Factors associated with longer survival among older medicare patients after diagnosis of supratentorial primary brain malignancies: a retrospective cohort study.

OBJECTIVES: Despite recent advances, the prognosis for primary malignant brain tumors (PMBTs) remains poor. Some commonly prescribed medications may exhibit anti-tumor properties in various cancers, and neurodegenerative diseases may activate pathways that counteract gliomagenesis. Our study is focused on determining if there is a correlation between the use of metformin, beta-blockers, angiotensin converting enzyme inhibitors (ACEIs), and angiotensin receptor blockers (ARBs), or the presence of Parkinson's disease (PD), and the survival rates following a diagnosis of a PMBT. METHODS: This analysis of the 100% Texas Medicare Database identified patients aged 66+ years diagnosed with a supratentorial PMBT from 2014-2017. Cox proportional hazards regression was employed to analyze survival following diagnosis and associations of survival with surgical intervention, radiation, PD diagnosis, and prescription of metformin, beta-blockers, ACEIs, or ARBs. RESULTS: There were 1,943 patients who met study criteria, and the median age was 74 years. When medication utilization was stratified by none, pre-diagnosis only, post-diagnosis only, or both pre- and post-diagnosis (continuous), continuous utilization of metformin, beta-blockers, ACEIs, or ARBs was associated with prolonged survival compared to no utilization (hazard ratio [HR]:0.45, 95% CI:0.33-0.62; HR:0.71. 95% CI:0.59-0.86; HR:0.59, 95% CI:0.48-0.72; and HR:0.45, 95% CI:0.35-0.58 respectively). PD was also associated with longer survival (HR:0.59-0.63 across the four models). DISCUSSION: Our study suggests that metformin, beta-blockers, ACEIs, ARBs, and comorbid PD are associated with a survival benefit among geriatric Medicare patients with supratentorial PMBTs.

Neurosurgery at Baylor Scott & White Health: Recent History and a Decade of Neurosurgery Residency Training.

Neurosurgery at Baylor Scott & White Memorial Hospital in Temple, Texas began as a division in the Department of Surgery many decades ago. The hospital has long served as the flagship tertiary referral center for the Baylor Scott & White healthcare system, which merged in 2013 with Baylor University Medical Center, a hospital system based in Dallas. It is now the largest non-profit hospital system as well as the most awarded hospital system by the US News and World Report within the state of Texas. The Department of Neurosurgery was established at Baylor Scott & White Memorial Hospital in the 2006-2007 academic year. Between then and 2014, four neurosurgeons served as department chair or interim chair: Dr. Robert Buchanan, Dr. Gerhard Friehs, Dr. Ibrahim El Nihum, and Dr. David Garrett Jr. In 2014, Dr. Jason Huang was appointed chairman after a national search and established the neurosurgery residency program in 2015. The department has undergone tremendous growth under the leadership of Dr. Huang, and the residency program is a priority of the department. Surgical excellence is honed at primarily three campuses: Baylor Scott & White Memorial Hospital, Baylor Scott & White McLane Children's Medical Center, and Baylor Scott & White Medical Center - Hillcrest. In this editorial, we provide a brief history of the institution, a recent history of the neurosurgical presence at Baylor Scott & White Memorial Hospital in Temple, Texas, and briefly describe the program's future directions under the continued leadership of Dr. Jason Huang.

Exploring Spinal Subarachnoid Hemorrhage: A Neurosurgical Case Series.

Spinal subarachnoid hemorrhage (SSAH) is a rare condition that can cause spinal cord or nerve root compression and permanent neurologic damage. The reported etiologies include trauma, vascular malformations or aneurysms, coagulopathies, neoplasms, autoimmune disease, and spontaneous hemorrhage. If there is evidence of neurologic deterioration, it is commonly managed as a surgical emergency, but cases of conservative management have also been reported. In this case series, we present three patients who suffered from SSAH. The first was a spontaneous cervical SSAH that occurred following cardiac catheterization, the second was a spontaneous thoracolumbar SSAH in a patient with a known history of coagulopathy, and the third was a thoracolumbar SSAH that was caused by a dural arteriovenous fistula (dAVF). All three patients exhibited neurologic deficits and thus underwent emergent decompression and hematoma evacuation. The patient with the dAVF also required open ligation of the fistula. Following surgical intervention, all three patients regained at least partial neurologic function, but one patient developed symptomatic arachnoid cysts that required further intervention. The presented case series highlights the importance and time-sensitivity of surgical decompression in patients experiencing neurologic deficits from SSAH. These cases underscore the urgency of timely neurosurgical intervention to mitigate neurologic impairment and add insights to the existing literature on this rare condition.

