The environment and male reproductive system: the potential role and underlying mechanisms of cadmium in testis cancer.

Cadmium is a known human carcinogen, and has been shown to profoundly affect male reproductive function, at multiple levels, by exerting both endocrine and non-endocrine actions. Nevertheless, the potential role of cadmium in the etiology of testis cancer has been scantly investigated in humans, and, currently, available epidemiological observational studies are insufficient to draw definitive conclusions in this regard. On the contrary, experimental studies in laboratory animals demonstrated that cadmium is a strong inducer of testis tumors, mostly represented by benign Leydig cell adenoma; moreover, malignant transformation was also reported in few animals, following cadmium treatment. Early experimental studies in animals proposed an endocrine-dependent mechanism of cadmium-induced testis tumorigenesis; however, more recent findings from cell-free assays, in vitro studies, and short-term in vivo studies, highlighted that cadmium might also contribute to testis tumor development by early occurring endocrine-independent mechanisms, which include aberrant gene expression within the testis, and genotoxic effects, and take place well before the timing of testis tumorigenesis. These endocrine-independent mechanisms, however, have not been directly investigated on testis tumor samples retrieved from affected, cadmium-treated animals so far. The present review focuses on the relationship between cadmium exposure and testis cancer, by reporting the few epidemiological observational human studies available, and by providing animal-based experimental evidences of cadmium implication in the pathogenesis and progression of testis tumor. Moreover, the relevance of experimental animal studies to human cadmium exposure and the translational potential of experimental findings will be extensively discussed, by critically addressing strengths and weaknesses of available data.

The prognostic value of 123I-mIBG SPECT cardiac imaging in heart failure patients: a systematic review.

This systematic review aimed to evaluate the prognostic value of Iodine123 Metaiodobenzylguanidine (123I-mIBG) SPECT myocardial imaging in patients with heart failure (HF) and to assess whether semi-quantitative SPECT scores can be useful for accurate risk stratification concerning arrhythmic event (AE) and sudden cardiac death (SCD) in this cohort. A systematic literature search of studies published until November 2020 regarding the application of 123I-mIBG SPECT in HF patients was performed, in Pubmed, Scopus, Medline, Central (Cochrane Library) and Web Of Science databases, including the words "MIBG", "metaiodobenzylguanidine", "heart", "spect", and "tomographic". The included studies had to correlate 123I-mIBG SPECT scores with endpoints such as overall survival and prevention of AE and SCD in HF patients. According to the sixteen studies included, the analysis showed that 123I-mIBG SPECT scores, such as summed defect score (SDS), regional wash-out (rWO), and regional myocardial tracer uptake, could have a reliable prognostic value in patients with HF. An increased SDS or rWO, as well as a reduced 123I-mIBG myocardial uptake, have proven to be effective in predicting AE- and SCD-specific risk in HF patients. Despite achieved results being promising, a more reproducible standardized method for semi-quantitative analysis and further studies with larger cohort are needed for 123I-mIBG SPECT myocardial imaging to be as reliable and, thus, accepted as the conventional 123I-mIBG planar myocardial imaging.

Cortisol Circadian Rhythm and Insulin Resistance in Muscle: Effect of Dosing and Timing of Hydrocortisone Exposure on Insulin Sensitivity in Synchronized Muscle Cells.

