Biomedical subjects

Ronald D Alvarez

Publications and source records attributed to Ronald D Alvarez.

At least 37 records · Page 2Linked to original sources

PubMed2005

Targeted gene therapy for ovarian cancer.

Despite advances in therapy, advanced ovarian cancer maintains a dismal overall survival of 15-30%. Thus, the need for novel therapeutic modalities exists. Gene therapy represents one such approach and the purpose of this review is to present a logical rationale for the investigation of gene therapy for the treatment of ovarian cancer. The different strategies of gene therapy (molecular chemotherapy (prodrugs), mutation compensation, immunotherapy approaches, altered drug sensitivity, and virotherapy) for cancer treatment are discussed separately with attention to investigations with clinical applicability. Furthermore, the different viral vectors utilized for improvements in targeted therapy are presented. The advancements, discovery, and shortcomings are reviewed which lend itself to future directions. These future directions involve coxsackie-adenovirus receptor (CAR) independent pathways to improve infectivity and specificity to ovarian tumor cells, the potential of utilizing gene therapy as an imaging modality in detecting cancer, and incorporating the recently described technique of RNA interference. Due to the advancements in detection and targeting of ovarian cancer, coupled with the containment to the intraperitoneal cavity, gene therapy remains a promising treatment modality for ovarian cancer.

Clinical Trials as Topic↗

PubMed2005

Incorporating the survivin promoter in an infectivity enhanced CRAd-analysis of oncolysis and anti-tumor effects in vitro and in vivo.

Conditionally replicating adenoviruses (CRAds) represent a promising new modality for the treatment of cancer. A key contribution in this regard was the introduction of tumor-selective viral replication for amplification of the initial inoculum. Specifically, following cellular infection, the virus replicates selectively in the infected tumor cells and kills the cells by cytolysis. Next, the progeny virions infect surrounding target cells, replicate and eradicate the infected tumor cells, leaving normal cells unaffected. However, to date there have been two limitations to clinical application of these CRAd agents; i.e., both infectivity and tumor specificity are poor. Survivin protein is a novel member of the inhibitor of apoptosis (IAP) protein family, which plays an important role in the survival of cancer cells and progression of malignancies. Previous data have shown the survivin promoter has high activities in multiple cancer cells with a low activity in mouse liver. In this study, we propose an improved CRAd agent to circumvent the obstacles. We constructed a novel CRAd agent, CRAd-Survivin-RGD, which contains both the survivin promoter (either the short version, S-S, or the long version, S-L) to selectively drive E1 gene expression in tumor cells and a capsid modification and RGD4C to specifically enhance the tumor infectivity of CRAd agents. Both CRAd agents (S-S and S-L) showed high replication rates in the breast cancer cell line, MDA-MB-361, and low promoter activity in both normal mouse and human liver, thus signifying the CRAd agents have the phenotype of 'tumor on/liver off'. In cytocidal experiments, the CRAd agents demonstrated a high cytocidal effect on multiple cancer cell lines, including the breast cancer cell line, MDA-MB-231; the glioma cell line, D65, the melanoma cell line, MEL-28; and mesothelioma, Meso2374. The results also showed the tumor growth was dramatically inhibited by intertumoral administration of the CRAd agents in a breast cancer (MDA-MB-361) xenograft animal model. These data clearly demonstrate that CRAd-Survivin-RGD is a potential novel therapeutic agent for treatment in many, but not all, human cancers.

Adenoviridae↗

PubMed2004

A novel ex vivo model system for evaluation of conditionally replicative adenoviruses therapeutic efficacy and toxicity.

