Effects of glucocorticoid replacement therapy in patients with pituitary disease: A new perspective for personalized replacement therapy.

Secondary adrenal insufficiency (SAI) is an endocrine disorder due to impaired secretion of ACTH resulting from any disease affecting the pituitary gland. Glucocorticoid replacement therapy is mandatory to ensure patient survival, haemodynamic stability, and quality of life. In fact, a correct dose adjustement is mandatory due to the fact that inappropriately low doses expose patients to hypoadrenal crisis, while inappropriately high doses contribute to glucose metabolic and cardiovascular deterioration. This review analyses the current evidence from available publications on the epidemiology and aetiology of SAI and examines the association between glucocorticoid replacement therapy and glucometabolic and cardiovascular effects.

Hypophysitis in COVID-19: a systematic review.

PURPOSE: This systematic review aims to collect and examine recent research findings regarding hypophysitis in COVID-19 patients. METHOD: We conducted a comprehensive literature review in English on the topic "Hypophysitis in COVID-19," using the MEDLINE (PubMed) database in July 2024. The selected articles were systematically tabulated and we have assessed in this review patient demographics, symptom presentation, imaging results, diagnosis, clinical management, and outcomes. RESULTS: Seven reported cases of post-COVID-19 hypophysitis were identified, comprising 4 (57%) females and 3 (43%) males, with a median age of 37 years. The interval between COVID-19 infection symptoms and the onset of hypophysitis ranged from 2 to 3 weeks. Initial symptoms included frontal headache in 4 (57%) cases and polyuria and polydipsia in 3 (43%) cases. Anterior or posterior hypopituitarism was observed in 6 (85%) patients. Radiological findings varied: 2 (28.5%) cases showed panhypophysitis, 3 (43%) cases exhibited gland enlargement with homogeneous contrast enhancement on magnetic resonance imaging (MRI), 1 case involved the loss of the posterior pituitary bright spot, and 1 case involved pituitary apoplexy/enlargement of the gland and infundibulum. No pituitary biopsies were performed. Four (57%) patients received glucocorticoid (GC) treatment. Long-term follow-up was documented in only one case, a 16-year-old female followed for 2 years reporting complete clinical and radiological resolution. CONCLUSION: Although rare, hypophysitis related to COVID-19 is documented in the literature exhibiting distinct characteristics such as a homogeneous gender prevalence, an average age of onset around 35 years, and primary symptoms of headache, polyuria, and polydipsia which are indicative of angiotensin-vasopressin deficiency. This is in contrast with primary autoimmune hypophysitis characterized by a female prevalence and typical symptoms with headache and visual impairment. Longer-term follow-up of these patients is needed to better understand the potential lasting impact on pituitary function and radiological improvement. Future research should also explore the presence of anti-pituitary antibodies and the other possible pathophysiological mechanisms potentially involved in these cases.

Vitamin D in pituitary driven osteopathies.

The evidence that pituitary hormones may bypass peripheral endocrine glands to exert remarkable effects on the skeleton is gaining ground. Both hormonal excess and deficit may determine impairment in bone structure, and they commonly result in bone loss in patients affected by pituitary and neuroendocrine disorders. Vertebral fractures are the most common skeletal alterations and may occur independently of bone mass. Use of vitamin D (VD) supplementation is still debated in this setting. This review will focus on the interactions between different metabolites of VD and pituitary hormones, and the effects of VD supplementation on bone metabolism in patients with pituitary diseases.

Bone health and skeletal fragility in second- and third-line medical therapies for acromegaly: preliminary results from a pilot single center experience.