INTRODUCTION/AIM: Circadian clock disruption is emerging as a risk factor for metabolic disorders, and particularly, alterations in clock genes circadian expression have been shown to influence insulin sensitivity. Recently, the reciprocal interplay between the circadian clock machinery and hypothal-amus-pituitary-adrenal axis has been largely demonstrated: the circadian clock may control the physiological circadian endogenous glucocorticoid (GC) secretion and action; GCs, in turn, are potent regulators of the circadian clock and their inappropriate replacement has been associated with metabolic impairment. The aim of the current study was to investigate in vitro the interaction between the timing-of-the-day exposure to different hydrocortisone (HC) concentrations and muscle insulin sensitivity. METHODS: Serum-shock synchronized mouse skeletal muscle C2C12 cells were exposed to different HC concentrations resembling the circulating daily physiological cortisol profile (standard cortisol profile) and the circulating daily cortisol profile that reached in adrenal insufficient (AI) patients treated with once-daily modified-release HC (flat cortisol profile) and treated with thrice-daily conventional immediate-release HC (steep cortisol profile). The 24 h spontaneous oscillation of the clock genes in synchronized C2C12 cells was used to align the timing for in vitro HC exposure (Bmal1 acrophase, midphase, and bathyphase) with the reference times of cortisol peaks in AI patients treated with IR-HC (8 a.m., 1 p.m., and 6 p.m.). A panel of 84 insulin sensitivity-related genes and intracellular insulin signaling proteins were analyzed by RT-qPCR and Western blot, respectively. RESULTS: The steep profile, characterized by a higher HC exposure during Bmal1bathyphase, produced significant downregulation in 21 insulin sensitivity-related genes including Insr, Irs1, Irs2, Pi3kca, and Adipor2, compared to the flat and standard profile. Reduced intracellular IRS1 Tyr608, AKT Ser473, AMPK Thr172, and ACC Ser79 phosphorylations were also observed. CONCLUSIONS: The current study demonstrated that late-in-the-day cortisol exposure modulates insulin sensitivity-related gene expression and intracellular insulin signaling in skeletal muscle cells.

Bisphenol A: an emerging threat to female fertility.

Bisphenol-A (BPA) has been reported to be associated to female infertility. Indeed, BPA has been found to be more frequently detected in infertile women thus leading to hypothesize a possible effect of BPA on natural conception and spontaneous fecundity. In addition, in procedures of medically assisted reproduction BPA exposure has been found to be negatively associated with peak serum estradiol levels during gonadotropin stimulation, number of retrieved oocytes, number of normally fertilized oocytes and implantation. BPA deleterious effects are more critical during perinatal exposure, causing dysregulation of hypothalamic-pituitary-ovarian axis in pups and adults, with a precocious maturation of the axis through a damage of GnRH pulsatility, gonadotropin signaling and sex steroid hormone production. Further, BPA exposure during early lifestage may have a transgenerational effect predisposing the subsequent generations to the risk of developing BPA related disease. Experimental studies suggested that prenatal, perinatal and postnatal exposure to BPA can impair several steps of ovarian development, induce ovarian morphology rearrangement and impair ovarian function, particularly folliculogenesis, as well as can impair uterus morphology and function, in female adult animal and offspring. Finally, studies carried out in animal models have been reported the occurrence of endometriosis-like lesions after BPA exposure. Moreover, BPA exposure has been described to encourage the genesis of PCOS-like abnormalities through the impairment of the secretion of sex hormones affecting ovarian morphology and functions, particularly folliculogenesis. The current manuscript summarizes the evidence regarding the association between BPA exposure and female infertility, reviewing both clinical and preclinical studies.

Smoke, alcohol and drug addiction and female fertility.

