Trends and current aspects of reconstructive surgery for gynecological cancers.

Gynecologic cancers can lead to gynecologic tract destruction with extension into both the gastrointestinal and urinary tracts. Recurrent disease can also affect the surrounding bony pelvis and pelvic musculature. As opposed to advanced ovarian cancer, where cytoreduction is the goal, in these scenarios, an oncologic approach to achieve negative margins is critical for benefit. Surgeries aimed at achieving a R0 resection in gynecologic oncology can have a significant impact on pelvic anatomy, and require reconstruction. Overall, it appears that these types of radical surgery are less frequently performed; however, when required, multidisciplinary teams at high-volume centers can potentially improve short-term morbidity. There are few data to examine the long-term, quality-of-life outcomes after reconstruction following oncologic resection in advanced and recurrent gynecologic cancers. In this review we outline considerations and approaches for reconstruction after surgery for gynecologic cancers. We also discuss areas of innovation, including minimally invasive surgery and the use of 3D surgical anatomy models for improved surgical planning.In the era of 'less is more', pelvic exenteration in gynecologic oncology is still indicated when there are no other curative-intent alternatives in persistent or recurrent gynecological malignancies confined to the pelvis or with otherwise unmanageable symptoms from fistula or radiation necrosis. Pelvic exenteration is one of the most destructive procedures performed on an elective basis, which inevitably carries a significant psychologic, sexual, physical, and emotional burden for the patient and caregivers. Such complex ultraradical surgery, which requires removal of the vagina, vulva, urinary tract, and/or gastrointestinal tract, subsequently needs creative and complex reconstructive procedures. The additional removal of sidewall or perineal structures, like pelvic floor muscles/vulva, or portions of the musculoskeletal pelvis, and the inclusion of intra-operative radiation further complicates reconstruction. This review paper will focus on the reconstruction aspects following pelvic exenteration, including options for urinary tract restoration, reconstruction of the vulva and vagina, as well as how to fill large empty spaces in the pelvis. While the predominant gastrointestinal outcome after exenteration in gynecologic oncology is an end colostomy, we also present some novel new options for gastrointestinal tract reconstruction at the end.

Predictive factors of surgical complications after pelvic exenteration for gynecological malignancies: a large single-institution experience.

OBJECTIVE: To evaluate pre-operative predictors of early (<30 days) severe complications (grade Dindo 3+) in patients with gynecological malignancy submitted to pelvic exenteration (PE). METHODS: We retrospectively analyzed 129 patients submitted to surgery at Fondazione Policlinico Gemelli between 2010 and 2019. We included patients affected by primary or recurrent/persistent cervical, endometrial, or vulvar/vaginal cancers. Post-operative complications were graded according to the Dindo classification. Logistic regression was used to analyze potential predictors of complications. RESULTS: We performed 63 anterior PE, 10 posterior PE, and 56 total PE. The incidence of early severe post-operative complications was 27.9% (n=36), and the early mortality rate was 2.3% (n=3). More frequent complications were related to the urinary diversion and intestinal surgery. In univariable analysis, hemoglobin ≤10 g/dL (odds ratio [OR]=4.2; 95% confidence interval [CI]=1.65-10.7; p=0.003), low albumin levels (OR=3.9; 95% CI=1.27-12.11; p=0.025), diabetes (OR=4.15; 95% CI=1.22-14.1; p=0.022), 2+ comorbidities at presentation (OR=5.18; 95% CI=1.49-17.93; p=0.012) were predictors of early severe complications. In multivariable analysis, only low hemoglobin and comorbidities at presentation were independent predictors of complications. CONCLUSION: Pelvic exenteration is an aggressive surgery characterized by a high rate of post-operative complications. Pre-operative assessment of comorbidities and patient health status are crucial to better select the right candidate for this type of surgery.

Robotic surgery in ovarian cancer.

