Author Correction: Oral supplementation of α-lipoic acid (ALA), magnesium, vitamin B6 and vitamin D stabilizes cervical changes in women presenting risk factors for preterm birth.

Correction to: European Review for Medical and Pharmacological Sciences 2022; 26 (23): 8879-8886. DOI: 10.26355/eurrev_202212_30560-PMID: 36524507-published online on December 15, 2022. After publication, the authors found out that in Figure 1 a box, including 63 patients included in the final analysis was missing. There are amendments to this paper. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/30560.

Clinical relevance of gene mutations and rearrangements in advanced differentiated thyroid cancer.

BACKGROUND: Tumor genotyping is becoming crucial to optimize the clinical management of patients with advanced differentiated thyroid cancer (DTC); however, its implementation in clinical practice remains undefined. We herein report our single-center experience on molecular advanced DTC testing by next-generation sequencing approach, to better define how and when tumor genotyping can assist clinical decision making. MATERIALS AND METHODS: We retrospectively collected data on all adult patients with advanced DTC who received molecular profiling at the IRCSS Sant'Orsola-Malpighi Hospital from 2008 to 2022. The genetic alterations were correlated with radioactive iodide refractory (RAI-R), RAI uptake/disease status, and time to RAI resistance (TTRR) development. RESULTS: A significant correlation was found between RAI-R development and genetic alterations (P = 0.0001). About 48.7% of RAI-R cases were positive for TERT/TP53 mutations (as both a single event and comutations with other driver gene alterations, such as BRAF mutations, RAS mutations, or gene fusions), while the great majority of RAI-sensitive cases carried gene fusions (41.9%) or were wild type (WT; 41.9%). RAI uptake/disease status and time to TTRR were significantly associated with genetic alterations (P = 0.0001). In particular, DTC with TERT/TP53 mutations as a single event or as comutations displayed a shorter median TTRR of 35.4 months (range 15.0-55.8 months), in comparison to the other molecular subgroups. TERT/TP53 mutations as a single event or as comutations remained independently associated with RAI-R after Cox multivariate analysis (hazard ratio 4.14, 95% CI 1.51-11.32; P = 0.006). CONCLUSIONS: Routine testing for genetic alterations should be included as part of the clinical workup, for identifying both the subset of more aggressive tumors and the subset of tumors harboring actionable gene fusions, thus ensuring the appropriate management for all patients with advanced DTC.

Oral supplementation of α-lipoic acid (ALA), magnesium, vitamin B6 and vitamin D stabilizes cervical changes in women presenting risk factors for preterm birth.

OBJECTIVE: Recently, the PTB risk has been related to the objective measurement of cervical length (CL), since a CL of less than 25 mm is an accurate predictor of increased risk of PTB. Primary prevention of preterm labor is based on the early identification of symptoms and on pharmacological treatments with tocolytic drugs for inhibition of uterine contractions that are associated with a shortening of the cervix. Unfortunately, most of these drugs have important side effects. PATIENTS AND METHODS: This study aimed to evaluate whether the administration of a combination of oral α-lipoic acid (ALA), magnesium, vitamin B6 and vitamin D to pregnant women presenting risk factors for PTB could reduce the rate of cervical shortening at 19-22 weeks of gestational age. RESULTS: A total of 122 women attending the first-trimester aneuploidy screening at 11-14 weeks of pregnancy and presenting risk factors for PTB were included in the study. Cervical length significantly decreased in the control group compared with the treatment group (-3.86 ± 1.97 vs. 1.50 ± 1.26; p=0.02). Although the rate of preterm birth did not significantly decrease (9.5% vs. 5.1%), admission for threatened PTB was statistically reduced in the treatment group compared with the control group (3.4% vs. 14.3%). CONCLUSIONS: Oral supplementation of ALA, magnesium, vitamin B6 and vitamin D significantly counteracted cervix shortening in pregnant women presenting risk factors for PTB.

First-trimester prediction of gestational hypertension through the bioelectrical impedance analysis of the body composition.

