The Role of Oncogenic Viruses in the Pathogenesis of Sporadic Breast Cancer: A Comprehensive Review of the Current Literature.

Breast cancer is the most common malignancy in the female sex; although recent therapies have significantly changed the natural history of this cancer, it remains a significant challenge. In the past decade, evidence has been put forward that some oncogenic viruses may play a role in the development of sporadic breast cancer; however, data are scattered and mostly reported as sparse case series or small case-control studies. In this review, we organize and report current evidence regarding the role of high-risk human papillomavirus, mouse mammary tumor virus, Epstein-Barr virus, cytomegalovirus, bovine leukemia virus, human polyomavirus 2, and Merkel cell polyomavirus in the pathogenesis of breast cancer.

The role of neutrophil-lymphocytes ratio (NLR) in the prognosis of CIN2+ 2 recurrence after excisional treatment.

OBJECTIVES: The main risk factor involved in CIN2+ recurrence after treatment is the HPV persistent infection. The dysregulation of the immune system permits only HR-HPVs to become persistent infections, to promote cancer development and to increase the risk of recurrence after treatment. Therefore, there is a shift to a Th2-type cytokine pattern during the carcinogenesis pathway; for this reason, the neutrophil-lymphocytes ratio (NLR) could be a marker of this immunological change. The study aims to analyse the predictive role of NLR in the recurrence of High-grade CIN (CIN2+) after excisional treatment in a real-world life setting of patients treated for CIN2+ Design: cross-sectional study Participants/Materials, Setting, Methods: We examined a retrospective database of 444 patients, who attended the Colposcopy Service of our Department from 2011 to 2020 due to an abnormal screening pap smear and we compared the clinical characteristics to NLR performed at the time of diagnosis. All analysed patients were treated according to an established protocol (colposcopy every 6 months for the first two years, and every year for the over three years,) and HPV-DNA test and cervical biopsy were performed at entry and the end of follow-up. All patients underwent a blood sample examination, including complete white blood cell counts and collecting neutrophil and lymphocyte values expressed as 103/ml. Results The sensitivity (SE) and specificity (SP) of the NLR cut-off point of 1.34 for the diagnosis of CIN2+ recurrence were 0.76 and 0.67, respectively. We found that CIN2+ recurrences were significantly higher in patients with NLR < 1.34 (3.7% vs. 0.6%, p = 0.033) and the 5-year recurrence-free survival was higher in patients with NLR ≥ 1.34 (97% vs. 93%, p=0.030). Limitations First, the retrospective analysis and low incidence of recurrence may limit the conclusions. Second, for the retrospective design of the study, we did not take into consideration the patient's comorbidities and habits (smoking), that may influence the NLR. On the other hand, the median duration of follow-up in our study was 26 months (IQR 22-31), which fully reflects the incidence of recurrences. Conclusions It is well known that CIN2+ lesions are sustained by deregulation of the immune system caused by persistent HPV infection, which may lead to cervical cancer. Among the actors underlying dysregulation of immunity, lymphocytes are involved in the permission of persistent infection and for this reason, NRL could be a reliable and cost-effective biomarker in predicting the risk of recurrence, especially for high-grade cervical lesions.

Retrospective Investigation of Human Papillomavirus Cervical Infection and Lymphoma Incidence: A Clinical and Pathological Evaluation.

