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.

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.

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.

Distinguishing tubal metaplasia from endocervical dysplasia on cervical Papanicolaou smears.

Tubal metaplasia is a benign endocervical lesion. There may be confusion, however, in distinguishing tubal metaplasia from endocervical gland dysplasia on Papanicolaou smear. We present a case in which a cervical smear diagnosis initially reported as endocervical atypia was corrected to a diagnosis of tubal metaplasia upon cytologic review, thus altering patient management. The presence of terminal bars and cilia are the most helpful features in the cytologic recognition of tubal metaplasia. The evaluation of endocervical gland dysplasia suggested by Papanicolaou smear may include diagnostic conization; therefore, to prevent unnecessary intervention, it is important to distinguish endocervical gland dysplasia from tubal metaplasia.

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.

Interleukin-1 inhibits growth of normal human endometrial stromal cells.

OBJECTIVE: To understand growth regulation of the endometrium by studying the effect of interleukin-1 beta (IL-1) on human endometrial stromal cell proliferation in vitro. METHODS: Endometrial stromal cells from human endometrium were separated and purified and placed in culture. Fresh and first- and sixth-passage cells were incubated with IL-1 (0.025, 0.25, and 2.5 ng/mL) for 24, 48, and 72 hours, respectively. Proliferation as a function of DNA synthesis was assessed by measuring 3H-thymidine incorporation. Experiments were then repeated in the presence of indomethacin to determine whether IL-1 effects were dependent upon prostaglandin synthesis. We evaluated overall growth by adding IL-1 to cell cultures of sixth-passage stromal cells every 3 days and by performing cell count studies. RESULTS: Interleukin-1 beta significantly inhibited 3H-thymidine uptake in freshly explanted endometrial stromal cells at all doses in a dose-dependent manner; a 44% inhibition was seen at 2.5 ng/mL IL-1 after 72 hours of incubation. In first- and sixth-passage cells, 3H-thymidine uptake was inhibited only at intermediate and high doses of IL-1. Cell count studies showed that sixth-passage cells were significantly inhibited by IL-1 after 23 days of growth (22%; P less than .01). Adding indomethacin did not affect inhibition of growth. CONCLUSION: Interleukin-1 beta inhibits growth of normal human endometrial stromal cells in vitro and does not appear to be mediated by arachidonic acid metabolites. This inhibition of growth may be important for maintenance of a normal endometrial phenotype.

Acetic acid visualization of the cervix to detect cervical dysplasia.

OBJECTIVE: To determine whether acetic acid visualization of the cervix can identify cervical dysplasia and improve detection of lesions missed by Papanicolaou test screening. METHODS: During a 2-year period, patients attending family planning clinics for regular gynecologic examinations had acetic acid applied to the cervix, followed by gross visualization without magnification. Patients with suspicious acetowhite lesions and normal Papanicolaou tests were referred for colposcopic evaluation. Findings from these examinations and corresponding biopsy results were analyzed retrospectively. RESULTS: Eighty-five women were referred for colposcopy because of abnormal acetowhite areas on the cervix. Thirteen patients (15%) had cervical intraepithelial neoplasia (CIN) (nine CIN I, four CIN II), 22 (26%) had koilocytosis, and 16 (19%) had benign histologic findings. In total, 51 patients had suspicious lesions at colposcopy for which biopsies were performed, and 34 (40%) had normal colposcopic examinations. CONCLUSIONS: Acetic acid visualization of the cervix can detect dysplasia otherwise missed by Papanicolaou test screening. However, further refinements in technique are required to decrease false-positive findings and unnecessary referrals for colposcopy.

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.

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.

Computed tomographic and ultrasonographic findings in women with acute fatty liver of pregnancy.

Acute fatty liver of pregnancy is associated with complications that can influence antepartum management and necessitate delivery. To date, liver biopsy has been regarded as the "gold standard" for diagnosis. Radiologic evaluation of the liver has been suggested as a less invasive means of diagnosing this entity. Five patients with acute fatty liver of pregnancy underwent ultrasonography; three underwent concomitant computed tomography (CT) of the liver. The liver appeared to be normal in all the patients undergoing CT evaluation and all undergoing ultrasonography except one. Normal liver examinations are not unusual findings in patients with acute fatty liver of pregnancy.

Accidental use of low-dose 5-fluorouracil in pregnancy.

