resection in stage IIIA NSCLC was called into question. An Intergroup trial addressing this issue randomized 392 patients to induction chemoradiotherapy followed by surgery versus definitive chemoradiotherapy. Surgery following induction chemoradiotherapy was associated with a significant improvement in progression-free survival and almost a 50% reduction in local failure. As distant relapse is common, survival is likely to be enhanced only in those patients who respond to the systemic arm of treatment. Identification of genetic or biochemical markers of response, minimally invasive techniques to pathologically restage, or improved statistical or chemosensitivity analyses are needed to enhance our ability to select patients who will benefit from resection.
Novel Antiangiogenic Therapies for Renal Cell Cancer
Authors: Gordon Michael S.
Published: September 2005

Renal cell cancer remains a disease for which highly effective therapy for the majority of patients with metastatic disease is lacking. The biology of clear cell carcinomas and their association with mutations of the von Hippel-Lindau gene and its resultant increased expression of vascular endothelial growth factor (VEGF) make angiogenesis a potentially pathophysiologic mechanism for tumor development. As a result, the use of antiangiogenic therapy is an intriguing concept for the treatment of renal cell cancer. Various agents, aside from the inhibitors of VEGF, have been studied, including thalidomide, low-dose interferon, and novel antiangiogenic agents such as the thrombospondin-1 mimetics. Use of these agents has been associated with some degree of objective response or prolonged stabilization of disease, and their true value needs to be assessed in ongoing prospective studies. Combinations of antiangiogenic agents either with other similarly acting drugs or as a component of a “cocktail” with other noncytotoxic therapies should be explored in this patient population.
Nonmyeloablative Transplantation
Authors: Takahashi Yoshiyuki , Childs Richard W.
Published: September 2005

High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation has been explored as a method to enhance the efficacy of chemotherapy for advanced solid tumors. The failure of autologous hematopoietic stem cell transplantation to prolong survival in patients with metastatic solid tumors has sparked interest recently in studies exploring the potential of allogeneic hematopoietic stem cell transplantation for such patients. Allogeneic hematopoietic stem cell transplantation is widely accepted as a potent form of immunotherapy capable of curing patients with chemotherapy-refractory hematologic malignancies. However, it was not until the end of the 20th century that investigators initiated trials to test the potential of allogeneic hematopoietic stem cell transplantation as immunotherapy in malignancies of epithelial origin. Early pilot trials have established proof-of-principle that graft-versus-tumor effects can induce complete or partial remission in some treatment-refractory metastatic solid tumors. In this review, we discuss the rationale for pilot trials investigating the potential of nonmyeloablative allogeneic hematopoietic stem cell transplantation in advanced cytokine-refractory renal cancer, highlighting the preliminary success, limitations, and future clinical directions of this approach.
Effect of Renal Cell Carcinomas on the Development of Type 1 T-Cell Responses
Authors: Rayman Patricia , Wesa Amy K. , Richmond Amy L. , Das Tanya , Biswas Kaushik , Raval Gira , Storkus Walter J. , Tannenbaum Charles , Novick Andrew , Bukowski Ronald , Finke James
Published: September 2005

Purpose: We reported that in renal cell carcinoma patients with active disease, T-cell reactions to the tumor-associated antigens MAGE-6 and EphA2 are highly skewed toward TH2-type cytokine responses [interleukin (IL) 5]. Herein, we determined whether tumor-derived products, including gangliosides isolated from renal cell carcinoma patients, participate in the down-regulation of type 1 T-cell responses.

Experimental Design: T cells from healthy volunteers or renal cell carcinoma patients were cultured in the presence and absence of supernatants derived from renal cell carcinoma explants or with gangliosides isolated from those tumor supernatants. T cells were stimulated or not with either autologous dendritic cells pulsed with superantigen (Staphylococcus enterotoxin B) or with phorbol 12-myristate 13-acetate and ionomycin and then were assessed for type 1 or type 2 responses (cytokine production and gene expression) and apoptosis.