Ovarian cancer (OC) represents one of the most lethal cancers in women. The aim of surgical treatment is complete cytoreduction in advanced stages and a surgical staging in early stages. Although the guidelines still suggest laparotomy as the standard approach, in recent years minimally invasive surgery (MIS) has become increasingly popular in the treatment of OC, especially in early stages, because the 5-year relative survival exceeds 90% and the patients' quality of life cannot be overshadowed. However, MIS has been demonstrated to have a role even in advanced stages, in the prediction of optimal cytoreduction, identification patients who may benefit from neoadjuvant chemotherapy, and, more recently, in the interval debulking surgery, as in selected cases of secondary cytoreduction for recurrent ovarian cancer. The aim of this review is to describe the MIS (especially robotic surgery), with its advantages and pitfalls, in the treatment of OC.

Ovarian preservation in gynecologic oncology: current indications and techniques.

PURPOSE OF REVIEW: Early menopause represents a relevant clinical issue for women. Nevertheless, this issue should be balanced with the risks of ovarian metastasis, ovarian recurrence, and the risk of recurrence in hormone-sensitive gynecological cancers. The purpose of this review was to provide an overview on current indications and techniques of ovarian preservation in patients with gynecological cancers. RECENT FINDINGS: The potential discussion about ovarian conservation could be proposed to patients with FIGO-stage IA grade 1-2 endometrioid endometrial cancer aged 40 years or less, FIGO-stage IB1-IB2 node-negative cervical cancer with squamous cell carcinoma and HPV-associated adenocarcinoma, FIGO-stage IA-IC grade 1-2 serous, endometrioid, mucinous expansile pattern ovarian cancer, any stage germ cell ovarian tumors, and FIGO-stage IA sex cord-stromal tumors. Technique to perform ovarian transposition in cervix cancer is also reported. SUMMARY: Ovarian conservation is a surgical approach that involves preserving one or both ovaries during the treatment of gynecologic cancers. This approach has gained popularity in recent years, as it offers several benefits to the patient, including the preservation of hormonal function and fertility. The decision to perform ovarian conservation depends on several factors, such as the stage and type of cancer, the patient's age, fertility desire, and should be carefully discussed with patients.

Dual inhibition of CDK12 and CDK13 uncovers actionable vulnerabilities in patient-derived ovarian cancer organoids.

BACKGROUND: High grade serous ovarian cancer (HGSOC) is highly lethal, partly due to chemotherapy resistance and limited availability of targeted approaches. Cyclin dependent kinases 12 and 13 (CDK12/13) are promising therapeutic targets in human cancers, including HGSOC. Nevertheless, the effects of their inhibition in HGSOC and the potential synergy with other drugs are poorly known. METHODS: We analyzed the effects of the CDK12/13 inhibitor THZ531 in HGSOC cells and patient-derived organoids (PDOs). RNA sequencing and quantitative PCR analyses were performed to identify the genome-wide effects of short-term CDK12/13 inhibition on the transcriptome of HGSOC cells. Viability assays with HGSOC cells and PDOs were performed to assess the efficacy of THZ531 as single agent or in combination with clinically relevant drugs. RESULTS: The CDK12 and CDK13 genes are deregulated in HGSOC and their concomitant up-regulation with the oncogene MYC predicts poor prognosis. HGSOC cells and PDOs display high sensitivity to CDK12/13 inhibition, which synergizes with drugs in clinical use for HGSOC. Transcriptome analyses revealed cancer-relevant genes whose expression is repressed by dual CDK12/13 inhibition through impaired splicing. Combined treatment with THZ531 and inhibitors of pathways regulated by these cancer relevant genes (EGFR, RPTOR, ATRIP) exerted synergic effects on HGSOC PDO viability. CONCLUSIONS: CDK12 and CDK13 represent valuable therapeutic targets for HGSOC. We uncovered a wide spectrum of CDK12/13 targets as potential therapeutic vulnerabilities for HGSOC. Moreover, our study indicates that CDK12/13 inhibition enhances the efficacy of approved drugs that are already in use for HGSOC or other human cancers.

Role of minimally invasive secondary cytoreduction in patients with recurrent ovarian cancer.

