Effect of pituitary adenoma consistency on surgical outcomes in patients undergoing endonasal endoscopic transsphenoidal surgery.

BACKGROUND: Most pituitary adenomas (PAs) are considered to have a soft tumor consistency. However, there is a non-negligible percentage (5-13%) of tumors presenting or exhibiting a fibrous consistency that would entail a more difficult and complicated surgical excision with higher surgical morbidity and mortality rates. PURPOSE: To analyze the clinical consequences of PA tumor consistency on the surgical outcomes in patients undergoing endonasal endoscopic transsphenoidal (EET) pituitary surgery. METHODS: An ambispective study of patients with PAs operated on through an EET approach in two Spanish tertiary hospitals over the last 12 years. A total of 226 consecutive interventions were carried out in the Neurosurgery Departments of the Hospital Universitario Ramón y Cajal (HURC) and the Hospital Universitario Puerta del Sur by the same neurosurgeon. PAs were grouped into soft (n = 150) and fibrous (n = 76). All patients underwent hormonal and magnetic resonance imaging (MRI) studies before and after surgery. In addition, neurosurgical complications were recorded in each patient. RESULTS: Fibrous adenomas were independently associated with lower resection rates compared to soft adenomas (fibrous gross total resection [GTR] rate 48.7% vs. 76.3%, p < 0.001), even in those adenomas without invasion of the cavernous sinus (Knosp grades 0, I, and II). There were more intraoperative cerebrospinal fluid (CSF) leaks in patients with fibrous PAs. Moreover, fibrous PAs showed higher rates of postoperative hypopituitarism, permanent diabetes insipidus (DI) and postoperative treatments (hormonal treatment and radiotherapy). The excision of a fibrous PA required a longer surgical time (22.5 min more than soft PAs, p = 0.014), regardless of other factors. CONCLUSION: The consistency of the PAs significantly conditions both the results of surgery (lower resections rates), complications (higher incidence of postoperative hypopituitarism, permanent DI), and the prognosis (higher incidence of postoperative treatments) of the patient undergoing EET.

Patterns of proliferation and cell differentiation during hepatic ontogeny in the alpaca.

The liver has multiple functions that change throughout ontogeny. South American camelids (SAC) have unique characteristics related to adaptation to extreme environments and metabolism. However, the process of hepatic cell differentiation has not been studied in any SAC. We study the patterns of cell differentiation and proliferation in the liver of the alpaca at different times of the ontogeny, excluding the hematopoietic components. Immunohistochemical techniques were performed in 66 specimens, including embryos, fetuses, neonates and adults. Supplementary analyses were performed by lectinhistochemistry. The hepatocytic differentiation was performed by the identification of Hepatocyte (Clone: ​​OCH1ES Dako®). It began in the specimens of 1.8-2.5 cm of crown to rump length (CRL), from Days 25-29 (ovulation = Day 0), continued during gestation and intensified towards its end. The cholangiocytic differentiation was performed by the identification of cytokeratin 7 (CK7, Dako®). It was manifested at the final of gestation (specimens of 28.4 cm CRL, from Day 223 onwards). Parenchymal cells underwent a process of gradual differentiation (differentiation of hepatocytes preceded that of cholangiocytes). Cell proliferation was observed along gestation using the nuclear proliferation antigen (PCNA) and Ki-67. Hepatic organogenesis in the alpacas shares similar differentiation and proliferation mechanisms with other altricial, but phylogenetically distant, species.

Pheochromocytoma: A three-decade clinical experience in a multicenter study.

