Defining the role of mTOR pathway in the regulation of stem cells of glioblastoma.

The mechanistic target of rapamycin (mTOR), a serine/threonine kinase, functions by forming two multiprotein complexes termed mTORC1 and mTORC2. Glioblastoma (GBM) is a uniformly fatal brain tumor that remains incurable partly due to the existence of untreatable cancer stem cells (CSC). The pathogenesis of GBM is largely due to the loss of the tumor suppressor gene PTEN, which is implicated in the aberrant activation of the mTOR pathway. The major cause of tumor recurrence, growth, and invasion is the presence of the unique population of CSC. Resistance to conventional therapies appears to be caused by both extensive genetic abnormalities and dysregulation of the transcription landscape. Consequently, CSCs have emerged as targets of interest in new treatment paradigms. Evidence suggests that inhibition of the mTOR pathway can also be applied to target CSCs. Here we explored the role of the mTOR pathway in the regulation of stem cells of GBM by treating them with inhibitors of canonical PI3K/AKT/mTOR pathways such as rapamycin (mTORC1 inhibitor), PP242 (ATP binding mTORC1/2 inhibitor), LY294002 (PI3K inhibitor), and MAPK inhibitor, U0126. A significant number of GBM tumors expressed stem cell marker nestin and activated mTOR (pmTORSer2448), with most tumor cells co-expressing both markers. The expression of stem cell marker NANOG was suppressed following rapamycin treatment. The neurospheres were disrupted following rapamycin and LY294002 treatments. Rapamycin or PP242 along with differentiating agent All-trans-retinoic acid reduced stem cell proliferation. Treatment with novel small molecule inhibitors of mTORC1/2 demonstrated that Torin1 and Torin2 suppressed the proliferation of GBM CSC, while XL388 was less effective. Torin1 and XL388 delay the process of self-renewal as compared to controls, whereas Torin2 halted self-renewal. Torin2 was able to eradicate tumor cells. In conclusion, Torin2 effectively targeted CSCs of GBM by halting self-renewal and inhibiting cell proliferation, underscoring the use of Torin2 in the treatment of GBM.

Intrasellar hemorrhagic chordoma masquerading as pituitary apoplexy: case report and review of the literature.

BACKGROUND AND IMPORTANCE: Chordomas are centrally located, expansile soft tissue neoplasms that arise from the remnants of the embryological notochord. Hemorrhagic presentation is exceedingly rare and can resemble pituitary apoplexy. Moreover, a purely intrasellar location of a chordoma is extremely uncommon. We report a case of a hemorrhagic intrasellar chordoma in an adult male, which presented similarly to pituitary apoplexy and was resolved with surgical resection. CLINICAL PRESENTATION: A 69-year-old male presented with a 4 week history of acute onset headache and concurrent diplopia, with significantly reduced testosterone and slightly reduced cortisol. His left eye demonstrated a sixth cranial nerve palsy. Magnetic resonance imaging of the brain showed a large hemorrhagic mass in the pituitary region with significant compression of the left cavernous sinus and superior displacement of the pituitary gland. The patient underwent an endoscopic endonasal transsphenoidal approach for the resection of the lesion. Near total resection was achieved. Final pathology revealed chordoma with evidence of intratumoral hemorrhage, further confirmed by immunopositive stain for brachyury. Post-operatively, the patient had improved diplopia and was discharged home on low dose hydrocortisone. At 3-month follow-up, his diplopia was resolved and new MRI showed stable small residual disease. CONCLUSIONS: Apoplectic chordomas are uncommon given chordoma's characteristic lack of intralesional vascularity and represent a diagnostic challenge in the sellar region. Our unique case demonstrates that despite our initial impression of pituitary apoplexy, this was ultimately a case of apoplectic chordoma that responded well to endoscopic endonasal surgery.

Fatal acute respiratory distress syndrome caused by blastomycosis after recent orthotopic liver transplantation in a non-endemic area.

