Sunitinib and Evofosfamide (TH-302) in Systemic Treatment-Naïve Patients with Grade 1/2 Metastatic Pancreatic Neuroendocrine Tumors: The GETNE-1408 Trial.

BACKGROUND: Sunitinib (SUN)-induced hypoxia within the tumor could promote the activation of the prodrug evofosfamide (EVO), locally releasing the cytotoxic DNA alkylator bromo-isophosphoramide mustard. SUNEVO, a phase II, open-label, single-arm trial, investigated the potential synergy of SUN plus EVO in advanced progressive pancreatic neuroendocrine tumors (panNETs). METHODS: Systemic treatment-naïve patients with advanced or metastatic, unresectable, grade 1/2 panNETs with a Ki67 ≤20%, received EVO 340 mg/m2 on days 8, 15, and 22 every 4 weeks and sunitinib 37.5 mg/day continuously. The primary endpoint was objective response rate, measured every 8 weeks by RECIST version 1.1. RESULTS: From 2015 to 2018, 17 patients were enrolled. The median age was 62.4 years, 47% had a Ki67 >10%, and 70.6% had liver metastasis. Patients received a median of five and four cycles of SUN and EVO, respectively. After a median follow-up of 15.7 months, 17.6% of patients achieved a complete (n = 1) or partial response (n = 2), and 11 patients had stable disease (64.7%). The median progression-free survival was 10.4 months (95% confidence interval, 2.6-18.0). Treatment-related adverse events (grade ≥3) were observed in 64.7% of the patients, the most frequent being neutropenia (35.3%), fatigue (17.6%), and thrombopenia (11.8%). Treatment discontinuation due to toxicity was reported in 88.2% of the patients. No correlation was found between treatment response and DAXX, ATRX, MEN1, SETD2, and PTEN gene mutations. CONCLUSION: SUN plus EVO had a negative toxicity profile that should be taken into account for further clinical research in advanced panNETs. The combination showed moderate activity in terms of treatment response that did not correlate with somatic mutations. (Clinical trial identification number: NCT02402062) IMPLICATIONS FOR PRACTICE: Addition of hypoxia-activated prodrugs has been proposed as a potential mechanism to overcome tumor resistance to antiangiogenic agents. Sunitinib and evofosfamide, which were widely proposed as a potential synergistic option, showed modest efficacy in pancreatic neuroendocrine tumors (panNETs), reaching a median objective response rate of 17.6% and median progression-free survival of 10.4 months. Treatment response does not correlate with the biomarkers analyzed. The high systemic toxicity, with 88.2% of patients discontinuing the treatment, makes this therapeutic approach unfeasible and encourages future research to overcome panNETs' resistance to antiangiogenic agents with other therapies with a safer profile.

Late Recovery of Parathyroid Function After Total Thyroidectomy: A Case-Control Study.

The clinical characteristics of patients with postoperative hypoparathyroidism who recover parathyroid function more than 12 months after surgery have not been studied. We aimed to evaluate whether the intensity of replacement therapy with calcium and calcitriol is related to the late recovery of parathyroid function. We compared the demographic, surgical, pathological, and analytical features of two groups of patients: cases, i. e., late recovery patients (those who recover parathyroid function>1 year after thyroidectomy, n=40), and controls, i. e., patients with permanent hypoparathyroidism (n=260). Replacement therapy with calcium and calcitriol was evaluated at discharge of surgery, 3-6 months, 12 months, and last visit. No significant differences were found in clinical, surgical, pathological, or analytical characteristics between cases and controls. The proportion of cases who required treatment with calcium plus calcitriol at 12 months was significantly lower than that found in controls (p<0.001). Furthermore, daily calcium and calcitriol doses in controls were significantly higher than those in cases at 3-6 months (p=0.014 and p=0.004, respectively) and at 12 months (p<0.001 and p=0.043, respectively). In several models of logistic regression analysis therapy with calcium and calcitriol at 12 months was negatively related to late recovery of parathyroid function. Although delayed recuperation of parathyroid function after total thyroidectomy is uncommon (13%), follow-up beyond 12 months is necessary in patients with postoperative hypoparathyroidism, especially in those whose needs of treatment with Ca and calcitriol are reducing over time.

