A prime/boost vaccine platform efficiently identifies CD27 agonism and depletion of myeloid-derived suppressor cells as therapies that rationally combine with checkpoint blockade in ovarian cancer.

Cancer immunotherapies have generated remarkable clinical responses for some patients with advanced/metastatic disease, prompting exploration of rational combination therapies to bolster anti-tumor immunity in patients with limited response or those who experience tumor progression following an initial response to immunotherapy. In contrast to other tumor indications, objective response rates to single-agent PD-1/PD-L1 blockade in ovarian cancer are limited, suggesting a need to identify combinatorial approaches that lead to tumor regression in a setting where checkpoint blockade alone is ineffective. Using a pre-clinical model of aggressive intraperitoneal ovarian cancer, we have previously reported on a heterologous prime/boost cancer vaccine that elicits robust anti-tumor immunity, prolongs survival of tumor-bearing mice, and which is further improved when combined with checkpoint blockade. As tumor control in this model is CD8 + T cell dependent, we reasoned that the prime/boost vaccine platform could be used to explore additional treatment combinations intended to bolster the effects of CD8 + T cells. Using whole tumor transcriptomic data, we identified candidate therapeutic targets anticipated to rationally combine with prime/boost vaccination. In the context of a highly effective cancer vaccine, CD27 agonism or antibody-mediated depletion of granulocytic cells each modestly increased tumor control following vaccination, with anti-PD-1 therapy further improving treatment efficacy. These findings support the use of immunotherapies with well-defined mechanisms(s) of action as a valuable platform for identifying candidate combination approaches for further therapeutic testing in ovarian cancer.

Immunotherapy in ovarian cancer.

Immunological destruction of tumors is a multistep, coordinated process that can be modulated or targeted at several critical points to elicit tumor rejection. These steps in the cancer immunity cycle include: (i) generation of sufficient numbers of effector T cells with high avidity recognition of tumor antigens in vivo; (ii) trafficking and infiltration into the tumor; (iii) overcoming inhibitory networks in the tumor microenvironment; (iv) direct recognition of tumor antigens and generation of an effector anti-tumor response; and (v) persistence of the anti-tumor T cells. In an effort to understand whether the immune system plays a role in controlling ovarian cancer, our group and others demonstrated that the presence of tumor infiltrating lymphocytes (TILs) is associated with improved clinical outcome in ovarian cancer patients. Recently, we hypothesized that the quality of infiltrating T cells could also be a critical determinant of outcome in ovarian cancer patients. In the past decade, several immune-based interventions have gained regulatory approval in many solid tumors and hematologic malignancies. These interventions include immune checkpoint blockade, cancer vaccines, and adoptive cell therapy. There are currently no approved immune therapies for ovarian cancer. Immunotherapy in ovarian cancer will have to consider the immune suppressive networks within the ovarian tumor microenvironment; therefore, a major direction is to develop biomarkers that would predict responsiveness to different types of immunotherapies, and allow for treatment selection based on the results. Moreover, such biomarkers would allow rational combination of immunotherapies, while minimizing toxicities. In this review, the current understanding of the host immune response in ovarian cancer patients will be briefly reviewed, progress in immune therapies, and future directions for exploiting immune based strategies for long lasting durable cure.

The CD47 "don't eat me signal" is highly expressed in human ovarian cancer.

OBJECTIVES: The CD47 "don't eat me" signal allows tumor immune evasion. We tested the association of CD47 expression with outcomes in EOC. METHODS: CD47 expression was examined within the TCGA database for ovarian carcinoma. For validation, IHC was performed on a TMA consisting of specimens from 265 patients with EOC. The medical records of the patients were also retrospectively reviewed to correlate demographic and survival data. RESULTS: CD47 was amplified in 15/316 (5%) ovarian serous cancers in TCGA. In the validation cohort, the majority of patients had stage III/IV disease (208/265, 78.4%). CD47 expression was seen in 210/265 (79.2%). Patients were categorized into CD47hi (129/265; 48.7%) versus CD47lo (136/265; 51.3%). Patients with CD47lo tumors were more likely to have a complete response to adjuvant therapy than CD47hi (65% vs 50%, p=0.026). Although there was a trend towards an increase in median OS (37.64 vs 45.26months, p=0.92) in the CD47lo group compared with CD47hi, the difference was not significant. CONCLUSIONS: CD47 is expressed at high frequency in EOC. Patients with CD47lo EOC had a better treatment response to standard therapy, and trended towards improved OS. This demonstrates that while CD47 may be an immunologic shield that may be considered for targeted therapies, it is likely that it operates in concert with other mechanisms of immune evasion. Future studies to evaluate CD47 expression with other known mechanisms of immune escape in the tumor microenvironment may help further define its role.