OBJECTIVE: To analyze the clinical and analytical features, diagnostic tests, therapies, and outcomes of pheochromocytoma (PCC). DESIGN AND METHODS: A multicenter retrospective study in surgically treated patients with PCC followed in 3 Spanish tertiary referral hospitals. RESULTS: A total of 106 patients (61 [57.5%] women, mean age 52.3 ±â€¯14.8 years) were evaluated. At diagnosis, PCC was symptomatic in 62% and sporadic in 83%. Patients with familial PCC were significantly younger than those with sporadic disease (40.8 ±â€¯14.2 years vs 54.5 ±â€¯13.9 years, p < .001). Familial PCCs were more frequently associated with MEN2A (n = 8). Levels of 24-h urinary fractionated metanephrines were positively related to tumor size. The maximum tumor diameter was 4.3 cm (3-6 cm); 27.7% of the patients had tumors ≥6 cm. Incidental PCCs were significantly smaller than symptomatic PCCs (3.4 cm [2.4-5.0 cm] vs 5.6 cm [4.0-7.0 cm], p < .001). Scintigraphy by ¹²³I-metaiodobenzylguanidine showed a high sensitivity (81.9%). Preoperative alpha blockade with phenoxybenzamine was used in 93.6% and doxazosin in the rest. Laparoscopic surgery was used in 2/3 of the patients, with a low conversion (1.9%) to open surgery. Perioperative complications appeared in approximately 20% of patients, mainly hypertensive crisis (9.4%). Recurrent disease appeared in 10%, and malignant PCC was uncommon (6.3%). CONCLUSIONS: PCCs surgically treated in Spain are usually large, symptomatic, and sporadic tumors diagnosed around the sixth decade of life. Hereditary PCC is usually associated with MEN2A. The main type of surgical technique used is laparoscopic surgery, and the prevalence of metastatic PCC is low.

Pheochromocytoma: A three-decade clinical experience in a multicenter study. / Feocromocitoma: experiencia clínica de tres décadas en un estudio multicéntrico.

OBJECTIVE: To analyze the clinical and analytical features, diagnostic tests, therapies, and outcomes of pheochromocytoma (PCC). DESIGN AND METHODS: A multicenter retrospective study in surgically treated patients with PCC followed in 3 Spanish tertiary referral hospitals. RESULTS: A total of 106 patients (61 [57.5%] women, mean age 52.3 ± 14.8 years) were evaluated. At diagnosis, PCC was symptomatic in 62% and sporadic in 83%. Patients with familial PCC were significantly younger than those with sporadic disease (40.8 ± 14.2 years vs. 54.5 ± 13.9 years, p<.001). Familial PCCs were more frequently associated with MEN2A (n=8). Levels of 24-h urinary fractionated metanephrines were positively related to tumor size. The maximum tumor diameter was 4.3cm (3-6cm); 27.7% of the patients had tumors ≥6cm. Incidental PCCs were significantly smaller than symptomatic PCCs (3.4cm [2.4-5.0cm] vs. 5.6cm [4.0-7.0cm], p<.001). Scintigraphy by 123I-metaiodobenzylguanidine showed a high sensitivity (81.9%). Preoperative alpha blockade with phenoxybenzamine was used in 93.6% and doxazosin in the rest. Laparoscopic surgery was used in 2/3 of the patients, with a low conversion (1.9%) to open surgery. Perioperative complications appeared in approximately 20% of patients, mainly hypertensive crisis (9.4%). Recurrent disease appeared in 10%, and malignant PCC was uncommon (6.3%). CONCLUSIONS: PCCs surgically treated in Spain are usually large, symptomatic, and sporadic tumors diagnosed around the sixth decade of life. Hereditary PCC is usually associated with MEN2A. The main type of surgical technique used is laparoscopic surgery, and the prevalence of metastatic PCC is low.

Results of a nationwide survey on multidisciplinary teams on thyroid cancer in Spain.

