Heparin-binding epidermal growth factor and fibroblast growth factor 2 rescue Müller glia-derived progenitor cell formation in microglia- and macrophage-ablated chick retinas.

Recent studies have demonstrated the impact of pro-inflammatory signaling and reactive microglia/macrophages on the formation of Müller glial-derived progenitor cells (MGPCs) in the retina. In chick retina, ablation of microglia/macrophages prevents the formation of MGPCs. Analyses of single-cell RNA-sequencing chick retinal libraries revealed that quiescent and activated microglia/macrophages have a significant impact upon the transcriptomic profile of Müller glia (MG). In damaged monocyte-depleted retinas, MG fail to upregulate genes related to different cell signaling pathways, including those related to Wnt, heparin-binding epidermal growth factor (HBEGF), fibroblast growth factor (FGF) and retinoic acid receptors. Inhibition of GSK3ß, to simulate Wnt signaling, failed to rescue the deficit in MGPC formation, whereas application of HBEGF or FGF2 completely rescued the formation of MGPCs in monocyte-depleted retinas. Inhibition of Smad3 or activation of retinoic acid receptors partially rescued the formation of MGPCs in monocyte-depleted retinas. We conclude that signals produced by reactive microglia/macrophages in damaged retinas stimulate MG to upregulate cell signaling through HBEGF, FGF and retinoic acid, and downregulate signaling through TGFß/Smad3 to promote the reprogramming of MG into proliferating MGPCs.

The Natural History of Cervical Intraepithelial Neoplasia Grades 1, 2, and 3: A Systematic Review and Meta-analysis.

OBJECTIVE: The aim of the study was to obtain an updated overview of regression, persistence, and progression rates of conservatively managed cervical intraepithelial neoplasia grade 1 (CIN 1)/CIN 2/CIN 3. METHODS: Data sources were MEDLINE, Embase, and Cochrane (January 1, 1973-April 14, 2020). Two reviewers extracted data and assessed risk of bias. To estimate outcome rates, we pooled proportions of the individual study results using random-effects meta-analysis, resulting in point estimates and corresponding 95% CIs. Heterogeneity was quantified by the I2 and τ2 measures. RESULTS: Eighty-nine studies were included, 63 studies on CIN 1 (n = 6,080-8,767), 42 on CIN 2 (n = 2,909-3,830), and 7 on CIN 3 (n = 245-351). The overall regression, persistence, and progression to CIN 2 or worse and CIN 3 or worse rates for women with conservatively managed CIN 1 were 60% (95% CI = 55-65, I2 = 92%), 25% (95% CI = 20-30, I2 = 94%), 11% (95% CI = 8-13, I2 = 89%), and 2% (95% CI = 1-3, I2 = 82%), respectively. The overall regression, persistence, and progression rates for CIN 2 were 55% (95% CI = 50-60, I2 = 85%), 23% (95% CI = 19-28, I2 = 83%), and 19% (95% CI = 15-23, I2 = 88%), respectively. Finally, for CIN 3, these were 28% (95% CI = 17-41, I2 = 68%), 67% (95% CI = 36-91, I2 = 84%), and 2% (95% CI = 0-25, I2 = 95%), respectively. Cervical intraepithelial neoplasia grade 2 regression was significantly higher in women 30 years or younger and high-risk human papillomavirus-negative women (66%, 95% CI = 62-70, I2 = 76%; 94%, 95% CI = 84-99, I2 = 60%). Only 2/7,180 (0.03%) and 10/3,037 (0.3%) of the CIN 1 and CIN 2 cases progressed to cervical cancer. CONCLUSIONS: Most CIN 1/CIN 2 will regress spontaneously in less than 24 months, with the highest rates in high-risk human papillomavirus-negative and young women, whereas progression to cancer is less than 0.5%. Conservative management should be considered, especially in fertile women and with expected high compliance. Given the heterogeneity in regression rates of high-grade histology, this should be classified as CIN 2 or CIN 3 to guide management.

Post-Colposcopy Management and Progression Predictors of Biopsy-Proven CIN1 in Women Under 25 Years.

