Pituitary abscess: a descriptive analysis of a series of 19 patients-a multi-center experience.

OBJECTIVES: Pituitary abscess (PA) accounts for only 0.3-0.5% of sellar masses, and the lack of specific clinical symptoms makes diagnosing PA difficult without a surgical biopsy. In clinical practice, PA is often mistaken for cystic pituitary adenoma, craniopharyngioma, and Rathke's cyst. Thus, this study aims to investigate challenges in diagnosing PA and evaluate the importance of combining intraoperative surgery with postoperative antibiotic treatment. METHODS: We conducted a retrospective analysis of 19 patients diagnosed with PA through histopathology. All patients underwent transsphenoidal surgery (TSS) for pituitary adenomas after undergoing comprehensive preoperative evaluations, including routine tests, endocrine assay, and imaging examination. Furthermore, we compared different treatments for pituitary abscess (PA) to determine the most effective approach for achieving a favorable prognosis. RESULTS: The most prevalent symptom of PA was headache, especially in the frontal-temporal and vertex regions, ranging from mild to moderate severity. Hypopituitarism-related symptoms were also frequently observed, including hypaphrodisia, cold sensitivity, fatigue, weight loss, polyuria, and amenorrhea. Twelve patients exhibited abnormalities in endocrinology examinations. Diagnosing PA correctly is challenging. In our study, none of the patients were correctly diagnosed with PA prior to surgery, and many sellar lesions were misdiagnosed. The favorable prognosis was largely attributed to surgical intervention and active postoperative antibiotic therapy. CONCLUSIONS: Given the lack of clarity in preoperative diagnosis, typical intraoperative findings and effective antibiotics treatment are more indicative of the correct diagnosis than other tests. In terms of therapy, optimal surgical intervention and active postoperative antibiotic treatment contribute to resolving the challenges posed by PA.

The biological behavior and clinical outcome of pituitary adenoma are affected by the microenvironment.

BACKGROUND: Pituitary adenoma is one of the most common brain tumors. Most pituitary adenomas are benign and can be cured by surgery and/or medication. However, some pituitary adenomas show aggressive growth with a fast growth rate and are resistant to conventional treatments such as surgery, drug therapy, and radiation therapy. These tumors, referred to as refractory pituitary adenomas, often relapse or regrow in the early postoperative period. The tumor microenvironment (TME) has recently been identified as an important factor affecting the biological manifestations of tumors and acts as the main battlefield between the tumor and the host immune system. MAIN BODY: In this review, we focus on describing TME in pituitary adenomas and refractory pituitary adenomas. Research on the immune microenvironment of pituitary adenomas is currently focused on immune cells such as macrophages and lymphocytes, and extensive research and experimental verifications are still required regarding other components of the TME. In particular, studies are needed to determine the role of the TME in the specific biological behaviors of refractory pituitary adenomas, such as high invasion, fast recurrence rate, and high tolerance to traditional treatments and to identify the mechanisms involved. CONCLUSION: Overall, we summarize the similarities and differences between the TME of pituitary adenomas and refractory pituitary adenomas as well as the changes in the biological behavior of pituitary adenomas that may be caused by the microenvironment. These changes greatly affect the outcome of patients.

Treatment of hyperprolactinemia in women: A Position Statement from the Brazilian Federation of Gynecology and Obstetrics Associations (Febrasgo) and the Brazilian Society of Endocrinology and Metabolism (SBEM).

Dopamine agonists are the first line of treatment for patients with symptomatic hyperprolactinemia due to prolactinomas and in those with idiopathic hyperprolactinemia. Treatment with these agents is effective in 80%-90% of the cases. Infertility treatment of patients with hyperprolactinemia is also carried out with dopamine agonists, aiming for the normalization of prolactin levels. The risk of symptomatic growth of prolactinomas during pregnancy is dependent on the tumor's size, duration of previous treatments, and prolactin levels. Notably, the corresponding risk is relatively low in cases of microprolactinomas (<5%). Remission of hyperprolactinemia occurs in about 30% of the patients after drug treatment and may also occur after pregnancy and menopause. The use of some drugs, such as antidepressants and antipsychotics, is a frequent cause of hyperprolactinemia, and managing this occurrence involves unique considerations. This position statement by the Brazilian Federation of Gynecology and Obstetrics Associations (Febrasgo) and Brazilian Society of Endocrinology and Metabolism (SBEM) addresses the recommendations for measurement of serum prolactin levels and the investigations of symptomatic and asymptomatic hyperprolactinemia and drug-induced hyperprolactinemia in women.

