ABSTRACT
BACKGROUND: Craniopharyngiomas, primary brain tumors of the pituitary-hypothalamic axis, can cause clinically significant sequelae. Treatment with the use of surgery, radiation, or both is often associated with substantial morbidity related to vision loss, neuroendocrine dysfunction, and memory loss. Genotyping has shown that more than 90% of papillary craniopharyngiomas carry BRAF V600E mutations, but data are lacking with regard to the safety and efficacy of BRAF-MEK inhibition in patients with papillary craniopharyngiomas who have not undergone previous radiation therapy. METHODS: Eligible patients who had papillary craniopharyngiomas that tested positive for BRAF mutations, had not undergone radiation therapy previously, and had measurable disease received the BRAF-MEK inhibitor combination vemurafenib-cobimetinib in 28-day cycles. The primary end point of this single-group, phase 2 study was objective response at 4 months as determined with the use of centrally determined volumetric data. RESULTS: Of the 16 patients in the study, 15 (94%; 95% confidence interval [CI], 70 to 100) had a durable objective partial response or better to therapy. The median reduction in the volume of the tumor was 91% (range, 68 to 99). The median follow-up was 22 months (95% CI, 19 to 30) and the median number of treatment cycles was 8. Progression-free survival was 87% (95% CI, 57 to 98) at 12 months and 58% (95% CI, 10 to 89) at 24 months. Three patients had disease progression during follow-up after therapy had been discontinued; none have died. The sole patient who did not have a response stopped treatment after 8 days owing to toxic effects. Grade 3 adverse events that were at least possibly related to treatment occurred in 12 patients, including rash in 6 patients. In 2 patients, grade 4 adverse events (hyperglycemia in 1 patient and increased creatine kinase levels in 1 patient) were reported; 3 patients discontinued treatment owing to adverse events. CONCLUSIONS: In this small, single-group study involving patients with papillary craniopharyngiomas, 15 of 16 patients had a partial response or better to the BRAF-MEK inhibitor combination vemurafenib-cobimetinib. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT03224767.).
Subject(s)
Antineoplastic Agents , Craniopharyngioma , Pituitary Neoplasms , Humans , Craniopharyngioma/drug therapy , Craniopharyngioma/genetics , Disease Progression , Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors , Mitogen-Activated Protein Kinase Kinases/genetics , Pituitary Neoplasms/drug therapy , Pituitary Neoplasms/genetics , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Proto-Oncogene Proteins B-raf/genetics , Vemurafenib/adverse effects , Vemurafenib/therapeutic use , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Remission InductionABSTRACT
Glioblastoma is both the most common and lethal primary malignant brain tumor. Extensive multiplatform genomic characterization has provided a higher-resolution picture of the molecular alterations underlying this disease. These studies provide the emerging view that "glioblastoma" represents several histologically similar yet molecularly heterogeneous diseases, which influences taxonomic classification systems, prognosis, and therapeutic decisions.
Subject(s)
Brain Neoplasms/classification , Brain Neoplasms/genetics , Glioblastoma/classification , Glioblastoma/genetics , Brain Neoplasms/pathology , Gene Expression Profiling , Genes, Tumor Suppressor , Genomics , Glioblastoma/pathology , Humans , Neovascularization, Pathologic/genetics , Transcription, GeneticABSTRACT
High-grade serous ovarian cancers are characterized by widespread recurrent copy number alterations. Although some regions of copy number change harbor known oncogenes and tumor suppressor genes, the genes targeted by the majority of amplified or deleted regions in ovarian cancer remain undefined. Here we systematically tested amplified genes for their ability to promote tumor formation using an in vivo multiplexed transformation assay. We identified the GRB2-associated binding protein 2 (GAB2) as a recurrently amplified gene that potently transforms immortalized ovarian and fallopian tube secretory epithelial cells. Cancer cell lines overexpressing GAB2 require GAB2 for survival and show evidence of phosphatidylinositol 3-kinase (PI3K) pathway activation, which was required for GAB2-induced transformation. Cell lines overexpressing GAB2 were as sensitive to PI3K inhibition as cell lines harboring mutant PIK3CA. Together, these observations nominate GAB2 as an ovarian cancer oncogene, identify an alternative mechanism to activate PI3K signaling, and underscore the importance of PI3K signaling in this cancer.
Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Gene Amplification , Gene Expression Regulation, Neoplastic , Ovarian Neoplasms/genetics , Adaptor Proteins, Signal Transducing/genetics , Animals , Cell Line, Tumor , Cell Proliferation , Cell Transformation, Neoplastic , Female , Genomics , Humans , Mice , Mice, Nude , Neoplasm Transplantation , Oligonucleotide Array Sequence Analysis , Open Reading Frames , Ovarian Neoplasms/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Signal TransductionABSTRACT
Background: Ventriculoperitoneal shunt (VPS) can be placed solely by a neurosurgeon often via an open-laparotomy approach, or laparoscopically as a collaborative effort between a neurosurgeon and a general surgeon. Prior studies have shown conflicting results when examining outcomes regarding infection, revision rate, hospital charges, length of stay, and mortality between the open mini-laparotomy and the laparoscopic approaches. Objective: The current study uses the National Inpatient Sample (NIS) to compare outcomes of open mini-laparotomy vs. laparoscopic collaborative approach in VPS placement. Methods: We performed a retrospective database study of the NIS from October 2015-December 2017 utilizing International Classification of Diseases, 10th Revision coding to identify all cases of VPS placement. All analyses accounted for the sampling design of the NIS. Results: A total of 6580 cases (4969 with open mini-laparotomy approach and 1611 with laparoscopic collaborative approach) met inclusion criteria. Hospital charges, infection rates, and revision rates were similar between approaches. There were no significant differences in length of stay, mortality, or complication rates between the two approaches. Conclusion: The collaborative, laparoscopic approach to VPS placement has similar outcomes and is non-inferior to the traditional open mini-laparotomy approach.
ABSTRACT
BACKGROUND: A bilateral infraoptic origin of the anterior cerebral arteries (ACAs) is a rare anatomical variant that can be encountered during anterior skull base surgery. The ACAs arise from the internal carotid artery (ICA) at the level of the ophthalmic artery and course medially, traveling inferior to the ipsilateral optic nerves. Herein, the authors discuss the different configurations of the anatomical variant, its prevalence, and hypotheses leading to the variable configuration of this anomaly. OBSERVATIONS: A 67-year-old woman presented with worsening dizziness over a week-long period and was found to have a large left sphenocavernous meningioma with optic, cavernous, and suprasellar extension. The tumor incorporated the left supraclinoid ICA and its branches. She underwent a left modified orbitozygomatic craniotomy for tumor resection. Early identification of the aberrant ACA anatomy was crucial in avoiding vascular injury. LESSONS: While this variant is typically encountered during the treatment of vascular pathologies-namely, intracranial aneurysms-its existence should be kept in mind during the treatment of any anterior skull base pathology. Failure to account for the presence of this variant may lead to potential intraoperative complications.
ABSTRACT
BACKGROUND: The neutrophil-lymphocyte ratio (NLR) is emerging as an important biomarker of acute physiologic stress in a myriad of medical conditions, and is a confirmed poor prognostic indicator in COVID-19. OBJECTIVE: We sought to describe the role of NLR in predicting poor outcome in COVID-19 patients undergoing mechanical thrombectomy for acute ischemic stroke. METHODS: We analyzed NLR in COVID-19 patients with large vessel occlusion (LVO) strokes enrolled into an international 12-center retrospective study of laboratory-confirmed COVID-19, consecutively admitted between March 1, 2020 and May 1, 2020. Increased NLR was defined as ≥7.2. Logistic regression models were generated. RESULTS: Incidence of LVO stroke was 38/6698 (.57%). Mean age of patients was 62 years (range 27-87), and mortality rate was 30%. Age, sex, and ethnicity were not predictive of mortality. Elevated NLR and poor vessel recanalization (Thrombolysis in Cerebral Infarction (TICI) score of 1 or 2a) synergistically predicted poor outcome (likelihood ratio 11.65, p = .003). Patients with NLR > 7.2 were 6.8 times more likely to die (OR 6.8, CI95% 1.2-38.6, p = .03) and almost 8 times more likely to require prolonged invasive mechanical ventilation (OR 7.8, CI95% 1.2-52.4, p = .03). In a multivariate analysis, NLR > 7.2 predicted poor outcome even when controlling for the effect of low TICI score on poor outcome (NLR p = .043, TICI p = .070). CONCLUSIONS: We show elevated NLR in LVO patients with COVID-19 portends significantly worse outcomes and increased mortality regardless of recanalization status. Severe neuro-inflammatory stress response related to COVID-19 may negate the potential benefits of successful thrombectomy.