OBJECTIVE: Human papillomavirus (HPV) persistence is considered the main risk factor for neoplastic progression, and evidence suggests that regulatory T cells play an important role in the failure of viral elimination. Regulatory T cells may be involved in maintaining a microenvironment favourable for viral persistence and neoplasticity, through a deregulation of the local immune response. The association between altered immune function and the development of chronic infections, cancer (solid and haematological), and autoimmune diseases is documented in the literature. The purpose of this retrospective analysis was to evaluate the possible correlation between HPV cervical infection and lymphoma incidence in women attending colposcopy due to an abnormal Pap smear during a period of 15 years. DESIGN: This is a cross-sectional study. PARTICIPANTS: We investigated retrospectively the incidence of haematological diseases in women aged 21-84 with an abnormal Pap smear who referred to our centre between 2004 and 2019. SETTING: This study was conducted at the university hospital. METHODS: In our analysis, we included women with diagnoses of HL and NHL after the detection of abnormal Pap smears and HPV infections. We excluded patients with a diagnosis of lymphoma preceding the date of the abnormal Pap smear and HPV test. RESULTS: We divided the patients into two groups in order to analyse the standard incidence ratio (SIR): HL patients (19/7,064, 0.26%) and NHL patients (22/7,064, 0.31%). In our sample, we reported a significant risk of developing lymphoma compared to the general population, both for HL and NHL disease, at age <45 years. Regarding HL, the SIR of disease in women <45 years was 4.886 (95% CI 2.775-9.6029) and in women between 45 and 59 years was 2.612 (95% CI 0.96-7.108804). On the other hand, for NHL in women <45 years, we reported an SIR of about 3.007 (95%, CI 1.273-7.101575), in women aged 45-59 years, the SIR was 4.291 (95% CI 2.444-7.534399), and in women aged 60-74 years, the SIR was 3.283 (95% CI 1.054-10.22303). LIMITATIONS: This retrospective analysis was conducted in a single centre in Northern Italy and did not consider all interregional differences existing in the country in terms of HPV genotypes, ethnicity, and population characteristics. Regarding the analysis of SIR for HL and NHL, we did not divide the disease into subtypes because of the small sample of cases. Finally, we considered in our analysis only women with an abnormal Pap smear and not the general population. CONCLUSIONS: Women with chronic and persistent HPV infections may have a higher relative risk of developing lymphoma. This possible association may be caused by the deregulation of the immune system response against HPV and the failure of viral clearance, especially in younger women.

Placental pathologic features in obesity.

INTRODUCTION: Obesity in pregnancy is associated with adverse long-term consequences both in the mother and in offspring. Maternal obesity induces a metabolic-inflammatory state that could impact on placental function and could mediate the adverse outcomes. The purpose of this study was to compare the major placental histological characteristics of non-diabetic obese women to lean controls, focusing on uncomplicated pregnancies. METHODS: Prospective case-control study comparing placental histopathological features between 122 non-diabetic obese women and 185 non-obese controls. The analysis was performed on overall subjects, then uncomplicated pregnancies from both groups were analyzed. Placenta pathologic findings were recorded according to standard classification. RESULTS: Both in overall analysis and among the subset of subjects with an uncomplicated pregnancy, obese subjects had higher risks of maternal vascular malperfusion (MVM) (respectively OR=2.2, 95%CI =1.3-3.7 and OR=4.2, 95%CI=2.1-8.5), fetal vascular malperfusion (FVM) (respectively OR=6.3, 95%CI=3.1-12.5 and OR=7.2, 95%CI=3-17.2), maternal and fetal inflammatory response placental lesions and villitis (VUE) (respectively OR=2.5, 95%CI=1.1-5.6 and OR=10.8, 95%CI=3.3-35.3) compared to controls. Among uncomplicated pregnancies and after adjustment for confounders, first trimester BMI was significantly associated with overall MVM, overall FVM, maternal inflammatory, fetal inflammatory response and VUE. DISCUSSION: Placentas from obese women showed a significantly higher risk of maternal and fetal vascular and inflammatory placental lesions, both in overall population and in the subgroup with uncomplicated pregnancies. The metabolic and inflammatory dysfunctions typical of obesity could have an impact on placental development and function, which could be a mediator of the detrimental effects of obesity on pregnancy outcome and on future health of the offspring.

