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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.
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BACKGROUND: The pseudo-Cushing's encompass several disorders that can occur in high-stress situations and that show biochemical features like those of Cushing's syndrome. We present a case with difficult differential diagnosis for overlapping laboratory findings. CASE REPORT: A 74-year-old man was admitted to our hospital for worsening dyspnoea for a month, 15 kilograms of weight loss in the previous months, asthenia, hypotonia, and muscle hypotrophy. Moreover, due to the onset of acute hypoxic-hypercapnic respiratory failure, the patient was treated with non-invasive ventilation and then admitted to the intensive care unit, for pneumonia and respiratory failure due to Meticillin-sensitive Staphylococcus aureus and Klebsiella Aerogenes. Antibiotic therapy was started. During the treatment in the ICU, the patient underwent endotracheal intubation for the worsening of respiratory function, and inotropic drug therapy was introduced for the development of septic shock. Hormones were tested, showing an ACTH-dependent hypercortisolism. The results of Nugent, Liddle, and the dexamethasone- suppressed CRH stimulation tests suggested a not-neoplastic ACTH-dependent hypercortisolism. The pituitary contrasted magnetic resonance image showed gland hypertrophy, and the abdominal computed tomography ruled out adrenal lesions. Unfortunately, the patient developed a multi-organ failure and died. The autopsy finding confirmed the absence of pituitary and other neuroendocrine tumors and showed bilateral adrenal hypotrophy. CONCLUSION: Our clinical case described a patient with pseudo-Cushing's syndrome during sepsis and pre-agonist phase, with a difficult differential diagnosis, in which the combination of the low-dose dexamethasone suppression test and the CRH test allowed a conclusive and correct diagnostic orientation.
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INTRODUCTION: Hypophysitis is an inflammatory disorder of the pituitary gland. It can manifest variously, with endocrinological and neuro-ophthalmologic symptoms and signs, due to the compression of sellar and parasellar structures. CASE REPRESENTATION: Although hypophysitis is rare, this pituitary disease can occur during pregnancy or in the postpartum period. In this report, we describe the case of a woman with partial hypopituitarism secondary to autoimmune hypophysitis who, five years after the diagnosis and the immunosuppressive treatment, had an uneventful pregnancy and successfully delivered a healthy infant at term. CONCLUSION: We reported the clinical history of the patient and the evolution of the disease and also reviewed the management and treatment of autoimmune hypophysitis during pregnancy.
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The review explores the 2022 update to the World Health Organization (WHO) classification of pituitary adenomas, now referred to as pituitary neuroendocrine tumors (PitNETs), and his possible impact on the clinical management of PitNET patients. The review highlights the differences and the evolution from the 2017 to 2022 version, with the current classification considering the lineage of the tumor cells, cell type, hormones produced, and other auxiliary characteristics for a comprehensive histological classification. The revision in terminology reflects a broader perspective on neuroendocrine neoplasia. The new approach based on transcription factors, hormone expression and other biomarkers has allowed a major revision of the nomenclature and a more accurate classification of pituitary adenomas. Furthermore, in some cases this approach is also assuming a prognostic value, useful in clinical practice. However, despite this elaborate classification and stratification, the review points out the lack of a robust grading or staging system and suggests the need for further research and validation of diagnostic methods. Despite these limitations, the revised classification presents a significant step towards understanding and managing PitNETs patients.
