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Background: The purpose of this study was to determine the effect of retroperitoneal (RP) exploration on progression-free survival (PFS) and overall survival (OS) in epithelial ovarian cancer (EOC) patients with stage IIIC disease who underwent optimal debulking surgery., Methods: Data were collected from records of the Gynecologic Oncology Group 182 (GOG-182) study of stage IIIC EOC patients cytoreduced to no gross residual disease (R0) or minimal gross residual (<1 cm) disease (MGRD) at primary surgery. Patients with stage IIIC disease by intraperitoneal (IP) tumor were included and divided into 3 groups: 1) > 2 cm IP tumor without lymph node involvement (IP/RP-), 2) > 2 cm IP tumor with lymph node involvement (IP/RP+), and 3) > 2 cm IP tumor with no RP exploration (IP/RP?). The effects of disease distribution and RP exploration on PFS and OS were assessed using Kaplan-Meier and proportional hazards methods., Results: There were 1871 stage IIIC patients in GOG-182 who underwent optimal primary debulking surgery. Of these, 689 (36.8%) underwent RP exploration with removal of lymph nodes from at least 1 para-aortic site, and 1182 (63.2%) did not. There were 269 patients in the IP/RP- group, 420 patients in the IP/RP + group, and 1182 patients in the IP/RP? group. Improved PFS (18.5 vs 16.0 months; P < .0001) and OS (53.3 vs 42.8 months; P < .0001) were associated with RP exploration versus no exploration. Patients with MGRD had improved PFS (16.8 vs 15.1 months, P = 0.0108) and OS (44.9 vs 40.5 months, P = 0.0076) versus no exploration., Conclusions: RP exploration at the time of primary surgery in patients with optimally debulked stage IIIC EOC is associated with a survival benefit. Cancer 2017;123:985-93. © 2016 American Cancer Society., (© 2016 American Cancer Society.)

Objective: To estimate whether a rapid recovery program would reduce length of stay among patients undergoing laparotomy on a gynecologic oncology service., Methods: We conducted a prospective, randomized, controlled trial comparing an enhanced recovery after surgery protocol with routine postoperative care among women undergoing laparotomy on the gynecologic oncology service. Protocol elements included: preoperative counseling, regional anesthesia, intraoperative fluid restriction, and early postoperative ambulation and feeding. A sample size of 50 per group (N=100) was planned to achieve 80% power to detect a two-day difference in our primary outcome, length of hospital stay; secondary outcomes included: total daily narcotics used, time to postoperative milestones, and complications., Results: A total of 112 women were enrolled between 2013 and 2015. Nine patients did not undergo laparotomy and were excluded, leaving 52 and 51 patients in the control and intervention groups, respectively. There was no difference in length of stay between the two groups (median 3.0 in both groups; P=.36). Enhanced recovery after surgery patients used less narcotics on day 0 (10.0 compared with 5.5 morphine equivalents in the control and intervention arms, respectively, P=.09) and day 2 (10.0 compared with 7.5 morphine equivalents, respectively; P=.05); however, there was no statistically significant difference between groups in any of the secondary outcomes. Post hoc analysis based on actual anesthesia received also failed to demonstrate a difference in time to discharge., Conclusion: When compared with usual care, introducing a formal enhanced recovery after surgery protocol did not significantly reduce length of stay., Clinical Trial Registration: ClinicalTrials.gov, https://clinicaltrials.gov, NCT01705288.

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of cancer therapy with few efficacious treatments., Methods: We enrolled 70 patients with CIPN in a randomized, double-blinded, sham-controlled, cross-over trial to determine if photobiomodulation (PBM)±physiotherapy reduced the symptoms of neuropathy compared to sham treatment. At the conclusion of follow-up, sham-arm patients could cross-over into a third arm combining PBM and physiotherapy to determine if multimodal treatment had additive effects. Treatment included 30minute sessions 3-times weekly for 6weeks using either PBM or sham therapy. Neuropathy was assessed using the modified total neuropathy score (mTNS) at initiation and 4, 8, and 16weeks after initiating treatment., Results: Sham-treated patients experienced no significant change in mTNS scores at any point during the primary analysis. PBM patients experienced significant reduction in mTNS scores at all time points. Mean changes in mTNS score (and corresponding percent drop from baseline) for sham and PBM-group patients respectively were -0.1 (-0.7%) and -4.2 (-32.4%) at 4weeks (p<0.001), 0.2 (0.0%) and -6.8 (-52.6%) at 8weeks (p<0.001), and 0.0 (0.1%) and -5.0 (-38.8%) at 16weeks (p<0.001). Patients who crossed over into the PBM/PT-group experienced similar results to those treated primarily; changes in mTNS score from baseline were -5.5 (-40.6%) 4weeks (p<0.001), -6.9 (-50.9%) at 8weeks (p<0.001), and -4.9 (-35.9%) at 16weeks (p<0.001). The addition of physiotherapy did not improve outcomes over PBM alone., Conclusion and Relevance: Among patients with CIPN, PBM produced significant reduction in neuropathy symptoms., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: We aimed to evaluate the feasibility and tolerability of hyperthermic intraperitoneal carboplatin (HIPEC-carboplatin) following secondary cytoreduction for recurrent, platinum-sensitive ovarian cancer., Methods: In a single institution prospective, pilot study, ten patients underwent secondary cytoreductive surgery followed by HIPEC-carboplatin at 1000 mg/m(2). Consolidation (6 cycles) was with platinum-based regimens. Adverse and quality of life were measured throughout treatment., Results: Twelve patients were enrolled of which 2 were excluded (one each for extra-abdominal disease indentified before surgery and suboptimal cytoreduction). All 10 remaining patients received prescribed HIPEC-carboplatin. There were no intra-operative complications or AEs attributable to HIPEC-therapy. Grade 1/2 nausea was the most common post-operative toxicity (6/10 patients). Two patients had grade 4 post-operative neutropenia and thrombocytopenia but only one experienced transient treatment delay. The median hospital stay was 5.5 days. 69/70 (98%) of planned chemotherapy doses were ultimately delivered with 1 patient electively forgoing her final treatment. At a median (range) follow-up of 16 (6-23) months, three patients have recurred at 8, 14, and 16 months from surgery. The median disease-free and overall survivals have not been reached. Fact-O scores were significantly lower following surgery (126 vs. 108, p<.01), but improved by completion of therapy (108 vs. 113, p=0.27)., Conclusions: HIPEC-carboplatin at 1000 mg/m(2) following optimal cytoreduction for ovarian cancer is feasible. Surgical complications were not observed, and post-operative AEs were largely within expected ranges. Consolidation using standard platinum-based regimens was feasible following HIPEC-carboplatin, and preliminary survival data suggests efficacy. Further investigation of HIPEC-carboplatin in the setting of debulkable cancer recurrence is warranted., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objectives: Despite increased use of integrative medicine in cancer therapy, little data exist on its efficacy. This prospective, randomized, pilot trial sought to evaluate the feasibility of combined modality integrative medicine (CM-IM) in women with ovarian cancer (OvCA) and evaluate its effects on quality of life (QoL), chemotherapy toxicity and immunologic profiles., Methods: Women with newly diagnosed OvCA requiring chemotherapy were offered enrollment. Those randomized to the experimental arm received hypnosis, therapeutic massage and healing touch with each cycle of chemotherapy. The control arm received chemotherapy without CM-IM. All patients completed QoL questionnaires prior to cycles 1, 3 and 6, and 6-months after chemotherapy. Immunologic profiles were measured. Statistical analysis was based on intent-to-treat. Student's t-test and Fischer's exact-test were used to determine differences., Results: Forty-three women enrolled. All women randomized to CM-IM were successfully treated. There were no statistical differences between the groups in age, stage, grade, histologic cell type, CA125 levels, or surgical cytoreductive status. There was no difference in overall QoL measurements. Re-hospitalization rates, treatment delays, anti-emetic use, and infection rates were similar. Immunologic profiles revealed no difference between arms for WBC or salivary IgA levels. Women receiving CM-IM had consistently higher levels of CD4, CD8 and NK cells, although this did not reach statistical significance., Conclusions: Prospective clinical evaluation of integrative medicine for women with gynecologic malignancy is feasible. This first, pilot study of CM-IM in gynecologic oncology demonstrated no improvement in QoL or chemotherapy toxicity. Integrative medicine-associated improvements in immunologic profiles warrant further investigation., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: To determine the disease characteristics and comorbidities predictive of vulvar cancer specific mortality and five year overall survival among older women, ages 65 and above., Methods: A retrospective analysis was conducted of women diagnosed with vulvar cancer at a single regional cancer center from 1989 to 2003, with a follow up to 2009. Treatment records were extracted for: demographics and treatment information, Eastern Cooperative Oncology Group (ECOG) performance status and Charlson comorbidity index score. Probability of death from vulvar cancer was estimated using cumulative incidence, treating death by other known and unknown causes as competing risks. Predictors of overall survival were determined using multivariate Cox regression analyses., Results: One hundred forty-six women were identified, with a median age at diagnosis of 79 years (range 65-95). Median follow up was 5.0 years (range 0.1-16.7 years). The cumulative incidence of vulvar cancer-specific mortality was 13% (95% CI: 0.08-0.19) at year one, 24% (95% CI: 0.17-0.31) at year three and 26% (95% CI: 0.19-0.33) at year five. Use of adjuvant therapy or surgical procedure performed did not differ by age at diagnosis (p=0.807 and 0.663) according to age group (65-74, 74-84 and 85+). Increasing age, Charlson comorbidity index score, lymph node involvement and type of surgery performed were associated with increased risk of death from any cause (all p<0.05)., Conclusion: Among women aged ≥65, vulvar cancer specific mortality was most significant in the first three years after diagnosis. Conversely other causes of mortality which can be attributed to comorbid conditions steadily increased with time., (Copyright © 2010. Published by Elsevier Inc.)

