Hereditary Syndromes Associated with Pancreatic and Lung Neuroendocrine Tumors.

Pancreatic neuroendocrine tumors (PanNETs) and lung NETs (LNETs) represent a rare but clinically significant subgroup of neoplasms. While the majority is sporadic, approximately 17% of PanNETs and a subset of LNETs develop in the context of monogenic familial tumor syndromes, especially multiple endocrine neoplasia type 1 (MEN1) syndrome. Other inherited syndromes associated with PanNETs include MEN4, von Hippel-Lindau (VHL) syndrome, neurofibromatosis type 1 (NF1), and tuberous sclerosis complex (TSC). These syndromes are highly penetrant and their clinical manifestations may vary even among members of the same family. They are attributed to genetic mutations involving key molecular pathways regulating cell growth, differentiation, and angiogenesis. Pancreatic NETs in hereditary syndromes are often multiple, develop at a younger age compared to sporadic tumors, and are associated with endocrine and nonendocrine tumors derived from multiple organs. Lung NETs are not as common as PanNETs and are mostly encountered in MEN1 syndrome and include typical and atypical lung carcinoids. Early detection of PanNETs and LNETs related to inherited syndromes is crucial, and specific follow-up protocols need to be employed to optimize diagnosis and management. Genetic screening is recommended in childhood, and diagnostic screening starts often in adolescence, even in asymptomatic mutation carriers. Optimal management and therapeutic decisions should be made in the context of a multidisciplinary team in specialized centers, whereas specific biomarkers aiming to identify patients denoted to follow a more aggressive course need to be developed.

The Long Journey towards Personalized Targeted Therapy in Poorly Differentiated Thyroid Carcinoma (PDTC): A Case Report and Systematic Review.

BACKGROUND: Poorly differentiated thyroid carcinoma (PDTC) has an intermediate prognosis between indolent well-differentiated thyroid carcinoma (TC) and anaplastic carcinoma. Herein, we present a case report with a PDTC component, along with a systematic review of the literature. CASE REPORT: We report a case of a 45-year-old man diagnosed with a PDTC component, along with hobnail and tall-cell variant features positive for BRAFV600E mutation, after a total thyroidectomy and neck dissection. Radioactive iodine (RAI)-131 therapy was applied, but an early recurrence led to complementary surgeries. The anti-Tg rise, the presence of new lymph nodes, and the negative whole-bodyradioiodine scan were suggestive of a radioiodine-resistant tumor. Lenvatinib, sorafenib, dabrafenib/trametinib, cabozantinib and radiotherapy were all administered, controlling the tumor for a period of time before the patient ultimately died post-COVID infection. Systematic Review: We searched PubMed, Scopus, and WebofScience to identify studies reporting clinicopathological characteristics, molecular marker expression, and management of non-anaplastic TC with any proportion of PDTC in adult patients. Of the 2007 records retrieved, 82were included in our review (PROSPERO-ID545847). CONCLUSIONS: Our case, together with the systematic review, imply that a combination of molecular-targetedtreatments may be safe and effective in patients with RAI-resistantBRAF-mutated advanced PDTC when surgery has failed to control tumor progression.

When rare diseases crisscross within the same patient: von Hippel-Lindau and type 1 gastric neuroendocrine tumor.

Von-Hippel-Lindau (VHL) is a genetic multisystem disorder characterized by visceral cysts and benign and malignant tumors in various organs. Herein, we present the case of a 23-year-old woman with VHL presenting with multiple gastric neuroendocrine neoplasms (gNENs) type 1 in the context of chronic autoimmune gastritis (CAG). Although gNENs are not acknowledged as a typical entity in VHL patients, in the present case, gNENs were composed of neoplastic cells with clear cytoplasm usually seen in tumors related to VHL disease. We additionally performed a literature review on the presence of neuroendocrine clear cell tumors and report on further cases of clear cell NENs. The present case illustrates that clear-cell transformation in gNENs may be due to the dual genetic background of the patient; the real oncogenic stimulus may be more closely related to CAG than to VHL disease accompanied by an interplay between neoplastic and autoimmune processes. Therefore, close monitoring of patients with clear cell NENs appears to be important before excluding VHL disease, even in the context of phenotypically unrelated diseases.

