Late cardiac effects of chemotherapy in breast cancer survivors treated with adjuvant doxorubicin: 10-year follow-up.

Doxorubicin (Dox), a mainstay of adjuvant breast cancer treatment, is associated with cardiac toxicity in the form of left ventricular dysfunction (LVD), LV diastolic dysfunction, or LV systolic dysfunction. Study objectives were to evaluate the prevalence of LVD in long-term breast cancer survivors treated with Dox and determine if brain-type natriuretic peptide (BNP) may help identify patients at risk for LVD. Patients who participated in prospective clinical trials of adjuvant Dox-based chemotherapy for breast cancer with a baseline left ventricular (LV) ejection fraction evaluation from 1999 to 2006 were retrospectively identified from the St Vincent's University Hospital database. Patients were invited to undergo transthoracic echocardiography, BNP analysis, and cardiovascular (CV) risk factor assessment. LVDD was defined as left atrial volume index >34 mL/m(2) and/or lateral wall E prime <10 m/s, and LVSD as LVEF <50 %. Of 212 patients identified, 154 participated, 19 patients had died (no cardiac deaths), and 39 declined. Mean age was 60.7 [55:67] years. A majority of the patients (128, 83 %) had low CV risk (0/1 risk factors), 21 (13.6 %) had 2 RFs, and 5 (3.2 %) ≥3 RFs. BMI was 27.2 ± 4.9 kg/m(2). Median Dox dose was 240 mg/m(2) [225-298]; 92 patients (59.7 %) received ≤240 mg/m(2) and 62 (40.3 %) > 240 mg/m(2). Baseline LVEF was 68.2 ± 8 %. At follow-up of 10.8 ± 2.2 years, LVEF was 64.4 ± 6 %. Three (1.9 %) subjects had LVEF <50 % and one (0.7 %) had LVDD. Dox >240 mg/m2 was associated with any LVEF drop. BNP levels at follow-up were 20.3 pg/ml [9.9-36.5] and 21.1 pg/ml [9.8-37.7] in those without LVD and 61.5 pg/ml [50-68.4] in those with LVD (p = 0.04). Long-term prospective data describing the impact of Dox on cardiotoxicity are sparse. At over 10 years of follow-up, decreases in LVEF are common, and dose related, but LVD as defined is infrequent (2.6 %). Monitoring with BNP for subclinical LVD needs further evaluation.

Fresh vs. frozen embryo transfer in assisted reproductive techniques: a single center retrospective cohort study and ethical-legal implications.

OBJECTIVE: Several studies have shown higher pregnancy rates and better perinatal outcomes with frozen embryo transfers than with fresh techniques, with better results in patients with polycystic ovary syndrome (PCOS) but with a higher rate of pregnancy complications such as preeclampsia. This retrospective cohort study aims to compare the cumulative live birth rates, maternal and neonatal complications of fresh embryo transfers (ET) and frozen-embryo transfers (FET) in infertile women who underwent assisted reproduction techniques (ART) at the Azienda Ospedaliera Ospedali Riuniti (AOOR) Villa Sofia Cervello, Palermo, Italy. In addition, the authors have focused on the legislative and ethical complexities which such a procedure entails. PATIENTS AND METHODS: Out of 475 women undergoing in vitro fertilization programs from January 2017 to January 2021, 128 were enrolled; 70 patients underwent ET, and 58 patients FET. The main outcome measure was live birth rates. Secondary outcomes were clinical pregnancy, ongoing pregnancy, pregnancy loss, low birth weight (LBW), ectopic pregnancy, and obstetrical and perinatal complications. RESULTS: The cumulative live birth rates were similar between the fresh transfer (95.7%) and frozen transfer (93.1%). Biochemical pregnancy rates, clinical pregnancy, ongoing pregnancy, and pregnancy loss were similar between the groups. CONCLUSIONS: Obstetrical outcomes were not statistically different between the two groups; a higher preterm delivery rate was reported in the FET group. ET birth weights were notably lower for singletons compared to the freeze-all strategy. ET patients also had higher LBW rates, with a 2.5-fold higher rate compared to FET. No significant differences were found in cumulative live birth rates between ET and FET, which is consistent with earlier studies. FET protocols are linked to higher neonatal birth weight and lower risk of LBW than fresh ET. The ethical and legal quandaries inherent in such techniques, as technology moves on and outpaces current legislative frameworks, cannot be discounted.

