Phase 1 study of safety and preliminary efficacy of intranasal transplantation of human neural stem cells (ANGE-S003) in Parkinson's disease.

BACKGROUND: Intranasal transplantation of ANGE-S003 human neural stem cells showed therapeutic effects and were safe in preclinical models of Parkinson's disease (PD). We investigated the safety and tolerability of this treatment in patients with PD and whether these effects would be apparent in a clinical trial. METHODS: This was a 12-month, single-centre, open-label, dose-escalation phase 1 study of 18 patients with advanced PD assigned to four-time intranasal transplantation of 1 of 3 doses: 1.5 million, 5 million or 15 million of ANGE-S003 human neural stem cells to evaluate their safety and efficacy. RESULTS: 7 patients experienced a total of 14 adverse events in the 12 months of follow-up after treatment. There were no serious adverse events related to ANGE-S003. Safety testing disclosed no safety concerns. Brain MRI revealed no mass formation. In 16 patients who had 12-month Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) data, significant improvement of MDS-UPDRS total score was observed at all time points (p<0.001), starting with month 3 and sustained till month 12. The most substantial improvement was seen at month 6 with a mean reduction of 19.9 points (95% CI, 9.6 to 30.3; p<0.001). There was no association between improvement in clinical outcome measures and cell dose levels. CONCLUSIONS: Treatment with ANGE-S003 is feasible, generally safe and well tolerated, associated with functional improvement in clinical outcomes with peak efficacy achieved at month 6. Intranasal transplantation of neural stem cells represents a new avenue for the treatment of PD, and a larger, longer-term, randomised, controlled phase 2 trial is warranted for further investigation.

Resting-state functional connectivity in a non-human primate model of cortical ischemic stroke in area F1.

BACKGROUND: The application of functional MRI to non-human primates after stroke has not yet been undertaken. This is the first study to explore the functional connectivity changes in non-human primate models during acute stages after stroke onset. METHODS: Nineteen healthy male cynomolgus monkeys (4-5 years) were used in this study. The photothrombosis model was employed to induce focal ischemic stroke in F1 area in the monkey's left hemisphere. T1-weighted structural images and resting-state functional magnetic resonance imaging (rs-fMRI) of all subjects were obtained using a 3.0 Tesla MRI system on the third day following stroke. Based on the D99 atlas, the structural and functional changes of bilateral F1 areas in monkeys were analyzed using region of interest (ROI)-based functional connectivity (FC). The bilateral F1 areas were selected as the seed regions due to their crucial role in motor control and their potential to unveil the comprehensive functional reorganization of the motor system at a whole-brain level following stroke. RESULTS: Ischemic lesions were observed after the stroke, with larger lesion volumes associated with poorer neurological dysfunction. Compared with baseline condition, left area F1 demonstrated decreased FC with the left cerebellum, left ventral pons and left 5_(PEa). When the ROI was located in the right area F1, ischemic monkeys showed decreased FC in left ventral pons, left cerebellum, left primary visual cortex and left 5_(PEa), accompanied by increased FC in the right orbitofrontal cortex. Importantly, the degree of altered FC between left area F1 and left cerebellum was associated with upper limb tone. CONCLUSIONS: These results provide valuable insights into the early-stage functional connectivity changes in the F1 areas of monkeys under ischemic conditions, highlighting the potential involvement of specific brain regions in the pathophysiology of ischemic injury.

Exosomal RNAs in the development and treatment of pituitary adenomas.

Exosomes are small extracellular vesicles that carry various bioactive molecules including various RNAs that modulate the activities of recipient cells. It has drawn considerable attention as means of cell communication and drug delivery. Exosome plays important role in various tumors, but it is rarely summarized in pituitary adenoma (PA). PA is the second most common primary central nervous system tumor, and its recurrence and persistent postoperative hormone hypersecretion lead to compromised quality of life. How exactly exosomes impact tumor development and hormone secretion is important for the development of this tumor diagnosis and treatment. In this review, we discuss how exosomal RNAs impact PAs and their potential as future clinical therapies. In our literature review, first, we found that exosomal microRNA hsa-miR-1180-3p is a potential early biomarker for NFPAs. Since NFPAs are typically difficult to diagnose, this is an especially important finding. Second, exosomal protein transcripts are potential invasive biomarker, such as MMP1, N-cadherin, CDK6, RHOU, INSM1, and RASSF10. Third, exosomal contents such as hsa-miR-21-5p promote distant bone formation of GHPA patients. Fourth, tumor suppressors in the exosome constitute novel therapeutic application of exosome, including long noncoding RNA (lncRNA) H19, miR-149-5p, miR-99a-3p, and miR-423-5p. This review discusses the possible mechanisms of exosome and their contents in PA and promotes the use of exosomes in both clinical diagnosis and treatment of this tumor.

