An economic analysis of cisplatin alone versus cisplatin doublets in the treatment of women with advanced or recurrent cervical cancer.

PURPOSE OF INVESTIGATION: Randomized trials have demonstrated improvements in overall survival when using platinum doublets com- pared to single agent platinum in the treatment of women with advanced or recurrent cervical cancer. The authors sought to evaluate the cost effectiveness of these regimens. METHODS: A decision model was developed based on Gynecologic Oncology Group (GOG) protocols 179 and 204. Cisplatin alone was compared to cisplatin/paclitaxel (CP), cisplatin/topotecan (CT), cisplatin/gemcitabine (GC), cisplatin/vinorelbine (CV), and a hypothetical novel agent. Parameters included overall survival (OS), cost, and complications. One way sensitivity analyses were performed. In further sensitivity analysis, a hypothetical agent that added 3.7 months survival to CP's survival was studied. RESULTS: The chemotherapy drug costs for six cycles of cisplatin was 89 USD while for cisplatin/paclitaxel it was 489 USD. The highest chemotherapy cost was for GC at 18,306 USD. The average total cost of six cycles CP was 13,250 USD while the average cost of cisplatin alone was 14,573 USD. The highest average cost for six cycles was for GC at 33,559 USD. With cisplatin/paclitaxel being the most effective, the cost effectiveness analysis showed that cisplatin, CT, GC, and VC were all dominated by CP. Because of the regimens being dominated, no baseline ICERs compared to CP were calculable. Sensitivity analyses demonstrate that even all of the chemotherapies were given for free, CP would still be the regimen of choice. CONCLUSIONS: In this model, CP is the most cost effective regimen for the treatment of these patients with an average cost of 13,250 USD. With the fact that GOG 204 also showed statistically significantly improved survival for CP, CP should be considered the regimen of choice.

Cyclin E is overexpressed by clear cell carcinomas of the endometrium and is a prognostic indicator of survival.

OBJECTIVE: Upregulation of cyclin E and cyclin D1-6 accelerates the transition from G1 to S phase. The objective of this study was to determine if cyclin D1 and E are prognostic indicators in endometrial cancer. MATERIALS AND METHODS: Surgically-treated patients with endometrial carcinoma had their tumors stained for nuclear expression of cyclin D1 and E. Quantification of staining and measurement of growth phase fraction were performed using image analysis. FIGO stage, grade, and histology were also analyzed. RESULTS: Cyclin D1 and E expression was unrelated to DNA index (p = 0.93). While cyclin D1 expression did not correlate with S+G2M phase fraction (p = 0.69), increased cyclin E expression was directly correlated with increased S+G2M phase fraction (p = 0.002). Cyclin E expression was highest in clear cell carcinomas (p = 0.042) while cyclin D1 expression was highest in adenosquamous carcinomas (p = 0.028). Patients dying from cancer had significantly higher expression of cyclin D1 (p = 0.042) and E (p = 0.02) as compared to patients surviving their disease. Multivariate logistic regression revealed FIGO stage, grade, and lack of cyclin E overexpression to be independent prognostic indicators of survival. CONCLUSION: Cyclin E expression is related to increased growth fraction, clear cell histology, and decreased survival in patients with endometrial cancer.

Total colectomy in primary ovarian cytoreduction.

OBJECTIVE: To review the indications, procedure, and complications associated with total colectomy with ileorectal anastamosis in women undergoing primary debulking of ovarian cancer. METHODS: Charts were reviewed to determine all patients undergoing total colectomy with ileorectal anastamosis during primary debulking of ovarian, peritoneal, or fallopian tube cancer. Charts were also reviewed for perioperative morbidity and mortality, as well as rates of fecal incontinence. RESULTS: Nine patients underwent the above procedures during primary debulking of ovarian cancer. The mean age was 61 years with a mean BMI of 31 kg/m2. The average postoperative hospital stay was 11 days with an average estimated blood loss of 700 ml. There was no perioperative mortality. Although all patients had greatly increased frequency of stools, no patients had incontinence of stool after eight weeks. CONCLUSIONS: Radical surgery, including total colectomy, can be performed in select patients with primary ovarian cancer. Acceptable morbidity, mortality, and rectal continence can be obtained.

