Portable Pocket colposcopy performs comparably to standard-of-care clinical colposcopy using acetic acid and Lugol's iodine as contrast mediators: an investigational study in Peru.

OBJECTIVE: Our goal was to develop a tele-colposcopy platform for primary-care clinics to improve screening sensitivity and access. Specifically, we developed a low-cost, portable Pocket colposcope and evaluated its performance in a tertiary healthcare centre in Peru. DESIGN AND SETTING: Images of the cervix were captured with a standard-of-care and Pocket colposcope at la Liga Contra el Cáncer in Lima, Peru. POPULATION: Two hundred Peruvian women with abnormal cytology and/or human papillomavirus positivity were enrolled. METHODS: Images were collected using acetic acid and Lugol's iodine as contrast agents. Biopsies were taken as per standard-of-care procedures. MAIN OUTCOME MEASURES: After passing quality review, images from 129 women were sent to four physicians who provided a diagnosis for each image. RESULTS: Physician interpretation of images from the two colposcopes agreed 83.1% of the time. The average sensitivity and specificity of physician interpretation compared with pathology was similar for the Pocket (sensitivity = 71.2%, specificity = 57.5%) and standard-of-care (sensitivity = 79.8%, specificity = 56.6%) colposcopes. When compared with a previous study where only acetic acid was applied to the cervix, results indicated that adding Lugol's iodine as a secondary contrast agent improved the percent agreement between colposcopes for all pathological categories by up to 8.9% and the sensitivity and specificity of physician interpretation compared with pathology by over 6.0 and 9.0%, respectively. CONCLUSIONS: The Pocket colposcope performance was similar to that of a standard-of-care colposcope when used to identify precancerous and cancerous lesions using acetic acid and Lugol's iodine during colposcopy examinations in Peru. TWEETABLE ABSTRACT: The Pocket colposcope performance was similar to that of a standard-of-care colposcope when identifying cervical lesions.

Predictors of suboptimal surgical cytoreduction in women with advanced epithelial ovarian cancer treated with initial chemotherapy.

The objective of this study was to retrospectively evaluate predictors of suboptimal surgical cytoreduction (SSC) in women with advanced epithelial ovarian cancer (EOC) treated with initial chemotherapy (IC). All women with EOC treated with IC at our hospital between January 1, 1995, and January 1, 2003, were eligible; 128 patients met inclusion criteria and underwent retrospective chart review. Eighty-four patients (66%) had an optimal surgical cytoreduction (OSC), 14 patients (11%) had an SSC, and 30 (23%) patients were treated with chemotherapy only (CO). Patients in the SSC group had more small-bowel mesentery disease on preoperative computed tomography (CT) scan compared to the OSC group (38% SSC vs 6% OSC, P = 0.024). Patients in the SSC group were also more likely to have disease on the liver surface, small-bowel surface, large-bowel mesentery, bladder peritoneum, spleen, and diaphragm that was not reported on preoperative CT but found at surgery. More patients in the SSC group had chemoresistant disease (indicated by stable or progressive disease on CT scan [56% SSC vs 17% OSC, P = 0.05]) and less of a decrease in their CA-125 values (69% SSC vs 93% OSC, P

Vulvar melanoma: a retrospective analysis and literature review.

OBJECTIVE: This review focuses on current directions in the staging and treatment of melanoma of the vulva. METHODS: All women treated for invasive melanoma of the vulva at the University of Virginia Health Sciences Center from 1980 through 2000 were identified through a retrospective review of the records of the Division of Gynecologic Oncology. Their treatments and outcomes were then analyzed and presented. RESULTS: Over the 20-year study period, 14 cases of melanoma of the vulva were identified. Of the 14 patients treated with curative intent, 6 developed recurrences following the completion of primary therapy, and all are dead from their disease. The mean duration from completion of therapy to recurrence was 7.5 months; the mean survival following recurrence was 17 months. CONCLUSION: One-centimeter skin margins appear adequate for vulvar melanomas <1 mm thick, and 2-cm margins appear adequate for intermediate-thickness melanomas (1-4 mm). In all cases it is necessary to include at least a 1-cm-deep margin extending through the subcutaneous fat to the muscular fascia below. Elective node dissection seems to offer no additional advantage in superficial lesions <0.76 mm thick, and its role in deeper lesions is still uncertain.