Objective: To determine feasibility and efficacy of administering docetaxel and carboplatin chemotherapy followed by pelvic radiotherapy and then consolidation chemotherapy in patients with advanced or recurrent endometrial cancer., Methods: Patients with surgically staged III-IV (excluding IIIA from positive cytology alone) endometrial cancer or biopsy confirmed recurrent disease were eligible. Treatment consisted of 3 cycles of docetaxel (75 mg/m²) and carboplatin (AUC 6) on a q21 day schedule followed by involved field irradiation (45 Gy)± brachytherapy and three additional cycles of docetaxel and carboplatin. Kaplan-Meier (KM) methods estimated overall survival (OS) and progression free survival (PFS)., Results: Forty-two patients enrolled, 7 did not complete therapy. 95% (39/41) had primary disease. Median age=58 years (range: 21-81 years). 78% (32/41)=endometrioid histology. Stages=10 IIIA, 21 IIIC, 1 IVA, 7 IVB, (recurrent=1 IC, 1 IIA). There were 23 non-hematologic and 14 grade 3 and 16 grade 4 hematologic toxicities. Seven patients died following treatment with a median follow-up of 28 months (range: 7-70 months). KM estimates and 95% confidence intervals for OS at 1 year were 95% (82-99%), at 3 years 90% (75-96%), and at 5 years 71% (45-86%). Of the 39 with primary disease, 11 progressed or died within 5 years of study enrollment. KM estimates and 95% confidence intervals for PFS at 1 year were 87% (72-94%), at 3 years 71% (51-83%), and at 5 years 64% (42-80%)., Conclusions: "Sandwiching" radiation between chemotherapy for advanced or recurrent endometrial cancer merits further development based on the reported PFS and OS., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Objectives: (1) To determine the response rate of advanced, recurrent, or persistent carcinoma of the cervix to ifosfamide, paclitaxel, and carboplatin chemotherapy; (2) to determine the progression free interval and survival rate in patients treated with this regimen; (3) to describe the toxicities associated with this regimen; and (4) to evaluate the quality of life of patients while on treatment., Methods: Eligible patients had histologically proven stage IVB, recurrent, or persistent carcinoma of the cervix not amenable to curative treatment with surgery and/or radiation therapy. Chemotherapy was given on day 1 of a 28-day cycle: mesna (600 mg/m(2)) prior to ifosfamide (2 g/m(2)), paclitaxel (175 mg/m(2)), carboplatin (AUC 5). Response rates were determined according to RECIST criteria. Toxicity was graded according the National Cancer Institute's common toxicity criteria. Quality of life measurements were obtained using the FACT-Cx., Results: Twenty-eight patients participated in this study, with 21 evaluable for response rate. Overall, 7 patients (33%) had a demonstrated objective response (4 complete responses, 3 partial responses). Stable disease was documented in 3 patients. The overall median survival for all patients was 10 months. Median progression free survival for evaluable patients was 5.0 months. Bone marrow suppression was the most common toxicity. There were no negative effects of this treatment regimen on quality of life assessments., Conclusion: Ifosfamide, paclitaxel, and carboplatin is an effective regimen in treating advanced or recurrent carcinoma of the cervix and has an acceptable toxicity profile., (Copyright © 2010. Published by Elsevier Inc.)

Background: Natural killer (NK) cells derived from patients with cancer exhibit diminished cytotoxicity compared with NK cells from healthy individuals. We evaluated the tumor response and in vivo expansion of allogeneic NK cells in recurrent ovarian and breast cancer., Methods: Patients underwent a lymphodepleting preparative regimen: fludarabine 25 mg/m(2) × 5 doses, cyclophosphamide 60 mg/kg × 2 doses, and, in seven patients, 200 cGy total body irradiation (TBI) to increase host immune suppression. An NK cell product, from a haplo-identical related donor, was incubated overnight in 1000 U/mL interleukin (IL)-2 prior to infusion. Subcutaneous IL-2 (10 MU) was given three times/week × 6 doses after NK cell infusion to promote expansion, defined as detection of ≥100 donor-derived NK cells/μL blood 14 days after infusion, based on molecular chimerism and flow cytometry., Results: Twenty (14 ovarian, 6 breast) patients were enrolled. The median age was 52 (range 30-65) years. Mean NK cell dose was 2.16 × 10(7)cells/kg. Donor DNA was detected 7 days after NK cell infusion in 9/13 (69%) patients without TBI and 6/7 (85%) with TBI. T-regulatory cells (Treg) were elevated at day +14 compared with pre-chemotherapy (P = 0.03). Serum IL-15 levels increased after the preparative regimen (P = <0.001). Patients receiving TBI had delayed hematologic recovery (P = 0.014). One patient who was not evaluable had successful in vivo NK cell expansion., Conclusions: Adoptive transfer of haplo-identical NK cells after lymphodepleting chemotherapy is associated with transient donor chimerism and may be limited by reconstituting recipient Treg cells. Strategies to augment in vivo NK cell persistence and expansion are needed.

Background: The primary objective was to study the antitumor activity of prolonged subcutaneous dosing of systemic 852A, a Toll-like receptor-7 agonist (TLR-7), in recurrent breast, ovarian and cervix cancer. Secondary objectives included assessment of safety and immune system activation., Methods: Adults with recurrent breast, ovarian or cervix cancer failing multiple therapies received 0.6 mg/m(2) of 852A subcutaneously twice weekly for 12 weeks. Doses increased by 0.2 mg/m(2)/week to a maximum of 1.2 mg/m(2). Serum was collected to assess immune activation., Results: Fifteen patients enrolled: 10 ovarian, 2 cervix and 3 breast. Three completed all 24 injections. There were two grade 2 (decreased ejection fractions), nine grade 3 (1 cardiovascular, 1 anorexia, 3 dehydration, 2 infections, 2 renal) and two grade 4 (hepatic and troponin elevation) unanticipated toxicities. Cardiac toxicities included three cardiomyopathies (2 asymptomatic) and one stress-related non-ST elevated myocardial infarction. Five patients discontinued therapy due to possibly associated side effects. One who had stable disease (SD) following 24 doses received 17 additional doses. A cervix patient with SD following 24 doses received chemotherapy after progressing 3 months later, and remains disease free at 18 months. Immune activation, as evidenced by increased IP-10 and IL-1ra, was observed., Conclusions: In this first human experience of a TLR-7 agonist delivered subcutaneously using a prolonged dosing schedule, 852A demonstrated sustained tolerability in some patients. Clinical benefit was modest, but immune activation was seen suggesting further study of antitumor applications is warranted. Because of cardiac toxicity; 852A should be used cautiously in heavily pretreated patients.