Results: Tumor supernatants efficiently inhibited the TH1-type responses [interferon (IFN) γ] of T cells stimulated with either S. enterotoxin B or phorbol 12-myristate 13-acetate and ionomycin but had no inhibitory effect on activated T-cell production of type 2 cytokines (IL-4, IL-5, and IL-10). Likewise, IFN-γ mRNA and protein production were inhibited when T cells were cocultured with either renal cell carcinoma supernatant-derived gangliosides or a commercial source of purified GD1a. It was also determined that gangliosides impair type 1 responses by inducing apoptosis of activated T cells.

Conclusions: We propose that renal cell carcinoma-derived tumor products such as gangliosides can induce a type 2 bias in antitumor immunity by initiating apoptosis in the IFN-γ-producing type 1 effector cells. This represents a relevant mechanism by which renal cell carcinoma can inhibit protective antitumor immunity.
Detection of Micrometastatic Disease and Monitoring of Perioperative Tumor Cell Dissemination in Primary Operable Breast Cancer Patients Using Real-Time Quantitative Reverse Transcription-PCR
Authors: Ismail Mohamed Saad , Wynendaele Wim , Aerts Joeri L. E. , Paridaens Robert , Gaafar Rabab , Shakankiry Nayera , Khaled Hussein M. , Christiaens Marie-Rose , Wildiers Hans , Omar Sherif , Vandekerckhove Philippe , van Oosterom Allan T.
Published: September 2005

Purpose: We previously found a statistically significant number of cytokeratin 19 (CK19)+ cells in peripheral blood (PB) of stage IV breast cancer (BC) patients compared with those of healthy volunteers, using a quantitative real-time reverse transcription-PCR. We aimed to apply the technique on bone marrow (BM) of primary operable BC patients. Pre- and postoperative PB samples of these patients were further analyzed to investigate possible shedding of CK19+ cells during the operation.

Experimental Design: In 54 primary operable BC patients, we analyzed 50 BM samples taken preoperatively and 297 PB samples. PB samples were collected before surgery; immediately after surgery; on the first, second, and fifth day postoperatively; and one month postoperatively.

Results: In BM of controls and BC patients, we detected a median of 28 and 568 CK19+ cells/5 × 106 leukocytes, respectively (P < 0.001). In preoperative blood (B-1) samples, we measured a median of 109 CK19+ cells. Using the upper limit of 95% confidence interval of controls as cutoff, 74% and 52% of BM and (B-1), respectively were considered CK19+. There was no significant correlation between CK19+ cells in BM and (B-1) and classical prognostic factors. We found no significant difference between blood samples at different time points with respect to the average CK19+ cells.

Conclusions: In primary BC patients, we detected high numbers of CK19+ cells in BM and PB (B-1) samples compared with controls. However, no significant correlation between the presence of CK19+ cells in BM and PB and classical prognostic factors was found. We detected no statistically significant influence of surgical manipulation on CK19+ cells.
Detection of Residual Subclinical Ovarian Carcinoma after Completion of Adjuvant Chemotherapy
Authors: Nouriani Mory , Bahador Afshin , Berek Jonathan S. , Cheng Joan P. , Chi Dennis S. , Cliby William A. , Del Priore Giuseppe , Dodson Mark K. , Duggan Bridgette D. , Gershenson David M. , Lentz Scott E. , Penson Richard T. , Robinson William R. , Rodriguez Mildred , Roman Lynda D. , Yu Mimi C. , Zempolich Karen , Dubeau Louis
Published: September 2005

Purpose: We sought to test the hypothesis that the presence of telomerase activity in peritoneal washings of patients treated for ovarian carcinoma is a sensitive and specific indicator of the presence of residual disease. We hypothesized that this test, if added to second-look procedure protocols, could help determine whether residual disease is present or not in patients who have completed their adjuvant chemotherapy for ovarian carcinoma.