High urine 1-hydroxypyrene glucuronide concentrations in Linxian, China, an area of high risk for squamous oesophageal cancer.

Most squamous cell carcinomas of the oesophagus in low-risk populations are attributable to alcohol and tobacco consumption, but the aetiologic agents in many high-risk populations have yet to be definitively identified. Linxian, China has some of the highest oesophageal cancer rates in the world. Recent studies suggest that an association exists between high-level exposure to carcinogenic polycyclic aromatic hydrocarbons (PAHs), such as benzo[a]pyrene (B[a]P), and the development of oesophageal cancer. The inhabitants of this high-risk region extensively use coal and wood for cooking and heating in unvented stoves, and thus may be exposed to PAHs produced during the incomplete combustion of these fuel sources. High levels of B[a]P were recently detected in staple food samples from Linxian and histopathologic changes that may be associated with PAH exposure have also been identified in oesophagectomy specimens from the region. In an effort to determine whether this high-risk population is exposed to high levels of PAHs, voided urines from non-smokers (n = 22) without occupational exposure were collected and analysed using immunoaffinity chromatography and synchronous fluorescence spectroscopy for 1-hydroxypyrene glucuronide, a PAH metabolite and index biomarker for mixed PAH exposure. The median urine 1-hydroxypyrene glucuronide concentration (2.06 pmol ml(-1)) was equivalent to concentrations detected in current smokers. To the authors' knowledge, this represents the first report of elevated urine 1-hydroxpyrene glucuronide concentrations in Linxian, and the first biologic confirmation that the inhabitants of this rural, non-industrial, high oesophageal cancer risk region are exposed to carcinogenic PAHs.

Late uterine wedge resection of placenta increta.

BACKGROUND: Recently, preferences for preserving reproductive potential has sparked increasing interest in the conservative management of placenta accreta, increta, and percreta. CASE: A 23-year-old gravida 3 para 2 had a vaginal delivery complicated by retained placenta. The placenta was delivered in multiple fragments followed by sharp curettage. Her postpartum course was complicated by pelvic pain and menorrhagia, unrelieved by sharp curettage. Four months postpartum, transvaginal ultrasonography and magnetic resonance imaging demonstrated an intramyometrial mass. Exploratory laparotomy was done with wedge resection of the anterior wall of the uterus under real-time ultrasonographic guidance. Pathologic examination found placenta increta. CONCLUSION: Conservative management of placenta increta can be used selectively to preserve reproductive potential.

Human germ cell tumours: expression of gamma-glutamyl transpeptidase and sensitivity to cisplatin.

Previous studies have shown that the enzyme-glutamyl transpeptidase (GGT) is essential for the nephrotoxicity of cisplatin. This study was designed to determine whether GGT activity is necessary for the therapeutic effect of the drug. The relationship between GGT expression and clinical response to platinum-based chemotherapy was examined in 41 human germ cell tumours. Sections of formalin-fixed, paraffin-embedded tumours were immunohistochemically stained with an antibody directed against human GGT. There was no expression of GGT in any of the 17 seminomas or four dysgerminomas; whereas, 12/12 ovarian yolk sac tumours and 4/4 embryonal carcinomas of the testis were GGT-positive. In stage I tumours fewer tumour cells expressed GGT than in later stage tumours. In four germ cell tumours of mixed histology, the seminomatous and dysgerminoma areas were GGT-negative while the areas of the tumour with yolk sac or embryonal histology contained GGT-positive tumour cells. The patients with seminomas or dysgerminomas who were treated with cisplatin-based chemotherapy, all had a complete response despite the absence of GGT expression in these tumours. Fifteen of the 16 patients with yolk sac or embryonal carcinomas received cisplatin-based chemotherapy following surgery. Twelve had a complete response, while three failed to respond to platinum-based therapy. There was no correlation between the level of GGT-expression and response to therapy in this group. Three of the four patients with tumours of mixed histology were treated with cisplatin-based therapy, and had a complete response. Therefore, expression of GGT is not necessary for the therapeutic effect of cisplatin in germ cell tumours. The results from this study suggest that systemic inhibition of GGT would inhibit the nephrotoxic side-effect of cisplatin without interfering with its activity towards germ cell tumours.

