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Aromatase inhibitors (AI) have become a cornerstone of adjuvant treatment for postmenopausal patients with estrogen receptor (ER)- positive early breast cancer. This chapter reviews the available evidence on endocrine effects of AI. Pharmacological activity of AI produces estradiol suppression, which represents the only known mechanism of action of such drugs, determining both side effects and antineoplastic efficacy. Overall, all third-generation AI (anastrozole, exemestane, letrozole) produce a significant suppression of estradiol levels, but there are some data suggesting that this effect might be less extensive than commonly thought and there are few comparative data to verify whether estradiol suppression varies with different AI. The most frequent side effects, related to estradiol suppression and reported in largescale clinical trials of adjuvant treatment with AI, are gynecological symptoms (less frequent and less severe than with tamoxifen, with the exception of vaginal dryness) and musculoskeletal symptoms (worse than with tamoxifen, which even has a positive effect on bone health). Disorders of lipid metabolism and cardiovascular side effects are less frequent. Among the latter, thromboembolism is less frequent with AI than with tamoxifen. There are many issues still of interest for clinical research on endocrine effects of AI. For example, it seems of utmost importance to verify whether endocrine effects might be predictive of AI efficacy and help to select the patients who can derive the greatest benefit from treatment with these drugs.

To evaluate the hormonal profile in three breast cancer patients who underwent controlled ovarian stimulation in the presence of the aromatase inhibitor letrozole.In IVF University referral center, a case series of three breast cancer patients who underwent controlled ovarian stimulation (COS) with recombinant FSH and letrozole were investigated. Ovulation was induced with hCG (case No. 1) or with GnRH agonist (case No. 2-3). The primary outcome of our study was the detection of progesterone levels in the luteal phase.Very high progesterone values (mean 186.6 ± 43.6 ng/mL) during the luteal phase were recorded in all three cases.High progesterone levels can be related to the use of letrozole independently of the most commonly used trigger regimen. Although progesterone has long been considered a protective factor against breast cancer, several studies have demonstrated that progesterone could expand a transformation-sensitive stem cell population in the mammary glands. The estrogen negative feedback effect on the hypothalamus-pituitary axis and the disruption of steroid biosynthesis and could represent an intriguing reason behind this phenomenon. Our results highlight the need to evaluate further the increase in progesterone levels in the luteal phase in women with breast cancer undergoing COS with letrozole.

The aim of this study was to evaluate the effect of acute human corticotropin (ACTH)-releasing hormone (CRH) administration (100 micrograms, as i.v. bolus) on tumor necrosis factor-alpha (TNF alpha) levels in the inferior petrosal sinuses and in the peripheral blood of 7 patients with Cushing's disease subjected to diagnostic inferior petrosal sinus sampling. Blood samples for ACTH, beta-endorphin (beta-EPH) and TNF alpha were collected from inferior petrosal sinuses and periphery simultaneously. In addition, TNF alpha concentrations were measured after CRH administration (10 nmol/l, 100 nmol/l and 1 mumol/l) in culture medium from primary cultures obtained in 3 of 7 patients. At baseline, plasma ACTH and beta-EPH levels were significantly higher in the inferior petrosal sinus ipsilateral to the ACTH-secreting adenoma than in the contralateral one and in the periphery (p < 0.001) whereas no significant difference was found as far as serum TNF alpha levels were concerned. CRH administration caused a significant increase of ACTH (p < 0.001), beta-EPH (p < 0.01) and TNF alpha (p < 0.01) levels greater in the ipsilateral inferior petrosal sinus than in the contralateral one and in the periphery. In addition, CRH increased ACTH, beta-EPH and TNF alpha levels in the culture medium of three ACTH-secreting tumors at the doses of 100 nmol/l and 1 mumol/l (greater than 300, 200 and 110% of baseline pretreatment incubation levels, respectively). These data suggest that CRH may increase TNF alpha concentrations in the inferior petrosal sinus ipsilateral to the ACTH-secreting adenoma and in the peripheral blood as well. In addition, it stimulated TNF alpha release both in vivo and in vitro. These findings suggest the possibility that an imbalanced intrapituitary TNF alpha production can be detected in ACTH-secreting adenomas.

