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Background Sexual dimorphisms in immune responses contribute to coronavirus disease 2019 (COVID-19) outcomes, but the mechanisms governing this disparity remain incompletely understood. Methods We carried out sex-balanced sampling of peripheral blood mononuclear cells from hospitalized and non-hospitalized individuals with confirmed COVID-19, uninfected close contacts, and healthy control individuals for 36-color flow cytometry and single-cell RNA sequencing. Findings Our results revealed a pronounced reduction of circulating mucosal-associated invariant T (MAIT) cells in infected females. Integration of published COVID-19 airway tissue datasets suggests that this reduction represented a major wave of MAIT cell extravasation during early infection in females. Moreover, MAIT cells from females possessed an immunologically active gene signature, whereas cells from males were pro-apoptotic. Conclusions Our findings uncover a female-specific protective MAIT cell profile, potentially shedding light on reduced COVID-19 susceptibility in females. Funding This work was supported by NIH/NIAID (U01AI066569 and UM1AI104681), the Defense Advanced Projects Agency (DARPA; N66001-09-C-2082 and HR0011-17-2-0069), the Veterans Affairs Health System, and Virology Quality Assurance (VQA; 75N93019C00015). The content is solely the responsibility of the authors and does not necessarily represent the official view of the National Institutes of Health. COVID-19 samples were processed under Biosafety level 2 (BSL-2) with aerosol management enhancement or BSL-3 in the Duke Regional Biocontainment Laboratory, which received partial support for construction from NIH/NIAID (UC6AI058607)., Graphical abstract, Context and significance Why are women twice as less likely than men to experience severe COVID-19? Answering this question may help us more completely understand the immune defenses that counter SARS-CoV-2. This study from researchers at Duke University suggests that a type of white blood cells, mucosal-associated invariant T (MAIT) cells, is superior in women with COVID-19. The potential importance of the finding is that these highly specialized white blood cells have been shown to contribute critically to immune defenses in other viral and bacterial infections. These findings may shed light on the underlying reasons for reduced COVID-19 susceptibility in women and highlights the potential role of MAIT cells in countering SARS-CoV-2., Responses in COVID-19 patients are distinct across sexes. Yu et al. show that, compared with male patients, female COVID-19 patients exhibit evidence of a major recruitment wave of circulating mucosal-associated invariant T (MAIT) cells into the airways and demonstrate that these cells display an immunologically active phenotype.

Infection of respiratory mucosa with viral pathogens triggers complex immunologic events in the affected host. We sought to characterize this response through proteomic analysis of nasopharyngeal lavage in human subjects experimentally challenged with influenza A/H3N2 or human rhinovirus, and to develop targeted assays measuring peptides involved in this host response allowing classification of acute respiratory virus infection. Unbiased proteomic discovery analysis identified 3285 peptides corresponding to 438 unique proteins, and revealed that infection with H3N2 induces significant alterations in protein expression. These include proteins involved in acute inflammatory response, innate immune response, and the complement cascade. These data provide insights into the nature of the biological response to viral infection of the upper respiratory tract, and the proteins that are dysregulated by viral infection form the basis of signature that accurately classifies the infected state. Verification of this signature using targeted mass spectrometry in independent cohorts of subjects challenged with influenza or rhinovirus demonstrates that it performs with high accuracy (0.8623 AUROC, 75% TPR, 97.46% TNR). With further development as a clinical diagnostic, this signature may have utility in rapid screening for emerging infections, avoidance of inappropriate antibacterial therapy, and more rapid implementation of appropriate therapeutic and public health strategies.

In this paper, we describe a surface-enhanced Raman scattering (SERS)-based detection approach, referred to as “molecular sentinel” (MS) plasmonic nanoprobes, to detect an RNA target related to viral infection. The MS method is essentially a label-free technique incorporating the SERS effect modulation scheme associated with silver nanoparticles and Raman dye-labeled DNA hairpin probes. Hybridization with target sequences opens the hairpin and spatially separates the Raman label from the silver surface thus reducing the SERS signal of the label. Herein, we have developed a MS nanoprobe to detect the human radical S-adenosyl methionine domain containing 2 (RSAD2) RNA target as a model system for method demonstration. The human RSAD2 gene has recently emerged as a novel host-response biomarker for diagnosis of respiratory infections. Our results showed that the RSAD2 MS nanoprobes exhibits high specificity and can detect as low as 1 nM target sequences. With the use of a portable Raman spectrometer and total RNA samples, we have also demonstrated for the first time the potential of the MS nanoprobe technology for detection of host-response RNA biomarkers for infectious disease diagnostics.

Objective. To determine the outcomes of patients with intermediate-risk Stages IC and II uterine corpus cancer treated with surgery alone or surgery followed by radiation therapy. Methods. Patients with uterine corpus cancer diagnosed in 1995 were identified from hospitals in the United States with tumor registry databases. Data were collected on histology, surgical treatment, radiation therapy, recurrence, and survival. Survival analysis was performed using life-table computational method. Results. 713 hospitals submitted data on 10,726 patients with uterine corpus cancer. 9977 patients (93.0%) underwent surgery, and 2624 patients (26.3%) received radiation therapy. Patients with clinical Stages IC and IIA disease who underwent surgery followed by radiation therapy compared to surgery alone had a trend toward improved 5-year relative survival (RS) (81.2% vs. 92.5%; 74.3% vs. 96.0%, respectively). The 5-year RS of patients with surgical Stage IC disease was not statistically different between the surgery alone group and the radiation group (93.9% vs. 91.7%). Patients with surgical Stage IIA and IIB disease did not benefit from radiation therapy compared to surgery alone (5-year RS; 83.7% vs. 98.0% and 82.3% vs. 81.8%, respectively). Conclusion. There is a trend toward improved survival in patients with clinical Stages IC and IIA uterine corpus cancer when radiation therapy is utilized following surgery. The survival of patients with surgical Stages IC and II uterine corpus cancer is not improved with adjuvant radiation therapy.

Background. Conservative treatment with progestins is a reasonable treatment option for endometrial complex atypical hyperplasia and, in the experimental setting, for some women with grade 1 endometrial endometrioid adenocarcinoma. The risk of progression to a high-stage endometrial cancer is quite low, with only two previously reported cases in the English literature. Case. A 40-year-old woman with endometrial complex atypical hyperplasia diagnosed by dilatation and curettage was managed conservatively with progestin therapy (initially, megesterol acetate; then, a combination oral contraceptive). More than 2 years after her original diagnosis, she developed endometrial endometrioid adenocarcinoma, FIGO grade 2, with lymph node metastasis. The tumor was microsatellite instability-high due to methylation of MLH1 and loss of MLH1 protein. Conclusion. Currently, there are no good criteria for predicting which patients with complex atypical hyperplasia/grade 1 endometrioid adenocarcinoma will optimally respond to progestin therapy. There is some evidence that endometrial complex hyperplasia demonstrating loss of MLH1 protein by immunohistochemistry is strongly related to subsequent or concurrent endometrial cancer, especially tumors of higher grade and stage. In a woman with a biopsy diagnosis of endometrial hyperplasia, evaluation of MLH1 protein status by immunohistochemistry may provide useful information when medical management is being considered.

