bluuebunny/crossref_metadata_2025_split huggingface dataset:
Detection of Human Papillomavirus (HPV) 16-Specific CD4+ T-cell Immunity in Patients with Persistent HPV16-Induced Vulvar Intraepithelial Neoplasia in Relation to Clinical Impact of Imiquimod Treatment
Authors: van Poelgeest Mariëtte I.E. , van Seters Manon , van Beurden Marc , Kwappenberg Kitty M.C. , Heijmans-Antonissen Claudia , Drijfhout Jan W. , Melief Cornelis J.M. , Kenter Gemma G. , Helmerhorst Theo J.M. , Offringa Rienk , van der Burg Sjoerd H. 
Published: September 2005

AbstractPurpose: Topical application of the immune response modifier imiquimod is an alternative approach for the treatment of human papillomavirus (HPV)–positive vulvar intraepithelial neoplasia (VIN) and aims at the immunologic eradication of HPV-infected cells. We have charted HPV16-specific immunity in 29 patients with high-grade VIN and examined its role in the clinical effect of imiquimod treatment.Experimental Design: The magnitude and cytokine polarization of the HPV16 E2-, E6-, and E7-specific CD4+ T-cell response was charted in 20 of 29 patients by proliferation and cytokine bead array. The relation between HPV16-specific type 1 T-cell immunity and imiquimod treatment was examined in a group of 17 of 29 patients.Results: HPV16-specific proliferative responses were found in 11 of the 20 patients. In eight of these patients, T-cell reactivity was associated with IFNγ production. Fifteen of the women treated with imiquimod were HPV16+, of whom eight displayed HPV16 E2- and E6-specific T-cell immunity before treatment. Imiquimod neither enhanced nor induced such immunity in any of the subjects. Objective clinical responses (complete remission or &gt;75% regression) were observed in 11 of the 15 patients. Of these 11 responders, eight patients displayed HPV16-specific type 1 CD4+ T-cell immunity, whereas three lacked reactivity. Notably, the four patients without an objective clinical response also lacked HPV16-specific type 1 T-cell immunity.Conclusions: HPV16-specific IFNγ-associated CD4+ T-cell immunity, although not essential for imiquimod-induced regression of VIN lesions, may increase the likelihood of a strong clinical response (P = 0.03).
Isolated Loss of PMS2 Expression in Colorectal Cancers: Frequency, Patient Age, and Familial Aggregation
Authors: Gill Sharlene , Lindor Noralane M. , Burgart Lawrence J. , Smalley Regenia , Leontovich Olga , French Amy J. , Goldberg Richard M. , Sargent Daniel J. , Jass Jeremy R. , Hopper John L. , Jenkins Mark A. , Young Joanne , Barker Melissa A. , Walsh Michael D. , Ruszkiewicz Andrew R. , Thibodeau Stephen N. 
Published: September 2005

Abstract
Purpose: Most colorectal cancers that have high levels of microsatellite instability (MSI-H) show loss of immunohistochemical expression of proteins that participate in the DNA mismatch repair process, most often involving MLH1 and MSH2. Less commonly, a third DNA mismatch repair protein, MSH6, may also be lost as the primary event. Rarely, tumors with MSI-H show normal expression of these three proteins. The genetic deficiency leading to the MSI-H phenotype in such cases is unknown. PMS2 is another member of the DNA mismatch repair complex. Its expression is generally lost in tumors with MLH1 loss of expression. Rarely, there is selective loss of PMS2 expression. We sought to describe the frequency and clinical correlates of selective loss of expression of PMS2 with the MSI-H tumor phenotype.
Experimental Design: Two thousand seven hundred nineteen colorectal cancers from both clinic- and research-based ascertainment were studied. Tumor MSI testing and immunohistochemistry for MLH1, MSH2, MSH6, and PMS2 were conducted. Medical records were abstracted for age at diagnosis, gender, colorectal cancer site, and family history.
Results: Five hundred thirty-five of the 2,719 tumors were MSI-H. Of these, 93% showed loss of expression of MLH1, MSH2, and/or MSH6. Thirty-eight showed normal expression for these proteins. PMS2 immunohistochemical staining was successful in 32 of 38 of these tumors. Of the 32, 23 showed selective loss of expression of PMS2. This was associated with young age of diagnosis and right-sided location but not with a striking family history of cancer.
Conclusions: Overall, 97% of the MSI-H tumors showed loss of expression for one or more of these four mismatch repair proteins. Selective loss of expression of PMS2 was present in 72% of cases in which colorectal cancers had an MSI-H phenotype but no alteration of expression of MLH1, MSH2, and MSH6. The underlying mechanism involved cannot be determined from this study but could involve point mutations in other DNA mismatch repair genes with retention of immunohistochemical expression, somatic inactivation of PMS2, or germ line mutation of PMS2.
Molecular Evidence Supporting Field Effect in Urothelial Carcinogenesis
Authors: Jones Timothy D. , Wang Mingsheng , Eble John N. , MacLennan Gregory T. , Lopez-Beltran Antonio , Zhang Shaobo , Cocco Amy , Cheng Liang 
Published: September 2005