AIM: There is an important lack of knowledge as to the functioning of multidisciplinary teams on thyroid cancer in current clinical practice. We aimed to retrieve data on the composition, structure, and procedures developed by the multidisciplinary units of thyroid cancer in Spain. METHODS: A nationwide survey consisting of questions about composition, structure, and functioning of multidisciplinary teams was designed. It was available online from November 15, 2017 to February 15, 2018. RESULTS: Seventy-two multidisciplinary units responded to our survey. Of these, 15 (20.8%) focused only in thyroid cancer, while 57 (79.2%) included other endocrine disorders or non-endocrine tumors. The median (interquartile range) of members of the teams was 11 (9-14). The most frequent medical specialties in the units were endocrinology (100%), surgery (94.4%), pathology (80.6%), radiology (75.0%), nuclear medicine (73.6%), and medical oncology (55.6%). The annual number of patients reviewed by the teams was 40 (20-74). 56.9% of the multidisciplinary teams have elaborated clinical protocols for local use. Apart from clinical case discussions in the meetings, 45.8% of the units included educational activities and 36.1% research subjects. Quality indicators were developed by 22% of the teams. CONCLUSIONS: These results suggest that there are some hopeful signs that international recommendations of having multidisciplinary approach to patients with thyroid cancer are being followed in Spain. This gives us the opportunity to proceed with further studies to analyze the real impact of this high standard of care on patient outcomes.

Pazopanib in pretreated advanced neuroendocrine tumors: a phase II, open-label trial of the Spanish Task Force Group for Neuroendocrine Tumors (GETNE).

BACKGROUND: The management of advanced neuroendocrine tumors (NETs) has recently changed. We assessed the activity of pazopanib after failure of other systemic treatments in advanced NETs. METHODS: This was a multicenter, open-label, phase II study evaluating pazopanib as a single agent in advanced NETs (PAZONET study). The clinical benefit rate (CBR) at 6 months was the primary end point. Translational correlation of radiological response and progression-free survival (PFS) with circulating and tissue biomarkers was also evaluated. RESULTS: A total of 44 patients were enrolled. Twenty-five patients (59.5%) were progression-free at 6 months (4 partial responses, 21 stable diseases) with a median PFS of 9.5 months [95% confidence interval (CI) 4.8-14.1]. The CBR varied according to prior therapy received, with 73%, 60% and 25% in patients treated with prior multitarget inhibitors, prior mTOR inhibitors and both agents, respectively. A nonsignificant increase in PFS was observed in patients presenting lower baseline circulating tumor cell (CTC) counts (9.1 versus 5.8 months; P = 0.22) and in those with decreased levels of soluble-vascular endothelial growth factor receptor-2 (sVEGFR-2) (12.6 versus 9.1 months; P = 0.067). A trend toward reduced survival was documented in patients with VEGFR3 rs307821 and rs307826 missense polymorphisms [hazard ratio (HR): 12.3; 95% CI 1.09-139.2; P = 0.042 and HR: 6.9; 95% CI 0.96-49.9; P = 0.055, respectively]. CONCLUSIONS: Pazopanib showed clinical activity in patients with advanced NETs regardless of previous treatments. Additionally, CTCs, soluble-s VEFGR-2 and VEGFR3 gene polymorphisms constitute potential biomarkers for selecting patients for pazopanib (NCT01280201). CLINICAL TRIAL NUMBER: NCT01280201.

Advances in thyroid cancer treatment: latest evidence and clinical potential.

Advanced thyroid carcinoma is an infrequent tumor entity with limited treatment possibilities until recently. The extraordinary improvement in the comprehension of genetic and molecular alterations involving the RAS/RAF/mitogen-activated protein kinase and phosphatidylinositide 3-kinase/Akt/mammalian target of rapamycin signaling and interacting pathways that are involved in tumor survival, proliferation, differentiation, motility and angiogenesis have been the rationale for the development of new effective targeted therapies. Data coming from phase II clinical trials have confirmed the efficacy of those targeted agents against receptors in cell membrane and cytoplasmic molecules. Moreover, four of those investigational drugs, vandetanib, cabozantinib, sorafenib and lenvatinib, have reached a phase III clinical trial with favorable results in progression-free survival and overall survival in medullary thyroid carcinoma and differentiated thyroid carcinoma. Further analysis for an optimal approach has been conducted according to mutational profile and tumor subtypes. However, consistent results are still awaited and the research for adequate prognostic and predictive biomarkers is ongoing. The following report offers a comprehensive review from the rationale to the basis of targeted agents in the treatment of thyroid carcinoma. In addition, current and future therapeutic developments by the inhibition of further molecular targets are discussed in this setting.

Macroprolactinoma: a diagnostic and therapeutic update.

