Intralymphatic injection of BCG into rhesus monkeys.

Since the route of administration of BCG may have an important function in immunotherapy, we investigated intralymphatic administration to direct BCG to the lymph nodes. Multiple injections of high doses of BCG were administered to 6 rhesus monkeys via the dorsal lymphatics of the lower limb. A suppurative lymphadenitis was observed along the lower limb and in the inguinal area in 5 of the 6 monkeys. However, many of the complications reported with other routes of administration were not observed. Granulomatous reactions and histiocytic responses developed in lymph nodes on the injected sides of the pelvis and distant nodes as well as in the liver. The intralymphatic route is the method by which high doses of nonspecific immunostimulants were delivered to regional lymph nodes. The efficacy of this approach remains to be established in tumor-bearing animals and humans.

Preoperative chemo-radiation for carcinoma of the vulva with N2/N3 nodes: a gynecologic oncology group study.

PURPOSE: To determine if patients with carcinoma of the vulva, with N2/N3 lymph nodes, could undergo resection of the lymph nodes and primary tumor following preoperative chemo-radiation. METHODS AND MATERILAS: Fifty-two patients were entered in the study, but six patients did not meet the criteria of the protocol and were excluded. The remaining 46 patients are the subject of this report. Patients underwent a split course of radiation, 4760 cGy to the primary and lymph nodes, with concurrent chemotherapy, cisplatin/5-FU, followed by surgery. RESULTS: Four patients did not complete the chemo-radiation, because three expired and one refused to complete the treatment. Four patients who completed chemo-radiation did not undergo surgery, because two of them died of non-cancer-related causes, and in the other two patients, the nodes remained unresectable. Following chemo-radiation, the disease in the lymph nodes became resectable in 38/40 patients. Two patients who completed the course of chemo-radiation did not undergo surgery as per protocol because of pulmonary metastasis. One underwent radical vulvectomy and unilateral node dissection and the other radical vulvectomy only. The specimen of the lymph nodes was histologically negative in 15/37 patients. Nineteen patients developed recurrent and/or metastatic disease. The sites of failure were as follows: primary area only, 9; lymph node area only, 1; primary area and distant metastasis, 1; distant metastasis only, 8. Local control of the disease in the lymph nodes was achieved in 36/37 and in the primary area in 29/38 of the patients. Twenty patients are alive and disease-free, and five have expired without evidence of recurrence or metastasis. Two patients died of treatment-related complications. CONCLUSION: High resectability and local control rates of the lymph nodes were obtained in patients with carcinoma of the vulva with N2/N3 nodes treated preoperatively with chemo-radiation.

Plasma hormones in DES-exposed females.

Random blood samples were obtained from 114 women with history of diethylstilbestrol (DES) exposure in utero and were analyzed for follicle-stimulating hormone (FSH), luteinizing hormone (LH), estrone (E1), estradiol (E2), androstenedione (A), testosterone (T), and progesterone (P) by respective radioimmunoassays. Colposcopic examinations of the lower genital tract and biopsies of suspicious areas of vaginal mucosa were performed in every patient. The mean age of these patients was 21.6 +/- 0.3 years (mean +/- SE) and mean age of menarche was 12.6 +/- 1.0 years. The incidence of irregular menses was 16.7%. A positive colposcopic finding was observed in 73.7% of all patients, 69.5% of patients with regular menses, and 94.7% of patients with irregular menses. Histologically confirmed vaginal adenosis was found in 43% of all patients, 46.3% of patients with regular menses, and 42.1% of patients with irregular menses. No significant differences were observed between DES-exposed versus unexposed females with regular menses in all hormones except testosterone. An elevated testosterone level was noted in postovulatory and perimenstrual phases of DES-exposed females. Elevated testosterone was also observed in DES-exposed females with irregular menses. Cross-analysis of hormone levels among the patients with lower genital tract pathology failed to show any statistical differences.

Extended carbon dioxide laser vaporization in the treatment of subclinical papillomavirus infection of the lower genital tract.