OBJECTIVE: Obesity is a risk factor for the development of gestational hypertension, with important consequences for both the mother and fetus. This prospective observational study aims to propose an early prediction model of hypertensive disorders in pregnancy among obese women, through the bioelectrical impedance analysis (BIA) at the first trimester, thus allowing early recognition of obese women that are at risk to develop gestational hypertension, in order to target preventive interventions. PATIENTS AND METHODS: Singleton obese women (BMI ≥ 30 kg/m2) between the 9th and 12th week of pregnancy were included in the study. The exclusion criteria were chronic diseases, like type 2 diabetes mellitus, hypertension, and other medical pre-existing conditions. Eligible women were followed up at 20, 28, and 36 weeks of gestation by measuring blood pressure, weight, and body composition with the use of the BIA. The diagnosis of gestational hypertension was made after the 20th week of gestation. Pregnancy and perinatal outcomes were then recorded. RESULTS: Of the 479 women included in the study, 85 (17.7%) developed gestational hypertension; the remaining 394 (82.3%) resulted to be normotensive. A higher rate of nulliparous women was found in the hypertensive group (50.6% vs. 37.6%, p = 0.02), together with a higher rate of induction of labor (55.3% vs. 40.9%, p = 0.02) and of small for gestational age (SGA) newborns (12.9% vs. 6.9%, p = 0.03). Significant differences emerged in the body composition between the two groups already from the first trimester, indeed women developing gestational hypertension showed elevated values of Total body Mass, FM, FFM, TBW (p < 0.02), and of leg's FM, FFM (p < 0.006). At the multivariate logistics regression, the risk of developing gestational hypertension resulted higher in women with elevated total body water levels in the first trimester (OR 1.10 95% CI 1.04 -1.92). CONCLUSIONS: The BIA is a rapid, easy, non-invasive, and inexpensive tool to evaluate the body composition of obese pregnant women. It represents a promising predictor of hypertensive disorders in pregnancy, which allows an early identification of the patients at risk of developing gestational hypertension, thus opening a window of opportunity for strictly monitoring and target preventive intervention.

Improved Survival and Quality of Life Through an Integrative, Multidisciplinary Oncological Approach: Pathophysiological Analysis of Four Clinical Cancer Cases and Review of the Literature.

Objectives: According to the National Cancer Institute, the integrative medicine (IM) approach to medical care combines standard medicine with complementary and alternative medicine practices that have proved safe and effective. Methods: We describe the clinical cases of four patients with malignant pleural mesothelioma (MPM), diffuse malignant peritoneal mesothelioma (DMPM), intrahepatic cholangiocarcinoma, and breast cancer (BC) who received supportive treatment (ST) according to an IM approach after the failure of standard cancer treatments or the appearance of serious adverse events caused by antiblastic chemotherapy. The critical role of complementary drugs in reducing the side effects of cancer treatments and normalizing the white cell count is especially apparent in the case of the patient with metastatic BC, who experienced prolonged neutropenia. Results: The IM approach was well-tolerated and had no adverse side effects. It improved the quality of life (QoL) of all patients and in two cases extended overall survival. Conclusion: The extended clinical and instrumental response to IM of the patients with malignant mesothelioma and the improved health-related QoL and good tolerance of the ST demonstrated in all cases support the value of this approach in patients whose cancer therapies have failed but who show a good performance status. Our data require confirmation in a well-designed prospective clinical trial.

[Combined approach of laparoscopy and mini-laparotomy for surgery of a voluminous pancreatic cystic lymphangioma]. / Approccio combinato laparoscopico e mini-laparotomico in un voluminoso linfangioma cistico pancreatico.

Cystic lymphangioma is a rare disease of lymphatic system; in particular, pancreatic cystic lymphangioma is an unusual localization. A correct differential diagnosis with more common glandular lesions allows to plan a proper therapeutic approach. The Authors report the observed last case, a lesion in the head of the pancreas laparoscopically treated, and discuss this uncommon disease.

Iatrogenic late preterm birth: when is it recommended? A Delphi survey promoted by the Italian Society of Perinatal Medicine.

BACKGROUND: The rate of iatrogenic Late Preterm (LP) Birth varies in different settings. This is due to the lack of strong evidence/guidelines on the management of the different maternal, fetal and placental complications affecting pregnancy in the LP window. Steroid prophylaxis is also under discussion. AIM: To build recommendations about the management of main medical complications (pregestational diabetes, placenta previa, preeclampsia, cholestasis, p-PROM, intrauterine growth restriction -IUGR-) occurring in the LP period to reduce clinical heterogeneity. METHODS: A group of Italian Perinatal experts were identified by Scientific Societies. A Delphi consensus methodology was used to reach agreement on different clinical sceneries. Two rounds of consultation by using a purpose built on-line survey and a third open panel discussion were performed. RESULTS: The panel of 50 experts reached agreement for the vast majority of clinical sceneries (Placenta Previa, Preeclampsia, Diabetes, Cholestasis). Overall, there was agreement to be conservative at 34 weeks and in favor of delivery at 36 weeks. The management of p-PROM and mostly of IUGR were characterized by a minor degree of consensus. Corticosteroids were found necessary at the 34th week and unnecessary at the 36th week. CONCLUSIONS: Besides providing some guidance on clinical indications for LP iatrogenic delivery, these results represent a stimulus for designing future trials investigating the grey areas in this field.