Prolactin-secreting pituitary adenomas: male-specific differences in pathogenesis, clinical presentation and treatment.

Prolactinomas (PRLomas) constitute approximately half of all pituitary adenomas and approximately one-fifth of them are diagnosed in males. The clinical presentation of PRLomas results from direct prolactin (PRL) action, duration and severity of hyperprolactinemia, and tumor mass effect. Male PRLomas, compared to females, tend to be larger and more invasive, are associated with higher PRL concentration at diagnosis, present higher proliferative potential, are more frequently resistant to standard pharmacotherapy, and thus may require multimodal approach, including surgical resection, radiotherapy, and alternative medical agents. Therefore, the management of PRLomas in men is challenging in many cases. Additionally, hyperprolactinemia is associated with a significant negative impact on men's health, including sexual function and fertility potential, bone health, cardiovascular and metabolic complications, leading to decreased quality of life. In this review, we highlight the differences in pathogenesis, clinical presentation and treatment of PRLomas concerning the male sex.

Consensus guideline for the diagnosis and management of pituitary adenomas in childhood and adolescence: Part 1, general recommendations.

Tumours of the anterior part of the pituitary gland represent just 1% of all childhood (aged <15 years) intracranial neoplasms, yet they can confer high morbidity and little evidence and guidance is in place for their management. Between 2014 and 2022, a multidisciplinary expert group systematically developed the first comprehensive clinical practice consensus guideline for children and young people under the age 19 years (hereafter referred to as CYP) presenting with a suspected pituitary adenoma to inform specialist care and improve health outcomes. Through robust literature searches and a Delphi consensus exercise with an international Delphi consensus panel of experts, the available scientific evidence and expert opinions were consolidated into 74 recommendations. Part 1 of this consensus guideline includes 17 pragmatic management recommendations related to clinical care, neuroimaging, visual assessment, histopathology, genetics, pituitary surgery and radiotherapy. While in many aspects the care for CYP is similar to that of adults, key differences exist, particularly in aetiology and presentation. CYP with suspected pituitary adenomas require careful clinical examination, appropriate hormonal work-up, dedicated pituitary imaging and visual assessment. Consideration should be given to the potential for syndromic disease and genetic assessment. Multidisciplinary discussion at both the local and national levels can be key for management. Surgery should be performed in specialist centres. The collection of outcome data on novel modalities of medical treatment, surgical intervention and radiotherapy is essential for optimal future treatment.

Consensus guideline for the diagnosis and management of pituitary adenomas in childhood and adolescence: Part 2, specific diseases.

Pituitary adenomas are rare in children and young people under the age of 19 (hereafter referred to as CYP) but they pose some different diagnostic and management challenges in this age group than in adults. These rare neoplasms can disrupt maturational, visual, intellectual and developmental processes and, in CYP, they tend to have more occult presentation, aggressive behaviour and are more likely to have a genetic basis than in adults. Through standardized AGREE II methodology, literature review and Delphi consensus, a multidisciplinary expert group developed 74 pragmatic management recommendations aimed at optimizing care for CYP in the first-ever comprehensive consensus guideline to cover the care of CYP with pituitary adenoma. Part 2 of this consensus guideline details 57 recommendations for paediatric patients with prolactinomas, Cushing disease, growth hormone excess causing gigantism and acromegaly, clinically non-functioning adenomas, and the rare TSHomas. Compared with adult patients with pituitary adenomas, we highlight that, in the CYP group, there is a greater proportion of functioning tumours, including macroprolactinomas, greater likelihood of underlying genetic disease, more corticotrophinomas in boys aged under 10 years than in girls and difficulty of peri-pubertal diagnosis of growth hormone excess. Collaboration with pituitary specialists caring for adult patients, as part of commissioned and centralized multidisciplinary teams, is key for optimizing management, transition and lifelong care and facilitates the collection of health-related quality of survival outcomes of novel medical, surgical and radiotherapeutic treatments, which are currently largely missing.

A proposed clinical classification for pituitary neoplasms to guide therapy and prognosis.

