Identification of tobacco-specific carcinogen in the cervical mucus of smokers and nonsmokers.

BACKGROUND: In 1996, an estimated 15,700 new cases of cancer of the uterine cervix and 4,900 deaths from this disease were expected to occur in the United States. In a recent international study, human papillomavirus DNA was found in more than 90% of cervical tumor specimens examined, irrespective of the nationality of the patients from whom the samples were obtained. Although infection with human papillomavirus is the major known risk factor for the development of cervical cancer, it alone is not sufficient. Other etiologic factors that have been associated with this disease include deficiencies in micronutrients, lower socioeconomic status, oral contraceptive use, and cigarette smoking. Several compounds from cigarette smoke (nicotine and its major metabolite, cotinine) have been identified in cervical mucus, and the occurrence of smoking-related DNA damage in the cervical epithelium has been documented. PURPOSE: This investigation was conducted to determine for the first time whether carcinogenic tobacco-specific N-nitrosamines are present in the cervical mucus of cigarette smokers and of nonsmokers (most likely as a result of environmental exposure). METHODS: Cervical mucus specimens from 15 smokers and 10 nonsmokers were subjected to supercritical fluid extraction with the use of carbon dioxide that contained 10% methanol, and the resultant extracts were analyzed for tobacco-specific nitrosamines by use of a very sensitive method that involved gas chromatography and mass spectroscopy analyses. RESULTS: In a total of 16 samples obtained from 15 women who were current smokers (two samples from the same woman), we detected the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) at concentrations that ranged from 11.9 to 115.0 ng/g of mucus. Only one of a total of 10 cervical mucus specimens obtained from 10 women who claimed to be nonsmokers did not contain detectable NNK, and NNK concentrations ranged from 4.1 to 30.8 ng/g of mucus in the specimens from the remaining nine women. The concentrations of NNK in specimens from cigarette smokers were significantly higher than those from nonsmokers (mean +/- standard deviation: 46.9 +/- 32.5 ng/g of mucus versus 13.0 +/- 9.3 ng/g of mucus; two-tailed Student's t test, P = .004). CONCLUSION: The cervical mucus of cigarette smokers contains measurable amounts of the potent carcinogen NNK. This compound represents the first tobacco-specific carcinogen identified in this physiologic fluid of women who smoke cigarettes. The presence of NNK in the cervical mucus of nonsmokers is likely due to environmental exposure or to the fact that some of the subjects in this study may not have revealed that they occasionally smoked cigarettes. IMPLICATIONS: The presence of NNK in human cervical mucus further strengthens the association between cervical cancer and tobacco smoking.

Phase I trial of escalating doses of paclitaxel combined with fixed doses of cisplatin and doxorubicin in advanced endometrial cancer and other gynecologic malignancies: a Gynecologic Oncology Group study.

PURPOSE: The primary objective of this phase I trial was to determine the feasibility of administering a combination of paclitaxel, cisplatin, and doxorubicin with or without granulocyte colony-stimulating factor (G-CSF) in patients with advanced endometrial and other gynecologic cancers. PATIENTS AND METHODS: Patients were chemotherapy-naive. Doxorubicin was administered as a brief infusion, paclitaxel for 3 hours, and cisplatin for 60 minutes. Treatments were repeated every 3 weeks. For most dose levels, the cisplatin and doxorubicin were fixed at 60 mg/m(2) and 45 mg/m(2), whereas the paclitaxel was escalated in successive cohorts from 90 to 250 mg/m(2). Patients who had received previous radiotherapy to the whole pelvis were escalated separately from those who had not. RESULTS: Eighty patients received 320 cycles of therapy. When G-CSF was not used, myelosuppression prevented escalation beyond the starting dose for patients with or without previous pelvic radiotherapy. When G-CSF was added, neurotoxicity became dose-limiting for both groups. Ten patients were removed from the study for asymptomatic declines in ejection fraction, but no symptomatic congestive heart failure was observed. Major antitumor responses occurred in 46% of patients (six of 13) with measurable endometrial carcinoma and 50% of patients (eight of 16) with measurable cervical carcinoma. CONCLUSION: The combination of paclitaxel, doxorubicin, and cisplatin at relevant single-agent doses is active and feasible with the addition of G-CSF. A regimen of cisplatin 60 mg/m(2), doxorubicin 45 mg/m(2), and paclitaxel 160 mg/m(2) with G-CSF support is recommended for further testing.

