Marta Caretto

Objective: To evaluate whether first‐trimester abdominal subcutaneous fat thickness (ASFT) and renal fat thickness (RFT) provide incremental value for early identification of gestational diabetes mellitus (GDM) and their association with obstetric complications. Methods: This prospective observational cohort study included 268 singleton pregnancies undergoing first‐trimester aneuploidy screening (11–13 ⁺⁶ weeks) at the Division of Obstetrics and Gynecology, University of Pisa, Italy (2019–2020). ASFT and RFT were measured by transabdominal ultrasound. Fasting glycemia, pre‐gestational body mass index (BMI), and weight gain were recorded. GDM was diagnosed by standard oral glucose tolerance test. Associations with GDM were evaluated using univariate and multivariable logistic regression analyses. Predictive performance was assessed using receiver operating characteristic (ROC) curves and model comparison. Obstetric complications were prospectively documented. Results: GDM developed in 23.9% of the cohort. Women with GDM had higher BMI, first‐trimester glycemia, upper and lower ASFT (all P < 0.001), and RFT ( P < 0.01). After adjustment for BMI, ASFT—but not RFT—remained associated with GDM. A composite ASFT variable based on predefined cutoffs remained independently associated with GDM (odds ratio [OR] 2.31, 95% confidence interval [CI]: 1.17–4.72; P = 0.016). Inclusion of ASFT slightly improved model discrimination (area under the curve [AUC] 0.75 vs. 0.71). Using guideline‐based risk factors alone, sensitivity for GDM detection was 85.9%, increasing to 95.3% after addition of ASFT, with reduced specificity. Neither ASFT nor RFT predicted obstetric complications. Conclusion: First‐trimester ASFT measurement was independently associated with GDM risk and showed incremental predictive value beyond conventional clinical risk factors. These findings support further investigation of ultrasound markers of maternal adiposity for early risk assessment in pregnancy.

Introduction The tumor microenvironment (TME) plays an essential role in promoting cancer initiation, progression and metastasis. Cancer-associated fibroblasts (CAFs) are a major constituent of the TME, but universal CAFs’ markers have not yet been identified. We selected several new biomarkers [p16 and α-smooth muscle actin (α-SMA)] to investigate the molecular landscape in epithelial ovarian cancer (EOC), given to the unique TME of this malignancy. Methods In total, 64 patients with a diagnosis of EOC who underwent primary debulking surgery (PDS) at the Department of Gynecology and Obstetrics of the University of Pisa were enrolled between January 2019 and June 2021. The stromal expression of α-SMA and p16 was investigated by using immunohistochemistry, and the correlations between p16 and α-SMA immunoreactivity and BRCA mutational status were analyzed. Results Positive p16 stromal expression was found in 6 out of 38 (15,78%) patients with wild-type BRCA and in only 1 of the 22 (4,50%) patients with mutated BRCA. Conversely, positive α-SMA expression was detected in 34 of 38 patients with wild-type BRCA (89,47%) and in 21 of 22 patients (95,45%) with mutated BRCA. There was a significant difference (r = −0,32) between the negative stromal p16 expression and the positive stromal expression of α-SMA. Conclusion This study suggests a new correlation between stromal expression of p16 and α-SMA and BRCA mutational status in EOC. Further investigations are strongly warranted to improve the understanding of the landscape of this malignancy.

Objective Missing occult para-aortic lymph node metastasis is one of the primary concerns of sentinel lymph node biopsy in endometrial cancer. Our study aimed to evaluate the relationship between intrauterine cancer site and isolated para-aortic lymph node metastasis to tailor treatment and reduce the false negative rate of the sentinel lymph node procedure. Methods A retrospective, multicenter, case control study was performed in four international centers. All patients with positive lymph nodes who had complete surgical staging with pelvic and para-aortic lymphadenectomy, between January 2013 and December 2023, were included. Detailed descriptions of the cancer location within the uterine cavity on the cranio-caudal plane and the myometrial wall involvement on the cranio-caudal and ventro-dorsal planes were collected, as were clinical data and cancer histological features. Patients with isolated para-aortic lymph node metastasis were allocated to group 1; patients with pelvic lymph node metastasis and those with both pelvic and para-aortic lymph node metastasis were allocated to group 2. The groups were compared according to the variables collected. Results 200 preoperative early stage endometrial cancer patients with postoperative International Federation of Gynecology and Obstetrics 2009/2023 stage IIIC1/IIIC2 were included in our study: 42 patients (21%) with isolated para-aortic lymph node metastasis were allocated to group 1 and the remaining patients to group 2. The two groups had comparable clinical and pathological characteristics (p>0.05): mean age was 66.5±10.3 (group 1) and 63.5±11.9 (group 2); endometrioid histotype was the predominant one for both groups (50%); most patients had myometrial infiltration >50% (80.9% and 79.7%), grade 3 (61.9% and 63.9%), and lymph vascular space invasion (78.5% and 82.2%). Cancers involving the fundal uterine cavity, the fundal myometrial wall, or the anterior myometrial wall were 3.11 (1.04–9.27), 3.03 (1.12–8.21), and 2.12 (0.77–5.80) times more likely to metastasize only to para-aortic lymph nodes compared with cancers located in other uterine sites. Conclusions In this study, the intrauterine location of the cancer determined the site of lymph node metastasis. When the tumor involved the fundus (cavity or wall) and infiltrated exclusively the anterior wall, the baseline risk of spreading only into the para-aortic area increased significantly in selected patients at risk of nodal disease.

