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PURPOSE: Silent corticotroph adenomas (SCAs) present clinically as non-functioning adenomas (NFAs) but are immunopositive for adrenocorticotrophic hormone (ACTH) without biochemical and clinical manifestation of hypercortisolism. Pathologic examination of resected NFAs that demonstrate positive ACTH and/or TPIT expression confirms its corticotroph lineage. SCAs comprise up to 20% of NFAs and exhibit a higher rate of recurrence. Studies of molecular mechanisms have generated multiple hypotheses on SCA tumorigenesis, pathophysiology, and growth that as yet remain to be proven. An improved understanding of their pathologic and clinical characteristics is needed. METHODS: A literature review was performed using PubMed to identify research reports and clinical case series on SCAs. RESULTS: Up to date findings regarding epidemiology, mechanisms of pathogenesis, differentiation, progression, and growth, as well as clinical presentation, postoperative course, and treatment options for patients with SCAs are presented. Pooled results demonstrate that 25-40% of cases show cavernous sinus invasion, preoperative hypopituitarism, new-onset hypopituitarism, and recurrence. CONCLUSION: This article reviews the incidence, molecular pathology, and clinical behavior of these unique non-functioning pituitary corticotroph adenomas, and highlights the need for rigorous monitoring for recurrences and hypopituitarism in patients with SCAs.
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Neoplasias Hipofisárias/epidemiologia , Adenoma Hipofisário Secretor de ACT/epidemiologia , Adenoma Hipofisário Secretor de ACT/patologia , Adenoma/epidemiologia , Adenoma/patologia , Feminino , Humanos , Incidência , Masculino , Neoplasias Hipofisárias/patologiaRESUMO
PURPOSE: Parasellar plasmacytomas are rare tumors localized to the sellar region arising from plasma cells. Knowledge of clinical, imaging, surgical, and pathological characteristics is limited to single case reports. METHODS: A retrospective analysis of five primary cases was conducted, followed by systematic review of English language articles using PubMed in accordance with PRISMA guidelines. RESULTS: Five primary case patients include four men and one woman, ages 60-77, followed up to 3 years. A systematic review identified 65 additional patients, of whom 65% presented with cranial nerve palsies and 15% with hypopituitarism. Sixteen percent had history of known multiple myeloma (MM) while 37% were diagnosed concurrently with MM on presentation of parasellar plasmacytoma. Imaging showed median tumor size of 38 mm (range, 4-70 mm), with MRI intensity similar to that of other sellar masses. Surgical biopsy with immunohistochemical studies confirmed plasmacytoma diagnosis. Eighty-one percent underwent parasellar radiotherapy, and chemotherapy initiated in 59% of the 69 patients with MM. Overall survival rate was 74% at follow-up (median 12 months), with 18% having parasellar recurrences and 38% progressing to systemic MM after presentation of a solitary plasmacytoma (median 3 months). CONCLUSIONS: Parasellar plasmacytomas are rare tumors that should be considered in the differential diagnosis for lesions involving the sella and arising from the clivus, especially when cranial nerve paresis is apparent, even in the absence of known MM. Although recurrence rates for parasellar plasmacytoma is low, patients should be monitored for progression to MM. Treatment depends on the presence of systemic disease at diagnosis.
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Plasmocitoma/metabolismo , Idoso , Feminino , Humanos , Masculino , Mieloma Múltiplo/metabolismo , Estudos RetrospectivosRESUMO
PURPOSE: Silent corticotroph adenomas (SCAs) comprise 20% of all corticotroph adenomas and 3-19% of nonfunctioning adenomas (NFAs). As they do not manifest clinical or biochemical hypercortisolism, they are diagnosed after pathologic examination of resected tumor tissue demonstrates positive ACTH expression. While preoperative features are similar to those of NFAs, SCAs may have more cavernous sinus invasion. Further, patients with SCAs tend to have more frequent and earlier recurrences than those with NFAs, often necessitating multiple surgeries and other modalities of treatment. This article reviews the incidence, pathogenesis, and clinical behavior of SCAs. METHODS: A systematic literature review was performed using PubMed for information regarding SCAs. RESULTS: Up to date findings regarding epidemiology, pathogenesis, pathology, clinical presentation, postoperative course, and management of patients with SCAs are presented. CONCLUSION: This review highlights the necessity of rigorous monitoring for recurrences and hypopituitarism in patients with SCAs.
