Alzheimer's disease CSF biomarkers correlate with early pathology and alterations in neuronal and glial gene expression.

INTRODUCTION: Normal pressure hydrocephalus (NPH) patients undergoing cortical shunting frequently show early Alzheimer's disease (AD) pathology on cortical biopsy, which is predictive of progression to clinical AD. The objective of this study was to use samples from this cohort to identify cerebrospinal fluid  (CSF) biomarkers for AD-related central nervous system (CNS) pathophysiologic changes using tissue and fluids with early pathology, free of post mortem artifact. METHODS: We analyzed Simoa, proteomic, and metabolomic CSF data from 81 patients with previously documented pathologic and transcriptomic changes. RESULTS: AD pathology on biopsy correlates with CSF ß-amyloid-42/40, neurofilament light chain (NfL), and phospho-tau-181(p-tau181)/ß-amyloid-42, while several gene expression modules correlate with NfL. Proteomic analysis highlights seven core proteins that correlate with pathology and gene expression changes on biopsy, and metabolomic analysis of CSF identifies disease-relevant groups that correlate with biopsy data. DISCUSSION: As additional biomarkers are added to AD diagnostic panels, our work provides insight into the CNS pathophysiology these markers are tracking. HIGHLIGHTS: AD CSF biomarkers correlate with CNS pathology and transcriptomic changes. Seven proteins correlate with CNS pathology and gene expression changes. Inflammatory and neuronal gene expression changes correlate with YKL-40 and NPTXR, respectively. CSF metabolomic analysis identifies pathways that correlate with biopsy data. Fatty acid metabolic pathways correlate with ß-amyloid pathology.

Alzheimer's disease CSF biomarkers correlate with early pathology and alterations in neuronal and glial gene expression.

INTRODUCTION: Normal pressure hydrocephalus (NPH) patients undergoing cortical shunting frequently show early AD pathology on cortical biopsy, which is predictive of progression to clinical AD. The objective of this study was to use samples from this cohort to identify CSF biomarkers for AD-related CNS pathophysiologic changes using tissue and fluids with early pathology, free of post-mortem artifact. METHODS: We analyzed Simoa, proteomic, and metabolomic CSF data from 81 patients with previously documented pathologic and transcriptomic changes. RESULTS: AD pathology on biopsy correlates with CSF ß-amyloid-40/42, neurofilament light chain (NfL), and phospho-tau-181(p-tau181)/ß-amyloid-42, while several gene expression modules correlate with NfL. Proteomic analysis highlights 7 core proteins that correlate with pathology and gene expression changes on biopsy, and metabolomic analysis of CSF identifies disease-relevant groups that correlate with biopsy data.. DISCUSSION: As additional biomarkers are added to AD diagnostic panels, our work provides insight into the CNS pathophysiology these markers are tracking.

Chronic convection-enhanced delivery of topotecan for patients with recurrent glioblastoma: a first-in-patient, single-centre, single-arm, phase 1b trial.

BACKGROUND: Topotecan is cytotoxic to glioma cells but is clinically ineffective because of drug delivery limitations. Systemic delivery is limited by toxicity and insufficient brain penetrance, and, to date, convection-enhanced delivery (CED) has been restricted to a single treatment of restricted duration. To address this problem, we engineered a subcutaneously implanted catheter-pump system capable of repeated, chronic (prolonged, pulsatile) CED of topotecan into the brain and tested its safety and biological effects in patients with recurrent glioblastoma. METHODS: We did a single-centre, open-label, single-arm, phase 1b clinical trial at Columbia University Irving Medical Center (New York, NY, USA). Eligible patients were at least 18 years of age with solitary, histologically confirmed recurrent glioblastoma showing radiographic progression after surgery, radiotherapy, and chemotherapy, and a Karnofsky Performance Status of at least 70. Five patients had catheters stereotactically implanted into the glioma-infiltrated peritumoural brain and connected to subcutaneously implanted pumps that infused 146 µM topotecan 200 µL/h for 48 h, followed by a 5-7-day washout period before the next infusion, with four total infusions. After the fourth infusion, the pump was removed and the tumour was resected. The primary endpoint of the study was safety of the treatment regimen as defined by presence of serious adverse events. Analyses were done in all treated patients. The trial is closed, and is registered with ClinicalTrials.gov, NCT03154996. FINDINGS: Between Jan 22, 2018, and July 8, 2019, chronic CED of topotecan was successfully completed safely in all five patients, and was well tolerated without substantial complications. The only grade 3 adverse event related to treatment was intraoperative supplemental motor area syndrome (one [20%] of five patients in the treatment group), and there were no grade 4 adverse events. Other serious adverse events were related to surgical resection and not the study treatment. Median follow-up was 12 months (IQR 10-17) from pump explant. Post-treatment tissue analysis showed that topotecan significantly reduced proliferating tumour cells in all five patients. INTERPRETATION: In this small patient cohort, we showed that chronic CED of topotecan is a potentially safe and active therapy for recurrent glioblastoma. Our analysis provided a unique tissue-based assessment of treatment response without the need for large patient numbers. This novel delivery of topotecan overcomes limitations in delivery and treatment response assessment for patients with glioblastoma and could be applicable for other anti-glioma drugs or other CNS diseases. Further studies are warranted to determine the effect of this drug delivery approach on clinical outcomes. FUNDING: US National Institutes of Health, The William Rhodes and Louise Tilzer Rhodes Center for Glioblastoma, the Michael Weiner Glioblastoma Research Into Treatment Fund, the Gary and Yael Fegel Foundation, and The Khatib Foundation.

