Unexplained infertility and age-related infertility: indistinguishable diagnostic entities but different IVF prognosis.

STUDY QUESTION: Is IVF indicated for couples with age-related infertility? SUMMARY ANSWER: IVF may be of doubtful utility for age-related infertility. WHAT IS KNOWN ALREADY: A diagnosis of unexplained infertility is drawn when the diagnostic work-up fails to identify any patent cause. Although typically managed uniformly, unexplained infertility is likely to comprise a wide range of conditions, including age-related infertility (at least in older women). Unfortunately, no validated tests for the identification of age-related infertility exist and these women are typically treated as unexplained cases. However, homologous ART may be less effective for these women because these techniques may be unable to treat the detrimental effects of ageing on oocyte competence. STUDY DESIGN, SIZE, DURATION: Women aged 18-42 years who underwent IVF procedures between January 2014 and December 2021 were selected retrospectively. In the first part of the study, we aimed to assess whether the proportion of women with unexplained infertility (i.e. without patent causes of infertility) increased with age. In the second part of the study, women with unexplained infertility were matched 1:1 by age, study period, and duration of infertility, to those with a patent cause of infertility. If our hypothesis is valid, the first part of the study should highlight an increase in the proportion of unexplained infertility with age. Moreover, in the second part of the study, one should observe a sharper decrease in the rate of IVF success of the procedure with age in women with an unremarkable work-up compared to those with a definite cause of infertility. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women were included if: they had been trying to conceive for more than 2 years, they had retrieved more than three oocytes, and had not undergone previous IVF attempts. We exclude couples with severe male factor (criptozoospermia), chronic anovulation, untreated hydrosalpinx, or intracavitary diseases. The first part of the study aimed at investigating the relative proportion of unexplained infertility with age. The outcome of the second part was the distribution of the live births between unexplained versus explained infertility, in women younger or older than 35 years. Only the results of the first IVF cycle were considered (including both fresh and frozen cycles). The live birth rate corresponded to the cumulative chance of a live birth per oocyte retrieval. MAIN RESULTS AND THE ROLE OF CHANCE: One thousand five hundred and thirty-five women were selected for the first part of the study; 742 of them had unexplained infertility (48%). The frequency of this diagnosis was lower among women aged <35 years (40%) compared to those ≥35 years (52%) (P < 0.001). A clear gradient emerged when considering smaller intervals of age (P < 0.001). A total of 1134 women (567 unexplained cases and 567 explained cases) were selected for the second part of the study. Baseline variables were comparable between women with unexplained and explained infertility. Among women younger than 35 years (n = 229 unexplained cases and 229 explained cases), 108 live births were observed in women with unexplained infertility (47%) and 88 in those with explained infertility (38%). In comparison, among women older than 35 years, the live births occurred in 90 (27%) and 114 (34%) couples, respectively (P = 0.03). The adjusted odds ratio (OR) for a live birth in older women with unexplained infertility was 0.63 (95% CI: 0.43-0.94). In other words, the effectiveness of IVF in older women with unexplained infertility is reduced by an additional 37% when compared to women of similar age with a patent cause of infertility. Moreover, when considering smaller intervals of age, a gradient of the adverse effect of age on the distribution of live births between unexplained and explained infertility emerged (P = 0.003). Overall, these results support the hypothesis that IVF may be of modest benefit in women with age-related infertility. The decline in IVF success is sharper in women with unexplained infertility compared to those with explained infertility, indirectly suggesting that IVF cannot effectively treat age-related infertility. LIMITATIONS, REASONS FOR CAUTION: We postulated that the greater decline in IVF success with age in the unexplained group could be related to the concomitant increase in the proportion of women with age-related infertility. However, even if this is theoretically logical, the unavailability of validated tools to diagnose age-related infertility makes our inference speculative. We cannot exclude that the prevalence of other unknown causes of infertility that cannot also be effectively overcome with IVF could increase with age. WIDER IMPLICATIONS OF THE FINDINGS: Our findings suggest that IVF may be of modest utility for treating age-related infertility. Offering this procedure to older women with an unremarkable infertility work-up may be questioned. However, the diagnosis of age-related infertility remains challenging and identifying a biomarker that could reliably diagnose age-related infertility is a priority. STUDY FUNDING/COMPETING INTEREST(S): The study was partially funded by the Italian Ministry of Health-current research IRCCS and by a specific grant supported by Ferring. ES declares receiving honoraria for lectures at meetings from IBSA and Gedeon-Richter and he also handles private grants of research from Ferring, IBSA, Theramex, and Gedeon-Richter. All the other authors do not have any conflict of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Polycystic Ovary Syndrome and Alteration of Vocal Function: A Systematic Review and Meta-Analysis.