Docetaxel and nab-paclitaxel are safe alternative options for patients with gynecologic malignancies following hypersensitivity reaction to paclitaxel.

Docetaxel and nab-paclitaxel are safe alternatives to paclitaxel after hypersensitivity reaction occurs. There was no significant difference in overall survival between those that had paclitaxel, docetaxel, and nab-paclitaxel.

Evidence for a time-dependent association between FOLR1 expression and survival from ovarian carcinoma: implications for clinical testing. An Ovarian Tumour Tissue Analysis consortium study.

BACKGROUND: Folate receptor 1 (FOLR1) is expressed in the majority of ovarian carcinomas (OvCa), making it an attractive target for therapy. However, clinical trials testing anti-FOLR1 therapies in OvCa show mixed results and require better understanding of the prognostic relevance of FOLR1 expression. We conducted a large study evaluating FOLR1 expression with survival in different histological types of OvCa. METHODS: Tissue microarrays composed of tumour samples from 2801 patients in the Ovarian Tumour Tissue Analysis (OTTA) consortium were assessed for FOLR1 expression by centralised immunohistochemistry. We estimated associations for overall (OS) and progression-free (PFS) survival using adjusted Cox regression models. High-grade serous ovarian carcinomas (HGSC) from The Cancer Genome Atlas (TCGA) were evaluated independently for association between FOLR1 mRNA upregulation and survival. RESULTS: FOLR1 expression ranged from 76% in HGSC to 11% in mucinous carcinomas in OTTA. For HGSC, the association between FOLR1 expression and OS changed significantly during the years following diagnosis in OTTA (Pinteraction=0.01, N=1422) and TCGA (Pinteraction=0.01, N=485). In OTTA, particularly for FIGO stage I/II tumours, patients with FOLR1-positive HGSC showed increased OS during the first 2 years only (hazard ratio=0.44, 95% confidence interval=0.20-0.96) and patients with FOLR1-positive clear cell carcinomas (CCC) showed decreased PFS independent of follow-up time (HR=1.89, 95% CI=1.10-3.25, N=259). In TCGA, FOLR1 mRNA upregulation in HGSC was also associated with increased OS during the first 2 years following diagnosis irrespective of tumour stage (HR: 0.48, 95% CI: 0.25-0.94). CONCLUSIONS: FOLR1-positive HGSC tumours were associated with an increased OS in the first 2 years following diagnosis. Patients with FOLR1-negative, poor prognosis HGSC would be unlikely to benefit from anti-FOLR1 therapies. In contrast, a decreased PFS interval was observed for FOLR1-positive CCC. The clinical efficacy of FOLR1-targeted interventions should therefore be evaluated according to histology, stage and time following diagnosis.

Adjuvant treatment for uterine leiomyosarcoma.

The aims of this study were to evaluate outcomes in women diagnosed with uterine leiomyosarcoma (LMS). A retrospective chart review was conducted. Fifty-eight women with LMS were identified. Of the evaluable 52 patients (six patients were excluded), 73% had Stage I/II disease, and 27% had Stage III/IV disease. Sixty-three percent of patients received chemotherapy (97% doxorubicin-based therapy), eight percent received radiation alone, and 29% received no therapy. For patients with Stage I/II disease, no improvement in OS was demonstrated when adjuvant therapy was administered. There was a significant difference in OS (p = 0.0005) for patients with advanced Stage (III/IV) disease that received adjuvant chemotherapy. OS of the entire group, when adjusted for stage, failed to reveal a significant survival advantage for those receiving chemotherapy-based (p = 0.22). The present findings suggest further research into the role of chemotherapy in early stage disease is needed to better refine optimal treatment.

Bevacizumab for the treatment of recurrent ovarian cancer: a retrospective cohort study.

