Clinical cancer research : an official journal of the American Association for Cancer Research, 2002
The purpose of our study was to characterize a human papillomavirus (HPV) 16 DNA integration in t... more The purpose of our study was to characterize a human papillomavirus (HPV) 16 DNA integration in the genome of a rapidly progressive, lethal cervical cancer in a 39-year-old woman. An HPV 16 integration site from cervical cancer tissue was cloned and analyzed using Southern blot hybridization, nucleotide sequencing, fluorescence in situ hybridization analysis for chromosomal localization and comparison with the draft human genome sequence. HPV 16 DNA (3826 bp) was integrated into the genome of the tumor sample and contained an intact upstream regulatory region and E6 and E7 open reading frames. Both 5' and 3' viral-cell junction regions contained direct repeat and palindrome sequences. The chromosomal location of the viral integration and cellular deletion was mapped to chromosome 14q32.3 using both a somatic cell hybrid panel and fluorescence in situ hybridization. Search of the draft human genome sequence confirmed the chromosomal location and revealed a disruption of the TNFAIP2 cytokine/retinoic acid-inducible gene. On the basis of the lack of sequence homology between the viral and cellular site of integration and the structure of the viral-cell junctions, it seems that HPV 16 DNA integrates into the host genome by a mechanism of nonhomologous recombination. We suggest that, taken together, maintenance of E6 and E7 expression, loss of the E2 gene and disruption of the TNFAIP2 gene through viral integration contributed to the rapid progression of cervical cancer in this patient. Availability of the human genome sequence will facilitate identification of cellular genes involved in cervical cancer by high-throughput analysis of viral integration sites.
Human papillomavirus (HPV) has been established as an important etiological factor for the develo... more Human papillomavirus (HPV) has been established as an important etiological factor for the development of cervical cancer. This DNA virus primarily infects the epithelium and can induce benign and malignant lesions of the mucous membranes and skin. Some HPVs are considered high risk due to their role in malignant progression of cervical tumors. Genital HPV infections are common and usually transient among young sexually active women. Only a small fraction of infected women develop cervical cancer, implying the involvement of environmental and genetic cofactors in cervical carcinogenesis. Classification, virology, pathology, natural history, epidemiological features of genital HPV infection, and future prospects for cervical cancer prevention with HPV vaccines will be reviewed here.
We review the recent literature on anogenital neoplasms in AIDS, with emphasis on cancers associa... more We review the recent literature on anogenital neoplasms in AIDS, with emphasis on cancers associated with HPV infection. Immune reactivity to HPV as well as novel immunotherapeutic and preventative strategies are discussed. Many AIDS-associated neoplasms are associated with HPV infection. Whether cervical cancer is truly an AIDS-associated neoplasm has recently been questioned, while the association of anal cancer with AIDS in both males and females is more convincing. Recent reports cast doubt on the efficacy of HAART therapy for HPV-induced anogenital neoplasms, despite efficacy in improving disease caused by other infectious agents. We include here new data on humoral and cellular immune responses to HPV. VLP serology has been reported to be associated with outcome of cervical cancer. VLP seropositivity has been reported to be a favorable prognostic sign in women with HPV 16 positive cervical carcinoma. Several investigators have questioned the immunogenicity of the oncogenic HPV type 16 compared with other HPV types. It has recently been found that in HIV-infected patients, lymphoproliferative cellular immune responses (CMI) to HPV 16 peptides are not associated with CD4 counts, whereas responses to recall antigens and mitogens are associated with CD4 counts. CD4 + T cells may not be responsible for protective cellular immune responses to HPV. VLP serology and CMI responses may be the future intermediate surrogate biomarkers for HPV-associated anogenital neoplasia trials. Several new therapeutic vaccine strategies for management of HPV-induced neoplasia are reviewed. Most anogenital neoplasms occurring with increased frequency in patients with HIV/AIDS are associated with HPV infections. Current treatment strategies are not effective in clearing anogenital HPV infection and need improvement. Immunotherapy with novel vaccines will provide both prevention and therapy for these common malignancies.
Cervical disease burden continues to be especially high in HIV-infected women, even in the era of... more Cervical disease burden continues to be especially high in HIV-infected women, even in the era of effective antiretroviral medications. This review discusses the multiple issues surrounding HIV-associated cervical cancer. Also, the unique treatment-related issues in HIV-associated cervical cancer are addressed. The incidence of invasive cervical cancer has remained stable in industrialized nations; however, it is only estimated in developing countries secondary to a relative lack of data collection and registries. Trends in HIV-associated cervical cancer have changed in the highly active antiretroviral therapy (HAART) era. Recent molecular pathways suggest that the natural progression of human papillomavirus infection, the causal agent in all cervical cancers, may be related to immune system dysfunction as well as HIV/human papillomavirus synergistic mechanisms. When highly active retroviral therapies are used, invasive cervical cancer treatments are impacted by concomitant drug toxicities that could potentially limit therapeutic benefit of either HAART or the standard of care treatment for locally advanced cervical cancer, concomitant chemoradiotherapy. The significance and care of the patient with invasive cervical cancer is becoming a geographically relevant phenomenon such that it may be time to re-address the global definition. Further studies in treatment issues and drug-drug interactions with cervical cancer treatments in the setting of HIV are paramount.