Neural Stem Cells in the Treatment of Alzheimer's Disease: Current Status, Challenges, and Future Prospects.

Alzheimer's disease (AD), a progressive dementia, is one of the world's most dangerous and debilitating diseases. Clinical trial results of amyloid-ß (Aß) and tau regulators based on the pretext of straightforward amyloid and tau immunotherapy were disappointing. There are currently no effective strategies for slowing the progression of AD. Further understanding of the mechanisms underlying AD and the development of novel therapeutic options are critical. Neurogenesis is impaired in AD, which contributes to memory deficits. Transplanted neural stem cells (NSCs) can regenerate degraded cholinergic neurons, and new neurons derived from NSCs can form synaptic connections with neighboring neurons. In theory, employing NSCs to replace and restore damaged cholinergic neurons and brain connections may offer new treatment options for AD. However there remain barriers to surmount before NSC-based therapy can be used clinically. The objective of this article is to describe recent advances in the treatment of AD models and clinical trials involving NSCs. In addition, we discuss the challenges and prospects associated with cell transplant therapy for AD.

An Update on Silent Corticotroph Adenomas: Diagnosis, Mechanisms, Clinical Features, and Management.

With the introduction of 2017 World Health Organization (WHO) classification of endocrine tumors, T-PIT can serve as a complementary tool for identification of silent corticotroph adenomas (SCAs) in some cases if the tumor is not classifiable by pituitary hormone expression in pathological tissue samples. An increase of the proportion of SCAs among the non-functioning pituitary adenomas (NFPAs) has been witnessed under the new rule with the detection of T-PIT-positive ACTH-negative SCAs. Studies of molecular mechanisms related to SCA pathogenesis will provide new directions for the diagnosis and management of SCAs. A precise pathological diagnosis can help clinicians better identify SCAs. Understanding clinical features in the context of the pathophysiology of SCAs is critical for optimal management. It could provide information on appropriate follow-up time and aid in early recognition and treatment of potentially aggressive forms. Management approaches include surgical, radiation, and/or medical therapies.

Corrigendum: Xanthomatous Hypophysitis: A Case Report and Comprehensive Literature Review.

[This corrects the article DOI: 10.3389/fendo.2021.735655.].

Suprasellar Mature Cystic Teratoma Mimicking Rathke's Cleft Cyst: A Case Report and Systematic Review of the Literature.

In this article, we present a 31-year-old female who presented with intermittent headache and oligomenorrhea of over 10 years' duration. Imaging revealed a large suprasellar mass with sellar extension. The patient underwent an endoscopic endonasal trans-sphenoidal surgery to resection of the mass. Clinical, radiological, and operative findings from this patient were initially considered to be Rathke's cleft cyst (RCC). However, postoperative histological examinations revealed a mature cystic teratoma. No radiotherapy was performed after surgery. At the most recent follow-up, approximately 1 year later, the patient is doing well with no headache and no recurrence of the teratoma.

Xanthomatous Hypophysitis: A Case Report and Comprehensive Literature Review.

Purpose: Xanthomatous hypophysitis (XHP) is an extremely rare form of primary hypophysitis for which there is a lack of clinical experience. A comprehensive understanding of its clinical characteristics, diagnosis and treatment is needed. Methods: Here, we report a case study and conduct a systematic review of XHP. Thirty-six cases were included, and their clinical manifestations, endocrine assessment, imaging features, treatment and follow-up data were collected and analyzed. Results: The mean age at diagnosis was 39.1 years, and females were predominant (75.0%). The most common symptom was headache (68.6%), and 66.7% of female patients presented menstrual disorders. The most common pituitary dysfunction was growth hormone (GH) deficiency. More than half of patients exhibited central diabetes insipidus (CDI). The majority of patients had an imaging presentation of a cystic lesion with peripheral enhancement. Pituitary stalk thickening was observed in half of the patients. Total lesion resection was achieved in 57.1% of cases. The recurrence rate after partial resection and biopsy was significantly higher than that after total lesion resection (57.1% vs. 0.0%, P = 0.0147). The most common pituitary hormone abnormalities to resolve after surgery were hyperprolactinemia (100.0%) and GH deficiency (91.7%). The typical pathological feature was inflammatory infiltration of foamy histiocytes, which showed positivity for CD68. Conclusion: Diagnosis of XHP is difficult when relying on clinical symptoms and imaging features. Therefore, surgical histopathology is necessary. Based on the available evidence, total lesion resection is recommended for treatment. However, the long-term prognosis for this rare disease remains unclear.