INTRODUCTION: Polycystic ovary syndrome (PCOS) is a common hormonal disorder among young women, correlated with hyperandrogenism. Among the symptoms of PCOS, vocal alterations are quite unknown. Dysphonia may be related to hyperandrogenism, and there is no consensus about its prevalence and the severity of vocal disorders, which can cause noticeable discomfort. METHODS: A systematic review of the literature was conducted. Four studies on PCOS that evaluated the phonatory system were included for a total of 174 patients (96 PCOS, 78 controls), and a meta-analysis on comparable data was performed. RESULTS: Four studies evaluated parameters related to vocal symptomatology, altered audiometric examination, and findings at the laryngoscopy in patients affected by PCOS versus controls. Although the individual studies showed increased incidence of alterations and a tendency to develop speech fatigue in women with PCOS, when the results of studies were pulled in meta-analysis, the overall difference was not statistically significant. The studies themselves were very different from each other; therefore, it is hard to draw any firm conclusions. DISCUSSION: The aim of this study was to assess the prevalence of vocal alterations, the correlation with hyperandrogenism, the quality of life, and the voice changes after starting a therapy for PCOS. The present meta-analysis failed to find any difference in terms of PCOS and control cohort. However, the lack of high-quality studies makes it difficult to draw firm conclusions. New and larger studies or big population program data are therefore warranted.

Spotlight on Compounded Bioidentical Hormones.

BACKGROUND: The role of hormonal replacement therapy in menopause is under debate. The premature closure of the Women's Health Initiative (WHI) study in 2002 is still a source of concern among treating physicians. OBJECTIVES: The interest in alternatives to conventional hormone therapy has significantly increased. The adoption of personalized steroid hormone galenic preparations, formulated by compounding pharmacies, has recently spread. METHODS: In June 2023, an extensive literature search was conducted by different authors to identify relevant studies in various databases (MEDLINE, Embase, PubMed, and Cochrane). The studies that met the inclusion and exclusion criteria were further analyzed, and relevant data were extracted and analyzed for each paper. Any discrepancies between the investigators were resolved through a consensus approach. OUTCOMES: The primary outcomes observed included the clinical utility of CBHT. This study reviewed the current evidence on the utility of compounded bioidentical hormones, concluding that improving knowledge and awareness of bioidentical hormones is necessary to consider their use in clinical practice. CONCLUSION AND OUTLOOK: These formulations might provide effective options to best tailor therapies to each patient.

Rescue intrauterine insemination in women failing to retrieve oocytes at ovum pick-up: report of a case series.

PURPOSE: Failure to collect oocytes at the time of oocyte pick-up is an unfavorable outcome of in vitro fertilization (IVF) cycles. In these cases, prompt intrauterine insemination (IUI) could be an option (rescue IUI), but this possibility has been poorly studied. METHODS: Rescue IUI is routinely offered in our unit in women failing to retrieve oocytes, provided that they have at least one patent tube, normal male semen analysis, and the total number of developed follicles is ≤ 3. We therefore reviewed all oocyte retrievals performed from 2006 to 2022 in our unit to identify these cases. As a comparator, we referred to preplanned IUI performed during the same study period. The 95% confidence interval (95% CI) of proportions was calculated using a binomial distribution model. RESULTS: Rescue IUI was performed in 96 out of 3531 oocyte retrievals (2.7%; 95% CI 2.2-3.3%). Six live births were obtained, corresponding to 6.2% (95% CI 2.3-13.1). All pregnancies were singletons. CONCLUSIONS: Rescue IUI in women failing to retrieve oocytes is a possible option that may be considered in selected cases. The efficacy is low, but the procedure is simple, and without significant risks. Generalizability to a conventional IVF protocol setting is however limited.