INTRODUCTION: Skeletal fragility is a clinically relevant and not-reversible complication of acromegaly, involving around 30-40% of patients since the disease diagnosis. Few studies have investigated the effects on skeletal health of medical therapies for acromegaly. In this retrospective longitudinal monocentre study, we investigated the outcome of skeletal fragility in patients treated with Pasireotide Lar in combination with Pegvisomant (Pasi-Lar + Peg-V), also comparing those observed in patients treated with conventional therapies. RESULTS: We included 6 patients treated with Pasi-Lar + Peg-V, 5 patients treated with Peg-V in monotherapy (m-Peg-V), 16 patients treated with Peg-V plus first-generation somatostatin receptor ligands (fg-SRLs + Peg-V), 9 patients treated with Pasi-Lar. None of the patients treated with Pasi-Lar + Peg-V experienced worsening of spine and femoral bone mineral density (BMD) and incident vertebral fractures (i-VFs). Eight patients experienced i-VFs. The frequency of i-VFs was significantly lower in patients treated with the Pasi-Lar + Peg-V (0/8; 0%), as compared to those observed in m-Peg-V treated patients (4/8; 50%, p = 0.02). The frequency of i-VFs was slightly but not significantly higher in Pasi-Lar treated patients (1/8; 12.5% p = 0.6) and in fg-SRLs + Peg-V treated patients (3/8; 37.5% p = 0.364), concerning those treated with Pasi-Lar + Peg-V (0/8; 0%). I-VFs occurred more frequently in patients with higher GH levels at acromegaly diagnosis (p < 0.001), and in patients who experienced a BMD worsening (p = 0.005). CONCLUSION: Our preliminary data suggested that in conventional and multi-drug resistant acromegaly, the combination therapy Pasi-Lar + Peg-V may prevent the worsening of BMD and the occurrence of i-VFs. Prospective and translational studies should further validate these results and ascertain underlying physiopathology mechanisms.

Pediatric craniopharyngiomas: magnetic resonance imaging assessment for hypothalamus-pituitary axis dysfunction and outcome prediction.

BACKGROUND: In adamantinomatous craniopharyngiomas, tumor topographical categories, cystic component volume, and magnetic resonance signal intensity may impact prognosis. OBJECTIVE: To identify magnetic resonance imaging (MRI) variables associated with pituitary-hypothalamic axis dysfunction and predictive of outcome in children with cystic adamantinomatous craniopharyngiomas. MATERIALS AND METHODS: We evaluated 40 preoperative MRIs of adamantinomatous craniopharyngiomas to classify tumor topography, volume, and signal intensity of the cystic components and peritumoral edema. Volumes and normalized signal intensity minimum values were extracted from coronal T2-weighted images (nT2min). Radiological variables were compared to pituitary-hypothalamic axis dysfunction-related clinical data and surgical outcomes. RESULTS: Adamantinomatous craniopharyngiomas were categorized into five topographic classes (12 patients, sellar-suprasellar; seven patients, pseudo-intraventricular; six patients, strict intraventricular; 14 patients, secondary intraventricular; one patient, not strict intraventricular). All cases exhibited a predominant (30 patients, 80%) or total (10 patients, 20%) cystic tumor component and displayed low nT2min percentage values compared to cerebrospinal fluid (42.3% [interquartile range 28.4-54.6%]). Significant associations between tumor topographic classes and pituitary dysfunction (P<0.001), and between peritumoral edema and hypothalamic dysfunction (P<0.001) were found. Considering extent of surgical removal and tumor relapse, volume of the cystic tumor component displayed a positive correlation (P=0.002; r=0.48; P=0.02; r=0.36), while nT2min intensity values exhibited a negative correlation (P=0.01; r= - 0.40; P=0.028; r= - 0.34). CONCLUSION: Severe hypothalamic-pituitary axis dysfunction is associated with tumors along the pituitary stalk and peritumoral edema. Tumor invasion of the third ventricle, tight adherence to the hypothalamus, larger volumes, and lower nT2min intensity of the tumor cystic component are independent predictors of extent of adamantinomatous craniopharyngioma excision and recurrence.

The Pathogenic RET Val804Met Variant in Acromegaly: A New Clinical Phenotype?

Several genetic investigations were conducted to identify germline and somatic mutations in somatotropinomas, a subtype of pituitary tumors. To our knowledge, we report the first acromegaly patient carrying a RET pathogenic variant: c.2410G>A (rs79658334), p.Val804Met. Alongside the fact that the patient's father and daughter carried the same variant, we investigated the clinical significance of this variant in the context of somatotropinomas and other endocrine tumors, reviewing the RET mutations' oncogenic mechanisms. The aim was to search for new targets to precisely manage and treat acromegaly. Our case describes a new phenotype associated with the RET pathogenic variant, represented by aggressive acromegaly, and suggests consideration for RET mutation screening if NGS for well-established PitNET-associated gene mutations renders negative.

The immune microenviroment in somatotropinomas: from biology to personalized and target therapy.