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Adenoma Hipofisário Secretor de ACT , Adenoma , Adenoma Hipofisário Secretor de ACT/epidemiologia , Adenoma Hipofisário Secretor de ACT/patologia , Adenoma Hipofisário Secretor de ACT/cirurgia , Adenoma/epidemiologia , Adenoma/patologia , Adenoma/cirurgia , Doenças Assintomáticas , Humanos , Recidiva Local de Neoplasia , Resultado do TratamentoRESUMO
The objective of this study was to evaluate outcomes of endoscopic transsphenoidal surgery using a single-surgeon technique as an alternative to the more commonly employed two-surgeon, three-hand method. Three hundred consecutive endoscopic transsphenoidal procedures performed over a 5 year period from 2006 to 2011 were reviewed. All procedures were performed via a binasal approach utilizing a single surgeon two handed technique with a pneumatic endoscope holder. Expanded enodnansal cases were excluded. Surgical technique, biochemical and surgical outcomes, and complications were analyzed. 276 patients underwent 300 consecutive surgeries with a mean follow-up period of 37 ± 22 months. Non-functioning pituitary adenoma (NFPA) was the most common pathology (n = 152), followed by growth hormone secreting tumors (n = 41) and Rathke's cleft cysts (n = 30). Initial gross total cyst drainage based on radiologic criteria was obtained in 28 cases of Rathke's cleft cyst, with 5 recurrences. For NFPA and other pathologies (n = 173) gross total resection was obtained in 137 cases, with a 92% concordance rate between observed and expected extent of resection. For functional adenoma, remission rates were 30/41 (73%) for GH-secreting, 12/12 (100%) for ACTH-secreting, and 8/17 (47%) for prolactin-secreting tumors. Post-operative complications included transient (11%) and permanent (1.4%) diabetes insipidus, hyponatremia (13%), and new anterior pituitary hormonal deficits (1.4%). CSF leak occurred in 42 cases (15%), and four patients required surgical repair. Two carotid artery injuries occurred, both early in the series. Epistaxis and other rhinological complications were noted in 10% of patients, most of which were minor and diminished as surgical experience increased. Fully endoscopic single surgeon transsphenoidal surgery utilizing a binasal approach and a pneumatic endoscope holder yields outcomes comparable to those reported with a two-surgeon method. Endoscopic outcomes appear to be better than those reported in microscope-based series, regardless of a one or two surgeon technique.
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Endoscopia/métodos , Procedimentos Neurocirúrgicos/métodos , Adulto , Cistos do Sistema Nervoso Central/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Hipofisárias/cirurgiaRESUMO
Osteoporosis related fractures contribute to morbidity and mortality in U.S. patients, placing a heavy financial burden on society. Randomized clinical trials involving over 30,000 subjects have established bisphosphonates' efficacy in reducing the incidence of fragility fractures. However, as bisphosphonates are retained for years in the skeleton, reports of adverse events from prolonged use are surfacing in the literature, namely, esophageal cancer, atrial fibrillation, osteonecrosis of the jaw, and atypical fracture development. The concept of a drug holiday has been proposed to potentially reduce incidence of these adverse events. This review will highlight the benefits and risks of bisphosphonate therapy and discuss the extension data available from the bisphosphonate trials. As randomized clinical trial evidence is not yet available on who may qualify for drug holiday, this review will provide suggestions for clinicians on identification of possible candidates and monitoring during a bisphosphonate drug holiday.
