GH-secreting Pituitary Adenomas Research Articles

“An Unexpected Pit” - Ectopic Pituitary Adenoma

Background: Ectopic pituitary adenomas (EPAs) are exceedingly rare neoplasms, comprising about 0.5% of all pituitary adenomas. These are often misdiagnosed radiologically, while the correct diagnosis requires high index of suspicion on pathology and immunohistochemistry analysis. Clinical Case: 62-year-old female presented to the ED with transient unilateral visual loss. She denied orbital pain, headache, or motor or sensory deficit. Following unremarkable ophthalmology evaluation, initial MRI brain was suggestive of pituitary adenoma. MRI of the pituitary with gadolinium contrast showed nonenhancing focus of about 1.5 cm within the posterior sphenoid sinus adjacent to a normal-appearing pituitary gland. Lab assessment showed no pituitary hormone excess or insufficiency. ENT evaluation with repeat MRI brain with contrast showed a T2 heterogeneously enhancing hyperintense lesion in the clivus measuring 2.1 x 1.9 x 1.3 cm (transverse, AP and CC, respectively) with bony thinning/erosion of the sellar floor, the posterior wall of sphenoid sinus and dorsal clivus. Patient underwent transnasal transsphenoidal resection of the tumor with sample submitted as clival chordoma. Pathology report showed a 3.3 x 2.7 x 0.9 cm tumor with immunohistochemistry positive for ACTH, FSH, synaptophysin, chromogranin, S100 and cytokeratin while staining negative for GH, LH, TSH, prolactin and epithelial membrane antigen (EMA). Reticulin stain showed loss of reticulin network and Ki-67 labeling index was 1%. Neurosurgery and ENT teams confirmed no gross manipulation of the pituitary gland had been performed and findings supported a diagnosis of ectopic pituitary adenoma. On 6-month follow-up patient continued to do well clinically and MRI showed normal-appearing pituitary gland with no residual or recurrent tumor. Conclusion: EPA is a rare entity with about 133 cases described in literature. EPAs are generally benign, however up to 79% are functionally active and more likely than their sellar counterparts to secrete multiple pituitary hormones. EPAs arise from remnants of embryonic pituitary tissue in the migratory part of the Rathke’s pouch during early fetal development. The most common locations for EPA are in the sphenoid sinus, clivus, nasopharynx, cavernous sinus and suprasellar space and these are often misdiagnosed on initial radiology as neuroendocrine tumors, sino-nasal carcinomas, clival chordomas or even fungal infections. It is vital to consider EPA in the differential diagnosis of tumors removed from the mentioned anatomic locations as establishing the correct diagnosis helps to avoid the significant morbidity associated with treatments employed for other tumors. Reference: Riccio, L., Donofrio, C.A., Tomacelli, G. et al. Ectopic GH-secreting pituitary adenoma of the clivus: systematic literature review of a challenging tumour. Pituitary 23, 457-466 (2020)

2010 versus the 2000 consensus criteria in patients with normalised insulin-like growth factor 1 after transsphenoidal surgery has high predictive values for long-term recurrence-free survival in acromegaly.

The present study investigated the factors associated with recurrence during long-term follow-up in acromegaly and compared the recurrence rate between patients in remission with 2010 vs 2000 consensus criteria. We retrospectively recruited 133 adult acromegalic patients who had undergone transsphenoidal surgery (TSS) from January 2013 to December 2014 and assessed their clinical characteristics, surgical outcomes and recurrence. Surgical remission was defined as normalised insulin-like growth factor 1 (IGF-1) with nadir growth hormone (GH) during an oral glucose tolerance test (OGTT) <1μg/L no less than 3months after TSS without adjuvant therapy. Recurrence was defined as persistently reelevated IGF-1 after surgical remission. Cox regression analysis and Kaplan-Meier survival analysis were performed to evaluate the factors associated with recurrence. Remission was achieved in 77 cases (57.9%) after TSS alone. Recurrence was seen in five cases (6.5%) at 12, 12, 12, 36 and 54months, respectively, after surgery. Cox regression analysis showed that a nadir GH<0.4μg/L (vs 0.4-1.0μg/L) at surgical remission (odds ratio [OR]=0.106; 95% confidence interval [CI]=0.017-0.645; P=0.015) and Ki-67 index (OR=2.636; 95% CI=1.023-6.791; P=0.045) were independent factors influencing recurrence. Kaplan-Meier survival analysis showed that the median recurrence-free survival was 36months (95% CI=20-52) for patients with nadir GH 0.4-1.0μg/L at surgical remission. The median recurrence-free survival for patients with nadir GH<0.4μg/L at surgical remission was much longer (ie, required further follow-up to estimate). A failure of GH suppression under 0.4μg/L during an OGTT in patients with normalised IGF-1 and a higher Ki-67 index are independent predictors of recurrence after surgical remission in GH-secreting pituitary adenomas. Compared to patients with nadir GH<0.4μg/L, those with nadir GH 0.4-1.0μg/L appear to have a significantly higher risk of recurrence.