Abstract
Purpose: Human urothelial carcinoma is thought to arise from a field change that affects the entire urothelium. Multifocality of urothelial carcinoma is a common finding at endoscopy and surgery. Whether these coexisting tumors arise independently or are derived from the same tumor clone is uncertain. Molecular analysis of microsatellite alterations and X-chromosome inactivation status in the cells from each coexisting tumor may further our understanding of urothelial carcinogenesis.
Experimental Design: We examined 58 tumors from 21 patients who underwent surgical excision for urothelial carcinoma. All patients had multiple separate foci of urothelial carcinoma (two to four) within the urinary tract. Genomic DNA samples were prepared from formalin-fixed, paraffin-embedded tissue sections using laser-capture microdissection. Loss of heterozygosity (LOH) assays for three microsatellite polymorphic markers on chromosome 9p21 (IFNA and D9S171), regions of putative tumor suppressor gene p16, and on chromosome 17p13 (TP53), the p53 tumor suppressor gene locus, were done. X-chromosome inactivation analysis was done on the urothelial tumors from 11 female patients.
Results: Seventeen of 21 (81%) cases showed allelic loss in one or more of the urothelial tumors in at least one of the three polymorphic markers analyzed. Concordant allelic loss patterns between each coexisting urothelial tumor were seen in only 3 of 21 (14%) cases. A concordant pattern of nonrandom X-chromosome inactivation in the multiple coexisting urothelial tumors was seen in only 3 of 11 female patients; of these 3 cases, only one displayed an identical allelic loss pattern in all of the tumors on LOH analysis.
Conclusion: LOH and X-chromosome inactivation assays show that the coexisting tumors in many cases of multifocal urothelial carcinoma have a unique clonal origin and arise from independently transformed progenitor urothelial cells, supporting the “field effect” theory for urothelial carcinogenesis.
The Role of Targeted Agents in Adjuvant Therapy for Non–Small Cell Lung Cancer
Authors: Kelly Karen 
Published: September 2005

Abstract
The recent survival benefit of adjuvant chemotherapy in early stage non–small cell lung cancer provides optimism for the future success of targeted therapy in this setting. It is important that we begin to explore molecularly targeted agents in the adjuvant arena, but how best to accomplish this in the face of these new findings presents a challenge. Criteria for selecting promising targeted therapies and optimal trial designs to evaluate them expeditiously in the adjuvant setting are clearly needed.
Tyrosine Kinase Inhibitors in Renal Cell Carcinoma
Authors: Potti Anil , George Daniel J. 
Published: September 2005

Abstract
Current standard treatments for patients with metastatic (stage IV) renal cell carcinoma involve both surgical removal of tumors and treatment with biological agents such as interleukin 2 and/or IFN-α. Unfortunately, such approaches are inadequate for most patients with stage IV disease; the result is a median time to progression of 2 to 4 months and an overall survival of 6 to 17 months. Standard chemotherapy has been uniformly disappointing in this disorder. It is clear that new therapies are needed to approach these patients. Recently, a greater understanding of cancer genetics has led to the successful development of novel therapeutics directed against targets linked to specific types of cancer. During the past decade, researchers have identified the von Hippel-Lindau (VHL) gene as an important tumor suppressor in clear cell carcinoma of the kidney. Elucidation of the VHL gene product (pVHL) and its regulation of hypoxia-inducible factor signaling have created a potential genetic basis for growth factor-targeted strategies in this disease. This review will focus on the potential growth factor targets in clear cell carcinoma, their relation to VHL and hypoxia-inducible factor, and the clinical challenges that face their development.
Vascular Targeting Agents as Cancer Therapeutics
Authors: Thorpe Philip E. 
Published: September 2005

