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Objective: To examine the suitability of estradiol labeled with iodine I 123 at 16α for imaging estrogenreceptor—positive breast carcinoma using imaging instrumentation that is widely available. Design: Single-photon emission computed tomographic imaging survey of 29 women with suspected primary or expected recurrent breast carcinoma. Setting: University-based referral center. Participants: Twenty-nine women undergoing diagnosis for primary or recurrent breast carcinoma. Selection was voluntary. Main Outcome Measure: Qualitative imaging study designed to provide tomographic data of radioligand retention and descriptive data of imaging results. Results: Single-photon emission computed tomographic imaging using 123 I-estradiol at 16α was performed for patients with breast carcinoma. Independent readers, without knowledge of receptor status or proven disease, interpreted the films. Scintigraphic detection was most noteworthy in patients with chest wall tumors and inflammatory breast cancer. Agreement between readers was 98% for true-negative readings and 94% for true-positive readings, but only 60% for false-positive and false-negative film readings. Conclusions: Our results indicated that areas shown on imaging were also found to have estrogen-receptor activity and that radioligand accumulation can occur with low frequency in some surgically explored tissue. Radioligand imaging with 16α- 123 I-estradiol can locate estrogen-receptor—positive breast tumors, including some that may be difficult to detect using conventional diagnostic imaging. (Arch Surg. 1993;128:1373-1381)

The frequent finding of loss of heterozygosity (LOH) for a specific chromosomal marker in tumor DNA compared to normal DNA suggests the presence of a closely linked tumor-suppressor gene. Using Southern blot analysis, 34 primary ovarian epithelial tumors were examined for the presence of tumor-specific allelic losses, using six probes for chromosomes 6q, 11p, 13q, 16q, and 17p. A high incidence of LOH was observed on 11p, 13q, and 17p. LOH for 17p was present in 3 of 4 (75%) informative benign ovarian tumors, 1 of 5 (20%) borderline tumors, and 16 of 24 (67%) invasive ovarian cancers. Allelic loss with the H-ras1 probe on 11p was present in 10 of 19 (53%) invasive tumors but was not identified in 6 benign or borderline tumors. LOH on 13q was present in 18 of 31 (58%) informative cases including 8 of 10 (80%) Stage 1 tumors. This preliminary study suggests that loss of tumor-suppressor genes on chromosomes 13q and 17p may be early events in ovarian tumorigenesis and that changes on chromosome 11p are later events.

The analysis of data generated on a flow cytometer (FCM) is often performed on a computer obtained especially for dedicated use with the flow cytometer. This computer component can be expensive and also presents the FCM user with the added burden of mastering specialized programming language or of accepting the secret analytical processes of protected proprietary program routines. We believe that the evolution of more accurate and efficient FCM analyses that have the power to consider complex signal distributions can be assisted by the availability of analysis programs written in languages common to many users. DNA analysis routines written for a relatively inexpensive micro-computer (IBM PC/XT) in Basic and Pascal are described here. The routines can automatically process multiple FCM data files and can provide high-resolution graphic hardcopy. A foreground/background utilization is also described that allows the computer to be available for other uses in the laboratory.

From 1975 to 1987, 80 patients with bulky or barrel-shaped Stage IB cervical cancer were treated with preoperative irradiation and Cs-137 intracavitary implant therapy, before a planned extrafascial abdominal hysterectomy, using a consistent treatment policy. Of the hysterectomy specimens obtained, 37% were positive histologically at 89 +/- 2.3 days after the start of radiotherapy and at 4 to 6 weeks after the completion of radiation therapy. Sixty-three percent were negative after a total external and internal cervix irradiation dose of 9642 cGy at point T. The average point A dose contributed by intracavitary therapy was 2104 cGy. The survival rate at 5 years was 84%: At 10 years the survival rate was 78%. The failure pattern was analyzed for patients who had positive and negative specimens. The patients with positive specimens failed pelvically or pelvically and distantly. Patients with negative specimens failed in extrapelvic or distant metastatic sites. Preoperative radiotherapy led to excellent local and pelvic control of tumor, and the failures became predominantly distant metastases. The combined radiosurgical therapy was tolerated well and allowed surgical staging of disease. This permitted earlier and selective consideration of adjunctive therapy (i.e., paraaortic irradiation, chemotherapy, or chemoradiotherapy). The dose-response data give insight intomore » the effects of photon radiotherapy on bulky or barrel Stage IB cervical cancers and correlate histologic status with failure pattern, outcome, and long-term survival.« less