Objective: Effective patient -clinician communication at diagnosis is important, yet decreased provider time for face-to-face interactions makes traditional paradigms in cancer care difficult. We evaluated the effects of an educational video on patients' distress, cancer knowledge, coping skills and attitudes regarding learning about cancer at the time of ovarian cancer diagnosis., Methods: An educational video was developed in which oncology professionals, women with ovarian cancer, and their relatives discussed cancer information and experiences. Women admitted for initial diagnostic surgical staging for ovarian cancer were randomized to the educational or placebo video. Before and after the video, patients completed measures of (1) ovarian cancer information, (2) emotional distress, (3) learning attitudes, and (4) coping self-efficacy. Outcomes were analyzed for differences in mean change between intervention and placebo groups using t-tests., Results: Fifty-nine subjects were randomized (30 intervention/29 placebo). The majority were advanced staged, white, insured, high school educated, employed, and rated their disease seriousness as high. Anxiety, general distress and cancer-specific distress were high. Pre-post video: distress and self-efficacy between groups were unchanged, intervention subjects answered more knowledge items correctly (p=0.0004) and developed more negative learning attitudes (p=0.037). Following the educational video, patients who developed more negative attitudes also had increased intrusive thinking (p=0.046), a sign of increased distress., Conclusions: Video presentation of cancer-related information increases learning under conditions of high distress and disease threat however, it is not without risk for some. Differing information needs may affect women's emotional response under these conditions., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Objective. The goal of treating recurrent ovarian cancer is disease control while minimizing toxicity. Fulvestrant, a novel estrogen receptor (ER) antagonist, has proven clinically beneficial and well-tolerated in treating recurrent breast cancer. Ovarian cancer often expresses ER and may respond to anti-estrogen therapy. We evaluated fulvestrant in women with recurrent ovarian or primary peritoneal cancer. Methods. Patients with ER-positive, multiply recurrent ovarian or primary peritoneal carcinoma and either measurable disease according to RECIST criteria or an abnormal and rising CA-125 were eligible for enrollment. Treatment consisted of single agent fulvestrant, 500 mg IM on Day 1, 250 mg IM on Day 15, and 250 mg IM on Day 29 and every 28 days thereafter until either intolerance or disease progression. Disease response was assessed by monthly physical exams and CA-125 levels as well as CT scans bimonthly. The primary endpoint was clinical benefit (CB=complete response (CR)+partial response (PR)+stable disease (SD)) at 90 days. Results. Thirty-one women were enrolled and 26 women (median age of 61) met inclusion criteria and received at least one dose. Patients had received a median of 5 prior chemotherapeutic regimens (range: 2-13). We observed one CR (4%), one PR (4%), and 9 patients with SD (35%) using modified-Rustin criteria (CA-125 level). Using modified-RECIST criteria 13 patients (50%) achieved SD. The median time to disease progression was 62 days (mean 86 days). Grade 1 toxicity included headache (1 patient) and bromidrosis (2 patients). Conclusions. Fulvestrant is well-tolerated and efficacious. Objective response rates are low, but disease stabilization was common.

Black men "on the down low" have been considered prime agents of HIV transmission in the Black community despite little empirical evidence. We assessed the relationship between down-low identification and sexual risk outcomes among 1151 Black MSM. Down-low Identification was not associated with unprotected anal or vaginal sex with male or female partners. Future HIV prevention programs and research should target sexual risk behaviors of Black men, irrespective of identity, and not focus on the "down low."

Background: Thalidomide is an antiangiogenic agent with immune modulating potential. The objective of this study was to determine response rates among women who were treated for recurrent ovarian cancer using topotecan with or without thalidomide., Methods: Women were enrolled in this multicenter, prospective, randomized phase 2 trial between April 2001 and July 2005. Eligible patients had recurrent epithelial ovarian carcinoma with measurable disease or elevated CA 125 values. Patients had received prior platinum-based chemotherapy. Treatment arms received topotecan at a dose of 1.25 mg/m(2) on Days 1 through 5 of a 21-day cycle with or without thalidomide starting at a dose of 200 mg per day and then increasing the dose as tolerated. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria. The chi-square test was used to assess differences in response and toxicity, and the log-rank test was used to compare Kaplan-Meier survival curves., Results: The analysis included 69 women (39 women in the control arm and 30 women in the thalidomide arm). Known prognostic factors, including platinum sensitivity, were represented equally in each arm. The median thalidomide dose was 200 mg per day. The overall response rate in the control arm was 21% (complete response [CR] rate, 18%; partial response [PR] rate, 3%) compared with 47% in the thalidomide arm (CR rate, 30%; PR rate, 17%) (P= .03). The median progression-free survival for the control arm was 4 months compared with 6 months in the thalidomide arm (P= .02). The median overall survival was 15 months in the control arm and 19 months in the thalidomide arm (P= .67). Toxicities were similar between groups., Conclusions: The addition of thalidomide to topotecan for the treatment of recurrent ovarian cancer appears to improve response rates, and the authors believe that it warrants study through larger phase 3 trials.

Objective: To determine if pelvic examination affected management in patients undergoing first-line chemotherapy for ovarian cancer and to determine a threshold of change in tumor size reliably detectable by pelvic examination., Study Design: We reviewed 501 encounters among 47 women with ovarian cancer to see if pelvic examination prompted a management change. Clinicians then evaluated synthetic model "tumors" and were retested at intervals of 3-48 hours to determine change needed for reliable detection., Results: The median number of examinations was 3 during 8 cycles of chemotherapy. Fifteen examinations (10.5%) revealed palpable anomalies, attributable to known tumor in 10 instances. The most common events preceding management change were elevation in serum CA-125 (57%) or chemotherapy toxicity (20%). No changes were made based on pelvic examination alone. When assessing "tumor" volume in a model, estimates ranged from 33-309% of actual volume. Determination of volume change following a delay was poor. No reliable threshold of detection of volume change was established., Conclusion: Pelvic examination findings rarely dictated management changes in this study. Further, our results call into question the potential of routine pelvic examination to add significantly to clinical management during initial treatment given the wide range of error in "tumor" size estimates.

Objective: To investigate the efficacy and safety of bevacizumab in heavily pretreated patients with recurrent ovarian cancer., Methods: Patients with recurrent ovarian cancer were treated with intravenous bevacizumab 10 mg/kg every other week plus oral cyclophosphamide 50 mg daily until disease progression or undue toxicity. Adverse events were graded according to the NCI Common Toxicity Criteria. Response rates were determined by CA-125 levels or changes in target lesions according to RECIST., Results: Fifteen patients were treated. Median age was 57 years (range 42-69). The median number of previous chemotherapy regimens was 8 (range 5-15). The median time from the first diagnosis to treatment with bevacizumab was 68.9 months (range, 26.5-177.2). The median number of bevacizumab infusions was 8 (range, 2-12), and the total number was 113. Two patients (13.3%) had a complete response after 4 months of therapy. Six patients (40.0%) had a partial response. The median duration of this response was 3.9 months (range, 2.3-10.4). Three patients (20%) had stable disease of 4.0, 5.2 and 5.5 months' duration, and 4 patients (26.7%) had progressive disease. Despite being heavily pre-treated and having confirmed intra-abdominal cancer, no gastrointestinal perforations developed. Other toxicities included: grade 3 pancreatitis in 1 patient; grade 2 proteinuria and hypertension in another, which resolved with the cessation of bevacizumab., Conclusion: In our population of very heavily pre-treated patients, with at least five prior regimens, bevacizumab in combination with oral cyclophosphamide has significant activity with a response rate of 53%, without significant toxicity.

Introduction: Chemo-potentiation of radiation improves survival in women with cervical cancer. Our group has previously demonstrated the tolerability of weekly paclitaxel combined with cisplatin during radiation therapy. We sought to determine the efficacy of this regimen in patients with "high risk" cervical cancer, and to determine the short- and long-term toxicity of this approach., Methods: We prospectively enrolled surgically staged patients with positive peritoneal cytology, resectable nodal metastases, or primary tumor > 6 cm. Patients were treated using external beam radiation with concomitant cisplatin (50 mg/m2) during weeks 1, 4, and 7, and weekly paclitaxel (50 mg/m2), followed by four courses of adjuvant cisplatin (50 mg/m2) and paclitaxel (135 mg/m2). Toxicity, overall, and disease-free survival were evaluated., Results: Twenty-three patients were enrolled, and 21 were evaluable. Patient allotment by FIGO stage was: IB1 - seven, IB2 - five, IIA - two, IIB - four, IIIB - two, IV - three. Twenty patients (95%) completed radiation treatment (median dose to point A was 8278 cGy). Seventeen patients (81%) completed all chemotherapy. At a median follow-up of 58 months the overall survival was 68%. Overall survival for patients with clinical Stage I and II disease was 82% at a median of 64 months. Hematologic toxicity was common but rarely resulted in treatment delays. Late complications requiring intervention (obstruction, fistula, significant lymphocyst) occurred in 11 patients (52%)., Conclusion: The combination of paclitaxel and cisplatin appears efficacious in "high-risk" cervical cancer patients. Hematologic toxicity was common but tolerable. Long-term survival was common in these patients, however late toxicity was significant. This regimen should be investigated in collaborative phase III trials.