OBJECTIVE: The post-colposcopy management and outcome of cervical intraepithelial neoplasia grade 1 (CIN1) in women under 25 years of age was reviewed, and potential predictors for progression were identified. METHODS: Women under 25 with biopsy-proven CIN1 between January 1, 2010, and December 31, 2012 who were seen in the colposcopy clinic at the Queen Elizabeth II Hospital in Halifax, Nova Scotia were retrospectively reviewed. The regression, persistence, and progression rates of CIN1 were evaluated, and the relevant behavioural and biologic factors were reviewed. RESULTS: Of the 326 women with a biopsy-proven CIN1, 234 (71.8%) women returned to the regular screening program, and 92 women remained in the colposcopy clinic during follow-up, with a median follow-up time of 26 months. Sixty-two percent of the women had no cervical abnormality, 23.6% of the women had persistent CIN1, and 14.4% of the women showed progression. Eight percent showed progression to CIN2 with a median time of 13 months, whereas 6.4% showed progression to CIN3+ within a median time of 17.5 months. The extent of the lesion (hazard ratio 2.33; 95% CI 1.17-4.64, P = 0.02) and the Pap test result at the initial visit (hazard ratio 2.16; 95% CI 1.22-3.82, P = 0.008) were significantly associated with progression to CIN2+. CONCLUSION: On the basis of the 6% risk of CIN3+ and the median time to progression of 17.5 months, follow-up with cytology at 12 months seems acceptable. The extent of the lesion and the Pap test result at the initial visit were identified as risk factors for progression of CIN1.

Regression and Progression Predictors of CIN2 in Women Younger Than 25 Years.

OBJECTIVE: The purpose of this study was to review the management and outcome of cervical intraepithelial neoplasia 2 (CIN2) in women younger than 25 years. METHODS: A retrospective review was performed, investigating women younger than 25 years at the time of diagnosis with biopsy-proven CIN2 between January 1, 2010, and December 31, 2014, who were seen in the colposcopy clinic at the Queen Elizabeth II Hospital in Halifax, Nova Scotia, Canada. The regression, persistence, and progression rate of CIN2 in conservative managed women were evaluated, and potential risk factors were examined. Colposcopy, cytologic, and histopathologic findings were compared with women with immediate treatment (<6 months). RESULTS: Of the 319 women included in the study, 108 women received immediate treatment, and 211 women were managed conservatively; of these, 144 women remained untreated, and 67 women received treatment 6 months or greater. From the women managed conservatively, 150 women (71.1%) showed regression, 26 women (12.3%) had persistent disease, and 35 women (16.6%) progressed, with a median follow-up of 15.1 months. None of the women included in the study progressed to invasive cancer. The hazard ratio for time to progression was 2.40 for women who smoked (p = 0.006). CONCLUSIONS: A conservative approach of CIN2 is the preferred management option for women younger than 25 years. Smoking was identified as a risk factor for progression.

Luteinized Thecomas ("Thecomatosis") with Sclerosing Peritonitis (LTSP): Report of 2 Cases and Review of an Enigmatic Syndrome Associated with a Peritoneal Proliferation of Specialized (vimentin+/keratin+/CD34+) Submesothelial Fibroblasts.

OBJECTIVE: To present the clinicopathologic features of two cases of luteinized thecomas with sclerosing peritonitis (LTSP), characterize the cellular proliferation in the sclerosing peritonitis (SP), and review the literature. METHODS: The clinical, laboratory, and imaging data, operative findings, and pathology materials were reviewed and summarized. Samples of the SP were stained with keratin AE1/AE3, vimentin, CD34, calretinin, smooth muscle actin, ER/PR, CD10 and desmin. A literature search was performed to identify cases of LTSP for comparison. RESULTS: A total of 43 cases of LTSP syndrome were identified. Frequent clinical features included ascites (74%), abdominal pain (35%), bowel obstruction (42%), and bilateral masses (84%). We isolated a distinct form of ovarian luteinized thecoma (thecomatosis) and peculiar sclerosing peritonitis (SP). IHC analysis shows a proliferation of specialized (vimentin+/keratin+/CD34+) submesothelial fibroblasts (SMF) with patchy expression of calretinin and hormone receptors. CONCLUSION: LTSP syndrome is a rare entity presenting with abdominal pain, bowel obstruction, ascites, ovarian masses, and SP containing specialized (vimentin+/keratin+/CD34+) SMF. LTSP must be distinguished from abdominal cocoon, isolated SP, Meigs' syndrome, and peritoneal carcinomatosis. The importance of recognizing the diagnosis is stressed, as failure to manage this disease conservatively leads to significant morbidity and mortality. The SP and bowel obstruction may persist for months, even after resection of the tumours, resulting in extended medical therapy. Based on the immunophenotype of the peritoneal lesions, strategies to elucidate 'targeted' pharmacologic agents that could inhibit the proliferation of specialized (vimentin+/keratin+/CD34+) SMF may be of benefit.