Robotically-assisted laparoscopic radical parametrectomy and radical vaginectomy.

BACKGROUND: Radical parametrectomy is a technically challenging operation used for women found to have occult cervix cancer after a hysterectomy for benign reasons. A similar operation, radical vaginectomy, is rarely performed because of the its technical difficulty in getting adequate margins without an attached uterus. CASE REPORTS: A 41-year-old woman was found to have a presumed surgical Stage IB1 squamous cell carcinoma of the cervix at time of surgery for uterine prolapse. The patient was offered multiple options of surgery and chemoradiation. A second case, a 55-year-old woman, was found to have 1 cm vaginal cancer nine years after a total vaginal hysterectomy for carcinoma in situ of the cervix. She was also offered chemoradiation versus surgery. For the robotically-assisted laparoscopic radical parametrectomy operating time was 186 minutes with an estimated blood loss of 250 ml. For the robotically-assisted laparoscopic radical vaginectomy operating time was 154 minutes with an estimated blood loss of 150 ml. Neither patient had a hospitalization over 24 hours. There were no intraoperative or postoperative complications. CONCLUSIONS: Robotically-assisted laparoscopic radical paremetrectomy and vaginectomy are both technically feasible procedures.

Estrogen receptor alpha and beta expression in a case matched series of serous and endometrioid adenocarcinomas of the ovary.

OBJECTIVE: The purpose of this study was to analyze estrogen receptor alpha and beta (ERalpha, ERbeta) expression in a stage and grade matched cohort of patients with serous and endometrioid adenocarcinoma of the ovary. METHODS: Forty-two patients from 1991 to the present were found to have the diagnosis of endometrioid adenocarcinoma of the ovary and have tissue available for analysis. Of these 42, ten were selected for analysis. These were stage and grade matched with ten patients having serous adenocarcinoma of the ovary during the same time period. ERalpha and ERbeta mRNA was detected by a multiplex RT-PCR and amplification of random hexamer generated cDNA using a housekeeping gene (G3PD) as a control for mRNA quality and quantity. Methylation specific PCR (MS-PCR) was used to correlate methylation of the ERalpha and ERbeta CpG islands with mRNA expression status. RESULTS: ERalpha expression was present in ten of ten endometrioid adenocarcinomas but in only five of ten serous carcinomas (chi2, p = 0.01). ERbeta expression was present in six of ten endometrioid adenocarcinomas and in four of ten serous caricinomas (chi2, p = 0.65). Methylation of the ERalpha and ERbeta CpG islands was found in tumors without mRNA expression but not in the tumors with mRNA expression (p = 0.005). CONCLUSIONS: ERalpha expression, but not ERbeta expression, is significantly more common in endometrioid than serous adenocarcinomas of the ovary when controlled for stage and grade. The role of methylation in ER silencing may lead to potential therapeutic interventions.

Tunneled central venous catheters in a gynecologic oncology service: operative and short-term complications.

PURPOSE: To determine the difference in the immediate complication rate between placement of long-term central venous catheters (LTCVCs) by the percutaneous versus jugular venous cutdown method. METHOD: Case lists were examined to determine the number of LTCVCs placed during the designated time period. Medical records, operative reports, and chest roentgenograms were examined to extract pertinent information. Immediate complications included complications occurring in the operating room until 30 days postoperatively. Complications included misplacement of the catheter requiring an adjustment or a repeat procedure, pneumothorax, hydrothorax, or hemothorax, operative site or tunnel infection, and line migration requiring removal. RESULTS: Five hundred and one patients had LTCVCs placed during the period of this study. This included 399 totally implantable venous access devices (TIVADs) and 102 free access venous access devices (FAVADs) with 163 placed percutaneously into subclavian veins and 338 placed by cutdown into jugular veins. There was a significant increased risk in the overall immediate complication rate for the percutaneous placement compared to venous cutdown (p < 0.001). Also, pneumothorax was more common with the percutaneous approach compared to the venous cutdown approach (p < 0.001). CONCLUSIONS: Immediate complications, especially pneumothorax, were more common when placing catheters by the percutaneous approach as compared to the venous cutdown approach.

