Efficacy and safety of therapies for COVID-19 in pregnancy: a systematic review and meta-analysis.

BACKGROUND: Clinical evidence suggests that pregnant women are more vulnerable to COVID-19, since they are at increased risk for disease progression and for obstetric complications, such as premature labor, miscarriage, preeclampsia, cesarean delivery, fetal growth restriction and perinatal death. Despite this evidence, pregnant women are often excluded from clinical trials, resulting in limited knowledge on COVID-19 management. The aim of this systematic review and meta-analysis is to provide better evidence on the efficacy and safety of available COVID-19 treatment in pregnant women. METHODS: Four authors searched major electronic databases from inception until 1 st November-2022 for controlled trials/observational studies, investigating outcomes after the administration of anti-SARS-CoV-2 treatments in pregnant women affected by COVID-19. The analyses investigated the cumulative incidence of delivery and maternal outcomes in pregnant women, comparing those taking active medication vs standard care. Risk ratios (RRs) with 95% confidence intervals were calculated. Statistical significance was assessed using the random effects model and inverse-variance method. This systematic review and meta-analysis was conducted in accordance with the updated 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The protocol has been registered in Prospero (number registration: CRD42023397445). RESULTS: From initially 937 non duplicate records, we assessed the full texts of 40 articles, finally including ten studies. In six studies, including 1627 patients, the use of casirivimab/imdevimab (CAS/IMD), remdesivir, and IFN-alpha 2b significantly decreased the need of cesarean section ((RR = 0.665; 95%CI: 0.491-0.899; p = 0.008; I 2 = 19.5%;) (Table 1, (Fig. 1). Treatments did not decrease the risk of preterm delivery, admission to neonatal ICU, or stillbirth/perinatal loss (p-values > 0.50 for all these outcomes) and did not prevent the progression of disease towards severe degrees (k = 8; 2,374 pregnant women; RR = 0.778; 95%CI: 0.550-1.099; p = 0.15; I 2 = 0%). Moreover, the use of medications during pregnancy did not modify the incidence of maternal death in two studies (Table 2). CONCLUSIONS: To our analysis, CAS/IMD, remdesivir, and IFN alpha 2b reduced the number of cesarean sections but demonstrated no effect on disease progression and other obstetric and COVID-19 related outcomes. The inability to evaluate the influence of viral load on illness development in pregnant women was attributed to lack of data. In our systematic review, no major side effects were reported. Though, it is essential for the medical community to focus more on clinical trials and less on episodic case reports and case series, with standardization of fetal and maternal outcomes.

The Crowded Crosstalk between Cancer Cells and Stromal Microenvironment in Gynecological Malignancies: Biological Pathways and Therapeutic Implication.

The tumor microenvironment plays a pillar role in the progression and the distance dissemination of cancer cells in the main malignancies affecting women-epithelial ovarian cancer, endometrial cancer and cervical cancer. Their milieu acquires specific properties thanks to intense crosstalk between stromal and cancer cells, leading to a vicious circle. Fibroblasts, pericytes, lymphocytes and tumor associated-macrophages orchestrate most of the biological pathways. In epithelial ovarian cancer, high rates of activated pericytes determine a poorer prognosis, defining a common signature promoting ovarian cancer proliferation, local invasion and distant spread. Mesenchymal cells also release chemokines and cytokines under hormonal influence, such as estrogens that drive most of the endometrial cancers. Interestingly, the architecture of the cervical cancer milieu is shaped by the synergy of high-risk Human Papilloma Virus oncoproteins and the activity of stromal estrogen receptor α. Lymphocytes represent a shield against cancer cells but some cell subpopulation could lead to immunosuppression, tumor growth and dissemination. Cytotoxic tumor infiltrating lymphocytes can be eluded by over-adapted cancer cells in a scenario of immune-tolerance driven by T-regulatory cells. Therefore, the tumor microenvironment has a high translational potential offering many targets for biological and immunological therapies.

Tracking Endometrial Malacoplakia Through the Evolution of 2D and 3D Ultrasound and Histopathological Features.