No comprehensive classification system that guides prognosis and therapy of pituitary adenomas exists. The 2022 WHO histopathology-based classification system can only be applied to lesions that are resected, which represent few clinically significant pituitary adenomas. Many factors independent of histopathology provide mechanistic insight into causation and influence prognosis and treatment of pituitary adenomas. We propose a new approach to guide prognosis and therapy of pituitary adenomas by integrating clinical, genetic, biochemical, radiological, pathological, and molecular information for all adenomas arising from anterior pituitary cell lineages. The system uses an evidence-based scoring of risk factors to yield a cumulative score that reflects disease severity and can be used at the bedside to guide pituitary adenoma management. Once validated in prospective studies, this simple manageable classification system could provide a standardised platform for assessing disease severity, prognosis, and effects of therapy on pituitary adenomas.

[Tumor predisposition in endocrinology - from MEN to FIPA]. / Tumorprädisposition in der Endokrinologie ­ von MEN bis FIPA.

Understanding genetic predisposition has a significant impact on the management of patients with endocrine tumours, including therapy, early detection and prevention. These tumours, which develop as part of a familial predisposition, often manifest early in life and frequently affect several endocrine organs. In the following article, both common syndromes, such as multiple endocrine neoplasia (MEN) syndromes, and rare syndromes, such as familial isolated pituitary adenoma (FIPA), are presented based on their indicator diseases.

Clinical Characteristics and Management of Cosecreting Thyroid Stimulating Hormone or Prolactin Pituitary Growth Hormone Adenomas: A Case-Control Study.

OBJECTIVE: Cosecreting thyroid stimulating hormone (TSH) or prolactin (PRL) in patients with pituitary growth hormone (GH) adenomas has been rarely reported. Our study aimed to elucidate their clinical characteristics. METHODS: We retrospectively collected data of 22 cases of cosecreting GH and TSH pituitary adenomas [(GH+TSH)oma] and 10 cases of cosecreting GH and PRL pituitary adenomas [(GH+PRL)oma] from Beijing Tiantan Hospital, Capital Medical University between January 2009 and January 2023. The clinical manifestation, preoperative hormone levels, imaging features, pathologic characteristics, and biochemical remission rates were compared among 335 patients with solo-secreting GH adenomas (GHoma) and 49 patients with solo-secreting TSH adenoma (TSHoma). Patients with (GH+TSH)oma and (GH+PRL)oma were grouped according to biochemical remission to explore the risk factors leading to biochemical nonremission. RESULTS: Cosecreting pituitary GH adenomas had various clinical manifestations and a larger tumor volume and were more likely to invade the cavernous sinus bilaterally and compress the optic chiasm. GH and TSH levels were lower in (GH+TSH)oma than in GHoma or TSHoma. Solo part remission was observed both in (GH+TSH)oma and (GH+PRL)oma. Cavernous sinus invasion was an independent risk factor for biochemical nonremission in patients with (GH+TSH)oma and (GH+PRL)oma. CONCLUSIONS: The clinical manifestation of (GH+TSH)oma and (GH+PRL)oma may be atypical. When screening for pituitary adenomas, a comprehensive evaluation of all pituitary target gland hormones is needed. Cosecreting pituitary GH adenomas are more aggressive and surgery is often unable to completely remove the tumor, requiring pharmacologic or radiological treatment if necessary. Clinicians should give high priority to biochemical remission, although solo part remission may occur.

Integrating Systemic Therapies into the Multimodality Therapy of Patients with Craniopharyngioma.

OPINION STATEMENT: The integration of targeted therapy into the multimodal management of craniopharyngiomas represents a significant advancement in the field of neuro-oncology. Historically, the management of these tumors has been challenging due to their proximity to vital brain structures, necessitating a delicate balance between tumor control and the preservation of neurological function. Traditional treatment modalities, such as surgical resection and radiation, while effective, carry their own set of risks, including potential damage to surrounding healthy tissues and the potential for long-term side effects. Recent insights into the molecular biology of craniopharyngiomas, particularly the discovery of the BRAF V600E mutation in nearly all papillary craniopharyngiomas, have paved the way for a targeted systemic treatment approach. However, advances have been limited for adamantinomatous craniopharyngiomas. The success of BRAF/MEK inhibitors in clinical trials underscores the potential of these targeted therapies not only to control tumor growth but also to reduce the need for more invasive treatments, potentially minimizing treatment-related complications. However, the introduction of these novel therapies also brings forth new challenges, such as determining the optimal timing, sequencing, and duration of targeted treatments. Furthermore, there are open questions regarding which specific BRAF/MEK inhibitors to use, the potential need for combination therapy, and the strategies for managing intolerable adverse events. Finally, ensuring equitable access to these therapies, especially in healthcare systems with limited resources, is crucial to prevent widening healthcare disparities. In conclusion, targeted therapy with BRAF/MEK inhibitors holds great promise for improving outcomes and quality of life for patients with BRAF-mutated craniopharyngiomas. However, additional research is needed to address the questions that remain about its optimal use and integration into comprehensive treatment plans.