Intensity-modulated whole pelvic radiation therapy in patients with gynecologic malignancies.

PURPOSE: To evaluate the ability of intensity-modulated radiation therapy (IMRT) to reduce the volume of small bowel irradiated in women with gynecologic malignancies receiving whole pelvic radiotherapy (WPRT). METHODS AND MATERIALS: Ten women with cervical (5) or endometrial (5) cancer undergoing WPRT were selected for this analysis. A planning CT scan of each patient was obtained following administration of oral, i.v., and rectal contrast. The clinical target volume (CTV) was defined as the proximal vagina, parametrial tissues, uterus (if present), and regional lymph nodes. The CTV was expanded uniformly by 1 cm in all directions to produce a planning target volume (PTV). The bladder, rectum, and small bowel were also delineated in each patient. Two plans were created: a standard "4-field box" with apertures shaped to the PTV in each beam's eye view and an IM-WPRT plan designed to conform to the PTV while minimizing the volume of normal tissues irradiated. Both plans were normalized to deliver 45 Gy to the PTV. Isodose distributions and dose-volume histograms (DVH) were compared. RESULTS: The IM-WPRT plan reduced the volume of small bowel irradiated in all 10 patients at doses above 30 Gy. At the prescription dose, the average volume of small bowel irradiated was reduced by a factor of two (17.4 vs. 33.8%, p = 0.0005). In addition, the average volume of rectum and bladder irradiated at the prescription dose was reduced by 23% in both cases (p = 0.0002 and p = 0.0005, respectively). The average PTV doses delivered by the conventional and IM-WPRT plans were 47.8 Gy and 47.4 Gy, respectively. Corresponding maximum doses were 50.0 Gy and 54.8 Gy, respectively. However, on average, only 3.2% of the PTV received greater than 50.0 Gy in the IM-WPRT plans. CONCLUSION: Our results suggest that IM-WPRT is an effective means of reducing the volume of small bowel irradiated in women with gynecologic malignancies receiving WPRT. This approach potentially offers a method for reducing small bowel complications in patients with gynecologic malignancies.

Significant pelvic recurrence in high-risk pathologic stage I--IV endometrial carcinoma patients after adjuvant chemotherapy alone: implications for adjuvant radiation therapy.

OBJECTIVE: To evaluate the risk of pelvic recurrence (PVR) in high-risk pathologic Stage I--IV endometrial carcinoma patients after adjuvant chemotherapy alone. METHODS: Between 1992 and 1998, 43 high-risk endometrial cancer patients received adjuvant chemotherapy. All patients underwent primary surgery consisting of total abdominal hysterectomy and bilateral salpingo-oophorectomy. No patients received preoperative radiation therapy (RT). Regional lymph nodes and peritoneal cytology were sampled in 62.8% and 83.7% of cases, respectively. Most patients had Stage III--IV disease (83.7%) or unfavorable histology tumors (74.4%). None had evidence of extra-abdominal disease. All patients received 4-6 cycles of chemotherapy as the sole adjuvant therapy, consisting primarily of cisplatin and doxorubicin. Recurrent disease sites were divided into pelvic (vaginal, nonvaginal) and extrapelvic (para-aortic, upper abdomen, liver, and extra-abdominal). Median follow-up was 27 months (range, 2--96 months). RESULTS: Twenty-nine women (67.4%) relapsed. Seventeen (39.5%) recurred in the pelvis and 23 (55.5%) in extrapelvic sites. The 3-year actuarial PVR rate was 46.5%. The most significant factors correlated with PVR were cervical involvement (CI) (p = 0.01) and adnexal (p = 0.05) involvement. Of the 17 women who developed a PVR, 8 relapsed in the vagina, 3 in the nonvaginal pelvis, and 6 in both. The 3-year vaginal and nonvaginal PVR rates were 37.8% and 26%, respectively. The most significant factor correlated with vaginal PVR was CI (p = 0.0007). Deep myometrial invasion (p = 0.02) and lymph nodal involvement (p = 0.03) were both correlated with nonvaginal PVR. Nine of the 29 relapsed patients (31%) developed PVR as their only (6) or first site (3) of recurrence. Factors associated with a higher rate of PVR (as the first or only site) were CI and Stage I--II disease. CONCLUSIONS: PVR is common in high-risk pathologic Stage I-IV endometrial cancer patients after adjuvant chemotherapy alone. These results support the continued use of locoregional RT in patients undergoing adjuvant chemotherapy. Further studies are needed to test the addition of chemotherapy to locoregional RT.

