Sporadic pituitary adenoma with somatic double-hit loss of MEN1.

PURPOSE: Pituitary adenomas commonly arise in patients with MEN1 syndrome, an autosomal dominant condition predisposing to neuroendocrine tumor formation, and typically diagnosed in patients with a relevant family cancer history. In these patients with existing germline loss of MEN1 on one allele, somatic loss of the second MEN1 allele leads to complete loss of the MEN1 protein, menin, and subsequent tumor formation. METHODS: Whole exome sequencing was performed on the tumor and matching blood under an institutional board approved protocol. DNA extraction and analysis was conducted according to previously described methods. RESULTS: We describe a 23 year-old patient with no significant past medical history or relevant family history who underwent surgical resection of a symptomatic and medically resistant prolactinoma. Whole exome sequencing of tumor and blood samples revealed somatic loss of MEN1 at both alleles, suggesting a double hit mechanism, with no underlying germline MEN1 mutation. CONCLUSION: To our knowledge, this is the first case of pituitary adenoma to arise from somatic loss of MEN1 and in the absence of an underlying germline MEN1 mutation.

Pre-operative headaches and obstructive hydrocephalus predict an extended length of stay following suboccipital decompression for pediatric Chiari I malformation.

PURPOSE: For young children and adolescents with Chiari malformation type I (CM-I), the determinants of extended length of hospital stay (LOS) after neurosurgical suboccipital decompression are obscure. Here, we investigate the impact of patient- and hospital-level risk factors on extended LOS following surgical decompression for CM-I in young children to adolescents. METHODS: The Kids' Inpatient Database year 2012 was queried. Pediatric CM-I patients (6-18 years) undergoing surgical decompression were identified. Weighted patient demographics, comorbidities, complications, LOS, disposition, and total cost were recorded. A multivariate logistic regression was used to determine the odds ratio for risk-adjusted LOS. The primary outcome was the degree patient comorbidities or post-operative complications correlated with extended LOS. RESULTS: A total of 1592 pediatric CM-I patients were identified for which 328 (20.6%) patients had extended LOS (normal LOS, 1264; extended LOS, 328). Age, gender, race, median household income quartile, and healthcare coverage distributions were similar between the two cohorts. Patients with extended LOS had significantly greater admission comorbidities including headache symptoms, nausea and vomiting, obstructive hydrocephalus, lack of coordination, deficiency anemias, and fluid and electrolyte disorders. On multivariate logistic regression, several risk factors were associated with extended LOS, including headache symptoms, obstructive hydrocephalus, and fluid and electrolyte disorders. CONCLUSIONS: Our study using the Kids' Inpatient Database demonstrates that presenting symptoms and signs, including headaches and obstructive hydrocephalus, respectively, are significantly associated with extended LOS following decompression for pediatric CM-I.

Laser interstitial thermal therapy (LITT) vs. bevacizumab for radiation necrosis in previously irradiated brain metastases.

PURPOSE: Both laser interstitial thermal therapy (LITT) and bevacizumab have been used successfully to treat radiation necrosis (RN) after radiation for brain metastases. Our purpose is to compare pre-treatment patient characteristics and outcomes between the two treatment options. METHODS: Single-institution retrospective chart review identified brain metastasis patients who developed RN between 2011 and 2018. Pre-treatment factors and treatment responses were compared between those treated with LITT versus bevacizumab. RESULTS: Twenty-five patients underwent LITT and 13 patients were treated with bevacizumab. The LITT cohort had a longer overall survival (median 24.8 vs. 15.2 months for bevacizumab, p = 0.003) and trended to have a longer time to local recurrence (median 12.1 months vs. 2.0 for bevacizumab), although the latter failed to achieve statistical significance (p = 0.091). LITT resulted in an initial increase in lesional volume compared to bevacizumab (p < 0.001). However, this trend reversed in the long term follow-up, with LITT resulting in a median volume decrease at 1 year post-treatment of - 64.7% (range - 96.0% to + > 100%), while bevacizumab patients saw a median volume increase of + > 100% (range - 63.0% to + > 100%), p = 0.010. CONCLUSIONS: Our study suggests that patients undergoing LITT for RN have longer overall survival and better long-term lesional volume reduction than those treated with bevacizumab. However, it remains unclear whether our findings are due only to a difference in efficacy of the treatments or the implications of selection bias.

Laser interstitial thermal therapy for treatment of cerebral radiation necrosis.

