Immunological signatures and predictive biomarkers for first-generation somatostatin receptor ligand resistance in Acromegaly.

PURPOSE: Predicting resistance to first-generation Somatostatin Receptor Ligands (fg-SRL) in Acromegaly patients remains an ongong challenge. Tumor-associated immune components participate in various pathological processes, including drug-resistance. We aimed to identify the immune components involved in resistance of fg-SRL, and to investigate biomarkers that can be targeted to treat those drug-resistant Acromegaly. METHODS: We conducted a retrospective study involving 35 Acromegaly patients with somatotropinomas treated postoperatively with fg-SRL. Gathering clinicopathological data, SSTR2 expression, and immunological profiles, we utilized univariate, binary logistic regression, and ROC analyses to assess their predictive roles in fg-SRL resistance. Spearman correlation analysis further examined interactions among interested characteristics. RESULTS: 19 patients (54.29%) exhibited resistance to postoperative fg-SRL. GH level at diagnosis, preoperative tumor volume, T2WI-MRI intensity, granularity, PD-L1, SSTR2, and CD8 + T cell infiltration showed association with clinical outcomes of fg-SRL. Notably, T2WI-MRI hyperintensity, PD-L1-IRS > 7, CD8 + T cell infiltration < 14.8/HPF, and SSTR2-IRS < 5.4 emerged as reliable predictors for fg-SRL resistance. Correlation analysis highlighted a negative relationship between PD-L1 expression and CD8 + T cell infiltration, while showcasing a positive correlation with preoperative tumor volume of somatotropinomas. Additionally, 5 patients with fg-SRL resistance underwent re-operation were involved. Following fg-SRL treatment, significant increases in PD-L1 and SSTR5 expression were observed, while SSTR2 expression decreased in somatotropinoma. CONCLUSION: PD-L1 expression and CD8 + T cell infiltration, either independently or combined with SSTR2 expression and T2WI-MRI intensity, could form a predictive model guiding clinical decisions on fg-SRL employment. Furthermore, targeting PD-L1 through immunotherapy and embracing second-generations of SRL with higher affinity to SSTR5 represent promising strategies to tackle fg-SRL resistance in somatotropinomas.

Surgical and non-surgical interventions for primary and salvage treatment of growth hormone-secreting pituitary adenomas in adults.

