C-Cell Hyperplasia and Cystic Papillary Thyroid Carcinoma in a Patient with Type 1B Pseudohypoparathyroidism and Hypercalcitoninaemia: Case Report and Review of the Literature.

Hypercalcitoninaemia has been described in patients with pseudohypoparathyroidism (PHP) type 1A and 1B. Elevated calcitonin levels are thought to result from impaired Gsα receptor signaling, leading to multiple hormone resistance. Evidence on the risk of medullary thyroid carcinoma (MTC) or C-cell hyperplasia in PHP patients with hypercalcitoninaemia is lacking. A 43-year-old Caucasian man was referred to our endocrinology clinic for chronic hypocalcemia associated with elevated serum parathormone levels and a single cystic thyroid nodule. The patient did not show skeletal deformities, and screening for concomitant hormone resistances was negative, except for the presence of elevated serum calcitonin levels. The workup led to a molecular diagnosis of sporadic PHP1B. Fine needle aspiration of the thyroid nodule was not diagnostic. The calcium stimulation test yielded an abnormal calcitonin response. Given the scarcity of data on the risk of thyroid malignancy in PHP and calcium stimulation test results, total thyroidectomy was performed. Histological examination revealed cystic papillary thyroid cancer in a background of diffuse C-cell hyperplasia. To our knowledge, we are the first to describe a rare form of thyroid cancer combined with C-cell hyperplasia in a patient with PHP and hypercalcitoninaemia. In the present case, a mere receptor resistance might not fully explain the elevated calcitonin levels, suggesting that hypercalcitoninaemia should be carefully evaluated in PHP patients, especially in the case of concomitant thyroid nodules. Further studies on larger cohorts are needed to elucidate this topic.

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.

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.

Carcinoid Syndrome: Preclinical Models and Future Therapeutic Strategies.

Carcinoid syndrome represents a debilitating paraneoplastic disease, caused by the secretion of several substances, occurring in about 10-40% of patients with well-differentiated neuroendocrine 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.

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.

Phytotherapic approach in menopause: light and darkness.

INTRODUCTION: Menopause is a critical period of the woman life, characterized by a peculiar modification in estrogens concentration and accompanied by different signs and symptoms. To prevent and contrast unfavorable consequences of menopause, different therapeutic approaches could be evaluated. The hormone replacement therapy (HRT) is the most known, but it has several contraindications. The increasing interest in phytotherapy introduces the necessity for endocrinologist involved in menopause to suggest different therapeutic approaches, considering the state of health of patient and the real efficacy of the drugs. We aim to outline the main phytotherapy treatments to choose in menopause. EVIDENCE ACQUISITION: This review is based on focused research of the current literature on PubMed and Scopus such as research databases. We selected 4120 papers through these keywords: "MENOPAUSE" AND "phytotherapy," "natural therapy," "phytoterapy drugs." Then, the literature was scanned selecting English papers of last 10 years (last research on October 1, 2021), excluding reviews. Separately, two researchers MGT and CP examined and read 212 full selected papers. We included clinical trials and randomized clinical trials written in English and excluded duplicates, animal studies and studies with lack of group of interest, non-relevant outcomes, inappropriate methodology. Retrospective studies, case reports, case series, original articles, brief communications, and letter to the editor were included in our research. We furthermore completed our research by the examination of every study's bibliography. EVIDENCE SYNTHESIS: Phytotherapy involves the use of plants or plant extracts for the treatment of diseases thanks to the activities of their compounds and metabolites. In particular, many of them have an estrogen-like activity and are identified as phytoestrogens, because thanks to their chemical structure are able to bind the estrogen receptors and carry out biological estrogenic or antiestrogenic activities. The supplementing diet with these compounds can ensure an advantage on various aspects of the climacteric syndrome and some of them also have a beneficial impact on cardiovascular risk, bone health and sleep complaint. These substances can be used with safety due to their good tolerability and low rate of side effects. There are no known serious adverse events associated with their consumption, but as a precaution, its use is not recommended during pregnancy and in association with hormonal therapies or in women with hormone responsive cancers. CONCLUSIONS: Phytotherapy must be considered an interesting tool in the treatment of signs and symptoms in selected menopause woman.

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, NETest performed 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.

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.

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.