This study examined the use of extended carbon dioxide laser vaporization in 25 women with histologically confirmed, multicentric subclinical papillomavirus infection of the lower genital tract to determine whether carbon dioxide laser can eradicate subclinical papillomavirus infection. An extended carbon dioxide laser procedure involved vaporization of the epithelium of the entire lower genital tract. We performed the procedure under colposcopic guidance. Vaporization was carried out in continuity, to an appropriate tissue depth, while using recommended power densities for the respective target tissue. For sexually active study patients, male consorts were evaluated and treated concurrently to reduce the risk of recurrent infection. Postoperative morbidity was considerable, with moderate to severe vulvar pain and febrile reactions occurring in 100 and 76% of patients, respectively. Histologic persistence of subclinical papillomavirus infection was documented in 88% of study patients at follow-up examination. Neither treatment of the male consort nor sexual abstinence significantly improved treatment outcome. These data suggest that extended carbon dioxide laser procedures cause significant short-term morbidity without effectively eradicating subclinical papillomavirus infection of the female lower genital tract.

Elevated serum cathepsin B1 and vaginal pathology after prenatal DES exposure.

Activities of the lysosomal enzymes, cathepsin B1 (CBI), beta-glucuronidase, and beta-N-acetyl-D-glucosaminidase, as well as sialyl transferase, alkaline phosphatase, and placenta-like alkaline phosphatase, were determined on blind-coded serums from 99 women exposed to diethylstilbestrol (DES) in utero and 40 unexposed subjects of comparable age range. Cathepsin B1 averaged 100%, 1040% (P less than 0.001), 2720 % (P less than 0.001), and 4760% (P less than 0.001) of controls in DES-exposed women with no genital tract abnormalities (N = 11), adenosis (N = 68), adenosis with concomitant dysplasia (N = 15), and clear-cell adenocarcinoma (N = 5), respectively. The later two groups also exhibited 0.01). Activities of the other four enzymes in serums of DES-exposed women were unchanged from those controls, suggesting that alterations in CBI were not due to generalized increases in lysosomal membrane instability or other gross cellular damage. In 2 DES-exposed women with clear-cell adenocardinoma, from whom serial samples were available, preoperative levels of serum CBl fell from a mean of 4280% to values indistinguishable from controls by 7--12 days after tumor excision, concurrently with objective signs of remission. Recrudescence of serum CBI levels preceded by at least 3 months clinical evidence of persistent adenosis accompanied by vaginal dysplasia. Although the nature of the increments in CBI-like activity in the majority of subjects with DES-related pathology remains to be determined, the findings may complement present methods of physical diagnosis and prognosis.

Pregnancy outcome in 98 women exposed to diethylstilbestrol in utero, their mothers, and unexposed siblings.

The reproductive capability and labor complications of 98 women exposed to diethylstilbestrol (DES) in utero were compared with those of 3 separate control groups. The controls consisted of 167 age-matched, normal women, 20 siblings not exposed to DES who had achieved pregnancy, and their mothers. Spontaneous abortion, ectopic pregnancy, incompetent cervix, and premature labor occurred significantly more often in the DES-exposed population than in the normal controls. The controls also achieved a higher percentage of desired pregnancies overall; this was statistically significant (89.6 versus 75.0%, P less than .001). When compared with their mothers, however, the DES-exposed population achieved a greater percentage of desired, viable pregnancies (75.6 versus 67.0%, P less than .001). The unexposed siblings of the DES women achieved a higher percentage of desired, viable pregnancies than did their exposed sisters (86.9 versus 73.6%, P = .274), but less than the normal population (86.9 versus 89.6%).

Applications of the monitoring process model to coping with severe long-term medical threats.

Guided by the monitoring process model (MPM), the authors explored the illness responses of 2 samples: high monitors (who are cognitively vigilant to and amplify threat-related cues) and low monitors (who avoid them and blunt their impact). Both samples-101 women with human papillomavirus-related precancerous cervical dysplasia and 75 HIV-infected gay men-were undergoing long-term medical follow-up and management. Structural equation analysis showed an adequate fit of the MPM to the data within each sample, supporting the model's heuristic value: High monitors experienced greater disease-related intrusive ideation, which triggered greater avoidant ideation to forestall panic, particularly in the more threatened HIV-positive sample. However, efforts to avoid disturbing intrusive thoughts were ineffective, requiring increasingly extreme defensive strategies (i.e., denial and mental and behavioral disengagement).