BACKGROUND: Growth hormone (GH)-secreting pituitary adenoma is a severe endocrine disease. Surgery is the currently recommended primary therapy for patients with GH-secreting tumours. However, non-surgical therapy (pharmacological therapy and radiation therapy) may be performed as primary therapy or may improve surgical outcomes. OBJECTIVES: To assess the effects of surgical and non-surgical interventions for primary and salvage treatment of GH-secreting pituitary adenomas in adults. SEARCH METHODS: We searched CENTRAL, MEDLINE, WHO ICTRP, and ClinicalTrials.gov. The date of the last search of all databases was 1 August 2022. We did not apply any language restrictions. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs of more than 12 weeks' duration, reporting on surgical, pharmacological, radiation, and combination interventions for GH-secreting pituitary adenomas in any healthcare setting. DATA COLLECTION AND ANALYSIS: Two review authors independently screened titles and abstracts for relevance, screened for inclusion, completed data extraction, and performed a risk of bias assessment. We assessed studies for overall certainty of the evidence using GRADE. We estimated treatment effects using random-effects meta-analysis. We expressed results as risk ratios (RR) for dichotomous outcomes together with 95% confidence intervals (CI) or mean differences (MD) for continuous outcomes, or in descriptive format when meta-analysis was not possible. MAIN RESULTS: We included eight RCTs that evaluated 445 adults with GH-secreting pituitary adenomas. Four studies reported that they included participants with macroadenomas, one study included a small number of participants with microadenomas. The remaining studies did not specify tumour subtypes. Studies evaluated surgical therapy alone, pharmacological therapy alone, or combination surgical and pharmacological therapy. Methodological quality varied, with many studies providing insufficient information to compare treatment strategies or accurately judge the risk of bias. We identified two main comparisons, surgery alone versus pharmacological therapy alone, and surgery alone versus pharmacological therapy and surgery combined. Surgical therapy alone versus pharmacological therapy alone Three studies with a total of 164 randomised participants investigated this comparison. Only one study narratively described hyperglycaemia as a disease-related complication. All three studies reported adverse events, yet only one study reported numbers separately for the intervention arms; none of the 11 participants were observed to develop gallbladder stones or sludge on ultrasonography following surgery, while five of 11 participants experienced any biliary problems following pharmacological therapy (RR 0.09, 95% CI 0.01 to 1.47; 1 study, 22 participants; very low-certainty evidence). Health-related quality of life was reported to improve similarly in both intervention arms during follow-up. Surgery alone compared to pharmacological therapy alone may slightly increase the biochemical remission rate from 12 weeks to one year after intervention, but the evidence is very uncertain; 36/78 participants in the surgery-alone group versus 15/66 in the pharmacological therapy group showed biochemical remission. The need for additional surgery or non-surgical therapy for recurrent or persistent disease was described for single study arms only. Surgical therapy alone versus preoperative pharmacological therapy and surgery Five studies with a total of 281 randomised participants provided data for this comparison. Preoperative pharmacological therapy and surgery may have little to no effect on the disease-related complication of a difficult intubation (requiring postponement of surgery) compared to surgery alone, but the evidence is very uncertain (RR 2.00, 95% CI 0.19 to 21.34; 1 study, 98 participants; very low-certainty evidence). Surgery alone may have little to no effect on (transient and persistent) adverse events when compared to preoperative pharmacological therapy and surgery, but again, the evidence is very uncertain (RR 1.23, 95% CI 0.75 to 2.03; 5 studies, 267 participants; very low-certainty evidence). Concerning biochemical remission, surgery alone compared to preoperative pharmacological therapy and surgery may not increase remission rates up until 16 weeks after surgery; 23 of 134 participants in the surgery-alone group versus 51 of 133 in the preoperative pharmacological therapy and surgery group showed biochemical remission. Furthermore, the very low-certainty evidence did not suggest benefit or detriment of preoperative pharmacological therapy and surgery compared to surgery alone for the outcomes 'requiring additional surgery' (RR 0.48, 95% CI 0.05 to 5.06; 1 study, 61 participants; very low-certainty evidence) or 'non-surgical therapy for recurrent or persistent disease' (RR 1.22, 95% CI 0.65 to 2.28; 2 studies, 100 participants; very low-certainty evidence). None of the included studies measured health-related quality of life. None of the eight included studies measured disease recurrence or socioeconomic effects. While three of the eight studies reported no deaths to have occurred, one study mentioned that overall, two participants had died within five years of the start of the study. AUTHORS' CONCLUSIONS: Within the context of GH-secreting pituitary adenomas, patient-relevant outcomes, such as disease-related complications, adverse events and disease recurrence were not, or only sparsely, reported. When reported, we found that surgery may have little or no effect on the outcomes compared to the comparator treatment. The current evidence is limited by the small number of included studies, as well as the unclear risk of bias in most studies. The high uncertainty of evidence significantly limits the applicability of our findings to clinical practice. Detailed reporting on the burden of recurrent disease is an important knowledge gap to be evaluated in future research studies. It is also crucial that future studies in this area are designed to report on outcomes by tumour subtype (that is, macroadenomas versus microadenomas) so that future subgroup analyses can be conducted. More rigorous and larger studies, powered to address these research questions, are required to assess the merits of neoadjuvant pharmacological therapy or first-line pharmacotherapy.

Variable anatomical features of acromegaly in the nasal cavity and paranasal sinuses: implications for endoscopic endonasal transsphenoidal surgery.