[Chinese expert consensus on diagnosis and treatment of craniopharyngioma (2024)].

Craniopharyngioma is a sellar tumor with benign pathology and malignant clinical manifestations. Partial resection plus radiotherapy, internal radiation therapy and chemotherapy are the conventional treatment strategies forcraniopharyngioma in most hospitals, which cause many patients to lose the best time to cure and make reoperation more difficult after recurrence. Therefore, the Pediatric Group of Chinese Society of Neurosurgery, Chinese Medical Association organized domestic experts from Pediatrics, Pediatric Neurosurgery, Genetics and Endocrinology to reach a consensus on the following topics: pathological and molecular genetic classification of craniopharyngioma, basic principles of curing tumors, surgical classification of tumors, surgical approach, perioperative and long-term treatment plan. This is expected to improve the quality of life and prognosis of patients, and further standardize the diagnosis and treatment of craniopharyngioma.

Sleep-related challenges and family functioning in children and adolescents previously treated for craniopharyngioma.

PURPOSE: We investigated sleep-related challenges and their association with family functioning in children and adolescents previously treated for craniopharyngioma. DESIGN: Quantitative approach using psychometrically validated measures. SAMPLE: Thirty-nine children and adolescents who had been treated for craniopharyngioma and their primary caregivers. METHODS: Caregivers and youth completed measures of family functioning, family routines, daytime sleepiness, and children's sleep patterns. FINDINGS: Children and adolescents with craniopharyngioma had significantly higher ratings of self-reported excessive daytime sleepiness, bedtime fears/worries, and restless legs symptoms compared to their relatively healthy peers. Lack of family routines and poor family functioning were related to poor sleep-related outcomes and increased excessive daytime sleepiness. IMPLICATIONS FOR PSYCHOSOCIAL PROVIDERS: Providers should consider assessing sleep difficulties in pediatric brain tumor survivors from a family systems perspective. Intervening on family-related factors may help improve sleep and other health-related outcomes, whereas intervening on sleep may help improve family functioning.

Metabolic Syndrome Components in Patients with Pituitary Adenoma.

Pituitary adenomas are benign tumors of the anterior portion of the pituitary gland (adenohypophysis), representing the 25% of all the tumor alterations. Pituitary adenomas are classified by the type of hormone secreted, cellularity, size, and structural alterations by the hormonal segregation. The diagnosis consists on the histopathological identification of cell types and the image-guided by magnetic resonance or tomography; the treatment can be both pharmacological and surgical. Metabolic Syndrome is the set of clinical conditions that increase the risk of cardiovascular diseases with an estimated prevalence of 25% worldwide. The alterations of metabolic syndrome are obesity, hypertension, dyslipidemia, insulin resistance, and diabetes mellitus type II. Pituitary adenomas and metabolic syndrome have an important relationship, hormone-secreting by pituitary adenomas affects a myriad of signaling pathways, which allows a favorable environment for the appearance of the metabolic syndrome. Moreover, patients with pituitary adenomas are shown to have an improvement in metabolic parameters after the medical/surgical treatment. The objective of this review is to explore the possible mechanisms through which PAs contributes to MetSx.

The feasibility and acceptability of mobile ecological momentary assessment to evaluate sleep, family functioning, and affect in patients with pediatric craniopharyngioma.