Objective. The purpose of surgical staging is to better determine prognosis and treatment. The International Federation of Gynecology and Obstetrics (FIGO) stage IIIA endometrial cancer is a heterogenous disease, and adjuvant therapy is not well-defined. The aim of this study was to survey the Society of Gynecologic Oncologists (SGO) members and fellows about their approach to the treatment of patients with stage IIIA endometrial cancer. Methods. All 850 members of the SGO were mailed surveys that asked how they would manage various case scenarios of stage IIIA endometrial cancer. Data were collected using an Internet survey database. Frequency distributions were determined, and nonparametric tests were performed. Results. Fifty-three percent of SGO members and fellows responded. For the treatment of stage IIIA disease with malignant cytology only, adjuvant therapy was recommended 46%, 62%, and 98% of the time for women with grades 1, 2, and UPSC, respectively. Sixty-six percent of respondents would not remove malignant cytology from the current staging criteria. Ninety-nine percent of respondents recommended adjuvant therapy for patients with adnexal or serosal involvement. Eighty-six percent indicated that a hysteroscopy for diagnosis would not alter their treatment recommendations. Conclusions. While most gynecologic oncologists in our survey recommend adjuvant therapy for stage IIIA endometrial carcinoma, our results showed that patients with malignant cytology only would receive different treatments than patients with adenxal or serosal involvement. Histology and grade of the tumor are predictors of therapy recommendations over malignant cytology. Most respondents agreed that patients with malignant cytology should remain in stage IIIA.

Objective We compared the efficacy and side effects of taxanes, with or without platinum, to bleomycin, etoposide, and cisplatin (BEP) in treating sex cord-stromal ovarian tumors. Methods We conducted a retrospective review of all patients with sex cord-stromal ovarian tumors seen at our institution from 1985 to 2002. Eligible patients were those who underwent pathologic confirmation, clinical evaluation, and treatment with a taxane or BEP for initial or recurrent disease. Results Of 222 patients identified, 21 received BEP for new ( n = 11) or recurrent disease ( n = 10); 44 received a taxane during 48 treatment episodes (four patients on two occasions each) for new ( n = 11) or recurrent disease ( n = 37). Newly diagnosed patients treated with BEP vs. taxanes had no significant difference in response rate (Fisher's exact test, P = 1), progression-free survival (PFS) (log-rank test, P = 0.213), or overall survival (log-rank test, P = 0.994). Among patients treated for recurrent measurable disease, the response rate was higher for BEP-treated (71%) than for taxane-treated patients (37%), but this was not statistically significant. In all patients treated for recurrent disease, there was no significant difference in failure to progress at chemotherapy completion between BEP- (70%) and taxane-treated patients (62%) or in median PFS (11.2 vs. 7.2 months). The presence of platinum in taxane-containing regimens correlated with response. Taxane-related side effects included neutropenia ( n = 6), anemia ( n = 1), thrombocytopenia ( n = 1), myelodysplasia ( n = 1), and hypersensitivity ( n = 1). BEP-related side effects included pulmonary fibrosis ( n = 3) and neutropenia ( n = 2). Conclusions Taxanes demonstrated activity against sex cord-stromal tumors of the ovary and may be less toxic than BEP. Taxane and platinum combination chemotherapy warrants further investigation in this disease.

Purpose Patients with completely resected high-risk endometrial cancer have a risk of disease recurrence even with the addition of adjuvant pelvic radiotherapy (RT). A Phase II study was completed by the Radiation Therapy Oncology Group to assess the safety and toxicity of chemotherapy when combined with pelvic RT for these patients. Methods and materials Eligibility requirements included a total abdominal hysterectomy and bilateral salpingo-oophorectomy with Grade 2 or 3 endometrial adenocarcinoma with >50% myometrial invasion, stromal invasion of the cervix, or pelvic-confined extrauterine disease. This study was designed to administer 4500 cGy in 25 fractions to the pelvis, along with cisplatin (50 mg/m2) on Days 1 and 28. Vaginal brachytherapy with a low-dose-rate applicator (1 × 20 Gy to the surface) or high-dose-rate applicator (3 × 6 Gy to the surface) was performed after external beam RT. Four courses of cisplatin (50 mg/m2) and paclitaxel (175 mg/m2) were given at 4-week intervals after RT completion. Results Forty-six patients were entered between October 1997 and April 1999. Two patients were ineligible (one with previous bladder cancer and one who had undergone surgery >8 weeks before the start of RT). Follow-up ranged from 6.9 to 48.8 months (median, 28.7 months). The disease was Stage III, II, and I in 66%, 16%, and 18% of patients, respectively. Two patients were not assessable because of incomplete treatment data. The protocol completion rate was 98% (41 of 42 assessable patients). Acute toxicity during RT/chemotherapy was Grade 1 in 27%, Grade 2 in 43%, Grade 3 in 27%, and Grade 4 in 2%. During adjuvant chemotherapy, the toxicity was Grade 1 in 7%, Grade 2 in 7%, Grade 3 in 21%, and Grade 4 in 62%. Severe toxicity was primarily hematologic. Chronic toxicity was Grade 1 in 20%, Grade 2 in 39%, Grade 3 in 16%, and Grade 4 in 2%, including 1 patient with a Grade 4 small bowel complication. At 24 months, the pelvic recurrence, regional recurrence, distant recurrence, disease-free survival, and overall survival rate was 2%, 3%, 17%, 83%, and 90%, respectively. Conclusion This treatment protocol demonstrated an excellent treatment completion rate and expected toxicity. Longer follow-up is needed to assess the outcome. To assess the efficacy of this adjuvant treatment program, a Phase III trial (Radiation Therapy Oncology Group 9905) was designed with high-risk uterine-confined disease to be randomized between pelvic RT alone and pelvic RT with chemotherapy.