BACKGROUND: Considerable interest has been gathered on the relevant impact of preventable factors, including incorrect lifestyle and unhealthy habits, on female fertility. Smoking, alcohol and addictive drugs consumption represent a major concern, given the broad range of diseases which might be favored or exacerbated by these dependable attitudes. Despite the well-characterized effects of prenatal exposure on pregnancy outcomes and fetus health, a substantial proportion of women of reproductive age is still concerned with these habits. At present, the impact of smoke, alcohol and addictive drugs on women fertility, and, particularly, the specific targets and underlying mechanisms, are still poorly understood or debated, mainly due to the scarcity of well-designed studies, and to numerous biases. OBJECTIVE: The current review will provide a comprehensive overview of clinical and experimental studies in humans and animals addressing the impact of smoke, alcohol and addictive drugs on female fertility, by also embracing effects on ovary, oviduct, and uterus, with particular reference to primary endpoints such as ovarian reserve, steroidogenesis, ovulation and menstrual cycle, oviduct function and uterus receptivity and implantation. A brief focus on polycystic ovary syndrome and endometriosis will be also included. METHODS: A Pubmed literature search was performed with selected keywords; articles were individually retrieved by each author. No limitation was set for publication date. Articles in languages other than English were excluded. Additional articles were retrieved from references list of selected manuscripts. RESULTS AND CONCLUSIONS: Currently, the most consistent evidences of a detrimental effect of smoke, alcohol and addictive drugs on specific domains of the female reproductive function are provided by experimental studies in animals. Overall, clinical studies suggest that smoking is associated to decreased fertility, although causal inference should be further demonstrated. Studies addressing the effect of alcohol consumption on female fertility provide conflicting results, although the majority reported lack of a correlation. Extremely scarce studies investigated the effects of addictive drugs on female fertility, and the specific actions of selected drugs have been difficult to address, due to multidrug consumption.

Smoke, alcohol and drug addiction and male fertility.

In recent decades, the decline in human fertility has become increasingly more worrying: while therapeutic interventions might help, they are vexing for the couple and often burdened with high failure rates and costs. Prevention is the most successful approach to fertility disorders in males and females alike. We performed a literature review on three of the most common unhealthy habits - tobacco, alcohol and drug addiction - and their reported effects on male fertility. Tobacco smoking is remarkably common in most first-world countries; despite a progressive decline in the US, recent reports suggest a prevalence of more than 30% in subjects of reproductive age - a disturbing perspective, given the well-known ill-effects on reproductive and sexual function as well as general health. Alcohol consumption is often considered socially acceptable, but its negative effects on gonadal function have been consistently reported in the last 30 years. Several studies have reported a variety of negative effects on male fertility following drug abuse - a worrying phenomenon, as illicit drug consumption is on the rise, most notably in younger subjects. While evidence in these regards is still far from solid, mostly as a result of several confounding factors, it is safe to assume that cessation of tobacco smoking, alcohol consumption and recreational drug addiction might represent the best course of action for any couple trying to achieve pregnancy.

Air pollution and female fertility: a systematic review of literature.

Air pollution is a cause of concern for human health. For instance, it is associated with an increased risk for cancer, cardiovascular and respiratory disorders. In vitro and in vivo studies suggested that air pollutants could act as endocrine disruptors, promote oxidative stress and exert genotoxic effect. Whether air pollution affects female infertility is under debate. The aim of the present study was to conduct a systematic review of studies that evaluated the impact of air pollution on female infertility. We systematically searched the MEDLINE (PubMed) and SCOPUS databases to identify all relevant studies published before October 2017. No time or language restrictions were adopted, and queries were limited to human studies. We also hand-searched the reference lists of relevant studies to ensure we did not miss pertinent studies. The risk of bias and quality assessment of the studies identified were performed using the Newcastle-Ottawa Scale. Primary outcomes were conception rate after spontaneous intercourse and live birth rate after in vitro fertilization (IVF) procedures. Secondary outcomes were first trimester miscarriage, stillbirths, infertility, number of oocytes and embryo retrieved. Eleven articles were included in the analysis. We found that in the IVF population, nitrogen dioxide and ozone were associated with a reduced live birth rate while particulate matter of 10 mm was associated with increased miscarriage. Furthermore, in the general population, particulate matter of 2.5 mm and between 2.5 and 10 mm were associated with reduced fecundability, whereas sulfur dioxide, carbon monoxide and nitrogen dioxide might promote miscarriage and stillbirths. The main limitation of our findigns resides in the fact that the desegn of studies included are observational and retrospective. Furthermore, there was a wide heterogenity among studies. Although larger trials are required before drawing definitive conclusions, it seems that air pollution could represent a matter of concern for female infertility.

