The endometrial transcriptome of infertile women with and without implantation failure.

INTRODUCTION: Implantation failure after transferring morphologically "good-quality" embryos in in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) may be explained by impaired endometrial receptivity. Analyzing the endometrial transcriptome analysis may reveal the underlying processes and could help in guiding prognosis and using targeted interventions for infertility. This exploratory study investigated whether the endometrial transcriptome profile was associated with short-term or long-term implantation outcomes (ie success or failure). MATERIAL AND METHODS: Mid-luteal phase endometrial biopsies of 107 infertile women with one full failed IVF/ICSI cycle, obtained within an endometrial scratching trial, were subjected to RNA-sequencing and differentially expressed genes analysis with covariate adjustment (age, body mass index, luteinizing hormone [LH]-day). Endometrial transcriptomes were compared between implantation failure and success groups in the short term (after the second fresh IVF/ICSI cycle) and long term (including all fresh and frozen cycles within 12 months). The short-term analysis included 85/107 women (33 ongoing pregnancy vs 52 no pregnancy), excluding 22/107 women. The long-term analysis included 46/107 women (23 'fertile' group, ie infertile women with a live birth after ≤3 embryos transferred vs 23 recurrent implantation failure group, ie no live birth after ≥3 good quality embryos transferred), excluding 61/107 women not fitting these categories. As both analyses drew from the same pool of 107 samples, there was some sample overlap. Additionally, cell type enrichment scores and endometrial receptivity were analyzed, and an endometrial development pseudo-timeline was constructed to estimate transcriptomic deviations from the optimum receptivity day (LH + 7), denoted as ΔWOI (window of implantation). RESULTS: There were no significantly differentially expressed genes between implantation failure and success groups in either the short-term or long-term analyses. Principal component analysis initially showed two clusters in the long-term analysis, unrelated to clinical phenotype and no longer distinct following covariate adjustment. Cell type enrichment scores did not differ significantly between groups in both analyses. However, endometrial receptivity analysis demonstrated a potentially significant displacement of the WOI in the non-pregnant group compared with the ongoing pregnant group in the short-term analysis. CONCLUSIONS: No distinct endometrial transcriptome profile was associated with either implantation failure or success in infertile women. However, there may be differences in the extent to which the WOI is displaced.

Management of Uterine Fibroids and Sarcomas: The Palermo Position Paper.

BACKGROUND: Uterine fibroids are benign monoclonal tumors originating from the smooth muscle cells of the myometrium, constituting the most prevalent pathology within the female genital tract. Uterine sarcomas, although rare, still represent a diagnostic challenge and should be managed in centers with adequate expertise in gynecological oncology. OBJECTIVES: This article is aimed to summarize and discuss cutting-edge elements about the diagnosis and management of uterine fibroids and sarcomas. METHODS: This paper is a report of the lectures presented in an expert meeting about uterine fibroids and sarcomas held in Palermo in February 2023. OUTCOME: Overall, the combination of novel molecular pathways may help combine biomarkers and expert ultrasound for the differential diagnosis of uterine fibroids and sarcomas. On the one hand, molecular and cellular maps of uterine fibroids and matched myometrium may enhance our understanding of tumor development compared to histologic analysis and whole tissue transcriptomics, and support the development of minimally invasive treatment strategies; on the other hand, ultrasound imaging allows in most of the cases a proper mapping the fibroids and to differentiate between benign and malignant lesions, which need appropriate management. CONCLUSIONS AND OUTLOOK: The choice of uterine fibroid management, including pharmacological approaches, surgical treatment, or other strategies, such as high-intensity focused ultrasound (HIFU), should be carefully considered, taking into account the characteristics of the patient and reproductive prognosis.

Extra-axial cranial nerve enhancement: a pattern-based approach.

