Long-Term Safety and Efficacy of Transcatheter Microwave and Radiofrequency Denervation in a Chronic Ovine Model.

BACKGROUND: Transcatheter renal denervation (RDN) has had inconsistent efficacy and concerns for durability of denervation. We aimed to investigate long-term safety and efficacy of transcatheter microwave RDN in vivo in normotensive sheep in comparison to conventional radiofrequency ablation. METHODS AND RESULTS: Sheep underwent bilateral RDN, receiving 1 to 2 microwave ablations (maximum power of 80-120 W for 240 s-480 s) and 12 to 16 radiofrequency ablations (180 s-240 s) in the main renal artery in a paired fashion, alternating the side of treatment, euthanized at 2 weeks (acute N=15) or 5.5 months (chronic N=15), and compared with undenervated controls (N=4). Microwave RDN produced substantial circumferential perivascular injury compared with radiofrequency at both 2 weeks [area 239.8 (interquartile range [IQR] 152.0-343.4) mm2 versus 50.1 (IQR, 32.0-74.6) mm2, P <0.001; depth 16.4 (IQR, 13.9-18.9) mm versus 7.5 (IQR, 6.0-8.9) mm P <0.001] and 5.5 months [area 20.0 (IQR, 3.4-31.8) mm2 versus 5.0 (IQR, 1.4-7.3) mm2, P=0.025; depth 5.9 (IQR, 1.9-8.8) mm versus 3.1 (IQR, 1.2-4.1) mm, P=0.005] using mixed models. Renal denervation resulted in significant long-term reductions in viability of renal sympathetic nerves [58.9% reduction with microwave (P=0.01) and 45% reduction with radiofrequency (P=0.017)] and median cortical norepinephrine levels [71% reduction with microwave (P <0.001) and 72.9% reduction with radiofrequency (P <0.001)] at 5.5 months compared with undenervated controls. CONCLUSIONS: Transcatheter microwave RDN produces deep circumferential perivascular ablations without significant arterial injury to provide effective and durable RDN at 5.5 months compared with radiofrequency RDN.

Somatostatin receptor expression and clinical outcome of multilineage pituitary tumours expressing PIT1 and SF1.

The application of transcription factor immunohistochemistry to pituitary neuroendocrine tumour (PitNET) assessment has allowed identification of tumours that do not conform to a single lineage. Multilineage pituitary transcription factor 1 (PIT1) and steroidogenic factor 1 (SF1) PitNETs are a rare and relatively newly described tumour subtype. These tumours express both transcription factors and may also express combinations of hormones corresponding to both lineages. Histological and clinical characteristics can vary, and overall clinical behaviour and prognosis is not known. We describe the clinical outcomes and somatostatin receptor status (SSTR) of a series of nine cases identified from our cohort of pituitary tumours at Westmead Hospital. Eight PitNETs (88.9%) expressed growth hormone and caused acromegaly at presentation. Of the seven macrotumours that caused acromegaly, one had cavernous sinus invasion. The Ki-67 labeling index score ranged from 0.6% to 3.6%. About 88% of tumours that secreted excess growth hormone exhibited strong immunostaining for SSTR 2 and all tumours displayed weak immunoreactivity for SSTR5. In 62.5% of patients with acromegaly, cure was achieved after surgical resection. Somatostatin receptor ligands resulted in clinical remission in cases where medical treatment was initiated. There was no new tumour recurrence or regrowth over an overall mean follow-up period of 62.5 months.

Successful stereoelectroencephalography re-evaluation in epilepsy patients after failed initial subdural grid evaluation.

OBJECTIVE: Epilepsy surgery success is dependent on accurate localization of the epileptogenic zone. Despite the use of invasive EEG using subdural grids and strips, surgical failures can occur. In this series, we explore the utility of a second evaluation with stereoelectroencephalography in patients whose initial invasive evaluation with subdural grid electrodes was unsuccessful in localizing seizure origin. METHODS: We conducted a retrospective review of patients who underwent subdural grid evaluation (SDE) at our center and identified patients who underwent a re-evaluation with stereoelectroencephalography (SEEG). RESULTS: We identified three patients who had both subdural and SEEG electrodes in the region of the identified epileptogenic zone in whom the initial SDE evaluation failed to make the patients seizure-free. Two of these patients underwent a second resection and became seizure-free. SIGNIFICANCE: Stereoelectroencephalography can be useful in the re-evaluation and re-operation of patients who previously had surgical failure using SDE.