Clinicopathological Features of Growth Hormone-producing Pituitary Adenomas and Correlation With Preoperative Laboratory Findings.

The histopathological variability of each type of pituitary adenoma (PA) that causes growth hormone (GH) excess influences the phenotype, radiological characteristics and therapy response of acromegaly patients. We correlated the immunohistochemical (IHC) features of GH-secreting PAs with their clinical, laboratory and imaging data. We included 32 patients with documented acromegaly; tumour specimens were histologically and IHC examined: anterior pituitary hormones, pituitary-specific transcription factor-1 (PIT-1), Ki-67 labelling index were evaluated. Macroadenomas represented 93.75%. Post-surgery disease control negatively correlated with the maximum initial tumour diameter (p=0.04). Ki-67 did not predict remission. No correlation was found between GH serum levels and IHC expression (p=0.45). PIT-1 was positive in all specimens, two had a weak expression. Four were considered PIT-1 positive plurihormonal adenomas and several had unusual IHC combinations. PIT-1 accurately classifies GH-secreting PAs. The IHC classification as well as radiological dimensions and extent influence disease control, probably being the best prognosis factors.

Genetics of Acromegaly and Gigantism.

Growth hormone (GH)-secreting pituitary tumours represent the most genetically determined pituitary tumour type. This is true both for germline and somatic mutations. Germline mutations occur in several known genes (AIP, PRKAR1A, GPR101, GNAS, MEN1, CDKN1B, SDHx, MAX) as well as familial cases with currently unknown genes, while somatic mutations in GNAS are present in up to 40% of tumours. If the disease starts before the fusion of the epiphysis, then accelerated growth and increased final height, or gigantism, can develop, where a genetic background can be identified in half of the cases. Hereditary GH-secreting pituitary adenoma (PA) can manifest as isolated tumours, familial isolated pituitary adenoma (FIPA) including cases with AIP mutations or GPR101 duplications (X-linked acrogigantism, XLAG) or can be a part of systemic diseases like multiple endocrine neoplasia type 1 or type 4, McCune–Albright syndrome, Carney complex or phaeochromocytoma/paraganglioma-pituitary adenoma association. Family history and a search for associated syndromic manifestations can help to draw attention to genetic causes; many of these are now tested as part of gene panels. Identifying genetic mutations allows appropriate screening of associated comorbidities as well as finding affected family members before the clinical manifestation of the disease. This review focuses on germline and somatic mutations predisposing to acromegaly and gigantism.

Сучасні погляди на генетичну детермінованість СТГ-секретуючих аденом гіпофіза (огляд літератури та власні дослідження)

