Overall survival in patients with endometrial cancer treated with dostarlimab plus carboplatin-paclitaxel in the randomized ENGOT-EN6/GOG-3031/RUBY trial.

BACKGROUND: Part 1 of the RUBY trial (NCT03981796) evaluated dostarlimab plus carboplatin-paclitaxel compared with placebo plus carboplatin-paclitaxel in patients with primary advanced or recurrent endometrial cancer (EC). At the first interim analysis, the trial met one of its dual primary endpoints with statistically significant progression-free survival benefits in the mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) and overall populations. Overall survival (OS) results are reported from the second interim analysis. PATIENTS AND METHODS: RUBY is a phase III, global, double-blind, randomized, placebo-controlled trial. Part 1 of RUBY enrolled eligible patients with primary advanced stage III or IV or first recurrent EC who were randomly assigned (1 : 1) to receive either dostarlimab (500 mg) or placebo, plus carboplatin-paclitaxel every 3 weeks for 6 cycles followed by dostarlimab (1000 mg) or placebo every 6 weeks for up to 3 years. OS was a dual primary endpoint. RESULTS: A total of 494 patients were randomized (245 in the dostarlimab arm; 249 in the placebo arm). In the overall population, with 51% maturity, RUBY met the dual primary endpoint for OS at this second interim analysis, with a statistically significant reduction in the risk of death [hazard ratio (HR) = 0.69, 95% confidence interval (CI) 0.54-0.89, P = 0.0020] in patients treated with dostarlimab plus carboplatin-paclitaxel versus carboplatin-paclitaxel alone. The risk of death was lower in the dMMR/MSI-H population (HR = 0.32, 95% CI 0.17-0.63, nominal P = 0.0002) and a trend in favor of dostarlimab was seen in the mismatch repair-proficient/microsatellite stable population (HR = 0.79, 95% CI 0.60-1.04, nominal P = 0.0493). The safety profile for dostarlimab plus carboplatin-paclitaxel was consistent with the first interim analysis. CONCLUSIONS: Dostarlimab in combination with carboplatin-paclitaxel demonstrated a statistically significant and clinically meaningful OS benefit in the overall population of patients with primary advanced or recurrent EC while demonstrating an acceptable safety profile.

A phase II evaluation of motesanib (AMG 706) in the treatment of persistent or recurrent ovarian, fallopian tube and primary peritoneal carcinomas: a Gynecologic Oncology Group study.

OBJECTIVES: Vascular endothelial growth factors (VEGF) and their receptors have a critical role in stimulating the growth of ovarian cancer cells. Motesanib is a small molecule inhibitor of multiple receptor tyrosine kinases including VEGF receptors 1-3, as well as c-KIT and platelet-derived growth factor which are related to the VEGF family. PATIENTS AND METHODS: Twenty-two eligible patients with recurrent ovarian, fallopian tube or primary peritoneal carcinoma were treated with an oral daily dose of 125 mg of motesanib. Peripheral blood was analyzed for circulating tumor cells (CTC) and circulating endothelial cells/circulating endothelial progenitors (CEC/CEP), VEGF levels and cell-free circulating DNA (cfDNA). RESULTS: The study was abruptly halted after four patients developed posterior reversible encephalopathy syndrome. One patient had a partial response and seven patients had stable disease at the time they were removed from study treatment. Twelve of the 22 patients (50%) had indeterminate responses at trial closure. Early closure without clinical efficacy data precludes meaningful correlative studies. CONCLUSIONS: The serious central nervous system toxicity observed in patients with recurrent ovarian cancer precluded full examination of this agent in this population. There were no clear cut explanations for the high incidence of this known class effect in the study population compared with patients with other cancers.

Inadequate vitamin D status in adolescents with substantial bone mineral density loss during the use of depot medroxyprogesterone acetate injectable contraceptive: a pilot study.