OBJECTIVE: Retrospective series have shown minimally invasive secondary cytoreductive surgery is a feasible approach in selected cases of recurrent ovarian cancer. However, no predictors of minimally invasive secondary cytoreductive surgery feasibility are currently available. This study aims to identify predictive factors of minimally invasive secondary cytoreductive surgery feasibility and to compare perioperative and survival outcomes in a matched series of recurrent ovarian cancer patients who underwent secondary cytoreduction via an open or minimally invasive surgical approach. METHODS: We retrospectively identified all platinum-sensitive recurrent epithelial ovarian cancer patients who underwent minimally invasive or laparotomic secondary cytoreductive surgery between January 2013 and July 2020. Each patient underwent a preoperative positron emission tomography (PET) computerized tomography (CT) scan and diagnostic laparoscopy before secondary cytoreductive surgery. A 1:2 propensity score-matched analysis was performed to balance predictive factors of minimally invasive secondary cytoreductive surgery. RESULTS: Overall, 276 patients were identified (62 minimally invasive and 214 open), and a complete gross resection was achieved in 262 (94.9%) patients. At multivariate analysis, predictive factors for minimally invasive secondary cytoreductive surgery were neoadjuvant chemotherapy at first diagnosis (p=0.007), site of recurrence (p=0.031), and number of lesions (p=0.001). In the 1:2 propensity-matched population (39 minimally invasive and 78 open), complete gross resection was similar for both groups (p=0.082). Early post-operative complications were significantly higher in the laparotomy (33.3%) than in the minimally invasive surgery (10.3%) group (p=0.004). Only one (2.6%) patient experienced a grade >3 early post-operative complication in the minimally invasive surgery group compared with 13 (16.7%) patients in the open cohort (p<0.001). The median follow-up period was 32 months (range: 1-92) in the propensity-matched population. The median post-recurrence survival was 81 months in the minimally invasive surgery group and was not reached in the open group (p=0.11). CONCLUSIONS: Patients with single or oligometastatic recurrences can be offered minimally invasive secondary cytoreductive surgery, mainly if localized in the lymph-nodes, and/or if they received neoadjuvant chemotherapy at primary diagnosis. Minimally invasive secondary cytoreductive surgery is associated with favorable perioperative outcomes with no differences in terms of post-recurrence survival with respect to open approach.

Minimally invasive versus open pelvic exenteration in gynecological malignancies: a propensity-matched survival analysis.

OBJECTIVE: The primary endpoint of this study was to compare the disease-free survival of patients undergoing open versus minimally invasive pelvic exenteration. The secondary endpoints were cancer-specific survival and peri-operative morbidity. METHODS: A multi-center, retrospective, observational cohort study was undertaken. Patients undergoing curative and palliative anterior or total pelvic exenteration for gynecological cancer by a minimally invasive approach and an open approach between June 2010 and May 2021 were included. Patients with distant metastases were excluded. A 1:2 propensity match analysis between patients undergoing minimally invasive and open pelvic exenteration was performed to equalized baseline characteristics. RESULTS: After propensity match analysis a total of 117 patients were included, 78 (66.7%) and 39 (33.3%) in the open and minimally invasive group, respectively. No significant difference in intra-operative (23.4% vs 10.3%, p=0.13) and major post-operative complications (24.4% vs 17.9%, p=0.49) was evident between the open and minimally invasive approach. Patients undergoing open pelvic exenteration received higher rates of intra-operative transfusions (41.0% vs 17.9%, p=0.013). Median disease-free survival was 17.0 months for both the open and minimally invasive groups (p=0.63). Median cancer-specific survival was 30.0 months and 26.0 months in the open and minimally invasive groups, respectively (p=0.80). Positivity of surgical margins at final histology was the only significant factor influencing the risk of recurrence (hazard ratio (HR) 2.38, 95% CI 1.31 to 4.31) (p=0.004), while tumor diameter ≥50 mm at the time of pelvic exenteration was the only significant factor influencing the risk of death (HR 1.83, 95% CI 1.08 to 3.11) (p=0.025). CONCLUSION: In this retrospective study no survival difference was evident when minimally invasive pelvic exenteration was compared with open pelvic exenteration in patients with gynecological cancer. There was no difference in peri-operative complications, but a higher intra-operative transfusion rate was seen in the open group.