Актуальність. В роботі наведений огляд сучасних даних літератури щодо генетичної складової в етіології та патогенезі гормонально активної аденоми гіпофіза, що секретує соматотропний гормон (СТГ) і клінічними проявами якої є синдром акромегалії та/або гігантизму— синдром множинної ендокринної неоплазії 1, синдром Мак-К’юна— Олбрайта, комплекс Карні, акрогігантизм (Х-зчеплений), сімейні ізольовані аденоми гіпофіза (FIPA). Матеріали та методи. Для виявлення мутацій в гені AIP та з метою верифікації FIPA були обстежені 26 хворих української популяції (19 жінок та 7 чоловіків), в яких акромегалія була діагностована в підлітковому або молодому віці, і проведений генетичний аналіз. Для визначення генетичної детермінованості щодо розвитку СТГ-секретуючої аденоми гіпофіза та диференціальної діагностики синдромів FIPA та MEN1 методом секвенування (MLPA— Ligation-dependent Probe Amplification) було проведене дослідження генів (MLPA, P244-C1) за участю екзонів 1–6 MEN1, (MLPA, P017-D1) AIP. Результати. Серед обстежених тільки у двох осіб були визначені мутації гена AIP. В одного хворого генетичний скринінг на мутацію гена MEN1 був негативним, і жодних клінічних симптомів, що свідчать про синдром Мак-К’юна— Олбрайта, не було виявлено. Варіант гетерозиготного місенсу c.714C&gt;G (p.Cys238Trp) виявлений у гені AIP. Цей аналіз гена AIP сумісний з генетичною схильністю до аденом гіпофіза. У нащадків даного пацієнта 50% шансів успадкувати цей варіант. У іншої хворої з діагнозом «синдром множинної ендокринної неоплазії типу1 (синдром Вермера): інсулінома, аденоми прищитоподібних залоз (2), первинний гіперпаратиреоз» встановлений варіант гетерозиготного місенсу c.134A&gt;G (p.Glu45Gly), що був виявлений у гені MEN1. Варіант c.l34A&gt;G (p.Glu45Gly), клас 4, ймовірно, є патогенним. Поширеність цього варіанта в загальній популяції невідома, тому він є дуже рідкісним. Висновки. Проведення генетичного аналізу є доцільним у хворих дитячого та молодого віку або в осіб, у яких СТГ-секретуюча макро-/гігантська аденома гіпофіза була діагностована в молодому віці (до 35 років), незалежно від сімейної обтяженості щодо аденом гіпофіза. У хворих з обтяженою спадковістю генетичний аналіз доцільно проводити у будь-якому разі для виявлення FIPA та прогнозування подальшого перебігу захворювання та ефективності лікування аналогами соматостатину.

Acromegaly and it's cardiovascular implications

Acromegaly is a chronic and slowly progressive disease that results from the hypersecretion of growth hormone (GH) and consequently insulin-like growth factor type 1 (IGF-1), due to a GH-secreting pituitary adenoma in 95-98% of cases. There are several complications or co-morbidities associated with acromegaly, the most frequent being cardiovascular, metabolic and neoplastic. The cardiovascular complications of acromegaly go from arterial hypertension to a peculiar form of cardiomyopathy and are the result of the long-standing exposure to high GH and IGF-1 levels. The pathophysiology of these complications is complex and includes an increased tubular reabsorption of sodium and the direct effects of GH and IGF-1 on the endothelium and the cardiac tissue itself. Frequently, the cardiovascular comorbidities of acromegaly occur concomitantly with metabolic complications such as diabetes and respiratory abnormalities such as the sleep apnea syndrome. In this brief review we analyze the pathophysiology, the clinical manifestations and the management of the cardiovascular complications of acromegaly.

Up-regulation of sex-determining region Y-box 9 (SOX9) in growth hormone-secreting pituitary adenomas

BackgroundPituitary adenomas are benign brain tumors that cause considerable morbidity and neurological symptoms. SOX9 as a regulatory transcriptional mediator affects normal and tumor cell growth with an undefined role in pituitary adenomas pathogenesis. Thus, in the present study, the expression pattern of SOX9 in GH-secreting pituitary tumors and normal pituitary tissues is investigated.MethodsThe SOX9 gene expression level was evaluated in 60 pituitary tissues including different types of GH-secreting adenomas and normal pituitary tissues through Real-Time PCR. The protein level of SOX9 was assessed using immunohistochemistry. The correlations of SOX9 gene and protein expression level with the patient’s clinical and pathological features were considered.ResultsThe SOX9 over-expression was detected in GH-secreting adenomas tumor tissues compared to normal pituitary tissues which were accompanied by overexpression of SOX9 protein in tumor tissues. The over-expression of SOX9 had a significant impact on GH-secreting adenomas tumor incidence with the odds ratio of 8.4 and the diagnostic value of SOX9 was considerable. The higher level of SOX9 expression was associated with invasive and macro tumors in GH-secreting pituitary adenoma patients. The positive correlation of SOX9 gene and protein level was observed and the tumor size and tumor invasive features were valuable in predicting SOX9 expression level in GH-producing pituitary tumors.ConclusionThe study provided the first shreds of evidence regarding the expression pattern of SOX9 in the GH- secreting pituitary adenomas at both gene and protein levels which may emphasize the possible involvement of SOX9 as a mediator in pituitary adenoma tumor formation also open up new intrinsic molecular mechanism regarding pituitary adenoma pathogenesis.