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BACKGROUND: Hypophysitis is a rare inflammatory disorder of the pituitary gland. Symptoms and signs of hypophysitis can be various, and its recognition may be challenging. Arginine vasopressin deficiency (AVP-D) due to exposure to a variety of drugs and toxic substances is rare, but some cases have been reported. Only 2 cases of AVP-D following toxic exposure to toluene, an aromatic hydrocarbon, have been reported in the literature. To our knowledge, our case represents the first description of an infundibulo neurohypophysitis (INH), manifested with AVP-D, secondary to inhalation of toluene. CASE REPORT: A 59-year-old man with an unremarkable medical history was referred to our department for headache, polyuria, and polydipsia after the inhalation of spray film containing toluene. The blood tests revealed a hyperosmolar plasma hypernatremia with normal kidney function. A desmopressin test was performed, with an improvement in water balances, blood electrolytes, and diuresis contraction. A pituitary MRI detected the absence of a normal hyperintense signal of the neuro-pituitary in the T1-weighted images. In consideration of the clinical signs and radiological imaging suggestive of INH, a therapy with desmopressin and corticosteroids was instituted, with gradual improvement of polyuria and resolution of the radiological features of INH. CONCLUSION: The exceptional finding of INH, manifested with AVP-D, following toluene inhalation could represent a new secondary cause of hypophysitis. The possibility that drugs or toxic substances never reported before could induce INH should not be excluded since the study on hypophysitis is relatively recent but emerging, predictably destined to increase exponentially in the coming years.
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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.
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Pasireotide-LAR is recommended as a second-line treatment for patients with acromegaly. Although the effects of pasireotide-LAR have been well characterized in clinical studies, real-practice evidence is scant, especially in the long term and within the individualization of therapy in patients with comorbidities. To provide additional insight on the individualized approach to acromegaly management, six clinical cases of complex acromegaly treated with pasireotide-LAR for more than 5 years were reported. Pasireotide-LAR allowed the normalization of insulin-like growth factor 1 (IGF1) values in all patients and reduced tumour residue volume where present. A good safety profile and long-term tolerability were also reported.
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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.
Subject(s)
Acromegaly , Bone Density , Human Growth Hormone , Somatostatin , Humans , Acromegaly/drug therapy , Bone Density/drug effects , Middle Aged , Female , Male , Retrospective Studies , Adult , Somatostatin/analogs & derivatives , Somatostatin/therapeutic use , Human Growth Hormone/analogs & derivatives , Pilot Projects , Aged , Longitudinal StudiesABSTRACT
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.
Subject(s)
Acromegaly , Proto-Oncogene Proteins c-ret , Humans , Acromegaly/genetics , Germ-Line Mutation , Multiple Endocrine Neoplasia Type 2a/genetics , Mutation , Phenotype , Proto-Oncogene Proteins c-ret/genetics , Thyroid Neoplasms/geneticsABSTRACT
BACKGROUND: Pancreatic metastases from medullary thyroid carcinoma (MTC) are exceptional. Imaging and treatment based on somatostatin receptors may play a role, though the evidence is unconvincing. CASE PRESENTATION: We have, herein, documented a unique case of metastatic MTC, where pancreatic metastasis was identified by 68Ga-PET/CT, with the disease showing very slow progression during treatment with lanreotide autogel. A 51-year-old woman underwent total thyroidectomy for goiter in 2000, with a postoperative diagnosis of MTC. Due to persistent disease, somatostatin analogues (SSA) treatment commenced in 2005, following a positive acute octreotide test. In 2012, a pathology-confirmed pancreatic metastasis was diagnosed via 68Gallium-positron emission tomography (68Ga-PET/CT). The disease progressed very slowly over 17 years of SSA treatment. CONCLUSION: This uncommon case of pancreatic metastasis from MTC indicates that nuclear medicine techniques might offer valuable additional information. Extended treatment with lanreotide autogel appears to correlate with very slow disease progression in selected patients.
