ß-thalassemia patients and gynecological approach: review and clinical experience.

Significant improvements in therapy and life expectancy of ß-thalassemia patients in last decades result in the need of commitment for gynecologists and obstetricians as the complexity of organ impairment needs a specific multidisciplinary approach. After a review of clinical manifestations of ß-thalassemia from a gynecologic point of view, we present the experience of a gynecologic center in treating ß-thalassemia patients from more than 20 years.

An insulin-like growth factor-II intronic variant affects local DNA conformation and ovarian cancer survival.

Insulin-like growth factor-II (IGF-II) may be a prognostic marker in ovarian cancer, and its intronic single nucleotide polymorphism (SNP) rs4320932 has been associated with risk of the disease. We determined whether rs4320932 is associated with IGF-II expression and patient survival in ovarian cancer, and explored whether the SNP variation affects DNA conformation both in the absence of and presence of carboplatin. IGF-II genotype (rs4320932) and phenotype were analyzed in 212 primary invasive epithelial ovarian cancer tissue samples with Taqman® SNP genotyping assays, quantitative reverse transcription-polymerase chain reaction and commercial enzyme-linked immunosorbent assay. DNA conformation was evaluated by circular dichroism (CD) spectra. Kaplan-Meier survival curves and Cox proportional hazard regression models were used to analyze the SNP associations with patient survival. The C allele of rs4320932, previously associated with decreased risk of ovarian cancer development, was here associated with significantly elevated risks of relapse (Ptrend = 0.0002) and death (Ptrend = 0.0006), remaining significant in multivariate analyses. The adjusted hazard ratios were 3.05 (95% confidence interval [CI]: 1.47-6.37) for relapse and 3.28 (95% CI: 1.64-6.57) for death, respectively. The variant was also significantly associated with chemotherapy response, but not with other clinicopathologic variables or with IGF-II expression. DNA with genotypes TT and CC had distinct CD spectra in both the absence of and presence of carboplatin. These findings suggest that the intronic SNP rs4320932 affects patient survival and chemotherapy response via alteration of DNA conformation, but not through regulation of IGF-II expression. This novel finding may have implications in individualized medicine for the design of specific molecules targeting DNA of specific conformations.

MITO39: Efficacy and Tolerability of Pegylated Liposomal Doxorubicin (PLD)-Trabectedin in the Treatment of Relapsed Ovarian Cancer after Maintenance Therapy with PARP Inhibitors-A Multicenter Italian Trial in Ovarian Cancer Observational Case-Control Study.

OBJECTIVE: While PLD-Trabectedin is an approved treatment for relapsed platinum-sensitive ovarian cancer, its efficacy and tolerability has so far not been tested extensively in patients who progress after poly ADP-ribose polymerase inhibitor (PARPi) treatment. METHODOLOGY: This multicenter, retrospective analysis had the objective of comparing patients receiving PLD-Trabectedin after being treated with PARP-I (cases) with PARPi-naïve patients. Descriptive and survival analyses were performed for each group. RESULTS: Data from 166 patients were collected, composed of 109 cases and 57 controls. In total, 135 patients were included in our analyses, composing 46 controls and 89 cases. The median PFS was 11 months (95% IC 10-12) in the control group vs. 8 months (95% IC 6-9) in the case group (p value 0.0017). The clinical benefit rate was evaluated, with an HR for progression of 2.55 (1.28-5.06) for the case group (p value 0.008), persisting when adjusted for BRCA and line with treatment. We compared hematological toxicity, gastro-intestinal toxicity, hand-foot syndrome (HFS), fatigue, and liver toxicity, and no statistically significant disparity was noted, except for HFS with a p value of 0.006. The distribution of G3 and G4 toxicities was also equally represented. CONCLUSION: The MITO39 study showed a statistically significant difference in terms of PFS, suggesting that previous exposure to PARPi might inhibit the efficacy of PLD-Trabectedin. Regarding tolerability, no remarkable disparity was noted; PLD-Trabectedin was confirmed to be a well-tolerated scheme in both groups. To our knowledge, these are the first data regarding this topic, which we deem to be of great relevance in the current landscape.

