Endocrine disruptors, aryl hydrocarbon receptor and cortisol secretion.

PURPOSE: Endocrine disruptors exert a plethora of effects in endocrine tissues, from altered function to carcinogenesis. Given its lipophilic nature, the adrenal cortex represents an ideal target for endocrine disruptors and thus, possibly, xenobiotic-induced adrenocortical dysfunction. However, there is no clear understanding of the effect of endocrine disruptors on adrenal steroidogenesis, in particular as regards the aryl hydrocarbon receptor (AHR) pathway, one of the key mediators. METHODS: The present review recapitulates available evidence on the effects of AHR ligands on adrenal steroidogenesis, with focus on cortisol secretion. RESULTS: Short-term exposure to AHR ligands most often induced a stress-like corticosteroid response followed by decreased responsiveness to stressors with long-term exposure. This was observed in several experimental models across species as well as in animals and humans in real-life settings. Prenatal exposure led to different effects according to sex of the offspring, as observed in murine models and in children from mothers in several countries. In vitro findings proved highly dependent on the experimental setting, with reduced cortisol response and steroidogenic enzyme synthesis mostly observed in fish and increased cortisol synthesis and secretion observed in murine and human adrenal cell lines. Of note, no AHR-binding element was detected in steroidogenic enzyme promoters, suggesting the involvement of additional factors. CONCLUSION: Our review provides evidence for the impact of AHR ligands on adrenocortical function and indicates further avenues of research to better clarify its effects.

Post-diagnosis serum 25-hydroxyvitamin D concentrations in women treated for breast cancer participating in a lifestyle trial in Italy.

OBJECTIVE: To report cross-sectionally serum levels of 25-hydroxyvitamin D [25(OH)D] in women living in Italy within 12 months from breast cancer (BC) diagnosis. METHODS: Baseline data were obtained from 394 women diagnosed with primary BC, enrolled from 2016 to 2019 in a lifestyle trial conducted in Italy. Subjects' characteristics were compared between two 25(OH)D concentrations (hypovitaminosis D<20 and ≥20 ng/mL) with the Chi-squared test or Fisher's exact test for small-expected counts. Using multiple logistic regression-adjusted models, we estimated odds ratios (ORs) of hypovitaminosis D with 95% confidence intervals (CIs) in the total sample and in the unsupplemented subgroup. RESULTS: Hypovitaminosis D was found in 39% of all subjects, 60% in unsupplemented subjects, and 10% in supplemented subjects. Increasing ORs of hypovitaminosis D were found with increasing body mass index, 25-30, >30, and ≥35 versus <25 kg/m2 (ORs: 2.50, 4.64, and 5.81, respectively, in the total cohort and ORs: 2.68, 5.38, and 7.08 in the unsupplemented); living in the most southern Italian region (OR 2.50, 95%CI 1.22-5.13); and with hypertriglyceridemia (OR 2.46; 95%CI 1.16-5.22), chemotherapy history (OR 1.86, 95%CI 1.03-3.38), and inversely with anti-estrogenic therapy (OR 0.43, 95%CI 0.24-0.75) in the total sample. CONCLUSIONS: Hypovitaminosis D in women recently diagnosed with BC and participating in a lifestyle trial in Italy was widespread and highest with obesity, hypertriglyceridemia, and chemotherapy use. Considering that hypovitaminosis D is a risk factor for lower efficacy of bone density treatments and possibly BC mortality, our results suggest the need to promptly address and treat vitamin D deficiency.

Final results of the real-life observational VICTOR-6 study on metronomic chemotherapy in elderly metastatic breast cancer (MBC) patients.