PURPOSE: Growth hormone (GH)-secreting pituitary neuroendocrine tumors (PitNETs) are the most common cause of acromegaly. The endoscopic endonasal transsphenoidal approach (EEA) is commonly employed to remove them. Although morphological differences in the nasal cavity exist between acromegaly patients and those with other types of PitNET, few quantitative studies have been performed. This study aimed to evaluate the anatomical features of the nasal cavity and paranasal sinuses in patients with acromegaly. METHODS: Preoperative computed tomography images of the nasal cavity and paranasal sinuses were compared between 20 patients with a GH-secreting PitNET (acromegaly group) and 22 with a non-functioning PitNET (control group). In the acromegaly group, the relationships between preoperative GH and/or insulin-like growth factor 1 (IGF-1) levels and anatomical characteristics were assessed. RESULTS: In the acromegaly group, the distance between the nostril and dorsum sellae was significantly longer and the distance between the parasellar internal carotid arteries was significantly shorter (p = 0.0022 and 0.0092, respectively). Pneumatization volume in the nasal cavity did not differ between the groups. Nasal mucosa and bony hypertrophy were observed in the acromegaly group. Preoperative GH level was correlated with the width of the piriform aperture (p = 0.0171). CONCLUSION: The nasal and paranasal changes associated with acromegaly can make EEA challenging to perform. Widening the surgical corridor anterior to the sphenoid sinus is important in these patients.

Complete Shrinking of Mixed Growth Hormone and Prolactin-Secreting Pituitary Adenoma With Bromocriptine Therapy Alone.

A 40-year-old man presented with acromegaly, reduction of visual acuity and visual field, and elevated blood sugar. Imaging examinations demonstrated a large sellar adenoma with suprasellar extension that compresses the optic chiasma upward, spreads downward to the sphenoid sinus, and invades the cavernous sinus bilaterally. Random prolactin and growth hormone were beyond the scope of normal. The patient achieved complete shrinking of the adenoma by taking bromocriptine orally. For some kinds of giant mixed growth hormone-prolactin adenomas, surgical treatment is not necessary, and drug treatment can also achieve good results.

Caloric restriction as a possible pitfall for persistent acromegaly follow-up - case report.

BACKGROUND: Acromegaly diagnosis is established when plasma levels of IGF-1 are increased and the Oral Glucose Tolerance Test (OGTT) with 75gr of glucose can't suppress Growth Hormone (GH) levels. These two parameters are also useful during follow-up, after surgical/radiologic therapy and/or during medical therapy. CASE PRESENTATION: A 29-year-old woman was diagnosed with acromegaly after a severe headache. Previous amenorrhea and facial and acral changes were noticed. A pituitary macroadenoma was found, biochemical evaluation was in agreement with the suspected acromegaly and a transsphenoidal adenectomy was performed. As the disease recurred, a surgical reintervention and radiosurgery (Gamma Knife, 22 Gy) were necessary. No normalization of IGF-1 was achieved during three years after radiosurgery. Surprisingly, then, and although clinical features seemed getting worse, IGF-1 levels became consistently controlled to 0.3-0.8 times the upper limit of the reference range. Questioned, the patient referred that she was following an intermittent fasting dietary plan. However, based on the dietary questionnaire, she was found to be under severe caloric restriction. First OGTT (under caloric restriction) showed absence of GH suppression and an IGF-1 value of 234 ng/dL (Reference Range 76-286 ng/mL). A second OGTT, one month after an eucaloric diet was instituted, showed an increased IGF-1 of 294 ng/dL, maintaining an unsuppressed, yet less elevated, GH. CONCLUSIONS: GHRH/GH/IGF-1 axis controls somatic growth. Regulation is complex, and nutrition status and feeding pattern have a recognized role. Like systemic inflammation or chronic liver disease, fasting and malnutrition decrease the expression of hepatic GH receptors, with consequent reduction of IGF-1 levels, through resistance to GH. This clinical report shows that caloric restriction may represent a pitfall in acromegaly follow-up.

Refractory somatotroph adenomas.

Somatotroph adenomas are usually controlled with standard therapy, which can include surgery, medical treatment and radiotherapy. Some tumors have a more aggressive behavior and are refractory to standard therapy. In this review, we summarize the phenotype of these tumors and the current options for their management.

Predictors of postoperative biochemical remission in lower Knosp grade growth hormone-secreting pituitary adenomas: a large single center study.