When the Embryo Meets the Endometrium: Identifying the Features Required for Successful Embryo Implantation.

Evaluation of the optimal number of embryos, their quality, and the precise timing for transfer are critical determinants in reproductive success, although still remaining one of the main challenges in assisted reproduction technologies (ART). Indeed, the success of in vitro fertilization (IVF) treatments relies on a multitude of events and factors involving both the endometrium and the embryo. Despite concerted efforts on both fronts, the overall success rates of IVF techniques continue to range between 25% and 30%. The role of the endometrium in implantation has been recently recognized, leading to the hypothesis that both the "soil" and the "seed" play a central role in a successful pregnancy. In this respect, identification of the molecular signature of endometrial receptivity together with the selection of the best embryo for transfer become crucial in ART. Currently, efforts have been made to develop accurate, predictive, and personalized tests to identify the window of implantation and the best quality embryo. However, the value of these tests is still debated, as conflicting results are reported in the literature. The purpose of this review is to summarize and critically report the available criteria to optimize the success of embryo transfer and to better understand current limitations and potential areas for improvement.

The role of immunotherapy in advanced and recurrent MMR deficient and proficient endometrial carcinoma.

Endometrial cancer is the most common gynecological disease in developed countries. Although it is considered an indolent disease, advanced and recurrent endometrial carcinomas are characterized by poor prognosis. In the metastatic setting, after the failure of first-line platinum-based chemotherapy, patients have limited therapeutic options. However, endometrial cancer should not be considered as a single entity but as a group of heterogeneous diseases with specific genomic, molecular, and biological features by suggested the analysis of The Cancer Genome Atlas (TCGA). Accumulating data highlighted the effectiveness and safety of the adoption of immune checkpoint inhibitors (ICIs) for several types of solid tumors. In particular, immunotherapy showed promising results in MSI-H/dMMR solid tumors. Endometrial cancer is not an exception. Endometrial cancer has the highest prevalence of MSI across human cancer types, and approximately 30% of primary endometrial cancers are MSI-H/dMMR and 13% to 30% of recurrent endometrial cancers are MSI-H/dMMR. The preliminary results of the KEYNOTE-158, the Australian NCT03015129 and the GARNET trial strongly supported the adoption of ICIs as monotherapy in patients with advanced or recurrent endometrial cancer, after the failure of first-line treatments. Unfortunately, those impressive results are not achieved in patients with MMR proficient disease. Hence, other combinations were tested. In particular, the adoption of ICIs plus tyrosine kinase inhibitors (TKI) showed very compelling results. Recently, the updated results of the KEYNOTE-775 showed that pembrolizumab plus lenvatinib led to significantly longer progression-free and overall survival than chemotherapy among patients with advanced endometrial cancer, irrespective of MMR status. After EMA approval, pembrolizumab plus lenvatinib represents the new standard second-line treatment in endometrial cancer patients, regardless MMR status. Further studies are investigating the role of ICIs and TKIs in the first line and are testing new combinations (e.g. ICIs plus PARP inhibitors).

Ten-year outcomes following laparoscopic and open abdominal radical hysterectomy for "low-risk" early-stage cervical cancer: A propensity-score based analysis.

