Dysregulated Genes and Signaling Pathways in the Formation and Rupture of Intracranial Aneurysm.

Intracranial aneurysm (IA) has the potential to rupture. Despite scientific advances, we are still not in a position to screen patients for IA and identify those at risk of rupture. It is critical to comprehend the molecular basis of disease to facilitate the development of novel diagnostic strategies. We used transcriptomics to identify the dysregulated genes and understand their role in the disease biology. In particular, RNA-Seq was performed in tissue samples of controls, unruptured IA, and ruptured IA. Dysregulated genes (DGs) were identified and analyzed to understand the functional aspects of molecules. Subsequently, candidate genes were validated at both transcript and protein level. There were 314 DGs in patients with unruptured IA when compared to control samples. Out of these, SPARC and OSM were validated as candidate molecules in unruptured IA. PI3K-AKT signaling pathway was found to be an important pathway for the formation of IA. Similarly, 301 DGs were identified in the samples of ruptured IA when compared with unruptured IAs. CTSL was found to be a key candidate molecule which along with Hippo signaling pathway may be involved in the rupture of IA. We conclude that activation of PI3K-AKT signaling pathway by OSM along with up-regulation of SPARC is important for the formation of IA. Further, regulation of Hippo pathway through PI3K-AKT signaling results in the down-regulation of YAP1 gene. This along with up-regulation of CTSL leads to further weakening of aneurysm wall and its subsequent rupture.

Phosphorylation of ß-catenin at Serine552 correlates with invasion and recurrence of non-functioning pituitary neuroendocrine tumours.

Non-functioning pituitary tumours (NF-PitNETs) are common intracranial benign neoplasms that can exhibit aggressive behaviour by invading neighbouring structures and, in some cases, have multiple recurrences. Despite resulting in severe co-morbidities, no predictive biomarkers of recurrence have been identified for NF-PitNETs. In this study we have used high-throughput mass spectrometry-based analysis to examine the phosphorylation pattern of different subsets of NF-PitNETs. Based on histopathological, radiological, surgical and clinical features, we have grouped NF-PitNETs into non-invasive, invasive, and recurrent disease groups. Tumour recurrence was determined based on regular clinical and radiological data of patients for a mean follow-up of 10 years (SD ± 5.4 years). Phosphoproteomic analyses identified a unique phosphopeptide enrichment pattern which correlates with disease recurrence. Candidate phosphorylated proteins were validated in a large cohort of NF-PitNET patients by western blot and immunohistochemistry. We identified a cluster of 22 phosphopeptides upregulated in recurrent NF-PitNETs compared to non-invasive and invasive subgroups. We reveal significant phosphorylation of the ß-catenin at Ser552 in recurrent and invasive NF-PitNETs, compared to non-invasive/non-recurrent NF-PitNET subgroup. Moreover, ß-catenin pSer552 correlates with the recurrence free survival among 200 patients with NF-PitNET. Together, our results suggest that the phosphorylation status of ß-catenin at Ser552 could act as potential biomarker of tumour recurrence in NF-PitNETs.

Assessing the value of healthcare innovations: a proposal for an integrated health technology assessment-responsible innovation in health approach in the "new normal".

There has been tremendous technological innovation in the healthcare sector, but it has also raised serious ethical and social concerns. The COVID-19 pandemic has only magnified these existing challenges. Hence, addressing these challenges becomes imperative in the "new normal." In this context, this article uses a narrative synthesis approach to discuss the linkages of health technology, innovation, and policy to identify the challenges of this complex interaction by applying the principles of pragmatism and historicity to the existing literature. Moreover, the existing scientific mechanisms in the form of health technology assessment (HTA) and responsible innovation in health (RIH) are described to address these challenges. Using inductive epistemology, the linkages between HTA and RIH within a health innovation ecosystem framework are discussed for the future application of an integrated approach to address societal challenges. The proposed integrated approach of HTA and RIH is a work in progress and conceptualized as transdisciplinary, flexible, and adaptive, which is expected to facilitate future discussion, research, and policy action.

Recurrent epistaxis due to cribriform plate dural arteriovenous fistula: are they related? Should the treatment be from venous, pial or arterial side?

