Clinical calculator predictive of chemotherapy benefit in stage 1A uterine papillary serous cancers.

OBJECTIVE: Determine the utility of a clinical calculator to predict the benefit of chemotherapy in stage IA uterine papillary serous cancer (UPSC). PATIENTS AND METHODS: Data were collected from NCDB from years 2010-2014. Based on demographic and surgical characteristics, a clinical score was developed using the random survival forest machine learning algorithm. RESULTS: Of 1,751 patients with stage IA UPSC, 1,012 (58%) received chemotherapy and 739 (42%) did not. Older age (HR 1.06), comorbidities (HR 1.31), larger tumor size (HR 1.27), lymphovascular invasion (HR 1.86), positive peritoneal cytology (HR 2.62), no pelvic lymph node dissection (HR 1.51), and no chemotherapy (HR 2.16) were associated with poorer prognosis. Compared to no chemotherapy, patients who underwent chemotherapy had a 5-year overall survival of 80% vs. 67%. To better delineate those who may derive more benefit from chemotherapy, we designed a clinical calculator capable of dividing patients into low, moderate, and high-risk groups with associated 5-year OS of 86%, 73%, and 53%, respectively. Using the calculator to assess the relative benefit of chemotherapy in each risk group, chemotherapy improved the 5-year OS in the high (42% to 64%; p < 0.001) and moderate risk group (66% to 79%; p < 0.001) but did not benefit the low risk group (84% to 87%; p = 0.29). CONCLUSION: Our results suggest a clinical calculator is useful for counseling and personalizing chemotherapy for stage IA UPSC.

Uterine serous carcinoma: a comparison of therapy for advanced-stage disease.

Management of advanced-stage uterine serous carcinoma (USC) is uncertain, and postsurgical therapeutic options swing between radiation and chemotherapy. The aim of this study is to evaluate the utility of radiotherapy compared to platinum-based chemotherapy in women with advanced-stage USC. We retrospectively identified cases of USC at our institution. Survival distributions were calculated by the Kaplan-Meier method. Two-tailed t-tests were used to compare time to progression and time to death. We identified 24 women diagnosed with either stage III or IV USC. Time to progression for women receiving radiotherapy was 5.3 months as compared with 12.4 months for women receiving chemotherapy (P = 0.01). Mean time to death for the radiotherapy group was 8 months compared to 18 months in the chemotherapy group (P = 0.04). Kaplan-Meier survival curves were significantly different between the two groups (P = 0.01). While radiotherapy appears to control USC recurrences in the pelvis, the disease often recurs distantly. When compared to radiotherapy, platinum-based chemotherapy appears to increase disease-free survival and time to death in women with advanced-stage USC.

The role of omentectomy during the surgical staging of uterine serous carcinoma.

Uterine serous carcinoma (USC) has a propensity for extrauterine spread, and some suggest that this disease be staged as an ovarian cancer, and thus include omental sampling. However, given the primary organ involved, the staging recommendations do not include omental sampling. The aim of this study is to evaluate the role of omental sampling during the surgical staging of USC. We retrospectively identified cases of USC at our institution from January 1990 to June 2000 and abstracted surgical procedures, stage, and sites of metastasis. Fisher's exact test was used to calculate sensitivity, specificity, and positive and negative predictive value. We identified 65 women with USC, of which 52 underwent omental evaluation. Thirty four of the omentums were visually normal and benign on histologic review. Two were visually negative and histologically positive for metastatic serous carcinoma. The remaining 16 specimens were grossly involved with histologic confirmation of disease. The sensitivity of a visually negative omentum is 0.89 (P < 0.0001). Microscopic omental metastasis from USC is rare. When the omentum is involved, thereby upstaging the patient to stage IVB disease, the disease is generally diagnosed by gross visualization. We conclude that omental sampling does not need to be included in the routine surgical staging of USC.

Appendix cancer mimicking ovarian cancer.