Placental fetal vascular malperfusion, neonatal neurologic morbidity, and infant neurodevelopmental outcomes: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to evaluate the association of placental fetal vascular malperfusion lesions with neonatal brain injury and adverse infant neurodevelopmental outcomes. DATA SOURCES: PubMed and Medline, Scopus, and Cochrane databases were searched from inception to July 2022. STUDY ELIGIBILITY CRITERIA: We included cohort and case-control studies reporting the associations of fetal vascular malperfusion lesions with neonatal encephalopathy, perinatal stroke, intracranial hemorrhage, periventricular leukomalacia, and infant neurodevelopmental and cognitive outcomes. METHODS: Data were analyzed by including fetal vascular malperfusion lesions as an exposure variable and brain injuries or neurodevelopmental impairment as outcomes using random-effects models. The effect of moderators, such as gestational age or study type, was assessed by subgroup analysis. Study quality and risk of bias were assessed by applying the Observational Study Quality Evaluation method. RESULTS: Out of the 1115 identified articles, 26 were selected for quantitative analysis. The rates of neonatal central nervous system injury (neonatal encephalopathy or perinatal stroke) in term or near-term infants were more common among fetal vascular malperfusion cases (n=145) than among controls (n=1623) (odds ratio, 4.00; 95% confidence interval, 2.72-5.90). In premature deliveries, fetal vascular malperfusion lesions did not influence the risk of intracranial hemorrhage or periventricular leukomalacia (odds ratio, 1.40; 95% confidence interval, 0.90-2.18). Fetal vascular malperfusion-associated risk of abnormal infant neurodevelopmental outcome (314 fetal vascular malperfusion cases and 1329 controls) was modulated by gestational age being higher in term infants (odds ratio, 5.02; 95% confidence interval, 1.59-15.91) than in preterm infants (odds ratio, 1.70; 95% confidence interval, 1.13-2.56). Abnormal infant cognitive development and mental development were more common among fetal vascular malperfusion cases (n=241) than among controls (n=2477) (odds ratio, 2.14; 95% confidence interval, 1.40-3.27). The type of study (cohort vs case-control) did not influence the association between fetal vascular malperfusion and subsequent infant brain injury or abnormal neurodevelopmental outcome. CONCLUSION: The findings of cohort and case-control studies indicate a considerable association between fetal vascular malperfusion placental lesions and increased risk of brain injury in term neonates, and neurodevelopmental impairment in both term and preterm infants. A diagnosis of placental fetal vascular malperfusion should be taken into consideration by both pediatricians and neurologists during the follow-up of infants at risk of adverse neurodevelopmental outcomes.

De novo RANBP2 variant in a fetal demise case with cerebral intraparenchymal hemorrhage.

Fetal intracranial hemorrhage (ICH) may result from a wide array of causes, either associated with maternal or fetal risk factors. In the last decade, monogenic causes of susceptibility to fetal ICH have been described, in particular in association with COL4A1 and COL4A2 genes. A peculiar form of ICH is acute necrotizing encephalitis (ANE), which is characterized by a rapid-onset severe encephalopathy following an abnormal inflammatory response to an otherwise banal infection. It usually affects healthy children and it is thought to be multifactorial, with a genetic predisposition. RANBP2 gene has been extensively associated with ANE susceptibility. We hereby present a unique case of a 42-year-old secundigravida with intrauterine fetal demise at 35 weeks of gestation. Trio-based whole-exome sequencing performed on both parents and fetal DNA showed a de novo likely pathogenic variant in the RANBP2 gene on 2q13. At the fetal autopsy, subtentorial hematoma and cerebral intraparenchymal hemorrhage were present. We speculate that this might be a new phenotypic presentation of RANBP2-associated disease. However, more similar fetal cases need to be reported in order to reinforce this hypothesis.

Low-Grade Cervical Intraepithelial Neoplasia (CIN1) Evolution: Analysis of Opportunistic Preventive Vaccination Role.