Cranial nerve enhancement is a common and challenging MRI finding that requires a meticulous and systematic evaluation to identify the correct diagnosis. Literature mainly describes the various pathologies with the associated clinic-radiological characteristics, while the radiologist often needs a reverse approach that starts from the radiological findings to reach the diagnosis. Therefore, our aim is to provide a new and practical pattern-based approach to cranial nerve enhancement, which starts from the radiological findings and follows pattern-driven pipelines to navigate through multiple differential diagnoses, guiding the radiologist to reach the proper diagnosis. Firstly, we reviewed the literature and identified four patterns to categorize the main pathologies presenting with cranial nerve enhancement: unilateral linear pattern, bilateral linear pattern, unilateral thickened pattern, and bilateral thickened pattern. For each pattern, we describe the underlying pathogenic origin, and the main radiological features are displayed through high-quality MRI images and illustrative panels. A suggested MRI protocol for studying cranial nerve enhancement is also provided. In conclusion, our approach for cranial nerve enhancement aims to be an easy tool immediately applicable to clinical practice for converting challenging findings into specific pathological patterns.

Eco-evolutionary drivers of avian migratory connectivity.

Migratory connectivity, reflecting the extent by which migrants tend to maintain their reciprocal positions in seasonal ranges, can assist in the conservation and management of mobile species, yet relevant drivers remain unclear. Taking advantage of an exceptionally large (~150,000 individuals, 83 species) and more-than-a-century-long dataset of bird ringing encounters, we investigated eco-evolutionary drivers of migratory connectivity in both short- and long-distance Afro-Palearctic migratory birds. Connectivity was strongly associated with geographical proxies of migration costs and was weakly influenced by biological traits and phylogeny, suggesting the evolutionary lability of migratory behaviour. The large intraspecific variability in avian migration strategies, through which most species geographically split into distinct migratory populations, explained why most of them were significantly connected. By unravelling key determinants of migratory connectivity, our study improves knowledge about the resilience of avian migrants to ecological perturbations, providing a critical tool to inform transboundary conservation and management strategies at the population level.

The Mitogenome Relationships and Phylogeography of Barn Swallows (Hirundo rustica).

The barn swallow (Hirundo rustica) poses a number of fascinating scientific questions, including the taxonomic status of postulated subspecies. Here, we obtained and assessed the sequence variation of 411 complete mitogenomes, mainly from the European H. r. rustica, but other subspecies as well. In almost every case, we observed subspecies-specific haplogroups, which we employed together with estimated radiation times to postulate a model for the geographical and temporal worldwide spread of the species. The female barn swallow carrying the Hirundo rustica ancestral mitogenome left Africa (or its vicinity) around 280 thousand years ago (kya), and her descendants expanded first into Eurasia and then, at least 51 kya, into the Americas, from where a relatively recent (<20 kya) back migration to Asia took place. The exception to the haplogroup subspecies specificity is represented by the sedentary Levantine H. r. transitiva that extensively shares haplogroup A with the migratory European H. r. rustica and, to a lesser extent, haplogroup B with the Egyptian H. r. savignii. Our data indicate that rustica and transitiva most likely derive from a sedentary Levantine population source that split at the end of the Younger Dryas (YD) (11.7 kya). Since then, however, transitiva received genetic inputs from and admixed with both the closely related rustica and the adjacent savignii. Demographic analyses confirm this species' strong link with climate fluctuations and human activities making it an excellent indicator for monitoring and assessing the impact of current global changes on wildlife.

Experimental nest cooling reveals dramatic effects of heatwaves on reproduction in a Mediterranean bird of prey.