Ki67 as a Predictor of Response to PARP Inhibitors in Platinum Sensitive BRCA Wild Type Ovarian Cancer: The MITO 37 Retrospective Study.

BACKGROUND: There is compelling need for novel biomarkers to predict response to PARP inhibitors (PARPi) in BRCA wild-type (WT) ovarian cancer (OC). METHODS: MITO 37 is a multicenter retrospective study aiming at correlating Ki67 expression at diagnosis with a clinical outcome following platinum treatment and PARPi maintenance. Clinical data were collected from high grade serous or endometroid BRCAWT OC treated with niraparib or rucaparib maintenance between 2010-2021 in 15 centers. Ki67 expression was assessed locally by certified pathologists on formalin-fixed paraffin embedded (FFPE) tissues. Median Ki67 was used as a cut-off. RESULTS: A total of 136 patients were eligible and included in the analysis. Median Ki67 was 45.7% (range 1.0-99.9). The best response to platinum according to median Ki67 was 26.5% vs. 39.7% complete response (CR), 69.1% vs. 58.8% partial response (PR), 4.4% vs. 1.5% stable disease (SD). The best response to PARPi according to median Ki67 was 19.1% vs. 36.8% CR, 26.5% vs. 26.5% PR, 26.5 vs. 25% SD, 27.9% vs. 16.2% progressive disease (PD). No statistically significant differences in progression free survival (PFS) and overall survival (OS) were identified between low and high Ki67. PFS and OS are in line with registration trials. CONCLUSIONS: Ki67 at diagnosis did not discriminate responders to PARPi.

Adjuvant capecitabine in triple negative breast cancer patients with residual disease after neoadjuvant treatment: real-world evidence from CaRe, a multicentric, observational study.

Background: In triple negative breast cancer patients treated with neoadjuvant chemotherapy, residual disease at surgery is the most relevant unfavorable prognostic factor. Current guidelines consider the use of adjuvant capecitabine, based on the results of the randomized CREATE-X study, carried out in Asian patients and including a small subset of triple negative tumors. Thus far, evidence on Caucasian patients is limited, and no real-world data are available. Methods: We carried out a multicenter, observational study, involving 44 oncologic centres. Triple negative breast cancer patients with residual disease, treated with adjuvant capecitabine from January 2017 through June 2021, were recruited. We primarily focused on treatment tolerability, with toxicity being reported as potential cause of treatment discontinuation. Secondarily, we assessed effectiveness in the overall study population and in a subset having a minimum follow-up of 2 years. Results: Overall, 270 patients were retrospectively identified. The 50.4% of the patients had residual node positive disease, 7.8% and 81.9% had large or G3 residual tumor, respectively, and 80.4% a Ki-67 >20%. Toxicity-related treatment discontinuation was observed only in 10.4% of the patients. In the whole population, at a median follow-up of 15 months, 2-year disease-free survival was 62%, 2 and 3-year overall survival 84.0% and 76.2%, respectively. In 129 patients with a median follow-up of 25 months, 2-year disease-free survival was 43.4%, 2 and 3-year overall survival 78.0% and 70.8%, respectively. Six or more cycles of capecitabine were associated with more favourable outcomes compared with less than six cycles. Conclusion: The CaRe study shows an unexpectedly good tolerance of adjuvant capecitabine in a real-world setting, although effectiveness appears to be lower than that observed in the CREATE-X study. Methodological differences between the two studies impose significant limits to comparability concerning effectiveness, and strongly invite further research.

Risk of unexpected uterine leiomyosarcoma during laparoscopic procedures: Experience from a single tertiary institute in Italy.