PURPOSE: Dural arteriovenous fistula (DAVF) of the anterior cranial fossa with cortical venous reflux is an aggressive neurovascular entity with a high rate of intracranial bleeding. Only two cases of anterior cranial fossa DAVF presenting with epistaxis alone have been reported. Endovascular approaches have emerged as the primary and safer treatment modality for most DAVFs. Certain fistulas are better treated with open surgical approaches and disconnection. CASE DESCRIPTION: A 55 years old male presented with the history of multiple episodes of severe epistaxis. Cerebral angiography revealed an anterior cranial fossa DAVF of the cribriform plate with cortical venous reflux and a venous varix. The patient was successfully managed with a bifrontal craniotomy and disconnection from the arterial side. CONCLUSION: Atypical or severe epistaxis may arise from a DAVF. Surgical arterial disconnection my be a curative treatment option.

Phosphorylated EGFR (pEGFR T693) as a Novel Predictor of Recurrence in Non-Functioning Pituitary Adenomas.

Purpose: Non-functioning pituitary adenomas (NFPAs) exhibit high recurrence rates after surgery. However, the determinants of recurrence are inconsistent in the available literature. The present study sought to investigate the association between nuclear phosphorylated EGFR (pEGFR) levels and recurrence of NFPAs. Methods: Tissue microarrays from patients undergoing adenomectomy for NFPAs at our tertiary care center from 2003 to 2015 and having a minimum of 60 months of follow-up (n=102) were accessed. Immunohistochemical analysis (IHC) was performed to determine the expression of nuclear pEGFR T693. h-score was calculated as the product of staining intensity and the number of positively staining cells. Radiological surveillance (MRI) was performed to categorize NFPAs as recurrent or non-recurrent on follow-up. Results: The mean age of the cohort was 50 ± 11 years with a male preponderance (61.1%). Recurrence was observed in 46.1% of the patients at a median of 123 months (IQR 72-159) of follow-up. pEGFR T693 positivity was higher in a significantly greater number of recurrent NFPAs as compared to non-recurrent NFPAs (95.7% vs 81%, p=0.02). h-scores were also significantly higher in recurrent NFPAs (122.1 ± 6 vs 81.54 ± 3.3, p<0.0001). pEGFR T693 positivity significantly predicted recurrence in NFPAs (HR=4.9, CI 2.8-8.8, p<0.0001). ROC analysis revealed an h-score cutoff of 89.8 as being associated significantly with recurrence (sensitivity 80%, specificity 78%, AUC 0.84, p<0.0001). Conclusion: pEGFR T693 was expressed in significantly higher number of recurrent NFPAs. The h-scores were also higher in recurrent NFPAs. Nuclear pEGFR T693 may serve as a predictor of recurrence in NFPAs.

Toward achieving persistent behavior change in household water conservation.

Achieving persistence in household behavior modification has been a central but elusive goal of environmental conservation attempts that rely on behavioral interventions. We implemented a habit change intervention, designed to achieve persistent change in household water conservation behavior in an affluent residential community in urban India. We found a 15 to 25% reduction in household water consumption in the absence of any volumetric pricing. Most importantly, the effects of our 5-wk intervention persisted for more than a year, after which marginal pricing was introduced. The treatment gap was not bridged even after a year under the marginal price regime.

Endonasal endoscopic versus microscopic transsphenoidal surgery in pituitary tumors among the young: A comparative study & meta-analysis.

PURPOSE: The transsphenoidal approach presents unique challenges in young, with scanty literature. This study compares the outcome of pituitary tumors among young in our center between endoscopic(EES) and microscopic(MTS) transsphenoidal surgery, with a meta-analysis. METHODS: Patients within 20 years were studied for their surgical approach to a favorable outcome of endocrine remission (ER) (functioning) or Gross/Near-Total resection (nonfunctioning), besides the need for retreatment. Relevant studies were pooled and analyzed according to PRISMA guidelines. RESULTS: Out of 64 young patients with pituitary tumors, 48 underwent transsphenoidal surgery using MTS(33) or EES(15). Of these, 21, 14, 5, and 8 had Cushing's, somatotropinomas, prolactinomas, and non-secreting tumors, respectively. Mean symptom duration was 28months, with weight gain(50 %) and visual complaints(29 %) most prevalent. Hypogonadism(21 %) was the most frequent endocrinopathy. The mean tumor volume was 3.8 cm3. Over mean follow-up of 4.4years, favorable outcome was significantly higher after EES than MTS(78.6 % vs. 46.7 %)(odds ratio 4.18, p = 0.05). EES's better outcome was homogeneous across subgroups of age and tumor type, with no significant subgroup difference. Symptom duration was significantly higher among those who required retreatment(p = 0.05), while ER had a non-significant association with tumor volume(p = 0.07). Overall, 40 %, 27 %, 17 %, and 8% were on hydrocortisone, thyroxine, sex hormone, and desmopressin, respectively, at follow-up with no significant difference between EES and MTS. In pooled analysis of literature, both favorable outcome(74 % vs. 48 %,p = 0.02) and retreatment rate(8% vs. 37 %,p = 0.004) were significantly better with EES than MTS. CONCLUSION: Among young patients with pituitary tumors, the favorable outcome and retreatment rates are better with endonasal endoscopy and associated with symptom duration and tumor volume.

