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  • Hypophysitis: An update on the novel forms, diagnosis and management of disorders of pituitary inflammation
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2019-12-12
    Sriram Gubbi; Fady Hannah-Shmouni; Joseph G. Verbalis; Christian A. Koch

    Hypophysitis is a heterogeneous condition that leads to inflammation of the sella and/or suprasellar region, potentially resulting in hormonal deficiencies and/or mass effects. A preponderance of hypophysitis subtypes have an underlying autoimmune aetiology. The overall incidence and prevalence of hypophysitis has dramatically increased over the past decade, mainly due to increased awareness of the condition in the medical community, improvements in imaging techniques, and a rise in the occurrence of certain forms of hypophysitis such as IgG4 hypophysitis (IgG4Hy) and immune checkpoint inhibitor induced hypophysitis (ICIHy). The clinical presentation varies from an asymptomatic condition to a fatal disease often as a result of electrolyte abnormalities due to glucocorticoid deficiency in the context of adrenal crisis from central adrenal insufficiency. Milder forms of hypophysitis are treated with replacement of deficient hormones while more acute presentations with mass effects require glucocorticoid therapy, immunosuppressive therapy or surgery. Timely diagnosis and interventions are keys to prevention of the lethal complications of this disease. In this review, we provide an update on the recent advances in the field of pituitary autoimmunity, with an emphasis on autoimmune hypophysitis and novel forms of hypophysitis such as anti-PIT1 hypophysitis, IgG4Hy and ICIHy.

    更新日期:2019-12-13
  • The aggregation between AITD with rheumatologic, or dermatologic, autoimmune diseases
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2019-12-11
    Poupak Fallahi, Giusy Elia, Francesca Ragusa, Ilaria Ruffilli, Stefania Camastra, Claudia Giusti, Sabrina Rosaria Paparo, Debora Gonnella, Yehuda Shoenfeld, Silvia Martina Ferrari, Alessandro Antonelli

    Autoimmune thyroid diseases (AITD) are organ-specific autoimmune disorders mediated by Th1 lymphocytes, whose main clinical presentations are Hashimoto’s thyroiditis (HT), or Graves’ disease (GD). HT, GD, thyroid autoantibodies and thyroid dysfunctions have been shown in systemic rheumatologic diseases (as Sjögren’s syndrome, systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, or cryoglobulinemia). New associations of AITD with other autoimmune diseases are being discovered, for example with psoriatic arthritis and dermatological diseases. Several investigations suggest the importance of a shared genetic susceptibility and of environmental factors in patients with AITD and associated systemic autoimmunity. A major Th1 autoimmune response occurs in the initial, and/or active phases of organ-specific autoimmune disorders and/or systemic rheumatologic diseases with increased serum, or tissue, expressions of the Th1 chemokine CXCL10. Thyroid dysfunctions might have an important clinical impact, so a periodic thyroid screening in women with systemic or dermatological autoimmunity, overall in presence of thyroid autoantibodies is suggested.

    更新日期:2019-12-11
  • New insight in endocrine-related adverse events associated to immune checkpoint blockade
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2019-12-11
    Giusy Elia, Silvia Martina Ferrari, Maria Rosaria Galdiero, Francesca Ragusa, Sabrina Rosaria Paparo, Ilaria Ruffilli, Gilda Varricchi, Poupak Fallahi, Alessandro Antonelli

    Anticancer immunotherapy, in the form of immune checkpoint inhibition (ICI), is a paradigm shift that has transformed the care of patients with different types of solid and hematologic cancers. The most notable improvements have been seen in patients with melanoma, non-small-cell lung, bladder, renal, cervical, urotherial, and colorectal cancers, Merkel cell carcinoma, and Hodgkin lymphoma. Monoclonal antibodies (mAbs) targeting immune checkpoints (i.e., anti-CTLA: ipilimumab; anti-PD-1: nivolumab, pembrolizumab; anti-PD-L1: durvalumab, atezolizumab, avelumab) unleash the immune system against tumor cells targeting mainly T cells. Treatment with ICIs is associated with a variety of diverse and distinct immune-related adverse events (irAEs), reflecting the mechanistic underpinning of each target (i.e., CTLA-4, and PD-1/PD-L1 network). The most frequent endocrine irAEs associated with anti-PD-1 mAb treatment are thyroid dysfunctions, whereas hypophysitis is mostly linked to anti-CTLA-4 treatment. Type 1 diabetes mellitus and adrenalitis are rare irAEs. Combination therapy (anti-CTLA-4 plus anti-PD-1/PD-L1) can be associated with an increased risk and prevalence of endocrine irAEs. In this paper we discuss the pathophysiological and clinical aspects of irAEs with specific emphasis on endocrine irAEs associated with ICIs. With a growing number of patients treated with ICIs, a tight collaboration among oncologists, endocrinologists and immunologists appears necessary when the circumstances are more challenging and for better management of severe endocrine irAEs. Further investigations are urgently needed to better understand the mechanisms by which different ICIs can induce a variety of endocrine irAEs.

    更新日期:2019-12-11
  • Thyro-entero-gastric autoimmunity: pathophysiology and implications for patient management
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2019-12-11
    Edith Lahner, Laura Conti, Francesco Cicone, Silvia Capriello, Maria Cazzato, Marco Centanni, Bruno Annibale, Camilla Virili

    The association between autoimmune atrophic gastritis and thyroid disorders has been observed since the early 1960s and the expression “thyrogastric syndrome” was coined to indicate the presence of thyroid autoantibodies or autoimmune thyroid disease in patients with pernicious anemia, a late clinical stage of autoimmune atrophic gastritis. More recently, it was confirmed that autoimmune thyroid disorders, in particular Hashimoto’s thyroiditis, may be frequently associated with other organ-specific, immune-mediated disorders, such as autoimmune atrophic gastritis or celiac disease. The association of Hashimoto’s thyroidits with autoimmune atrophic gastritis or celiac disease in adult patients is currently considered part of the polyglandular autoimmune syndromes which include several autoimmune disorders associated with an autoaggressive impairment of endocrine glands. From a clinical point of view, the thyro-entero-gastric autoimmunity may lead to potentially serious consequences like anemia, micronutrients deficiencies, and drugs malabsorption, as well as to an increased risk for malignancies. These alterations may frequently present in an underhand manner, with consequent diagnostic and treatment delays. Many aspects of the association between thyroid, gastric and intestinal autoimmune diseases still await clarification. The present review focuses on the embryological, genetic and pathophysiological aspects of thyro-entero-gastric autoimmunity. In particular, the current diagnostic criteria of autoimmune thyroid disease, autoimmune atrophic gastritis, and celiac disease are reviewed, along with the evidences for their association in poly-autoimmunity syndromes. The benefits of proactive screening of autoimmune thyroid disorders in patients with autoimmune gastritis or enteropathy and viceversa are also discussed.

    更新日期:2019-12-11
  • Prevalence, Diagnosis and Outcomes of Treatment for Primary Aldosteronism
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2019-12-05
    Yuhong Yang, Martin Reincke, Tracy Ann Williams

    Primary aldosteronism (PA) is the most common potentially curable form of hypertension. The overproduction of aldosterone leads to an increased risk of cardiovascular and cerebrovascular events as well as adverse effects to the heart and kidney and psychological disorders. PA is mainly caused by unilateral aldosterone excess due to an aldosterone-producing adenoma or bilateral excess due to bilateral adrenocortical hyperplasia. The diagnostic work-up of PA comprises three steps: screening, confirmatory testing and differentiation of unilateral surgically-correctable forms from medically treated bilateral PA. These specific treatments can mitigate or reverse the increased risks associated with PA. Herein we summarise the prevalence, outcomes and current and future clinical approaches for the diagnosis of primary aldosteronism.

    更新日期:2019-12-05
  • Infertility in women with systemic autoimmune diseases
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2019-12-02
    Jamilya Khizroeva, Cecilia Nalli, Victoria Bitsadze, Andrea Lojacono, Sonia Zatti, Laura Andreoli, Angela Tincani, Yehuda Shoenfeld, Alexander Makatsariya

    Infertility consists by definition in ” failure to achieve a clinical pregnancy after 12 months or more of regular unprotected intercourse” while the term subfertility means a delay to achieve pregnancy. Several factors can contribute to infertility or subfertility in patients with systemic autoimmune diseases. The association of systemic autoimmune conditions with endometriosis, celiac disease and thyroid autoimmunity that are well known causes of infertility and/or subfertility need to be taken in consideration when difficulties in the onset of pregnancy is reported. The majority of the used antirheumatic drugs do not interfere with fertility. However, the use of cyclophosphamide, limited to severe disease, can provoke premature ovarian failure; to preserve fertility a preventive treatment is available. Nonsteroidal anti-inflammatory drugs can cause temporary infertility and corticosteroids are associated to a prolonged time to pregnancy in some rheumatic diseases. Data on the association of antiphospholipid antibodies (aPL) with infertility are still debated but in general an increased rate of aPL is described patients undergoing medically assisted reproductive techniques. In systemic lupus erythematosus aPL and other autoantibodies (i.e. anti-oocytes) can contribute to the infertility of some patients. Subfertility, rather than infertility, is observed in patients with rheumatoid arthritis; the particular physical conditions of these women can also account for this. Physicians should not forget the patients’ age, that is mandatory in order to preserve their chance to have children.

