A bitter pill to swallow: adjustments to oral contraceptive pill use in polycystic ovary syndrome.

INTRODUCTION: This Special Report aims to highlight the importance of tailored therapies in women with Polycystic Ovary Syndrome (PCOS), avoiding prescribing generalized or unsuitable therapies based on oral contraceptive pills (OCPs). AREAS COVERED: This article discusses the benefits and risks of OCP-based therapy, highlighting the possible undesirable effects, especially in those patients exhibiting risk factors as women with PCOS, and the importance of carefully evaluated tailored therapeutic approaches. Literature searches were performed with the use of PubMed, Google Scholar, and Web of Science between January and February 2024. EXPERT OPINION: Considering the recent re-analysis of PCOS Rotterdam Criteria by the Expert Group on Inositol in Basic and Clinical Research, and on PCOS (EGOI-PCOS), the traditional Rotterdam phenotypes can be reclassified to achieve more efficacious therapy choices. Using personalized therapies that consider the specific clinical characteristics of the patient allows to improve the management of the syndrome, thus avoiding the generalized use of OCPs, which risk treating only symptoms of PCOS rather than the underlying cause. In cases when contraceptive purpose is desired, patients may benefit from combined therapy with diet or insulin-sensitizer agents, as inositol, to rebalance the metabolic profile, thus reducing the risk of developing future complications.

The Network Structure of Cognitive Impairment: From Subjective Cognitive Decline to Alzheimer's Disease.

It was proposed that a reorganization of the relationships between cognitive functions occurs in dementia, a vision that surpasses the idea of a mere decline of specific domains. The complexity of cognitive structure, as assessed by neuropsychological tests, can be captured by exploratory graph analysis (EGA). EGA was applied to the neuropsychological assessment of people (humans) with subjective cognitive decline (SCD), mild cognitive impairment (MCI), and Alzheimer's disease (AD; total N = 638). Both sexes were included. In AD, memory scores detach from the other cognitive functions, and memory subdomains reduce their reciprocal relation. SCD showed a pattern of segregated neuropsychological domains, and MCI showed a noisy and less stable pattern. Results suggest that AD drives a reorganization of cognitive functions toward a less-fractionated architecture compared with preclinical conditions. Cognitive functions show a reorganization that goes beyond the performance decline. Results also have clinical implications in test interpretations and usage.

The use of oral nomegestrol acetate/estradiol in rapid and random start preparation of endometrium before office hysteroscopic polypectomies: A multicenter, prospective, randomized controlled trial.

OBJECTIVE: To evaluate the use of oral nomegestrol acetate/estradiol in random start rapid preparation of endometrium before office hysteroscopic polypectomy. STUDY DESIGN: Multicenter, prospective, randomized controlled trial. SETTING: University hospitals. PARTICIPANTS: 80 adult women undergoing office hysteroscopic polypectomy between January 2023 and March 2024 were randomized to intervention (n = 40) or control (n = 40). Exclusion criteria included the presence of endouterine pathology other than endometrial polyps solely. METHODS: Subjects in the intervention group were treated with oral nomegestrol acetate/estradiol 1.5 mg/2.5 mg/day started taking the drug from an indefinite time in the menstrual cycle (random start) for 14 days. Subjects in the control group did not receive any pharmaceutical treatment and underwent polypectomy between days 8 and 11 of the menstrual cycle. RESULTS: On the day of the procedure, the difference in pre- and post-office hysteroscopic polypectomy endometrial ultrasound thickness was statistically significant between the two groups, with endometrial thickness in both measurements being thinner for the intervention group (p < 0.001). In the nomegestrol acetate/estradiol-treated group, compared with the control, there was also a statistically significant difference in the physician's assessment of the quality of endometrial preparation (p < 0.001), the quality of visualization of the uterine cavity (p < 0.001), and satisfaction with the performance of the procedure (p < 0.001). Finally, all surgical outcomes analyzed were better in the treatment group. CONCLUSION: Treatment with nomegestrol acetate/estradiol could provide rapid, satisfactory and low-cost preparation of the endometrium before office polypectomy, thus improving surgical performance and woman's compliance. TRIAL REGISTRATION: ClinicalTrials.gov NCT06316219.

Long-term therapy with dienogest or other oral cyclic estrogen-progestogen can reduce the need for ovarian endometrioma surgery.