STUDY OBJECTIVE: To examine vitamin D and parathormone (PTH) levels in adolescents who experienced substantial bone mineral density (BMD) loss during depot medroxyprogesterone acetate (DMPA) use. DESIGN: A non-randomized, multi-center study, during which DMPA was administered every 12 weeks and evaluation of lumbar spine and hip BMD by dual-energy X-ray absorptiometry (DXA) was conducted every 6 months. A blood sample for vitamin D and PTH measurements was obtained from adolescents who experienced >5% BMD loss. Vitamin D deficiency was defined as 25-hydroxyvitamin D (25OHD) level of <20 ng/mL, insufficiency as 25OHD level of 20-30 ng/mL, and sufficiency as 25OHD level of >30 ng/mL. RESULTS: Evaluation of vitamin D and PTH was carried out in 15 participants who experienced BMD loss of > or = 5% during DMPA use. At initiation of DMPA, participants had mean (+SE) age 17+1 years, gynecologic age 61+4 months, and body mass index 24+1.5 kg/m2. Racial/ethnic distribution was: Caucasian--7 girls, Hispanic--4 girls, African-American--3 girls, and other--1 girl. Six participants had BMD loss of >5% after 2 DMPA injections, five after 3 injections, one after 5 injections, one after 8 injections, one after 10 injections, and one after 13 injections. Only one girl (7%) had sufficient vitamin D. The other participants had vitamin D insufficiency (50%) or deficiency (43%). Participants' mean (+SE) PTH was 22+4 pg/mL (reference range 7-53 pg/mL), and mean (+SE) 1,25-dihydroxyvitamin D was 56+5 pg/mL (reference range 22-67 pg/mL). CONCLUSIONS: Inadequate vitamin D status was evident among the majority of female adolescents who experienced a substantial BMD loss while using DMPA.

Associations between depressive symptoms and sexual risk behavior in a diverse sample of female adolescents.

STUDY OBJECTIVE: To determine associations between depressive symptoms, locus of control, and sexual outcomes in a predominantly African-American cohort of female adolescents. DESIGN: A computerized assessment was administered to participants as part of a larger randomized clinical trial. We assessed sexual risk behaviors (SRBs) via self-report, and we assessed depressive symptoms using the Center for Epidemiologic Studies Depression Scale. We used multivariate regression to determine associations between depressive symptoms and outcomes while controlling for covariates. SETTING: This was a secondary analysis of baseline data collected during a randomized clinical trial intended to prevent unintended pregnancy and sexually transmitted infections (STIs). PARTICIPANTS: 572 adolescent females, ages 13 to 21 years, were recruited via a hospital-based adolescent clinic and community-wide advertisements. MAIN OUTCOME MEASURES: Participants reported on prior sexual intercourse, number of lifetime partners, frequency of intercourse, history of pregnancies and STIs, and locus of control. RESULTS: Two thirds of the sample had been sexually active. In a model that controlled for all covariates, those with a high level of depressive symptoms had higher odds of having had intercourse (adjusted OR = 2.29; 95% CI = 1.18-4.43). High levels of depressive symptoms were also independently associated with increased numbers of lifetime sexual partners and an external locus of control. However, when depression and locus of control were included in the same model, locus of control was not independently associated with SRBs. CONCLUSION: These findings support other literature demonstrating an association between depression and SRBs, particularly in a largely African-American population. They further suggest that perceived control does not fully explain the relationship between depression and SRBs.

Evaluation of linear array human papillomavirus genotyping using automatic optical imaging software.

Variations in biological behavior suggest that each carcinogenic human papillomavirus (HPV) type should be considered individually in etiologic studies. HPV genotyping assays might have clinical applications if they are approved for use by the FDA. A widely used genotyping assay is the Roche Linear Array HPV genotyping test (LA). We used LA to genotype the HPV isolates from cervical specimens from women with the full spectrum of cervical disease: cervical cancer, cervical intraepithelial neoplasia (CIN), and HPV infections. To explore the feasibility and value of the automated reading of the LA results, we custom-designed novel, optical imaging software that provides optical density measurements of LA bands. We compared unmagnified visual examination with the automated measurements. The two measurements were highly associated. By either method, the threshold between a negative and a positive result was fairly sharp, with a clear bimodal distribution. Visually, most positive results were judged to be strong or medium, with fewer equivocal results categorized as weak (9.5% of positive samples), very weak (6.5% of positive samples), or extremely weak (7.7% of positive samples). The automated measurements of the intensities were significantly associated with the strength of the visual categories (P < 0.001). At the extremes of the automated signal intensities (< or = 20 units or > or = 120 units), the bands were almost always categorized visually as negative and positive, respectively. In the equivocal zone (20 to 119 units), specimens were more increasingly likely to be judged to be visually positive as the number of other, definite infections on the same strip increased (P for trend < 0.001). Multiple, concurrent infections comprise > or = 25% of HPV infections; thus, any systematic visual tendency that influences their evaluation when the result is equivocal should be minimized. Therefore, automated reading is probably worth development if easy-to-calibrate hardware and software can be optimized.