Primary Pituitary Carcinoids Do Not Exist: A Reappraisal in the Era of Pituitary Neuroendocrine Tumours.

The World Health Organization classification of pituitary tumours, published in 2022, supported a change in the terminology from "pituitary adenoma" to "pituitary neuroendocrine tumour" (PitNET). The neuroendocrine cells represent an integral part of the diffuse neuroendocrine system, including, among others, thyroid C cells, the parathyroid chief cells, and the anterior pituitary. Normal and neoplastic adenohypophyseal neuroendocrine cells have light microscopic, ultrastructural features and an immunoprofile compatible with the neuroendocrine cells and neuroendocrine tumours from other organs. Moreover, neuroendocrine cells of pituitary origin express transcription factors which indicate their cell-lineage origin. Thus, pituitary tumours are now considered as a continuum with other neuroendocrine tumours. PitNETs may occasionally be aggressive. In this context, the term "pituitary carcinoid" has no specific meaning: it either represents a PitNET, or a metastasis to the pituitary gland of a neuroendocrine tumour (NET). An accurate pathological evaluation, combined where necessary with functional radionuclide imaging, can define the origin of the tumour. We recommend that clinicians liaise with patient groups to understand the terminology to define primary tumours of adenohypophyseal cells. It is incumbent upon the responsible clinician to explain the use of the word "tumour" in a given clinical context.

Emerging therapies for advanced insulinomas and glucagonomas.

Pancreatic neuroendocrine neoplasms (panNENs) are rare relatively malignancies that, despite their frequently slow-growing pattern, have the ability to metastasize. Metastatic and/or advanced insulinomas and glucagonomas are functioning panNENs emerging from the pancreas displaying unique peculiarities, depending on their hormonal syndromes and increased malignant potential. Advanced insulinomas management follows usually the panNENs therapeutic algorithm, but some distinctions are well advised together with aiming to control hypoglycemias that occasionally can be severe and refractory to treatment. When first-generation somatostatin analogues (SSAs) fail to control hypoglycemia syndrome, second-generation SSAs and everolimus have to be considered for exploiting their hyperglycemic effect. There is evidence that everolimus is still effective after rechallenge retaining its hypoglycemic effect independently of its antitumor effect that seems to be mediated by different molecular pathways. Peptide receptor radionuclide therapy (PRRT) constitutes a promising therapeutic option for both its antisecretory and antitumoral action. Similarly, advanced and/or metastatic glucagonomas management also follows the panNENs therapeutic algorithm, but the clinical syndrome has to be addressed by aminoacid infusion and by first-generation SSAs to improve the patient performance status. PRRT seems to be an effective treatment when surgery and SSAs fail. The application of these therapeutic modalities has been shown to be efficacious in controlling the manifestations of the secretory syndrome and prolonging the overall survival of patients suffering from these malignancies.

Surgical Treatment of Solitary Metachronous Adrenal Metastasis from Urothelial Carcinoma of the Urinary Bladder.

Urothelial cancer is a common neoplasm and metastatic disease correlates with a poor prognosis. Isolated adrenal gland metastases of urothelial carcinoma are quite rare, and management options can decide a patient's prognosis. Herein we report the case of a 76-year-old man with a metachronous solitary adrenal metastasis from a bladder carcinoma, who underwent adrenalectomy as part of his treatment. Furthermore, we discuss the cases of solitary adrenal metastases of urothelial carcinoma available in the literature, to identify key features to direct appropriate treatment of this rare metastatic site of urothelial cancer and improve prognosis and survival. Still, further prospective studies are needed to design effective therapeutic strategies.

The Role of Somatostatin Analogues in the Control of Diarrhea and Flushing as Markers of Carcinoid Syndrome: A Systematic Review and Meta-Analysis.