Appendiceal adenocarcinoma is a rare malignancy for which there is no characteristic clinical presentation. We describe five women who presented with signs and symptoms characteristic of advanced ovarian cancer but whose final diagnosis was stage IV appendiceal cancer. Between 1998 and 1999, five women treated for presumed ovarian cancer were identified as having primary appendiceal cancer. Medical records and pathology were retrospectively reviewed. The median age was 47 years (range 36-61 years). All had elevated preoperative CA125 levels with a median value of 171 micro/ml (range 46-383). Four women underwent right hemicolectomy with two requiring radical surgical tumor debulking to render them optimally debulked. Four had postoperative chemotherapy, the most common agent used was 5-flourouracil. Median survival was 6.75 months (range 19 days-11 months). Primary adenocarcinoma of the appendix is rare; therefore, the clinical utility of radical tumor debulking and chemotherapy is not well described. Given the poor survival in our series, all efforts should be considered palliative. Although this disease process is uncommon, it should be entertained by gynecologic oncologists in the differential diagnosis of an intra-abdominal mass and ascites. The ability to make the correct diagnosis and differentiate between an ovarian and appendiceal primary is critical as the treatment modalities vary.

Oral topotecan as single-agent second-line chemotherapy in patients with advanced ovarian cancer.

PURPOSE: To evaluate oral topotecan as single-agent, second-line therapy in patients with ovarian cancer previously treated with a platinum-based regimen. PATIENTS AND METHODS: Patients (N = 116) received oral topotecan 2.3 mg/m2 daily for 5 days every 21 days. Eligibility criteria included histologic diagnosis of International Federation of Gynecology and Obstetrics stage III or IV epithelial ovarian cancer, bidimensionally measurable disease, prior platinum-containing chemotherapy, age > or = 18 years, performance status < or = 2, and life expectancy > or = 12 weeks. RESULTS: Overall response rate was 21.6% (25 of 116 patients). Median duration of response was 25.0 weeks; median time to response was 8.4 weeks. Median time to progression was 14.1 weeks; median survival was 62.2 weeks. Grade 4 neutropenia was experienced by 50.4% of patients in 13.4% of courses administered. Grade 4 thrombocytopenia was experienced by 22.1% of patients in 5.1% of courses. Grade 3 or 4 anemia was experienced by 29.2% of patients in 8.5% of courses. Most frequent nonhematologic toxicities were predominantly (> 90%) grade 1 or 2 and included nausea, alopecia, diarrhea, and vomiting. CONCLUSION: Second-line oral topotecan administered at 2.3 mg/m2 for 5 days every 21 days demonstrated activity in patients with progressive or recurrent ovarian cancer after first-line platinum-based chemotherapy. This activity was comparable to that seen in previous studies with intravenous topotecan. Grade 4 neutropenia was less frequent with oral topotecan than previously reported for intravenous topotecan. Oral topotecan is an active, tolerable, and convenient formulation of an established agent for the second-line treatment of advanced epithelial ovarian cancer and may also facilitate exploring prolonged treatment schedules.

Phase II trial of topotecan in patients with advanced, persistent, or recurrent uterine leiomyosarcomas: a Gynecologic Oncology Group Study.

From October 1995 to March 1997, a phase II trial of topotecan was carried out in chemotherapy-naive women with advanced, persistent, or recurrent uterine leiomyosarcomas. Thirty-six patients were entered. Median age was 53 years. Performance status was 0 (50%) in 18, 1 (36%) in 13, and 2 (14%) in 5. Most patients, 33 (92%), had undergone prior surgery, and 8 (22%) prior radiation therapy. Topotecan, 1.5 mg/m2. was administered intravenously daily for 5 days, every 3 weeks, until progression of disease or adverse affects prohibited further therapy. Patients received 1 to 13 courses with a median of 3 courses. The most frequent grade 4 adverse effects were neutropenia in 28 (78%), leukopenia in 8 (22%), thrombocytopenia in 3 (8%), and anemia in 3 (8%). Complete response was seen in 1 (3%), partial response in 3 (8%), stable disease in 12 (33%), and increasing tumor in 20 (56%). Thus topotecan at this dose and schedule does not appear to have major activity in uterine leiomyosarcomas.