PURPOSE: Growth hormone-secreting pituitary adenomas (GH-PAs) with a low Knosp grade are typically associated with a good postoperative biochemical remission (BR) rate. However, a proportion of patients do not achieve remission. In this study, we aimed to investigate predictive factors of postoperative remission for lower Knosp GH-PAs. METHODS: In this retrospective study, we enrolled 140 patients who were diagnosed with lower Knosp (0-2) GH-PAs and received trans-sphenoidal surgery between December 2016 and June 2021 from the largest pituitary tumor surgery center in southern China. The univariate, binary Logistic regression, and receiver operating characteristic curve (ROC) analyses were employed to determine independent predictors and cutoff values of remission. The postoperative outcome was defined as remission using the 2010 consensus criteria of acromegaly. RESULTS: One hundred and thirty six patients (97.1%) achieved gross total resection. The postoperative long-term BR was 68.6%. Empty sella, tumor maximum diameter and postoperative GH levels were independent factors predicting remission. ROC revealed that postoperative 24 h GH ≤ 1.3 ng/mL and ≤ 1.23 ng/mL were valuable predictors for 3-month and long-term remission respectively, and that postoperative 3-month GH ≤ 1.6 ng/mL and tumor maximum diameter ≤ 17 mm were predictors for delayed remission. CONCLUSION: Early postoperative GH levels can be used as predictors of remission. However, BR was not associated with preoperative somatostatin analogs therapy or Knosp grade (0-2). For patients without residual tumor or recurrence and whose GH levels are slightly elevated within 1 year after surgery, adjuvant treatments may not be necessary.

Long-term control of acromegaly after pituitary surgery in South-Eastern Norway.

PURPOSE: Sustained cure of acromegaly can only be achieved by surgery. Most growth hormone (GH) secreting pituitary adenomas are macroadenomas (≥ 10 mm) at diagnosis, with reported surgical cure rates of approximately 50%. Long-term data on disease control rates after surgery are limited. Our aim was to estimate short- and long-term rates of biochemical control after pituitary surgery in acromegaly and identify predictive factors. METHODS: Patients operated for GH-secreting pituitary adenomas between 2005-2020 were included from the local pituitary registry (n = 178). Disease activity and treatment data were recorded at one-year (short-term) and five-year (long-term) postoperative follow-up. Biochemical control was defined as insulin-like growth factor 1 (IGF-1) ≤ 1.2 × upper limit of normal value. Multivariate regression models were used to identify factors potentially predicting biochemical control. RESULTS: A total of 178 patients with acromegaly (median age at diagnosis 49 (IQR: 38-59) years, 46% women) were operated for a pituitary adenoma. Biochemical control was achieved by surgery in 53% at short-term and 41% at long-term follow-up, without additional treatment for acromegaly. Biochemical control rates by surgery were of same magnitude in paired samples (45% vs. 41%, p = 0.213) for short- and long-term follow-up, respectively. At short-term, 62% of patients with microadenomas and 51% with macroadenomas, achieved biochemical control. At long-term, the biochemical control rate was 58% for microadenomas and 37% for macroadenomas (p = 0.058). With adjunctive treatment, 82% achieved biochemical control at long-term. Baseline IGF-1 levels significantly predicted biochemical control by surgery at short-term (OR: 0.98 (95% CI: 0.96-0.99), p = 0.011), but not at long-term (OR: 0.76 (95% CI: 0.57-1.00), p = 0.053). CONCLUSION: In unselected patients with acromegaly, the long-term biochemical control rate remains modest. Our findings indicate a need to identify patients at an earlier stage and improve therapeutic methods and surgical outcomes.

Growth hormone secreting pituitary adenomas show distinct extrasellar extension patterns compared to nonfunctional pituitary adenomas.

