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.

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.

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.

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.

Substance use among adolescents with diabetes mellitus: preliminary findings.

Alcohol and drug use frequency was assessed by means of an anonymous, self-administered questionnaire in 79 diabetic adolescents who attended a diabetic sleep away camp. More than half of the participants reported using tobacco or alcohol at least once and 12%-25% reported greater that five times use in their lifetime. The overall frequency of drug and alcohol use was less than the general adolescent population. A modified Michigan Alcohol Screening Test (MAST) was used to evaluate abnormal drinking patterns, and 40%-50% of 12- and 16-year-old campers had an abnormal score, indicating that almost one-quarter of diabetic teens drink dangerously. There was a high correlation between campers who use drugs or alcohol and a positive family history of alcohol or substance abuse. Few campers perceived alcohol or drug use to affect their diabetic control, and the majority believed their control to be good to excellent, thus demonstrating the impact of denial in diabetic adolescent substance use. Adolescent diabetic assessments should include a psychosocial history, with emphasis on patterns of substance use, family substance abuse, and use of the MAST to identify high-risk individuals.

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.

Pressure changes within a chronic subdural hematoma during hemodialysis.

Spontaneous intracranial hemorrhage is not an infrequent complication of systemic anticoagulation, as occurs in hemodialysis. The neurological symptoms of subdural hematoma may be similar to those of dialysis disequilibrium. The pressure within a subdural fluid collection was monitored in a patient undergoing hemodialysis. The patient was known to become unresponsive during previous dialysis treatments. The initial pressure within the subdural cavity was measured to be -10.0 cm H2O prior to dialysis. The pressure within the collection decreased to a minimum value of -19.4 cm H2O during dialysis and stabilized at -16.4 cm H2O at the termination of dialysis. The neurological status changed subjectively during the procedure, with the patient becoming unresponsive to verbal stimuli as the intracranial pressure reached a minimum. These findings represent a syndrome similar to aliquorrhea, or low cerebrospinal fluid pressure within an otherwise asymptomatic subdural hematoma. Previously only increased intracranial pressure has been reported with hemodialysis.

Bilateral absence of the ovaries and distal fallopian tubes. A case report.

BACKGROUND: Bilateral tuboovarian absence is extremely rare and is associated with infantile sexual development, primary amenorrhea and primary infertility. CASE: A 23-year-old woman presented for evaluation of primary amenorrhea. Her examination revealed hypoplastic breasts, genitalia and uterus; ovaries could not be identified. Marked estrogen deficiency was confirmed by endocrinologic testing. The karyotype was normal female. The patient was started on combined hormone replacement therapy and subsequently developed normal menses; physical maturation progressed normally. At the age of 29 she underwent diagnostic laparoscopy for evaluation of her fertility potential, at which time the absence of both ovaries and distal fallopian tubes was confirmed. CONCLUSION: Bilateral tuboovarian absence is an extremely rare cause of primary amenorrhea and is associated with infantile sexual development and primary infertility. Its etiology includes tuboovarian torsion and congenital malformation. In this case, congenital malformation appears to have been the more likely cause.

Young women's attitudes toward injectable and implantable contraceptives.

STUDY OBJECTIVE: To assess the potential acceptability of implantable and injectable contraceptive characteristics by young women of diverse ethnic and educational backgrounds. DESIGN: A cross-sectional self-administered survey. SETTINGS: The waiting room of three clinical sites: an elite women's college health service, a coeducational state university health service, and an inner city hospital-based adolescent clinic. PARTICIPANTS: 328 young women awaiting medical care in one of three clinical sites, aged 13 to 21 years (85% 18-21 years); ethnic distribution differed significantly by site. The majority (83%) were sexually active, and of those who were sexually experienced, 25% had been pregnant. OUTCOME MEASURES: A 47-item questionnaire examining attitudes toward characteristics of injectable and implantable contraceptive methods, menstrual, sexual, and gynecologic history. RESULTS: Sixty-two percent of the sample agreed that they would get an injectable method. There was little variation in agreement to get an injectable method by sexual or pregnancy history. Fewer subjects (24%) agreed that they would like to get subdermal implants and agreement to get an implantable method of contraception did not vary by sexual history; however, ever-pregnant young women (33%) were significantly more likely to agree to implants than never-pregnant subjects (21%; chi2, 4.109; p = 0.04). Seventy-four percent of subjects said they would stop using a contraceptive that caused irregular menses, whereas 65% would stop using a method that caused amenorrhea. CONCLUSIONS: An injectable contraceptive method has universal appeal across ethnic, educational, and age categories, whereas implants are less appealing. Irregular bleeding and amenorrhea are poorly perceived side effects of long-acting contraceptives.

