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Background Pathogen-based diagnostics for acute respiratory infection (ARI) have limited ability to detect etiology of illness. We previously showed that peripheral blood-based host gene expression classifiers accurately identify bacterial and viral ARI in cohorts of European and African descent. We determined classifier performance in a South Asian cohort. Methods Patients ≥15 years with fever and respiratory symptoms were enrolled in Sri Lanka. Comprehensive pathogen-based testing was performed. Peripheral blood ribonucleic acid was sequenced and previously developed signatures were applied: a pan-viral classifier (viral vs nonviral) and an ARI classifier (bacterial vs viral vs noninfectious). Results Ribonucleic acid sequencing was performed in 79 subjects: 58 viral infections (36 influenza, 22 dengue) and 21 bacterial infections (10 leptospirosis, 11 scrub typhus). The pan-viral classifier had an overall classification accuracy of 95%. The ARI classifier had an overall classification accuracy of 94%, with sensitivity and specificity of 91% and 95%, respectively, for bacterial infection. The sensitivity and specificity of C-reactive protein (>10 mg/L) and procalcitonin (>0.25 ng/mL) for bacterial infection were 100% and 34%, and 100% and 41%, respectively. Conclusions Previously derived gene expression classifiers had high predictive accuracy at distinguishing viral and bacterial infection in South Asian patients with ARI caused by typical and atypical pathogens., Host biomarkers can identify bacterial versus viral acute respiratory infection (ARI). Previously, we derived host gene expression classifiers that accurately identify bacterial versus viral ARI. Here, we show that our classifiers had high predictive accuracy in a South Asian cohort.

Tumor necrosis factor alpha (TNF-α) is produced in Langerhans cell histiocytosis (LCH) lesions and is elevated in plasma of patients with active LCH. It has been postulated that TNF-α may play a role in the pathophysiology of LCH. Etanercept, an anti-TNF-α antibody, has been used in TNF-modulated diseases such as rheumatoid arthritis (RA). We conducted a phase II study to determine the efficacy of etanercept for patients with refractory or relapsed LCH. Five LCH patients who had failed at least 2 prior treatments (range 2-9) received etanercept at a dose of 0.4 mg/kg twice weekly for up to a total of 24 doses. Disease response was assessed at 4 and 8 weeks. None of the five patients had improvement in their disease with etanercept treatment. Three progressed at week 4 and 1 progressed at week 8. One subject died after 3 weeks of treatment from disease progression. During the study, only one drug-related toxicity was noted which spontaneously resolved. The study was concluded early due to lack of response to etanercept and insufficient accrual rate. This data suggests that etanercept as given in this study may not be effective for relapsed or refractory LCH. However, the number of patients treated was not adequate enough to power this study and it is possible that a different dose and regimen of etanercept may be required to successfully treat this disease.

Background Difficulty distinguishing bacterial and viral infections contributes to excess antibiotic use. A host response strategy overcomes many limitations of pathogen-based tests, but depends on a functional immune system. This approach may therefore be limited in immunocompromised (IC) hosts. Here, we evaluated a host response test in IC subjects, which has not been extensively studied in this manner. Methods An 81-gene signature was measured using qRT-PCR in previously enrolled IC subjects (chemotherapy, solid organ transplant, immunomodulatory agents, AIDS) with confirmed bacterial infection, viral infection, or non-infectious illness (NI). A regularized logistic regression model estimated the likelihood of bacterial, viral, and noninfectious classes. Clinical adjudication was the reference standard. Results A host gene expression model trained in a cohort of 136 immunocompetent subjects (43 bacterial, 41 viral, and 52 NI) had an overall accuracy of 84.6% for the diagnosis of bacterial vs. non-bacterial infection and 80.8% for viral vs. non-viral infection. The model was validated in an independent cohort of 134 IC subjects (64 bacterial, 28 viral, 42 NI). The overall accuracy was 73.9% for bacterial infection (p=0.03 vs. training cohort) and 75.4% for viral infection (p=0.27). Test utility could be improved by reporting probability ranges. For example, results divided into probability quartiles would allow the highest quartile to be used to rule in infection and the lowest to rule out infection. For IC subjects in the lowest quartile, the test had 90.1% and 96.4% sensitivity for bacterial and viral infection, respectively. For the highest quartile, the test had 91.4% and 84.0% specificity for bacterial and viral infection, respectively. The type or number of immunocompromising conditions did not impact performance. Illness Etiology Probabilities Conclusion A host gene expression test discriminated bacterial, viral, and non-infectious etiologies at a lower overall accuracy in IC patients compared to immunocompetent patients, though this difference was only significant for bacterial vs non-bacterial disease. With modified interpretive criteria, a host response strategy may offer clinically useful and complementary diagnostic information for IC patients. Disclosures Thomas W. Burke, PhD, Predigen, Inc (Consultant) Geoffrey S. Ginsburg, MD PhD, Predigen, Inc (Shareholder, Other Financial or Material Support) Christopher W. Woods, MD, MPH, FIDSA, Predigen, Inc (Shareholder, Other Financial or Material Support) Ephraim L. Tsalik, MD, MHS, PhD, FIDSA, Predigen, Inc (Scientific Research Study Investigator, Shareholder, Other Financial or Material Support)