Expression of gamma-glutamyl transpeptidase in stage III and IV ovarian surface epithelial carcinomas does not alter response to primary cisplatin-based chemotherapy.

OBJECTIVE: Gamma-glutamyl transpeptidase activity has been shown to be essential for the nephrotoxicity of cisplatin. The purpose of this study was to determine whether expression of gamma-glutamyl transpeptidase in ovarian carcinomas is necessary for the antitumor effect of cisplatin. STUDY DESIGN: Tumor tissue from 18 patients with stage III or IV ovarian serous papillary carcinoma or poorly differentiated adenocarcinoma was analyzed for expression of gamma-glutamyl transpeptidase by histochemical or immunohistochemical staining. Response to cisplatin-based combination chemotherapy was evaluated on the basis of clinical response, progression-free interval, and survival. RESULTS: Gamma-glutamyl transpeptidase expression in the tumors ranged from 0% to 100% of the tumor cells gamma-glutamyl transpeptidase positive. Patient survival ranged from 15 months to 9 years. Twelve of the 18 patients had a complete response to the initial course of cisplatin-based combination chemotherapy. There was no statistically significant correlation between either response or time to relapse and gamma-glutamyl transpeptidase expression. However, there was a correlation between high levels of gamma-glutamyl transpeptidase in the tumor and acute ototoxicity in patients treated with cisplatin. Expression of high levels of gamma-glutamyl transpeptidase in the tumor was also found to be associated with shorter patient survival, suggesting that gamma-glutamyl transpeptidase might have a role in resistance to drugs used in second- and third-line therapy. CONCLUSIONS: Expression of gamma-glutamyl transpeptidase in ovarian serous papillary or poorly differentiated adenocarcinomas is not necessary for the antitumor activity of cisplatin. A correlation was found between high levels of gamma-glutamyl transpeptidase in the tumor and both increased ototoxicity from cisplatin and decreased patient survival. These data suggest that administering an inhibitor of gamma-glutamyl transpeptidase activity to block the nephrotoxicity of cisplatin would not interfere with its therapeutic effect.

Malignant melanoma of the vagina and locoregional control: radical surgery revisited.

BACKGROUND: Anecdotal reports and retrospective case reviews suggest improved locoregional control, and possibly overall survival, with radical surgical extirpation as the primary management of vaginal melanoma. This study seeks to reevaluate, through case presentation and literature review, the usefulness of radical pelvic surgical procedures in the management of vaginal melanoma. CASE: Seven cases of primary vaginal melanoma were seen at the University of Virginia Hospital from 1966 to 1996; each was compared in terms of primary management, disease-free interval, sites of relapse, and overall survival. All patients who died of their disease relapsed locally prior to their death, with the exception of two patients who underwent wide local excision (WLE) followed by postoperative high-dose fractionation teletherapy. CONCLUSIONS: The use of WLE followed by high-dose fractionation teletherapy in the primary management of vaginal melanoma appears to provide excellent locoregional control, without the attendant morbidity and physical disfigurement associated with more radical surgical resection. The results reported here, as well as other published reports, suggest that locoregional control may be obtained with even large melanomas with radiotherapy when administered in high individual fractions (greater than 400 cGy/fx). This type of response is consistent with the higher response rate seen with cutaneous melanomas when large individual fractions are compared to conventional fractionation. Because of the extremely poor survival with vaginal melanoma regardless of primary therapy, novel therapeutic strategies, including further investigation into the use of high-dose fractionation irradiation, are urgently needed.

Surgical staging endometrial cancer.

Nothing improves the subsequent care of a woman with endometrial cancer more than the accurate determination of the extent of her disease. A significant number of women whose malignancy is apparently confined to the uterus will have extrauterine disease after careful, complete surgical staging. The failure to detect and effectively treat unrecognized metastatic disease can have fatal consequences; the decision to prescribe potentially harmful therapy to women who do not have metastatic disease also has deleterious effects. Although the optimal surgical management of any patient must be individualized, careful and complete surgical staging at the time of hysterectomy offers the most complete data for future management.

Cisplatin nephrotoxicity: inhibition of gamma-glutamyl transpeptidase blocks the nephrotoxicity of cisplatin without reducing platinum concentrations in the kidney.

