Purpose: Persistent infection with oncogenic human papillomaviruses (HPV) plays a central etiologic role in the development of squamous carcinomas of the cervix and their precursor lesions, cervical intraepithelial neoplasias (CIN). We carried out a prospective observational cohort study evaluating known, quantifiable prognostic variables of clinical behavior in women with high-grade cervical lesions. Experimental Design: Our study cohort included healthy women with high-grade cervical lesions (CIN2/3) with residual visible lesions after colposcopically directed biopsy. We prospectively followed 100 women over 15 weeks before standard resection. HPV typing was done using PCR and a reverse line blot detection method. Results: The rate of spontaneous histologic regression, defined as (CIN1 or less at resection) was 28%. The overall rate of HPV infection was 100%. HPV16 was identified in 68% of the lesions. Women with HPV16 only were significantly less likely to regress, compared with women with HPV types other than HPV16 (odds ratio, 0.342; 95% confidence interval, 0.117-0.997; P = 0.049). In the cohort with HPV16 only, patients who had an HLA*A201 allele had similar outcomes to those who did not carryA201. However, among patients with HPV types other than HPV16, the HLA*A201 allele interaction was significant; patients with HLA*A201 were the least likely to resolve. Conclusions: CIN2/3 lesions associated with HPV16 alone are significantly less likely to resolve spontaneously than those caused by other types. Interactions among HPV type, HLA type, and regression rate support a role for HLA-restricted HPV-specific immune responses in determining disease outcome.Persistent infection with a high risk, or oncogenic type of human papillomavirus (HPV) is necessary but not sufficient for the development of most squamous carcinomas of the cervix and their precursor lesions, cervical intraepithelial neoplasia (CIN; ref. 1). CIN1, CIN2, and CIN3 lesions represent a spectrum of disease. Low-grade, or CIN1 lesions, represent a chronic HPV infection, in which HPV DNA is episomal and intact virion production and shedding occur. In women who are immunocompetent, many low-grade, or CIN1 lesions, will nonetheless eventually regress without intervention (1, 2). Reported rates of regression range up to 58% over 24 months (3). A very small percentage (f2%) will progress to high-grade lesions.In contrast, most high-grade, or CIN2/3 lesions are thought to be much more likely to persist than to regress. However, reported rates of spontaneous regression vary from 6% to 50%, depending on diagnostic criteria, and length of follow-up (4). The risk for progression to invasive cancer at 24 months in women with high-grade lesions is f1% to 2%.The mechanisms by which HPV-associated intraepithelial lesions resolve are not well understood. As a prelude to interventional clinical trials in women with biopsy-proven CIN2/3, we carried out a prospective observational cohort study evaluating known, quantifiable prognostic variables in immune ...

Purpose: Because the combination of multiple modalities for cancer treatment is more likely to generate more potent therapeutic effects for the control of cancer, we have explored the combination of chemotherapy using cisplatin, which is routinely used in chemotherapy for advanced cervical cancer, with immunotherapy using DNA vaccines encoding calreticulin (CRT) linked to human papillomavirus type 16 E7 antigen (CRT/E7) in a preclinical model. Experimental Design: We characterized the combination of cisplatin with CRT/E7 DNA vaccine using different regimen for its potential ability to generate E7-specific CD8 + T-cell immune responses as well as antitumor effects against E7-expressing tumors. Results: Our results indicate that treatment of tumor-bearing mice with chemoimmunotherapy combining cisplatin followed by CRT/E7 DNA generated the highest E7-specific CD8 + T-cell immune response and produced the greatest antitumor effects and long-term survival as well as significant levels of E7-specific tumor-infiltrating lymphocytes compared with all the other treatment regimens. Furthermore, we found that treatment with cisplatin leads to the cellmediated lysis of E7-expressing tumor cells in vitro and increased number of E7-specific CD8 + T-cell precursors in tumor-bearing mice. In addition, we observed that E7-specific CD8 + T cells migrate to and proliferate in the location of TC-1tumors in mice treated with cisplatin. Conclusions: Thus, our data suggest that chemoimmunotherapy using cisplatin followed by CRT/E7 DNA vaccine is an effective treatment against E7-expressing tumors and may potentially be translated into the clinical arena.Multimodality treatments that combine conventional cancer therapies with antigen-specific immunotherapy have emerged as promising approaches for the control of cancer (see refs. 1, 2 for reviews). Antigen-specific immunotherapy is an attractive approach for the treatment of cancers because it has the potency to specifically eradicate systemic tumors and control metastases without damaging normal cells. A favorable approach to antigen-specific immunotherapy is the use of DNA vaccines based on their safety, stability, and ease of preparation (see refs. 3, 4 for review). However, DNA vaccines are poorly immunogenic. Thus, the potency of DNA vaccines needs to be enhanced by using methods to target DNA to the professional antigen-presenting cells and by modifying the properties of antigen-expressing antigen-presenting cells to boost vaccine-elicited immune responses. Several approaches have been developed to enhance DNA vaccine potency (see refs. 5, 6 for review).One particular approach to enhance DNA vaccine potency involves the use of intracellular targeting strategies to enhance MHC class I and class II antigen presentation in dendritic cells. Our previous studies have explored the linkage of calreticulin (CRT), a Ca 2+ -binding protein located in the endoplasmic reticulum (see ref. 7 for review) to a model tumor antigen, human papillomavirus type 16 (HPV-16) E7, for the develo...

The potency of naked DNA vaccines is limited by their inability to amplify and spread in vivo. VP22, a HSV-1 protein, has demonstrated the remarkable property of intercellular transport and may thus provide a unique approach for enhancing vaccine potency. Therefore, we created a novel fusion of VP22 with a model Ag, human papillomavirus type 16 E7, in a DNA vaccine that generated enhanced spreading and MHC class I presentation of Ag. These properties led to a dramatic increase in the number of E7-specific CD8+ T cell precursors in vaccinated mice (around 50-fold) and converted a less effective DNA vaccine into one with significant potency against E7-expressing tumors. In comparison, nonspreading VP221–267 mutants failed to enhance vaccine potency. Our data indicated that the potency of DNA vaccines may be dramatically improved through intercellular spreading and enhanced MHC class I presentation of Ag.

Background: A bleeding pseudoaneurysm in patients with chronic pancreatitis is a rare and potentially lethal complication. Optimal treatment of bleeding peripancreatic pseudoaneurysm remains controversial. This study reports on experience at Chang Gung Memorial Hospital (CGMH) in managing of bleeding pseudoaneurysms associated with chronic pancreatitis.

Immunotherapy and chemotherapy are generally effective against small tumors in animal models of cancer. However, these treatment regimens are generally ineffective against large, bulky tumors. We have found that a multimodality treatment regimen using DNA vaccination in combination with chemotherapeutic agent epigallocatechin-3-gallate (EGCG), a compound found in green tea, is effective in inhibiting large tumor growth. EGCG was found to induce tumor cellular apoptosis in a dose-dependent manner. The combination of EGCG and DNA vaccination led to an enhanced tumor-specific T-cell immune response and enhanced antitumor effects, resulting in a higher cure rate than either immunotherapy or EGCG alone. In addition, combined DNA vaccination and oral EGCG treatment provided longterm antitumor protection in cured mice. Cured animals rejected a challenge of E7-expressing tumors, such as TC-1 and B16E7, but not a challenge of B16 7 weeks after the combined treatment, showing antigen-specific immune responses. These results suggest that multimodality treatment strategies, such as combining immunotherapy with a tumor-killing cancer drug, may be a more effective anticancer strategy than singlemodality treatments. [Cancer Res 2007;67(2):802-11]