Choosing the right patient: planning for laparotomy or laparoscopy in the patient with endometrial cancer.

OBJECTIVE: Endometrial cancer remains the most commonly diagnosed gynaecologic cancer in North America. The staging and initial treatment of endometrial cancer involves surgery. Laparoscopic surgery is increasingly used as an alternative to laparotomy. Patient selection for laparoscopy can be optimized by examining factors involved in both the choice of surgical approach and the ultimate procedure performed. We wished to identify factors that might be barriers to laparoscopic surgery in women with endometrial cancer who had surgery performed by the gynaecologic oncology group at the Capital District Health Authority (CDHA) in Halifax, Nova Scotia. METHODS: We conducted a retrospective review of the records of women with endometrial cancer, histologically confirmed preoperatively between 2005 and 2007, who underwent surgery at the CDHA. RESULTS: Between 2005 and 2007 in Nova Scotia, 428 cases of endometrial cancer were diagnosed, and 289 women with a preoperative diagnosis of endometrial cancer underwent surgery at the CDHA. Of these, 66.1% (191/289) underwent a planned laparotomy, and 33.9% (98/289) had a planned laparoscopy. The proportion of attempted laparoscopies increased from 21.9% to 57.1% (P = 0.002) over time, while there was no change in the conversion rate (P = 0.23). Patients with abnormal findings on pelvic examination were more likely to have a laparotomy (RR = 1.5; 95% CI 1.34 to 1.68). Independent predictors of laparoscopic conversion to laparotomy were age 75 years or over (P = 0.03) and non-endometrioid histology (P = 0.002). CONCLUSION: Our data identify age and non-endometrioid histology as independent factors for conversion of surgery for endometrial cancer from laparoscopy to laparotomy. With this information we can optimize patient selection for laparoscopic surgery. Patients undergoing a conversion to laparotomy do not have a significant increase in surgery time or perioperative morbidity.

Efficacy of pegylated liposomal doxorubicin (PLD) plus carboplatin in ovarian cancer patients who recur within six to twelve months: a phase II study.

OBJECTIVES: Pegylated liposomal doxorubicin is one of the preferred alternatives for ovarian cancer patients with early relapse (<6 months) and taxane/carboplatin for late relapse (>12 months), but the optimal therapy for the partially platinum-sensitive (6-12 months) population has not been defined. This single-arm phase II trial was designed to assess the efficacy of pegylated liposomal doxorubicin (PLD)/carboplatin in ovarian cancer patients who relapse between 6 and 12 months after initial treatment with platinum-based chemotherapy. METHODS: Ovarian cancer patients who previously completed a course of therapy with paclitaxel/carboplatin were administered PLD 30 mg/m(2) followed by carboplatin AUC 5 mg/mL/minute every 4 weeks. RESULTS: Fifty-eight patients were enrolled in the study and 54 were eligible for the efficacy analysis, of whom most (75%) received at least 6 cycles of PLD/carboplatin. The objective response rate was 46% (4% CR and 42% PR), with an additional 33% experiencing disease stabilization >6 months. For those patients with measurable CA-125, the response rate was 66% (28% CR and 38% PR), with an additional 18% experiencing disease stabilization >6 months. Median time-to-progression was 10 months (1.5-25). Median overall survival was 19.1 months (2.2-38.9). The most frequent adverse effects were neutropenia, thrombocytopenia, and constipation. CONCLUSIONS: The combination of PLD/carboplatin is efficacious and well tolerated in women with partially platinum-sensitive ovarian cancer and represents a valuable alternative for patients who relapse within 6-12 months of completing paclitaxel/carboplatin chemotherapy.

Maternal age-related rates of gestational trophoblastic disease.