Shedding new light on female fertility: The role of vitamin D.

In the last decades several studies suggested that vitamin D is involved in the modulation of the reproductive process in women due to the expression of VDR and 1α-hydroxylase in reproductive tissues such as ovary, uterus, placenta, pituitary and hypothalamus. Vitamin D has also a role in the regulation of sex hormone steroidogenesis. Increasing evidence suggests that vitamin D might have a regulatory role in polycystic ovary syndrome (PCOS)-associated symptoms, including ovulatory dysfunction, insulin resistance and hyperandrogenism. Vitamin D deficiency also has been reported to contribute to the pathogenesis of endometriosis due to its immunomodulatory and anti-inflammatory properties. Although most of the studies supported a role of vitamin D in the onset of these diseases, randomized controlled trials to assess the efficacy of vitamin D supplementation have never been performed. In this review we critically discuss the role of vitamin D in female fertility, starting from in vitro and in vivo studies, focusing our attention on the two most frequent causes of female infertility: PCOS and endometriosis.

The role of vitamin D in male fertility: A focus on the testis.

In the last decade, vitamin D has emerged as a pleiotropic molecule with a multitude of autocrine, paracrine and endocrine functions, mediated by classical genomic as well as non-classical non-genomic actions, on multiple target organs and systems. The expression of vitamin D receptor and vitamin D metabolizing enzymes in male reproductive system, particularly in the testis, suggests the occurrence of vitamin D synthesis and regulation as well as function in the testis. The role of vitamin D in the modulation of testis functions, including hormone production and spermatogenesis, has been investigated in animals and humans. Experimental studies support a beneficial effect of vitamin D on male fertility, by modulating hormone production through genomic and non-genomic actions, and, particularly, by improving semen quality essentially through non-genomic actions. However, clinical studies in humans are controversial. Indeed, vitamin D seems to contribute to the modulation of the bioavailable rather than total testosterone. Moreover, although an increased prevalence or risk for testosterone deficiency was reported in men with vitamin D deficiency in observational studies, the majority of interventional studies demonstrated the lack of effect of vitamin D supplementation on circulating levels of testosterone. The most consistent effect of vitamin D was reported on semen quality. Indeed, vitamin D was shown to be positively associated to sperm motility, and to exert direct actions on spermatozoa, including non-genomic driven modulation of intracellular calcium homeostasis and activation of molecular pathways involved in sperm motility, capacitation and acrosome reaction. The current review provides a summary of current knowledge on the role of vitamin D in male fertility, by reporting clinical and experimental studies in humans and animals addressing the relationship between vitamin D and testis function.

Effect of chronic cabergoline treatment and testosterone replacement on metabolism in male patients with prolactinomas.

INTRODUCTION: Hyperprolactinemia and hypogonadism are reportedly associated with an impaired metabolic profile. The current study aimed at investigating the effects of testosterone replacement and cabergoline (CAB) treatment on the metabolic profile in male hyperprolactinemic patients. PATIENTS AND METHODS: Thirty-two men with prolactinomas, including 22 with total testosterone (TT) <8 nmol/l (HG, 69%) and 10 with TT >8 nmol/l (non-HG, 31%), were entered in the study. In all patients, metabolic parameters were assessed at diagnosis and after 12- and 24-month treatment. RESULTS: Compared to non-HG patients, at baseline the HG patients had higher waist circumference (WC). TT significantly correlated with body mass index (BMI). Twelve-month CAB induced PRL normalization in 84%. HG prevalence significantly decreased (28%) and non-HG prevalence significantly increased (72%). Anthropometric and lipid parameters, fasting insulin (FI), insulin sensitivity index (ISI0), homeostatic model assessment of insulin secretion (HOMA-ß) and homeostatic model assessment of insulin resistance (HOMA-IR) significantly improved compared to baseline. TT was the best predictor for FI. Percent change (Δ) of TT significantly correlated with ΔCholesterol, ΔWeight and ΔBMI. Compared to non-HG patients, the HG patients had a higher weight, BMI, WC and HOMA-ß. In HG, testosterone replacement was started. After 24 months, PRL normalized in 97%. HG prevalence significantly decreased (6%) and non-HG prevalence significantly increased (94%). Anthropometric and lipid parameters, FI, ISI0, HOMA-ß and HOMA-IR significantly improved compared to baseline, with FI, ISI0, HOMA-ß and HOMA-IR further ameliorating compared to the 12-month evaluation. Compared to non-HG patients, the HG patients still had a higher weight, BMI and WC. CONCLUSIONS: In hyperprolactinemic hypogonal men, proper testosterone replacement induces a significant improvement in the metabolic profile, even though the amelioration in the lipid profile might reflect the direct action of CAB.