BACKGROUND: Low-grade cervical lesions have a high percentage of clearance in young women, even if 71-82% of low-grade intraepithelial lesion/atypical squamous cells of undetermined significance (LSIL/ASCUS) reported a High-Risk Human Papillomavirus (HR-HPV) infection, which correlates with an increased risk of Cervical Intraepithelial Neoplasia (CIN)2+. The immunogenic effect of the anti-HPV vaccine appears to be significant. The aim of the study is to evaluate the effect, two years after the diagnosis, of the anti-HPV preventive vaccination on patients with low-grade cervical lesions. METHODS: We collected clinical, colposcopic, histological, and virological data from patients aged 21-45 years who attended the colposcopy service of the department of Obsetrics and Gynecology of IRCCS Foundation Policlinico San Matteo, Pavia, Italy. In the 2005-2019 period and had a low-grade pap-smear. RESULTS: We enrolled 422 women consecutively, divided into two groups (vaccinated and not vaccinated) for the retrospective analysis. The rate of persistence and progression of CIN were higher in the not-vaccinated group (p = 0.019). The relative risk (RR) to develop CIN2+ during follow-up vs. the the CIN1 persistence was 1.005 (95% Confidence Interval-CI 0.961-1.051) vs. 0.994 (95% CI 0.994-1.018) for age, 3.472 (95% CI 1.066-11.320) vs. 1.266 (95% CI 0.774-2.068) for non-vaccinated, 0.299 (95% CI 0.088-1.018) vs. 0.518 (95% CI 0.242-1.109) for HIV status negative, respectively. Analyzing the time to negativity, the odds ratio (OR) was 1.012 (95% CI 1-1.024) for age and 1.591 (95% CI 1.223-2.069) for vaccination; on the other hand, considering the relationship between the time to negative and the HPV genotypes contained in the 9-valent HPV vaccines, the OR was 1.299 (95% CI 1.026-1.646) for at least one of these at recruitment and 0.631 (95% CI 0.471-0.846) at follow-up. Furthermore, the presence of at least one of the HPV genotypes targeted by the HPV nonavalent vaccine is a key indicator of the risk of progression to CIN2+: OR was 3.443 (95% CI 1.065-11.189) for the presence of at least one HPV genotype at enrollment and 5.011 (95% CI 1.899-13.224) for the presence of at least one HPV genotype at follow-up, respectively. CONCLUSIONS: We reported in a retrospective study the benefit of anti-HPV vaccination in promoting negativity and increasing low-grade cervical lesions regression.

Intralymphatic Histiocytosis Associated With Tubo-ovarian High-grade Serous Carcinoma: Case Report and Review of the Literature.

Intralymphatic histiocytosis is a condition characterized by the accumulation of mononuclear phagocytes within lymphatic vessels and lymph nodes that may be isolated or secondary to autoimmune or neoplastic diseases. Secondary intralymphatic histiocytosis frequently involves the skin and is associated with malignancies in up to a tenth of cases. We describe a case of intralymphatic histiocytosis associated with high-grade serous carcinoma and reviewed the literature on neoplasia associated with the broader category of histiocytoses with raisinoid nuclei. Moreover, we try to elucidate the pathogenesis of these rare and intriguing disorders.

Pathologic Findings at Risk Reducing Surgery in BRCA and Non-BRCA Mutation Carriers: A Single-Center Experience.

Risk-reducing surgery (RRS) is recommended in BRCA-mutated carriers because of their increased risk of developing ovarian cancer, while its role is still discussed for women harboring mutations in non-BRCA homologous repair genes. The aim of this study was to retrospectively evaluate the occurrence of pathological findings in a high-risk population undergoing RRS in San Matteo Hospital, Pavia between 2012 and 2022, and correlate their genetic and clinical outcomes, comparing them with a control group. The final cohort of 190 patients included 85 BRCA1, 63 BRCA2, 11 CHEK2, 7 PALB2, 4 ATM, 1 ERCC5, 1 RAD51C, 1 CDH1, 1 MEN1, 1 MLH1 gene mutation carriers and 15 patients with no known mutation but with strong familial risk. Occult invasive serous carcinoma (HGSC) and serous tubal intraepithelial carcinoma (STIC) were diagnosed in 12 (6.3%) women, all of them BRCA carriers. No neoplastic lesion was diagnosed in the non-BRCA group, in women with familial risk, or in the control group. Oral contraceptive use and age ≤45 at surgery were both found to be favorable factors. While p53 signature and serous tubal intraepithelial lesion (STIL) were also seen in the control group and in non-BRCA carriers, STIC and HGSC were only found in BRCA1/2 mutation carriers.