Subject(s)
Arterial Occlusive Diseases , Brain Ischemia , COVID-19 , Ischemic Stroke , Stroke , Adult , Aged , Aged, 80 and over , Humans , Middle Aged , Arterial Occlusive Diseases/complications , Brain Ischemia/surgery , Cerebral Infarction/etiology , COVID-19/complications , Ischemic Stroke/etiology , Lymphocytes , Neutrophils , Retrospective Studies , Stroke/etiology , Thrombectomy/methods , Treatment Outcome , Male , FemaleABSTRACT
The sellar and parasellar region of the skull base is an area that can harbor a broad range of pathologic conditions. Formulating a differential diagnosis of a lesion in this region relies heavily on neuroimaging in addition to clinical and laboratory data. In this article, the authors briefly discuss some of the common pathologic conditions and their associated radiographic and clinical features.
Subject(s)
Pituitary Diseases , Pituitary Neoplasms , Diagnosis, Differential , Humans , Magnetic Resonance Imaging/methods , Pituitary Diseases/diagnostic imaging , Pituitary Diseases/pathology , Pituitary Neoplasms/diagnostic imaging , Pituitary Neoplasms/pathology , Sella Turcica/pathologyABSTRACT
Intracranial Rosai-Dorfman disease may be indistinguishable from meningioma. This distinction is essential, as they are treated very differently. We present two cases where perfusion imaging helped make this distinction, allowing one to be treated successfully without craniotomy. Perfusion imaging may be a powerful adjunct in cases where RDD mimics meningioma.
ABSTRACT
A stroke volume of arterial blood that arrives to the brain housed in the rigid cranium must be matched over the cardiac cycle by an equivalent volume of ejected venous blood. We hypothesize that the brain maintains this equilibrium by organizing coherent arterial and venous pulse waves. To test this hypothesis, we applied wavelet computational methods to diagnostic cerebral angiograms in four human patients, permitting the capture and analysis of cardiac frequency phenomena from fluoroscopic images acquired at faster than cardiac rate. We found that the cardiac frequency reciprocal phase of a small region of interest (ROI) in a named artery predicts venous anatomy pixel-wise and that the predicted pixels reconstitute venous bolus passage timing. Likewise, a small ROI in a named vein predicts arterial anatomy and arterial bolus passage timing. The predicted arterial and venous pixel groups maintain phase complementarity across the bolus travel. We thus establish a novel computational method to analyze vascular pulse waves from minimally invasive cerebral angiograms and provide the first direct evidence of arteriovenous coupling in the intact human brain. This phenomenon of arteriovenous coupling may be a physiologic mechanism for how the brain precisely maintains mechanical equilibrium against volume displacement and kinetic energy transfer resulting from cyclical deformations with each heartbeat. The study also paves the way to study deranged arteriovenous coupling as an underappreciated pathophysiologic disturbance in a myriad of neurological pathologies linked by mechanical disequilibrium.
ABSTRACT
BACKGROUND: Posterior fossa surgery is particularly prone to cerebrospinal fluid (CSF) leakage. Several methods have been introduced to address and/or prevent this complication. However, to the best of our knowledge, the use of a vascularized fascial flap based on the occipital artery for the purpose of reconstruction has not been reported. We introduce the occipital fascial flap (OFF) for reconstruction of a craniectomy defect after the retrosigmoid approach. METHODS: A 57-year-old woman with a large cerebellar metastasis underwent gross total resection of the mass followed by reconstruction of the craniectomy defect using OFF. RESULTS: Postoperative imaging showed flap viability and no CSF leak occurred during follow-up. CONCLUSIONS: We report the first use of OFF for reconstruction of a craniectomy defect in a retrosigmoid approach. The vascularized fascial flap in posterior fossa surgery is a potentially helpful technique to reduce the risk of CSF leak in high-risk patients.