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CONTEXT: The prompt control of acromegaly is a primary treatment aim for reducing related disease morbidity and mortality. First-generation somatostatin receptor ligands (fg-SRLs) are the cornerstone of medical therapies. A non-negligible number of patients do not respond to this treatment. Several predictors of fg-SRL response were identified, but a comprehensive prognostic model is lacking. OBJECTIVE: We aimed to design a prognostic model based on clinical and biochemical parameters, and pathological features, including data on immune tumor microenvironment. METHODS: A retrospective, monocenter, cohort study was performed on 67 medically naïve patients with acromegaly. Fifteen clinical, pathological, and radiological features were collected and analyzed as independent risk factors of fg-SRLs response, using univariable and multivariable logistic regression analyses. A stepwise selection method was applied to identify the final regression model. A nomogram was then obtained. RESULTS: Thirty-seven patients were fg-SRLs responders. An increased risk to poor response to fg-SRLs were observed in somatotropinomas with absent/cytoplasmatic SSTR2 expression (OR 5.493 95% CI 1.19-25.16, P = .028), with low CD68+/CD8+ ratio (OR 1.162, 95% CI 1.01-1.33, P = .032). Radical surgical resection was associated with a low risk of poor fg-SRLs response (OR 0.106, 95% CI 0.025-0.447 P = .002). The nomogram obtained from the stepwise regression model was based on the CD68+/CD8+ ratio, SSTR2 score, and the persistence of postsurgery residual tumor and was able to predict the response to fg-SRLs with good accuracy (area under the curve 0.85). CONCLUSION: Although our predictive model should be validated in prospective studies, our data suggest that this nomogram may represent an easy to use tool for predicting the fg-SRL outcome early.
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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.
Subject(s)
Neuroendocrine Tumors , Pituitary Neoplasms , Animals , Humans , Pituitary Neoplasms/pathology , Pituitary Gland/metabolism , Neuroendocrine Tumors/genetics , Neuroendocrine Tumors/therapy , Neuroendocrine Tumors/metabolism , Aggression , Tumor Microenvironment/geneticsABSTRACT
Hypophysitis, a rare inflammatory disorder of the pituitary gland, has seen an uptick in reported cases in recent years. Our objective is to summarize the most recent research on the etiopathogenesis, molecular mechanisms, and genetics of both primary and secondary hypophysitis. Primary autoimmune hypophysitis (PAH): During the acute phase of the disease, the pituitary gland in enlarged due to the infiltration of T and B lymphocytes. The chronic phase is characterized by progressive and irreversible pituitary atrophy. APA may play a role in the management, diagnosis, and prognosis of PAH. Specific autoantibodies such as anti-GH, anti-PIT-1, and anti-T-PIT have been found in patients with hypophysitis and hypopituitarism. A recent study suggested that a mechanism of escaping clonal deletion and mounting an immune response against self antigens can explain the unusual nature of the immune response observed in PAH patients. A cytokine array shows the presence of gamma-interferon and interleukin-17. Patients carrying mutations in the PIT1 or PROP1 genes may present PAH. Individuals carrying the HLA DQ8 haplotype are four times more likely to develop PAH. Immune checkpoint inhibitors induce hypophysitis (IIHs): IIHs is an increasingly frequent toxicity of in patients on treatment with inhibitors targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death-1 (PD-1). ICIs inhibit the CTLA-4 pathway, leading to overactivation of T lymphocytes. The binding of PD-1/PD-L1 suppresses the activity of T cells, promotes the conversion of T-helpers into T-regulatory cells, and activates pro-survival signaling pathways in cancer cells. Cytokines play a crucial role in IIHs. B-cell infiltration has been observed in IIHs, suggesting that antibody-mediated pituitary injury may contribute. Genetic polymorphisms of CTLA-4 and PD-1 genes can increase the risk of IIHs. HLA alleles may also be involved in the onset of IIHs; this HLA association presents a possible alternative mechanistic hypothesis. IIHs may also be linked to a paraneoplastic syndrome triggered by ectopic expression of pituitary specific antigens. SARS-CoV-2-related hypophysitis: Recently, the literature has reported occurrences of hypophysitis associated with the SARS-CoV-2 virus; long COVID-19 may also present as infundibulo-neuro-hypophysitis. The virus enters the central nervous system because of its distinct interaction with angiotensin-converting enzyme receptors via spike proteins binding the capillary endothelium, and it directly damages the pituitary cells. The effect of SARS-CoV-2 can occur indirectly through inflammation and the release of cytokines. The exact mechanism remains ambiguous. The available data on endocrine complications associated with the SARS-CoV-2 vaccine are scant. Nonetheless, isolated cases of hypophysitis have been documented. Treatment of hypophysitis: Glucocorticoids are the cornerstone in managing primary hypophysitis, given their targeted action on inflammation. A better understanding of the etiopathogenesis and molecular mechanism of hypophysitis can lead to more effective and personalized treatment strategies.