Objective Distinguishing bacterial, viral, or other etiologies of acute illness is diagnostically challenging with significant implications for appropriate antimicrobial use. Host gene expression offers a promising approach, although no clinically useful test has been developed yet to accomplish this. Here, Qvella’s FAST HR (Richmond Hill, Ontario, Canada) process was developed to quantify previously identified host gene expression signatures in whole blood in Method Whole blood was collected from 128 human subjects (mean age 47, range 18–88) with clinically adjudicated, microbiologically confirmed viral infection, bacterial infection, noninfectious illness, or healthy controls. Stabilized mRNA was released from cleaned and stabilized RNA-surfactant complexes using e-lysis, an electrical process providing a quantitative real-time reverse transcription polymerase chain reaction-ready sample. Threshold cycle values (CT) for 10 host response targets were normalized to hypoxanthine phosphoribosyltransferase 1 expression, a control mRNA. The transcripts in the signature were specifically chosen to discriminate viral from nonviral infection (bacterial, noninfectious illness, or healthy). Classification accuracy was determined using cross-validated sparse logistic regression. Results Reproducibility of mRNA quantification was within 1 cycle as compared to the difference seen between subjects with viral versus nonviral infection (up to 5.0 normalized CT difference). Classification of 128 subjects into viral or nonviral etiologies demonstrated 90.6% overall accuracy compared to 82.0% for procalcitonin (P = .06). FAST HR achieved rapid and accurate measurement of the host response to viral infection in less than 45 minutes. Conclusions These results demonstrate the ability to translate host gene expression signatures to clinical platforms for use in patients with suspected infection. Clinical Trials Registration NCT00258869.

Background Host response-based diagnostics are an alternative to pathogen-based tests. Host response strategies include proteomic and transcriptomic approaches. Here, we compare three host response strategies for ARI diagnosis: Procalcitonin (PCT), a 3-protein panel, and an mRNA panel. Methods PCT, a 3-protein panel (CRP, IP-10, TRAIL), and a host gene expression mRNA panel were measured in a cohort of 286 participants presenting to one of the four Emergency Departments with ARI due to bacterial (n = 47), viral (n = 162), or noninfectious (n = 77) etiologies. Multinomial logistic regression and leave-one-out cross-validation were used to train and evaluate the protein and mRNA panels. Performance characteristics were calculated for each method, and their combination, for the ability to discriminate bacterial vs. non-bacterial infection and viral vs. nonviral infection. PCT was not evaluated for viral vs. nonviral discrimination since it does not discriminate viral and noninfectious etiologies. McNemar’s test was used to compare overall accuracy of mRNA and protein panels. Results For discriminating bacterial vs. non-bacterial etiologies, the mRNA panel had an AUC of 0.93 vs. 0.83 for both the protein panel and PCT. A model utilizing all three strategies was the same as mRNA alone. Using previously established cutoffs, overall accuracy was similar between mRNA and protein panels, but the protein panel had widely discordant sensitivity (43%) and specificity (92%). When selecting an optimal cutoff for the protein panel that balanced the two (82% and 73%, respectively), the mRNA panel had a significantly greater overall accuracy (P < 0.001). Similar results were found when discriminating viral vs. non-viral subjects: the mRNA panel (AUC = 0.93) outperformed the protein panel (AUC = 0.84). Combining the mRNA and protein panels was equivalent to the mRNA panel alone. Conclusion A host-based gene expression signature is the most effective platform for classifying subjects with bacterial, viral, or noninfectious ARI. A gene expression approach, when translated to a clinically available platform, may facilitate diagnosis and clinical management of acute infectious diseases, mitigating antibiotic overuse. Disclosures Ephraim L. Tsalik, MD, MHS, PhD, Immunexpress: Consultant; Predigen, Inc.: Officer or Board Member, Research Grant.

BackgroundSystemic therapy for advanced uterine carcinosarcoma (CS) has been disappointing. The most widely studied regimen is ifosfamide and cisplatinum. Moderate success has been documented using paclitaxel in ovarian CS. The purpose of this study was to evaluate carboplatin/paclitaxel in advanced and recurrent uterine CS.MethodsA single-arm, prospective, phase II trial opened in October 2001. Primary end points were time to progression (TTP) and response rate (RR). Quality-of-life data were obtained. Patients treated adjuvantly received 6 cycles of carboplatin/paclitaxel every 21 days. Patients with disease at study entry were treated until response, progression, or toxicity.ResultsOf 23 patients enrolled, 9 received adjuvant treatment, 13 had documented disease, 1 was inevaluable. Eight of 13 patients with measurable disease had a complete or partial response (62% RR). Overall, median TTP was 9.5 months. In the adjuvant group, median TTP was 15 months. With measurable disease, median TTP was 7.9 months. Median overall survival was 21.1 months. There was no difference in survival between patients with or without measurable disease. For patients having prior radiation, median TTP with recurrence in the radiated field was 13.3 months, and 14.5 months if outside the field (P= 0.71). Two patients (9%) had treatment-limiting toxicity. Quality-of-life scores improved from baseline over time.ConclusionsCarboplatin and paclitaxel have improved tolerability and RR (62%) compared with previous reports of ifosfamide/cisplatin or ifosfamide/paclitaxel in treating uterine CS. This regimen seems promising and should be considered in combined therapies with targeted agents.

