The efficacy of topical imiquimod in high-grade cervical intraepithelial neoplasia: A systematic review and meta-analysis.

OBJECTIVE: A major side effect of cervical excision for high-grade cervical intraepithelial neoplasia (CIN) is premature birth. A non-invasive treatment for reproductive age women is warranted. The aim of the present study was to determine the efficacy of topical imiquimod in the treatment of high-grade CIN, defined as a regression to ≤CIN 1, and to determine the clearance rate of high-risk human papillomavirus (hr-HPV), compared with surgical treatment and placebo. METHODS: Databases were searched for articles from their inception to February 2023.The study protocol number was INPLASY2022110046. Original studies reporting the efficacy of topical imiquimod in CIN 2, CIN 3 or persistent hr-HPV infections were included. The study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses checklist. RESULTS: Five studies were included (n = 463). Histological regression to ≤CIN 1 was 55% in imiquimod versus 29% in placebo, and 93% in surgical treatment. Imiquimod-treated women had a greater odds of histological regression to ≤CIN 1 than placebo (odds ratio [OR] 4.17, 95% confidence interval [CI] 2.03-8.54). In comparison to imiquimod, surgical treatment had an OR of 14.81(95% CI 6.59-33.27) for histological regression to ≤CIN 1. The hr-HPV clearance rate was 53.4% after imiquimod and 66% after surgical treatment (95% CI 0.62-23.77). CONCLUSIONS: The histological regression rate is highest for surgical treatment followed by imiquimod treatment and placebo.

Immunologic factors involved in the malignant transformation of endometriosis to endometriosis-associated ovarian carcinoma.

INTRODUCTION: Endometriosis is a risk factor for low-grade serous, clear cell, and endometroid ovarian carcinoma. In both endometriosis and ovarian carcinoma, immunological factors are associated with clinical outcome. Chronic inflammation in endometriosis may be linked to tumorigenesis, but exact processes contributing to endometriosis-associated ovarian carcinoma remain unknown. This review aims to describe potential immunological factors involved in the malignant transformation of endometriosis into ovarian carcinoma. METHODS: PubMed and Embase were searched from inception up to October 2020 for studies comparing immunological processes in endometriosis and endometriosis-associated ovarian carcinoma. RESULTS: Detailed analysis of immune components in the malignant transformation of endometriosis into endometriosis-associated ovarian carcinoma is lacking. Altered levels of chemokines and cytokines as IL-6, IL-8, IL-10, and TNF-α are reported and the function, number and polarization of NK cells, dendritic cells, and monocytes differ between endometriosis and associated ovarian carcinoma compared to healthy tissue. In addition, altered inflammasome and complement systems, indicate a role for the immune system in the carcinogenesis of endometriosis. CONCLUSION: Chronic inflammation in endometriosis may potentially drive inflammation-induced carcinogenesis in endometriosis-associated ovarian carcinoma. Exact immunological pathways and cellular processes remain unknown and require more thorough investigation.

Non-digestible oligosaccharides modulate intestinal immune activation and suppress cow's milk allergic symptoms.

BACKGROUND: Cow's milk allergy is a common food allergy in childhood and no effective preventive or curative treatment is available. This study aimed at comparing single short-chain galacto- (scGOS), long-chain fructo- (lcFOS) or pectin-derived acidic oligosaccharides (pAOS) and/or mixtures of scGOS/lcFOS (GF) or scGOS/lcFOS/pAOS (GFA) to prevent or treat food allergy. METHODS: In the preventive protocol, C3H/HeOuJ mice were fed diets containing single oligosaccharides or mixtures GF or GFA throughout the study protocol. In the treatment protocol, GF or GFA was provided for 4 wk starting after the last sensitization. The allergic skin response and anaphylaxis scores were determined, after oral challenge whey-specific immunoglobulins were measured, and qPCR for T-cell markers and Foxp3 counts using immunohistochemistry were performed on the small intestine and colon. RESULTS: Only in the preventive setting, the GF or GFA mixture, but not the single oligosaccharides, reduced the allergic skin response and whey-IgG(1) levels in whey-sensitized mice, compared to the control diet. Both GF and GFA increased the number of Foxp3+ cells in the proximal small intestine of whey - compared to sham-sensitized mice. Expression of Th2 and Th17 mRNA markers increased in the middle part of the small intestine of whey-sensitized mice, which was prevented by GF. By contrast, GFA enhanced Tbet (Th1), IL-10 and TGF-ß mRNA expression compared to GF which was maintained in the distal small intestine and/or colon. CONCLUSIONS: Dietary supplementation with scGOS/lcFOS or scGOS/lcFOS/pAOS during sensitization, both effectively reduce allergic symptoms but differentially affect mucosal immune activation in whey-sensitized mice.