Epigenetics connects genetic and environmental factors: it includes DNA methylation, histone post-translational modifications and the regulation of chromatin accessibility by non-coding RNAs, all of which control constitutive or inducible gene transcription. This plays a key role in harnessing the transcriptional programs of both innate and adaptive immune cells due to its plasticity and environmental-driven nature, piloting myeloid and lymphoid cell fate decision with no change in their genomic sequence. In particular, epigenetic marks at the site of lineage specific transcription factors and maintenance of cell type-specific epigenetic modifications, referred to as "epigenetic memory", dictate cell differentiation, cytokine production and functional capacity following repeated antigenic exposure in memory T cells. Moreover, metabolic and epigenetic reprogramming occurring during a primary innate immune response leads to enhanced responses to secondary challenges, a phenomenon known as "trained immunity". Here we discuss how stable and dynamic epigenetic states control immune cell identity and plasticity in physiological and pathological conditions. Dissecting the regulatory circuits of cell fate determination and maintenance is of paramount importance for understanding the delicate balance between immune cell activation and tolerance, in healthy conditions and in autoimmune diseases. This article is protected by copyright. All rights reserved.

Purpose: Chemotherapy-induced nausea and vomiting (CINV) is a common adverse event with cancer chemotherapy, despite the availability of effective antiemetic agents. This is a prospective observational study of Italian breast cancer patients treated with anthracycline plus cyclophosphamide (AC), assessed CINV incidence, adherence to national antiemetic guidelines (AIOM 2012), and the relationship with CINV outcomes. Methods: Patients with breast cancer scheduled to receive their first cycle of an AC-based regimen were enrolled at 12 Italian centers and their clinical data prospectively recorded. CINV incidence was assessed from patient diaries after the first chemotherapy cycle. The relationship between guideline adherence and CINV outcomes was examined using multiple logistic regression. Results: The overall incidence rates of nausea and vomiting among 246 evaluable patients were 63.0 and 25.4%, respectively. Most patients received a 5-HT3-RA agent and dexamethasone for acute phase CINV prophylaxis, whereas a triple combination including aprepitant (NK1-RA), consistent with national guidelines, was used in only 45.5% of cases. In the delayed phase, the guideline adherence was 48.8%, while the overall adherence was 43.5%. After adjusting for confounding factors, adherence to antiemetic prophylaxis guidelines was associated with a significant reduction in the odds of three endpoints, namely any nausea, “significant nausea,” and vomiting (OR = 0.49, OR = 0.54, and OR = 0.48, respectively), and a 90% increase in the odds of overall complete protection (OR = 1.90). Conclusions: CINV is still a critical issue in AC-treated patients, despite antiemetic treatment. Non-adherence to antiemetic guidelines may lead to poorer outcomes and indicates the need for strategies to enhance the use of guidelines in clinical practice.

Aim The aim of the study is to analyse whether letrozole (L) and zoledronic acid plus L (ZL) are more effective than tamoxifen (T) as adjuvant endocrine treatment of premenopausal patients with breast cancer with hormone receptor–positive (HR+) tumours. Patients and methods In a phase 3 trial, 1065 premenopausal patients with HR + early breast cancer received triptorelin to suppress ovarian function and were randomly assigned (1:1:1) to adjuvant T, L or ZL for 5 years. Cancer recurrence, second breast or non-breast cancer and death were considered events for the intention-to-treat disease-free survival (DFS) analysis. Results With a 64-month median follow-up and 134 reported events, the disease-free rate at 5 years was 85.4%, 93.2% and 93.3% with T, L and ZL, respectively (overall P = 0.008). The hazard ratio for a DFS event was 0.52 (95% confidence interval [CI], 0.34 to 0.80; P = 0.003) with ZL vs T, 0.72 (95% CI, 0.48 to 1.07; P = 0.06) with L vs T and 0.70 (95% CI, 0.44 to 1.12; P = 0.22) with ZL vs L. With 36 deaths, there was no significant difference in overall survival (P = 0.14). Treatment was stopped for toxicity or refusal in 7.3%, 7.3% and 16.6% patients, and in the safety population, grade 3–4 side-effects were reported in 4.2%, 6.9% and 9.1% patients treated with T, L or ZL, respectively. Conclusion HOBOE study shows that in premenopausal patients with early breast cancer undergoing ovarian function suppression with triptorelin, ZL significantly improves DFS, while worsening compliance and toxicity, as compared with T. ( NCT00412022 )