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CONTEXT: Skeletal fragility is observed in 30% to 60% of acromegaly patients, representing an emerging complication of the disease that increases disability. Despite several studies having investigated the clinical and hormonal prognostic factors for the occurrence of vertebral fractures (VFs) in acromegaly, very few data are available on their prevention/treatment including the effect of vitamin D (VD) supplementation, which has been reported to have a fracture-protective effect in several studies in patients with osteoporosis. OBJECTIVE: We aimed to investigate the role of cholecalciferol (D3) supplementation in the prevention of incident VFs (i-VFs) in acromegaly. METHODS: A longitudinal, retrospective and multicenter study was performed on 61 acromegaly patients treated and untreated with D3 supplementation. RESULTS: Twenty-six patients were treated with D3 supplementation according to clinical guidelines. The median D3 weekly dosage was 8500 IU (interquartile range [IQR]: 3900). The median duration of D3 supplementation was 94 months (IQR: 38). At last follow-up, i-VFs were diagnosed in 14 patients (23%). I-VFs were less prevalent in patients on D3 supplementation (14.3% of cases) compared to patients not treated with D3 (85.7%; P = .02). The final level of serum V25OH-D was significantly lower in patients who developed i-VFs (28.6 ng/mL, IQR: 4.1) compared to patients who did not develop i-VFs (34.2 ng/mL, IQR: 9.6; P = .05). The logistic regression confirmed the protective role of D3 supplementation on the occurrence of i-VFs (odds ratio: 0.16; 95% CI, 0.03-0.79; P = .01). CONCLUSION: It is likely that D3 supplementation could lead to a reduction in i-VFs in acromegaly.
Subject(s)
Acromegaly , Spinal Fractures , Humans , Acromegaly/complications , Acromegaly/drug therapy , Retrospective Studies , Cholecalciferol/therapeutic use , Bone Density , Spinal Fractures/epidemiology , Spinal Fractures/etiology , Spinal Fractures/prevention & controlABSTRACT
Growth Hormone-secreting adenomas exhibits variable biological behavior and heterogeneous natural history, ranging from small adenomas and mild disease, to invasive and aggressive neoplasms with more severe clinical picture. Patients not cured or controlled after neurosurgical and first-generation somatostatin receptor ligands (SRL) therapy could require multiple surgical, medical and/or radiation treatments to achieve disease control. To date, no clinical, laboratory, histopathological, or neuroradiological markers are able to define the aggressiveness or predict the disease prognosis in patients with acromegaly. Therefore, the management of these patients requires careful evaluation of laboratory assessments, diagnostic criteria, neuroradiology examinations, and neurosurgical approaches to choose an effective and patient-tailored medical therapy. A multidisciplinary approach is particularly useful in difficult/aggressive acromegaly to schedule multimodal treatment, which includes radiation therapy, chemotherapy with temozolomide and other, recent emerging treatments. Herein, we describe the role of the different members of the multidisciplinary team according to our personal experience; a flow-chart for the therapeutic approach of difficult/aggressive acromegaly patients is proposed.