Management of thyrotoxicosis occurring after surgery for Cushing's disease: a case series.

BACKGROUND: Thyrotoxicosis is a rare complication of surgery for Cushing's disease (CD). In clinical practice, given the rarity of this condition, patients may be misdiagnosed, and thus not treated appropriately. This study describes the clinical features and management of thyrotoxicosis in this context. METHODS: We retrospectively screened a pituitary database for CD patients who underwent surgery at Peking Union Medical College Hospital between 2010 and 2017. The electronic medical records and documentation of 732 patients were searched in order to identify instances of thyrotoxicosis. RESULTS: Fourteen patients developed postoperative thyrotoxicosis after CD remission, representing 1.9% of all the CD patients who underwent surgery and 2.5% of the CD patients who were in remission after surgery. The onset of thyrotoxicosis occurred at a median of 3.5 months after surgery. At the onset, 13 patients (92.9%) were on a maintenance dose of hydrocortisone and were managed using a higher dose of hydrocortisone. One patient had normal adrenal function and was managed by observation first, then using anti-thyroid drugs. Thyrotoxicosis was transient in all but one patient, and lasted 1.9±0.7 months (range, 1-3.2 months). CONCLUSIONS: Thyrotoxicosis is a rare complication that develops during the recovery period following surgery for CD. It occurs only after the surgical resolution of hypercortisolism, and in particular alongside adrenal insufficiency during the 4 months following CD remission. Awareness of this situation should be promoted among physicians, and patients should be managed on the basis of the clinical setting and manifestation.

Clinical profiles of silent corticotroph adenomas compared with silent gonadotroph adenomas after adopting the 2017 WHO pituitary classification system.

PURPOSE: Silent corticotroph adenomas (SCAs) can be redefined according to the 2017 World Health Organization pituitary classification system with the introduction of T­PIT, a transcription factor. We studied the clinical features of these redefined SCAs. METHODS: We compared 112 patients with SCAs and 198 patients with silent gonadotroph adenomas (SGAs) who underwent surgery from January 2019 to May 2020. RESULTS: The prevalence of SCAs increased from 21.3 to 30.2% under the new classification rules. T-PIT-positive, adrenocorticotropic hormone-negative SCAs and T-PIT-positive, adrenocorticotropic hormone-positive SCAs exhibited similar clinical features. SCAs exhibited significant female preponderance (90.2% vs. 29.8%, P < 0.0001); more frequent invasion (36.6% vs. 7.6%, P < 0.0001), especially multiple-site invasion (P < 0.0001); and marked cystic changes on imaging compared with SGAs (54.5% vs. 19.2%, P < 0.0001). SCAs had a softer tumor consistency (89.2% vs. 61.1%, P < 0.0001). Gross total resection was achieved in 66.1% of SCAs and 66.2% of SGAs (P > 0.9999). The overall recurrence/progression rates of SCAs and SGAs were 9.8% and 6.6% at 14.1 and 13.5 months of follow-up, respectively (P = 0.3765). The proportion of patients with more than two recurrences requiring multiple surgeries and radiation was similar between SCAs and SGAs (7.1% vs. 3.0%, P = 0.1514). However, multiple recurrences of SCAs affected younger patients than SGAs (39.0 vs. 53.5 years, P = 0.0433). CONCLUSIONS: The prevalence of SCAs increased with the introduction of T-PIT. SCAs and SGAs exhibited comparable size and recurrence/progression rates, but SCAs showed increased invasion and more marked cystic change. Aggressive SCAs tended to affect younger patients. Close long-term monitoring for SCA recurrence/progression is required.

Surgical treatment of a 72-year-old patient with headache, hyponatremia and oculomotor nerve palsy: a case report and literature review.

