Carcinoid Syndrome. Preclinical Models and Future Therapeutic Strategies

Carcinoid syndrome represents a debilitating paraneoplastic disease, caused by the se- cretion of several substances, occurring in about 10–40% of patients with well-differentiated neu- roendocrine tumors (NETs). The main signs and symptoms associated with carcinoid syndrome are flushing, diarrhea, hypotension, tachycardia, bronchoconstriction, venous telangiectasia, dyspnea and fibrotic complications (mesenteric and retroperitoneal fibrosis, and carcinoid heart disease). Although there are several drugs available for the treatment of carcinoid syndrome, the lack of therapeutic response, poor tolerance or resistance to drugs are often reported. Preclinical models are indispensable tools for investigating the pathogenesis, mechanisms for tumor progression and new therapeutic approaches for cancer. This paper provides a state-of-the-art overview of in vitro and in vivo models in NETs with carcinoid syndrome, highlighting the future developments and therapeutic approaches in this field

Predictors of Response and Survival to Multikinase Inhibitors in Radioiodine Resistant Differentiated Thyroid Cancer

Sorafenib and lenvatinib are the only multikinase inhibitors (MKIs) approved for the treatment of radioactive iodine refractory differentiated thyroid cancer (RR-DTC). Although they have been demonstrated to improve progression free survival and overall response rate, the risk of toxicities is very high, worsening patients’ quality of life. Therefore, predicting MKI treatment outcomes in the setting of RR-DTC is very challenging for optimizing patients’ management. The current review provides an overview of the predictive factors for the response and survival of sorafenib and lenvatinib in RR-DTC. In this setting, a systemic therapy should be considered after conducting a multidisciplinary discussion aimed at evaluating the risk-benefit ratio of the treatment and taking into account several clinical, biochemical, and molecular factors. Age, performance status, and cancer-related symptoms are the most important clinical markers to be considered prior to starting MKI treatment, together with tumor burden. Some tissue and circulating biomarkers have been investigated, those involved in the angiogenic pathways being the most promising. Finally, prospective clinical trials aimed at evaluating predictive markers for therapeutic response are needed for tailoring patient management and allowing more appropriate treatment choices

Epicardial Adipose Tissue: A Novel Potential Imaging Marker of Comorbidities Caused by Chronic Inflammation

The observation of correlations between obesity and chronic metabolic and cardiovascular diseases has led to the emergence of strong interests in “adipocyte biology”, in particular in relation to a specific visceral adipose tissue that is the epicardial adipose tissue (EAT) and its pro-inflammatory role. In recent years, different imaging techniques frequently used in daily clinical practice have tried to obtain an EAT quantification. We provide a useful update on comorbidities related to chronic inflammation typical of cardiac adiposity, analyzing how the EAT assessment could impact and provide data on the patient prognosis. We assessed for eligibility 50 papers, with a total of 10,458 patients focusing the review on the evaluation of EAT in two main contexts: cardiovascular and metabolic diseases. Given its peculiar properties and rapid responsiveness, EAT could act as a marker to investigate the basal risk factor and follow-up conditions. In the future, EAT could represent a therapeutic target for new medications. The assessment of EAT should become part of clinical practice to help clinicians to identify patients at greater risk of developing cardiovascular and/or metabolic diseases and to provide information on their clinical and therapeutic outcomes

The Dark Side of Ultrasound Imaging in Parathyroid Disease

The diagnosis of parathyroid diseases by imaging still has some intrinsic technical limitations due to the differential diagnosis of different structures of the neck that mimic the parathyroid glands. In this view, ultrasound (US) is an established, low-cost, and non-invasive imaging technique that still represents the first-line approach for evaluating patients with parathyroid disease. The objective of this article is to provide a comprehensive review of the applications of USs in clinical practice, discussing the histopathological and US characteristics of the parathyroid glands in normal and pathological conditions, the advantages of preoperative imaging, and novel updates on the most useful and currently available multiparameter US techniques

Impact of Sarcopenia and Inflammation on Patients with Advanced Non-Small Cell Lung Cancer (NCSCL) Treated with Immune Checkpoint Inhibitors (ICIs): A Prospective Study