Impaired glucose tolerance and diabetes are risk factors for the development of uterine cancer. A... more Impaired glucose tolerance and diabetes are risk factors for the development of uterine cancer. Although greater progression free survival among diabetic patients with ovarian and breast cancers using metformin has been reported, no studies have assessed the association of metformin use with survival in women with endometrial cancer (EC). We conducted a single-institution retrospective cohort study of all patients treated for uterine cancer from January 1999 through December 2009. Demographic, medical, social, and survival data were abstracted from medical records and the national death registry. Overall survival (OS) was estimated using Kaplan-Meier methods. Cox models were utilized for multivariate analysis. All statistical tests were two-sided. Of 985 patients, 114 (12%) had diabetes and were treated with metformin, 136 (14%) were diabetic but did not use metformin, and 735 (74%) had not been diagnosed with diabetes. Greater OS was observed in diabetics with non-endometrioid EC who used metformin than in diabetic cases not using metformin and non-endometrioid EC cases without diabetes (log rank test (p=0.02)). This association remained significant (hazard ratio=0.54, 95% CI: 0.30-0.97, p<0.04) after adjusting for age, clinical stage, grade, chemotherapy treatment, radiation treatment and the presence of hyperlipidemia in multivariate analysis. No association between metformin use and OS in diabetics with endometrioid histology was observed. Diabetic EC patients with non-endometrioid tumors who used metformin had lower risk of death than women with EC who did not use metformin. These data suggest that metformin might be useful as adjuvant therapy for non-endometrioid EC.
High-risk (HR) human papillomavirus (HPV) testing is important in cervical cancer screening for t... more High-risk (HR) human papillomavirus (HPV) testing is important in cervical cancer screening for triage to colposcopy. This study evaluated the clinical performance of the Cervista HPV HR and 16/18 genotyping tests for detection of HPV in cervical cytology specimens. The tests were prospectively evaluated in a multicenter clinical study. DNA was extracted from approximately 4000 residual liquid-based cytology specimens collected during routine liquid-based Papanicolaou tests at standard of care visits and was assessed for the presence of HR HPV and/or HPV types 16 and 18. All women with cytology results of atypical squamous cells of undetermined significance (ASC-US) or greater underwent colposcopic examination and biopsies were collected. Test results were compared with local colposcopy and histology results from a central pathology review panel. There were 1347 subjects with complete data sets of cytology, HR HPV, colposcopy, and histology included in the analysis of the HPV HR test. Sensitivity of the HPV HR test for detection of cervical intraepithelial neoplasia (CIN) 2+ among women with ASC-US cytology was 92.8% (95% confidence interval [CI]: 84.1-96.9) and the negative predictive value (NPV) was 99.1% (95% CI: 98.1-99.6). Sensitivity for detection of > or =CIN 3 in women with ASC-US was 100% (95% CI: 85.1-100) and the NPV was 100% (95% CI: 99.4-100). The specificity of the test for detection of > or =CIN 2 and > or =CIN 3 was 44.2% (95% CI: 41.5-46.9) and 43% (95% CI: 40.3-45.7), respectively. The HPV 16/18 genotyping test also performed as expected in women with ASC-US cytology who were positive for HR HPV. The Cervista HPV HR test can be clinically used for detecting HR HPV types in conjunction with cervical cytology for use in triage of women with ASC-US cytology during routine cervical cancer screening.
American journal of obstetrics and gynecology, Jan 31, 2014
The objective of the study was to investigate the efficacy and safety of hexaminolevulinate (HAL)... more The objective of the study was to investigate the efficacy and safety of hexaminolevulinate (HAL) photodynamic therapy (PDT), a novel therapy for women with cervical intraepithelial neoplasia (CIN)1/2, to define the appropriate population and endpoints for a phase 3 program. This was a double-blind, randomized, placebo-controlled, dose-finding study that included a total of 262 women with biopsy-confirmed CIN 1/2 based on local pathology. Patients received 1 or 2 topical treatments of HAL hydrochloride 0.2%, 1%, 5%, and placebo ointment and were evaluated for response after 3-6 months based on biopsy, Papanicolaou test, and oncogenic human papillomavirus (HPV) test. All efficacy analyses were performed on blinded central histology review to avoid interreader variability. Adverse events, blood biochemistry, and vital signs were assessed after 3 months. There were no statistically significant differences between placebo and either the CIN 1 or combined CIN 1/2 populations. A clear dose effect with a statistically significant response in the HAL 5% group of 95% (18/19 patients) compared to 57% (12/21 patients) in the placebo group (P < .001) was observed at 3 months in women with CIN2, including an encouraging 83% (5/6 patients) clearance of HPV 16/18 compared to 33% (2/6 patients) in the placebo group at 6 months. The treatment was easy to use and well accepted by patients and gynecologists. Only local self-limiting adverse reactions including discharge, discomfort, and spotting were reported. HAL PDT is a novel therapy that shows promise in the treatment of CIN2 including clearance of oncogenic HPV, but not of CIN1. The positive risk/benefit balance makes HAL PDT a tissue-preserving alternative in women of childbearing age who wish to preserve the cervix. Confirmatory studies are planned.
In 2011, the American Cancer Society, the American Society for Colposcopy and Cervical Pathology,... more In 2011, the American Cancer Society, the American Society for Colposcopy and Cervical Pathology, and the American Society for Clinical Pathology updated screening guidelines for the early detection of cervical cancer and its precursors. Recommended screening strategies were cytology and cotesting (cytology in combination with hrHPV testing). These guidelines also addressed the use of hrHPV testing alone as a primary screening approach, which was not recommended for use at that time. There is now a growing body of evidence for screening with primary hrHPV testing, including a prospective US-based registration study. Thirteen experts including representatives from the Society of Gynecologic Oncology, American Society for Colposcopy and Cervical Pathology, American College of Obstetricians and Gynecologists, American Cancer Society, American Society of Cytopathology, College of American Pathologists, and the American Society for Clinical Pathology, convened to provide interim guidance for primary hrHPV screening. This guidance panel was specifically triggered by an application to the FDA for a currently marketed HPV test to be labeled for the additional indication of primary cervical cancer screening. Guidance was based on literature review and review of data from the FDA registration study, supplemented by expert opinion. This document aims to provide information for healthcare providers who are interested in primary hrHPV testing and an overview of the potential advantages and disadvantages of this strategy for screening as well as to highlight areas in need of further investigation.