The prognostic value and clinical utility of estrogen and progesterone receptors in endometrial carcinoma.

In the United States, endometrial carcinoma is the most common gynecologic malignancy, and accounts for 4,900 deaths per year in the United States. While this disease has relatively good cure rates, there is motivation to describe other determinants, which may help in the treatment of this disease. Attempts have been made to correlate hormone receptor status with disease-free intervals and survival in patients with endometrial carcinoma. The weight of evidence seems to support that of the two hormone receptors, progesterone is the more significant predictor of patient outcome. If hormone receptors are to be used in the management of endometrial carcinoma, they should be determined by immunohistochemistry. In the adjuvant setting, patients with progesterone positive tumors are more amenable to treatment with progestational agents than are patients with receptor negative tumors. Future areas of research include the use of tamoxifen and selective estrogen receptor modulators in the chemoprevention and treatment of endometrial carcinoma.

Expression of Ki-67 in vulvar carcinoma and vulvar intraepithelial neoplasia III: correlation with clinical prognostic factors.

OBJECTIVES: In vulvar carcinoma, the expression of Ki-67 has been previously found to correlate with patient outcome. The objective of the study was to determine whether a specific pattern of expression was associated with occult vulvar cancer in patients with vulvar intraepithelial neoplasia (VIN) III and whether patterns of Ki-67 expression correlated with other clinical prognostic factors. METHODS: 19 women with only VIN III, 16 women with both vulvar cancer and VIN III, and 15 women with only vulvar cancer were identified. Immunostaining, using a monoclonal antibody for Ki-67, was then performed on representative tissue blocks and slides were assessed for diffuse or localized patterns of expression. For the patients with vulvar cancer, the type of staining was correlated with FIGO stage, tumor grade, lymph nodes status, and associated VIN III. RESULTS: All 35 patients with VIN III exhibited a diffuse staining pattern. In the 31 patients with vulvar carcinoma, 11 (35%) expressed a diffuse staining pattern while 20 (65%) showed a localized pattern. Poorly differentiated tumors were associated with a diffuse staining pattern (P = 0.013, RR 3.59, CI 1.59-7.60). For vulvar carcinoma, there were no statistically significant relationships between Ki-67 expression pattern and stage, associated VIN III, or lymph node involvement. CONCLUSION: VIN III, regardless of a concomitant vulvar cancer, always expressed a diffuse pattern; thus Ki-67 staining was not useful as a marker for occult cancer. In women with vulvar carcinoma, however, a diffuse Ki-67 expression was significantly associated with poorly differentiated tumors.

Estrogen receptor status, determined by immunohistochemistry, as a predictor of the recurrence of stage I endometrial carcinoma.

BACKGROUND: The aim of this study was to compare the concordance between immunohistochemical (IHC) and biochemical (RIA) methods for determining hormone receptor status in patients with endometrial carcinoma and to determine whether IHC expression of estrogen and progesterone receptors (ER and PR) has prognostic significance. METHODS: Paraffin blocks were obtained from patients diagnosed with endometrial carcinoma between 1987 and 1991. IHC analysis for ER and PR expression was performed and scored based on staining intensity and the percentage of tumor cells with nuclear staining. Biochemical assays were performed on frozen tissues. Concordance between the two methods was evaluated and hormone receptor status was correlated with tumor grade, stage, recurrence and survival. RESULTS: ER and PR expression, determined by IHC, correlated well with RIA levels (Spearmans correlation coefficient, P = 0.006 and 0.0005, respectively). Determination of ER and PR expression by both methods was correlated with tumor grade. Hazards ratios revealed that the absence of ER and PR expression, determined by both IHC and RIA, independently correlated with recurrence in early stage disease (P < 0.05). CONCLUSIONS: Historically, receptors have been determined by RIA. In this study, IHC and RIA were equally suitable for determination of ER and PR. This is significant clinically as IHC has several advantages over RIA, including easier processing, lower cost, greater speed, and applicability to fixed tissue samples. In addition, ER negative status was predictive of the recurrence of Stage I tumors independent of tumor grade. ER status may aid the clinician in planning treatment when adjuvant treatment is controversial.