Topotecan (1.5 mg/m(2)/day for 5 consecutive days of a 21-day cycle) is an established recurrent ovarian cancer treatment, but myelosuppression can be dose limiting. This study evaluates the activity and tolerability of low-dose topotecan in our clinical experience. Case records were reviewed for patients with recurrent ovarian cancer in first through third relapse. Eligible patients had received > or =2 cycles of < or =1.25 mg/m(2) topotecan. Adverse events were evaluated using laboratory and clinical evaluation data. Twenty-seven eligible patients, most with advanced disease, received a total of 209 cycles (median, six cycles). Grade 3 or 4 hematologic toxicities during 184 cycles in 24 assessed patients were neutropenia, leukopenia, thrombocytopenia, and anemia in 35%, 28%, 36%, and 11% of cycles, and 21, 19, 16, and 10 patients, respectively. Only four grade 4 toxicities occurred: anemia (one) and thrombocytopenia (three). Myelosuppression was reversible, noncumulative, and manageable. Moreover, nonhematologic toxicity was generally mild to moderate, and the only two grade 3 events were constipation and deep vein thrombosis. Low-dose topotecan was active in this setting. Lower-dose topotecan is generally well tolerated and active in patients with pretreated ovarian cancer. Prospective clinical trials of low-dose topotecan in recurrent ovarian cancer are warranted.

Background: Lymphatic and hematologic metastases are rare in microinvasive cervical cancers (FIGO stage IA1), supporting a role for conservative treatment. Cervical conization followed by prolonged surveillance is an accepted treatment in patients with low-risk features and negative surgical margins. This option is particularly appealing for younger or nulliparous patients, in whom fertility may be highly desired., Case: We report a case of a 22-year-old, HIV-negative female with stage IA1 squamous cell cervical carcinoma who was found to have bilateral lymph node metastases in both pelvic and para-aortic distributions after electing to undergo hysterectomy., Conclusion: Clinicians treating patients with microinvasive cervical cancer conservatively must be aware of the possibility of lymph node involvement and should consider radiological imaging to look for metastatic disease.

Objectives: To determine progression-free survival (PFS) and overall survival (OS) in women with completely resected stage I or II carcinosarcoma of the uterus treated with adjuvant ifosfamide and cisplatin, and to assess the toxicity of this regimen., Methods: Eligible patients had histologically confirmed carcinosarcoma (mixed mesodermal tumor) and no postoperative radiotherapy following complete resection for clinical stage I or II disease. They were to have adequate renal, hepatic, and hematologic functions and performance status of 2 or less. Study entry was to be within 8 weeks of hysterectomy. Patients with previous chemotherapy, or other noncutaneous malignancies, were ineligible. Ifosfamide was administered 1.5 g/m2 intravenously (IV) over 1 h and cisplatin was given 20 mg/m(2) over 15 min followed by mesna 120 mg/m2 IV bolus, then 1.5 g/m2/24 h as a continuous infusion. Initial doses (daily x 5 every 21 days x 3 cycles) were reduced by 20% (to 4 days) for myelotoxicity., Results: Nine of seventy-six patients enrolled were deemed ineligible and another two who did not receive protocol treatment were inevaluable. Of the 65 evaluable patients, median age was 65 years; 50 patients (77%) were stage I and 15 (23%) were stage II. PFS and OS, respectively, were 69% and 82% at 24 months, and 54% and 52% at 84 months. Overall 5-year survival was 62%. Leukopenia was the most commonly reported, but manageable, toxicity., Conclusion: Adjuvant ifosfamide and cisplatin after primary surgery for stage I or II carcinosarcoma of the uterus is tolerable. In the absence of concurrent controls, the impact on PFS and OS is unclear. Pelvic relapse remains problematic.

Introduction: Endometrial stromal sarcomas (ESS) are a rare gynecologic malignancy. The optimal management of this cancer remains unclear, although previous reports have failed to demonstrate a clear benefit to adjuvant chemotherapy or radiation. With the successful application of directed biological therapy in other sarcomas, a review of the behavior and biology of this disease is warranted., Objectives: To review outcomes and patterns of failure in patients with endometrial stromal sarcoma diagnosed over 31 years at our institution and the relationship to protooncogene c-kit expression., Materials and Methods: Hospital records and pathology were reviewed for 28 patients with endometrial stromal sarcomas [19 low-grade (LGESS) and 9 high-grade (HGESS)] treated between 1972 and 2003. Archival tissue samples from 16 patients were available and stained with CD 117 (c-kit) antibody (1:25 dilution). Staining intensity was graded 1+ to 3+ and distribution of the cellular staining as focal (10-30% of the cells), intermediate (30-60% of the cells), or diffuse (>60% of the cells). Positive tumors had more than 10% of cells comprising the neoplasm display immunoreactivity. RESULTS.: We found a significant difference in 5-year overall survival between LGESS and HGESS (P = 0.001). There was no significant difference in overall survival for patients with local versus advanced disease (P = 0.53) or in overall survival for those who underwent lymphadenectomy and those who did not (P = 0.92). 50% of patients received postoperative radiation with no difference in disease-free or overall survival (P = 0.68 and P = 0.53). Ten patients relapsed (36%, four HGESS and six LGESS). Seven of sixteen (43.8%) tumor samples expressed detectable c-kit. Five of seven (71%) were HGESS, and the other two (22%) were LGESS tumors. The median survival of patients with c-kit-positive versus c-kit-negative tumors was 12 and 47 months, respectively., Conclusions: This study confirms the superior overall prognosis of LGESS relative to HGESS, despite the similar rates of relapse. Although hard to assess, due to population heterogeneity and small numbers, adjuvant chemotherapy and radiation appear to be of limited benefit. Expression of c-kit was common, especially in high-grade lesions and may represent a potential therapeutic target.

Objectives: To determine toxicity and establish a maximum tolerated dose of outpatient therapy with ifosfamide, paclitaxel, and carboplatin in women with advanced and recurrent cervical cancer., Methods: Eligible patients had stage IVB, recurrent or persistent cervical cancer that was not amenable to curative treatment with surgery or radiation therapy. A dose escalation through four dose levels was planned. Dose limiting toxicities were defined as grade 3 or grade 4 hematologic toxicity persistent to day 1 of the next scheduled cycle, grade 2 or higher central neurologic symptoms related to ifosfamide and grade 3 or grade 4 peripheral neuropathy., Results: Twelve patients, aged 29 to 71, received 64 treatments and were evaluable for toxicity. No patient was withdrawn from the study due to toxicity. Two patients had received prior radiation therapy without chemotherapy, and seven patients had received radiation therapy with concurrent chemotherapy. No dose limiting toxicity occurred at dose levels 1 or 2. Three dose reductions occurred at dose level 3 due to neutropenia and thrombocytopenia. The maximum tolerated dose is ifosfamide 2 g/m(2) over 2 h, paclitaxel 175 mg/m(2) over 1 h, and carboplatin at an AUC of 5 over 45 min. Grade 3 or grade 4 neutropenia was seen in 11 subjects. Two patients required growth factor support. Grade 3 or grade 4 anemia was seen in one patient. Grade 3 or grade 4 neuropathy was seen in one patient. Other grade 3 or grade 4 non-hematologic toxicity included muscle weakness, myalgia, cough, and shortness of breath., Conclusions: Combination therapy with ifosfamide 2 g/m(2), paclitaxel 175 mg/m(2), carboplatin AUC = 5 appears to be a safe regimen for the outpatient treatment of women with advanced or recurrent cervical cancer and warrants phase II investigation.