BACKGROUND: Somatostatin analogues (SSAs) are the cornerstone of treatment for carcinoid syndrome (CS)-related symptoms. The aim of this systematic review and meta-analysis is to evaluate the percentage of patients achieving partial (PR) or complete response (CR) with the use of long-acting SSAs in patients with CS. METHODS: A systematic electronic literature search was conducted in PubMed, Cochrane, and Scopus to identify eligible studies. Any clinical trials reporting data on the efficacy of SSAs to alleviate symptoms in adult patients were considered as potentially eligible. RESULTS: A total of 17 studies reported extractable outcomes (PR/CR) for quantitative synthesis. The pooled percentage of patients with PR/CR for diarrhea was estimated to be 0.67 (95% confidence interval (CI): 0.52-0.79, I2 = 83%). Subgroup analyses of specific drugs provided no evidence of a differential response. With regards to flushing, the pooled percentage of patients with PR/CR was estimated to be 0.68 (95% CI: 0.52-0.81, I2 = 86%). Similarly, no evidence of a significant differential response in flushing control was documented. CONCLUSIONS: We estimate there is a 67-68% overall reduction in symptoms of CS associated with SSA treatment. However, significant heterogeneity was detected, possibly revealing differences in the disease course, in management and in outcome definition.

New developments and concepts in the diagnosis and management of diabetes insipidus (AVP-deficiency and resistance).

Diabetes insipidus (DI) is a disorder characterised by the excretion of large amounts of hypotonic urine, with a prevalence of 1 per 25,000 population. Central DI (CDI), better now referred to as arginine vasopressin (AVP)-deficiency, is the most common form of DI resulting from deficiency of the hormone AVP from the pituitary. The less common nephrogenic DI (NDI) or AVP-resistance develops secondary to AVP resistance in the kidneys. The majority of causes of DI are acquired, with CDI developing when more than 80% of AVP-secreting neurons are damaged. Inherited/familial CDI causes account for approximately 1% of cases. Although the pathogenesis of NDI is unclear, more than 280 disease-causing mutations affecting the AVP2 protein or AVP V2 receptor, as well as in aquaporin 2 (AQP2), have been described. Although the cAMP/protein kinase A pathway remains the major regulatory pathway of AVP/AQP2 action, in vitro data have also revealed additional cAMP independent pathways of NDI pathogenesis. Diagnosing partial forms of DI, and distinguishing them from primary polydipsia, can be challenging, previously necessitating the use of the water deprivation test. However, measurements of circulating copeptin levels, especially after stimulation, are increasingly replacing the classical tests in clinical practice because of their ease of use and high sensitivity and specificity. The treatment of CDI relies on desmopressin administration, whereas NDI requires the management of any underlying diseases, removal of offending drugs and, in some cases, administration of diuretics. A better understanding of the pathophysiology of DI has led to novel evolving therapeutic agents that are under clinical trial.

Prognostic Biomarkers in Pituitary Tumours: A Systematic Review.

Pituitary tumours (PTs) are the second most common intracranial tumour. Although the majority show benign behaviour, they may exert aggressive behaviour and can be resistant to treatment. The aim of this review is to report the recently identified biomarkers that might have possible prognostic value. Studies evaluating potentially prognostic biomarkers or a therapeutic target in invasive/recurrent PTs compared with either non-invasive or non-recurrent PTs or normal pituitaries are included in this review. In the 28 included studies, more than 911 PTs were evaluated. A systematic search identified the expression of a number of biomarkers that may be positively correlated with disease recurrence or invasion in PT, grouped according to role: (1) insensitivity to anti-growth signals: minichromosome maintenance protein 7; (2) evasion of the immune system: cyclooxygenase 2, arginase 1, programmed cell death protein 1 (PD-1)/programmed death ligand 2, cluster of differentiation (CD) 80/CD86; (3) sustained angiogenesis: endothelial cell-specific molecule, fibroblast growth factor receptor, matrix metalloproteinase 9, pituitary tumour transforming gene; (4) self-sufficiency in growth signals: epidermal growth factor receptor; and (5) tissue invasion: matrix metalloproteinase 9, fascin protein. Biomarkers with a negative correlation with disease recurrence or invasion include: (1) insensitivity to anti-growth signals: transforming growth factor ß1, Smad proteins; (2) sustained angiogenesis: tissue inhibitor of metalloproteinase 1; (3) tissue invasion: Wnt inhibitory factor 1; and (4) miscellaneous: co-expression of glial fibrillary acidic protein and cytokeratin, and oestrogen receptors α36 and α66. PD-1/programmed cell death ligand 1 showed no clear association with invasion or recurrence, while cyclin A, cytotoxic T lymphocyte-associated protein 4, S100 protein, ephrin receptor, galectin-3 , neural cell adhesion molecule, protein tyrosine phosphatase 4A3 and steroidogenic factor 1 had no association with invasion or recurrence of PT. With the aim to develop a more personalized approach to the treatment of PT, and because of the limited number of molecular targets currently studied in the context of recurrent PT and invasion, a better understanding of the most relevant of these biomarkers by well-d esigned interventional studies will lead to a better understanding of the molecular profile of PT. This should also meet the increased need of treatable molecular targets.

