Safety Run-in of Intramuscular pNGVL4a-Sig/E7(detox)/HSP70 DNA and TA-CIN Protein Vaccination as Treatment for HPV16+ ASC-US, ASC-H, or LSIL/CIN1.

Patients with human papillomavirus type 16 (HPV16) infection and low-grade cervical dysplasia [low-grade squamous intraepithelial lesion (LSIL)/CIN1] or atypical squamous cells [atypical squamous cells of undetermined significance (ASC-US)/atypical squamous cells- cannot exclude high-grade squamous intraepithelial lesion (ASC-H)] require active surveillance for disease progression. A safe and effective immunotherapy to clear HPV16 is an unmet medical need. The safety run-in cohort of a randomized double-blind, placebo-controlled phase II trial of PVX2 [vaccination twice with HPV16-targeting pNGVL4a-Sig/E7(detox)/HSP70 plasmid and once with the HPV16 L2E7E6 fusion protein "TA-CIN"] as immunotherapy for patients with HPV16+ ASC-US, ASC-H, or LSIL/CIN1 (NCT03911076) was recently completed. The primary objective of this cohort was to determine the safety and tolerability of PVX2 vaccination. Subjects were confirmed to have HPV16 infection and LSIL/CIN1, ASC-US, or ASC-H. Adverse events were evaluated using Common Terminology Criteria for Adverse Events v5.0. HPV typing by HPV16 18/45 Aptima Assay was done at baseline, month 6, and month 12, with simultaneous cytology analysis. Cervical biopsies and endocervical curettage were performed at baseline and month 6. In the safety run-in cohort 12 eligible patients were enrolled. Each received three monthly immunizations. One was lost to follow-up after week 12. There were no serious adverse events. A total of five adverse events were noted by 4 patients; 4 were considered not vaccine-related, and one 'unlikely related' by the investigator. At month 6, 45% (5/11) of participants converted to HPV16-negative and 2 others developed CIN2+ and received a loop electrosurgical excision procedure. At month 12, 64% (7/11) were HPV16-negative, including those HPV16-negative at month 6. In conclusion, PVX2 immunotherapy was well tolerated and associated with viral regression, supporting further testing. PREVENTION RELEVANCE: This safety run-in study cohort suggests that PVX2 immunotherapy is well tolerated in the target population and is sufficiently safe to warrant further clinical testing in a randomized study. The combined vaccines may facilitate higher-than-expected rate of human papillomavirus type 16 viral clearance 6 and 12 months after treatment, although this requires validation.

Rate of detecting CIN3+ among patients with ASC-US using digital colposcopy and dynamic spectral imaging.

The present study compared two methods for the detection of severe cervical dysplasia in women with atypical squamous cells of underdetermined significance (ASC-US) cytology; digital colposcopy with adjunctive dynamic spectral imaging (DSI) and conventional colposcopy. IMPROVE-COLPO was a two-arm cross-sectional study of US community-based colposcopy. The active (prospective) arm of this study recruited patients examined by digital colposcopy and adjunctive DSI. Preceding consecutive patients that had been examined with conventional methods were used as historical controls in the retrospective arm of the study after being matched in number to those in the prospective arm by a colposcopist. In the present study, the primary measure was the number of women detected with cervical intraepithelial neoplasia (CIN) grade 3 or worse (CIN3+) following punch biopsy. The study included 1,353 retrospective and 1,226 prospective patients eligible for this analysis who were examined by 146 colposcopists in 42 community-based clinics. The patient baseline characteristics were comparable between the two arms. The average number of biopsies taken per patient was higher among the prospective arm patients (including standard and DSI-assisted biopsies) compared with the retrospective arm control patients (1.21 vs. 0.97 respectively). Biopsy detected 31 patients with CIN3+ [2.29%; 95% confidence interval (CI), 1.56-3.24] in the retrospective arm, and 48 patients with CIN3+ (3.92%; 95% CI, 2.90-5.16) in the prospective arm. The difference in the number of patients detected with CIN3+ in the two arms of the study was 1.62% (95% CI, 0.30-3.04; P=0.022), which corresponds to a 70.9% relative increase in the prospective compared with the retrospective arm. Biopsy appeared less efficient in detecting patients with CIN3+ in the retrospective arm compared with the prospective arm. However, there was no statistically significant difference between the retrospective arm and the prospective arm in terms of: i) Biopsies taken (over the entire population) per patient detected with CIN3+ (42.2 in the retrospective arm vs. 30.8 in the prospective arm; P=0.164) and ii) positive predictive value of using biopsies to identify patients with CIN3+ (2.83 vs. 3.92; P=0.118). Adoption of digital colposcopy with DSI increased the number of biopsies collected from ASC-US patients compared with retrospective controls of standard colposcopy and detected a significantly higher number of patients who were CIN3+. The number of additional biopsies taken in the prospective arm compared with the retrospective arm was too small to explain the increased detection of patients with CIN3+ observed in the prospective arm, suggesting that biopsies in the prospective arm were better at identifying CIN3+.