In blastomycosis, immunosuppression such as that following solid organ transplantation appears to be a risk factor for the development of overwhelming lung infection fulfilling criteria for the acute respiratory distress syndrome. Our transplant center, located outside traditional endemic areas for Blastomyces spp, experienced a case of fatal acute respiratory distress syndrome secondary to blastomycosis pneumonia in a recipient of recent orthotopic liver transplantation. The patient expired despite support with veno-venous extracorporeal membrane oxygenation.

Repair of fungal pseudoaneurysm of the common brachiocephalic trunk.

BACKGROUND AND AIM: To date, little is known about the aneurysms of the bovine aortic arch, known as a "common brachiocephalic trunk (CBT)" from where the left carotid and innominate arteries bifurcate. PATIENT AND RESULTS: Here we report a case of a fungal pseudoaneurysm of the bovine aortic arch in a patient who had prior history of multiple aortic valve replacement, hepatitis C infection, and human immunodeficiency virus infection. A re-operative replacement of the aortic arch repair utilizing a bifurcated graft was successfully performed under deep hypothermia and selective antegrade cerebral perfusion. Pathological examination demonstrated a pseudoaneurysm of the CBT. Intraoperative cultures from the aneurysmal wall showed Aspergillus fumigatus DISCUSSION AND CONCLUSION: we experienced a complex surgical repair of CBT pseudoaneurysm caused by Aspergillus species.

Intraventricular Choroid Plexus Cavernoma Resection Using Tubular Retractor System and Exoscope Visualization: A Technical Case Report.

BACKGROUND AND IMPORTANCE: Cavernous malformations (CMs) account for approximately 5% to 10% of all CNS vascular malformations, and intraventricular CMs (IVCMs) are a rare subtype, accounting for 2.5% to 10.8% of all intracranial CMs. IVCMs can expand rapidly, leading to compression of adjacent structures, intraventricular hemorrhage, and obstructive hydrocephalus. Diagnosis is challenging because it can mimic a variety of other lesions. CLINICAL PRESENTATION: A 71-year-old man presented after a fall because of imbalance. MRI of the head showed a homogenously enhancing 2-cm mass in the posterior aspect of the right lateral ventricle, with blood layering in the right occipital horn and adjacent parietal edema and leptomeningeal enhancement, as well as a pituitary lesion. DISCUSSION: The patient underwent a right parietal craniotomy for resection of the mass. The ventricle was accessed through a transsulcal approach through the intraparietal sulcus using a tubular retractor system. The mass was arising from the choroid plexus and dissected free in a piecemeal fashion. Postoperative imaging confirmed gross total resection, and the patient had an uneventful recovery. CONCLUSION: Here, we present the first case of a choroid plexus IVCM removed using a tubular retractor system. We demonstrate that this is a safe and effective approach for this rare lesion given the minimal traction on brain parenchyma and enhanced visualization of a deep-seated cavernoma in the lateral ventricle.

Acute amiodarone pulmonary toxicity in the form of organizing pneumonia triggered by orthotopic heart transplantation.

We report a case of a 60-year-old man who underwent orthotopic heart transplantation after short-term receipt of low-dose oral amiodarone for the management of ventricular tachycardia. Prior to transplant surgery, he had a normal chest radiograph and was free of supplemental oxygen. His initial postoperative chest radiograph showed subtle infiltrates, and thereafter his chest imaging continued to worsen. Although he was eventually able to wean off mechanical ventilation via a tracheostomy, he remained dyspneic and oxygen-dependent with persistently abnormal chest imaging as his post-transplant corticosteroid regimen was being tapered. In light of progressively worsening diffuse lung disease, he underwent bronchoscopy with transbronchial biopsies. Histology revealed foamy macrophages in association with foci of organizing pneumonia, a picture consistent with amiodarone pulmonary toxicity. Given these findings, corticosteroid dosing was increased for the clinical diagnosis of acute amiodarone pulmonary toxicity with subsequent normalization of oxygen saturation and chest radiography. Our case is the first to identify orthotopic heart transplantation as a potential trigger for acute amiodarone pulmonary toxicity. It is also only the second documented example of organizing pneumonia as the histological substrate of amiodarone pulmonary toxicity, which is an association that has therapeutic implications.