What is known about neuroplacentology in fetal growth restriction and in preterm infants: A narrative review of literature.

The placenta plays a fundamental role during pregnancy for fetal growth and development. A suboptimal placental function may result in severe consequences during the infant's first years of life. In recent years, a new field known as neuroplacentology has emerged and it focuses on the role of the placenta in fetal and neonatal brain development. Because of the limited data, our aim was to provide a narrative review of the most recent knowledge about the relation between placental lesions and fetal and newborn neurological development. Papers published online from 2000 until February 2022 were taken into consideration and particular attention was given to articles in which placental lesions were related to neonatal morbidity and short-term and long-term neurological outcome. Most research regarding the role of placental lesions in neurodevelopment has been conducted on fetal growth restriction and preterm infants. Principal neurological outcomes investigated were periventricular leukomalacia, intraventricular hemorrhages, neonatal encephalopathy and autism spectrum disorder. No consequences in motor development were found. All the considered studies agree about the crucial role played by placenta in fetal and neonatal neurological development and outcome. However, the causal mechanisms remain largely unknown. Knowledge on the pathophysiological mechanisms and on placenta-related risks for neurological problems may provide clues for early interventions aiming to improve neurological outcomes, especially among pediatricians and child psychiatrists.

SIMPSON-GOLABI-BEHMEL syndrome type 1: How placental immunohistochemistry can rapidly Predict the diagnosis.

INTRODUCTION: Glypican-3 (GPC3) is an oncofetal protein involved in cellular signaling, strongly expressed in the placenta, absent or diminished in postnatal life, but often increased in human malignancies. Germline loss-of-function variants of GPC3 gene are associated with Simpson-Golabi-Behmel syndrome type 1 (SGBS1), a rare recessive X-linked overgrowth disease characterized by typical facial features, congenital abnormalities, and an increased risk of developing childhood cancers. METHODS: A clinical suspicion of SGBS1 was postulated for a newborn with prenatal history of overgrowth and polyhydramnios, presenting with neonatal weight and length >99th percentile, coarse facies, iris and retinal coloboma, supernumerary nipples, and splenomegaly. While waiting for whole-genome sequencing (WGS) results, we investigated placental GPC3 immunohistochemical expression in the proband, in three additional cases of SGBS1, and disorders commonly associated with fetal macrosomia and/or placentomegaly. RESULTS: WGS in the proband identified a likely pathogenic maternally inherited missense variant in GPC3: c.1645A > G, (p.Ile549Val), and GPC3 immunohistochemistry demonstrated full-thickness loss of stain of the placental parenchyma. The same pattern ("null") was also present in the placentas of three additional cases of SGBS1, but not in those of unaffected controls. DISCUSSION: Immunohistochemical expression of GPC3 in the placenta is highly reproducible. Our findings showed that a "null pattern" of staining is predictive of SGBS1 and represents a valuable aid in the differential diagnosis of fetal macrosomias, allowing targeted genetic testing and earlier diagnosis.

Clinical Correlates of Placental Pathologic Features in Early-Onset Fetal Growth Restriction.