Experimental Design: Peritoneal washings were obtained from 100 consecutive patients undergoing a second-look procedure after treatment for ovarian carcinoma (cases) and from 100 patients undergoing surgery for benign gynecological conditions (controls). The washings were assayed for telomerase activity using the telomerase repeat amplification protocol. The results were compared to the histological and cytological findings.

Results: Among our 100 cases, 82 (82%) had either positive second-look procedures or expressed telomerase in their peritoneal washings. Fifty-three (53%) had positive second-look procedures, whereas 66 (66%) tested positive for telomerase. Twenty-nine of the 47 patients (62%) with negative second-look procedures tested positive for telomerase. Of the 53 patients with positive second-look procedures, 37 (70%) tested positive for telomerase. None of the 100 controls (0%) expressed telomerase in their peritoneal washings.

Conclusions: Telomerase activity in peritoneal washings of patients treated for ovarian carcinoma and undergoing a second-look procedure may provide a means of increasing the sensitivity of such procedures for the detection of residual disease while maintaining a high level of specificity.
Predictive Markers for Late Cervical Metastasis in Stage I and II Invasive Squamous Cell Carcinoma of the Oral Tongue
Authors: Lim Sang-Chul , Zhang Shichuan , Ishii Genichiro , Endoh Yasushi , Kodama Keiji , Miyamoto Shinichi , Hayashi Ryuichi , Ebihara Satoshi , Cho Jae-Shik , Ochiai Atsushi
Published: September 2005

Purpose: Patients with oral tongue carcinoma treated by intraoral excision only should be followed up carefully for cervical lymph node metastasis and salvaged immediately if found, because some patients have a more aggressive clinical course. The purpose of this study was to find useful markers for predicting late cervical metastasis in patients with stage I and II invasive squamous cell carcinoma of the oral tongue.

Experimental Design: We investigated clinicopathologic factors and immunohistochemical biomarkers predicting late cervical metastasis in surgical specimens from 56 patients with T1–2N0M0 invasive squamous cell carcinoma of the oral tongue who did not undergo elective neck dissection. Histopathologic factors including tumor thickness, mode of invasion, Broders grade, total score of three different malignancy grading systems, eight other clinicopathologic parameters, and immunohistochemical expression of p53, cyclin D1, Ki-67, epidermal growth factor receptor, microvessel density, cyclooxygenase-2, MUC1, laminin-5 γ2, E-cadherin, and β-catenin were examined. All of the clinicopathologic factors and immunohistochemical expression of biomarkers were compared in terms of survival.

Results: In the univariate analysis, tumor thickness (P = 0.009), Broders grade (P = 0.017), nest shape (P = 0.005), mode of invasion (P < 0.001), Anneroth score (P = 0.029), Bryne score (P < 0.001), and E-cadherin expression (P = 0.003) were correlated with late cervical metastasis. Multivariate analysis on late cervical metastasis revealed that tumor thickness >4 mm, mode of invasion grade 3 or 4, and E-cadherin expression were independent factors. Late cervical metastasis was the only prognostic factor for overall survival (P = 0.002).

Conclusions: Our results indicate that patients with stage I and II invasive squamous cell carcinoma of the oral tongue with tumor thickness >4 mm, mode of invasion grade 3 or 4, and low expression of E-cadherin should be considered a high-risk group for late cervical metastasis when a wait-and-see policy for the neck is adopted.
Osteopontin But Not Osteonectin Messenger RNA Expression Is a Prognostic Marker in Curatively Resected Non-Small Cell Lung Cancer
Authors: Schneider Sylke , Yochim JiMin , Brabender Jan , Uchida Kazumi , Danenberg Kathleen D. , Metzger Ralf , Schneider Paul M. , Salonga Dennis , Hölscher Arnulf H. , Danenberg Peter V.
Published: September 2005

Purpose: The purpose of this study was to better define the role of osteopontin (OPN) and osteonectin [also known as secreted protein acidic and rich in cysteine (SPARC)] in lung tumorigenesis by comparing the expressions of these genes in lung tumor tissue and matched normal tissue and by determining the prognostic significance of the gene expressions.