Subject(s)
Cerebrospinal Fluid Leak/prevention & control , Fascia , Plastic Surgery Procedures/methods , Skull Base/surgery , Surgical Flaps , Cerebellar Neoplasms/surgery , Cerebrospinal Fluid Leak/etiology , Craniotomy/adverse effects , Female , Humans , Middle AgedABSTRACT
BACKGROUND: While there are reports of acute ischemic stroke (AIS) in coronavirus disease 2019 (COVID-19) patients, the overall incidence of AIS and clinical characteristics of large vessel occlusion (LVO) remain unclear. OBJECTIVE: To attempt to establish incidence of AIS in COVID-19 patients in an international cohort. METHODS: A cross-sectional retrospective, multicenter study of consecutive patients admitted with AIS and COVID-19 was undertaken from March 1 to May 1, 2020 at 12 stroke centers from 4 countries. Out of those 12 centers, 9 centers admitted all types of strokes and data from those were used to calculate the incidence rate of AIS. Three centers exclusively transferred LVO stroke (LVOs) patients and were excluded only for the purposes of calculating the incidence of AIS. Detailed data were collected on consecutive LVOs in hospitalized patients who underwent mechanical thrombectomy (MT) across all 12 centers. RESULTS: Out of 6698 COVID-19 patients admitted to 9 stroke centers, the incidence of stroke was found to be 1.3% (interquartile range [IQR] 0.75%-1.7%). The median age of LVOs patients was 51 yr (IQR 50-75 yr), and in the US centers, African Americans comprised 28% of patients. Out of 66 LVOs, 10 patients (16%) were less than 50 yr of age. Among the LVOs eligible for MT, the average time from symptom onset to presentation was 558 min (IQR 82-695 min). A total of 21 (50%) patients were either discharged to home or discharged to acute rehabilitation facilities. CONCLUSION: LVO was predominant in patients with AIS and COVID-19 across 2 continents, occurring at a significantly younger age and affecting African Americans disproportionately in the USA.
Subject(s)
Brain Ischemia/diagnostic imaging , Brain Ischemia/epidemiology , COVID-19/diagnostic imaging , COVID-19/epidemiology , Ischemic Stroke/diagnostic imaging , Ischemic Stroke/epidemiology , Adult , Aged , Aged, 80 and over , Brain Ischemia/therapy , COVID-19/therapy , Cerebrovascular Disorders/diagnostic imaging , Cerebrovascular Disorders/epidemiology , Cerebrovascular Disorders/therapy , Cohort Studies , Cross-Sectional Studies , Female , Humans , Incidence , Internationality , Ischemic Stroke/therapy , Male , Middle Aged , Retrospective Studies , Thrombectomy/adverse effects , Treatment OutcomeABSTRACT
The contemporary management of projectile head injuries owes much to the lessons neurosurgeons have distilled from their experiences in war. Through early investigation and an increasingly detailed account of wartime clinical experience, neurosurgeons--including the field's early giants--began to gain a greater understanding not only of intracranial missile pathophysiology but also of appropriate management. In this paper, the authors trace the development of the principles of managing intracranial projectile injury from the Crimean War in the 19th century through the Vietnam War to provide a context that frames a summary of today's core management principles.