Surgery and postoperative radiation therapy in FIGO Stage IIIC endometrial carcinoma.

OBJECTIVE: To determine the outcome, pattern(s) of failure, and optimal treatment volume in Stage IIIC endometrial carcinoma patients treated with surgery and postoperative radiation therapy (RT). METHODS: Between 1983 and 1998, 30 Stage IIIC endometrial carcinoma patients were treated with primary surgery and postoperative RT at the University of Chicago. All underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy, sampling of pelvic lymph nodes (PLN), and peritoneal cytology. All were noted to have PLN involvement. Para-aortic lymph nodes (PALN) were sampled in 26 cases, and were positive in 14 cases (54%). Twenty women received whole-pelvic RT (WPRT) and 10 (WPRT), plus paraortic RT (extended-field RT, EFRT). One EFRT patient also underwent concomitant whole-abdominal RT (WART). Adjuvant vaginal brachytherapy (VB) was delivered in 10, chemotherapy in 5, and hormonal therapy in 7 patients. RESULTS: At a median follow-up of 32 months, the actuarial 5-year disease-free and cause-specific survivals of the entire group were 33.9% and 55.8%, respectively. Overall, 16 women (53%) relapsed. Sites of failure included the pelvis (23%), abdomen (13%), PALN (13%), and distant (40%). Of the 7 pelvic failures, 4 were vaginal (3 vaginal only). Patients treated with VB had a trend to a lower vaginal recurrence rate (0/10 vs. 4/20, p = 0.12) than those not receiving VB. All 4 PALN failures were in women treated with WPRT (2 negative, 1 unsampled, and 1 positive PALN). None of the 10 EFRT patients (2 negative, 8 positive PALN) recurred in the PALN. No patient developed an isolated abdominal recurrence. Two patients developed significant RT sequelae: chronic diarrhea in 1 patient treated with WPRT and VB, and small bowel obstruction in 1 patient treated with EFRT. CONCLUSION: FIGO Stage IIIC disease comprises a small percentage of endometrial carcinoma patients but carries a poor prognosis. Our failure pattern suggests that the optimal adjuvant RT volume is EFRT, even in women with negative PALN sampling. VB should also be administered to improve local control. The low rate of abdominal recurrence does not support the routine use of WART in these women. Given the predominance of failure in distant sites, attention should be focused on the development of systemic chemotherapy protocols.

Race and clinical outcome in endometrial carcinoma.