Experimental Design: Quantitative real-time reverse transcription-PCR was used to analyze OPN and SPARC mRNA expression in normal lung tissue and matching tumor samples from 82 patients with non-small cell lung cancer. Gene expression data for each patient were matched to survival data.

Results: The overall median mRNA expression level of OPN was about 20-fold higher in tumor tissues than in matching normal lung tissues (P < 0.001), whereas SPARC gene expression was not significantly different in both tissue types. Forty of 82 patients had high (≥4.1) intratumoral OPN expression, and 15 of 82 patients had high (≥15.5) SPARC expression. High OPN expression in the tumor tissue was associated with inferior survival (P = 0.014), whereas high SPARC expression showed a trend toward longer survival (P = 0.095). The impact of high OPN and low SPARC expression on patient survival was additive (P = 0.001).

Conclusions: The large increase in OPN expression in tumors compared with normal tissue and its association with survival suggest a role for OPN in lung tumorigenesis.
Nuclear Factor-κB Is Constitutively Activated in Prostate Cancer
In vitro
and Is Overexpressed in Prostatic Intraepithelial Neoplasia and Adenocarcinoma of the Prostate
Authors: Sweeney Christopher , Li Lang , Shanmugam Rajasubramaniam , Bhat-Nakshatri Poornima , Jayaprakasan Vetrichelvan , Baldridge Lee Ann , Gardner Thomas , Smith Martin , Nakshatri Harikrishna , Cheng Liang
Published: September 2005

Purpose: The transcription factor nuclear factor-κB (NF-κB) promotes the production of angiogenic, antiapoptotic, and prometastatic factors that are involved in carcinogenesis.

Experimental Design: Electromobility gel shift assays were used to evaluate NF-κB DNA binding in vitro. The functional relevance of NF-κB DNA binding was assessed by both cDNA array analyses and proliferation assays of prostate cancer cells with and without exposure to an NF-κB inhibitor, parthenolide. Immunohistochemistry staining for the p65 NF-κB subunit was used to determine the frequency and location of NF-κB in 97 prostatectomy specimens. The amount of staining was quantified on a 0–3+ scale.

Results: An electromobility gel shift assay confirmed the presence of NFκB DNA binding in all four prostate cancer cell lines tested. The binding was inhibited by parthenolide, and this agent also decreased multiple gene transcripts under the control of NF-κB and inhibited proliferation of prostate cancer cells. The staining results revealed overexpression of p65 in the prostatic intraepithelial neoplasia and cancer compared with the benign epithelium. Specifically, there was a predominance of 1+ and 2+ with no 3+ staining in benign epithelium, whereas there was only 2+ and 3+ staining (30 and 70%, respectively) in the cancerous areas. These differences were statistically different. There was no correlation with tumor grade or stage.

Conclusions: NF-κB is constitutively activated in prostate cancer and functionally relevant in vitro. Immunohistochemistry of human prostatectomy specimens demonstrated overexpression of the active subunit of NF-κB, p65, and that this occurs at an early stage in the genesis of prostate cancer. This work supports the rationale for targeting NF-κB for the prevention and/or treatment of prostate cancer.
Gene Expression Profiles Predict Survival and Progression of Pleural Mesothelioma
Authors: Pass Harvey I. , Liu Zhandong , Wali Anil , Bueno Raphael , Land Susan , Lott Daniel , Siddiq Fauzia , Lonardo Fulvio , Carbone Michele , Draghici Sorin
Published: September 2005

Purpose: Clinical outcomes for malignant pleural mesothelioma (MPM) patients having surgery are imprecisely predicted by histopathology and intraoperative staging. We hypothesized that gene expression profiles could predict time to progression and survival in surgically cytoreduced pleural mesothelioma of all stages.