Five percent 5-fluorouracil (5-FU), an antineoplastic agent, is often applied to the lower genital tract in the treatment of vaginal and vulvar human papillomavirus infections. Little is known regarding possible teratogenic effects from its topical use in pregnancy. Five cases of antenatal lower genital tract 5-FU use were correlated with pregnancy outcome. Topical 5-FU was applied up to 16 weeks' gestation. Intravaginal doses ranged from 1 to 2.5 g; one patient applied 5-FU to the vulva. Antenatal ultrasound performed on four patients did not show any fetal structural abnormalities. One patient underwent antenatal genetic amniocentesis that detected a 47,XXX complement of chromosomes. All the pregnancies continued without complications and with subsequent term delivery of healthy infants. The unwitting vaginal and vulvar use of 5-FU in pregnancy did not result in significant morbidity or mortality; expectant management of such pregnancies should be considered.

Successful pregnancy outcome after cervical dilation with multiple laminaria tents in preparation for second-trimester elective abortion: a report of two cases.

Two patients at 22 weeks' gestation underwent extensive cervical dilation with laminaria tents for elective abortion but continued their pregnancies instead. Both had normal deliveries. For the unusual patient who chooses not to carry out an abortion initiated with cervical dilation, successful pregnancy is possible and therapeutic intervention such as cervical cerclage seems inadvisable.

PIP: 2 patients at 22 weeks' gestation underwent extensive cervical dilation with laminaria tents for elective abortion but continued their pregnancies instead. Case 1 was 23 years old, gravida, 4, para, 1, elective abortions 2. She was a heroin addict. 12 laminaria tents were inserted over 2 days, and were apparently expelled on the 3rd day, with no effect on the pregnancy. After 37 weeks' gestation without prenatal care, she gave birth to a healthy 2790g female with Apgar scores of 8 and 8, and with no labor or postpartum complications. Case 2 was 27 years old, gravida 6, para 3, spontaneous abortions 2. She desired termination because of her home situation, and had 17 small tents placed over 2 days, but on the day of the scheduled abortion, she changed her mind. The tents were removed, and she was given oral erythromycin. At 40 weeks' gestation, she was spontaneously delivered of a 3080g male with Apgar scores 9 and 9. In both patients, the cervical dilation of 2-3cm, normally worrisome at this gestation, returned to normal within 1 week. For the unusual patient who chooses not to carry out an abortion initiated with cervical dilation, successful pregnancy is possible. Therapeutic intervention such as cervical cerclage seems inadvisable. Antibiotic treatment and referral for prenatal care seems the best course, and patients should be warned about the possibility of amniotitis and premature labor.

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.

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.

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.

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.

Preventing cervical conization by achieving satisfactory colposcopy with hygroscopic cervical dilators.

Eighteen women with abnormal cervical cytologic findings and unsatisfactory colposcopic examinations underwent cervical dilatation with Dilapan (Gynotech), a hygroscopic dilator. Dilatation exposed the entire squamocolumnar junction, converting an unsatisfactory colposcopic examination into a satisfactory one and avoiding cervical conization in 17 of the 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 interleukin-1 and interleukin-1 receptor antagonists in endometrial cancer.

The cytokine interleukin-1 (IL-1) can inhibit growth of breast cancer cells in culture and promote cellular differentiation in synergism with other growth factors. A secreted IL-1 receptor antagonist (sIL-1ra) has been described and an intracellular version (icIL-1ra) has been cloned; both antagonists block IL-1-dependent responses. We compared mRNA expression of IL-1 and both receptor antagonists in normal and neoplastic endometrium. RNA was extracted from five benign endometrial and five endometrial cancer whole-tissue specimens, reverse transcribed into cDNA, then amplified by polymerase chain reaction using specific primers for IL-1 alpha, IL-1 beta, sIL-1ra, and icIL-1ra. IL-1 alpha and IL-1 beta were expressed in variable amounts in all tissues; there was no difference in expression between normal and cancer specimens. In contrast, high levels of icIL-1ra were expressed in four of five cancer specimens compared with none of five normal tissues (P = 0.02). There was no expression of sIL-1ra in cancer and normal tissues. These preliminary experiments suggest that IL-1 is ubiquitously expressed in endometrial tissues whereas endometrial cancer preferentially expresses icIL-1ra. IcIL-1ra may regulate IL-1-mediated events such as growth and differentiation in endometrial neoplasia.