Clizia Zichi

Role of mineralocorticoid receptors on the hypothalamus-pituitary-adrenal axis in humans.

This clinical review will summarize the available data regarding the role of mineralocorticoid receptors (MRs) on the hypothalamus–pituitary–adrenal (HPA) axis control in physiological and pathological conditions and in the memory processes involved in the control and appraisal of a stress event. MRs are predominantly expressed in the limbic structures, with the hippocampus being the main localization, although MRs are also found at the hypothalamic level. It is known that hyppocampal MRs control the proactive feedback involved in the maintenance of the basal HPA activity, mainly at the nadir of the circadian rhythm. In physiological conditions, the administration of pharmacological doses of both MR antagonists and agonists is able to interact with the HPA activity, modifying the quiescent phase-nadir of the circadian rhythm, although some data in the literature do not support these observations. Also, in a physiological condition such as aging, an enhanced HPA axis activity is found in the time window, when MRs are predominantly occupied by cortisol circulating levels, possibly reflecting an MR impairment in this period of life. In pathology, major depression has been correlated to MR qualitative-quantitative alterations which could reflect differences on psychological and physiological responses, possibly predicting psychopathologies. Most of the remarks reported in this review seem to indicate, in agreement with animal data, a role played by MRs in the delicate control of the HPA axis in humans and the possible predisposition to the development of pathologies in case of their alterations.

Enhanced oxidative stress and platelet activation in patients with Cushing's syndrome.

Cushing Syndrome (CS) is implicated by increased cardiovascular risk (CVR) leading to increased morbidity and mortality. Oxidative stress (OS) and platelet activation (PA) are associated with increased CVR. However, scarce data of OS in CS exist. Our objective was to determine the oxidant–antioxidant balance in CS.

Immunotherapy for Patients with Advanced Urothelial Cancer: Current Evidence and Future Perspectives

In recent years, immunotherapy has produced encouraging results in a rapidly increasing number of solid tumors. The responsiveness of bladder cancer to immunotherapy was first established in nonmuscle invasive disease in 1976 with intravesical instillations of bacillus Calmette-Guérin (BCG). Very recently immune checkpoint inhibitors demonstrated good activity and significant efficacy in metastatic disease. In particular the best results were obtained with programmed death-ligand-1 (PD-L1) and programmed death-1 (PD-1) inhibitors, but many other immune checkpoint inhibitors, including anti-cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) antibodies, are currently under investigation in several trials. Simultaneously other therapeutic strategies which recruit an adaptive immune response against tumoral antigens or employ externally manipulated tumor infiltrating lymphocytes might change the natural history of bladder cancer in the near future. This review describes the rationale for the use of immunotherapy in bladder cancer and discusses recent and ongoing clinical trials with checkpoint inhibitors and other novel immunotherapy agents.

Antiandrogen withdrawal syndrome (AAWS) in the treatment of patients with prostate cancer

Antiandrogen withdrawal syndrome is an unpredictable event diagnosed in patients with hormone-sensitive prostate cancer treated with combined androgen blockade therapy. It is defined by prostate-specific antigen value reduction, occasionally associated with a radiological response, that occurs 4-6 weeks after first-generation antiandrogen therapy discontinuation. New-generation hormonal therapies, such as enzalutamide and abiraterone acetate, improved the overall survival in patients with metastatic castration-resistant prostate cancer, and recent trials have also shown the efficacy of abiraterone in hormone-sensitive disease. In the last few years, several case reports and retrospective studies suggested that the withdrawal syndrome may also occur with these new drugs. This review summarizes literature data and hypothesis about the biological rationale underlying the syndrome and its potential clinical relevance, focusing mainly on new-generation hormonal therapies. Several in vitro studies suggest that androgen receptor gain-of-function mutations are involved in this syndrome, shifting the antiandrogen activity from antagonist to agonist. Several different drug-specific point mutations have been reported. The association of the withdrawal syndrome for enzalutamide and abiraterone needs confirmation by additional investigations. However, new-generation hormonal therapies being increasingly used in all stages of disease, more patients may experience the syndrome when stopping the treatment at the time of disease progression, although the clinical relevance of this phenomenon in the management of metastatic castration-resistant prostate cancer remains to be defined.