Human growth hormone proteoform pattern changes in pituitary adenomas: Potential biomarkers for 3P medical approaches.

Human growth hormone (hGH) is synthesized, stored, and secreted by somatotroph cells in the pituitary gland, and promotes human growth and metabolism. Compared to a normal pituitary, a GH-secreting pituitary adenoma can secrete excessive GH to cause pathological changes in body tissues. GH proteoform changes would be associated with GH-related disease pathogenesis. This study aimed to elucidate changes in GH proteoforms between GH-secreting pituitary adenomas and control pituitaries for the predictive diagnostics, targeted prevention, and personalization of medical services. The isoelectric point (pI) and relative molecular mass (Mr) are two basic features of a proteoform that can be used to effectively array and detect proteoforms with two-dimensional gel electrophoresis (2DGE) and 2DGE-based western blot. GH proteoforms were characterized with liquid chromatography (LC) and mass spectrometry (MS). Phosphoproteomics, ubiquitinomics, acetylomics, and bioinformatics were used to analyze post-translational modifications (PTMs) of GH proteoforms in GH-secreting pituitary adenoma tissues and control pituitaries. Sixty-six 2D gel spots were found to contain hGH, including 46 spots (46 GH proteoforms) in GH-secreting pituitary adenomas and 35 spots (35 GH proteoforms) in control pituitaries. Further, 35 GH proteoforms in control pituitary tissues were matched with 35 of 46 GH proteoforms in GH-secreting pituitary adenoma tissues; and 11 GH proteoforms were presented in only GH-secreting pituitary adenoma tissues but not in control pituitary tissues. The matched 35 GH proteoforms showed quantitative changes in GH-secreting pituitary adenomas compared to the controls. The quantitative levels of those 46 GH proteoforms in GH-secreting pituitary adenomas were significantly different from those 35 GH proteoforms in control pituitaries. Meanwhile, different types of PTMs were identified among those GH proteoforms. Phosphoproteomics identified phosphorylation at residues Ser77, Ser132, Ser134, Thr174, and Ser176 in hGH. Ubiquitinomics identified ubiquitination at residue Lys96 in hGH. Acetylomics identified acetylation at reside Lys171 in hGH. Deamination was identified at residue Asn178 in hGH. These findings provide the first hGH proteoform pattern changes in GH-secreting pituitary adenoma tissues compared to control pituitary tissues, and the status of partial PTMs in hGH proteoforms. Those data provide in-depth insights into biological roles of hGH in GH-related diseases, and identify hGH proteoform pattern biomarkers for treatment of a GH-secreting pituitary adenoma in the context of 3P medicine -predictive diagnostics, targeted prevention, and personalization of medical services. The online version contains supplementary material available at 10.1007/s13167-021-00232-7.

ACROMEGALY UNVEILED DURING A NASAL RECONSTRUCTION SURGERY: A CASE REPORT

Acromegaly is a condition of excessive somatic growth and distorted proportion due to hypersecretion of growth hormone(GH) and insulin-like growth factor 1 (IGF-1). Insidious clinical manifestation of GH excess as a result of GH-secreting pituitary adenoma renders acromegaly a disease with typically delayed diagnosis. We report a 29-year old male planned to undergo reconstruction of the nose. The patient was referred for medical tness. Given the clinical features consistent with acromegaly the patient was evaluated further for diagnosis. Laboratory investigation showed raised IGF-1and non-suppressed GH post 75gms glucose, amid normal cortisol, corticotropin(ACTH), prolactin, testosterone, and thyroid function tests. He did not have dysglycemia. Magnetic resonance imaging (MRI) of the pituitary revealed a pituitary macroadenoma consistent with acromegaly. This case highlights the notable absence of recognizing the clinical presentation of acromegaly in this patient by his medical care physician and surgeons, and therefore the importance of thorough history taking, attention, and observation in making a new diagnosis that has the potential to alter a patient's health care and alleviate impending complications, morbidity and/or mortality

Outcomes of Transsphenoidal Surgery in Growth Hormone-Secreting Pituitary Adenomas