Isolated ACTH deficiency induced by cancer immunotherapy: a systematic review.

Immunotherapy with immune checkpoint inhibitor (ICI) monoclonal antibodies has shown to be an effective therapeutic alternative in several malignant tumors. However, adverse effects related to an activation of the immune system may accompany ICI therapy. Among the immune-related adverse events (irAEs) are autoimmune endocrine adverse effects, such as thyroiditis, and hypophysitis. Secondary adrenal insufficiency due to isolated ACTH deficiency (IAD) has also been recently reported to be associated with ICI antibodies. We carried out a systematic review of IAD cases induced by cancer immunotherapy published to date using PubMed's database. We selected 35 articles that reported 60 cancer patients diagnosed with IAD induced by ICI therapy. The prevalence was higher in men (ratio 1.6/1). Mean age at diagnosis was 63.2 ± 11.6 (range,30-87). Melanoma was the tumor most commonly reported (35%) followed by lung (28.3%) and kidney cancer (18.3%). The ICI monoclonal antibody most frequently associated was nivolumab in monotherapy (60%), followed by pembrolizumab (18.3%). Median (IQR) time to develop IAD after starting ICI therapy was 6 (4-8) months. The main symptoms at IAD diagnosis were fatigue (82.8%) and anorexia (67.2%). Hyponatremia (68%) and eosinophilia (31.8%) were the laboratory abnormalities most frequently associated with IAD. Pituitary magnetic resonance imaging (MRI) was normal in most patients (93%). Thyroiditis was the most prevalent (35%) endocrine irAE associated with IAD. In conclusion, ICI-induced IAD is a rare and potentially life-threatening condition that must be taken into account whenever treatment with immunotherapy in cancer patients is started due to their potential serious prognostic implications.

The PALBONET Trial: A Phase II Study of Palbociclib in Metastatic Grade 1 and 2 Pancreatic Neuroendocrine Tumors (GETNE-1407).

LESSONS LEARNED: Palbociclib demonstrated no detectable activity in molecularly unselected and heavily pretreated patients with advanced grade 1/2 pancreatic neuroendocrine tumors. Predictive biomarkers that improve patient selection should be investigated in future studies of palbociclib. BACKGROUND: Palbociclib, a CDK4/6 inhibitor, has shown in vitro activity in pancreatic neuroendocrine tumor (pNET) cell lines. Here we prospectively assessed the activity and safety of palbociclib in monotherapy in metastatic refractory pNETs. METHODS: This was a nonrandomized, open-label, phase II study of patients with metastatic grade (G)1/2 pNETs recruited from 10 centers in Spain. Palbociclib 125 mg was orally administered once daily for 21 of 28 days until disease progression or unacceptable toxicity. RESULTS: Twenty-one patients were included; 52.4% were men, and median age was 57.4 years (range, 37.4-73.4). Patients had previously received a median of three prior lines of systemic therapy (range, 1-10) for advanced disease (somatostatin analogues, 71.4%; sunitinib, 81.0%; everolimus, 47.6%; chemotherapy, 47.6%). Nineteen patients were evaluated for objective response rate (ORR), with a median follow-up of 12.4 months (range, 7.53-19.33). No objective and confirmed responses were observed (0%); 11 (57.9%) patients had stable disease, and 6 of them lasted more than 6 months; 8 (42.1%) patients had disease progression as best response. Median progression-free survival (PFS) was 2.6 months (95% confidence interval [CI], 0-14.4) and median overall survival (OS) was 18.7 months (95% CI, 7.4-29.9; Fig. 1). Most frequent toxicities of any grade were asthenia (76.2%), neutropenia (42.9%), diarrhea (33.3%), and nausea (33.3%). Five (23.8%) patients developed G3-4 neutropenia and two (9.5%) patients developed G3-4 thrombocytopenia. CONCLUSION: Lack of activity was observed with palbociclib as a single agent in molecularly unselected and heavily pretreated patients with advanced G1/2 pNETs.