Laparoscopic Ovarian Transposition with Extraperitonealization of the Infundibulopelvic Ligament for Cervical Cancer in Ten Steps.

Preservation of ovarian function is important for the physical and psychosexual well-being of young patients with cancer. Patients with pelvic malignancies such as cervical or rectal cancer planned for radiotherapy may benefit from ovarian transposition with the aim of moving the ovaries outside the radiation field.1 Different surgical techniques have been reported previously.2,3 With the present video, we aim to standardize the surgical technique of laparoscopic ovarian transposition in ten steps. We present the case of a 30-year-old nulliparous woman diagnosed with grade 3 squamous cell cervical carcinoma having a largest tumor diameter of 41 mm on magnetic resonance imaging (MRI) scan. The tumor was staged as FIGO 2018 stage IIIC1r with a common iliac lymphadenopathy reported on both MRI and positron emission tomography (PET)/computed tomography (CT) scan. The multidisciplinary team recommended exclusive chemoradiation extended to paraaortic area. The patient underwent laparoscopic bilateral salpingectomy and bilateral ovarian transposition with extraperitonealization of the infundibulopelvic ligament. The procedure was divided into the following ten steps: division of uteroovarian ligament, incision of lateral pelvic peritoneum, identification of ureter, incision of medial pelvic peritoneum, skeletonization of the infundibulopelvic ligament, retroperitoneal tunnel in paracolic gutter, creating the window (as high as possible), mobilization of the ovary without torsion, intraperitonealization of the ovary, and fix ovary with clips (Fig. 1). Surgical time was 30 min, with minimal estimated blood loss. No intra- or postoperative complication was recorded. The patient started radiotherapy 14 days after the procedure. In conclusion, we showed that laparoscopic ovarian transposition in cervical cancer before radiotherapy can be standardized in ten steps with encouraging perioperative results, making it an easily reproducible procedure. Ovarian function is reported to be preserved in 62-65% of cases undergoing ovarian transposition and radiation therapy.4,5 Fig. 1 Laparoscopic view of right ovary transposed below the liver edge after extraperitonealization of the infudibulopelvic ligament.

The impact of secondary cytoreductive surgery in platinum sensitive recurrent ovarian cancer treated with upfront neoadjuvant chemotherapy and interval debulking surgery.

OBJECTIVE: The aims of the present study were to assess the oncological outcomes of platinum-sensitive recurrent ovarian cancer patients undergoing secondary cytoreduction (SCS) after treatment with neoadjuvant chemotherapy (NACT) and interval debulking surgery (IDS) at diagnosis and to compare the performance of different selection models in these patients. METHODS: Retrospective, observational, single-center cohort study including patients with platinum-sensitive recurrent epithelial ovarian cancer with abdominal/inguinal/cardiophrenic disease between November 2012 and November 2020. Patients were selected as surgical candidates with PET/CT-scan and with diagnostic laparoscopy. RESULTS: 272 patients were included in the study. Of these, 165 (60.7%) patients were treated with PDS at diagnosis and 107 (39.3%) with IDS. SCS was performed in 178 (65.4%) cases, with complete gross resection achieved in 155/178 (87.1%). No progression-free survival (PFS) difference was demonstrated when patients treated with PDS were compared with those treated with NACT+IDS at first diagnosis (median 21 versus 21 months; p = 0.684); no post-recurrence survival (PRS) difference was evident between the two groups (median 81 versus 77 months, respectively; p = 0.574). Current selection models to candidate patients to SCS adequately performed in patients treated with IDS at diagnosis, as well as in the PDS group, with combination of PET/CT-scan and laparoscopy being an accurate tool in prediction of no gross residual disease at SCS in this pre-selected population. CONCLUSIONS: Patients with platinum-sensitive recurrent epithelial ovarian cancer treated with NACT/IDS as primary treatment have similar post-recurrence survival outcomes of those treated with PDS. Current models to select patients for SCS can be safely applied to IDS patients.