Background Acute febrile illness is a frequent cause of hospitalization in the tropics and often presents with respiratory symptoms, even when caused by nonrespiratory pathogens. Previously, host-based gene expression signatures accurately identified acute respiratory infections as being bacterial or viral in a U.S. cohort. We determined signature performance in a Sri Lankan cohort with acute febrile respiratory illness (AFRI). Methods We enrolled patients with AFRI in Sri Lanka from July 2012 to May 2013 and collected nasopharygeal swabs, acute/ convalescent sera, and blood in PAXgene RNA tubes. Bacterial (Orientia tsutsugamushi, Leptospira spp.) and viral (influenza A/B, dengue) infections were confirmed using polymerase chain reaction, virus isolation, enzyme immunoassay, and/or microscopic agglutination testing. We extracted total RNA and performed host RNA sequencing (Illumina). We aligned reads to hg38 reference genome using Bowtie2, quantified at isoform level using Express version 1.5.1, and normalized using trimmed-mean normalization. The original model estimated three classes and separate signatures predicted bacterial infections, viral infections, and non-infectious illnesses. Regularized regression was used to predict bacterial and viral infections based on prior signatures. Accuracy was estimated using leave-one-out cross-validation. Results Among 43 patients with viral infections (14 dengue, 29 influenza) and 16 patients with bacterial infections (six Leptospira spp., 10 O. tsutsumagushi), median age was 37 years (IQR 23–51) and 49% were male. Of five respiratory symptoms (cough, sore throat, rhinitis/ congestion, shortness of breath, and pain with breathing), median (IQR) number of symptoms was 2 (1–2) for influenza, 2 (1–2) for dengue, 2 (2–3) for Leptospira spp., and 1.5 (1–2) for O. tsutsumagushi. We observed high predictive accuracy in discriminating bacterial and viral infections: AUROC 0.91 for the bacterial and AUROC 0.81 for the viral model. At enrollment, 65% of viral and 50% of bacterial AFRI patients received antibiotics. Conclusion Host gene expression classifiers performed well in a Sri Lankan population with AFRI, even with nonrespiratory pathogens that may not be readily identified. Host-based diagnostics may play a critical role in improving diagnostic ability and antibiotic use globally. Disclosures E. L. Tsalik, Host Response, Inc.: Founder, Equity. G. S. Ginsburg, Host Response Inc.: Board Member, Founder, Scientific Advisor and Shareholder, Stock (currently worth

Background Bacterial and viral infections are difficult to clinically distinguish, leading to antibiotic overuse and resistance. Host response signatures are an alternative to traditional pathogen-detection methods to differentiate these etiologies. Several gene expression signatures have been described although performance in ambiguous clinical phenotypes is unknown. Here, we validate a host response signature and explore its performance in microbiology-negative and co-infection cases. Methods RT-PCR taqman low-density array (TLDA) was used to measure 87 gene targets in a training cohort of 151 samples from patients with microbiologically confirmed and clinically adjudicated phenotypes (48 bacterial; 54 viral; 49 non-infectious illness [NI]). This data were used to construct three distinct classifiers: bacterial vs. nonbacterial; viral vs. nonviral; and non-infectious vs. infectious. This model was then applied to 75 subjects with co-infection and 40 suspected bacterial cases without microbiological confirmation. Results Leave-one-out cross validation on the training cohort demonstrated AUC values of 0.85, 0.89, and 0.88 for bacterial, viral, and NI, respectively. In 40 subjects with microbiology-negative bacterial infections, a bacterial or co-infection signature was present in 72%. Of 75 subjects with co-infection, 53 included a bacterial infection following recent viral infection and 22 were bacterial infections in patients with chronic viral infection (e.g., HCV, HIV). Bacterial infection and co-infection were successfully identified in these varied scenarios. Conclusion This gene expression signature distinguished bacterial, viral, and noninfectious causes of illness. The host response was able to confirm the majority of suspected bacterial infection without confirmatory microbiology but also highlighted a viral response in many. Furthermore, the use of distinct viral and bacterial signatures was capable of identifying co-infection. Such a host gene expression strategy, when translated to a clinically useful platform, can offer new insights into the etiology of both simple and complex cases that are not currently available. Disclosures G. S. Ginsburg, Host Response Inc.: Board Member, Founder, Scientific Advisor and Shareholder, Stock (currently worth

Background Asthma exacerbations often occur due to infectious triggers. However, determining whether an infection is present and whether it is bacterial or viral remains clinically challenging leading to antibiotic overuse. A diagnostic strategy that clarifies these uncertainties can enable personalized asthma treatment and mitigate antibiotic resistance. Host gene expression is a promising alternative to pathogen-detection methods. Methods Forty-six patients presenting to the emergency department with asthma exacerbations were enrolled. Cases were clinically adjudicated as having bacterial, viral, or non-infectious etiologies. RT-PCR taqman low density array (TLDA) was used to quantify 87 gene targets, followed by logistic regression modeling to define class. Etiologies were correlated with clinical information including symptoms and antibiotic prescriptions. Results Most clinical parameters were similar between groups including duration of symptoms, presence of sick contacts, and severity of nasal symptoms, cough, headache, throat discomfort, and malaise. Only fever/chills (P = 0.006) and a composite of all symptoms (P = 0.02) were significantly different. In contrast to clinically adjudicated phenotypes, host response signatures identified very few bacterial triggers. Notably, none of the adjudicated bacterial cases had positive confirmatory microbiology. Instead, 29 and 57% were identified as having a viral infection or no infection, respectively. Despite the absence of bacterial infections identified using host gene expression, antibiotics were prescribed in 47.8% of all cases. Conclusion Host response signatures indicated that asthma exacerbation is infrequently caused by bacterial infections, even when clinical adjudications suggest this to be the case. Instead, most are either of viral or non-infectious etiologies. Despite most cases being classified as nonbacterial, empiric antibiotics were prescribed nearly half the time. A host gene expression approach can offer clinically useful diagnostic information to guide more appropriate antibiotic use among patients with asthma exacerbation. Disclosures G. S. Ginsburg, Host Response Inc.: Board Member, Founder, Scientific Advisor and Shareholder, Stock (currently worth < $100). C. W. Woods, Host Response: Founder, Licensing agreement or royalty; Qvella: Collaborator, Research support; BioFire: Collaborator, none. E. L. Tsalik, Host Response, Inc.: Founder, Equity.