Diagnosis, treatment and follow-up of patients with acromegaly in a clinical practice setting in Spain: the ACROPRAXIS program Delphi survey.

AIM: The ACROPRAXIS program aims to describe the management of acromegaly in Spain and provide guidance. METHODS: Ninety-three endocrinologists were organized into 13 panels to discuss the practical issues in managing acromegaly. Based on the key learnings, an online Delphi survey with 62 statements was performed, so those statements achieving consensus could be used as guidance. Statements were rated on a 9-point scale (9, full agreement; consensus > 66.6% of response in the same tertile). RESULTS: Ninety-two endocrinologists (98.8%) answered two rounds of the survey (mean age 47.6 years; 59.8% women; median 18.5 years of experience). Consensus was achieved for 49 (79%) statements. DIAGNOSIS: The levels of insulin-like growth factor I (IGFI) is the preferred screening test. If IGFI levels 1-1.3 ULN, the test is repeated and growth hormone (GH) after oral glucose tolerance test (OGTT) is assessed. A pituitary magnetic resonance is performed after biochemical diagnosis. TREATMENT: Surgery is the first treatment choice for patients with microadenoma or macroadenoma with/without optical pathway compression. Pre-surgical somatostatin analogues (SSA) are indicated when surgery is delayed and/or to reduce anaesthesia-associated risks. After unsuccessful surgery, reintervention is performed if the residual tumor is resectable, while if non-resectable, SSA are administered. Follow-up First biochemical and clinical controls are performed 1-3 months after surgery. Disease remission is considered if random GH levels are < 1 µg/L or OGTT is < 1 or ≤ 0.4 µg/L, depending on the assay's sensitivity. CONCLUSION: Current clinical management for acromegaly is homogeneous across Spain and generally follows clinical guidelines.

Giant Prolactinoma in Men: Clinical Features and Therapeutic Outcomes.

The aim of the study was to evaluate the clinical features and long-term therapeutic outcome of giant prolactinoma (gPRLoma) in men and to compare them with those of a group of male patients with non-gPRL macroprolactinomas (non-gPRLomas). A retrospective and multicenter study of gPRLomas in men diagnosed in a 20-year period was performed. Clinical data and treatment outcome were registered. The diagnosis of gPRLoma was established when the maximal tumor diameter was ≥40 mm or the tumor had ≥20 mm of suprasellar extension associated to hyperprolactinemia (PRL>1000 ng/ml). Non-gPRLoma was considered when tumor diameter was ≥ 10 mm and<40 mm associated to hyperprolactinemia (PRL≥200 ng/ml). Twenty-three patients with gPRLoma (age 38.3±13.5 years) followed for at least 3 months (follow-up 87.1±60.5 months, range 3-211 months) were evaluated. A group of 42 patients with non-gPRLoma (age 42±16.6 years; NS; follow-up 89±65.9 months, range 3-222 months; NS) served as a control group. More than half (56.5%) of the gPRLoma patients were younger than 40 years at diagnosis. Visual disturbances were significantly more common in gPRLoma than in non-gPRLoma patients (65.2 vs. 25.6%; p=0.004). Prevalence of hypopituitarism was similar in both groups of patients (73.9% vs. 80.9%; gPRLoma vs non-gPRLoma; NS). Serum PRL concentrations were significantly higher in gPRLoma than in non-gPRLoma patients [median (IR), 3978 ng/ml (1179-9012) vs. 907 ng/ml (428-3119); p<0.001]. Maximum tumor diameter in gPRLomas was 4.8±0.8 cm and 2.4±0.7 cm in non-gPRLoma (p<0.001). All patients were treated with dopamine agonists (DA). Twelve (52.2%) gPRLoma patients and 32 (73.8%) non-gPRLoma patients were treated with DA as monotherapy (p=0.045). Surgery was used in 12 (52.2%) gPRLoma patients and in 12 (28.6%) non-gPRLoma patients (p=0.054). Lastly, radiotherapy was used in 5 (21.7%) gPRLoma patients and in 6 (14.2%) non-gPRLoma patients (NS). At last visit, PRL was similar in both groups of patients [16 ng/ml (4-30) vs. 11 ng/ml (4-25); gPRLomas vs. non-gPRLomas; ns] and tumor size decreased significantly (p<0.001) in both groups of patients. Clinical cure (maintained normoprolactinemia without therapy for>1 year and no radiological evidence of pituitary tumor) was achieved in 2 (8.7%) gPRLoma patients and in 2 (4.8%) non-gPRLoma patients (NS). gPRLomas in men are usually diagnosed at a mean age of 40 years, an age similar to that of non-gPRLomas. The only clinical difference with non-gPRLomas is their greater prevalence of visual disturbances. The therapeutic approaches and tumor outcomes were similar to those obtained in patients with non-gPRLomas. Complete cure in gPRLoma is rare, but similar to that achieved in non-gPRLomas, reached in less than 10% of patients.