AbstractGrowth hormone (GH)-secreting pituitary adenomas (PA) make up 15 to 20% of total amount of hormonally active adenomas. In addition to acromegaly and gigantism, these tumors cause deep metabolic disturbances. Its systemic impact leads to increased mortality ratio of 1.32 compared with general population. Surgical removal remains the priority treatment option in controlling acromegaly and provides endocrinologic remission in up to 72% patients. A total of 92 patients were included in the study. All surgeries were performed via microscopic transsphenoidal approach (TSA) by the senior author in our institution between December 2009 and October 2019. Only patients who were followed-up with 75 g oral glucose tolerance tests (OGTTs), GH, and insulin-like growth factor I (IFG-I) measurements preoperatively, 1 week, and every 6 months postoperatively were analyzed. Based on standard preoperative 1.5-T MR imaging with contrast enhancement, the adenomas were identified and distributed according to the size and KNOSP classification. The efficacy depends on KNOSP grade, which is directly correlated with invasiveness to cavernous sinus (CS). Grades 3 and 4 are unfavorable factors influencing prognosis. Excluding grade 0 adenomas, as the surgery was not difficult with the excellent outcomes, we reached 75% (36 out of 48) remission in grade 1 to 2 groups. In contrast, only 17% (2 out of 12) had successful outcomes after surgery alone. In conclusion, the study demonstrates the efficiency of TS surgery in patients with confirmed GH-secreting PA.

Acromegaly coexisting with turner syndrome

IntroductionAcromegaly is a clinical syndrome associated with overexpression of the growth hormone (GH). Turner syndrome (TS) is a rare chromosomal disorder resulting from partial or complete loss of X chromosome and is a common chromosome anomaly in humans. MethodsFor the patient due to the presence of short stature and primary ovarian insufficiency, karyotype analysis was performed. Results43-year-old acromegalic woman was that detected with a pituitary tumor during the assessment of her GH level and the exploration of the typical phenotype. The patient underwent transsphenoidal pituitary and the pathological result was reported as GH-secreting pituitary adenoma. A karyotype analysis was requested for the patient due to the presence of short stature and primary ovarian insufficiency and her karyotype was determined to be 45,X0/46,x,i(Xq)(q10). ConclusionBased on these signs and symptoms, coexistence of acromegaly and TS was diagnosed in our patient, which is an extremely rare occurrence that has been reported only in two patients. The evaluation of the clinical profile and karyotype pattern of our patient in line with the findings of recent studies indicated that the intact X chromosome could be inactivated in the cells of our patient that contained the 46,X,i(Xq) karyotype and that an extra copy of the GPR101 gene that is located in the Xq isochromosome could be expressed. This phenomenon may explain the emergence of this disease in middle ages, as seen in our patient who had a mosaic karyotype.

Characterization of the ability of a, second-generation SST-DA chimeric molecule, TBR-065, to suppress GH secretion from human GH-secreting adenoma cells.

Somatostatin (SST) and dopamine (DA) inhibit growth hormone (GH) secretion and proliferation of GH-secreting pituitary adenomas (GHomas) through binding to SSTR2 and D2R receptors. Chimeric SST-DA compounds (Dopastatins) display increased potency in inhibiting GH secretion, as compared with individual SST or DA analogs (alone or combined). To assess the efficacy of a second-generation dopastatin, TBR-065, in suppressing GH secretion from human GH- and GH/prolactin(PRL)-omas. We compared the ability of TBR-065 to inhibit GH secretion from primary cultures of human GH- or GH/PRLoma cells to that of the first generation dopastatin, TBR-760 (formerly BIM-23A760), octreotide (OCT) and cabergoline (CAB), the later either alone or combined. We investigated whether there was any impact of BIM-133, the metabolite of TBR-065, on the ability of TBR-065 to inhibit GH in these cultures. 17 GH- and GH/PRLomas were included in this study. Inhibition of GH secretion by TBR-065, TBR-760, OCT and CAB (0.1pM to 0.1µM) was assessed over a period of 8h. All tumors expressed SSTR2 and D2R mRNAs. GH suppression was higher with TBR-065 as compared with TBR-760 (Emax = 57 ± 5.6% vs. 41.1 ± 12.5%, respectively, p < 0.001) or with OCT + CAB (Emax = 56.8 ± 7.2% vs. 44.4 ± 9.4%, p < 0.001). BIM-133 did not have any impact on the activity of TBR-065. TBR-065 has significantly improved efficacy in suppressing GH secretion as compared to current available therapies and may represent a new promising option for the treatment of acromegaly.