Experimental Design: Gene expression analyses from 21 MPM patients having cytoreductions and identical postoperative adjuvant therapy were performed using the U95 Affymetrix gene chip. Using both dChip and SAM, neural networks constructed a common 27 gene classifier, which was associated with either the high-risk and low-risk group of patients. Data were validated using real-time PCR and immunohistochemical staining. The 27 gene classifier was also used for validation in a separate set of 17 MPM patients from another institution.

Results: The groups predicted by the gene classifier recapitulated the actual time to progression and survival of the test set with 95.2% accuracy using 10-fold cross-validation. Clinical outcomes were independent of histology, and heterogeneity of progression and survival in early stage patients was defined by the classifier. The gene classifier had a 76% accuracy in the separate validation set of MPMs.

Conclusions: These data suggest that pretherapy gene expression analysis of mesothelioma biopsies may predict which patients may benefit from a surgical approach.
Expression of Matrix Metalloproteinases and Their Inhibitors in Medulloblastomas and Their Prognostic Relevance
Authors: Özen Özlem , Krebs Bjarne , Hemmerlein Bernhard , Pekrun Arnulf , Kretzschmar Hans , Herms Jochen
Published: September 2005

Purpose and Experimental Design: The cellular mechanisms leading to metastatic disease in medulloblastoma (MB), the most common malignant brain tumor in childhood, are mainly unknown. Recently, however, the involvement of matrix metalloproteinases (MMPs) has been suggested. We examined the expression and localization of four MMPs—MMP-2 and -9, membrane-type 1 and 2 MMP (MT1- and MT2-MMP)—and correlated the data with those for their main inhibitors, tissue inhibitors of metalloproteinases (TIMP-1, -2, and -3), in 83 classical and 18 desmoplastic MBs.

Results: Independent of the histological subtype, MMP-2 expression was found in a small percentage of tumors, whereas MMP-9 and MT1- or MT2-MMP were expressed in >75% of tumor samples. The expression of TIMP-1, -2, and -3, on the other hand, was found to depend on the histological subtype: TIMP-3 was often found in classical MB, whereas TIMP-2 was often expressed in desmoplastic MB (P = 0.007–0.001). In addition, both TIMP-3 and -2 correlated significantly with the expression of all studied metalloproteinases except MMP-2. TIMP-1, detected only in classical MB in a low percentage, was the only TIMP that correlated with the expression of MMP-2. Kaplan-Meier estimation revealed significantly reduced long-term survival of patients with strong MMP expression in tumor samples. In multivariate logistic regression analysis, however, the prognosis was significantly determined only by clinical parameters.

Conclusions: TIMP-3 and -2 expression is highly correlated with histological subtypes of MBs and strongly associated with the expression of certain MMPs. The expression of TIMPs and MMPs, however, does not determine prognosis independently of clinical parameters.
Epstein-Barr Virus and Cancer
Authors: Thompson Matthew P. , Kurzrock Razelle
Published: September 2005

EBV was the first human virus to be directly implicated in carcinogenesis. It infects >90% of the world’s population. Although most humans coexist with the virus without serious sequelae, a small proportion will develop tumors. Normal host populations can have vastly different susceptibility to EBV-related tumors as demonstrated by geographical and immunological variations in the prevalence of these cancers. EBV has been implicated in the pathogenesis of Burkitt’s lymphoma, Hodgkin’s disease, non-Hodgkin’s lymphoma, nasopharyngeal carcinoma, and lymphomas, as well as leiomyosarcomas arising in immunocompromised individuals. The presence of this virus has also been associated with epithelial malignancies arising in the gastric region and the breast, although some of this work remains in dispute. EBV uses its viral proteins, the actions of which mimic several growth factors, transcription factors, and antiapoptotic factors, to usurp control of the cellular pathways that regulate diverse homeostatic cellular functions. Recent advances in antiviral therapeutics, application of monoclonal antibodies, and generation of EBV-specific CTLs are beginning to show promise in the treatment of EBV-related disorders.
Macrophage Colony-Stimulating Factor-1 Receptor Expression Is Associated with Poor Outcome in Breast Cancer by Large Cohort Tissue Microarray Analysis
Authors: Kluger Harriet M. , Dolled-Filhart Marisa , Rodov Sofya , Kacinski Barry M. , Camp Robert L. , Rimm David L.
Published: September 2005