Thyroid dysfunction and kidney disease: An update.

Thyroid hormones influence renal development, kidney hemodynamics, glomerular filtration rate and sodium and water homeostasis. Hypothyroidism and hyperthyroidism affect renal function by direct renal effects as well as systemic hemodynamic, metabolic and cardiovascular effects. Hypothyroidism has been associated with increased serum creatinine and decreased glomerular filtration rate. The reverse effects have been reported in thyrotoxicosis. Most of renal manifestations of thyroid dysfunction are reversible with treatment. Kidney disease may also cause thyroid dysfunction by several mechanisms. Nephrotic syndrome has been associated to changes in serum thyroid hormone concentrations. Different forms of glomerulonephritis and tubulointerstitial disease may be linked to thyroid derangements. A high prevalence of thyroid hormone alteration has been reported in acute kidney injury. Thyroid dysfunction is highly prevalent in chronic kidney disease patients. Subclinical hypothyroidism and low triiodothyronine syndrome are common features in patients with chronic kidney disease. Patients treated by both hemodialysis and peritoneal dialysis, and renal transplantation recipients, exhibit thyroid hormone alterations and thyroid disease with higher frequency than that found in the general population. Drugs used in the therapy of thyroid disease may lead to renal complications and, similarly, drugs used in kidney disorders may be associated to thyroid alterations. Lastly, low thyroid hormones, especially low triiodothyronine levels, in patients with chronic kidney disease have been related to a higher risk of cardiovascular disease and all-cause mortality. Interpretation of the interactions between thyroid and renal function is a challenge for clinicians involved in the treatment of patients with thyroid and kidney disease.

Prevalence, Clinical Features, and Natural History of Incidental Clinically Non-Functioning Pituitary Adenomas.

The objective of the study was to assess the prevalence and clinical features of incidentally discovered clinically non-functioning pituitary adenoma (CNFPA) and to analyze its natural history. A multicenter retrospective study in patients diagnosed with incidental CNFPA periodically followed-up in 3 specialized neuroendocrinology units from 1992 to 2015 was performed. Out of a total of 189 CNFPA patients, 57 cases (30.1%; 29 women; age at diagnosis 55.8±16.7 years) were incidental. Most patients (n=55, 96.5%) were diagnosed by magnetic resonance imaging (MRI). A sum of 71.9% (n=41) were macroadenomas; 2 of them (3.5%) were giant adenomas (≥4 cm). Patients with macroadenomas were older than those with microadenomas (59.5±16.7 vs. 46.4±18.1 years, p=0.007). Macroadenomas were more common in men (85.7% vs. 58.6%, p=0.023). Twenty-eight patients (49.1%) showed suprasellar extension; of these, 19 were accompanied by chiasmatic compression. Hypopituitarism was present in 14 (24.6%) patients; which was partial in 13 patients (22.8%) and complete in one patient (1.8%). The gonadal axis was the most frequently affected (n=13, 22.8%). Twenty four patients (42.1%) underwent surgery. Of the non-operated patients, 26 patients could be evaluated morphologically after a median follow-up of 15.5 months (interquartile range, 5.7-32.7 months). No significant changes were found in the maximum tumor diameter at the end of follow-up (1.2±0.6 vs 1.2±0.7 cm). The majority of CNFPAs evaluated (n=23, 88.5%) did not show any changes in size. In 2 cases (7.7%) tumor size decreased, and in one patient (3.8%) increased. In our series of CNFPA patients, approximately one-third were incidental. These tumors were diagnosed by MRI preferably from the 5th decade of life without sex predilection. Most of them were macroadenomas, more commonly diagnosed in men and at an older age, compared to microadenomas. The suprasellar extension with chiasmatic compression and hypopituitarism were frequent at diagnosis. Most of the non-operated incidental CNFPAs remain with stable tumor size over time, growth being an unusual event.