PURPOSE/OBJECTIVES: We aimed to assess the feasibility and acceptability of mobile ecological momentary assessment (mEMA) for youth with craniopharyngioma and evaluate daily associations among family functioning, affect, and sleep difficulties. DESIGN/RESEARCH APPROACH: Youth completed two mEMA diaries per day for one week. SAMPLE/PARTICIPANTS: Thirty-nine youth who underwent surgery and proton radiotherapy (when indicated) for craniopharyngioma. METHODS/METHODOLOGICAL APPROACH: Descriptive statistics and multi-level modeling were used to examine feasibility and acceptability of mEMA and daily associations among family functioning, affect, and sleep. FINDINGS: Youth reported satisfaction and minimal burden from completing daily mEMA diaries. Poorer family functioning was not related to lower sleep efficiency. CONCLUSIONS/INTERPRETATION: mEMA is an acceptable and feasible method for evaluating sleep and related variables in children and adolescents with craniopharyngioma. IMPLICATIONS FOR PSYCHOSOCIAL PROVIDERS OR POLICY: Results highlight the utility of gathering mEMA data in youth at elevated risk for sleep difficulties as a function of their illness/treatment.

Global pediatric craniopharyngioma management modalities and outcomes.

INTRODUCTION: Pediatric craniopharyngioma is a complex pathology, with optimal management involving a multidisciplinary approach and thoughtful care coordination. To date, no studies have compared various treatment modalities and outcomes described in different global regions. We conducted a comprehensive systematic review to compare demographics, clinical presentation, treatment approach and outcomes of children diagnosed with craniopharyngioma globally. METHODS: A systematic review was conducted in accordance with the Preferred Reporting Item for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Search terms included "craniopharyngioma" and country-specific terms. Inclusion criteria included full-text studies published between 2000-2022, primarily examining pediatric patients 18-years old or younger diagnosed with craniopharyngioma, and reporting management and outcomes of interest. Data extracted included country of origin, demographical data, initial presentation and treatment modality, and outcomes. Descriptive statistics and between-group comparisons based on country of origin were performed. RESULTS: Of 797 search results, 35 articles were included, mostly originating from high-income countries (HIC) (n = 25, 71.4%). No studies originated from low-income countries (LIC). When comparing HIC to middle-income countries (MIC), no differences in patient demographics were observed. No differences in symptomatology at initial presentation, tumor type, surgical approach or extent of surgical resection were observed. HIC patients undergoing intracystic therapy were more likely to receive bleomycin (n = 48, 85.7%), while the majority of MIC patients received interferon therapy (n = 10, 62.5%). All MIC patients undergoing radiation therapy underwent photon therapy (n = 102). No statistically significant differences were observed in postoperative complications or mean follow-up duration between HIC and MIC (78.1 ± 32.2 vs. 58.5 ± 32.1 months, p = 0.241). CONCLUSION: Pediatric craniopharyngioma presents and is managed similarly across the globe. However, no studies originating from LICs and resource-poor regions examine presentation and management to date, representing a significant knowledge gap that must be addressed to complete the global picture of pediatric craniopharyngioma burden and management.

Pediatric craniopharyngioma: a 20-year study on epidemiological features, clinical presentation, and survival outcomes in a tertiary care center from LMIC.

INTRODUCTION: Craniopharyngioma constitutes approximately 10% of primary brain tumors in children. It can cause considerable morbidity and mortality due to the local aggressiveness of the tumor itself or its management affecting the hypothalamus-pituitary axis and optic pathway involvement. There is very scarce data available from LMIC which makes the management controversial where multidisciplinary teams are already not available in most of the centers. This is a single-center cross-sectional retrospective review of 20-year record of 49 patients with craniopharyngioma treated between 2001 and 2020 at Aga Khan University Hospital, a tertiary care center in Karachi, Pakistan. METHODS: We have assessed the epidemiological data of children presenting with the diagnosis of craniopharyngioma, treatment modalities used, and neurological, endocrine, and hypothalamic complications in these patients. The assessment involved a retrospective review of medical records and medical follow-up. RESULTS: Out of a total of 49 patients, 26 (53%) were male, and 23 (46.9%) were female. The mean age was 9.5 years (SD ± 4.5 years). Most common symptoms at initial presentation were headache 41 (83.6%), visual deficit 40 (81.6%), nausea and vomiting 26 (53%), and endocrine abnormalities 16 (32%). Treatment modalities used at our center include gross total resection 11 (22%) and subtotal resection 38 (77%) out of total, while 6 (12.2%) patients received intracystic interferon. Histopathologic findings of the majority of patients (40 (81%)) revealed an adamantinomatous type of tumor. Only 23 (46.9%) children followed in clinic post-op. Median follow-up after craniopharyngioma presentation was 5 years (± 2.1 SD, range: 2-10 years). Pituitary hormone deficiencies (98%) and visual disturbances (75%) were the most common long-term health conditions observed. CONCLUSIONS: Since pituitary hormone deficiencies and visual disturbance were the most common long-term health conditions observed in our study, these patients require a multidisciplinary team follow-up to improve their quality of life.