Subject(s)
Brain Injuries/history , Brain Injuries/surgery , Case Management/history , Military Medicine/history , Neurosurgery/history , Warfare , Craniocerebral Trauma/history , Craniocerebral Trauma/surgery , History, 19th Century , History, 20th Century , Humans , United States , Vietnam Conflict , Wounds, Penetrating/history , Wounds, Penetrating/surgeryABSTRACT
BACKGROUND: The transradial approach (TRA) is frequently used for neurointerventional procedures as it is safer, improves patient comfort, and decreases costs and procedural time in comparison with the transfemoral approach (TFA). Patients with arteria lusoria, or an aberrant right subclavian artery (ARSA), provide a unique challenge for cerebral angiography and interventions when using the TRA. OBJECTIVE: To examine the hypothesis that the extreme angulation encountered while accessing the great vessels from the right TRA could be overcome by reversing the approach to the left distal TRA (dTRA). METHODS: A prospectively maintained database of transradial neurointerventional cases since 2018 was searched. Six cases from 850 were identified, in which the left dTRA was used. Three cases were for patients with an ARSA. For the three cases of interest, patient history, pathology, imaging, and access techniques were reviewed. RESULTS: Two diagnostic cerebral angiography cases and one intervention were successfully performed through a left dTRA. CONCLUSIONS: Proper positioning of the left wrist and familiarity with forming the Simmons catheter can overcome this anatomical challenge. This technique and results further demonstrate that the left distal radial artery is a feasible access site for catheterization of bilateral carotid, left vertebral, and right subclavian arteries for patients with an ARSA.
Subject(s)
Cardiovascular Abnormalities/diagnostic imaging , Cardiovascular Abnormalities/surgery , Cerebral Angiography/methods , Radial Artery/diagnostic imaging , Radial Artery/surgery , Subclavian Artery/abnormalities , Brachiocephalic Trunk/diagnostic imaging , Female , Humans , Male , Middle Aged , Prospective Studies , Subclavian Artery/diagnostic imaging , Subclavian Artery/surgeryABSTRACT
BACKGROUND: Rathke cleft cysts (RCCs) are sellar-based cystic lesions that are often found incidentally but occasionally become symptomatic with significant visual and/or endocrine deficits. The standard of treatment is surgery, but rare cases of multiply recurrent RCCs can be refractory to surgical drainage, leading to significant morbidity. OBJECTIVE: To demonstrate the safety and feasibility of fractionated stereotactic radiotherapy (SRT) as salvage therapy in multiply recurrent RCCs refractory to surgical drainage. METHODS: An IRB-approved retrospective review at a single institution was conducted to identify and describe patients with multiply recurrent RCCs refractory to surgical drainage who underwent SRT. RESULTS: From 1994 to 2015, 6 patients (5 female) who underwent SRT for recurrent RCCs were identified. A total of 4 presented with visual deficits, and 2 presented with endocrine dysfunction and severe headaches prior to their initial drainage. All patients had initial postoperative improvement but then developed multiple, symptomatic recurrences. Median number of surgical drainage procedures prior to radiotherapy was 3. A total of 3 patients underwent LINAC-based SRT, and 3 had proton-based SRT. Treatment doses were 45 Gy over 25 fractions (n = 5) and 50.4 Gy over 28 fractions (n = 1). Median follow-up after radiation therapy was 69 mo (range 24-154 mo). In the follow-up period, stabilization of the RCC was achieved, although 2 patients required additional drainage procedures. Only 1 patient developed new hypothyroidism and hypoadrenalism after SRT. CONCLUSION: In rare cases of multiply recurrent RCCs refractory to repeat surgical drainage, stereotactic fractionated radiation therapy is a safe and effective salvage therapy.