Future climatic scenarios forecast increases in average temperatures as well as in the frequency, duration, and intensity of extreme events, such as heatwaves. Whereas behavioral adjustments can buffer direct physiological and fitness costs of exposure to excessive temperature in wild animals, these may prove more difficult during specific life stages when vagility is reduced (e.g., early developmental stages). By means of a nest cooling experiment, we tested the effects of extreme temperatures on different stages of reproduction in a cavity-nesting Mediterranean bird of prey, the lesser kestrel (Falco naumanni), facing a recent increase in the frequency of heatwaves during its breeding season. Nest temperature in a group of nest boxes placed on roof terraces was reduced by shading them from direct sunlight in 2 consecutive years (2021 and 2022). We then compared hatching failure, mortality, and nestling morphology between shaded and non-shaded (control) nest boxes. Nest temperature in control nest boxes was on average 3.9°C higher than in shaded ones during heatwaves, that is, spells of extreme air temperature (>37°C for ≥2 consecutive days) which hit the study area during the nestling-rearing phase in both years. Hatching failure markedly increased with increasing nest temperature, rising above 50% when maximum nest temperatures exceeded 44°C. Nestlings from control nest boxes showed higher mortality during heatwaves (55% vs. 10% in shaded nest boxes) and those that survived further showed impaired morphological growth (body mass and skeletal size). Hence, heatwaves occurring during the breeding period can have both strong lethal and sublethal impacts on different components of avian reproduction, from egg hatching to nestling growth. More broadly, these findings suggest that the projected future increases of summer temperatures and heatwave frequency in the Mediterranean basin and elsewhere in temperate areas may threaten the local persistence of even relatively warm-adapted species.

Long-term treatment outcomes of temozolomide-based chemoradiation in patients with adult-type diffuse IDH-mutant grade 2 astrocytoma.

PURPOSE: To report the long-term outcomes in adult patients with grade 2 IDH-mutant astrocytoma treated with temozolomide (TMZ)-based chemoradiation. METHODS: One hundred and three patients with histologically proven grade 2 astrocytoma received radiation therapy (RT), 50.4-54 Gy in 1.8 Gy fractions, and adjuvant TMZ up to 12 cycles. Fifty-two patients received RT at the time of tumor progression and 51 in the early postoperative period for the presence of at least one high-risk feature (age > 40 years, preoperative tumor size > 5 cm, large postoperative residual tumor, tumor crossing the midline, or presence of neurological symptoms). Overall survival (OS) and progression-free survival (PFS) were calculated from the time of diagnosis. RESULTS: With a median follow-up time of 9.0 years (range, 1.3-15 years), median PFS and OS times were 9 years (95%CI, 6.6-10.3) and 11.8 years (95%CI, 9.3-13.4), respectively. Median PFS was 10.6 years in the early treatment group and 6 years in delayed treatment group (hazard ratio (HR) 0.30; 95%CI 0.16-0.59; p = 0.0005); however, OS was not significantly different between groups (12.8 vs. 10.4 years; HR 0.64; 95%CI 0.33-1.25; p = 0.23). Extent of resection, KPS, and small residual disease were associated with OS, with postoperative tumor ≤ 1 cc that emerged as the strongest independent predictor (HR: 0.27; 95%CI 0.08-0.87; p = 0.01). CONCLUSIONS: TMZ-based chemoradiation is associated with survival benefit in patients with grade 2 IDH-mutant astrocytoma. For this group of patients, chemoradiation can be deferred until time of progression in younger patients receiving extensive resection, while early treatment should be recommended in high-risk patients.

Influence of ventilatory parameters on the concentration of exhaled volatile organic compounds in mechanically ventilated patients.

Analysis of volatile organic compounds (VOC) within exhaled breath is subject to numerous sources of methodological and physiological variability. Whilst breathing pattern is expected to influence the concentrations of selected exhaled VOCs, it remains challenging to investigate respiratory rate and depth accurately in awake subjects. Online breath sampling was performed in 20 mechanically ventilated patients using proton transfer reaction time-of-flight mass spectrometry (PTR-ToF-MS). The effect of variation in respiratory rate (RR) and tidal volume (TV) on the VOC release profiles was examined. A panel of nineteen VOCs were selected, including isoprene, acetone, propofol, volatile aldehydes, acids and phenols. Variation in RR had the greatest influence on exhaled isoprene levels, with maximum and average concentrations being inversely correlated with RR. Variations in RR had a statistically significant impact on acetone, C3-C7 linear aldehydes and acetic acid. In comparison, phenols (including propofol), C8-C10 aldehydes and C3-C6 carboxylic acids were not influenced by RR. Isoprene was the only compound to be influenced by variation in TV. These findings, obtained under controlled conditions, provide useful guidelines for the optimisation of breath sampling protocols to be applied on awake patients.