PURPOSE: Current animal tumor models are inadequate for the evaluation of toxicity and efficacy of conditionally replicative adenoviruses. A novel model system is needed that will provide insight into the anticipated therapeutic index of conditionally replicative adenoviruses preclinically. We endeavored to show a novel model system, which involves ex vivo evaluation of conditionally replicative adenovirus toxicity and therapeutic efficacy in thin, precision-cut slices of human primary tumor and liver. EXPERIMENTAL DESIGN: The Krumdieck thin-slice tissue culture system was used to obtain and culture slices of tumor xenografts of ovarian cancer cell lines, human primary ovarian tumors, and human liver. We determined the viability of slices in culture over a period of 36 to 48 hours by ([3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxphenyl-2-(4-sulfophenyl)-2H-tetrazolium, inner salt)]) (MTS) assay. In vitro Hey cells, slices of Hey xenografts, and human ovarian tumor or human liver slices were infected with 500vp/cell of either replication competent wild-type adenovirus (Ad5/3wt), conditionally replicative adenovirus (Ad5/3cox-2), or the replication deficient adenovirus (Ad5/3luc1). At 12-, 24-, and 36-hour intervals, the replication of adenoviruses in these slices was determined by quantitative reverse transcription-PCR of adenoviral E4 copy number. RESULTS: Primary tumor slices were able to maintain viability for up to 48 hours after infection with nonreplicative virus (Ad5luc1). Infection of Hey xenografts with Ad5/3cox-2 showed replication consistent with that seen in Hey cells infected in an in vitro setting. Primary tumor slices showed replication of both Ad5/3wt and Ad5/3cox over a 36-hour time period. Human liver slices showed replication of Ad5/3wt but a relative reduction in replication of Ad5/3cox-2 indicative of conditional replication "liver off" phenotype, thus predicting lower toxicity. CONCLUSIONS: The thin-slice model system represents a stringent method of ex vivo evaluation of novel replicative adenoviral vectors and allows assessment of human liver replication relative to human tumor replication. This is the first study to incorporate this system for evaluation of therapeutic efficacy and replicative specificity of conditionally replicative adenoviruses. Also, the study is the first to provide a valid means for preclinical assay of potential conditionally replicative adenovirus-based hepatotoxicities, thus providing a powerful tool to determine therapeutic index for clinical translation of conditionally replicative adenoviruses.

Adenoviridae↗

PubMed2004

Gene transfer to cervical cancer with fiber-modified adenoviruses.

Successful adenoviral (Ad) vector-mediated strategies for cancer gene therapy mandate gene-delivery systems that are capable of achieving efficient gene delivery in vivo. In many cancer types, in vivo gene-transfer efficiency remains limited due to the low or highly variable expression of the primary Ad receptor, the coxsackie Ad receptor (CAR). In this study, we evaluated the expression of CAR on cervical cancer cells as well as CAR-independent targeting strategies to integrins (Ad5.RGD), heparan sulfate proteoglycans (Ad5.pK7) or both (Ad5.RGD.pK7). We used a panel of established cervical cancer cell lines and primary cervical cancer cells isolated from patients to quantify the expression of CAR mRNA and to evaluate the gene-transfer efficiency of fiber-modified Ads. Of the fiber-modified vectors, Ad5.pK7 and Ad5.RGD.pK7 displayed significantly enhanced gene-transfer efficiency in vitro. Gene-delivery efficiency in vivo was evaluated using an s.c. cervical cancer mouse model. Ad5.RGD.pK7 significantly improves tumor targeting in vivo, resulting in a significantly improved tumor/liver ratio in mice. Our results suggest that the double-modified Ad5.RGD.pk7 vector enhances gene transfer to clinically relevant cervical cancer substrates, while the infectivity of nontarget cells in the mouse is not increased and comparable to Ad5. The fiber-modified virus described here can help achieve higher clinical efficacy of cervical cancer gene therapy.

Adenoviridae↗

PubMed2004

Transport across a polarized monolayer of Caco-2 cells by transferrin receptor-mediated adenovirus transcytosis.

Adenoviral vectors have a poor record of transgene delivery efficiency through physical barriers such as the epithelium or endothelium. We report here the construction of an adenoviral vector that has the capability to be transported across polarized epithelial monolayers of Caco-2 cells (a colon carcinoma cell line) by transcytosis. This transcytosis is transferrin receptor (TfR)-mediated with use of a bifunctional adaptor, soluble coxsackie adenovirus receptor (sCAR)-Tf, and is both temperature and iron dependent. Under experimental conditions, the adenoviral transcytosis was inhibited by pretreatment of Caco-2 cells with colchicine, an inhibitor of transcytosis, and was not enhanced by pretreatment with Brefeldin A (BFA), an enhancer of transcytosis. In these Caco-2 cells, the transcytosis rate was 0.3 +/- 1.3% (SD). The transcytosed adenoviruses remain biologically functional. These data suggest the potential clinical benefit under conditions where drug delivery is a challenge, such as within the airway epithelium, at the bladder lumen urothelial cell interface, and across the blood-brain barrier for clinical treatment of lung, urogenital, and brain disorders, respectively, by adenoviral transcytosis of transgene delivery.