Performance indicators of organized cervical screening in Romagna (Italy).

The availability of published data from organized cervical screening programmes in southern Europe is scant. In the Italian area of Romagna, a first round of organized screening (based on a 3-yearly Pap smear for women aged 25-64 years) was initiated between December 1995 and January 1997 and was completed in an average of 42 months (range 36-48 months). The target population included 305 478 women. Of these, 253 949 were eligible and received a personal letter of invitation. Age-specific screening performance indicators were calculated according to standard methods. The response rate within 6 months of invitation was 49.1% (n=124 621). The total participation rate including women who presented later was 61.7% (n=156 735). The recall rate was 35.2 per 1000 of participants (n=5514). Positive cytology results were distributed as follows: atypical squamous cells of un-determined significance/atypical glandular cells of undetermined significance (ASCUS/AGUS) 40.1%, low-grade squamous intraepithelial neoplasia (LGSIL) 48.6%, high-grade squamous intraepithelial neoplasia (HGSIL) 10.7% and carcinoma 0.7%. Compliance to colposcopy follow-up was 93.4% (n=5149). The biopsy rate was 52.4% (n=2696) of patients undergoing colposcopy. The detection rate was 4.5 per 1000 of participants (n=707) for CIN2-3 and 0.5 (n=75) for invasive carcinoma. The proportion of microinvasive carcinomas was 36.0% (n=27). The positive predictive value for CIN2-3/carcinoma was 5.8% for the cytology reports of ASCUS/AGUS, 7.6% for those of LGSIL, 76.5% for those of HGSIL, and 100.0% for those of carcinoma (80.4% for combined HGSIL/carcinoma). The ratio of observed to expected (or prevalent to incident) cases of invasive carcinoma was 2.35 (95% confidence interval (CI) 1.85-2.95). In conclusion, most early results of the programme were compatible with an acceptable performance.

Fetal bacterial infections in antepartum stillbirth: a case series.

OBJECTIVES: This study aims to assess the frequency of fetal bacterial infections in stillbirth (SB) and to evaluate the best samples for the diagnosis of infection-related SB. STUDY DESIGN: Consecutive cases of antepartum SB were enrolled. Vaginal and placental swabs, as well as heart blood cultures and surface swabs from the neonate, were collected. Histological examinations were performed by the same examiner. Immunohistochemistry for leukocyte common antigen was performed in the placenta and fetus. Each case was discussed in a multidisciplinary audit. RESULTS: One hundred and nine cases were enrolled. Fetal blood cultures were positive in 20/95 cases (21%). Significant histological findings in the placenta/cord and in at least one fetal organ were observed in 8 cases of them (4 Group B Streptococcus GBS, 2 Listeria monocytogenes, 1 Coagulase negative Staphylococcus, 1 Pseudomonas aeruginosa). Neither tissue damage nor inflammatory infiltrate was found in the 12 remnant cases. Funisitis while not histological chorioamnionitis was associated with microbiological findings. Positive findings in maternal/placental/fetal swabs occurred in 18-32% of cases with both negative fetal blood cultures and histopathological findings. With the exception of GBS, no other bacteria agent could be detected by any of the swabs. CONCLUSIONS: Eight cases (8.4%) fulfilled both microbiological and histology criteria allowing the diagnosis of SB-related fetal infection demonstrating that search for infections is essential in SB evaluation. Fetal blood culture, placenta swab for GBS and search for histological funisitis are mandatory actions within the SB work-up in order to guide pathology examination and reach clinical conclusions.

Usefulness of 124I PET/CT imaging to predict absorbed doses in patients affected by metastatic thyroid cancer and treated with 131I.