The introduction of CDK4/6 inhibitors in combination with endocrine therapy (ET) represents the most relevant advance in the management of hormone receptor (HR) positive, HER2-negative metastatic breast cancer over the last few years. This meta-analysis of randomized controlled trials (RCTs) is aimed to better characterize the efficacy of CDK4/6 inhibitors in some relevant subgroups and to test heterogeneity between different compounds with a particular focus on their ability to improve overall survival (OS). Pooled estimates of hazard ratios (HRs) were computed for progression-free survival (PFS), OS, and objective response rate (ORR) analysis in predefined subgroups to better understand treatment effect concerning specific patients’ characteristics. To estimate the absolute benefit in terms of PFS, pooled survival curves were generated by pooling the data of all trials. A total of eight RCTs were included. Adding a CDK4/6 inhibitor to ET is beneficial in terms of PFS, irrespective of the presence or not of visceral metastases, the number of metastatic sites, and the length of the treatment-free interval (TFI). The addition of CDK4/6 inhibitors produces a significant OS improvement, both in aromatase inhibitor (AI)-sensitive (HR 0.75, 95% CI) and AI-resistant patients (HR 0.77, 95% CI [0.67–0.89]). Pooled data from each single drug show that palbociclib remains the only class member not showing a statistically significant HR for OS (HR 0.83, 95% CI [0.68–1.02]).

Purpose To compare the endocrine effects of 6 months of adjuvant treatment with letrozole + triptorelin or tamoxifen + triptorelin in premenopausal patients with early breast cancer within an ongoing phase 3 trial (Hormonal Adjuvant Treatment Bone Effects study). Patients and Methods Prospectively collected hormonal data were available for 81 premenopausal women, of whom 30 were assigned to receive tamoxifen + triptorelin and 51 were assigned letrozole + triptorelin ± zoledronate. Serum 17-β-estradiol (E2), follicle-stimulating hormone (FSH), luteinizing hormone (LH), Δ4-androstenedione, testosterone, dehydroepiandrosterone-sulfate, progesterone, adrenocorticotropic hormone (ACTH), and cortisol were measured at baseline and after 6 months of treatment. For each hormone, 6-month values were compared between treatment groups by the Wilcoxon-Mann-Whitney exact test. Results Median age was 44 years for both groups of patients. Letrozole + triptorelin (± zoledronate) induced a stronger suppression of median E2 serum levels (P = .0008), LH levels (P = .0005), and cortisol serum levels (P < .0001) compared with tamoxifen + triptorelin. Median FSH serum levels were suppressed in both groups, but such suppression was lower among patients receiving letrozole, who showed significantly higher median FSH serum levels (P < .0001). No significant differences were observed for testosterone, progesterone, ACTH, androstenedione, and dehydroepiandrosterone between the two groups of patients. Conclusion Letrozole in combination with triptorelin induces a more intense estrogen suppression than tamoxifen + triptorelin in premenopausal patients with early breast cancer.

Background —The reason why patients with growth hormone (GH) deficiency (GHD) are at increased risk for premature cardiovascular death is still unclear. Although a variety of vascular risk factors have been identified in GHD, little is known regarding vascular reactivity and its contribution to premature arteriosclerosis. Methods and Results —We assessed vascular function in 7 childhood-onset, GH-deficient nontreated patients (age 22±3 years, body mass index [BMI] 25±1 kg/m 2 ) and 10 healthy subjects (age 24±0.4 years, BMI 22±1 kg/m 2 ) by using strain gauge plethysmography to measure forearm blood flow in response to vasodilatory agents. The increase in forearm blood flow to intrabrachial infusion of the endothelium-dependent vasodilator acetylcholine was significantly lower in GH-deficient nontreated patients than in control subjects ( P P P P 2 ) who were receiving stable GH replacement therapy. In these patients, the response to both endothelium-dependent and -independent vasodilators, as well as forearm nitrite and cGMP, release was not different from that observed in normal subjects. Peak hyperemic response to 5-minute forearm ischemia was significantly reduced in GH-deficient nontreated patients (17.2±2.6 mL · dL −1 · min −1 , P −1 · min −1 ) compared with normal subjects (29.5±3.2 mL · dL −1 · min −1 ). Conclusions —The data support the concept that GH plays an important role in the maintenance of a normal vascular function in humans.