Pituitary tumors are rare neoplasms, with a heterogeneous biological and clinical behavior, due to their clinical course, local invasive growth, resistance to conventional therapies and the risk of disease progression. Recent studies on tumor microenvironment (TME) provided new knowledge on the biology of these neoplasia, that may explain the different phenotypes of these tumors and suggest new biomarkers able to predict the prognosis and the treatment outcome. The identification of molecular markers that act as targets for biological therapies may open new perspectives in the medical treatments of aggressive pituitary tumors.In this paper, we will review data of TME and target therapies in somatotropinomas.

Reliability of intraoperative visual evoked potentials (iVEPs) in monitoring visual function during endoscopic transsphenoidal surgery.

OBJECTIVE: To refine a reliable and reproducible intraoperative visual evoked potentials (iVEPs) monitoring protocol during endoscopic transsphenoidal surgery. To assess the reliability of baseline iVEPs in predicting preoperative visual status and perioperative iVEP variation in predicting postoperative visual outcome. METHODS: Sixty-four patients harboring tumors of the pituitary region were included. All patients underwent endoscopic endonasal approach (EEA) with iVEPs monitoring, using a totally intravenous anesthetic protocol. Ophthalmological evaluation included visual acuity and visual field studies. RESULTS: Preoperatively, visual acuity was reduced in 86% and visual field in 76.5% of cases. Baseline iVEPs amplitude was significantly correlated with preoperative visual acuity and visual field (p = 0.001 and p = 0.0004, respectively), confirming the reliability of the neurophysiological/anesthetic protocol implemented. Importantly, perioperatively the variation in iVEPs amplitude was significantly correlated with the changes in visual acuity (p < 0.0001) and visual field (p = 0.0013). ROC analysis confirmed that iVEPs are an accurate predictor of perioperiative visual acuity improvement, with a 100% positive predictive value in patients with preoperative vision loss. CONCLUSIONS: iVEPs during EEA is highly reliable in describing preoperative visual function and can accurately predict postoperative vision improvement. SIGNIFICANCE: iVEPs represent a promising resource for carrying out a more effective and safe endoscopic transsphenoidal surgery.

Aggressive PitNETs and Potential Target Therapies: A Systematic Review of Molecular and Genetic Pathways.

Recently, advances in molecular biology and bioinformatics have allowed a more thorough understanding of tumorigenesis in aggressive PitNETs (pituitary neuroendocrine tumors) through the identification of specific essential genes, crucial molecular pathways, regulators, and effects of the tumoral microenvironment. Target therapies have been developed to cure oncology patients refractory to traditional treatments, introducing the concept of precision medicine. Preliminary data on PitNETs are derived from preclinical studies conducted on cell cultures, animal models, and a few case reports or small case series. This study comprehensively reviews the principal pathways involved in aggressive PitNETs, describing the potential target therapies. A search was conducted on Pubmed, Scopus, and Web of Science for English papers published between 1 January 2004, and 15 June 2023. 254 were selected, and the topics related to aggressive PitNETs were recorded and discussed in detail: epigenetic aspects, membrane proteins and receptors, metalloprotease, molecular pathways, PPRK, and the immune microenvironment. A comprehensive comprehension of the molecular mechanisms linked to PitNETs' aggressiveness and invasiveness is crucial. Despite promising preliminary findings, additional research and clinical trials are necessary to confirm the indications and effectiveness of target therapies for PitNETs.

Impact of the diagnostic delay of acromegaly on bone health: data from a real life and long term follow-up experience.

INTRODUCTION: Acromegaly is a chronic disease with systemic complications. Disease onset is insidious and consequently typically burdened by diagnostic delay. A longer diagnostic delay induces more frequently cardiovascular, respiratory, metabolic, neuropsychiatric and musculoskeletal comorbidities. No data are available on the effect of diagnostic delay on skeletal fragility. We aimed to evaluate the effect of diagnostic delay on the frequency of incident and prevalent of vertebral fractures (i-VFs and p-VFs) in a large cohort of acromegaly patients. PATIENTS AND METHODS: A longitudinal, retrospective and multicenter study was conducted on 172 acromegaly patients. RESULTS: Median diagnostic delay and duration of follow-up were respectively 10 years (IQR: 6) and 10 years (IQR: 8). P-VFs were observed in 18.6% and i-VFs occurred in 34.3% of patients. The median estimated diagnostic delay was longer in patients with i-VFs (median: 11 years, IQR: 3), in comparison to those without i-VFs (median: 8 years, IQR: 7; p = 0.02). Age at acromegaly diagnosis and at last follow-up were higher in patients with i-VFs, with respect to those without i-VFs. The age at acromegaly diagnosis was positively associated with the diagnostic delay (p < 0.001, r = 0.216). A longer history of active acromegaly was associated with a high frequency of i-VFs (p = 0.03). The logistic regression confirmed that patients with a diagnostic delay > 10 years had 1.5-folds increased risk of developing i-VFs (OR: 1.5; 95%CI: 1.1-2; p = 0.017). CONCLUSION: Our data showed that the diagnostic delay in acromegaly has a significant impact on VF risk, further supporting the clinical relevance of an early acromegaly diagnosis.