Purpose: Macrophage colony-stimulating factor-1 receptor (CSF-1R) is a transmembrane tyrosine kinase receptor, which is abnormally expressed in invasive breast cancer. Small cohort studies have demonstrated that increased expression of CSF-1R is associated with ipsilateral breast cancer recurrence. Correlation with survival has not been reported. Our aim was to further evaluate the role of CSF-1R in breast cancer, by studying the expression of CSF-1R in a large cohort of clinical specimens.

Experimental Design: Tissue microarrays containing 301 node-negative and 280 node-positive cases were used. Immunohistochemical staining was performed and correlated with overall survival, nodal status, and other clinicopathological data.

Results: CSF-1R expression was strongly associated with nodal status. Of the node-negative cases, 114 (38.9%) stained positive for CSF-1R, whereas 189 (67.5%) of the node-positive cases expressed CSF-1R (P < 0.0001). CSF-1R expression is also associated with larger tumor size (P = 0.02). Positive staining was strongly associated with decreased survival (P = 0.0003). Among node-negative patients, CSF-1R expression was associated with decreased overall survival (P = 0.045), whereas among node-positive patients, it was not (P = 0.47). In multivariate analysis, CSF-1R was not independent of nodal status as a predictor of survival.

Conclusions: CSF-1R expression is a strong predictor of poor outcome in nonmetastatic breast cancer. It is significantly more frequently expressed in patients with nodal involvement. Among the node-negative patients, it has a stronger association with survival than among the node-positive patients. Our findings support other preclinical findings that CSF-1R may be involved in local invasion and metastasis. Thus, this receptor may be an effective target for therapeutic agents.
Effects of Acyclic Retinoid on Growth, Cell Cycle Control, Epidermal Growth Factor Receptor Signaling, and Gene Expression in Human Squamous Cell Carcinoma Cells
Authors: Shimizu Masahito , Suzui Masumi , Deguchi Atsuko , Lim Jin T. E. , Weinstein I. Bernard
Published: September 2005

We described recently the growth inhibitory effects of the novel compound acyclic retinoid (ACR) in human hepatoma cell lines (M. Suzui et al., Cancer Res., 62: 3997–4006, 2002). In this study we examined the cellular and molecular effects of ACR on human squamous cell carcinoma (SCC) cells. ACR inhibited growth of the esophageal SCC cell line HCE7, and the head and neck SCC cell lines YCU-N861 and YCU-H891, with IC50 values of ∼10, 25, and 40 μm, respectively. Detailed studies were then done with HCE7 cells. Treatment of these cells with 10 μm ACR caused an increase of cells in G0-G1 and induced apoptosis. This was associated with two phases of molecular events. During phase 1, which occurred within 6–12 h, there was an increase in the retinoic acid receptor β (RARβ) and p21CIP1 proteins, and their corresponding mRNAs, and a decrease in the hyperphosphorylated form of the retinoblastoma protein. During phase 2, which occurred at ∼24 h, there was a decrease in the cellular level of transforming growth factor α, and the phosphorylated (i.e., activated) forms of the epidermal growth factor receptor, Stat3, and extracellular signal-regulated kinase proteins, and a decrease in both cyclin D1 protein and mRNA. Reporter assays indicated that ACR inhibited the transcriptional activity of the cyclin D1, c-fos, and activator protein promoters. On the other hand, ACR markedly stimulated the activity of a retinoic acid response element-CAT reporter when the cells were cotransfected with a RARβ expression vector. A hypothetical model explaining these two phases is presented. The diverse effects that we obtained with ACR suggest that this agent might be useful in the chemoprevention and/or therapy of human SCCs.
Quantitative Analysis of Biomarkers Defines an Optimal Biological Dose for Recombinant Human Endostatin in Primary Human Tumors
Authors: Davis Darren W. , Shen Yu , Mullani Nizar A. , Wen Sijin , Herbst Roy S. , O’Reilly Michael , Abbruzzese James L. , McConkey David J.
Published: September 2005