BACKGROUND: Almost 10% of women in reproductive age are diagnosed with ovarian endometriomas and can experience symptoms and infertility disorders. Ovarian endometriomas can be treated with medical or surgical therapy. OBJECTIVE: To assess whether long-term therapy with dienogest or oral cyclic estrogen-progestogens is effective in reducing the size of ovarian endometriomas, alleviating associated symptoms, and reducing the requirement for surgery. DESIGN: Prospective non-interventional cohort study. METHODS: We enrolled childbearing women diagnosed with ovarian endometriomas. We collected demographic, clinical, and surgical data, including the evaluation of ovarian endometrioma-associated symptoms and pain using the visual analog scale. We grouped the women according to treatment regimen into dienogest, estrogen-progestogens, and no-treatment. Patient's assessment was performed at baseline and after 12 months evaluating the largest ovarian endometrioma diameter (in millimeters) and the associated symptoms. Furthermore, we analyzed the impact of hormonal treatment in a sub-group of women fulfilling at baseline the criteria for a first-line surgical approach (ovarian endometrioma > 30 mm with visual analog scale > 8 or ovarian endometrioma > 40 mm before assisted reproductive treatments or any ovarian endometrioma(s) > 60 mm). RESULTS: We enrolled 142 patients: 62, 38, and 42 in dienogest, estrogen-progestogens, and no-treatment groups, respectively. No significant differences were found regarding baseline characteristics. After 12 months, the mean largest ovarian endometrioma diameter increased in the no-treatment group (31.1 versus 33.8; p < 0.01), while a significant reduction was registered in the dienogest (35.1 versus 25.8; p < 0.01) and estrogen-progestogens (28.4 versus 16.7; p < 0.01) groups; no significant difference in ovarian endometrioma diameter reduction between these two latter groups was noted (p = 0.18). Ovarian endometrioma-associated symptoms and pain improved in dienogest and estrogen-progestogens groups, with a significantly greater effect for dienogest than for estrogen-progestogens for dysmenorrhea (74% versus 59%; p < 0.01). In the sub-group of women eligible for first-line surgery at baseline, long-term treatment with dienogest and estrogen-progestogens reduced surgical eligibility by 30%. CONCLUSIONS: Decreased mean largest ovarian endometriomas'diameter after 12 months and reduction of the need for surgical treatment by 30% were observed in dienogest and estrogen-progestogens groups. Long-term treatment with dienogest had a greater effect in alleviating dysmenorrhea and pain.

Adjuvant Radiotherapy for Groin Node Metastases Following Surgery for Vulvar Cancer: A Systematic Review.

Background: Lymph node metastasis in vulvar cancer is a critical prognostic factor associated with higher recurrence and decreased survival. A survival benefit is reported with adjuvant radiotherapy but with potential significant morbidity. We aim to clarify whether there is high-quality evidence to support the use of adjuvant radiotherapy in this setting. Objectives: The aim of the study was to assess the effectiveness and safety of adjuvant radiotherapy to locoregional metastatic nodal areas. Search Methods: We conducted a comprehensive and systematic literature search of MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Google Scholar, ClinicalTrials.gov, and the National Cancer Institute. We considered only randomized controlled trials (RCTs). Main Results: We identified 1,760 records and finally retrieved only one eligible RCT (114 participants with positive inguinofemoral lymph nodes). All women had undergone radical vulvectomy and bilateral inguinal lymphadenectomy and had been randomized to adjuvant radiotherapy or to intraoperative ipsilateral pelvic lymphadenectomy without adjuvant radiotherapy. At 6 years, the overall survival (OS) was 51% versus 41% in favor of radiotherapy (HR 0.61; 95% CI 0.30-1.3) without significance and with very low certainty of evidence. At 6 year, the cumulative incidence of cancer-related deaths was 29% versus 51% in favor of adjuvant radiotherapy (HR 0.49; 95% CI 0.28-0.87). Recurrence-free survival at 6 years was 59% after adjuvant radiotherapy versus 48% after pelvic lymphadenectomy (HR 0.39; 95% CI 0.17-0.88). Three (5.3%) versus 13 (24.1%) groin recurrences were noted, respectively, in the adjuvant radiotherapy and pelvic lymphadenectomy groups. There was no significant difference in acute toxicities for pelvic lymphadenectomy compared to radiotherapy. In women with positive pelvic lymph nodes (20%), the OS at 6 year was 36% compared with 13% in favor of adjuvant radiotherapy. Late cutaneous toxicity rate appeared to be greater after radiotherapy (19% vs. 15%) but with less chronic lymphedema (16% vs. 22%). Conclusion: There is only very low-quality evidence on administering adjuvant radiotherapy for inguinal lymph node metastases. Although the identified study was a multicenter RCT, there was a reasonable imprecision and inconsistency because of small study numbers, wide confidence intervals in the data, and early trial closure, resulting in downgrading of the evidence.