Overexpression of focal adhesion kinase, a protein tyrosine kinase, in ovarian carcinoma.

BACKGROUND: Focal adhesion kinase (FAK) is a tyrosine kinase that is important to such key functions such as cell adhesion, motility, and invasion. A MEDLINE search of the years 1980-1998 found no previous reports of FAK expression in human ovarian carcinoma. The authors performed experiments to determine whether FAK expression is elevated in this disease. METHODS: Ten normal human ovarian tissue samples and 26 cancer samples from patients with Stage I-IV ovarian carcinoma were obtained. Two ovarian carcinoma cell lines were also analyzed. FAK expression was determined by Western blot analysis with the V39 anti-human FAK polyclonal antibody. The level of FAK protein expression was determined using densitometric scanning of the 125 kD band on autoradiographs of Western immunoblots. RESULTS: Serous cancers expressed fourfold-increased values of FAK relative to normal ovarian tissue (P < 0.0001), and nonserous adenocarcinomas expressed threefold- to fourfold-increased values of FAK (P < 0. 0006). Ovarian carcinoma cell lines also expressed increased values of FAK. With a cutoff of 40, an elevated FAK level was associated with a sensitivity of 93% and specificity of 100%. There was no significant difference in FAK expression with regard to grade or stage of tumor. CONCLUSIONS: FAK is significantly overexpressed in ovarian carcinoma, implying that FAK may play an important role in ovarian carcinogenesis. FAK expression may be useful as a screening tool to identify newly developed disease or as a tumor marker in confirmed cases of epithelial ovarian carcinoma. FAK may also serve as a potential target for therapeutic disruption of ovarian carcinoma progression.

Vulvar intraepithelial neoplasia III: occult cancer and the impact of margin status on recurrence.

OBJECTIVE: To determine the impact of margin status on disease recurrence and the incidence of occult cancer in women diagnosed with vulvar intraepithelial neoplasia (VIN) III and treated with surgical excision. METHODS: Between 1989 and 1995, 73 women were diagnosed preoperatively with VIN III by vulvar biopsy and were treated with surgical resection. Patients were examined postoperatively, and recurrence was diagnosed when a biopsy of suspicious lesions confirmed VIN III. RESULTS: The mean age was 45 years; 81% of the patients were white, and 18% were black. Eighty-two percent of the women had used tobacco, 56% had prior cervical dysplasia, and 37% had prior genital warts. An underlying squamous vulvar cancer was found in 22% of patients at initial treatment for VIN III. Fifty-nine women had follow-up of at least 7 months. Of these, 66% (39 of 59) had positive surgical margins, 31% (18 of 59) had negative margins and 3% had unknown margins (two of 59). With positive margins, 46% (18 of 39) suffered recurrent disease; with negative margins, only 17% (three of 18) had recurrent disease (P = .03). Multifocal disease and a history of genital warts also correlated with VIN III recurrence (P = .03 for both). CONCLUSION: A significant number of women diagnosed initially with VIN III on a vulvar biopsy harbored occult vulvar cancer. Recurrences were almost threefold higher when margins were positive for residual VIN III. We conclude that surgical resection is an appropriate method of treatment of VIN III for both diagnostic and therapeutic purposes.

Prolonged oral etoposide in recurrent or advanced squamous cell carcinoma of the cervix: a gynecologic oncology group study.

OBJECTIVE: Previous studies by the Gynecologic Oncology Group have demonstrated no activity with bolus etoposide in squamous cell carcinoma of the cervix. Prolonged oral etoposide, which exploits the schedule dependency of this agent, has demonstrated activity in non-small cell carcinoma of the lung and has been studied in combination therapy with cisplatin. To evaluate prolonged oral etoposide in previously treated squamous cell carcinoma of the cervix, the current Phase II trial was conducted. METHODS: Eligibility included squamous cell cancer of the cervix, measurable disease, allowed no more than one prior chemotherapy regimen which did not include etoposide, WBC >/=3000/microliter, platelet count >/=100, 000/microliter, serum creatinine

Use of a saline breast implant to cover the pelvic floor.