Abstract
Vascular targeting agents (VTAs) for the treatment of cancer are designed to cause a rapid and selective shutdown of the blood vessels of tumors. Unlike antiangiogenic drugs that inhibit the formation of new vessels, VTAs occlude the pre-existing blood vessels of tumors to cause tumor cell death from ischemia and extensive hemorrhagic necrosis. Tumor selectivity is conferred by differences in the pathophysiology of tumor versus normal tissue vessels (e.g., increased proliferation and fragility, and up-regulated proteins). VTAs can kill indirectly the tumor cells that are resistant to conventional antiproliferative cancer therapies, i.e., cells in areas distant from blood vessels where drug penetration is poor, and hypoxia can lead to radiation and drug resistance. VTAs are expected to show the greatest therapeutic benefit as part of combined modality regimens. Preclinical studies have shown VTA-induced enhancement of the effects of conventional chemotherapeutic agents, radiation, hyperthermia, radioimmunotherapy, and antiangiogenic agents. There are broadly two types of VTAs, small molecules and ligand-based, which are grouped together, because they both cause acute vascular shutdown in tumors leading to massive necrosis. The small molecules include the microtubulin destabilizing drugs, combretastatin A-4 disodium phosphate, ZD6126, AVE8062, and Oxi 4503, and the flavonoid, DMXAA. Ligand-based VTAs use antibodies, peptides, or growth factors that bind selectively to tumor versus normal vessels to target tumors with agents that occlude blood vessels. The ligand-based VTAs include fusion proteins (e.g., vascular endothelial growth factor linked to the plant toxin gelonin), immunotoxins (e.g., monoclonal antibodies to endoglin conjugated to ricin A), antibodies linked to cytokines, liposomally encapsulated drugs, and gene therapy approaches. Combretastatin A-4 disodium phosphate, ZD6126, AVE8062, and DMXAA are undergoing clinical evaluation. Phase I monotherapy studies have shown that the agents are tolerated with some demonstration of single agent efficacy. Because efficacy is expected when the agents are used with conventional chemotherapeutic drugs or radiation, the results of Phase II combination studies are eagerly awaited.
A Phase I Dose-Escalation and Pharmacokinetic Study of Brostallicin (PNU-166196A), a Novel DNA Minor Groove Binder, in Adult Patients with Advanced Solid Tumors
Authors: Lockhart A. Craig , Howard Martin , Hande Kenneth R. , Roth Bruce J. , Berlin Jordan D. , Vreeland Franzanne , Campbell Angela , Fontana Erminia , Fiorentini Francesca , Fowst Camilla , Paty Victoria A. , Lankford Odessa , Rothenberg Mace L. 
Published: September 2005

Abstract
Purpose: This study was performed to determine the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetics of brostallicin, a nonalkylating DNA minor groove binder and a synthetic derivative of distamycin A, given as a weekly i.v. infusion.
Experimental Design: Using an accelerated dose escalation design, patients with advanced solid tumor malignancies were treated with brostallicin administered as a 10-min i.v. infusion on days 1, 8, and 15 of a 28-day cycle. The starting dose of brostallicin was 0.3 mg/m2/week. To study the pharmacokinetic behavior of brostallicin, serial blood samples were obtained before and after the first and last infusions during cycle 1, and in cycles 2 and 4 in a limited number of patients.
Results: Fourteen patients received 32 complete cycles of brostallicin. Dose-limiting toxicity was febrile neutropenia and was observed in 3 of 5 patients treated at 4.8 mg/m2/week. The maximum tolerated dose and recommended Phase II dose was 2.4 mg/m2/week. The mean ± SD terminal half-life at the maximum tolerated dose was 4.6 ± 4.1 h. There was moderate distribution of brostallicin into tissues, and the clearance was ∼20% of the hepatic blood flow. The area under the concentration time curve0-∞ of brostallicin increased in a dose-linear fashion. No significant relationship was observed between any plasma pharmacokinetic parameter and clinical toxicities. There were no objective responses during the trial, but 5 patients had stable disease after two cycles of treatment.
Conclusions: The dose-limiting toxicity of weekly brostallicin was neutropenia. Systemic exposure increases linearly with dose. The recommended dose for Phase II studies is 2.4 mg/m2 on days 1, 8, and 15 of a 28-day cycle.
Levels of Expression of
CYR61
and
CTGF
Are Prognostic for Tumor Progression and Survival of Individuals with Gliomas
Authors: Xie Dong , Yin Dong , Wang He-Jing , Liu Gen-Tao , Elashoff Robert , Black Keith , Koeffler H. Phillip 
Published: September 2005