Salvage of isolated vaginal recurrences in women with surgical stage I endometrial cancer: a multiinstitutional experience.

The objective of this study was to evaluate the treatment outcomes and risk factors of women with surgical stage I endometrial adenocarcinoma who were initially treated with surgery alone and subsequently developed isolated vaginal recurrences. Patients with surgical stage I endometrial adenocarcinoma diagnosed from 1975 to 2002 were identified from tumor registry databases at seven institutions. All patients were treated with surgery alone including a total hysterectomy, bilateral salpingo-oophorectomy, pelvic (+/- para-aortic) lymph node dissection, and peritoneal cytology and did not receive postoperative radiation therapy. Vaginal recurrences were documented histologically. Metastatic disease in the chest and abdomen was excluded by radiologic studies. Overall survival was calculated by the Kaplan-Meier method. Sixty-nine women with surgical stage I endometrial cancer with isolated vaginal recurrences were identified. Of the 69 patients, 10 (15%) were diagnosed with stage IA disease, 43 (62%) were diagnosed with stage IB disease, and 16 (23%) were diagnosed with stage IC disease. Patients diagnosed with grade 1 disease were 22 (32%), grade 2 disease were 26 (38%), and grade 3 disease were 21 (30%). Among women, 81% with isolated vaginal recurrences were salvaged with radiation therapy. The mean time to recurrence was 24 months, and the mean follow-up was 63 months. Among women, 18% died from subsequent recurrent disease. The 5-year overall survival was 75%. The majority of isolated vaginal recurrences in women with surgical stage I endometrial cancer can be successfully salvaged with radiation therapy, further questioning the role of adjuvant therapy for patients with uterine-confined endometrial cancer at the time of initial diagnosis.

Ovarian cancer metastatic to the brain: what is the optimal management?

PURPOSE: To better define determinants of survival and optimal management strategies for patients with ovarian cancer and brain metastases. METHODS: A review of literature using Medline identified 15 case series of ovarian cancer patients with brain metastases (OBM). Each article was abstracted for survival data, and in all cases, the intervals between ovarian cancer diagnosis and brain metastasis identification, and between brain metastasis identification and last follow-up were recorded. Cases were categorized by patient characteristics and treatment modality for brain metastases. Estimated survival probabilities were plotted using the Kaplan-Meier method with differences between subgroups analyzed by the log-rank test. Cox proportional hazards model was used to identify independent prognostic factors age, number of metastasis, and treatment modality associated with survival. RESULTS: The median interval from ovarian cancer diagnosis to brain metastasis in 104 identified patients was 19.5 months. Brain metastasis was single in 43%, multiple in 41%, and not reported in 16% of cases. About 81.7% of patients were treated for their brain metastases using external radiation therapy (XRT), chemotherapy, and surgery. XRT was utilized in 76% of 104 patients and in 93% of treated patients. The most commonly used modalities were XRT alone (40%) and craniotomy and XRT (17%). The median survival (MS) for all patients regardless of treatment type was 6 months. Patients who received any treatment lived longer than those not receiving surgery/chemotherapy/XRT (MS; 7 months vs. 2 months, P = 0.0001). Patients with single brain metastasis had a longer median survival (21 months vs. 6 months, P = 0.049) when treated with craniotomy plus radiation and/or chemotherapy compared to treatment regimens that excluded craniotomy. In a multivariate analysis, only treatment type was significant in predicting survival. CONCLUSION: OBM portends a poor prognosis, however, long-term survival is possible. Patients appear to benefit from therapy, especially selected groups of OBM patients with single brain metastasis treated with radiation therapy and surgery.