Secondary Adrenal Insufficiency: Where Is It Hidden and What Does It Look Like?

Adrenal failure secondary to hypothalamic-pituitary disease is a common although underestimated and underdiagnosed condition, with serious consequences. Corticotropin deficiency can be isolated or more frequently occur in association with other pituitary hormones deficiencies. The most frequent endogenous cause of secondary adrenal insufficiency (SAI) is a tumor of the hypothalamic-pituitary region, usually associated with panhypopituitarism secondary to tumor growth or to its treatment with surgery or irradiation. Less commonly, SAI is due to nontumoral disorders including infiltrative lesions, infective processes, vascular alterations, traumatic brain injury, empty sella or genetic disorders. Finally, long-term administration of exogenous glucocorticoids can determine secondary and/or tertiary hypoadrenalism acting at the hypothalamic level and leading to prolonged suppression of the hypothalamic-pituitary-adrenal axis. It is essential to perform validated diagnostic procedures in order to promptly diagnose hypoadrenalism so as to prevent an adrenal crisis. At the same time, diagnosis is complex as no single test has sufficient sensitivity to identify all patients with SAI. Therefore, clinical judgment and follow-up are crucial for the assessment of corticotropin deficiency. Patients with persisting suggestive symptoms and/or a clinical history of higher risk for adrenal insufficiency deserve careful subsequent reassessments.

Role of radiotherapy in improving activity of immune-modulating drugs in advanced renal cancer: Biological rationale and clinical evidences

In the last few years, immune checkpoint inhibitors have been extensively investigated in renal cell carcinoma and led to remarkable results. Radiation therapy may increase the activity of immune modulating agents through different mechanisms, priming the immune system, recruiting immune cells to the tumor environment, and altering the immunosuppressive effects of the tumor microenvironment. Preclinical studies reported increased loco-regional control when radiation is combined with immune-checkpoint blockade. Moreover, increased systemic disease control has been demonstrated when local radiation is combined with both anti-CTLA-4 and anti-PD-1/PD-L1 inhibitors. Actually, several trials are ongoing testing the activity of radiation therapy in combination with different immune-modulating agents for the treatment of metastatic renal cell carcinoma. The aim of this paper is to focus on the biological rationale of adding radiation therapy to immune-modulating agents in renal cell carcinoma and to review the currently available clinical evidence about the combination of radiotherapy and immunotherapy.

Prognostic impact of the cumulative dose and dose intensity of everolimus in patients with pancreatic neuroendocrine tumors

The aim of this work is to assess if cumulative dose (CD) and dose intensity (DI) of everolimus may affect survival of advanced pancreatic neuroendocrine tumors (PNETs) patients. One hundred and sixteen patients (62 males and 54 females, median age 55 years) with advanced PNETs were treated with everolimus for ≥3 months. According to a Receiver operating characteristics (ROC) analysis, patients were stratified into two groups, with CD ≤ 3000 mg (Group A; n = 68) and CD > 3000 mg (Group B; n = 48). The response rate and toxicity were comparable in the two groups. However, patients in group A experienced more dose modifications than patients in group B. Median OS was 24 months in Group A while in Group B it was not reached (HR: 26.9; 95% CI: 11.0–76.7; P < 0.0001). Patients who maintained a DI higher than 9 mg/day experienced a significantly longer OS and experienced a trend to higher response rate. Overall, our study results showed that both CD and DI of everolimus play a prognostic role for patients with advanced PNETs treated with everolimus. This should prompt efforts to continue everolimus administration in responsive patients up to at least 3000 mg despite delays or temporary interruptions.

Immune-checkpoint inhibitors in previously treated patients with advanced or metastatic urothelial carcinoma: A systematic review and meta-analysis

Immunotherapy represents a new hope for patients with advanced urothelial carcinoma (UC). However, to date, only one of two randomized studies showed a clear survival advantage with these treatments. Aimed to investigate the role of immune-checkpoint inhibitors in patients with platinum progressed metastatic UC we performed a systematic review and meta-analysis of clinical trials to evaluate the efficacy and activity, in terms of Overall Survival (OS) and Objective Response Rate (ORR). Immune checkpoint inhibitors have showed to improve OS compared to chemotherapy in unselected patients (HR 0.80, 95% CI 0.69-0.93, p = 0.003), while the difference was not significant in patients selected for PD-L1 expression (HR 0.72, 95% CI 0.48-1.09, p = 0.12). Pooled probability of response was 0.18 (95% CI 0.16-0.20) in unselected patients and 0.27 (95% CI 0.25-0.32) in PD-L1 selected patients. Immunotherapy results in a significant survival advantage in PD-L1 unselected patients suggesting that PD-L1 expression may not be a reliable marker in previously platinum treated patients.