OBJECTIVE: To compare the outcomes of black and white women who have surgically staged endometrial carcinoma. METHODS: We retrospectively compared the clinicopathologic factors, socioeconomic status, treatments, and outcomes of 70 black and 302 white women who were treated for surgically staged endometrial carcinoma at our institution. RESULTS: Black women had higher-grade tumors, less favorable histologic findings, more comorbid illnesses, and lower socioeconomic indices. A nonsignificant trend was also seen toward more advanced-stage disease. The extent of surgical staging and types of adjuvant therapies were similar. On univariate analysis, black women had worse 5-year disease-free survival than white women (52.8% versus 75.2%; P = .001). Other significant factors included stage, grade, lymph node status, extension to the uterine serosa, cervical involvement, histology, adnexal involvement, lymphovascular invasion, myometrial invasion, positive peritoneal cytology, level of education, and household income. After controlling for pathologic and socioeconomic differences in multivariate analysis, race remained a significant prognostic factor (P = .008; hazard rate 2.0; 95% confidence interval 1.2, 3.5). CONCLUSION: In a large cohort of surgically staged and uniformly treated patients with endometrial carcinoma, black race was associated with significantly worse outcomes, even after controlling for clinicopathologic and socioeconomic factors.

Human papillomavirus detection and p53 expression in clear-cell adenocarcinoma of the vagina and cervix.

OBJECTIVE: To determine whether infection with oncogenic human papillomavirus (HPV) and/or altered expression of the tumor suppressor protein p53 is associated with clear-cell adenocarcinoma of the vagina or cervix. METHODS: Paraffin-embedded tissue specimens were studied from 14 women with clear-cell adenocarcinoma of the vagina or cervix. Nine women had a history of intrauterine diethylstilbestrol exposure. Human papillomavirus DNA was amplified via the polymerase chain reaction using consensus L1 primers and was detected by dot blot hybridization with a generic HPV probe and type-specific oligonucleotide probes. P53 protein was detected by immunohistochemical analysis with a mouse monoclonal antibody, DO-7. RESULTS: Three tumors contained HPV 31 DNA sequences. Eight tumors were HPV DNA-negative and three were indeterminate for HPV. P53 was detected in ten tumors; it was undetectable in the three tumors containing HPV 31 and in one tumor indeterminate for HPV. Three patients presented with or later developed metastatic disease. In each case, the tumor, including sites of metastasis, was HPV-negative and p53-positive. CONCLUSIONS: These findings suggest that infections with oncogenic HPVs may be a cofactor in the development of clear-cell adenocarcinoma of the vagina or cervix, though this association is less than that reported for squamous or non-clear-cell adenocarcinomas. Prior studies have shown that detection of the p53 protein by immunohistochemistry correlates with mutations in the p53 tumor suppressor gene. The detection of p53 in HPV-negative clear-cell adenocarcinoma suggests a second mechanism in the etiology of these rare tumors.

Phase I study of treatment with oral 13-cis-retinoic acid, subcutaneous interferon alfa-2a, cisplatin, and 24-hour infusion 5-fluorouracil/leucovorin.

UNLABELLED: A combination of oral 13-cis-retinoic acid (cis-RA) and subcutaneous interferon alfa-2a (IFN) has been reported to yield high response rates in patients with squamous cell carcinomas (SCCAs) of the cervix and skin. Cisplatin and 5-fluorouracil with leucovorin (5-FU/LV) are chemotherapeutic agents commonly used for SCCAs. PURPOSE: To determine the maximum tolerated doses (MTDs) of cisplatin and 5-FU/LV when combined with IFN and cis-RA, and to define a recommended phase II regimen for testing in cervical cancer and other appropriate tumor types. METHODS: Phase I cohort design. Cisplatin was administered every 3 weeks. 5-FU and LV were administered together as a weekly 24-h infusion. Cis-RA was given orally twice daily. IFN was initially given subcutaneously at a dose of 3 million units (MU) daily. RESULTS: A total of 31 patients were treated. The IFN dose was reduced to 3 MU three times weekly because of patient intolerance. Cytopenias prevented the administration of weekly 5-FU/LV. Single-agent cisplatin with three times weekly IFN and twice daily cis-RA was tolerable. Four partial responses were observed, in patients with adrenal cancer, bladder cancer, gastric cancer, and adenocarcinoma of unknown primary. CONCLUSIONS: The recommended phase II regimen is cisplatin 100 mg/m2 every 3 weeks, IFN 3 MU three times weekly, and cis-RA 1 mg/kg daily. This appears to be more toxic than single-agent cisplatin, but the preliminary activity observed warrants further testing.