Characteristics and patterns of care of endometrial cancer before and during COVID-19 pandemic.

OBJECTIVE: Coronavirus disease 2019 (COVID-19) outbreak has correlated with the disruption of screening activities and diagnostic assessments. Endometrial cancer (EC) is one of the most common gynecological malignancies and it is often detected at an early stage, because it frequently produces symptoms. Here, we aim to investigate the impact of COVID-19 outbreak on patterns of presentation and treatment of EC patients. METHODS: This is a retrospective study involving 54 centers in Italy. We evaluated patterns of presentation and treatment of EC patients before (period 1: March 1, 2019 to February 29, 2020) and during (period 2: April 1, 2020 to March 31, 2021) the COVID-19 outbreak. RESULTS: Medical records of 5,164 EC patients have been retrieved: 2,718 and 2,446 women treated in period 1 and period 2, respectively. Surgery was the mainstay of treatment in both periods (p=0.356). Nodal assessment was omitted in 689 (27.3%) and 484 (21.2%) patients treated in period 1 and 2, respectively (p<0.001). While, the prevalence of patients undergoing sentinel node mapping (with or without backup lymphadenectomy) has increased during the COVID-19 pandemic (46.7% in period 1 vs. 52.8% in period 2; p<0.001). Overall, 1,280 (50.4%) and 1,021 (44.7%) patients had no adjuvant therapy in period 1 and 2, respectively (p<0.001). Adjuvant therapy use has increased during COVID-19 pandemic (p<0.001). CONCLUSION: Our data suggest that the COVID-19 pandemic had a significant impact on the characteristics and patterns of care of EC patients. These findings highlight the need to implement healthcare services during the pandemic.

Indocyanine Green to Assess Vascularity of Ileal Conduit Anastomosis During Pelvic Exenteration for Recurrent/Persistent Gynecological Cancer: A Pilot Study.

INTRODUCTION: Pelvic exenteration performed for recurrent/persistent gynecological malignancies has been associated with urological short- and long-term morbidity due to altered vascularization of tissues for previous radiotherapy. The aims of the present study were to describe the use of intravenous indocyanine green (ICG) to assess vascularity of urinary diversion (UD) after pelvic exenteration for gynecologic cancers, to evaluate the feasibility and safety of this technique, and to assess the postoperative complications. METHODS: Prospective, observational, single-center, pilot study including consecutive patients undergoing anterior or total pelvic exenteration due to persistent/recurrent gynecologic cancers between August 2020 and March 2021 at Fondazione Policlinico Gemelli IRCCS, Rome, Italy. All patients underwent intravenous injection of 3-6 ml of ICG (1.25 mg/ml) once the UD was completed. A near-infrared camera was used to evaluate ICG perfusion of anastomoses (ileum-ileum, right and left ureter with small bowel, and colostomy or colorectal sides of anastomosis) a few seconds after ICG injection. RESULTS: Fifteen patients were included in the study. No patient reported adverse reactions to ICG injection. Only 3/15 patients (20.0%) had an optimal ICG perfusion in all anastomoses. The remaining 12 (80.0%) patients had at least one ICG deficit; the most common ICG deficit was on the left ureter: 3 (20.0%) vs. 1 (6.7%) patient had no ICG perfusion on the left vs. right ureter, respectively (p = 0.598). 8/15 (53.3%) and 6/15 (40.0%) patients experienced grade ≥3 30-day early and late postoperative complications, respectively. Of these, two patients had early and one had late postoperative complications directly related to poor perfusion of anastomosis (UD leak, ileum-ileum leak, and benign ureteric stricture); all these cases had a suboptimal intraoperative ICG perfusion. CONCLUSION: The use of ICG to intraoperatively assess the anastomosis perfusion at time of pelvic exenteration for gynecologic malignancy is a feasible and safe technique. The different vascularization of anastomotic stumps may be related to anatomical sites and to previous radiation treatment. This approach could be in support of selecting patients at higher risk of complications who may need personalized follow-up.