Objectives: Based on the reduced morbidity seen in our retrospective study, we undertook a prospective, randomized trial to determine whether transposition of the sartorius muscle improves post-operative morbidity in women with squamous cell carcinoma of the vulva undergoing inguinal-femoral lymphadenectomy., Methods: Patients with squamous carcinoma of the vulva requiring inguinal-femoral lymphadenectomy were randomized to undergo sartorius transposition or not. All patients received perioperative antibiotics, DVT prophylaxis, and closed suction surgical site drainage. Outcomes assessed include wound cellulitis, wound breakdown, lymphocyst formation, lymphedema, and/or rehospitalization. Cohorts were compared using Fisher's exact test. Baseline characteristics were compared using Student's t test or Fischer's exact test as appropriate. Logistic regression was used to assess the impact of sartorius transposition, after adjusting for other factors., Results: From June 1996 to December 2002, 61 patients underwent 99 inguinal-femoral lymphadenectomies, 28 with sartorius transposition, and 33 without. The mean (SD) age for controls and patients undergoing sartorius transposition was 63.5 (15.2) and 73.8 (13.7) years, respectively (P < 0.05). There were no statistically significant differences in BSA, tobacco use, co-morbid medical conditions, past surgical history, medication use, size of incision, duration of surgery, number of positive lymph nodes, pathologic stage, pathologic grade, pre- or postoperative hemoglobin, or length of hospitalization. There were no statistically significant differences in the incidence of wound cellulitis, wound breakdown, lymphedema, or rehospitalization. The incidence of lymphocyst formation was increased in the sartorius transposition group. After adjusting for age, however, the groups appeared similar., Conclusions: Sartorius transposition after inguinal-femoral lymphadenectomy does not reduce postoperative wound morbidity.

Objectives: To assess the antitumor activity of Temozolomide, a novel alkylating agent, in patients with persistent or recurrent ovarian or primary peritoneal carcinoma who have failed other second-line chemotherapy agents. To identify the nature and degree of toxicity of Temozolomide in this group of patients., Methods: Temozolomide was administered orally at an initial dose of 150 mg/m(2) daily for 5 days, every 4 weeks. If the initial course was tolerated without dose-limiting toxicity, then the dose was increased to 200 mg/m(2). Patients were evaluated for response and toxicity., Results: Fifteen patients were enrolled and evaluated. The median number of prior treatment regimens was 3. Hematologic toxicity was encountered in 26% of patients and was manageable. There were no complete or partial responses. One patient had stable disease with significant improvement in her performance status while on treatment., Conclusion: This dose and schedule of Temozolomide had insignificant activity in this heavily pretreated group of patients with persistent or recurrent ovarian or primary peritoneal carcinoma.

Objectives: Studies in several solid tumors have shown that the presence of occult metastasis in the bone marrow or peripheral blood is highly predictive of decreased disease-free and overall survival. Our objective was to determine the incidence of circulating ovarian or primary peritoneal cancer cells in the peripheral blood at the time of disease diagnosis, or recurrence, and to determine the prognostic significance of these occult metastasis., Methods: Peripheral blood was drawn preoperatively from 91 women thought to have newly diagnosed or recurrent epithelial ovarian or primary peritoneal carcinoma. All samples underwent a tumor-enriched immunocytochemical assay., Results: Sixty-four women were found to have epithelial ovarian or primary peritoneal cancer. Of the 64 women with cancer, 12 had evidence of circulating cancer cells in their peripheral blood (18.7%). Characteristics were compared between those with circulating cancer cells and those without, using Fisher's exact test or the Wilcoxon-Mann-Whitney test, as appropriate. Women with circulating cancer cells had statistically more grade 3 tumors than women without. At a mean follow-up of 18.7 months (SD 6.7 months), analysis using Kaplan-Meier estimation and the log-rank test indicated that survival curves did not differ between patients with and without circulating cancer cells., Conclusions: Ovarian and primary peritoneal cancer, which historically has been thought to spread primarily by direct cell seeding throughout the abdominal cavity, can have circulating cancer cells in the peripheral blood. The clinical utility of identifying circulating cancer cells is yet to be defined.

Objectives: From May 1993 until June 1997, the Gynecologic Oncology Group undertook a study of women with cancer of the cervix (Stage IA, IB, and IIA) who were about to undergo radical abdominal hysterectomy, pelvic lymphadenectomy, and aortic lymph node sampling. Immediately before this surgery, laparoscopy was performed and removal of the lymph nodes was attempted. There were two objectives: (1) to obtain information on the adverse effects and difficulties associated with laparoscopic lymph node removal and (2) to determine the adequacy of the lymph node removal., Methods: Four methods determined the adequacy of the lymph node removal: (1) the surgeon's opinion during laparoscopy, (2) a photographic record reviewed by two independent observers, (3) inspection of the surgical sites at laparotomy, and (4) lymph node count., Results: Seventy-three women were entered onto the study. Four patients were judged ineligible; 2 did not undergo laparoscopy and 17 women did not complete laparoscopic surgery because of metastatic lymph nodes judged unresectable or complications. Ten women were inevaluable. The remaining 40 women were completely evaluable for protocol objectives. All cases of bilateral laparoscopic aortic lymph node sampling were judged adequate by all four methods of evaluation. For laparoscopic pelvic lymphadenectomy 6 were judged incomplete at laparotomy, 3 of which were judged incomplete by independent reviewers. The mean number of right pelvic nodes removed was 16.6; left pelvic nodes 15.5; right aortic nodes 6.2; and left aortic nodes 5.9., Conclusions: Laparoscopic bilateral aortic lymph node sampling appeared to be reasonably safe and feasible. Laparoscopic therapeutic bilateral pelvic lymphadenectomy, although having a reasonable complication rate, demonstrated problems regarding adequacy, which are probably correctable.

Objectives: The aim of this study was to determine cervical cancer cell sensitivity to chemotherapy-induced apoptosis based on human papillomavirus (HPV) status., Methods: CaSki (HPV-positive) and C33A (HPV-negative) cells were treated with camptothecin or cisplatin. Cellular viability was determined by trypan blue exclusion. Apoptotic indexes were determined by flow cytometric analysis of annexin V labeling and morphological changes. Mitochondrial release of cytochrome c was determined by immunofluorescence using confocal microscopy. Caspase 3 activation and bax expression were assessed by immunoblotting., Results: CaSki cells displayed chemoresistance to both camptothecin and cisplatin. Low response to apoptogenic stimuli was evidenced by a marginal increase in the apoptotic cell fraction after camptothecin treatment (22.9 +/- 2.56%) compared with control (17.8 +/- 1.95%). Cisplatin (14.8 +/- 1.01%) caused a slight decrease in apoptosis. Mitochondrial release of cytochrome c and cleavage of caspase 3 could not be demonstrated in CaSki cells after treatment. Despite p53 mutation, C33A cells were sensitive to the antiproliferative effects of camptothecin and cisplatin. Mean apoptotic events were 17.5 +/- 0.33 for control, 42 +/- 1.76 for cisplatin, and 38.1 +/- 0.75 for camptothecin. An intact cytochrome c pathway was demonstrated in C33A cells leading to cleavage of caspase 3 after camptothecin treatment. The constitutive bax expression demonstrated in both cell lines displayed no change after camptothecin treatment., Conclusion: HPV-positive cervical cancer cells have an inherent resistance to chemotherapy-induced apoptosis. HPV-dependant inactivation of apoptotic regulators such as p53 and blockage of downstream events such as cytochrome c release and caspase 3 activation might be elemental to this cellular survival advantage provided by high-risk oncogenic papillomavirus.