Nowadays, treatment of metastatic breast cancer (MBC) has been enriched with novel therapeutical strategies. Metronomic chemotherapy (mCHT) is a continuous and frequent administration of chemotherapy at a lower dose and so whit less toxicity. Thus, this strategy could be attractive for elderly MBC patients. Aim of this analysis is to provide insights into mCHT's activity in a real-life setting of elderly MBC patients. Data of patients ≥ 75 years old included in VICTOR-6 study were analyzed. VICTOR-6 is a multicentre, Italian, retrospective study, which collected data on mCHT in MBC patients treated between 2011 and 2016. A total of 112 patients were included. At the beginning of mCHT, median age was 81 years (75-98) and in 33% of the patients mCHT was the first line choice. Overall Response Rate (ORR) and Disease Control Rate (DCR) were 27.9% and 79.3%, respectively. Median PFS ranged between 7.6 and 9.1 months, OS between 14.1 and 18.5 months. The most relevant toxicity was the hematological one (24.1%); severe toxicity (grade 3-4) ranged from 0.9% for skin toxicity up to 8% for hematologic one. This is a large study about mCHT in elderly MBC patients, providing insights to be further investigated in this subgroup of frail patients.

Epidemiology, course, and outcomes of Sars-CoV-2 infection in patients with acromegaly and Cushing's disease: a monocentric experience in Southern Italy.

PURPOSE: Acromegaly (AC) and Cushing's disease (CD) increase morbidity and mortality due to cardio-metabolic alterations, and overall cause frailty in the affected patients, potentially making them more susceptible to infective diseases. However, up to now, very few studies evaluated the course of COVID-19 disease in this setting. METHODS: We investigated epidemiology, course, and outcomes of COVID-19 disease in patients with AC or CD, managed in the Endocrine Unit of a Sicilian University Hospital during 2 years of pandemic outbreak. RESULTS: We enrolled 136 patients with AC or CD (74 and 62 cases, respectively, 39 males) from Sicily and Calabria regions. Incidence of Sars-CoV-2 infection in these subjects was lower than in the general population, becoming quite similar after vaccines introduction (11%). No difference was observed concerning prevalence. Mean age of infected patients (IPs) was significantly lower than the unaffected ones (p < 0.02). No differences were found for sex, BMI, disease control, occurrence of diabetes mellitus, OSAS, cardiomyopathy, and hypopituitarism. The rate of IPs was similar in AC and CD patients' groups. None of them died. CONCLUSIONS: In conclusion, we did not find a significantly different incidence of Sars-CoV-2 infection in AC or CD patients compared to the general population. IPs were younger than the unaffected patients, but sex, BMI, or diabetes mellitus were not risk factors for infection/worse outcomes. Nevertheless, these results could have been biased by a safer behavior probably adopted by older and more complicated patients.

Global Cushing's disease epidemiology: a systematic review and meta-analysis of observational studies.

PURPOSE: Cushing's disease (CD), 70% of endogenous hypercortisolism cases, is a rare disease caused by adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas. To date, no systematic reviews and meta-analyses on its global epidemiology have been published. We provide a systematic review and meta-analysis of CD global epidemiology, also evaluating the quality of study reporting for the identified studies. METHODS: MEDLINE and EMBASE databases were searched for studies on CD epidemiology from inception until November 30th, 2020, including original observational studies in English about CD prevalence and/or incidence for well-defined geographic areas. Two reviewers independently extracted data and assessed reporting quality. CD prevalence/incidence pooled estimates were derived from a random-effects meta-analysis. Reporting quality was assessed using a STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) checklist adapted for observational studies on rare diseases, heterogeneity using the Cochran's Q-test and its derived measure of inconsistency (I2). RESULTS: Thirteen studies were included. The pooled CD prevalence was 2.2 [95% CI 1.1-4.8] per 100,000, while the incidence rate was 0.24 [95% CI 0.15-0.33] per 100,000 person-years. For both parameters, considerable between-studies heterogeneity was found (I2 = 78.8% and 87.8%, respectively). The quality of study reporting was rated as medium for 11 (84.6%) studies and as low for 2 (15.4%). CONCLUSION: Overall, our systematic meta-analysis demonstrated CD epidemiology to be similarly reported across different areas of the world, with some exceptions regarding regional differences or observation period intervals. Keeping into account the methodological differences between each paper, large-scale studies on CD epidemiology are warranted. Setting up national specific registries, based on standardized diagnostic and clinical parameters, with clearly defined selection and analysis criteria, and a strong cooperation between the scientific national societies for endocrinology is crucial to exclude other causes of variability (i.e. geographical differences due to other factors like (epi)genetic changes), and to support public health decision making.