OBJECTIVE: To evaluate the incidence of occult uterine sarcomas and investigate whether an accurate and well-established preoperative assessment for uterine fibroids could help identify uterine sarcomas more effectively. METHODS: A retrospective analysis of patients who underwent gynecological laparoscopic surgery for presumed uterine fibroids at Sant'Anna Hospital, a single tertiary institute in Turin, Italy, between January 2003 and December 2019. RESULTS: Over the 17-year period, 5826 laparoscopic surgical procedures (myomectomies or subtotal/total hysterectomies) were performed for presumed uterine fibroids. A total of 48 patients with a final diagnosis of uterine sarcoma were identified, the majority of which (n = 39; 81.3%) were recognized as suspicious uterine sarcomas during the preoperative assessment, and morcellement was avoided. The occurrence of unexpected uterine sarcomas was 0.1% (6/5826). Morcellation was conducted in one patient with uterine sarcoma. CONCLUSION: Analysis of our data showed that unexpected uterine sarcomas are uncommon. Accurate preoperative evaluation can help avoid, but does not exclude, the possibility of morcellation of unknown uterine sarcomas.

Oncophone20 study: Patients' perception of telemedicine in the COVID-19 pandemic during follow-up visits for gynecological and breast cancers.

OBJECTIVE: To analyze oncological patients' perception of telemedicine during the COVID-19 pandemic. METHODS: A total of 345 women, of whom 267 experienced breast cancer and 78 experienced a gynecological cancer, were enrolled. Specific questionnaires about their experiences and feelings about telemedicine in the COVID-19 era were collected. RESULTS: In the breast group, "enhanced care" showed moderate positive perception (mean 4.40) among less-educated women that was slightly lower among better-educated women (mean 4.14) with a significant difference (P = 0.034). "satisfaction" had an opposite pattern: a mean of 3.99 for a lower level of education and 4.78 for a higher level of education, with a strong significant difference (P < 0.001). "privacy and discomfort" approached neutrality for less-educated women, while for higher-educated women the lower mean of 2.93 indicted a more positive perception (P = 0.007). In the pelvic group, younger women had a better perception towards telemedicine for "telemedicine as a substitution" (mean 3.68) compared to older women (mean 3.05). The privacy and discomfort subscale was in favor of better-educated women (mean 2.57) compared to less-educated women (mean 3.28; P = 0.042). CONCLUSION: Telemedicine was generally well accepted, not only among younger and higher-educated women but also by women needing intensive care, in both cancer groups.

Maternal age over 40 years and pregnancy outcome: a hospital-based survey.

OBJECTIVE: Increased risk for adverse pregnancy outcomes with advancing maternal age has been described but the strength of association remains debated, particularly in presence of confounding factors such as parity, twin pregnancy and pregnancy from assisted reproductive technologies. The aim of this study was to evaluate pregnancy outcomes in a large cohort of women aged over 40 years. The hypothesis was that advanced maternal age may be an independent risk factor for adverse pregnancy outcome. STUDY DESIGN: We reviewed the clinical records of 56,211 women who delivered at Sant'Anna University Hospital, Turin, Italy, in the period between 2009 and 2015. Of these, 3798 women aged over 40 years were divided into two age groups (40 - 44 years and ≥45 years). Women of any parity, with singleton or twin pregnancies, or with assisted reproductive technology pregnancies were included. Women aged less than 40 years were considered as controls. Primary outcome measures were maternal and perinatal complications. Comparisons were performed using Chi-square test and Fisher's exact test. Univariate analysis and logistic regression analysis were performed to test the possible independent role of maternal age as a risk factor for adverse pregnancy outcome. RESULTS: Maternal age was an independent risk factor for gestational diabetes (age 40-44 years: odds ratios (OR) 2.10, 95% CI 1.80-2.45; age ≥45 years: OR 2.83, 95% CI 1.79-4.46) and early-onset preeclampsia (age 40-44 years: OR 2.10, 95% CI 1.63-2.70; age ≥45 years: OR 3.16, 95% CI 1.68-5.94). The risk for placenta praevia was higher in the women aged 40-44 years (OR 1.87, 95% CI 1.36-2.57). Neonatal outcomes were similar among groups, except for the rate of birth weight less than 2500 g, which was higher in women aged 40-44 years (OR 1.27, 95% CI 1.12-1.42). However, older women showed an overall higher incidence of preterm birth. CONCLUSIONS: Maternal age over 40 years is an independent risk factor for adverse pregnancy outcomes, particularly for the mother. Pregnancies in women over 40 years should be considered at risk and carefully monitored with individualized care protocols.