OBJECTIVE: Accumulating evidence suggested the detrimental effects of adopting minimally invasive surgery in the management of early-stage cervical cancer. However, long-term evidence on the role of minimally invasive radical hysterectomy in "low-risk" patients exists. METHODS: This is multi-institutional retrospective study comparing minimally invasive and open radical hysterectomy in low-risk early-stage cervical cancer patients. A propensity-score matching algorithm (1:2) was used to allocate patients into the study groups. Kaplan-Meir model was used to estimate 10-year progression-free and overall survival. RESULTS: Charts of 224 "low-risk" patients were retrieved. Overall, 50 patients undergoing radical hysterectomy were matched with 100 patients undergoing open radical hysterectomy. Minimally invasive radical hysterectomy was associated with a longer median operative time (224 (range, 100-310) vs. 184 (range, 150-240) minutes; p < 0.001), lower estimated blood loss (10 (10-100) vs. 200 (100-1000) ml, p < 0.001), and shorter length of hospital stay (3.8 (3-6) vs. 5.1 (4-12); p < 0.001). Surgical approach did not influence the risk of having intra-operative (4% vs. 1%; p = 0.257) and 90-day severe (grade 3+) postoperative complication rates (4% vs. 8%; p = 0.497). Ten-year disease-free survival was similar between groups (94% vs. 95%; p = 0.812; HR:1.195; 95%CI:0.275, 5.18). Ten-year overall survival was similar between groups (98% vs. 96%; p = 0.995; HR:0.994; 95%CI:0.182, 5.424). CONCLUSIONS: Our study appears to support emerging evidence suggesting that, for low-risk patients, laparoscopic radical hysterectomy does not result in worse 10-year outcomes compared to the open approach. However, further research is needed and open abdominal radical hysterectomy remains the standard treatment for cervical cancer patients.

Magnetic resonance imaging-radiomics in endometrial cancer: a systematic review and meta-analysis.

OBJECTIVE: Endometrial carcinoma is the most common gynecological tumor in developed countries. Clinicopathological factors and molecular subtypes are used to stratify the risk of recurrence and to tailor adjuvant treatment. The present study aimed to assess the role of radiomics analysis in pre-operatively predicting molecular or clinicopathological prognostic factors in patients with endometrial carcinoma. METHODS: Literature was searched for publications reporting radiomics analysis in assessing diagnostic performance of MRI for different outcomes. Diagnostic accuracy performance of risk prediction models was pooled using the metandi command in Stata. RESULTS: A search of MEDLINE (PubMed) resulted in 153 relevant articles. Fifteen articles met the inclusion criteria, for a total of 3608 patients. MRI showed pooled sensitivity and specificity 0.785 and 0.814, respectively, in predicting high-grade endometrial carcinoma, deep myometrial invasion (pooled sensitivity and specificity 0.743 and 0.816, respectively), lymphovascular space invasion (pooled sensitivity and specificity 0.656 and 0.753, respectively), and nodal metastasis (pooled sensitivity and specificity 0.831 and 0.736, respectively). CONCLUSIONS: Pre-operative MRI-radiomics analyses in patients with endometrial carcinoma is a good predictor of tumor grading, deep myometrial invasion, lymphovascular space invasion, and nodal metastasis.

Endometrial carcinosarcoma.

Endometrial carcinosarcoma is a rare and aggressive high-grade endometrial carcinoma with secondary sarcomatous trans-differentiation (conversion theory). The clinical presentation and diagnostic work-up roughly align with those of the more common endometrioid counterpart, although endometrial carcinosarcoma is more frequently diagnosed at an advanced stage. Endometrial carcinosarcoma is not a single entity but encompasses different histological subtypes, depending on the type of carcinomatous and sarcomatous elements. The majority of endometrial carcinosarcomas are characterized by p53 abnormalities. The proportion of POLE and microsatellite instablity-high (MSI-H) is directly related to the epithelial component, being approximately 25% and 3% in endometrioid and non-endometrioid components.The management of non-metastatic disease is based on a multimodal approach with optimal surgery followed by (concomitant or sequential) chemotherapy and radiotherapy, even for early stages. Palliative chemotherapy is recommended in the metastatic or recurrent setting, with carboplatin/paclitaxel doublet being the first-line regimen. Although the introduction of immunotherapy plus/minus a tyrosine kinase inhibitor shifted the paradigm of treatment of patients with recurrent endometrial cancer, patients with endometrial carcinosarcoma were excluded from most studies evaluating single-agent immunotherapy or the combination. However, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved the use of pembrolizumab and lenvatinib in endometrial cancer (all histotypes) after progression on chemotherapy and single-agent immunotherapy in MSI-H cancers. In the era of precision medicine, emerging knowledge on molecular endometrial carcinosarcoma is opening new promising therapeutic options for more personalized treatment. The present review outlines state-of-the-art knowledge and future directions for patients with endometrial carcinosarcoma.