PURPOSE: Patterns of extension of pituitary adenomas (PA) may vary according to PA subtype. Understanding extrasellar extension patterns in growth hormone PAs (GHPA) vis-a-vis nonfunctional PAs (NFPAs) may provide insights into the biology of GHPA and future treatment avenues. METHODS: Preoperative MR imaging (MRI) in 179 consecutive patients treated surgically for NFPA (n = 139) and GHPA (n = 40) were analyzed to determine patterns of extrasellar growth. Extension was divided into two principal directions: cranio-caudal (measured by infrasellar/suprasellar extension), and lateral cavernous sinus invasion (CSI) determined by Knosp grading score of 3-4. Suprasellar extension was defined as tumor extension superior to the tuberculum sellae- dorsum sellae line, and inferior extension as invasion through the sellar floor into the sphenoid sinus or clivus. Categorical analysis was performed using Fisher's exact test. RESULTS: GHPAs were overall more likely to remain purely intrasellar compared to NFPA (50% vs 26%, p < 0.001). GHPAs, however, were 7 times more likely to exhibit isolated infrasellar extension compared to NFPA (20% vs 2.8%, p = 0.001). Conversely, NFPAs were twice as likely to exhibit isolated suprasellar extension compared to GHPA (60% vs 28%, p < 0.001), as well as combined suprasellar/infrasellar extension (25% vs 3%, p = 0.011). There were no overall differences in CSI between the two subgroups. DISCUSSION: GHPA and NFPA demonstrate distinct extrasellar extension patterns on MRI. GHPAs show proclivity for inferior extension with bony invasion, whereas NFPAs are more likely to exhibit suprasellar extension through the diaphragmatic aperture. These distinctions may have implications into the biology and future treatment of PAs.

Machine learning as a clinical decision support tool for patients with acromegaly.

OBJECTIVE: To develop machine learning (ML) models that predict postoperative remission, remission at last visit, and resistance to somatostatin receptor ligands (SRL) in patients with acromegaly and to determine the clinical features associated with the prognosis. METHODS: We studied outcomes using the area under the receiver operating characteristics (AUROC) values, which were reported as the performance metric. To determine the importance of each feature and easy interpretation, Shapley Additive explanations (SHAP) values, which help explain the outputs of ML models, are used. RESULTS: One-hundred fifty-two patients with acromegaly were included in the final analysis. The mean AUROC values resulting from 100 independent replications were 0.728 for postoperative 3 months remission status classification, 0.879 for remission at last visit classification, and 0.753 for SRL resistance status classification. Extreme gradient boosting model demonstrated that preoperative growth hormone (GH) level, age at operation, and preoperative tumor size were the most important predictors for early remission; resistance to SRL and preoperative tumor size represented the most important predictors of remission at last visit, and postoperative 3-month insulin-like growth factor 1 (IGF1) and GH levels (random and nadir) together with the sparsely granulated somatotroph adenoma subtype served as the most important predictors of SRL resistance. CONCLUSIONS: ML models may serve as valuable tools in the prediction of remission and SRL resistance.

First but not second postoperative day growth hormone assessments as early predictive tests for long-term acromegaly persistence.

PURPOSE: Postoperative assessment of acromegaly activity is typically performed at least 3 months after neurosurgery (NS). Few studies have evaluated the use of early postoperative growth hormone (GH) levels as a test to predict short- and long-term remission of acromegaly. Our objective was to evaluate the diagnostic performance of serum random GH on a postoperative day one (D1-rGH) and two (D2-rGH), particularly in predicting long-term disease persistence. MATERIALS AND METHODS: Forty-one subjects with acromegaly who were undergoing NS were enrolled (mean age ± SD 47.4 ± 13.1 years at diagnosis; women 54%; macroadenomas 71%). The final assessment of disease activity was performed one year after NS. ROC curves were used to evaluate the diagnostic performance of D1-rGH and D2-rGH. RESULTS: After a 1-year follow-up, the overall remission rate was 55%. ROC analysis identified an optimal D1-rGH cut-off value of 2.1 ng/mL for diagnosing long-term disease persistence (55.6% SE; 90.9% SP). The cut-off point became 2.5 ng/mL after maximizing specificity for disease persistence (yielding a 100% positive predictive value) and 0.3 ng/mL after maximizing sensitivity for disease remission. The optimal D2-rGH cut-off value was 0.6 ng/mL (81.8% SE; 50% SP); the cut-off point became 2.9 ng/mL after maximizing specificity and 0.1 ng/mL after maximizing sensitivity, with no clinical utility. CONCLUSIONS: D1-rGH could be a highly specific test for the early diagnosis of long-term acromegaly persistence, which is predicted by a value > 2.5 ng/mL with a great degree of certainty. The diagnostic performance of D2-rGH was insufficient. Further research is required to validate these preliminary results prior to modifying the postoperative management of acromegaly.

Pituitary surgery during Covid-19: a first hand experience and evaluation.