Aerobic exercise interventions to address impaired quality of life in patients with pituitary tumors.

Patients with pituitary tumors may experience persistent fatigue and reduced physical activity, based on subjective measures after treatment. These symptoms may persist despite gross total resection of their tumors and biochemical normalization of pituitary function. While reduced quality of life has been commonly acknowledged in pituitary tumor patients, there is a lack of studies on what interventions may be best implemented to ameliorate these issues, particularly when hormonal levels have otherwise normalized. Aerobic exercise programs have been previously described to ameliorate symptoms of chronic fatigue and reduced physical capacity across a variety of pathologies in the literature. As such, a prescribed aerobic exercise program may be an underrecognized but potentially impactful intervention to address quality of life in pituitary tumor patients. This review seeks to summarize the existing literature on aerobic exercise interventions in patients with pituitary tumors. In addition, future areas of study are discussed, including tailoring exercise programs to the hormonal status of the patient and incorporating more objective measures in monitoring response to interventions.

What Are Pituitary Adenomas?

This JAMA Patient Page describes the types and symptoms of pituitary adenomas and their diagnosis and treatment.

Update on Current Evidence for the Diagnosis and Management of Nonfunctioning Pituitary Neuroendocrine Tumors.

Pituitary neuroendocrine tumors (PitNETs) are the third most frequently diagnosed intracranial tumors, with nonfunctioning PitNETs (nfPitNETs) accounting for 30% of all pituitary tumors and representing the most common type of macroPitNETs. NfPitNETs are usually benign tumors with no evidence of hormone oversecretion except for hyperprolactinemia secondary to pituitary stalk compression. Due to this, they do not typically present with clinical syndromes like acromegaly, Cushing's disease or hyperthyroidism and instead are identified incidentally on imaging or from symptoms of mass effects (headache, vision changes, apoplexy). With the lack of effective medical interventions, first-line treatment is transsphenoidal surgical resection, however, nfPitNETs often have supra- or parasellar extension, and total resection of the tumor is often not possible, resulting in residual tumor regrowth or reoccurrence. While functional PitNETs can be easily followed for recurrence using hormonal biomarkers, there is no similar parameter to predict recurrence in nfPitNETs, hence delaying early recognition and timely management. Therefore, there is a need to identify prognostic biomarkers that can be used for patient surveillance and as therapeutic targets. This review focuses on summarizing the current evidence on nfPitNETs, with a special focus on potential new biomarkers and therapeutics.

Diagnosis and management of prolactin-secreting pituitary adenomas: a Pituitary Society international Consensus Statement.

This Consensus Statement from an international, multidisciplinary workshop sponsored by the Pituitary Society offers evidence-based graded consensus recommendations and key summary points for clinical practice on the diagnosis and management of prolactinomas. Epidemiology and pathogenesis, clinical presentation of disordered pituitary hormone secretion, assessment of hyperprolactinaemia and biochemical evaluation, optimal use of imaging strategies and disease-related complications are addressed. In-depth discussions present the latest evidence on treatment of prolactinoma, including efficacy, adverse effects and options for withdrawal of dopamine agonist therapy, as well as indications for surgery, preoperative medical therapy and radiation therapy. Management of prolactinoma in special situations is discussed, including cystic lesions, mixed growth hormone-secreting and prolactin-secreting adenomas and giant and aggressive prolactinomas. Furthermore, considerations for pregnancy and fertility are outlined, as well as management of prolactinomas in children and adolescents, patients with an underlying psychiatric disorder, postmenopausal women, transgender individuals and patients with chronic kidney disease. The workshop concluded that, although treatment resistance is rare, there is a need for additional therapeutic options to address clinical challenges in treating these patients and a need to facilitate international registries to enable risk stratification and optimization of therapeutic strategies.