Monitoring styles in women at risk for cervical cancer: implications for the framing of health-relevant messages.

We explored the interaction effects of individual attentional style (high versus low monitoring) and the framing of informational messages on the responses of women undergoing diagnostic follow-up (colposcopy) for precancerous cervical lesions. Prior to the colposcopic procedure, patients (N=76) were randomly assigned to one of three preparatory conditions: (a) Loss-framed message, which emphasized the cost of nonadherence to screening recommendations; (b) Gain-framed message, which emphasized the benefit of adherence; and (c) Neutrally-framed message. It was hypothesized that low monitors (who are more positively biased about their health) would show a more adaptive pattern of response to loss-framed information than high monitors (who are more negatively biased about their health). The results of a series of hierarchical multiple regression analyses were consistent with this prediction. Low monitoring was associated with greater knowledge retention (beta=.61, p<.05) and less canceling/rescheduling of follow-up appointments in the loss condition than in the neutral condition (beta=.82, p<.002). High monitoring, however, was associated with greater intrusive ideation when information was presented in the loss-oriented frame as compared to the neutral frame (beta=.99, p<.01). Knowledge retention and screening adherence were not affected by the framing manipulation. The differences between high versus low monitors as a function of loss or neutral frame suggest an interaction effect, wherein both the type of framing message and the individual's attentional style lead to distinctive cognitive-affective and behavioral patterns. The findings may have clinical implications for the tailoring of health messages to the individual's signature style.

Interacting effects of information and coping style in adapting to gynecologic stress: should the doctor tell all?

This study explored the interacting effects of personal dispositions and situational conditions on the stress response. Forty gynecologic patients about to undergo a diagnostic procedure (colposcopy) were divided into information seekers (monitors) and information avoiders (blunters). Half in each group were exposed to voluminous preparatory information, and half to the usual low level of information. Subjective, physiological, and behavioral measures of arousal and discomfort were obtained before, during, and after the procedure. Overall, low-information patients expressed less subjective arousal than high-information patients, and blunters showed less subjective and behavioral arousal than monitors. In addition, patients' level of psychophysiological arousal was lower when the level of preparatory information was consistent with their coping style; that is, blunters were less aroused with low information and monitors were less aroused with high information. Further evidence was gained for the utility and validity of a new scale for identifying monitors and blunters.

Levels of urinary cathepsin B-like substance in patients with gynecologic malignancy.

Because certain proteolytic enzymes are thought to be released by malignant cells, we have measured the activity of cathepsin B in the urine samples of 57 patients with gynecologic malignancies and 60 disease-free controls. A unit (U) of enzyme activity is the release of one n-mol of 7-amino-4-fluoromethylcoumarin (AFC) from BZ-val-lys-lys-arg-MNA min-1 ml-1. Units of activity in the malignant group (10.6 +/- 9.8) differed significantly (p less than 0.0001) from controls (2.8 +/- 3.3). Although enzyme activity in both groups correlated with increasing age, the difference between those subjects with malignancies and those with none remained significant (p = 0.049) by analysis of covariance after adjusting for age. There was no correlation between titers and the race or weight of the subjects in either group. Enzyme activity of subjects with malignant disease correlated (p = 0.003) with the clinical stage of disease. Optimum sensitivity and specificity as determined by Receiver Operator Characteristic Analysis with an upper normal level of 5 U were 84.2% and 86.7%, respectively. Our findings suggest that measurement of urinary cathepsin B might be useful in detecting and managing patients with gynecologic tumors.

Vaginal and vulvar adenosis. An unsuspected side effect of CO2 laser vaporization.

During a 15-month period, September 1984 through January 1986, 10 women who were treated in the Section of Gynecologic Oncology, Department of Obstetrics and Gynecology, Pennsylvania Hospital, Philadelphia, Pennsylvania, developed vaginal or vulvar adenosis after CO2 laser vaporization. The indications for therapy were condylomata of the cervix, vagina and vulva refractory to conservative management in 3 patients, vulvar intraepithelial neoplasia in 3, lichen sclerosus in 1 and cervical intraepithelial neoplasia with condylomata on the cervix and vagina in 3. All the patients underwent treatment of the vagina. Most underwent treatment of the cervix, and some underwent treatment of the vulva at various degrees of intensity and depth. During the posttreatment colposcopic follow-up examination, all the patients demonstrated lesions colposcopically consistent with adenosis of the vagina or vulva within the area treated with the CO2 laser. Biopsies of the lesions were performed, adenosis was confirmed histologically, and endometriosis was ruled out histologically. This entity has not been previously associated with CO2 laser vaporization, and its clinical significance is undetermined. Further follow-up is indicated.