Alterations in classical and nonclassical HLA expression in recurrent and progressive HPV-induced usual vulvar intraepithelial neoplasia and implications for immunotherapy.

Immunotherapy of usual vulvar intraepithelial neoplasia (uVIN) is promising; however, many patients still fail to show clinical responses, which could be explained by an immune escape through alterations in human leukocyte antigen (HLA) expression. Therefore, we analyzed a cohort of patients with a primary (n = 43) and subsequent recurrent uVIN lesion (n = 20), vaccine-treated uVIN patients (n = 12), patients with human papillomavirus (HPV)-induced vulvar carcinoma (n = 21) and healthy controls (n = 26) for the expression of classical HLA-class I/II and nonclassical HLA-E/-G and MHC class I chain-related molecule A (MICA). HLA-class I was downregulated in 70% of uVIN patients, including patients with a clinical response to immunotherapy. Downregulation of HLA-class I is probably reversible, as only 15% of the uVIN cases displayed loss of heterozygosity (LOH) and HLA-class I could be upregulated in uVIN keratinocyte cultures by interferon γ. HLA-class I downregulation is more frequently associated with LOH in vulvar carcinomas (25-55.5%). HLA-class II was found to be focally expressed in 65% of uVIN patients. Of the nonclassical molecules, MICA was downregulated in 80% of uVIN whereas HLA-E and -G were expressed in a minority of cases. Their expression was more prominent in vulvar carcinoma. No differences were found between the alterations observed in paired primary and recurrent uVIN. Importantly, downregulation of HLA-B/C in primary uVIN lesions was associated with the development of recurrences and progression to cancer. We conclude that downregulation of HLA is frequently observed in premalignant HPV-induced lesions, including clinical responders to immunotherapy, and is associated with worse clinical outcome. However, in the majority of cases downregulation may still be reversible.

Sebaceous gland metaplasia in the oesophagus of a cynomolgus monkey (Macaca fascicularis).

Microscopical evaluation of tissues from a mature female cynomolgus monkey assigned to a 13-week oral toxicity study revealed nests of sebaceous cells within the mucosa of the distal oesophagus. The sebaceous cell nests showed normal differentiation from basally-oriented seboblasts to centrally-orientated mature sebocytes. No excretory ducts were found, but solitary or small groups of vacuolated sebocytes were present in the overlying normal, non-keratinized squamous epithelium. The finding of sebaceous cells, of presumed ectodermal origin, in the oesophageal mucosa, which is of endodermal origin, is of scientific interest. Different theories may explain the existence of this peculiarity, but sebaceous gland metaplasia is the most plausible. The mucosal change was thought to be unrelated to treatment and is the first case of sebaceous gland metaplasia reported in the oesophagus of a non-human primate.

Detection of PRRSV circulation in herds without clinical signs of PRRS: comparison of five age groups to assess the preferred age group and sample size.