    更新日期:2019-12-02
  • Novel Therapies for Thyroid Autoimmune Diseases: an update
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2019-11-28
    Silvia Martina Ferrari, Poupak Fallahi, Giusy Elia, Francesca Ragusa, Stefania Camastra, Sabrina Rosaria Paparo, Claudia Giusti, Debora Gonnella, Ilaria Ruffilli, Yehuda Shoenfeld, Alessandro Antonelli

    A Th1 immune-preponderance has been shown in the immunopathogenesis of autoimmune thyroiditis (AT), Graves’ disease (GD) and Graves’ Ophthalmopathy (GO), in which the Th1-chemokines (CXCL9, CXCL10, CXCL11), and their (C-X-C)R3 receptor, have a crucial role. Methimazole, and corticosteroids have been shown to modulate these chemokines; several efforts have been done to modulate the autoimmune reaction with other drugs, i.e. PPAR-γ, or -α ligands, or antibodies, or small molecules directed against CXCL10, or CXCR3. Antigen-specific therapy for GD, by inducing T cell tolerance through an immunization with TSH-R peptides, has been published. Drugs targeting cytokines [anti-TNFα (Etanercept), and anti-IL-6 (Tocilizumab)], and RTX (a chimeric monoclonal antibody vs. CD20) have been used in GO, with promising results. Teprotumumab (a human monoclonal anti-IGF-1R blocking antibody) has been investigated in a trial, showing it was very effective in GO patients. Still, more studies are needed for new therapies targeting autoimmune thyroid disorders.

    更新日期:2019-11-28
  • Hashimotos’ Thyroiditis: epidemiology, pathogenesis, clinic and therapy
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2019-11-26
    Francesca Ragusa, Poupak Fallahi, Giusy Elia, Debora Gonnella, Sabrina Rosaria Paparo, Claudia Giusti, Leonid.P. Churilov, Silvia Martina Ferrari, Alessandro Antonelli

    Hashimoto’s thyroiditis (HT), the most frequent autoimmune thyroid disorders (AITDs), is the leading cause of hypothyroidism in the iodine-sufficient areas of the world. About 20-30% of patients suffers from HT, whose cause is thought to be a combination of genetic susceptibility and environmental factors that causes the loss of immunological tolerance, with a consequent autoimmune attack to the thyroid tissue and appearance of the disease. The pathologic features of lymphocytic infiltration, especially of T cells, and follicular destruction are the histological hallmark of autoimmune thyroiditis (AIT), that lead to gradual atrophy and fibrosis. An important role in the immune-pathogenesis of AITDs is due to chemokines and cytokines. In about 20% of patients, AITDs are associated with other organ specific/systemic autoimmune disorders. Many studies have demonstrated the relationship between papillary thyroid cancer (PTC) and AITD. The treatment of hypothyroidism, as result of AIT, consists in daily assumption of synthetic levothyroxine.

    更新日期:2019-11-27
  • Primary Aldosteronism: treatment of the disease, and new therapeutic approaches
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2019-11-26
    John Funder

    Primary aldosteronism is currently considered to represent 5-13% of hypertension, yet fewer than 1% of patients with the disorder are ever diagnosed and treated. Current management of patients screened and confirmed positive for primary aldosteronism involves imaging, and with very few exceptions adrenal venous sampling to lateralize (or not) hyperaldosteronism. Unilateral disease is treated by adrenalectomy: bilateral disease by mineralocorticoid receptor antagonists and conventional antihypertensives as/if required. New therapeutic approaches include (i) routine screening on first presentation for hypertension; (ii) harmonisation of cut-offs for renin and aldosterone, plus use of 24-hour urinary rather than spot plasma values for the latter; (iii) adoption of a dexamethasone enhanced seated saline suppression test for confirmation exclusion; (iv) enhanced imaging and steroid profiles as partial replacement for adrenal venous sampling; and finally (v), inclusion of low dose spironolactone in first-line therapy for hypertension.

    更新日期:2019-11-27
  • Thyroid Gland And Brain: Enigma Of Hashimoto’s Encephalopathy
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2019-11-23
    Leonid P. Churilov, Polina A. Sobolevskaia, Yuri I. Stroev

    The versatile clinical manifestations of the Hashimoto’s chronic autoimmune thyroiditis often include psycho-neurological disorders. Although hypothyroidism disturbs significantly the ontogenesis and functions of central nervous system, causing in severe cases of myxoedema profound impairment of cognitive abilities and even psychosis, the behavioural, motor and other psychoneurological disorders accompany euthyroid and slightly hypothyroid cases and periods of Hashimoto’s disease as well, thus constituting the picture of so called “Hashimoto encephalopathy”. The entity, although discussed and explored for more than 50 years since its initial descriptions, remains an enigma of thyroidology and psychiatry, because its aetiology and pathogenesis are obscure. The paper describes the development of current views on the role of thyroid in ontogeny and functions of brain, as well as classical and newest ideas on the aetiology and pathogenesis of Hashimoto encephalopathy. The synopsis of the world case reports and research literature on this disorder is added with authors’ own results obtained by study of 17 cases of Hashimoto’s thyroiditis with schizophrenia-like clinical manifestations. The relation of the disease to adjuvant-like aetiological factors is discussed. Three major mechanistic concepts of Hashimoto encephalopathy are detailed, namely cerebral vasculitis theory, hormone dysregulation theory and concept, explaining the disease via direct action of the autoantibodies against various thyroid (thyroperoxidase, thyroglobulin, and TSH-receptor) and several extrathyroid antigens (alpha-enolase and other enzymes, gangliosides and MOG-protein, onconeuronal antigens) – all of them expressed in the brain. The article demonstrates that all above mentioned concepts intermingle and prone to unification, suggesting the unified scheme of pathogenesis for the Hashimoto encephalopathy. The clinical manifestations, criteria, forms, course, treatment and prognosis of Hashimoto encephalopathy and its comorbidity to other diseases – are also discussed in brief. The relation between Hashimoto encephalopathy and non-vascilitis autoimmune encephalomyelitides of paraneoplastic and non-paraneoplastic origin is emphasized. [1 figure, bibliography – 200 references]

    更新日期:2019-11-26
  • Thyroid Nodules and Cancer during Pregnancy, Post-partum and Preconception Planning: Addressing the Uncertainties and Challenges
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2019-11-22
    Maria Papaleontiou, Megan R. Haymart

    Thyroid nodules and thyroid cancer have become increasingly common worldwide. When discovered during pregnancy, they pose unique diagnostic and therapeutic challenges for both the treating physician and the patient. The benefits of treatment should be carefully weighed against risks that may adversely impact maternal and fetal health. In this review, we present current knowledge and controversies surrounding the management of thyroid nodules and thyroid cancer in pregnancy, in the post-partum period and during preconception planning.

    更新日期:2019-11-22
  • Volume–outcome relationship in parathyroid surgery
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2019-06-15
    Neeta J. Erinjeri, Robert Udelsman

    Background Since its first description, several studies have highlighted the role of the surgeon's experience in the outcome of parathyroid surgery, however, no uniform consensus exists regarding the minimum operative experience required for good surgical outcomes. This work aims to summarize the current data regarding the surgeon volume–outcome relationship for parathyroidectomy. Methods An electronic literature review identified 85 publications, and after study selection 11 were included. An additional nine publications were added based on reference review and inclusion of publications not initially captured. Conclusions There are insufficient data to dogmatically conclude a minimum number of cases required to achieve optimal surgical results. However, extrapolation from the inclusive studies support the conclusions that higher operative volumes improve cure rates and decrease the rates of complications, recurrent disease, and perioperative costs. Endocrine Surgery fellowships or mentorships may help prepare the less experienced surgeon for successful outcomes. Although reticent to offer firm minimal volume requirements, we have made suggestions in this manuscript.