On the Centennial of Vitamin D-Vitamin D, Inflammation, and Autoimmune Thyroiditis: A Web of Links and Implications.

The 100th anniversary of the discovery of vitamin D3 (VitD3) coincides with significant recent advances in understanding its mechanism of action along with accumulating knowledge concerning its genomic and nongenomic activities. A close relationship between VitD3 and the immune system, including both types of immunity, innate and adaptive, has been newly identified, while low levels of VitD3 have been implicated in the development of autoimmune thyroiditis (AIT). Active 1,25(OH)2 D3 is generated in immune cells via 1-α-hydroxylase, subsequently interacting with the VitD3 receptor to promote transcriptional and epigenomic responses in the same or adjacent cells. Despite considerable progress in deciphering the role of VitD3 in autoimmunity, its exact pathogenetic involvement remains to be elucidated. Finally, in the era of coronavirus disease 2019 (COVID-19), brief mention is made of the possible links between VitD3 deficiency and risks for severe COVID-19 disease. This review aims to commemorate the centennial of the discovery of VitD3 by updating our understanding of this important nutrient and by drawing up a framework of guidance for VitD3 supplementation, while emphasizing the necessity for personalized treatment in patients with autoimmune thyroid disease. A tailored approach based on the specific mechanisms underlying VitD3 deficiency in different diseases is recommended.

Hobnail Papillary Thyroid Carcinoma, A Systematic Review and Meta-Analysis.

Although papillary thyroid carcinoma (PTC) is considered to have an excellent prognosis, some recently identified more aggressive variants show reduced overall survival rates. Hobnail PTC (HPTC) was newly recognized as one of these aggressive forms, affecting recurrence, metastasis, and overall survival rates. Herein, we performed a systematic review and meta-analysis of studies including cases or case series with patients with HPTC. Furthermore, we included our individual case series consisting of six patients. The pooled mortality rate in the cohort, consisting of 290 patients, was 3.57 (95% CI 1.67−7.65) per 100 person/years. No sex differences could be observed concerning mortality (p = 0.62), but older age and tumor size significantly affected mortality (p = 0.004 and p = 0.02, respectively). The percentage of hobnail cells did not affect mortality (p = 0.97), neither did the presence of BRAF mutations. Classical characteristics such as the presence of extrathyroidal extension (p = 0.001), distant metastases (p < 0.001), and lymph node metastases (p < 0.001) all had a significant impact on mortality. Thus, HPTC appears to correlate with worse overall survival, and all PTC cases should be carefully assessed for this variant.

Adrenal insufficiency and pregnancy.

INTRODUCTION: Adrenal insufficiency is a disorder characterized by the failure of adrenocortical function because of distorted function of hypothalamic-pituitary- adrenal (HPA) axis. Pregnancy is a state of a physiological glucocorticoid excess as the HPA axis is functioning at a higher level. PURPOSE OF REVIEW: The aim of the present review was to shed light on current evidence of adrenal insufficiency management during pregnancy, along with maternal and neonatal outcomes. RECENT FINDINGS: A recent multicenter study under the auspices of the European Network for the Study of Adrenal Tumours (ENSAT) presented real-life data of pregnant women with adrenal insufficiency documenting an increased use of hydrocortisone (or mineralocorticoids when needed according to the level of disorder) replacement treatment, increased rates of caesarean section, preterm delivery and adrenal crises along with peripartum and postpartum complications but no maternal or neonatal fatality. These data were in agreement with those obtained from previously published studies. CONCLUSION: The limited published evidence is in line with the present guidelines as real-life data did not document any increased fatality among pregnant women or newborns. Prospective data with prolonged follow-up are needed to shed more light on appropriate dose adjustments to avoid the risks of under-replacement or over-replacement of glucocorticoid and/or mineralocorticoid drugs and their sequelae. SUMMARY: A recent multicenter study by ENSAT presented real-life data of pregnant women with adrenal insufficiency documenting an increased use of hydrocortisone as replacement treatment during pregnancy, along with an increased rate of caesarean section and preterm delivery, adrenal crises, peripartum and postpartum complications but no maternal or neonatal fatality. These data are in agreement with those of a previously published study and also confirm the statements made by the recent guidelines. Prospective data are needed aiming to develop precise therapeutic protocols during each trimester of pregnancy according to the different causes of adrenal insufficiency.