A fast-neutron-emitting radioisotope, 252Cf, is being tested in clinical trials of neutron brachytherapy for cervical cancer. The efficacy for histological eradication of bulky stage IB cervical tumors (mean diameter, approximately 6 cm) using combined radiation and surgery was studied in 65 patients treated with 137Cs or 252Cf before surgery during 1983-1986. Forty-four patients were treated with 137Cs and 21 were treated with 252Cf at equivalent doses of radiation. Fifteen of the 44 specimens (34%) were positive after 137Cs therapy. Only one of the 21 specimens was positive after 252Cf therapy (P = .025), and that patient was treated in a delayed schedule 21 days after the start of external-beam irradiation rather than early in the course. 252Cf therapy required a much lower radiation dose and shorter treatment time. The study compared tumor destruction of an identically staged human cervical tumor in situ by direct histological means, using 252Cf neutron therapy or conventional photon therapy at an identical and equivalent dose adjusted by a relative biological effectiveness of 6.0 for 252Cf.

and occurred most frequently in poorly differentiated tumors with deep myometrial penetration. Tumor recurrence developed in 44% of patients whose tumors demonstrated lymph-vascular space invasion as opposed to only 2% of patients without this finding (p < 0.001). Of seven patients with lymph-vascular space invasion who experienced tumor recurrence, five developed extra-pelvic metastases. Discriminant function analysis of these data revealed a statistically significant correlation between lymph-vascular space invasion and tumor recurrence, independent of histologic differentiation of myometrial penetration. These findings suggest that lymph-vascular space invasion by tumor cells is an important prognostic variable in Stage I endometrial cancer which should be considered in treatment planning. Cancer 55:1753-1757, 1985. ARCINOMA OF THE ENDOMETRIIJM remains the C most common invasive gynecologic malignancy in the United States with over 39,000 new cases predicted to be diagnosed during the present year.' Although the majority of endometrial cancer patients present with Stage I disease, a significant number of these patients experience tumor recurrence. In many cases, tumor control is achieved locally but the patient dies of extrapelvic metastases. Much effort has been directed toward the identification of prognostic factors which can be used to define those patients with early stage disease who are at high risk for the development of recurrent cancer. Such factors include age, cell type, histologic differentiation, and myometrial Recent evi

Estrogen receptor activation has been examined in murine uteri by characterizing binding to ATP-Sepharose. Determinations were performed under conditions in which specific binding to estrogen receptors was demonstrated by both agonist and antagonist without participation by nonreceptor antiestrogen-binding components. Cell-free activation of estrogen receptors in cytosol was more effectively promoted by [3H]estradiol estradiol than by [3H]4-hydroxytamoxifen or [3H]tamoxifen aziridine. However, when in situ activation was examined after intact uteri were exposed to [3H]estradiol or [3H]4-hydroxytamoxifen, virtually all extracted nuclear receptors demonstrated activated binding to ATP-Sepharose within 20 min of hormone exposure. Profiles of nuclear receptor activation were remarkably similar after exposure to either agonist or antagonist. Estrogen receptors in cytosol prepared after exposing intact uteri to 3H-labeled ligands were characterized by much less ability to bind to ATP-Sepharose than nuclear receptors. After uteri were exposed to [3H]estradiol, the activated receptor fraction in the cytosol progressively increased in contrast to preparations obtained after uteri were exposed to [3H]4-hydroxytamoxifen, which demonstrated a constant level of activation. Thus, even when activation has occurred within the intact uterus, agonists and antagonists may be characterized by different apparent levels of receptor activation in the cytosol fraction. These differences in the cytosol, however, are considerably overshadowed by the extensive activation occurring within the nuclear fraction, which we have observed to be similar with agonist and antagonist. Since estrogen receptors appear to act within chromatin, and cytosol receptors may be produced by receptor redistribution during preparation, we interpret these observations to indicate that in situ receptor activation is very similar after exposure to either agonist or antagonist. Consequently, antagonism does not appear to be associated with antiestrogens that impede receptor activation within intact murine uteri.