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Difosfonatos/efeitos adversos , Difosfonatos/uso terapêutico , Osteoporose/tratamento farmacológico , Fraturas por Osteoporose/prevenção & controle , Seleção de Pacientes , Fibrilação Atrial/induzido quimicamente , Fibrilação Atrial/epidemiologia , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/epidemiologia , Neoplasias Esofágicas/induzido quimicamente , Neoplasias Esofágicas/epidemiologia , Humanos , Incidência , Osteoporose/complicações , Fraturas por Osteoporose/epidemiologia , Medição de RiscoRESUMO
CONTEXT: Postoperative hyponatremia leads to prolonged hospital length of stay and readmission within 30 days. OBJECTIVE: To assess 3 strategies for reducing rates of postoperative hyponatremia and analyze risk factors for hyponatremia. DESIGN: Two retrospective analyses and 1 prospective study. SETTING: Tertiary referral hospital. PATIENTS: Patients undergoing transsphenoidal surgery for pituitary adenomas and other sellar and parasellar pathologies. INTERVENTION(S): Phase 1: no intervention. Phase 2: postoperative day (POD) 7 sodium testing and patient education. Phase 3: fluid restriction to 1 L/day on discharge in addition to phase 2 interventions. MAIN OUTCOME MEASURES: Rates of early and delayed hyponatremia and readmissions. Secondary outcomes were risk factors for hyponatremia and readmission costs. RESULTS: In phase 1, 296 patients underwent transsphenoidal surgery. Twenty percent developed early and 28% delayed hyponatremia. Thirty-eight percent underwent POD 7 sodium testing. Readmission rates were 15% overall and 4.3% for hyponatremia. In phase 2 (n = 316), 22% developed early and 25% delayed hyponatremia. Eighty-nine percent complied with POD 7 sodium testing. Readmissions were unchanged although severity of hyponatremia was reduced by 60%. In phase 3 (n = 110), delayed hyponatremia was reduced 2-fold [12.7%, relative risk (RR) = 0.52] and readmissions 3-fold [4.6%, RR = 0.30 (0.12-0.73)]; readmissions for hyponatremia were markedly reduced. Hyponatremia readmission increased costs by 30%. CONCLUSIONS: Restricting fluid to 1 L/day on discharge decreases rates of delayed hyponatremia and readmissions by 50%. Standardized patient education and POD 7 sodium testing decreases severity of hyponatremia but does not impact readmission rates. These protocols should be considered standard practice for patients undergoing transsphenoidal surgery.
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Hiponatremia , Neoplasias Hipofisárias , Humanos , Hiponatremia/epidemiologia , Hiponatremia/etiologia , Hiponatremia/prevenção & controle , Readmissão do Paciente , Neoplasias Hipofisárias/cirurgia , Neoplasias Hipofisárias/complicações , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Estudos Prospectivos , Estudos Retrospectivos , SódioRESUMO
BACKGROUND: Predictive markers of aggressive pituitary tumors have not been consistently demonstrated. Dural invasion and invasion-associated proteins, including matrix metalloproteinase-9 (MMP9) and cofilin, have been proposed to predict aggressive behavior and recurrence, but findings to date have been inconsistent. OBJECTIVE: To assess whether microscopic dural invasion predicts aggressive pituitary adenoma behavior and whether MMP9 and cofilin expression correlates with pathological and clinical invasion markers. METHODS: We retrospectively studied 328 consecutive pituitary mass resections by a single neurosurgeon at a single center; 254 were adenomas, and 98 had dural biopsies sent for routine pathological evaluation. Assessments included clinical features, postoperative course, and immunochemical expression of MMP9, cofilin, and phospho-cofilin. Recurrence was evaluated in those with at least 12 months of postoperative follow-up. RESULTS: Dural invasion was evident in 48% of biopsy specimens and was associated with male sex, larger tumors, suprasellar extension and sphenoid sinus invasion, cranial nerve palsies, and hypogonadism. Recurrence rates and the expression of MMP9, cofilin, and phospho-cofilin did not differ between those with and without dural invasion. However, differential expression of phospho-cofilin was associated with growth hormone deficiency and compressive pituitary mass effects. CONCLUSION: Dural invasion is associated with larger tumors, suprasellar and sphenoid sinus invasion, and pituitary failure but is not predictive of a more aggressive postoperative course. Routine dural biopsy is therefore of limited benefit in predicting postoperative recurrences. Cofilin expression may be an adjunctive biomarker of invasion in recurrent tumors, but MMP9 expression does not predict tumor behavior.