A cross-sectional study was conducted to find the most effective diagnostic approach to detect circulation of porcine reproductive and respiratory syndrome virus (PRRSV). The study was performed in 10 Dutch swine herds, with sows and fattening pigs or breeding stock. Herds did not experience clinical signs of PRRS during the last 6 months before sampling, but a PRRSV infection was confirmed at most 2 years before sampling. Blood samples were collected from 5 age groups: sows during early and late gestation, weaners at 9 weeks of age, fatteners or breeding stock at 16 and 22 weeks of age. For each category, 20 serum samples were examined; in total 100 serum samples per herd. Samples were analysed for PRRSV antibodies with ELISA (n=1002), and rt-PCR when ELISA S/P-ratios were above 1.5 (n=307) or below 0.4 (n=187; random selection from each age group). A logistic regression analysis was used to obtain factors associated with the probability of virus detection in a pig (PCR positive test result). Herd, ELISA-result, and age group were included as explanatory variables. Variables remained in the model when statistically significant. ELISA results showed that none of the herds could be considered to be free of PRRSV infection. Mean PRRSV seroprevalence in unvaccinated animals varied between 18% and 82%, and mean PRRS-virus prevalence varied between 0% and 41%. In only one of the 10 herds, no PRRS-virus could be detected. The odds of finding PRRS-virus in blood samples were 8.6 (95% CI, 5.3-13.9) in pigs of 9 weeks of age and 4.6 (95% CI, 3.0-7.0) in pigs of 16 weeks of age, compared with fatteners of 22 weeks of age. This result indicates that 9- to 16-week-old pigs are the preferred age group to detect PRRS-virus, in herds without clinical signs of PRRS. We concluded that PRRS-virus circulation could be detected in 8 out of 9 of the study-herds, with a relatively low number of blood samples. Testing 12 blood samples in both rt-PCR and ELISA, with 6 samples in pigs 9 weeks of age and 6 samples in pigs 16 weeks of age, will lead to a cost-efficient first evaluation of the PRRSV infection-status in herds without clinical signs of PRRS.

The diagnostic and therapeutic approach of a primary bilateral leiomyoma of the ovaries: a case report and a literature review.

INTRODUCTION: A primary fibroid (leiomyoma) arising from both ovaries is rare and can be difficult to diagnose as a result of the low incidence and its indistinctive presentation. A literature review on the diagnostic and therapeutic approach of this rare benign tumour is presented. We describe a case of bilateral primary ovarian fibroid with an unusual presentation to illustrate our recommendations for treatment. CASE PRESENTATION: A 37-year-old woman was admitted with symptoms of acute severe abdominal pain. She had a history of faint abdominal discomfort. Due to the acute deterioration of the abdominal pain a diagnostic laparoscopy was performed. A tumour arising from both ovaries was seen and a biopsy was taken in order to decide on further therapy. Histology showed a fibroid for which excision by a second laparoscopic intervention was planned. Due to excessive adhesions conversion to laparotomy was necessary. CONCLUSION: We recommend that in the case of an abnormal adnexal mass, particularly in women who want to preserve their fertility, frozen section histology be performed laparoscopically. A frozen section diagnostic procedure, instead of a regular biopsy, seems to be a useful tool during an elective diagnostic laparoscopic procedure in order to prevent potential morbidity as a result of possible future laparoscopy or even laparotomy. Previous laparoscopic procedures can cause massive adhesions that could impede a subsequent laparoscopic approach.

Spontaneous malignant mixed Müllerian tumor in a Wistar rat: a case report including immunohistochemistry.

This report presents a rare, spontaneous, heterologous, malignant mixed Müllerian tumor observed in a 98-week-old untreated Wistar rat. At necropsy, the right uterine horn was dilated and contained a mass of approximately 10 × 15 mm. Histopathologically the mass consisted of 2 parts with different morphologic characteristics, a polypoid mass protruding into the uterine lumen and a more solid part that replaced the adjacent uterine wall. The solid part exhibited characteristics of a highly infiltrative adenocarcinoma, whereas the composition of the polypoid mass was heterogeneous, consisting of a variety of benign and malignant epithelial and mesenchymal elements. The epithelial components included well-differentiated endometrial and squamous epithelium juxtaposed to carcinosarcomatous areas. The mesenchymal components consisted of well-differentiated cartilage and bone along with chondrosarcomatous, rhabdomyomatous, and other mesenchymal elements. Immunohistochemical analysis further supported the diagnosis of malignant mixed Müllerian tumor.

The value of hysteroscopy in the diagnostic approach to a rudimentary horn pregnancy.

A 33-year-old woman presented with an ectopic pregnancy without any complaints. Laparoscopy was performed since a tubal pregnancy was expected. However, both fallopian tubes appeared normal and it was not possible to differentiate accurately between a pregnancy in a non-communicating horn and a pregnancy in a bicornuate uterus. We therefore performed MRI which showed a thin myometrium around the pregnancy. In order to differentiate between a communicating and a non-communicating uterine horn the authors performed a hysteroscopy. Since there was only one cervical os, and an entrance to the second uterine cavity was not seen along the cervical canal, it was concluded that this pregnancy was situated in a non-communicating rudimentary horn. The non-communicating uterine horn, with the pregnancy in situ, was completely removed. Since a pregnancy in a bicornuate uterus is viable in contrast to a pregnancy in a non-communicating horn, accurate diagnosis is important.