Subject(s)
Acromegaly , Adenoma , Human Growth Hormone , Pituitary Neoplasms , Humans , Acromegaly/etiology , Acromegaly/therapy , Acromegaly/pathology , Growth Hormone , Pituitary Neoplasms/drug therapy , Human Growth Hormone/therapeutic use , Adenoma/pathologyABSTRACT
Somatotropinomas are pituitary tumors with a heterogenous clinical behavior. The tumor microenvironment regulates the interaction between tumor cells and the host immune system, potentially modulating tumor behavior. Here, we aimed to investigate the tumor immune infiltration in a cohort of medically naïve acromegaly patients. A retrospective, monocenter study was designed to analyze the presence of CD3+, CD20+, CD138+, CD4+, CD8+, CD68+ immune cells in samples of somatotropinomas and their prognostic significance on tumor behavior and response to first generation somatostatin analogs (fg-SSA). Thirty-six patients (23 females) were included in the study. Macroadenomas were identified in 23 cases: 12 with cavernous sinus invasion. The number of CD8+ lymphocytes positively correlated with CD4+ lymphocytes (p = .05, r:0.245) and with CD68+ macrophages (p = .01, r = 0.291). The CD8+/CD4+ ratio inversely correlated with CD68+/CD8+ ratio (p < .001, r = -0.626). CD68+ macrophages positively correlated with tumor size (maximum diameter p = .003, r = 0.574; volume p = .009, r = 0.566) and were more numerous in somatotropinomas with Ki-67 > 3% (median 65/HPF, IQR:15), compared to cases with Ki67 < 3% (median 50/HPF, IQR:22, p < .001). CD8+ and CD138+ lymphocytes were more numerous in cases responsive to fg-SSA (respectively median 18/HPF IQR:18 and median 8/HPF IQR: 6.5) as compared to fg-SSA nonresponsive cases (median 14.5/HPF IQR:40 p = .03; median 3.5/HPF IQR: 14 p = .03). CD8+ lymphocytes act as single predictor of response to fg-SSA, independently from age, GH and IGF-I levels, tumor dimension and invasion. Our results support that lymphocytes and macrophages generate an immune network in somatotropinomas and the characteristic of the immune infiltrate may predict treatment outcome.
Subject(s)
Pituitary Neoplasms , Somatotrophs , Female , Humans , Somatostatin , Pituitary Neoplasms/pathology , Retrospective Studies , Prognosis , CD8-Positive T-Lymphocytes/pathology , Tumor MicroenvironmentABSTRACT
BACKGROUND: Immune checkpoint inhibitor hypophysitis (IIHs) is an emerging problem in cancer patients treated with immune checkpoint inhibitors (ICIs). We aimed to describe the clinical and molecular features of a multicenter series of IIHs. METHODS: Demographic and clinical features were retrospectively collected for all cases. Anti-pituitary and anti-hypothalamus autoantibodies were also measured. RESULTS: Nine patients were included. Six patients were treated with nivolumab and three with ipilimumab. Secondary hypoadrenalism was diagnosed in all patients. Pituitary MRI showed pituitary enlargement in two cases and no abnormalities in the other seven. Anti-pituitary antibodies were positive in 57.1% of cases and anti-hypothalamus antibodies in 85.7% of cases. Multidisciplinary treatments were established by a neuroendocrinologist and oncologists: all patients were treated with hydrocortisone replacement; ICI was withdrawn in two cases. At follow-up, hypoadrenalism persisted in all cases. Pituitary enlargement on MRI spontaneously recovered in the two affected patients. We found that the typical features of hypophysitis involved more frequently females and patients treated with ipilimumab. CONCLUSIONS: Although this study did not clarify if autoimmune secondary hypoadrenalism and ICI hypophysitis on brain imaging are two sides of the same disease, our preliminary data underline the need for molecular studies of IIHs and of autoimmune ICIs-related hypopituitarism.