Insulin-like growth factor-I inhibition with pasireotide decreases cell proliferation and increases apoptosis in pre-malignant lesions of the breast: a phase 1 proof of principle trial.

INTRODUCTION: Estrogen inhibition is effective in preventing breast cancer in only up to 50% of women with precancerous lesions and many experience side effects that are poorly tolerated. As insulin-like growth factor I (IGF-I) underlies both estrogen and progesterone actions and has other direct effects on mammary development and carcinogenesis, we hypothesized that IGF-I inhibition might provide a novel approach for breast cancer chemoprevention. METHODS: In total, 13 women with core breast biopsies diagnostic of atypical hyperplasia (AH) were treated for 10 days with pasireotide, a somatostatin analog which uniquely inhibits IGF-I action in the mammary gland. They then had excision biopsies. 12 patients also had proliferative lesions and one a ductal carcinoma in situ (DCIS). Primary outcomes were changes in cell proliferation and apoptosis after treatment. Expression of estrogen receptor (ER), progesterone receptor (PR), and phosphorylated Insulin-like growth factor I receptor (IGF-1R), protein kinase B (AKT) and extracellular signal-regulated kinases 1/2 (ERK1/2) were also assessed. Core and excision biopsies from 14 untreated patients served as non-blinded controls. Hyperglycemia and other side effects were carefully monitored. RESULTS: Pasireotide decreased proliferation and increased apoptosis in all AH (from 3.6 ± 2.6% to 1.3 ± 1.2% and from 0.3 ± 0.2% to 1.5 ± 1.6%, respectively) and proliferative lesions (from 3.8 ± 2.5% to 1.8 ± 1.8% and from 0.3 ± 0.2% to 1.3 ± 0.6%, respectively). The DCIS responded similarly. ER and PR were not affected by pasireotide, while IGF-1R, ERK1/2 and AKT phosphorylation decreased significantly. In contrast, tissue from untreated controls showed no change in cell proliferation or phosphorylation of IGF-1R, AKT or ERK 1/2. Mild to moderate hyperglycemia associated with reduced insulin levels was found. Glucose fell into the normal range after discontinuing treatment. Pasireotide was well tolerated and did not cause symptoms of estrogen deprivation. CONCLUSIONS: IGF-I inhibition by pasireotide, acting through the IGF-1R, was associated with decreased proliferation and increased apoptosis in pre-malignant breast lesions and one DCIS. Assuming hyperglycemia can be controlled, these data suggest that inhibiting the IGF-I pathway may prove an effective alternative for breast cancer chemoprevention. TRIAL REGISTRATION: NCT01372644 Trial date: July 1, 2007.

68Ga-PSMA PET/CT in Recurrent Prostate Cancer after Radical Prostatectomy Using PSMA-RADS Version 2.0.