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Adenoma , Neoplasias Hipofisárias , Fatores de Despolimerização de Actina , Adenoma/patologia , Biomarcadores , Humanos , Masculino , Metaloproteinase 9 da Matriz , Neoplasias Hipofisárias/patologia , Estudos RetrospectivosRESUMO
Diabetic ketoacidosis (DKA) is a commonly encountered diagnosis in the general inpatient and intensive care unit settings. We report a rare case of pembrolizumab-induced DKA in a patient with bladder carcinoma in situ with no prior diagnosis of diabetes. Our case highlights the importance of understanding immune-related adverse events (IRAEs) as immunotherapy is becoming a mainstay of treatment for a variety of diagnoses. The rare side effect of DKA presented in this case is compared to the classical presentation of DKA secondary to type 1 diabetes mellitus (T1DM). We found that pembrolizumab-induced DKA presented with fewer symptoms than T1DM-induced DKA and did not present with serum antibodies that are typically present in T1DM. While management of DKA in the acute setting is unchanged regardless of the precipitating factor, this case demonstrates the importance of identifying the precipitant in order to pursue the appropriate diagnostic workup and long-term management.
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Management of aggressive pituitary adenomas is challenging due to a paucity of rigorous evidence supporting available treatment approaches. Recent guidelines emphasize the need to maximize standard therapies as well as the use of temozolomide and radiation therapy to treat disease recurrence. However, often these adenomas continue to progress over time, necessitating the use of additional targeted therapies which also impact quality of life and long-term outcomes. In this review, we present 9 cases of aggressive pituitary adenomas to illustrate the importance of a multidisciplinary, individualized approach. The timing and rationale for surgery, radiation therapy, temozolomide, somatostatin receptor ligands, and EGFR, VEGF, and mTOR inhibitors in each case are discussed within the context of evidence-based guidelines and clarify strategies for implementing an individualized approach in the management of these difficult-to-treat-adenomas.
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Adenoma/terapia , Neoplasias Hipofisárias/terapia , Adenoma/patologia , Adolescente , Adulto , Criança , Terapia Combinada , Feminino , Humanos , Masculino , Neoplasias Hipofisárias/patologia , Prognóstico , Adulto JovemRESUMO
CONTEXT: Approximately 10% to 20% of prolactinomas are resistant to dopamine agonist therapy. The ErbB signaling pathway may drive aggressive prolactinoma behavior. OBJECTIVE: We evaluated lapatinib, an ErbB1-epidermal growth factor receptor (EGFR)/ErbB2 or human EGFR2 (HER2) tyrosine kinase inhibitor (TKI), in aggressive prolactinomas. DESIGN: A prospective, phase 2a multicenter trial was conducted. SETTING: This study took place at a tertiary referral pituitary center. PATIENTS: Study participants included adults with aggressive prolactinomas showing continued tumor growth despite maximally tolerated dopamine agonist therapy. INTERVENTION: Intervention included oral lapatinib 1250 mg/day for 6 months. MAIN OUTCOME MEASURES: The primary end point was 40% reduction in any tumor dimension assessed by magnetic resonance imaging at study end; tumor response was assessed by Response Evaluation Criteria in Solid Tumors criteria. Secondary end points included prolactin (PRL) reduction, correlation of response with EGFR/HER2 expression, and safety. RESULTS: Owing to rigorous inclusion criteria, of 24 planned participants, only 7 consented and 4 were treated. None achieved the primary end point but 3 showed stable disease, including 2 with a 6% increase and 1 with a 16.8% decrease in tumor diameter. PRL response was not always concordant with tumor response, as 2 showed 28% and 59% increases in PRL. The fourth participant had a PRL-secreting carcinoma and withdrew after 3 months of lapatinib because of imaging and PRL progression. EGFR/HER2 expression did not correlate with treatment response. Lapatinib was well tolerated overall, with reversible grade 1 transaminitis in 2 patients, grade 2 rash in 2 patients, and grade 1 asymptomatic bradycardia in 2 patients. CONCLUSIONS: An oral TKI such as lapatinib may be an effective option for a difficult-to-treat patient with an aggressive prolactinoma.