INTRODUCTION: The purpose of this study was to evaluate the association between placental pathologic features of maternal (MVM) or fetal (FVM) vascular malperfusion and clinical characteristics, sonographic findings and neonatal outcome in a cohort of pregnancies complicated by early-onset (diagnosed before 32 weeks of gestational age) fetal growth restriction (FGR). METHODS: A prospective cohort study included 250 singleton early-onset FGR pregnancies diagnosed, followed up and delivered at a single center. Placental pathologic lesions were classified according to standard recommendations. Logistic regression and Cox analysis were used to evaluate outcomes adjusting for confounders. RESULTS: Overall features of severe placental MVM and FVM were observed in 29.6% (74/250) and 12.8% (32/250) of the subjects, respectively. Severe placental MVM lesions were more common among subjects with umbilical artery Doppler Pulsatility Index >95th than ≤95th percentile (50/120 as opposed to 24/130, Adj odds ratio [OR] = 3, 95% CI = 1.6-5.4) and Cerebroplacental ratio <5th than ≥5th percentile (48/115 as opposed to 26/135, Adj OR = 2.7, 95% CI = 1.5-4.9). Mean time from FGR diagnosis to delivery was shorter among subjects with severe MVM (25.5 days, 95% CI = 20.6-30.2, Adj. OR = 1.9, 95% CI = 1.9, 95% CI = 1.4-2.5) when compared to both those with mild/moderate MVM (36.5 days [95% CI = 27.2-45, p = 0.04]) or no MVM (39.4, 95% CI = 35.4-43.4, p < 0.001). Finally, severe FVM was associated with an increased risk of perinatal/neonatal death or severe brain lesions (9/28 in subjects with perinatal/neonatal death/brain lesions as compared to 23/222 in controls, Adj OR = 3, 95% CI = 1.05-8.6) or severe adverse neonatal outcomes (13/46 in subjects with severe adverse outcome as compared to 19/204 among controls, Adj OR = 3.2, 95% CI = 1.2-8.5). CONCLUSIONS: In early-onset FGR, placental pathologic features of MVM and FVM are, in different regards, associated to severity of clinical picture, abnormal Doppler markers of placental and fetal circulation and of neonatal outcome, respectively.

Tubal histopathological abnormalities in BRCA1/2 mutation carriers undergoing prophylactic salpingo-oophorectomy: a case-control study.

OBJECTIVE: To describe tubal histopathological abnormalities in women with germline BRCA1/2 mutations and in controls. METHODS: Consecutive women with BRCA1/2 mutations undergoing bilateral salpingo-oophorectomy between 2010 and 2020 in two centers (San Gerardo Hospital, Monza and San Matteo Hospital, Pavia) were considered in this analysis and compared with controls who had the same surgical procedure for benign conditions. Frequency of p53 signature, serous tubal intraepithelial carcinoma, and high-grade serous ovarian cancer were compared between the two groups. RESULTS: A total of 194 women with pathogenic BRCA1/2 mutations underwent prophylactic salpingo-oophorectomy. Of these, 138 women (71%) had a completely negative histological examination, while in 56 (29%) patients an ovarian or tubal alteration was reported. Among controls, 84% of patients had a p53wt signature, while 16% had a p53 signature. There was no difference in the frequency of a p53 signature between cases and controls; however, women with BRCA1/2 mutations were more likely to have pre-malignant or invasive alterations of tubal or ovarian epithelium (p=0.015). Among mutation carriers, older age both at genetic testing and at surgery was associated with an increased risk of having malignancies (OR=1.07, p=0.006 and OR=1.08, p=0.004, respectively). The risk of malignancy seems to be increased in patients with a familial history of high-grade serous ovarian cancer. Previous therapy with tamoxifen was significantly more frequent in patients with malignant lesions (40.0% vs 21.3%, p=0.006). CONCLUSION: We found that a p53 signature is a frequent finding both in BRCA1/2 mutation carriers and in controls, while pre-invasive and invasive lesions are more frequent in BRCA1/2 mutation carriers. Genetic and clinical characteristics are likely to affect the progression to malignancy.

Placental Histological Features and Neurodevelopmental Outcomes at Two Years in Very-Low-Birth-Weight Infants.

