Quantitation by gas chromatography-chemical ionization-mass spectrometry of phenylalanine mustard in plasma of patients.

An unambiguous and sensitive method based on gas chromatography-chemical ionization-mass spectrometry has been developed to quantitate L-phenylalanine mustard and has been applied to measure levels in plasma of five patients receiving 0.15 to 0.25 mg/kg (10 to 17 mg) of the drug p.o. Peak plasma levels of 50 to 190 ng/ml were found to occur between 0.7 and 2.3 hr after ingestion. The time for the plasma level to fall to one-half of the peak value varied from 0.6 to 3 hr, and very low levels (less than 2 ng/ml) were present by 24 hr.

Large-scale serial analysis of gene expression reveals genes differentially expressed in ovarian cancer.

Difficulties in the detection, diagnosis, and treatment of ovarian cancer result in an overall low survival rate of women with this disease. A better understanding of the pathways involved in ovarian tumorigenesis will likely provide new targets for early and effective intervention. Here, we have used serial analysis of gene expression (SAGE) to generate global gene expression profiles from various ovarian cell lines and tissues, including primary cancers, ovarian surface epithelia cells, and cystadenoma cells. The profiles were used to compare overall patterns of gene expression and to identify differentially expressed genes. We have sequenced a total of 385,000 tags, yielding >56,000 genes expressed in 10 different libraries derived from ovarian tissues. In general, ovarian cancer cell lines showed relatively high levels of similarity to libraries from other cancer cell lines, regardless of the tissue of origin (ovarian or colon), indicating that these lines had lost many of their tissue-specific expression patterns. In contrast, immortalized ovarian surface epithelia and ovarian cystadenoma cells showed much higher similarity to primary ovarian carcinomas than to primary colon carcinomas. Primary tissue specimens therefore appeared to be a better model for gene expression analyses. Using the expression profiles described above and stringent selection criteria, we have identified a number of genes highly differentially expressed between nontransformed ovarian epithelia and ovarian carcinomas. Some of the genes identified are already known to be overexpressed in ovarian cancer, but several represent novel candidates. Many of the genes up-regulated in ovarian cancer represent surface or secreted proteins such as claudin-3 and -4, HE4, mucin-1, epithelial cellular adhesion molecule, and mesothelin. Interestingly, both apolipoprotein E (ApoE) and ApoJ, two proteins involved in lipid homeostasis, are among the genes highly up-regulated in ovarian cancer. Selected serial analysis of gene expression results were further validated through immunohistochemical analysis of ApoJ, claudin-3, claudin-4, and epithelial cellular adhesion molecule in archival material. These experiments provided additional evidence of the relevance of our findings in vivo. The publicly available expression data reported here should stimulate and aid further research in the field of ovarian cancer.

Ovarian cancer in patients with dermatomyositis.

A consensus regarding adequate screening to detect early malignancy in the setting of dermatomyositis (DMM) has yet to be reached. This issue is particularly relevant with regard to ovarian cancer, as early detection with routine examinations, ultrasound, and abdominal CT may not be successful. Four of 15 women diagnosed with and seen in our department for DMM between 1986 and 1993 were subsequently diagnosed with metastatic papillary serous ovarian carcinoma. One additional patient developed metastatic pelvic papillary adenocarcinoma, believed to be of ovarian origin. These diagnoses of advanced cancer were unexpected, as all women had undergone repeated cancer screenings beyond what is normally recommended for patients with DMM. The 5 women were strikingly similar in their initial presentations and subsequent courses. In each, the diagnosis of DMM was delayed from 2 to 10 months, as they were initially misdiagnosed with a photoinduced or contact dermatitis. All except 1 had severe, recalcitrant skin disease despite attempted therapy with antimalarial and immunosuppressive agents. All 4 patients who survived the postoperative period after tumor debulking showed either improvement or resolution of their DMM. It appears that women with DMM have an increased incidence of ovarian cancer, which is usually diagnosed months to a few years (range, 0 d to 6 y) after DMM has been diagnosed. Although recommendations have been made regarding cancer screening in these individuals, recommendations for initial and surveillance examinations vary from routine history and physical examination to evaluations including extensive radiologic evaluation.(ABSTRACT TRUNCATED AT 250 WORDS)

Interaction between bisantrene and radiation.

The interaction between Bisantrene, a new anthracene derivative, and radiation was studied in vitro. Chinese hamster lung (V-79-171) cells grown as monolayers were exposed to three different concentrations (0.4 mcg/ml, 2 mcg/ml, 10 mcg/ml) of Bisantrene for 120 min. during their exponential growth phase. Immediately after drug exposure, the cells were irradiated with escalating doses of radiation (100-1200 rad). Isoeffect curves (99% cell kill) were calculated using dose-survival curves generated for each modality. Curve I assumed that the agents act by independent mechanisms; Curve II assumed that the agents act by a similar mechanism. The dose combinations of the two modalities producing a 99% kill were plotted against the calculated isoeffect curves. The experimental points were found to lie along the calculated lines. Pre-treatment with Bisantrene prior to radiation resulted in an additive effect, similar to that reported with Adriamycin.