Multidimensional geriatric evaluation in acromegaly: a comparative cross-sectional study.

BACKGROUND: Improvement in acromegaly management increased disease survival and prevalence. Evidence regarding acromegaly in older adults are sparse. We aim to explore acromegaly impact on aging process quality. METHODS: Multicenter case-control study conducted on 42 older adults (≥ 65 years) acromegaly patients (ACRO) compared to an age- and gender-matched control group (CTR). Each participant underwent a multidimensional geriatric evaluation. RESULTS: Mean age in both groups was 73 ± 6 years and female gender was most represented (69%). All comorbidities were more frequent in ACRO than CTR. Thirteen ACRO were in remission and 29 had active disease controlled by medical therapy except for one patient. ACRO showed worse physical performance and mobility skills worsening with age as compared to CTR. ACRO performed poorly in functional status assessment, and age negatively correlated with instrumental and basic daily activities execution. Cognitive evaluation scores were significantly lower in ACRO vs. CTR, worsening with age. No difference was found concerning nutritional and psychological status. Musculoskeletal and bone diseases were more frequent in ACRO than in CTR (52% vs. 12%; 64% vs. 10%; P < 0.05) and independently associated with geriatric outcomes in ACRO. ACRO reported a less satisfactory quality of life concerning physical activity and pain, general health, vitality, social activities. CONCLUSIONS: Our study demonstrates increased frailty of older acromegaly patients as compared to non-acromegaly patients with a consequent negative impact on their quality of life. Therefore, it seems advisable to include physical, functional, cognitive, nutritional, and psychological status assessments in routine clinical practice. Further studies are needed to identify the most appropriate geriatric tools.

Human leucocyte antigens coeliac haplotypes and primary autoimmune hypophysitis in caucasian patients.

PURPOSE: Primary hypophysitis is a rare disease, with an autoimmune aetiology. As few papers have investigated genetic of hypophysitis, our aim was to evaluate HLA status in a single-centre series of patients. PATIENTS AND METHOD: A retrospective, longitudinal and cross-sectional study was conducted. In consecutive Caucasian patients, clinically or histologically diagnosed for primary autoimmune hypophysitis (PAH), the HLA genotype having been determined. This cohort was compared with a control group. Anti-pituitary and anti-hypothalamus auto-antibodies evaluation was included. RESULTS: 16 patients were enrolled. Fourteen patients were female (87.5%). According to HLA-DR status, we found the following: 9 of 16 patients (56.3%) haplotypes that were associated with coeliac disease (CD). Among these, 5 carried the DR7-DQ2 heterozygote haplotype (55.5%) while the remaining ones only the following haplotypes: DR3-DQ2 homozygote (25%), DR4-DQ2 heterozygote (25%), DR4-DQ8 heterozygote (50%) and DR4-DQ8 homozygote (25%), respectively. A total of 12 CD-associated haplotypes were identified. In PAH, we found a significantly higher frequency of patients carrying CD-associated HLA haplotypes as compared to the control group (respectively, 75% vs 48% P = .03; OR: 3.25 95%IC:1.1-10.3), particularly, for DQ2 and DQ8 haplotypes. DQ2 haplotype was detected in 50% of PAH and 38.4% of the control group (P = .3), while DQ8 haplotype in 25% of PAH and 7.2% of the control group (P = .01 OR:4.3 95%IC:1.3-14.7). CONCLUSION: Our data suggest that PAH and CD share some HLA haplotypes, reinforcing the knowledge of their association. HLA haplotypes, particularly DQ8, may play a role in PAH management and diagnosis, also suggesting the predisposition to other autoimmune diseases.

Correction to: Effects of pegvisomant and somatostatin receptor ligands on incidence of vertebral fractures in patients with acromegaly.