OBJECTIVE: Inhibition of gamma-glutamyl transpeptidase activity by acivicin or a large bolus of intravenous glutathione blocks the nephrotoxicity of cisplatin. The purpose of this study was to determine whether these compounds inhibit nephrotoxicity by reducing the amount of platinum retained by the kidney. STUDY DESIGN: The platinum concentration in urine and kidney of cisplatin-treated rats was determined by graphite furnace atomic absorption spectroscopy. Tissues from three experimental groups of rats were analyzed. The first group was treated with a nephrotoxic dose of cisplatin. The second group was treated with acivicin before cisplatin. The third group received a bolus of glutathione before cisplatin. Urine collected for 3 hours after the injection of cisplatin and kidney tissue from animals 5 days after treatment were analyzed for platinum content. RESULTS: Urine from animals pretreated with acivicin had the same concentration of platinum as that of control animals treated with cisplatin alone. Analysis of kidney tissue, blood urea nitrogen and serum creatinine 5 days after treatment showed that pretreatment with acivicin or glutathione blocked the nephrotoxicity of cisplatin. However, these agents did not alter the concentration of platinum in the kidney. CONCLUSIONS: The data in this study reveal that pretreatment with acivicin or glutathione does not block the uptake of platinum into the kidney nor do these agents reduce the concentration of platinum retained by the kidney. The mechanism by which these agents may inhibit the nephrotoxicity of cisplatin is discussed.

Cytologic diagnosis of ovarian tumors: factors influencing accuracy in previously undiagnosed cases.

OBJECTIVES: Cytologic diagnosis of ovarian masses by needle aspiration techniques remains controversial. This review proposes to define the accuracy of the technique, report complications, and relate clinical situations in which the technique was used. STUDY DESIGN: In a retrospective review all patients undergoing cytologic aspiration biopsy diagnosis of ovarian masses at the University of Virginia Health Sciences Center from 1986 through 1993 were identified, and 74 women with corresponding histologic material were used. Clinical data were abstracted and all cytologic and pathologic material was reviewed. RESULTS: The overall sensitivity of the 74 aspiration biopsies to predict the histologic diagnosis of malignancy was 78%; specificity was 92%. Two patients had complications, one necessitating operative intervention. Correct diagnoses were influenced by menopausal status, patient age, sample type, aspiration method, and cytologic quality. CONCLUSIONS: The cytologic diagnoses of ovarian tumors, while quite specific, lack the sensitivity for general application. Use of this diagnostic technique must remain individualized, and the factors that influence the accuracy of the technique must be kept in mind. There remains the need for standardization of reporting fine needle aspiration results.

Biopsy of lesions of the female genital tract.

Surgical biopsies are often the bedrock of contemporary medical care--the foundation upon which many subsequent and important medical decisions are based. The methods described herein have been found to be very reliable and to produce diagnostic material of high quality. Although some clinics have been reluctant to rely on FNA cytopathologic diagnoses, always insisting on traditional biopsies for histopathologic study, we have relied on both biopsy methods for more than 15 years. The diagnostic accuracy of both methods is greatly improved by attention to technical detail and adherence to an established protocol. Neither method is exclusively applicable in all clinical settings.

Diagnostic testing during pregnancy: a descriptive analysis of utilisation data.

To describe patterns of diagnostic testing during the antenatal period and to assess the potential benefit of using Medicare claims data in monitoring testing practice, we examined the matched claims data (with identifying details removed) on approximately 10,000 women having a confinement for which a Medicare benefit was claimed between 1 July and 30 September 1990. The results showed that almost all the women included in the study sample had an ultrasound and blood group and antibody examination. A smaller proportion had serological tests for syphilis (77 per cent), rubella (51 per cent) and hepatitis B carriage (73 per cent). Two-thirds had urine microscopy and culture, and under half (40 per cent) had serum alpha-fetoprotein estimation. Few (18 per cent) had a claim processed for microscopy and culture of a genital swab and fewer than 8 per cent claimed for any other pathology tests. There were differences in the proportions having tests, depending on whether the clinician managing the confinement was a specialist obstetrician or a general practitioner, and depending on geographic area and age group. While the data do not represent all women having a confinement in New South Wales, the selective use of antenatal diagnostic tests found in this study is of considerable public health importance and analysis of claims data can provide useful information for health professionals.

Gynaecological surgery after endometrial ablation.