5-Fluorouracil cardiotoxicity complicating treatment of stage IIB cervical cancer--case report.

A 31-year-old female was found to have FIGO Stage IIB squamous cell carcinoma of the cervix. The patient began her prescribed radiation therapy and 5-fluorouracil radio-sensitizing chemotherapy. During the first day of infusion, she began having severe shortness of breath. Cardiac evaluation revealed acute congestive heart failure with a cardiac ejection fraction of 19%. Radiation was continued without chemotherapy. Four years later, the patient is alive and well with an ejection fraction of 53%.

Pelvic and para-aortic lymphadenectomy in patients with endometrioid adenocarcinoma of the endometrium.

BACKGROUND: The purpose is to determine the rate of lymph node metastases in women with endometrioid adenocarcinoma of the endometrium (EAE) undergoing systematic lymphadenectomy. METHODS: Patients (349) underwent a complete pelvic and para-aortic lymphadenectomy from caudal to the median circumflex to the level of the renal vessels. RESULTS: Grade 1 tumors accounted for 32.7% of the tumors and 31.0% of the positive nodes, grade 2 accounted for 47.3% of the tumors (37.9% of positive nodes), and grade 3 accounted for 20.1% of the tumors and 31.0% of the positive nodes (P>0.05). Positive nodes were found in 15.8% of grade 1 tumors, 13.3% of grade 2 tumors and 25.7% of grade 3 tumors (P>0.05). Isolated para-aortic involvement without pelvic nodal involvement occurred in 29% of patients with positive nodes. CONCLUSIONS: When complete lymphadenectomies are performed in EAE, positive lymph nodes (including isolated para-aortic lymph nodes) are common in all grades.

The efficacy of adjuvant platinum-based chemotherapy in Stage I uterine papillary serous carcinoma (UPSC).

OBJECTIVE: To determine the efficacy of adjuvant platinum-based chemotherapy in Stage I uterine papillary serous carcinoma (UPSC). METHODS: A retrospective multi-institutional investigation was performed to identify surgically staged patients with Stage I UPSC who were (1) treated after surgery with 3-6 courses of platinum-based chemotherapy without radiation from 1990-2003, and (2) followed for a minimum of 12 months, or until recurrence. RESULTS: Six patients (IA-2, IB-3, IC-1) were treated with carboplatin (AUC 6) or cisplatin (50 mg/m2) alone. One patient recurred to the vagina, was treated with chemo-radiation, and is alive and well at 122 months. One patient recurred to the lung, liver, and brain, and died of disease at 24 months. The remaining 4 patients are alive with no evidence of disease 15-124 months (mean 62 months) after treatment. Two patients (IB-1, IC-1) were treated with cisplatin (50 mg/m2) and cyclophosphamide (1000 mg/m2), and both are alive and well with no evidence of disease 75 and 168 months after treatment. Twenty-one patients (IA-5, IB-13, IC-3) were treated with a combination of carboplatin (AUC 6) and paclitaxel (135 mg/m2-175 mg/m2). One patient recurred to the vagina after 3 cycles of carboplatin/paclitaxel, and was treated with chemo-radiation. She is now without evidence of disease 10 months after treatment. At present, all 21 patients with Stage I UPSC treated following surgical staging with carboplatin/paclitaxel chemotherapy are alive and well with no evidence of disease 10-138 months (mean 41 months) after treatment. CONCLUSION: Combination carboplatin/paclitaxel chemotherapy following surgery is effective in the treatment of Stage I UPSC.

Evaluation of DNA methylation in the human genome: why examine it and what method to use.