Abstract
The biological properties of CCN proteins include stimulation of cell proliferation, migration, and adhesion, as well as angiogenesis and tumorigenesis. We quantified CYR61, CTGF, WISP-1, and NOV mRNA expression levels in samples from sixty-six primary gliomas and five normal brain samples using quantitative real-time PCR assay. Statistical analysis was performed to explore the links between expression of the CCN genes and clinical and pathological parameters. Overexpression of CYR61, CTGF, WISP-1, and NOV occurred in 48% (32 of 66), 58% (38 of 66), 36% (24 of 66), and 15% (10 of 66) of primary gliomas, respectively. Interestingly, significant associations were found between CYR61 expression versus tumor grade, pathology, gender, and age at diagnosis. Also, a significant correlation existed between CTGF mRNA levels versus tumor grade, gender, and pathology. In contrast to CYR61 and CTGF, no significant association was found between expression of either WISP-1 or NOV versus any of the pathological features. Furthermore, Cox regression analysis showed that CYR61 and CTGF expression had a significant correlation with patient survival. These results suggest that CYR61 and CTGF may play a role in the progression of gliomas; their levels at diagnosis may have prognostic significance; and these proteins might serve as valuable targets for therapeutic intervention.
Elevated Serum Insulin-Like Growth Factor Binding Protein-2 as a Prognostic Marker in Patients with Ovarian Cancer
Authors: Baron-Hay Sally , Boyle Frances , Ferrier Alan , Scott Carolyn 
Published: September 2005

Abstract
Purpose: The purpose of this research was to examine the diagnostic and prognostic significance of elevated serum insulin-like growth factor binding protein (IGFBP)-2 levels in women with ovarian cancer from diagnosis through treatment to relapse or remission.
Experimental Design: Serum collected pre- and postoperatively in women newly diagnosed with ovarian cancer, during adjuvant chemotherapy cycles, at 6 months follow-up and at relapse was analyzed for IGFBP-2. Control serum was from women undergoing pelvic or abdominal surgery for benign ovarian disease or nonovarian pathology.
Results: IGFBP-2 at diagnosis was significantly elevated (P &lt; 0.0001) in women with ovarian cancer (887 ± 62 ng/ml) compared with benign controls (337 ± 25 ng/ml), and women undergoing nonovarian surgery (439 ± 49 ng/ml) and correlated positively with tumor stage and cellular differentiation but not with CA125. Unexpectedly, IGFBP-2 levels increased additionally 1-week postoperatively in ovarian cancer patients (1581 ± 90 ng/ml; P = 0.0027) as well as controls (977 ± 95 ng/ml; P &lt; 0.0001) and was higher in women who had suboptimal debulking compared with optimal debulking of their tumor. IGFBP-2 levels returned to normal in women without evidence of progressive disease, but remained significantly elevated in women who later relapsed. Patients with IGFBP-2 levels in the highest tertile at diagnosis had a significantly shorter progression-free interval and overall survival.
Conclusion: In ovarian cancer IGFBP-2 is elevated at diagnosis, and corresponds to stage and histology with patients in the highest tertile of IGFBP-2 more likely to relapse and have a poorer outlook. Identification of these patients at diagnosis may allow more individualized, aggressive adjuvant treatment and follow-up, and IGFBP-2 may therefore be an important additional prognostic marker in this disease.
Intratumoral CD8+ T Lymphocytes as a Prognostic Factor of Survival in Endometrial Carcinoma
Authors: Kondratiev Svetlana , Sabo Edmond , Yakirevich Evgeny , Lavie Ofer , Resnick Murray B. 
Published: September 2005

Abstract
Purpose: CTLs are a prominent immune component infiltrating many solid tumors. These cells are considered to be a manifestation of host-immune response to the tumor; however, their prognostic significance remains a subject of considerable debate. The objective of this study was to evaluate the distribution pattern and prognostic value of CD8+ T cells in endometrial carcinoma.
Experimental Design: We studied 90 cases of endometrial carcinoma, including 75 endometrioid and 15 papillary serous carcinomas. Immunohistochemical staining for CD8 and granzyme B was performed on paraffin-embedded sections. The number of immunohistochemically staining CD8+ T cells was enumerated in the following four regions: lymphocytes infiltrating the tumor epithelium at the invasive border, within the underlying tumor stroma, within the superficial tumor epithelium, and in the perivascular areas of the myometrium.
Results: Patients with &gt;10 CD8+ T lymphocytes/high-power field within the tumor epithelium at the invasive border displayed improved overall survival compared with patients with fewer intraepithelial CD8+ T lymphocytes (87 and 50%, respectively; P = 0.027). Multivariate analysis revealed that stage, vascular invasion, grade, and the number of intraepithelial CD8+ T lymphocytes at the invasive border were the only independent predictors of survival (P &lt; 0.0001, P = 0.001, P = 0.011, and P = 0.025, respectively). Granzyme B+ cytoplasmatic granules were detected in a high proportion of CTLs, confirming their activated cytotoxic phenotype.
Conclusions: Our study demonstrates for the first time that increased numbers of CTLs at the invasive border may be a reliable independent prognostic factor of survival in patients with endometrial carcinoma.
The Effects of Standard Anthracycline-Based Chemotherapy on Soluble ICAM-1 and Vascular Endothelial Growth Factor Levels in Breast Cancer
Authors: Mills Paul J. , Parker Barbara , Jones Vicky , Adler Karen A. , Perez Christy J. , Johnson Sherella , Cohen-Zion Mairav , Marler Matthew , Sadler Georgia R. , Dimsdale Joel E. , Ancoli-Israel Sonia 
Published: September 2005