Subject(s)
Brain Neoplasms/radiotherapy , Central Nervous System Cysts/radiotherapy , Neoplasm Recurrence, Local/radiotherapy , Radiosurgery/methods , Salvage Therapy/methods , Aged , Brain Neoplasms/surgery , Central Nervous System Cysts/surgery , Drainage , Female , Humans , Male , Middle Aged , Neoplasm Recurrence, Local/surgery , Retrospective StudiesABSTRACT
BACKGROUND AND IMPORTANCE: Persistent trigeminal artery (PTA) is a rare but important anatomic variant that contributes to trigeminal neuralgia (TN). Microvascular decompression (MVD) of the responsible vessel(s) away from the trigeminal nerve provides the most complete and durable relief from TN. The role and technique of MVD for TN associated with a PTA has not been fully defined in the literature. Furthermore, assessment of PTA anatomy intraoperatively with a microscope is challenging. We report the first 3-dimensional (3D) microscopic video and first intraoperative endoscopic video of a successful MVD of the trigeminal nerve in a patient who suffered TN from a tortuous, compressive PTA. CLINICAL PRESENTATION: A 66-yr-old right-handed female presented with right facial pain in V2 and V3 distributions with a clinical picture of TN. Imaging demonstrated trigeminal nerve compression secondary to a PTA and MVD was performed with a 3D operative microscope and an endoscope. The PTA appeared to compress the nerve directly at the trigeminal porus and also had compressive superior cerebellar artery variant branches. The nerve was decompressed at all points of compression with Teflon pledgets along its entire cisternal length. Postoperatively, she is free with trigeminal pain episodes at 4-mo follow-up. CONCLUSION: In cases of TN associated with a PTA, we recommend decompression along the entire length of the nerve wherever there is compression. Furthermore, we find both the operative microscope and particularly the endoscope useful to assess vascular anatomy intraoperatively.
Subject(s)
Carotid Arteries/abnormalities , Carotid Arteries/surgery , Microvascular Decompression Surgery/methods , Trigeminal Neuralgia/surgery , Aged , Female , Humans , Treatment OutcomeABSTRACT
BACKGROUND: Recurrent atypical and malignant meningiomas have poor outcomes with surgical therapy alone. Neither adjuvant chemotherapy nor postoperative radiation therapy remedies this problem. OBJECTIVE: To evaluate our experience with the treatment of 15 patients treated with I-125 or Cs-131 brachytherapy radiation seeds as an adjuvant in these difficult cases. METHODS: Patients with high-grade recurrent meningioma who underwent resection and intraoperative placement of brachytherapy seeds at our institution from 2002 to 2014 were identified and studied by retrospective chart review. RESULTS: Fifteen patients with median age of 68.8 yr were treated with I-125 (n = 13) or Cs-131 (n = 2) brachytherapy seeds for cases of recurrent, grade II (n = 8), or grade III (n = 7) meningioma at our institution from 2002 to 2014. These lesions originated from a variety of locations including, convexity (3), falcine (3), frontal (2), occipital (1), parietal (2), 2 sphenoid wing (2), and temporal (2), based recurrent meningiomas. Patients had a median of 2 prior open surgical interventions and received local radiation therapy with a median dose of 55 Gy prior to brachytherapy. Survival at 2.5 yr was 56% for grade II and 17% for grade III lesions. Survival was significantly associated with patient age but not tumoral pathology. Forty percent of patients required reoperations for wound complications following brachytherapy. CONCLUSION: Brachytherapy with implantation of permanent radiation seeds provides a viable alternative treatment for recurrent meningioma while carrying a significant clinical risk of wound infection and need for reoperation.
Subject(s)
Brachytherapy/methods , Brain Neoplasms/radiotherapy , Meningioma/radiotherapy , Adult , Aged , Aged, 80 and over , Brain Neoplasms/surgery , Cesium Radioisotopes , Combined Modality Therapy , Female , Follow-Up Studies , Humans , Iodine Radioisotopes , Male , Meningioma/surgery , Middle Aged , Neoplasm Recurrence, Local , Radiotherapy, Adjuvant/methods , Retrospective Studies , Survival Analysis , Treatment OutcomeABSTRACT
OBJECTIVE: Choroid plexus carcinoma (CPC) has been associated with TP53 germline mutations and Li-Fraumeni syndrome (LFS). We describe our finding of a novel germline mutation in the TP53 gene in a family with multiple malignancies and in association with a child presenting with CPC. METHOD: An 8-month-old male presented with seizure-like activity; imaging disclosed a 1.5-cm left ventricular mass confirmed to be CPC intra- and postoperatively. Family history was significant for a half-sister who died of a primary CNS sarcoma and a paternal grandmother negative for BRCA1, BRCA2, MLH1, and MSH2 mutations with multiple (>6) LFS spectrum malignancies. RESULTS: Familial TP53 testing revealed an A-->T substitution at DNA position 13071, creating a deleterious Asn-->Ile substitution at amino acid 131 in exon 5. CONCLUSION: Physicians treating patients with CPC should be attuned to reviewing family history for risk factors suggestive of genetic cancer syndromes such as LFS. These syndromes markedly influence both the patient and family members and may alter postoperative treatment regimens.