Human Cord Blood Derived Unrestricted Somatic Stem Cells Restore Aquaporin Channel Expression, Reduce Inflammation and Inhibit the Development of Hydrocephalus After Experimentally Induced Perinatal Intraventricular Hemorrhage.

Intraventricular hemorrhage (IVH) is a severe complication of preterm birth associated with cerebral palsy, intellectual disability, and commonly, accumulation of cerebrospinal fluid (CSF). Histologically, IVH leads to subependymal gliosis, fibrosis, and disruption of the ependymal wall. Importantly, expression of aquaporin channels 1 and 4 (AQP1 and AQP4) regulating respectively, secretion and absorption of cerebrospinal fluids is altered with IVH and are associated with development of post hemorrhagic hydrocephalus. Human cord blood derived unrestricted somatic stem cells (USSCs), which we previously demonstrated to reduce the magnitude of hydrocephalus, as having anti-inflammatory, and beneficial behavioral effects, were injected into the cerebral ventricles of rabbit pups 18 h after glycerol-induced IVH. USSC treated IVH pups showed a reduction in ventricular size when compared to control pups at 7 and 14 days (both, P < 0.05). Histologically, USSC treatment reduced cellular infiltration and ependymal wall disruption. In the region of the choroid plexus, immuno-reactivity for AQP1 and ependymal wall AQP4 expression were suppressed after IVH but were restored following USSC administration. Effects were confirmed by analysis of mRNA from dissected choroid plexus and ependymal tissue. Transforming growth factor beta (TGF-ß) isoforms, connective tissue growth factor (CTGF) and matrix metalloprotease-9 (MMP-9) mRNA, as well as protein levels, were significantly increased following IVH and restored towards normal with USSC treatment (P < 0.05). The anti-inflammatory cytokine Interleukin-10 (IL-10) mRNA was reduced in IVH, but significantly recovered after USSC injection (P < 0.05). In conclusion, USSCs exerted anti-inflammatory effects by suppressing both TGF-ß specific isoforms, CTGF and MMP-9, recovered IL-10, restored aquaporins expression towards baseline, and reduced hydrocephalus. These results support the possibility of the use of USSCs to reduce IVH consequences in prematurity.

COVID-19-Induced Neurovascular Injury: a Case Series with Emphasis on Pathophysiological Mechanisms.

Coronavirus disease 2019 (COVID-19) is associated with a high inflammatory burden that can induce severe respiratory disease among other complications; vascular and neurological damage has emerged as a key threat to COVID-19 patients. Risk of severe infection and mortality increases with age, male sex, and comorbidities including cardiovascular disease, hypertension, obesity, diabetes, and chronic pulmonary disease. We review clinical and neuroradiological findings in five patients with COVID-19 who suffered severe neurological disease and illustrate the pathological findings in a 7-year-old boy with COVID-19-induced encephalopathy whose brain tissue sample showed angiocentric mixed mononuclear inflammatory infiltrate. We summarize the structural and functional properties of the virus including the molecular processes that govern the binding to its membrane receptors and cellular entry. In addition, we review clinical and experimental evidence in patients and animal models that suggests coronaviruses enter into the central nervous system (CNS), either via the olfactory bulb or through hematogenous spread. We discuss suspected pathophysiological mechanisms including direct cellular infection and associated recruitment of immune cells and neurovirulence, at least in part, mediated by cytokine secretion. Moreover, contributing to the vascular and neurological injury, coagulopathic disorders play an important pathogenic role. We survey the molecular events that contribute to the thrombotic microangiopathy. We describe the neurological complications associated with COVID-19 with a focus on the potential mechanisms of neurovascular injury. Our thesis is that following infection, three main pathophysiological processes-inflammation, thrombosis, and vascular injury-are responsible for the neurological damage and diverse pathology seen in COVID-19 patients.