Intracranial Aneurysm Biomarker Candidates Identified by a Proteome-Wide Study.

The scientific basis of intracranial aneurysm (IA) formation, its rupture and further development of cerebral vasospasm is incompletely understood. Aberrant protein expression may drive structural alterations of vasculature found in IA. Deciphering the molecular mechanisms underlying these events will lead to identification of early detection biomarkers and in turn, improved treatment outcomes. To unravel differential protein expression in three clinical subgroups of IA patients: (1) unruptured aneurysm, (2) ruptured aneurysm without vasospasm, (3) ruptured aneurysm who developed vasospasm, we performed untargeted quantitative proteomic analysis of aneurysm tissue and serum samples from three subgroups of IA patients and control subjects. Candidate molecules were then validated in a larger cohort of patients using enzyme-linked immunosorbent assay. A total of 937 and 294 proteins were identified from aneurysm tissue and serum samples, respectively. Several proteins that are known to maintain structural integrity of vasculature were found to be dysregulated in the context of aneurysm. ORM1, a glycoprotein, was significantly upregulated in both tissue and serum samples of unruptured aneurysm patients. We employed a larger cohort of subjects (n = 26) and validated ORM1 as a potential biomarker for screening of unruptured aneurysms. Samples from ruptured aneurysms with vasospasm showed significant upregulation of MMP9, a protease, compared with ruptured aneurysms without vasospasm. We validated MMP9 as a potential biomarker for vasospasm in a larger cohort (n = 52). This study reports the first global proteomic analysis of the entire clinical spectrum of IA. Furthermore, this study suggests ORM1 and MMP9 as potential biomarkers for unruptured aneurysm and cerebral vasospasm, respectively.

COVID-19 and lockdown: Insights from Mumbai.

BACKGROUND: Mumbai is facing the full brunt of the COVID-19 pandemic epidemiologically and economically. OBJECTIVES: The objective was to understand the spatial distribution and trends of the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) in Mumbai during the lockdown period and draw insights for effective actions. METHODS: Spatial and trend analysis was conducted to trace the spread of the virus during the lockdown period in April 2020. The administrative divisions of Mumbai, in the form of wards and zones, have been used as units of analysis. RESULTS: Greater Mumbai area occupies only 0.015% of the landmass of India, but is contributing to over 20% of the SARS-CoV-2 cases in India. Cases of SARS-CoV-2 infections have increased over 375 times within 50 days of the lockdown. An analysis of trends across the wards during the 3-week period (April 4 to April 25) shows a skewed pattern, with three zones out of six contributing to the vast majority of cases in Mumbai. The wards with higher formal economic activity are relatively less affected than the other wards. The test positivity rate in Mumbai is much higher than the rest of India. CONCLUSION: The study suggests that the virus had already spread to the community in Mumbai before the lockdown started.

Intracranial Germinoma Masquerading as Secondary Granulomatous Hypophysitis: A Case Report and Review of Literature.