The effect of progestin therapy in advanced and recurrent endometrial cancer: A systematic review and meta-analysis.

BACKGROUND: Fifteen percent of patients with endometrial cancer (EC) have advanced stage disease or develop a recurrence. Progestins have been applied as systemic treatment for decades, but there is limited evidence on response prediction with biomarkers and toxicity. OBJECTIVES: To review the response and toxicity of progestin therapy and stratify response to progesterone receptor (PR) expression and tumour grade. SEARCH STRATEGY: We used the search terms 'Endometrial cancer', 'Progestins', 'Disease progression', 'Recurrence' and related terms in Pubmed, Embase and Cochrane databases. SELECTION CRITERIA: Studies on patients with advanced stage or recurrent EC treated with progestin monotherapy were included. Studies on adjuvant therapy, with fewer than ten cases and with sarcoma histology were excluded. DATA COLLECTION AND ANALYSIS: Evaluation for bias was performed with the Revised Cochrane RoB2 tool for randomised studies and the ROBINS-I tool for non-randomised studies. A random effects meta-analysis was performed with the overall response rate (ORR), clinical benefit rate and toxicity as primary outcome measures. MAIN RESULTS: Twenty-six studies (1639 patients) were included. The ORR of progestin therapy was 30% (95% CI 25-36), the clinical benefit rate was 52% (95% CI 42-61). In PR-positive EC, the ORR was 55%, compared with 12% in PR-negative disease (risk difference 43%, 95% CI 15-71). Severe toxicity occurred in 6.5%. CONCLUSIONS: Progestin therapy is a viable treatment option in patients with advanced stage and recurrent EC with low toxicity and high ORR in PR-positive disease. The role of PR expression in relation to progression-free survival and overall survival is unclear.

Epidural bleeding secondary to a synovial cyst rupture: a case report and review of literature.

Hemorrhage into a juxtafacet cyst is rare and cyst rupture with hemorrhagic extension into the epidural space is even less commonly seen. We describe the case of a patient with a hemorrhagic synovial cyst with rupture associated to abundant bleeding in the epidural space. A 61-year-old man had a 5-month history of worsening low back pain radiating into the right leg with associated weakness and numbness. A magnetic resonance imaging scan showed the presence of a mild anterior spondylolisthesis of L5 on S1 with increased synovial fluid into both facet joints. A suspected synovial cyst of the right facet joint at level L5-S1, with signal characteristics consistent with hemorrhage was seen. Caudally, epidural blood was evident from S1 to S2 that involved spinal canal and right S1 and S2 foramens. These findings were confirmed at surgery.

Advances in the Application of Direct Injection Mass Spectrometry Techniques to the Analysis of Grape, Wine and Other Alcoholic Beverages.

Direct injection mass spectrometry (DIMS) entails the direct introduction of a gaseous sample into a mass analyser without prior treatment or separation. DIMS techniques offer the opportunity to monitor processes in time, with limits of detection as low as 0.5 parts per trillion in volume (for a 1 s measurement time) while providing results with high informational content. This review provides insight into current and promising future developments of DIMS in the analysis of grape, wine and other alcoholic beverages. Thanks to its unique characteristics, DIMS allows the online monitoring of volatile organic compounds (VOCs) released by grapes during fermentative bioprocesses or by wine directly from the glass headspace or during drinking. A DIMS-based approach can also be adopted to perform quality control and high-throughput analysis, allowing us to characterise the volatile profile of large sample sets rapidly and in a comprehensive fashion. Furthermore, DIMS presents several characteristic elements of green analytical chemistry approaches, catalysing an interest linked to the development of sustainable paths in research and development activities in the field of viticulture and oenology.