OBJECTIVE: To determine the number of patients requiring further gynaecological surgery after endometrial ablation. DESIGN: A retrospective 20-26-month follow-up of private patients who underwent endometrial ablation, tracking subsequent surgical procedures through the Medicare database. Data were analysed on a national and State basis. SETTING AND PARTICIPANTS: 1853 private patients who had had an endometrial ablation from 1 April 1991 to 30 September 1991. Seven different groups of subsequent gynaecological surgical procedures were investigated. MAIN OUTCOME MEASURES: The need for subsequent endometrial ablation, hysterectomy (by any means) and other forms of gynaecological surgery within the defined time period. RESULTS: After initial ablation, 382 patients (21%) required further gynaecological surgery: 10% required hysterectomy; 6% required repeat ablation; and 5% of patients required other gynaecological procedures related to the uterus. These rates for further procedures were generally higher than reported previously after transcervical hysteroscopic endometrial ablation or resection. CONCLUSIONS: Endometrial ablation is associated with a significant medium and long term failure rate, necessitating further intervention. This failure rate may have been previously underestimated, and our higher rate may still be an underestimate.

Inhibition of gamma-glutamyl transpeptidase activity by acivicin in vivo protects the kidney from cisplatin-induced toxicity.

Cisplatin [cis-dichlorodiammineplatinum(II)] is a widely used chemotherapeutic drug that is toxic to the proximal tubule cells of the kidney. gamma-Glutamyl transpeptidase (GGT) is localized to the luminal surface of the renal proximal tubules. GGT catalyzes the initial step in the metabolism of glutathione-conjugated drugs to mercapturic acids, some of which are severely nephrotoxic. We proposed that the nephrotoxicity of cisplatin was dependent on the cleavage of a cisplatin-glutathione conjugate by GGT. To test this hypothesis, renal GGT activity was blocked in male Sprague-Dawley rats by acivicin, a non-competitive inhibitor of GGT. Treatment with cisplatin alone caused extensive acute necrosis of the proximal tubules, but the proximal tubule cells appeared normal in rats treated with acivicin prior to cisplatin. Blood urea nitrogen and serum creatinine levels confirmed the protective effect of acivicin. Glutathione is a physiological substrate for GGT. Administration of an 83-fold excess of glutathione 30 min prior to cisplatin also inhibited cisplatin-induced nephrotoxicity. These data provide important new evidence that a large bolus of glutathione blocks the nephrotoxicity of cisplatin by competitively inhibiting GGT. These results indicate that cisplatin is conjugated to glutathione in vivo. The platinum-glutathione conjugate is nontoxic until metabolized by the proximal tubule cells. Formation of the nephrotoxic derivative of cisplatin requires GGT activity.

Human ovarian tumors express gamma-glutamyl transpeptidase.

Gamma-glutamyl transpeptidase (GGT) is a cell surface enzyme that initiates the cleavage of extracellular glutathione, thereby providing the cell with the amino acids necessary for increased synthesis of glutathione. GGT is induced in ovarian tumor cell lines selected in vitro for resistance to cisplatin. No study has examined GGT expression in primary human ovarian tumors. We analyzed frozen sections of 80 normal human ovaries and 56 ovarian tumors for expression of GGT. Histochemical staining showed that GGT was not expressed in the cells of the follicle or surface germinal epithelium of the normal ovary. GGT was expressed in some epithelial inclusion glands and occasionally in a small subset of stromal cells. Granulosa-stromal cell tumors were largely GGT-negative. In contrast, GGT-positive neoplastic cells were observed in 33 of 45 common epithelial ovarian tumors. None of the patients had been treated with chemotherapy. Some of the tumors had only rare GGT-positive cells, while others consisted almost entirely of GGT-positive cells. Among the low malignant potential and invasive tumors, at least one-half of the cells were GGT-positive in 6 of 9 serous borderline tumors (2 with mucinous foci), 0 of 1 borderline mucinous tumor, 3 of 12 serous papillary carcinomas, 2 of 3 mucinous carcinomas, 1 of 2 endometrioid carcinomas, 2 of 2 clear cell carcinomas, 0 of 2 transitional cell carcinomas, and 4 of 5 undifferentiated carcinomas. There was no correlation between the stage of the tumor and GGT expression, indicating that a GGT-negative tumor does not become GGT-positive as it progresses to a more widely disseminated lesion. In addition, there was no correlation between serum levels of CA 125 and GGT expression. These data show that GGT is expressed in many common ovarian epithelial neoplasms. We are currently following the response of these patients to chemotherapy to determine if expression of GGT serves as a marker for identifying neoplasms with enhanced resistance to platinum-based therapy.