Patient-controlled analgesia (PCA) is currently being evaluated as an alternative to prn intramuscular injections for the relief of postoperative pain in patients with gynecologic malignancies. From June 1985 to May 1986, twenty patients undergoing abdominal hysterectomy received PCA rather than traditional intramuscular injections for relief of postoperative pain. PCA was administered by a lightweight, wearable, disposable system, the Travenol Infuser with Patient Control Module. The PCA device delivered a 1-mg intermittent intravenous injection of morphine upon patient demand with a delay of 6 min between allowable administrations. The mean amount of morphine utilized postoperatively by the PCA patients (66 mg over 48 hr) was not significantly different from the amount used by a control group receiving prn im morphine injections. No cases of respiratory or cardiac depression were observed, and patients were generally alert throughout the period of analgesia. These data suggest that PCA is a safe and effective mode of analgesia administration. In addition, the unique characteristics of this new compact device were well accepted.

The authors reviewed the records of 2261 patients with histologically proven cervical cancer. Among the 1042 patients with carcinoma in situ, four neurologic complications occurred (0.4%), including three strokes and one seizure. None of the neurologic complications were related to cervical cancer. Among the 1219 patients with International Federation of Gynecology and Obstetrics (FIGO) Stage I or greater disease, 99 neurologic complications occurred (8%). Metastatic neurologic complications were twice as common as nonmetastatic neurologic complications and included lumbosacral plexopathy (50 patients), peripheral nerve compressions (eight patients), spinal cord compressions (two patients), and brain metastases (six patients). Nonmetastatic neurologic complications were less frequent and included stroke (11 patients), encephalopathies (three patients), infectious complications (two patients), effects of therapy (six patients), and seizures (11 patients). In conclusion, neurologic complications are rare in cervical cancer and virtually nonexistent in Stage 0 disease. Metastatic neurologic complications were more common than nonmetastatic complications and lumbosacral plexopathy caused by retroperitoneal lymph node metastases was the most common neurologic complication.

Size-exclusion high-performance liquid chromatography was used to characterize the hydrodynamic molecular properties of estrogen receptors complexed with estradiol and the antiestrogen 4-hydroxytamoxifen. Cytoplasmic estrogen receptors complexed with [3H]-4-hydroxytamoxifen did not undergo reductions in hydrodynamic size after exposure to KCl or urea. Nuclear receptors complexed with 4-hydroxytamoxifen eluted as hydrodynamically larger molecules than nuclear receptors complexed with estradiol. Because identical hydrodynamic characterizations were obtained with the covalent ligand [3H]tamoxifen aziridine, these differences in chromatographic behavior are due to differences in ligand-mediated receptor properties and are not the result of ligand dissociation. When estrogen receptors, complexed with either [3H]estradiol or [3H]-4-hydroxytamoxifen, were exposed to trypsin, the receptors complexed with 4-hydroxytamoxifen eluted as larger hydrodynamic forms than receptors complexed with estradiol. These observations are interpreted to indicate that estradiol and 4-hydroxytamoxifen mediate contrasting transitions in the molecular orientation of estrogen receptors. The consequences of the transitions mediated by 4-hydroxytamoxifen appear to be that intermolecular associations become difficult to disrupt with KCl or urea and that the accessibility of trypsin-sensitive proteolytic sites becomes altered. Chromatin fractionation using DNase I and hypotonic Mg2+ solubilization identified a chromatin region that was less readily penetrated by receptors complexed with 4-hydroxytamoxifen than receptors complexed with estradiol.(ABSTRACT TRUNCATED AT 250 WORDS)

Seven patients with Stage I uterine sarcomas (greater than or equal to 10 mitoses/10 high-power fields) were treated with surgery plus adjuvant vincristine, dactinomycin, and cyclophosphamide (VAC) chemotherapy in a pilot study conducted at the University of Kentucky Medical Center from 1978 to 1983. Surgery consisted of total abdominal hysterectomy, bilateral salpingo-oophorectomy, and para-aortic lymph node sampling. Chemotherapy was begun within 1 week of surgery, and all patients received at least six monthly courses of VAC. This chemotherapeutic regimen was well-tolerated, and toxicity was minimal. Two patients had recurrent sarcoma, and one of them has died of disease. The remaining five patients are alive and well with no evidence of disease 48 to 73 months after therapy. The recurrence rate of patients with Stage I uterine sarcomas treated with adjuvant VAC chemotherapy was significantly (P less than 0.02) less than that for similar patients treated at this institution (1964-1977) by surgery alone or surgery plus pelvic radiation. These results suggest that primary adjuvant chemotherapy is beneficial in patients with Stage I uterine sarcomas.