Objective: The purpose of this study was to attempt to reduce the small bowel volume in cervical cancer patients undergoing radiation therapy using the belly board device and a four-field technique., Methods: From 1994 through 1997, twenty-one patients with cervical cancer were referred to the University of Minnesota Medical Center and underwent surgical staging with or without radical hysterectomy followed by postoperative external beam radiotherapy for various indications including positive nodal disease (n = 11), lymph-vascular space invasion (n = 2), poor histology (n = 3), parametrial disease (n = 4), and positive vaginal margin (n = 1)., Results: The median age of the 21 patients was 42 years (25-54 years) and a median external beam pelvic radiation dose of 4775 cGy (range, 4200-5075 cGy) was administered. All patients were evaluated for amount of small bowel in the field in both the supine and prone positions, with and without the belly board device (BBD), using a four-field technique. With a full bladder, abdominal radiographs with contrast were obtained to evaluate the volume of small bowel within the radiation fields. In most patients, the BBD was effective at minimizing the amount of small bowel in the lateral fields, whereas a prone position on the treatment table (without the BBD) spared the most small bowel with the AP/PA fields. Therefore over a 2-day cycle, the most small bowel sparing was obtained with the patients treated prone on the BBD for the lateral fields on Day 1 and prone on the table for the AP/PA fields on Day 2. Patients had FIGO stage IB (n = 18), IA2 (n = 1), and IIA (n = 2). The median follow-up was 37 months (24-65 months). No significant acute gastrointestinal or genitourinary toxicity was experienced and no patients have experienced a bowel obstruction to date., Conclusions: The BBD may offer a means for positioning the mobile small intestine out of the radiation field and improving the tolerance of radiotherapy. The BBD provides a noninvasive technique for reduction of acute and chronic gastrointestinal morbidity., (Copyright 2001 Academic Press.)

Objectives: The aim of the study is to determine whether critical pathways can be implemented at an academic institution to limit cost, without compromising patient satisfaction and quality of care., Patients and Methods: Patients undergoing a hysterectomy with either cervical or endometrial cancer were placed on specific critical pathways consecutively for an 18-month study period. Preoperative teaching was intensified to educate the patient regarding expectations during the postoperative period. All patients were started on early feeding and patients were also placed on separate care pathways addressing pain and deep vein thrombosis prophylaxis. Total direct costs and patient satisfaction were obtained throughout the study period. During the year prior to care pathway implementation, patient data and direct costs were obtained for the preintervention group utilized for comparison. Postintervention groups were summarized every 6 months during the study period., Results: From January 1997 through June 1998, 63 patients with cervical carcinoma undergoing a radical hysterectomy (DRG 353) and 21 patients with endometrial cancer who underwent a hysterectomy and lymph node sampling (DRG 355) were utilized as the preintervention group. During the 18-month study period (July 1998-December 1999), 42 patients (DRG 353) and 25 patients (DRG 355) were accrued. The average length of stay was reduced from 5.2 (DRG 353) and 4.7 days (DRG 355) prior to implementation of pathways to 3.4 days in both groups. In addition, total direct costs were reduced by 29 (DRG 353) and 32% (DRG 355) after implementation of care pathways. Patient satisfaction data recorded during the study did not demonstrate any change throughout the study period nor were there any higher rates of readmission after implementation of the care pathways., Conclusions: Critical pathways in gynecologic oncology can be implemented in a managed care environment in order to maintain high quality of care, maintain outcomes, and help reduce costs., (Copyright 2001 Academic Press.)

Objective: The goal of this work was to develop a combination chemotherapy regimen consisting of ifosfamide and paclitaxel to be evaluated in the management of gynecologic malignancies., Methods: The Gynecologic Oncology Group conducted a Phase I trial of the regimen, initially with paclitaxel (24-h infusion) delivered on Day 1 and ifosfamide (1 h) administered (with Mesna) over the subsequent 4 days. All patients received granulocyte colony-stimulating factor (G-CSF) starting 24 h after the Day 5 chemotherapy. Treatment was repeated on a 28-day schedule. A cohort of patients also received the alternate sequence of ifosfamide (4 days) followed by paclitaxel., Results: Twenty-two patients were evaluated. Even at the lowest dose level tested (paclitaxel 135 mg/m(2) followed by ifosfamide 1 g/m(2)/day x 4 days) grade 4 neutropenia was almost universal, despite the routine use of G-CSF. The alternate drug administration sequence resulted in marrow suppression of similar severity., Conclusion: The combination of 24-h infusional paclitaxel with ifosfamide delivered over 4 days results in severe neutropenia, despite the administration of G-CSF, and is not recommended for further evaluation. In view of the known activity of the two agents in several malignancies, including cervix cancer, it would be reasonable to investigate the delivery of the agents employing alternative treatment schedules predicted to result in less severe marrow suppression (e.g., 3-h infusional paclitaxel)., (Copyright 2001 Academic Press.)

Purpose: To compare the progression-free and overall survival in small-volume residual ovarian cancer after treatment with intravenous (IV) cisplatin and paclitaxel or an experimental regimen of IV carboplatin followed by IV paclitaxel and intraperitoneal cisplatin., Patients and Methods: Patients were randomized to receive either IV paclitaxel 135 mg/m(2) over 24 hours followed by IV cisplatin 75 mg/m(2) every 3 weeks for six courses or IV carboplatin (area under curve 9) every 28 days for two courses, then IV paclitaxel 135 mg/m(2) over 24 hours followed by intraperitoneal (IP) cisplatin 100 mg/m(2) every 3 weeks for six courses., Results: Of the 523 patients who entered this trial, 462 were determined to be assessable, with prognostic factors well balanced between the treatments. Neutropenia, thrombocytopenia, and gastrointestinal and metabolic toxicities were greater in the experimental arm. As a result, 18% of the patients received < or = two courses of IP therapy. Progression-free survival was superior for patients randomized to the experimental treatment arm (median, 28 v 22 months; relative risk, 0.78; log-rank P =.01, one-tail). There was a borderline improvement in overall survival associated with this regimen (median, 63 v 52 months; relative risk, 0.81; P =.05, one-tail)., Conclusion: An experimental regimen including moderately high-dose IV carboplatin followed by IP paclitaxel and IV cisplatin yielded a significant improvement in progression-free survival when compared with a standard regimen of IV cisplatin and paclitaxel. Because the improvement in overall survival was of borderline statistical significance and toxicity was greater, the experimental arm is not recommended for routine use. However, the results provide direction for further clinical investigation in small-volume ovarian cancer.

Objective: Complement system plays an important role in host defense mechanisms against microorganisms and tumor cells. To protect themselves from autologous complement-mediated damage, normal host tissues express cell membrane-associated complement regulatory proteins (CRPs). To investigate whether neoplastic endometrial tissues overexpress these proteins to escape complement damage, we examined the distribution of complement receptor type 1 (CR1, CD35), membrane cofactor protein (MCP, CD46), decay-accelerating factor (DAF, CD55), and protectin (MACIF, CD59) on frozen endometrial tissue samples., Methods: A total of 54 endometrial tissue samples were collected. Cryosections were obtained of 31 benign and 23 malignant tissue specimens. Tissue sections were stained by immunohistochemical staining procedure using specific antibodies and employing the avidin-biotin technique. Quantitation of the protein content of these CRPs was determined using the Samba 4000 image analysis system., Results: For all four of the CRPs studied, a statistically significant difference in protein expression between the benign and malignant endometrial tissue specimens (P < 0.0001) was observed., Conclusions: Overexpression of all the CRPs studied (CD35, CD46, CD55, CD59) was observed in the malignant as compared with the benign endometrial tissues. The upregulation of these CRPs may promote resistance of the endometrial malignant tissue to complement-mediated damage, thereby allowing the tumor cells to escape from cytolysis and thus promoting carcinogenesis., (Copyright 2000 Academic Press.)

Objectives: To determine the underlying prevalence of cervical intraepithelial neoplasia (CIN) in women with benign cellular changes on a Papanicolaou smear, and to evaluate follow-up strategies to identify women at high risk for serious underlying pathology., Methods: Nonpregnant women aged 18 to 75 years with benign cellular changes on a Papanicolaou smear were recruited from primary care clinics of an urban teaching hospital. The subjects (N = 132) were tested at baseline for the presence of human papillomavirus using the polymerase chain reaction technique, and underwent repeated cervicovaginal smears at 3, 6, and 9 months. At 12 months colposcopy was performed. The main study outcome was the proportion of subjects with CIN as determined by colposcopic biopsy specimens. We determined the sensitivity, specificity, and predictive values of historical risk factor information, human papillomavirus testing, and repeated cervicovaginal smears for the detection of CIN., Results: Cervical intraepithelial neoplasia was found in 30 of 132 women, of whom 27 (20%) had low-grade CIN (CIN I) and 3 (2%) had high-grade CIN (CIN II). Underlying CIN was significantly more common in women younger than 35 years or who had a history of Trichomonas infection or venereal warts, a positive human papillomavirus test result, or abnormal follow-up smears. However, no follow-up strategy combined high sensitivity with a low referral rate for colposcopy., Conclusions: The prevalence of underlying high-grade CIN in women with benign cellular changes is low. However, further prospective studies in other settings are needed before routine follow-up can unequivocally be recommended.