Malacoplakia is an uncommon disease characterized by chronic and granulomatous inflammation, which rarely involves the female genital tract. We describe the ecographic and histological evolution of the first case of a patient developing endometrial malacoplakia as a complication after a cesarean section. The patient, a 43-year-old woman, presented with pelvic pain one month after delivering by cesarean section and the initial suspicion was of retention of placental rests. We discuss the diagnostic challenges for this rare disease, highlighting the importance of considering endometrial malacoplakia as a possible diagnosis in patients with similar clinical presentations and the important role of 2D and 3D ultrasound in the diagnostic pathway. In literature, ultrasound findings in cases of endometrial malacoplakia are represented by hypoechoic thickening of the endometrial lining; hyperechoic thickening of the myometrium, and the presence of masses, nodules, cystic areas, or anechoic fluid within the endometrium. For the first time, we describe the evolution of endometrial malacoplakia through both ultrasound, 2D and 3D, and histopathological findings, from the acute to chronic stage of the disease.

SARS-CoV-2 Infection in the Second Trimester of Pregnancy: A Case Report of Fetal Intraventricular Hemorrhage After Critical COVID-19 Infection and a Brief Review of the Literature.

More than three and a half years have passed since the start of the coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and there have been several studies in the literature about the different damage and symptom patterns related to the condition; particular attention has been paid to the transmission of the disease from pregnant mothers to fetus. In this report, we present the case of a 36-year-old patient with a history of two cesarean sections (CS), two miscarriages, and hypothyroidism on replacement therapy, who contracted COVID-19 during the 15th week of gestation. Ultrasound (US) examination at 22 weeks revealed regular fetal biometry and bilateral ventriculomegaly, highly suggestive of massive intracerebral hemorrhage. The patient opted for the interruption of pregnancy. Given the critical maternal COVID-19 complications, especially tracheoesophageal fistula and the patient's two previous cesareans, we decided on an abortive CS at 23 weeks of gestation, and the samples were sent to the Pathology Department. Histologic analysis showed massive intervillous deposition of fibrin and inflammatory infiltration with hotspots of necrotic deciduitis and confirmed massive cerebral hemorrhage in the fetus. This morphological appearance was consistent with COVID-19 infection and probable fetal oxygenation compromise related to deciduitis. Immunoexpression of anti-SARS-CoV-2 S1 antibody was almost entirely positive at the level of syncytiotrophoblast cells and maternal leukocytes in the absence of a clear signal in the fetal circulation. Conversely, in the brain, immunoexpression of angiotensin-converting enzyme 2 (ACE2) and the S1 subunit of the spike protein of SARS-CoV-2, detected by a monoclonal antibody, was almost entirely negative, suggesting that there was no infection in the brain and that the massive intraventricular hemorrhage was probably a secondary effect of placental damage.

COVID-19 Infection in Pregnancy: Obstetrical Risk Factors and Neonatal Outcomes-A Monocentric, Single-Cohort Study.

The effects of coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus 2 on pregnant women and neonates are mainly unknown, since limited data are available in the literature. We conducted a monocentric and cross-sectional study enrolling 122 un-vaccinated pregnant women with COVID-19 infection tested by RT-PCR nasopharyngeal swab. Only 4.1% of the patients had severe COVID-19 symptoms together with major respiratory symptoms and intensive care unit admission, whereas 35.25% of women had comorbidities and two-thirds of them were overweight or obese. COVID-19 was detected mainly in the third trimester (98.36%) and multiparous women (59.02%). The mode of delivery was influenced by mild-severe COVID-19 symptoms, with a higher number of urgent or emergent cesarean sections than spontaneous or operative vaginal births. Preterm births were associated with high BMI, mode of delivery (higher among cesarean sections), nulliparity, and severe COVID-19 symptoms. In cases of severe COVID-19 symptoms, there was a higher rate of respiratory distress syndrome among newborns. In the end, only the presence of a severe COVID-19 infection worsened the obstetrical and neonatal outcomes, with higher rates of urgent or emergent cesarean section, preterm births, and neonatal respiratory distress syndrome.

Adverse Maternal Outcomes in Pregnant Women Affected by Severe-Critical COVID-19 Illness: Correlation with Vaccination Status in the Time of Different Viral Strains' Dominancy.