Objective . To evaluate patients with vulvar cancer who experienced a recurrence after undergoing lymphatic mapping and sentinel lymph node (SLN) biopsy. Methods . We reviewed the records of 52 patients who underwent vulvectomy and lymphatic mapping with blue dye for treatment of vulvar cancer at our institution from 1993 to 1999 and identified patients who experienced recurrent disease. Results . Fourteen (27%) of 52 patients experienced a recurrence. The patients' median age was 60 years (range 35–84 years). Nine patients had squamous lesions, four patients had melanoma, and one patient had Paget's disease with stromal invasion. Four tumors were stage T1, seven were T2, and three were T3. Eight lesions were located at the midline and six were lateral. Thirteen patients underwent superficial inguinal lymphadenectomy while one patient underwent SLN biopsy only. Postoperatively, seven patients underwent no further treatment, six underwent radiation therapy, and one patient underwent chemotherapy. The median follow-up was 46 months and the median disease-free interval was 21 months. Primary recurrence was in the vulva in eight patients (57%), in the groin in three patients (21%), and distant in three patients (21%). Nine of 32 (22%) squamous lesions recurred, four (57%) of seven melanomas recurred, and the sole patient with invasive Paget's recurred. Patient weight was found to be significantly different between patients who experienced a recurrence and those who did not ( P = 0.05). At least one SLN was identified in 46 (88%) of the 52 patients. One (17%) of six patients in whom no SLN was identified experienced a recurrence, and 13 (28%) of 46 patients in whom a SLN was identified experienced a recurrence ( P = 0.5). In the 41 patients with negative SLNs and negative non-SLNs, the recurrence rate was 24%; in the six patients with positive SLNs and negative non-SLNs, the recurrence rate was 40%; and in the five patients with positive SLNs and positive non-SLNs, the recurrence rate was 40% ( P = 0.6). No patients had a negative SLN and positive non-SLN. Of the three patients who experienced a recurrence in the groin, one had a negative SLN and negative non-SLN, one had a positive SLN and positive non-SLN, and one had no SLN identified and a negative non-SLN. Conclusions . This heterogeneous group of patients who underwent lymphatic mapping with blue dye had similar patterns of recurrence to reported series of patients who did not undergo lymphatic mapping. Groin relapse following a negative SLN biopsy is of concern and suggests that long-term follow-up data are required before lymphatic mapping and SLN biopsy alone can be considered standard treatment for patients with vulvar cancer.

The objective of this study was to investigate the cause of groin recurrence in patients with vulvar cancer who had negative nodes in their superficial inguinal lymphadenectomy (SIL) specimens.The records of patients with vulvar cancer treated at M. D. Anderson Cancer Center between 1986 and 1997 were reviewed to identify patients with squamous histology, clinical and surgical stage I or II, depth of invasion greater than 1 mm, and primary treatment consisting of radical wide excision and SIL. One hundred four patients met these criteria. Among these, nine experienced recurrent disease that involved one or both of the groins. All of the original hematoxylin and eosin (HE)-stained slides were reviewed by one pathologist (AM). Then, each paraffin block containing nodal tissue was recut at 40 microm intervals to obtain five sections for HE staining and two unstained sections to be used for cytokeratin immunostaining if necessary.The median age at diagnosis and primary surgery was 65 years and the median depth of invasion was 4 mm. Seven patients underwent bilateral, and two underwent unilateral, groin dissections. The median number of lymph nodes removed per groin was seven. The median time to recurrence was 22 months. A total of 785 additional HE-stained slides were prepared and examined at 100x and 400x magnification. No micrometastases were identified, and there were no other suspicious findings. Therefore, immunohistochemical staining was not performed. At recurrence, one patient had a biopsy only, and eight had attempted surgical resection. In two patients, tumor was identified in fibroadipose tissue only; no lymph nodes were identified. Among the other six patients, the median number of lymph nodes resected at the time of the recurrence was five (range 1 to 10). At last report, six patients had died and three were alive and free of disease. Median follow-up for survivors was 63 months (range 42 to 71).These data strongly suggest that groin relapse in patients with negative nodes on SIL is caused by metastatic disease in unresected inguinal nodes. SIL as performed on the patients in this study did not eliminate all sites of nodal metastasis.

Objective The aim of this study was to determine the efficacy of cisplatin, ifosfamide, and mesna in uterine malignant mixed mullerian tumor (MMMT) and to evaluate the expression of clinically relevant molecular markers. Methods Women with advanced or recurrent MMMT were treated every 28 days with cisplatin (75 mg/m 2 ), ifosfamide (1.2 gm/m 2 ), and mesna (240 mg/m 2 ). Treatment continued until disease progression or for six courses in the case of nonmeasurable disease. Immunohistochemical analysis for estrogen receptor (ER), progesterone receptor (PR), HER-2/neu, C-kit, Abl, and PDGFR-β expression were performed. Results Sixteen patients received 1–10 cycles; 2 died of disease progression after 1 cycle; 3 stopped after 1 cycle because of toxicity. Of 6 with measurable disease, 2 had a partial response, 1 had stable disease (SD), and 3 had progression (RR 33%). Partial response durations were 6 and 9 months; SD duration was 6 months. Of 5 patients without measurable disease, 4 received 6 cycles; 1 received 4 cycles. Four died of recurrent disease and 1 was without disease 6.5 years after treatment. Thirty-six percent experienced at least one neutropenic G3 or G4 event. All experienced G1 gastrointestinal toxicity. Four required dose reductions. At 7.5 months, only 1 with measurable disease was still living. Immunohistochemical analyses revealed that 24% expressed ER or PR, 19% expressed HER-2/neu , and none expressed C-kit . However, 45% expressed Abl and 100% expressed PDGFR-β. Conclusions Although the combination of cisplatin, ifosfamide, and mesna in patients with MMMT had moderate activity, the high toxicity and short response duration in this uncommon, aggressive malignancy suggest that this regiment continues to be a disappointing treatment choice for uterine MMMT. HER-2/Neu , Abl , or PDGFR-β expression may be of value in order to investigate novel multimodality treatment strategies.

To determine the outcome of patients after radical radiotherapy (RT) for isolated vaginal recurrence of endometrial carcinoma and to determine the clinical and pathologic predictors of outcome.We reviewed the records of 91 patients treated at our institution between 1960 and 1997 with radical RT for vaginal recurrence after definitive surgery for endometrial carcinoma. Thirty-one percent of the patients received external beam RT (EBRT) alone, 12% received brachytherapy alone, and 57% received a combination. The median dose of radiation was 75 Gy (range 34-122). All end points were measured from the time of the first recurrence. The median duration of follow-up after recurrence was 58 months (range 1-289).The 2- and 5-year local control (LC) rate and overall survival rate was 82% and 75% and 69% and 43%, respectively. The median time from initial diagnosis of endometrial cancer to death from disease was 38 months. On univariate analysis, a dose to the relapse site ofor =80 Gy and EBRT plus brachytherapy vs. single-modality therapy were significant predictors of improved LC. On multivariate analysis, only the type of treatment correlated significantly with LC (p = 0.03). On univariate analysis, Grade 1 or 2 vs. Grade 3 tumor and EBRT plus brachytherapy vs. single-modality therapy were significant predictors of improved overall survival.RT provides excellent LC of isolated vaginal recurrences of endometrial carcinoma, particularly when high doses are given using a combination of EBRT and brachytherapy. However, distant metastases frequently develop despite local disease control, contributing to a 5-year overall survival rate of50%. For patients who have an isolated vaginal recurrence, the time from initial diagnosis of endometrial cancer to death from disease is usually3 years. For this reason, in studies of adjuvant RT, long-term follow-up is required to permit evaluation of the impact of treatment on survival.