OBJECTIVE: To determine response rates (RR), progression-free survival (PFS), overall survival (OS), and toxicity in patients treated with cytotoxic chemotherapy, in combination with bevacizumab compared to cytotoxic chemotherapy alone, in the setting of recurrent ovarian cancer. MATERIALS AND METHODS: After obtaining Institutional Review Board approval, two cohorts of patients with recurrent ovarian cancer were identified: 1) patients that received cytotoxic chemotherapy with bevacizumab from January 2006 to June 2009; 2) patients that received cytotoxic chemotherapy alone. RR were measured using RECIST criteria or by CA-125 levels using modified Rustin criteria. RR, OS, and PFS were determined using Kaplan-Meier survival analysis. RESULTS: Thirty-two patients that received bevacizumab in combination with cytotoxic chemotherapy and 32 patients that received cytotoxic chemotherapy alone were identified. The control patients were matched for age, platinum response, histology, surgical outcome, grade, and number of previous chemotherapy regimens. There were no differences between the two cohorts in the rates of venous thromboembolism (VTE) (p = 0.39), bleeding (p = 0.15) or bowel obstruction (p = 0.40). The rate of hypertension in the bevacizumab cohort was greater than in the comparison cohort (p < 0.005). There were no differences in response rates PR/CR vs SD/PD (p = 0.46), OS (p = 0.79) or PFS (p = 0.43). CONCLUSIONS: With increased toxicity, increased cost of therapy and no improvement in PFS or OS, the role of bevacizumab in patients with recurrent ovarian cancer warrants further investigation.

Photodynamic therapy effectively palliates gynecologic malignancies.

BACKGROUND: There is a need for novel therapies for women with recurrent gynecologic malignancies. In this paper, the authors report their experience with photodynamic therapy (PDT). PDT involves administering a systemic injection of Photofrin II, a selective tumor photosensitizer hematoporphyrin derivative, followed by exposure of tumor tissue to visible light at 630 nm. The photodynamic destruction of tumor exhibits both cytocidal and vascular effects that may contribute to the tumoricidal effects observed. MATERIALS AND METHODS: Patients were injected intravenously with two mg/kg Photofrin II. Approximately 48 hours post-injection, the tumor was exposed to red light (wavelength 630 nm +/- 2 nm) from a laser through a flexible 400-um quartz fiber with an attached microlens to produce a spot of uniform intensity and/or diffuser tip fiber to uniformly illuminate the cavity. RESULTS: Thirty-two patients with recurrent gynecologic malignancies were treated with photodynamic therapy using Photofrin II dye and laser. A total of 45 PDT treatments were given; 25 patients received only one treatment, five patients received two treatments, two patients received three treatments, and one patient received four treatments. There were nine cervical, six vulvar, six vaginal, five ovarian, five endometrial carcinomas, and one recurrent pagets of the anal canal. Nine out of 11 (82%) patients with metastatic cutaneous lesions had a complete response. Five out of 21 patients (24%) with vaginal, cervical or anal recurrences had a complete response to therapy with median response time of 28 months. Toxicity associated with treatment was limited to burning sensation, pain, and edema at treatment site. There were no treatment related deaths. CONCLUSIONS: PDT is an effective therapy in patients with recurrent gynecologic malignancies and limited treatment options. PDT is an alternative therapy that offers the possibility of complete response in select groups of patient populations. Specifically, it provides palliation for superficial recurrent lesions of skin, cervix, vagina and vulva, in the absence of distant disease.

Comparison of outcomes in patients treated with multi-agent regiments of cisplatin, adriamycin, and VP-16 versus carboplatin and paclitaxel for advanced and recurrent endometrial cancer.

OBJECTIVE: The objective of this study was to compare the efficacy of two multi-agent chemotherapeutic regiments that were previously used at the Institution for treatment of advanced and recurrent endometrial cancer. METHODS: A retrospective review of patients with Stage III, IV, and recurrent endometrial cancer who received adjuvant chemotherapy at Roswell Park Cancer Institute over a period of 21 years. Two patient groups were defined based on treatment received: cisplatin, adriamycin, and VP-16 with or without megace (PAV-M), or carboplatin and paclitaxel (CT). RESULTS: Forty-two patients with advanced or recurrent endometrial cancer were included in this review based on regimen received. Median duration of follow up was 55 months. Treatment with PAV-M resulted in more dose modifications compared to CT group (42% vs 11%, respectively). There were no significant differences in disease-free survival or overall survival. CONCLUSIONS: PAV/PAV-M is active in patients with advanced or recurrent endometrial cancer. However, toxicity associated with this triplet regimen may limit clinical use.