Metronomic chemotherapy (mCHT) in metastatic triple-negative breast cancer (TNBC) patients: results of the VICTOR-6 study.

PURPOSE: Triple-negative breast cancer (TNBC) represents a subtype of breast cancer which lacks the expression of oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2): TNBC accounts for approximately 20% of newly diagnosed breast cancers and is associated with younger age at diagnosis, greater recurrence risk and shorter survival time. Therapeutic options are very scarce. Aim of the present analysis is to provide further insights into the clinical activity of metronomic chemotherapy (mCHT), in a real-life setting. METHODS: We used data included in the VICTOR-6 study for the present analysis. VICTOR-6 is an Italian multicentre retrospective cohort study, which collected data of metastatic breast cancer (MBC) patients who have received mCHT between 2011 and 2016. Amongst the 584 patients included in the study, 97 were triple negative. In 40.2% of the TNBC patients, mCHT was the first chemotherapy treatment, whereas 32.9% had received 2 or more lines of treatment for the metastatic disease. 45.4% out of 97 TNBC patients received a vinorelbine (VRL)-based regimen, which resulted in the most used type of mCHT, followed by cyclophosphamide (CTX)-based regimens (30.9%) and capecitabine (CAPE)-based combinations (22.7%). RESULTS: Overall response rate (ORR) and disease control rate (DCR) were 17.5% and 64.9%, respectively. Median progression free survival (PFS) and overall survival (OS) were 6.0 months (95% CI: 4.9-7.2) and 12.1 months (95% CI: 9.6-16.7). Median PFS was 6.9 months for CAPE-based regimens (95% CI: 5.0-18.4), 6.1 months (95% CI: 4.0-8.9) for CTX-based and 5.3 months (95% CI: 4.1-9.5) for VRL-based ones. Median OS was 18.2 months (95% CI: 9.1-NE) for CAPE-based regimens and 11.8 months for VRL- (95% CI: 9.3-16.7 and CTX-based ones (95%CI: 8.7-52.8). Tumour response, PFS and OS decreased proportionally in later lines. CONCLUSION: This analysis represents the largest series of TNBC patients treated with mCHT in a real-life setting and provides further insights into the advantages of using this strategy even in this poor prognosis subpopulation.

What we have to know about corticosteroids use during Sars-Cov-2 infection.

PURPOSE: Glucocorticoids (GCs), alone or associated to other drugs, were widely used in the management of patients affected by severe acute respiratory syndrome caused by SARS-CoV-2 infection, during the recent COVID-19 outbreak. This review summarizes the available data on HPA axis impairment in GC-treated SARS-CoV-2 patients, focusing on the risk of adrenal insufficiency and on potential drug interactions during concomitant treatments. METHODS: Literature on the impact of GCs therapy on HPA axis and on the consequences of coadministration of GCs and other drugs in SARS-CoV-2 patients has been reviewed. RESULTS: GC treatment can cause symptoms of hypercortisolism, especially in patients with individual hypersensibility, or hypoadrenalism after drug withdrawal, due to hypothalamic-pituitary-adrenal (HPA) axis suppression, with consequences in terms of increased morbidity and mortality risk. On the other hand, in SARS-CoV-2-infected patient's cortisol secretion could be insufficient also due to critical illness-related corticosteroid insufficiency (CIRCI). In addition, in this clinical context, the co-administration of antiretroviral drugs and corticosteroids may trigger drug-drug interaction and enhance the exposure to the latter ones, metabolized through the CYP450 CYP3A pathway, severely impacting on HPA axis. CONCLUSION: Physicians involved in the management of patients affected by COVID-19 should be aware of the need of an appropriate GC dose tapering, and of potential interaction of GCs with antiviral therapy and drugs used to treat associated co-morbidities.