A variety of cytokines have been identified to play a role in ovarian cancer. In this pilot study, we sought to determine whether transforming growth factor-alpha (TGF-alpha) was detectable in the serum and ascites of women with advanced stage epithelial ovarian cancer. TGF-alpha was measured using an enzyme-linked immunosorbent assay and was present in 18 of 25 control sera. Prior to treatment for stage III or IV epithelial ovarian cancer, 18 patients had undetectable serum levels of TGF-alpha, while 18 had values ranging from 10.6 to 531.7 pg/ml. The group with undetectable levels had a 6-month greater median survival; detectable TGF-alpha might be a negative prognostic indicator. In a separate group undergoing second-look laparotomy, differences in median TGF-alpha values versus controls and the primary study group approached significance. TGF-alpha was detected in significantly more control peritoneal fluid samples than in patient ascites. A larger study is warranted.

Background: The routine use of extraperitoneal surgical staging prior to radiation therapy in patients with bulky or locally advanced cervical carcinoma remains controversial., Methods: A review was performed of 266 patients with cervical carcinoma who underwent extraperitoneal pelvic and paraaortic lymphadenectomy prior to receiving radiotherapy. Patients were divided into groups based on their lymph node status. Group A had negative lymph nodes; Group B had resected, microscopic lymph node metastases; Group C had macroscopically positive lymph nodes that were resectable at the time of surgery; and Group D had unresectable lymph nodes. All patients received standard radiotherapy utilizing external beam and brachy-therapy. Patients with lymph node metastases received extended field irradiation. Survival probabilities were computed by the Kaplan-Meier product limits method with statistical significance determined by the Mantel-Cox log rank test., Results: Lymph node metastases were detected in 50% of patients. Five- and 10-year disease free survival rates were similar for all patients in Groups B and C. All patients in Group D recurred. There was a 10.5% incidence of severe radiation-related morbidity and a 1.1% incidence of treatment-related deaths., Conclusions: Pretreatment extraperitoneal staging of patients with bulky or locally advanced cervical carcinoma may afford a survival benefit via the debulking of macroscopically positive lymph nodes without significantly increasing treatment-related morbidity or mortality.

Background: Animal models of stress and sepsis demonstrate increased hypophyseal gene expression of the transcription factor c-fos and the cytokines interleukin-1 and interleukin-6. Chronic central nervous system exposure to interleukin-1 results in hypermetabolism, accelerated nitrogen loss, anorexia, and cachexia. We test the hypothesis that the host response to ovarian carcinoma recapitulates the host response to sepsis regarding the elaboration of the transcription factors and cytokines in the central nervous system, liver, and lung., Materials and Methods: Nude mice were seeded intraperitoneally with either ovarian carcinoma (MA-148) or vehicle. The animal subjects were observed for 5 weeks and sacrificed for brain, pituitary, lung, and liver mRNA. We studied the mRNA accumulation of the transcription factors c-fos, c-jun, and C/EBP alpha and the cytokines interleukin-1 and interleukin-6 using reverse-transcriptase polymerase chain reaction., Results: Compared with the control, ovarian carcinoma in the mouse model resulted in the following: (1) Pituitary c-fos and c-jun mRNA increased 3-fold (P = 0.012) and 6-fold (P < 0.001), respectively; (2) pituitary IL-1 and IL-6 mRNA increased 4-fold (P < 0.001) and 8-fold (P = 0.037), respectively; (3) liver c-fos mRNA increased > 8-fold (P < 0.001); and (4) lung C/EBP alpha mRNA decreased greater than 10-fold (P < 0.001)., Conclusions: We conclude that the host response to ovarian carcinoma in this animal model recapitulates many aspects of the host response to bacterial sepsis especially concerning pituitary gene expression. These data suggest that, as in sepsis, a hypothalamic-hypophyseal-mediated cytokine response in ovarian carcinoma may result in hypermetabolism, accelerated nitrogen loss, anorexia, and cachexia.

Vascular endothelial growth factor (VEGF) expression and microvessel density were studied in cases of advanced epithelial ovarian carcinoma to evaluate their usefulness as prognostic variables. Tumor samples from 18 patients with advanced stage serous epithelial ovarian cancer were evaluated for VEGF expression by reverse-transcriptase polymerase chain reaction (RT-PCR) analysis. Immunohistochemical study of corresponding archival tissues with an antibody to von Willebrand factor (vWF; FVIII-RA) was used for tumor microvessel count determinations. The correlation of VEGF expression and mean microvessel counts was determined by an unpaired t-test. Survival analysis for known prognostic factors and VEGF expression was performed. Survival distributions were calculated by the product limit of Kaplan and Meier and significant differences between distributions were analyzed with a log rank test. From the RT-PCR analysis of tumor VEGF expression, 12 samples were found to be strongly positive, whereas six samples had low/negative VEGF expression. The median survival was 60 months for the VEGF-low/negative group and 28 months for the VEGF-positive group (P = 0.058). Other prognostic variables had minimal impact on survival, i.e. age < 65 years (P = 0.873), FIGO stage (P = 0.06), grade (P = 0.236) and debulking status (P = 0.842). Fourteen of 18 tumor specimens were suitable for microvessel counting. The mean microvessel counts of the VEGF-positive group and the VEGF-negative group were 27/hpf and 35/hpf, respectively (P = 0.16). In this preliminary analysis, high VEGF expression in epithelial ovarian carcinomas was associated with poor overall survival. Further study will be necessary to elucidate the lack of association of VEGF expression and tumor microvessel counts.

Background: Although the ascites of patients with ovarian carcinoma has been reported to contain immunosuppressive factors, the identity and source of this activity has not been fully elucidated. The objective of this study was to describe the purification of a single immunosuppressive protein, alpha-1 acid glycoprotein, from ovarian carcinoma ascites, identify its site of production, and describe a possible mechanism by which it inhibits lymphocytes., Methods: Ascites from proteins from five patients with epithelial ovarian carcinoma first were differentially precipitated by size with different concentrations of polyethylene glycol and then separated on the basis of isoelectric focusing. The protein factions then were placed in a lymphocyte proliferation assay to determine immunosuppressive activity. Western blot analysis was used to identify alpha-1 acid glycoprotein as an immunosuppressive protein in ascites. Total RNA was extracted from ovarian and hepatic cell lines as well as primary and recurrent ovarian tumor samples. Reverse-transcriptase polymerase chain reaction then was utilized to identify the site of production of this protein. Purified alpha-1 acid glycoprotein was placed in lymphocyte culture and its effects on lymphocyte interleukin-2 (IL-2) production were measured by enzyme-linked immunoadsorbent assay., Results: Addition of purified alpha-1 acid glycoprotein to the lymphocyte assay resulted in a 60% decrease in lymphocyte proliferation (P < 0.05). Alpha-1 acid glycoprotein transcript was not identified in ovarian tumor cells. The addition of purified alpha-1 acid glycoprotein to the lymphocyte culture resulted in a 65% decrease in IL-2 secretion into the media (P < 0.05)., Conclusions: Alpha-1 acid glycoprotein is an immunosuppressive protein purified from ovarian carcinoma ascites. It is not expressed primarily by ovarian carcinoma cells. It appears to inhibit IL-2 secretion by lymphocytes.