Pituitary apoplexy is a life-threatening syndrome caused by acute infarction of the pituitary gland. The most common symptoms associated with pituitary apoplexy are headache, nausea, vomiting, visual symptoms, hypopituitarism, and altered mental status. Both oculomotor nerve palsy and hyponatremia are relatively rare complications of pituitary apoplexy. The treatment of pituitary apoplexy is controversial. We report a case of a 72-year-old man with severe headache, nausea, vomiting, confusion and left oculomotor nerve palsy, who was initially considered as posterior communicating artery aneurysm (PCOAA) based on the presenting symptoms. Initial biochemical evaluation showed severe hyponatremia, hormonal evaluation identified multiple pituitary hormone deficiency and enhanced magnetic resonance imaging showed a large pituitary adenoma with signs of hemorrhage. A diagnosis of pituitary apoplexy and secondary hypopituitarism was finally made. The patient was treated with intravenous hydrocortisone 100 mg twice daily and oral levothyroxine 100 mg once daily. Appropriate venous transfusion with sodium was also used concomitantly to correct hyponatremia. After seven days of treatment, the patient's serum electrolytes normalized and he gradually recovered alertness. Then, the patient underwent transsphenoidal surgery for tumor removal. Left ptosis and oculomotor nerve palsy completely recovered three months after surgery. Postoperatively, hormone replacement therapy was essential for the patient with 20 mg hydrocortisone and 50 mg levothyroxine once daily. During the last follow up 4 years later, the patient was still on hormonal replacement and in good condition. So, for patients with pituitary apoplexy, we have shown that a semi-elective surgery after conservative treatment when the patient becomes clinically stable and hypopituitarism has been corrected is a good approach.

Preoperative Somatostatin Analogues in Patients with Newly-diagnosed Acromegaly: A Systematic Review and Meta-analysis of Comparative Studies.

Biochemical remission after transsphenoidal surgery is still unsatisfied in acromegaly patients with macroadenomas, especially with invasive macroadenomas. Concerning the impact of preoperative somatostatin analogues (SSAs) on surgical outcomes, previous studies with limited cases reported conflicting results. To assess current evidence of preoperative medical treatment, we performed a systematic review and meta-analysis of comparative studies. A literature search was conducted in Pubmed, Embase, and the Cochrane Library. Five randomized controlled trials (RCT) and seven non-RCT comparative studies were included. These studies mainly focused on pituitary macroadenomas though a small number of microadenoma cases were included. For safety, preoperative SSAs were not associated with elevated risks of postoperative complications. With respect to efficacy, the short-term cure rate was improved by preoperative SSAs, but the long-term cure rate showed no significant improvement. For invasive macroadenomas, the short-term cure rate was also improved, but the long-term results were not evaluable in clinical practice because adjuvant therapy was generally required. In conclusion, preoperative SSAs are safe in patients with acromegaly, and the favorable impact on surgical results is restricted to the short-term cure rate in macroadenomas and invasive macroadenomas. Further well-designed RCTs to examine long-term results are awaited to update the finding of this meta-analysis.

Machine Learning-Based Radiomics Predicts Radiotherapeutic Response in Patients With Acromegaly.

Background: Prediction of radiotherapeutic response before radiotherapy could help determine individual treatment strategies for patients with acromegaly. Objective: To develop and validate a machine-learning-based multiparametric MRI radiomics model to non-invasively predict radiotherapeutic response in patients with acromegaly. Methods: This retrospective study included 57 acromegaly patients who underwent postoperative radiotherapy between January 2008 and January 2016. Manual lesion segmentation and radiomics analysis were performed on each pituitary adenoma, and 1561 radiomics features were extracted from each sequence. A radiomics signature was built with a support vector machine using leave-one-out cross-validation for feature selection. Multivariable logistic regression analysis was used to select appropriate clinicopathological features to construct a clinical model, which was then combined with the radiomics signature to construct a radiomics model. The performance of this radiomic model was assessed using receiver operating characteristics (ROC) analysis and its calibration, discriminating ability, clinical usefulness. Results: At 3-years after radiotherapy, 25 patients had achieved remission and 32 patients had not. The clinical model incorporating seven clinical features had an area under the ROC (AUC) of 0.86 for predicting radiotherapeutic response, and performed better than any single clinical feature. The radiomics signature constructed with six radiomics features had a significantly higher AUC of 0.92. The radiomics model showed good discrimination abilities and calibration, with an AUC of 0.96. Decision curve analysis confirmed the clinical utility of the radiomics model. Conclusion: Using pre-radiotherapy clinical and MRI data, we developed a radiomics model with favorable performance for individualized non-invasive prediction of radiotherapeutic response, which may help in identifying acromegaly patients who are likely to benefit from radiotherapy.