The original version of the article contained an error in the results section of the Abstract. The vertebral fractures (VFs) odds ratio is incorrectly published as 61.0 and the correct value is 6.10.

Effects of pegvisomant and somatostatin receptor ligands on incidence of vertebral fractures in patients with acromegaly.

PURPOSE: Acromegalic osteopathy is an emerging complication of acromegaly characterized by increase in bone turnover, deterioration in bone microarchitecture and high risk of vertebral fractures (VFs). Somatostatin receptor ligands (SRLs) and pegvisomant (PegV) are used for treatment of acromegaly and there is evidence that both drugs may exert direct effects on peripheral targets regardless of biochemical control of disease. However, whether or not SRLs and PegV may directly influence skeletal health its is unknown. METHODS: In this longitudinal study, we evaluated the incidence of radiological VFs in 83 patients (48 females, 35 males; median age 47 years, range 18-80 years) who were treated with SRLs alone (42 cases), PegV alone (6 cases) or in combination with SRLs (35 cases) for median period of 82 months (range 36-126). PegV was given when acromegaly was not controlled by SRLs alone. RESULTS: During the follow-up, 29 patients (34.9%) developed incident VFs. In patients receiving PegV due to active disease during SRL therapy, incidence of VFs decreased significantly from 43.9 to 26.8% (p = 0.039). When acromegaly was controlled by PegV, the incidence of VFs was slightly but not significantly lower as compared to that observed in patients with biochemical control of disease by SRLs (10.0 vs. 26.7%; p = 0.09). In the multivariate logistic regression analysis, incident VFs were independently predicted by pre-existing VFs (odds ratio 61.0; p = 0.009), duration of active acromegaly (odds ratio 1.01; p = 0.05) and mean serum IGF-I during the follow-up (odds ratio 5.26; p = 0.03), regardless of the therapeutic regimen (odds ratio 1.05; p = 0.94). CONCLUSIONS: PegV and SRLs had comparable effects on VF risk in acromegaly. The activity of disease was the main determinant of VFs independently of the drug used to control acromegaly.

Neuro-radiological features can predict hypopituitarism in primary autoimmune hypophysitis.

Primary autoimmune hypophysitis (PAH) is considered an underdiagnosed disease, due to the difficulty in reaching a definitive diagnosis. PAH clinical diagnosis remains an exclusion diagnosis. We aimed to correlate PAH neuro-radiological signs to endocrine features and evaluate their prognostic role. 24 PAH cases were enrolled and classified according to neuro-radiological signs: in 12 adeno-hypophysitis (AHs), 8 infundibulo-neuro-hypophysitis (INHs) and 4 pan-hypophysitis (PHs). Secondary hypogonadism developed more frequently in INHs as compared to AHs (54.5% vs. 27.3%, p = 0.05), without no difference with PHs (p = 0.6). Diabetes insipidus occurred more frequently in INHs cases (72.7%, p < 0.001) and in PHs cases (27.3%, p = 0.007), as compared to AHs cases (0%). Similarly, all cases of GHD occurred in INHs (100%) as compared to AHs (0%, p < 0.001) and PHs (0%, p < 0.001). The pituitary stalk (PS) showed a pseudo-triangular shape (larger at the optical chiasma) in INHs and a pseudo-cylindrical shape (larger both at the optical chiasma and at the pituitary insertion) in PHs. The PS pseudo-triangular shape correlated to the occurrence of GHD and diabetes insipidus (p < 0.001/p = 0.03). At the 1-year follow-up, improvement of baseline radiological features positively correlated with the loss of the neuro-pituitary "bright spot" on T1-weighted images (OR 0.16; 95% CI 0.03-0.9 p = 0.02) and with a PS diameter at the optical chiasma level larger than 4.1 mm (AUC 0.97, sensibility 80%, specificity 100%, OR 6; 95% CI1.1-28.8, p = 0.01) Our data suggest that neuro-radiological PAH classification in PH, AH and INH can predict pituitary dysfunction and that some neuro-radiological features, such as the pituitary stalk diameter and the loss of the neuro-pituitary bright spot on T1w images can play a role as a positive prognostic marker of the radiological hypophysitis outcome.

An Overview of Diagnosis of Primary Autoimmune Hypophysitis in a Prospective Single-Center Experience.