Background: Sarcopenia is a condition characterized by loss of skeletal muscle mass associated with worse clinical outcomes in cancer patients. Data on sarcopenia in patients undergoing immune checkpoint inhibitors (ICI) therapy are still limited. The aim of this prospective observational study was to investigate the relationship between sarcopenia, ICI treatment response and immunological profile, in patients with advanced non-small cell lung cancer (NSCLC). Methods: Forty-seven stage IV NSCLC patient candidates for starting ICI, were enrolled from the Policlinico Umberto I outpatient Oncology. Patients underwent baseline blood test, inflammatory markers, cytokine assessment and body composition with dual-energy X-ray absorptiometry (DXA). Sarcopenia was defined with appendicular skeletal muscle mass over height2 (ASM/heigh2). Results: Overall, 19/47 patients (40.4%) results were sarcopenic. Sarcopenic patients showed significantly shorter PFS than non-sarcopenic ones (20.3 weeks, 95% CI 7.5–33.1 vs. 61 weeks, 95% CI 22.5–99.4, p = 0.047). Specifically, they had an 8.1 times higher risk of progression disease (PD) than non-sarcopenic patients (OR 8.1, 95%, p = 0.011). Conclusions: Sarcopenic patients showed worse PFS and had a higher risk of PD compared to non-sarcopenic ones. Therefore, sarcopenia may reflect the increased metabolic activity of more aggressive tumors, which involves systemic inflammation and muscle wasting and could be considered a negative predictive factor for ICI response

Circulating natural killer cells as prognostic value for non-small-cell lung cancer patients treated with Immune checkpoint inhibitors: correlation with sarcopenia

Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of tumors. Natural killer (NK) cells can play an important role in cancer immune surveillance. The aim of this prospective observational study was to analyze peripheral blood mononuclear cells (PBMCs) in patients with advanced non-small-cell lung cancer (NSCLC) receiving ICIs in order to identify predictive factors for better survival outcomes. Methods: Forty-seven stage IV NSCLC patients were enrolled. Patients underwent baseline (T0) and longitudinal (T1) evaluations after ICIs. Peripheral immune blood cell counts were analyzed using flow cytometry. Results: Basal levels of CD3−CD56+ NK cells were higher in patients with controlled disease (DC) compared to progression disease (PD) patients (127 cells/µL vs. 27.8 cells/µL, p < 0.001). Lower NK cell values were independent prognostic factors for shorter overall survival (OS) (HR 0.992; 95% CI 0.987–0.997, p < 0.001) and progression-free survival (PFS) (HR 0.988; 95% CI 0.981–0.994, p < 0.001). During the longitudinal evaluation, CD3−CD56+ NK cells (138.1 cells/µL vs. 127 cells/µL, p = 0.025) and CD56bright NK cells (27.4 cells/µL vs. 18.1 cells/µL, p = 0.034) significantly increased in the DC group. Finally, lower values of CD3−CD56+ NK cells (28.3 cells/µL vs. 114.6 cells/µL, p = 0.004) and CD56dim NK cells (13.2 cells/µL vs. 89.4 cells/µL, p < 0.001) were found in sarcopenic patients compared to patients without sarcopenia. Conclusions: Peripheral NK cells could represent a non-invasive and useful tool to predict ICI therapy response in NSCLC patients, and the association of low NK cell levels with sarcopenia deserves even more attention in clinical evaluation

NETest: a systematic review focusing on the prognostic and predictive role

The NETest is a standardized and reproducible liquid biopsy for neuroendocrine tumors (NETs). It evaluates the expression of 51 NET genes by real-time polymerase chain reaction, providing an accurate molecular profile of the neoplasm. Diagnostic utility of NETest has been widely demonstrated, while its role in predicting prognosis and treatment response is less studied. This systematic review aims to collect and discuss the available evidence on the prognostic and predictive role of NETest, trying to answer 3 questions, frequently raised in clinical practice. Is NETest able to differentiate stable from progressive disease? Increased NETest levels (at least >40%) correlate with disease progression. Is NETest able to predict tumor progression and tumor response to treatment? Some studies demonstrated that the baseline NETest score >33–40% could predict tumor progression. Moreover, NETestperformed after treatment (as peptide receptor radionuclide therapy) could predict treatment response also before radiological findings, since the decrease or stability of NETest score predicts tumor response to treatment. Is NETest able to evaluate tumor recurrence risk after surgery? NETest can predict surgical treatment outcome detecting minimal residual disease after radical surgery, which is characterized by a lower but positive NETest score (20–40%), while a higher score (>33–40%) is associated with nonradical surgery. In conclusion, in addition to its demonstrated diagnostic role, this systematic review highlights the efficacy of NETest to assess disease status at the moment of the NETest execution and to predict tumor recurrence after surgery. The efficacy for other applications should be proven by additional studies