Germinomas are highly immunogenic tumors eliciting a strong peri-tumoral immune response that can spillover into the surrounding healthy tissues. This phenomenon can also occur in intracranial germinomas, manifesting as secondary hypophysitis. Herein, we report a case of 12-year-old-girl presenting with polyuria and polydispsia. She had central diabetes insipidus (CDI) and panhypopituitarism. Imaging revealed a sellar-suprasellar mass with infundibular stalk thickening. Transphenoidal biopsy revealed epithelioid granulomas with immunostaining negative for germinomatous cells. Other causes of hypophysitis were ruled out. Accordingly, she was diagnosed as primary granulomatous hypophysitis and treated with high-dose corticosteroids. Three years later she again presented with headache, vomiting and diminution of vision. Imaging showed a heterogeneous, solid-cystic peripheral rim-enhancing lesion at the same location with involvement of hypothalamus, ependyma and pineal gland. Cerebrospinal fluid beta-human chorionic gonadotropin was markedly elevated, confirming the diagnosis of an intracranial germ cell tumor. She was started on chemotherapy; however, she succumbed to febrile neutropenia. We performed a literature search and found 18 anecdotal cases of secondary hypophysitis associated with intracranial germinomas. There was a slight male preponderance (male:female 5:4). Two-thirds of the cases were below 18 years of age. Polyuria was the most common presenting manifestation (83%). CDI and panhypopituitarism were seen in 89 and 78% cases, respectively. Imaging evidence of pituitary stalk thickening was seen in 12 cases (67%), while pituitary enlargement and/or sellar mass were reported in 11 cases (61%). Pineal involvement was extremely rare, being reported in only 1 case, implying the predilection of suprasellar (rather than pineal) germinomas in causing secondary hypophysitis. Histologically, 82% had lymphocytic hypophysitis, while 18% had granulomatous hypophysitis. Initially, the diagnosis of germinoma was missed in 60% of the cases who were wrongly treated with corticosteroids. To conclude, physicians should make it a dictum that all children and adolescents presenting with CDI and pituitary stalk thickening should be rigorously screened for an underlying intracranial germinoma before labeling them as primary hypophysitis.

The Safety and Efficacy of Bevacizumab for Radiosurgery - Induced Steroid - Resistant Brain Edema; Not the Last Part in the Ship of Theseus.

BACKGROUND: Radiation-induced brain edema (RIBE) is a serious complication of radiation therapy. It may result in dramatic clinico-radiological deterioration. At present, there are no definite guidelines for management of the complication. Corticosteroids are the usual first line of treatment, which frequently fails to provide long-term efficacy in view of its adverse complication profile. Bevacizumab has been reported to show improvement in cases of steroid-resistant radiation injury. The objective of this study is to evaluate the role of Bevacizumab in post-radiosurgery RIBE. MATERIAL AND METHODS: Since 2012, 189 out of 1241 patients who underwent radiosurgery at our institution developed post-radiosurgery RIBE, 17 of which did not respond to high-dose corticosteroids. We systematically reviewed these 17 patients of various intracranial pathologies with clinic-radiological evidence of RIBE following gamma knife radiosurgery (GKRS). All patients received protocol-based Bevacizumab therapy. The peer-reviewed literature was evaluated. RESULTS: 82 percent of the patients showed improvement after starting Bevacizumab. The majority began to improve after the third cycle started improvement after the third cycle of Bevacizumab. Clinical improvement preceded radiological improvement by an average of eight weeks. The first dose was 5 mg/kg followed by 7.5-10 mg/kg at with two-week intervals. Bevacizumab needs to be administered for an average of seven cycles (range 5-27, median 7) for best response. Steroid therapy could be tapered in most patients by the first follow-up. One patient did not respond to Bevacizumab and needed surgical decompression for palliative care. One noncompliant patient died due to radiation injury. CONCLUSION: Bevacizumab is a effective and safe for treatment of RIBE after GKRS. A protocol-based dose schedule in addition to frequent clinical and radiological evaluations are required. Bevacizumab should be considered as an early treatment option for RIBE.

The predictors of recovery from diabetes mellitus following neurosurgical treatment of acromegaly: A prospective study over a decade.