Minimal information about T cell assays: the process of reaching the community of T cell immunologists in cancer and beyond.

Many assays to evaluate the nature, breadth, and quality of antigen-specific T cell responses are currently applied in human medicine. In most cases, assay-related protocols are developed on an individual laboratory basis, resulting in a large number of different protocols being applied worldwide. Together with the inherent complexity of cellular assays, this leads to unnecessary limitations in the ability to compare results generated across institutions. Over the past few years a number of critical assay parameters have been identified which influence test performance irrespective of protocol, material, and reagents used. Describing these critical factors as an integral part of any published report will both facilitate the comparison of data generated across institutions and lead to improvements in the assays themselves. To this end, the Minimal Information About T Cell Assays (MIATA) project was initiated. The objective of MIATA is to achieve a broad consensus on which T cell assay parameters should be reported in scientific publications and to propose a mechanism for reporting these in a systematic manner. To add maximum value for the scientific community, a step-wise, open, and field-spanning approach has been taken to achieve technical precision, user-friendliness, adequate incorporation of concerns, and high acceptance among peers. Here, we describe the past, present, and future perspectives of the MIATA project. We suggest that the approach taken can be generically applied to projects in which a broad consensus has to be reached among scientists working in fragmented fields, such as immunology. An additional objective of this undertaking is to engage the broader scientific community to comment on MIATA and to become an active participant in the project.

Primary fallopian tube carcinoma: a retrospective clinicopathologic study.

INTRODUCTION: Primary fallopian tube carcinoma is a rare tumor. The aim of this study was to evaluate clinical characteristics and management of fallopian tube malignancies at a large tertiary care cancer institute. METHODS: A retrospective review of the Tumor Registry was conducted to identify all primary fallopian tube carcinomas between 1980 and 2001. Medical charts were retrospectively reviewed. Primary endpoints were overall survival and disease recurrence. RESULTS: Thirty-five patients had histology consistent with fallopian tube carcinoma. The median age at diagnosis was 56 years. The most common signs or symptoms were abnormal vaginal bleeding (29%) and abdominal/pelvic mass (26%). The most common histology was adenocarcinoma in 16 (46%) patients. Five patients (14%) were Stage I, seven patients (20%) Stage II, 17 patients (49%) Stage III and six patients (17%) Stage IV. Thirty-two (91%) patients received adjuvant chemotherapy and 77% received platinum-based chemotherapy. Twenty-seven (77%) patients underwent second-look surgery, of which 17 patients (63%) were positive for disease. The 5-year survival rate was 64% for Stage I, 42% for Stage II, 32% for Stage III, and 17% for Stage IV. CONCLUSIONS: Fallopian tube malignancies are rare and carry a poor prognosis. More extensive research needs to be performed to have definitive etiologic, diagnostic and treatment guidelines.

Non-redundant requirement for CXCR3 signalling during tumoricidal T-cell trafficking across tumour vascular checkpoints.

T-cell trafficking at vascular sites has emerged as a key step in antitumour immunity. Chemokines are credited with guiding the multistep recruitment of CD8(+) T cells across tumour vessels. However, the multiplicity of chemokines within tumours has obscured the contributions of individual chemokine receptor/chemokine pairs to this process. Moreover, recent studies have challenged whether T cells require chemokine receptor signalling at effector sites. Here we investigate the hierarchy of chemokine receptor requirements during T-cell trafficking to murine and human melanoma. These studies reveal a non-redundant role for Gαi-coupled CXCR3 in stabilizing intravascular adhesion and extravasation of adoptively transferred CD8(+) effectors that is indispensable for therapeutic efficacy. In contrast, functional CCR2 and CCR5 on CD8(+) effectors fail to support trafficking despite the presence of intratumoral cognate chemokines. Taken together, these studies identify CXCR3-mediated trafficking at the tumour vascular interface as a critical checkpoint to effective T-cell-based cancer immunotherapy.