This is a report of 52 patients with vulvar cancer who were injected with isosulfan blue dye at the time of their primary surgical treatment. The intent was to identify the sentinel nodes, which are the first nodes to receive metastases from the primary tumor, All patients who had their primary surgical treatment for vulvar cancer at the authors' institutions between 1993 and 1999 were included in the study (N = 52; median age = 58 years, range = 18-92). After preparation for surgery and before the skin incision was made, 1 to 4 ml of isosulfan blue dye were injected into the dermis at the edge of the tumor closest to the groin. Bilateral injections were made when the tumor was located with 2 cm of the midline, Injection sites were massaged for 5 minutes, a deep groin incision was made, and the afferent lymphatic channel was identified. This channel was followed until one or more blue nodes were found. These sentinel nodes were excised and sent for gross histological examination. If the findings were suspicious, a frozen section analysis was done. All nonsentinel nodes were excised and examined separately. The blue dye disappeared within 45 minutes of injection. In 22 of the 52 patients (42%), tumor was diagnosed in the labium. Fourteen patients (27%) had disease in the clitoris. Other tumor sites included the perineum, fourchette, and Bartholin's gland. Squamous cell (67%) and adenocarcinoma (17%) were the most frequent tumor types. Melanoma and Paget's disease were also diagnosed (13 and 2%, respectively). Most patients (81%) underwent superficial inguinal lymphadenectomy. The others had inguinal femoral lymphadenectomy (12%) or sentinel lymph node biopsy (8%). Unilateral groin dissection was performed in the 25 women with lateral tumors and in 3 of the 27 women with a midline tumor. The other 24 patients had bilateral dissection. The blue dye was well tolerated by all patients. Forty-six patients (88%) had at least one sentinel node diagnosed. In all, 76 groin dissections were performed, and the sentinel node was identified in 57 of the dissected groins (75%). When incisional or excisional biopsy preceded the node mapping, the sentinel node could not be identified in 44% of the groin dissections. When only a punch biopsy was performed, the percentage of patients in whom no sentinel node was found was significantly lower (16%, P =.007). The tumor location also had a significant effect on the identification of sentinel nodes. Successful identification was made in 22 of the 25 of women with lateral tumors (88%) and 35 of the 51 women with midline tumors (65%) (P =.067). Sentinel nodes were less likely to be identified in the early years of the study (P =.034). In all, 556 nodes were removed from the 52 women (median = 7 per groin). A total of 83 sentinel nodes were identified (median = 1 in each groin, range = 1-4). Tumor metastases were found in the lymph nodes of 11 patients, 10 with involvement on one side and 1 with a midline tumor. No sentinel node was found in 2 of the 12 groins with metastases, both in patients enrolled during the first 2 years of the study. No false-positive nodes were seen. Since 1995, a successful sentinel node identification has been made in 100% of the patients with T 1 or T 2 primary vulvar squamous cell cancer who had clinically nonsuspicious nodes.

Objective. The aim of this study was to determine the effectiveness and toxicity of monthly treatment with intravenous paclitaxel for women with advanced or recurrent uterine papillary serous carcinoma (UPSC). Methods. Consenting women with histologically confirmed advanced (FIGO stage III or IV) or recurrent UPSC were treated on an Institutional Review Board approved protocol of a 24-h intravenous infusion of 200 mg/m 2 of paclitaxel every 3 weeks. Both measurable and nonmeasurable disease cases were enrolled. Treatment was continued until disease progression, patient intolerance, or (in women with nonmeasurable disease) completion of six courses. Results. Twenty patients received from 1 to 11 cycles of therapy. Two women died of disease after 1 cycle of therapy and were not evaluable for response. Among 13 women with measurable tumor receiving 2 or more cycles of therapy, 4 had a complete clinical response and 6 had a partial response (objective response rate, 77%). The median time to progression was 7.3 months (range, 2–21 months). All 3 remaining patients with measurable disease had stable disease for a median of 6 months. The 5 patients without evaluable disease received 5 to 6 cycles of adjuvant paclitaxel. Three developed recurrence (range, 4–10 months; median, 7.2 months). Neutropenia was the major toxicity. Eleven of the 20 patients required G-CSF support, and 9 were hospitalized for neutropenic fever. One woman had reversible cardiac symptoms, which might have been related to paclitaxel treatment. At the time of analysis (mean follow-up, 23 months; range, 4.3–59.9 months), 13 women had died of disease, 4 were alive with disease, and 2 were disease free. All 3 disease-free patients had been treated for nonmeasurable advanced stage disease. Conclusion. Paclitaxel appears to have excellent activity in the treatment of advanced or recurrent UPSC, an uncommon but aggressive malignancy. Longer survival appears to be more common among women with small-volume disease.

The minichromosome maintenance (MCM) proteins, together with the origin recognition complex (ORC) proteins and Cdc6, play an essential role in eukaryotic DNA replication through the formation of a pre-replication complex at origins of replication. We used a yeast two-hybrid screen to identify MCM2-interacting proteins. One of the proteins we identified is identical to the ORC1-interacting protein termed HBO1. HBO1 belongs to the MYST family, characterized by a highly conserved C2HC zinc finger and a putative histone acetyltransferase domain. Biochemical studies confirmed the interaction between MCM2 and HBO1 in vitro and in vivo. An N-terminal domain of MCM2 is necessary for binding to HBO1, and a C2HC zinc finger of HBO1 is essential for binding to MCM2. A reverse yeast two-hybrid selection was performed to isolate an allele of MCM2 that is defective for interaction with HBO1; this allele was then used to isolate a suppressor mutant of HBO1 that restores the interaction with the mutant MCM2. This suppressor mutation was located in the HBO1 zinc finger. Taken together, these findings strongly suggest that the interaction between MCM2 and HBO1 is direct and mediated by the C2HC zinc finger of HBO1. The biochemical and genetic interactions of MYST family protein HBO1 with two components of the replication apparatus, MCM2 and ORC1, suggest that HBO1-associated HAT activity may play a direct role in the process of DNA replication.

Objectives. To evaluate the efficacy of radiation therapy and potential prognostic factors in patients treated for pelvic recurrence of cervical carcinoma after radical hysterectomy. Materials. The records of 50 patients treated between 1964 and 1994 for an isolated pelvic recurrence of cervical carcinoma a median of 10.5 months after initial radical hysterectomy were retrospectively reviewed. Patients were categorized according to the extent of disease on clinical examination as group 1, mucosal involvement only (5); group 2, paravaginal extension (11); group 3, central recurrence with pelvic wall extension (13); and group 4, recurrences limited to the pelvic sidewall (21). Seven patients with group 3 or 4 disease who had a poor performance status were treated with palliative intent using hypofractionated radiotherapy. The remaining 43 patients were treated with curative intent, 33 with radiotherapy only and 10 with a combination of cisplatin-based chemotherapy and radiotherapy. Survival rates were calculated from the date of initial recurrence. Median follow-up of surviving patients was 109 months. Results. The overall 5-year survival rate was 33% for all 50 patients (median survival, 18 months), 39% for the 43 patients treated with curative intent, and 25% for patients with isolated sidewall recurrences treated with curative intent. The survival rate was 69% for patients with group 1 and 2 disease and 18% for those treated with curative intent for group 3 disease ( P = 0.07). The survival rate was better for patients with recurrent squamous carcinomas (51%) than for those with adenocarcinomas (14%) ( P = 0.05). Three group 4 patients who survived more than 5 years were treated with external-beam radiation alone. Eight-one percent of patients who had a second recurrence had evidence of disease progression. Three patients experienced late treatment complications. Conclusions. Patients who experience an isolated recurrence of cervical cancer after initial radical hysterectomy have an excellent prognosis if disease does not involve the pelvic wall. Occasional long-term survivors of recurrent disease involving the pelvic wall justify an aggressive treatment approach.