ATPases Associated with Diverse Cellular Activitie↗

PubMed2004

Transcriptional blocks limit adenoviral replication in primary ovarian tumor.

PURPOSE: Despite the success of conditionally replicating adenoviruses in tumor models, clinical success has been limited when they are used as a single modality agent. Overcoming the disparity in efficacy between in vivo animal models and human use is a key hurdle for better conditionally replicating adenovirus therapy in humans. We endeavored to identify biological blocks to adenoviral infection and replication in tumor cells. EXPERIMENTAL DESIGN: We hypothesized that the differences in adenoviral replication between ovarian cancer cell lines and patient tumor samples are the result of a block in viral RNA transcription. To test this hypothesis, established ovarian cancer cell lines and purified patient ovarian cancer cells were infected with wild-type adenovirus. RNA for early adenoviral genes E1A and E1B as well as the late transcripts for fiber and hexon were measured using real-time PCR. RESULTS: Established ovarian cancer cell lines treated with wild-type virus had a lower E1A:E1B ratio than the patient samples. Additionally, the levels of fiber and hexon relative to E1A were also decreased in the patient samples compared with the established cell lines. These findings were consistent with an early- to late-phase block in the adenovirus replication cycle. CONCLUSIONS: These data suggest that the biology of abortive infection in the patient samples may be linked to a defect in the production of early and late viral transcripts. Identification of factors leading to abortive infection will be crucial to understanding the low viral replication in patient samples.

Adenoviridae↗

PubMed2004

Expression of sperm protein 17 (Sp17) in ovarian cancer.

Sperm protein 17 (Sp17) is an antigenic protein highly expressed in spermatozoa. Sp17 expression was demonstrated recently in multiple myeloma, suggesting that it may be a novel cancer-testis antigen. Expression of Sp17 mRNA and protein was examined in human ovarian tumors. Sp17 mRNA was evaluated by reverse transcription-polymerase chain reaction (RT-PCR) and Northern blot analysis of RNA derived from epithelial ovarian tumors and normal tissues. RT-PCR analysis detected Sp17 transcripts in 15 of 18 (83%) primary ovarian tumors. The transcript was not detected in RNA derived from normal uterus or cervix, whereas weak expression was noted in some normal ovarian tissue samples. Northern blot analysis showed no detectable Sp17 mRNA expression in normal tissues, including normal ovary, but showed Sp17 expression in 17 of 25 ovarian tumors (68%). To evaluate protein expression, mouse monoclonal antibodies were produced against recombinant Sp17 protein and used in Western blot and immunohistochemical analyses of normal reproductive tissue and primary ovarian tumor samples. Sp17 protein was detected by Western blot analysis in normal spermatozoa and in 8 of 19 ovarian tumor samples. Immunohistochemical studies showed Sp17 expression in spermatozoa, ciliated cells of the female reproductive tract, and most ovarian tumors evaluated. Tumors showed a predominantly nuclear localization of Sp17 expression, with some cytoplasmic staining. These results demonstrate that Sp17, a protein with restricted expression in somatic tissues, is expressed in ovarian tumors. Because Sp17 is immunogenic, it may represent a novel target for immunotherapeutic interventions for ovarian cancer patients.

Antibodies, Monoclonal↗

PubMed2004

Inter-patient variation in efficacy of five oncolytic adenovirus candidates for ovarian cancer therapy.