This is a monocentric and cross-sectional study conducted at the COVID-19 Division of the Obstetrical and Gynecological Unit and Intensive Care Units (ICUs) of Policlinico di Bari, in Bari, Italy, between September 2020 and April 2022. This study aimed to identify the prevalence of severe-critical COVID-19 illness requiring access to the Intensive Care Unit (ICU) among 287 pregnant patients, and possible correlations between the SARS-CoV-2 variants, the specific pandemic wave (dominated by wild, Alpha, Delta, and Omicron strains), and severe-critical adverse maternal outcomes. The prevalence of severe-critical COVID-19 illness was 2.8% (8/287), reaching 4.9% (8/163) excluding the 4th wave (Omicron dominant). The Delta variant determined the highest risk ratio and odds for access to the ICU due to severe-critical COVID-19-related symptoms compared to the other variants (wild, Alpha, Omicron). During the third wave (Delta), the ICU cases underwent a higher rate of hyperimmune plasma infusion (75%), antibiotic therapy (75%), and remdesivir (33%); all of the patients were intubated. During the Omicron wave, the patients were asymptomatic or with few symptoms: most of them (70%) were vaccinated with a median of two doses. The maternal outcome worsened in the case of Alpha and, especially, Delta variants for severe-critical COVID-19-related symptoms and ICU access.

Beyond BRCA1/2: Homologous Recombination Repair Genetic Profile in a Large Cohort of Apulian Ovarian Cancers.

BACKGROUND: Pathogenic variants in homologous recombination repair (HRR) genes other than BRCA1/2 have been associated with a high risk of ovarian cancer (OC). In current clinical practice, genetic testing is generally limited to BRCA1/2. Herein, we investigated the mutational status of both BRCA1/2 and 5 HRR genes in 69 unselected OC, evaluating the advantage of multigene panel testing in everyday clinical practice. METHODS: We analyzed 69 epithelial OC samples using an NGS custom multigene panel of the 5 HRR pathways genes, beyond the genetic screening routine of BRCA1/2 testing. RESULTS: Overall, 19 pathogenic variants (27.5%) were detected. The majority (21.7%) of patients displayed a deleterious mutation in BRCA1/2, whereas 5.8% harbored a pathogenic variant in one of the HRR genes. Additionally, there were 14 (20.3%) uncertain significant variants (VUS). The assessment of germline mutational status showed that a small number of variants (five) were not detected in the corresponding blood sample. Notably, we detected one BRIP1 and four BRCA1/2 deleterious variants in the low-grade serous and endometrioid histology OC, respectively. CONCLUSION: We demonstrate that using a multigene panel beyond BRCA1/2 improves the diagnostic yield in OC testing, and it could produce clinically relevant results.

Dynamic crosstalk within the tumor microenvironment of uterine cervical carcinoma: baseline network, iatrogenic alterations, and translational implications.

Uterine cervical cancer is the fourth most frequent gynecological tumor worldwide. The tumor microenvironment of cervical cancer is the result of persistent high-risk human papillomavirus infection together with stromal activation of estrogen receptor alpha and the pro-angiogenic and pro-inflammatory activity of immune cells, mainly T-helper 17 cells and tumor-associated macrophages. Therapeutic management (e.g., immunotherapy, especially in advanced cases) may be influenced by the translational implications of tumoral stroma crosstalk and an abundance of tumor-infiltrating lymphocytes within the tumor microenvironment. The prognosis of cervical cancer is inversely correlated with microvessel density, making anti-angiogenic strategies with agents such as bevacizumab crucial for improving both progression-free survival and overall survival in patients with advanced and recurrent tumors.

Endometrial causes of recurrent pregnancy losses: endometriosis, adenomyosis, and chronic endometritis.

Chronic inflammatory processes affecting the endometrium, as encountered in endometriosis, adenomyosis, and chronic endometritis, alter endometrial receptivity. These disorders are associated with early pregnancy losses and possibly recurrent pregnancy losses (RPL). In the cases of endometriosis, other factors associated with the disease also are susceptible of causing miscarriages and possibly RPL, such as an impact of intrapelvic inflammatory processes affecting the oocyte and embryo in case of natural conception. Conversely these latter effects obviously are bypassed in case of assisted reproductive technology. Chronic inflammation of the endometrium in the condition known as chronic endometritis also causes early pregnancy losses and RPL with beneficial effects achieved when specific treatment is undertaken.

The Role of Nasal Nitric Oxide and Anterior Active Rhinomanometry in the Diagnosis of Allergic Rhinitis and Asthma: A Message for Pediatric Clinical Practice.