Treatment of endometriosis-associated pain with linzagolix, an oral gonadotropin-releasing hormone-antagonist: a randomized clinical trial.

OBJECTIVE: To study the effect of a new investigational oral gonadotropin-releasing hormone antagonist, linzagolix, on endometriosis-associated pain (EAP). DESIGN: A multinational, parallel group, randomized, placebo-controlled, double-blind, dose-ranging trial. SETTING: Clinical centers. PATIENT(S): Women aged 18-45 years with surgically confirmed endometriosis and moderate-to-severe EAP. INTERVENTION(S): The interventions were 50, 75, 100, or 200 mg linzagolix (or matching placebo) administered once daily for 24 weeks. MAIN OUTCOME MEASURE(S): The primary endpoint was the number of responders (≥30% reduction in overall pelvic pain) after 12 weeks. Other endpoints included dysmenorrhea, non-menstrual pelvic pain, serum estradiol, amenorrhea, quality of life (QoL) measures, and bone mineral density (BMD). RESULT(S): Compared with placebo, doses ≥ 75 mg resulted in a significantly greater proportion of responders for overall pelvic pain at 12 weeks (34.5%, 61.5%, 56.4%, and 56.3% for placebo, 75, 100, and 200 mg, respectively). A similar pattern was seen for dysmenorrhea and non-menstrual pelvic pain. The effects were maintained or increased at 24 weeks. Serum estradiol was suppressed, QoL improved, and the rate of amenorrhea increased in a dose-dependent fashion. Mean BMD loss (spine) at 24 weeks was <1% at doses of 50 and 75 mg and increased in a dose-dependent fashion up to 2.6% for 200 mg. BMD of femoral neck and total hip showed a similar pattern. CONCLUSION(S): Linzagolix significantly reduced EAP and improved QoL at doses of 75-200 mg and decreased BMD dose-dependently. CLINICAL TRIAL REGISTRATION NUMBER: NCT02778399.

The road to zero preventable birth injuries.

BACKGROUND: The Seton Family of Hospitals' experience in developing and implementing transformational practices in labor and delivery (L&D) units aimed at reducing the rate of birth trauma at our facilities was previously reported. METHODS: Seton began its individual perinatal safety effort in earnest in October 2003. The endeavor brought together the four hospitals that offer obstetrical services, resulting in the establishment of an interdisciplinary team. The team meets monthly to develop and monitor best practices that are then shared, executed, and validated by each respective site's perinatal councils. RESULTS: A 36% reduction in the use of vacuum and forceps (from a frequency of 7.4% to 4.7%) was previously reported; the current rate (fiscal year [FY] 2007-FY 2008 year-to-date; July 1, 2006-December 31, 2007) was 4.1%. The incidence of associated birth trauma decreased to 0% for the last 15 months (ending December 31, 2007). During the first three project years (FY 2004-FY 2006), the average length of stay for infants admitted to the neonatal intensive care unit for birth injury declined by 80% (as compared with the previous three years), from 15.8 to 3.1 days. DISCUSSION: The perinatal safety team developed processes that have resulted in large and sustained reductions in the rate of serious birth trauma at all obstetric facilities.

Electrical impedance scanning as a new breast cancer risk stratification tool for young women.