Sleep disturbance in clinical and preclinical scrapie-infected sheep measured by polysomnography.

Neurodegenerative diseases are characterised by neuronal loss and abnormal deposition of pathological proteins in the nervous system. Among the most common neurodegenerative diseases are Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease and transmissible spongiform encephalopathies (TSEs). Sleep and circadian rhythm disturbances are one of the most common symptoms in patients with neurodegenerative diseases. Currently, one of the main objectives in the study of TSEs is to try to establish an early diagnosis, as clinical signs do not appear until the damage to the central nervous system is very advanced, which prevents any therapeutic approach. In this paper, we provide the first description of sleep disturbance caused by classical scrapie in clinical and preclinical sheep using polysomnography compared to healthy controls. Fifteen sheep classified into three groups, clinical, preclinical and negative control, were analysed. The results show a decrease in total sleep time as the disease progresses, with significant changes between control, clinical and pre-clinical animals. The results also show an increase in sleep fragmentation in clinical animals compared to preclinical and control animals. In addition, sheep with clinical scrapie show a total loss of Rapid Eye Movement sleep (REM) and alterations in Non Rapid Eyes Movement sleep (NREM) compared to control sheep, demonstrating more shallow sleep. Although further research is needed, these results suggest that prion diseases also produce sleep disturbances in animals and that polysomnography could be a diagnostic tool of interest in clinical and preclinical cases of prion diseases.

A significant response to sunitinib in a patient with anaplastic thyroid carcinoma.

Anaplastic thyroid cancer (ATC) is a rare disease with an incidence of less than three cases per million of habitants in western countries. ATC accounts for 1-10% of all tumors derived from the thyroid gland. Classic chemotherapy approach based on platinum and anthracyclines regimens have been considered standard for the last decades. Novel multitarget agents have shown promising responses; however, no positive randomized clinical trials are available up to now. To our knowledge, the case we are presenting here is the first reported case showing clinical and visual activity using sunitinib as a salvage treatment in an ATC patient who was not fit to receive systemic chemotherapy treatment.

Hepatic hematopoiesis in the alpaca (Vicugna pacos), a species with development in hypoxic environments.

Hematopoiesis occurs in different anatomical niches throughout the life of the individual. The first hematopoietic extra-embryonic stage is replaced by a intra-embryonic stage that occurs in a region that is adjacent to the dorsal aorta. Then, the prenatal hematopoietic function is continued by the liver and spleen, and later by the bone marrow. The objective of the present work was to describe the morphological characteristics of hepatic hematopoiesis in the alpaca and to analyze the proportion of the hematopoietic compartment of the organ and the cell types, at different times of ontogeny. Sixty-two alpaca samples were collected from the municipal slaughterhouse of Huancavelica, Perú. They were processed by routine histological techniques. Hematoxylin-eosin staining, special dyes, immunohistochemical techniques and supplementary analyses by lectinhistochemistry, were performed. The prenatal liver is an important structure in the expansion and differentiation of hematopoietic stem cells. Their hematopoietic activity was characterized by four stages: initiation, expansion, peak, and involution. The liver started its hematopoietic function at 21 days EGA and it was maintained until shortly before birth. Differences were found in the proportion and morphology of the hematopoietic tissue in the different groups corresponding to each gestational stage.