Background The inability to reliably discriminate bacterial, viral, and non-infectious illness has led to an epidemic of antibiotic overuse and rising rates of antimicrobial resistance. Host gene expression provides a powerful approach to distinguish infection etiologies and guide appropriate therapy. However, existing platforms for transcriptomic analysis are not amenable for clinical application. The FilmArray platform is a sample-to-answer multiplex RT-PCR system that automates transcriptomic analysis including sample preparation and data analysis. Here we report the validation of a host gene expression FilmArray test to discriminate bacterial, viral, and non-infectious etiologies of illness. Methods Research use only (RUO) FilmArray pouches were manufactured with 45 host response assays previously shown to discriminate bacterial, viral, and non-infectious illness. These pouches were tested on whole blood samples from 226 patients with acute respiratory illness (ARI). Using clinical adjudication as the reference standard, there were 52 bacterial, 100 viral, and 75 non-infectious cases. Quantification cycles were recorded for each assay and normalized to an internal control. A logistic regression model generated probabilities of each condition, which were used to classify subjects. Results Beginning with 100 µL of blood, the FilmArray host response panel provided results in ~45 minutes from sample to answer. Overall accuracy for bacterial ARI relative to clinical adjudication was 85% with an area under the receiver operating characteristic curve (AUC) of 0.92. Accuracy and AUC for viral infection were 85% and 0.91, respectively. Ill patients without infection were correctly identified 86% of the time with an AUC of 0.88. Conclusion These results show that the FilmArray system can rapidLy measure host gene expression to accurately discriminate bacterial, viral, and non-infectious illness. The development of such a system creates a new option to mitigate inappropriate antibiotic use. It also presents opportunities to use host gene expression as a diagnostic modality for a variety of disease states. Disclosures E. L. Tsalik, Host Response, Inc.: Founder, Equity. J. Montgomery, BioFire Diagnostics: Employee, Salary. J. Nawrocki, BioFire Diagnostics, LLC.: Employee, Salary. M. Deneris, BioFire Diagnostics, LLC.: Employee, Salary. C. Gritzen, BioFire Diagnostics, LLC.: Employee, Salary. J. Jones, BioFire Diagnostics, LLC.: Employee, Salary. R. Crisp, BioFire Diagnostics, LLC: Employee, Salary. G. S. Ginsburg, Host Response Inc: Board Member, Founder, Scientific Advisor and Shareholder, Stock (currently worth < $100). A. Hemmert, BioFire Diagnostics, LLC.: Employee and Investigator, Salary. C. W. Woods, Host Response, Inc.: Founder, Equity.

This study reviews the experience at the University of Texas M.D. Anderson Cancer Center with elderly patients treated for advanced epithelial ovarian cancer with cisplatin-based combination chemotherapy.From 1978 through 1988, 215 patients with Stage III or IV, Grade 2 or 3 epithelial ovarian cancer were entered onto one of three consecutive trials involving cisplatin-based combination chemotherapy. The treatment plans were as follows: Trial 1: 12 cycles of cisplatin-melphalan (75 patients); Trial 2: 12 cycles of cisplatin-cyclophosphamide (49 patients); and Trial 3: 6 cycles of cisplatin-cyclophosphamide (91 patients). End-points of analysis included the effect of age on other prognostic factors, clinical response rate, surgical response rate, toxicity, progression-free survival, and survival.Of the entire study group, 57 patients (27%) were 65 years of age and older at diagnosis. There was no effect of age on FIGO stage or histologic grade distribution, but 61% of patients younger than 65 years of age had residual tumors less than or equal to 2 cm compared with only 33% of patients 65 years of age and older (P = 0.00027). There were no differences between the two age groups with respect to response rates, recurrence rate after negative second-look surgery, toxicity, or progression-free survival. Patients in the younger than 65 years of age group, however, had a significantly longer median survival time than those 65 years of age and older (30 versus 19 months, respectively) (P = 0.0038).This analysis suggests that elderly patients are more likely to begin chemotherapy with bulky residual disease and to have a significantly shorter survival time than their younger counterparts.

BACKGROUND: The objective of this study was to determine the efficacy of mifepristone (RU-486) in women with advanced or recurrent endometrioid adenocarcinoma or low-grade endometrial stromal sarcoma (LGESS). METHODS: Mifepristone (RU-486; 200 mg orally) was given daily to patients with progesterone receptor-positive advanced or recurrent endometrioid adenocarcinoma or LGESS. Patients were evaluated every 4 weeks for toxicity and response. Quality-of-life data were obtained using the Memorial Symptom Assessment Scale and Functional Assessment for Cancer Therapy. RESULTS: Twelve of 13 enrolled patients were evaluable in the first phase of accrual. Stable disease was noted in 3 of 12 patients (at 8 weeks, 12 weeks, and ≥77 weeks, respectively), and the median time to disease progression was 48 days. Among the patients who had stable disease, 2 women had endometrioid endometrial cancer, and 1 woman had LGESS. No partial or complete responses were observed. The most frequent grade 1 and 2 toxicities were anorexia, fatigue, and mood alterations observed in 50%, 50%, and 58% of patients, respectively. The most common grade 3 toxicities were fatigue and dyspnea observed in 25% and 17% of patients, respectively. One patient experienced grade 4 dyspnea. Thirty-three percent of patients had asymptomatic elevations of corticotropin. No serious treatment-related adverse events occurred. There were no significant changes in quality of life. CONCLUSIONS: Single-agent mifepristone used in the treatment of recurrent endometrioid adenocarcinoma or LGESS resulted in a stable disease rate of 25%. One patient who had a biopsy-positive disease recurrence remained stable at 77 weeks. Although mifepristone was tolerated well, as a single agent, it provided limited response as a single agent in women with progesterone receptor-positive uterine tumors. Recently, was been recognized that biologic agents used as single agents may result only in stable disease unless they are combined with cytotoxic agents. The authors concluded that further research into the best mode of application for mifepristone in the treatment of endometrial cancer is needed. Cancer 2009. © 2009 American Cancer Society.