What factors have impact on glucocorticoid replacement in adrenal insufficiency: a real-life study.

PURPOSE: The impact of patient's characteristics on glucocorticoid (GC) replacement therapy in adrenal insufficiency (AI) is poorly evaluated. Aims of this study were to assess the influence of sex and body weight on GC dosing and to describe the choice of GC in AI of different etiologies. METHODS: We retrospectively evaluated hydrocortisone (HC) equivalent total daily dose (HC-TDD) and per-kg-daily dose (HC-KDD) in 203 patients (104 primary AI [pAI], 99 secondary AI [sAI]) followed up for ≥ 12 months. They were treated with HC, modified-release HC (MRHC) or cortisone acetate (CA) and fludrocortisone acetate (FCA) in pAI. RESULTS: At baseline, CA was preferred both in pAI and sAI; at last visit, MRHC was most used in pAI (49%) and CA in sAI (73.7%). Comparing the last visit with baseline, in pAI, HC-TDD and HC-KDD were significantly lower (p = 0.04 and p = 0.006, respectively), while FCA doses increased during follow-up (p = 0.02). The reduction of HC-TDD and HC-KDD was particularly relevant for pAI women (p = 0.04 and p = 0.002, respectively). In sAI patients, no change of HC-KDD and HC-TDD was observed, and we found a correlation between weight and HC-TDD in males (r 0.35, p = 0.02). CONCLUSIONS: Our real-life study demonstrated the influence of etiology of AI on the type of GC used, a weight-based tailoring in sAI, a likely overdosage of GC treatment in pAI women at the start of treatment and the possibility to successfully increase FCA avoiding GC over-treatment. These observations could inform the usual clinical practice.

MicroRNAs expression in pituitary tumors: differences related to functional status, pathological features, and clinical behavior.

BACKGROUND: MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression at post-transcriptional level, having a role in many biological processes, such as control of cell proliferation, cell cycle, and cell death. Altered miRNA expression has been reported in many neoplasms, including pituitary adenomas (PAs). PURPOSE: In this study, we aimed to evaluate the expression of 20 miRNAs involved in pathways relevant to pituitary pathophysiology, in PAs and normal pituitary tissue and to correlate their expression profile with clinical and pathological features. METHODS: Pituitary tumor samples were obtained during transphenoidal surgery from patients with non-functioning (NFPA, n = 12) and functioning (n = 11, 5 GH-, 3 ACTH-, 3 PRL-omas) PAs. The expression of selected miRNAs in PAs and in normal pituitary was analyzed by RT-qPCR. miRNAs expression was correlated with demographic, clinical, and neuroradiological data and with histopathological features including pituitary hormones immunostaining, Ki-67 proliferation index, and p53 immunohistochemistry evaluation. RESULTS: All evaluated miRNAs except miR-711 were expressed in both normal and tumor pituitary tissue. Seventeen miRNAs were significantly down-regulated in pituitary tumors compared to normal pituitary. miRNAs were differentially expressed in functioning PAs or in NFPAs, as in the latter group miR-149-3p (p = 0.036), miR-130a-3p (p = 0.014), and miR-370-3p (p = 0.026) were significantly under expressed as compared to functioning tumors. Point-biserial correlation analysis demonstrated a negative correlation between miR-26b-5p and Ki-67 (p = 0.031) and between miR-30a-5p and 'atypical' morphological features (p = 0.038) or cavernous sinus invasion (p = 0.049), while 508-5p was inversely correlated with clinical aggressiveness (p = 0.043). CONCLUSIONS: In this study, we found a significant down-regulation of 17 miRNAs in PAs vs normal pituitary, with differential expression profile related to functional status and tumor aggressiveness.