Adenoid cystic carcinoma of Bartholin's gland: a review of the literature and report of a patient.

We report the case of a 77-year-old white female with adenoid cystic carcinoma of Bartholin's gland. To date only 45 cases of adenoid cystic carcinoma of Bartholin's gland have been reported in the world literature. The longest reported survival is 27 years. This patient was originally diagnosed 33 years ago and presented with her fourth recurrence. She was treated with radical surgery and did well for 6 months, but later died secondary to renal failure. Adenoid cystic carcinoma of the Bartholin's gland is a rare tumor of the vulva. When diagnosed the treatment should be tailored to the patient. When margins are found to be positive, adjuvant radiotherapy may prove to be beneficial.

The 'problem' radical hysterectomy.

This is a study of 243 radical hysterectomy and pelvic lymphadenectomy procedures performed for gynecologic malignancy. The term 'problem' radical hysterectomy was applied to those patients with one of the following conditions: (1) recent cervical conization (within 21 days). (2) previous total or supravaginal hysterectomy, (3) pregnancy, or (4) previous pelvic radiation. There were 88 patients in theses categories. One hundred and fifty-five patients had none of these predisposing problems which might influence operative or postoperative complications. There were two deaths (0.82 per cent). There was no statistically significant difference in operative injuries to the bladder, ureters, or rectum or in the mean operative time and mean blood loss across the categories. However, there was a statistically significant difference across the categories in postoperative complicatons, both major and minor. The greatest incidence of such complications occurred in patients who had previous radiation therapy and the second greatest incidence was in patients who had recent cervical conization. Pregnant patients had the least number of complications.

Lymph node nomenclature in gynecologic oncology.

The nomenclature of the lymph node groups draining the pelvic organs has been poorly standardized. This has impaired understanding of the natural history of gynecologic malignancies and led to difficulties in communication among specialists treating those diseases. In order to assess the extent of this problem, members of the Society of Gynecologic Oncologists and other physicians treating pelvic malignancy were asked to label a diagram of the pelvic lymph nodes. The lack of uniformity in the answers confirms the need for a simple, clinically relevant system of nomenclature. Such a system is proposed.

Evaluation of gemcitabine in patients with squamous cell carcinoma of the cervix: a Phase II study of the gynecologic oncology group.

PURPOSE: A multicenter Phase II trial was conducted to evaluate the activity and toxicity of gemcitabine in patients with previously treated squamous cell carcinoma of the uterine cervix. PATIENTS AND METHODS: Patients were required to have measurable disease with adequate performance status, bone marrow, hepatic, and renal function. Histologic confirmation of the primary diagnosis as squamous cell cancer of the uterine cervix was mandatory. Patients were allowed one prior chemotherapy regimen, usually cisplatin-based. The initial dose of gemcitabine was 800 mg/m(2) weekly times three with 1 week off until progressive disease or adverse effects prohibited further therapy. Doses were escalated or reduced based on previous cycle toxicity. RESULTS: Twenty-seven patients were entered into the trial. One patient never received the drug and 1 patient was inevaluable for response. A median of two cycles were administered to each patient (range: 1-7 cycles). The overall response rate (two partial responses) was 8% with 21% of patients having stable disease. The median progression-free interval was 1.9 months (range: 0.5-9.0) and overall survival was 4.9 months (range: 1.5-16.3). Two patients had grade 4 neutropenia; 1 patient had grade 4 anemia. The median WBC nadir in the 13 patients experiencing any leukopenia was 2300/microl (range: 400-3800). There was only one episode of grade 4 gastrointestinal toxicity. CONCLUSIONS: Gemcitabine as a single agent demonstrated minimal antitumor activity in previously treated patients with squamous cell cancer of the uterine cervix. Since gemcitabine in the dose and schedule employed is known to potentiate the cytotoxicity of cisplatin and radiotherapy (the current standard therapies for this disease), further development of gemcitabine would only be indicated in combination with these treatment modalities.