What matters for people with brain cancer? Selecting clinical quality indicators for an Australian Brain Cancer Registry.

BACKGROUND: The goal of a clinical quality registry is to deliver immediate gains in survival and quality of life by delivering timely feedback to practitioners, thereby ensuring every patient receives the best existing treatment. We are developing an Australian Brain Cancer Registry (ABCR) to identify, describe, and measure the impact of the variation and gaps in brain cancer care from the time of diagnosis to the end of life. METHODS: To determine a set of clinical quality indicators (CQIs) for the ABCR, a database and internet search were used to identify relevant guidelines, which were then assessed for quality using the AGREE II Global Rating Scale. Potential indicators were extracted from 21 clinical guidelines, ranked using a modified Delphi process completed in 2 rounds by a panel of experts and other stakeholders, and refined by a multidisciplinary Working Group. RESULTS: Nineteen key quality reporting domains were chosen, specified by 57 CQIs detailing the specific inclusion and outcome characteristics to be reported. CONCLUSION: The selected CQIs will form the basis for the ABCR, provide a framework for achievable data collection, and specify best practices for patients and health care providers, with a view to improving care for brain cancer patients. To our knowledge, the systematic and comprehensive approach we have taken is a world first in selecting the reporting specifications for a brain cancer clinical registry.

FISH analysis of brain smears obtained at intraoperative diagnosis - An accurate and fast method to detect 1p/19q-codeletion in gliomas.

The importance of molecular testing of gliomas is highlighted in the 2016 revised 4th edition of the WHO Classification of Tumours of the Central Nervous System, which applies an integrated diagnosis of histological and molecular features. In this classification system, oligodendrogliomas (ODG) are defined as IDH-mutant and 1p/19q-codeleted. Fluorescence in situ hybridization (FISH) analysis of formalin-fixed paraffin-embedded (FFPE) tissue is a standard method of determining 1p/19q-codeletion. However, it has several disadvantages, including requiring lengthy pretreatment, truncation artefact and lack of on-site access in many centers. In an effort to address these issues, we analysed FISH performed on smears obtained at intraoperative frozen section on 51 gliomas and compared this to FISH performed on subsequent FFPE sections. Four cases were excluded due to uninterpretable FISH results. Of the remaining 47 cases, 17 were concordant for 1p/19q-codeletion, 29 were concordant for lack of 1p/19q-codeletion, and 1 was discordant with 1p/19q-codeletion found on FFPE tissue but not on intraoperative smears. The discordant case was most likely due to sampling error, as the frozen section had not shown definite tumor. The FISH results on intraoperative smears were received within 24-48 h after the sample was collected, compared with 3-4 days for FFPE tissue. FISH on smears obtained at intraoperative frozen section is an accurate and fast method for determining 1p/19q-codeletion.

New onset headache caused by histiocytic sarcoma of the spinal cord and leptomeninges: a case report.

BACKGROUND: Headache due to raised intracranial pressure is rarely caused by spinal lesions. We describe a patient with primary histiocytic sarcoma who presented with a new onset headache with features of raised intracranial pressure and subtle signs of cauda equina syndrome due to predominant lower spinal cord infiltration and minimal intracranial involvement. CASE: A previously well 54-year-old man presented with a 2-month history of new onset headache with features of raised intracranial pressure. Progression of lower limb weakness was delayed and mild with diagnostic delay resulting from the primary presentation with headache leading to an initial focus on cerebral pathology. Subsequent investigations revealed a previously unreported presentation of primary histiocytic sarcoma infiltrating the cauda equina causing raised intracranial pressure headache. CONCLUSION: This case highlights the importance of a broad search in the investigation of new onset raised intracranial pressure headache, including imaging of the lower spinal cord. Primary histiocytic sarcoma should be considered in the differential diagnosis of this rare syndrome.

Relationship between PD-L1 expression and outcome in EGFR-mutant lung cancer patients treated with EGFR tyrosine kinase inhibitors.