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INTRODUCTION: Pasireotide long-acting release (LAR) is approved for second-line treatment of acromegaly. Starting pasireotide LAR 40 mg every 4 weeks is recommended and then up-titrate to 60 mg monthly in case of IGF-I uncontrolled levels. We present three patients treated with a de-escalation approach with pasireotide LAR. CASE 1: A 61-year-old female diagnosed with resistant acromegaly was treated with pasireotide LAR 60 mg every 28 days. When IGF-I reached the lower age range, therapy was decreased to pasireotide LAR 40 mg and then to 20 mg. In 2021 and 2022, IGF-I value remained within the normal range. CASE 2: A 40-year-old female diagnosed with resistant acromegaly underwent three neurosurgeries. In 2011, she was enrolled in the PAOLA study and assigned to pasireotide LAR 60 mg. Due to IGF-I overcontrol and radiological stability, therapy was downscaled to 40 mg in 2016 and to 20 mg in 2019. The patient developed hyperglycemia, which was treated with metformin. CASE 3: A 37-year-old male diagnosed with resistant acromegaly was treated with pasireotide LAR 60 mg in 2011. In 2018, therapy was decreased to 40 mg due to IGF-I overcontrol and in 2022 to 20 mg. He developed hyperglycemia, but HbA1c values remained under 48 nmol/L for 7 years. CONCLUSION: De-escalation treatment with pasireotide LAR may allow a greater proportion of patients to achieve control of acromegaly, particularly in selected cases of clinically aggressive acromegaly potentially responsive to pasireotide (high IGF-I values, invasion of the cavernous sinuses, partial resistance to first-line somatostatin analogues and positive expression of somatostatin receptor 5). Another benefit may be IGF-I oversuppression overtime. The major risk seems to be hyperglycemia.
Subject(s)
Acromegaly , Hyperglycemia , Male , Female , Humans , Middle Aged , Adult , Acromegaly/drug therapy , Insulin-Like Growth Factor I/metabolism , Treatment Outcome , Somatostatin , Octreotide/therapeutic use , Delayed-Action Preparations/therapeutic useABSTRACT
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.
Subject(s)
Pituitary Neoplasms , Humans , Pituitary Neoplasms/genetics , Biomarkers , Treatment Outcome , Immunotherapy , Biology , Tumor MicroenvironmentABSTRACT
INTRODUCTION: Acromegaly is a rare but potentially life-threatening disease, if not promptly managed, for the systemic complications due to the GH/IGF-I hypersecretion. According to the increased population life span, the number of older acromegaly patients is growing. We aim to investigate clinical features of elderly acromegaly (elderly-ACRO) and to identify the risk factors for the occurrence of comorbidities in elderly-ACRO. MATERIALS AND METHODS: A retrospective and multi-center study was performed on acromegaly patients. Acromegaly comorbidities were compared among elderly-ACRO (>65 years), young acromegaly patients (young-ACRO if ≤65 years) and a control group of age and gender-matched subjects. RESULT: Fifty of the 189 enrolled patients were elderly-ACRO (26.5%). Cardiovascular, metabolic, neurological/psychiatric and joint/articular disorders, nodular thyroid disease, sleep apnoea syndrome and skeletal fragility occurred more frequently in elderly-ACRO as compared to controls. Cardiovascular and metabolic disorders, nodular thyroid disease occurred significantly more frequently in elderly-ACRO as compared to young-ACRO and controls. On the other hand, neurological/psychiatric, joint/articular disorders and bone fragility occur with a similar frequency among elderly and young-ACRO. We found that elderly-ACRO had an increased risk for the occurrence of systemic arterial hypertension (p < 0.001, OR: 5.4 95%IC:2.6-10.9), left ventricular hypertrophy (p = 0.01, OR: 3 95%IC: 1.5-5.8) and metabolic disorders (p = 0.006, OR: 4.1 95%IC: 2-8.3). CONCLUSION: Our results may suggest that some acromegaly comorbidities may be predominantly due to acromegaly "per-se" rather than to aging. On the contrary, cardiovascular and metabolic disorders seem to be due to aging as well.