The Sledgehammer in Precision Medicine: Dexamethasone and Immunotherapeutic Treatment of Glioma.

Understanding dexamethasone's effect on the immune microenvironment in glioma patients is of key importance. We performed a comprehensive literature review using the NCBI PubMed database for all articles meeting the following search criteria. ((dexamethasone[All Fields]) AND (glioma or glioblastoma)[Title/Abstract]) AND (immune or T cell or B cell or monocyte or neutrophil or macrophage). Forty-three manuscripts were deemed relevant to the topic at hand. Multiple clinical studies have linked dexamethasone use to decreased overall survival while preclinical studies in murine glioma models have demonstrated decreased tumor-infiltrating lymphocytes after dexamethasone administration.

Convection Enhanced Delivery of Topotecan for Gliomas: A Single-Center Experience.

A key limitation to glioma treatment involves the blood brain barrier (BBB). Convection enhanced delivery (CED) is a technique that uses a catheter placed directly into the brain parenchyma to infuse treatments using a pressure gradient. In this manuscript, we describe the physical principles behind CED along with the common pitfalls and methods for optimizing convection. Finally, we highlight our institutional experience using topotecan CED for the treatment of malignant glioma.

Impact of venous thromboembolism during admission for meningioma surgery on hospital charges and postoperative complications.

Surgical resection of meningiomas has been associated with high rates of venous thromboembolic events (VTE) as compared with all other intracranial tumors. There is a paucity of data regarding the clinical complications and comorbidities associated with this cohort yet the underlying pathophysiological mechanism for this tumor-specific finding remains unclear. Our goal was to determine the various impacts of VTE on meningioma surgery in a large cohort of inpatient admissions. This retrospective analysis utilized discharge data from the National Inpatient Sample (NIS) from 2002 to 2010. Patient demographics, comorbidities, length of stay, hospital charges, and postoperative complications were compared between patients with and without VTE. Of 20,259 patients, 426 (2.1%) experienced a VTE. Compared to the non-VTE cohort, patients that experienced a VTE were older (62.7 ±â€¯13.7 vs. 57.2 ±â€¯14.7; p < 0.001), were more commonly male (38.0% vs 30.1%; p = 0.001), had longer hospitalizations (18.8 vs 6.6 days; p < 0.001), and incurred significantly greater hospital charges ($195,837 vs $74,434; p < 0.001). VTE patients experienced significantly higher rates of acute postoperative complications including shock, hemorrhage, wound dehiscence, infection, intracerebral hemorrhage, hemiparesis/hemiplegia, stroke, and death during admission. Odds ratio of aforementioned postsurgical complications remained significantly higher both before and after adjusting for age and sex (all p < 0.01). Occurrence of VTE in patients undergoing meningioma resection portends greater hospital charges, most likely attributed to longer lengths of admission. Increased postoperative complications and mortality in the VTE group warrants further investigation and wariness of the surgeon when treating surgical candidates of meningioma.

Laryngeal Verrucous Carcinoma.

Objective Laryngeal verrucous carcinoma (LVC) is a rare, locally invasive neoplasm comprising 1% to 3.4% of laryngeal carcinomas. Management strategies are a topic of ongoing conversation, and no definitive treatment protocol based on T stage and presentation exists. This review examines characteristics, treatment modalities, and patient outcomes of LVC. Data Sources PubMed, MEDLINE, EMBASE, and Web of Science. Methods Databases were searched through October 29, 2015, for literature detailing individual patient cases of LVC. Variables analyzed included patient demographics, tumor characteristics, tumor size, treatment, and outcomes. Results Thirty-seven articles with 369 cases were included. LVC was found more commonly in males (13.8:1), at an average age of 58.7 years, and located in the glottis (74.0%). Most patients had local disease at presentation (94.9%). The most common presenting symptom was hoarseness (92.3%). The most common primary treatment was surgery alone (72.3%), with local excision as the most common technique (56.8%). In patients with data available on both surgical modality and T stage, most patients who presented as T1 and were managed surgically underwent local excision (79.2%). Surgical treatment alone led to high rates of disease-free survival at follow-up (86.8%). A large number of patients presenting with T1 disease were disease free at follow-up (88.6%). Overall survival was 80.3%. Conclusion LVC is most often managed surgically. The extent of surgical resection may be guided by T stage, with smaller tumors resected via local excision and larger tumors via partial or total laryngectomy. Regardless of T stage or therapy, LVC has a good posttreatment prognosis.