OBJECTIVES: Predictive biomarkers for poor response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is an area of ongoing research. This multicentre retrospective study sought to determine the impact of programmed death-ligand 1 (PD-L1) tumour proportional score (TPS) on outcome in EGFR TKI treated patients. MATERIALS AND METHODS: Patients with Stage IIIB/IV lung adenocarcinoma harbouring a sensitising EGFR mutation treated with first-line TKI at five metropolitan hospitals were included. PD-L1 TPS was determined using the Ventana anti-PD-L1 (SP263) assay. High PD-L1 expression was defined as TPS ≥ 50 %. Determinants of progression and survival hazards were modelled using Cox regression. RESULTS: A total of 186 patients were included. Mean age was 67 years, 66 % were female and 54 % were Asian. Patients with high PD-L1 expression (n = 23; 12 %) had significantly shorter progression free survival (6.6 vs 13.0 months, hazard ratio (HR) 2.6 95 % CI 1.6-4.2, p < 0.0001) and overall survival (11.5 vs 32.9 months, HR 3.3, 95 % CI 1.9-5.7, p < 0.0001) compared to patients with PD-L1 low/negative tumours. This remained significant in multivariate analyses. High PD-L1 in post-TKI progression biopsies was not associated with poorer survival. CONCLUSION: In this large, real-world cohort of EGFR-mutant lung adenocarcinoma patients, high PD-L1 expression was associated with early resistance to 1st generation EGFR TKIs and shorter survival, regardless of ethnicity.

Ectopic insulin secretion by a large-cell neuroendocrine carcinoma of the cervix.

In patients presenting with hyperinsulinemic hypoglycemia with a nonpancreatic neuroendocrine tumor, the diagnosis of an ectopic insulin-secreting tumor should be considered, and investigated further with confirmatory insulin staining.

Transvascular Pacing of Aorticorenal Ganglia Provides a Testable Procedural Endpoint for Renal Artery Denervation.

OBJECTIVES: This study sought to develop a method to assess renal sympathetic nerve function through localization and pacing of aorticorenal ganglia (ARG). BACKGROUND: Transcatheter renal denervation procedures often fail to produce complete renal denervation because of the lack of a physiological procedural endpoint. METHODS: High-frequency pacing was performed in the inferior vena cava and aorta in sheep (n = 19) to identify ARG pace-capture sites. Group A (n = 5) underwent injection at the ARG pace-capture site for histological verification, group B (n = 6) underwent unilateral irrigated radiofrequency ablation of ARG pace-capture sites and assessment of renal innervation at 1 week post-procedure; and group C (n = 8) underwent ARG pacing before and 2 to 3 weeks after unilateral microwave renal denervation. RESULTS: ARG pace-capture responses were observed at paired discrete sites above the ipsilateral renal artery eliciting a change in mean arterial blood pressure of 22.2 (interquartile range [IQR]: 15.5 to 34.3 mm Hg; p < 0.001) with concurrent ipsilateral renal arterial vasoconstriction, change in main renal artery diameter of -0.42 mm (IQR: -0.64 to -0.24 mm; p < 0.0001), and without consistent contralateral renal vasoconstriction. Sympathetic ganglionic tissue was observed at ARG pace-capture sites, and ganglion ablation led to significant ipsilateral renal denervation. Circumferential renal denervation resulted in immediate and sustained abolition of ARP pacing-induced renal vasoconstriction and significant ipsilateral renal denervation. CONCLUSIONS: Transvascular ARG pace-capture is feasible and recognized by concurrent hypertensive and ipsilateral renal arterial vasoconstrictive responses. Abolition of ARG pacing-induced vasoconstriction may indicate successful renal sympathetic denervation and serve as a physiological procedural endpoint to guide transcatheter renal denervation.

Transcatheter microwave ablation can deliver deep and circumferential perivascular nerve injury without significant arterial injury to provide effective renal denervation.

BACKGROUND: Clinical studies of transcatheter radiofrequency renal denervation for treating hypertension have been hampered by the lack of consistent denervation efficacy. We aimed to demonstrate the short-term efficacy and safety of transcatheter microwave renal denervation. METHODS: A novel 7F microwave system was validated in a sheep model of unilateral renal denervation. Up to two microwave ablations were delivered to each artery with maximum power at 100-110 W for 480 s. RESULTS: Catheter deployment and ablation was successful in all 19 targeted vessel segments, and ablation produced substantial circumferential perivascular injury; median ablation lesion area greater than 395 [interquartile range (IQR) 251-437] mm, depth 17.1 (IQR 15.8-18.4) mm, length 16 (IQR 12-20) mm, without collateral visceral injury. Limiting power to 100 W minimized arterial injury, while maintaining a deep circumferential perivascular ablation. Microwave denervation reduced median functional sympathetic nerve surface area at the renal hilum on antityrosine hydroxylase staining by 100% (IQR 87-100%, P = 0.0039), and median renal cortical norepinephrine content by 83% (IQR 76-92%, P = 0.0078), compared to the paired control kidney at 2-3 weeks postprocedure. CONCLUSION: Transcatheter microwave ablation can produce deep circumferential perivascular ablations over a long segment of the renal artery without significant arterial or collateral visceral injury to provide effective renal denervation.

