Sustained efficacy and immunogenicity of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine: analysis of a randomised placebo-controlled trial up to 6.4 years.

BACKGROUND: Prophylactic human papillomavirus (HPV) vaccines have to provide sustained protection. We assessed efficacy, immunogenicity, and safety of the HPV-16/18 AS04-adjuvanted vaccine up to 6.4 years. METHODS: Women aged 15-25 years, with normal cervical cytology, who were HPV-16/18 seronegative and oncogenic HPV DNA-negative (14 types) at screening participated in a double-blind, randomised, placebo-controlled initial study (n=1113; 560 vaccine group vs 553 placebo group) and follow-up study (n=776; 393 vs 383). 27 sites in three countries participated in the follow-up study. Cervical samples were tested every 6 months for HPV DNA. Management of abnormal cytologies was prespecified, and HPV-16/18 antibody titres were assessed. The primary objective was to assess long-term vaccine efficacy in the prevention of incident cervical infection with HPV 16 or HPV 18, or both. We report the analyses up to 6.4 years of this follow-up study and combined with the initial study. For the primary endpoint, the efficacy analysis was done in the according-to-protocol (ATP) cohort; the analysis of cervical intraepithelial neoplasia grade 2 and above (CIN2+) was done in the total vaccinated cohort (TVC). The study is registered with ClinicalTrials.gov, number NCT00120848. FINDINGS: For the combined analysis of the initial and follow-up studies, the ATP efficacy cohort included 465 women in the vaccine group and 454 in the placebo group; the TVC included 560 women in the vaccine group and 553 in the placebo group. Vaccine efficacy against incident infection with HPV 16/18 was 95.3% (95% CI 87.4-98.7) and against 12-month persistent infection was 100% (81.8-100). Vaccine efficacy against CIN2+ was 100% (51.3-100) for lesions associated with HPV-16/18 and 71.9% (20.6-91.9) for lesions independent of HPV DNA. Antibody concentrations by ELISA remained 12-fold or more higher than after natural infection (both antigens). Safety outcomes were similar between groups: during the follow-up study, 30 (8%) participants reported a serious adverse event in the vaccine group versus 37 (10%) in the placebo group. None was judged related or possibly related to vaccination, and no deaths occurred. INTERPRETATION: Our findings show excellent long-term efficacy, high and sustained immunogenicity, and favourable safety of the HPV-16/18 AS04-adjuvanted vaccine up to 6.4 years. FUNDING: GlaxoSmithKline Biologicals (Belgium).

Quantitation of secretory component levels in cyst fluids, ascitic fluids, and sera from ovarian adenocarcinoma patients.

A secretory component (SC) was detected by radioimmunoassay in the cyst fluids, ascitic fluids, and sera from patients with ovarian adenocarcinomas. Serous cyst fluids and ascitic fluids showed lower levels (expressed as means +/- SE) of SC (1.37 +/- 0.37 and 1.24 +/- 0.24 microgram/ml, respectively) than mucinous cyst fluids (181.50 +/- 50.40 microgram/ml). SC levels in the sera of all patients with ovarian adenocarcinoma were high (12.67 +/- 1.43 microgram/ml) when compared to SC levels in the sera of normal individuals (2.34 +/- 0.41 microgram/ml). Sera from patients with ovarian cancers diagnosed as serous, mucinous, papillary, and poorly differentiated adenocarcinomas showed SC levels of 9.93 +/- 1.68, 22.44 +/- 3.24, 7.35 +/- 1.13, and 10.10 +/- 1.58 microgram/ml, respectively.

Inhibition of human lymphoblastoid cell line proliferation by ascites fluids from ovarian cancer patients.

Ascitic fluids from ovarian cancer patients which contained a component (lymphocyte-inhibitory activity) that inhibited the blastogenic responses of normal lymphocytes were tested for their effect on established lymphoblastoid cell lines. These ascites fluids inhibited proliferation as measured by [3H]thymidine uptake and cell growth in vitro of two different B- (SB and IM-1) and two different T- (HSB and CEM) lymphoblastoid cell lines but were not cytotoxic. No difference in the sensitivity of T- and B-lymphoblastoid cell lines to the active component in the ascites fluids could be demonstrated. In contrast, established nonlymphoid cell lines (HEp-2, oligodendroglioma, and bladder tumor cell lines) were unaffected by the ascites fluids. Two different preparations of partially purified lymphocyte inhibitory activity from these ascites fluids also inhibited lymphoblastoid cell line proliferation. In addition, both B- and T-lymphoblastoid cell lines absorbed and/or metabolized the lymphocyte-inhibitory activity at 37 degrees but not at 4 degrees. These data suggest that the inhibition of lymphoblastoid cell line proliferation and the inhibition of the blastogenic responses of normal lymphocytes by the ascites fluids are attributable to the same or similar factors.