Metastatic Renal Medullary Carcinoma Treated With Immune Checkpoint Inhibitor: Case Report and Literature Review

Renal medullary carcinoma (RMC) is an uncommon type of kidney cancer. Most patients present with advanced disease at diagnosis, and the prognosis is extremely poor, with a median overall survival of 4 months. RMC is refractory to common target therapies used to treat renal-cell carcinoma. Vascular endothelial growth factor or mammalian target of rapamycin inhibitors demonstrate poor activity. Platinum-based combination chemotherapy provides the best palliative clinical benefit. There is no accepted standard second-line treatment. Greater understanding of the molecular mechanisms of malignancies have led to the development of immunotherapy. In renal-cell carcinoma, nivolumab, an antieprogrammed cell death 1 monoclonal antibody, showed an improvement in median overall survival and overall response rate compared to everolimus as second-line therapy. Because of RMC’s rarity, no prospective studies or large retrospective series are currently available. Only few case reports have reported responses with antieprogrammed cell death 1 immune checkpoint therapy in patients with RMC. This case report describes a clinical and radiologic response in a RMC patient treated with second-line nivolumab.

Chemotherapy-Induced Neutropenia and Outcome in Patients With Metastatic Castration-Resistant Prostate Cancer Treated With First-Line Docetaxel

Micro‐Abstract The aim of the study was to retrospectively investigate the association between chemotherapy‐induced neutropenia and survival in metastatic castration‐resistant prostate cancer (mCRPC) patients receiving first‐line docetaxel treatment. Docetaxel‐induced neutropenia is associated with better overall and progression‐free survival in mCRPC. These findings support the hypothesis that chemotherapy‐induced neutropenia might be a surrogate indicator of the biological activity of chemotherapy in patients with mCRPC. Background: Neutropenia is a common side effect associated with docetaxel use. We retrospectively investigated the association between chemotherapy‐induced neutropenia and survival in metastatic castration‐resistant prostate cancer (mCRPC) patients receiving first‐line docetaxel. Patients and Methods: Metastatic castration‐resistant prostate cancer patients treated with first‐line docetaxel, with known neutrophils value 10 days after first administration, were included in this retrospective analysis. Neutropenia was categorized in Grade 0 to 1 (G0‐1), Grade 2 to 3 (G2‐3), and Grade 4 (G4). Outcome measures were progression‐free survival (PFS) and overall survival (OS). Results: Eighty patients were analyzed. Median PFS was 5.4 months in patients with G0‐1 neutropenia, 6.9 months with G2‐3 neutropenia (hazard ratio [HR] vs. G0‐1, 0.69; 95% confidence interval [CI], 0.35‐1.35; P = .27) and 9.5 months with G4 neutropenia (HR vs. G0‐1, 0.30; 95% CI, 0.16‐0.57; P < .0001). Median OS was 11.6 months in patients with G0‐1 neutropenia, 25.5 months in patients with G2‐3 neutropenia (HR vs. G0‐1, 0.36; 95% CI, 0.16‐0.80; P = .012) and 39.3 months in patients with G4 neutropenia (HR vs. G0‐1, 0.19; 95% CI, 0.09‐0.41; P < .0001). In multivariate analysis, the occurrence of severe neutropenia showed a statistically significant association with OS (HR G4 vs. G0‐1, 0.14; 95% CI, 0.03‐0.67; P = .013; HR G2‐3 vs. G0‐1, 0.42; 95% CI, 0.11‐1.57; P = .20) and PFS (HR G4 vs. G0‐1, 0.28; 95% CI, 0.09‐0.86; P = .03; HR G2‐3 vs. G0‐1, 1.07; 95% CI, 0.38‐2.96; P = .90). Conclusion: Docetaxel‐induced neutropenia is associated with better survival of mCRPC.