BACKGROUND: Allergic rhinitis (AR) and asthma are two common atopic diseases, often associated with a common ethiopathogenesis characterized by a Th2 inflammatory response with the release of many biomarkers, such as nitric oxide (NO). PURPOSE: To evaluate and compare inflammatory (nFeNO and eFeNO) and functional (mNF and FEV1) parameters in AR children with or without asthma in comparison to controls. Secondly, we aimed to identify nFeNO cut-off values and verify their reliability to predict the presence of rhinitis or asthma alone or in combination. PATIENTS AND METHODS: We enrolled 160 children (6-12 years of age) with AR and/or asthma divided into four groups: controls, AR, asthma, and AR + asthma. All children underwent the following inflammatory and functional measurements: nFeNO, eFeNO, mNF and FEV1. RESULTS: We observed that levels of nFeNO were extremely higher in children with AR and even more in those with AR + asthma in respect to controls. Notably, all the pathological conditions, especially AR + asthma, showed significantly lower values of mNF compared to healthy children. A negative correlation linked mNF and nFeNO. Then, we found eFeNO values significantly higher in all the pathological groups compared to controls, with major values of this marker in patients affected by asthma and AR + asthma, as well as FEV1 values significantly lower in all the disease groups, especially in children with asthma and AR+ asthma. ROC curve analysis showed that nFeNO was a great predictor for rhinitis alone or with asthma, revealing an accurate cut-off of 662 ppb. CONCLUSION: nFeNO measurement is non-invasive, easy to perform, economic and a valuable test in case of AR alone or in association with asthma. Thus, it should be used in patients with rhinitis, together with anterior active rhinomanometry (AAR) to diagnose and estimate the degree of nasal obstruction but also in children with asthma to assess their nasal involvement and improve the therapeutic management.

Updates on Children with Allergic Rhinitis and Asthma during the COVID-19 Outbreak.

BACKGROUND: During the lockdown period caused by the SARS-CoV-2 pandemic, we monitored via online survey the trend of allergic symptoms and the therapeutic compliance in patients followed at our center. MATERIAL AND METHODS: In June 2020, we selected children followed at the Allergy and Immunology Service of Umberto I Hospital, aged between 6 and 16 years old, diagnosed with asthma and/or rhinitis and sensitized to grass pollen or dust mite. We sent an email with 12 multiple-choice questions investigating several areas: type of disease and sensitization, recurrence of symptoms, medication use during lockdown compared to the same period of the previous year. RESULTS: The results of 82 questionnaires showed that 17.8% of patients suffered from asthma, 24.4% from rhinitis, and 57.8% from both. Within the group of asthmatic children, most of them presented an improvement of their symptoms. Likewise, with regard to allergic rhinitis, most of them reported better clinical conditions. Regarding treatment, we observed a global decrease in the use of on-demand therapies (salbutamol, nasal corticosteroid, and antihistamine) for both pathologies. In addition, there was a reduction in the use of basal therapy for asthma and rhinitis from 2019 (23.3%) to 2020 (15.5%). CONCLUSIONS: Our data show a general trend of clinical improvement and a reduction in the use of on-demand and basal therapy in allergic children during the lockdown.

Management of placental site trophoblastic tumor: Two case reports.

RATIONALE: Placental site trophoblastic tumor (PSTT) is a very rare malignant tumor, belonging to a family of pregnancy-related illnesses, called gestational trophoblastic diseases (GTD). Less than 300 cases of PSTT have been reported in literature, with an incidence of ≈ 1/50,000-100,000 pregnancies representing only 0.23% to 3.00% of all GTDs. PATIENT CONCERNS: Our report describes 2 additional cases of PSTT outlining their main diagnostic features and the subsequent management. The first case presented contemporary to a persistent hydatidiform mole in a 37-year-old woman, para 2042; whereas the second one originated 5 years after a miscarriage in 43-year-old woman, para 1031 with a previous diagnosis of breast cancer, and shared some features with placental site nodule (PSN), a benign condition. DIAGNOSIS: The first case had a difficult diagnosis because there was an amenorrhea of 11th week with high serum beta-human chorionic gonadotropin (beta-HCG) and an initial ultrasound image of vesicular mole. After the Dilatation and Curettage, histology confirmed the previous hypothesis. However, the final histology of PSTT was obtained after major surgery. On the contrary, the diagnosis of the second case was less challenging but surprising, thanks to a routine trans-vaginal ultrasound showing a suspicious endometrial thickness positive for PSTT at a subsequent hysteroscopic guided biopsy. INTERVENTIONS: The treatment consisted of hysterectomy and subsequent follow up. Lymphadenectomy or lymph node sampling were not performed due to the initial stage of the disease. OUTCOMES: In the first case, there were high values of serum beta-HCG that plummeted after the surgery, whereas in the second one they had been always negative. Hereafter, both went through a follow up with periodic serum oncological markers, imaging studies and clinical evaluation, which have showed negative result for 3 years and 15 months, respectively. LESSONS: A detailed gynecological ultrasound examination could be extremely helpful to understand the next diagnostic step of echo-guided D&C or hysteroscopic biopsy and for a pre-operative staging assessment. On the contrary, determining the serum beta-HCG's curve is crucial just in case of an initial positive value to pursue clinical evaluation and follow-up. In case of good prognostic factors, the main therapy remains hysterectomy.