How to Manage Endometriosis in Adolescence: The Endometriosis Treatment Italian Club Approach.

The evaluation of endometriosis in an adolescent girl is a challenging topic. The initial stage of the disease and the limited diagnostic instrument appropriate for the youth age and for its typical features can reduce the ability of the gynecologist. At the same time, missing a prompt diagnosis can delay the beginning of specific and punctual management of endometriosis, which could avoid a postponed diagnosis from 6 to 12 years, typical of adolescent girls complaining of dysmenorrhea. This article aimed to answer all the potential questions around the diagnosis and management of endometriosis in adolescents starting from a clinical case looking at the possible solution that is easily reproducible in the clinical practice.

Trends in the incidence of major birth defects after assisted reproductive technologies in Lombardy Region, Northern Italy.

PURPOSE: The incidence of birth defects is increased in children born after assisted reproductive technologies (ART). However, changes in ART over time could influence this incidence. To investigate this issue, we present the frequency and trends of birth defects in ART and natural pregnancies in Lombardy, Northern Italy, during the period 2014-2020. METHODS: This is a population-based study using automated system of healthcare utilization (HCU) databases. ART pregnancies included only those obtained with conventional IVF or ICSI. After identifying the total number of deliveries, the rate of newborns with birth defects was compared between natural and ART pregnancies. A logistic regression model was used to calculate the adjusted odd ratio (OR). Analyses were repeated for every calendar year. RESULTS: Overall, 508,421 deliveries were identified, of which 14,067 (2.8%) were achieved after IVF-ICSI. A decreasing trend in birth defects over time was highlighted. The adjusted OR dropped from 1.40 (95%CI: 1.03-1.91) in 2014 to 0.92 (95%CI: 0.69-1.22) in 2020. During the study period, a significant reduction in multiple pregnancy and in the ratio of ICSI to conventional IVF was also observed, explaining at least in part the positive trend observed for birth defects. CONCLUSION: The increased risk of birth defects in children born after IVF-ICSI is not steady over time. A decline of this risk emerged in our region. Policy changes in ART may explain this beneficial effect.

Follicular steroidogenesis in random start protocols for oocyte cryopreservation.

PURPOSE: Random start protocols are commonly used for oocyte cryopreservation in women with cancer. However, albeit generally reassuring, available evidence is still insufficient to rule out a sub-optimal cycle outcome. This study aimed to compare follicular steroidogenesis between women initiating the random start protocol in the luteal phase and those initiating in the follicular phase. METHODS: Consecutive women with cancer scheduled for oocyte cryostorage were prospectively recruited. We excluded those requiring a concomitant letrozole assumption. All women received a standardized protocol with recombinant FSH and GnRH antagonists. At the time of oocyte retrieval, follicular fluids were pooled, and a sample was collected and frozen at -80 °C. All samples were assayed concomitantly after thawing by liquid chromatography-tandem mass spectrometry. The concentration of 15 different steroid hormones was determined. RESULTS: Seventy-one women were recruited. Thirty-three initiated the ovarian stimulation in the luteal phase, while the remaining 38 initiated in the follicular phase. Baseline characteristics were generally similar. Cycle outcome did also not differ; the median (interquartile range) number of frozen mature oocytes was 9 (5-14) and 10 (5-21), respectively (p = 0.42). None of the 15 tested steroid hormones differed. CONCLUSIONS: The endocrine microenvironment surrounding oocytes is not markedly influenced by the phase of the menstrual cycle at the initiation of ovarian stimulation. This result further supports the validity of random start protocols.