    更新日期:2019-11-18
  • Surgical approaches and results of treatment for hereditary paragangliomas
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2019-07-27
    Maurizio Iacobone, Amanda Belluzzi, Francesca Torresan

    Paragangliomas (PGL) are rare neuroendocrine tumours; parasympathetic PGL are predominantly non-secreting and located at the skull base and neck, while sympathetic PGL are typically catecholamine-secreting and located at abdomino-pelvic level. Approximately 40% of PGL may be caused by germline mutations; hereditary variants should be suspected especially in case of positive family history, early onset, multifocal, or recurrent PGL. Significant genotype–phenotype correlation has been recognized, including syndromic presentation, location, multifocality and risk of malignancy. Surgical resection remains the only curative strategy, but the outcomes may be unsatisfactory because of surgical morbidity and recurrence rate. However, due to the rarity of the disease, most data derive from case-report or limited series. This paper was aimed to review the available literature on the epidemiology, diagnosis, clinical features, treatment of PGL in order to discuss the surgical approach and the results of treatment in hereditary PGL.

    更新日期:2019-11-18
  • Volume–outcome relationship in adrenal surgery: A review of existing literature
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2019-07-12
    Hadiza S. Kazaure, Julie A. Sosa

    The relationship between operative volume and perioperative outcomes after several oncologic operations is well documented. Recent studies on adrenalectomy reveal a robust association between higher surgeon volume and improved patient outcomes. Statistical analyses have demonstrated that outcomes are improved when surgeons perform at least six adrenalectomies annually; based on this threshold definition of a ‘high-volume’ surgeon, more than 80% of adrenalectomies in the United States are performed by ‘low-volume’ surgeons. When compared to low-volume surgeons, high-volume surgeons on average achieve lower rates of postoperative complications and mortality, as well as a shorter length of hospital stay, and lower cost of hospitalization. There does not appear to be a similar association between hospital adrenalectomy volume and improved patient outcomes; however, there is evidence of benefit for the subset of patients with adrenocortical carcinoma. Despite limitations of existing literature, evidence is sufficient to recommend the referral of patients with adrenal tumors to high-volume surgeons.

    更新日期:2019-11-18
  • Pre- and intraoperative diagnostic requirements, benefits and risks of minimally invasive and robotic surgery for neuroendocrine tumors of the pancreas
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2019-07-10
    Joseph Gharios, Elisabeth Hain, Anthony Dohan, Fréderic Prat, Benoit Terris, Jérôme Bertherat, Romain Coriat, Bertrand Dousset, Sébastien Gaujoux

    Pancreatic neuroendocrine tumours (PanNET) are rare tumours, accounting for 1%–2% of all pancreatic neoplasms. These tumors are classified as functioning neuroendocrine tumours (F-PanNETs) or non-functioning (NF-PanNETs) depends on whether the tumour is associated with clinical hormonal hypersecretion syndrome or not. In the last decades, diagnosis of PanNETs has increased significantly due to the widespread of cross-sectional imaging. Whenever possible, surgery is the cornerstone of PanNETs management and the only curative option for these patients. Indeed, after R0 resection, the 5-year overall survival rate is around 90–100% for low grade lesions but significantly drops after incomplete resections. Compared to standard resections, pancreatic sparing surgery, i.e. enucleation and central pancreatectomy, significantly decreased the risk of pancreatic insufficiency. It should be performed in patients with good general condition and normal pancreatic function to limit the operative risk and enhance the benefit of surgery. Nowadays, due to many known advantages of minimally invasive surgery, there is an ongoing trend towards laparoscopic and robotic pancreatic surgery. The aim of this study is to describe the pre- and intraoperative diagnostic requirements for the management of PanNETs and the benefits and risks of minimally invasive surgery including laparoscopic and robotic approach in view of the recent literature.

    更新日期:2019-11-18
  • Endoscopic, transanal, laparoscopic, and transabdominal management of rectal neuroendocrine tumors
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2019-07-09
    Louis de Mestier, Diane Lorenzo, Caroline Fine, Jérôme Cros, Olivia Hentic, Thomas Walter, Yves Panis, Anne Couvelard, Guillaume Cadiot, Philippe Ruszniewski

    Rectal neuroendocrine tumors (RNET) are rare tumors but their prevalence is constantly increasing due to a prolonged survival and rising incidence related to a growing number of colonoscopies and improved knowledge. Their main prognostic determinant is tumor stage. While most RNET are localized, their management should be tailored depending on the presence or absence of the factors predictive of lymph-node metastases including tumor size, endoscopic aspect, T stage, grade and lymphovascular invasion. Endoscopic ultrasonography is the most relevant technique for locoregional assessment. Low-risk RNET can be treated using advanced endoscopic resection techniques or transanal endoscopic microsurgery, in expert centers because they require technicity and experience. Conversely, radical surgery with lymphadenectomy should be proposed in the presence of any pejorative factor. The long-term evolution of RNET remains to be specified, and prospective studies should be conducted in order to determine the relevance of the current management strategies.

    更新日期:2019-11-18
  • Primary hyperparathyroidism
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2018-09-28
    Barbara C. Silva, Natalie E. Cusano, John P. Bilezikian

    Primary hyperparathyroidism (PHPT), the most common cause of hypercalcemia, is most often identified in postmenopausal women with hypercalcemia and parathyroid hormone (PTH) levels that are either frankly elevated or inappropriately normal. The clinical presentation of PHPT includes three phenotypes: target organ involvement of the renal and skeletal systems; mild asymptomatic hypercalcemia; and more recently, high PTH levels in the context of persistently normal albumin-corrected and ionized serum calcium values. The factors that determine which of these three clinical presentations is more likely to predominate in a given country include the extent to which biochemical screening is employed, the prevalence of vitamin D deficiency, and whether a medical center or practitioner tends to routinely measure PTH levels in the evaluation of low bone density or frank osteoporosis. When biochemical screening is common, asymptomatic primary hyperparathyroidism is the most likely form of the disease. In countries where vitamin D deficiency is prevalent and biochemical screening is not a feature of the health care system, symptomatic disease with skeletal abnormalities is likely to predominate. Finally, when PTH levels are part of the evaluation for low bone mass, the normocalcemic variant is seen. Guidelines for surgical removal of hyperfunctioning parathyroid tissue apply to all three clinical forms of the disease. If guidelines for surgery are not met, parathyroidectomy can also be an appropriate option if there are no medical contraindications to surgery. In settings where either the serum calcium or bone mineral density is of concern, and surgery is not an option, pharmacological approaches are available and effective. Referencing in this article the most current published articles, we review the different presentations of PHPT, with particular emphasis on recent advances in our understanding of target organ involvement and management.

    更新日期:2019-11-18
  • Metastatic Pheochromocytoma and Paraganglioma: Management of Endocrine Manifestations, Surgery and Ablative Procedures, and Systemic Therapies
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2019-10-24
    Sina Jasim, Camilo Jimenez

    Metastatic pheochromocytomas and paragangliomas (MPPGs) are rare neuroendocrine tumors. Most patients present with advanced disease that is associated with manifestations of catecholamine release. Surgical resection of the primary tumor and ablative therapies of metastases—whenever possible—may improve clinical outcomes and, perhaps, lengthen the patient’s overall survival. Significant steps in understanding the genetic alterations linked to MPPGs and scientific progress made on cancers that share a similar pathogenesis are leading to the recognition of potential systemic therapeutic options. Data derived from clinical trials evaluating targeted therapies such as tyrosine kinase inhibitors, radiopharmaceuticals, immunotherapy, and combinations of these will likely improve the outcomes of patients with advanced and progressive MPPGs. Exemplary of this success is the recent approval in the United States of the high-specific-activity iodine131 meta-iodine-benzylguanidine (MIBG) for patients with unresectable and progressive MPPGs that express the noradrenaline transporter. This review will discuss the therapeutic approaches for patients with MPPGs.

    更新日期:2019-10-25
  • Pheochromocytoma: An Approach To Diagnosis
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2019-10-22
    Emilia Sbardella, Ashley B. Grossman

    Pheochromocytomas are rare neuroendocrine chromaffin-derived tumors that arise within the adrenal medulla. They are usually benign, but if not diagnosed or if left untreated, they can have devastating consequences. Clinical consideration of the diagnosis is paramount, as they may have protean manifestations, and a high index of suspicion is essential if serious consequences are to be avoided. An accurate biochemical diagnosis is crucial for the management of these patients: either plasma or urinary metanephrines are both highly sensitive and specific if correctly employed, but knowledge of pre- and post-analytic interference is essential. Diagnostic imaging with cross-sectional CT and/or MRI offer high sensitivity in their detection, but lack specificity. The introduction of PET/CT/MR has led to a dramatic improvement in the localization of both pheochromocytomas and paragangliomas, together with the increasing availability of new functional imaging radionuclides. Optimal investigation and accurate diagnosis is best achieved at ‘centers of excellence’ with expert multidisciplinary teams.