Laryngeal adenocarcinoma not otherwise specified: A population-based perspective.

OBJECTIVES/HYPOTHESIS: Laryngeal adenocarcinoma not otherwise specified (LAdC NOS) is a category to which variants of minor salivary gland tumors of the larynx that do not fit other well-characterized histological subtypes are assigned. Its rare nature and inconsistency in available reports has hindered the investigation and further understanding of this malignancy. In this study, a national population-based resource was used to evaluate the epidemiology and survival of this rare entity. STUDY DESIGN: Retrospective population-based analysis. METHODS: The Surveillance, Epidemiology, and End Results database was searched for patients diagnosed with LAdC NOS between 1973 and 2012. Patient demographics, tumor location, TNM stage, grade, incidence, and survival trends were collected and analyzed. RESULTS: One hundred eleven patients met criteria for diagnosis of LAdC NOS, of which the majority were male (80.2%), white (84.7%), with a mean age of 65 years. The supraglottis was the most common site at presentation (38.7%). The majority presented with grade II tumor (45.7%). TNM staging revealed T2 (36.8%), N0 (72.2%), and M0 (88.9%) to be the most common classification. The overall incidence between the years of 2000 and 2012 was 0.008/100,000 individuals. The overall 5-year disease-specific survival (DSS) was 60.1%, compared to 85.7% in patients treated with combination surgery and radiotherapy. CONCLUSIONS: LAdC NOS is an uncommon malignancy. It most commonly affects men in their mid-60s, indiscriminate of race. Lesions most commonly present in the supraglottis and are more often low grade histologically. DSS is highest in patient treated with combination surgery and radiotherapy. LEVEL OF EVIDENCE: 4 Laryngoscope, 2016 127:424-429, 2017.

Impact of Diabetes Mellitus on Head and Neck Cancer Patients Undergoing Surgery.

OBJECTIVE: The impact of diabetes mellitus (DM) on surgical outcomes and cost of care for patients undergoing surgery for head and neck cancer (HNCA) is not well established. We used the Nationwide Inpatient Sample to analyze the postoperative impact of DM on HNCA patients. STUDY DESIGN: Population-based inpatient registry analysis. SETTING: Academic medical center. SUBJECTS AND METHODS: Discharge data from the Nationwide Inpatient Sample were analyzed for patients undergoing HNCA surgery from 2002 to 2010. Patient demographics, comorbidities, length of stay, hospital charges, and postoperative complications were compared between HNCA patients with and without DM. RESULTS: Of 31,075 patients, 4029 patients (13.0%) had a DM diagnosis. DM patients were older (65.7 ± 10.8 vs 61.1 ± 14.1 years old; P < .001), had more preexisting comorbidities, had longer hospitalizations, and incurred greater hospital charges. Compared with the non-DM cohort, DM patients experienced significantly higher rates of postoperative infections (2.6% vs 2.1%, P = .025), cardiac events (9.0% vs 4.3%, P < .001), pulmonary edema/failure (6.6% vs 5.7%, P = .023), acute renal failure (3.3% vs 1.5%, P < .001), and urinary tract infections (2.8 % vs 2.1%, P = .005). No differences in surgical wound healing rates were observed (0.1 vs 0.1, P = .794). On multivariate logistic regression corrected for age and race, DM patients had greater odds of postoperative infections (1.382, P = .007), cardiac events (1.893, P < .001), and acute renal failure (2.023, P < .001). CONCLUSIONS: DM is associated with greater length of stay and hospital charges among HNCA patients. DM patients have significantly greater rates of postoperative complications, including postoperative infections, cardiac events, and acute renal failure.

Lateral skull base Inflammatory pseudotumor: A systematic review.