Facilitated light microscopic cytochemical diagnosis of acute myelogenous leukemia.

Hydroperoxidase-positive Phi bodies and rods are much more prominent and prevalent than rods visualized with a Romanovsky-type stain (Auer rods) in immature leukocytes of patients with active acute myelogenous leukemia (AML). They are readily observed with the light microscope in peripheral blood or marrow films of AML patients stained to show their peroxidatic activity. In many of these patients, Auer rods, which apparently constitute only a small subpopulation of the hydroperoxidase-positive Phi bodies and rods, were detected with difficulty, if at all. The hydroperoxidase-positive Phi bodies and rods were observed in 92% of 36 patients with active disease. They were never observed in leukocytes of patients with other hematopoietic disorders or of normal individuals. Thus, they facilitated the distinction of AML from acute lymphocytic leukemia and chronic granulocytic leukemia in blast crisis. They were absent in full clinical remission after chemotherapy and were greatly diminished in partial remission. They were present in disease relapse and reappeared in five patients who had been in full remission. These results suggest that these hydroperoxidase-positive enlarged particles are pathognomonic of AML and that monitoring them with the light microscope may aid in guiding its clinical management.

Beneficial effects of endotracheal extubation on ventricular performance. Implications for early extubation after cardiac operations.

Early endotracheal extubation has been shown to be a safe postoperative management option in patients having cardiac operations. However, few objective data exist on the response of ventricular performance to early termination of controlled ventilation. Seven patients undergoing routine elective coronary artery bypass grafting or adult repair of atrial septal defect were studied after intraoperative placement of left ventricular micromanometers, left ventricular minor axis dimension crystals, and left atrial and intrapleural pressure catheters. Physiologic data were recorded intraoperatively, during controlled mandatory ventilation in the intensive care unit, and during spontaneous respiration immediately after extubation. Extubation to spontaneous breathing was associated with a significant decline in intrapleural pressure and significant increases in left ventricular end-diastolic diameter, ejection diameter shortening, stroke work, and cardiac output. The augmented left ventricular diastolic filling seemed to result from the fall in intrapleural pressure and perhaps from normalization of right ventricular afterload. The preload recruitable stroke work relationship showed that myocardial contractility remained constant after extubation, and ventricular function improved primarily because of increased preload associated with shifting of the capacitance blood volume toward the chest. Thus endotracheal extubation enhances cardiac performance after uncomplicated cardiac surgical procedures, and by this mechanism early extubation may be clinically beneficial as a routine adjunct to postoperative care.

Left ventricular adaptation to aortic regurgitation in conscious dogs.

OBJECTIVE: Cardiac failure as a result of valvular heart disease remains a major clinical problem that frequently leads to ventricular dysfunction, myocardial failure, and even death. The development of irreversible myocardial damage may be especially insidious in volume overload as a result of aortic or mitral regurgitation. METHODS AND RESULTS: Left ventricular wall volume, ventricular function, and myocardial performance were assessed in 10 chronically instrumented conscious dogs before and after creation of aortic regurgitation. Left ventricular wall volume was measured by serial echocardiography. Left ventricular function was assessed by total cardiac output, stroke work, the slope of the Frank-Starling relationship, and the slope of the end-systolic pressure-volume relationship. Myocardial performance was assessed by the slope of the myocardial power output versus end-diastolic strain relationship. End-diastolic wall stress and volume both increased acutely and remained elevated after creation of aortic regurgitation. Peak systolic wall stress increased initially (1 to 3 weeks) from 336 +/- 30 to 369 +/- 55 mm Hg but returned to control values as left ventricular wall volume increased from 78 +/- 13 to 88 +/- 16 ml after development of compensatory hypertrophy. Left ventricular systolic function remained constant or increased and was maintained initially by increased myocardial performance, which returned to baseline levels after the development of compensatory hypertrophy. CONCLUSIONS: Myocardial performance and ventricular function vary independently in aortic regurgitation. Measures of myocardial performance such as the myocardial power output versus end-diastolic strain relationship may be useful in clinical assessment of aortic regurgitation.

Interferon alpha-n1 (Wellferon) for refractory genital warts: efficacy and tolerance of low dose systemic therapy.