Purpose: The involvement of phosphatase and tensin homologue deleted on chromosome ten (PTEN) in endometrial carcinoma has implicated phosphatidylinositol 3-kinase signaling and mammalian target of rapamycin (mTOR) activation in this disease. Understanding the extent of mTOR involvement and the mechanism responsible for activation is important, as mTOR inhibitors are currently being evaluated in clinical trials for endometrial carcinoma. Although tuberous sclerosis complex 2 (TSC2) is the “gatekeeper” for mTOR activation, little is known about defects in the TSC2 tumor suppressor or signaling pathways that regulate TSC2, such as LKB1/AMP-activated protein kinase, in the development of endometrial carcinoma. Experimental Design: We determined the frequency of mTOR activation in endometrial carcinoma (primary tumors and cell lines) and investigated PTEN, LKB1, and TSC2 defects as underlying cause(s) of mTOR activation, and determined the ability of rapamycin to reverse these signaling defects in endometrial carcinoma cells. Results: Activation of mTOR was a consistent feature in endometrial carcinomas and cell lines. In addition to PTEN, loss of TSC2 and LKB1 expression occurred in a significant fraction of primary tumors (13% and 21%, respectively). In tumors that retained TSC2 expression, phosphorylation of tuberin at S939 was observed with a high frequency, indicating that mTOR repression by TSC2 had been relieved via AKT phosphorylation of this tumor suppressor. In PTEN-null and LKB1-null endometrial carcinoma cell lines with functional inactivation of TSC2, phosphatidylinositol 3-kinase (PI3K) inhibitors wortmannin and LY294002 were able to inhibit AKT and mTOR signaling and reverse TSC2 phosphorylation. In contrast, although rapamycin inhibited mTOR signaling, it did not relieve phosphorylation of TSC2 at S939. Conclusions: Inactivation of TSC2 via loss of expression or phosphorylation occurred frequently in endometrial carcinoma to activate mTOR signaling. High-frequency mTOR activation supports mTOR as a rational therapeutic target for endometrial carcinoma. However, whereas rapamycin and its analogues may be efficacious at inhibiting mTOR activity, these drugs do not reverse the functional inactivation of TSC2 that occurs in these tumors.

Purpose: DB-67 is a silatecan, 7-silyl-modified camptothecin, with enhanced lipophilicity and increased blood stability of the active-lactone ring. The generation of a liposomal formulation of DB-67 may be an attractive method of intravenous (IV) administration and may maintain DB-67 in the active-lactone form. We evaluated the tissue and plasma disposition of DB-67 lactone and hydroxy acid after administration of non-liposomal (NL) and liposomal (L) DB-67 in severe combined immunodeficient (SCID) mice. Methods: NL-DB-67 and L-DB-67 10 mg/kg IV × 1 were administered via a tail vein in SCID mice. After dosing, mice (n = 3 per time point) were euthanized and blood (∼1 ml) and tissue were collected from 5 min to 48 h after administration. DB-67 lactone and hydroxy acid concentrations in plasma and DB-67 total (sum of lactone and hydroxyl acid) concentrations in tissues were determined by high-performance liquid chromatography (HPLC) with fluorescence detection. Results: Clearance of DB-67 lactone after administration of NL-DB-67 and L-DB-67 were 1.6 and 3.5 l/h/m2, respectively; DB-67 lactone half-lives after administration of NL-DB-67 and L-DB-67 were 1.4 and 0.9 h, respectively. The percentages of DB-67 lactone in plasma after administration of NL-DB-67 and L-DB-67 were 92% and 89%, respectively. Liver, kidney, spleen, and lung tissues had longer exposure times to DB-67 after administration of L-DB-67 compared with NL-DB-67. Conclusion: In plasma, the majority of DB-67 remained in the lactone form after administration of NL-DB-67 and L-DB-67. The plasma disposition of DB-67 was similar after administration of NL-DB-67 and L-DB-67, suggesting that most of the DB-67 is immediately released from the L-DB-67 formulation. Following administration of L-DB-67, the higher and longer exposure of DB-67 in the spleen, as compared with NL-DB-67, is consistent with splenic clearance of liposomes by the reticuloendothelial system.

Early, presymptomatic intervention with oseltamivir (corresponding to the onset of a published host-based genomic signature of influenza infection) resulted in decreased overall influenza symptoms (aggregate symptom scores of 23.5 vs 46.3), more rapid resolution of clinical disease (20 hours earlier), reduced viral shedding (total median tissue culture infectious dose [TCID50] 7.4 vs 9.7), and significantly reduced expression of several inflammatory cytokines (interferon-γ, tumor necrosis factor-α, interleukin-6, and others). The host genomic response to influenza infection is robust and may provide the means for early detection, more timely therapeutic interventions, a meaningful reduction in clinical disease, and an effective molecular means to track response to therapy.

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 To determine the efficacy and side effects of taxanes, with or without platinum, for the treatment of sex cord-stromal tumors of the ovary. Patients and Methods We conducted a retrospective review of all patients seen from 1985 to 2002 at The University of Texas M.D. Anderson Cancer Center with ovarian sex cord-stromal tumors. Eligible patients underwent pathology confirmation and clinical evaluation at M.D. Anderson and received a taxane for initial or recurrent disease. Results Of 222 patients identified, 44 were eligible for analysis. For nine patients treated in the first-line adjuvant setting, median progression-free survival (PFS) was not reached at 51 months. Of two patients treated for measurable disease in the first-line setting, one had a complete response. Median PFS was 34.3 months; median overall survival (OS) was not reached. Median follow-up was 90.3 months (range, 39.4 to 140.5 months). Response rate for 30 patients treated with a taxane ± platinum for recurrent, measurable disease was 42%. Median PFS was 19.6 months; median OS was not reached. Median follow-up was 100.7 months (range, 8.1 to 361.3 months). The presence of platinum correlated with response in the recurrent, measurable disease setting. The number of patients was insufficient to detect relative efficacy of paclitaxel and docetaxel. Adverse effects of paclitaxel included neutropenia (n = 6), anemia (n = 1), thrombocytopenia (n = 1), myelodysplasia (n = 1), and hypersensitivity (n = 1). Conclusion Taxanes seem to be active agents in the treatment of patients with sex cord-stromal tumors of the ovary. The combination of taxanes with platinum in the treatment of this disease deserves additional investigation.