OBJECTIVE: The natural history of glucose intolerance (GI) in patients with acromegaly undergoing surgical treatment has not been fully understood. This study was aimed to unravel the prevalence and predictors of recovery from GI in these patients in a prospective multivariate model. MATERIALS AND METHODS: Patients with acromegaly treated between 2007 and 2016 were prospectively studied with respect to demographics, clinicoradiological features, comorbidities, and hormonal investigations before surgery and at regular follow-up. The independent predictors of recovery from diabetes were analyzed. RESULTS: There were a total of 151 patients with active acromegaly included in the study. The median baseline growth hormone (GH) and insulin-like growth factor (IGF)-1 levels were 25 and 811 ng/mL, respectively. Diabetes mellitus (DM) and pre-diabetes were noted in 93 (61.6%) and 20 (13.2%) patients, respectively. Following surgical treatment, the median HbA1c decreased significantly from 6.4% to 5.5% (P < 0.001), with 46.8% having complete recovery from DM or pre-diabetes. This glycemic recovery had significant association with both biochemical (P = 0.001) and radiological remission (P = 0.01). The recovery from DM had a greater association with post-operative IGF-1 than GH, especially among those with discordant GH and IGF-1 levels (60% in normal IGF-1 and high GH vs. 20% in high IGF-1 and normal GH). Post-operative IGF-1 had a significant impact on recovery from DM (P = 0.01) independent of age, body mass index, duration of DM, and pre-operative HbA1c. CONCLUSION: Nearly half of the patients with acromegaly with DM or pre-diabetes had glycemic recovery, influenced by biochemical and radiologic remission. Post-operative IGF-1 appears to be the strongest independent determinant of recovery from DM.

Prolactin-adjusted ACTH Ratio in Predicting Lateralization of ACTH Source During Simultaneous Bilateral Inferior Petrosal Sinus Sampling in Patients with Cushing's Disease.

INTRODUCTION: Prolactin-adjusted adrenocorticotropic hormone (ACTH) ratio is used to improve the diagnostic accuracy of bilateral inferior petrosal sinus sampling (BIPSS) for lateralization of pituitary adenoma. OBJECTIVE: To study the use of prolactin for successful catheterization during BIPSS, the role of prolactin-normalized ACTH ratio for confirmation of Cushing's disease (CD) and prolactin-adjusted ACTH ratio in predicting the lateralization. PATIENTS AND METHODS: BIPSS was done in patients with CD; prolactin-adjusted ACTH ratio was compared with intersinus ACTH ratio, magnetic resonance imaging, and intraoperative findings for localization of pituitary adenoma. Histopathology was taken as "gold standard" for the diagnosis of CD. RESULTS: Eight patients underwent BIPSS. All the patients underwent transsphenoidal surgery. All these patients had proper venous sampling during BIPSS as determined by inferior petrosal sinus (IPS):Peripheral prolactin ratio of ≥1.8. Prolactin-normalized ACTH ratio of ≥1.3 was achieved in all the eight patients, which was consistent with the diagnosis of CD. Concordance of intersinus ACTH ratio ≥1.4 with the intraoperative findings was found in five of eight (62.5%) patients depicting correct lateralization. Concordance of prolactin-adjusted ACTH ratio with intraoperative findings was found in four of eight (50%) patients. Seven of eight patients had concordance of intersinus ACTH ratio with prolactin-adjusted ACTH ratio. CONCLUSION: Prolactin is a useful marker for successful catheterization, confirming the diagnosis of CD during BIPSS, and prolactin-adjusted ACTH ratio does not add to the accuracy of lateralization of pituitary adenoma compared with intersinus ACTH ratio.

Glucose-dependent Insulinotropic Polypeptide (GIP) Resistance and ß-cell Dysfunction Contribute to Hyperglycaemia in Acromegaly.

Impaired insulin sensitivity (IS) and ß-cell dysfunction result in hyperglycaemia in patients of acromegaly. However, alterations in incretins and their impact on glucose-insulin homeostasis in these patients still remain elusive. Twenty patients of active acromegaly (10 each, with and without diabetes) underwent hyperinsulinemic euglycaemic clamp and mixed meal test, before and after surgery, to measure indices of IS, ß-cell function, GIP, GLP-1 and glucagon response. Immunohistochemistry (IHC) for GIP and GLP-1 was also done on intestinal biopsies of all acromegalics and healthy controls. Patients of acromegaly, irrespective of presence or absence of hyperglycaemia, had similar degree of insulin resistance, however patients with diabetes exhibited hyperglucagonemia, and compromised ß-cell function despite significantly higher GIP levels. After surgery, indices of IS improved, GIP and glucagon levels decreased significantly in both the groups, while there was no significant change in indices of ß-cell function in those with hyperglycaemia. IHC positivity for GIP, but not GLP-1, staining cells in duodenum and colon was significantly lower in acromegalics with diabetes as compared to healthy controls possibly because of high K-cell turnover. Chronic GH excess induces an equipoise insulin resistance in patients of acromegaly irrespective of their glycaemic status. Dysglycaemia in these patients is an outcome of ß-cell dysfunction consequent to GIP resistance and hyperglucagonemia.