Comparative study between obstetric antiphospholipid syndrome and obstetric morbidity related with antiphospholipid antibodies.

BACKGROUND AND OBJECTIVES: To compare clinical, laboratory, treatment and live birth rate data between women with aPL-related obstetric complications (OMAPS) not fulfilling the Sydney criteria and women fulfilling them (OAPS). MATERIALS AND METHODS: Retrospective and prospective multicentre study. Data comparison between groups from The European Registry on Antiphospholipid Syndrome included within the framework of the European Forum on Antiphospholipid Antibody projects. RESULTS: 338 women were analysed: 247 fulfilled the Sydney criteria (OAPS group) and 91 did not (OMAPS group). In the OMAPS group, 24/91 (26.37%) fulfilled laboratory Sydney criteria (subgroup A) and 67/91 (74.63%) had a low titre and/or non-persistent aPL-positivity (subgroup B). Overall, aPL laboratory categories in OAPS vs. OMAPS showed significant differences: 34% vs. 11% (p<0.0001) for category I, 66% vs. 89% (p<0.0001) for category II. No differences were observed when current obstetric complications were compared (p=0.481). 86.20% of OAPS women were treated vs. 75.82% of OMAPS (p=0.0224), particularly regarding the LDA+LMWH schedule (p=0.006). No differences between groups were observed in live births, gestational, puerperal arterial and/or venous thrombosis. CONCLUSIONS: Significant differences were found among aPL categories between groups. Treatment rates were higher in OAPS. Both OAPS and OMAPS groups had similarly good foetal-maternal outcomes when treated. The proposal to modify OAPS classification criteria, mostly laboratory requirements, is reinforced by these results.

Inherited thrombophilia in women with poor aPL-related obstetric history: prevalence and outcomes. Survey of 208 cases from the European Registry on Obstetric Antiphospholipid Syndrome cohort.

AIM: To analyse the prevalence and effects of inherited thrombophilic disorders (ITD) on maternal-foetal outcomes in cases of antiphospholipid antibody related to obstetric complications. METHODS: Women with obstetric complaints who tested positive for aPL and with inherited thrombophilia were prospectively and retrospectively included. RESULTS: ITD data were available in 208 of 338: 147 had obstetric antiphospholipid syndrome (OAPS) and 61 aPL-related obstetric morbidity (OMAPS). 24.1% had ITD. Laboratory categories I and IIa were more related to OAPS-ITD and IIb and IIc to OMAPS-ITD. No significant differences in obstetric complaints were observed. Regarding ITD carriers, treatment rates were higher in OAPS than in OMAPS for LMWH and LDA plus LMWH (P=.002). CONCLUSION: Cases with aPL-related OAPS/OMAPS showed no differences in maternal-foetal outcomes regardless of the presence of one ITD. Maternal thrombotic risk was low, with ITD-positive cases included. Registry data concur with Sydney criteria, whereby aPL-ITD-positive patients are classified as having antiphospholipid syndrome.

The European Registry on Obstetric Antiphospholipid Syndrome (EUROAPS): A survey of 247 consecutive cases.