Attitudes of inner-city female adolescents toward medical and surgical abortion.

STUDY OBJECTIVE: To explore the attitudes of inner-city minority female adolescents toward medical and surgical abortion to determine if medical abortion methods, which have been shown to be both effective and safe, might have greater appeal than surgical abortion. DESIGN: A cross-sectional, self-administered survey. SETTING: The waiting room of an inner-city hospital-based adolescent clinic. PARTICIPANTS: At total of 157 female adolescents aged 13 to 21 years; Hispanic (56%) and African American (31%). Most (94%) were sexually active, 43% had been pregnant, and 29% had previously had a surgical abortion. OUTCOME MEASURES: An 86-item questionnaire examining attitudes toward medical and surgical abortion safety and impact on future fertility, and pregnancy, abortion, and sexual history. RESULTS: A total of 68% believe that abortion is safe, and 55% believe that having an abortion is better than having an unwanted child. Belief in the safety of abortion was significantly associated with older age and with never having had an abortion. Almost three fourths (72%) believe that having an abortion might impair future fertility either from surgical damage (73%) or "as a punishment for having an abortion" (38%). The majority (72%) believe that "the more abortions you have, the harder it will be to get pregnant in the future." Regardless of personal abortion experience, 51% believe that a medical abortion would be safer than a surgical abortion. A minority (34%) believe that it would be easier to get pregnant after a medical abortion than after a surgical one. CONCLUSIONS: Although most inner-city, minority adolescents believe that abortion is safe, they also believe they risk their future fertility by having an abortion. The availability of medical abortion regimens would greatly influence decisions regarding abortion.

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.

New progestin oral contraceptives and the female condom.

PIP: Recent advances in contraceptive technology offer US adolescent females the potential to reduce their risk of unwanted pregnancy and sexually transmitted diseases (STDs) without unacceptable side effects. Newly developed oral contraceptives that contain the progestins desogestrel or norgestimate (Desogen, Ortho-Cept, Ortho-Cyclen, and Ortho Tri-Cyclen) have fewer metabolic and androgen-related side effects yet maintain the progestational suppression of ovulation and the endometrium. The failure rate for these progestin pills is under 1%. A Sunday start regimen may be most appropriate for adolescents who have intercourse on weekends. To avoid discontinuation, adolescents should be counseled that breakthrough bleeding may occur for the first three cycles. Also recommended for use by adolescents is the new female condom--the only female-controlled method that confers protection against both pregnancy and STDs. With careful, consistent use, the female condom has a failure rate of 2.6% in the first six months.^ieng

Contraception update: implantable and injectable methods.

There are currently more options available to pediatricians caring for sexually active adolescents who wish to prevent pregnancy. The two progestin-only methods, levonorgestrel subdermal implants and DMPA injections, minimize or entirely remove the obstacle of patient compliance from contraceptive efficacy. Adolescents considering a progestin-only method of contraception should be counseled explicitly about the likelihood of menstrual irregularity with use. Perhaps more importantly, adolescents should be reminded that hormonal methods of contraception do not provide protection from sexually transmitted disease. Thus, male condom use should not only be recommended, but also concrete discussion and instruction on appropriate use should be given.

PIP: Two new progestin-only contraceptive methods--levonorgestrel subdermal implants and Depo-Provera injection--have the potential to overcome adolescents' traditional poor compliance with family planning methods. Both methods provide safe, highly effective, reversible fertility control, but require virtually no ongoing patient compliance. The levonorgestrel implants provide continuous contraception for up to five years and have a failure rate under 1%. The primary side effect is an alteration in menstrual patterns: prolonged bleeding in 40%, irregular bleeding in 38%, intermenstrual spotting in 32%, more frequent bleeding in 16%, and amenorrhea in 12%. An average weight gain of five pounds over the five-year period of use is expectable given the appetite stimulation associated with progestins. Depo-Provera, injected every three months, has a failure rate of 0.1-0.7% in the first year of use. Amenorrhea is the most commonly reported menstrual side effect. Although both methods are highly effective in preventing pregnancy, they confer no protection against sexually transmitted diseases; thus, adolescent acceptors should be counseled to use condoms concomitantly.

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.

Large ovarian cellular fibroma during pregnancy mimicking a lipid cell tumor.

Lipid cell tumors are extremely rare tumors of the ovary which are usually malignant when larger than eight centimeters. Fibromas, on the other hand, are the most common type of benign ovarian solid tumors. Neither one of these tumors are known to be accelerated by the pregnant state. We report a case of a healthy 15-year-old female who was found to have an ovarian mass during pregnancy. This fibroma weighed more than 3,800 grams and mimicked a lipid cell tumor. Cesarean section and unilateral oophorectomy resulted in a good outcome for both mother and child.

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.