Approaches to prevention of gynecological malignancies.

Gynecological malignancies represent one of the prevalent diseases in the female sex and prevention is essential to limit their incidence and mortality. Nowadays, not all malignancies benefit from adequate screening methods for this reason new biomarkers and methods are being developed to undertake timely and effective therapies.

Health-related quality of life after hysterectomy for endometrial cancer: the impact of enhanced recovery after surgery (ERAS) shifting paradigm.

OBJECTIVES: Enhanced recovery after surgery (ERAS) protocols provide well-known benefits in the immediate recovery with a shorter length of stay (LOS) also in gynecological surgery. However, the impact of ERAS has not been clearly showed yet regarding long-term consequences and health-related quality of life (HRQL). The aim of this study is to investigate the impact of ERAS on HRQL after hysterectomy for endometrial cancer. DESIGN: Observational retrospective study with propensity score matching (PSM). Participants We administered the SF-36 validated questionnaire to women underwent hysterectomy and lymph nodal staging before and after introducing ERAS protocol, getting, respectively, a standard practice (SP) and ERAS group Settings Academic hospital Methods We collected demographic, clinical, surgical and postoperative data and performed a PSM of the baseline coufouders. We administered the questionnaire four weeks after the surgery. The SF-36 measures HRQL using eight scales: physical functioning (PF), role physical (RLP), bodily pain (BP), general health (GH), vitality (Vt), social functioning (SF), role emotional (RLE) and mental health (MH). Results After PSM, we enrolled a total of 154 patients, 77 in each group (SP and ERA). The two groups were similar in terms of age, BMI, anaesthesiologic risk, Charlson comorbidity index (CCI) and surgical technique (minimally invasive versus open access). Median LOS was shorter for ERAS group (5 versus 3 days; p = 0.02), while no significant differences were registered in the rates of postoperative complications (16.9% versus 17.4%; p = 0.66). Response rates to SF-36 questionnaire were 89% and 92%, respectively, in SP and ERAS group. At multivariate analyzes, the mean scores of SF-36 questionnaire, registered at 28 days weeks after surgery (range 26-32 days), were significantly higher in ERAS group for PF (73.3 vs 91.6; p < 0.00), RLP (median 58.3 vs 81.2; p = 0.02) and SF (37.5 versus 58.3; p = 0.01) domains, when compared to SP patients. Limitations Further follow-up was not possible due to the anonymized data derived from clinical audit. Conclusions ERAS significantly increases HRQL of women underwent surgery for endometrial cancer. HRQL assessment should be routinary implemented in the ERAS protocol.

Robotic surgery for deep-infiltrating endometriosis: is it time to take a step forward?

Endometriosis is a chronic debilitating disease that affects nearly 10% of women of the reproductive age. Although the treatment modalities of endometriosis are numerous, surgical excision of the endometriotic implants and nodules remains the sole cytoreductive approach. Laparoscopic excision of endometriosis was proven to be beneficial in improving the postoperative pain and fertility. Moreover, it was also proved to be safe and efficient in treating the visceral localization of deep endometriosis, such as urinary and colorectal endometriosis. More recently, robotic-assisted surgery gained attention in the field of endometriosis surgery. Although the robotic technology provides a 3D vision of the surgical field and 7-degree of freedom motion, the safety, efficacy, and cost-effectiveness of this approach are yet to be determined. With this paper, we aim to review the available evidence regarding the role of robotic surgery in the management of endometriosis along with the current practices in the field.

Topographic mapping of the sensorimotor qualities of empathic reactivity: A psychophysiological study in people with spinal cord injuries.