Pelvic exenteration is one of the most radical procedures in the repertoire of gynecologic oncology procedures. Postoperative complications include sepsis, hemorrhage, formation of adhesions resulting in bowel obstruction, and fistulas resulting from large denuded pelvic surfaces. To date there is no clear consensus as to the best way to cover the pelvis after the destructive phase of an exenteration. Herein, we present a different approach to pelvic coverage by placement of a 300 cc saline breast implant. Use of a saline-filled breast implant to fill the pelvis represents a possible approach to addressing the denuded pelvic space created during extensive gynecologic surgery.

Lymph node metastases and prognosis in patients with stage IA2 cervical cancer.

Ninety-four patients with squamous cell carcinoma invading the cervical stroma to a depth of >3.0-5.0 mm with 7 mm or less in horizontal spread (FIGO Stage IA2) were evaluated. Depth and lateral extent of stromal invasion were verified using an ocular micrometer. Cell type and lymph vascular space invasion (LVSI) were recorded in each case. Patients were treated primarily by radical hysterectomy with pelvic lymphadenectomy, and those with lymph node metastases were offered postoperative radiation. Following treatment, patients were seen at 3-month intervals for 2 years, and every 6 months thereafter. The mean duration of follow-up was 6.9 years (range 0.4-23.5 years). Seven of 94 patients (7.4%) had lymph node metastases. Five patients had 1 positive node, 1 patient had 2 positive nodes, and 1 patient had 3 positive nodes. Five patients developed recurrent cancer and 4 died of disease. LVSI was present in 31 cases (33%). Tumor recurrence was significantly increased in patients with positive LVSI (9.7% vs 3.2%). The 5-year survival rate of patients with LVSI was 89% vs 98% in patients without this finding (P = 0.058). The 5-year survival rate of all Stage IA2 cervical cancer patients was 95%. Patients with Stage IA2 cervical cancer have a significant risk of lymph node metastases and should be treated by radical hysterectomy with pelvic lymphadenectomy. LVSI is an important prognostic variable in these patients and should be recorded in all cases.

Diethylstilbestrol-induced immortalization of human endometrial cells: alterations in p53 and estrogen receptor.

Carcinogenesis is a process requiring multiple steps. Immortalization is one step in this process and may be rate limiting. To further our understanding of estrogen-induced carcinogenesis, we evaluated diethylstilbestrol (DES)-induced immortalization of human endometrial stromal cells. This was achieved by assessing at the restrictive temperature the colony-forming efficiency of cells that were conditionally immortalized with a temperature-sensitive simian virus 40 large T antigen. Treatment with DES for 1 wk did not increase the immortalization frequency; however, cultures that were treated for 20 wk had a twofold increase in immortalization frequency, and continued treatment for a total of 44 wk produced a threefold increase in immortalization frequency that was dose dependent. DES-treated restrictive temperature variants (RTVs) but not spontaneous RTVs lost the temperature-sensitive phenotype. DES-RTVs also had a shorter doubling time than spontaneous RTVs did. p53 expression was increased in DES-RTVs, and its localization within the cell was altered. Conversely, expression of the estrogen receptor was decreased in DES-immortalized cells. These changes in gene expression often occur in estrogen-related malignancies, and our results are consistent with a causal role for estrogens in these p53 and the estrogen receptor alterations. Immortalization of human cells may be analogous to initiation of rodent cells, and our results suggest that estrogen-induced alterations in p53 or other genes that regulate life span could contribute to estrogen-induced initiation.

Primary non-clear-cell adenocarcinomas of the vagina in older DES-exposed women.

The association between in utero diethylstilbestrol (DES) exposure and the development of clear-cell adenocarcinoma of the vagina and cervix has been well described. However, non-clear-cell mucin-secreting adenocarcinoma in women with DES exposure has not been previously reported. We present two cases of non-clear-cell mucinous adenocarcinoma in women having a history of in utero DES exposure. These cancers were found in older women and were more advanced than the clear-cell adenocarcinoma associated with DES. Histologic features of these tumors were notable for atypical, irregular glands lined by endocervical, intestinal, and endometrioid epithelium. The development of non-clear-cell adenocarcinoma of the vagina in these patients may be associated with DES exposure in utero. Long-term surveillance of DES-exposed women may be warranted.