PURPOSE: During the Covid-19 pandemic every hospital has had to change its internal organization. Different institutions have highlighted the risks connected with endoscopic endonasal surgery. The goal of this paper is to illustrate the feasibility of pituitary region surgery during the SARS-CoV-2 pandemic. METHODS: After two negative Covid tests were obtained, three patients with macro GH-secreting tumors, and two patients with micro ACTH-secreting tumors resistant to medical treatment underwent surgery during the pandemic. During the surgery, every patient was treated as if they were positive. RESULTS: Neither operator, nor patient have developed Covid symptoms. The two neurosurgeons performing the operations underwent two Covid swab, which resulted negative. CONCLUSIONS: Pituitary surgery is a high risk non-urgent surgery. However, the method described has so far been effective and is safe for both patients and healthcare providers.

Ectopic GH-secreting pituitary adenoma of the clivus: systematic literature review of a challenging tumour.

PURPOSE: Acromegaly is usually due to growth hormone (GH)-secreting pituitary adenomas, but it may be exceptionally caused by GH-secreting ectopic pituitary adenomas (EPA). EPA are defined as extra-sellar pituitary tumours, extra- or intra-cranially sited, entirely separated from the pituitary stalk and gland. The aim of the study is to address the challenges in the management of clival GHEPA. METHODS: We reported a case of a 53-year-old acromegalic patient with a primary clival GHEPA and reviewed systematically the relevant English literature between 1975 and 2019, in keeping with the PRISMA guidelines. RESULTS: Four cases of primary clival GHEPA have been described in literature apart from ours. All patients presented with acromegalic features, elevated circulating GH and/or insulin-like growth factor-1 levels. Hyperprolactinemia and empty sella were described in two cases, respectively. These tumours show the typical imaging characteristics of pituitary adenomas, but their neuroradiological diagnosis may be challenging due to their sizes and the difficulty in defining the absence of connections with the pituitary fossa. CONCLUSION: Although primary clival GHEPA are exceedingly rare, even if likely under-reported in literature, they should be considered in the differential diagnosis of clival tumours because of their specific management. Surgery represents the first-line treatment option, while medical and radiation therapies can be adopted as neo-adjuvant, adjuvant or primary treatments according to tumour and patient characteristics.

Suprasellar pituitary adenomas: a 10-year experience in a single tertiary medical center and a literature review.

BACKGROUND: Suprasellar pituitary adenomas (SPAs) are a special type of pituitary adenoma. Although dozens of SPA cases have been reported, the exact definition and the characteristics of SPA have not been exhaustively discussed before. METHODS: In a retrospective electronic medical records review, 13 patients with SPA were identified in our hospital between January 2010 and December 2019. A literature review was performed by searching the online database PubMed, and 39 cases conformed to the criteria based on the previous literature. Data regarding clinical symptoms, imaging manifestations, surgical information and follow-ups were analyzed. RESULTS: The mean age at diagnosis of 52 patients with SPA was 36.73 years, and most of the patients were female (61.5%). The most common hormone-secreting subtypes of SPA were nonfunctioning (36.5%) and ACTH-secreting (34.6%) SPA. Macroadenomas (68.9%) were more common than microadenomas (31.1%). The origins of the SPAs included the intrasellar pituitary gland (type I), the subdiaphragmatic (type IIa) and supradiaphragmatic (type IIb) part of the pituitary stalk, and the suprasellar peri-infundibular region (type III). The most common anatomic subtype of SPA was type III, and type IIb was also common. The most common presentations of SPA were visual symptoms, especially for type III SPA. In addition, 64.7% and 73.1% of type IIb and III SPAs, respectively, were suspected to be of suprasellar origin based on presurgical imaging examination. Patients with tumors of suspected suprasellar origin were more likely to receive transcranial surgery (TCS) initially than those with tumors of suspected intrasellar origin (70.6% vs. 22.2%, p = 0.0013). The intact rate for the pituitary stalk after surgery for type II SPA was lower than that for type I and III SPA (52.6% vs. 92.6%, p = 0.0036). More patients with type II SPA experienced postoperative central diabetes insipidus (CDI) than those with type I and III SPA (57.9% vs. 11.1%, p = 0.0011). There was no significant difference in the incidence of postoperative CDI between transsphenoidal surgery (TSS) and TCS (p = 0.1304). Nine patients in our hospital received extended endoscopic TSS; only one experienced tumor recurrence, and no severe complications occurred after surgery. CONCLUSIONS: SPAs could be defined as pituitary adenomas completely or partially located in the suprasellar region. There were both similarities and differences among the different anatomic subtypes of SPA. For patients who were suspected of having SPAs, visual field tests, pituitary hormone evaluation and MRI were necessary. Because imaging examination is not a reliable method, surgery is the only way to confirm the tumor origin. Extended endoscopic TSS might be a safe and efficient approach to remove these tumors, but more studies are needed to verify this conclusion. For type II SPA, the pituitary stalk should be carefully protected during surgery, and postoperative CDI should be monitored.