The experience of empathy for pain is underpinned by sensorimotor and affective dimensions which, although interconnected, are at least in part behaviorally and neurally distinct. Spinal cord injuries (SCI) induce a massive, below-lesion level, sensorimotor body-brain disconnection. This condition may make it possible to test whether sensorimotor deprivation alters specific dimensions of empathic reactivity to observed pain. To explore this issue, we asked SCI people with paraplegia and healthy controls to observe videos of painful or neutral stimuli administered to a hand (intact) or a foot (deafferented). The stimuli were displayed by means of a virtual reality set-up and seen from a first person (1PP) or third person (3PP) visual perspective. A number of measures were recorded ranging from explicit behaviors like explicit verbal reports on the videos, to implicit measures of muscular activity (like EMG from the corrugator and zygomatic muscles that may represent a proxy of sensorimotor empathy) and of autonomic reactivity (like the electrodermal response and Respiratory Sinus Arrhythmia that may represent a general proxy of affective empathy). While no across group differences in explicit verbal reports about the pain stimuli were found, SCI people exhibited reduced facial muscle reactivity to the stimuli applied to the foot (but not the hand) seen from the 1PP. Tellingly, the corrugator activity correlated with SCI participants' neuropathic pain. There were no across group differences in autonomic reactivity suggesting that SCI lesions may affect sensorimotor dimensions connected to empathy for pain.

Hepatocellular carcinoma in pregnancy: A systematic review.

INTRODUCTION: Hepatocellular carcinoma (HCC) is the most frequent primary malignant liver tumor and typically develops in the context of chronic liver disease, such as liver cirrhosis or chronic hepatitis B virus infection. Ultrasound evaluation, CT scan, and MRI are used to detect HCC. α-fetoprotein (AFP) is a common marker used to detect HCC in the non-pregnant population, which notoriously increases in pregnant women in relation to gestational age. Treatment is driven by the extent of the disease and the severity of underlying liver disease. Pregnancy may represent an obstacle to diagnosis and appropriate treatment of HCC. The aim of this descriptive systematic review was to describe the clinical features and maternal and neonatal outcomes of HCC in pregnancy. MATERIAL AND METHODS: We performed a systematic review of the literature about HCC diagnosed in pregnancy and the postpartum period, with signs or symptoms arising in pregnancy. We included case reports and case series describing the clinical features of women diagnosed with HCC, fibrolamellar variant of HCC, and mixed HCC and cholangiocarcinoma during pregnancy or the postpartum period (with onset of symptoms during pregnancy), from inception to March 2023. The study protocol was registered with the PROSPERO database (Registration number: ID CRD42021275584). RESULTS: We identified 180 records. The articles included in this systematic review were 47 case reports and 5 case series, for a total of 63 pregnancies. The two most frequent predisposing conditions were hepatitis B virus infection (30/63; 47%) and liver cirrhosis (14/63; 22%). Ultrasound evaluation was the most used technique to detect HCC. AFP was higher than normal in 28/46 patients tested (61%). Surgical treatment was the most used therapy, both during pregnancy and after delivery. Twenty-six patients (26/63; 42%) died within 6 months of diagnosis. Survival >24 months was 9% (4/46) in symptomatic and 29% (5/17) in asymptomatic women. No patient with cirrhotic liver survived more than 12 months. Thirty-eight newborns were alive at 28 days of age (38/63; 61%). CONCLUSIONS: Hepatocellular carcinoma in pregnancy is associated with a high risk of maternal and neonatal mortality. Diagnosis in asymptomatic high-risk women or following abnormal maternal serum AFP screening is associated with better maternal outcomes.

Human Papillomavirus Genotype Richness and the Biodiversity of Squamous and Glandular Cervical Dysplasias: A Cross-Sectional Study.

The impact of multiple infections on the risk of cervical lesions is a subject of ongoing debate. This study aims to explore whether the richness of HPV genotype infections and the biodiversity of squamous and glandular cervical dysplasias could influence the progression of precancerous lesions. We conducted a cross-sectional analysis involving 469 women who attended the Colposcopy Unit at the European Institute of Oncology in Milan, Italy, from December 2006 to December 2014. HPV type richness was measured as the number of different genotypes per patient. We calculated the associations between richness and age, as well as histologic grade, along with Simpson's biodiversity index for cervical dysplasias. We observed significant inverse relationships between the richness of high-risk (HR) genotypes and both age (p = 0.007) and histologic grade (p < 0.001). Furthermore, as the histologic grade increased, the mean biodiversity index of cervical dysplasias decreased, with exceptions noted in cases of normal histology and adenocarcinoma in situ. Different histologic grades formed five clusters with distinct mean ages and mean biodiversity indices. These findings suggest that HPV genotype richness and the biodiversity of cervical dysplasias may play a crucial role in predicting the risk of high-grade cervical lesions, enabling personalized management of precancers.