    更新日期:2019-10-23
  • Disease monitoring of patients with pheochromocytoma or paraganglioma by biomarkers and imaging studies
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2019-10-21
    Florentine Schreiner, Felix Beuschlein

    Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors, a large proportion of which secrete catecholamines. PPGL are associated with a high cardiovascular morbidity and come with a risk of malignancy. The therapy of choice is surgical resection. Nevertheless, PPGL are associated with a lifelong risk of tumor persistence or recurrence. Currently, there are no clinical, biochemical, histopathological or imaging characteristics, which can predict or exclude malignant behavior or tumor recurrence. Therefore, long-term follow-up is recommended even after apparent complete surgical removal. Early detection of recurrence is essential to reduce cardiovascular morbidity and mortality due to catecholamine secretion, to prevent morbidity by mass effects of paraganglioma (PGL) or by metastatic spread of disease. Due to the rarity of these tumors, no prospective data on long-term surveillance exist. In fact, current recommendations are based on retrospective analyses, expert opinions and case studies. The aim of this review is to provide an overview on the current state of knowledge with regard to known factors that increase the risk of recurrence and might impact disease monitoring as well as the available possibilities for biochemical and imaging follow-up. Based on this overview, we aim to propose a practical approach for a patient-oriented follow-up after surgical removal of a PPGL.

    更新日期:2019-10-22
  • Autoimmune Polyglandular Diseases
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2019-10-04
    George J. Kahaly, Lara Frommer

    Autoimmune polyglandular diseases (APD) are defined as the presence of two autoimmune –induced endocrine failures. With respect to the significant morbidity and potential mortality of APD, the diagnostic objective is to detect APD at an early stage, with the advantage of less frequent complications, effective therapy and better prognosis. This requires that patients at risk be regularly screened for subclinical endocrinopathies prior to clinical manifestation. Regarding the time interval between manifestation of first and further endocrinopathies, regular and long-term follow-up is warranted. Quality of life and psychosocial status are poor in APD patients and involved relatives. Familial clustering is high in patients with APD. Considering the high incidence of one or more endocrinopathies in first-degree relatives of patients with APD, family members should be regularly screened since they may also develop autoimmune endocrinopathies. Multidisciplinary management of these multiplex families in specialized centers is warranted.

    更新日期:2019-10-04
  • Insights into the autoimmune aspect of premature ovarian insufficiency
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2019-09-16
    Kassem Sharif, Abdulla Watad, Charlie Bridgewood, Darja Kanduc, Howard Amital, Yehuda Shoenfeld

    Premature ovarian insufficiency (POI) refers to a continuum of decreasing ovarian function in women before the age of 40. To date, the cause of POI in the majority of cases remain unresolved. Many cases has been linked to genetic, toxic, infections, enzymatic and iatrogenic causes. A key function of the immune system is to identify and differentiate “self” and “non self” i.e. tolerance. Loss of self-tolerance results in an immune response against self-tissues and thus autoimmunity. Various investigations have highlighted the role of autoimmunity and its pertinence to POI. Several potential immune antigenic targets in the ovary have been reported to be involved in autoantibody induced autoimmune attack. The presence of lymphocytic oöphorits in ovarian samples of patients with POI provides histopathological evidence of autoimmune ovarian involvement. Finally, POI is strongly associated with other autoimmune conditions including for instance Addison disease, autoimmune polyglandular syndrome (APS) -1, APS-4, hypothyroidism, and diabetes mellitus among other autoimmune diseases. Taken together, these lines of evidence provide strong basis that support the role of autoimmunity as a potential cause of disease etiopathogenesis. Continuing research is increasingly providing more insight into the complex disease process. The aim of this review is to summarize the current literature related to the autoimmune nature of POI.

    更新日期:2019-09-17
  • Exacerbations of autoimmune diseases during pregnancy and postpartum
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2019-09-11
    Vânia Vieira Borba, Gisele Zandman-Goddard, Yehuda Shoenfeld

    Autoimmune diseases represent a complex heterogeneous group of disorders that occur as a results of immune homeostasis dysregulation and loss of self-tolerance. Interestingly, more than 80% of the cases are found among women at reproductive age. Normal pregnancy is associated with remarkable changes in the immune and endocrine signaling required to tolerate and support the development and survival of the placenta and the semi-allogenic fetus in the hostile maternal immune system environment. Gravidity and postpartum represent an extremely challenge period, and likewise the general population, women suffering from autoimmune disorders attempt pregnancy. Effective preconception counseling and subsequent gestation and postpartum follow-up are crucial for improving mother and child outcomes. This comprehensive review provides information about the different pathways modulating autoimmune diseases activity and severity, such as the influence hormones, microbiome, infections, vaccines, among others, as well as updated recommendations were needed, in order to offer those women better medical care and life quality.

    更新日期:2019-09-11
  • “Autoimmune Diseases and Pregnancy”
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2019-09-11
    Angela Tincani, Cecilia Nalli, Jamilya Khizroeva, Victoria Bitsadze, Andrea Lojacono, Laura Andreoli, Yehuda Shoenfeld, Alexander Makatsariya

    Pregnancy in autoimmune diseases remains an argument of debate. In last years great improvements were done and with the correct medical support women with disease such as Systemic Lupus Erythematosus or Antiphospholipid Syndrome can afford a pregnancy and have healthy babies. The starting point is a good counselling. Women should be informed about risks that can occur taking some medications while pregnant and, on the other hand, that there are medications that can be safety assumed during pregnancy. Furthermore, there are known maternal risks factor such as the presence of antiphospholipid antibodies or anti-Ro/SSA antibodies that must be carefully manage by both rheumatologists and obstetrics. In addition, also disease activity during pregnancy can represent an issue. For all these reason, a multidisciplinary approach is mandatory in order to give our patients an optimal medical support, before, during and after pregnancy.

    更新日期:2019-09-11
  • Prolactin and autoimmunity: the hormone as an inflammatory cytokine
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2019-09-11
    Vânia Vieira Borba, Gisele Zandman-Goddard, Yehuda Shoenfeld

    Nowadays, more than 80 autoimmune disorders are recognized, in which an aberrant immune response against different organs and tissues plays a crucial role. Hormonal homeostasis has great influence in achieving competent and healthy immune system function. Prolactin has a bioactive function acting as a hormone and a cytokine. It influences the immune system modulation, mainly inhibiting the negative selection of autoreactive B lymphocytes. Hyperprolactinemia has been detected in many patients with different autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, Sjögren syndrome, multiple sclerosis, autoimmune thyroid disease, systemic sclerosis, among others, and its believed to play a crucial role in disease pathogenesis. A direct correlation between prolactin levels and disease activity was not clear. Genetic factors may have a role in humans as in animal models. Dopamine agonists have proven to offer clinical benefits among autoimmune patients and represent a promising therapy to be explored. In this review, the authors attempt to provide a critical overview on the role of prolactin in the immune system, exploring its contribution to the development of autoimmune diseases.

    更新日期:2019-09-11
  • Universal Screening For Thyroid Disease During Pregnancy Should Be Performed
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2019-09-06
    Alex Stagnaro-Green, Allan Dong, Mary D. Stephenson

    Thyroid disease can significantly impact the pregnant woman and her child. Human and animal studies have firmly linked overt hypothyroidism and overt hyperthyroidism to miscarriage, preterm delivery and other adverse pregnancy outcomes. Overt hypothyroidism and overt hyperthyroidism affect 1% of all pregnancies. Treatment is widely available, and if detected early, results in decreased rates of adverse outcomes. Universal screening for thyroid disease in pregnancy can identify patients with thyroid disease requiring treatment, and ultimately decrease rates of complications. Universal screening is cost-effective compared to the currently accepted practice of targeted screening and may even be cost-saving in some healthcare systems. Targeted screening, which is recommended by most professional associations, fails to detect a large proportion of pregnant women with thyroid disease. In fact, an increasing number of providers are performing universal screening for thyroid disease in pregnancy, contrary to society guidelines. Limited evidence concerning the impact of untreated and treated subclinical disease and thyroid autoimmunity has distracted from the core rationale for universal screening – the beneficial impact of detecting and treating overt thyroid disease. Evidence supporting universal screening for overt disease stands independently from that of subclinical and autoimmune disease. The time to initiate universal screening is now.

    更新日期:2019-09-06
  • Constitutional delay of puberty versus congenital hypogonadotropic hypogonadism: genetics, management and updates
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2019-09-05
    Taneli Raivio, Päivi J. Miettinen

    Delayed puberty (DP) affects approximately 2% of adolescents. In the vast majority of patients in both sexes, it is due to constitutional delay of growth and puberty (CDGP), a self-limited condition in which puberty starts later than usual but progresses normally. However, some CDGP patients may benefit from medical intervention with low-dose sex steroids or peroral aromatase inhibitor letrozole (only for boys). Other causes of DP include permanent hypogonadotropic hypogonadism, functional hypogonadotropic hypogonadism (due to chronic diseases and conditions), and gonadal failure. In this review we discuss these themes along with the latest achievements in the field of puberty research, and include a brief synopsis on the differential diagnosis and management of patients with CDGP and congenital hypogonadotropic hypogonadism.