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Antineoplásicos/uso terapêutico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Lapatinib/uso terapêutico , Neoplasias Hipofisárias/tratamento farmacológico , Prolactinoma/tratamento farmacológico , Receptor ErbB-2/antagonistas & inibidores , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Receptores ErbB/antagonistas & inibidores , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Hipofisárias/patologia , Prognóstico , Prolactinoma/patologia , Estudos Prospectivos , Adulto JovemRESUMO
BACKGROUND: A 40-year-old woman presented with galactorrhea and oligomenorrhea. She had a history of multiple ovarian cysts and pelvic pain. INVESTIGATIONS: Laboratory evaluation included measurements of the levels of estradiol, follicle-stimulating hormone, luteinizing hormone, prolactin, thyroid-stimulating hormone, free endogenous T4, the glycoprotein hormone alpha subunit, cortisol, adrenocorticotropic hormone, and insulin-like growth factor I. Radiological studies included MRI of the pituitary. DIAGNOSIS: Ovarian hyperstimulation syndrome caused by a pituitary adenoma, secreting follicle-stimulating hormone. MANAGEMENT: The patient underwent trans-sphenoidal resection of the adenoma, with subsequent normalization of hormonal values and symptoms.
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Hormônio Foliculoestimulante/metabolismo , Síndrome de Hiperestimulação Ovariana/etiologia , Neoplasias Hipofisárias/metabolismo , Adulto , Feminino , Hormônio Foliculoestimulante/sangue , Humanos , Hormônio Luteinizante/sangue , Imageamento por Ressonância Magnética , Síndrome de Hiperestimulação Ovariana/sangue , Neoplasias Hipofisárias/sangue , Neoplasias Hipofisárias/cirurgia , Prolactina/sangueRESUMO
Dopamine agonists (DA) are well established as first-line therapy for prolactinomas. These tumors express high levels of dopamine 2 receptors (D2R), leading to the strong efficacy of DA in reducing tumor size and hormonal secretion. Other pituitary tumor subtypes express D2R to varying degrees, leading to an extensive body of research into potential off-label use of DA in non-prolactinoma pituitary tumors. Preclinical models of Cushing's disease, acromegaly, and nonfunctioning pituitary tumors (NFPT) demonstrate D2R expression in cell lines and cultured tumors as well as effectiveness of DA in reducing hormonal secretion in functioning tumors and arresting tumor proliferation. Clinical studies have shown some efficacy of DA in treatment of these tumors. In Cushing's disease, DA therapy results in normalization of urinary cortisol levels in approximately 25% of patients, but reported rates of tumor shrinkage are very low; in acromegaly, DA therapy leads to normalization of insulin-like growth factor I and tumor shrinkage in approximately one-third of patients, and improved responses when used in combination with somatostatin receptor ligands. Among patients with NFPT, pooled results show 30% experience reduction of tumor size and 58% show stabilization of disease. DA therapy appears to have some clinical benefit in patients with non-prolactinoma pituitary tumors, and may be an option for medical therapy in some clinical scenarios.
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PURPOSE OF REVIEW: Treatment of aggressive pituitary tumours often yields suboptimal control of the tumour and confers significant morbidity. Lactotroph and corticotroph-derived tumours express ErbB receptors and ligands, and mutations in ubiquitin-specific protease 8 (USP8), which alters epidermal growth factor receptor (EGFR) degradation, have been implicated in Cushing disease pathogenesis. EGFR tyrosine kinase inhibitor (TKI) therapy has emerged as a potential new therapeutic approach for patients with aggressive prolactinomas and Cushing disease. RECENT FINDINGS: Using EGFR or human epidermal growth factor receptor 2-driven prolactin (PRL) promoters, transgenic mice develop large tumours that respond to TKI inhibition. In human corticotroph primary cultures, treatment with the pan-ErbB TKI canertinib as well as the EGFR TKI gefitinib suppresses proopiomelanocortin mRNA. USP8 mutations, detected in up to two-thirds of Cushing disease, may underlie the increase in EGFR signalling in these tumours. Human prolactinomas have differential ErbB receptor expression associated with aggressive behaviour and data from an ongoing clinical trial suggest that resistant prolactinomas may respond to the EGFR TKI lapatinib. SUMMARY: Preclinical and clinical models substantiate the role of the EGFR pathway in corticotroph and lactotroph adenomas. Although further study is needed, results to date suggest that targeting the ErbB pathway may be an effective therapeutic approach for patients with aggressive pituitary tumours.