BACKGROUND: 68Ga-PSMA PET/CT is superior to standard-of-care imaging for detecting regional and distant metastatic recurrent prostate cancer. The objective of our study was to evaluate the performance of 68Ga-PSMAPET/CT in our patient population, using the new PSMA-RADS version 2.0. METHODS: A total of 128 patients scanned with 68Ga-PSMA PET/CT for detection of recurrence after RP were analyzed with PSMA-RADS version 2.0. For the analysis of the detection rate, categories PSMA-RADS 3 to 5 were considered as "positive for malignancy" and 1-2 as "negative". RESULTS: According to PSMA-RADS v2.0, we classified patients as follows: 23 patients without PSMA-RADS because they were negative; PSMA-RADS 1: 10 patients; PSMA-RADS 2: 4 patients; PSMA-RADS 3A: 11 patients; PSMA-RADS 3B: 2 patients; PSMA-RADS 3C: 2 patients; PSMA-RADS 3D: 2 patients; PSMA-RADS 4: 13 patients; PSMA-RADS 5: 61 patients. CONCLUSIONS: The overall detection rate of 68Ga-PSMA PET/CT was 71%. By dividing the patients into fourgroups according to PSA level before examination, we obtained the following detection rates: PSA < 0.2 ng/mL 38%; 0.2 ≤ PSA < 0.5 ng/mL 57%; 0.5 ≤ PSA ≤ 1 ng/mL 77%; and PSA > 1 ng/mL 95%. CONCLUSION: Using PSMA-RADS version 2.0, we obtained detection rate values comparable with recent literature both in absolute terms and in relation to different PSA levels.

Fertility in Acromegaly: A Single-Center Experience of Female Patients During Active Disease and After Disease Remission.

CONTEXT: Fertility represents a major concern in patients with acromegaly. OBJECTIVE: The current retrospective study aimed to investigate gonadal function and fertility rates in acromegalic women. METHODS: In this referral-center study, 50 acromegalic women with disease onset within reproductive age were evaluated for prevalence of gonadal dysfunction and infertility. Anthropometric, metabolic, hormonal parameters, and gynecological ultrasound were evaluated at diagnosis and after disease control. Data about menstrual disturbances, pregnancy, and polycystic ovarian morphology (PCOM) were investigated at disease onset, at diagnosis, and after disease control. RESULTS: At presumed disease onset, menstrual disturbances were reported in 32% of patients. Uterine leiomyoma, ovarian cysts, and PCOM were diagnosed in 18%, 12%, and 8%, respectively; 36.8% of patients were infertile. At diagnosis, menstrual disturbances were found in 58.1% (P = .02), being significantly more prevalent in patients with higher insulin-like growth factor-I quartiles (Q) (P = .03, Q1 vs Q4). Gynecological ultrasound revealed uterine leiomyoma, ovarian cysts, and PCOM in 39.1% (P = .04), 28.2% (P = .09), and 13% (P = .55), respectively. The infertility rate was 100% (P = .02). At disease control, menstrual disturbances were slightly decreased as compared to diagnosis (P = .09). Noteworthy, menstrual disturbances (P = .05) and particularly amenorrhea (P = .03) were significantly more frequent in patients with active disease duration greater than 5 years (median) as compared to those achieving disease control in less than 5 years. Among patients with pregnancy desire, 73.3% conceived at least once, with resulting infertility significantly decreased compared to diagnosis (26.7%; P = .01). At-term deliveries, preterm deliveries, and spontaneous abortions were recorded in 86.7%, 6.6%, and 6.6%, respectively, of the 15 pregnancies reported by the patients. No neonatal malformations and/or abnormalities were recorded. CONCLUSION: Gonadal dysfunction and infertility are common in acromegalic women within reproductive age, being directly influenced by disease status and/or duration.

Seminal cadmium affects human sperm motility through stable binding to the cell membrane.