Emerging targeted therapies in triple-negative breast cancer.

Standard chemotherapy regimens can prove effective for patients with early triple-negative breast cancer (TNBC); however, patients with advanced disease typically respond poorly and rapidly progress, and the outcome is poor. New targeted therapies are therefore an urgent unmet medical need for this patient population. Translational and clinical studies into new TNBC treatments have been facilitated by the increased understanding of the aberrant signal transduction pathways regulating growth and survival and the development of chemoresistance in TNBC. Some of the established targeted agents that have been approved in other indications may prove beneficial to patients with TNBC; however, in the absence of approved targeted agents for the treatment of TNBC, most new agents remain experimental. Increased understanding of molecular profiles of TNBC subtypes is likely to improve therapeutic strategies with targeted agents. Novel strategies have reached clinical evaluation in patients with TNBC, including targeting angiogenesis vascular endothelial growth factor and proliferation signalling (receptor tyrosine kinases and mammalian target of rapamycin). Aggressive TNBCs have been found to associate closely with BRCA1 mutation or dysregulation. The recent development of new investigational agents targeting DNA repair, either directly with poly(adenosine disphosphate-ribose) polymerase inhibitors or indirectly through DNA-binding or DNA-damage potentiation, is a major focus of current clinical studies. These and other targeted therapies represent a new approach to TNBC therapy.

The best interest of children born through medically assisted procreation procedures as construed in 2021 Italian Constitu- tional Court rulings 32 and 33.

ABSTRACT: The authors have set out to briefly analyze the 2021 Constitutional Court rulings n.32 and 33, regarding the situation of children born in, or otherwise being raised by, same-sex couples. Such judgments address the problem by taking into account the fundamental principle of the child's best interests. This article is meant to highlight the issues that may arise if such interests were to be translated into specific law provisions or safeguards for the children's sake. Moreover, the authors aimed to focus on the valuable elements laid out in the Court rulings, while also highlighting the more critical and controversial elements therein.

Does Alpha-lipoic acid improve effects on polycystic ovary syndrome?

Alpha-lipoic acid (ALA) plays a key role in many physiological processes, exerting anti-inflammatory, immunomodulatory, antioxidant, detoxifying, and insulin sensitizing activities. Since ALA improves insulin resistance (IR), it has been suggested that ALA could be beneficial it in the treatment of PCOS. The natural polyol myo-Inositol (myo-Ins) and its isomers (D-Chiro-Inositol, D-Chiro-Ins) has proven to improve PCOS features and clinical outcome, according to a compelling body of available studies. Few studies have proposed to strengthen the inositol effect by associating ALA. ALA does not seem to influence significantly reproductive hormones, while its beneficial effects are presumably restricted to the metabolic features of insulin resistant PCOS women. Therefore, ALA usefulness in improving inositol activity still awaits convincingly confirmation.  Experimental studies as well as proper randomized clinical trials, should be specifically tailored to assess this hypothesis. In absence of reliable evidence, ALA should not be recommended in the routinary clinical management of PCOS, even if associated to myo-Ins.

Ovarian tissue cryopreservation and transplantation in menopause: new perspective of therapy in postmenopausal women and the importance of ethical and legal frameworks.