From 1973 to 1987, 16 patients with International Federation of Gynecology and Obstetrics (FIGO) Stage I serous papillary endometrial carcinoma were evaluated and treated at the University of Kentucky Medical Center (Lexington, KY). All patients were 60 years of age or older, and all were postmenopausal. Patients were treated with total abdominal hysterectomy, bilateral salpingo-oophorectomy, and paraaortic lymph node sampling, and 38% were noted to have more extensive disease than appreciated clinically. Nine patients were given adjuvant postoperative radiation. Seven patients (44%) developed recurrent cancer with liver, lung, and upper abdomen being the most common sites of spread. Prognosis was most directly related to the presence of lymph vascular space invasion and the depth of myometrial penetration. No patient with serous papillary carcinoma confined to the endometrium developed recurrent cancer. In contrast, the recurrence rate of patients having myometrial invasion was 70% (P less than 0.03). Hormonal therapy was of limited value in the treatment of recurrent disease. This data suggests the need for adjuvant systemic therapy in the treatment of patients with Stage I serous papillary carcinoma of the endometrium who have myometrial invasion.

From 1962 to 1985, 2201 patients with invasive cervical cancer were staged, evaluated, and treated at the University of Kentucky Medical Center. After a thorough evaluation, 25 cases (1.1%) fulfilled the histologic criteria for small cell cancer defined by Reagan and coworkers. These patients were computer-matched for age, disease stage, and lesion size to 25 patients with large cell nonkeratinizing cancer and 25 patients with keratinizing squamous cell cancer. Morphometric analyses of nuclear size and maximum nuclear diameter were performed on all cases without knowledge of cell type. Small cell cancers were characterized by a nuclear area of 160 mu 2 or less and a maximum nuclear diameter of 16.2 mu, which was significantly lower than that for large cell tumors. Thirty-three percent of the small cell carcinomas stained positively for the neuroendocrine markers (neuron-specific enolase [NSE] and chromogranin [CGR]), whereas the remainder contained only epithelial markers such as cytokeratin (CYK) and epithelial membrane antigen (EMA). Small cell cancers were associated with a high frequency of lymph-vascular space invasion and a diminished lymphoplasmacytic response. Patients with small cell cancer had a significantly higher recurrence rate, particularly to extrapelvic sites, than the matched patients with large cell cancers, and their survival was lower. Clinical trials to determine the efficacy of adjuvant chemotherapy in the treatment of small cell cervical cancer are needed.

Prognostic parameters were evaluated in 22 patients with small (less than or equal to 2 cm) superficially invasive (less than 5 mm) squamous cell carcinoma of the vulva. Primary surgery included radical vulvectomy with bilateral superficial and deep inguinal lymph node dissection in 11 patients, and wide local excision with ipsilateral superficial inguinal lymph node dissection in 11 patients. Of the 22 patients studied, only 2 (9%) had lymph node metastases. Both patients had a single positive ipsilateral superficial inguinal node. Perineural invasion was strongly associated with lymph node metastases (P less than 0.01). In this group of patients, grade, depth of invasion, lymph-vascular space invasion, and lymphoplasmacytic infiltration were not predictive of lymph node metastases (P greater than 0.05). Two patients initially treated with wide local excision and ipsilateral superficial inguinal lymph node dissection developed recurrent vulvar neoplasia on the contralateral vulva, and both were successfully retreated by wide local excision. All patients are presently alive and well with no evidence of disease. None of the histomorphologic parameters studied were predictive of tumor recurrence. These data suggest that wide local excision with ipsilateral superficial inguinal lymphadenectomy is effective in the treatment of patients with small, superficially invasive carcinomas of the vulva.