Environmental pollutants are claimed to be major factors involved in the progressive decline of the fertility rate worldwide. Exposure to the heavy metal Cadmium (Cd) has been associated with reproductive toxicity due to its ionic mimicry. However, the possible direct accumulation of Cd in human sperm cells has been poorly investigated. In this study, we aimed to clarify the possible direct effect of Cd exposure on sperm function through the analysis of its cell accumulation. Semen samples from 30 male subjects residing in high environmental impact areas and adhering to the "Exposoma e Plurifocalità nella Prevenzione Oncologica" campaign for testis cancer prevention were compared with semen samples from 15 males residing in low exposure areas. Semen levels and cell Cd content were quantified by inductively coupled plasma (ICP) spectroscopy. Cell Cd distribution was assessed by scanning electron microscopy coupled with energy dispersive spectroscopy (SEM-EDS). The impact of Cd on sperm function was evaluated by the in vitro exposure to the heavy metal, whilst possible scavenging approaches/agents were assessed. In addition to higher values of semen Cd, exposed subjects showed a reduction in total motile sperm fraction compared to not-exposed controls (59.6% ± 13.6% vs. 66.3% ± 7.3%, p = 0.037). Semen Cd levels were also significantly correlated with SEM-EDS signals of Cd detected on the head and neck of sperm (respectively p = 0.738, p < 0.001 and ρ = 0.465, p < 0.001). A total of 2 h of in vitro exposure to 0.5 µM Cd was associated with a significant reduction of sperm progressive motility. Scavenging approaches with either hypo-osmotic swelling or 10 µM reduced glutathione were ineffective in blunting cell Cd and restoring motility. The reduction of exposure levels appears to be the main approach to reducing the reproductive issues associated with Cd.

Imaging of primary retroperitoneal neoplasms.

Retroperitoneal soft tissue tumors are frequently incidental findings on imaging tests as Computed tomography (CT) or Magnetic Resonance Imaging (MRI). Retroperitoneal soft tissue tumors are rare and therefore not common in daily radiological practice. Clinician and radiologist'skills to set retroperitoneal soft tissue tumors at presentation is crucial for a correct patient management. So far, several diagnostic algorithms have been proposed to assess retroperitoneal masses, which have not been validated by case histories (2-5). The aim of this article is to evaluate a new classification of retroperitoneal masses using CT and MRI. KEY WORDS: CT, Diagnosis, MRI, Retroperitoneum, Soft tissue sarcoma.

Vitamin D Reverts the Exosome-Mediated Transfer of Cancer Resistance to the mTOR Inhibitor Everolimus in Hepatocellular Carcinoma.

Several multi-kinase inhibitors were widely tested as potential first-line or second-line therapy in patients with advanced hepatocellular carcinoma (HCC). However, acquired drug resistance limits their clinical efficacy. Exosomes are microvesicles secreted by tumor and stromal cells that participate in many biological processes, including drug resistance. The current study evaluated the capability of exosomes derived from everolimus (EVE)-resistant HCC cells in inducing drug resistance in parental human HCC cells and the effect of 1,25(OH)2Vitamin D (VitD) treatment in restoring EVE sensitivity. The internalization of exosomes from EVE-resistant (EveR) cells into parental cells conferred the transmission of aggressive phenotype by promoting the transition of epithelial-to-mesenchymal phenotype, as demonstrated by immunofluorescence, and the acquisition of EVE resistance, as demonstrated by cell proliferation and colony formation assays. Moreover, the internalization of exosomes from EveR into parental cells induced deregulation of the mTOR pathway mainly by triggering the activation of the serine/threonine protein kinase Akt, involved in the cellular survival pathway, as demonstrated by Western blot analysis. Interestingly, the treatment with VitD prevented exosome-induced EVE resistance in HCC cells, significantly inhibiting cell proliferation but also partially reducing colony and size number when combined with EVE compared with control. In conclusion, the results of the current study demonstrated that exosomes derived from EveR cells could induce EVE resistance in EVE-sensitive HCC cells and that VitD can revert the exosome-induced EVE resistance by resensitizing to EVE treatment.

Severe impact of late diagnosis of congenital adrenal hyperplasia on gender identity, sexual orientation and function: case report and review of the literature.