Mixed Endometrial Epithelial Carcinoma: Epidemiology, Treatment and Survival Rates-A 10-Year Retrospective Cohort Study from a Single Institution.

Mixed endometrial carcinoma (MEEC) refers to rare endometrial tumours that are composed of two or more distinct histotypes, at least one of which is serous or clear cell. The aim of this study was to evaluate the epidemiology, treatment outcomes and survival rates of patients with mixed endometrial carcinoma. The medical records of 34 patients diagnosed with MEEC between March 2010 and January 2020 were reviewed retrospectively. Clinicopathological variables and treatment strategies were assessed, and overall survival and disease-free survival rates were evaluated. The histology of endometrioid and serous component was found in 26 (76.5%) patients, followed by serous and clear-cell components (5/34, 14.5%) and mixed endometrioid serous and clear-cell components (3/34, 8.8%). The median age at diagnosis was 70 years (range 52-84), and the median follow-up time was 55 months. The 5-year disease-free survival and the 5-year overall survival were 50.4% and 52.4%, respectively. Advanced disease stage was identified as an independent predictor of inferior disease-free (<0.003) and overall survival (p < 0.001). Except for stage, none of the traditional prognostic factors was associated with disease recurrence or death from disease. MEECs represent rare high-risk endometrial carcinomas with significant diagnostic and treatment challenges. Undoubtedly, the implementation of a molecular analysis can offer further diagnostic and management insights.

Molecular and Cellular Advances in Endometriosis Research: Paving the Way for Future Directions.

Molecular and cellular research in the field of endometriosis is moving forward in giant steps [...].

Feasibility and Surgical Outcomes of Hysteroscopic Myomectomy of FIGO Type 3 Myoma: A Systematic Review.

The latest classification from the Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) has reclassified type 3 myomas, changing their classification from intramural to submucosal. While hysteroscopic myomectomy is considered the gold standard treatment for patients experiencing symptoms from submucosal myomas, there are currently no specific guidelines available for managing type 3 myomas, and the optimal surgical approach remains uncertain. Methods: The search for suitable articles published in English was carried out using the following databases (PROSPERO ID CRD42023418602): MEDLINE, EMBASE, Global Health, The Cochrane Library (Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Cochrane Methodology Register), Health Technology Assessment Database, Web of Science and search register. Only original studies reporting data on hysteroscopic myomectomy of type 3 myoma were considered eligible. The main outcomes investigated were the effectiveness and feasibility of hysteroscopic myomectomy and reproductive outcomes after surgical treatment. Results: Two hundred and sixty-one studies were screened and nineteen of these were read for eligibility. Three studies encompassing 56 patients in total were included. Among the overall population studied, three patients needed an additional procedure to completely remove the myoma and five cases of post-surgical synechiae were recorded. No complications were reported. Of 42 patients wishing for pregnancy, the cumulative live birth rates before and after the hysteroscopic myomectomy were 14.3% and 42.9%, respectively. Conclusions: Hysteroscopic myomectomy appears to be a safe and feasible approach. Nevertheless, data reported in the literature are extremely scarce and based on studies with few patients enrolled. New evidence is needed to assess the safety and effectiveness of hysteroscopic treatment for FIGO type 3 myomas.

Diagnosis, Treatment and Prognosis of Mesonephric Adenocarcinoma of the Vagina: A Literature Review and a Case Report.

BACKGROUND: Mesonephric adenocarcinoma (MA) of the vagina is a rare tumor that arises from mesonephric remnants (Wolffian) in the female genital tract. It is a neoplasm with no significant evidence about its diagnosis, treatment, follow-up and prognosis. METHODS: Systematic research of the literature was conducted in Scopus, PubMed/MEDLINE, ScienceDirect and the Cochrane Library, including observational prospective and retrospective studies, case series and case reports. We collected data regarding studies related to diagnosis and treatment options evaluating the following aspects: study design, population, treatment type, rate of surgical complications and fertility outcome. We further included a case report of laparoscopic management of MA with pictorial assays. RESULTS: Thirteen cases of MA of the vagina are available in the literature, including our case report. The median age at diagnosis was 52 years old; the majority of patients reported vaginal bleeding as a symptom (38%); and ultrasound, followed by a magnetic resonance and CT scan were the diagnostic tools most used. In 54% of the cases, a surgical biopsy was performed, and 92% of the patients underwent upfront surgery with an open access or vaginal resection except one case fully managed by minimally invasive surgery. Most of the patients (68%) received adjuvant treatment with chemotherapy or radiotherapy or a combination of them. The mean follow-up period was 6 years. CONCLUSIONS: Despite the rarity of this cancer and bizarre location, a minimally invasive approach seems feasible after multidisciplinary evaluation. According to the rarity of this tumor, any future case and follow-up data must be reported in the literature in order to enlarge the knowledge about it.