PURPOSE: Since its discovery 50 years ago, DNA methylation has been found to be an important part of gene regulation. Newer methods of analysis over the last decade have helped further the understanding of this epigenetic phenomenon. The purpose of this article is to describe current methods of analysis and discuss advantages and disadvantages of each and their possible roles in gynecologic malignancies. RESULTS: The methods for analysis of DNA methylation are divided into two major categories: 1) methods which utilize chemical methods or restriction enzymes to differentially cleave at cytosine versus 5-methylcytosine sites, 2) methods which utilize sodium bisulfite (NaHSO3) to specifically convert unmethylated cytosines to uracil (thymine after PCR). This recently developed method appears to be more sensitive and allows the investigator to specifically delineate the study site(s). CONCLUSION: DNA methylation is important in the human genome. Its role in tumorigenesis is just beginning to be understood. While relying upon newly designed methods of analysis, further understanding of this epigenetic phenomenon and its role in gene expression and tumorigenesis will be forthcoming.

HSP27 in patients with ovarian carcinoma: still an independent prognostic indicator at 60 months follow-up.

OBJECTIVE: Heat shock protein 27 (HSP27) is produced in response to pathophysiologic stress in animal cells. The authors have previously shown that HSP27 is an independent prognostic indicator in patients with ovarian carcinoma. The present study was performed to see whether HSP27 remained an independent prognostic indicator with longer follow-up. METHODS: One hundred and three consecutive patients with epithelial ovarian carcinoma were studied. Slides were prepared from fresh tissue. HPS27 staining was performed as previously described. Patient records were examined for FIGO stage, grade, histology, level of cytoreduction and survival. RESULTS: One hundred and three patients were followed for a mean of 60 months. Twenty patients had FIGO Stage I disease, four Stage II, 59 Stage III, and 20 Stage IV. Immunohistochemical (IHC) staining for HSP27 was not related to histologic grade, level of cytoreduction or histologic subtype. A statistically significant decrease in HSP27 staining was found to correlate with increased FIGO stage (p = 0.008). Using cox-regression analysis, HSP27 staining (p = 0.025), stage (p = 0.0012), and level of cytoreduction (p < 0.0001) were independent predictors of survival in these patients. CONCLUSION: Cox-regression analysis found HSP27 to be an independent indicator of prognosis and survival in patients with ovarian carcinoma who had longer follow-up. Decreased HSP27 staining was related to decreased survival. This study confirms the authors' earlier report on the importance of HSP27 as a prognostic indicator in ovarian carcinoma.

Heat shock protein 27 in the placentas of women with and without severe preeclampsia.

BACKGROUND: Although not fully understood, heat shock proteins (HSP) are well known stress response proteins. The purpose of this analysis was to determine whether staining for HSP27 was different between placentas from pregnancies complicated by severe pre-eclampsia with intrauterine growth restriction (IUGR) as compared to controls. METHODS: Sterile placental tissue was collected from ten women whose pregnancies were complicated by severe preeclampsia with IUGR and from ten women with uncomplicated by severe pre-eclampsia with IUGR and from ten women with uncomplicated term pregnancies. The tissue was then stained for HSP27. RESULTS: The median age of the patients was 27 years (mean 27, range 17-37). The median estimated gestational age at delivery was 38 weeks (mean 37, range 29-41). Overall 12 of 20 placentas stained positively for HSP27 (nuclear and/or cytoplasmic). Eight of ten placentas from women with pre-eclampsia and IUGR stained positively for HSP27 (p = 0.046). CONCLUSION: HSP27 staining of the placenta is twice as common in patients with severe preeclampsia as compared to patients with normal term gestations. These preliminary results warrant the inauguration of a similar but larger study to examine the significance of these findings.

Nuclear and cytoplasmic c-myc staining in endometrial carcinoma and their relationship to survival.