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Neoplasias Hipofisárias/tratamento farmacológico , Prolactinoma/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pesquisa Translacional Biomédica , Animais , Linhagem Celular Tumoral , Receptores ErbB/antagonistas & inibidores , Gefitinibe , Humanos , Lapatinib , Camundongos , Camundongos Transgênicos , Neoplasias Hipofisárias/patologia , Prolactinoma/patologia , Quinazolinas/administração & dosagem , Pesquisa Translacional Biomédica/métodos , Pesquisa Translacional Biomédica/tendênciasRESUMO
OBJECTIVES: Posttraumatic stress disorder (PTSD) is associated with hypothalamus-pituitary-adrenal (HPA) axis response to stressors, but links to neurophysiological and neuroanatomical changes are unclear. The purpose of this study was to determine whether stress-induced cortisol alters negative feedback on pituitary corticotroph function and pituitary volume. DESIGN: Prospective controlled study in an outpatient clinic. METHODS: Subjects with PTSD and matched control subjects underwent pituitary volume measurement on magnetic resonance imaging, with pituitary function assessed by 24-hour urine free cortisol (UFC), 8:00 am cortisol, and adrenocorticotropic hormone (ACTH) levels, and ACTH levels after 2-day dexamethasone/corticotropin-releasing hormone test. Primary outcome was pituitary volume; secondary outcomes were ACTH area under the curve (AUC) and 24-hour UFC. RESULTS: Thirty-nine subjects were screened and 10 subjects with PTSD were matched with 10 healthy control subjects by sex and age. Mean pituitary volume was 729.7 mm3 [standard deviation (SD), 227.3 mm3] in PTSD subjects vs 835.2 mm3 (SD, 302.8 mm3) in control subjects. ACTH AUC was 262.5 pg/mL (SD, 133.3 pg/mL) L in PTSD vs 244.0 pg/mL (SD, 158.3 pg/mL) in control subjects (P = 0.80). In PTSD subjects, UFC levels and pituitary volume inversely correlated with PTSD duration; pituitary volume correlated with ACTH AUC in control subjects (Pearson correlation coefficient, 0.88, P = 0.0009) but not in PTSD subjects. CONCLUSIONS: The HPA axis may be downregulated and dysregulated in people with PTSD, as demonstrated by discordant pituitary corticotroph function and pituitary volume vs intact HPA feedback and correlation of pituitary volume with ACTH levels in healthy control subjects. The results suggest a link between pituitary structure and function in PTSD, which may point to endocrine targeted therapeutic approaches.