Clinical usefulness of nutraceutics with acetyl-L-carnitine, α-lipoic acid, phosphatidylserine, curcumin, C, E and B-group vitamins in patients awaiting for carpal tunnel release during COVID-19 pandemic: a randomized controlled open label prospective study.

BACKGROUND AND AIM OF THE WORK: Carpal Tunnel Syndrome (CTS) is provoked by the compression of the median nerve, leading to nerve ischemia, endoneural edema, venous congestion, and subsequent metabolic alterations. Conservative treatments could be considered. The present study investigates the efficacy of a specific blend of a 600 mg dietary integrator composed of acetyl-L-carnitine, α-lipoic acid, phosphatidylserine, Curcumin, C, E and B1, B2, B6 and B12 vitamins in patients with mild to moderate CTS. METHODS: The present investigation involved the outpatients who were planned to undergo open surgical decompression of the median nerve awaiting surgery from June 2020 and February 2021. CTS surgery has been significantly reduced in our institutions during the COVID-19 pandemic. Patients were randomized into Group A (dietary integration 600 mg twice day for 60 days) and Group B (control group, no drug administration). Clinical and functional improvement was prospectively measured after 60 days Results: One-hundred forty-seven patients completed the study, 69 from group A and 78 from group B. BCTQ was significantly improved with the drug administration, as well as BCTQ symptoms subscale, and the pain. BCTQ function subscale and Michigan Hand Questionnaire was not significantly improved. Ten patients in group A (14.5%) declared that they didn't need further treatment. No major side effects were noticed. CONCLUSIONS: Dietary integration could be considered as an option in patients who could not undergo surgery. Symptoms and pain could improve, but surgery remains the gold standard for recovery of function in mild to moderate CTS.

The Prognostic Characteristics and Recurrence Patterns of High Grade Endometrioid Endometrial Cancer: A Large Retrospective Analysis of a Tertiary Center.

High grade endometrioid endometrial cancer (HGEEC) is a heterogeneous group of tumors with unclear prognostic features. The aim of the present study is to evaluate the independent risk factors for recurrence and mortality and to describe the recurrence patterns of HGEEC. Ninety-six consecutive cases of HGEEC treated with primary surgery in a single Tertiary Center were retrospectively reviewed. Clinicopathological and treatment details were recorded, and all patients were closely followed up. Disease-free, overall and cancer-specific survival rates were 83.8%, 77.8% and 83.6%, respectively. Cervical stromal involvement was independently related to recurrence (HR = 25.67; 95%CI 2.95-223.30; p = 0.003) and cancer-related death (HR = 15.39; 95%CI 1.29-183.43; p = 0.031) after adjusting for other pathological and treatment variables. Recurrence rate was 16%, with 60% of these cases having lung metastases and only one case with single vaginal vault recurrence. 81.81% of the recurrences presented with symptoms and not a single recurrence was diagnosed in routine follow-up clinical examination. In conclusion, the recurrence pattern may suggest that patient-initiated follow-up (PIFU) could be considered a potential alternative to clinical-based follow-up for HGEEC survivors, especially for patients without cervical involvement and after two years from treatment. Additional caution is needed in patients with cervical stromal involvement.

Personalised progression prediction in patients with monoclonal gammopathy of undetermined significance or smouldering multiple myeloma (PANGEA): a retrospective, multicohort study.