Delayed split whole abdominal irradiation in the combined modality treatment of ovarian cancer.

Fifty-eight patients with ovarian malignancies have been treated using a delayed split whole abdominal irradiation technique (DSA) allowing the entire tumor volume to be irradiated with tumoricidal fractional doses without undue toxicity. The lower hemiabdomen was irradiated with 2 Gy per fraction to a total dose of 40 Gy. A 2-6 hour delay was used between the irradiation of each half of the abdomen to avoid excessive acute gastrointestinal toxicity. The upper hemiabdomen was irradiated with 1.5 Gy per fraction to a total dose of 30 Gy. The acute toxicity was acceptable, with 53 of 58 patients able to complete the prescribed course of treatment. Three patients (5%) experienced grade 3 or greater acute gastrointestinal toxicity. Fourteen of 60 patients (24%) required treatment breaks because of thrombocytopenia. Nadir platelet counts were lower in patients who had received previous chemotherapy than in previously untreated patients (80,000 vs 118,000; p = .02). However, only 4 out of 60 patients were unable to complete DSA because of prolonged thrombocytopenia. In addition to DSA, patients were also treated with intraperitoneal 32P (52 patients), intraperitoneal human ovarian antitumor serum (14 patients), and prior (14 patients) or subsequent (32 patients) chemotherapy. Granulocytopenia was more severe among patients who had received prior chemotherapy (mean nadir 900 vs 2200). Seven patients (11.5%) developed delayed bowel obstruction in the absence of recurrence. There was one death caused by hepatitis, presumably related to colloidal 32P and DSA. Twenty-five percent of Stage III optimally cytoreduced patients were disease-free at 5 years; these patients had a median survival of 45 months. DSA irradiation is an acceptable technique for delivering a high fractional dose of radiation to the entire peritoneal cavity. Shielding of the iliac crests spares bone marrow allowing DSA irradiation to be integrated into an aggressive combined modality treatment plan.

Uterine serous carcinoma. A morphologically diverse neoplasm with unifying clinicopathologic features.

This study compares the clinicopathologic features of 13 pure uterine papillary serous carcinomas (UPSC) with 19 tumors consisting of UPSC admixed with other types of endometrial carcinoma and nine UPSC associated with endometrial polyps. The mean patient age, frequency of preoperative clinical understaging, postoperative pathologic stage, and survival of patients was similar for the three groups. Surprisingly, widespread metastasis, recurrence, and death occurred even in those cases where myometrial invasion amounted to less than 1 mm or where tumor was confined to an endometrial polyp. Poor prognosis appeared to be related to a propensity for vascular invasion and multifocal carcinogenesis. The latter was manifested by the presence of cytologically malignant cells closely resembling the invasive serous carcinoma in the surface endometrium adjacent to the tumor in 89% of cases and in multiple sites in the genital tract and abdomen. This lesion, designated "intraepithelial carcinoma," was present in the endocervix in nine (22%) of the 41 cases, in the fallopian tube in two cases (5%), on the surface of the ovary in four cases (10%), and on peritoneal surfaces or omentum in 10 cases (25%). In addition, we found that UPSC display considerable morphologic heterogeneity. Foci of clear-cell carcinoma were identified in 13 (32%) of the 41 tumors. In five (12%) neoplasms, the invasive component was composed primarily of glands; and in 22 (54%) tumors, thin as opposed to thick papillae predominated. Accordingly, UPSC may be broadly defined as a carcinoma that displays foci of well-differentiated papillae lined by cells that are markedly atypical cytologically. UPSC frequently contain areas of clear cells. Glands with papillary infoldings sometimes predominate in the invasive component. Because the behavior of endometrial neoplasms, in which at least 25% of the carcinoma exhibits a glandular or papillary architecture with serous differentiation, is similar, the term "uterine serous carcinoma" is an appropriate designation for these tumors, regardless of whether other patterns of differentiation are present or whether the tumor is associated with a polyp.

Cervical cancer screening practices among older women: results from the Maryland Cervical Cancer Case-Control Study.