Use of the APACHE II scoring system to determine mortality of gynecologic oncology patients in the intensive care unit.

OBJECTIVE: To determine if an elevated score on the Acute Physiology and Chronic Health Evaluation II (APACHE II) scoring system is associated with mortality of acutely ill gynecologic oncology patients. METHODS: Gynecologic oncology patients admitted to the surgical intensive care unit (ICU) were identified from the ICU data base. Their admission APACHE II score and type of gynecologic cancer were also extracted from the data base. Charts were reviewed to determine the disease status and reason for admission to the surgical ICU. Patient mortality was correlated with APACHE II scores. RESULTS: Forty-five gynecologic oncology patients were admitted to the surgical ICU from June 1988 to January 1992. They had a mean age of 62 years and various cancers: ovarian (24), cervical (16), and endometrial (five). The mean APACHE II score was 12 (range 2-26). Eight of 45 (18%) patients died. There was a significant correlation between APACHE II scores and mortality; patients with an APACHE II score of 20 or greater had a 78% risk of death compared to a 3% risk if the score was less than 20 (P < .001, chi 2 test). CONCLUSION: Elevated APACHE II scores are associated with mortality in acutely ill gynecologic oncology patients.

Pleural effusions: outpatient management with pigtail catheter chest tubes.

Pulmonary effusions associated with ovarian cancer indicate advanced disease. Although many patients tolerate these effusions, some are symptomatic and manifest respiratory distress. Therapeutic sclerosis of the pleural cavity is successful in some patients; however, not all patients are relieved of respiratory symptoms. We present two symptomatic patients in whom sclerosis was unsuccessful or not an option; their respiratory symptoms were relieved with placement of pigtail catheter chest tubes that allowed discharge from the hospital and management at home. Catheters were easy to manage at home and there were no infectious complications.

Expression of three forms of melanoma growth stimulating activity (MGSA)/gro in human retinal pigment epithelial cells.

PURPOSE: To characterize mRNA expression and protein production of the cytokine MGSA/gro in human retinal pigment epithelial (RPE) cells and to determine whether expression of MGSA/gro is modulated by serum and the cytokines interleukin 1 beta (IL-1 beta), tumor necrosis factor alpha (TNF alpha), or transforming growth factor beta (TGF beta) mediators implicated in proliferative vitreoretinopathy (PVR). METHODS: Reverse-transcription polymerase chain reaction was used to determine the steady-state mRNA expression of three forms of MGSA/gro, alpha, beta, and gamma, by cultured human RPE cells in the presence or absence of recombinant IL-1 beta, TNF alpha, or TGF beta, or when serum-starved cells were re-fed with medium containing serum. Immunocytochemistry was used to characterize RPE cell-associated MGSA/gro protein, and immunoprecipitation of MGSA/gro from cell-conditioned medium was used to demonstrate MGSA/gro secretion. RESULTS: MGSA/gro mRNA was expressed minimally under basal conditions. Expression for all three forms of MGSA/gro mRNA was induced in a dose- and time-dependent manner after exposure to IL-1 beta, to a lesser extent after exposure to TNF alpha, but not after exposure to TGF beta. Serum induced MGSA/gro alpha and gamma transcripts, but not beta transcripts. Cell-associated MGSA/gro was identified on RPE cells grown in the absence of cytokines, but MGSA/gro was not secreted under these conditions. Exposure to IL-1 beta did not consistently cause increased cell-associated MGSA/gro; however, IL-1 beta induced secretion of MGSA/gro in a time-dependent manner. CONCLUSION: MGSA/gro is produced by human RPE in response to mediators implicated in PVR. Because MGSA/gro is a pleiotropic modulator of cell proliferation and inflammation, it may contribute to the intraocular wound healing response that characterizes PVR.