OBJECTIVE: To estimate the incidence of gestational trophoblastic disease in Nova Scotia and to evaluate the effect of time and maternal age on these rates. METHODS: Information on women with a pathologically confirmed diagnosis of gestational trophoblastic disease was extracted from the Nova Scotia Gestational Trophoblastic Disease Registry between 1990 and 2005. The total numbers of deliveries and pregnancies were determined from the Nova Scotia Atlee Perinatal Database and consensus data derived from Statistics Canada. RESULTS: Four-hundred twenty-eight women were identified with gestational trophoblastic disease. Hydatidiform moles showed rates of 220/100,000 pregnancies, 264/100,000 total births, and 266/100,000 live births. Rates of partial mole were twofold higher than complete mole (P<.001). The rates of hydatidiform mole were highest in both younger (younger than 20 years old, P=.02) and older age groups (30-34 years old, P=.04, and at least 35 years old, P=.02). The rates of hydatidiform mole were highest in both younger (less than 20 years old, P=.02) and older age groups (30-34 years old, P .04, and 35 or more years old P=.02). The rates of partial moles were significantly higher in women older than 20 years of age (P<.001) and increased with increasing age (P<.001); the reverse trend was seen in complete mole (P<.001). There was no temporal change in rates or average age of hydatidiform mole during the study period. CONCLUSION: The rates of hydatidiform mole in Nova Scotia estimated by this population-based study using comprehensive validated information, are higher than most previously reported. Maternal age was a significant factor in the risk for molar pregnancies.

Complementary and alternative medicine in gynaecologic oncology.

OBJECTIVES: To explore complementary and alternative medicine (CAM) use among gynaecologic oncology patients in Nova Scotia. METHODS: Over a 3-month period, 163 patients were asked to fill out a questionnaire concerning CAM. Those entering the study provided demographic information such as age, address, and employment status, as well as medical information and details of their use of alternative therapies. RESULTS: A total of 152 patients were entered into the study, giving a response rate of 93.3%. Of these, 116 had used at least one type of CAM, classifying them as users (76.3%). Women who considered themselves "more religious" were more likely to be CAM users (P = 0.001). There were no significant differences found between users and nonusers with respect to other patient characteristics reported. Patients with cervical cancer were less likely to use CAM than participants with another primary gynaecological malignancy (P = 0.040). The most frequent CAM therapy practised was spirituality/prayer (52.6%). Most women used CAM to improve their physical well-being, and 53.3% of the women were interested in receiving more information on CAM. CONCLUSION: A significant number of women undergoing conventional treatment for gynaecologic cancer in Halifax, Nova Scotia, also use CAM. Women are using CAM for numerous reasons and believe they are benefiting from CAM in many ways. Physicians need to be aware of this high usage rate and should explore their patients' attitudes to and opinions about CAM.

The effect of loop electrosurgical excision procedure on future pregnancy outcome.

OBJECTIVE: To estimate whether the loop electrosurgical excision procedure (LEEP) is associated with an adverse effect on the outcome of subsequent pregnancies. METHODS: A retrospective cohort study was performed. The study group comprised women who had a LEEP in Halifax County between 1992 and 1999 and then had a subsequent singleton pregnancy of greater than 20 weeks of gestation with delivery at the IWK Health Centre in Halifax, Nova Scotia. The comparison group comprised women with no history of cervical surgery who were matched for age, parity, smoking status, and year of delivery. There were 571 women in each group. The primary outcome was rate of preterm delivery at less than 37 weeks of gestation. Secondary outcomes included delivery at less than 34 weeks and various neonatal and maternal outcomes. The effect of specific LEEP characteristics was analyzed separately. RESULTS: Women who had a LEEP were more likely to deliver preterm overall (7.9% versus 2.5%; odds ratio [OR] 3.50, 95% confidence interval [CI] 1.90-6.95; P < .001) and to deliver preterm after premature rupture of membranes (PROM) (3.5% versus 0.9%; OR 4.10, 95% CI 1.48-14.09). The increase in delivery at less than 34 weeks was not statistically significant (1.25% versus 0.36%; OR 3.50, 95% CI 0.85-23.49; P = .12). Women with LEEP also delivered more low birth weight (LBW) infants (5.4% versus 1.9%; OR 3.00, 95% CI 1.52-6.46; P = .003). There were no differences in other neonatal or maternal outcomes. No association was found between the characteristics of the LEEP, including depth, and the rate of preterm delivery. CONCLUSION: Loop electrosurgical excision procedure is associated with an increased risk of overall preterm delivery, preterm delivery after PROM, and LBW infants in subsequent pregnancies at greater than 20 weeks of gestation. Women who are considering future pregnancies should be counseled about these risks during informed consent for LEEP. LEVEL OF EVIDENCE: II-2.