Panniculectomy with simultaneous gynecologic oncology surgery.

OBJECTIVE: The objective was to report the utility and morbidity of panniculectomy in obese gynecologic oncology patients undergoing exploratory laparotomy. METHODS: A retrospective chart review of 41 consecutive women who had a panniculectomy as part of an abdominal gynecologic oncology procedure between July 1996 and May 2000 was performed. Obese patients possessing a large pannus, the majority with a BMI > or = 30 kg/m(2), were included. Demographic, preoperative, operative, and postoperative data were obtained. Statistical analyses were performed using Statistical Analysis System (SAS) Version 6.13. RESULTS: Panniculectomy was performed on 41 patients with a mean age of 55, weight of 126 kg, and BMI of 48 kg/m(2). The most common comorbidities in this population were hypertension, diabetes, and osteoarthritis. Wound infection occurred in 4 (9.8%) patients; 88% of the patients received a hysterectomy. The average EBL was 358 cc. Operative time and length of hospital stay were on average 203 min and 5.5 days, respectively. A prior history of diabetes increased the risk of early complications (P = 0.03). Late complications were more likely to occur in older women (P = 0.05). Wound complications were increased in patients with larger BMI's (P = 0.05). CONCLUSIONS: This study supports the safety of the panniculectomy procedure in this high-risk group of morbidly obese patients for whom a technical advantage may be achieved by improved operative exposure.

Surgical management of early-stage endometrial cancer in the elderly: is laparoscopy feasible?

OBJECTIVE: To give insight into the utility of laparoscopic staging of endometrial cancer in the elderly population by reviewing the surgical management of clinically stage I endometrial cancer patients. METHODS: A retrospective analysis evaluating patients that were > or =65 years old and had planned laparoscopic staging, traditional staging via a laparotomy, or a transvaginal hysterectomy as management of their early endometrial cancer. The laparoscopic group had complete staging with bilateral pelvic and paraaortic lymph node dissections and was compared to the group who had staging performed via laparotomy. Patients were identified by our institution's database and data were collected by review of their medical records. Data were collected on demographics, pathology, and procedural information including completion rates, operating room (OR) time, estimated blood loss (EBL), transfusions, lymph node count, complications, and length of stay. Associations between variables were analyzed by Student's t tests and chi(2) testing using Excel v. 9.0. RESULTS: From February 25, 1994, through December 21, 2000, 125 elderly patients were identified. Sixty-seven patients had planned laparoscopic staging (Group 1), 45 patients had staging via planned laparotomy (Group 2), and 13 patients had a transvaginal hysterectomy (Group 3). Group 1 and Group 2 were compared regarding surgical and postoperative data. Age was not different between these groups (75.9 vs 74.7 years, P = NS). Quetelet index was also similar (29.4 vs 29.9, P = NS) 32.8% of Group 1 had > or =1 previous laparotomy compared to 51.1% in Group 2 (P = NS). In Group 1, 53/67 (79.1%) had stage I or II disease compared to 29/45 (64.4%) in Group 2 (P = NS). Laparoscopy was completed in 52/67 (77.6%) attempted procedures. The reasons for conversion to laparotomy were obesity 7/67 (10.4%), bleeding 4/67 (6.0%), intraperitoneal cancer 3/67 (4.5%), and adhesions 1/67 (1.5%). OR time was significantly longer in successful Group 1 patients compared to Group 2 patients (236 vs 148 min, p = 0.0001). EBL was similar between these groups (298 vs 336 ml, P = NS). Ten of 52 (19.2%) of successful Group 1 patients received a blood transfusion compared to 1/45 (2.2%) of Group 2 patients (P < 0.0001). Pelvic, common iliac, and paraaortic lymph node counts were similar between successful Group 1 patients and those in Group 2 combined with those that received a laparotomy in Group 1 (17.8, 5.2, 6.6 vs 19.1, 5.1, 5.2, P = NS). Length of stay (LOS) was significantly shorter in Group 1 versus Group 2 (3.0 vs 5.8 days, P < 0.0001). There were less fevers (6.0 vs 15.6%, P = 0.01), less postoperative ileus's (0 vs 15.6%, P < 0.001), and less wound complications (6.0 vs 26.7%, P = 0.002) in Group 1 compared to Group 2. Group 3 average age was 77.5 years. Concurrent medical comorbidities were the main reason for the transvaginal approach. OR time averaged 104.5 min. The average length of stay was 2.1 days with no procedural or postoperative complications. CONCLUSIONS: The favorable results from this retrospective study refute the bias that age is a relative contraindication to laparoscopic surgery. Laparoscopic staging was associated with an increased OR time and an increased rate of transfusion but equivalent blood loss and lymph node counts. Possible advantages are decreased length of stay, less postoperative ileus, and less infections complications. Transvaginal hysterectomy still remains a proven option for women with serious comorbid medical problems with short OR times, minimal complications, and short lengths of stay.