Purpose: In a recent study, we presented preliminary evidence for biological activity in a Phase I dose-finding study (15–600 mg/m2) of recombinant human endostatin in patients with refractory solid tumors. Here, we conducted additional biomarker analyses to correlate changes in tumor biology with dose.

Experimental Design: Excisional tumor biopsies were obtained at baseline and after 56 days of endostatin therapy. Laser scanning cytometry (LSC) was used to quantify biomarker levels in whole tissue sections. Apoptosis in tumor cells (TCs) and tumor-associated endothelial cells (ECs) was quantified by fluorescent three-color anti-CD31/terminal deoxynucleotidyl transferase-mediated nick end labeling staining. Microvessel densities were measured by LSC-guided vessel contouring. Levels of tumor-associated EC BCL-2 and hypoxia-inducible factor 1α were determined by immunofluorescence and LSC quantification. The results, including tumor blood flow measured by positron emission tomography, were analyzed using a quadratic polynomial model.

Results: Significant increases in EC death and decreases in tumor microvessel density were observed, with maximal effects of endostatin at a dose of 249 mg/m2 (95% confidence interval, 159–338) and 257 mg/m2 (95% confidence interval, 183–331), respectively. In contrast, levels of TC death were uniformly low and did not correlate with endostatin dose. Maximal nuclear hypoxia-inducible factor 1α and minimal EC Bcl-2 levels were observed at ∼250 mg/m2, although the changes did not reach statistical significance.

Conclusions: The data suggest that endostatin had optimal biological activity at doses ∼250 mg/m2 in our cohort of patients. Endostatin’s failure to induce high levels of TC death may explain its lack of significant clinical activity in this Phase I trial.
Allelic Loss of a Common Microsatellite MarkerMYCL1
Authors: Kambara Takeshi , Sharp Gerald B. , Nagasaka Takeshi , Takeda Masanori , Sasamoto Hiromi , Nakagawa Hitoshi , Isozaki Hiroshi , MacPhee Donald G. , Jass Jeremy R. , Tanaka Noriaki , Matsubara Nagahide
Published: September 2005

Purpose: Allelic loss involving chromosome arms 5q, 8p, 17p, and 18q is commonly detected in colorectal cancer (CRC). The short arm of chromosome 1 is also frequently affected in a whole range of cancer types, including CRC. Our aim in the present study was to determine whether allelic losses on 1p were likely to be of much value in predicting the prognosis of CRC cases.

Experimental Design: Genomic DNA was prepared from tumor and corresponding normal tissue specimens from 90 patients who had undergone curative resection for CRC. Loss of heterozygosity (LOH) on chromosome arms 1p, 2p, 5q, 7q, 8p, 17p, 17q, and 18q was examined using 14 microsatellite markers, and possible correlations between LOH and clinicopathological factors (including tumor recurrence and patient survival) were investigated. LOH at the MYCL1 microsatellite marker at 1p34 was detected in 12 of 74 (16.2%) patients who were informative for this marker.

Results: After controlling for tumor stage and gender and excluding findings for patients with remote metastasis, we found that patients who were positive for LOH at MYCL1 were 31 times more likely to experience recurrence than those who were negative for LOH at this locus (95% confidence intervals, 2.27-∞; P = 0.04). There were indications of a similar tendency for LOH at the 14-3-3-σ-TG microsatellite marker at 1p35, but we could find no evidence of a significant association between LOH at this site and tumor recurrence or patient survival. We were also unable to detect significant association between LOH at the various sites on 2p, 5q, 7q, 8p, 17p, 17q, and 18q and either tumor recurrence or patient survival.