Purpose Uterine papillary serous carcinoma (UPSC) is an aggressive subtype of endometrial cancer characterized by early metastasis, resistance to therapy, and a high mortality rate. Little is known about the biology of these tumors. Smaller studies suggest that Her-2/neu may be involved in the tumorigenesis of this disease. The purpose of this study was to evaluate the protein expression and gene amplification of Her-2/neu in UPSC and to determine its prognostic value. Patients and Methods Tumor tissue from 68 patients with UPSC treated at The University of Texas M.D. Anderson Cancer Center from 1989 to 2002 was available. Her-2/neu expression was evaluated by immunohistochemistry (IHC). Overexpression was defined as complete membrane staining in greater than 10% of the cells. In tumors with overexpression of Her-2/neu by IHC, fluorescence in situ hybridization (FISH) was performed to assess gene amplification. Clinical and pathologic information was obtained from medical records. Results Twelve (18%) of 68 tumors demonstrated Her-2/neu overexpression. Of these, only two showed gene amplification. When evaluating all 68 patients, Her-2/neu overexpression was associated with a poorer overall survival (OS; P = .008). In our multivariate Cox proportional hazards models, Her-2/neu IHC overexpression, lymph node status, and stage were each associated with OS (P ≤ .05). Conclusion Positive IHC overexpression of Her-2/neu was seen in 18% of UPSCs but was rarely correlated with Her-2/neu gene amplification. Overexpression of Her-2/neu was associated with a worse overall prognosis. The use of trastuzumab (Herceptin; Genentech, South San Francisco, CA) in women with UPSC should be further evaluated in a clinical trial setting.

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.

Circulating insulin-like growth factors (IGFs) and their binding proteins have been associated with increased risk of breast, prostate, colon, and lung cancer. To examine the association of IGFs and endometrial cancer risk, we measured the plasma levels of IGF-1, IGF-2, and IGF binding protein 3 (IGFBP-3) by ELISA in 80 women with endometrial cancer and 80 age-matched control subjects with no history of cancer. Mean plasma levels of IGF-2 were significantly higher in women with cancer versus controls (670 ng/ml versus 380 ng/ml, P < 0.001). In contrast, significantly lower mean plasma levels of IGF-1 (155 mg/ml versus 185 ng/ml, P < 0.01) and IGFBP-3 (1703 ng/ml versus 2170 ng/ml, P < 0.001) were observed among cases compared to the control group. Women in the highest quartile of IGF-2 were found to have 9.67 (95% confidence interval 3.29–28.43) times the risk of endometrial cancer than women in the lowest quartiles. Women in the highest quartile of IGFBP-3 were associated with a significantly decreased risk for developing endometrial cancer (odds ratio = 0.23, 95% confidence interval 0.09–0.60). These data suggest that increased plasma levels of IGF-2 and decreased levels of IGFBP-3 are associated with an increased risk of endometrial cancer. Further validation of these results is needed to determine the potential usefulness of risk assessment.

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.

Our objective was to assess the value of lymphangiography in selecting patients for surgical staging of locally advanced cervical cancer. We reviewed our computerized database to identify patients with cervical cancer who had abnormal findings on lymphangiography and underwent retroperitoneal lymph node dissection between September 1991 and January 1996. The records of these patients were retrospectively reviewed, and the following data were retrieved: clinical tumor stage and findings on lymphangiography at surgery, and on pathologic examination of resected lymph nodes. The lymphangiograms were reviewed and reinterpreted in blinded fashion by two of the authors. The positive and negative predictive values of lymphangiography for the presence of lymph node metastases were calculated, with findings on pathologic examination of lymph nodes used as the gold standard. The positive and negative predictive values of surgeons' clinical assessments at surgery were also calculated. Fifty patients met the selection criteria and constituted the study population. Fourteen patients (28%) had histologically negative nodes, and 36 patients (72%) had lymph node metastases. Thirty-three patients had metastases to pelvic nodes, 1515 patients had metastases to common iliac nodes, and 1616 patients had metastases to para-aortic nodes. The positive predictive value of lymphangiography for lymph node metastases was 74% for pelvic nodes, 73% for common iliac nodes, and 88% for para-aortic nodes. The negative predictive value of lymphangiography for lymph node metastasis was 76% for common iliac nodes and 77% for para-aortic nodes. Overall, 46% of the patients selected for surgical exploration had histologic findings of either common iliac or para-aortic lymph node metastases; these findings led clinicians to extend radiation fields to cover the para-aortic lymph nodes. Lymphangiography is helpful in selecting patients with cervical cancer who have a high risk of common iliac or para-aortic lymph node metastasis. However, more accurate and more readily available noninvasive methods of evaluating cervical patients for the presence of regional disease continue to be needed.

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.