BACKGROUND: We evaluated the rates of placental pathologic lesions and their relationship with two-year neurodevelopmental outcomes in very-low-birth-weight (VLBW) infants. METHODS: This is a cohort observational study comprising 595 VLBW infants during 2007 to 2015. Neurodevelopmental assessment was carried out at 24 months corrected age. RESULTS: In univariate analysis the rates of survival with normal neurodevelopmental outcomes were lower in pregnancies with severe histologic chorioamnionitis (38 of 43, 88.4% when compared with 305 of 450, 67.8%), severe maternal vascular malperfusion (MVM) (17 of 37, 45.9% when compared with 326/492, 66.3%), and intravillous hemorrhage (37 of 82, 45.1% when compared with 306 of 449, 68.1%). In logistic models, severe MVM (adjusted odds ratio [adj. OR] = 0.45, 95% confidence interval [CI] = 0.22 to 0.92), severe fetal vascular malperfusion (FVM) (adj. OR = 0.46, 95% CI = 0.22 to 0.45), and intravillous hemorrhage (adj. OR = 0.38, 95% CI = 0.22 to 0.62) were associated with lower rates of infant survival with normal neurodevelopmental outcome. FVM (adj. OR = 0.46, 95% CI = 0.21 to 0.97) and intravillous hemorrhage (adj. OR = 0.37, 95% CI = 0.22 to 0.62) were also the only placental lesions that were independent predictors of a lower rate of intact survival in stepwise analysis for prognostic factors of the entire cohort. CONCLUSIONS: Placental pathologic findings such as severe MVM, FVM, and intravillous hemorrhage are significant predictors of neonatal survival and subsequent adverse neurodevelopmental outcomes. Data on the placental pathology could be useful in the neurodevelopmental follow-up of VLBW infants.

Human Papillomavirus Distribution in Women with Abnormal Pap Smear and/or Cervical Intraepithelial Neoplasia in Vaccination Era. A Single-Center Study in the North Italian Population.

Time trends prevalence of human papillomavirus (HPV) genotypes including negative and untypable infections were analyzed during a 15-year period (2005-2019) among 5807 subjects with abnormal pap-smears and/or cervical intraepithelial neoplasia (CIN). The rates of HPV16 dropped by 13% every 3 years (Prevalence Ratio, PR = 0.87, 95% CI = 0.82-0.93) in the CIN1 biopsy, while HPV16 status was unchanged over time in the CIN2+ biopsy. In CIN1 lesions, there was a corresponding increase of HR-HPV types unrelated to nonavalent vaccine. The rates of HPV 18, 31, and 52, decreased by 35% (PR = 0.65, 95% CI = 0.54-0.79), 19% (PR = 0.81, 95% CI = 0.73-0.91), and 21% (PR = 0.79, 95% CI = 0.73-0.86) every 3-year interval in CIN2+, respectively. Overall, the prevalence of negative/untypable HPV specimens in the entire database increased from 9.6% (129/1349) in the period 2011-2013 to 17.6% (161/913) and 28.4% (224/790) in the 2014-2016 period and in the 2017-2019 period, respectively (PR = 1.69, 95% CI = 1.52-1.88). HPV 16 prevalence decreased significantly among subjects with low-grade cervical squamous lesions. A significant increase of both HPV types unrelated to nonavalent vaccination and negative/untypable HPV infections was reported. The prevalence of HPV types among subjects with abnormal pap smears in Northern Italy is changing. Many variables including demographic factors and possibly vaccination could be responsible for this modification.

Placental features of fetal vascular malperfusion and infant neurodevelopmental outcomes at 2 years of age in severe fetal growth restriction.