A case of fatal pulmonary thromboembolism associated with the use of intravenous estrogen therapy.

OBJECTIVE: To report a case of fatal pulmonary embolism associated with the use of i.v. estrogen therapy for menometrorrhagia. DESIGN: Case report. SETTING: University hospital. PATIENT(S): A 52-year-old woman with fibroid uterus treated with GnRH analogues with add-back therapy who presented with excessive vaginal bleeding. INTERVENTION(S): Intravenous conjugated estrogens were administered for a total of six doses. MAIN OUTCOME MEASURE(S): Fatal thromboembolic event. RESULT(S): The day after i.v. conjugated estrogens were administered, the patient had only scant vaginal bleeding, but she experienced the sudden onset of respiratory distress, became comatose, and subsequently had ventricular fibrillation leading to asystole. All resuscitative efforts failed. Postmortem examination revealed bilateral pulmonary artery thromboembolism (saddle embolus). CONCLUSION(S): Intravenous conjugated estrogen therapy may be complicated by fatal thromboembolic events. This potential adverse effect must be considered in the use of such therapy for severe menometrorrhagia, especially when treating a patient at increased risk.

Motif analysis of HLA class II molecules that determine the HPV associated risk of cervical carcinogenesis.

In previous studies, the HLA class II haplotype HLA DRB1*0401-DQB1*0301 was shown to correlate with susceptibility to HPV infection, CIN and cervical cancer while DRB1*0101-DQB1*0501 indicated protection. The present study was designed to identify naturally processed peptide sequences bound to the susceptibility and protective HLA DR-DQ molecules, and use this for T-helper epitope prediction from HPV 16. The HLA class II molecules were obtained by immuno-affinity purification of Epstein-Barr virus B lymphoblastoid cell lines (BCL) homozygous for HLA DQA1*0301-DQB1*0301 and HLA DQA1*0101-DQB1*0501. Peptide pools eluted from the HLA molecules were sequenced by Edman degradation. On the basis of the peptide sequence data obtained, the E6, E7, L1 and L2 proteins of HPV 16 were examined to identify sequences which are likely to bind to HLA DQB1*0301 and DQB1*0501. In addition, motif prediction as well as the binding affinity of predicted peptide motifs for HLA DRB1*0401 and DRB1*0101, the DR alleles associated with susceptibility and protection respectively, was accomplished using published data and a prediction algorithm for the naturally processed peptide sequences bound to these molecules. The HLA DQB1*0501 peptide ligand sequence showed that proline gives an outstanding signal at position 2, Asn/Arg at P1, aliphatic/aromatic amino acids in the central portion, a hydrophobic cluster at P5 with a small contribution by small polar residues and another cluster of aromatic residues towards the C-terminus. The HLA DQB1*0301 sequence also showed that proline gives an outstanding signal at position 2, Thr/Arg at P1, aliphatic/aromatic amino acids in the central portion and an aliphatic cluster with a small contribution by small polar residues at P5. There were no differences in the number of HPV peptides that were predicted as being capable of binding to HLA DQB1*0301 and HLA DQB1*0501, but more HPV peptide motifs were predicted to bind with high affinity to HLA DRB1*0101 than DRB1*0401. The results suggest that HPV 16 peptide epitopes bind with higher affinity to the protective than to susceptible HLA DR-DQ molecules which may lead to a more effective immune response.

Human ovarian cancer, lymphoma spleen, and bovine milk GlcNAc:beta1,4Gal/GalNAc transferases: two molecular species in ovarian tumor and induction of GalNAcbeta1,4Glc synthesis by alpha-lactalbumin.