Seven cases of ovarian dysgerminoma are presented and the recent literature reviewed. The majority of the cases reviewed had tumor confined to one ovary at the time of diagnosis, and nearly 50% occurred in women less than 20 years of age. The 5-year survival rate was 91% for 211 patients with stage I disease and 65% for 60 patients with stage II to IV dysgerminoma. The addition of contralateral adnexectomy, abdominal hysterectomy, and radiation therapy was not beneficial when disease was confined to one ovary. The survival of patients with advanced disease treated with chemotherapy was comparable with that of patients who received radiation. Analysis of the present data suggests that the use of unilateral oophorectomy should be limited to those patients with disease confined to one ovary and no histologic evidence of lymph node metastasis. Abdominal hysterectomy, bilateral adnexectomy, and adjuvant radiation is currently the treatment of choice for patients with more advanced dysgerminoma.

Intracavitary Californium-252 combined with whole-pelvis photon radiotherapy was tested as the sole form of treatment for 22 patients with Stage IB carcinoma of the cervix. Californium-252 (Cf) is a fast neutron-emitting radioisotope currently being tested in trials of neutron brachytherapy (NT). The outcomes of the treated group of patients were traced for local tumor control, survival, patterns of failure, and complications. The Cf intracavitary therapy combined with whole-pelvis photon radiotherapy resulted in 95% 2-year and 91% 5-year actuarial survival. There were 9% Grade II-III complications by the Stockholm scale and 4% local failures. These results were obtained in an early clinical trial with a group of largely poor-risk patients with tumors of mean diameter of 4.3 cm.

Endodermal sinus tumor of the ovary can be differentiated histologically and immunohistochemically from ovarian embryonal cell carcinoma. A case report of a patient with endodermal sinus tumor is presented in which a long-term remission was achieved by unilateral adnexectomy and combination chemotherapy. Review of the current literature indicates that tumor removal followed by combination chemotherapy with vincristine, actinomycin D, and cyclophosphamide is the most effective method of therapy for this highly malignant ovarian neoplasm. The addition of hysterectomy with contralateral ovariectomy or radiation therapy does not appear to significantly improve the survival of patients with this tumor. Serial plasma determinations of alpha fetoprotein provide biochemical monitoring of response to therapy and may be useful in predicting occult tumor recurrence.

From June 1977 to June 1983, 32 patients with bulky (greater than 4 cm diameter), barrel-shaped Stage IB cervical cancer were treated at the University of Kentucky Medical Center by a combination of outpatient neutron brachytherapy using californium 252 (252Cf) and external pelvic radiation followed by extrafascial hysterectomy. Nineteen patients had cervical tumors 4 to 6 cm in diameter, and 13 patients had lesions in excess of 6 cm in diameter. A dose of 4500 rad external photon therapy was given from a linear accelerator, and one or two 6-hour 252Cf implants were given during or immediately after external radiation. Extrafascial hysterectomy with bilateral salpingo-oophorectomy was performed 6 weeks after completion of radiation therapy. Complications during and after radiation were minimal and included vaginal stenosis (three) and proctitis (two). Tumor clearance in the hysterectomy specimen was complete in 23 patients (72%) and residual cervical tumor was present in 9 patients (28%). Two patients developed tumor recurrence and died of disease 15 and 27 months after therapy, respectively. Thirty patients remain free of disease 26 to 96 months (median, 52 months) after treatment, and none have been lost to follow-up. The actuarial survival of these patients is 97% at 2 years and 94% at 5 years. Intracavitary neutron therapy is well tolerated and is effective when combined with external radiation and hysterectomy in the treatment of bulky, barrel-shaped Stage IB cervical cancer.