Age-dependent and sex-dependent disparity in mortality in patients with adrenal incidentalomas and autonomous cortisol secretion: an international, retrospective, cohort study.

BACKGROUND: The association between cortisol secretion and mortality in patients with adrenal incidentalomas is controversial. We aimed to assess all-cause mortality, prevalence of comorbidities, and occurrence of cardiovascular events in uniformly stratified patients with adrenal incidentalomas and cortisol autonomy (defined as non-suppressible serum cortisol on dexamethasone suppression testing). METHODS: We conducted an international, retrospective, cohort study (NAPACA Outcome) at 30 centres in 16 countries. Eligible patients were aged 18 years or older with an adrenal incidentaloma (diameter ≥1 cm) detected between Jan 1, 1996, and Dec 31, 2015, and availability of a 1 mg dexamethasone suppression test result from the time of the initial diagnosis. Patients with clinically apparent hormone excess, active malignancy, or follow-up of less than 36 months were excluded. Patients were stratified according to the 0800-0900 h serum cortisol values after an overnight 1 mg dexamethasone suppression test; less than 50 nmol/L was classed as non-functioning adenoma, 50-138 nmol/L as possible autonomous cortisol secretion, and greater than 138 nmol/L as autonomous cortisol secretion. The primary endpoint was all-cause mortality. Secondary endpoints were the prevalence of cardiometabolic comorbidities, cardiovascular events, and cause-specific mortality. The primary and secondary endpoints were assessed in all study participants. FINDINGS: Of 4374 potentially eligible patients, 3656 (2089 [57·1%] with non-functioning adenoma, 1320 [36·1%] with possible autonomous cortisol secretion, and 247 [6·8%] with autonomous cortisol secretion) were included in the study cohort for mortality analysis (2350 [64·3%] women and 1306 [35·7%] men; median age 61 years [IQR 53-68]; median follow-up 7·0 years [IQR 4·7-10·2]). During follow-up, 352 (9·6%) patients died. All-cause mortality (adjusted for age, sex, comorbidities, and previous cardiovascular events) was significantly increased in patients with possible autonomous cortisol secretion (HR 1·52, 95% CI 1·19-1·94) and autonomous cortisol secretion (1·77, 1·20-2·62) compared with patients with non-functioning adenoma. In women younger than 65 years, autonomous cortisol secretion was associated with higher all-cause mortality than non-functioning adenoma (HR 4·39, 95% CI 1·93-9·96), although this was not observed in men. Cardiometabolic comorbidities were significantly less frequent with non-functioning adenoma than with possible autonomous cortisol secretion and autonomous cortisol secretion (hypertension occurred in 1186 [58·6%] of 2024 patients with non-functioning adenoma, 944 [74·0%] of 1275 with possible autonomous cortisol secretion, and 179 [75·2%] of 238 with autonomous cortisol secretion; dyslipidaemia occurred in 724 [36·2%] of 1999 patients, 547 [43·8%] of 1250, and 123 [51·9%] of 237; and any diabetes occurred in 365 [18·2%] of 2002, 288 [23·0%] of 1250, and 62 [26·7%] of 232; all p values <0·001). INTERPRETATION: Cortisol autonomy is associated with increased all-cause mortality, particularly in women younger than 65 years. However, until results from randomised interventional trials are available, a conservative therapeutic approach seems to be justified in most patients with adrenal incidentaloma. FUNDING: Deutsche Forschungsgemeinschaft, Associazione Italiana per la Ricerca sul Cancro, Università di Torino.