Has Outcome of Subarachnoid Hemorrhage Changed With Improvements in Neurosurgical Services?

Background and Purpose- Though reports suggest decreasing fatality rates of subarachnoid hemorrhage with time, trends in outcome are not reported much especially from developing countries. This study was to analyze changes in outcome across 2 decades and elucidate probable factors. Methods- Prospective databases during 1996 to 2015 were reviewed for neurological outcome at 3 months in relation to demographics, Hunt and Hess grade, Fisher grade, and definitive treatment; and compared between 2 decades, contrasted by establishment of intensive care unit with continuous monitoring and other advancements. Univariate and multivariate analyses were performed. Results- Of the total 2039 patients, 1035 were managed in the former and 1004 in the recent decades. Compared with the former decade, there is delayed age at presentation (46 versus 49 years, P<0.001), poorer Fisher grades (81% versus 87%, P<0.001), and more patients with Hunt and Hess grade 2 (24% versus 39%, P<0.001) in the recent decade. While all patients in databases of the former decade had undergone clipping, 6% in the recent decade underwent coiling. 11% in the recent decade could not undergo definitive treatment. Despite this, there was significantly higher overall favorable outcome (50% versus 60%; odds ratio, 1.5; P<0.001) in recent decade. Favorable outcome of surgical clipping per se improved significantly from 50% to 67% (odds ratio 2.0; P<0.001). Though the improvement was across subgroups, it was more marked among Hunt and Hess grade 3 and Fisher grades 3 and 4. In multivariate analyses, both overall outcome (adjusted odds ratio, 1.7; 95% CI, 1.4-2.1; P<0.001) and surgical outcome (adjusted odds ratio, 1.8; 95% CI, 1.5-2.2; P<0.001) were significantly better in recent decade, independent of known prognostic factors. Conclusions- This is probably the first report to show independent improvement in outcome of subarachnoid hemorrhage with betterment in neurosurgical services from developing country. Dedicated intensive care unit care and focused management protocols could be the likely causes for improvement. Resource-constrained institutions may target patients in Hunt and Hess grade 3 and Fisher grades 3 and 4 for optimal intensive care unit utilization.

Imatinib Inhibits GH Secretion From Somatotropinomas.

Background: Imatinib, a tyrosine kinase inhibitor, causes growth failure in children with chronic myeloid leukemia probably by targeting the growth hormone (GH)/insulin like growth factor-1 (IGF-1) axis. We aim to explore the imatinib targets expression in pituitary adenomas and study the effect of imatinib on GH secretion in somatotropinoma cells and GH3 cell line. Materials and Methods: The expression pattern of imatinib's targets (c-kit, VEGF, and PDGFR-α/ß) was studied using immunohistochemistry and immunoblotting 157 giant (≥4 cm) pituitary adenomas (121 non-functioning pituitary adenomas, 32 somatotropinomas, and four prolactinomas) and compared to normal pituitary (n = 4) obtained at autopsy. The effect imatinib on GH secretion, cell viability, immunohistochemistry, electron microscopy, and apoptosis was studied in primary culture of human somatotropinomas (n = 20) and in rat somato-mammotroph GH3 cell-line. A receptor tyrosine kinase array was applied to human samples to identify altered pathways. Results: Somatotropinomas showed significantly higher immunopositivity for c-kit and platelet-derived growth factor receptor-ß (PDGFR-ß; P < 0.009 and P < 0.001, respectively), while staining for platelet-derived growth factor receptor-α (PDGFR-α) and vascular endothelial growth factor (VEGF) revealed a weaker expression (P < 0.001) compared to normal pituitary. Imatinib inhibited GH secretion from both primary culture (P < 0.01) and GH3 cells (P < 0.001), while it did not affect cell viability and apoptosis. The receptor tyrosine kinase array showed that imatinib inhibits GH signaling via PDGFR-ß pathway. Conclusion: Imatinib inhibits GH secretion in somatotropinoma cells without affecting cell viability and may be used as an adjunct therapy for treating GH secreting pituitary adenomas.