BACKGROUND: Gene therapy offers a new strategy for cancer treatment. Adenoviruses represent the most widely used gene therapy vector and feature an excellent safety record. Conditionally replicative adenoviruses (CRAds) effect solid tumor penetration and tumor selective oncolysis and consequently offer potential efficacy for metastatic disease treatment. We evaluated five CRAds as candidate clinical agents for ovarian cancer therapy: RGDCRADcox-2R, Ad5VEGFE1, Ad5/3VEGFE1, Ad5-Delta24RGD, and Ad5/3-Delta24. METHODS: DNA replication by these five CRAds, wild-type adenovirus, and an E1-deleted control was measured in purified primary ovarian cancer cell spheroids by quantitative PCR. CRAd-mediated oncolysis was quantified in ovarian cancer cell monolayers and three-dimensional spheroids by cellular viability assays. The therapeutic efficacy of each CRAd was tested by intraperitoneal administration in mice with peritoneally disseminated human ovarian cancer. RESULTS: An increase in viral DNA was noted in primary tumor cell spheroids for all replicative viruses tested. Variation was noted in viral DNA replication between patient samples. All five CRAds induced remarkable oncolysis. They also prolonged survival in vivo compared with the wild-type control group. CONCLUSIONS: All five CRAds tested showed robust DNA replication, oncolysis, and in vivo therapeutic efficacy. Each virus has potential for clinical testing, and such further testing will ultimately determine its safety and relative usefulness. Variation of CRAd DNA replication between different patient samples suggests that target tissue features, such as surface receptors and endogenous transcription factors, may affect CRAd infectivity and replicativity. Evaluation of such factors may become important to optimize cancer therapy for individual patients.

Adenocarcinoma↗

PubMed2004

Optical detection of high-grade cervical intraepithelial neoplasia in vivo: results of a 604-patient study.

OBJECTIVE: The purpose of this study was to assess the in vivo optical detection of high-grade cervical intraepithelial neoplasia (2/3+) on the whole cervix with a noncontact, spectroscopic device. STUDY DESIGN: Cervical scanning devices collected intrinsic fluorescence and broadband white light spectra and video images from 604 women during routine colposcopy examinations at 6 clinical centers. A statistically significant dataset was developed of intrinsic fluorescence and white light-induced cervical tissue spectra that was correlated to expert histopathologic determination. On the basis of a retrospective analysis of the acquired data, a classification algorithm was developed, validated, and optimized. RESULTS: Intrinsic fluorescence, backscattered white light, and video imaging each contribute complementary information to diagnostic algorithms for high-grade cervical neoplasia. More than 10000 measurements that were made on colposcopically identified tissue from >500 subjects were the basis for algorithm training and testing. Algorithm performance demonstrated a sensitivity of approximately 90%. This performance was confirmed by various training methods. With the use of a multivariate classification algorithm, optical detection is predicted to detect 33% more high-grade cervical intraepithelial neoplasia (2/3+) than colposcopy alone. CONCLUSION: Full cervix optical interrogation for the detection of high-grade cervical intraepithelial neoplasia is feasible and appears capable of detecting more high-grade cervical intraepithelial neoplasia than colposcopy alone. With the use of this classification algorithm, a multisite, randomized controlled trial is underway that compares the combination of optical detection and colposcopy versus colposcopy alone.

Adolescent↗

PubMed2004

The role of radical parametrectomy in the treatment of occult cervical carcinoma after extrafascial hysterectomy.

OBJECTIVES: To assess the morbidity and efficacy of radical parametrectomy (RP) performed following extrafascial hysterectomy in patients with occult cervical carcinoma. METHODS: An IRB approved retrospective chart review identified 23 patients that underwent RP with pelvic and/or para-aortic lymphadenectomy and upper vaginectomy. Data were collected on demographics, tumor stage, grade, histology, indication for hysterectomy, surgical findings, complications, recurrence, and survival. RESULTS: Of the 23 patients, 2 patients had a stage IA(2) lesion while 21 patients had a stage IB(1) lesion. There were 5 patients with a grade 1 tumor, 10 with grade 2, 4 with grade 3, and 4 with unknown grade. Median age was 41 years (range 27-59). The most common indication (48%) for extrafascial hysterectomy was CIS of the cervix. Four patients (17%) had metastasis to pelvic nodes or evidence of tumor at the margin at the time of RP. Three of these 4 patients with a positive specimen received adjuvant radiation and all are alive (mean follow-up 66 months). One patient declined radiation and is alive at 42 months. There were 7 (30%) operative complications: Most notably 4 patients received blood transfusions. Two of 19 patients (11%) with no residual tumor in RP specimen recurred and 1 patient was salvaged with radiation (follow-up 103 months). With a median follow-up of 61 months (range 9-103), overall 5-year survival is 96%. CONCLUSIONS: RP is an acceptable option for patients diagnosed with an occult cervical carcinoma at the time of extrafascial hysterectomy. Careful selection of RP for patients unlikely to have residual tumor will obviate the need for radiation in most instances.