ADEM after ChAdOx1 nCoV-19 vaccine: A case report.

Acute disseminated encephalomyelitis (ADEM) is an inflammatory demyelinating disease of the central nervous system (CNS), clinically defined by an acute polyfocal neurological syndrome usually with monophasic course. ADEM often occurs after infections, but 5%-10% of cases are preceded by vaccinations. Several cases of ADEM have been described after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, whereas no case has been reported after adenovirus-vectored or mRNA COVID-19 vaccine administration. Here we describe a case of ADEM presenting 2 weeks after receiving the first dose of ChAdOx1 nCoV-19 vaccine. Patient clinical/magnetic resonance imaging (MRI) status spontaneously improved and rapidly resolved with corticosteroids. A 4-month follow-up showed complete recovery and no relapses.

Exploring volatile organic compound emission from thermally modified wood by PTR-ToF-MS.

Thermal modification of wood is a well-known industrial process performed to increase the durability and dimensional stability or to change the colour of natural wood. The treatment influences many other properties of wood including the emission of volatile organic compounds (VOCs). VOC release ultimately affects the quality of indoor air and the capability of having low VOC emission is often included as a key parameter for the attribution of quality labels. In the present work, wood from six tree species was subjected to different types of treatment and VOC profiling was carried out on both treated and untreated samples by means of PTR-ToF-MS. Different types of thermal treatment were tested, involving either overpressure or vacuum and the effect of different temperature profiles was evaluated. Hardwood and softwood showed different release profiles under all tested conditions: the headspace of softwood was richer in several VOCs, such as terpenes, phenols and C6-C9 aldehydes and carboxylic acids. Upon thermal treatment, terpene emissions decreased, whereas several other VOCs, such as formic acid, formaldehyde, furfural and acetic acid, were released in higher amounts. With its high sensitivity and throughput, PTR-ToF-MS appears to be a very powerful analytical tool, useful in supporting the selection of wood materials for different end uses.

Factors Affecting the Outcome of Symptomatic Carotid Stenosis Surgical Treatment in a Single Center Series.

BACKGROUND: The aim of this study is to evaluate the role of preoperative ischemic brain lesion (IBL) volume, assessed by Diffusion-weighted magnetic resonance brain imaging (DW-MRI) with RAPID® processing, and surgery timing in predicting post-operative neurological outcomes in symptomatic carotid stenosis (SCS) patients treated with carotid endarterectomy (CEA). MATERIALS AND METHODS: All patients with SCS who underwent CEA between January 2010 and June 2020 were considered. IBLs ipsilateral to the stenosis were identified in the preoperative magnetic resonance brain (MRI). The volume was quantified in mL and correlated with 30-day rates of stroke and stroke/death by χ2 and receiver operating characteristic (ROC) curve. RESULTS: One hundred thirty-four patients were surgically treated for SCS during the entire study period. CEA procedures were defined as emergent, urgent, or elective if performed within 48 hr, between 48 hr and 14 days, or after 14 days from symptoms onset, respectively. Cumulative new ipsilateral stroke rate was 4,5%, with a statistically higher neurological complications in emergent patients compared to urgent and elective patients (10,6%, 1,47% and 0% respectively, P 0,039). ROC curve analysis showed a volume of 10 mL was predictive of postoperative stroke with 100% sensitivity and 80% specificity. An IBL volume >10 mL was an independent risk factor for postoperative stroke. In fact, the perioperative neurological complication rate was significantly different in high-IBL volume patients (>10 mL) compared with low-IBL volume patients (<10 mL) (P 0,003) CONCLUSIONS: The present study suggests that the optimal timing for CEA is between 48 hr and 14 days. Furthermore, the present study suggests that the presence of the IBL, by itself, is not definitively related with an unsatisfactory neurological outcome. However, an IBL higher than 10 mL should be as a reliable threshold value adverse neurological result in SCS patients.