Therapeutic Management and Long-Term Outcome of Hyperthyroidism in Patients with Antithyroid-Induced Agranulocytosis: A Retrospective, Multicenter Study.

BACKGROUND: Antithyroid drug-induced agranulocytosis (AIA) (neutrophils <500/µL) is a rare but serious complication in the treatment of hyperthyroidism. METHODOLOGY: Adult patients with AIA who were followed up at 12 hospitals in Spain were retrospectively studied. A total of 29 patients were studied. The etiology of hyperthyroidism was distributed as follows: Graves' disease (n = 21), amiodarone-induced thyrotoxicosis (n = 7), and hyperfunctioning multinodular goiter (n = 1). Twenty-one patients were treated with methimazole, as well as six patients with carbimazole and two patients with propylthiouracil. RESULTS: The median (IQR) time to development of agranulocytosis was 6.0 (4.0-11.5) weeks. The most common presenting sign was fever accompanied by odynophagia. All of the patients required admission, reverse isolation, and broad-spectrum antibiotics; moreover, G-CSF was administered to 26 patients (89.7%). Twenty-one patients received definitive treatment, thirteen patients received surgery, nine patients received radioiodine, and one of the patients required both treatments. Spontaneous normalization of thyroid hormone values occurred in six patients (four patients with amiodarone-induced thyrotoxicosis and two patients with Graves' disease), and two patients died of septic shock secondary to AIA. CONCLUSIONS: AIA is a potentially lethal complication that usually appears around 6 weeks after the initiation of antithyroid therapy. Multiple drugs are required to control hyperthyroidism before definitive treatment; additionally, in a significant percentage of patients (mainly in those treated with amiodarone), hyperthyroidism resolved spontaneously.

Clinical relevance of tumor consistency in pituitary adenoma.

PURPOSE: To review the clinical relevance of pituitary adenoma (PA) consistency and its relationship to clinical presentation, radiologic and histopathological characteristics, and surgical outcomes. BACKGROUND: PA consistency is a critical factor influencing operative planning, surgical outcomes, and patient counseling. There is no validated classification of PA consistency in the literature, and there are no current preoperative variables capable of predicting it. REVIEW: We conducted a thorough literature review of the Medline, Embase, Web of Science, and Cochrane Library databases. The inclusion criteria were all articles that described PA consistency and correlated it with preoperative aspects, radiological, pathological, and operative findings, or clinical outcomes. DISCUSSION: Although most authors differentiate easily aspirated (soft) tumors from those that are not (fibrous, might require prior fragmentation), there is no universally accepted PA consistency classification. Fibrous PA tends to be hypointense on T2WI and has lower apparent diffusion coefficient (ADC) values. Fibrous tumors seemed to present higher invasion into neighboring structures, including the cavernous sinus. Several articles suggest that dopamine agonists could increase PA consistency and that prior surgery and radiotherapy also make PA more fibrous. The anatomopathological studies identify collagen as being mainly responsible for fibrous consistency of adenomas. CONCLUSIONS: Preoperative knowledge of PA consistency affords the neurosurgeon substantial benefit, which clearly appears to be relevant to surgical planning, risks, and surgery outcomes. It could also encourage the centralization of these high complexity tumors in reference centers. Further studies may be enhanced by applying standard consistency classification of the PA and analyzing a more extensive and prospective series of fibrous PA.

Hay meadow vibroscape and interactions within insect vibrational community.

Our experiences shape our knowledge and understanding of the world around us. The natural vibrational environment (vibroscape) is hidden to human senses but is nevertheless perceived and exploited by the majority of animals. Here, we show that the vibroscape recorded on plants in a temperate hay meadow is a dynamic low-frequency world, rich in species-specific vibrational signals. The overall vibroscape composition changed throughout the season and also depended on the plant species, as well as on the spatial position of individual plants within the meadow. Within the studied community, vibrationally signaling species sharing this communication channel avoided interference primarily by partitioning vibrational space on a fine temporal scale. The vibroscape is a reliable source of information in the environment and expands our understanding of ecological and evolutionary processes.