Purpose: To evaluate the role of surgical debulking in patients with stage IV ovarian cancer. Methods: We conducted a retrospective review of patients with advanced epithelial ovarian cancer treated at M. D. Anderson Cancer Center. Eligible patients included women with stage IV disease treated with platinum-based chemotherapy. Surgical debulking was considered optimal if the diameter of the largest residual tumor was 2 cm or less. Survival analysis and comparisons were performed using the Kaplan–Meier method and the log-rank test. Results: One hundred eight women with stage IV ovarian cancer were identified. The extraperitoneal metastatic sites were the liver parenchyma in 16 patients, the pleura in 54 patients, a variety of other organs in 22, and two or more sites in the remaining 16. Median age of the patient population was 58 years (range 35–81 years). Surgery to reduce the primary tumor was performed in 100 patients. The procedures included salpingo-oophorectomy with or without hysterectomy in 94 patients, omentectomy in 90, small bowel resection in 4, large bowel resection in 23, and splenectomy in 2. At the completion of surgery, tumor reduction was considered optimal in 31 patients, suboptimal in 61, and undetermined in 8. The overall median survival for optimally debulked patients was 25 months compared to 15 months for suboptimally debulked patients (P< 0.02). The progression-free survival, on the other hand, was not statistically different between the two groups. Conclusion: Residual tumor seems to be an important prognostic factor in patients with stage IV ovarian cancer. Surgical debulking may play a significant role in the treatment of these patients.

Objective: To describe and analyze the outcome of urinary conduits utilizing the transverse colon over an 11-year period. Materials and Methods: All patients undergoing a urinary conduit on the gynecologic oncology service from 1983 to 1993 were identified and a retrospective review was conducted. Results: Transverse colon urinary conduits (TCC) were performed in 86 patients. The majority of patients had a history of cervical cancer (81%), and all but one patient had prior pelvic radiotherapy. TCC was performed in conjunction with pelvic exenteration in 47 patients (55%) and alone as palliation for the effects of progressive malignancy in 10 patients (12%). Other indications for conduit construction included urinary fistulas (19%), ureteral or urethral obstruction (7%), conduit revision (5%), overflow incontinence (2%), or intraoperative ureteral injury (1%). Abnormal preoperative renal morphology was common (48%). A total of 165 ureterocolic anastomoses were performed. Ureteral stents and intestinal staplers were used routinely. The perioperative mortality rate was 3%. Loss of renal function occurred in 10 of 165 renal units (6%). Nineteen (22%) patients had partial ureteral obstruction managed by percutaneous nephrostomy or indwelling stents. Conduit reconstruction was undertaken in 7 patients (8%). Renal calculi were noted in 3 patients. Overall median survival was 30 months. Conclusion: The complications of TCC are similar to those experienced in other urinary diversions. No distinct advantage to using the transverse colon was observed. Management of progressive ureteral obstruction by conservative methods, such as percutaneous nephrostomy or ureteral stents, was frequent and provided a reasonable alternative to reoperation in the poor operative candidate.

Objective: To determine the feasibility of intraperitoneal lymphatic mapping of the uterine fundus as a means of identifying target sites for lymph node biopsy during staging laparotomy and to develop preliminary experience with the technique. Methods: Fifteen women with high-risk endometrial tumors were entered on this Institutional Review Board-approved pilot study. At laparotomy, isosulfan blue dye (1.0 ml) was injected into the subserosal myometrium at three sites: the superior midpoint of the fundus, 2 cm inferiorly on the anterior wall, and 2 cm inferiorly on the posterior wall. Dye uptake into lymphatic channels was observed for 10 min. The retroperitoneal spaces were opened. Blue lymphatic channels and nodes within the pelvic and paraaortic regions were identified. Nodes demonstrating dye uptake were biopsied as separate specimens: the locations of these nodes were carefully recorded. Hysterectomy and selective lymphadenectomy were then performed as usual. Results: Lymphatic channels coursing into the broad ligament and along the ovarian vessels were identified from all uteri injected. Deposition of dye into grossly identifiable lymph nodes was seen in 10 of 15 cases (67%). A total of 31 nodes demonstrated dye uptake. The locations of these nodes included paraaortic sites in 12, common iliac in 6, and pelvic in 13. No dye-containing paraaortic nodes were seen below the origin of the inferior mesenteric artery. Lymphatic channels coursing above the renal vessels were seen routinely. Microscopic nodal metastases to sentinel nodes were identified in 2 of 4 women with proven lymphatic spread. Conclusions: Lymphatic mapping of the uterine fundus is feasible and can identify targets for selective nodal biopsy in some women. Preliminary observations confirm that the lymphatic network draining the uterus is complex and involves both pelvic and paraaortic nodes. Lymphatic channels that parallel the ovarian vessels were not observed to enter nodes until reaching the level of the midabdomen. Further experience and refinement of techniques may lead to the development of a selective lymphadenectomy based upon direct visualization of the lymphatic drainage of the uterus rather than the current random sampling.

Objective: To survey the surgical practice of gynecologic oncologists regarding the extent of groin dissection for early vulvar cancer. Methods: A 14-item questionnaire was developed and presented to the Annual Meeting of the Felix Rutledge Society. Gynecologic oncologists were asked to describe in descriptive, categorical, and visual terms the groin procedure that they perform as part of management of early vulvar cancers. Three ink-line drawings were created by a medical illustrator for the purpose. Fifty returned surveys were evaluable. Results: The most commonly performed procedures were removal of the lymph nodes above the cribriform fascia and those medial to the femoral vein (40%), removal of lymph nodes above the cribriform fascia (34%), and removal of all nodes above and below the cribriform fascia (22%). Respondents performing the first procedure termed it "superficial inguinal lymphadenectomy" (40%), "inguinal femoral lymphadenectomy" (25%), and a variety of other names (35%). Respondents performing the second two procedures were much more consistent in the figure and name that they matched with their description of the nodes removed. When respondents were asked to match the figures with categorical definitions based on their understanding of the literature, the figure depicting Scarpa's triangle following removal of the superficial inguinal and medial femoral nodes was named superficial inguinal lymphadenectomy by 24% despite the fact that the femoral vein was clearly visible and labeled. Conclusions: We conclude that (1) among this group of gynecologic oncologists superficial inguinal and medial femoral lymphadenectomy is the most commonly performed procedure for women with early vulvar cancer and that the procedure is frequently called superficial inguinal lymphadenectomy; (2) publications and protocols on this topic must provide complete descriptions of procedures performed, and investigators must assure that individual surgeons are performing the same procedure; and (3) treatment results with superficial inguinal and medial femoral lymphadenectomy are poorly described and a fertile area for further study.