Prolactinomas are the most common type of pituitary adenomas. Macroprolactinomas are the name used for these tumors when their size is ≥ 1 cm. These tumors commonly cause symptoms due to the excessive production of prolactin as well as complaints caused by tumor mass and compression of neural adjacent structures. Clinical diagnosis and assessment of macroprolactinoma are based on the measurement of serum prolactin concentrations and the morphological evaluation of the pituitary gland by magnetic resonance imaging. Dopamine agonists are the first-line treatment modality, with cabergoline being preferred to bromocriptine, because of its better tolerance and feasibility of administration. Cabergoline therapy has been reported to achieve normalization of prolactin levels and gonadal function and reduction of tumor volume in >50% of patients with macroprolactinoma. Resistance or intolerance to dopamine agonists are the main indications for transsphenoidal adenomectomy in patients with macroprolactinoma. External radiation therapy has been used in patients with poor response to medical and surgical procedures. Clinically significant tumor growth may occur during pregnancy in women with macroprolactinomas, especially if they have not received prior surgical or radiation therapy. Visual fields should be assessed periodically during pregnancy and therapy with dopamine agonists is indicated if symptomatic tumor growth occurs. Cystic and giant prolactinomas as well as the rare cases of malignant prolactinomas have special peculiarities and entail a therapeutic challenge.

Clinical significance of anaemia associated with prolactin-secreting pituitary tumours in men.

BACKGROUND: An association between prolactin-secreting pituitary adenomas and anaemia in male patients has been recently reported. Our aim has been to evaluate the prevalence of anaemia in men with prolactinomas and to assess the relationships between haemoglobin concentrations and pituitary function at diagnosis in these patients. METHODS: In a retrospective analysis, 26 male patients with prolactinomas (22 macroprolactinomas and 4 microprolactinomas) were studied. Blood haemoglobin concentration, haematocrit value and baseline hormonal levels were collected at the time of prolactinoma diagnosis. The presence or absence of partial or total hypopituitarism was also evaluated at diagnosis. Logistic regression analysis was used to assess the presence of anaemia as a function of serum hormone concentrations and pituitary dysfunction. RESULTS: Patient bearing macroprolactinomas showed significant lower haemoglobin concentrations than those found in patients with microprolactinomas (13.5 ± 1.2 g/dl vs. 15.1 ± 0.9 g/dl, p < 0.05). Anaemia (haemoglobin < 13 g/dl) was present in nine (34.6%) patients, all of them with macroprolactinomas. The degree of anaemia was mild (haemoglobin > 11 g/dl) in all patients. No correlation between haemoglobin and serum prolactin was found. Haemoglobin concentration was significantly lower in men with hypogonadism (n = 14) than in eugonadal men. Haemoglobin value was also significantly lower in patients with total hypopituitarism in comparison with patients with partial hypopituitarism (12.4 ± 1.0 g/dl, n = 7 vs. 14.0 ± 1.2 g/dl, n = 13, p = 0.007). The number of affected pituitary axes was found to be related with the presence of anaemia. Logistic regression analysis showed that anaemia was related with FT4 (OR 0.23; 95% CI 0.06-0.81, p = 0.02), cortisol (OR 0.81; 95% CI 0.68-0.96, p= 0.02) and the presence of hypopituitarism (OR 20.0; 95% CI 1.68-238.63, p = 0.02). CONCLUSIONS: Anaemia was found in about a third of men with prolactinomas. Our results also suggest that the presence of anaemia in these patients seems to be associated with panhypopituitarism.

Current treatments in the management of patients with primary hyperparathyroidism.