Absence of major peripheral neuropathy in a phase II trial of ifosfamide with vinorelbine in patients with ovarian cancer previously treated with platinum and paclitaxel.

Both ifosfamide and vinorelbine have been shown to produce responses in women with previously treated ovarian cancer. However, vinorelbine has been reported to cause severe neuropathy in patients previously treated with paclitaxel. We assessed a regimen consisting of ifosfamide 1.6 g/m2/d and vinorelbine 30 mg/m2/d for 3 days consecutively every 21 days. Because these doses resulted in severe neutropenia despite the use of granulocyte colony-stimulating factor, doses were reduced to a final level of ifosfamide 960 mg/m2/d and vinorelbine 20 mg/m2/d. Peripheral sensory neuropathy was evaluated by questionnaire. A total of 30 women were treated. All had previously been treated with both a platinum compound and paclitaxel. One partial response was observed among 23 patients with measurable disease, and two CA-125 responses were noted among seven patients without measurable disease. Severe progressive neurotoxicity was not observed. Despite the fact that almost half the patients had not been exposed to cyclophosphamide, this regimen produced few responses. Superior response rates have been reported with single-agent vinorelbine at doses that do not require growth factor support. With this dose and schedule, vinorelbine is reasonably safe therapy for patients who have received prior paclitaxel and who have have mild baseline sensory neuropathy.

Venous air embolism through a Groshong catheter.

Individuals with cancer frequently require long-term central venous access to deliver chemotherapy, blood products, and other fluids. A rare, but potentially lethal complication associated with central venous catheterization is venous air embolism which occurs most commonly after damage or disconnection at the catheter hub. The Groshong (Bard Access Systems, UT) catheter is a device with a unique three-position valve at its distal tip which eliminates the need for routine heparin flushing and minimizes the risk of venous air embolism. This report describes for the first time a near fatal venous air embolism in a patient with an externally accessed Groshong catheter.

Effect of nicotine on proliferation of normal, malignant, and human papillomavirus-transformed human cervical cells.

Nicotine is concentrated in the cervical mucus of smokers relative to serum levels. In this experiment, the effect of nicotine on cellular proliferation of human ectocervical, endocervical, malignant, and human papillomavirus (HPV) 16 DNA-transformed cervical cell lines was studied. Ectocervical and endocervical cell lines were derived from benign hysterectomy specimens and cultured in keratinocyte growth medium. HPV 16 DNA-transformed cell lines were derived through transfection of ectocervical cells with cloned HPV 16 DNA. HPV-transformed lines and malignant cell lines established from three women with newly diagnosed cervical cancer were maintained in E-media with 5% fetal calf serum. Cells (2500-5000) were cultured in 96-well tissue culture plates with varying concentrations of nicotine (100 to 10 mg/ml) and proliferation was assessed 72 hr later with a semiautomated colorimetric assay. Experiments were performed three times and proliferation of nicotine-exposed cells was compared to unexposed cells with one-way analysis of variance. Nicotine, at 100 ng/ml to 10 micrograms/ml, significantly stimulated epithelial cell growth in two ectocervical and three HPV DNA-transformed cell lines (proliferation 118-180% of control, P < .05). Nicotine at 100 ng/ml to 10 micrograms/ml did not significantly alter proliferation of four endocervical, three malignant, and two other ectocervical cell lines. Toxic effects of nicotine (> 50% inhibition of cellular proliferation) were noted between 100 micrograms/ml and 10 mg/ml and exceed the concentrations of nicotine reported in smoker's cervical mucus. These findings demonstrate that nicotine, in physiologically attainable concentrations, does not impair and occasionally enhances the proliferation of human cervical cells in vitro. The selective mitogenic effect noted among normal ectocervical and HPV-transformed ectocervical cells may relate to epidemiologic studies showing, among smokers, an increased risk of squamous cell carcinoma, and not adenocarcinoma, of the cervix.