Virus-induced Volatile Organic Compounds Are Detectable in Exhaled Breath during Pulmonary Infection.

Rationale: Chronic obstructive pulmonary disease (COPD) is a condition punctuated by acute exacerbations commonly triggered by viral and/or bacterial infection. Early identification of exacerbation triggers is important to guide appropriate therapy, but currently available tests are slow and imprecise. Volatile organic compounds (VOCs) can be detected in exhaled breath and have the potential to be rapid tissue-specific biomarkers of infection etiology. Objectives: To determine whether volatile organic compound measurement could distinguish viral from bacterial infection in COPD. Methods: We used serial sampling within in vitro and in vivo studies to elucidate the dynamic changes that occur in VOC production during acute respiratory viral infection. Highly sensitive gas chromatography-mass spectrometry techniques were used to measure VOC production from infected airway epithelial-cell cultures and in exhaled breath samples from healthy subjects experimentally challenged with rhinovirus (RV)-A16 and from subjects with COPD with naturally occurring exacerbations. Measurements and Main Results: We identified a novel VOC signature comprising decane and other long-chain alkane compounds that is induced during RV infection of cultured airway epithelial cells and is also increased in the exhaled breath from healthy subjects experimentally challenged with RV and from patients with COPD during naturally occurring viral exacerbations. These compounds correlated with the magnitude of antiviral immune responses, viral burden, and exacerbation severity but were not induced by bacterial infection, suggesting that they represent a specific virus-inducible signature. Conclusions: Our study highlights the potential for measurement of exhaled breath VOCs as rapid, noninvasive biomarkers of viral infection. Further studies are needed to determine whether measurement of these signatures could be used to guide more targeted therapy with antibiotic/antiviral agents for COPD exacerbations.

Single brain metastasis versus glioblastoma multiforme: a VOI-based multiparametric analysis for differential diagnosis.

PURPOSE: The authors' purpose was to create a valid multiparametric MRI model for the differential diagnosis between glioblastoma and solitary brain metastasis. MATERIALS AND METHODS: Forty-one patients (twenty glioblastomas and twenty-one brain metastases) were retrospectively evaluated. MRIs were analyzed with Olea Sphere® 3.0. Lesions' volumes of interest (VOIs) were drawn on enhanced 3D T1 MP-RAGE and projected on ADC and rCBV co-registered maps. Another two VOIs were drawn in the region of hyperintense cerebral edema, surrounding the lesion, respectively, within 5 mm around the enhancing tumor and into residual edema. Perfusion curves were obtained, and the value of signal recovery (SR) was reported. A two-sample T test was obtained to compare all parameters of GB and BM groups. Receiver operating characteristics (ROC) analysis was performed. RESULTS: According to ROC analysis, the area under the curve was 88%, 78% and 74%, respectively, for mean ADC VOI values of the solid component, the mean and max rCBV values in the perilesional edema and the PSR. The cumulative ROC curve of these parameters reached an area under the curve of 95%. Using perilesional max rCBV > 1.37, PSR > 75% and mean lesional ADC < 1 × 10-3 mm2 s-1 GB could be differentiated from solitary BM (sensitivity and specificity of 95% and 86%). CONCLUSION: Lower values of ADC in the enhancing tumor, a higher percentage of SR in perfusion curves and higher values of rCBV in the peritumoral edema closed to the lesion are strongly indicative of GB than solitary BM.

Prenatal yolk corticosterone exposure promotes skeletal growth and induces oxidative imbalance in yellow-legged gull embryos.