Radiation necrosis is a well described complication after radiosurgical treatment of intracranial pathologies - best recognized after the treatment of patients with arteriovenous malformations and brain metastases but possibly also affecting patients treated with radiosurgery for meningioma. The pathophysiology of radiation necrosis is still not well understood but is most likely a secondary local tissue inflammatory response to brain tissue injured by radiation. Radiation necrosis in brain metastases patients may present radiographically and behave clinically like recurrent tumor. Differentiation between radiation necrosis and recurrent tumor has been difficult based on radiographic changes alone. Biopsy or craniotomy therefore remains the gold standard method of diagnosis. For symptomatic patients, corticosteroids are first-line therapy, but patients may fail medical management due to intolerance of chronic steroids or persistence of symptoms. In these cases, open surgical resection has been shown to be successful in management of surgically amenable lesions but may be suboptimal in patients with deep-seated lesions or extensive prior cranial surgical history, both carrying high risk for peri-operative morbidity. Laser interstitial thermal therapy has emerged as a viable, alternative surgical option. In addition to allowing access to tissue for diagnosis, thermal treatment of the lesion can also be delivered precisely and accurately under real-time imaging guidance. This review highlights the pertinent studies that have shaped the impetus for use of laser interstitial thermal therapy in the treatment of radiation necrosis, reviewing indications, outcomes, and nuances toward successful application of this technology in patients with suspected radiation necrosis.

Laser-interstitial thermal therapy compared to craniotomy for treatment of radiation necrosis or recurrent tumor in brain metastases failing radiosurgery.

PURPOSE: Many publications report laser-interstitial thermal therapy (LITT) as a viable alternative treatment to craniotomy for radiation necrosis (RN) and re-growing tumor occurring after stereotactic radiosurgery (SRS) for brain metastases. No studies to-date have compared the two options. The aim of this study was to retrospectively compare outcomes after LITT versus craniotomy for regrowing lesions in patients previously treated with SRS for brain metastases. METHODS: Data were collected from a single-institution chart review of patients treated with LITT or craniotomy for previously irradiated brain metastasis. RESULTS: Of 75 patients, 42 had recurrent tumor (56%) and 33 (44%) had RN. Of patients with tumor, 26 underwent craniotomy and 16 LITT. For RN, 15 had craniotomy and 18 LITT. There was no significant difference between LITT and craniotomy in ability to taper off steroids or neurological outcomes. Progression-free survival (PFS) and overall survival (OS) were similar for LITT versus craniotomy, respectively: %PFS-survival at 1-year = 72.2% versus 61.1%, %PFS-survival at 2-years = 60.0% versus 61.1%, p = 0.72; %OS-survival at 1-year = 69.0% versus 69.3%, %OS-survival at 2-years = 56.6% versus 49.5%, p = 0.90. Craniotomy resulted in higher rates of pre-operative deficit improvement than LITT (p < 0.01). On subgroup analysis, the single factor most significantly associated with OS and PFS was pathology of the lesion. About 40% of tumor lesions needed post-operative salvage with radiation after both craniotomy and LITT. CONCLUSIONS: LITT was as efficacious as craniotomy in achieving local control of recurrent irradiated brain metastases and facilitating steroid taper, regardless of pathology. Craniotomy appears to be more advantageous for providing symptom relief in those with pre-operative symptoms.

Erythrocytosis in hepatocellular carcinoma portends poor prognosis by respiratory dysfunction secondary to mitochondrial DNA mutations.

Erythrocytosis is a common paraneoplastic syndrome associated with hepatocellular carcinoma. Although increased erythropoietin (EPO) is found in these patients, the clinical significance and molecular mechanisms underlying this observation are unclear. We demonstrate an inverse relationship between EPO production and overall prognosis in our cohort of 664 patients as well as in data from The Cancer Genome Atlas. In the subset of hepatocellular carcinoma patients with erythrocytosis, we identified somatic mutations of mitochondrial DNA, resulting in impairment of respiratory metabolism, which sequentially led to depletion of α-ketoglutarate, stabilization of hypoxia inducible factor-α, and expression of target genes such as EPO. Cell lines and patient-derived xenograft models were used to demonstrate that EPO promoted cancer stem cell self-renewal and expansion in an autocrine/paracrine manner through enhanced Janus kinase/signal transducer and activator of transcription signaling both in vitro and in vivo. Furthermore, to explore the therapeutic targeting of EPO-induced tumor changes, we found that blocking EPO signaling with soluble EPO receptor extracellular domain Fc fusion protein could inhibit tumor growth both in vitro and in vivo. CONCLUSION: These findings suggest clinical and therapeutic implications for erythrocytosis in hepatocellular carcinoma. There is an underlying link between mitochondrial function and hypoxia inducible factor alpha signaling, revealing a mechanism of erythrocytosis in a subset of hepatocellular carcinoma patients who may benefit from treatment involving EPO signaling interference. (Hepatology 2017;65:134-151).