Improve teaching with modalities and collaborative groups in an LMS: an analysis of monitoring using visualisation techniques.

Monitoring students in Learning Management Systems (LMS) throughout the teaching-learning process has been shown to be a very effective technique for detecting students at risk. Likewise, the teaching style in the LMS conditions, the type of student behaviours on the platform and the learning outcomes. The main objective of this study was to test the effectiveness of three teaching modalities (all using Online Project-based Learning -OPBL- and Flipped Classroom experiences and differing in the use of virtual laboratories and Intelligent Personal Assistant -IPA-) on Moodle behaviour and student performance taking into account the covariate "collaborative group". Both quantitative and qualitative research methods were used. With regard to the quantitative analysis, differences were found in student behaviour in Moodle and in learning outcomes, with respect to teaching modalities that included virtual laboratories. Similarly, the qualitative study also analysed the behaviour patterns found in each collaborative group in the three teaching modalities studied. The results indicate that the collaborative group homogenises the learning outcomes, but not the behaviour pattern of each member. Future research will address the analysis of collaborative behaviour in LMSs according to different variables (motivation and metacognitive strategies in students, number of members, interactions between students and teacher in the LMS, etc.).

Adenohypophyseal hyperfunction syndromes and posterior pituitary tumors: prevalence, clinical characteristics, and pathophysiological mechanisms.

Posterior pituitary tumors are rare nonneuroendocrine neoplasms originating in the neurohypophysis that lack hormonal secretory capacity. Surprisingly, these tumors are relatively frequently associated with adenohypophyseal syndromes of hormonal hypersecretion such as Cushing's disease and acromegaly. Fifteen cases of posterior pituitary tumor associated with hypercortisolism have been reported to date, 13 of them were pituicytomas (Pi) and 2 were granular cell tumors (GCT). Six patients with posterior pituitary tumor associated with acromegaly have been reported (4 Pi and 2 GCT). The main forms of clinical presentation and the possible pathophysiological mechanisms of this association are reviewed.

The pituitary in nuclear medicine imaging.

The pituitary is an endocrine gland with ability to uptake diverse radiopharmaceuticals and, therefore, susceptible to be investigated by nuclear medicine diagnostic procedures. Although this topic has been scarcely scrutinized, we have data indicating that somatostatin receptor scintigraphy with111In-DTPA-D-Phe-octreotide or 99mTc-EDDA/HYNIC-TOC may be of clinical utility in the diagnosis of some pituitary adenomas (PA). Only a few studies have evaluated the diagnostic performance of 99mTc-MIBI and 99mTc (V)-DMSA scintigraphy in pituitary disease. Scintigraphy using 123I-methoxybenzamide (123I-IBZM) might be useful in macroprolactinomas expressing dopamine D2 receptors. Pituitary gland does not usually accumulate 2-deoxy-2-[18F]fluoro-d-glucose (18F-FDG) and, therefore, it is not visualized on positron emission tomography (PET) imaging studies with this radiotracer. The pituitary uptake on18F-FDG PET/CT scans performed in the follow-up of oncological patients are uncommon. However, 60% of these incidental findings are due to PA, mainly non-functioning pituitary macroadenomas, and a small percentage to metastases or other pituitary lesions. Interestingly, 18F-FDG PET/CT may identify hypophysitis induced by different immunotherapeutic agents used in cancer patients. Positive 18F-FDG uptake has been reported in a high percentage of patients with PA, mainly macroadenomas and it seems that there is correlation between tumor size and SUVmax. 68Ga-DOTA-TATE PET/CT may identify functioning and non-functioning PA, although this technique is more useful in the detection of remaining normal pituitary tissue after transsphenoidal adenomectomy, and in the confirmation of recurrence of functioning PA, such as thyrotroph-secreting PA. Furthermore, 68Ga-DOTA-TATE uptake has potential therapeutic implications on molecular-targeted therapy. Lastly, other radiopharmaceuticals that have shown to be taken up in some patients with pituitary disease include 18F-DOPA (prolactinoma), 11C-methionine (residual or recurrent PA), O-(2-18F-fluoroethyl)-l-tyrosine (metastasis), 18F-choline (silent adenoma, ectopic corticotropinoma), and 13N-ammonia (hypopituitarism).