Autotaxin is a novel molecular identifier of type I endometrial cancer.

Endometrial cancer is the most common cancer of the female genital tract in Western Countries, with an incidence of 150.000 new cases/year. Despite high incidence, little is known about the molecular pathogenesis of this tumor. Phospholipids including lysophosphatidic acid (LPA) are involved in proliferation and dissemination of cancer. LPA is a potent bioactive phospholipid synthesized by autotaxin (ATX) through its lysophospholipase D activity. Recent evidence suggests that the ATX/LPA signaling axis plays a role in endometrial cancer. We carried out a prospective study involving two groups of patients classified in accordance to hysteroscopic-guided biopsy. Patients with histological diagnosis of endometrial cancer were enrolled into group one, whereas control patients with pelvic organ prolapse were assigned group two. Both groups underwent hysterectomy, with either open or laparoscopic surgery. After uterine extraction, a second endometrial biopsy was performed to collect tissues. Real-Time PCR was performed to evaluate ATX gene expression in collected tissues. Statistical analysis including unpaired two-way or one-way Student's t test and ANOVA was performed. We found ATX gene expression significantly higher in neoplastic endometrium compared with normal tissue (P value = 0.0002). In particular, the expression of ATX was significantly elevated in type I endometrial cancer (i.e., endometrioid histotype) compared to type II, in premenopausal women and in patients affected either by obesity (BMI > 30) or diabetes. We propose ATX as a novel potential biomarker particularly implicated in the pathobiology of type I endometrial cancer. Also, we propose ATX as a useful theranostic target in endometrial cancer.

Clinical management of a unique case of PNET of the uterus during pregnancy, and review of the literature.

RATIONALE: PNETs (primitive neuroectodermal tumors) are a family of highly malignant neoplasms characterized by small round cells of neuroepithelial origin. They usually involve bone and soft tissues, and have a higher incidence in childhood. PATIENT CONCERNS: In this case report, we describe the obstetric and oncological outcome of a huge mass diagnosed as a leiomyoma in a 39-year-old pregnant woman who complained of low back pain, dysuria, and urinary frequency at 22 weeks of gestation. DIAGNOSES: During the 25th week of pregnancy, the patient was referred to our hospital at night with severe anemia and suspected hemoperitoneum. She underwent an emergency caesarean section, delivering a female fetus weighing 400 g, with an Apgar score of 7 at 1 minute and 9 at 5 minutes. INTERVENTION: During surgery, we found a huge uterine sarcoma-like metastatic tumor, invading the pelvic peritoneum and parametria bilaterally; the adnexae seemed disease-free. We performed a type B radical hysterectomy, bilateral salpingo-oophorectomy, pelvic peritonectomy, omentectomy, appendectomy, and excision of a bulky lymph node. Seven days after delivery, staging computed tomography (CT) scan demonstrated a large lombo-aortic lymph node compressing the left renal vein and we completed debulking with a second surgery, including diaphragmatic peritonectomy and excision of a huge lymph node by lombo-aortic lymphadenectomy, requiring partial reconstruction of an infiltrated renal vein. OUTCOME: Ten days after the second surgery, echo-color Doppler showed a regular microcirculation in the left kidney. The patient was discharged after 10 days, and the baby after 1 month, both in good health.Histological examination revealed a uterine body cPNET (central primitive neuroectodermal tumor) orienting the clinical management toward chemotherapy with cisplatin and etoposide. LESSONS: PNETs are aggressive neoplasms, usually diagnosed at an advanced stage. Due to their low incidence, universally accepted guidelines are still unavailable. Radical surgery leaving no macroscopic residual disease is mandatory in advanced stages. A good fertility-sparing procedure can be performed only in young women at early stages of disease, when the wish for childbearing is not yet fulfilled.