Maternally derived hormones induce variation in offspring phenotype, with consequences that can carry over into post-natal life and even into adulthood. In birds, maternal egg corticosterone (CORT) is known to exert contrasting effects on offspring morphology, physiology and behaviour after hatching. However, information on the effects of CORT exposure on pre-hatching embryonic development is limited. We experimentally increased yolk CORT levels in yellow-legged gull (Larus michahellis) eggs, and assessed the effects on embryo pre-hatching development and oxidative status of brain and liver. CORT-supplemented embryos reached a larger skeletal size and liver mass compared with controls. Embryos from CORT-injected last-laid eggs showed decreased activity of the hepatic antioxidant enzymes superoxide dismutase and catalase, while intermediate-laid eggs showed increased levels of lipid peroxidation. However, elevated yolk CORT did not affect oxidative stress endpoints in the brain. Our results indicate that elevated yolk CORT levels affect prenatal embryo development by promoting skeletal growth, and induce laying sequence- and organ-specific oxidative imbalance, with potential adverse consequences during postnatal life, especially for late-hatched offspring.

Impact of hormonal biomarkers on response to hormonal therapy in advanced and recurrent endometrial cancer.

BACKGROUND: Approximately 20% of women with endometrial cancer have advanced-stage disease or suffer from a recurrence. For these women, prognosis is poor, and palliative treatment options include hormonal therapy and chemotherapy. Lack of predictive biomarkers and suboptimal use of existing markers for response to hormonal therapy have resulted in overall limited efficacy. OBJECTIVE: This study aimed to improve the efficacy of hormonal therapy by relating immunohistochemical expression of estrogen and progesterone receptors and estrogen receptor pathway activity scores to response to hormonal therapy. STUDY DESIGN: Patients with advanced or recurrent endometrial cancer and available biopsies taken before the start of hormonal therapy were identified in 16 centers within the European Network for Individualized Treatment in Endometrial Cancer and the Dutch Gynecologic Oncology Group. Tumor tissue was analyzed for estrogen and progesterone receptor expressions and estrogen receptor pathway activity using a quantitative polymerase chain reaction-based messenger RNA model to measure the activity of estrogen receptor-related target genes in tumor RNA. The primary endpoint was response rate defined as complete and partial response using the Response Evaluation Criteria in Solid Tumors. The secondary endpoints were clinical benefit rate and progression-free survival. RESULTS: Pretreatment biopsies with sufficient endometrial cancer tissue and complete response evaluation were available in 81 of 105 eligible cases. Here, 22 of 81 patients (27.2%) with a response had estrogen and progesterone receptor expressions of >50%, resulting in a response rate of 32.3% (95% confidence interval, 20.9-43.7) for an estrogen receptor expression of >50% and 50.0% (95% confidence interval, 35.2-64.8) for a progesterone receptor expression of >50%. Clinical benefit rate was 56.9% for an estrogen receptor expression of >50% (95% confidence interval, 44.9-68.9) and 75.0% (95% confidence interval, 62.2-87.8) for a progesterone receptor expression of >50%. The application of the estrogen receptor pathway test to cases with a progesterone receptor expression of >50% resulted in a response rate of 57.6% (95% confidence interval, 42.1-73.1). After 2 years of follow-up, 34.3% of cases (95% confidence interval, 20-48) with a progesterone receptor expression of >50% and 35.8% of cases (95% confidence interval, 20-52) with an estrogen receptor pathway activity score of >15 had not progressed. CONCLUSION: The prediction of response to hormonal treatment in endometrial cancer improves substantially with a 50% cutoff level for progesterone receptor immunohistochemical expression and by applying a sequential test algorithm using progesterone receptor immunohistochemical expression and estrogen receptor pathway activity scores. However, results need to be validated in the prospective Prediction of Response to Hormonal Therapy in Advanced and Recurrent Endometrial Cancer (PROMOTE) study.

Sex-opposed inflammatory effects of 27-hydroxycholesterol are mediated via differences in estrogen signaling.