OBJECTIVE: Inflammatory pseudotumor (IPT) of the lateral skull base is a rare nonneoplastic inflammatory process of unknown cause often mistaken for malignancy or infection. This systematic review aims to analyze all reported cases of lateral skull base IPT to date in order to provide insight into the management of this uncommon lesion. DATA SOURCES: MEDLINE/PubMed database. REVIEW METHODS: The MEDLINE/PubMed databases were searched for articles related to lateral skull base IPT. A bibliography review of the search results was then performed for additional articles. Demographics, presentation, radiographic findings, treatment, follow-up, and outcome were analyzed. RESULTS: Thirty articles describing 39 patients were reviewed. The most common presenting symptom was hearing loss (53.8%). The mastoid bone had the highest incidence of IPT (61.5%). Computed tomography (CT) was the most utilized imaging modality. The lesion appeared isointense on T1-weighted magnetic resonance imaging (MRI) (75.0%) and hypointense on T2-weighted MRI (62.5%). Histopathological analysis showed fibrosis (96.9%) with inflammatory cell infiltration (100.0%). Surgical resection (alone or in combination with other treatments) was the most common treatment modality (92.3%), producing the greatest number of disease-free patients overall (96.0%). The mean follow-up time was 21.6 months, at which point 34.4% of patients showed improvement and 31.3% were completely disease-free. CONCLUSION: This review is the most comprehensive analysis of lateral skull base IPT to date. A thorough workup including clinical exam, imaging, and biopsy is essential for diagnosis. Surgical excision is the most common and most successful treatment modality, followed by surgery with corticosteroids.

Impact and cost of care of venous thromboembolism following pituitary surgery.

OBJECTIVES/HYPOTHESIS: In 2008, the Centers for Medicare and Medicaid Services discontinued reimbursement for postoperative venous thromboembolism (VTE) events such as deep venous thrombosis and pulmonary embolism, citing them as preventable postoperative complications. We examined the impact of postoperative VTE on patients undergoing pituitary surgery. METHODS: The Nationwide Inpatient Sample (NIS) was evaluated for patients undergoing pituitary resection from 2002 to 2010. Patient demographics, comorbidities, length of stay, hospital charges, and postoperative complications were analyzed. RESULTS: Eighty-seven patients who underwent pituitary surgery developed a VTE. Patients who underwent pituitary surgery that developed VTE were older (55.9 ± 15.2 years) than those who did not develop VTE (50.1 ± 17.2 years) (P = 0.002). VTE occurred at a significantly higher rate in patients with coagulopathy, peripheral vascular disorder, and weight loss (P < 0.05). VTE was associated with increased rates of postoperative neurological, pulmonary, cardiac, urinary, renal, hemorrhage, fluid and electrolytes, diabetes insipidus, and cerebrospinal fluid rhinorrhea complications (P < 0.01)-as well as increased mortality rate (P < 0.001), length of stay (P < 0.001), and cost of care (P < 0.001). CONCLUSIONS: Analysis of the data from the NIS database showed that risk factors for the development of VTE following pituitary surgery include older age, preexisting coagulopathy, peripheral vascular disorder, and weight loss. Patients who developed postoperative VTE had a longer length of hospital stay, higher hospital charges, and increased morbidity and mortality.

Sinonasal and ventral skull base inflammatory pseudotumor: a systematic review.

OBJECTIVES/HYPOTHESIS: Inflammatory pseudotumor is a benign idiopathic inflammatory process often misdiagnosed as an infection or neoplasm. This review analyzes all reported cases of sinonasal and ventral skull base inflammatory pseudotumor to date, and provides a framework for evaluation and management of this uncommon condition. DATA SOURCES: MEDLINE/PubMed database. REVIEW METHODS: A search for articles related to sinonasal and ventral skull base inflammatory pseudotumor, along with bibliographies of those articles, was performed. Demographics, presentation, radiographic findings, treatment, follow-up, and outcome were analyzed. RESULTS: Thirty-three articles were reviewed, including a total of 87 patients. The most common presenting symptom was vision change (58.6%). Sinonasal and ventral skull base inflammatory pseudotumor was found in the cavernous sinus in 46.0% of cases. The lesion appeared isointense (66.7% of cases) and homogeneously enhancing on T1-weighted magnetic resonance imaging (MRI), whereas it appeared hypointense on T2-weighted MRI in 90.7% of cases. Inflammatory pseudotumor appeared hyperdense on computed tomography in 78.9% of cases. Histopathological analysis of biopsied specimens revealed presence of inflammatory cells (94.4%) and fibrosis (80.3%). Corticosteroids alone were the most common treatment modality (55.2%), resulting in disease-free patients in 22.9% of cases over a median follow-up period of 17.6 months. Surgical management alone was uncommon (8.0%), but showed high success rate (57.1%). CONCLUSION: This review is the most comprehensive analysis of sinonasal and ventral skull base inflammatory pseudotumor to date. Radiologic findings and histopathological analysis are essential for diagnosis. Corticosteroids are the most common treatment modality. Surgery, although uncommon, appears to be an efficacious treatment modality.