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) represents the most frequent form of CAH and of 46, XX disorder of sex development in female newborns. In the majority of cases, particularly in developed countries, female patients suffering from the classic forms of CAH reach the diagnosis at birth or in the early childhood, allowing a prompt treatment with a correct gender assignment. The current manuscript describes an unusual case of an Italian 46-year-old woman, homeborn in the 60s, receiving an extraordinarily late diagnosis of simple virilising classic form of CAH due to 21-OHD, determining a relevant impairment of both physical and psychosexual development. The patient presented primary amenorrhea, height under target, overweight with visceral adiposity, hypercholesterolemia and insulin resistance, hirsutism with a typical male-pattern hair growth, external genital ambiguity, and a severe impairment in the entire series of psychological dimensions, particularly severe depressive symptoms, together with gender dysphoria relative to the female gender assigned at birth, cross-gender behaviours, and body image discomfort, which were associated with homosexual orientation, and sexual dysfunction. Following diagnosis and glucocorticoid (GC) replacement therapy, the hyperandrogenism control and familial and socio-cultural factors changes, particularly, living alone and the interruption of social isolation, were accompanied by menarche appearance, improvement in hirsutism and metabolic profile, and a resolution in all psychological dimensions, depressive symptoms, and gender dysphoria. The patient began to perceive homosexual orientation without discomfort, and ameliorating sexual function. Few cases of female patients with CAH due to 21-OHD receiving an extremely delayed diagnosis have been published. However, to the best of our knowledge, this is the first case including a complete psychosexual assessment at diagnosis with a detailed re-evaluation after 5 years of disease treatment.

Clinical application of 18F-DOPA PET/TC in pediatric patients.

The use 18F-DOPA PET/CT for oncologic and non-oncologic pediatric diseases is well consolidated in clinical practice. The indications include brain tumors, neuroendocrine malignancies and congenital hyperinsulinism. The number of papers involving pediatric subjects is steadily growing. However, literature still lacks clinical trials and large multicentric studies in contrast with the extensive literature available for adult patients. The aim of this review is to discuss the main clinical indications of 18F-DOPA in pediatric oncologic and nononcologic diseases and to analyze its role in diagnosis, staging, biopsy and surgical planning. The high resolution of PET/CT tomographs in addition to the high sensitivity and specificity of 18F-DOPA imaging exceeds the downsides linked to this nuclear medicine imaging modality. In fact, few potential limitations could discourage the use of PET/CT imaging. For example, similarly to MRI studies the long acquisition time of a PET/CT scan often requires sedation especially in infants. Moreover, the radiation exposure of a PET/CT scan may be high, but the clinical benefit deriving from nuclear medicine imaging outruns the risk connected to the use of ionizing radiations.

Seminal Vesicle Urinary Reflux After TURP Mimicking Vesicular Invasion From Prostate Cancer on 18F-Choline PET/CT.

Seminal vesicles are paired secretory glands located posterior to the bladder in men that produce seminal fluid to maintain sperm. Seminal vesicle reflux into the prostatic ducts may be associated with prostatitis in older patients or may represent a very rare complication of transurethral prostate resection in patients with prostatic cancer. This condition is frequently accidentally diagnosed on excretory urography and/or retrograde urethrogram. Clinical presentation includes pain, fever, recurrent epididymitis-prostatitis, and post void dribbling.

Radium-223 Treatment in mCRPC Patient with Polycythemia Vera

There have been several studies on the clinical outcomes of Radium-223 treatment in patients with metastatic castration-resistant prostate cancer (mCRPC) who may have an increased risk of hematologic comorbidities. To the best of our knowledge, this is the first study to explore the potential bone marrow adverse effects (AEs) of Radium-223 administered with specific drugs used for hematologic conditions, such as polycythemia vera (PV). We report the case of a patient with mCRPC who was administered a combined treatment of Radium-223 and hydroxyurea for PV, aiming to support clinicians in predicting eventual AEs.