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BACKGROUND: Long-term remission rates from endoscopic transsphenoidal surgery for acromegaly and their relationship to prognostic indicators of disease aggressiveness are not well documented. OBJECTIVE: To investigate long-term remission rates in patients with acromegaly after endoscopic transsphenoidal surgery, and correlate this with molecular and radiographic markers of disease aggressiveness. METHODS: We identified all patients undergoing endoscopic transsphenoidal surgery for acromegaly from 2005 to 2013 at Cedars-Sinai Pituitary Center. Hormonal remission was established by normal insulin-like growth factor (IGF)-1, basal serum growth hormone <2.5 ng/mL, and growth hormone suppression to <1 ng/mL following oral glucose tolerance test. Oral glucose tolerance test was performed at 3 months after surgery, and then as indicated. IGF-1 was measured at 3 months and then at least annually. We evaluated tumor granularity, nuclear expression of p21, Ki67 index, and extent of cavernous sinus invasion, and correlated these with remission status. RESULTS: Fifty-eight patients that underwent surgery had follow-up from 38 to 98 months (mean 64 ± 32.2 months). There were 21 microadenomas and 37 macroadenomas. Three months after surgery 40 of 58 patients (69%) were in biochemical remission. Four additional patients were in remission at 6 months after surgery, and 1 patient had recurrence within the first year after surgery. At last follow-up, 43 of 44 (74.1%) of patients remained in remission. Cavernous sinus invasion by tumor predicted failure to achieve remission. CONCLUSIONS: Prognostic markers of disease aggressiveness other than cavernous sinus invasion did not correlate with surgical outcome. Long-term remission after surgery alone was achieved in 74% of patients, indicating long-term efficacy of endoscopic surgery.
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Acromegalia , Endoscopia , Osso Esfenoide/cirurgia , Acromegalia/epidemiologia , Acromegalia/cirurgia , Adulto , Idoso , Endoscopia/métodos , Endoscopia/estatística & dados numéricos , Feminino , Hormônio do Crescimento/sangue , Humanos , Fator de Crescimento Insulin-Like I/análise , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
As ErbB receptors are expressed in prolactinomas and exhibit downstream effects on prolactin (PRL) production and cell proliferation, we generated transgenic mice using a PRL enhancer/promoter expression system to restrict lactotroph-specific expression of human epidermal growth factor receptor (EGFR) or human EGFR2 (HER2). EGFR or HER2 transgenic mice developed prolactinomas between 13 and 15 months, and confocal immunofluorescence and Western blot analysis confirmed lactotroph-restricted PRL and EGFR or HER2 coexpression. Circulating PRL levels in EGFR and HER2 transgenic mice were increased 5- and 3.8-fold, respectively. Inhibiting EGFR or HER2 signaling with oral lapatinib (100 mg/kg), a dual tyrosine kinase inhibitor for both EGFR and HER2, suppressed circulating PRL by 72% and attenuated tumor PRL expression by 80% and also attenuated downstream tumor EGFR/HER2 signaling. This model demonstrates the role of ErbB receptors underlying prolactinoma tumorigenesis and the feasibility of targeting these receptors for translation to treatment of refractory prolactinomas.
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Antineoplásicos/uso terapêutico , Receptores ErbB/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Hipofisárias/tratamento farmacológico , Prolactinoma/tratamento farmacológico , Quinazolinas/uso terapêutico , Animais , Elementos Facilitadores Genéticos , Receptores ErbB/genética , Feminino , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Lapatinib , Camundongos , Camundongos Transgênicos , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/metabolismo , Prolactinoma/genética , Prolactinoma/metabolismo , Regiões Promotoras GenéticasRESUMO
CONTEXT: GH-secreting pituitary adenomas exhibit heterogeneous natural history ranging from small tumors to large aggressive adenomas. OBJECTIVE: To rigorously classify an acromegaly patient cohort defined by clinical, radiological, histopathological, and outcome characteristics. DESIGN: Cross-sectional study. SETTING: Tertiary referral pituitary center. PATIENTS: Subjects were selected from a pituitary tumor research registry that includes 1178 patients with pituitary disease. Cluster analysis was performed on 338 acromegaly patients. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Biochemically active disease with elevated IGF-1 levels at follow-up. RESULTS: Cluster analysis of all patients yielded 292 who were rigorously classified to three acromegaly types. Type 1 (50%) comprised older patients with the longest follow-up and most favorable outcomes, characterized by densely granulated, nonaggressive microadenomas and macroadenomas. Type 1 tumors extend to the sphenoid sinus more frequently than suprasellar extension (concave tumor image) and express abundant immunoreactive p21 and somatostatin receptor 2. Type 2 (19%) comprised noninvasive, densely or sparsely granulated macroadenomas, without significant extension (flat tumor image), with intermediate biochemical outcome. Type 3 (31%) was characterized by sparsely granulated aggressive macroadenomas and comprised patients with adverse therapeutic outcomes, despite receiving more treatments. These tumors extend to both the sphenoid sinus and suprasellar regions with commonly encountered optic chiasm compression ("peanut" magnetic resonance image), with low tumor p21 and somatostatin receptor 2 expression. CONCLUSIONS: After validation, this classification may be useful to accurately identify acromegaly patients with distinctive patterns of disease aggressiveness and outcome, as well as to provide an accurate tool for selection criteria in clinical studies.