Considerable evidence shows a large proportion of older women have either never had a Pap test or have significant gaps in their history of cervical cancer screening. Differences in health care utilization patterns by age, cohort differences in use of medical subspecialities, and provider reluctance to perform cancer screening within the general medical care encounter have been suggested as reasons for underscreening. Our study conducted in 1985 documents prior health care utilization patterns of 153 cases of Maryland women with invasive cervical cancer compared with a matched control group. Analysis within three age groups showed that cases were significantly less likely to have ever had a Pap test or to receive regular Pap testing, primarily due to differences in medical care utilization patterns. Never having an obstetrician-gynecology visit, a recent (less than 3 years) internist visit, or not having any out-patient visit were significant risk factors. Other risks included older age at first Pap test, reporting not being told to have routine Pap tests, and not using contraceptives. In a multiple logistic regression analysis, recent out-patient visits and lifetime use of an obstetrician-gynecologist remained significant after adjusting for age interactions with recent Pap test history, underscoring the importance of medical care utilization patterns for screening of cancer of the uterine cervix among the elderly.

Condylomata acuminata arising in a neovagina.

A case is reported in which condylomata acuminata arose in a McIndoe neovagina. Histopathologic and virologic evidence are provided to support the characterization of these lesions as benign warty processes secondary to human papillomavirus-6. Factors influencing viral site specificity are discussed.

Primary breast cancer of the vulva.

Adenocarcinoma originating in a focus of mammary tissue in the vulva is an extremely rare occurrence. Only three such cases have been reported in the literature. Herein, the fourth example of a primary cancer developing in vulvar mammary tissue is described. Extension to regional lymph nodes is documented, as well as the presence of estrogen receptors in this tumor. Immunohistochemical evidence is rendered supporting an origin from mammary anlage.

Vaginal hemangiopericytoma: a histopathologic and ultrastructural evaluation.

The hemangiopericytoma is an uncommon stromovascular neoplasm that arises from the pericyte of Zimmerman. Since their original description in the female genital tract in 1954, the majority of these lesions have been of uterine origin. Presented is a clinicopathologic description of a hemangiopericytoma arising in the vagina and occupying the rectovaginal septum. Light and electron microscopic characterization is rendered. Current understanding of these lesions is reviewed and therapeutic options are discussed.

Spontaneous rupture of benign cystic teratomas.

Spontaneous preoperative rupture and/or perforation of an adjacent organ by a benign cystic teratoma is rare. Between 1952 and 1979 there were 4 documented cases at The Johns Hopkins Hospital. The incidence, etiology, and pathology of this complication are discussed.

Ovarian carcinoma and paraneoplastic cerebellar degeneration.

A case of paraneoplastic cerebellar degeneration complicating ovarian cancer is presented. This rare disorder is characterized by vertigo, nystagmus, diplopia, and ataxia. Neurologic sequelae are progressive, ultimately culminating in complete incapacitation and death. Symptoms of paraneoplastic cerebellar degeneration precede the diagnosis of malignancy in the majority of cases. Marked elevation in the anti-Purkinje cell antibody titer together with immunofluorescent staining techniques suggest that an autoimmune mechanism plays a role in the etiology of this disorder.

Tumor heterogeneity and histopathology in epithelial ovarian cancer.

The histopathology of the original and the persistent or recurrent epithelial ovarian cancer in 34 patients was simultaneously reviewed by two pathologists. The time between removal of the primary tumor and removal of the persistent or recurrent tumor ranged from four to 132 months (median, 13 months; mean, 25 months). The initial operation was followed by multiagent chemotherapy in 23 patients, single-agent chemotherapy in seven, radiation and chemotherapy in two, radiation in one, and no therapy in one patient. In four of the 34 primary tumors, a mixed tumor composition was initially identified. In comparing the initial histopathology with that of persistent or recurrent tumors, a change was identified in nine patients. In four patients, the tumor changed from a mixed to an undifferentiated histologic type; in four patients there was a change from a lower to a higher tumor grade, and two of these patients also had a change in tumor cell type from serous to undifferentiated. In the ninth patient, the tumor changed from a large cell undifferentiated to a small cell undifferentiated carcinoma. The observed changes could be the result of 1) modification of the tumor by cytotoxic therapy, 2) spontaneous dedifferentiation of the initial tumor, 3) tumor cell heterogeneity with preferential growth of one cell type over the others, or 4) the development of a second primary tumor.

Microinvasive cervical cancer after five negative Papanicolaou smears.

In view of the controversy regarding the appropriate frequency for cytologic screening, a 28-year-old woman who developed microinvasive carcinoma of the cervix less than one year after her fifth negative Papanicolaou smear is described. The lesion was found not high in the endocervical canal, but at the squamocolumnar junction well out on the portio of the cervix. This case documents that the risk of less frequent screening is not zero.

Ultrasonic surgical aspiration in the treatment of vulvar disease.