Objective: We describe early results of and potentially important anatomic findings with intraoperative lymphatic mapping in patients with vulvar cancer. Methods: Isosulfan blue was injected into the dermis at the leading edge of the vulvar lesion in 21 patients. One to five minutes later a standard groin incision was made and carried to the superficial fascia. After gentle dissection, the afferent lymphatic channel and/or sentinel lymph node was identified by its bright blue color. The sentinel node was removed and then the superficial inguinal lymphadenectomy was completed. Results: The 21 patients, ranging in age from 23 to 85 years (median, 52 years), underwent intraoperative lymphatic mapping. The clinical stages were as follows: T1in 9, T2in 10, T3in 1, and unknown in 1 patient with a prior wide local excision. Two patients had palpably suspicious nodes. Ten patients had lateral lesions, and 11 had midline tumors. Eight of the 11 patients had bilateral groin dissections, making a total of 29 groins dissected. The sentinel node was identified in 18 patients (86%) and in 19 groins (66%). Five patients had unilateral node metastases, and one patient had bilateral node metastases. A sentinel node was found in five of these seven groins. A total of 238 nodes were removed (median, 8.2 nodes per groin). In no case was a nonsentinel node positive if the sentinel node was negative. In one patient the only metastasis was microscopic tumor in the sentinel lymph node. In one case, the sentinel node was found below the cribriform fascia. The sentinel node could not be identified in either groin in one patient with a clitoral primary; however, dye was seen in lymphatic channels passing under the symphysis pubis. The sentinel node was identified in various sites within the superficial compartment including lateral to the femoral artery and at the extreme medial border of the dissection. No complication related to the injection of isosulfan blue was seen. Conclusion: Intraoperative lymphatic mapping is safe and simple to perform and may help identify the sentinel node, define the extent of superficial inguinal lymphadenectomy, and identify uncommon anatomic variations.

Twelve patients ages 37-85 years (mean, 59 years) with locoregionally advanced vulvar carcinoma were treated with a combination of irradiation and chemotherapy using prolonged continuous infusions of 5-fluorouracil (5-FU) and cisplatin. Eleven patients had advanced vulvar disease with tumors 5-18 cm in maximum diameter (mean, 8.7 cm), eight had palpable inguinal nodes with biopsy-proven metastatic carcinoma, and five had fixed nodes. Patients received weekly 96-hr infusions of cisplatin (4 mg/m2/day) and 5-FU (250 mg/m2/day) for a total of 64 mg/m2 of cisplatin and 4 g/m2 of 5-FU in 4 weeks. Concurrent radiation therapy was delivered to the lower pelvis, vulva, and inguinal nodes to a total dose of 40-50 Gy at 2 Gy per fraction in 11 patients. One patient who had been previously treated for cervical cancer received radiation only to the vulva with an appositional electron beam field. Chemoradiation was well tolerated with virtually no hematologic toxicity and no unscheduled breaks in treatment. Eleven of 12 patients had at least a partial clinical response; one patient had a minimal response of unresectable vulvar disease. Of eight patients who underwent vulvar resection 6 weeks after chemoradiation, four had no residual disease in the resected vulvar specimen and remain disease-free 17, 20, 25, and 37 months, respectively, after surgery. Another patient is disease-free 28 months after a complete clinical response without vulvar resection. However, of four patients who had residual disease in the vulvar surgical specimen, disease has recurred within the irradiation field in three. Overall, 6 of 12 patients treated with this chemoradiation regimen remain disease-free 17-30 months after treatment. This is a well-tolerated outpatient regimen that yields a high response rate in patients with massive vulvar carcinomas.

Twenty-one patients who underwent pelvic exenteration for primary ( n = 8) or recurrent ( n = 13) vulvar malignancy at the M. D. Anderson Cancer Center between 1956 and 1989 were evaluated. A posterior exenteration was performed in 12 patients, anterior exenteration was performed in 6, and total exenteration was performed in 3. In patients with primary tumors, radical vulvectomy and inguinal lymphadenectomy were also performed. The median patient age was 57 years. The mean tumor diameters were 5 cm (primary) and 4 cm (recurrent). Infections were the most frequent postoperative complications ( n = 15), followed by pulmonary ( n = 4) and cardiac problems ( n = 3). There were no treatment-related deaths. Five patients required further surgery to correct late postoperative sequelae. Four of eight patients experienced recurrence after treatment of their primary tumor; the recurrences were local only ( n = 1), in the inguinal area ( n = 2), or local and in the pelvis ( n = 1). Nine of the 13 patients treated for recurrent tumors developed a second recurrence; the second recurrences were all within the pelvis, although two also had a distant component. The 5-year survival rates were 70% for patients treated for primary disease and 38% for patients treated for recurrent disease, Pelvic exenteration is indicated for selected patients with advanced vulvar malignancy.

Uterine papillary serous adenocarcinoma (UPSC) is one of the most aggressive endometrial tumors. UPSC has been associated with an increased propensity for extrauterine spread. Survival rates of not more than 50% are commonly reported even for tumors which appear to be confined to the uterus. Small areas of UPSC can be found in otherwise well-differentiated endometrial lesions and yet still determine the overall prognosis. In the present study we evaluated histologic criteria that might be helpful in diagnosing small-volume UPSC, including silver-stained nucleolar organizer regions (AgNOR) which have prognostic importance in a variety of tumors, and nuclear size which has been used for prognostication in endometrial cancer. We examined 25 UPSC specimens and compared them to grade III (GIII, n = 10) and grade I (GI, n = 10) typical endometrial adenocarcinoma using the following parameters: mean AgNOR count per cell was UPSC 6, GIII 6.0, and GI 4.3; mean AgNOR area was UPSC 1.28 microns2, GIII 1.35 microns2, and GI 0.86 microns2; total AgNOR area per cell was UPSC 7.5 microns2, GIII 8.13 microns2, GI 4.47 microns2; and nuclear size was UPSC 66.9 microns2, GIII 60.3 microns2, GI 34.8 microns2. All differences between UPSC or GIII tumors and GI lesions were statistically significant. Overexpression of p53, as determined histochemically, was seen in 64% of the UPSC specimens. UPSC is characterized by high AgNOR count and area per cell, large nuclear size, and a high rate of p53 overexpression. Evaluation of these parameters in biopsy material may aid in selecting high-risk patients for adjuvant therapy trials.

To investigate the structure and regulation of the genes encoding components of the basal RNA polymerase II transcriptional machinery, the Drosophila melanogaster genes encoding transcription factor IIB (TFIIB) and the TATA-box-binding protein (TBP) were isolated and characterized. In the TBP gene, a single intron bisects the sequences that encode the two repeated DNA-binding domains of TBP, which supports the notion that TBP evolved from an earlier form that possessed only a single domain. The transcription start points (tsp) were determined, and there was a good correlation between the tsp that were used in vivo and transcription reactions in vitro. The TFIIB and TBP genes have several similar features, which include high A+T content (68 to 74%) upstream from the tsp, multiple copies of an ATTATTATT sequence motif in the proximal promoter region, the absence of a consensus TATA-box element, and small introns (55 to 64 nucleotides). These genes should be useful in the combined genetic and biochemical analysis of TFIIB and TBP in D. melanogaster.