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Acromegalia/classificação , Adenoma Hipofisário Secretor de Hormônio do Crescimento/classificação , Neoplasias Hipofisárias/classificação , Acromegalia/patologia , Adulto , Idoso , Estudos Transversais , Feminino , Adenoma Hipofisário Secretor de Hormônio do Crescimento/metabolismo , Adenoma Hipofisário Secretor de Hormônio do Crescimento/patologia , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Pessoa de Meia-Idade , Neoplasias Hipofisárias/metabolismo , Neoplasias Hipofisárias/patologiaRESUMO
Endocrine and metabolic abnormalities are common in human immunodeficiency virus (HIV) disease and have been attributed to both the disease and its treatment. Other risk factors and behaviors may also be important. Approximately 28% of new HIV infections occur in users of injection drugs, such as opiates. We focus on the effects of opiates on multiple endocrine systems and their potential to contribute to the metabolic and endocrine problems in HIV. Opiate use has been associated with hypogonadism, adrenal dysfunction, reduced bone mineral density, and growth-hormone abnormalities. In addition, some studies have suggested abnormalities in glucose and lipid metabolism among opiate users. Although much of the evidence should be viewed as preliminary, these potential abnormalities should be kept in mind when treating opiate-dependent patients infected with HIV.
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Doenças do Sistema Endócrino/etiologia , Infecções por HIV/complicações , Doenças Metabólicas/etiologia , Transtornos Relacionados ao Uso de Opioides/complicações , Composição Corporal , Doenças Ósseas Metabólicas/etiologia , Gônadas/fisiologia , Hormônio do Crescimento/fisiologia , Infecções por HIV/fisiopatologia , Humanos , Hiperlipidemias/etiologia , Hipogonadismo/etiologia , Sistema Hipotálamo-Hipofisário/fisiologia , Resistência à Insulina , Transtornos Relacionados ao Uso de Opioides/fisiopatologia , Sistema Hipófise-Suprarrenal/fisiologiaRESUMO
As ErbB signaling is a determinant of prolactin synthesis, role of ErbB receptors was tested for prolactinoma outcomes and therapy. The objective of this study was to characterize ErbB receptor expression in prolactinomas and then perform a pilot study treating resistant prolactinomas with a targeted tyrosine kinase inhibitor (TKI). Retrospective analysis of prolactinomas and pilot study for dopamine agonist resistant prolactinomas in tertiary referral center. We performed immunofluorescent staining of a tissue array of 29 resected prolactinoma tissues for EGFR, ErbB2, ErbB3, and ErbB4 correlated with clinical features. Two patients with aggressive resistant prolactinomas enrolled and completed trial. They received lapatinib 1,250 mg daily for 6 months with tumor and hormone assessments. Main outcome measures were positive tumor staining of respective ErbB receptors, therapeutic reduction of prolactin levels and tumor shrinkage. Treated PRL levels and tumor volumes were suppressed in both subjects treated with TKI. EGFR expression was positive in 82 % of adenomas, ErbB2 in 92 %, ErbB3 in 25 %, and ErbB4 in 71 %, with ErbB2 score > EGFR > ErbB4 > ErbB3. Higher ErbB3 expression was associated with optic chiasm compression (p = 0.03), suprasellar extension (p = 0.04), and carotid artery encasement (p = 0.01). Higher DA response rates were observed in tumors with higher ErbB3 expression. Prolactinoma expression of specific ErbB receptors is associated with tumor invasion, symptoms, and response to dopamine agonists. Targeting ErbB receptors may be effective therapy in patients with resistant prolactinomas.