Abstract
Purpose: The circulating soluble form of intercellular adhesion molecule-1 (sICAM-1) and vascular endothelial growth factor (VEGF) are elevated in women with breast cancer and associated with tumor progression and poor prognosis. This study examined the effects of anthracycline-based chemotherapy on plasma sICAM-1 and VEGF, as well as soluble P-selectin, von Willebrand factor, and interleukin-6 levels.
Experimental Design: Twenty-six women diagnosed with stage I–IIIA breast cancer (mean age, 48.4 ± 10.4 years; range, 34–79 years) were studied before (week 1) and at weeks 2 and 3 of cycles 1 and 4 of chemotherapy.
Results: The initial effect of chemotherapy was to reduce sICAM-1 levels; compared with pretreatment, sICAM-1 levels were decreased at week 2 of both cycles (P values &lt; 0.01). sICAM-1 levels were elevated, however, at the start of cycle 4 as compared with pretreatment (P &lt; 0.01). Chemotherapy led to an increase in sICAM-1 levels in node-positive but not node-negative patients (P &lt; 0.01). VEGF levels were decreased at week 2 of cycle 4 (P = 0.001) and remained so at week 3. Similar to sICAM-1, VEGF levels were elevated at the start of cycle 4 as compared with pretreatment (P &lt; 0.006). Soluble P-selectin levels decreased during week 2 of cycle 4 (P = 0.026). Neither interleukin-6 or von Willebrand factor were significantly changed in response to chemotherapy.
Conclusions: The findings support prior studies suggesting that sICAM-1 levels derive from sources other than endothelial cells. In addition, whereas the more immediate effect of chemotherapy is to reduce sICAM-1 and VEGF, continued treatment may lead to significant elevations.
Role of Estrogen Receptor in the Regulation of Ecto-5′-Nucleotidase and Adenosine in Breast Cancer
Authors: Spychala Jozef , Lazarowski Eduardo , Ostapkowicz Anna , Ayscue Lanier H. , Jin Aiwen , Mitchell Beverly S. 
Published: September 2005

AbstractPurpose: The purpose is to understand the expression of ecto-5′-nucleotidase (eN), an adenosine producing enzyme with potential roles in angiogenesis, growth, and immunosuppression, in estrogen receptor (ER)-negative and -positive breast cancer.Experimental Design: We investigated the regulation of eN expression at the mRNA and protein levels by α in a panel of breast cancer cell lines that differ in ER status and invasive and metastatic potential. We also determined rates of adenosine formation in cells with high and low eN expression and in ER+ cells treated with estradiol.Results: ER-negative cells express high eN protein and mRNA levels and produce up to 104-fold more adenosine from AMP and ATP. Estradiol and antiestrogen treatments confirm that eN mRNA and protein expression and adenosine generation are negatively regulated through the ER. Endogenous expression of eN in ER− cells transfected with ERα and phorbol ester-induced eN expression in ER+ cells was strongly suppressed by estradiol, suggesting a dominant function of ER. Finally, an examination of 18 clinical breast cancer samples that were analyzed for both ER status and eN expression by Martin et al. (Cancer Res., 60: 2232–2238, 2000) revealed a significant inverse correlation between ER and eN status.Conclusions: Our results show for the first time that eN is negatively regulated by ERα in dominant fashion and suggests that eN expression and its generation of adenosine may relate to breast cancer progression. Additionally, increased expression of eN in a subset of ER-negative cells may serve as a novel marker for a subset of more aggressive breast carcinoma.