The Effect of Menopause Hypoestrogenism on Osteogenic Differentiation of Periodontal Ligament Cells (PDLC) and Stem Cells (PDLCs): A Systematic Review.

(1) Background: Menopause is a physiological condition typified by drastic hormonal changes, and the effects of this transition have long-term significant clinical implications on the general health, including symptoms or physical changes. In menopausal women, the periodontium can be affected directly or through neural mechanism by oestrogen (E2) deficiency. The majority of the biological effects of E2 are modulated via both oestrogen receptor-α (ERα) and oestrogen receptor- ß (ERß). There is evidence that hypoestrogenism has a substantial impact on the aetiology, manifestation and severity of periodontitis, via the regulation of the expression of osteoprogesterin and RANKL in human periodontal ligament cells through ERß. However, the mechanistic understanding of oestrogen in periodontal status has been partially clarified. The aim of this paper was to synopsize the recent scientific evidence concerning the link between the menopause and periodontitis, through the investigation of physio-pathological impact of the oestrogen deficiency on osteogenic differentiation of PDLSCs and PDLSC, as well as the dynamic change of ERα and ERß. (2) Methods: Search was conducted for significant studies by exploring electronic PubMed and EMBASE databases, and it was independently performed by two researchers. All studies on the impact of oestrogen level on alveolar bone resorption were searched from 2005 to July 2020. Data selection was in concordance with PRISMA guidelines. (3) Results: Eight studies met the criteria and were included in this systematic review. All studies reported that oestrogen deficiency impairs the osteogenic and osteoblastic differentiation of PDL cells and oestrogen affects the bone formation capacity of cells. Seven studies were conducted on animal samples, divided into two groups: the OVX animals and animals who received the sham operation. (4) Conclusions: There is a multitude of data available showing the influence of menopause on periodontal status. However, the evidence of this line to investigation needs more research and could help explain the physiological linkage between menopause state and periodontal disease.

Myomectomy during pregnancy: an obstetric overview.

INTRODUCTION: Uterine fibroids (UFs) are the most common benign disease affecting female reproductive system, and occurring in 20-40% of women, and in 10% of pregnancies. The aim of the investigation was to summarize evidence about the management and treatment of UFs and related complications in pregnancy. EVIDENCE ACQUISITION: A literature review was performed using scientific databases, including all case report and case series, using a combination of key words related to the problem exposed. Data about gestational age at diagnosis, maximum fibroids diameter, type of surgery and gestational age at surgery, delivery and perinatal outcome were collected. Two clinical cases were also included. EVIDENCE SYNTHESIS: Sixty-six articles were selected, and 199 patients were included. In 76% of patients the gestational age at myomectomy was lower than 20 weeks, in 85% laparotomic surgery was chosen, in 41% of cases the maximum fibroid diameter was between 7-20 cm, in 41% of pregnancies the route of delivery was the Cesarean section. In the eight percent of cases there was a complication given by miscarriage, fetal demise or neonatal death. CONCLUSIONS: Myomectomy is a feasible procedure in those pregnancies complicated by symptomatic fibroids, though surgery in pregnancy is associated with an increased risk of obstetric complications.

Patient-derived organoids and high grade serous ovarian cancer: from disease modeling to personalized medicine.

BACKGROUND: High grade serous ovarian cancer (HGSOC) is among the deadliest human cancers and its prognosis remains extremely poor. Tumor heterogeneity and rapid acquisition of resistance to conventional chemotherapeutic approaches strongly contribute to poor outcome of patients. The clinical landscape of HGSOC has been radically transformed since the advent of targeted therapies in the last decade. Nevertheless, the lack of predictive biomarkers informing on the differential clinical benefit in select subgroups, and allowing patient-centric approaches, currently limits the efficacy of these novel therapies. Thus, rational selection of the best possible treatment for each patient represents a clinical priority in order to improve outcome, while limiting undesirable effects. MAIN BODY: In this review, we describe the state of the art and the unmet needs in HGSOC management, illustrate the treatment options that are available and the biomarkers that are currently employed to orient clinical decisions. We also describe the ongoing clinical trials that are testing new therapeutic approaches for HGSOC. Next, we introduce the organoid technology as a promising, expanding strategy to study cancer and to develop personalized therapeutic approaches. In particular, we discuss recent studies that have characterized the translational potential of Patient's Derived Organoids (PDOs) to inform on drug sensitivity of HGSOC patients. CONCLUSIONS: PDOs can predict the response of patients to treatments and may therefore guide therapeutic decisions. Although preliminary results appear encouraging, organoids still need to be generated and expanded efficiently to enable drug screening in a clinically meaningful time window. A new generation of clinical trials based on the organoid technology should guarantee tailored approaches to ovarian cancer management, as it is now clear that the one-size-fits-all approach cannot lead to efficient and meaningful therapeutic advancements.