Objective: The present study aimed to assess long-term follow-up outcomes in women with in situ/microinvasive adenocarcinoma (AC) of the uterine cervix treated conservatively. Methods: Retrospective multi-institutional study including women with early glandular lesions and 5-year follow-up undergoing fertility-sparing treatment. Independent variables associated with recurrence were evaluated. Logistic regression analysis and Kaplan–Meier survival analysis with Logrank test were performed. Results: Of 269 women diagnosed with in situ/microinvasive AC, 127 participants underwent conservative treatment. During follow-up, recurrences were found in nine women (7.1%). The only factor associated with recurrence during follow-up was positive high-risk Human Papillomavirus (hr-HPV) testing (odds ratio 6.21, confidence interval 1.47–26.08, p = 0.012). HPV positivity in follow-up showed a recurrence rate of 21.7% against 3.8% in patients who were HPV-negative (p = 0.002, Logrank test). Among women with negative high-risk HPV tests in follow-up, recurrences occurred in 20.0% of non-usual-type histology vs. 2.1% of usual-type cases (p = 0.005). Conclusion: HPV testing in follow-up is of pivotal importance in women with early glandular lesions undergoing conservative treatment, given its recurrence predictive value. However, women who are high-risk HPV-negative in follow-up with non-usual-type histopathology may represent a sub-population at increased risk of recurrences. Further studies should confirm these findings.

It is unknown whether human papillomavirus (HPV) status impacts the prognosis of early stage cervical glandular lesions. This study assessed the recurrence and survival rates of in situ/microinvasive adenocarcinomas (AC) according to HPV status during a 5-year follow-up. The data were retrospectively analyzed in women with available HPV testing before treatment. One hundred and forty-eight consecutive women were analyzed. The number of HPV-negative cases was 24 (16.2%). The survival rate was 100% in all participants. The recurrence rate was 7.4% (11 cases, including four invasive lesions (2.7%)). Cox proportional hazards regression showed no difference in recurrence rate between HPV-positive and HPV-negative cases (p = 0.148). HPV genotyping, available for 76 women and including 9/11 recurrences, showed a higher relapse rate for HPV-18 than HPV-45 and HPV-16 (28.5%, 16.6%, and 9.52%, p = 0.046). In addition, 60% and 75% of in situ and invasive recurrences, respectively, were HPV-18 related. The present study showed that most ACs were positive for high-risk HPV, and the recurrence rate was unaffected by HPV status. More extensive studies could help evaluate whether HPV genotyping may be considered for recurrence risk stratification in HPV-positive cases.

Exposure to environmental stressors during pregnancy plays an important role in influencing subsequent susceptibility to certain chronic diseases through the modulation of epigenetic mechanisms, including DNA methylation. Our aim was to explore the connections between environmental exposures during gestation with DNA methylation of placental cells, maternal and neonatal buccal cells by applying artificial neural networks (ANNs). A total of 28 mother–infant pairs were enrolled. Data on gestational exposure to adverse environmental factors and on mother health status were collected through the administration of a questionnaire. DNA methylation analyses at both gene-specific and global level were analyzed in placentas, maternal and neonatal buccal cells. In the placenta, the concentrations of various metals and dioxins were also analyzed. Analysis of ANNs revealed that suboptimal birth weight is associated with placental H19 methylation, maternal stress during pregnancy with methylation levels of NR3C1 and BDNF in placentas and mother’s buccal DNA, respectively, and exposure to air pollutants with maternal MGMT methylation. Associations were also observed between placental concentrations of lead, chromium, cadmium and mercury with methylation levels of OXTR in placentas, HSD11B2 in maternal buccal cells and placentas, MECP2 in neonatal buccal cells, and MTHFR in maternal buccal cells. Furthermore, dioxin concentrations were associated with placental RELN, neonatal HSD11B2 and maternal H19 gene methylation levels. Current results suggest that exposure of pregnant women to environmental stressors during pregnancy could induce aberrant methylation levels in genes linked to several pathways important for embryogenesis in both the placenta, potentially affecting foetal development, and in the peripheral tissues of mothers and infants, potentially providing peripheral biomarkers of environmental exposure.

Depressive disorders and anxiety states represent one of the most frequent psychiatric pathologies occurring transiently in vulnerable women throughout their life, from puberty to menopause. It is now known that sex hormones play a key role on the nervous system, interfering with neuronal plasticity and enhancing the processes of learning, memory, cognition, and mood. Numerous mechanisms are at the base of these processes, displaying interactions between estrogen and serotoninergic, dopaminergic, and GABAergic receptors at the central level. Therefore, given the sexual steroids fluctuations throughout the entire female lifespan, and considering the role played by sex hormones at the central level, it is not surprising to observe the onset of mood or neurodegenerative disorders over time. This is especially true for women in hormonal transition phase, such as puberty, postpartum and the menopausal transition. Moreover, all these conditions are characterized by hormone withdrawal, imbalance, or modifications due to menopausal hormone therapies or contraceptives which could prompt to a deterioration of mood and cognition impairment or to an improvement in the quality of life. More studies are needed to better understand the hormone-related effects on the nervous system, and the underlying pathways involved in transitional or chronic mood disorders, to promote new patient-specific therapeutic strategies more effective than the current ones and tailored according to the individual need and women’s life period.

Bogani G, et al. J Gynecol Oncol. 2021 Nov;33(1):e10. https://doi.org/10.3802/jgo.2022.33.e10