Affinity Gel-UDP was utilized to purify GlcNAc:beta1,4Gal/GalNAc transferases (Ts) from human lymphoma spleen, ovarian tumor, and ovarian cancer sera. Mn(2+) was found to be an absolute requirement for activity. Two molecular species containing both beta1,4Gal/GalNAc-T activities were discernible when the purified ovarian tumor microsomal enzyme was subjected to Sephacryl S-100 HR column chromatography as well as native polyacylamide gel-electrophoresis. Acceptor specificity studies of the affinity-purified lymphoma spleen and ovarian tumor microsomal enzymes and the conventionally purified, as well as the cloned, bovine milk GlcNAc:beta1,4Gal-Ts using a number of synthetic acceptors showed that the beta(1,6)-linked GlcNAc moiety to alpha-GalNAc was the most efficient acceptor. As compared to the purified milk enzyme, the recombinant form exhibited sixfold GlcNAc:beta1,4 GalNAc-T activity and up to eightfold GlcNAc6SO3beta-:beta1,4Gal-T activity. Further, the recombinant enzyme catalyzed the transfer of GalNAc to the terminal beta-linked GlcNAc6SO3 moiety. Alpha-lactalbumin (alpha-LA) inhibited up to 85%, the transfer of Gal to the GlcNAc moiety linked either to Man or GlcNAc. On the contrary, alpha-LA had no significant influence on the transfer of GalNAc to the above acceptors. alpha-LA had no appreciable effect on the recombinant enzyme, except for the transfer of Gal or GalNAc to Glc. Both alpha- and beta-glucosides, as well as alpha-N-acetylglucosaminide, did not serve as acceptors.

Evaluation of chemical tests for fetal bleeding from vasa previa.

OBJECTIVES: To evaluate different alkaline denaturation tests and compare with hemoglobin electrophoresis and the Kleihauer test, and to identify the simplest and most sensitive test that may help to rapidly show the presence of fetal hemoglobin and establish the diagnosis of fetal bleeding from vasa previa. METHODS: Maternal and fetal cord blood were obtained from 20 women with uncomplicated deliveries and the samples were mixed in known concentrations ranging from 0-100% fetal blood. Further samples were prepared in which maternal and fetal blood mixtures were diluted with amniotic fluid so that the final concentration of fetal hemoglobin similarly ranged from 0-100%. Alkaline denaturation tests (Apt, Ogita, Loendersloot), hemoglobin electrophoresis and Kleihauer tests were performed on all 40 samples. RESULTS: The Apt and Loendersloot tests were clearly positive at 60% concentrations of fetal blood. It took approximately 7 and 4 min, respectively, to complete the tests. The Ogita test was positive from fetal blood concentrations of 20% and took approximately 5 min. Hemoglobin electrophoresis took approximately 1 h to complete and the Hb-F band was present even at 0% concentration of fetal blood and the band became more marked with increasing fetal blood concentration. The Kleihauer test was negative at 0% but positive from 0.01% fetal blood concentration. The test took approximately 45 min to perform. CONCLUSIONS: The Ogita test is the best all round alkaline denaturation test that may help to rapidly identify the presence of fetal hemoglobin and so establish the need to expedite delivery when there is fetal bleeding from vasa previa. It is simple to perform, does not require sophisticated equipment, unlikely to give false positive results, and takes only 5 min. The simplicity of the test makes it attractive for routine use on the labor ward.

Clinicopathologic outcomes of laser conization for high-grade cervical dysplasia.

PURPOSE OF INVESTIGATION: To evaluate the incidence of thermal artifact and rates of persistent disease and recurrence in laser conization for cervical dysplasia. METHODS: A retrospective study examined the cases of 110 patients who underwent carbon dioxide laser conization for high-grade cervical dysplasia at our institution between January 1999 and March 2002. Rates of thermal artifact, persistent disease, recurrence, hemorrhage and cervical stenosis were investigated. Dysplasia severity and recurrence rates in smokers were also evaluated. RESULTS: One hundred and five (95.5%) of 110 laser cones had negative margins, and only five (4.5%) had significant thermal artifact, with two (1.8%) noted to interfere with adequate evaluation of margins. Seventy-eight patients returned to Roswell Park Cancer Institute (RPCI) for follow-up with a mean follow-up period of 15.7 months. Fourteen (12.7%) patients had persistent disease detected within two visits, and one (0.9%) patient had a recurrence of dysplasia at ten months. One (0.9%) patient had same-day postoperative hemorrhage requiring hemostatic suturing. There were no cases of cervical stenosis detected at follow-up. Smokers had an increased incidence of high-grade lesions on cone biopsy when compared to non-smokers (46/57 and 30/53 patients, 80.7% and 56.7%, respectively; p = 0.008). The rate of persistent disease or recurrence was 8/57 (14%) in smokers and 7/53 (13.2%) in non-smokers (p = not significant). CONCLUSION: Laser conization is an efficacious and safe procedure for the treatment of high-grade cervical dysplasia, with a very low incidence of thermal artifact and postoperative complications, and a relatively low rate of persistent disease. Smokers had a significantly increased incidence of high-grade lesions on cone biopsy.