Some fundamental influences on the pathology requesting behaviour of Victorian general practitioners--preliminary study results.

The results are presented of a preliminary study of Australian medical practitioners who graduated in Victoria in the years 1983 to 1988, which was conducted to ascertain if there were fundamental influences that affected how these practitioners requested pathology services. Multivariate linear regression was used to analyze the data. The study suggests that the year of graduation, the hospital of first post-graduate attachment and the gender of the practitioner were significant influences on the requesting of pathology (p = 0.0001 for each of the 3 influences). The university of graduation was not found to be a significant influence in its own right, but became significant in some two-way and three-way interactions. Some possible explanations for the effect of these influences are discussed, and further study is now being undertaken by the author.

A portable tensiometer for assessing surgeon's knot tying technique.

The purpose of this study was to determine the influence of surgeon's tying technique on knot security using O and 2-O monofilament and multifilament nylon sutures. By use of an Instron Tensile Tester and a portable tensiometer, knot security was achieved with these sutures using four-throw square knots (1 = 1 = 1 = 1). After didactic and psychomotor skill training, medical students were taught to construct the four-throw square knot using either a two-hand tie or an instrument tie. By use of the portable tensiometer, their knot tying techniques were judged to be superior to those used by a cohort of obstetricians and gynecologists. The surgeon's faulty technique can easily be corrected by didactic information and psychomotor skill training.

The Bethesda classification for squamous intraepithelial lesions: histologic, cytologic, and viral correlates.

In applying the Bethesda System of classification to cervical squamous lesions, we evaluated the Papanicolaou smears, cervical biopsies, and human papillomavirus (HPV) DNA status of 76 clinic patients. The biopsy specimens and concurrent Papanicolaou smears were analyzed using criteria for low-grade and high-grade squamous intraepithelial lesions, and the biopsies were analyzed for HPV DNA by in situ hybridization. Two independent observers produced good agreement in both cytologic (kappa = 0.62) and histologic (kappa = 0.71) diagnoses. Predictive values of high-grade cytology (for high-grade histology) were high (0.95 for reviewer 1; 0.97 for reviewer 2), and both high-grade cytology and histology correlated strongly with certain "high-risk" HPV types. In contrast, the predictive value of low-grade cytology for either low-grade histology or HPV types other than "high risk" was poor. This study supports the use of certain histologic criteria for distinguishing squamous intraepithelial lesions into two grades. Limitations in cytologic-histologic correlation appear to reflect the absence of cytologic criteria for distinguishing well-differentiated precursor lesions associated with high-risk HPV types.

Seroreactivity to HPV-16 proteins in women with early cervical neoplasia.

Although serological reactivity to human papillomavirus type 16 (HPV-16) proteins has been demonstrated in patients with invasive cervical carcinoma, the degree of seroreactivity to these proteins in women with preinvasive disease and its relationship to the HPV type associated with the disease are unclear. We obtained sera from 27 women undergoing cone biopsy for cervical precursor lesions and 22 controls and analyzed seroreactivity by Western blot to fusion proteins containing portions of the HPV-16 E4, L1 and L2 open-reading frames (ORFs). Positives were analyzed by scanning densitometry and intensity values for each case plotted relative to controls. Cervical biopsy specimens from patients were analyzed for HPV-16 nucleic acids by DNA.DNA in situ hybridization. Mean intensity values for seroreactivity to the pATH-E4 protein approached significance (P = 0.058) and a significantly higher proportion of cases vs controls registered values over 4.0 for pATH-E4 (26% vs 4.5%; P = 0.04) and pATH-L2 (48% vs 18%; P = 0.03) proteins. A significantly higher mean intensity value for E4 was observed for cases containing HPV-16 DNA vs HPV-16 negative cases or controls. Thus, seroreactivity to HPV-16-derived proteins may be more common in women with preinvasive cervical disease, and for some protein targets (E4) may indicate a relatively type-specific response.