Sperm DNA Fragmentation and Sperm-Borne miRNAs: Molecular Biomarkers of Embryo Development?

The evaluation of morpho-functional sperm characteristics alone is not enough to explain infertility or to predict the outcome of Assisted Reproductive Technologies (ART): more sensitive diagnostic tools are needed in clinical practice. The aim of the present study was to analyze Sperm DNA Fragmentation (SDF) and sperm-borne miR-34c-5p and miR-449b-5p levels in men of couples undergoing ART, in order to investigate any correlations with fertilization rate, embryo quality and development. Male partners (n = 106) were recruited. Semen analysis, SDF evaluation and molecular profiling analysis of miR-34c-5p and miR-449b-5p (in 38 subjects) were performed. Sperm DNA Fragmentation evaluation- a positive correlation between SDF post sperm selection and the percentage of low-quality embryos and a negative correlation with viable embryo were found. SDF > 2.9% increased the risk of obtaining a non-viable embryo by almost 4-fold. Sperm miRNAs profile­we found an association with both miRNAs and sperm concentration, while miR-449b-5p is positively associated with SDF. Moreover, the two miRNAs are positively correlated. Higher levels of miR-34c-5p compared to miR-449b-5p increases by 14-fold the probability of obtaining viable embryos. This study shows that SDF, sperm miR-34c-5p, and miR-449b-5p have a promising role as biomarkers of semen quality and ART outcome.

"Better late than never but never late is better", especially in young women. A multicenter Italian study on diagnostic delay for symptomatic endometriosis.

PURPOSE: The aim of the study was to assess the length of diagnostic delay of symptomatic endometriosis in Italy and analyse the presence of correlations between the socio-demographic status of patients and the clinical characteristics/type of diagnosis. MATERIALS AND METHODS: This multicenter cross-sectional questionnaire-based study was conducted in 10 tertiary Italian referral centres for diagnosis and treatment endometriosis. A total of 689 respondents with histologically proven endometriosis and onset of the disease with pain symptoms completed an on-line self-reported questionnaire written in their own language (World Endometriosis Research Foundation-Endometriosis Phenome and Biobanking Harmonisation Project-Endometriosis Patient Questionnaire-Minimum) evaluating endometriosis related symptoms, family history of endometriosis and chronic pelvic pain, demographic data, as well as medical, reproductive, and obstetric history. RESULTS: The mean diagnostic delay found was of 11.4 years. The mean time (14.8 years) from symptoms onset to diagnosis was significantly longer among patients aged 9-19 vs patients aged 20-30 (mean 6.9 years, p < 0.001) and patients aged 31-45 (mean 2.9, p < 0.001). No significant association were found between a delayed diagnosis and any of the clinically relevant factors such as the number or severity of the reported symptoms, familiarity, hormonal therapy intake or methodology of diagnosis. CONCLUSIONS: The mean diagnostic delay of endometriosis in Italy is about 11 years. The delay can be up to 4 years longer in patients with pain symptoms onset under 20 years. Educating clinicians and patients on pathologic nature of endometriosis related pelvic pain is advisable to reduce waiting time to diagnosis, especially for young women.

Potential Protective Role of Pregnancy and Breastfeeding in Delaying Onset Symptoms Related to Multiple Sclerosis.