Structuring group medical practices: liability insurance, retirement plan considerations, and ownership transition.

This article is the fourth in a series addressing the structuring of group medical practice entities, shareholder relationships, and general representation factors. In this article, important considerations relating to liability insurance and pension plans, and both the phasing in and phasing out of shareholders are discussed.

Ultrasound guidance for placement of difficult intracavitary implants.

Placement of a radiation implant in patients with cervical cancer may be difficult because of distortion of the canal by tumor or fibrosis from previous radiation. The objective of this study was to determine whether ultrasound may be useful in recognizing or preventing complications associated with placement of an intracavitary implant. Transabdominal ultrasound was used during and after 20 intracavitary implants in patients with cervical cancers. In placing 20 implants, there were 9 placed in less than satisfactory relation to the anatomy of the uterus. In 6 patients, occult perforations occurred, with two-thirds not detected by the operator. Increased difficulty was seen at the time of placement of a second implant after external radiation. By using ultrasound, correction of the misplaced tandem could be made immediately without resorting to more invasive surgical approaches.

Case-control analysis of clostridium difficile-associated diarrhea on a gynecologic oncology service.

OBJECTIVE: The incidence, morbidity, and risk factors associated with Clostridium difficile-associated diarrhea (CDAD) were studied in a group of gynecologic oncology patients. METHODS: A case-control analysis of gynecologic oncology patients with CDAD was carried out from August 1986 through January 1989 in a university medical center. RESULTS: One hundred twenty-three stool samples were tested for C. difficile using the CDT latex agglutination test (Marion Diagnostics, Kansas City, MO). Thirty episodes of CDAD developed in 23 patients. From August 1986 through July 1988, the incidence was stable at 1.5 episodes/100 admissions. From August 1988 through January 1989, the incidence increased to 9.9 episodes/100 admissions (P = 0.005). Compared with patients with nonspecific antibiotic-associated diarrhea, the study patients were hospitalized longer prior to the development of symptoms (mean 15.2 vs. 9.2 days, P = 0.006) and were admitted more frequently with diarrhea (37% vs. 11%, P = 0.015). The rates of surgery, chemotherapy, and radiation therapy were similar. Fever (57% vs. 14%, P < 0.001), abdominal pain (40% vs. 6%, P < 0.001), bloody stools (27% vs. 3%, P = 0.006), and leukocytosis (64% vs. 26%, P = 0.011) were more common among the study cases. The duration, indication, and number of antibiotics administered were similar, though once started, the mean time to symptoms was longer in the study cases (13.7 vs. 6.1 days, P = 0.004). Seven relapses, 1 death, and 1 unplanned colostomy occurred among women with CDAD. CONCLUSIONS: C. difficile is a serious cause of nosocomial morbidity in gynecologic oncology patients. Diarrhea developing after antibiotic exposure is more likely to be associated with C. difficile in patients whose symptoms develop several days after completing antibiotics and in patients with a history of CDAD.

Intraperitoneal therapy administered through a Groshong catheter.

This report describes a new device for delivery of intraperitoneal therapy. From October 1989 through March 1991, 27 externally accessed Groshong (Bard Access Systems, UT) catheters were placed transabdominally into 24 patients with presumed epithelial ovarian cancer at the conclusion of primary or second-look laparotomy. Total duration of catheter use was 81 months (range, 1-62 weeks). Fifty-seven cycles of intraperitoneal therapy were administered through 18 catheters (range, 1-11). Nine catheters were removed without being used after patients randomized off intraperitoneal treatment arms or were ineligible for intraperitoneal protocols. There were no complications associated with catheter placement or removal. None of the catheters became obstructed or dislodged while in place. There were no cases of infectious peritonitis, although one patient developed an exit-site skin infection. Surgery is not required to remove the Groshong catheter which fosters empiric placement of the device at the time of laparotomy in all patients potentially eligible for intraperitoneal therapy. The device-related infection rate of 4.2 per 100 patients is similar to that described using other implanted devices. Catheter maintenance is easy and patient acceptance is good. The Groshong catheter is a safe, reliable, and acceptable means of delivering intraperitoneal therapy.