Our purpose was to study the incidence, severity, timing, clinical management, and outcome for patients who developed hemorrhagic cystitis following pelvic radiotherapy for stage Ib cancer of the cervix. A total of 1784 patients with stage Ib cancer of the cervix were treated with pelvic radiotherapy at the University of Texas M. D. Anderson Cancer Center between 1960 and 1989. The majority received a combination of external-beam and intracavitary treatments. Patients with hemorrhagic cystitis were identified through retrospective review of their medical records, and a grade was assigned to each occurrence. A total of 116 (6.5%) patients with hemorrhagic cystitis were identified. The initial occurrence was grade 1 (minor occurrence) in 59%, grade 2 (repeated minor bleeding) in 23%, and grade 3 (hospitalization for medical management) in 18%. The median interval from the beginning of radiotherapy to the onset of hematuria was 35.5 months (mean 58 months). The median time to initial grade 3 occurrences was 37.5 months (mean 84 months). Actuarial life table analysis revealed that the risk of hematuria is 5.8% at 5 years, 7.4% at 10 years, and 9.6% at 20 years. The risk for a grade 3, 4 (requiring surgical intervention), or 5 (death) complication is 1.0, 1.4 and 2.3% at 5, 10, and 20 years, respectively. Approximately one-third of the patients with a grade 3 occurrence were rehospitalized for management of bladder complications a median of 3.5 months following the first grade 3 occurrence, although some of these readmissions occurred many years later. Associated urinary-tract infection was common. In no case did a cystoscopic bladder biopsy reveal recurrent tumor or a second primary tumor when visual inspection revealed typical radiation changes. The incidence of severe hemorrhagic cystitis following radiation for stage Ib cancer of the cervix is low and can occur many years following treatment. Minor episodes of hematuria are managed by empiric antibiotic therapy until the results of urine cultures are available. Cystoscopy is reserved for patients with persistent bleeding to rule out clot retention or the slight possibility of a second primary tumor or recurrent disease. Biopsy should be avoided if obvious radiation changes are present. Clot evacuation and continuous bladder irrigation remain the standard treatment for patients with heavy bleeding.

This study was undertaken to determine whether secondary surgical debulking is beneficial for patients with malignant ovarian germ cell tumors (OGCT). Twenty patients with OGCT treated at our institution between 1975 and 1992 were retrospectively identified and analyzed. Survival was analyzed using the life-table methods of Kaplan and Meier and the statistical significance of various perioperative factors was tested by both the log-rank and the Wilcoxon tests. Histologic tumor type included 8 immature teratomas, 6 mixed tumors, 5 endodermal sinus tumors, and 1 dysgerminoma. After primary surgery, all patients received chemotherapy--non-platinum-based in 12 patients, platinum-based in 5, and both types in 3 patients. Treatment failure was classified as progression in 14 patients, persistence in 3, and recurrence in 3. Salvage surgery consisted of exploratory laparotomy and tumor debulking in 18 patients, inguinal lymphadenectomy in 1, and thoracotomy and wedge resection in 1. Sixteen patients subsequently received salvage chemotherapy. At the time of analysis, 11 patients were alive disease-free, 1 was alive with tumor, 6 had died of tumor progression, and 2 had died of treatment-related complications. Survival of patients with immature teratoma who underwent salvage surgery was significantly better than survival of those with other tumor cell types (P = 0.006). In conclusion, although the role of secondary debulking in chemorefractory OGCT remains undetermined, it may have some benefit for a select group of patients, particularly those with immature teratoma.

Between March 1990 and July 1992, 42 women with squamous carcinoma of the uterine cervix were prospectively treated with carboplatin (260 mg/m 2 ) on Day 1 and cisplatin (50 mg/m 2 ) on Day 2 every 28 days. Patients had either stage IVb (FIGO) cancer (5 patients) or recurrent cancer (37 patients) and a Zubrod score ⩽2. Forty-one patients had received either radiation or surgery as primary therapy; 179 cycles of chemotherapy were delivered. The mean number of cycles administered to each patient was 4 (range, 2-8 cycles). Dose escalation was possible in 32 cycles (23.4%) and dose reduction was required in 10 cycles (7.3%). The dose-limiting toxic effect was myelosuppression, with grade 3-4 thrombocytopenia in 39 cycles (22%) and neutropenia in 19 cycles (11%). Neurotoxic effects were observed in 3 patients. Forty-two patients were evaluable for response: 1 had a complete response and 11 had a partial response (response rate 28.6%, 95% confidence interval, 14.9-42.3%). For all patients and for responders, median progression-free interval was 4.4 and 9.5 months, respectively, and median length of survival was 8.9 and 9.5 months, respectively. This regimen was well tolerated and had significant activity in the treatment of cervical cancer. Comparison to other platinum-based regimens in a Phase III trial should be considered.

SUMMARY Secondary cytoreduction to optimal levels can be successfully accomplished in a substantial number of ovarian cancer patients and in a variety of clinical settings. Although frequently complex, secondary operations can be performed with acceptable morbidity. All operations should be undertaken by experienced oncologic surgeons. Prospective randomized clinical trials to evaluate the survival benefits of secondary cytoreduction will probably never be conducted. Consequently, estimates of survival benefit must be derived from the evaluation of outcome in clinically homogeneous subsets. There is good evidence that a survival advantage can be obtained in patients whose gross disease is completely resected at second-look laparotomy and in patients whose disease recurs after a complete response to primary cytoreduction and cisplatin-based chemotherapy. Patients who fail to respond to primary treatment are probably not appropriate candidates for a secondary resection. Because most patients are left with at least microscopic residual disease, the lack of effective second-line chemotherapy limits the survival impact of secondary cytoreduction.

The long-term survival of women with stage I cervical cancers is excellent. Microinvasive tumors can be acceptably treated with low morbidity by simple extrafascial hysterectomy. Tumors beyond the microscopic stage require more aggressive therapy with either radical hysterectomy or radiotherapy. Within stage I, tumor volume is the major predictor of complete response and cure. Most often, this is estimated by the clinical measurement of cervical diameter. Lymph node spread is also correlated with risk of treatment failure and death from disease. Patients with tumor diameters of 4 cm or less can usually be offered either therapy option. Although different complications are associated with each modality, the overall incidence of severe problems is small for both. We favor radical hysterectomy for premenopausal women who wish to retain natural hormonal function and who have no major contraindications to surgery. Postmenopausal patients, those with larger tumors, and, perhaps, those with high-grade tumors may be better treated by irradiation. Women with very large tumors and those with lymph node metastases represent significant treatment challenges and should be considered for experimental protocols.