BACKGROUND: Electrical impedance scanning (EIS) measures changes in breast tissue associated with breast cancer (Br-Ca) development. The T-Scan(tm2000 (ED is designed to use EIS to identify women ages 30-39 with elevated risk of breast cancer (i.e., T-Scan+ women). AIM: To estimate the relative probability of breast cancer in a T-Scan+ woman compared to a randomly selected young woman. METHODS: A prospective, two-cohort trial was conducted in pre-menopausal women. The Specificity (S(p))-Cohort evaluated T-Scan specificity in 1,751 asymptomatic women ages 30-39. The Sensitivity)S(n))-Cohort evaluated T-Scan sensitivity in 390 women ages 45-30 scheduled for biopsy. Specificity, sensitivity, and conservative estimate of disease prevalence were used to calculate relative probability. RESULTS: In the S(p)-Cohort, 93 of 1,751 women were T-Scan+ (S(p) = 94.7%; 95% CI: 93.7-95.7%). In the S(n)-Cohort, 23 of 87 biopsy-proven cancers were T-Scan+ (S(n) = 26.4%; 95% CI: 17.4-35.4%). Given S(p) = 94.7%, S(n) = 26.4% and prevalence of 1.5 cancers/1,000 women (ages 30-39), the relative probability of a T-Scan+ woman having Br-Ca is 4.95: (95% CI: 3.16-7.14). CONCLUSION: EIS can identify a subset of young women with a relative probability of breast cancer almost five times greater than in the population of young women at-large. T-Scan+ women have a sufficiently high risk of Br-Ca to warrant further surveillance or imaging.

Continuous, low-level, topical heat wrap therapy as compared to acetaminophen for primary dysmenorrhea.

OBJECTIVE: To determine if pain relief provided by a wearable heat wrap (continuous, low-level, topical heat therapy) is superior to oral acetaminophen for primary dysmenorrhea. STUDY DESIGN: A randomized, active-controlled, multisite, single-blind (investigator), parallel-design study compared an abdominal wrap to an oral medication (acetaminophen, 1000 mg) over I day. Pain relief (0-5) and abdominal muscle tightness/cramping (0-100) were recorded at 12 time points. At 24 and 48 hours, menstrual symptom-based quality of life was assessed. RESULTS: Three hundred sixty-seven subjects entered the study, with 344 subjects evaluable. The heat wrap was superior to acetaminophen for pain relief over an 8-hour period (means of 2.48 and 2.17, p = 0.015) and at t hours 3, 4, 5 and 6 (p < or = 0.05). Tightness/cramping was less for the heat wrap versus acetaminophen over 8 hours (means of 40.4 and 44.5, p = 0.04) and at hours 4, 5 and 6 (p < or = 0.05). There was significantly decreased fatigue, fewer mood swings and less lower abdominal cramping (p < or = 0.05) with heat therapy. CONCLUSION: Continuous, low-level, topical heat therapy was superior to acetaminophen for the treatment of dysmenorrhea.

Comparison of the efficacy and safety of nonprescription doses of naproxen and naproxen sodium with ibuprofen, acetaminophen, and placebo in the treatment of primary dysmenorrhea: a pooled analysis of five studies.

BACKGROUND: Dysmenorrhea is the most common menstrual complaint in young women, with a prevalence as high as 90%. It is responsible for substantial repeated short-term absenteeism from school and work in young women. Effective treatments are available, including nonsteroidal anti-inflammatory drugs (NSAIDs). In many countries, a variety of NSAIDs have become available as over-the-counter (OTC) drugs. OBJECTIVE: The goal of this study was to compare the efficacy and safety of OTC doses of naproxen (400 mg) and naproxen/naproxen sodium (200/220 mg) with acetaminophen (1000 mg), ibuprofen (200 mg), and placebo in the treatment of primary dysmenorrhea. METHODS: A pooled analysis of 5 trials was performed. Efficacy was assessed by pain relief, relief of other dysmenorrheic symptoms, time to backup medication or remedication, and treatment preference. Tolerability was assessed by recording adverse events (AEs). RESULTS: A total of 443 women were enrolled in the combined studies. Naproxen 400 mg provided greater pain relief than acetaminophen and placebo within 30 minutes of administration (P < 0.01 and P < 0.05, respectively). Furthermore, naproxen 400 mg and 200 mg provided greater pain relief than both acetaminophen (P < 0.01 and P < 0.05, respectively) and ibuprofen (P < 0.001 and P < 0.01, respectively) at 6 hours after administration. Both doses of naproxen had higher scores than placebo for symptom relief and drug preference (all P < 0.001). The AEs and their frequency were similar among the treatment groups. No serious AEs were reported. CONCLUSION: When administered at OTC doses, naproxen was effective in the relief of pain and other symptoms of primary dysmenorrhea and had a good safety profile in the population studied.