Menopausal transition entails a progressive decrease in hormone production by the ovaries that lead to important physical and psychological changes that could significantly affect quality of life. Hormone replacement therapy (HRT) administered from the onset of menopausal symptoms usually improves quality of life and life expectancy. Nevertheless, it is not risk-free. Ovarian tissue cryopreservation (OTC) has been investigated as a potential new strategy for delaying menopause and/or to avoid HRT. This review analyzes the critical points of HRT to assess whether OTC and subsequent reimplantation can affect postmenopausal management. We assessed available randomized clinical trials in PubMed, Cochrane Library, ISI web of science, and Scopus from August 2021 to November 2022, including studies and trials evaluating the efficacy of OTC in both cancer and menopausal patients, the efficacy of freezing techniques and the possible clinical scenarios that OTC can open, even from the standpoint of legal and ethical issues arising as such innovative techniques become mainstream. Lower duration of the graft and efficacy on estrogen secretions at a physiological and safer concentration of estrogen than conventional HRT based on hormonal supplements. OTC can reportedly trigger estrogen secretions at a lower and safer physiological concentration than conventional HRT. OTC and subsequent reimplantation remain a valid fertility-sparing approach in patients undergoing gonadotoxic treatments. Further studies are needed to better evaluate its safety and efficacy within postmenopausal therapy management and in order to lay out widely shared and evidence-based guidelines and best practices and perform such novel and innovative techniques in a legally and ethically safe fashion, in the best interest of patients and healthcare professionals.

From the maternal uterus to the "uterus device"? Ethical and scientific considerations on partial ectogenesis.

The article aims to elaborate the progress made in partial ectogenesis research on sheep as well as human embryos. Since the ban on embryos experimentation after the 14-day window is a major roadblock in terms of partial ectogenesis research, the authors have weighed the possibility that such a ban could be reconsidered. In favor of easing such a restriction, it may be argued that: (a) unlike the Catholic approach, prevalent ethics precepts hold that the embryo's interest ought to be balanced against the interests of the other parties involved; (b) an extension of the 14-day deadline would no longer make ethically untenable practices acceptable; hence, the "slippery slope" argument, although generally worthy, would not conclusively apply to partial ectogenesis; (c) in mainstream embryo research efforts, there is a conflict between the lives of embryos and the health of individuals already born; as for partial ectogenesis, however, such a conflict would be between the lives of embryos and the lives of fetuses which would not survive otherwise. Still, in light of the embryo's status as a human being, the authors conclude that such research practices should only be allowed on supernumerary embryos.

Membrane transport proteins in human melanoma: associations with tumour aggressiveness and metastasis.

BACKGROUND: Malignant melanoma, generally described as incurable, is notoriously refractory to chemotherapy. The mechanisms contributing to this have not yet been defined and the contributions of drug efflux pumps, implicated in chemo-resistance of many other cancer types, have not been extensively investigated in melanoma. METHODS: In this study, expression of multi-drug resistant (MDR1/P-gp and MRP-1) proteins was examined, by immunohistochemistry, in archival specimens from 134 melanoma patients. This included 92 primary tumours and 42 metastases. RESULTS: On assessing all specimens, MRP-1 and MDR1/P-gp expression was found to be common, with the majority (81%) of melanomas expressing at least one of these efflux pumps. Although there is significant association between expression of these pumps (P=0.007), MRP-1 was found to be the predominant (67% of cases) form detected. chi(2) analysis showed significant associations between expression of MRP-1 and/or MDR1/P-gp and the aggressive nature of this disease specifically increased Breslow's depth, Clark's level and spread to lymph nodes. This association with aggressiveness and spread is further supported by the observation that a significantly higher percentage of metastases, than primary tumours, express MRP-1 (91% vs 57%; P<0.0001) and MDR1/P-gp (74% vs 50%; P=0.010). CONCLUSION: The predominant expression of these pumps and, in particular, MRP-1 suggests that they may be important contributors to the inherent aggressive and resistant nature of malignant melanoma.

Sinusal localization of nodal micrometastases is a prognostic factor in breast cancer.