Influence of in utero diethylstilbestrol exposure on the prognosis and biologic behavior of vaginal clear-cell adenocarcinoma.

Most young women with clear-cell adenocarcinoma (CCA) of the vagina have a history of prenatal exposure to diethylstilbestrol (DES). Some, however, develop vaginal CCA without a prior history of DES exposure. We hypothesized that the natural history of DES-exposed vaginal CCA and DES-unexposed vaginal CCA may differ. Cases were identified from the Registry for Research on Hormonal Transplacental Carcinogenesis which maintains information on cases of CCA of the lower genital tract occurring in women born after 1940. Four hundred and thirty-one cases satisfied FIGO criteria for primary vaginal carcinoma of which 318 had prenatal, hospital, obstetrician, or pharmacy records available for review. Of these, 80% (255/318) had written documentation of prenatal exposure to DES (DES+) and 20% (63/318) had no evidence of DES exposure (DES-) in their medical records. DES exposure was undetermined in 113 cases due to lack of appropriate medical records. Among cases with documentation, DES exposure was not associated with mean age at diagnosis, (DES+, 20.3 years, DES-, 21.1 years), stage (stage I: DES+, 59%, DES-, 54%; stage II: DES+, 32%, DES-, 33%; stage III: DES+, 7%, DES-, 11%; stage IV: DES+, 2%, DES-, 2%, mean tumor diameter or surface area, grade, histology, cell type, or initial therapy. Among cases which underwent pelvic and paraaortic lymph node sampling (DES+, 63%; DES-, 56%; P = NS) the prevalence of pelvic node involvement was similar (DES+, 18.6%; DES-, 17.1%). However, only 1.2% (2/161) of DES+ cases had positive paraaortic lymph nodes compared to 8.6% (3/35) of DES- cases (P = 0.041). Survival differed significantly between the two groups. Probability of survival at 5 and 10 years for DES+ cases was 84 and 78%, respectively, compared to 69 and 60%, respectively, for DES- cases (5 years, P = 0.007, and 10 years, P = 0.008). Presently, 21% (53/255) of DES+ cases are known to have died, compared to 37% (23/63) of DES- cases (P = 0.008). Sites of disease recurrence also differed. DES- cases were more likely than DES+ cases to present with or to later develop distant tumor to the lungs (24% vs 9%; P = 0.002) or metastases to supraclavicular lymph nodes (8% vs 1.6%; P = 0.017). Among the 113 cases with an uncertain history of DES exposure, survival was intermediate between the well-documented cases (79% at 5 years and 65% at 10 years with 35/113 or 31% known dead), as was frequency of metastases to the lungs (13%) or supraclavicular lymph nodes (5.3%).(ABSTRACT TRUNCATED AT 400 WORDS)

Human cervical tissue metabolizes the tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, via alpha-hydroxylation and carbonyl reduction pathways.