Adult↗

PubMed2004

Infectivity enhanced adenoviral-mediated mda-7/IL-24 gene therapy for ovarian carcinoma.

OBJECTIVE: Melanoma differentiation associated gene-7 [mda-7/Interleukin (IL)-24] has been identified as a novel anti-cancer agent, which specifically induces apoptosis in cancer cells but not in normal epithelial, endothelial and fibroblast cells. The objective of this study was to evaluate the anti-tumor effect of adenovirus-mediated mda-7/IL-24 (Ad.mda-7) gene therapy in ovarian carcinoma and further improve anti-tumor effect by enhancing infectivity of Ad.mda-7. METHODS: A panel of human ovarian carcinoma cells, OV-4, HEY, SKOV3, SKOV3.ip1 and control normal human mesothelial cells, were infected by a replication deficient recombinant adenovirus encoding mda-7/IL-24 and control virus Ad.CMV.Luc. After 72 h, apoptosis was evaluated by TUNEL and Hoechst staining and further quantified by fluorescent activated cell sorter (FACS) analysis. Infectivity of Ad.mda-7 was enhanced by retargeting it to CD40 or EGF receptors overexpressed on ovarian cancer cells. Subsequently, enhancement in apoptosis of CD40- or epidermal growth factor receptor (EGFR)-retargeted Ad.mda-7 was evaluated. RESULTS: Adenoviral-mediated delivery of mda-7 induces apoptosis ranging from 10-23% in human ovarian cancer cells tested with the highest percentage of apoptosis noted in SKOV3 cells. Minimal apoptosis was noted in normal mesothelial cells. CD40- or EGFR-retargeted Ad.mda-7 increased apoptosis by 10-32% when compared to that achieved with untargeted Ad.mda-7. CONCLUSION: Ad.mda-7 exhibits ovarian cancer-specific apoptosis, but does not affect normal human mesothelial cells. Infectivity enhanced CD40- and EGFR-retargeted Ad.mda-7 augments apoptosis induction, thus increasing the therapeutic index and translational potential of Ad.mda-7 gene therapy.

Adenoviruses, Human↗

PubMed2004

The impact of aborted radical hysterectomy in patients with cervical carcinoma.

OBJECTIVE: To determine the impact of an aborted radical hysterectomy on morbidity and overall survival in patients undergoing surgical treatment for early stage cervical carcinoma. METHODS: Following IRB approval, a computerized database identified 304 women treated with radical surgery for early stage cervical carcinoma from 1994 to 2000 of which 23 (8%) had an aborted radical hysterectomy. RESULTS: Of the 23 patients, 17 patients had a IB(1) lesion, 4 patients had a IB(2) lesion, and 2 patients had a IIA lesion. Median age was 42 years (range 28-60). Twenty-one patients had squamous cell carcinoma and two patients had adenocarcinoma. Radical hysterectomy was aborted for the following reasons: 11 patients had pelvic extension, seven had positive pelvic nodes, and five patients had positive paraaortic nodes. All 23 patients received postoperative radiation therapy; additionally, 12 patients received concurrent chemotherapy consisting of platinum with or without 5-FU. There were four operative complications (17%) including deep vein thrombosis, wound infection, blood transfusion, and an ileus. Four patients (17%) had radiation-associated complications. Six of 23 (26%) patients experienced a recurrence. The 5-year overall survival was 83% with a median follow-up of 59 months (range 12-107 months). CONCLUSIONS: A small percentage of patients (8%) with early stage cervical carcinoma will have an aborted radical hysterectomy for pelvic extension or positive nodes. Fortunately, these patients still have a favorable prognosis with postoperative radiation therapy. Aborted radical surgery does not significantly increase overall complications.