The impact of pregnancy and breastfeeding on the development and outcomes of Multiple sclerosis (MS) has been debated for decades. Since several factors can influence the evolution of the disease, the protective role of multiparity and breastfeeding remains uncertain, as well the role of hormone replacement therapy in the perimenopausal period. We report two cases of relatively late-onset MS in two parous women, who developed their first neurological symptoms after six and nine pregnancies, respectively. Both women breastfed each of their children for 3 to 12 months. One of them underwent surgical menopause and received hormone replacement therapy for 7 years before MS onset. We performed a systematic literature review to highlight the characteristics shared by women who develop the disease in similar conditions, after unique hormonal imbalances, and to collect promising evidence on this controversial issue. Several studies suggest that the beneficial effects of pregnancy and breastfeeding on MS onset and disability accumulation may only be realized when several pregnancies occur. However, these data on pregnancy and breastfeeding and their long-term benefits on MS outcomes suffer from the possibility of reverse causality, as women with milder impairment might choose to become pregnant more readily than those with a higher level of disability. Thus, the hypothesis that multiparity might have a protective role on MS outcomes needs to be tested in larger prospective cohort studies of neo-diagnosed women, evaluating both clinical and radiological features at presentation.

Early-stage cervical cancer treatment - what's new?

The gold standard of treatment for patients with early-stage cervical cancer is radical hysterectomy, in agreement with the entire scientific community. During the last decade, growing evidence has supported the minimally invasive approach. Several studies have suggested that the minimally invasive approach could improve surgical and perioperative outcomes. Because of these findings, ESCO/ESTRO/ESP guidelines state that a "minimally invasive approach is favoured" in comparison with open surgery, as a grade B recommendation. Because of the lack of a grade A recommendation, this randomized Laparoscopic Approach to Cervical Cancer trial evaluated open vs. minimally invasive approach in the early stage. It demonstrated an increase in mortality among patients treated with minimally invasive surgery, revolutionizing current thinking on the primary surgical approach to early cervical cancer. The aim of this study is to analyse which is the best treatment for early cervical cancer and which approach is the most effective at the moment. Further studies are needed to state with certainty the appropriateness of the treatments offered to patients with early cervical cancer.

Current protocols and clinical efficacy of human fetal liver cell therapy in patients with liver disease: A literature review.

The fetal liver is unique because of the coexistence of cells with endodermal and mesenchymal origins, making it a potential source of hepatic and pancreatic regenerative medicine. The liver appears at about the third week of gestation, growing rapidly from the fifth to the 10th week. We define fetal liver from 10 weeks of gestation, when hematopoietic progenitor cells gradually migrate from the aorta-mesonephros-gonad region to colonize the liver. Indeed, the fetal liver may be the most available source of cell therapy for liver disease. We conducted a review of the literature using Medline and EMBASE (up to May 2021) to identify clinical studies in which patients with liver disease had been given fetal liver cell therapy. This literature review highlighted the heterogeneity of cell isolation and selection protocols, which hinders the ability to pool data and perform a meta-analysis. A limitation of the studies analyzed was the scarcity of reports (n = 8) and the extremely small sample sizes (median sample size of treated patients was two), although there was a fairly long follow-up (median 12 months). The weeks after conception ranged from 16 to 34. There were no randomized controlled trials, and therefore no study was stratified as being of good methodological quality. Cryopreservation may help to circumvent the critical logistic issues that hamper the use of fetal liver cell therapy in clinical practice. To help consolidate the role of the fetal liver in regenerative medicine, good preclinical translational studies are necessary, whereas tracing strategies and biopsy-based endpoints are crucial in the clinic, along with well-designed, large, multicenter, randomized controlled trials using clinically applicable primary outcomes and refined imaging assessment.

Practice patterns and 90-day treatment-related morbidity in early-stage cervical cancer.