"The past is a different country, they do things differently there": using the SEER data-base to assess prognosis in neuroendocrine tumours.

Neuroendocrine neoplasms (NENs) are still considered to be rare neoplasms, and their epidemiology has been classically studied in large population-based cancer registries. Besides the benefits and the limitations that a cancer registry may have for all the registered cancers, the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Programme, has a number of drawbacks for the study of NENs. The change in management of NENs, either from diagnostic or from therapeutic points of view, the role of the Ki-67 labelling index and introduction of sensitive functional imaging, along with the misclassification of the more benign types of NENs, are the main limitations of the prognostic ability of the SEER data-base, particularly when including older data.

Transcriptomics, Epigenetics, and Metabolomics of Primary Aldosteronism.

INTRODUCTION: Primary aldosteronism (PA) is the most common cause of endocrine hypertension, mainly caused by aldosterone-producing adenomas or hyperplasia; understanding its pathophysiological background is important in order to provide ameliorative treatment strategies. Over the past several years, significant progress has been documented in this field, in particular in the clarification of the genetic and molecular mechanisms responsible for the pathogenesis of aldosterone-producing adenomas (APAs). METHODS: Systematic searches of the PubMed and Cochrane databases were performed for all human studies applying transcriptomic, epigenetic or metabolomic analyses to PA subjects. Studies involving serial analysis of gene expression and microarray, epigenetic studies with methylome analyses and micro-RNA expression profiles, and metabolomic studies focused on improving understanding of the regulation of autonomous aldosterone production in PA were all included. RESULTS: In this review we summarize the main findings in this area and analyze the interplay between primary aldosteronism and several signaling pathways with differential regulation of the RNA and protein expression of several factors involved in, among others, steroidogenesis, calcium signaling, and nuclear, membrane and G-coupled protein receptors. Distinct transcriptomic and metabolomic patterns are also presented herein, depending on the mutational status of APAs. In particular, two partially opposite transcriptional and steroidogenic profiles appear to distinguish APAs carrying a KCNJ5 mutation from all other APAs, which carry different mutations. CONCLUSIONS: These findings can substantially contribute to the development of personalized treatment in patients with PA.

Changing biological behaviour of NETs during the evolution of the disease: progress on progression.

Following improvements in the management and outcome of neuroendocrine neoplasms (NENs) in recent years, we see a subset, particularly of pancreatic NENs, which become more aggressive during the course of the disease. This is reflected by an increase in the Ki-67 labelling index, as a marker of proliferation, which may lead to an occasion of increase in grading, but generally does not appear to be correlated with histologically confirmed dedifferentiation. A systematic review of the literature was performed in PubMed, Cochrane Library, and Embase until May 2020 to identify cases that have behaved in such a manner. We screened 244 articles: only seven studies included cases in their cohort, or in a subset of the cohort studied, with a proven increase in the Ki-67 during follow-up through additional biopsy. In addition to these studies, we have also tried to identify possible pathophysiological mechanisms implicated in advanced NENs, although currently no studies appear to have addressed the mechanisms implicated in the switch to a more aggressive biological phenotype over the course of the disease. Such progression of the disease course may demand a change in the management. Summarising the overall evidence, we suggest that future studies should concentrate on changes in the molecular pathways during disease progression with sequential biopsies in order to shed light on the mechanisms that render a neoplasm more aggressive than its initial phenotype or genotype.

Surgical treatment outcome of primary aldosteronism assessed using new modified diagnostic tests.