Background: Tumor angiogenesis is essential for solid tumor growth. Yet, the importance of any particular factor in neoplastic proliferation is poorly defined. This study examines the clinical significance of increased expression of one of the angiogenic factors, vascular endothelial growth factor (VEGF), in early stage ovarian carcinoma., Methods: Tumor specimens from 68 patients with International Federation of Gynecology and Obstetrics Stage I and II ovarian carcinoma were evaluated for VEGF expression. Antisense and corresponding sense (control) RNA probes were transcribed from the pCRII construct (Invitrogen, San Diego, CA), which contained human VEGF cDNA. The antisense probe was designed to include a highly conserved region of the VEGF coding sequence and thus detect all known variants. After in situ hybridization, sections were assessed for overexpression of VEGF., Results: Twenty-nine of the tumor samples overexpressed VEGF, whereas 39 specimens did not. In patients whose tumors demonstrated elevated VEGF expression, 25% were without evidence of disease recurrence at last follow-up. In contrast, 75% of the patients whose tumors did not overexpress VEGF were without evidence of disease at last follow-up (P < 0.001). Median disease free survival for the VEGF positive group was 22 months, compared with > 108 months for the VEGF negative group (P < 0.001). When borderline tumors were excluded from the survival analysis, median disease free survival for the VEGF positive group was 18 months, compared with >120 months for the VEGF negative group (P < 0.001). Other possible prognostic variables had minimal impact on survival; these included age, stage, grade, cytology, and tumor size (P > 0.05). Assignment to a high risk group, as defined by the Gynecologic Oncology Group of the National Cancer Institute, was somewhat predictive of a shorter relapse free interval (P = 0.056). In a multivariate analysis, however, only elevated VEGF expression was associated with poorer survival., Conclusions: In this analysis, patients with early stage ovarian carcinoma with increased VEGF expression had a poorer prognosis. Further study of VEGF may ultimately lead to identification of patients with high risk lesions whose tumor biology portends a worse prognosis and who therefore may benefit from aggressive adjuvant therapy.

The objective of this study was to evaluate the efficacy of oral ciprofloxacin in preventing febrile morbidity superimposed on the neutropenia induced from a paclitaxel regimen in ovarian cancer patients. Eligible patients received paclitaxel at doses of 135 to 175 mg/m2 alone or in combination with a platinum agent. They were randomized to either an observation (control) group or a ciprofloxacin prophylaxis group. Patients in the ciprofloxacin group received 500 mg ciprofloxacin orally twice a day once the absolute neutrophil count (ANC) was less than 500/mm3 and continued until the ANC was greater than 1000/mm3. Ninety patients were enrolled between the control (n = 45) and ciprofloxacin (n = 45) groups. They received 371 cycles of a paclitaxel-based regimen with 177 and 194 cycles in the control and ciprofloxacin groups, respectively. Ciprofloxacin prophylaxis was prescribed for 138 (71%) of the cycles in the ciprofloxacin group and was given for a mean duration of 7.7 days per cycle. The groups were similar in disease status and risk factors for neutropenia. Fifteen patients in the control group developed febrile neutropenia versus 12 of those in the ciprofloxacin group (P = 0.69). The mean ANC and mean length of hospital stay for neutropenic fever were also similar between groups. There was a greater frequency of an ANC < 100 associated with those prophylaxed with ciprofloxacin (P = 0.01). Only 44% of the febrile episodes were associated with a positive culture. Staphylococcus aureus was the most frequently reported organism isolated. Considering these results, it does not appear that febrile neutropenia is reduced by ciprofloxacin during grade IV neutropenia.

Objective: The aim of this study was to determine if the prescription of prolonged cycles of chemotherapy to patients with a variety of gynaecologic cancers has an adverse effect on quality of life (QOL)., Methods: Patients attending a single gynaecologic oncology clinic who received greater than 6 cycles of chemotherapy were identified. Prior to each chemotherapy cycle, patients were asked to complete a modified Functional Assessment Cancer Therapy-General (FACT-G) quality of life form. QOL scores were compared to their baseline or pretreatment score (cycle 1 score), as well as to their score representing the completion of primary therapy (cycle 6 score)., Results: Seventeen patients were identified as having received greater than 6 cycles of systemic cytotoxic chemotherapy. The total number of chemotherapy cycles analyzed was 95. Comparing QOL scores for cycle 1 and 6 to cycles 7-16, we found no significant alteration (improvement or deterioration) in the following subscale scores: physical well being (PWB), social well being (SWB), and functional well being (FWB). Similarly, overall QOL as represented by the summed individual scores was also not affected by the prescription of up to 16 cycles of chemotherapy. Analysis of the emotional well being (EWB) subscale scores revealed a significant downward trend after the 12th cycle of therapy as compared to the 6th cycle (p = 0.04), however this trend was not significant when compared to the pretreatment or cycle 1 scores (p = 0.16). There was however a statistically significant progressive deterioration in the subscale score of the relationship with the doctor (RWD). This was most marked after the 10th cycle of therapy (p < 0.0001). When split by disease status, we again found no statistically significant alteration in PWB, SWB, RWD, EWB, FWB and overall QOL for cycle 1 and 6 as compared to cycles 7-17. However, those patients who were able to attain a complete clinical response (CCR) disease status, achieved a higher SWB (p = 0.003), RWD (p = 0.02), EWB (p = 0.03), and overall QOL scores (p = 0.04) while their PWB scores were not statistically different from patients with stable (p = 0.7) or progressive disease (p = 0.6)., Conclusion: In conclusion, the prescription of prolonged cycles of chemotherapy to patients with gynaecologic cancers does not result in an overall deterioration of QOL. Further more an improvement in subscale and overall QOL was demonstrated in those patients able to attain a complete clinical response (CCR).

The development of continent urinary diversions was an important step forward in improving the quality of life of patients undergoing pelvic exenteration. While the technique is relatively simple, it can be very time-consuming and uses a significant portion of the patient's colon in its construction. Here a modification of the technique for construction of a continent ileocolic reservoir which results in a similar reservoir that uses less colon and requires less time to construct is presented. We also report results of the use of this technique in seven patients.

In spite of efforts to reduce complications associated with inguinal-femoral lymphadenectomy (IFL), morbidity continues to be substantial. We sought to assess the efficacy of sartorius transposition (ST) in reducing groin wound complications following IFL, in patients with vulvar malignancy. The records of 101 patients with vulvar cancer undergoing IFL through separate incisions between March 1975 and December 1994 were examined. Sixty-two patients undergoing ST (group 1) were compared to 38 who did not (group 2). The groups were similar with respect to age, weight, tobacco/alcohol use, prior abdominal/vulvar surgery, prevalence of diabetes, hypertension, or peripheral vascular disease, and previous exposure to irradiation or chemotherapy. Additionally, there was no significant difference with respect to extent of disease, incidence of macro-/microscopic groin metastases, use of groin drains, and use of perioperative antibiotics or deep venous thrombosis prophylaxis. Groin wound complications were less frequent in patients undergoing ST (group 1). The incidence of groin cellulitis was 30% in group 1 compared with an incidence of 58% in group 2 (P = 0.011). Significant groin wound morbidity, defined as either wound breakdown or cellulitis, was seen less frequently in group 1 (41% vs 66%; P = 0.029). Employing a multivariate analysis, only patient weight < 150 lbs and performance of ST were established as independently associated with a reduction in groin morbidity following IFL (P = 0.0281 and P = 0.0075, respectively). In conclusion, despite waning enthusiasm for its performance, ST appeared to significantly reduce the incidence of wound morbidity after IFL. Our data confirmed that separate incisions, and improved perioperative antibiotics, have not eliminated the value inherent in this surgical modification. We suggest a prospective trial to further establish the benefit of sartorius transposition during IFL.

This series reports the outcomes and significant complications associated with the rectus myocutaneous flap when used for pelvic or inguinal reconstruction in patients with gynecologic cancers. Perioperative variables were retrospectively reviewed to identify social and medical risk factors as well as intraoperative and postoperative complications that predisposed to rectus flap failure. Fifteen patients with gynecologic malignancies underwent reconstructive procedures using a vertically oriented rectus abdominis myocutaneous flap for either vaginal (n = 14) or inguinal (n = 1) reconstruction. The patients' primary cancers were cervical (n = 11), rectal (n = 1), ovarian (n = 1), vulvar (n = 1), and vaginal (n = 1). The median age was 50 years. The median follow-up was 17 months. All flaps were mobilized in conjunction with a radical salvage operation. There were no cases of vaginal prolapse and no abdominal wound infections. However, 4 patients (27%) had major postoperative morbidity in this small series. There was one wound dehiscence and three episodes of necrosis of the subcutaneous and cutaneous portions of the flap. All 4 of these patients required additional operative intervention or debridement. Eleven patients had complete healing of the flap. The rectus abdominis myocutaneous flap is a valuable option for gynecologic reconstructive procedures. Perioperative strategies for improving flap viability include the identification of risk factors that may compromise flap perfusions such as prior abdominal incisions, peripheral vascular disease, and obesity. Meticulous surgical technique is required to preserve the vascular pedicle. These strategies may be useful in preoperative counseling, the perioperative evaluation, and the intraoperative management.