The second-look celiotomy in ovarian cancer.

Thirty-six patients with primary ovarian carcinoma who had 42 second-look procedures performed are reported. Twenty-three patients had no tumor found at the second-look celiotomy and were given no further treatment. Thirteen patients had tumor at the second-look procedure and were continued on therapy. Six patients have died with disease and all had a positive second-look celiotomy. Two patients have died with leukemia but with no evidence of ovarian cancer, one after a negative second-look and the other a negative third-look. No patient with a negative second-look celiotomy has died with disease. A correlation with respect to the findings at the second-look was found with respect to the stage of disease and the amount of residual tumor at the initial surgery. The use of the second-look celiotomy in patients with disease in the early stages and in patients treated with irradiation is discussed, along with the utilization of the laparoscopy.

Six years' experience with screening of a diethylstilbestrol-exposed population.

The physician population delivering obstetric care in Philadelphia between 1950 and 1970 was contacted to ascertain their use of diethylstilbesterol (DES) during pregnancy. Of the 31.8% of the physicians who responded to the questionnaire, 71.8% used DES during pregnancy and 12.7% desired assistance in review of their records. During the 6 years from the initial survey, 830 young women exposed to DES in utero were periodically screened for cervicovaginal abnormalities and clear cell adenocarcinoma. Of these 830 patients 61.7% were found to have cervicovaginal abnormalities, and 65.9% of the patients showed either adenosis or evidence of the prior existence of vaginal adenosis. Eight patients were treated for clear cell adenocarcinoma. Two cases were detected while asymptomatic. Seven of the patients are living with no evidence of cancer, and two of these have survived over 5 years.

PIP: A project, designed to locate the population at risk to diethylstilbestrol (DES) exposure in utero in the greater Philadelphia area from 1950-1970, was implemented by contacting area physicians who might have used the drug in their practices on pregnant women. 216 (31.8%) physicians responded to the questionaire; 155 (71.8%) responded that they had used DES. During the 6 years from initial survey, 830 young women exposed to DES in utero were periodically screened for cervicovaginal abnormalities and clear cell adenocarcinoma. Gross structural cervicovaginal abnormalities were found in 512 (61.7%) of the individuals evaluated. In 38 patients, vaginal adenosis existing alone was documented. In another 279 patients, metaplasia alone was noted in the vagina, and in another 230 patients, both metaplasia and adenosis coexisting in varying degrees were found. Thus, 547 (65.9%) showed either adenosis or evidence of the prior existence of vaginal adenosis. 8 patients with clear cell adenocarcinoma of the vagina or cervix were seen; each individual was born during the decade of the 1950s. 2 cases were detected while asymptomatic; 7 of the patients are living with no evidence of cancer, and 2 of these have survived over 5 years. These results showed a much lower incidence of significant dysplastic squamous changes (1.1%) than that of earlier reports, emphasizing the subjective element of earlier, more alarming reports.

Flow cytometric DNA and 5'-nucleotide phosphodiesterase in endometrium.

One hundred endometrium specimens have been studied with flow cytometry for DNA analysis (FCDA) and a proliferative enzyme marker, 5'-nucleotide phosphodiesterase (5'-NPD). FCDA data showed that aneuploidy was present in only 5 of 40 cancer specimens. However, with corrected histograms, a higher DNA value was observed in the G2/M (6%) of all cancer compared with noncancer specimens (4%). Thus, FCDA can be a useful diagnostic aid for endometrial cancer. The determination of 5'-NPD was done with a quenching method based on the use of 5'-(5-iodo-3-indoxyl)-thymidine phosphodiester as a substrate and 4',6-diamidino-2-phenylindole for DNA. This method could qualitatively define which population of the cell cycle had a higher enzyme level and also quantitatively gave the enzyme units per cell. It was found that 12.5% of all cancer specimens had 5'-NPD activity in the G0/G1 cells and 87.5% in the S and/or G2/M cells, whereas in the noncancer specimens 5'-NPD was found in 28.5% of the G0/G1 cells and 71.5% of the specimens had 5'-NPD in the S and/or G2/M cells. Furthermore, the concentration of 5'-NPD was found to be five times higher in the G2/M cells of the cancer specimens than that in the noncancer specimens. However, in the hyperplasia specimens, the activity was only two times higher in the same cell cycle fraction than in the normal specimens. The results of this investigation provided for the first time evidence that this exonuclease activity alters in the cell cycle fractions and that a decrease in the enzyme activity in G0/G1 cells and an increase in G2/M cells may be a useful marker for neoplastic development in human endometrial cancer.