Interleukin 4 (IL-4) is a multifunctional cytokine that plays an important role in hematopoiesis, tumor cell growth, and cellular immune responses. Expression of the IL-4 gene is tightly controlled at the level of gene transcription, and many positive regulatory cis-elements have been identified in the proximal IL-4 promoter region. Relatively little is known about factors that downregulate IL-4 transcription. We performed a detailed deletional analysis of the proximal human IL-4 promoter and studied reporter gene activity in transiently transfected Jurkat T lymphoblasts. In this report, we characterize a novel negative regulatory element (termed P2 NRE) that is adjacent to a binding site for nuclear factor of activated T cells. Mutation of P2 NRE significantly enhanced the activity of a 175 base pair IL-4 promoter construct in transiently transfected Jurkat T lymphoblasts. Using nuclear extracts from Jurkat cells, we identify a candidate factor (termed Rep-1) that binds uniquely to the P2 NRE in DNA-binding assays. Rep-1 is not related to other factors previously shown to interact with the IL-4 promoter, and by UV cross-linking and SDS-PAGE analysis, we found that it migrates with a molecular mass of approximately 150 kDa. Characterizing the molecular mechanisms responsible for downregulating the IL-4 promoter should enhance our understanding of IL-4-gene dysregulation in disease states.

mg/m 2 . In the second stage of the study, the doses of cisplatin and melphalan were fixed at 75 mg/m 2 and the MTD level, respectively, and the dose of paclitaxel was escalated. The planned dose escalation levels of paclitaxel were 150 mg/m 2 , 175 mg/m 2 , 200 mg/m 2 , 225 mg/m 2 , and 250 mg/m 2 . G-CSF was administered for 12‐19 days with each cycle, and cycles were repeated every 4 weeks for a total of 6 cycles. Other end points included clinical or surgical response, progression free survival, and survival. RESULTS. Between January 1993 and May 1996, 34 women with untreated advanced stage epithelial ovarian carcinoma or primary peritoneal carcinoma were treated with 192 cycles of therapy. The MTD of melphalan was 10 mg/m 2 , with the dose-limiting toxicity being thrombocytopenia. Paclitaxel was escalated to a dose level of 200 mg/m 2 with a toxicity rate of , 33%. The clinical response rate was 80% in 29 patients with measurable disease. Of 11 patients who underwent second-look surgery, 5 (45%) had a surgical pathologic complete response. The median progression free survival was 16.8 months and the median survival was 32.8 months. CONCLUSIONS. The combination of intravenous melphalan, paclitaxel, and cisplatin was found to have acceptable toxicity and good activity. A Phase II study of this combination appears to be warranted. Cancer 1999;86:2291‐300. © 1999 American Cancer Society.

BACKGROUND The purpose of the current study was to evaluate the current practice of surgical staging of ovarian serous borderline tumors. METHODS Women with a diagnosis of ovarian serous borderline tumors whose pathology slides were sent to the M. D. Anderson Cancer Center for second-opinion diagnostic consultation between 1990–1996 were identified. The original pathology reports and M. D. Anderson Cancer Center consultation reports of 255 cases were reviewed for the frequencies of frozen-section analyses and staging biopsies, biopsy results, the specialty of the surgeon, and hospital type. RESULTS The majority (78%) of ovarian borderline tumors primarily were encountered and staged by general obstetrician-gynecologists. Overall, 66% of patients had at least 1 staging biopsy performed. Approximately 12% of subjects underwent complete surgical staging, defined as having biopsy samples taken from pelvic and abdominal peritoneum, omentum, and retroperitoneal lymph nodes. Gynecologic oncologists performed complete staging in 50% of cases, obstetrician-gynecologists performed complete staging in 9% of cases, and general surgeons performed complete staging in 0% cases. The overall frequency of a positive staging biopsy was 37%. Approximately 47% (80 of 169) of patients who underwent biopsies were upstaged as a result of positive biopsies, - with 41% (70 of 169) having extrapelvic spread. CONCLUSIONS Currently, surgical staging for women with ovarian serous borderline tumors remains inadequate, although a significant proportion of patients who undergo staging are noted to have extrapelvic spread. Cancer 1999;85:905–11. © 1999 American Cancer Society.

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.

Background The objective of the current study was to update the authors' experience with patients with ovarian serous borderline tumors with invasive peritoneal implants to gain additional insight into the biologic behavior of these tumors and a better understanding of the effect of postoperative treatment. Methods Thirty-nine patients with ovarian serous borderline tumors with invasive peritoneal implants were identified through a retrospective review. Major endpoints selected for analysis were surgicopathologic response, time to recurrence, type of recurrence, progression free survival, and overall survival. Univariate and multivariate regression analyses also were performed. Results Median follow-up time was 111 months. Four of 7 evaluable patients who had second-look surgery (57%) had a response to chemotherapy. Twelve of 39 patients (31%) either developed progressive disease or had a recurrence. The median time from date of diagnosis to recurrence was 24 months. In 10 of these 12 patients with a recurrence, tissue was available; 9 had invasive low grade serous carcinoma and 1 had a recurrent borderline tumor. Macroscopic residual disease was the only factor studied that had a significant effect on survival; patients with no macroscopic residual tumor had a significantly better survival than those with any macroscopic residual tumor (P Conclusions Greater than 30% of patients with ovarian serous borderline tumors with invasive peritoneal implants will develop progressive or recurrent tumor, most commonly serous carcinoma. The presence of macroscopic residual disease appears to be the major predictor of recurrence and survival. However, in this study, the authors were unable to elucidate the role of postoperative therapy or the criteria for selection of patients for such therapy.

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.

