Induction of tumor-specific CD4+ and CD8+ T-cell immunity in cervical cancer patients by a human papillomavirus type 16 E6 and E7 long peptides vaccine.

PURPOSE: The study aims to evaluate the effect of a human papillomavirus type 16 (HPV16) E6 and E7 synthetic long peptides vaccine on the antigen-specific T-cell response in cervical cancer patients. EXPERIMENTAL DESIGN: Patients with resected HPV16-positive cervical cancer were vaccinated with an overlapping set of long peptides comprising the sequences of the HPV16 E6 and E7 oncoproteins emulsified in Montanide ISA-51. HPV16-specific T-cell immune responses were analyzed by evaluating the magnitude, breadth, type, and polarization by proliferation assays, IFN gamma-ELISPOT, and cytokine production and phenotyped by the T-cell markers CD4, CD8, CD25, and Foxp3. RESULTS: Vaccine-induced T-cell responses against HPV16 E6 and E7 were detected in six of six and five of six patients, respectively. These responses were broad, involved both CD4(+) and CD8(+) T cells, and could be detected up to 12 months after the last vaccination. The vaccine-induced responses were dominated by effector type CD4(+)CD25(+)Foxp3(-) type 1 cytokine IFN gamma-producing T cells but also included the expansion of T cells with a CD4(+)CD25(+)Foxp3(+) phenotype. CONCLUSIONS: The HPV16 E6 and E7 synthetic long peptides vaccine is highly immunogenic, in that it increases the number and activity of HPV16-specific CD4(+) and CD8(+) T cells to a broad array of epitopes in all patients. The expansion of CD4(+) and CD8(+) tumor-specific T cells, both considered to be important in the antitumor response, indicates the immunotherapeutic potential of this vaccine. Notably, part of the vaccine-induced T cells display a CD4(+)CD25(+)Foxp3(+) phenotype that is frequently associated with regulatory T-cell function, suggesting that strategies to disarm this subset of T cells should be considered as components of immunotherapeutic modalities against HPV-induced cancers.     

The number of pelvic lymph nodes in the quality control and prognosis of radical hysterectomy for the treatment of cervical cancer.

AIMS: To determine if the number of removed lymph nodes in radical hysterectomy with lymphadenectomy (RHL) influences survival of patients with early stage cervical cancer and to analyze the relation of different factors like patient age, tumour size and infiltration depth with the number of nodes examined in node-negative early stage cervical cancer patients. METHODS: Of consecutive patients, who underwent RHL between January 1984 and April 2005, 331 had negative nodes (group A) without adjuvant therapy and 136 had positive nodes (group B). The Kaplan-Meier method and Cox regression model were used to detect statistical significance. Factors associated with excision of nodes were confirmed with linear regression models. RESULTS: The median number of removed nodes was 19 and 18 for group A and group B, respectively. There was no significant relationship between the number of removed nodes and the cancer specific survival (CSS) or disease free survival (DSF) for patients of group A (p=0.625 and p=0.877, respectively). The number of removed nodes in group B was not significantly associated with the CSS (p=0.084) but it was for the DSF (p=0.014). Factors like patient age, tumour size and infiltration depth were not associated with the number of nodes. CONCLUSIONS: No relation was found between the number of negative nodes examined after RHL for the treatment of early stage cervical cancer and CSS or DFS. However, a higher amount of removed lymph nodes leaded to a better DFS for patients with positive nodes. It is suggested that patients with positive nodes benefit from a complete pelvic lymphadenectomy and a sufficient yield of removed nodes.     