    更新日期:2019-09-05
  • Contemporary surgical management of the Zollinger-Ellison syndrome in Multiple Endocrine Neoplasia type 1
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2019-08-31
    Max B. Albers, Jerena Manoharan, Detlef K. Bartsch

    About 30% of patients with MEN1 develop a Zollinger-Ellison syndrome. Meanwhile it is well established that the causative gastrinomas are almost exclusively localized in the duodenum and not in the pancreas, MEN1 gastrinomas occur multicentric and are associated with hyperplastic gastrin cell lesions and tiny gastrin-producing micro tumors in contrast to sporadic duodenal gastrinomas. Regardless of the high prevalence of early lymphatic metastases, the survival is generally good with an aggressive course of disease in only about 20% of patients. Symptoms can be controlled medically. The indication, timing, type, and extent of surgery are highly controversial and are discussed in detail in this article by a thorough and critical review of literature. More radical procedures, like partial pancreaticoduodenectomy, are weighed against less aggressive local excision of gastrinomas and the pros and cons of both approaches are discussed in terms of long-term morbidity, biochemical cure, and survival.

    更新日期:2019-09-03
  • Treatment of patients with Graves’ disease and the appropriate extent of thyroidectomy
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2019-08-31
    Iuliana D. Bobanga, Christopher R. McHenry

    Graves’ disease is an autoimmune disorder caused by thyroid stimulating auto-antibodies directed against the thyrotropin receptor on thyroid follicular cells. It is the most common cause of hyperthyroidism and is associated with cardiovascular, ophthalmologic and other systemic manifestations. Three treatment options are available for Graves’ disease: anti-thyroid drugs, radioactive iodine and thyroidectomy. While thyroidectomy is the least common option used for treatment of Graves’ disease, it is preferentially indicated for patients with a large goiter causing compressive symptoms, suspicious or malignant thyroid nodules or significant ophthalmopathy. The best operation for Graves’ disease has been a matter of debate. The standard operation was a subtotal thyroidectomy for much of the twentieth century, however, over the past 20 years total thyroidectomy has been increasingly performed. Herein, we provide a historical perspective and review the current literature, including randomized controlled trials, systematic reviews and meta-analyses and conclude that total thyroidectomy is the preferred option for the surgical treatment of Graves’ disease, with a nearly 0% recurrence rate, predictable postoperative hypothyroidism and a low complication rate comparable to subtotal thyroidectomy when performed by high-volume thyroid surgeons.

    更新日期:2019-09-03
  • Impact of surgical volume and surgical outcome assessing registers on the quality of thyroid surgery
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2019-08-31
    Neil Patel, David Scott-Coombes

    The available evidence concerning the relationship between volume and outcome for thyroid surgery is assessed in this article. Morbidity forms the principal surrogate marker of thyroid surgery quality for which postoperative hypocalcaemia and recurrent laryngeal nerve injuries are most commonly reported upon. Whilst there is an abundance of published data for these outcomes, interpretation to recommend annual volume thresholds is challenging. This is due to a lack of consensus on definitions not only for outcomes but high and low volume surgeons. The evidence reviewed in this article supports the notion that high volume surgeons achieve superior outcomes in thyroid surgery quality though it is not possible to recommend minimal annual volumes on the basis of this evidence alone. Every thyroid surgeon should know their own outcomes and how they compare with their peers and engagement in thyroid surgery registries can facilitate this.

    更新日期:2019-09-03
  • Surgical approach to the substernal goiter
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2019-08-22
    Martin A. Hanson, Ashok R. Shaha, James X. Wu

    Surgery for substernal goiters can be technically demanding. Extensive mediastinal extension brings the thyroid gland into close quarters with vital intrathoracic structures. Proper preoperative planning is required to determine the potential need for an extracervical approach. Assessing the risk of requiring an extracervical approach is typically based on findings from cross-sectional imaging of the neck and chest. This article addresses the important anatomical considerations when resecting a large substernal goiter, and also reviews various extracervical approaches.

    更新日期:2019-08-23
  • Impact of fluorescence and autofluorescence on surgical strategy in benign and malignant neck endocrine diseases
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2019-08-10
    Anatoliy V. Rudin, Eren Berber

    Fluorescence and autofluorescence have been shown by several recent studies to be valuable adjuncts in identifying parathyroid glands during thyroidectomy and parathyroidectomy. The aim of this chapter is to review the impact of this new technology on surgical strategy concerning preservation of parathyroid glands during thyroidectomy, identification of hyperactive parathyroid glands in hyperparathyroidism, and their potential role in advanced thyroid cancers.

    更新日期:2019-08-10
  • The role of intraoperative parathyroid hormone (IOPTH) determination for identification and surgical strategy of sporadic multiglandular disease in primary hyperparathyroidism (pHPT)
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2019-08-08
    Jagdeep Singh Bhangu, Philipp Riss

    Intraoperative PTH monitoring (IOPTH) made minimally invasive parathyroidectomy in patients with primary HPT possible. However, with the increasing accuracy of preoperative localization studies there is a growing discussion if IOPTH is necessary in patients with localized single gland disease (concordant preoperative localization studies). Different interpretation criteria have been developed – each with their particular advantages and disadvantages, but the “perfect” criterion is still missing. Despite several pitfalls, which can be recognized intraoperatively and do not necessarily lead to a more extensive surgery, IOPTH seems to be a useful adjunct in surgery for PHPT. However, according to current guidelines, selected patients may be operated without IOPTH but need to be informed about the possibly increased risk of recurrent disease.

    更新日期:2019-08-09
  • The burden of disease for pituitary patients
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2019-08-02
    Nienke R. Biermasz

    Pituitary diseases are rare conditions with severe chronic multiorgan and multisystemic morbidity requiring complex multidisciplinary treatment and usually life-long drug treatment. Most cases are caused by functioning or non-functioning pituitary adenoma. From the patient’s perspective, the burden of disease is caused by the tumour itself and associated compression symptoms, interventions, hormone excess and deficiencies, systemic manifestations of these endocrine abnormalities and general psychosocial issues that can manifest in patients with a chronic condition. In this review, patient burden is classified according to classic endocrine syndromes, with burden at diagnosis and after long-term remission, and also within the framework of value-based health care and the conceptual model of wellbeing. The recently developed patient-reported outcome measurement tool that helps to evaluate burden of patients is also discussed.

    更新日期:2019-08-03
  • MANAGEMENT OF DISORDERS OF SEX DEVELOPMENT With a focus on development of the child and adolescent through the pubertal years
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2019-07-27
    Jamal Raza, Syed Zafar Zaidi, Garry L. Warne

    Disorders of sex development, congenital conditions in which chromosomal, gonadal or anatomic sex is atypical at birth, require urgent assessment by a multidisciplinary team, to define whether there is a life threatening disorder of congenital adrenal hyperplasia or a healthy child with a complex condition. Uncertainty, stigma and taboo complicate counselling which must be knowledgeable, comprehensive and sensitive to different circumstances, religions and cultures. This articles will discuss clinical and genetic diagnosis, decisions regarding sex of rearing, ethical dilemmas, medical management of the infant and of the child or adolescent presenting for the first time with a DSD. Surgical options, timing and management are outlined.

    更新日期:2019-07-27
  • The optimal surgical techniques for pituitary tumors
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2019-07-27
    M. Buchfelder, S.M. Schlaffer, Y. Zhao

    In this paper, the currently used and well evaluated techniques for the surgery of pituitary tumors will be reviewed. Since the first surgical approaches to pituitary tumors more than 100 years have elapsed. Various surgical techniques have been developed, refined and standardized. Most of these tumors are to date treated via transsphenoidal approaches. Many pituitary adenomas, particularly, smaller, enclosed ones, can be completely excised and a selective adenomectomy is usually attempted. It leads to remission of hormonal oversecretion and also to recovery of pituitary function in many patients. The resection of pseudocapsule around the adenoma seems to improve the operative results further. Transcranial approaches, employing craniotomies, are still needed in some patients with pituitary adenomas and in many of those harbouring craniopharyngiomas. The operative techniques will be described and briefly commented. Moreover, the application and usefulness of several technical developments will be reviewed, such as the use of the endoscope, magnetic resonance imaging and neuronavigation. The use of the intraoperative Doppler probe, ultrasound and the value of intraoperative hormonal measurements will be briefly discussed. There is sufficient evidence that the best and optimal outcome in terms of tumor resection and correction of hormonal oversecretion as well as the lowest rate of complications are obtained in centers of excellence with sufficiently experienced, specialized surgeons and a high patient load.