Laparoscopic pelvic and paraaortic lymph node dissection: analysis of the first 100 cases.

OBJECTIVE: The aim of this study was to analyze the first 100 cases of planned laparoscopic pelvic and paraaortic lymph node dissection (LND) done for staging of gynecologic cancers. The goal of the study was to assess prognostic factors for conversion to laparotomy and document complications. METHODS: A retrospective review of patients who had planned laparoscopic bilateral pelvic and bilateral paraaortic LND for staging of their gynecologic cancer was performed. Patients were identified by our institutional database and data were collected by review of their medical records. Data were obtained regarding demographics, stage, histology, length of stay, and procedural information including completion rates, operating room time, estimated blood loss, assistant, lymph node count, and complications. Associations between variables were analyzed using Student t tests, analysis of variance, and chi(2) testing (Excel v7.0). RESULTS: A total of 103 patients were identified from 12/15/95 to 8/28/00. Demographics included mean age of 66.2 (25-92) and mean Quetelet index (QI) of 30.8 (15.9-56.1). A total of 34/103 (33.0%) had > or =1 previous laparotomy. Ninety-five patients had endometrial cancer and 8 had ovarian cancer. Eighty-six of 103 (83.5%) were stage I or II. The length of stay was shorter for those who had laparoscopy than for those who needed conversion to laparotomy (2.8 vs 5.6 days, P < 0.0001). Laparoscopy was completed in 73/103 (70.9%) of the cases. Completion rates were 62/76 (81.6%) with QI < 35 vs 11/27 (40.7%) with QI > or = 35, P < 0.001. Significantly more patients had their laparoscopy completed when an attending gynecologic oncologist was the first assistant compared to a fellow or a community obstetrician/gynecologist (92.9%, 69.0%, 64.5%, P < 0.0001). The top three reasons for conversion to laparotomy were obesity, 12/30 (29.1%), adhesions, 5/30 (16.7%), and intraperitoneal disease, 5/30 (16.7%). Pelvic, common iliac, and paraaortic lymph node counts did not differ when compared to those of patients who had conversion to laparotomy (18.1, 5.1, 6.8 vs 17.3, 5.7, 6.8, P = ns). Complications included 2 urinary tract injuries, 2 pulmonary embolisms, and 6 wound infections (all in the laparotomy group). Two deaths occurred, 1 due to a vascular injury on initial trocar insertion and 1 due to a pulmonary embolism after a laparotomy for bowel herniation through a trocar incision. CONCLUSION: Laparoscopic bilateral pelvic and paraaortic LND can be completed successfully in 70.9% of patients. Age, obesity, previous surgery, and the need to perform this procedure in the community were not contraindications. Advantages include a shorter hospital stay, similar nodal counts, and acceptable complications.

A retrospective analysis of radical hysterectomies done for cervical cancer: is there a role for the Pfannenstiel incision?