To explore the value of multiple clinical endpoints in the unique setting of ovarian cancer. A cl... more To explore the value of multiple clinical endpoints in the unique setting of ovarian cancer. A clinical trial workgroup was established by the Society of Gynecologic Oncology to develop a consensus statement via multiple conference calls, meetings and white paper drafts. Clinical trial endpoints have profound effects on late phase clinical trial design, result interpretation, drug development, and regulatory approval of therapeutics. Selection of the optimal clinical trial endpoint is particularly provocative in ovarian cancer where long overall survival (OS) is observed. The lack of new regulatory approvals and the lack of harmony between regulatory bodies globally for ovarian cancer therapeutics are of concern. The advantages and disadvantages of the numerous endpoints available are herein discussed within the unique context of ovarian cancer where both crossover and post-progression therapies potentially uncouple surrogacy between progression-free survival (PFS) and OS, the two most widely supported and utilized endpoints. The roles of patient reported outcomes (PRO) and health related quality of life (HRQoL) are discussed, but even these widely supported parameters are affected by the unique characteristics of ovarian cancer where a significant percentage of patients may be asymptomatic. Original data regarding the endpoint preferences of ovarian cancer advocates is presented. Endpoint selection in ovarian cancer clinical trials should reflect the impact on disease burden and unique characteristics of the treatment cohort while reflecting true patient benefit. Both OS and PFS have led to regulatory approvals and are clinically important. OS remains the most objective and accepted endpoint because it is least vulnerable to bias; however, the feasibility of OS in ovarian cancer is compromised by the requirement for large trial size, prolonged time-line for final analysis, and potential for unintended loss of treatment effect from active post-progression therapies. A large magnitude of effect in PFS improvement should establish benefit, and further communication with regulatory authorities to clarify acceptable endpoints should be undertaken.
To determine the safety and efficacy of the novel combination of docetaxel, oxaliplatin, and beva... more To determine the safety and efficacy of the novel combination of docetaxel, oxaliplatin, and bevacizumab as first-line treatment of advanced cancer of the ovary, peritoneum or fallopian tube after initial debulking surgery. Eligible patients (stage IB-IV) were treated with 6 cycles of oxaliplatin (85 mg/m(2)), docetaxel (75 mg/m(2)), and bevacizumab (15 mg/kg) every 3 weeks, followed by single-agent bevacizumab 15 mg/kg every 3 weeks to complete one year of therapy. The primary endpoint was 12-month progression-free survival (PFS). A total of 132 patients (80 with measurable disease at baseline; 52 with non-measurable, evaluable disease at baseline) enrolled and received study treatment. At diagnosis, 76.5% of patients had stage III disease and 20% had stage IV. 62.9% were optimally cytoreduced. The most common grade 3/4 adverse events were neutropenia (42.4%), leukopenia (13.6%), hypertension (8.3%), fatigue (6.1%), and nausea (6.1%). One patient (0.8%) had a fatal gastrointestinal perforation. The best overall confirmed response rate (complete response+partial response [measurable disease subgroup]) was 58.6% (95% CI 49%, 67%). CA-125 response rates for the measurable and non-measurable disease subgroups were 83.0% and 81.5%, respectively. The 12-month PFS rate for the measurable disease subgroup was 65.7% (95% CI 53.4%, 76.7%); median PFS was 16.3 (95% CI 12.6, 19.6) months. Median overall survival was 47.3 (95% CI 34.1, upper limit not applicable) months. This novel treatment regimen may provide a promising therapeutic approach for women with ovarian, primary peritoneal, or fallopian tube carcinoma. No unanticipated safety concerns were identified.
Background: Periumbilical extension of midline incision often results in an irregular, unaestheti... more Background: Periumbilical extension of midline incision often results in an irregular, unaesthetic scar with beveled edges.Technique: An Allis clamp is placed at the lateral margin of the umbilicus with subsequent medial traction. This straightens the proposed periumbilical incision, resulting in a symmetrical scar.Experience: We have used this technique extensively over the past several years with excellent results and no adverse sequelae.Conclusion: This simple technique results in the symmetrically curvilinear, nonbeveled periumbilical extension of a midline incision.
ABSTRACT Background In this prospective study we evaluate the sampling performance of HPV16 DNA E... more ABSTRACT Background In this prospective study we evaluate the sampling performance of HPV16 DNA E6 and L1 levels in detecting anal intraepithelial neoplasm using either a moistened Dacron swab (DS) or cytobrush (CB). Methods: We recruited HIV-infected (n=57) and organ-transplanted subjects (n=3) with an abnormal anal Pap smear who presented for high-resolution anoscopy (HRA). Prior to HRA, the first 30 subjects underwent sampling with a moistened DS, and the next 30 with a CB. HRA was then performed in the usual fashion. Samples were tested for HPV16 DNA E6 and L1 DNA using a validated qPCR technique. Anal biopsies were taken as per standard-of-care and categorised as negative, AIN 1/warts, or AIN 2 or 3. Results: 59 of 60 samples had adequate DNA and were evaluated for the comparison of HPV16 E6 and L1 DNA levels. A CB performed better than the DS in detecting low positive and positive levels of HPV16 E6 DNA (P=0.01). We then further evaluated the correlation of HRA-directed biopsies and HPV16 DNA E6 levels. There was a positive correlation of HRA-directed biopsy results stratified by increasing histological levels with HPV16 E6 DNA (P=0.018, Kruskal-Wallis test). Conclusions: A CB performed better than DS for molecular HPV testing. If molecular testing is included in anal cancer screening, consideration should be made for co-sampling with both a DS for cytology and CB for HPV testing. Further studies evaluating the sample yields should be performed to assist in implementation of anal cancer screening programs in defined populations of at-risk individuals.