Metronomic chemotherapy for advanced breast cancer patients in the real world practice: Final results of the VICTOR-6 study.

Metronomic chemotherapy (mCHT) refers to the minimum biologically effective dose of a chemotherapy agent given as a continuous dosing regimen, with no prolonged drug-free breaks, that leads to antitumor activity. Aim of the present study is to describe the use of mCHT in a retrospective cohort of metastatic breast cancer (MBC) patients in order to collect data regarding the different types and regimens of drugs employed, their efficacy and safety. Between January 2011 and December 2016, data of 584 metastatic breast cancer patients treated with mCHT were collected. The use of VRL-based regimens increased during the time of observation (2011: 16.8% - 2016: 29.8%), as well as CTX-based ones (2011: 17.1% - 2016: 25.6%), whereas CAPE-based and MTX-based regimens remained stable. In the 1st-line setting, the highest ORR and DCR were observed for VRL-based regimens (single agent: 44% and 88%; combination: 36.7% and 82.4%, respectively). Assuming VRL-single agent as the referee treatment (median PFS: 7.2 months, 95% CI: 5.3-10.3), the longest median PFS were observed in VRL-combination regimens (9.5, 95%CI 88.8-11.3, HR = 0.72) and in CAPE-single agent (10.7, 95%CI 8.3-15.8, HR = 0.70). The VICTOR-6 study provides new data coming from the real-life setting, by adding new information regarding the use of mCHT as an option of treatment for MBC patients.

Peptide receptor radionuclide therapy for aggressive pituitary tumors: a monocentric experience.

In aggressive pituitary tumors (PT) showing local invasion or growth/recurrence despite multimodal conventional treatment, temozolomide (TMZ) is considered a further therapeutic option, while little data are available on peptide receptor radionuclide therapy (PRRT). We analyzed PRRT effectiveness, safety and long-term outcome in three patients with aggressive PT, also reviewing the current literature. Patient #1 (F, giant prolactinoma) received five cycles (total dose 37 GBq) of 111In-DTPA-octreotide over 23 months, after unsuccessful surgery and long-term dopamine-agonist treatment. Patient #2 (M, giant prolactinoma) underwent two cycles (12.6 GBq) of 177Lu-DOTATOC after multiple surgeries, radiosurgery and TMZ. In patient #3 (F, non-functioning PT), five cycles (29.8 GBq) of 177Lu-DOTATOC followed five surgeries, radiotherapy and TMZ. Eleven more cases of PRRT-treated aggressive PT emerged from literature. Patient #1 showed tumor shrinkage and visual/neurological amelioration over 8-year follow-up, while the other PTs continued to grow causing blindness and neuro-cognitive disorders (patient #2) or monolateral amaurosis (patient #3). No adverse effects were reported. Including the patients from literature, 4/13 presented tumor shrinkage and clinical/biochemical improvement after PRRT. Response did not correlate with patients' gender or age, neither with used radionuclide/peptide, but PRRT failure was significantly associated with previous TMZ treatment. Overall, adverse effects occurred only in two patients. PRRT was successful in 1/3 of patients with aggressive PT, and in 4/5 of those not previously treated with TMZ, representing a safe option after unsuccessful multimodal treatment. However, at present, considering the few data, PRRT should be considered only in an experimental setting.

GSTP1 gene methylation and AHR rs2066853 variant predict resistance to first generation somatostatin analogs in patients with acromegaly.