OBJECTIVE: The goal of this work was to review patients with early-stage cervical cancer undergoing radical hysterectomy, comparing Pfannenstiel and vertical midline incisions for surgical feasibility, complications, and length of stay. METHODS: Patients were identified by searching our institutional database. Data were collected from review of each patient's medical record, including demographics, cancer stage, histology, procedural information, length of stay, and complications. Associations between variables were studied using chi(2) and two-tailed t tests. Multivariate analysis was performed using logistic regression. RESULTS: Between March 1996 and June 2000, 113 patients from the University and Presbyterian Hospitals, Oklahoma City, Oklahoma, underwent radical hysterectomy and pelvic and paraortic lymph node dissection with records available for review. Group 1 consisted of 40 patients who had vertical incisions and group 2 consisted of 73 patients who had Pfannenstiel incisions. There was no difference in race, number of previous abdominal surgeries, distribution of stage, histology, percentage of type III hysterectomies, estimated blood loss, nodal counts, pathologic margin positivity, and postoperative complications among the two groups. Group 2 were younger (41.6 vs 46.5, P = 0.02) and had a lower average QI than group 1 (24.9 vs 28.9, P = 0.001). Group 2 also had a shorter average hospital stay (4.6 days vs 5.8 days, P = 0.04) and shorter operative time (215 min vs 273 min, P = 0.09). Multivariate analysis resulted in Pfannenstiel incisions (P = 0.002), younger age (P = 0.004), and smaller body mass index (P = 0.01) being significant predictors of length of stay. CONCLUSIONS: Pfannenstiel incisions are feasible without increased morbidity and equal nodal retrieval as compared with vertical midline incisions in patients with early-stage cervical cancer. Pfannenstiel incisions may offer an advantage besides cosmesis in the form of shorter operating room time and earlier discharge from the hospital.

Effects of retinoids on cancerous phenotype and apoptosis in organotypic cultures of ovarian carcinoma.

BACKGROUND: Retinoic acid analogues, called retinoids, have shown promise in clinical trials in preventing breast and ovarian cancers. Classic retinoids bind to retinoic acid receptors, which regulate cell growth. Some novel retinoids, such as fenretinide, i.e., N-(4-hydroxyphenyl)retinamide (4-HPR), induce apoptosis through retinoic acid receptor-independent mechanisms; however, they appear to do so only at concentrations above those achieved in clinical chemoprevention trials. At lower concentrations (< or =1 microM), 4-HPR acts like classic retinoids, by inducing differentiation through a receptor-dependent mechanism. Our goal was to compare the effects of novel receptor-independent (apoptotic) retinoids with those of classic growth-inhibitory retinoids at clinically achievable doses on growth, differentiation, and apoptosis in ovarian tissue. METHODS: Four receptor-independent (apoptotic) and seven growth-inhibitory retinoids, including synthetic, low-toxicity compounds called heteroarotinoids, were administered at concentrations of 1 microM to organotypic cultures of ovarian primary and cancer cell lines: OVCAR-3, Caov-3, and SK-OV-3. After fixation, embedding, and sectioning, the growth fraction was quantified by measuring expression of the proliferation marker Ki-67/myb, differentiation was assessed by expression of mucin, and apoptosis was evaluated by the TUNEL assay. Spearman correlation analysis was performed on the data, and all P values were two-sided. RESULTS: All 11 retinoids reversed characteristics associated with the cancerous phenotype in all neoplastic cultures. Glandular structures were observed consistently in retinoid-treated, but not in untreated, OVCAR-3 and Caov-3 cultures. All retinoids decreased growth fractions, and some increased mucin expression. All receptor-independent retinoids and two receptor-dependent retinoids induced apoptosis, and the induction correlated significantly with increased expression of the mucin MUC1 (r =.83; P =.03). Retinoids with ester-linking groups did not induce apoptosis but decreased the growth fraction in correlation with MUC1 induction (r = -.93; P =.02). CONCLUSIONS: At clinically achievable concentrations, all retinoids tested decrease the growth fraction, induce differentiation and apoptosis. Induction of MUC1 expression is implicated in the mechanisms of action.

Factors affecting fellowship satisfaction among gynecologic oncology fellows.