OBJECTIVE: The role of the c-myc proto-oncogene in genomic instability is just becoming more fully understood. However, its role in endometrial cancer is essentially unknown. The objective of this study was to determine the relationship between cytoplasmic and nuclear c-myc staining, DNA index, and survival in patients with endometrial carcinoma. METHODS: One hundred and twenty-one patients with endometrial carcinoma were studied. Image analysis was used to determine DNA index. In addition to cytoplasmic and nuclear c-myc staining and DNA index, histologic type, stage, grade, depth of invasion, lymphvascular space invasion, and peritoneal cytology were evaluated as prognostic indicators. Univariate and multivariate analyses were performed. RESULTS: One hundred and twenty-one patients were followed for over 5 years. c-myc cytoplasmic staining was present in 75.2% of the patients' tumors, and nuclear staining was present in 66.9% (P = 0.99). DNA index was significantly higher in patients with nuclear c-myc staining and no cytoplasmic staining (DNA index 1.38) as compared to those patients whose tumors displayed cytoplasmic c-myc staining but no nuclear c-myc staining (1.18) (P = 0.016). Patients whose tumors stained positively for nuclear c-myc and negatively for cytoplasmic c-myc had significantly worse survival by Kaplan-Meier analysis (P < 0.0001). Seventeen patients died during the follow-up period of this study. By multivariate analysis, positive cytoplasmic c-myc staining with negative nuclear staining (P = 0.0076), negative cytoplasmic c-myc staining with positive nuclear staining (P = 0.011) and FIGO stage (P < 0.0001) were shown to be independent prognostic indicators predictive of survival. CONCLUSION: Nuclear and cytoplasmic c-myc staining, as well as FIGO stage, when assessed by multivariate analysis, were demonstrated to be important factors in predicting survival in the 121 patients in this study. While increasing FIGO stage was prognostic of decreased survival, the specific location of c-myc staining was also associated with prognosis. The expression of the c-myc protein is related to survival in patients with adenocarcinoma of the endometrium.

Nuclear size, shape, and density in endometrial carcinoma: relationship to survival at over 5 years of follow-up. Does analyzing only cells occupying the G0-G1 peak add useful information?

OBJECTIVE: The authors, using image analysis, previously demonstrated nuclear size and summed optical density to be independent prognostic indicators of recurrence in patients with endometrial carcinoma. The same tumors were analyzed by studying the optical features in the G0-G1 peak to see if this changed the values found as well as their importance as prognostic features at greater than 5 years of follow-up. METHODS: Tumors from 74 consecutive patients, surgically treated, with endometrial cancer, were evaluated. Survival, depth of invasion, lymphvascular space invasion, FIGO stage, grade, histology were analyzed. DNA index, progesterone receptor status, as well as nuclear size (NUSZ), shape (NUSH), and summed optical density (NUSD) were evaluated. NUSZ, NUSH, and NUSD were quantified using image analysis. RESULTS: Fifteen patients died from disease during the observation period of the study. Mean follow-up was 82 months with a median of 84 months. Forty-nine patients had stage I cancers, five stage II, 17 stage III, and three stage IV. NUSZ and NUSD were all significantly different between the original (entire cell cycle) and the re-measured (G0G1 only) values (both P < 0.001). Multivariate analysis showed both the original (P = 0.0001) and G0G1-only (P = 0.046) NUSZ and the original (P = 0.0002) and G0G1-only (P = 0.018) NUSD to be independent prognosticators of survival. CONCLUSION: Image analysis is able to quantify cellular and nuclear parameters not otherwise quantifiable. NUSD and NUSZ correlated with traditional prognostic indicators, were demonstrated independent predictors of survival at over 5 years of follow-up. Although the re-measured NUSZ and NUSD from only the G0-G1 peak were significantly different from the original NUSZ and NUSD, they were not as valuable as prognostic factors. Nuclear size and summed optical density measured from the entire cell cycle are independent prognostic indicators of survival at greater than 5 years of follow-up. Measuring nuclear morphometric features in the G0-G1 peak only does not add any new prognostic information.

Chemotherapy for ovarian cancer: an evidence-based approach.

Although cytoreductive surgery is the most influential factor in treatment for ovarian cancer, chemotherapy is needed for almost all patients diagnosed with this disease. The mainstay of chemotherapy is platinum. Different platinum compounds are used for different histologies, and different combinations are used for different histologies also. We will present the data so that each reader can understand the knowledge behind chemotherapy decisions.

Methylation: a second hit in the two-hit hypothesis.

This case illustrates that methylation of one BRCA1 allele may serve as the second hit in a patient with a diploid locus and missense mutation on the other allele.

Clonal heterogeneity of p53 mutations in ovarian cancer.