PURPOSE: Biomarkers of clinical and therapeutic outcome in acromegaly are needed. Polymorphisms or epigenetic changes of detoxification genes, such as those coding for the aryl hydrocarbon receptor (AHR) and the glutathione-S-transferase-P1 (GSTP1), could have a role in GH secreting pituitary tumors' pathophysiology and clinical expression. In this study, we assessed the contribution of GSTP1 gene promoter methylation status, per se or in combination with the occurrence of the AHR gene rs2066853 variant, on clinical features and response to somatostatin analogs (SSA) treatment in acromegaly patients. METHODS: This is an observational, retrospective study, carried out in the Endocrine Unit of an Italian University Hospital. We enrolled 77 wild-type AIP gene acromegaly patients, who have been screened for germline AHR rs2066853 variant and GSTP1 gene promoter methylation. Clinical and biochemical parameters were compared after patients' stratification according to GSTP1 methylation status and the presence of AHR rs2066853. We also evaluated the response to SSA treatment in 71 cases. RESULTS: 17 patients carried the AHR rs2066853 variant and 26 had methylated GSTP1 (GSTP1-methyl) gene promoter. GSTP1-methyl patients showed a higher prevalence of diabetes mellitus (p = 0.01), colonic polyps (p = 0.05), and were more resistant to SSA (p = 0.02) as compared to GSTP1 unmethylated patients (GSTP1-unmethyl). Patients GSTP1-unmethyl and AHR wild-type were the most sensitive to SSA treatment, while those with both GSTP1-methyl and AHR rs2066853 variant were all resistant to SSA (p = 0.01). CONCLUSIONS: In acromegaly, GSTP1 gene methylation associates with resistance to SSA treatment, especially in patients carrying also the AHR rs2066853 variant, and with increased prevalence of colonic polyps and diabetes mellitus.

Pasireotide treatment reduces cardiometabolic risk in Cushing's disease patients: an Italian, multicenter study.

PURPOSE: Patients with Cushing's disease (CD) experience metabolic alterations leading to increased cardiovascular mortality. Recently, the visceral adiposity index (VAI) has been proposed as a marker of visceral adipose tissue dysfunction (ATD) and of the related cardiometabolic risk. We aimed to evaluate the impact of 12-month pasireotide treatment on cardiometabolic risk in CD patients. METHODS: This is a multicentre, prospective, and observational study. Sixteen CD patients, referred to the Endocrine Units of the University Hospitals of Messina, Napoli, Padova, and Palermo (Italy), successfully treated with pasireotide for 12 month have been enrolled. In all patients, we assessed anthropometric, clinical, and biochemical parameters and calculated VAI, ATD severity, Framingham, and atherosclerotic cardiovascular disease (ASCVD) risk scores, before and after 6 and 12 months of treatment with pasireotide (1200-1800 mcg/daily). RESULTS: Before starting pasireotide treatment, ATD was present in 7/16 patients (mild in 2/16, moderate in 3/16, and severe 2/16). After 12 months of treatment: (i) 24h-urinary free cortisol levels (p = 0.003), BMI (p < 0.001), waist circumference (p = 0.001), LDL-cholesterol (p = 0.033), total-cholesterol (p = 0.032), triglycerides (p = 0.030), VAI (p = 0.015), and ATD severity (p = 0.026) were significantly decreased as compared to baseline; (ii) ATD was present in only 1/16 patients; (iii) prevalence of diabetes mellitus (p = 0.015) and HbA1c levels (p = 0.001) were significantly increased as compared to baseline; (iv) Framingham and ASCVD risk scores were not significantly different from pre-treatment values. CONCLUSIONS: Twelve-month pasireotide treatment significantly reduces VAI and ATD in CD patients. These positive effects on cardiometabolic risk occur despite no change in Framingham and ASCVD risk scores and the increase in the prevalence of diabetes mellitus.

A randomized, phase 2 study of cetuximab plus cisplatin with or without paclitaxel for the first-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck.