From November 1, 1987, to July 1, 1988, 506 asymptomatic patients 40 years or older underwent screening vaginal sonography at the University of Kentucky Medical Center. Eligibility requirements included no known pelvic symptoms or clinical abnormalities, no history of pelvic radiation, and no history of ovarian cancer. Each ovary was measured in three planes and ovarian volume was calculated using the prolate ellipsoid formula. Ovarian morphology was classified as uniformly hypoechogenic, cystic, solid, or complex. The upper limit of normal for ovarian volume was 18 cm3 in premenopausal women and 8 cm3 in post-menopausal women. With respect to these criteria, 12 patients (2.4%) were noted to have abnormal sonograms, and 10 agreed to surgery. All 10 patients had ovarian tumors with dimensions equal to those predicted by ultrasound. These tumors included four serous cystadenomas, three endometriomas, two cystic teratomas, and one adenocarcinoma. Vaginal sonography is a relatively simple test that can detect subtle changes in ovarian size and morphology. Further evaluation of this test as a screening method for ovarian cancer should be performed in the setting of controlled clinical trials that emphasize cost control and strict patient follow-up.

The mouse uterus has been used as a model system with which to examine the interaction of anticancer agents with steroid hormone receptors and to evaluate the effect of a single exposure to a cytotoxic anticancer agent on the subsequent elicitation of the uterotrophic response to estradiol. The uterotrophic response was interpreted in terms of the induction of progesterone receptors, uterine weight gain and increased uterine DNA content. Evaluation of 34 cytotoxic agents selected for this study provided little evidence to substantiate the interaction of these agents with estrogen or progesterone receptors. Although prior treatment with certain cytotoxic agents partially inhibited the subsequent responses to estradiol, some capacity to respond to estradiol was always retained. The majority of cytotoxic agents had little impact on the capacity to respond to estradiol. Thus, in these studies where high sublethal concentrations of cytotoxic agents were administered prior to estradiol, there was no indication that the mechanisms regulating subsequent hormonal responses were compromised.

Twenty patients with Stage IVA and IVB cervic cancers were treated with Californium-252 (Cf) neutron brachytherapy (NT) in a feasibility trial between 1976 and 1986. Eleven patients had Stage IVA disease; nine patients had Stage IVB disease. Patient compliance with therapy was poor in four of nine patients with Stage IVB disease, and the 50% survival time was 6 months. In Stage IVA disease there were 18% 3-year survivals. For those that failed, the 50% survival time was 7.5 months. Because of the frequency of disseminated metastases, effective adjuvant therapy needs to be developed to use after the tumor debulking therapy, especially for Stage IVB disease. A single early Cf-NT implant followed by 6000 cGy of whole-pelvis fractionated radiation would accomplish this adequately for local tumor control and palliation.

Seventy-five patients with bulky barrel-shaped Stage IB cervical cancers, treated at the University of Kentucky from 1965 to 1981, were the subjects of this investigation. Thirty-two of these patients were treated with radiation therapy alone and 43 were treated with radiation followed by extra-fascial hysterectomy. There were no significant differences in age, gravidity, or tumor cell type between the two treatment groups. Patients were seen at regular intervals from 2 to 11 years after treatment and none were lost to follow-up. Recurrent cancer was noted in 47% of patients treated by radiation alone as compared to 16% of those treated with combined therapy (P less than 0.01). The incidence of pelvic recurrence was reduced from 19% to 2% and extrapelvic recurrence from 16% to 7% in patients treated by combination therapy. No rectal or urinary tract fistulae were noted after extra-fascial hysterectomy. The findings of this study suggest that the use of extra-fascial hysterectomy following radiation therapy in patients with bulky Stage IB cervical cancer causes a significant reduction in tumor recurrence without producing an increase in treatment-related complications.

One hundred forty-four patients found to have cervical intraepithelial neoplasia (CIN) III on colposcopically directed biopsy who had completed childbearing were treated with a vaginal hysterectomy (112 patients) or abdominal hysterectomy (32 patients). The mean age of these patients was 28.6 years and the mean gravidity, 3.4. All patients had adequate colposcopy of the cervix and vagina. The transformation zone and lesion(s) were completely visualized. The uterus was submitted for histologic examination in all cases. The cervix was sectioned in a radial fashion (minimum 12 sections), and the proximal endocervix and lower uterine segment were sectioned transversely. CIN III was present in the cervix of 117 patients, CIN II in 9 patients, CIN I in 8 patients, and no evidence of residual neoplasia in 9 patients. Microinvasive cancer (1.3 mm stromal invasion without lymph-vascular space invasion) was present in one patient. After surgery, patients were seen every 3 months for 2 years and every 6 months thereafter. All 144 patients were followed up for at least 12 months, 124 patients for 24 months, 103 patients for 36 months, and 60 patients for 60 to 120 months. To date, all patients are alive and well and there have been no cases of recurrent vaginal neoplasia or cancer. These data suggest that: adequate colposcopy is an accurate method to rule out invasive cervical cancer and abdominal or vaginal hysterectomy is an effective therapeutic procedure in women with CIN III who have completed reproductive function.