Prognostic Factors of Acromegalic Patients with Growth Hormone–Secreting Pituitary Adenoma After Transsphenoidal Surgery

Acromegaly is a rare, chronic disorder that mostly results from growth hormone (GH)-secreting pituitary adenoma. Transsphenoidal surgery is the first-line treatment of this adenoma. This study aimed to identify factors associated with remission outcome in patients with GH-secreting pituitary adenomas following transsphenoidal surgery. Patients with GH-secreting pituitary adenomas who underwent transsphenoidal surgery for tumor removal at Songklanagarind Hospital between January 2003 and December 2019 were retrospectively reviewed. The primary outcome was the remission of disease at the last follow-up using 2000 and 2010 consensus criteria. Using logistic regression analysis, various factors were analyzed for association with disease remission outcome. This study included 51 patients. The remission rate of GH-secreting pituitary microadenomas and macroadenomas following transsphenoidal surgery were 100% and 43.75%, respectively. Multivariate analysis showed that preoperative insulin-like growth factor 1 index ≥2.5 and Knosp classification grade 3-4 were significantly associated with nonremission outcome (P < 0.001 and P=0.012, respectively). Patients with both of these factors had poor outcomes and never achieved remission after treatment, while patients with neither of these factors had high remission rates (87.5%) following surgery. Four of 6 (66.7%) patients who underwent repeat surgery gained remission. Preoperative insulin-like growth factor 1 index ≥2.5 and Knosp classification grade 3-4 were important prognostic factors that determined remission outcome after treatment. Patients who have both of these poor prognostic factors should be aggressively treated with surgery, medication, and probably radiation to optimally control the disease.

Gamma Knife radiosurgery for acromegaly: Evaluating the role of the biological effective dose associated with endocrine remission in a series of 42 consecutive cases.

Stereotactic radiosurgery (SRS) is a valuable treatment option for persistent and/or recurrent acromegaly secondary to growth hormone (GH) secreting pituitary adenoma (PA). Here, we assess the role of biological effective dose (BED) received by PA treated with SRS in relation with endocrine remission. Forty-two patients (minimum 6months follow-up) were included. Mean marginal dose was 27.7 (median 28, 20-35), and mean BED received by tumour was 193.1Gy2.47 (median 199.7, 64.1-237.1). Based on the median values, we divided the patients in high tumour BED group (H-BEDtm, 199.7-237.1Gy2.47, n=12) and low BED one (L- BEDtm, 64.1-199.7Gy2.47 , n=10). The two groups did not differ by pretherapeutic IGF-1 levels (p=.1) or by the prescribed dose (p=.6). Mean follow-up period was 62.5months (median 60.5, 9-127). Probability of IGF-1 normalization was 65% at 3years and 72.4% at 4years, remaining stable until last follow-up. Twenty-two (52.4%) patients had complete endocrine remission in absence of any Somatostatin analogues. Actuarial rates were 33% at 3years and 57.4% at 7years, further remaining stable during follow-up course. In univariate analysis, only statistically significant parameter was pretherapeutic serum IGF-1 and IGF-1 index (p=.01). Five patients (5/26, 19.3%) without previous hypopituitarism developed new pituitary insufficiency. H-BEDtm was associated with higher rates of endocrine remission compared with L-BEDtm, with actuarial probability of 70.2% versus 48.2% at 9years, although this did not reach statistical significance (p>.05). Our study confirms that SRS by Gamma Knife is safe and effective for GH-secreting PA. Pretherapeutic serum levels of IGF-1 were only statistically significant parameter for endocrine remission.

Machine learning in predicting early remission in patients after surgical treatment of acromegaly: a multicenter study.