BACKGROUND: Placental pathologic lesions suggesting maternal or fetal vascular malperfusion are common among pregnancies complicated by intrauterine growth restriction. Data on the relationship between pathologic placental lesions and subsequent infant neurodevelopmental outcomes are limited. OBJECTIVE: This study aimed to assess the relationship between placental pathologic lesions and infant neurodevelopmental outcomes at 2 years of age in a cohort of pregnancies complicated by intrauterine growth restriction. STUDY DESIGN: An observational cohort study included singleton intrauterine growth restriction pregnancies delivered at ≤34 weeks' gestation and with a birthweight of ≤1500 g at a single institution in the period between 2007 and 2016. Maternal and neonatal data were collected at discharge from the hospital. Infant neurodevelopmental assessment was performed every 3 months during the first year of life and every 6 months in the second year. Penalized logistic regression was used to test the association of maternal vascular malperfusion and fetal vascular malperfusion with infant outcomes adjusting for confounders. RESULTS: Of the 249 pregnancies enrolled, neonatal mortality was 8.8% (22 of 249). Severe and overall maternal vascular malperfusion were 16.1% (40 of 249) and 31.7% (79 of 249), respectively. Severe maternal vascular malperfusion was associated with an increased risk of neonatal mortality (adjusted odds ratio, 3.3; 95% confidence interval, 1.2-9.5). Among the 198 survivors after a 2-year neurodevelopmental follow-up evaluation, the rate of major and minor neurodevelopmental sequelae was 57.1% (4 of 7) among severe fetal vascular malperfusion (adjusted odds ratio, 24.5; 95% confidence interval, 4.1-146), 44.8% (13 of 29) among overall fetal vascular malperfusion (adjusted odds ratio, 5.8; 95% confidence interval, 5.1-16.2), and 7.1% (12 of 169) in pregnancies without fetal vascular malperfusion. Infants born from pregnancies with fetal vascular malperfusion also had lower 2-year general quotient, personal-social, hearing and speech, and performance subscales scores than those without fetal vascular malperfusion. Finally, in the presence of fetal vascular malperfusion, the likelihood of a 2-year infant survival with normal neurodevelopmental outcomes was reduced by more than 70% (adjusted odds ratio, 0.29; 95% confidence interval, 0.14-0.63). Noticeably, 10 of the 20 subjects with a 2-year major neurodevelopmental impairment (3 of 4 with severe fetal vascular malperfusion) had little or no abnormal neurologic findings at discharge from neonatal intensive care unit. CONCLUSION: In preterm intrauterine growth restriction, placental fetal vascular malperfusion is correlated with an increased risk of abnormal infant neurodevelopmental outcomes at 2 years of age even in the absence of brain lesions or neurologic abnormalities at discharge from the neonatal intensive care unit. In the case of a diagnosis of fetal vascular malperfusion, pediatricians and neurologists should be alerted to an increased risk of subsequent infant neurodevelopmental problems.

Role of placental inflammatory mediators and growth factors in patients with rheumatic diseases with a focus on systemic sclerosis.

OBJECTIVES: Pregnancy in SSc is burdened with an increased risk of obstetric complications. Little is known about the underlying placental alterations. This study aimed to better understand pathological changes and the role of inflammation in SSc placentas. Leucocyte infiltration, inflammatory mediators and atypical chemokine receptor 2 (ACKR2) expression in SSc placentas were compared with those in other rheumatic diseases (ORD) and healthy controls (HC). METHODS: A case-control study was conducted on eight pregnant SSc patients compared with 16 patients with ORD and 16 HC matched for gestational age. Clinical data were collected. Placentas were obtained for histopathological analysis and immunohistochemistry (CD3, CD20, CD11c, CD68, ACKR2). Samples from four SSc, eight ORD and eight HC were analysed by qPCR for ACKR2 expression and by multiplex assay for cytokines, chemokines and growth factors involved in angiogenesis and inflammation. RESULTS: The number of placental CD3, CD68 and CD11 cells was significantly higher in patients affected by rheumatic diseases (SSc+ORD) compared with HC. Hepatocyte growth factor was significantly increased in the group of rheumatic diseases patients (SSc+ORD) compared with HC, while chemokine (C-C motif) ligand 5 (CCL5) was significantly higher in SSc patients compared with ORD and HC. CCL5 levels directly correlated with the number of all local inflammatory cells and higher levels were associated with histological villitis. CONCLUSIONS: Inflammatory alterations characterize placentas from rheumatic disease patients and could predispose to obstetric complications in these subjects.