AIM: The aim of this work was the evaluation of the usefulness of 124I PET/CT sequential scans to predict absorbed doses to metastatic thyroid cancer in patients undergoing 131I therapy. METHODS: From July 2011 until April 2012 8 patients affected by metastatic thyroid cancer were enrolled. Each patient underwent 4 PET/CT scans at 4, 24, 48, 72 h after the administration of about 74 MBq of 124I. Blood samples and whole body exposure measurements were obtained to calculate blood and red marrow doses. Activity concentrations and lesion volumes obtained from PET/CT images were used to evaluate tumour doses with MIRD formalism and spheres model. The average administered 131I therapeutic activity was 6475 MBq (range: 3700-9250 MBq). RESULTS: 124I PET/CT images showed, with a very good resolution, all 131I avid lesions detected by post therapy whole body scans. The average dose rates for blood, red marrow and lesions were respectively: 6.58E-02 ± 1.64E-02 mGy/MBq, 5.73E-02 ± 1.57E-02 mGy/MBq, 2.22E+01 ± 1.62E+01 mGy/MBq. Three out of eight patients did not show any uptake of 124I in all PET/CT scans, despite high level of TSH and CT detectable lesions. Post-therapy 131I whole body scan confirmed the absence of focal iodine uptake. CONCLUSION: Negative 124I PET/CT images probably could be used as predictive of real absence of iodine avidity, avoiding all toxicity from useless 131I therapy. A higher number of patients is necessary to validate these preliminary results and a project is ongoing to compare MIRD results to voxel dosimetry based on Monte Carlo simulation.

Relation between maternal thrombophilia and stillbirth according to causes/associated conditions of death.

OBJECTIVE: To investigate maternal thrombophilia in cases of Stillbirth (SB), also an uncertain topic because most case series were not characterised for cause/associated conditions of death. STUDY DESIGN: In a consecutive, prospective, multicentre design, maternal DNA was obtained in 171 cases of antenatal SB and 326 controls (uneventful pregnancy at term, 1:2 ratio). Diagnostic work-up of SB included obstetric history, neonatologist inspection, placenta histology, autopsy, microbiology/chromosome evaluations. Results audited in each centre were classified by two of us by using CoDAC. Cases were subdivided into explained SB where a cause of death was identified and although no defined cause was detected in the remnants, 64 cases found conditions associated with placenta-vascular disorders (including preeclampsia, growth restriction and placenta abruption - PVD). In the remnant 79 cases, no cause of death or associated condition was found. Antithrombin activity, Factor V Leiden, G20210A Prothrombin mutation (FII mutation) and acquired thrombophilia were analysed. RESULTS: Overall, the presence of a thrombophilic defect was significantly more prevalent in mothers with SBs compared to controls. In particular, SB mothers showed an increased risk of carrying Factor II mutation (OR=3.2, 95% CI: 1.3-8.3, p=0.01), namely in unexplained cases. Such mutation was significantly associated also with previous SB (OR=8.9, 95%CI 1.2-70.5). At multiple logistic regression, Factor II mutation was the only significantly associated variable with SB (adj OR=3.8, 95% CI: 1.3-13.5). CONCLUSION: These data suggest that Factor II mutation is the only condition specifically associated with unexplained SB and could represents a risk of recurrence. PVD-associated condition is unrelated to thrombophilia.

[ASCUS in screening]. / ASCUS in screening.

The significance and use of the cytological diagnosis "atypical squamous cells of undetermined significance" (ASCUS) remain a major problem in cervical cancer screening. The prevalence of ASCUS by patient age has seldom been investigated. The present paper reports the prevalence of ASCUS in a large series of screening Pap smears from the Italian region of Emilia-Romagna. The study was based on the data collected by the Department of Health of the Emilia-Romagna Region for the first 3-year round (1997-1999) of a population-based screening programme (target age, 25-64 years). The age-specific frequency of ASCUS has been calculated as a prevalence rate per 1000 screened patients. A total of 597,386 women participated in the programme. Women diagnosed with ASCUS (n = 8205 or 13.7 per 1000) accounted for 49% of the recalls for colposcopy (n = 16,871, or 28.2 per 1000). The prevalence of diagnoses of low-grade squamous intraepithelial lesions (LG-SIL) decreased progressively with age while that of high-grade SIL was slightly higher between 30 and 39 years. The prevalence of ASCUS peaked at age 45-49 years (17.3 per 1000 subjects). The observed peak reflects the prevalence of (1) cytological changes closely associated with perimenopausal age and at least compatible with the ASCUS diagnosis, and (2) cytological abnormalities induced by hormone replacement therapy.