Integration of Metabolomics and Transcriptomics Reveals Major Metabolic Pathways and Potential Biomarker Involved in Prostate Cancer.

Prostate cancer is a highly prevalent tumor affecting millions of men worldwide, but poor understanding of its pathogenesis has limited effective clinical management of patients. In addition to transcriptional profiling or transcriptomics, metabolomics is being increasingly utilized to discover key molecular changes underlying tumorigenesis. In this study, we integrated transcriptomics and metabolomics to analyze 25 paired human prostate cancer tissues and adjacent noncancerous tissues, followed by further validation of our findings in an additional cohort of 51 prostate cancer patients and 16 benign prostatic hyperplasia patients. We found several altered pathways aberrantly expressed at both metabolic and transcriptional levels, including cysteine and methionine metabolism, nicotinamide adenine dinucleotide metabolism, and hexosamine biosynthesis. Additionally, the metabolite sphingosine demonstrated high specificity and sensitivity for distinguishing prostate cancer from benign prostatic hyperplasia, particularly for patients with low prostate specific antigen level (0-10 ng/ml). We also found impaired sphingosine-1-phosphate receptor 2 signaling, downstream of sphingosine, representing a loss of tumor suppressor gene and a potential key oncogenic pathway for therapeutic targeting. By integrating metabolomics and transcriptomics, we have provided both a broad picture of the molecular perturbations underlying prostate cancer and a preliminary study of a novel metabolic signature, which may help to discriminate prostate cancer from normal tissue and benign prostatic hyperplasia.

Mutant glucocerebrosidase in Gaucher disease recruits Hsp27 to the Hsp90 chaperone complex for proteasomal degradation.

Gaucher disease is caused by mutations of the GBA1 gene, which encodes the lysosomal anchored gluococerebrosidase (GCase). GBA1 mutations commonly result in protein misfolding, abnormal chaperone recognition, and premature degradation, but are less likely to affect catalytic activity. In the present study, we demonstrate that the Hsp90/HOP/Cdc37 complex recruits Hsp27 after recognition of GCase mutants with subsequent targeting of GCase mutant peptides to degradation mechanisms such as VCP and the 26S proteasome. Inhibition of Hsp27 not only increased the quantity of enzyme but also enhanced GCase activity in fibroblasts derived from patients with Gaucher disease. These findings provide insight into a possible therapeutic strategy for protein misfolding diseases by correcting chaperone binding and altering subsequent downstream patterns of protein degradation.

Nasoethmoid schwannoma with intracranial extension. Case report and review of the literature.

Nasoethmoid schwannomas with significant intracranial extension are rare tumours that typically present with visual and olfactory deficits. We describe a nasoethmoid schwannoma in a patient who was completely asymptomatic. Despite impressive intracranial involvement, nasoethmoid schwannomas may present asymptomatically and should be considered in the differential of contrast-enhancing anterior skull base lesions.

Metabolomics Study of Roux-en-Y Gastric Bypass Surgery (RYGB) to Treat Type 2 Diabetes Patients Based on Ultraperformance Liquid Chromatography-Mass Spectrometry.

Roux-en-Y gastric bypass (RYGB) is one of the most effective treatments for long-term weight loss and diabetes remission; however, the mechanisms underlying these changes are not clearly understood. In this study, the serum metabolic profiles of 23 remission and 12 nonremission patients with type 2 diabetes mellitus (T2DM) were measured at baseline, 6- and 12-months after RYGB. A metabolomics analysis was performed based on ultra-performance liquid chromatography-mass spectrometry. Clinical improvements in insulin sensitivity, energy metabolism, and inflammation were related to metabolic alterations of free fatty acids (FFAs), acylcarnitines, amino acids, bile acids, and lipids species. Differential metabolic profiles were observed between the two T2DM subgroups, and patients with severity fat accumulation and oxidation stress may be more suitable for RYGB. Baseline levels of tryptophan, bilirubin, and indoxyl sulfate measured prior to surgery as well as levels of FFA 16:0, FFA 18:3, FFA 17:2, and hippuric acid measured at 6 months after surgery best predicted the suitability and efficacy of RYGB for patients with T2DM. These metabolites represent potential biomarkers that may be clinically helpful in individualized treatment for T2DM patients by RYGB.