BACKGROUND: Patients with precursors to multiple myeloma are dichotomised as having monoclonal gammopathy of undetermined significance or smouldering multiple myeloma on the basis of monoclonal protein concentrations or bone marrow plasma cell percentage. Current risk stratifications use laboratory measurements at diagnosis and do not incorporate time-varying biomarkers. Our goal was to develop a monoclonal gammopathy of undetermined significance and smouldering multiple myeloma stratification algorithm that utilised accessible, time-varying biomarkers to model risk of progression to multiple myeloma. METHODS: In this retrospective, multicohort study, we included patients who were 18 years or older with monoclonal gammopathy of undetermined significance or smouldering multiple myeloma. We evaluated several modelling approaches for predicting disease progression to multiple myeloma using a training cohort (with patients at Dana-Farber Cancer Institute, Boston, MA, USA; annotated from Nov, 13, 2019, to April, 13, 2022). We created the PANGEA models, which used data on biomarkers (monoclonal protein concentration, free light chain ratio, age, creatinine concentration, and bone marrow plasma cell percentage) and haemoglobin trajectories from medical records to predict progression from precursor disease to multiple myeloma. The models were validated in two independent validation cohorts from National and Kapodistrian University of Athens (Athens, Greece; from Jan 26, 2020, to Feb 7, 2022; validation cohort 1), University College London (London, UK; from June 9, 2020, to April 10, 2022; validation cohort 1), and Registry of Monoclonal Gammopathies (Czech Republic, Czech Republic; Jan 5, 2004, to March 10, 2022; validation cohort 2). We compared the PANGEA models (with bone marrow [BM] data and without bone marrow [no BM] data) to current criteria (International Myeloma Working Group [IMWG] monoclonal gammopathy of undetermined significance and 20/2/20 smouldering multiple myeloma risk criteria). FINDINGS: We included 6441 patients, 4931 (77%) with monoclonal gammopathy of undetermined significance and 1510 (23%) with smouldering multiple myeloma. 3430 (53%) of 6441 participants were female. The PANGEA model (BM) improved prediction of progression from smouldering multiple myeloma to multiple myeloma compared with the 20/2/20 model, with a C-statistic increase from 0·533 (0·480-0·709) to 0·756 (0·629-0·785) at patient visit 1 to the clinic, 0·613 (0·504-0·704) to 0·720 (0·592-0·775) at visit 2, and 0·637 (0·386-0·841) to 0·756 (0·547-0·830) at visit three in validation cohort 1. The PANGEA model (no BM) improved prediction of smouldering multiple myeloma progression to multiple myeloma compared with the 20/2/20 model with a C-statistic increase from 0·534 (0·501-0·672) to 0·692 (0·614-0·736) at visit 1, 0·573 (0·518-0·647) to 0·693 (0·605-0·734) at visit 2, and 0·560 (0·497-0·645) to 0·692 (0·570-0·708) at visit 3 in validation cohort 1. The PANGEA models improved prediction of monoclonal gammopathy of undetermined significance progression to multiple myeloma compared with the IMWG rolling model at visit 1 in validation cohort 2, with C-statistics increases from 0·640 (0·518-0·718) to 0·729 (0·643-0·941) for the PANGEA model (BM) and 0·670 (0·523-0·729) to 0·879 (0·586-0·938) for the PANGEA model (no BM). INTERPRETATION: Use of the PANGEA models in clinical practice will allow patients with precursor disease to receive more accurate measures of their risk of progression to multiple myeloma, thus prompting for more appropriate treatment strategies. FUNDING: SU2C Dream Team and Cancer Research UK.

Effects of different progesterone levels on reproductive outcomes in assisted reproductive technologies: from molecular basis to treatment strategies.

PURPOSE: The aim of this narrative review is to offer an overview about the role of progesterone levels on pregnancy outcome in patients undergoing assisted reproductive technologies (ARTs). METHODS: A detailed computerized search of the literature was performed in the main electronic databases (MEDLINE, EMBASE, Web of Science) to determine the importance of elevated progesterone levels at different stages of the cycle for pregnancy rates in the in vitro fertilization (IVF) cycle. Our review also provides information on the differences between elevated progesterone levels and their interpretation in normal and in poorly responding women. RESULTS: After careful evaluation, our search strategy yielded a total of 15 included articles, showing the possible factors that may have had an impact on the increased progesterone level before human chorionic gonadotropin (HCG) injection and the different thresholds above which the pregnancy rate was lower. Furthermore, increased progesterone on cycle day 2 or 3 could serve as a marker for increased progesterone in the late follicular phase, which is associated with a lower pregnancy rate. CONCLUSION: Despite the literature data that support the negative effect of elevated progesterone on fresh cycles, due to lack of randomized controlled trials, the value of measuring progesterone in daily practice is questionable. Available evidence supports the detrimental effect of elevated progesterone in different subgroups of women, although there is still the need for defining different thresholds and durations of high progesterone exposure. The need for various thresholds for different cohorts of women, the inter-assay variability is making this decision harder.