BACKGROUND: To evaluate the impact of the Laparoscopic Approach to Cervical Cancer (LACC) Trial on patterns of care and surgery-related morbidity in early-stage cervical cancer. METHODS: This is a retrospective, a multi-institutional study evaluating 90-day surgery-related outcomes of patients undergoing treatment for early-stage cervical cancer before (period I: 01/01/2016-06/01/2018) and after (period II: 01/01/2019-06/01/2021) the publication of the results of the LACC trial. RESULTS: Charts of 1295 patients were evaluated: 581 (44.9%) and 714 (55.1%) before and after the publication of the LACC trial, respectively. After the publication of the LACC trial, the number of patients treated with minimally invasive radical hysterectomy decreased from 64.9% to 30.4% (p < 0.001). Overall, 90-day complications occurred in 110 (18.9%) and 119 (16.6%) patients in the period I and period II, respectively (p = 0.795). Similarly, the number of severe (grade 3 or worse) complications did not differ between the two periods (38 (6.5%) vs. 37 (5.1%); p = 0.297). Overall and severe 90-day complications were consistent between periods even evaluating stage IA (p = 0.471), IB1 (p = 0.929), and IB2 (p = 0.074), separately. CONCLUSIONS: The present investigation highlighted that in referral centers the shift from minimally invasive to open radical hysterectomy does not influence 90-day surgery-related morbidity.

Evaluating long-term outcomes of three approaches to retroperitoneal staging in endometrial cancer.

OBJECTIVE: Sentinel lymph node mapping (SNM) has gained popularity in managing apparent early-stage endometrial cancer (EC). Here, we evaluated the long-term survival of three different approaches of nodal assessment. METHODS: This is a multi-institutional retrospective study evaluating long-term outcomes of EC patients having nodal assessment between 01/01/2006 and 12/31/2016. In order to reduce possible confounding factors, we applied a propensity-matched algorithm. RESULTS: Overall, 940 patients meeting inclusion criteria were included in the study, of which 174 (18.5%), 187 (19.9%), and 579 (61.6%) underwent SNM, SNM followed by backup lymphadenectomy (LND) and LND alone, respectively. Applying a propensity score matching algorithm (1:1:2) we selected 500 patients, including 125 SNM, 125 SNM/backup LND, and 250 LND. Baseline characteristics of the study population were similar between groups. The prevalence of nodal disease was 14%, 16%, and 12% in patients having SNM, SNM/backup LND and LND, respectively. Overall, 19 (7.6%) patients were diagnosed with low volume nodal disease. The survival analysis comparing the three techniques did not show statistical differences in terms of disease-free (p = 0.750) and overall survival (p = 0.899). Similarly, the type of nodal assessment did not impact survival outcomes after stratification based on uterine risk factors. CONCLUSION: Our study highlighted that SNM provides similar long-term oncologic outcomes than LND.

Clear cell carcinoma of the endometrium.

Clear cell endometrial carcinoma represents an uncommon and poorly understood entity. Data from molecular/genomic profiling highlighted the importance of various signatures in assessing the prognosis of endometrial cancer according to four classes of risk (POLE mutated, MMRd, NSMP, and p53 abnormal). Unfortunately, data specific to clear cell histological subtype endometrial cancer are lacking. More recently, data has emerged to suggest that most of the patients (more than 80%) with clear cell endometrial carcinoma are characterized by p53 abnormality or NSMP type. This classification has important therapeutic implications. Although it is an uncommon entity, clear cell endometrial cancer patients with POLE mutation seem characterized by a good prognosis. Chemotherapy is effective in patients with NSMP (especially in stage III and IV) and patients with p53 abnormal disease (all stages). While, preliminary data suggested that patients with MMRd are less likely to benefit from chemotherapy. The latter group appears to benefit much more from immune checkpoint inhibitors: recent data from clinical trials on pembrolizumab plus lenvatinib and nivolumab plus cabozantinib supported that immunotherapy plus tyrosine kinase inhibitors (TKI) would be the most appropriate treatment for recurrent non-endometrioid endometrial cancer (including clear cell carcinoma) after the failure of platinum-based chemotherapy. Moreover, ongoing clinical trials testing the anti-tumor activity of innovative products will clarify the better strategies for advanced/recurrent clear cell endometrial carcinoma. Further prospective evidence is urgently needed to better characterize clear cell endometrial carcinoma.