Association between subjective sleep quality and depression on immunocompetence in low-income women at risk for cervical cancer.

OBJECTIVE: The purpose of this study was to investigate whether subjective sleep quality is more strongly associated with immunocompetence than depression among women at risk for cervical cancer. METHODS: Participants were 91 women referred for colposcopy because of abnormal results on a Pap smear. On the day of the procedure. participants completed the Center for Epidemiological Studies Depression Scale, two indices of subjective sleep quality (ie, satisfaction with sleep obtained and degree of sleep restfulness), and a health behaviors assessment questionnaire. Levels of peripheral blood lymphocyte subpopulations (helper T, cytotoxic/suppressor T, NK, and B cells) were also assessed at this time. Approximately 10 days later, the presence of depressive disorder was assessed using the Structured Clinical Interview for DSM-III-R. RESULTS: Hierarchical regression analyses revealed that satisfaction with the amount of sleep obtained was significantly associated with the circulating number and percentage of helper T cells (T(H)/CD4+) and the percentage of cytotoxic/suppressor T cells (T(C)/CD8+), after controlling for confounder variables (ie, age, smoking status, and drug use). Depression was significantly associated only with the percentage of T(C) cells. Sleep satisfaction remained significantly associated with the number and percentage of T(H) cells and percentage of T(C) cells after controlling for the variance explained by depression. CONCLUSIONS: Results of this study suggest that subjective sleep quality shares a significant and independent portion of the variance with immunity that is not accounted for by depression. Although the long-term impact of these immune alterations on disease progression needs to be directly explored, it may be important to systematically screen for and manage sleep disturbance in women at high risk for cervical cancer.

Hyperfractionated radiation therapy plus chemotherapy in locally advanced cervical cancer: results of two phase I dose-escalation Gynecologic Oncology Group trials.

OBJECTIVE: The aims of this study were to assess the early and late toxicities of multiple-daily-fraction whole pelvic radiation plus concurrent chemotherapy with either hydroxyurea or 5-fluorouracil (5-FU)/cisplatin and to determine the maximum tolerated external radiation dose in conjunction with brachytherapy, when given with either of these drug regimens, as treatment for locally advanced carcinoma of the cervix. METHODS: The first study (GOG 8801) of 38 patients utilized hydroxyurea as a single oral dose of 80 mg/kg to a maximum of 6 g at least 2 h prior to a radiation treatment twice every week. In the second study (GOG 8901) of 30 patients, cisplatin and 5-FU were used concomitantly with radiotherapy. Fifty milligrams per square meter of cisplatin was administered on days 1 and 17 of external radiation. 5-FU was given by continuous intravenous infusion at a dose of 1000 mg/m(2)/day for 4 consecutive days on days 2, 3, 4, 5, and 18, 19, 20, and 21 of external radiation therapy. Both studies utilized external radiation given by an accelerated hyperfractionated regimen of 1.2 Gy per fraction, two fractions per day. All patients were treated 5 days per week with a minimum of 4 h between fractions. RESULTS: Acute toxicity was manageable on both protocols but nausea, vomiting, and myelosuppression were more severe with hydroxyurea. Chronic toxicity was primarily enteric and appeared to be dose-related. There was no obvious correlation seen between pelvic failure rates and the radiation dose or between the chemotherapy regimens used. CONCLUSIONS: The defined maximal tolerated dose of whole pelvic radiation was 57.6 Gy in 48 fractions which could be delivered in a hyperfractionated setting with concomitant chemotherapy, followed by brachytherapy. Follow-up is now sufficient that further adverse events should be rare.