OBJECTIVE: The objective of this study was to determine fellowship satisfaction through a survey of gynecologic oncology fellows. METHODS: A survey was sent to all gynecologic oncology fellows in May 1998. Surveys were returned anonymously and confidentially. The questions focused on demographics, research and clinical experience, education, faculty involvement, future plans, and fellowship satisfaction. Association between variables were studied using chi(2) and two-tailed t tests. RESULTS: Of the surveys 53.8% were returned. Reputation, faculty, and clinical diversity were ranked the top three reasons for choosing a fellowship program. Eighty-seven and three-tenths percent were satisfied and 89.1% would recommend their fellowship. Fellows listed the two areas they were most satisfied with as surgical training and research support. Seventy-nine and four-tenths percent agreed they spent adequate time in the operating room and 94.1% had enough variety. Sixty percent or more of the clinical fellows felt they would be uncomfortable performing vaginal radical hysterectomies, splenectomies, radical vaginectomies, laparoscopic lymph node dissection (LND), scalene LND, skin grafts, creation of neovagina, tram flaps, and ureterovaginal fistula repairs by the end of their fellowship. Of the fellows surveyed, 94.7% were currently performing research. All believed they would finish their thesis by the end of their training. Thirty percent of fellows from Gynecologic Oncology Group institutions were not required to participate in their research trials. Among the clinical fellows 62.2% thought time for self-education was lacking compared with 35.3% of the research fellows, P = 0.07. The two areas fellows were least satisfied with were didactics and lack of time for other pursuits. Performance evaluations were received by 72.2%; however, evaluations of the program and of the attending staff occurred in only 51.3 and 34.0%, respectively. Sixty-seven and three-tenths percent stated they had a mentor and 34.0% an advisor. Fellows that did not have mentors or advisors thought they spent less time with faculty in educational pursuits (P = 0.03, 0.06). CONCLUSION: Areas that could improve fellowship satisfaction include formal didactics and time for self-education. Evaluations of the fellowship and faculty could provide a forum to continue to assess their needs. Requiring a more active role of fellows in research trials may prove to increase research productivity in the future.

New options in contraception for adolescents.

There have been several recent advances in the contraceptive methods available to adolescents in the United States. A new monthly injectable method combines efficacy and ease of compliance with excellent menstrual cycle control. Very low-dose oral contraceptive pills containing gonane progestins decrease the incidence of estrogen-related side effects, and are associated with low rates of breakthrough bleeding. Oral contraceptive pills prescribed in continuous cycles can provide relief from menstrual-related symptoms, and may improve contraceptive effectiveness. Noncontraceptive benefits of oral contraceptive pills, such as improvement in dysmenorrhea and acne, may motivate more consistent pill-taking, and should be identified as additional reasons for pill continuation. Maximizing the prescribing time limit of emergency contraception to 120 hours after unprotected intercourse may improve access. Emergency contraception is more effective the sooner it is used, and should be provided in advance to adolescents for immediate use in the event a postcoital method becomes necessary.

Emergency contraception.

High rates of adolescent pregnancy remain a challenge for health care providers. For most sexually active adolescents, pregnancy is unintended. Emergency contraception, also called the "morning-after-pill" or postcoital contraception, is a way to prevent pregnancy after unprotected intercourse. In the United States, three forms of emergency contraception currently are available: high-dose combination estrogen and progestin pills, high-dose progestin-only pills, and postcoital insertion of a copper intrauterine device. The postcoital intrauterine device is used infrequently. When emergency contraceptive pills (ECPs) are taken within 72 hours of unprotected intercourse, they reduce the risk of pregnancy by at least 75%. However, they are most effective if taken within 24 hours of coitus. Eleven brands of pills currently are marketed in the United States that conform to the regimens approved by the Food and Drug Administration (FDA) for this indication. Recently, two prepackaged ECPs were approved by the FDA. The only medical contraindication to prescribing ECPs is pregnancy. The most common side effects are nausea and vomiting, followed by menstrual disturbances, breast tenderness, abdominal cramping, dizziness, headache, and mood changes. Because vomiting can compromise the efficacy of ECPs, routine pretreatment with an antiemetic is recommended. Primary care providers can reduce unintended adolescent pregnancy by routinely counseling adolescents at all office visits about the existence of emergency contraception and by prescribing it in advance and over the telephone.

Cadet basic training: an ethnographic study of stress and coping.