Thirty-two patients with Stage III or IV epithelial ovarian cancer and residual tumor volumes in excess of 2 cm in diameter after initial debulking were treated with platinum and cyclophosphamide chemotherapy. Twenty-seven patients (84%) received at least six courses of chemotherapy. Six patients developed grade 3 or 4 hematologic toxicity and one patient died with granulocytopenia and sepsis. The actuarial survival of the total group of patients was 78% at 12 months, 27% at 24 months, and 11% at 36 month. Of patients with residual disease 2-4 cm in diameter, 82% were alive 12 months after diagnosis and 46% were alive at 24 months. In contrast, patients with greater than 4 cm residual disease had a 12-month survival of 73% and a 24-month survival of only 7%. The size of residual tumor after surgery remains a very important prognostic factor in patients treated with platinum-based combination chemotherapy. Reoperation with further tumor debulking should be considered in ovarian cancer patients referred for chemotherapy with large volume residual disease to maximize response to combination chemotherapy.

Antagonism to estradiol has been examined in murine uteri. When tamoxifen was administered simultaneously with estradiol (0.05 microgram/mouse), it was able to act as an antagonist over the dosage range 0.05-50 micrograms/mouse. The metabolite 4-hydroxytamoxifen (4OH-tamoxifen) had high affinity for estrogen receptors and was a slightly better antagonist over the dosage range 0.005-1 microgram/mouse. After uteri were exposed to either [3H] estradiol or [3H]4OH-tamoxifen, receptors complexed with [3H] estradiol penetrated a chromatin region, which was released as the Mg2+-soluble chromatin fraction after DNAase I treatment more readily than receptors complexed with [3H]4OH-tamoxifen. [3H]4OH-tamoxifen-receptor complexes could not be driven into the Mg2+-soluble chromatin fraction by increasing the ligand concentration during translocation. Relative to [3H]estradiol, significantly more [3H]4OH-tamoxifen was observed to associate with uterine cells and to penetrate the nucleus so that neither restricted entry nor extranuclear partitioning could explain the failure of [3H]4OH-tamoxifen-receptor complexes to enter the Mg2+-soluble chromatin. Bleomycin, an agent that interrupts DNA continuity, did not interfere with the appearance of estrogen receptor activity in the Mg2+-soluble chromatin fraction. Preincubation of intact uteri in the presence of molybdate (20 mM) did inhibit the appearance of receptor activity in this chromatin fraction; however, this effect did not occur through inhibition of receptor activation, but, rather, through the lowering of receptor activity in all chromatin fractions. In the studies reported here, the chromatin positioning of estrogen receptors complexed with estradiol appeared to be distinct from the positioning of receptors complexed with 4OH-tamoxifen. These observations suggest an additional basis from which the mechanisms separating the actions of estrogen agonists and antagonists can be approached.

A high mol wt estrogen receptor complex (mol wt: greater than 669,000) has been isolated from chromatin prepared from mouse uteri with the use of multiple protease inhibitors, exposure to DNAase I, and size exclusion HPLC (SEHPLC). This complex is stable in the presence of molybdate and 0.4 M KCl. Because receptors in the cytosol do not elute similarly to this large complex when investigated under a wide variety of conditions, it is unlikely that random receptor aggregation is responsible for the formation of this nuclear complex. Consequently, this complex may represent a collection of chromatin components that participate in the mechanisms of hormonal regulation. Since the large nuclear receptor complex can be isolated, this hypothesis can be readily subjected to extensive investigation.