We previously reported higher anti-HPV-16 and -18 immune responses induced by HPV-16/18 vaccine c... more We previously reported higher anti-HPV-16 and -18 immune responses induced by HPV-16/18 vaccine compared with HPV-6/11/16/18 vaccine at Month 7 (one month after completion of full vaccination series) in women aged 18-45 years in an observer-blind study NCT00423046; the differences of immune response magnitudes were maintained up to Month 24. Here we report follow-up data through Month 48. At Month 48, in according-to-protocol cohort for immunogenicity (seronegative and DNA-negative for HPV type analyzed at baseline), geometric mean titers of serum neutralizing antibodies were 2.0- to 5.2-fold higher (HPV-16) and 8.6- to 12.8-fold higher (HPV-18) in HPV-16/18 vaccine group than in HPV-6/11/16/18 vaccine group. The majority of women in both vaccine groups remained seropositive for HPV-16. The same trend was observed for HPV-18 in HPV-16/18 vaccine group; however, seropositivity rates in HPV-6/11/16/18 vaccine group decreased considerably, particularly in the older age groups. In the total vaccinated cohort (regardless of baseline serological and HPV-DNA status), anti-HPV-16 and -18 neutralizing antibody levels induced by HPV-16/18 vaccine were higher than those induced by HPV-6/11/16/18 vaccine. CD4+ T-cell response for HPV-16 and HPV-18 was higher in HPV-16/18 vaccine group than in HPV-6/11/16/18 vaccine group. Memory B-cell responses appeared similar between vaccine groups. Both vaccines were generally well tolerated. Overall, the higher immune response observed with the HPV-16/18 vaccine was maintained up to Month 48. A head-to-head study incorporating clinical endpoints would be required to confirm whether the observed differences in immune response between the vaccines influence the duration of protection they provided.
The observer-blind, randomized, age-stratified, head-to-head study (NCT00423046) comparing immuno... more The observer-blind, randomized, age-stratified, head-to-head study (NCT00423046) comparing immunogenicity and safety of HPV-16/18 and HPV-6/11/16/18 vaccines in healthy women aged 18-45 years was completed. Five years after vaccination, in subjects from the Month 60 according-to-protocol cohort (seronegative and DNA negative for HPV type analyzed at baseline), serum neutralizing antibody (nAb) responses induced by HPV-16/18 vaccine remained 7.8-fold (18-26-year stratum), 5.6-fold (27-35-year stratum) and 2.3-fold (36-45-year stratum) higher than those induced by HPV-6/11/16/18 vaccine for HPV-16. For HPV-18, the fold differences were 12.1, 13.0 and 7.8, respectively. At Month 60, all (100%) subjects in HPV-16/18 vaccine group and the majority (95.7%-97.5%) in HPV-6/11/16/18 vaccine group were seropositive for HPV-16. For HPV-18, the majority (98.1%-100%) of subjects in HPV-16/18 vaccine group were seropositive; however, seropositivity rates in HPV-6/11/16/18 vaccine group decreased considerably (61.1%-76.9%) across the three age strata. In the total vaccinated cohort (received ³1 dose regardless of baseline HPV serostatus and DNA status), geometric mean titers for anti-HPV-16 and anti-HPV-18 nAb were higher in HPV-16/18 vaccine group than in HPV-6/11/16/18 vaccine group. Based on the five-year data, piece-wise and modified power-law models predicted a longer durability of nAb response for HPV-16/18 vaccine compared to HPV-6/11/16/18 vaccine. Beyond the differences apparent between the vaccines in terms of immunogenicity and modeled persistence of antibody responses, comparative studies including clinical endpoints would be needed to determine whether differences exist in duration of vaccine-induced protection.
Survival in women with recurrent or metastatic cervical cancer remains poor. More effective and l... more Survival in women with recurrent or metastatic cervical cancer remains poor. More effective and less toxic regimens are needed. Cisplatin is an effective radiosensitizer, but its single agent activity in recurrent cervical cancer, especially after prior cisplatin exposure, is disappointing, with a response rate of only 13%. Oxaliplatin has preclinical activity in cisplatin-resistant tumors and may have synergic activity when combined with paclitaxel. Our objective is to determine the efficacy and toxicity of paclitaxel and oxaliplatin in patients with recurrent or metastatic cervical cancer. Patients with histologic confirmation of primary metastatic or recurrent cervical cancer not amenable to surgical management were eligible. Treatment consisted of paclitaxel 175 mg/m(2) IV and oxaliplatin 130 mg/m(2) IV every 21 days. The primary endpoints were toxicity, recorded every cycle, and response, determined by RECIST criteria and were assessed every 9 weeks, with subsequent confirmation as required. Sample size determinations were made using a Simon's two-stage design with a projected overall response proportion of 13% with cisplatin alone. Survival rates were calculated with Kaplan-Meier methods. Of the 35 patients enrolled, 32 were evaluable. The median age was 56 (27-78); 30 had had prior radiation (23 concomitant with cisplatin). Patients completed a mean of 4.2 cycles (1-11). There were 2 complete and 5 partial responses for a total response rate of 7/32 (22%; 95% CI: 9.3%-40.0%). Eight patients had stable disease for an overall clinical benefit rate of 15/32 (47%; 95% CI: 29.1%-65.3%). The mean time to best response was 13.5 weeks (95% CI: 10.6, 16.4). The mean progression-free survival was 21 weeks (95% CI: 14.7, 27.2) and mean overall survival was 52 weeks (95% CI: 39.4, 64.8). A total of 135 cycles were administered. There were 28 (20.1%) grade 3/4 hematologic toxicities and 46 (34.1%) grade 3/4 non-hematologic toxicities, which were predominantly sensory neuropathy. There were 13 treatment delays, 4 dose reductions, and no treatment-related deaths. The combination of paclitaxel and oxaliplatin is an effective regimen in patients with recurrent or persistent cervical cancer including a majority previously exposed to cisplatin. Further study and comparison with other platinum-based regimens is warranted.