Conclusions: CRC patients whose tumors exhibited LOH at MYCL1 at chromosome 1p34 were likely to have a poor prognosis, suggesting that this marker may have clinical relevance.
Correlation of Major Cytogenetic Response with a Pharmacogenetic Marker in Chronic Myeloid Leukemia Patients Treated with Imatinib (STI571)
Authors: Dressman Marlene A. , Malinowski Rachel , McLean Lee Anne , Gathmann Insa , Capdeville Renaud , Hensley Martee ,   IRIS (International Randomized Study of Interferon-α versus STI571) Study Group, Polymeropoulos Mihael H.
Published: September 2005

Purpose: Imatinib, an inhibitor of the Bcr-Abl tyrosine kinase, is indicated for the treatment of patients with Philadelphia chromosome-positive chronic myeloid leukemia. We examined genotypes from patients enrolled in the International Randomized Study of IFN-α versus STI571 in an attempt to identify factors that associate with cytogenetic response.

Experimental Design: Sixty-eight polymorphic loci in 26 genes were examined in a subset of 187 patients (imatinib-treated patients, n = 113; IFN + 1-β-d-arabinofuranosylcytosine-treated patients, n = 74). Correlations between genotype and major cytogenetic response (MCyR) were examined by Fisher’s exact tests. Multivariate and survival analyses were also performed.

Results: A significant association between MCyR and the rs2290573 polymorphism mapped to 15q22.33 was observed in imatinib-treated patients (P = 0.00037, Bonferroni corrected P = 0.025). Individuals with a CC genotype at this locus had a MCyR rate of 52% compared with individuals with a CT or TT genotype that had a MCyR rate of 89% (odds ratio, 6.72; 95% confidence interval, 1.51–29.91). In a multivariate analysis, the rs2290573 polymorphism was significant, whereas Sokal score was not. Time to progression analysis illustrated a significant difference based on genotype for the rs2290573 polymorphism.

Conclusions: A significant association was identified between the genetic polymorphism rs2290573 and MCyR in imatinib-treated patients. This polymorphism is located in the intronic sequence of a putative gene with a tyrosine kinase domain. Multivariate analysis suggests that an individual’s genotype for rs2290573 has more predictive value for MCyR than prognostic variables such as Sokal score. The clinical relevance of these results requires validation in future clinical trials.
Age-Dependent Prognostic Effects of Genetic Alterations in Glioblastoma
Authors: Batchelor Tracy T. , Betensky Rebecca A. , Esposito J. Matthew , Pham Loc-Duyen D. , Dorfman Molly V. , Piscatelli Nicole , Jhung Sarah , Rhee David , Louis David N.
Published: September 2005

Purpose: Although the genetic alterations in glioblastoma have been well characterized, reports regarding their prognostic effects have been inconsistent.

Experimental Design: In this series of 140 consecutive cases of glioblastoma treated at a single center, we analyzed the frequency, age dependency and prognostic effects of TP53 mutation, CDKN2A/p16 deletion, EGFR amplification, as well as loss of chromosome 1p, chromosome 10q, and chromosome 19q. The complete set of genetic alterations was available on 60 of 140 patients.

Results: In this cohort of glioblastoma cases, TP53 mutation was significantly associated with patient age. The prognostic effects of TP53 mutation, EGFR amplification, CDKN2A/p16 alterations, and loss of chromosome 1p were dependent on the age of the patient.

Conclusions: This is the first observation that the prognostic effects of TP53, 1p, and CDKN2A/p16 alterations are dependent on patient age. These observations concerning the interactions of age and genetic changes in glioblastoma suggest that tumorigenic pathways to glioblastoma vary with the age of the patient and that future molecular marker studies should carefully evaluate the potential age-dependent prognostic effects of these biological variables. The inconsistent or negative prognostic effects of molecular markers reported in prior studies of glioblastoma may be because different effects at different ages may have resulted in a cancellation of an overall effect in the entire cohort.