Prognostic relevance of TGF-beta1 and PAI-1 in cervical cancer

Cervical carcinoma is a human papilloma virus (HPV)-related immunogenic type of malignancy, in which escape of the tumor from the hosts' immune response is thought to play an important role in carcinogenesis. The multifunctional cytokine transforming growth factor-beta(1) (TGF-beta(1)) is involved in immunosuppression, stroma and extracellular matrix formation and controlling (epithelial) cell growth. The plasminogen activating (PA) system plays a key role in the cascade of tumor-associated proteolysis leading to extracellular matrix degradation and stromal invasion. Changes in expression of components of this system, including plasminogen activator inhibitor-1 (PAI-1), have been associated with poor prognosis in a variety of solid tumors. The present study was undertaken to assess the role of both components on relapse, survival and other clinicopathologic parameters in cervical cancer. The expression of TGF-beta(1) mRNA in 108 paraffin-embedded cervical carcinomas was detected by mRNA in situ hybridization. Immunohistochemistry was used to investigate the expression of PAI-1 protein. The presence of cytoplasmatic TGF-beta(1) mRNA in tumor cells was not significantly correlated with the other clinicopathologic parameters investigated or with a worse (disease-free) survival. Expression of the PAI-1 protein in tumor cells was strongly correlated with worse overall and disease-free survival, in addition to well-known prognostic parameters such as lymph node metastasis, depth of tumor infiltration, tumor size and vasoinvasion. In the multivariate analysis, PAI-1 turned out to be a strong independent prognostic factor. In a subgroup of patients without lymph node metastases, PAI-1 was predictive for worse survival and relapse of disease, too. Our results show that the (enhanced) expression of PAI-1 by carcinoma cells is correlated with worse (overall and disease-free) survival of patients with cancer of the uterine cervix. The expression of TGF-beta(1) in itself is not associated with worse survival in these patients. Although simultaneous presence of the 2 factors was observed in all tumors, induction of PAI-1 by TGF-beta(1) could not be demonstrated in our group of cervical carcinomas.     

Excess Risk for Contralateral Breast Cancer in CHEK2*1100delC Germline Mutation Carriers

We detected a significant excess risk for CHEK2*1100delC mutation carriers to develop a contralateral breast tumor, OR = 6.5 (95% CI 1.5-28.8, p = 0.005). The highest percentage of mutation carriers was detected among those bilateral breast cancer patients who had received radiation treatment for their first breast tumor. These results warrant prolonged medical surveillance and may indicate a clinically important interaction between CHEK2 heterozygosity and radiation in the development of contralateral breast cancer.     

Interscalene block for elective shoulder surgery

This study assessed patient experiences with interscalene block anesthesia for elective shoulder surgery. Routine use of interscalene anesthesia was introduced at our institution in 1997. All patients who underwent interscalene anesthesia during the first 3 years of our experience with this regional anesthetic technique were asked to respond to an anesthesia-related questionnaire. Overall patient satisfaction with interscalene anesthesia was 87%, and success rate in achieving a complete motor and sensory block was 79%. The duration of pain relief postoperatively was 10.5 hours for patients with a successful block. Patients consistently reported that having an interscalene block was less painful than anticipated; 90% said they would have interscalene anesthesia again for shoulder surgery. This study demonstrates that interscalene anesthesia for elective shoulder surgery is safe and well accepted in this patient population.     

The outcome of endometrial carcinoma surveillance by ultrasound scan in women at risk of hereditary nonpolyposis colorectal carcinoma and familial colorectal carcinoma

BACKGROUND: Endometrial carcinoma is the most common extracolonic malignancy associated with hereditary nonpolyposis colorectal carcinoma syndrome (HNPCC). The risk of endometrial carcinoma in HNPCC mutation carriers is approximately ten times that of the general population, and endometrial ultrasound surveillance to detect early cancer in asymptomatic individuals is recommended by the International Collaborative Group on HNPCC. There is little, if any, published data addressing the effectiveness of surveillance in HNPCC and familial colorectal carcinoma. METHODS: The outcomes of endometrial carcinoma surveillance scans were collected from the St Mark's Hospital Imperial Cancer Research Fund Family Cancer Clinic in the UK and the Netherlands Foundation for the Detection of Hereditary Tumors. Two hundred ninety two women from HNPCC (171) or HNPCC-like (98) families between the ages of 25-65 years were offered pelvic ultrasound surveillance scans for a period of up to 13 years. RESULTS: Results were available from 269 women. The study period included a total of 825.7 years of risk. Two cases of endometrial carcinoma were reported. Neither case was detected by surveillance scanning. Both cases presented at an early stage with symptoms and were subsequently cured. CONCLUSIONS: Endometrial carcinoma surveillance in hereditary colorectal carcinoma may not offer obvious clinical benefits.     