Estrogen Treatment Reverses Prematurity-Induced Disruption in Cortical Interneuron Population.

Development of cortical interneurons continues until the end of human pregnancy. Premature birth deprives the newborns from the supply of maternal estrogen and a secure intrauterine environment. Indeed, preterm infants suffer from neurobehavioral disorders. This can result from both preterm birth and associated postnatal complications, which might disrupt recruitment and maturation of cortical interneurons. We hypothesized that interneuron subtypes, including parvalbumin-positive (PV+), somatostatin-positive (SST+), calretinin-positive (CalR+), and neuropeptide Y-positive (NPY+) interneurons, were recruited in the upper and lower cortical layers in a distinct manner with advancing gestational age. In addition, preterm birth would disrupt the heterogeneity of cortical interneurons, which might be reversed by estrogen treatment. These hypotheses were tested by analyzing autopsy samples from premature infants and evaluating the effect of estrogen supplementation in prematurely delivered rabbits. The PV+ and CalR+ neurons were abundant, whereas SST+ and NPY+ neurons were few in cortical layers of preterm human infants. Premature birth of infants reduced the density of PV+ or GAD67+ neurons and increased SST+ interneurons in the upper cortical layers. Importantly, 17 ß-estradiol treatment in preterm rabbits increased the number of PV+ neurons in the upper cortical layers relative to controls at postnatal day 14 (P14) and P21 and transiently reduced SST population at P14. Moreover, protein and mRNA levels of Arx, a key regulator of cortical interneuron maturation and migration, were higher in estrogen-treated rabbits relative to controls. Therefore, deficits in PV+ and excess of SST+ neurons in premature newborns are ameliorated by estrogen replacement, which can be attributed to elevated Arx levels. Estrogen replacement might enhance neurodevelopmental outcomes in extremely preterm infants.SIGNIFICANCE STATEMENT Premature birth often leads to neurodevelopmental delays and behavioral disorders, which may be ascribed to disturbances in the development and maturation of cortical interneurons. Here, we show that preterm birth in humans is associated with reduced population of parvalbumin-positive (PV+) neurons and an excess of somatostatin-expressing interneurons in the cerebral cortex. More importantly, 17 ß-estradiol treatment increased the number of PV+ neurons in preterm-born rabbits, which appears to be mediated by an elevation in the expression of Arx transcription factor. Hence the present study highlights prematurity-induced reduction in PV+ neurons in human infants and reversal in their population by estrogen replacement in preterm rabbits. Because preterm birth drops plasma estrogen level 100-fold, estrogen replacement in extremely preterm infants might improve their developmental outcome and minimize neurobehavioral disorders.

A case of intramural coronary amyloidosis associated with hemodialysis.

Dialysis-related amyloidosis predominantly occurs in osteo-articular structures and dialysis-related amyloid (DRA) substances also deposit in extra-articular tissues. Clinical manifestations of DRA include odynophagia, gastrointestinal hemorrhage, intestinal obstruction, kidney stones, myocardial dysfunction, and subcutaneous tumors. The pathological characteristics of DRA in the heart of hemodialysis patients have rarely been reported. We report the case of a 73-year-old female with a history of cerebral palsy and end-stage renal disease status post two failed renal transplants who had been on hemodialysis for 30 years. The patient was admitted with the working diagnosis of pneumonia. An echocardiography showed markedly reduced biventricular function manifested by low blood pressure with systolic in the 70s and elevated pulmonary artery pressure of 45 mmHg, which did not respond to therapy. Following her demise, the autopsy revealed bilateral pulmonary edema and pleural effusions. There was cardiac amyloid deposition exclusively in the coronary arteries but not in the perimyocytic interstitium. Amyloids were also found in pulmonary and intrarenal arteries and the colon wall. Previous case reports showed that beta 2-microglobulin amyloid deposits in various visceral organs but less frequently in the atrial and/or the ventricular myocardium. In the present case, amyloids in the heart were present in the intramural coronary arteries causing myocardial ischemia and infarction, which was the immediate cause of death.