Cut-point for Ki-67 proliferation index as a prognostic marker for glioblastoma.

INTRODUCTION: Ki-67 proliferation index (Ki-67 index) is used to quantify cell proliferation during histopathological assessment of various tumors including glioblastoma (GB). AIM: We aimed to assess correlation between Ki-67 index and overall survival in patients with GB and determine a cut-point for Ki-67 index that predicts for poorer survival. METHOD: Records of adult patients diagnosed with GB on histopathological specimens at a tertiary cancer center in Sydney between 1 January 2002 and 30 July 2012 were retrieved. Specimens of these patients were examined for quantification of Ki-67 staining by two independent pathologists. Patient, disease, treatment, and survival data were collected from hospital and cancer care service records. Statistical analysis was performed using proportional hazards models, Kaplan-Meier curves, and the minimum P-value approach. RESULT: Of the eligible 71 patients, 58% were males with median age of 58 (range 18-87). Seventy-three percent of patients were of ECOG performance status 0-1. There was a statistically significant correlation between Ki-67 index and overall survival. In patients with Ki-67 > 22% (n = 36), 5-year survival was approximately 30% compared to 5% in those with Ki-67 ≤ 22% (n = 35; log-rank P-value = 0.04; hazard ratio (HR) = 0.53; 95% confidence intervals (CI), 0.29-0.97). CONCLUSION: This study demonstrates a positive correlation between Ki-67 index and overall survival in patients with GB. Percentage staining of Ki-67 < 22% appears to predict for poorer survival in GB.

Cryoglobulinemic Glomerulonephritis Associated With Nodal and Renal Infiltration by T-Cell Lymphoma of T-Follicular Helper Phenotype: A Case Report.

We present a unique case of cryoglobulinemic glomerulonephritis associated with nodal and renal infiltration by T-cell lymphoma of T-follicular helper phenotype. The patient presented with transient neurologic symptoms, severe nephritic syndrome with nephrotic-range proteinuria, and acute kidney injury. He had elevated double-stranded DNA levels, low complement levels, detectable cryoglobulin, and detectable immunoglobulin M (IgM) paraprotein. The kidney biopsy showed cryoglobulinemic glomerulonephritis with a membranoproliferative pattern and diffuse interstitial infiltrates on light microscopy; IgM, C3 but weak IgG, C1q, and negative C4d staining on immunofluorescence; and deposits with organized substructures on electron microscopy. Positron emission tomography showed diffuse uptake in bilaterally enlarged kidneys and a localized group of lymph nodes. Subsequent lymph node biopsy revealed Epstein-Barr virus-negative nodal T-cell lymphoma, which was also proven in renal tissue. The association between T-cell lymphoma, autoantibodies, and cryoglobulinemia may represent a paraneoplastic phenomenon. His renal prognosis has been excellent, but overall prognosis and survival is dictated by the clinical course of T-cell lymphoma.

The value of endomyocardial biopsy in diagnosis and guiding therapy.

Endomyocardial biopsy (EMB) is a highly-specialised procedure that is associated with some controversy as to its diagnostic role due to its inconsistency in diagnosing a wide variety of cardiac diseases. Given the advances and sophistication in echocardiography and cardiac magnetic resonance imaging (MRI), the vast majority of cardiac diseases can be diagnosed by these non-invasive procedures. Under-sampling and the fact that biopsy site is limited to the right side of the interventricular septum further limits its value. In spite of all these limitations, there still remains a group of pathological conditions that require biopsy for a conclusive diagnosis such as myocarditis, amyloidosis, sarcoidosis and giant cell myocarditis. Correct patient selection and the quantity of tissue samples impart a significant influence on the accuracy of the diagnosis, and thus the value of EMB is variable for each patient. The purpose of this study was to evaluate the role of EMB in patient care, through its ability to either change clinical diagnosis or alter patient management. Our study was based in a single teaching centre. An audit of cardiac biopsies performed over a 10 year period identified 250 patients. We assessed indications, histology, electron microscopic findings, final clinical diagnosis and how they influenced patient management. A definite diagnosis on histology was given in 44 of 250 patients (17.6%). Non-specific findings were observed in the remaining 206 patients (82.4%). Histology influenced patient management in 73 (29.2%) patients. Histological examination in the remaining 177 biopsies (70.8%) did not provide a definite diagnosis or influence patient management. It was additionally found that the number of tissue fragments sampled has significant impact on diagnostic accuracy. A more accurate diagnosis of 45% was obtained when ≥5 fragments were sampled, as compared to 1-3 fragments where accuracy dropped to 20%. Our study indicated that sampling for electron microscopy has very limited value. We found that of 245 biopsies sampled for electron microscopy, only three biopsies (1.2%) had diagnostically useful findings. In our institution procedure related complications were observed in 7 of 250 patients (2.8%). The diagnostic value of EMB is important but limited. Strict triaging of patients according to clinical suspicion and adequate sampling of tissue may increase useful diagnostic information.