Demyelination and axonal dystrophy in alpha A-crystallin transgenic mice.

Homozygous mice transgenic for alphaA-crystallin, one of the structural eye lens proteins, developed hindlimb paralysis after 8 weeks of age. To unravel the pathogenesis of this unexpected finding and the possible role of alphaA-crystallin in this pathological process, mice were subjected to a histopathological and immunohistochemical investigation. Immunohistochemistry showed large deposits of alphaA-crystallin in the astrocytes of the spinal cord, and in the Schwann cells of dorsal roots and sciatic nerves. Additionally, microscopy showed dystrophic axons in the spinal cord and digestion chambers as a sign of ongoing demyelination in dorsal roots and sciatic nerves. Apart from a few areas with slight alphaA-crystallin-immunopositive structures, the brain was normal. Because the alphaA-crystallin protein expression appeared in specific cells of the nervous system (astrocytes and Schwann cells), the most plausible explanation for the paralysis is a disturbance of cell function caused by the excessive intracytoplasmic accumulation of the alphaA-crystallin protein. This is followed by a sequence of secondary changes (demyelination, axonal dystrophy) and finally arthrosis. In conclusion, alphaA-crystallin transgenic mice develop a peripheral and central neuropathy primarily affecting spinal cord areas at the dorsal side, dorsal root and sciatic nerve.

Systemic and histopathologic changes in Beagle dogs after chronic daily oral administration of synthetic (ethinyl estradiol) or natural (estradiol) estrogens, with special reference to the kidney and thyroid.

ABSTRACT Four groups of 3 male and 3 female sexually mature Beagle dogs were treated daily po with either ethinyl estradiol (EE) or estradiol (E2). A fifth group of 4 males and 4 females acted as a control group. Three groups of dogs were treated with EE: One group was treated at dose levels of 2.0, 1.5, and 1.0 mg/kg for 6 mo; the other 2 groups received either 0.5 mg/kg or 1.0 mg/kg for 1 yr. The fourth group was treated with 5.0 mg/kg E2 for 1 yr. Results obtained for the clinical, hematological, and biochemical parameters and the histopathologic findings of most organs and tissues in EE- and E2-treated dogs were essentially comparable to those documented in the literature for dogs treated with synthetic or natural estrogens. Chronic treatment with EE or E2 induced similar effects, with the exception of mesothelial proliferation of the genital serosa, which was observed in EE-treated dogs only. Additional new estrogen-related findings were observed in the kidneys and thyroid glands of EE- and E2-treated dogs. Increased interstitial fibrous tissue occurred at the corticomedullary junction and in the outer cortex of the kidney. It appeared to originate primarily from the perivascular fibrous tissue of branches of the renal arteries and veins. Extension of this lesion into the renal parenchyma resulted in secondary atrophic changes of tubules and glomeruli. The treatment relationship and specific characteristics of this renal alteration differentiated it from other chronic renal interstitial and vascular diseases. Squamous metaplasia of urogenital tract epithelia, including renal cortical tubule epithelium, occurred as expected in both EE- and E2-treated dogs. Unexpectedly, squamous metaplasia of thyroid follicular epithelium also occurred. It was present in scattered follicles of both EE- and E2-treated dogs. The renal and thyroid changes did not alter clinicopathological function tests for either of these organs. These 2 new findings extend the list of estrogen-related effects in the dog.

Spontaneous hyperplastic and metaplastic duct epithelium in the sublingual salivary glands of Wistar rats.

Focal epithelial hyperplasia and metaplasia were observed in the intralobular ducts of the sublingual salivary glands of 302 out of 1142 Wistar rats. These rats (aged 16-145 weeks) served as controls in toxicological experiments. The ductal changes varied from small groups of irregular cylindrical cells with basophilic cytoplasm and vesicular nuclei, with often prominent nucleoli, to large areas of non-keratinized stratified squamous epithelium with marked mitotic activity and necrotic superficial cells being released in the lumen. Mononuclear inflammatory cells were often present in fibrous tissue surrounding altered ducts. Within certain limits the degree and incidence of the changes increased with increasing age; their aetiology is unknown.