This multi-center trial compared two doses of parenterally administered interferon alpha-n1 (Wellferon) in men and women with recurrent/resistant genital warts. Patients received either 1 or 3 MU/m2 daily for 14 days, then 3 times weekly for 4 weeks; non-responders could receive an additional four weeks of treatment. A total of 107 patients were enrolled, and 102 were evaluable after six weeks of study. The principal dose comparison was in 57 women assigned alternately to the two doses. Median lesion measurements were reduced significantly from baseline at weeks 2, 4 and 6 in both groups. Statistical analysis showed no difference in response to 1 versus 3 MU/m2. The overall complete response (CR) plus partial response (PR) rate at week 6 was 69% for the two doses. Two additional groups of 21 women and 24 men were treated at the higher dose with CR plus PR rates of 75 and 50%, respectively. Week 10 disease evaluations for all groups showed 19 of 77 patients to be completely cleared. Of these 19, only one had recurrent disease at the end of the 6-month study period. Analysis of the incidence of symptomatic side effects showed a significantly higher frequency among women treated with 3 MU/m2 than among women treated with 1 MU/m2. Five dose reductions and two withdrawals for toxicity occurred, all in the high dose group. This study demonstrates that parenterally administered Wellferon produces clearance of resistant genital warts in many patients, and that rates of clearance do not appear to vary between groups receiving moderate or low dose therapy.

Myocardial infarction in the third trimester of pregnancy secondary to an aortic valve thrombus.

BACKGROUND: Myocardial infarction during pregnancy is rare, at an estimated one case per 10,000 women delivered. The overall mortality rate is 28% and is even higher in the second and third trimesters. We report a myocardial infarction secondary to a thrombus that developed on an artificial aortic valve in a 25-year-old woman at 26 weeks' gestation. CASE: The patient, gravida 6, para 3-0-2-3, presented with an acute myocardial infarction despite antepartum anticoagulant therapy with heparin. During her hospitalization, she experienced a second ischemic event, preterm labor, and a small upper gastrointestinal hemorrhage. Nitroglycerin, sublingual nifedipine, and heparin were used to stabilize her cardiac problems, and her uterine contractions were inhibited with tocolytic agents. At 35 weeks' gestation, she underwent an uncomplicated vaginal delivery of a 2608-g viable male infant. CONCLUSION: Pregnancy complicated by myocardial infarction due to a valve thrombosis in the third trimester can be managed with careful attention to controlling the cardiac symptoms and preventing premature delivery.

Myasthenia gravis and pregnancy: a reappraisal of thymectomy.

A retrospective review of pregnancy in patients with myasthenia gravis at Duke University was conducted. Twelve new cases of pregnancy in eight myasthenic mothers are reported. In general, thymectomy was the primary treatment modality in these patients and preceded the gestational period in all cases. The clinical course of myasthenia gravis in these pregnancies prompted a literature review of previous case reports. Comparison of clinical symptomatology, course of disease, and maternal and perinatal morbidity and mortality revealed that the incidence of clinical exacerbation was less in the thymectomy than in the nonthymectomy group. The role of the thymus in the pathogenesis of myasthenia gravis is reviewed. The rationale for the use and timing of thymectomy in the treatment of the myasthenic patient is presented. This review supports the continued use of thymectomy for the initial treatment of the young, nonpregnant myasthenic female patient.

Comparative evaluation of clindamycin versus clindamycin plus tobramycin in the treatment of acute pelvic inflammatory disease.

Fifty-one hospitalized women were treated with either clindamycin phosphate alone (N = 23) or a combination of clindamycin phosphate plus tobramycin (N = 28) for community-acquired pelvic inflammatory disease. The overall regimen clinical success rates were 100 and 91% for the clindamycin/tobramycin and clindamycin-alone groups, respectively. Efficacy for patients with positive pre-treatment Neisseria gonorrhoeae cultures was eight of eight (100%) for the clindamycin/tobramycin group and seven of eight (88%) in the clindamycin-alone group. Of the total population studied, 15 of 51 (29%) had positive pre-treatment cultures for Chlamydia trachomatis, and a microbiologic cure was attained in 15 of 15 (100%). However, in two of 15 (14.5%), the patient did not return for the 6-week culture, although the culture at discharge from the hospital was negative. No serious adverse reactions were observed, although oral follow-up treatment with clindamycin had to be discontinued in one patient because of diarrhea, which resolved without additional therapy. The results suggest that intravenous clindamycin alone is a viable alternative to the use of clindamycin/tobramycin for women with acute pelvic inflammatory disease requiring hospitalization.

Rupture of the pregnant uterus: a 53-year review.