IDH mutations may not preclude distant, trans-tentorial spread in gliomas: a case report and review of the literature.

BACKGROUND: IDH mutations have been demonstrated to confer prolonged survival in patients suffering from gliomas, but the mechanisms underlying the improved prognosis are unclear. While some studies have attributed these observations to an enhanced sensitivity to genotoxic therapies, others have postulated that IDH-mutated gliomas exhibit less aggressive intrinsic biological behavior, including the propensity to invade distant sites. Although most gliomas recur local to the site of initial presentation, some tumors demonstrate distant recurrence, the vast majority of which involve the contralateral hemisphere. Trans-tentorial spread has been described once before, in which a supratentorial glioblastoma was reported to recur infratentorially in the cerebellum. CASE PRESENTATION: We describe a patient who underwent surgical resection, followed by adjuvant radiation and temozolomide of a World Health Organization (WHO) III anaplastic astrocytoma in the right temporal lobe, exhibiting an IDH1 (R132H) mutation. Twenty-two months after surgery, he developed a second lesion, located in the right cerebellum, suspicious for recurrent tumor versus radiation necrosis. A second surgery was performed, and pathology demonstrated recurrent tumor, consistent with IDH1-mutated anaplastic astrocytoma. CONCLUSIONS: This is the first example of trans-tentorial spread in an IDH-mutated glioma, suggesting that despite improved survival, IDH mutations may not preclude gliomas from exhibiting the ability to invade distant sites of the brain.

New developments in the pathogenesis and therapeutic targeting of the IDH1 mutation in glioma.

In the last five years, IDH1 mutations in human malignancies have significantly shaped the diagnosis and management of cancer patients. Ongoing intense research efforts continue to alter our understanding of the role of the IDH1 mutation in tumor formation. Currently, evidence suggests the IDH1 mutation to be an early event in tumorigenesis with multiple downstream oncogenic consequences including maintenance of a hypermethylator phenotype, alterations in HIF signalling, and disruption of collagen maturation contributing to a cancer-promoting extracellular matrix. The most recent reports elucidating these mechanisms is described in this review with an emphasis on the pathogenesis of the IDH1 mutation in glioma. Conflicting findings from various studies are discussed, in order to highlight areas warranting further research. Finally, the latest progress in developing novel therapies against the IDH1 mutation is presented, including recent findings from ongoing phase 1 clinical trials and the exciting prospect of vaccine immunotherapy targeting the IDH1 mutant protein.

Assessing Mobility in Patients With Glioblastoma Using Digital Phenotyping-Piloting the Digital Assessment in Neuro-Oncology.

BACKGROUND AND OBJECTIVES: Digital phenotyping (DP) enables objective measurements of patient behavior and may be a useful tool in assessments of quality-of-life and functional status in neuro-oncology patients. We aimed to identify trends in mobility among patients with glioblastoma (GBM) using DP. METHODS: A total of 15 patients with GBM enrolled in a DP study were included. The Beiwe application was used to passively collect patient smartphone global positioning system data during the study period. We estimated step count, time spent at home, total distance traveled, and number of places visited in the preoperative, immediate postoperative, and late postoperative periods. Mobility trends for patients with GBM after surgery were calculated by using local regression and were compared with preoperative values and with values derived from a nonoperative spine disease group. RESULTS: One month postoperatively, median values for time spent at home and number of locations visited by patients with GBM decreased by 1.48 h and 2.79 locations, respectively. Two months postoperatively, these values further decreased by 0.38 h and 1.17 locations, respectively. Compared with the nonoperative spine group, values for time spent at home and the number of locations visited by patients with GBM 1 month postoperatively were less than control values by 0.71 h and 2.79 locations, respectively. Two months postoperatively, time spent at home for patients with GBM was higher by 1.21 h and locations visited were less than nonoperative spine group values by 1.17. Immediate postoperative values for distance traveled, maximum distance from home, and radius of gyration for patients with GBM increased by 0.346 km, 2.24 km, and 1.814 km, respectively, compared with preoperative values. CONCLUSIONS: :Trends in patients with GBM mobility throughout treatment were quantified through the use of DP in this study. DP has the potential to quantify patient behavior and recovery objectively and with minimal patient burden.

Aerobic exercise interventions to address impaired quality of life in patients with pituitary tumors.