Cadet basic training (CBT) at the U.S. Military Academy at West Point is an initial cadet experience designed to transition freshmen (new cadets) into the military. Challenge is an inherent component of CBT, and some challenging activities may be stressful. However, the nature and the impact of stress on health status have not been systematically investigated. An ethnographic technique, participant observation, was used to identify stressors and coping strategies among cadets aged 18 to 21 years participating in CBT. A company of 183 cadets, consisting of 123 new cadets and 60 supervising upperclass cadets from the U.S. Military Academy, was followed throughout the 6-week CBT in the summer of 1993. The investigator observed daily activities and participated in select field training experiences. Daily field observations were taped, and field notes were generated chronicling the experience. After CBT, 10 of the 60 upperclass cadets participated in a 20-minute structured interview. Field and interview notes were systematically reviewed to identify and categorize stressors and coping techniques. Stressors included anticipatory stress, time management pressures, sleep deprivation, performance evaluations, conflicts between teamwork and competitive grading, and inexperience in the leadership role. Coping techniques identified included perceiving social support, humor, and rationalization. Three new hypotheses were generated from the observations.

Heteroarotinoids inhibit head and neck cancer cell lines in vitro and in vivo through both RAR and RXR retinoic acid receptors.

A class of less toxic retinoids, called heteroarotinoids, was evaluated for their molecular mechanism of growth inhibition of two head and neck squamous cell carcinoma (HNSCC) cell lines SCC-2 and SCC-38. A series of 14 heteroarotinoids were screened for growth inhibition activity in vitro. The two most active compounds, one that contained an oxygen heteroatom (6) and the other a sulfur heteroatom (16), were evaluated in a xenograph model of tumor establishment in nude mice. Five days after subcutaneous injection of 10(7) SCC-38 cells, groups of 5 nu/nu mice were gavaged daily (5 days/week for 4 weeks) with 20 mg/kg/day of all-trans-retinoic acid (t-RA, 1), 10 mg/kg/day of 6, 10 mg/kg/day of 16, or sesame oil. After a few days, the dose of t-RA (1) was decreased to 10 mg/kg/day to alleviate the side effects of eczema and bone fracture. No significant toxic effects were observed in the heteroarotinoid groups. All three retinoids caused a statistically significant reduction in tumor size as determined by the Student t-test (P < 0. 05). Complete tumor regression was noted in 3 of 5 mice treated with t-RA (1), 4 of 5 mice treated with 16, 1 of 5 mice treated with 6, and 1 of 5 mice treated with sesame oil. Reverse transcriptase polymerase chain reaction (RT-PCR) was used to determine that the expression levels of RARalpha, RXRalpha, and RXRbeta were similar in the two cell lines, while RARbeta expression was higher in SCC-2 over SCC-38, and RARgamma expression was higher in SCC-38 over SCC-2. Receptor cotransfection assays in CV-1 cells demonstrated that 16 was a potent activator of both RAR and RXR receptors, while 6 was selective for the RXR receptors. Transient cotransfection assays in CV-1 cells using an AP-1 responsive reporter plasmid demonstrated that t-RA (1), 6, and 16 each inhibited AP-1-driven transcription in this cell line. In conclusion, the growth inhibition activity of the RXR-selective 6 and the more potent growth inhibition activity of the RAR/RXR pan-agonist 16 implicate both RARs and RXRs in the molecular mechanism of retinoid growth inhibition. Moreover, the chemoprevention activity and the lack of toxicity of heteroarotinoids demonstrate their clinical potential in head and neck cancer chemoprevention.

Prescribing and managing oral contraceptive pills and emergency contraception for adolescents.

Combination OCPs are safe and effective ways to prevent unintended adolescent pregnancy if they are used properly. Numerous noncontraceptive benefits of OCPs can bolster continued combination OCP use. Progestin-only OCPs are an option, particularly for young women with medical contraindications to taking estrogens; however, because of their lower efficacy, progestin-only pills are not the first choice for oral contraception for adolescents. Health care providers can give young women a second chance to prevent unintended pregnancy by improving their access to emergency contraception through educating and counseling about emergency contraception at all office visits, by prescribing emergency contraceptive pills in advance, or by prescribing emergency contraceptive pills over the telephone.