Clinical cancer research : an official journal of the American Association for Cancer Research, 2002
The purpose of our study was to characterize a human papillomavirus (HPV) 16 DNA integration in t... more The purpose of our study was to characterize a human papillomavirus (HPV) 16 DNA integration in the genome of a rapidly progressive, lethal cervical cancer in a 39-year-old woman. An HPV 16 integration site from cervical cancer tissue was cloned and analyzed using Southern blot hybridization, nucleotide sequencing, fluorescence in situ hybridization analysis for chromosomal localization and comparison with the draft human genome sequence. HPV 16 DNA (3826 bp) was integrated into the genome of the tumor sample and contained an intact upstream regulatory region and E6 and E7 open reading frames. Both 5' and 3' viral-cell junction regions contained direct repeat and palindrome sequences. The chromosomal location of the viral integration and cellular deletion was mapped to chromosome 14q32.3 using both a somatic cell hybrid panel and fluorescence in situ hybridization. Search of the draft human genome sequence confirmed the chromosomal location and revealed a disruption of the TNFAIP2 cytokine/retinoic acid-inducible gene. On the basis of the lack of sequence homology between the viral and cellular site of integration and the structure of the viral-cell junctions, it seems that HPV 16 DNA integrates into the host genome by a mechanism of nonhomologous recombination. We suggest that, taken together, maintenance of E6 and E7 expression, loss of the E2 gene and disruption of the TNFAIP2 gene through viral integration contributed to the rapid progression of cervical cancer in this patient. Availability of the human genome sequence will facilitate identification of cellular genes involved in cervical cancer by high-throughput analysis of viral integration sites.
Human papillomavirus (HPV) has been established as an important etiological factor for the develo... more Human papillomavirus (HPV) has been established as an important etiological factor for the development of cervical cancer. This DNA virus primarily infects the epithelium and can induce benign and malignant lesions of the mucous membranes and skin. Some HPVs are considered high risk due to their role in malignant progression of cervical tumors. Genital HPV infections are common and usually transient among young sexually active women. Only a small fraction of infected women develop cervical cancer, implying the involvement of environmental and genetic cofactors in cervical carcinogenesis. Classification, virology, pathology, natural history, epidemiological features of genital HPV infection, and future prospects for cervical cancer prevention with HPV vaccines will be reviewed here.
We review the recent literature on anogenital neoplasms in AIDS, with emphasis on cancers associa... more We review the recent literature on anogenital neoplasms in AIDS, with emphasis on cancers associated with HPV infection. Immune reactivity to HPV as well as novel immunotherapeutic and preventative strategies are discussed. Many AIDS-associated neoplasms are associated with HPV infection. Whether cervical cancer is truly an AIDS-associated neoplasm has recently been questioned, while the association of anal cancer with AIDS in both males and females is more convincing. Recent reports cast doubt on the efficacy of HAART therapy for HPV-induced anogenital neoplasms, despite efficacy in improving disease caused by other infectious agents. We include here new data on humoral and cellular immune responses to HPV. VLP serology has been reported to be associated with outcome of cervical cancer. VLP seropositivity has been reported to be a favorable prognostic sign in women with HPV 16 positive cervical carcinoma. Several investigators have questioned the immunogenicity of the oncogenic HPV type 16 compared with other HPV types. It has recently been found that in HIV-infected patients, lymphoproliferative cellular immune responses (CMI) to HPV 16 peptides are not associated with CD4 counts, whereas responses to recall antigens and mitogens are associated with CD4 counts. CD4 + T cells may not be responsible for protective cellular immune responses to HPV. VLP serology and CMI responses may be the future intermediate surrogate biomarkers for HPV-associated anogenital neoplasia trials. Several new therapeutic vaccine strategies for management of HPV-induced neoplasia are reviewed. Most anogenital neoplasms occurring with increased frequency in patients with HIV/AIDS are associated with HPV infections. Current treatment strategies are not effective in clearing anogenital HPV infection and need improvement. Immunotherapy with novel vaccines will provide both prevention and therapy for these common malignancies.
Cervical disease burden continues to be especially high in HIV-infected women, even in the era of... more Cervical disease burden continues to be especially high in HIV-infected women, even in the era of effective antiretroviral medications. This review discusses the multiple issues surrounding HIV-associated cervical cancer. Also, the unique treatment-related issues in HIV-associated cervical cancer are addressed. The incidence of invasive cervical cancer has remained stable in industrialized nations; however, it is only estimated in developing countries secondary to a relative lack of data collection and registries. Trends in HIV-associated cervical cancer have changed in the highly active antiretroviral therapy (HAART) era. Recent molecular pathways suggest that the natural progression of human papillomavirus infection, the causal agent in all cervical cancers, may be related to immune system dysfunction as well as HIV/human papillomavirus synergistic mechanisms. When highly active retroviral therapies are used, invasive cervical cancer treatments are impacted by concomitant drug toxicities that could potentially limit therapeutic benefit of either HAART or the standard of care treatment for locally advanced cervical cancer, concomitant chemoradiotherapy. The significance and care of the patient with invasive cervical cancer is becoming a geographically relevant phenomenon such that it may be time to re-address the global definition. Further studies in treatment issues and drug-drug interactions with cervical cancer treatments in the setting of HIV are paramount.