BACKGROUND: B490 (EudraCT# 2011-002564-24) is a randomized, phase 2b, noninferiority study investigating the efficacy and safety of first-line cetuximab plus cisplatin with/without paclitaxel (CetCis versus CetCisPac) in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). PATIENTS AND METHODS: Eligible patients had confirmed R/M SCCHN (oral cavity/oropharynx/larynx/hypopharynx/paranasal sinus) and no prior therapy for R/M disease. Cetuximab was administered on day 1 (2-h infusion, 400 mg/m2), then weekly (1-h infusions, 250 mg/m2). Cisplatin was given as a 1-h infusion (CetCis arm: 100 mg/m2; CetCisPac arm: 75 mg/m2) on day 1 of each cycle for a maximum of six cycles. Paclitaxel was administered as a 3-h infusion (175 mg/m2) on day 1 of each cycle. After six cycles, maintenance cetuximab was administered until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS). We assumed a noninferiority margin of 1.40 as compatible with efficacy. RESULTS: A total of 201 patients were randomized 1 : 1 to each regimen; 191 were assessable. PFS with CetCis (median, 6 months) was noninferior to PFS with CetCisPac (median, 7 months) [HR for CetCis versus CetCisPac 0.99; 95% CI: 0.72-1.36, P = 0.906; margin of noninferiority (90% CI of 1.4) not reached]. Median overall survival was 13 versus 11 months (HR = 0.77; 95% CI: 0.53-1.11, P = 0.117). The overall response rates were 41.8% versus 51.7%, respectively (OR = 0.69; 95% CI: 0.38-1.20, P = 0.181). Grade ≥3 adverse event rates were 76% and 73% for CetCis versus CetCisPac, respectively, while grade 4 toxicities were lower in the two-drug versus three-drug arm (14% versus 33%, P = 0.015). No toxic death or sepsis were reported and cardiac events were negligible (1%). CONCLUSION: The two-drug CetCis regimen proved to be noninferior in PFS to a three-drug combination with CetCisPac. The median OS of both regimens is comparable with that observed in EXTREME, while the life-threatening toxicity rate appeared reduced. CLINICAL TRIAL NUMBER: EudraCT# 2011-002564-24.

Acromegaly, genetic variants of the aryl hydrocarbon receptor pathway and environmental burden.

Increasing evidence suggests that environmental contaminants can exert endocrine disruptors activities and that pollution exposition can have a role in tumorigenic processes. Several environmental pollutants have been shown to affect pituitary cells biology and function. The aryl hydrocarbon receptor (AHR) pathway is involved in xenobiotics' metabolism and in tumorigenesis. A deregulation of the AHR pathway could have a role in pituitary tumours' pathophysiology, especially in the GH secreting ones. AHR-interacting protein (AIP) is one of the key partners of AHR and is implicated in pituitary tumours' pathogenesis. Moreover, an increased prevalence of acromegaly has been reported in a highly polluted area of the province of Messina (Sicily, Italy). Nevertheless, at present, few data are available about the potential role of environmental factors in the pathogenesis and clinical expression of GH secreting pituitary tumours. This review is aimed at discussing the evidences on the potential links among environmental pollutants, the AHR pathway and the pathophysiology of GH-secreting pituitary adenomas.

Acromegaly Is More Severe in Patients With AHR or AIP Gene Variants Living in Highly Polluted Areas.

CONTEXT: An increased prevalence of acromegaly was found some years ago in a highly polluted area in North-Eastern Sicily, where high concentration of nonmethane hydrocarbons, volatile organic compounds, and cadmium was found. Aryl hydrocarbon receptor (AHR) pathway has a key role in detoxification of these compounds and in tumorigenesis. OBJECTIVE: We correlated the occurrence of AHR and/or AHR-interacting protein (AIP) gene variants with acromegaly severity according to pollution exposition. DESIGN, SETTING, and PATIENTS: This was an observational, perspective study conducted over 7 years in four Italian referral centers for pituitary diseases in which 210 patients with acromegaly were enrolled between 2008 and 2015. INTERVENTION: Genetic screening of patients for AHR and AIP variants. MAIN OUTCOME MEASURES: Clinical, biochemical, and radiological data of patients with and without AIP and/or AHR gene variants, living in polluted (high-risk for health, [HR]) or nonpolluted (NP) areas of five Italian regions were evaluated and compared. RESULTS: Among the 23 patients from HR areas, nine showed AHR or AIP variants. Mean IGF-I levels and pituitary tumor diameter were significantly higher in these nine patients (HR/VAR+) than in the other 14 (HR/VAR−) and in the 187 from NP areas (44 NP/VAR+). Somatostatin analogs significantly decreased mean GH and IGF-I levels in patients from NP areas and in HR/VAR− (GH P < .05; IGF-I times the upper limit of normal P < .01) but not in HR/VAR+ group. CONCLUSIONS: Genetic variants potentially inducing functional abnormalities of the aryl hydrocarbon receptor (AHR) pathway are associated with a more severe acromegaly, increased pituitary tumor size, and somatostatin analog resistance in patients living in HR areas.