Adenocarcinoma↗

PubMed2004

Retrospective analysis of weekly topotecan as salvage therapy in relapsed ovarian cancer.

OBJECTIVE: To retrospectively investigate the safety and efficacy of weekly topotecan in heavily pretreated patients with ovarian cancer. METHODS: Data were collected by retrospective review of patient records. Eligible patients had received > or =2 prior regimens for ovarian cancer before treatment with weekly topotecan. Efficacy was determined by measurable disease or CA 125 levels. Adverse event and growth factor support data were also collected. RESULTS: Fifty patients (median age, 61 years) were evaluable for safety and received a total of 244 4-week cycles of therapy (median, 3; range, 1-21 cycles). Most patients (84%) had measurable disease, and 30% had performance status of > or =2. Patients had received two to six prior treatments for ovarian cancer. Median weekly dose per patient was topotecan 3.7 mg/m(2). Grade 4 hematologic toxicities (generally manageable) occurred in 4% of patients. One patient had febrile neutropenia. Grade 3/4 nonhematologic toxicities were fatigue in two (4%) patients. Forty-two patients were evaluable for response. Of 35 evaluable patients with measurable disease, 11 (31%) had a partial response (median duration, 3 months), and 15 (43%) patients had stable disease (median duration, 3.5 months). Of 41 evaluable patients with elevated CA 125 (median, 154 U/l; range, 47-7200 U/l), 11 (27%) had > or =50% decreases or normalization of CA 125 levels. Median time to progression in all patients with stable disease has not been reached (follow-up range, 1.5-17.3 months). CONCLUSIONS: Weekly topotecan is active and well tolerated in heavily pretreated patients with relapsed ovarian cancer. Prospective studies of this regimen are warranted.

Adult↗

PubMed2004

Transcriptional targeting of tumors with a novel tumor-specific survivin promoter.

It has been demonstrated that survivin, a novel member of the inhibitor of apoptosis (IAP) protein family, is expressed in human cancers but is undetectable in normal differentiated tissues. We employed a recombinant adenoviral vector (reAdGL3BSurvivin) in which a tumor-specific survivin promoter and a luciferase reporter gene were inserted into the E1-deleted region of adenovirus vector. Luciferase activity was measured in both multiple tumor cell lines and two primary melanoma cells infected with reAdGL3BSurvivin. Human fibroblast and mammary epithelial cell lines were used as negative controls. A reAdGL3CMV, containing the CMV promoter and luciferase gene, was used as a positive control to normalize the luciferase activity generated by the survivin promoter. Our data revealed that the survivin promoter showed high activity in both established tumor cell lines and the primary melanoma cells. In contrast, the in vivo studies indicated that the activities of survivin promoter were extremely low in the major mouse organs. The survivin promoter appears to be a promising tumor-specific promoter exhibiting a "tumor on" and "liver off" profile, and therefore, it may prove to be a good candidate for transcriptional targeting of cancer gene therapy in a wide variety of tumors.

Adenoviridae↗

PubMed2004

Genetic replacement of the adenovirus shaft fiber reduces liver tropism in ovarian cancer gene therapy.

Approaches to alter the native tropism of adenoviruses (Ads) are beneficial to increase their efficacy and safety profile. Liver tropism is important with regard to potential clinical toxicity in humans. Ad5/3 chimeras in which the Ad5 knob is substituted by the Ad3 knob, such as Ad5/3luc1, have been recently shown to increase infectivity of ovarian cancer cell lines and primary tumor cells, which express low levels of the coxsackie-adenovirus receptor (CAR), without increasing infectivity of liver cells. A novel strategy to address the problem of liver uptake and improve the tumor/liver ratio is genetic replacement of the Ad fiber shaft. Ad5.Ad3.SH.luc1 is an Ad5-based vector that contains the fiber shaft from Ad serotype 3 but the fiber knob from Ad serotype 5. To compare tumor/liver of Ad5.Ad3.SH.luc1 and Ad5/3luc1 in vivo, we created three different tumor and treatment models of ovarian cancer in mice, simulating intraperitoneal and intravenous administration of tumors. Ad5.Ad3.SH.luc1 displayed the lowest liver tropism of all viruses in all models tested. Intravenous administration of all viruses resulted in higher tumor transduction rates compared to intraperitoneal administration. Genetic shortening of the Ad5 fiber shaft significantly increases relative tumor/liver gene transfer. This could improve the effective tumor dose and reduce side effects, thereby increasing the bioavailability of therapeutic agents.