Posterior pituitary tumours: the spectrum of a unique entity. A clinical and histological study of a large case series.

PURPOSE: In 2017, the WHO established that pituicytoma, granular cell tumour (GCT) and spindle cell oncocytoma (SCO) are posterior pituitary tumours (PPT). Recent data suggests that these tumours probably arise from the pituicytes and may constitute a spectrum of a unique histopathological entity. Our aim is to report the clinical findings and surgical outcomes of 16 patients with PPT. We also evaluated the tissue specimens available in light of current knowledge. METHOD: Cross-sectional study with retrospective data. RESULTS: PPT were 7 pituicytomas, 3 GCT and 6 SCO. Patients mean age was 55 years old and 75% were female. Basal hormonal study showed hyperprolactinemia (43.7%) and hypopituitarism (37.5%). There was no case of diabetes insipidus (DI). MRI showed sellar/suprasellar masses with mean size of 19.7mm. PPT was not suspected in any patient. Fifteen patients underwent surgery and complications were common: 20% had perioperative bleeding (one patient died because of a massive haemorrhage), 57.1% hypopituitarism, 35.7% permanent DI and 21.4% underwent a second surgery. Pathological findings shown positivity for thyroid transcription factor 1, vimentin and negativity for cytokeratin and chromogranin A in all specimens evaluated. S100 protein was positive in 88.8% of tumours. Ki67 was ≥ 3% in 66.6% and ranged from 4-7% in SCO. CONCLUSION: PPT have similar histology, clinical features and are frequently misdiagnosed as nonfunctioning pituitary tumours. However, post-surgical complications including haemorrhage are common. A high clinical suspicion is needed to presume the diagnosis prior surgery and diminish the high morbidity of these tumours.

Thyroid dysfunction induced by nivolumab: searching for disease patterns and outcomes.

PURPOSE: Nivolumab is a monoclonal antibody that blocks the activation of programmed death-1 receptor, promoting T-cell activation against cancer cells. Thyroid dysfunction (TD) is a common immune-related adverse event (irAE) induced by nivolumab. We report the prevalence, patterns and outcomes of nivolumab-induced TD among cancer patients in our center. METHODS: All patients treated with nivolumab during 2016 were included. We assessed thyroid function tests, thyroid autoimmunity, thyroid imaging, and clinical outcome during nivolumab therapy as well as overall survival (OS). RESULTS: Seventy-three patients (55 with non-small-cell lung cancer [NSCLC], 9 with melanoma and 9 with Hodgkin lymphoma) were included. Median of follow up: 390.5 days. Seventeen patients (23.3%) developed TD during treatment. Thyrotoxicosis was reported in seven patients. Serum thyroid-stimulating hormone (TSH) nadir occurred after a median of 51 days (95% CI: 35-71). Thyroid antibodies were positive in three of the seven patients. Five of the seven hyperthyroid patients became hypothyroid later, and four of them required levothyroxine treatment. Primary hypothyroidism occurred in ten patients. Serum TSH peak occurred after a median of 110 days [95% CI: 85.2-197]. Thyroid autoimmunity was positive in one patient. In patients with NSCLC, TD was associated with better OS (HR = 0.4 [95% CI: 0.17-0.94]; p = 0.035). CONCLUSIONS: TD induced by nivolumab is a common and heterogeneous irAE. Thyrotoxicosis develops earlier than hypothyroidism. A pattern consistent with a transient thyroiditis followed by hypothyroidism was observed in one-third of patients. Our results suggest that patients with NSCLC and nivolumab-induced TD might have better survival.