Four cases of immature teratoma of the ovary are presented and the recent literature is reviewed. The majority of these tumors were confined to one ovary at the time of diagnosis, and more than 75% occurred in women under 25 years of age. The two most important prognostic parameters were stage of disease and histologic grade. Optimal survival occurred when surgical tumor debulking was followed by combination chemotherapy. The addition of hysterectomy with contralateral adnexectomy did not improve the survival of patients with disease confined to one ovary. Similarly, postoperative radiation therapy was not shown to be beneficial in patients with this disease. Analysis of presently available data suggests that patients with teratocarcinoma of the ovary should be treated with tumor excision followed by at least 12 courses of chemotherapy with vincristine, actinomycin D, and cyclophosphamide. alpha-Fetoprotein may be useful as a biochemical marker of disease status in selected patients.

The clinical and histologic features of eight cases of carcinoma of the endometrium which developed following radiation therapy for squamous cell carcinoma of the cervix are described. No patient had a well-differentiated tumor and significant myometrial invasion was present in all cases. Three of the eight tumors were papillary serous adenocarcinoma. Five of the eight patients developed recurrent tumor and died of their disease. The risk of endometrial cancer in patients previously radiated for cervical cancer is evaluated.

Using hysterectomy specimens obtained 1 month after Cf-252 neutron brachytherapy plus fractionated radiotherapy, we determined the fraction of positive and negative specimens with neutron dose for bulky Stage IB cervical cancers. The specimens obtained and studied after an initial Cf-252 insertion when the sources were newer and less decayed were more frequently negative for histological evidence of cancer than after the sources had decayed and 2 insertions were needed. After two insertions to deliver a therapeutic dose preoperatively the specimens were more frequently positive. When a larger initial dose was delivered to the tumor a larger proportion of negative specimens was noted. The size of neutron dose fraction was important to local tumor clearance and to rendering the specimens negative as well as schedule in use.

A case of poor prognosis metastatic trophoblastic disease resistant to chemotherapy with methotrexate, dactinomycin, and cyclophosphamide is presented. The patient responded promptly to etoposide-based combination chemotherapy and has remained in complete remission since completion of therapy.

After exposure to ligand at 0-4 degrees C, estrogen receptors from mouse uteri characteristically eluted between thyroglobulin (Mr 669,000) and ferritin (Mr 443,000) during size-exclusion HPLC. However, when preparations were warmed with ligand under mild activating conditions, most or all of the receptor was observed as a much larger complex, which eluted between dextran blue 2000 and thyroglobulin. Formation of the large complex required ligand, was inhibited by molybdate, and occurred even in 0.4 M KCl. Slower ligand dissociation characterized the large complex, indicating that activated receptors were included preferentially. This large complex did not form when charged cytosols were aged, concentrated, or precipitated, indicating that formation was not the result of random aggregation. After exposure to conditions commonly used for activation (25 degrees C, 60 min), most receptor existed as a very large, monodisperse complex of finite size, predicting an ordered structure for these large complexes that should be useful for defining the types of proteins which can interact with estrogen receptors. Formation of the large complex was not impeded or disrupted by EDTA, RNase, DNase I, thiourea, or mercaptoethanol; however, the capacity to form this large complex was not demonstrated by preparations that had been exposed to trypsin or by the small receptor forms obtained after salt extraction. Proteolytic sensitivity and lack of sensitivity to RNase or DNase indicate that interactions between receptors and other proteins are involved in peak A formation.(ABSTRACT TRUNCATED AT 250 WORDS)

From November 1973 to May 1986, 50 patients with Stage I epithelial ovarian cancer were treated at the University of Kentucky Medical Center (Lexington, KY) with oral Alkeran (melphalan) chemotherapy after primary surgery. Twenty-two patients had Grade 1 tumors, 23 patients had Grade 2 tumors, and five patients had Grade 3 tumors. Patients with ovarian tumors of borderline malignancy were excluded from this study. Twenty-eight patients received from six to 11 courses of chemotherapy and 22 patients completed 12 courses of chemotherapy. Chemotherapy was well tolerated and no patient died of chemotherapy-related complications. Thirty-eight patients underwent second-look laparotomy died of disease 41 months after diagnosis and one patient died with no evidence of disease 6 months after treatment. The actuarial survival of the total group of patients was 98% at 2 years and 94% at 5 years. Fewer than 12 months of chemotherapy may be necessary to obtain long-term survival in these patients.