We determined the ability of human epithelial cervical cells, human cervical microsomes and cytosol to metabolize 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). All preparations metabolized NNK by alpha-hydroxylation, demonstrated by the presence of 4-oxo-4-(3-pyridyl)butyric acid (keto acid), and by carbonyl reduction, illustrated by the formation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL). Cervical cells metabolized NNK by the oxidative pathway to an extent comparable to that by the reductive pathway. In both human cervical cytosol and microsomes, the concentration of alpha-hydroxylation products ranged from undetectable to 10 times lower than those of NNAL. An apparent K(m) and V(max) of 7075 microM and 650 pmol/mg/min, respectively, were determined for the keto acid in one microsomal preparation. NNAL was formed in all preparations at the highest levels, ranging from 16.9 to 35.5 pmol/10(6) cells in incubations with ectocervical cells and 6.2 pmol/10(6) cells in incubations with endocervical cells. NNAL levels were 1.88-4.95 and 1.44-2.08 pmol/mg/min in human cervical microsomes and cytosolic fractions, respectively. An apparent K(m) of 739 microM and a V(max) of 1395 pmol/mg/min for NNAL formation were established in the same microsomal preparation used for the keto acid kinetics study. The stereochemistry of the NNAL formed in incubations of NNK with human cervical cells and subcellular fractions was determined by derivatization with (S)-(-)-methylbenzyl isocyanate. Human cervical cells and microsomes both formed the (R)-enantiomer of NNAL almost exclusively; incubations with human cervical cytosol resulted predominantly in the formation of the (S)-enantiomer. Substrates for 11 beta-hydroxysteroid dehydrogenase, cortisone, glycyrrhizic acid and metyrapone all inhibited the formation of NNAL in incubations with human cervical microsomes; the inhibition ranged from 16% to 80%. These studies illustrate that human cervical tissue can metabolize NNK by both oxidative and reductive pathways and that 11 beta-HSD may, in part, be responsible for the carbonyl reduction of NNK.

Role of chest CT in the follow-up of ovarian adenocarcinoma.

OBJECTIVE: We describe the prevalence of metastatic chest disease in ovarian adenocarcinoma as seen on CT. We sought to determine whether routine chest CT added any pertinent information to the follow-up examination of patients with ovarian adenocarcinoma. MATERIALS AND METHODS: Retrospective review of our tumor registry yielded 96 patients with ovarian adenocarcinoma who had only a single primary malignancy and at least one CT scan of the chest, abdomen, and pelvis. CT scans were reviewed to assess the presence of metastatic chest disease in relation to disease activity in the abdomen and pelvis. Chest CT findings were correlated with the physical examination findings and CA-125 levels and were reviewed in consultation with a gynecologic oncologist to select only those patients with chest abnormalities attributable to metastatic disease. RESULTS: A total of 266 CT scans were obtained. Forty (41.7%) of the 96 patients had abnormalities attributable to metastatic chest disease on one or more scans. In the absence of disease progression in the abdomen and pelvis, chest disease progression was seen in only six (2.7%) of the 226 follow-up CT scans. Five of the six patients had rising CA-125 levels. CONCLUSION: Correlation of the findings of abdominal and pelvic CT with the physical findings and the CA-125 levels serves as effective follow-up in patients with ovarian adenocarcinoma. The contribution of additional chest CT in these patients is small.

Phase II study of 96-hr continuous-infusion etoposide and doxorubicin with bolus cyclophosphamide in refractory epithelial ovarian cancer.

Effective salvage chemotherapy for patients with ovarian cancer who have failed platinum- and taxane-based regimens has not been identified. It has been reported that prolonged infusions of chemotherapy may be active in some malignancies which have become refractory to bolus treatments. We evaluated a regimen of 96-hr continuous-infusion doxorubicin (10 mg/m2/24 hr), etoposide (50 mg/m2/24 hr), and bolus cyclophosphamide (750 mg/m2) administered every 21 days to patients with ovarian cancer who had previously been treated with paclitaxel and a platinum compound. Nineteen women were treated, 15 of whom had platinum-refractory cancer. Six of the first 9 experienced a neutropenic fever after the first treatment cycle, and therefore all subsequent patients received prophylactic granulocyte-colony-stimulating factor. Other significant toxicities included hand and foot syndrome (1 patient) and mucositis (4 patients). There was one partial response in a patient with platinum-sensitive disease. We conclude that this regimen causes significant myelosuppression and does not have major activity in heavily pretreated patients with ovarian cancer.