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

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Magnetic resonance spectroscopy may serve as a presurgical predictor of somatostatin analog therapy response in patients with growth hormone-secreting pituitary macroadenomas.

PURPOSE: Somatostatin analogs (SSAs) are considered one of the most effective medical treatments for patients with growth hormone-secreting pituitary adenomas (GH-PAs). The postoperative electron microscopy (EM) pathological subtype and SSTR2 expression in the tumor are the most established predictors of patient response to SSA therapy. The aim of this study was to evaluate how will magnetic resonance spectroscopy (MRS) measurements before surgery predict the EM pathological subtypes and SSTR2 expression of tumors, and thereby serve as an indicator for the therapeutic sensitivity to SSAs of patients with GH-PAs. METHODS: Eighteen patients with GH pituitary macroadenomas who underwent transsphenoidal surgery were included in this retrospective study. The preoperative MRS data and T2 signal intensity were obtained from patients by 1.5 T MR spectroscopy of the sellar mass. The EM pathological subtypes of tumors were determined after surgery through examination of cell granulations. The expressions of somatostatin receptor 2 (SSTR2), SSTR5, P21, P27, and Ki-67 were evaluated by immunohistochemistry. RESULTS: The MRS parameters that were found to significantly predict the EM pathological subtypes of tumors, as calculated by the receiver operating characteristic curve, were the choline (Ch) value at 3140.5 MR units (sensitivity 69.2%, specificity 100%) and the choline/creatine (Ch/Cr) ratio at 1.27 (sensitivity 92.3%, specificity 100%). Further, the Ch/Cr ratio, but not other MRS data, was shown to negatively correlate with the expression of SSTR2 (P = 0.02). The Ch/Cr ratio was also found to positively correlate with the Ki-67 value (P < 0.05) and T2 signal (P < 0.05), but not with other factors that were examined in this study. Moreover, the Ch/Cr ratio could predict the EM pathological subtypes of tumors with an accuracy of 83.3% (5/6) for patients with an isointense T2 signal. CONCLUSION: The Ch/Cr ratio by MRS could effectively predict the tumor subtype and was significantly correlated with the expression of SSTR2, which was consistent with other predictors. It was also able to distinguish the patients with isointense T2 signals. Our results provide a potentially new and non-invasive method to predict the response to SSAs in patients with GH pituitary macroadenomas.

Transsphenoidal surgery for pituitary adenomas in pediatric patients: a multicentric retrospective study.