    更新日期:2019-07-27
  • Endocrine disrupters and possible contribution to pubertal changes
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2019-07-27
    Julie Fudvoye, David Lopez-Rodriguez, Delphine Franssen, Anne-Simone Parent

    The onset of puberty strongly depends on organizational processes taking place during the fetal and early postnatal life. Therefore, exposure to environmental pollutants such as Endocrine disrupting chemicals (EDCs) during critical periods of development can result in delayed/advanced puberty and long-term reproductive consequences. Human evidence of altered pubertal timing after exposure to endocrine disrupting chemicals is equivocal. However, the age distribution of pubertal signs points to a skewed distribution towards earliness for initial pubertal stages and towards lateness for final pubertal stages. Such distortion of distribution is a recent phenomenon and suggests environmental influences including the possible role of nutrition, stress and endocrine disruptors. Rodent and ovine studies indicate a role of fetal and neonatal exposure to EDCs, along the concept of early origin of health and disease. Such effects involve neuroendocrine mechanisms at the level of the hypothalamus where homeostasis of reproduction is programmed and regulated but also peripheral effects at the level of the gonads or the mammary gland.

    更新日期:2019-07-27
  • Primary Gonadal Failure
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2019-07-12
    Dr Asmahane Ladjouze, Dr Malcolm Donaldson

    The term primary gonadal failure encompasses not only testicular insufficiency in 46,XY males and ovarian insufficiency in 46,XX females, but also those disorders of sex development (DSD) which result in gender assignment that is at variance with the genotype and gonadal type. In boys, causes of gonadal failure include Klinefelter and other aneuploidy syndromes, bilateral cryptorchidism, testicular torsion, and forms of 46,XY DSD such as partial androgen insensitivity. Causes in girls include Turner syndrome and other aneuploidies, galactosemia, and autoimmune ovarian failure. Iatrogenic causes in both boys and girls include the late effects of childhood cancer treatment, total body irradiation prior to bone marrow transplantation, and iron overload in transfusion-dependent thalassaemia. In this paper, a brief description of the physiology of testicular and ovarian development is followed by a section on the causes and practical management of gonadal impairment in boys and girls. Protocols for pubertal induction and post-pubertal hormone replacement - intramuscular, oral and transdermal testosterone in boys; oral and transdermal oestrogen in girls - are then given. Finally, current and future strategies for assisted conception and fertility preservation are discussed.

    更新日期:2019-07-12
  • The Epidemiology, Diagnosis And Treatment Of Prolactinomas:The Old And The New
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2019-07-10
    Philippe Chanson, Dominique Maiter

    Prevalence and incidence of prolactinomas are approximately 50 per 100,000 and 3-5 new cases/100,000/year. The pathophysiological mechanism of hyperprolactinemia-induced gonadotropic failure involves kisspeptin neurons. Prolactinomas in males are larger, more invasive and less sensitive to dopamine agonists (DAs). Macroprolactin, responsible for pseudohyperprolactinemia is a frequent pitfall of prolactin assay. DAs still represent the primary therapy for most prolactinomas, but neurosurgery has regained interest, due to progress in surgical techniques and a high success rate in microprolactinoma, as well as to some underestimated side effects of long-term DA treatment, such as impulse control disorders or impaired quality of life. Recent data show that the suspected effects of DAs on cardiac valves in patients with prolactinomas are reassuring. Finally, temozolomide has emerged as a valuable treatment for rare cases of aggressive and malignant prolactinomas that do not respond to all other conventional treatments.

    更新日期:2019-07-10
  • The impact of childhood cancer and its treatment on puberty and subsequent hypothalamic pituitary and gonadal function, in both boys and girls
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2019-07-09
    Christina Wei, Elizabeth Crowne

    Childhood cancer survivors (CCS) are at an increased risk of endocrine disorders. Disorders of the hypothalamic-pituitary-gonadal (HPG) axis are a particular concern because of their impact on pubertal development and future fertility and may be of central (hypothalamic or pituitary damage) or primary (gonadal) origin. Hypogonadism may present as pubertal disorders during adolescence and subsequent infertility in adulthood but should be anticipated to ensure appropriate surveillance is in place to address these issues at an appropriate age. Those at risk of HPG axis dysfunction include those with tumours primarily affecting the hypothalamus, pituitary or gonads themselves or due to their treatment with surgery, radiotherapy and chemotherapy. CCS who have had cranial irradiation of more than 30 Gy are at risk of gonadotrophin deficiency. Those who have had gonadotoxic chemotherapy, especially alkylating agents or radiotherapy to the gonads are at risk of primary gonadal failure. HSCT survivors who have had chemotherapy and total body irradiation are at risk of primary gonadal failure but may also have gonadotrophin deficiency. Understanding those at risk is essential to appropriate counselling and long-term follow-up. This chapter gives an overview on the impact of childhood cancer and its treatment on puberty, gonadal function and fertility in childhood cancer survivors.

    更新日期:2019-07-10
  • The surgical dilemma of primary surgery for follicular thyroid neoplasms
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2019-07-09
    Julia I. Staubitz, Petra B. Musholt, Thomas J. Musholt

    Follicular thyroid carcinoma is the second most prevalent form of differentiated thyroid carcinoma, following papillary thyroid carcinoma. Preoperative diagnosis is hampered by the fact that fine-needle aspiration cytology as well as supplemental molecular analysis cannot unambiguously distinguish between follicular thyroid carcinoma and benign follicular thyroid adenoma. The 2017 WHO classification defines three histological subtypes of follicular thyroid carcinoma: minimally invasive (excellent prognosis), encapsulated angioinvasive, and widely invasive type (higher risk of recurrence and metastatic spread). The fact that definite characterization of follicular neoplasms is predominantly a postoperative histological diagnosis (core criteria: capsular, vascular and adjacent tissue invasion) translates into the challenge for the thyroid surgeon to plan preoperatively for presence of malignancy and, if required, to adapt the surgical strategy according to intraoperative (frozen section) or postoperative histological findings. Until improved tools for pre-/intraoperative diagnosis are available, the malignant potential of a follicular thyroid lesion can be assessed by stratifying the patient according to clinical risk factors (presence of metastases, advanced patient age, tumor size). A stepwise, escalating surgical approach with restricted primary resection (hemithyroidectomy) and completion surgery based on the definite histopathology is another option to solve this dilemma. The currently recommended surgical treatment strategies for FTCs as published by ATA, BTA, CAEK and ESES are discussed. There is consensus that prophylactic lymphadenectomy is not required for FTCs and that hemithyroidectomy is sufficient in low-risk FTCs (capsular invasion only) whereas thyroidectomy with postoperative radioiodine therapy is indicated in high-risk FTCs (angioinvasion; widely invasive FTC).

    更新日期:2019-07-10
  • Female Fertility preservation in DSD
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2019-07-09
    Dr Rashi Kalra, Dr Melissa Cameron, Catharyn Stern

    Disorders of sex development (DSD) are a group of complex conditions that can affect chromosomal, gonadal, and/or phenotypical sex with a highly variable fertility potential amongst affected individuals. In this review we discuss fertility issues facing patients affected by DSD and Turner syndrome and summarise the literature on fertility and reproductive outcomes. We will also discuss fertility preservation prior to gonadotoxic treatment in adolescent and prepubertal girls. Future directions in fertility preservation and ethical issues will also be addressed. Fertility preserving options that are established include ovarian tissue and oocyte cryopreservation. However, in many of the DSDs fertility is not possible and the discussion may need to move toward alternative methods of creating a family such as gamete donation or surrogacy.

    更新日期:2019-07-10
  • Towards complication-free assisted reproduction technology
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2018-11-03
    Samuel Santos-Ribeiro, Shari Mackens, Annalisa Racca, Christophe Blockeel

    Assisted reproductive technology (ART) has vastly improved over the last 40 years, from a frequently unsuccessful and complicated procedure requiring hospital admission and routine laparoscopy to a fairly simple outpatient technique with relatively high success rates. However, it is important to stress that ART is not without risk and medical complications may still occur. The incidence of most of these ART-related complications is associated with how women undergo ovarian stimulation. For this reason, physicians should be aware that a carefully thought-out ovarian stimulation protocol and cycle monitoring are of paramount importance to maximise the success of the treatment while avoiding potentially life-threating complications to occur in this frequently otherwise healthy patient population. This review discusses the rationale and evolution of ovarian stimulation strategies over the years and the current developments towards finding a balance between the retrieval of a sufficient number of oocytes and ART-related complication prevention.

    更新日期:2019-07-05
  • Pharmacology of medications used for ovarian stimulation
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2018-11-12
    Alexander M. Quaas, Richard S. Legro

    Medications to stimulate the ovaries may be used to induce ovulation in patients with anovulatory infertility or to hyperstimulate the ovaries in a controlled fashion in ovulatory patients as part of assisted reproductive treatments (ART). The pharmacology of all current major medications used to stimulate ovarian function is reviewed in this article, including letrozole, clomiphene citrate, gonadotropins, and pulsatile gonadotropin releasing hormone (GnRH). Novel potential compounds and adjuvant treatment approaches are also discussed, such as kisspeptin agonists and androgens.