Adenoviruses, Human↗

PubMed2004

High-risk human papillomavirus and cervical intraepithelial neoplasia at time of atypical squamous cells of undetermined significance cytologic results in a population with human immunodeficiency virus.

OBJECTIVE: Little information exists regarding high-risk human papillomavirus (HPV) subtypes in human immunodeficiency virus (HIV) patients with atypical squamous cells of undetermined significance (ASCUS) cytologic results. This study aimed to characterize further HPV prevalence and high-grade cervical intraepithelial neoplasia (CIN) in this sub-population of patients. MATERIALS AND METHODS: This is a secondary analysis of a prospective HPV natural history study involving 200 HIV-sero-positive patients. We analyzed 102 patients from this cohort with a cervical cytologic diagnosis of ASCUS for high-risk and low-risk HPV prevalence, clearance of HPV infection, progression or regression of cervical cytologic abnormality, and prevalence of CIN 2 or worse at the time of indicated colposcopy. Pap smears were slide-based and HPV testing was performed using nested polymerase chain reaction. RESULTS: Overall prevalence of ASCUS in the HIV population was 20% (40 of 200 patients). Despite a high prevalence of all HPV subtypes (74 of 102 subtypes; 73%), high-risk subtypes were present in only 32% of patients (33 of 102 patients) with ASCUS cytologic results. In 5 of 42 patients (12%) undergoing colposcopy within 6 months of ASCUS cytologic results, CIN 2 or worse was found. Sensitivity, specificity, positive predictive value, and negative predictive value of a high-risk or intermediate-risk HPV test for CIN 2,3 were 100%, 70%, 31%, and 100%, respectively. Progression to high-grade intraepithelial lesion cytologic results after ASCUS was rare (5/64 evaluable patients; 8%) but persistence of low-grade cytologic results (ASCUS or low-grade intraepithelial lesion) was common (43/64 evaluable patients; 67%). CONCLUSIONS: Despite a high rate of HPV infection in the HIV population with ASCUS Pap results, high-risk HPV subtypes represent a minority of patients and are significantly associated with presence of high-grade CIN at colposcopy. High-risk HPV testing should be investigated further in the HIV population.

Journal Article↗

PubMed2004

Novel therapies for recurrent ovarian cancer management.

The search for novel therapies has resulted in a number of biologic agents that target cellular processes and molecules involved in ovarian carcinogenesis. These drugs include cytokines, monoclonal antibodies, vaccines, protease inhibitors and gene replacement systems. Many of these have been evaluated in Phase I/II trials and are currently being investigated in Phase III trials. This paper will review the progress of and ongoing clinical studies evaluating the potential utility of these new agents in patients affected with ovarian cancer. Further development and investigation of these agents may eventually lead to a combination of treatments that ultimately results in improved survival for patients with ovarian cancer.

Adjuvants, Immunologic↗

PubMed2004

Single-chain antibodies: A therapeutic modality for cancer gene therapy (review).

Gene therapy has rapidly evolved into a field that is treating not only inborn errors of metabolism, but other diseases associated with poor outcomes such as malignancy, where transient gene expression can be therapeutic. Cancer gene therapy is a novel form of treatment that exploits differences at the molecular level between normal and malignant cells. Current gene therapy approaches that are being evaluated include the use of replication competent viruses, mutation compensation strategies, improved targeting with tumor specific promoters, and the utilization of enhanced infectivity viruses. An additional aspect of gene therapy that has gained increased interest in the last several years is the utilization of single-chain antibodies (scFv). Specifically, scFv have been utilized to target molecular processes associated with carcinogenesis, as well as to improve gene transfer efficiency. We will limit our discussion to the role of scFv in targeting molecular processes associated with carcinogenesis.

Forecasting↗