PURPOSE: Primary aldosteronism (PA) is the most frequent type of endocrine hypertension. In our previous studies, we introduced two modified diagnostic tests for PA, the post-dexamethasone saline infusion test (DSIT) and the overnight dexamethasone, captopril, and valsartan test (DCVT). In this study, we aimed to validate both tests in respect to the biochemical and clinical response of a cohort of hypertensive patients in pre- and post-surgical setting. METHODS: We retrospectively studied 41 hypertensive patients (16 males), with a median (IQR, range) age of 50 (16, 35-74) years and positive histology for adrenal adenoma. Preoperatively, all patients had a single adenoma on CT and a diagnosis of PA with either DSIT or DCVT. The defined daily dose (DDD) of hypertensive drugs was assessed pre- and postoperatively. DSIT or DCVT and basal ARR were reassessed postoperatively. RESULTS: Two of the 41 patients failed to suppress aldosterone post-surgery, leading to a post-adrenalectomy biochemical cure rate of 95%, while blood pressure was improved in 36 patients, leading to a clinical cure rate of 88% as assessed by the DDD methodology. CONCLUSIONS: The present study was a proof-of-concept process to validate two modified diagnostic tests for PA in clinical practice. These tests, used to diagnose a group of patients with PA, successfully assessed their biochemical cure post-adrenalectomy at rates similar to those reported in the literature.

Currently available treatment options for neuroendocrine liver metastases.

Neuroendocrine neoplasms (NEN) are frequently characterized by a high propensity for metastasis to the liver, which appears to be a dominant site of distant-stage disease, affecting quality of life and overall survival. Liver surgery with the intention to cure is the treatment of choice for resectable neuroendocrine liver metastases (NELM), aiming to potentially prolong survival and ameliorate hormonal symptoms refractory to medical control. Surgical resection is indicated for patients with NELM from well-differentiated NEN, while its feasibility and complexity are largely dictated by the degree of liver involvement. As a result of advances in surgical techniques over the past decades, complex 1- and 2-stage, or repeat liver resections are performed safely and effectively by experienced surgeons. Furthermore, liver transplantation for the treatment of NELM should be anchored in a multimodal and multidisciplinary therapeutic strategy and restricted only to highly selected individual cases. A broad spectrum of interventional radiology treatments for NELM have recently been available, with expanding indications that are more applicable, as they are less limited by patient- and tumor-related parameters, being therefore important adjuncts or alternatives to surgery. Overall, liver-targeted treatment modalities may precede the administration of systemic molecular targeted agents and chemotherapy for patients with liver-dominant metastatic disease; these appear to be a crucial component of multimodal management of patients with NEN. In the present review, we discuss surgical and non-surgical liver-targeted treatment approaches for NELM, each complementing the other, with a view to assisting physicians in optimizing multimodal NEN patient care.

Immunotherapeutics at the spearhead: current status in targeting neuroendocrine neoplasms.

PURPOSE: Recent advances in the field of immunotherapy have significantly prolonged the survival of patients with aggressive carcinomas, but the role of immunotherapy in neuroendocrine neoplasms (NENs) remains to be elucidated. METHODS AND RESULTS: We report a patient diagnosed with a well-differentiated grade 3 pancreatic NEN (pNEN) and type 3 liver metastases who received compassionate nivolumab as a fifth line treatment and achieved a durable partial response of more than 34 months. We have performed a systematic review to the literature on tumor microenvironment and potential biomarkers in the field of NEN including the tumor mutational burden, the tumor infiltrating lymphocytes, the programmed cell death ligand 1, and the mismatch repair system. The potential role of the immune system modulation together with a critical assessment of the recent phase II clinical studies in NEN including monotherapy with anti-PD-1/PD-L1 monoclonal antibodies, and combination therapies including anti-PD-1 along with anti-CTLA-4 monoclonal antibodies are also provided. CONCLUSION: Immunotherapeutics are gaining a post in the field of NENs in cases progressing during the course of the disease, dictating urgently the identification of biomarkers that will enable selection of NEN patients who may benefit from this treatment.

THE GREEK HOSPITAL AND PHARMACIES OF SMYRNA (1723-1922)

From the mid-18th century to the mid-20th century, Greek doctors in Smyrna collaborated with pharmacists, churches, and the city's Greek Orthodox community to create a state of-the-art health network and charitable foundation to serve physical and mental health needs of the local community. At Graekikon Nosokomion o Agios Haralampos (Greek Saint Charalampos Hospital), or the Greek Hospital, every citizen, regardless of origin, language, religion, or economic status, had access to the most appropriate medical and pharmaceutical care. Neighborhood pharmacists complemented this care by administering vaccinations and preparing medicines. Smyrna's pivotal influence on the Greek medical community ended in August 1922, when the Greek Hospital was destroyed during the Catastrophe of Smyrna.