A 53-year (1931-1983) review of 48 patients who experienced uterine rupture and were cared for at Duke University Medical Center was conducted. The observed incidence was one uterine rupture per 1424 deliveries. From January 1, 1963, through December 31, 1983, 24 cases of ruptured uterus were identified; a detailed review of these patients is presented.

Pulsatile administration of oxytocin for augmentation of labor.

In a randomized study, 94 patients with term pregnancies underwent augmentation of labor with either continuous or pulsed (every 8 minutes) intravenous oxytocin infusion. There were no significant differences with respect to the maternal characteristics, cervical dilatation and effacement, induction-to-labor interval, induction-to-delivery interval, cesarean section rate, analgesia for labor, or low Apgar scores. No hyperstimulation was noted in either group. In each group, 20% of the patients had dysfunctional labor patterns, with coupling and tripling of the uterine contractions. The mean +/- SEM oxytocin administered in the pulsed-infusion group was significantly lower than that in the continuous-infusion group (2.1 +/- 0.4 versus 4.1 +/- 0.4 mU/minute; P less than .001). The mean +/- SEM total amount of oxytocin administered was 1300 +/- 332 mU for the pulsed group and 1803 +/- 302 mU for the continuous group, indicating that lower amounts of oxytocin were required for pulsed administration. Our study demonstrates that pulsatile administration of oxytocin is similar in efficacy to our standard continuous oxytocin infusion and requires a lower total amount and rate of oxytocin administered, which may afford a greater margin of safety.

Human lymphoblastoid interferon (Wellferon) in primary therapy of two children with condylomata acuminata.

Human lymphoblastoid interferon (Wellferon) was administered parenterally to two prepubertal girls as primary therapy for genital condylomata acuminata. One child probably had contracted the disease as the result of sexual molestation. Both patients experienced minimal side effects during therapy and underwent complete remission within six weeks. These cases support use of interferon as primary therapy in young patients with extensive condylomata and in those who may have contracted the disease as the result of sexual abuse.

Efficacy of human lymphoblastoid interferon in the therapy of resistant condyloma acuminata.

The efficacy and tolerance of human lymphoblastoid interferon (Wellferon) were studied in an open label trial of 17 patients with resistant and persistent condyloma acuminata. Patients were treated intramuscularly with 5 X 10(6) U (5 MU)/m2 daily for 28 days followed by thrice weekly injections for two weeks. Sixteen patients were considered evaluable; eight experienced complete clearance, seven had significant reduction (greater than 50%) in lesion size, and one showed no response during the course of this trial. Biologic side effects of interferon occurred in all patients during initial dosing and diminished during thrice weekly therapy. Intramuscular injections and associated side effects were tolerated well. This study shows that systemic human lymphoblastoid interferon is active in treating severe recurrent genital warts in women with a history of recalcitrant disease.

Pregnancy-induced hypertension and postpartum maternal morbidity.

Prospective evaluation of 80 patients experiencing preeclampsia/eclampsia was conducted. Traditional antepartum clinical presentation, classification, and laboratory evaluation were found to be imprecise for the prediction of postpartum maternal morbidity. Serial urine samples were collected from all patients during the antepartum, intrapartum, and postpartum period. Urine albumin and immunoglobulin G (IgG) concentrations were measured by rate nephelometry. The degree of albumin and IgG excretion before and after standard treatment modalities correlates with the occurrence of postpartum morbidity. The nephelometric urinalysis appears to be of assistance in the evaluation of disease severity, the effectiveness of treatment modalities on renal function, and the identification of patients destined to develop postpartum morbidity. In addition, rapid nephelometric urinalysis makes the collection of 24-hour urine samples unnecessary for evaluation of renal function in pregnancy-induced hypertension.

Persistence of penicillin G benzathine in pregnant group B streptococcus carriers.

OBJECTIVE: To determine if streptococcicidal levels of penicillin G benzathine can be detected in maternal serum 4 weeks after treatment with 4.8 million units. METHODS: Thirty-seven pregnant women with positive group B streptococcus vaginal or urine cultures were each given 4.8 million units of penicillin G benzathine. Maternal blood samples were collected after injection and at delivery. Serum penicillin levels were measured by high-pressure liquid chromatography. Follow-up cultures were done when possible. RESULTS: None of the patients had serum penicillin levels below 0.20 microgram/mL 30 days after treatment. Cord blood levels were approximately 50% lower than maternal levels. In all but three subjects, cord blood levels exceeded 0.06 microgram/mL, the minimal inhibitory concentration for group B streptococcus. The three exceptions were patients who delivered more than 100 days after treatment. Group B streptococcus cultures were negative at the time of delivery in 72% of cases. None of the patients with positive cultures were moderately or heavily colonized. CONCLUSION: In pregnant women, penicillin G benzathine levels are high enough to inhibit the growth of group B streptococcus for more than 4 weeks after injection with 4.8 million units. Further studies are needed to evaluate whether this regimen can prevent neonatal colonization and invasive group B streptococcus disease.