Preparation for pelvic exenteration is a traumatic experience for every patient, especially so when the procedure has to be aborted because of advanced disease. This occurred in 111 of 394 patients who underwent exploration for possible pelvic exenteration for recurrent cervical cancer at the University of Texas M. D. Anderson Cancer Center between 1970 and 1990. We reviewed these cases to better delineate preoperative factors predictive of unresectability. Distributions of initial stages and pathological diagnoses were similar to those for all cases of primary cervical cancer. The median time from primary therapy to recurrence was 12 months. The reasons for aborting the procedure included the presence of peritoneal disease in 49 patients (44%), for which the only preoperative finding with significant correlation was the presence of a pelvic mass (P = 0.03). Other reasons for aborting the procedure included nodal disease in 45 patients (40%), related to a short interval from primary therapy (P = 0.008) and the notation of fibrosis on preoperative exam (P = 0.01), parametrial fixation in 15 patients (13%), and hepatic lesions or bowel involvement in 5 patients (4.5%). Peritoneal cytology was negative in 61 of 79 patients (77.2%) and was of predictive value only in patients with adenocarcinoma. In conclusion, disseminated disease can seldom be detected during preoperative work-up. Evaluation of nodal status with computed tomography, lymphangiogram and directed fine-needle aspiration, and examination of peritoneal cytology in cases with adenocarcinoma, are the best available means of reducing the number of aborted procedures.

Background. Uterine papillary serous carcinoma is an aggressive tumor with a high propensity for distant spread. Metastases to the heart or pericardium are rare in gynecologic malignancies and usually fatal. Case. A 64-year-old African American woman was diagnosed with recurrent uterine papillary serous carcinoma metastatic to the pericardium. Her case at presentation was significant for an elevated serum CA-125, evidence of metastatic disease to the liver, and massive cardiomegaly. Cytologic analysis of fluid obtained by pericardiocentesis confirmed recurrence. Despite treatment with paclitaxel and a pleuropericardial window, the patient succumbed to her disease. Conclusion. The prognosis for patients whose recurrent uterine papillary serous carcinoma has metastasized to the heart or pericardium is extremely poor. Effective adjuvant and salvage therapies are essential.

Although uncommonly performed in this setting, splenectomy is sometimes indicated in patients with gynecologic malignancies. From January 1970 through March 1989, 45 patients at The University of Texas M.D. Anderson Cancer Center underwent splenectomy during the course of gynecologic laparotomies. All procedures were performed by the gynecology staff and trainees. Twenty-seven patients (60%) had ovarian cancer; endometrial and cervical cancers were present in three patients each. The remaining 11 patients had other diseases. Splenectomy was planned preoperatively in only 9 patients (20%). Thirteen patients (29%) underwent splenectopmy because of injury to the spleen. Injury was most commonly due to traction during omentectomy, resulting in capsular laceration. The injury was immediately recognized in 12 patients; 1 patient required reexploration for hemoperitoneum. In 24 patients (53%), splenectomy was performed for tumor reduction. Pathologic examination showed that 11 of 24 patients had capsular involvement by tumor, 7 had parenchymal metastases, and 6 had no direct splenic involvement. Residual tumor following cytoreduction was smaller than 2 cm in 62.5% of patients. Splenectomy is a well-tolerated procedure and the operative approach can be tailored to the clinical situation and distribution of tumor. An attempt should be made to repair splenic injury when tumor involvement is not present.

Between 1965 and 1985, 160 patients had initial treatment at the M. D. Anderson Cancer Center for Stage I adenocarcinoma of the uterine cervix less than or equal to 4 cm in diameter. Of these patients, 84 were treated with radiation therapy (RT) alone, 20 were treated with external and intracavitary radiation followed by total hysterectomy (R + S), and 56 were treated with radical hysterectomy (RH). Survival rate was strongly correlated with tumor volume (P = 0.0008), lymphangiogram findings (P = 0.01), and tumor grade (P = 0.0018). Patients with a normal-appearing cervix or a small visible or palpable tumor that did not expand the cervix more than 3 cm had survival and pelvic-control rates of more than 90% after treatment with RH or RT. However, after 5 years, 45% of patients treated with RH for tumors 3-4 cm in diameter had disease recurrence in the pelvis, compared with 11% of patients treated with either RT or R + S (P = 0.025). For patients treated with RH, recurrence was also strongly correlated with findings of lymph/vascular space invasion (P = 0.0004) and poorly differentiated tumor (P = 0.018). Major complication rates were comparable for the three treatment groups. The high rate of pelvic recurrence following treatment with radical hysterectomy alone for patients with tumors greater than 3 cm in diameter, particularly in the presence of lymph/vascular space invasion, poorly differentiated features, and/or positive nodes, should be considered in planning the primary management of patients with Stage I adenocarcinoma of the cervix.

From 1967 through December 1987, 145 patients with endometrioid carcinoma of the ovary were treated at the University of Texas M. D. Anderson Cancer Center. Thirty-eight patients (26.2%) had stage I disease, 28 (19.3%) stage II, 60 (41.4%) stage III, and 11 (7.6%) stage IV; 8 patients (5.5%) were unstaged. Grade 2 or 3 histology was seen in 119 patients (82.1%). In addition to surgical therapy, 128 patients underwent chemotherapy, including single-agent therapy, noncisplatin combination therapy, and cisplatin-based therapy. No statistically significant improvement in median survival was noted among these three chemotherapy groups for stages II, III, and IV (P = 0.22). A significant improvement in median survival was noted for those patients who achieved a complete clinical response, regardless of type of chemotherapy (96 or more months for single-agent therapy, P = 0.001; 31.5 months for noncisplatin combination therapy, P = 0.016; and 85 months for cisplatin-based therapy, P = 0.0001). Synchronous ovarian and uterine malignancies were seen in 18 patients (12.4%). No difference in survival was seen for patients with endometriosis (P = 0.13) or endometrial cancer (P = 0.09) when compared with those who did not have these histologic findings.

Between October 1985 and January 1989, 33 patients with stage I (31) or clinically occult stage II (2) endometrial cancer at a high risk for recurrence were entered in a prospective study evaluating adjuvant cisplatin, doxorubicin, and cyclophosphamide (PAC) chemotherapy. Eligibility criteria included grade 2 tumors with middle- or outer-third myometrial invasion (16), grade 3 tumors with any degree of myometrial invasion (17), presence of extrauterine disease with no gross residual (17), or a high-risk histologic subtype including papillary serous (4), adenosquamous (5), or clear cell (1) tumors. Patients received PAC (50/50/500 mg/m 2 ) at 4-week intervals for six cycles. Thirty patients (90%) completed therapy. Toxicity included severe neutropenia in 14 patients, neutropenic sepsis in 2 patients, and doxorubicin-related cardiomyopathy in 1 patient. There were no treatment deaths. Current median follow-up is 25 months. Nine patients (27%) have developed a recurrence, 7 of whom died, after a median interval of 14 months. Eight of the 9 with recurrence initially had extrauterine disease ( P = 0.02). The resulting 2-year actuarial progression-free and overall survival rates were 79 and 83%, respectively. The median progression-free interval was 29 months for patients with extrauterine disease and 45 + months for those with no extrauterine disease ( P = 0.02). These results suggest that a phase 3 randomized trial comparing adjuvant PAC with radiation therapy is warranted.