A case of intramural coronary amyloidosis associated with hemodialysis

Dialysis-related amyloidosis predominantly occurs in osteo-articular structures and dialysis-related amyloid (DRA) substances also deposit in extra-articular tissues. Clinical manifestations of DRA include odynophagia, gastrointestinal hemorrhage, intestinal obstruction, kidney stones, myocardial dysfunction, and subcutaneous tumors. The pathological characteristics of DRA in the heart of hemodialysis patients have rarely been reported. We report the case of a 73-year-old female with a history of cerebral palsy and end-stage renal disease status post two failed renal transplants who had been on hemodialysis for 30 years. The patient was admitted with the working diagnosis of pneumonia. An echocardiography showed markedly reduced biventricular function manifested by low blood pressure with systolic in the 70s and elevated pulmonary artery pressure of 45 mmHg, which did not respond to therapy. Following her demise, the autopsy revealed bilateral pulmonary edema and pleural effusions. There was cardiac amyloid deposition exclusively in the coronary arteries but not in the perimyocytic interstitium. Amyloids were also found in pulmonary and intrarenal arteries and the colon wall. Previous case reports showed that beta 2-microglobulin amyloid deposits in various visceral organs but less frequently in the atrial and/or the ventricular myocardium. In the present case, amyloids in the heart were present in the intramural coronary arteries causing myocardial ischemia and infarction, which was the immediate cause of death.

Metastatic Mantle Cell Lymphoma to the Pituitary Gland: Case Report and Literature Review.

We present an unusual case of a metastatic mantle cell lymphoma (MCL) to the pituitary gland. The patient had a known history of MCL for which she previously received chemotherapy. She presented with new-onset diplopia and confusion, and reported a history of progressive vision blurriness associated with headache, nausea, and vomiting. MRI of the brain showed an enhancing lesion within the sella turcica involving the cavernous sinuses bilaterally, extending into Meckel's cave on the left, and abutting the optic nerves bilaterally. Following surgical excision, histopathology revealed the tumor to be a MCL. Metastatic pituitary tumors are rare and have been estimated to make up 1% of tumors discovered in the sellar region. The two most common secondary metastatic lesions to the sella are breast and lung carcinoma followed by prostate, renal cell, and gastrointestinal carcinoma. Metastatic lymphoma to the pituitary gland is especially rare and is estimated to constitute 0.5% of all metastatic tumors to the sella turcica. To our knowledge, this is the first reported case of MCL metastasizing to the pituitary gland.

Metastatic Renal Cell Carcinoma Mimicking Trigeminal Schwannoma in a Patient Presenting with Trigeminal Neuralgia.

We present an unusual case of a metastatic renal cell carcinoma (RCC) mimicking trigeminal schwannoma. The patient, with no prior history of RCC, presented with clinical symptoms and imaging consistent with trigeminal neuralgia secondary to trigeminal schwannoma. Magnetic resonance imaging of the brain showed a large bilobed cystic/solid mass primarily in the cerebellopontine angle cistern, with extension into the left middle cranial fossa, Meckel cave, and left cavernous sinus. Following surgical excision, histopathology revealed the tumor to be an RCC infiltrating into the trigeminal nerve fascicles. Further imaging and investigation revealed widespread metastasis to the vertebral bodies and long bones. Metastatic RCC to the trigeminal nerve is rare. Despite the development of more effective treatment modalities, the prognosis of metastatic RCC remains poor. To our knowledge, this is the first reported case of RCC metastasizing to the trigeminal nerve fascicles.