BACKGROUND: Autoimmune hypophysitis is a rare disease with a natural progression that is not well known. AIM: To collect representative data on clinical features of autoimmune hypophysitis and better characterize the disease. PATIENTS AND METHODS: A prospective single-center study was designed. Autoimmune hypophysitis-affected patients evaluated from 2011 at our tertiary care Pituitary Unit were enrolled. After ruling out other pituitary masses and secondary causes of hypophysitis, autoimmune hypophysitis was the diagnosis of exclusion. Autoimmune hypophysitis was classified as adenohypophysitis, panhypophysitis, and infundibuloneurohypophysitis according to clinical and neuroradiological findings. RESULTS: A total of 21 patients met the inclusion criteria: 9 were diagnosed with adenohypophysitis, 4 with panhypophysitis, and 8 with infundibuloneurohypophysitis. The frequency of secondary hypoadrenalism was similar in adenohypophysitis, panhypophysitis, and infundibuloneurohypophysitis. Growth hormone deficit and secondary hypogonadism occurred more frequently in infundibuloneurohypophysitis than in adenohypophysitis and panhypophysitis (p = 0.009; p = 0.04). All cases of multiple pituitary secretion deficits occurred in cases of infundibuloneurohypophysitis (p = 0.04). No correlations between hypophysitis subtype and anti-pituitary and anti-hypothalamus autoantibodies were found. A higher frequency of extractable nuclear antigens (ENA) and anti-nuclear antibodies (ANA) was found in cases of panhypophysitis (OR 5.0, 95% CI 0.86-28.8, p < 0.001, and OR 1.8, 95% CI 1.1-3.2, p = 0.02, respectively) as compared to adenohypophysitis and infundibuloneurohypophysitis. CONCLUSION: Infundibuloneurohypophysitis should be taken into account in the etiological diagnosis of hypopituitarism, particularly if it is associated with diabetes insipidus and in cases of growth hormone deficit, secondary hypogonadism, or multiple hormone deficits. Contrast-enhanced MRI is crucial for the clinical and noninvasive diagnosis of hypophysitis. Screening for autoantibodies, particularly anti-ENA and anti-ANA, is strongly suggested in the clinical context of hypophysitis.

Typical and atypical pituitary adenomas: a single-center analysis of outcome and prognosis.

BACKGROUND AND OBJECTIVE: In 2004, the World Health Organization defined atypical pituitary adenomas as those with a Ki-67 expression > 3%, an excessive p53 expression and increased mitotic activity. As the usefulness of this classification is controversial, we reviewed typical and atypical pituitary adenomas to compare the clinical and prognostic features. PATIENTS AND METHODS: We retrospectively reviewed 343 consecutive pituitary adenomas. Atypical pituitary adenomas represented 18.7% of cases. All patients were operated on at the Department of Neurosurgery of our institution and were followed up at the Hypothalamic-Pituitary Disease Unit of the same institution. The median follow-up time was 75 months (range 7-345). RESULTS: Younger age at diagnosis as well as immunohistochemical positivity for adrenocorticotropic hormone and prolactin correlated with a higher risk of atypical pituitary adenomas, whereas typical and atypical pituitary adenomas did not differ with regard to gender, tumor size, recurrence risk and disease-free survival time (DFST). Among the 219 patients who underwent radical surgery, a Ki-67 expression ≥ 1.5% was associated with a higher risk of recurrence and a worse DFST, even after correction for age at diagnosis, gender, immunohistochemical classification, tumor size, invasiveness and Knosp classification [p = 0.01; hazard ratio (HR) 2.572; 95% confidence interval (CI) 1.251-5.285). Pituitary adenomas with a Ki-67 expression ≥ 1.5% showed a worse DFST as compared to pituitary adenomas with a Ki-67 expression < 1.5% (HR 2.166; 95% CI 1.154-4.064). CONCLUSION: In this series, atypical and typical pituitary adenomas did not differ with regard to recurrence and DFST. Pituitary adenomas with a Ki-67 expression ≥ 1.5% showed a higher recurrence risk and a worse DFST as compared to those with a Ki-67 expression < 1.5%. We suggest that a Ki-67 expression ≥ 1.5% may be useful as a prognostic marker, though this will need to be confirmed by prospective, multicenter data.

Radically resected pituitary adenomas: prognostic role of Ki 67 labeling index in a monocentric retrospective series and literature review.