Primary hyperparathyroidism (PHP) develops as a consequence of autonomous hypersecretion of parathyroid hormone (PTH) by parathyroid glands usually because of a solitary parathyroid adenoma. Parathyroidectomy, a surgical procedure with a high success rate, is currently the treatment of choice. Pathological parathyroid tissue excision can be achieved by surgical and non-surgical ablative therapy. Bilateral cervical surgical exploration performed by an experienced parathyroid surgeon is curative in 95-98% of PHP and is associated with a low complication rate. In some patients, such as those with a single parathyroid adenoma adequately localised in presurgical imaging studies, this type of surgery may be more extensive than is needed. Moreover, the introduction of new intraoperative parathyroid-localising techniques, such as intraoperative PTH measurement and nuclear mapping, has boosted the development of new and less invasive parathyroid surgical techniques. Other non-surgical ablative techniques, such as selective percutaneous ethanol injection and transcatheter ablation of pathological parathyroid tissue, may be adequate in cases in which surgery is contraindicated. Lastly, among the therapeutic alternatives to parathyroidectomy are antiresorptive drugs (bisphosphonates, oestrogens and selective oestrogen receptor modulators) and inhibitors of PTH secretion (calcimimetics). A combination of drugs with diverse mechanisms of action may have a synergistic effect in the symptomatic control of PHP.

Thyroid dysfunction and kidney disease.

Thyroid hormones (TH) are essential for an adequate growth and development of the kidney. Conversely, the kidney is not only an organ for metabolism and elimination of TH, but also a target organ of some of the iodothyronines' actions. Thyroid dysfunction causes remarkable changes in glomerular and tubular functions and electrolyte and water homeostasis. Hypothyroidism is accompanied by a decrease in glomerular filtration, hyponatremia, and an alteration of the ability for water excretion. Excessive levels of TH generate an increase in glomerular filtration rate and renal plasma flow. Renal disease, in turn, leads to significant changes in thyroid function. The association of different types of glomerulopathies with both hyper- and hypofunction of the thyroid has been reported. Less frequently, tubulointerstitial disease has been associated with functional thyroid disorders. Nephrotic syndrome is accompanied by changes in the concentrations of TH due primarily to loss of protein in the urine. Acute kidney injury and chronic kidney disease are accompanied by notable effects on the hypothalamus-pituitary-thyroid axis. The secretion of pituitary thyrotropin (TSH) is impaired in uremia. Contrary to other non-thyroidal chronic disease, in uraemic patients it is not unusual to observe the sick euthyroid syndrome with low serum triodothyronine (T(3)) without elevation of reverse T(3) (rT(3)). Some authors have reported associations between thyroid cancer and kidney tumors and each of these organs can develop metastases into the other. Finally, data from recent research suggest that TH, especially T(3), can be considered as a marker for survival in patients with kidney disease.

Somatostatin analogs in the treatment of medullary thyroid carcinoma.

The medical therapy for advanced or metastatic medullary thyroid carcinoma has not been fully established. Somatostatin analogs have been used with variable success in the therapy of a few patients with medullary thyroid carcinoma. In the present study, we evaluated the effects of somatostatin analog therapy on calcitonin (ct) and carcinoembryonic antigen in patients with advanced medullary thyroid carcinoma. Five patients (2 men and 3 women, aged 35-57 yr) with post-operative recurrent medullary thyroid carcinoma received somatostatin analog therapy for 12 weeks. All had been previously treated with total thyroidectomy and lymphadenectomy. Four of them showed positive uptake in (111)In-pentetreotide scanning. One patient was treated with sc octreotide (100 microg/8 h), 3 patients received im slow release lanreotide (30 mg/14 days), and a further one received im octreotide LAR (30 mg/28 days). Serum samples for ct and carcinoembryonic antigen were obtained at 0, 1, 2, 4, 8 and 12 weeks of therapy. Therapy was well-tolerated in general, with minimal side-effects. One patient died after the first month of therapy because of advanced disease. Another patient showed normalization of his ct and carcinoembryonic antigen concentrations at the second week of therapy, maintaining elevated values thereafter. No clinically relevant changes in serum concentrations of ct and carcinoembryonic antigen were observed in the rest of the patients. One patient with positive (111)In-pentetreotide scan, showed no uptake after somatostatin analog therapy. No significant decrease in the size of metastases was evident in the remaining patients. In conclusion, therapy with different formulations of octreotide and lanreotide does not seem to modify serum concentrations of ct and carcinoembryonic antigen in patients with recurrent medullary thyroid carcinoma.