Clinical management of critically ill patients with Cushing's disease due to ACTH-secreting pituitary macroadenomas: effectiveness of presurgical treatment with pasireotide.

The management of critically ill Cushing's disease (CD) patients is extremely challenging. Pasireotide is indicated for the treatment of CD patients when pituitary surgery is unfeasible or has not been curative, but no data are available about the use of this drug as pre-operative treatment in critically ill patients. We report the effects of presurgical pasireotide therapy in CD patients in whom hypercortisolism caused life-threatening hypokalemia, alkalosis, and cardio-respiratory complications precluding surgical approach. Clinical, biochemical, and radiological data of two critically ill patients with ACTH-secreting pituitary macroadenoma, before and during first-line presurgical pasireotide treatment (600 µg s.c. bid). During the first 21 days of treatment, pasireotide therapy induced a rapid, partial decrease of plasma ACTH, serum cortisol, and urinary free cortisol levels, with the consequent normalization of serum potassium concentration and arterial blood gases parameters, in both the patients. They did not experience unmanageable side effects and underwent endoscopic transsphenoidal surgery after 4 weeks of effective treatment. Pre-operative MRI evaluation did not show pituitary tumor shrinkage. Surgical cure of CD was obtained in the first patient, while debulking allowed the pharmacological control of hypercortisolism in the second case. We suggest that pasireotide can induce a rapid improvement of clinical and metabolic conditions in critically ill CD patients in whom surgical approach is considered hazardous and need to be delayed.

Effect of a structured, active, home-based cancer-treatment program for the management of patients on oral chemotherapy.

INTRODUCTION: The advent of oral chemotherapy agents has had a strong impact on several aspects of the management of cancer patients, including survival rates, health-care expenditure, and health-related quality of life. However, access to care and adherence to oral chemotherapy are central to optimal outcomes. PATIENTS AND METHODS: In this multicenter observational study, we assessed the effect of the "Active Home Care" initiative - a structured, active, home-based cancer-treatment program - on quality of life, health-care utilization, and patient adherence and satisfaction using self-administered questionnaires. Sixty-two patients treated with oral chemotherapy (capecitabine, vinorelbine, imatinib, sunitinib, sorafenib, temozolomide, ibandronate) were enrolled in the program. Weekly home visits were scheduled, each one with a trained nurse who delivered the home-based chemotherapy and reviewed patients' compliance and treatment toxicity. An oncologist evaluated patients and modified the dosage of oral chemotherapy based on toxicity reported during the previous cycle at bi-weekly visits. RESULTS: A total of 460 home visits were performed between April 2012 and February 2013. The Active Home Care initiative was associated with significant improvements in physical functioning and symptoms, and reductions in the access to cancer facilities. Satisfaction with oral chemotherapy and care received was high. All patients reported having taken their medications according to their prescription, and no patient reported difficulties in managing the oral chemotherapy regimen. CONCLUSION: The Active Home Care program was associated with improvements in the quality of life of patients and caregivers, better adherence to treatment, and the effective management of therapy and cancer-related symptoms. Home-based cancer treatment may also optimize the utilization of health-care resources.