Impaired glucose tolerance and diabetes are risk factors for the development of uterine cancer. A... more Impaired glucose tolerance and diabetes are risk factors for the development of uterine cancer. Although greater progression free survival among diabetic patients with ovarian and breast cancers using metformin has been reported, no studies have assessed the association of metformin use with survival in women with endometrial cancer (EC). We conducted a single-institution retrospective cohort study of all patients treated for uterine cancer from January 1999 through December 2009. Demographic, medical, social, and survival data were abstracted from medical records and the national death registry. Overall survival (OS) was estimated using Kaplan-Meier methods. Cox models were utilized for multivariate analysis. All statistical tests were two-sided. Of 985 patients, 114 (12%) had diabetes and were treated with metformin, 136 (14%) were diabetic but did not use metformin, and 735 (74%) had not been diagnosed with diabetes. Greater OS was observed in diabetics with non-endometrioid EC who used metformin than in diabetic cases not using metformin and non-endometrioid EC cases without diabetes (log rank test (p=0.02)). This association remained significant (hazard ratio=0.54, 95% CI: 0.30-0.97, p<0.04) after adjusting for age, clinical stage, grade, chemotherapy treatment, radiation treatment and the presence of hyperlipidemia in multivariate analysis. No association between metformin use and OS in diabetics with endometrioid histology was observed. Diabetic EC patients with non-endometrioid tumors who used metformin had lower risk of death than women with EC who did not use metformin. These data suggest that metformin might be useful as adjuvant therapy for non-endometrioid EC.
High-risk (HR) human papillomavirus (HPV) testing is important in cervical cancer screening for t... more High-risk (HR) human papillomavirus (HPV) testing is important in cervical cancer screening for triage to colposcopy. This study evaluated the clinical performance of the Cervista HPV HR and 16/18 genotyping tests for detection of HPV in cervical cytology specimens. The tests were prospectively evaluated in a multicenter clinical study. DNA was extracted from approximately 4000 residual liquid-based cytology specimens collected during routine liquid-based Papanicolaou tests at standard of care visits and was assessed for the presence of HR HPV and/or HPV types 16 and 18. All women with cytology results of atypical squamous cells of undetermined significance (ASC-US) or greater underwent colposcopic examination and biopsies were collected. Test results were compared with local colposcopy and histology results from a central pathology review panel. There were 1347 subjects with complete data sets of cytology, HR HPV, colposcopy, and histology included in the analysis of the HPV HR test. Sensitivity of the HPV HR test for detection of cervical intraepithelial neoplasia (CIN) 2+ among women with ASC-US cytology was 92.8% (95% confidence interval [CI]: 84.1-96.9) and the negative predictive value (NPV) was 99.1% (95% CI: 98.1-99.6). Sensitivity for detection of > or =CIN 3 in women with ASC-US was 100% (95% CI: 85.1-100) and the NPV was 100% (95% CI: 99.4-100). The specificity of the test for detection of > or =CIN 2 and > or =CIN 3 was 44.2% (95% CI: 41.5-46.9) and 43% (95% CI: 40.3-45.7), respectively. The HPV 16/18 genotyping test also performed as expected in women with ASC-US cytology who were positive for HR HPV. The Cervista HPV HR test can be clinically used for detecting HR HPV types in conjunction with cervical cytology for use in triage of women with ASC-US cytology during routine cervical cancer screening.
American journal of obstetrics and gynecology, Jan 31, 2014
The objective of the study was to investigate the efficacy and safety of hexaminolevulinate (HAL)... more The objective of the study was to investigate the efficacy and safety of hexaminolevulinate (HAL) photodynamic therapy (PDT), a novel therapy for women with cervical intraepithelial neoplasia (CIN)1/2, to define the appropriate population and endpoints for a phase 3 program. This was a double-blind, randomized, placebo-controlled, dose-finding study that included a total of 262 women with biopsy-confirmed CIN 1/2 based on local pathology. Patients received 1 or 2 topical treatments of HAL hydrochloride 0.2%, 1%, 5%, and placebo ointment and were evaluated for response after 3-6 months based on biopsy, Papanicolaou test, and oncogenic human papillomavirus (HPV) test. All efficacy analyses were performed on blinded central histology review to avoid interreader variability. Adverse events, blood biochemistry, and vital signs were assessed after 3 months. There were no statistically significant differences between placebo and either the CIN 1 or combined CIN 1/2 populations. A clear dose effect with a statistically significant response in the HAL 5% group of 95% (18/19 patients) compared to 57% (12/21 patients) in the placebo group (P < .001) was observed at 3 months in women with CIN2, including an encouraging 83% (5/6 patients) clearance of HPV 16/18 compared to 33% (2/6 patients) in the placebo group at 6 months. The treatment was easy to use and well accepted by patients and gynecologists. Only local self-limiting adverse reactions including discharge, discomfort, and spotting were reported. HAL PDT is a novel therapy that shows promise in the treatment of CIN2 including clearance of oncogenic HPV, but not of CIN1. The positive risk/benefit balance makes HAL PDT a tissue-preserving alternative in women of childbearing age who wish to preserve the cervix. Confirmatory studies are planned.
In 2011, the American Cancer Society, the American Society for Colposcopy and Cervical Pathology,... more In 2011, the American Cancer Society, the American Society for Colposcopy and Cervical Pathology, and the American Society for Clinical Pathology updated screening guidelines for the early detection of cervical cancer and its precursors. Recommended screening strategies were cytology and cotesting (cytology in combination with hrHPV testing). These guidelines also addressed the use of hrHPV testing alone as a primary screening approach, which was not recommended for use at that time. There is now a growing body of evidence for screening with primary hrHPV testing, including a prospective US-based registration study. Thirteen experts including representatives from the Society of Gynecologic Oncology, American Society for Colposcopy and Cervical Pathology, American College of Obstetricians and Gynecologists, American Cancer Society, American Society of Cytopathology, College of American Pathologists, and the American Society for Clinical Pathology, convened to provide interim guidance for primary hrHPV screening. This guidance panel was specifically triggered by an application to the FDA for a currently marketed HPV test to be labeled for the additional indication of primary cervical cancer screening. Guidance was based on literature review and review of data from the FDA registration study, supplemented by expert opinion. This document aims to provide information for healthcare providers who are interested in primary hrHPV testing and an overview of the potential advantages and disadvantages of this strategy for screening as well as to highlight areas in need of further investigation.