Patients with pituitary tumors may experience persistent fatigue and reduced physical activity, based on subjective measures after treatment. These symptoms may persist despite gross total resection of their tumors and biochemical normalization of pituitary function. While reduced quality of life has been commonly acknowledged in pituitary tumor patients, there is a lack of studies on what interventions may be best implemented to ameliorate these issues, particularly when hormonal levels have otherwise normalized. Aerobic exercise programs have been previously described to ameliorate symptoms of chronic fatigue and reduced physical capacity across a variety of pathologies in the literature. As such, a prescribed aerobic exercise program may be an underrecognized but potentially impactful intervention to address quality of life in pituitary tumor patients. This review seeks to summarize the existing literature on aerobic exercise interventions in patients with pituitary tumors. In addition, future areas of study are discussed, including tailoring exercise programs to the hormonal status of the patient and incorporating more objective measures in monitoring response to interventions.

Subdural empyema secondary to pansinusitis after coronavirus disease 2019 infection in an immunocompetent patient: illustrative case.

BACKGROUND: Superimposed intracranial infection is an uncommon but clinically significant complication in patients with active coronavirus disease 2019 (COVID-19), particularly in those with predisposing immunocompromising conditions. OBSERVATIONS: The authors describe a case of subdural empyema, secondary to extension from pansinusitis, in a 20-year-old otherwise healthy immunocompetent male who was recently diagnosed with COVID-19. Despite his critical condition at time of presentation, he made a full clinical recovery with aggressive multidisciplinary surgical management between neurosurgery and otolaryngology, despite negative cultures to guide directed antimicrobial therapy. Ultimately, use of molecular-based polymerase chain reaction testing diagnosed Aspergillus fumigatus as the offending pathogen after the patient had already recovered and was discharged from the hospital. LESSONS: This case demonstrates the potential for significant superimposed intracranial infection even in young, healthy individuals, infected by COVID-19 and suggests an aggressive surgical approach to achieve source control, particularly in the absence of positive cultures to guide antimicrobial therapies, may lead to rapid clinical improvement.

Management of dynamic cervical kyphosis with dorsal epidural lipomatosis: a Hirayama disease variant? Illustrative case.

BACKGROUND: Hirayama disease, a cervical myelopathy characterized most commonly by a self-limiting atrophic weakness of the upper extremities, is a rare entity, scarcely reported in the literature. Diagnosis is made by spinal magnetic resonance imaging (MRI), which typically shows loss of normal cervical lordosis, anterior displacement of the cord during flexion, and a large epidural cervical fat pad. Treatment options include observation or cervical immobilization by collar or surgical decompression and fusion. OBSERVATIONS: Here, the authors report an unusual case of a Hirayama-like disease in a young White male athlete who presented with rapidly progressive paresthesia in all 4 extremities and no weakness. Imaging showed characteristic findings of Hirayama disease as well as worsened cervical kyphosis and spinal cord compression in cervical neck extension, which has not previously been reported. Two-level anterior cervical discectomy and fusion and posterior spinal fusion improved both cervical kyphosis on extension and symptoms. LESSONS: Given the disease's self-limiting nature, and a lack of current reporting, there remains no consensus on how to manage these patients. Such findings presented here demonstrate the potentially heterogeneous MRI findings that can be observed in Hirayama disease and emphasize the utility of aggressive surgical management in young, active patients whereby a cervical collar may not be tolerated.

Vascular steal and associated intratumoral aneurysms in highly vascular brain tumors: illustrative case.

BACKGROUND: Intratumoral aneurysms in highly vascular brain tumors can complicate resection depending on their location and feasibility of proximal control. Seemingly unrelated neurological symptoms may be from vascular steal that can help alert the need for additional vascular imaging and augmenting surgical strategies. OBSERVATIONS: A 29-year-old female presented with headaches and unilateral blurred vision, secondary to a large right frontal dural-based lesion with hypointense signal thought to represent calcifications. Given these latter findings and clinical suspicion for a vascular steal phenomenon to explain the blurred vision, computed tomography angiography was obtained, revealing a 4 × 2-mm intratumoral aneurysm. Diagnostic cerebral angiography confirmed this along with vascular steal by the tumor from the right ophthalmic artery. The patient underwent endovascular embolization of the intratumoral aneurysm, followed by open tumor resection in the same setting without complication, minimal blood loss, and improvement in her vision. LESSONS: Understanding the blood supply of any tumor, but highly vascular ones in particular, and the relationship with normal vasculature is undeniably important in avoiding potentially dangerous situations and optimizing maximal safe resection. Recognition of highly vascular tumors should prompt thorough understanding of the vascular supply and relationship of intracranial vasculature with consideration of endovascular adjuncts when appropriate.