AIM: To analyse the clinical features, laboratory data, foetal-maternal outcomes, and follow-up in a cohort of 247 women with obstetric antiphospholipid syndrome (OAPS). METHODS: The European Registry on APS became a Registry within the framework of the European Forum on Antiphospholipid Antibody projects and placed on a website in June 2010. Cases with obstetric complaints related to aPL who tested positive for aPL prospectively and retrospectively were included. The three-year survey results are reported. RESULTS: 338 women with 1253 pregnancy episodes were included; 915 were historical and 338 were latest episodes. All these women tested positive for aPL. 247 of the 338 fulfilled the Sydney criteria. According to the laboratory categories, 84/247 were in category I, 42 in IIa, 66 in IIb and 55 in IIc. Obstetric complications other than foetal losses, appeared in 129 cases (52.2%). 192 (77.7%) had a live birth and 55 (22.3%) did not. The latter group of only 38 cases (69%) received adequate treatment and 17 (31%) did not. 177/247 (72%) women were put on heparin plus LDA. Thrombosis appeared in two during pregnancy and in 14 during the puerperium. 7 (3%) women evolved to complete SLE. CONCLUSIONS: OAPS shows differential characteristics than classical APS. All laboratory test categories are needed to avoid false-negative diagnoses. In some cases, complement levels could act as a serological marker. OAPS has very good foetal-maternal outcomes when treated. Thrombosis and progression to SLE in mothers with OAPS are scarce compared with "classical APS", suggesting that they have different aPL-mediated pathogenic mechanisms.

Headache and adverse pregnancy outcomes: a prospective study.

OBJECTIVE: To investigate the association between headache, namely migraine and tension-type headache, and adverse pregnancy outcome. STUDY DESIGN: Prospective cohort study conducted in three tertiary care centres in Italy: 376 pregnant women suffering from headache and 326 non-headache pregnant women as controls were recruited. The diagnosis of headache was made at the beginning of pregnancy, according to the criteria of the International Classification of Headache Disorders (ICHD-II). Women were followed up until delivery, and gestational age at delivery, mode of delivery, indications for operative delivery or caesarean section, birth weight, and centile of neonatal weight at birth were carefully recorded. Main outcome measures of the study were: preterm delivery, newborns small for gestational age, and foetal losses. Odds ratios and 95% confidence intervals were calculated. RESULTS: The incidence of preterm delivery (Adj OR, 95% CI 2.74, 1.27-5.91) was significantly higher in women suffering from headache than in controls. There was no statistically significant difference in small for gestational age newborns between the groups. Fewer women in the headache group had preterm elective caesarean section or induction of labour, than did controls, indicating a higher chance of spontaneous preterm delivery. Multivariate analysis showed that the association between headache, either migraine or tension-type, and adverse perinatal outcomes was statistically significant regardless of pre-eclampsia. CONCLUSIONS: Women with headache should be considered at risk for adverse perinatal outcomes and should, therefore, be included in a high-risk pregnancy protocol of care throughout pregnancy.

Biochemistry of HELLP syndrome.

The HELLP syndrome is a serious complication of pregnancy characterized by hemolysis (H), elevated liver (EL) enzymes, and low platelet (LP) count that occurs in 0.2-0.6% of all pregnancies and in 10-20% of cases with severe preeclampsia and frequently leads to adverse maternal and perinatal outcome. The exact pathobiology of HELLP syndrome has not been clearly defined. As it is considered a form or a complication of severe preeclampsia, it likely has its origin in aberrant placental development and function resulting in ischemia-producing oxidative stress. However, there is still a debate on whether HELLP must be considered a severe form of preeclampsia or a separate disease entity. It can be described as a placenta-induced disease, as is preeclampsia itself, but with a more acute and predominant inflammatory process typically targeting the liver and with a greater activation of the coagulation system. This occurs during a disordered immunologic process and may be due to a genetic predisposition. In this review, we discuss the main biochemical characteristics of HELLP syndrome, particularly focusing on molecular aspects of placental involvement and maternal systemic responses.