The aim of the current study was to evaluate bone metabolism and mass before and after 2 years of GH replacement therapy in adults with childhood or adulthood onset GH deficiency. Thirty-six adults with GH deficiency, 18 with childhood onset, 18 with adulthood onset GH deficiency and 28 sex-, age-, height- and weight-matched healthy subjects entered the study. Biochemical indexes of bone turnover such as serum osteocalcin, serum carboxyterminal telopeptide of type-I procollagen, urinary hydroxyproline/creatinine and deoxypyridinoline/creatinine, of soft tissue formation such as aminoterminal propeptide of type-III and bone mineral density were evaluated. Childhood onset GH deficient patients had significantly decreased bone (osteocalcin: 2.5+/-1.3 vs 6.6+/-4.8 mcg/l, p

OBJECTIVE: The impairment of heart structure and function in adults with childhood onset GH deficiency has been recently described. However, previous echocardiographic studies have reported no differences in cardiac mass and function between adulthood onset GH deficient patients and healthy subjects. DESIGN: The aim of this study was to evaluate cardiac performance in adult patients with childhood and adulthood onset GH deficiency, using equilibrium radionuclide angiography, a method more accurate than echocardiography. PATIENTS: Eleven patients with childhood onset GH deficiency, 9 patients with adulthood onset GH deficiency and 12 age-, gender-, height- and weight-matched healthy subjects entered the study. MEASUREMENTS: All the study population underwent equilibrium radionuclide angiography at rest and during physical exercise. RESULTS: Both childhood and adulthood onset GH deficient patients had an impaired left ventricular systolic performance both at rest (ejection fraction was 55 +/- 6%, 55 +/- 10% and 66 +/- 6% in childhood and adulthood onset GH deficient patients and control group, respectively; P < 0.0001) and during physical exercise (ejection fraction was 54 +/- 9% in childhood onset GH deficient patients, 53 +/- 9% in adulthood onset GH deficient patients and 76 +/- 7% in normal subjects; P < 0.0001). Peak ejection rate was 3.2 +/- 0.8 end-diastolic volume/second, 3.0 +/- 0.6 end-diastolic volume/second and 3.9 +/- 0.8 end-diastolic volume/ second in childhood and adulthood onset GH deficient patients and control group, respectively (P < 0.01). Exercise-induced changes in end-systolic volume were increased in both groups of patients compared with healthy subjects. In contrast, exercise-induced end-diastolic volume changes were not different between GH deficient patients and controls. Resting peak filling rate was 2.6 +/- 0.7 end-diastolic volume/second, 2.5 +/- 0.7 end-diastolic volume/ second and 3.1 +/- 0.3 end-diastolic volume/second in the 2 groups of patients and healthy subjects, respectively (P < 0.05). Reduced exercise tolerance in all patients, as shown by the significantly lower values of peak workload (P < 0.0001), peak rate-pressure product (P < 0.01) and exercise duration (P < 0.0001) was observed. CONCLUSION: Patients affected by GH deficiency have left ventricular systolic dysfunction at rest and during physical exercise, suggesting that GH plays a physiological role in maintaining normal cardiac performance in humans. Furthermore, no difference between childhood and adulthood onset GH deficient patients was found indicating that both group of patients have an impairment of cardiac function.

An isovolumic normal rat heart Langendorff model was used to examine the effects of moderate (15 mmHg) and severe (35 mmHg) mechanical stretch on the time course (from 0 to 60 min) of myocardial expression of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and insulin-like growth factor (IGF)-1 and their cognate receptors. After 10 min of moderate stretch, TNF-alpha was de novo expressed, whereas constitutive IL-6 and IGF-1 levels were slightly upregulated; no further changes occurred up to 60 min. In comparison, severe stretch resulted in a higher and progressive increase in TNF-alpha, IL-6, and IGF-1 expression up to 20 min. After 20 min, whereas TNF-alpha expression further increased, IL-6 and IGF-1 levels progressively reduced to values lower than those observed under moderate stretch and in unstretched (5 mmHg) control myocardium (IL-6). Mechanical stretch did not significantly alter the expression of the cognate receptors. Indeed, the TNF-alpha receptor (p55) tended to be progressively upregulated under severe stretch over time. The current data provide the first demonstration that TNF-alpha, IL-6, and IGF-1 ligand-receptor systems are differentially expressed within the normal rat myocardium in response to graded mechanical stretch. Such findings may have potential implications with regard to compensatory hypertrophy and failure.