Lyme disease: a case report of a 17-year-old male with fatal Lyme carditis.

Lyme disease is a systemic infection commonly found in the northeastern, mid-Atlantic, and north-central regions of the United States. Of the many systemic manifestations of Lyme disease, cardiac involvement is uncommon and rarely causes mortality. We describe a case of a 17-year-old adolescent who died unexpectedly after a 3-week viral-like syndrome. Postmortem examination was remarkable for diffuse pancarditis characterized by extensive infiltrates of lymphocytes and focal interstitial fibrosis. In the cardiac tissue, Borrelia burgdorferi was identified via special stains, immunohistochemistry, and polymerase chain reaction. The findings support B. burgdorferi as the causative agent for his fulminant carditis and that the patient suffered fatal Lyme carditis. Usually, Lyme carditis is associated with conduction disturbances and is a treatable condition. Nevertheless, few cases of mortality have been reported in the literature. Here, we report a rare example of fatal Lyme carditis in an unsuspected patient.

Molecular, histopathological, and genomic variants of glioblastoma.

Glioblastoma (GBM), the most common primary brain tumor, has a poor median prognosis despite modern surgical, chemotherapeutic, and radiation modalities, which have shown little clinical efficacy. Initially categorized by clinicopathological classification into de novo primary GBM and secondary GBM, which arises from lower-grade glioma, genomic studies have elucidated several distinct genotypes. In addition, distinct patterns of dysregulated epidermal growth factor receptor, platelet-derived growth factor receptor, p53, phosphatase and tensin homolog, cell cycle proteins, and isocitrate dehydrogenase 1, as well as loss of heterozygosity in multiple chromosomes complicate the GBM mutational landscape. Even with the many approaches in targeting these mutations, a long-standing clinical cure remains limited because of the tremendous heterogeneity and challenges in developing targeted treatments. Furthermore, this cancer utilizes ingenious approaches to subvert targeted agents and pathological variants of GBM demonstrate distinct molecular signatures, which may impact prognosis. This review discusses the collective understanding of GBM heterogeneity, including molecular, histopathological, and genomic features; why treatments have failed in the past; and how future clinical trials and therapies can be devised.

Staged approach prevents spinal cord injury in hybrid surgical-endovascular thoracoabdominal aortic aneurysm repair: an experimental model.

BACKGROUND: In a porcine model, we investigated the impact of sudden stent graft occlusion of thoracic intercostal arteries after open lumbar segmental artery (SA) ligation. METHODS: After randomization into two groups, 20 juvenile Yorkshire pigs (27.1±0.6 kg) underwent open lumbar SA sacrifice (T13-L5) followed by endovascular coverage of all thoracic SAs (T4-T12) at 32°C, either in a single operation (group 1) or in two stages separated by seven days (group 2). Collateral network pressure (CNP) was monitored by catheterization of the SA L1, and postoperative hind limb function was assessed using a modified Tarlov score. RESULTS: The CNP in group 1 decreased to 34% of baseline, whereas CNP after lumbar SA ligation in group 2 fell to 55% of baseline (74±2.4 to 25±3.6 mm Hg vs 74±4.5 to 41±5.5 mm Hg; p<0.0001). Subsequent thoracic stenting (group 2) led to another significant but milder drop (p=0.002 versus stage 1) from the restored CNP (71±4.2 to 54±4.9 mm Hg). Five of ten pigs in group 1 suffered paraplegia, in contrast to none in group 2 (median Tarlov score 6, vs 9; p=0.0031). Histopathologic analysis showed more severe ischemic damage to the lower thoracic (p=0.05) and lumbar spinal cord (p=0.002) in group 1. CONCLUSIONS: These results underline the potential of the staged approach in hybrid procedures. Furthermore they highlight the need for established adjuncts for preventing paraplegia in hybrid and pure stent-graft protocols in which sudden occlusion of multiple SAs occurs.