BACKGROUND: Breast cancer micrometastases are frequently found during pathological examination of sentinel lymph nodes and complete axillary lymph node dissection. Despite this, their clinical relevance is still debated. The aim of this study is to investigate features that affect disease-free survival (DFS) and overall survival (OS) in patients with nodal micrometastases from breast cancer. MATERIAL AND METHODS: We retrospectively investigated the outcome of 122 patients with nodal micrometastases from breast cancer followed up for 60 months. RESULTS: At univariate analysis, worse DFS was related to features of primary tumor (multifocality P = 0.002; size >2 cm, P = 0.022; grade P = 0.022; absence of estrogen P < 0.001 and progesterone P < 0.001 receptors; HER-2 overexpression P = 0.006; vascular invasion P = 0.039; proliferative fraction > or =20% P = 0.034) and micrometastases (sinusal localization P = 0.010). Among the above-mentioned features, two were strongly associated with worse DFS in the multivariate model, i.e. negative receptorial status [hazard ratio (HR) = 11.24, 95% confidence interval (CI) 4.06-31.09; P < 0.001] and sinusal localization of micrometastasis (HR = 3.66, 1.18-11.36; P = 0.025). The OS was influenced by multifocality (P < 0.001) and receptor status (P = 0.005). CONCLUSION: Our results indicate that in patients affected by breast cancer, in addition to the well-known pathological features of primary tumor, sinusal localization of micrometastasis strongly impacts on the prognosis.

MDR1/P-glycoprotein and MRP-1 drug efflux pumps in pancreatic carcinoma.

BACKGROUND: Pancreatic cancer is one of the most challenging solid organ malignancies. This is due to its aggressiveness, frequent late presentation as advanced disease and chemoresistance. A better understanding of the molecular basis of its drug resistance is needed. MATERIALS AND METHODS: In this study, the first of its kind, the expression of both MDR1 P-gp and MRP-1 protein in pancreatic tumour specimens was examined by immunohistochemistry. Expression of these drug efflux pumps was examined using semi-quantitative immunohistochemistry according to the percentage of cells within the tumour, demonstrating another staining intencity. RESULTS: Overall, 93.3% of pancreatic carcinomas expressed MDR1 P-gp, approximately 31% co-expressed MRP-1 with MDR1 P-gp, while 6.7% expressed neither of these proteins. CONCLUSION: Our results show that drug efflux pumps, in particular that of MDR1 P-gp, are frequently expressed in pancreatic cancer. While a causative role for these efflux pumps in pancreatic cancer chemoresistance cannot necessarily be concluded, the information presented here should be considered when selecting chemotherapy/drug efflux pump inhibitors for future therapies.

Impact of receptor phenotype on nodal burden in patients with breast cancer who have undergone neoadjuvant chemotherapy.

BACKGROUND: Optimal evaluation and management of the axilla following neoadjuvant chemotherapy (NAC) in patients with node-positive breast cancer remains controversial. The aim of this study was to examine the impact of receptor phenotype in patients with nodal metastases who undergo NAC to see whether this approach can identify those who may be suitable for conservative axillary management. METHODS: Between 2009 and 2014, all patients with breast cancer and biopsy-proven nodal disease who received NAC were identified from prospectively developed databases. Details of patients who had axillary lymph node dissection (ALND) following NAC were recorded and rates of pathological complete response (pCR) were evaluated for receptor phenotype. RESULTS: Some 284 patients with primary breast cancer and nodal metastases underwent NAC and subsequent ALND, including two with bilateral disease. The most common receptor phenotype was luminal A (154 of 286 tumours, 53·8 per cent), with lesser proportions accounted for by the luminal B-Her2 type (64, 22·4 per cent), Her2-overexpressing (38, 13·3 per cent) and basal-like, triple-negative (30, 10·5 per cent) subtypes. Overall pCR rates in the breast and axilla were 19·9 per cent (54 of 271 tumours) and 37·4 per cent (105 of 281) respectively. Axillary pCR rates were highest in the Her2-overexpressing group (27 of 35, 77 per cent) and lowest in the luminal A group (35 of 153, 22·9 per cent) (P < 0·001). Nodal burden (median number of positive nodes excised) was lower in the Her2-overexpressing group compared with the luminal A group (0 versus 3; P < 0·001). CONCLUSION: Her2 positivity was associated with increased rates of axillary pCR and reduced nodal burden following NAC.