INTRODUCTION: Pediatric pituitary adenomas are rare lesions. Incidence is reported between 1 and 10% of all childhood brain tumors and between 3 and 6% of all surgically treated adenomas. Although pituitary adenomas present with symptoms of hormone hypersecretion or neurological disruptions secondary to mass effect, they are almost constantly benign. Characteristics of patients may vary in different studies according to age, gender, size of adenoma, hormonal activity, and recurrence rates. METHODS: Data on consecutive pediatric patients who were operated for pituitary adenoma with endoscopic endonasal transsphenoidal surgery (EETS) and transsphenoidal microsurgery (TMS) in the Department of Neurosurgery, Istanbul University Cerrahpasa Medical Faculty, Istanbul, Turkey, in the Neurosurgical Unit of the San Matteo Hospital, Pavia, Italy, and in the Division of Neurological Surgery Department of Biotechnology and Life Sciences, University of Insubria-Varese, ASST Sette Laghi, Ospedale di Circolo e Fondazione Macchi, Varese, Italy, between July 1997 and May 2018, were analyzed. Twenty-seven patients (11 males and 16 females), who were 18 years old or younger at the time of surgery, were included in the study. Medical records, images, and operative notes of patients were retrospectively reviewed. RESULTS: There were 16 females (59.3%) and 11 males (40.7%). Mean age was 15.3 ± 3.3 (4-18). Thirty-two surgical procedures were performed for 27 patients (6 children required second operation). Thirteen patients (48.14%) had Cushing's disease (CD), 5 patients (18.5%) had growth hormone (GH)-secreting adenoma, 5 patients (18.5%) had prolactinoma, and 4 patients (14.8%) had non-functional adenoma. Twenty-two patients (81.4%) met remission criteria, and 5 patients (18.5%) did not meet remission criteria. Four patients met remission criteria after the second operation. CONCLUSION: Transsphenoidal approach affords effective release of mass effect and not only restoration but also perpetuation of normal endocrine functions in the majority of pediatric pituitary adenoma patients. Satisfactory results are reported with both EETS and TMS in the literature. Despite the technical difficulties in pediatric age, transsphenoidal resection of adenoma is still the mainstay treatment that provides cure in pediatric patients.

Pediatric pituitary adenomas.

BACKGROUND: Pediatric pituitary adenomas are a rare medical entity that makes up a small portion of intracranial tumors in children and adolescents. Although benign, the majority of these lesions are secreting functional tumors with the potential for physiological sequela that can profoundly affect a child's development. FOCUS OF REVIEW: In this review, we discuss the medical and surgical management of these tumors with a focus on clinical presentation, diagnostic identification, surgical approach, and associated adjuvant therapies. We will also discuss our current treatment paradigm using endoscopic, open, and combined approaches to treat these tumors. The management of pituitary tumors requires a multidisciplinary team of surgeons, endocrinologists, and neuroanesthesiologists as well as neurocritical care specialists to deliver comprehensive care.

Postoperative Diabetes Insipidus and Hyponatremia in Children after Transsphenoidal Surgery for Adrenocorticotropin Hormone and Growth Hormone Secreting Adenomas.

OBJECTIVES: To define the incidence and risk factors of postoperative sodium alterations in pediatric patients undergoing transsphenoidal surgery (TSS) for adrenocorticotropic hormone and growth hormone secreting pituitary adenomas. STUDY DESIGN: We retrospectively reviewed 160 patients ≤18 years of age who had TSS for pituitary adenomas at our institution from 1999 to 2017. Variables included daily serum sodium through postoperative day 10, urine specific gravity, and medications administered. We examined associations between sex, repeat surgery, manipulation of the posterior pituitary (PP), tumor invasion into the PP, tumor type and size, cerebrospinal fluid (CSF) leak, lumbar drain insertion, body mass index, puberty, and development of diabetes insipidus (DI) or syndrome of inappropriate antidiuretic hormone secretion (SIADH). RESULTS: Mean age was 12.9 ± 3.4 years (female = 81). Patients had adrenocorticotropic hormone (150/160) and growth hormone (10/160) producing adenomas. Forty-two (26%) patients developed DI. Among the 37 of 160 who required desmopressin acutely, 13 of 37 required it long term. Risk of long-term need for desmopressin was significantly higher in patients who had CSF leak 9 of 48 (P = .003), lumbar drain 6 of 30 (P = .019), manipulation 11 of 50 (P < .001), or invasion 4 of 15 (P = .022) of the PP. Sixty patients developed hyponatremia, 19 because of SIADH, 39 to hypotonic fluids and 2 to cerebral salt wasting syndrome. Patients with SIADH were placed on fluid restriction; 1 received salt tablets. CONCLUSIONS: Among 160 children who underwent TSS for pituitary adenomas, the incidence of DI and SIADH after TSS was 26% and 14%, respectively. Combined risk factors for DI and/or SIADH include female sex, manipulation of and/or tumor invasion into the PP, and CSF leak or lumbar drain. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00001595 and NCT00060541.