Oncogene alterations in carcinomas of the uterine cervix: overexpression of the epidermal growth factor receptor is associated with poor prognosis.

The involvement of human papillomavirus (HPV) in the development of carcinomas of the uterine cervix has been firmly established. However, other genetic alterations also play an important role in the pathogenesis of cervical cancer. Therefore, we have investigated the role of several (onco)genes in cervical carcinoma. In tumors from 136 patients with stage I and II cancer of the uterine cervix, the expression of epidermal growth factor receptor (EGFR), c-erbB-2/neu, p53, and murine double minute 2 (MDM-2) was studied using immunohistochemistry. In 32 cases, amplification of EGFR, c-erbB-2/neu, MDM-2, and c-myc was studied by Southern blot hybridization. The expression levels of these proteins were correlated with HPV positivity, International Federation of Gynecologists and Obstetricians stage, lymph node metastases, tumor diameter, vessel invasion, and disease-free and overall survival. Moderate/strong expression of EGFR was observed in 54% of tumors. c-erbB-2/neu was focally positive in 12 cases. p53 showed moderate/strong expression in 32% of the tumors. Thirteen % of tumors showed a moderate/strong expression of MDM-2, and this expression was correlated to p53 expression (P<0.001). Only moderate/strong expression of EGFR was associated with reduced disease-free (P = 0.002) and overall survival (P = 0.003). In multivariate analysis, the association of EGFR overexpression with poor prognosis was independent from lymph node status. Gene amplification was found for EGFR (four cases), c-erbB-2/ neu (two cases), and c-myc (six cases). In two tumors, rearrangement of c-myc was found, probably due to the integration of HPV. In conclusion, overexpression of the EGFR is an independent predictor for prognosis in earlier stages (stage I and II) of cervical cancer. p53 and MDM-2 expression are correlated to each other and may play a role in the interaction with HPV. The importance of c-erbB-2/neu and c-myc amplification is relatively small in stage I and II cervical cancer.     

Tumor diameter and volume assessed by magnetic resonance imaging in the prediction of outcome for invasive cervical cancer

OBJECTIVE: The aim of this study was to evaluate the predictive value of pretherapeutic magnetic resonance imaging (MRI)-based measurements of tumor diameter and volume with regard to recurrent disease. METHODS: MRI on 0.5- or 1.5-T scanners was performed in 126 consecutive women with invasive carcinoma of the uterine cervix. Initial tumor diameter and volume were determined on T(2)-weighted images; volume was calculated by the standard technique of multiplying the sum of the areas by the slice thickness. Patients were treated by radical surgery, radiotherapy, or a combined approach based on clinical International Federation of Gynecology and Obstetrics (FIGO) stage and individual patient criteria. Clinical data (patient age and FIGO stage), MRI-derived tumor dimensions (diameter and volume), and histological findings (tumor invasion depth and lymph-node involvement) were associated and linked to patient outcome. RESULTS: MRI-based tumor diameter correlated strongly with histological tumor invasion depth and lymph-node status (P < 0.01 and P = 0.01) while tumor volume on MRI was significantly associated only with tumor invasion depth into adjacent tissues (P < 0.01). Univariate analysis demonstrated graphically that MRI-derived tumor diameter and volume and clinical FIGO stage are associated with progression-free survival. Correlation analysis showed a strong association between MRI-derived tumor diameter and volume on MRI (r = 68%, P < 0.01) and also demonstrated a correlation between tumor diameter on MRI and FIGO stage Ib (Ib1 versus Ib2) cervical tumors (r = 46.7%, P < 0.01). CONCLUSION: Tumor diameter and volume, determined by pretreatment MRI examinations, predict progression-free survival for patients with invasive cervical carcinoma. This study demonstrates the value of MRI as an adjunct to clinical evaluation of invasive cervical cancer, providing more complete assessment of morphological risk factors important in patient prognosis and treatment planning.