    更新日期:2019-07-05
  • The role of Natural Cycle IVF in assisted reproduction
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2018-11-09
    Michael von Wolff

    Natural Cycle IVF (NC-IVF) with and without modifications is being increasingly performed. NC-IVF and conventional gonadotropin-stimulated IVF (cIVF) should not be understood as competing treatments, but as complementary treatments with different target groups and to some extent other indications. NC-IVF is particularly interesting for couples who wish to save money, wish a treatment with as few risks as possible and for women who would like to avoid selection and cryopreservation of embryos. NC-IVF therefore contributes to the concept of individualized and patient-oriented therapy. The time to pregnancy is slightly longer than with conventional IVF. NC-IVF is particularly suitable for younger women and for women with a very low ovarian reserve. In this article, the principles of NC-IVF, i.e. monofollicular IVF without gonadotropin stimulation, are described and the technical differences to cIVF, advantages and disadvantages, perinatal outcome and indications for NC-IVF are highlightened.

    更新日期:2019-07-05
  • Assisted reproduction in endometriosis
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2018-11-03
    Dominique de Ziegler, Paul Pirtea, Marie Carbonnel, Marine Poulain, Ettore Cicinelli, Carlo Bulletti, Konstantinos Kostaras, George Kontopoulos, David Keefe, Jean Marc Ayoubi

    Endometriosis – a disease causing pain and infertility – is encountered in nearly 50% of infertile women. While medical treatment is effective on pain and recurrence of symptoms after surgical excision, it is of no help for treating infertility for which the only options considered are surgery and ART. Surgery enhances the chances of conceiving naturally during the 12–18 ensuing months irrespective of the stage of the disease. Surgery however is of no help when ART is considered, as it does not improve outcome and can only harm the ovarian response to stimulation. Today therefore, ART is commonly the primary option to be considered in women whose infertility is associated with endometriosis and whose ovarian reserve is compromised and/or who are over 35 years of age. When, ART is envisioned it is best to opt for a segmented ART approach with agonist trigger, freeze all and deferred embryo transfer.

    更新日期:2019-07-05
  • The endometrium during and after ovarian hyperstimulation and the role of segmentation of infertility treatment
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2018-09-13
    Pedro Montoya-Botero, Nikolaos P. Polyzos

    Controlled ovarian hyperstimulation (COH) is a crucial part of assisted reproductive technologies (ART) that resulted in a substantial increase in pregnancy rates from in vitro fertilization (IVF). However, in spite of the apparent benefit of COH on an increase in the number of follicles and the number of oocytes retrieved, allowing for extended embryo culture and enabling the selection of the best quality embryo for transfer, several reports has shown that the supraphysiologic hormonal levels may indeed have a detrimental effect at the endometrial level. The current article revises the pathophysiological mechanisms through which ovarian stimulation may negatively affect endometrial receptivity. Also, the evidence is analyzed explaining how segmentation of IVF treatment may allow us to overcome the deleterious effects of hyperstimulation on endometrial receptivity. Deferred embryo transfer may be performed in a more physiologic uterine environment in a subsequent cycle, improve endometrial receptivity, decrease uterine contractility, diminishes the impact of premature luteinization and allow individualized stimulation according to the level of response.

    更新日期:2019-07-05
  • Cryostorage and retransplantation of ovarian tissue as an infertility treatment
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2018-09-13
    Christiani A. Amorim, Ellen Cristina Rivas Leonel, Yousri Afifi, Arri Coomarasamy, Simon Fishel

    While still considered an experimental procedure in most countries, ovarian tissue cryopreservation and transplantation has been increasingly applied worldwide to restore fertility in patients with malignant and non-malignant pathologies with risk of premature ovarian insufficiency. It has yielded more than 130 live births up to now and almost all transplanted patients recovered their ovarian function. This study summarizes ovarian tissue cryopreservation and transplantation indications, procedures, their efficacy and main results and proposes different strategies to improve this strategy. Although the main focus of this study is on ovarian tissue cryopreservation and transplantation as a strategy to restore fertility, we believe that it is also important to discuss other applications for this approach.

    更新日期:2019-07-05
  • Cryostorage of testicular tissue and retransplantation of spermatogonial stem cells in the infertile male
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2018-11-03
    Marc Kanbar, Francesca de Michele, Christine Wyns

    Transplantation of own cryostored spermatogonial stem cells (SSCs) is a promising technique for fertility restoration when the SSC pool has been depleted. In this regard, cryopreservation of pre-pubertal testicular tissue or SSCs suspensions before gonadotoxic therapies is ethically accepted and increasingly proposed. SSC transplantation has also been considered to treat other causes of infertility relying on the possibility of propagating SSCs retrieved in the testes of infertile men before autologous re-transplantation. Although encouraging results were achieved in animals and in preclinical experiments, clinical perspectives are still limited by a number of unresolved technical and safety issues, such as the risk of cancer cell contamination of cells intended for transplantation and the genetic and epigenetic stability of SCCs when cultured before re-transplantation. Moreover, while genome editing techniques raise the hope of modifying the SSCs genome before re-transplantation, their application for reproductive purposes might be a step too far for the moment.

    更新日期:2019-07-05
  • Chromatin condensation, fragmentation of DNA and differences in the epigenetic signature of infertile men
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2018-11-03
    Monica Muratori, Christian De Geyter

    Epidemiological studies report an increase of pathologies of male reproductive tracts and suggest a link between this trend and the increased exposure of men to endocrine disruptors (EDs). The mechanisms by which EDs impact male fertility are far to be elucidated although DNA, chromatin and epigenome of spermatozoa appear to be relevant targets for these molecules. Indeed, many studies report associations between increased levels of sperm DNA fragmentation (sDF) or aberrant chromatin condensation or epigenetic modifications and poor semen quality and/or infertile phenotype. In this scenario, therapies able to reduce sperm damage to DNA, chromatin and epigenome are sought. Currently, antioxidants and FSH administration is proposed for treating high levels of sDF, but whether or not such therapies are really effective is still debated. Further studies are necessary to understand the link between endocrine disruptor exposure and damage to sperm function and/or structure and thus to define effective therapeutic strategies.

    更新日期:2019-07-05
  • National acromegaly registries
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2019-03-06
    Luigi Maione, Philippe Chanson

    Acromegaly is a rare disease, associated with multiple organs and systems damage. Thanks to implementation of registries, systematic data gathering, knowledge sharing and standardizing medical practices for optimal care greatly improved. Data concerning 19 national acromegaly registries are available, involving more than 16,000 patients. The weighted mean age of diagnosis is 45.2 years and seems stable over time. A macroadenoma is found in 75% of the cases. The proportion of patients operated (>80%) did not change along time. By contrast, use of radiotherapy has decreased while use of medical therapy increased. If judged on IGF-I levels, acromegaly is controlled in 61.3% of the patients. The disease control rate has improved over time. This is likely due to the development of medical treatment strategies. The collection of data about comorbidities in national registries is much less comprehensive than those about epidemiology, disease control or treatment strategies. The most reported comorbidities are arterial hypertension and diabetes. Data concerning mortality trends are controversial. It seems that cancer has become a leading cause of death in acromegaly patients in the last decade, period in which life expectancy improved, while cardiovascular mortality decreased. In conclusion, acromegaly registries offer a global view of the disease with no “a priori” assumptions. This is of outmost importance, because of the large amount of data and the huge number of associated comorbidities. This will help to establish guidelines for management of this rare disease.

    更新日期:2019-07-05
  • Hemithyroidectomy for benign euthyroid asymmetric nodular goitre
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2019-06-14
    Marcin Barczyński, Małgorzata Stopa-Barczyńska

    Background There is no consensus on the optimal surgery extent for patients with benign euthyroid asymmetric nodular goitre (AMNG). Methods We reviewed medical literature using the PubMed engine to address the following issues: definition and prevalence, rationale for hemithyroidectomy, long-term outcomes, follow-up, revision surgery and image-guided thermal ablation of contralateral benign thyroid nodules following hemithyroidectomy for AMNG. Results In total, 102 articles were found in MEDLINE using a keyword search strategy; subsequently, we selected 36 articles with clinical pertinence. Conclusions AMNG is a common clinical and surgical problem. Depending on the extent of the disease and individual surgeon preferences, either unilateral or bilateral thyroidectomy can be performed. Hemithyroidecomy can be considered for some patients with AMNG and the low risk of recurrent disease as a safer alternative to total thyroidectomy but it requires life-long follow-up, is associated with a higher recurrence risk and a need for revision thyroidectomy in selected subjects.