We analyzed clonal populations of ovarian cancer cells for heterogeneity in p53 mutations (exons 4-9) and chemosensitivity. UL-3A cells were developed from a patient with stage IIIC ovarian adenocarcinoma. Heterogeneity in p53 mutations was demonstrated, ranging from point mutations to deletions in exons 4, 6 and 7. UL-3A cells contained two point mutations, in codon 248 of exon 7 and in codon 76 of exon 4. Five groups of clones were identified according to the p53 mutations. UL-3A clones with low p53 levels were more sensitive to CDDP (LD50 <8.0 microg/ml). Heterogeneity of p53 mutations may provide growth advantage during disease progression or chemotherapy.

Loop electrosurgical excision procedure for partial upper vaginectomy.

OBJECTIVES: Partial upper vaginectomy consists of removal of the vaginal apex and is indicated for the diagnosis and treatment of vaginal intraepithelial neoplasia and recurrent cancer. We present a novel surgical approach to partial upper vaginectomy by use of the loop electrosurgical excision procedure. STUDY DESIGN: A total of 15 consecutive patients with abnormal vaginal cytologic results were treated by the loop electrosurgical excision procedure for partial upper vaginectomy. After submucosal injection of local anesthetic, the loop electrode was used to resect the upper third of the vagina. An iodoform vaginal pack was placed for 24 hours. All patients with high-grade vaginal intraepithelial neoplasia received intravaginal 5-fluorouracil cream postoperatively. RESULTS: The mean blood loss was 0 mL, and the mean surgical time was 30 minutes. A complication developed in 1 patient (7%). One case of invasive carcinoma was diagnosed. No recurrences have developed in any patients with vaginal intraepithelial neoplasia after hysterectomy. CONCLUSIONS: The loop electrosurgical excision procedure for partial upper vaginectomy can be performed quickly, with minimal blood loss, minimal complications, and minimal recurrence of neoplasia, and it provides a histologic specimen for evaluation.

Peritoneal fluid urea nitrogen and creatinine reference values.

OBJECTIVE: To evaluate urea nitrogen and creatinine levels in peritoneal fluid. METHODS: We prospectively evaluated 20 consecutive women having radical hysterectomy with lymphadenectomy. On postoperative days 2 and 3, serum, urine, and peritoneal fluid samples were tested for urea nitrogen and creatinine. Using power analysis we calculated an adequate sample size to be 16 patients. RESULTS: The mean urea nitrogen was 11 mg/dL in serum, 11 mg/dL in peritoneal fluid, and 469 mg/dL in urine. The mean creatinine was .9 mg/dL in serum, 1.0 mg/dL in peritoneal fluid, and 141 mg/dL in urine. Urea nitrogen and creatinine values in peritoneal fluid and serum were essentially identical. Urine urea nitrogen and creatinine values were significantly greater than serum and peritoneal values (47 to 157 times greater) (P < .011). On postoperative days 2 and 3, serial levels of serum, peritoneal fluid, and urine urea nitrogen and creatinine in the same subject showed no significant variation (P ranging from .19 to .31). CONCLUSION: Normal reference values of urea nitrogen and creatinine in peritoneal fluid are equivalent to serum values and significantly less than urine levels.

Modified radical vulvectomy without lymphadenectomy under local anesthesia in medically compromised patients.

INTRODUCTION: Our objective was to review our experience with vulvar cancer treated with modified radical vulvectomy without lymphadenectomy under local anesthesia and sedation. METHODS: A retrospective review of surgical case lists revealed five patients who underwent modified radical vulvectomy without lymphadenectomy under local anesthesia with sedation. All patients had significant medical diseases which precluded regional or general anesthesia. Modified radical vulvectomy was performed in standard fashion under sedation and local anesthesia. Inguinal lymphadenectomy was not performed. RESULTS: Median operative time was 1.5 h and median blood loss was 100 cc. Median diameter of tissue resected was 5 cm and median depth was 5 cm. Median length of hospital stay was 4 days. No patient complained of pain during the operative procedure. At a median follow-up of 2.5 years, there has been one local recurrence. CONCLUSION: Five patients with symptomatic vulvar cancer who were not candidates for regional or general anesthesia underwent modified radical vulvectomy without lymphadenectomy under local anesthesia with sedation. The procedure was well-tolerated and produced minimal morbidity and adequate short-term local control.