Myoinositol improves sperm parameters and serum reproductive hormones in patients with idiopathic infertility: a prospective double-blind randomized placebo-controlled study.

Male infertility is a multifactorial disorder that affects a significant percentage of couples. Its etiology and pathogenesis remain elusive in about one-third of the cases; this is referred to as idiopathic infertility. Inositols mediate the sperm processes involved into oocyte fertilization, such as penetration of the ovum cumulus oophorus, binding with the zona pellucida and the acrosome reaction. The aim of this double-blind, randomized, placebo-controlled trial was to evaluate the efficacy and safety of myoinositol (the most abundant form of inositols present in nature) treatment in men with idiopathic infertility. To accomplish this, we evaluated the effects of myoinositol on sperm parameters and reproductive hormones at baseline and after 3 months of treatment in men with idiopathic infertility. No adverse reaction was observed. Myoinositol significantly increased the percentage of acrosome-reacted spermatozoa, sperm concentration, and total count and progressive motility compared to placebo. In addition, myoinositol rebalanced serum luteinizing hormone, follicle-stimulating hormone, and inhibin B concentrations. The clinical improvement of idiopathic infertile patients should encourage myoinositol use for the treatment of this disorder, even though its detailed mechanisms at the testicular level remain still unclear.

An association of boswellia, betaine and myo-inositol (Eumastós) in the treatment of mammographic breast density: a randomized, double-blind study.

OBJECTIVE: Mammographic breast density is a recognized risk factor for breast cancer. The causes that lead to the proliferation of the glandular breast tissue and, therefore, to an increase of breast density are still unclear. However, a treatment strategy to reduce the mammary density may bring about very relevant clinical outcomes in breast cancer prevention. Myo-inositol is a six-fold alcohol of cyclohexane, has already been proved to modulate different pathways: inflammatory, metabolic, oxidative and endocrine processes, in a wide array of human diseases, including cancer and the genesis of mammary gland and breast diseases, like fibrosis, as well as metabolic and endocrine cues. Similarly, boswellic acid and betaine (three-methyl glycine) both inhibit inflammation and exert protective effects on breast physiology. Based on this scientific background, we hypothesized that a combination including, boswellic acid, betaine and myo-inositol would be able to reduce breast density working on different pathways. PATIENTS AND METHODS: In this study, seventy-six premenopausal women were randomly assigned to the placebo and the experimental drug arms (Eumastós) for six months. RESULTS: After 6 months of treatment, statistically significant difference between the two groups was recorded on the breast density reduction (60% vs. 9%), using mammographic as well as ultrasound examination. CONCLUSIONS: Preliminary data collected here with support the starting assumptions, that the association comprising boswellic acid, betaine and myo-inositol significantly reduces mammary density, providing the first evidence for a new and safe approach for the management of mammographic density treatment.

BRAF mutations in melanoma and colorectal cancer: a single oncogenic mutation with different tumour phenotypes and clinical implications.

BRAF is an oncogene encoding a serine-threonine protein kinase involved in the MAPK signalling cascade. BRAF acts as direct effector of RAS and through the activation of MEK, promotes tumour growth and survival. Approximately, 8% of cancers carry a BRAF mutation. However, the prevalence of this mutation varies significantly across different tumour types. There has been increasing interest in the specific role of BRAF mutations in cancer growth and progression over the last few years, especially since the clinical introduction of therapeutic BRAF inhibitors. In this paper we review the published literature on the role of BRAF mutations in melanoma and colorectal cancer, focusing on similarities and differences of BRAF mutations with respect to frequency, demographics, risk factors, mutation-associated clinico-pathologic and molecular features and clinical implications between these two diseases.