Despite the increased awareness of differences in the inflammatory response between men and women, only limited research has focused on the biological factors underlying these sex differences. The cholesterol derivative 27-hydroxycholesterol (27HC) has been shown to have opposite inflammatory effects in independent experiments using mouse models of atherosclerosis and non-alcoholic steatohepatitis (NASH), pathologies characterized by cholesterol-induced inflammation. As the sex of mice in these in vivo models differed, we hypothesized that 27HC exerts opposite inflammatory effects in males compared to females. To explore whether the sex-opposed inflammatory effects of 27HC translated to humans, plasma 27HC levels were measured and correlated with hepatic inflammatory parameters in obese individuals. To investigate whether 27HC exerts sex-opposed effects on inflammation, we injected 27HC into female and male Niemann-Pick disease type C1 mice (Npc1nih ) that were used as an extreme model of cholesterol-induced inflammation. Finally, the involvement of estrogen signaling in this mechanism was studied in bone marrow-derived macrophages (BMDMs) that were treated with 27HC and 17ß-estradiol (E2). Plasma 27HC levels showed opposite correlations with hepatic inflammatory indicators between female and male obese individuals. Likewise, hepatic 27HC levels oppositely correlated between female and male Npc1nih mice. Twenty-seven hydroxycholesterol injections reduced hepatic inflammation in female Npc1nih mice in contrast to male Npc1nih mice, which showed increased hepatic inflammation after 27HC injections. Furthermore, 27HC administration also oppositely affected inflammation in female and male BMDMs cultured in E2-enriched medium. Remarkably, female BMDMs showed higher ERα expression compared to male BMDMs. Our findings identify that the sex-opposed inflammatory effects of 27HC are E2-dependent and are potentially related to differences in ERα expression between females and males. Hence, the individual's sex needs to be taken into account when 27HC is employed as a therapeutic tool as well as in macrophage estrogen research in general. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Trends over time in the incidence and use of hormonal therapy in endometrial cancer: a population-based study in the Netherlands.

INTRODUCTION: According to current guidelines, hormonal therapy may be applied in endometrioid type endometrial cancer as an alternative to surgery for fertility preservation and in medically unfit patients. Since it is unknown how often hormonal therapy is applied, the objective of this study was to investigate trends over time in hormonal therapy use in the background of the overall incidence of endometrial cancer. METHODS: All patients with endometrial cancer (n=48 222) registered in the Netherlands Cancer Registry in the period 1989-2018 were included. European age-standardized incidence rates with corresponding estimated annual percentage change were calculated to describe trends in the incidence of endometrial cancer. The use of hormonal therapy was analyzed in the three periods 1989-1998, 1999-2008, and 2009-2018 for the following sub-groups: primary and adjuvant therapy, International Federation of Gynecology and Oncology (FIGO) stage I-II and III-IV, and by age group. RESULTS: The European age-standardized incidence rate of endometrioid endometrial cancer peaked in 2004 with a significant increase from 1989 to 2004 (annual percentage change 0.55; 95% CI 0.10 to 0.99, p=0.020) and a subsequent decrease from 2005 to 2018 (annual percentage change -1.79; 95% CI -2.28 to -1.31, p<0.001). The incidence rate of non-endometrioid type endometrial cancer increased significantly in the study period. Hormonal therapy was used in 1482 (3.5%) patients with endometrioid endometrial cancer. Among patients with FIGO stage I aged ≤40 years, hormonal therapy increased from 0% in 1989-1998 to 27% in 2009-2018. Primary hormonal treatment increased from 175 patients (5.5%) to 329 patients (7.8%) in those aged ≥75 years. Adjuvant hormonal treatment was mostly used in advanced stage endometrial cancer. CONCLUSIONS: The use of primary hormonal therapy in endometrioid type endometrial cancer increased over time in patients aged ≤40 years and among elderly patients. The observed trends in the current use of hormonal therapy support the need to study the effect of hormonal treatment in elderly patients and as adjuvant treatment in advanced stage endometrial cancer.