To explore the value of multiple clinical endpoints in the unique setting of ovarian cancer. A cl... more To explore the value of multiple clinical endpoints in the unique setting of ovarian cancer. A clinical trial workgroup was established by the Society of Gynecologic Oncology to develop a consensus statement via multiple conference calls, meetings and white paper drafts. Clinical trial endpoints have profound effects on late phase clinical trial design, result interpretation, drug development, and regulatory approval of therapeutics. Selection of the optimal clinical trial endpoint is particularly provocative in ovarian cancer where long overall survival (OS) is observed. The lack of new regulatory approvals and the lack of harmony between regulatory bodies globally for ovarian cancer therapeutics are of concern. The advantages and disadvantages of the numerous endpoints available are herein discussed within the unique context of ovarian cancer where both crossover and post-progression therapies potentially uncouple surrogacy between progression-free survival (PFS) and OS, the two most widely supported and utilized endpoints. The roles of patient reported outcomes (PRO) and health related quality of life (HRQoL) are discussed, but even these widely supported parameters are affected by the unique characteristics of ovarian cancer where a significant percentage of patients may be asymptomatic. Original data regarding the endpoint preferences of ovarian cancer advocates is presented. Endpoint selection in ovarian cancer clinical trials should reflect the impact on disease burden and unique characteristics of the treatment cohort while reflecting true patient benefit. Both OS and PFS have led to regulatory approvals and are clinically important. OS remains the most objective and accepted endpoint because it is least vulnerable to bias; however, the feasibility of OS in ovarian cancer is compromised by the requirement for large trial size, prolonged time-line for final analysis, and potential for unintended loss of treatment effect from active post-progression therapies. A large magnitude of effect in PFS improvement should establish benefit, and further communication with regulatory authorities to clarify acceptable endpoints should be undertaken.
To determine the safety and efficacy of the novel combination of docetaxel, oxaliplatin, and beva... more To determine the safety and efficacy of the novel combination of docetaxel, oxaliplatin, and bevacizumab as first-line treatment of advanced cancer of the ovary, peritoneum or fallopian tube after initial debulking surgery. Eligible patients (stage IB-IV) were treated with 6 cycles of oxaliplatin (85 mg/m(2)), docetaxel (75 mg/m(2)), and bevacizumab (15 mg/kg) every 3 weeks, followed by single-agent bevacizumab 15 mg/kg every 3 weeks to complete one year of therapy. The primary endpoint was 12-month progression-free survival (PFS). A total of 132 patients (80 with measurable disease at baseline; 52 with non-measurable, evaluable disease at baseline) enrolled and received study treatment. At diagnosis, 76.5% of patients had stage III disease and 20% had stage IV. 62.9% were optimally cytoreduced. The most common grade 3/4 adverse events were neutropenia (42.4%), leukopenia (13.6%), hypertension (8.3%), fatigue (6.1%), and nausea (6.1%). One patient (0.8%) had a fatal gastrointestinal perforation. The best overall confirmed response rate (complete response+partial response [measurable disease subgroup]) was 58.6% (95% CI 49%, 67%). CA-125 response rates for the measurable and non-measurable disease subgroups were 83.0% and 81.5%, respectively. The 12-month PFS rate for the measurable disease subgroup was 65.7% (95% CI 53.4%, 76.7%); median PFS was 16.3 (95% CI 12.6, 19.6) months. Median overall survival was 47.3 (95% CI 34.1, upper limit not applicable) months. This novel treatment regimen may provide a promising therapeutic approach for women with ovarian, primary peritoneal, or fallopian tube carcinoma. No unanticipated safety concerns were identified.
Background: Periumbilical extension of midline incision often results in an irregular, unaestheti... more Background: Periumbilical extension of midline incision often results in an irregular, unaesthetic scar with beveled edges.Technique: An Allis clamp is placed at the lateral margin of the umbilicus with subsequent medial traction. This straightens the proposed periumbilical incision, resulting in a symmetrical scar.Experience: We have used this technique extensively over the past several years with excellent results and no adverse sequelae.Conclusion: This simple technique results in the symmetrically curvilinear, nonbeveled periumbilical extension of a midline incision.
ABSTRACT Background In this prospective study we evaluate the sampling performance of HPV16 DNA E... more ABSTRACT Background In this prospective study we evaluate the sampling performance of HPV16 DNA E6 and L1 levels in detecting anal intraepithelial neoplasm using either a moistened Dacron swab (DS) or cytobrush (CB). Methods: We recruited HIV-infected (n=57) and organ-transplanted subjects (n=3) with an abnormal anal Pap smear who presented for high-resolution anoscopy (HRA). Prior to HRA, the first 30 subjects underwent sampling with a moistened DS, and the next 30 with a CB. HRA was then performed in the usual fashion. Samples were tested for HPV16 DNA E6 and L1 DNA using a validated qPCR technique. Anal biopsies were taken as per standard-of-care and categorised as negative, AIN 1/warts, or AIN 2 or 3. Results: 59 of 60 samples had adequate DNA and were evaluated for the comparison of HPV16 E6 and L1 DNA levels. A CB performed better than the DS in detecting low positive and positive levels of HPV16 E6 DNA (P=0.01). We then further evaluated the correlation of HRA-directed biopsies and HPV16 DNA E6 levels. There was a positive correlation of HRA-directed biopsy results stratified by increasing histological levels with HPV16 E6 DNA (P=0.018, Kruskal-Wallis test). Conclusions: A CB performed better than DS for molecular HPV testing. If molecular testing is included in anal cancer screening, consideration should be made for co-sampling with both a DS for cytology and CB for HPV testing. Further studies evaluating the sample yields should be performed to assist in implementation of anal cancer screening programs in defined populations of at-risk individuals.