Subject(s)
Genes, p53/genetics , Germ-Line Mutation/genetics , Amino Acid Substitution/genetics , Choroid Plexus Neoplasms/diagnosis , Choroid Plexus Neoplasms/genetics , Female , Humans , Infant , Li-Fraumeni Syndrome/diagnosis , Li-Fraumeni Syndrome/genetics , Male , Meningeal Neoplasms/diagnosis , Meningeal Neoplasms/genetics , Pedigree , Sarcoma/diagnosis , Sarcoma/geneticsABSTRACT
The ventricles of the brain remain perhaps the largest anatomic structure in the human body without established primary purpose, even though their existence has been known at least since described by Aristotle. We hypothesize that the ventricles help match a stroke volume of arterial blood that arrives into the rigid cranium with an equivalent volume of ejected venous blood by spatially configuring cerebrospinal fluid (CSF) to act as a low viscosity relay medium for arteriovenous pulse wave (PW) phase coupling. We probe the hypothesis by comparing the spatiotemporal behavior of vascular PW about the ventricular surfaces in piglets to internal observations of ventricle wall motions and adjacent CSF pressure variations in humans. With wavelet brain angiography data obtained from piglets, we map the travel relative to brain pulse motion of arterial and venous PWs over the ventricle surfaces. We find that arterial PWs differ in CF phase from venous PWs over the surfaces of the ventricles consistent with arteriovenous PW phase coupling. We find a spatiotemporal difference in vascular PW phase between the ventral and dorsal ventricular surfaces, with the PWs arriving slightly sooner to the ventral surfaces. In humans undergoing neuroendoscopic surgery for hydrocephalus, we measure directly ventricle wall motions and the adjacent internal CSF pressure variations. We find that CSF pressure peaks slightly earlier in the ventral Third Ventricle than the dorsal Lateral Ventricle. When matched anatomically, the peri-ventricular vascular PW phase distribution in piglets complements the endo-ventricular CSF PW phase distribution in humans. This is consistent with a role for the ventricles in arteriovenous PW coupling and may add a framework for understanding hydrocephalus and other disturbances of intracranial pressure.
Subject(s)
Cerebral Ventricles/metabolism , Cerebrospinal Fluid , Angiography , Animals , Cerebral Ventricles/physiology , Humans , Swine , ViscosityABSTRACT
Purpose: Pituitary adenomas are the second most common primary brain tumor, yet their genetic profiles are incompletely understood.Experimental Design: We performed whole-exome sequencing of 42 pituitary macroadenomas and matched normal DNA. These adenomas included hormonally active and inactive tumors, ones with typical or atypical histology, and ones that were primary or recurrent.Results: We identified mutations, insertions/deletions, and copy-number alterations. Nearly one-third of samples (29%) had chromosome arm-level copy-number alterations across large fractions of the genome. Despite such widespread genomic disruption, these tumors had few focal events, which is unusual among highly disrupted cancers. The other 71% of tumors formed a distinct molecular class, with somatic copy number alterations involving less than 6% of the genome. Among the highly disrupted group, 75% were functional adenomas or atypical null-cell adenomas, whereas 87% of the less-disrupted group were nonfunctional adenomas. We confirmed this association between functional subtype and disruption in a validation dataset of 87 pituitary adenomas. Analysis of previously published expression data from an additional 50 adenomas showed that arm-level alterations significantly impacted transcript levels, and that the disrupted samples were characterized by expression changes associated with poor outcome in other cancers. Arm-level losses of chromosomes 1, 2, 11, and 18 were significantly recurrent. No significantly recurrent mutations were identified, suggesting no genes are altered by exonic mutations across large fractions of pituitary macroadenomas.Conclusions: These data indicate that sporadic pituitary adenomas have distinct copy-number profiles that associate with hormonal and histologic subtypes and influence gene expression. Clin Cancer Res; 23(7); 1841-51. ©2016 AACR.