The impact of pre-therapy extraperitoneal surgical staging on the evaluation and treatment of patients with locally advanced cervical cancer.

OBJECTIVE: The use of extraperitoneal surgical staging prior to treatment in patients with bulky or locally advanced cervical cancer allows the detection and treatment of disease beyond the standard pelvic radiation fields. This study was conducted to evaluate the impact of extraperitoneal surgical staging in the treatment and outcome of patients with locally advanced cervical cancer. METHODS: 51 patients with locally advanced cervical cancer treated between 1985 and 1998 were retrospectively reviewed. Information on morbidity, usefulness, and results of surgery and patterns of disease recurrence were obtained. Survival distributions were calculated by the Kaplan-Meier product limit method and compared with the log-rank test. RESULTS: All 51 women were surgically staged by an extra-peritoneal approach. Preoperative CT scans (n=27) when compared with surgical findings showed sensitivity for pelvic and para-aortic lymph node metastasis of 39%, specificity of 88%, positive predictive value of 39% and negative predictive value of 88%. Lymph node metastases were found in 30/51 patients (59%). There were no significant treatment delays or surgical morbidity as a result of extra-peritoneal surgical staging. In 21 patients (41%), the highest level of involved nodes was in the pelvis and they were treated with pelvic radiation. The para-aortic nodes were involved in nine patients (18%) and were treated with extended field radiation. All patients also received concurrent radiosensitization with chemotherapy. The estimated survival for the entire group was 60% at 5 years. For node negative patients, estimated 5-year survival was 67% while it was 54% for all node positive patients (p=0.17). Analysis according to anatomic site of involved nodes showed that the estimated 2-year and 5-year survival for those with pelvic nodal involvement was 81% and 64%, respectively. However, in the group of nine patients with para-aortic nodal disease, the estimated 2-year survival was 44%. Five (56%) were dead of disease with a median time to death of 16.0 months and four patients (44%) were alive with a median duration of follow up of 16.1 months. There was a statistically significant difference in survival for the group of patients with positive pelvic nodes only compared to the group with positive para-aortic nodes (p=0.03). The estimated 5-year survival by FIGO stage was 80%, 70% and 51% for stages Ib, II, III, disease, respectively. Factors that did not significantly affect survival included age, histology and type of chemotherapy. CONCLUSIONS: Pre-therapy extra-peritoneal surgical staging resulted in treatment modification in 18% of patients with locally advanced cervical cancer. The morbidity from surgery and subsequent radiation therapy was acceptable. The procedure is recommended to allow for individualization of treatment in patients with local-regional cervical cancer.

Gene expression and prognostic significance in ovarian cancer.

Epithelial ovarian cancer (EOC) is the leading cause of death from gynecological malignancies in the United States. Most patients with EOC will respond to surgical debulking followed by platinum and paclitaxel based chemotherapy. Unfortunately, the relapse rate within 2 years is more than 70%. The molecular events leading to the development of EOC and the molecular factors that may predict response to treatment are not well established. Such knowledge would not only improve the understanding of the biology of EOC, but may help in the identification of new tumor markers and the design of molecular therapies for EOC. A literature review was conducted using MEDLINE to delineate studies that investigated gene expression in ovarian cancer correlated with outcome. A review is presented of the expression and role of the BRCA1 and 2 genes, p53, amplification of Her2/neu, PIK3CA, AKT2, K-ras, c-myc, BRCA1, p53, p16, and p27 in ovarian cancer. Additionally, a review of the use of microarray technology is presented and its use in determining expression patterns in ovarian cancer. The accumulation of data derived from new technologies, as well as that obtained from well-established methods, has provided new insights into gene expression profiles in EOC. The utilization of novel technologies that allow high throughput analysis of thousands of genes may lead to the development of new biomarkers or novel therapies that are urgently needed in this deadly disease.