Transcatheter non-contact microwave ablation may enable circumferential renal artery denervation while sparing the vessel intima and media.

AIMS: Trials of transcatheter renal artery denervation (RDN) have failed to show consistent antihypertensive efficacy. Procedural factors and limitations of radiofrequency ablation can lead to incomplete denervation. The aim of the study was to show that non-contact microwave catheter ablation could produce deep circumferential perivascular heating while avoiding injury to the renal artery intima and media. METHODS AND RESULTS: A novel microwave catheter was designed and tested in a renal artery model consisting of layers of phantom materials embedded with a thermochromic liquid crystal sheet, colour range 50-78°C. Ablations were performed at 140 W for 180 sec and 120 W for 210 sec, delivering 25,200 J with renal arterial flow at 0.5 L/min and 0.1 L/min. Transcatheter microwave ablations 100-160 W for 180 sec were then performed in the renal arteries of five sheep. In vitro, ablations at 140 W and 0.5 L/min flow produced circumferential lesions 5.9±0.2 mm deep and 19.2±1.5 mm long with subendothelial sparing depth of 1.0±0.1 mm. In vivo, transcatheter microwave ablation was feasible with no collateral visceral thermal injury. There was histological evidence of preferential outer media and adventitial ablation. CONCLUSIONS: Transcatheter microwave ablation for RDN appears feasible and provides a heating pattern that may enable more complete denervation while sparing the renal arterial intima and media.

Clinical presentation and surgical outcomes of an intramedullary C2 spinal cord cavernoma: a case report and review of the relevant literature.

BACKGROUND: The spinal cord intramedullary cavernoma (SCIC) is a rare form of hemangioma that typically behaves as a space-occupying lesion resulting in neurological symptoms, including bladder and bowel dysfunction. To date, there have been few reports characterizing the clinical presentations and surgical outcomes of cavernomas at the C2 spinal level or the potential for resolution of bladder and bowel symptoms postoperatively. This case details the clinical course of a patient with a C2 cavernoma with an atypical neurological presentation and rapid improvement in both bladder and bowel function postoperatively. This case reviews the relevant literature and describes the patient's clinical presentation, radiological and pathological findings and post-surgical progress. METHODS: A 56-year-old male presented with sensory changes in his right hand, which rapidly progressed over ensuing weeks to bilateral sensory changes in the upper and lower limbs, gait imbalance, urinary and faecal incontinence and loss of temperature perception. He subsequently developed significant weakness in the upper limbs. A MRI identified a hematoma in the cervical cord at the C2 level. Given his rapid neurological decline and the social and clinical implications of his bladder and bowel instability, a surgical approach to therapy was adopted. RESULTS: Postoperatively, there was steady improvement in motor and sensory function and a complete return of bladder and bowel function. CONCLUSIONS: Intramedullary spinal cord cavernomas, although rare, can cause significant neurological deficits and morbidity. Surgical excision can provide significant benefits, including restoration of bladder and bowel function.

Neuroendocrine Adenoma of the Middle Ear: A Rare Histopathological Diagnosis.

Neuroendocrine tumours occur throughout the body but are rare in the head and neck region and particularly rare in the middle ear. Clinical findings are often nonspecific and therefore pose a diagnostic challenge. Furthermore, the nomenclature of neuroendocrine tumours of the middle ear is historically controversial. Herein a case is presented of a middle ear adenoma in a 33-year-old patient who presented with otalgia, hearing loss, and facial nerve palsy. A brief discussion is included regarding the histopathological features of middle ear adenomas and seeks to clarify the correct nomenclature for these tumours.