Hormone therapy in female-to-male transgender patients: searching for a lifelong balance.

BACKGROUND: Reassignment of a female-to-male (FtM) person requires gender-affirming, androgenic hormonal treatment that is planned to induce appropriate structural changes. This therapy must be prolonged long term, even after the sex reassignment surgery (SRS). The purpose of this study is to evaluate the effects of hormone therapy with testosterone in FtM subjects during a 24-month follow-up in order to highlight the occasional need for early decompensation and to make adequate hormone therapy modulations. METHODS: Fifteen out of 23 FtM persons had been previously treated with SRS, while eight were still awaiting surgery. During hormone therapy, both groups were followed for 24 months, with evaluation of desired changes, adverse effects, and functional or metabolic indicators. RESULTS: In the group of operated FtM subjects (15/23), a significant increase of total testosterone (total T) and free testosterone (free T) was found after 24 months. Luteinizing hormone (LH) maintained a low level, decreasing after ovariectomy, while FSH increased. Voice deepening, facial and body hair variation, male-pattern balding, and body mass index (BMI) increase are all physical changes due to androgenization. In both groups of patients who have been closely monitored, the side effects and thromboembolic, metabolic, and cardiovascular risks of androgen therapy, even in the long term, appear to be irrelevant. CONCLUSION: Total T, free T, and LH dosages are shown to be reliable markers of correct androgenization. Strict monitoring of lipid profile, evaluation of BMI and hematocrit, avoidance of self-initiated therapeutic modifications, adherence to a healthy lifestyle, and avoidance of excessive daily calorie intake can limit risks linked to long-term testosterone administration. TRIAL REGISTRATION: Retrospectively registered.

Pregnancy Complications, Correlation With Placental Pathology and Neonatal Outcomes.

Purpose: We aimed to clarify and contribute to a better comprehension of associations and correlations between placental histological findings, pregnancy evolution, and neonatal outcomes. Study Design: This is a longitudinal and prospective observational study, performed between May 2015 and May 2019, on 506 pregnant women. Clinical data related to pregnancy outcome, neonatal health status, and placental histology were primarily collected. Twin pregnancies or malformed newborns were excluded and therefore the study was conducted on 439 cases. These cases have been then subdivided into the following study groups: (a) 282 placentas from pathological pregnancies; and, (b) a control group of 157 pregnancies over 33 weeks of gestational age, defined as physiological or normal pregnancies due to the absence of maternal, fetal, and early neonatal pathologies, most of which had undergone elective cesarean section for maternal or fetal indication. Results: A normal placenta was present in 57.5% of normal pregnancies and in 42.5% of pathological pregnancies. In contrast, placental pathology was present in 26.2% of normal pregnancies and 73.8% of pathological pregnancies. Comparison of the neonatal health status with the pregnancy outcome showed that, among the 191 newborns classified as normal, 98 (51.3%) were born from a normal pregnancy, while 93 (48.7%) were born from mothers with a pathological pregnancy. Among the 248 pathological infants, 59 (23.8%) were born from a mother with a normal pregnancy, while 189 (76.2%) were born from pregnancies defined as pathological. Conclusion: Placental histology must be better understood in the context of natural history of disease. Retrospective awareness of placental damage is useful in prevention in successive pregnancy, but their early identification in the evolving pregnancy could help in association with biological markers or more sophisticated instruments for early diagnosis.