Ki-67 Labeling Index is an immunocytochemical marker of cell proliferation. The correlation of Ki-67 expression with pituitary adenomas recurrence has been investigated and is highly debated. Aim of this study was to evaluate whether Ki-67 correlates with recurrence even in patients with an apparently completely removed pituitary adenoma. We retrospectively reviewed the database of the Hypothalamic-Pituitary Disease Unit at the Catholic University of Rome, collected between 2003 and 2011. Inclusion criteria were: patients who underwent surgery at the Department of Neurosurgery with an apparently complete removal of a pituitary adenoma; Ki-67 histological evaluation by the same operator and values of <3%. All patients underwent endocrine evaluation of the hypothalamic-pituitary function, ophthalmologic and neuro-radiological examinations, during the preoperative period and follow-up. Out of 490 patients recorded on the database of the Hypothalamic-Pituitary Disease Unit at the Catholic University of Rome, 191 cases met the inclusion criteria. Recurrence was observed in 49 cases (25.7% of the patients who had undergone radical excision). Optional cut-off value was identified at Ki-67 values of 1.50%. This was associated with worse disease-free survival time, even after correction for age at treatment, gender, positivity to p53, functional classification and Knosp grading. Ki-67 labeling index may be useful in postoperative management, even in patients who underwent radical PA removal. We suggest a Ki-67 cut-off value of 1.5% to plan an adequate clinical follow-up.

The Role of the GH Receptor Polymorphisms as a Prognostic Factor of Vertebral Fractures in Acromegalic Patients Resistant to First-generation SSAs and Treated with Pegvisomant or Pasireotide LAR.

BACKGROUND: Acromegaly is associated with skeletal fragility and increased prevalence of vertebral fractures (VF). Two isoforms of GH receptor (GHR) have been described, which differ in the presence or absence of a transcript of exon 3 of the GHR gene. Both isoforms produce a functional receptor, but the exon 3-deleted isoforms (d3-GHR) have greater sensitivity to endogenous and recombinant GH than the full-length isoform (fl-GHR). OBJECTIVE: We conducted a longitudinal, retrospective, observational, single-center study to investigate the role of GHR polymorphism as a prognostic factor of incidental VF (I-VF) in firstgeneration somatostatin analogs (fg-SSAs)-resistant acromegalic patients and treated with Pegvisomant or Pasireotide LAR. METHODS: Seventy-two patients with active acromegaly were included: 28 patients carried the d3-GHR isoform, and 44 patients carried the fl-GHR isoform. Forty-six patients were treated with Pegvisomant in combination with fg-SSAs, and 26 were treated with Pasireotide LAR. At the last follow-up, 58 patients achieved biochemical control of acromegaly. Eighteen patients carried prevalent VF (P-VFs), while 14 patients experienced the occurrence of I-VFs. RESULTS: From the group treated with Pegvisomant in combination with fg-SSAs, 32 patients carried the fl-GHR isoform, and 14 carried the d3-GHR isoform. From the group treated with Pasireotide LAR, 12 patients had the fl-GHR isoform, and 14 patients carried the d3-GHR isoform. I-VF occurred more frequently in patients with the fl-GHR isoform compared to d3-GHR (p =0.04); otherwise, I-VF occurred more frequently in patients with the d3-GHR isoform than fl-GHR (p =0.01). CONCLUSION: The GHR polymorphisms could improve the therapeutic approach in acromegaly, tailored to the individual patient, in the context of personalized medicine.

A Toluene-induced Infundibulo-neuro-hypophysitis: Presentation of a New Cause of Hypophysitis Secondary to Toxic Exposure and Review on Toluene Inhalation Endocrine Effects.

INTRODUCTION: Hypophysitis is a rare inflammatory disorder of the pituitary gland. Symptoms and signs of hypophysitis can be various, progressing insidiously, and its recognition may be challenging. CASE PRESENTATION: We report the clinical history and therapeutic management of a 59-year-old man diagnosed with arginine vasopressin deficiency (AVP-D) due to an infundibulo-neurohypophysitis (INH) that occurred after the patient had inhaled spray film containing toluene. In consideration of the clinical signs and radiological imaging suggestive of INH, therapy with desmopressin and corticosteroids was instituted, with gradual improvement of polyuria and resolution of the radiological features of INH. CONCLUSION: To our knowledge, we described the first case of INH, manifested with AVP-D, secondary to toluene exposure. In addition, the endocrine effects of toluene inhalation were discussed. Finally, given the scarcity of data available, an overview of all the known toxic substances inducing AVP-D was also provided.