The effects of prophylactic management and therapeutics on hypertensive disease in pregnancy: preliminary studies.

A controlled prospective evaluation of pregnancy complicated by chronic hypertension is proposed and preliminary data on population selection and pregnancy outcome are presented. Sixty-three women with evidence of underlying hypertensive disease were followed prospectively throughout pregnancy. Twenty-three patients were followed in a protocol of intensified prenatal care and randomized assignment of antihypertensive agents: placebo, hydralazine, or methyldopa. Forty patients were followed in the high-risk pregnancy clinics at Duke University. The incidence of preeclampsia in the randomized prophylactic antihypertensive group was statistically lower than that in the nonrandomized group (8.7 versus 32.5%; P less than .01). There were no other statistically significant differences between the groups. The 63 hypertensive women had a high incidence of diabetes mellitus diagnosed during pregnancy (49.2%) as compared to the authors' general obstetric population (8.1%).

Umbilical cord blood interleukin-6 levels and neonatal morbidity.

OBJECTIVE: To study umbilical cord interleukin-6 levels and the occurrence of neonatal sepsis, congenital pneumonia, necrotizing enterocolitis, and grade II-IV intraventricular hemorrhage. METHODS: Umbilical cord blood was collected from 133 preterm newborns. The study population was divided according to the presence or absence of neonatal complications. Interleukin-6 levels and clinical characteristics were compared by univariate and multivariate analyses. RESULTS: Sixteen neonates had adverse outcomes, and 117 were unaffected. The median interleukin-6 level was significantly higher in affected than in unaffected infants (145 pg/mL versus 0 pg/mL, P = .002). Elevated interleukin-6 levels were associated independently with neonatal morbidity in multiple logistic regression modeling that included gestational age, birth weight, and antenatal steroid exposure. CONCLUSION: Umbilical cord blood interleukin-6 levels are elevated in neonates who subsequently develop sepsis, congenital pneumonia, necrotizing enterocolitis, or grade II-IV intraventricular hemorrhage.

Weekly administration of prostaglandin E2 gel compared with expectant management in women with previous cesareans. Prepidil Gel Study Group.

OBJECTIVE: To compare the clinical effectiveness and safety of outpatient administration of intracervical prostaglandin (PG) E2 gel with expectant treatment for women desiring vaginal births after cesareans. METHODS: This was a randomized, multicenter investigation involving term pregnant women who each had one previous low-transverse cesarean and an unfavorable cervix (Bishop score no more than 6), and who was a candidate for vaginal delivery. They were assigned to receive 0.5 mg of PGE2, (Prepidil; Pharmacia-Upjohn, Kalamazoo, MI) intracervically at 39 weeks' gestation, repeated at weekly office visits for up to three doses, or expectant treatment. The main outcome variable was vaginal birth. RESULTS: Of 294 cases, 143 received gel and 151 were treated expectantly. No differences between groups were found for maternal age, race, or Bishop score. Compared with the expectant treatment group, the PGE2 gel group was not more likely to deliver sooner or vaginally (57% versus 55%, P = .68). The onset of labor, duration of labor among those delivering vaginally, and 1- and 5-minute Apgar scores were not different between groups. No uterine ruptures occurred, and adverse effects were equally likely in both groups. CONCLUSION: Although its safety was confirmed for outpatient use, weekly doses of intracervical PGE2 did not improve the likelihood of vaginal births after cesareans.

A trial of prophylactic cefamandole in extended gynecologic surgery.

A double-blind randomized trial of antibiotic prophylaxis was performed with 49 patients undergoing extended pelvic surgery for adenocarcinoma of the endometrium. In this series infections of the Hemovac drain site(s) were most common (8 of 10 infections); only 1 serious infection, pelvic cellulitis, occurred. Short-term perioperative cefamandole therapy significantly reduced infections and febrile morbidity in these patients as compared with patients who received a placebo. The average postoperative hospital stay for patients in the cefamandole group was 1 day less than for patients in the placebo group, but the difference was not statistically significant. The presence of 10 colony-forming units or more of a potential pathogen in lymph fluid collected through the Hemovac drains correlated with clinical infection. The low incidence of serious infection in this study precludes any conclusion regarding the impact of antibiotic prophylaxis in preventing serious infection after operation for gynecologic malignancy.