We previously reported higher anti-HPV-16 and -18 immune responses induced by HPV-16/18 vaccine c... more We previously reported higher anti-HPV-16 and -18 immune responses induced by HPV-16/18 vaccine compared with HPV-6/11/16/18 vaccine at Month 7 (one month after completion of full vaccination series) in women aged 18-45 years in an observer-blind study NCT00423046; the differences of immune response magnitudes were maintained up to Month 24. Here we report follow-up data through Month 48. At Month 48, in according-to-protocol cohort for immunogenicity (seronegative and DNA-negative for HPV type analyzed at baseline), geometric mean titers of serum neutralizing antibodies were 2.0- to 5.2-fold higher (HPV-16) and 8.6- to 12.8-fold higher (HPV-18) in HPV-16/18 vaccine group than in HPV-6/11/16/18 vaccine group. The majority of women in both vaccine groups remained seropositive for HPV-16. The same trend was observed for HPV-18 in HPV-16/18 vaccine group; however, seropositivity rates in HPV-6/11/16/18 vaccine group decreased considerably, particularly in the older age groups. In the total vaccinated cohort (regardless of baseline serological and HPV-DNA status), anti-HPV-16 and -18 neutralizing antibody levels induced by HPV-16/18 vaccine were higher than those induced by HPV-6/11/16/18 vaccine. CD4+ T-cell response for HPV-16 and HPV-18 was higher in HPV-16/18 vaccine group than in HPV-6/11/16/18 vaccine group. Memory B-cell responses appeared similar between vaccine groups. Both vaccines were generally well tolerated. Overall, the higher immune response observed with the HPV-16/18 vaccine was maintained up to Month 48. A head-to-head study incorporating clinical endpoints would be required to confirm whether the observed differences in immune response between the vaccines influence the duration of protection they provided.
The observer-blind, randomized, age-stratified, head-to-head study (NCT00423046) comparing immuno... more The observer-blind, randomized, age-stratified, head-to-head study (NCT00423046) comparing immunogenicity and safety of HPV-16/18 and HPV-6/11/16/18 vaccines in healthy women aged 18-45 years was completed. Five years after vaccination, in subjects from the Month 60 according-to-protocol cohort (seronegative and DNA negative for HPV type analyzed at baseline), serum neutralizing antibody (nAb) responses induced by HPV-16/18 vaccine remained 7.8-fold (18-26-year stratum), 5.6-fold (27-35-year stratum) and 2.3-fold (36-45-year stratum) higher than those induced by HPV-6/11/16/18 vaccine for HPV-16. For HPV-18, the fold differences were 12.1, 13.0 and 7.8, respectively. At Month 60, all (100%) subjects in HPV-16/18 vaccine group and the majority (95.7%-97.5%) in HPV-6/11/16/18 vaccine group were seropositive for HPV-16. For HPV-18, the majority (98.1%-100%) of subjects in HPV-16/18 vaccine group were seropositive; however, seropositivity rates in HPV-6/11/16/18 vaccine group decreased considerably (61.1%-76.9%) across the three age strata. In the total vaccinated cohort (received ³1 dose regardless of baseline HPV serostatus and DNA status), geometric mean titers for anti-HPV-16 and anti-HPV-18 nAb were higher in HPV-16/18 vaccine group than in HPV-6/11/16/18 vaccine group. Based on the five-year data, piece-wise and modified power-law models predicted a longer durability of nAb response for HPV-16/18 vaccine compared to HPV-6/11/16/18 vaccine. Beyond the differences apparent between the vaccines in terms of immunogenicity and modeled persistence of antibody responses, comparative studies including clinical endpoints would be needed to determine whether differences exist in duration of vaccine-induced protection.
Survival in women with recurrent or metastatic cervical cancer remains poor. More effective and l... more Survival in women with recurrent or metastatic cervical cancer remains poor. More effective and less toxic regimens are needed. Cisplatin is an effective radiosensitizer, but its single agent activity in recurrent cervical cancer, especially after prior cisplatin exposure, is disappointing, with a response rate of only 13%. Oxaliplatin has preclinical activity in cisplatin-resistant tumors and may have synergic activity when combined with paclitaxel. Our objective is to determine the efficacy and toxicity of paclitaxel and oxaliplatin in patients with recurrent or metastatic cervical cancer. Patients with histologic confirmation of primary metastatic or recurrent cervical cancer not amenable to surgical management were eligible. Treatment consisted of paclitaxel 175 mg/m(2) IV and oxaliplatin 130 mg/m(2) IV every 21 days. The primary endpoints were toxicity, recorded every cycle, and response, determined by RECIST criteria and were assessed every 9 weeks, with subsequent confirmation as required. Sample size determinations were made using a Simon's two-stage design with a projected overall response proportion of 13% with cisplatin alone. Survival rates were calculated with Kaplan-Meier methods. Of the 35 patients enrolled, 32 were evaluable. The median age was 56 (27-78); 30 had had prior radiation (23 concomitant with cisplatin). Patients completed a mean of 4.2 cycles (1-11). There were 2 complete and 5 partial responses for a total response rate of 7/32 (22%; 95% CI: 9.3%-40.0%). Eight patients had stable disease for an overall clinical benefit rate of 15/32 (47%; 95% CI: 29.1%-65.3%). The mean time to best response was 13.5 weeks (95% CI: 10.6, 16.4). The mean progression-free survival was 21 weeks (95% CI: 14.7, 27.2) and mean overall survival was 52 weeks (95% CI: 39.4, 64.8). A total of 135 cycles were administered. There were 28 (20.1%) grade 3/4 hematologic toxicities and 46 (34.1%) grade 3/4 non-hematologic toxicities, which were predominantly sensory neuropathy. There were 13 treatment delays, 4 dose reductions, and no treatment-related deaths. The combination of paclitaxel and oxaliplatin is an effective regimen in patients with recurrent or persistent cervical cancer including a majority previously exposed to cisplatin. Further study and comparison with other platinum-based regimens is warranted.
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