Accurate prediction of postoperative remission is beneficial for effective patient-physician communication in acromegalic patients. This study aims to train and validate machine learning prediction models for early endocrine remission of acromegalic patients. The training cohort included 833 patients with growth hormone (GH) secreting pituitary adenoma from 2010 to 2018. We trained a partial model (only using pre-operative variables) and a full model (using all variables) to predict off-medication endocrine remission at six-month follow-up after surgery using multiple algorithms. The models were validated in 99 prospectively collected patients from a second campus and 52 patients from a third institution. C-statistic and the accuracy of the best partial model was 0.803 (95% CI 0.757-0.849) and 72.5% (95% CI 67.6-77.5%), respectively. C-statistic and the accuracy of the best full model was 0.888 (95% CI 0.861-0.914) and 80.3% (95% CI 77.5-83.1%), respectively. The c-statistics (and accuracy) of using only Knosp grade, total resection, or postoperative day 1 GH level as the single predictor were lower than our partial model or full model (p < 0.001). C-statistics remained similar in the prospective cohort (partial model 0.798, and full model 0.903) and in the external cohort (partial model 0.771, and full model 0.871). A web-based application integrated with the trained models was published at https://deepvep.shinyapps.io/Acropred/ . We developed and validated interpretable and applicable machine learning models to predict early endocrine remission after surgical resection of a GH-secreting pituitary adenoma. Predication accuracy of the trained models were better than those using single variables.

Radiomics model predicts granulation pattern in growth hormone-secreting pituitary adenomas.

To investigate whether radiomic features from magnetic resonance image (MRI) can predict the granulation pattern of growth hormone (GH)-secreting pituitary adenoma patients. Sixty-nine pathologically proven acromegaly patients (densely granulated [DG] = 50, sparsely granulated [SG] = 19) were included. Radiomic features (n = 214) were extracted from contrast-enhancing and total tumor portions from T2-weighted (T2) MRIs. Imaging features were selected using a least absolute shrinkage and selection operator (LASSO) logistic regression model with fivefold cross-validation. Diagnostic performance for predicting granulation pattern was compared with that for qualitative T2 signal intensity assessment and T2 relative signal intensity (rSI) using the area under the receiver operating characteristics curve (AUC). Four significant radiomic features from the contrast-enhancing tumor (1 from shape, 1 from first order feature, and 2 from second order features) were selected by LASSO for model construction. The radiomics model showed an AUC, accuracy, sensitivity, and specificity of 0.834 (95% confidence interval [CI] 0.738-0.930), 73.7%, 74.0%, and 73.9%, respectively. The radiomics model showed significantly better performance than the model using qualitative T2 signal intensity assessment (AUC 0.597 [95% CI 0.447-0.747], P = 0.009) and T2 rSI (AUC 0.647 [95% CI 0.523-0.759], P = 0.037). Radiomic features may be useful biomarkers to differentiate granulation pattern of GH-secreting pituitary adenoma patients, and showed better performance than qualitative assessment or rSI evaluation.

A legendary sumo wrestler with gigantism or acromegaly? The case of Ikezuki Geitazaemon (1827–1850)

Sumo is a traditional Japanese full-contact wrestling sport. Among sumo wrestlers, Ikezuki Geitazaemon (1827–1850) was one of the most famous wrestlers due to his large body size. Here, we hypothesize that the legendary Japanese sumo wrestler could have had gigantism or acromegaly, which are disorders caused by the hypersecretion of growth hormone (GH). GH-secreting pituitary adenoma leads to the hypersecretion of GH and insulin-like growth factor-1 (IGF-1). If GH-secreting pituitary adenoma develops during childhood/puberty, it can cause gigantism. Adenomas also occur in over 95% of patients with acromegaly. Based on his substantial height (227 cm), Geitazaemon may have had gigantism, or acromegaly considering his characteristics of mandibular prognathism, enlarged fingertips, and heel pad thickness, as shown in woodblock prints (ukiyo-e). He would thus be the first recorded patient with gigantism or acromegaly in premodern Japan.

Acromegaly: 'You must know it to think of it'.

Acromegaly is a debilitating and disfiguring chronic disease, which occurs in both sexes at any age, associated with multiple comorbidities and increased mortality. It is typically caused by a GH-secreting pituitary adenoma that promotes exposure of body tissues to increased concentrations of GH and IGF-I. The diagnosis of acromegaly is still made very late in a substantial number of patients when the disease is already in advanced stages. An epidemiological study from Sweden has elegantly demonstrated that the longer the diagnostic delay in acromegaly, the higher the number of comorbidities. Moreover, about 25% of the Swedish patients had 10 years or more of diagnostic delay and in this group mortality rate was significantly increased. These results reinforce the importance of shortening the latency period between disease onset, diagnosis and treatment to improve patient outcomes. This commentary article discusses strategies to be embraced by the endocrine community to allow early identification of acromegaly among public and health professionals, as internists, primary care clinicians, different specialists and dentists are the first point of contact for most of the patients. We emphasize that acromegaly should be presented as a sporadic, rather than rare, insidious disease, meaning that there is a considerable chance for health professionals to see a patient with acromegaly throughout their careers. The motto 'you must know it to think of it' is advocated in awareness efforts to reduce time to diagnosis, which results in lower rates of morbidity and mortality and might positively impact healthcare costs.