    更新日期:2019-06-16
  • Gynaecology problems in puberty
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2019-06-14
    Sonia R. Grover, Director

    With the onset of puberty a range of problems may be encountered by the young girl. Some of these include a range of gynaecological issues relating to delayed onset of puberty, delayed menarche, atypical pubertal changes and the identification of anomalies of the genital tract. The distinction between physiological events and pathological problems is important to avoid unnecessary distress and anxiety. The onset of cyclic hormonal changes also provokes a number of “non-gynaecological” problems – where the link to cyclic hormonal events are often overlooked and an important opportunity to potentially intervene and assist are missed. From a global perspective there are a range of problems that are particularly encountered with the onset of puberty including the risks of sexual violence, which in the setting of having achieved the age of reproductive potential result in unplanned pregnancies, unsafe abortions and adolescent pregnancy all of which pose life threatening risks. Sex education in its broadest sense is important for all young people. Access to contraception for adolescents is vital, such that clinicians across all streams of health care who are involved in the care of young people should take the opportunity to educate and provide this care.

    更新日期:2019-06-16
  • Value of monopolar and bipolar radiofrequency ablation for the treatment of benign thyroid nodules
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2019-06-06
    Harald Dobnig, Karin Amrein

    Only a few thyroid nodules are perceived as functional or optically disturbing. If there is a need for action, surgical intervention is the long-term standard by which thermoablative procedures (radiofrequency-, laser-, microwave ablation, high intensity focused ultrasound) must be measured against in terms of safety, effectiveness and patient satisfaction. Prior to intervention assessment of the dignity of the nodule by ultrasound-guided fine needle aspiration is essential for cold and warm nodules, as is the confirmation of an inconspicuous cervical lymph node status. The short-term treatment results of these newer interventions in terms of nodule volume reduction and symptomatic improvement are promising and the general complication rate of the procedures is low. Since functional thyroid parenchyma is preserved, maintaining normal thyroid status is the rule. The procedure is usually performed on an outpatient basis, under local anesthesia and monitoring. The subsequent convalescence is usually very short. Most studies are available on monopolar radiofrequency ablation. Several professional societies have defined indications for radiofrequency ablation (RFA), but these need to be further refined based on practical experience and literature. An acceptable long-term recurrence rate still has to be proven for practically all thermoablative methods, for monopolar RFA limited long-term data are encouraging so far. The recurrence rate as well as patient satisfaction will provide the basis for a meaningful overall cost-benefit analysis in the future.

    更新日期:2019-06-07
  • Impact of continuous intraoperative vagus stimulation on intraoperative decision making in favor of or against bilateral surgery in benign goiter
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2019-06-06
    Rick Schneider, Andreas Machens, Gregory Randolph, Dipti Kamani, Kerstin Lorenz, Henning Dralle

    The advent of continuous vagus stimulation (CVS), eliminating lag time between nerve preparation with potential trauma and stimulation, has transformed the intraoperative surgical strategy in thyroid surgery. Continuous intraoperative nerve monitoring empowers the surgeon to be optimally aware of traction-related injury to the recurrent laryngeal nerve (RLN). Electromyographic precursor lesions, called combined events, prompt surgeons to cease harmful surgical maneuvers and release the nerve before damage to the nerve is established. Complete RLN recovery, defined as restitution of the nerve amplitude to ≥50 % of baseline, assures the surgeon that it is safe to pursue completion surgery of the contralateral side in one porcedure. If this restitution is incomplete or absent (<50 % of amplitude baseline) immediate vocal cord paralysis is likely and it is advisable to delay completion surgery until the nerve has fully recovered. This review summarizes the tremendous progress made in this dynamic field, delineating the extent to which CVS has changed the landscape: tailoring intraoperative decision making to determine the safest course of action for patients with benign goiter.

    更新日期:2019-06-07
  • Indications, Benefits And Risks Of Transoral Thyroidectomy
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2019-06-04
    Daqi Zhang, Dawon Park, Hui Sun, Angkoon Anuwong, Ralph Tufano, Hoon Yub Kim, Gianlorenzo Dionigi

    The advancement of minimally invasive surgery in the field of endocrine surgery over the last 2 decades has fostered the attempt of natural orifice transluminal endoscopic surgery (NOTES) for thyroidectomy and parathyroidectomy via oral incisions. This technically demanding surgery is currently being evaluated in a number of specialised centres. The procedure has gained popularity worldwide and is performed in more than 50 centres. By retrieving information from published or presented articles and direct personal communications, this study reports several issues to enable and optimise correct patient and surgeon candidacy, present the advantages and prevent novel complications under the standards of open thyroid surgery. Not all patients are eligible for the transoral approach. Transoral endoscopic and robotic procedures were described and critically analysed in this study.

    更新日期:2019-06-04
  • Surgical Management of the Compromised Recurrent Laryngeal Nerve in Thyroid Cancer
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2019-06-04
    Marika D. Russell, Dipti Kamani, Gregory W. Randolph

    Surgical management of thyroid cancer requires careful consideration of the recurrent laryngeal nerve and its impact on glottic function. Management of the compromised recurrent laryngeal nerve is a complex task, requiring synthesis of multiple elements. The surgeon must have an appreciation for preoperative recurrent laryngeal nerve function, intraoperative anatomic and electromyographic information, disease characteristics, and relevant patient factors. Preoperative clinical evaluation including preoperative laryngoscopy and assessment of recurrent laryngeal nerve risk is essential to formulating a surgical plan and providing appropriate patient counseling. Intraoperative neuromonitoring information has significant implications for surgical management of the injured or invaded recurrent laryngeal nerve and informs strategy with respect to staging of bilateral surgery. Disease characteristics and patient-related factors, including patient preference, must be considered with intraoperative decision-making. Multidisciplinary discussion and patient communication are essential for effective management and successful surgical outcome.

    更新日期:2019-06-04
  • Risk-Oriented Concept of Treatment for Intrathyroid Papillary Thyroid Cancer
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2019-06-04
    Dana M. Hartl, Julien Hadoux, Joanne Guerlain, Ingrid Breuskin, Fabienne Haroun, Sophie Bidault, Sophie Leboulleux, Livia Lamartina

    Adapting treatment and follow-up according to the risk of recurrence and/or death from thyroid cancer is a relatively recent concept of “personnalized” medicine, developed particularly to avoid overtreatment of low-risk thyroid cancer which represents the majority of thyroid cancers diagnosed in the world today. For low-risk thyroid cancer, this decrease in extent of treatment involves the extent of surgery—total thyroidectomy, lobectomy or no surgery with active surveillance—but also the indications, doses and methods of stimulation when or if administering radioactive iodine (RAI), the indication for suppressive thyroxin therapy and the extent and modalities for follow-up that should be adapted to the risk of recurrence. The aim is to optimize medical resources and quality of life, particulary for low-risk patients whose life expectancy is that of the general population.

    更新日期:2019-06-04
  • Modern neuro-ophthalmological evaluation of patients with pituitary disorders
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2019-05-30
    Anne-Laure Vié, Gérald Raverot

    Pituitary adenomas can manifest as ophthalmological symptoms, such as decreased vision, impaired visual field or diplopia. It is important to recognize these neuro-ophthalmological syndromes to achieve early diagnosis and treatment and to improve prognosis. Currently, ophthalmological examination includes precise measuring instruments, such as optical coherence tomography (OCT), which allows the evaluation of optic atrophy related to compression of the anterior optic tract. These measurements are reproducible and are useful for diagnostic and prognostic evaluation. In this review, we describe the ophthalmological syndromes associated with pituitary tumours: anterior optic pathway compression, followed by oculomotor disorders and pituitary apoplexy.

    更新日期:2019-05-31
  • Modern Imaging of Pituitary Adenomas
    Best Pract. Res. Clin. Endocrinol. Metab. (IF 3.808) Pub Date : 2019-05-28
    Waiel Bashari, Russell Senanayake, Antía Fernández-Pombo, Daniel Gillett, Olympia Koulouri, Andrew S. Powlson, Tomasz Matys, Daniel Scoffings, Heok Cheow, Iosif Mendichovszky, Mark Gurnell

    Decision-making in pituitary disease is critically dependent on high quality imaging of the sella and parasellar region. Magnetic resonance imaging (MRI) is the investigation of choice and, for the majority of patients, combined T1 and T2 weighted sequences provide the information required to allow surgery, radiotherapy (RT) and/or medical therapy to be planned and long-term outcomes to be monitored. However, in some cases standard clinical MR sequences are indeterminate and additional information is needed to help inform the choice of therapy for a pituitary adenoma (PA). This article reviews current recommendations for imaging of PA, examines the potential added value that alternative MR sequences and/or CT can offer, and considers how the use of functional/molecular imaging might allow definitive treatment to be recommended for a subset of patients who would otherwise be deemed unsuitable for (further) surgery and/or RT.

    更新日期:2019-05-29
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