Author(s): Lee, Larissa J; Ratner, Elena; Uduman, Mohamed; Winter, Kathryn; Boeke, Marta; Greven, Kathryn M; King, Stephanie; Burke, Thomas W; Underhill, Kelly; Kim, Harold; Boulware, Raleigh J; Yu, Herbert; Parkash, Vinita; Lu, Lingeng; Gaffney, David; Dicker, Adam P; Weidhaas, Joanne | Abstract: ObjectiveTo explore the association of a functional germline variant in the 3'-UTR of KRAS with endometrial cancer risk, as well as the association of microRNA (miRNA) signatures and the KRAS-variant with clinical characteristics and survival outcomes in two prospective RTOG endometrial cancer trials.Methods/materialsThe association of the KRAS-variant with endometrial cancer risk was evaluated by case-control analysis of 467 women with type 1 or 2 endometrial cancer and 582 age-matched controls. miRNA and DNA were isolated for expression profiling and genotyping from tumor specimens of 46 women with type 1 endometrial cancer enrolled in RTOG trials 9708 and 9905. miRNA expression levels and KRAS-variant genotype were correlated with patient and tumor characteristics, and survival outcomes were evaluated by variant allele type.ResultsThe KRAS-variant was not significantly associated with overall endometrial cancer risk (14% controls and 17% type 1 cancers), although was enriched in type 2 endometrial cancers (24%, p = 0.2). In the combined analysis of RTOG 9708/9905, miRNA expression differed by age, presence of lymphovascular invasion and KRAS-variant status. Overall survival rates at 3 years for patients with the variant and wild-type alleles were 100% and 77% (HR 0.3, p = 0.24), respectively, favoring the variant.ConclusionsThe KRAS-variant may be a genetic marker of risk for type 2 endometrial cancers. In addition, tumor miRNA expression appears to be associated with patient age, lymphovascular invasion and the KRAS-variant, supporting the hypothesis that altered tumor biology can be measured by miRNA expression, and that the KRAS-variant likely impacts endometrial tumor biology.

The approaches outlined in this report, coupled with a spirit of internal and external collaboration, enable complete translation of the MD Anderson multidisciplinary care model as well as extension of our organizational research mission. Quality management with the ability to benchmark quality metrics against our main Houston campus remains a cornerstone of our overarching strategy to maintain consistent high-quality care throughout our national network.

BACKGROUND Although the technique for gracilis myocutaneous vaginal reconstruction was first described in the mid-1970s and has been used in conjunction with pelvic exenteration since that time, there is little available information regarding sexual adjustment after such a procedure. The purpose of this study was to assess the sexual adjustment of women who underwent pelvic exenteration and gracilis myocutaneous vaginal reconstruction at the study institution. METHODS In a prospective study design, 95 patients were identified who underwent pelvic exenteration and gracilis myocutaneous vaginal reconstruction at the study institution from 1977 through 1989 and a convenience sample was selected of 44 patients who completed a modified version of the Sexual Adjustment Questionnaire (SAQ) when they returned to the gynecologic oncology outpatient clinic for routine follow-up care. A vaginal assessment was also performed by the attending physician. RESULTS Twenty-one of 40 patients (52.5%) completing the questionnaire reported not resuming sexual activity after surgery; 19 patients reported resuming sexual activity between 1.5 months to 12 years postoperatively. Of the patients who resumed sexual activity, 84% did so within 1 year of surgery. The most common problems noted by patients in adjusting to sexual activity after surgery were self-consciousness about the urostomy or colostomy and being seen in the nude by their partner, vaginal dryness, and vaginal discharge. The mean rank of preexenteration SAQ scores was 66.4, and the mean rank of postexenteration scores was 48.7 (P < 0.0001), demonstrating that sexual adjustment after exenteration was significantly poorer than before the surgery. On the basis of data gathered from a vaginal assessment form, 31 of 44 patients (70.4%) were judged to have a potentially functional neovagina. CONCLUSIONS Based on the findings of this questionnaire study, sexual adjustment is often significantly impaired in women after pelvic exenteration and gracilis myocutaneous vaginal reconstruction. Future modifications in surgical technique, more realistic patient counseling, and aggressive postoperative support will hopefully minimize such problems. Cancer 1996;78:2229-35.

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.

The untunneling of the ureters and the transsection of the parametria are two well-characterized steps of radical hysterectomy. Two sets of instruments were developed to facilitate the mobilization (untunneling) of the ureters and the dissection of the paravaginal and parametrial tissues during radical hysterectomy.Instrument set one consists of a modified Uchida spoon, two ureteral tunnel clamps, and a pair of tunnel scissors. Set two contains a long and a short sharply angled parametrial clamp with matching parametrial scissors.This technique permits one-step exposure of the ureter, protected from injury by the spoon. The instruments for parametrial transsection facilitate controlled transsection of the paravaginal and parametrial tissues while conserving surgical margins. They can also be conveniently used for transsection of the uterosacral ligaments.The authors believe that the instruments contribute to an enhanced safety and accuracy of radical hysterectomy with improved efficiency by shortened operating time.

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.

Background. Paclitaxel is a diterpenic plant product that has significant activity in several solid tumors, including epithelial ovarian cancer. After promising results in Phase I and II studies, its use has increased dramatically. With this increased use, isolated reports of local tissue reactions to paclitaxel have been described. The purpose of this study was to characterize further the presentation and clinical course of this toxic effect. Methods. Nine hundred fifty-five courses of paclitaxel were administered to patients with gynecologic malignancies at M.D. Anderson Cancer Center during a 13-month period. Nineteen (2%) local infusion-site injuries in 17 patients were observed. Results. The primary disease site was the ovary in 13 patients, the peritoneum in 2, and the endometrium in 2. Pacitaxel was administered as initial therapy in 6 patients and as salvage therapy in 11. Clinical evidence of infiltration was decumented during infusion in 8 of 19 (42%) reported episodes. Immediate reactions consisting of mild discomfort, erythema, and edema were observed in six patients, three of whom had complete resolution of the lesion within 1 month. The remaining patients noted initial development of injury between 3 and 13 days after paclitaxel infusion. The typical injury was a discolored, raised, rounded, and indurated lesion that was moderately painful. Two patients (11%) had Grade 1 lesions, 13 (68%) had Grade 2 lesions, and four (21%) had Grade 3 lesions with central ulceration. Cellulitis requiring intravenous antibiotic therapy was associated with two lesions. At last follow-up, 13 injuries had persistent discoloration and induration; one patient had persistent ulceration present at the timt of her death 6 months after presentation and one patient underwent excision of a persistent lesion at 12 months. Conclusion. Given the incidence of Grade 2 and Grade 3 local reactions, it appears that paclitaxel should be considered a vesicant.

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.