Comparing Stereotactic Radiosurgery and Fractionated Stereotactic Radiotherapy in Treating patients with Growth Hormone-Secreting Adenomas: A Systematic Review and Meta-analysis.

Context: Radiotherapy for patients with acromegaly was considered when patients have residual disease or tumor recurrence after surgery, or when surgery can't be carried out. There are two main modes of radiotherapy, including stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (FSRT). Objective: We conducted a systematic review and meta-analysis to present the effectiveness and safety of SRS and FSRT for GH secreting pituitary adenoma in clinical practice. Methods: We searched the published literature using following databases: Pub Med, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews and EMBASE up to March 22, 2020, for studies in which SRS or FSRT were used in patients with GH secreting pituitary. Results: A total of 33 studies were eligible, involving 2016 participants. No significant differences were observed in tumor shrinkage rate, local tumor control rate and adverse effect rate between SRS and FSRT. Compared to FSRT, SRS showed significant increase in biochemical remission rate (43% vs. 28%; p=0.023) and significant lower follow-up GH level (SMD: -1.20 vs. -0.37, p=0.006). Conclusions: SRS and FSRT showed comparable effectiveness and safety in the management of GH secreting pituitary adenoma patients. SRS might be associated with better biochemical remission.

Impact of tumor characteristics and pre- and postoperative hormone levels on hormonal remission following endoscopic transsphenoidal surgery in patients with acromegaly.

Acromegaly is a disease of acral enlargement and elevated serum levels of insulin-like growth factor-1 (IGF-1) and growth hormone (GH), usually caused by a pituitary adenoma. A lack of consensus on factors that reliably predict outcomes in acromegalic patients following endoscopic endonasal transsphenoidal surgery (EETS) warrants additional investigation. The authors identified 52 patients with acromegaly who underwent an endoscopic endonasal approach (EEA) for resection of a GH-secreting pituitary adenoma. Preoperative and postoperative tumor and endocrinological characteristics such as tumor size, invasiveness, and GH/IGF-1 levels were evaluated as potential indicators of postoperative hormonal remission. Endocrinological remission was defined as postoperative IGF-1 levels at or below the age- and sex-normalized values. The 52 patients had a mean age of 50.7 ± 13.4 years and a mean follow-up duration of 24.4 ± 19.1 months. Ten patients (19%) had microadenomas and 42 (81%) had macroadenomas. Five patients (9.6%) had giant adenomas. Forty-four tumors (85%) had extrasellar extension, with 40 (77%) exhibiting infrasellar invasion, 18 (35%) extending above the sella, and 7 (13%) invading the cavernous sinuses. Thirty-six patients (69%) underwent gross-total resection (GTR; mean maximal tumor diameter 1.47 cm), and 16 (31%) underwent subtotal resection (STR; mean maximal tumor diameter 2.74 cm). Invasive tumors were significantly larger, and Knosp scores were negatively correlated with GTR. Thirty-eight patients (73%) achieved hormonal remission after EEA resection alone, which increased to 87% with adjunctive medical therapy. Ninety percent of patients with microadenomas and 86% of patients with macroadenomas achieved hormonal remission. Preoperative IGF-1 and postoperative day 1 (POD1) GH levels were inversely correlated with hormonal remission. Postoperative CSF leakage occurred in 2 patients (4%), and none experienced vision loss, death, or injury to internal carotid arteries or cranial nerves. Endoscopic transsphenoidal resection of GH-secreting pituitary adenomas is a safe and highly effective treatment for achieving hormonal remission and tumor control in up to 87% of patients with acromegaly when combined with postoperative medical therapy. Patients with lower preoperative IGF-1 and POD1 GH levels, with less invasive pituitary adenomas, and who undergo GTR are more likely to achieve postoperative biochemical remission.