Ultrasonic surgical aspiration is a useful technique for safe and accurate tissue removal. This study was conducted to evaluate its role in noninvasive vulvar disease. From December 1988 to March 1990, 27 patients underwent ultrasonic surgery; nine patients had vulvar intraepithelial neoplasia (VIN) and 18 had condylomata acuminata. All surgical procedures were done under general anesthesia, with two patients requiring hospitalization for perineal care and pain control after extensive vulvar surgery. Recurrent or persistent disease occurred in four patients with condylomata acuminata and in two with VIN, with a mean follow-up of 50 weeks. Reepithelialization was completed within 5 weeks and no patients developed vulvar scarring. Adequate samples for histopathologic review were obtained in 26 patients. Identical histologic grading occurred in all 13 patients who had preoperative vulvar biopsies and an adequate aspiration specimen. Ultrasonic surgery permits precise and rapid removal of epithelial lesions with rapid healing, minimal patient discomfort, excellent cosmetic results, and histopathologic documentation.

Neoplastic and non-neoplastic mesothelial proliferations in pelvic lymph nodes.

Knowledge of gland-like inclusions in pelvic lymph nodes has existed since 1897. The histogeneses proposed to explain such alterations have included congenital rests, endometriosis, metastatic neoplasia, and mesothelial metaplasia. The correct interpretation of the lymph node involvement is important in order to institute appropriate therapy. In the present study, there were 12 examples of benign mesothelial inclusions found in routine sections from pelvic lymph nodes removed in the treatment of 337 cases of gynecologic cancer. In an additional 4 cases, an intraabdominal neoplasm was present. The variations in the histologic patterns are described as is the clinical course of the disease.

Primary, papillary peritoneal neoplasia.

Subsequent to the recognition of the intraperitoneal tumors of low malignant potential, clinicians have repeatedly faced the ambiguities inherent in a disease that seems aggressive on the basis of its wide distribution in the peritoneal cavity but benign on the basis of its histopathology and clinical course. Whereas the occasional case has been associated with extensive local reaction and ascites, except for a rare exception these tumors result in prolonged survival and in an absence of extraabdominal extension. The current review of 154 cases followed from 2 to 40 years, performed in an attempt to understand this perplexing disease, leads to the following conclusions: 1) Whereas frequently beginning on the ovary and showing a predilection for the pelvis, there are examples of widely disseminated peritoneal disease with minimal, if any, ovarian involvement; 2) the outcome without adjunctive therapy is excellent and thus such therapy is contraindicated in view of the death of only 2 of the 154 patients with disease, 1 of whom had had adjunctive intraperitoneal isotope therapy; and 3) this disease is best understood as a diffuse primary peritoneal tumor probably developing on the basis of irritating agents' reaching the abdominal cavity from the lower genital canal, a process similar to that proposed for the genesis of endometriosis. Such a low-grade primary in situ tumor that may involve the entire peritoneal cavity is compatible with prolonged survival.

Leiomyomatosis in pelvic lymph nodes.

A decidual reaction may occur in the pelvic lymph nodes during normal pregnancy. This reaction may be replaced by the same type of benign metaplastic reaction that gives rise to leiomyomatosis peritonealis disseminata. The occurrence of this apparent smooth muscle in the pelvic lymph nodes may result in an erroneous diagnosis of metastatic leiomyosarcoma, or of benign metastasizing leiomyoma.

Inter- and intra-pathologist variability in the diagnosis of gestational trophoblastic neoplasia.

All 190 cases of gestational trophoblastic neoplasia diagnosed in the Baltimore metropolitan area from 1975-1982 were identified. Histologic slides were requested and reviewed independently by two pathologists who agreed upon uniform criteria for the diagnosis of hydatidiform (complete) mole, invasive mole, and choriocarcinoma. A representative sample of the slides was selected and resubmitted to one of the study pathologists for a second review. The inter- and intra-pathologist variability in the diagnosis of gestational trophoblastic neoplasia was calculated using the kappa statistic (K). Our findings indicated that the variability in the diagnosis of gestational trophoblastic neoplasia was low whereas that for the related tumor of incomplete mole was high.

Utilization of obstetrician-gynecologists and prevention of cervical cancer.

In a case-control study, we examined health care utilization histories to determine whether Papanicolaou tests provided by an obstetrician-gynecologist, as opposed to other providers, are more protective of cervical cancer. Women with cervical cancer were less likely than matched controls to have had regular Papanicolaou test screening, to have received a Papanicolaou test within the last five years, or to have obtained a Papanicolaou test from an obstetrician-gynecologist. After controlling for traditional risk factors, we found that receiving any Papanicolaou tests within the last five years from an obstetrician-gynecologist was more protective than receiving Papanicolaou tests from other providers, although the difference did not attain statistical significance. Among both cases and controls, younger women and women who had used prescription contraceptives were more likely to have had a recent Papanicolaou test by an obstetrician-gynecologist. The results support the importance of regular Papanicolaou test screening among older women and suggest that the obstetrician-gynecologist helps prevent cervical cancer by providing continuity of screening services.