H3G34-Mutant Gliomas-A Review of Molecular Pathogenesis and Therapeutic Options.

The 2021 World Health Organization Classification of Tumors of the Central Nervous System reflected advances in understanding of the roles of oncohistones in gliomagenesis with the introduction of the H3.3-G34R/V mutant glioma to the already recognized H3-K27M altered glioma, which represent the diagnoses of pediatric-type diffuse hemispheric glioma and diffuse midline glioma, respectively. Despite advances in research regarding these disease entities, the prognosis remains poor. While many studies and clinical trials focus on H3-K27M-altered-glioma patients, those with H3.3-G34R/V mutant gliomas represent a particularly understudied population. Thus, we sought to review the current knowledge regarding the molecular mechanisms underpinning the gliomagenesis of H3.3-G34R/V mutant gliomas and the diagnosis, treatment, long-term outcomes, and possible future therapeutics.

Outcomes After Supratentorial Craniotomy for Primary Malignant Brain Tumor Resection in Adult Patients: A National Surgical Quality Improvement Program Analysis.

BACKGROUND: The rate of complications remains significant after craniotomy for supratentorial primary malignant brain tumors despite recent advances. OBJECTIVE: The goal of this study is to characterize factors associated with these complications. METHODS: Data were extracted from the National Surgical Quality Improvement Program database from 2016 to 2019. Patients who underwent a craniotomy for resection of supratentorial primary malignant brain tumors were included. Covariates included demographics/comorbidities, preoperative laboratory values, American Society of Anesthesiologists (ASA) classification, operative time, and postoperative complications. Multivariable logistic regression with backward and forward selection was used to evaluate independent predictors of death, prolonged hospitalization, postoperative stroke with neurologic deficit (CVA), and unplanned readmission. Predictive fit of the model was evaluated using the area under the receiver operating curve (AUC). RESULTS: Of 8965 included cases, the 30-day postoperative risks were 1.9% for CVA, 10.1% for unplanned readmission, 1.2% for prolonged hospitalization, and 2.4% for death. Age, ASA category, disseminated cancer, preoperative functional dependence, and postoperative respiratory complications were predictors of 30-day mortality (AUC, 0.83; P < 0.001). CVA was best predicted by increased operation time (P < 0.001), age, ASA category, and recent weight loss (AUC, 0.63; P = 0.009). Prolonged hospitalization was predicted by nonelective surgery status, time from admission to surgery, reintubation, and postoperative sepsis (AUC, 0.78; P < 0.001). Unplanned readmission was predicted by chronic steroid use, postoperative thrombotic complications after surgery, organ/space surgical site infection, deep vein thrombosis, postoperative systemic sepsis, and septic shock (AUC, 0.68; P < 0.001). CONCLUSIONS: Our study identifies predictors of major 30-day complications after craniotomy for this subset of patients with brain tumor.

Novel Superior Cerebellar Artery Aneurysm Coming from a Superior Cerebellar Artery-Posterior Cerebral Artery Anastomotic Branch.

A middle-aged patient presented with subarachnoid hemorrhage and was found to have a ruptured superior cerebellar artery (SCA) aneurysm arising from the origin of a rare anastomotic branch between the right SCA and right posterior cerebral artery (PCA). The aneurysm was secured by transradial coil embolization, and the patient made a good functional recovery. This case demonstrates an aneurysm arising from an anastomotic branch between the SCA and PCA, which may represent a remnant of a persistent primordial hindbrain channel. Although variations in basilar artery branches are common, aneurysms rarely can form at the site of seldom- seen anastomoses between the branches of the posterior circulation. The complex embryology of these vessels, which includes anastomoses and the involution of primitive arteries, may have contributed to the development of this aneurysm arising from an SCA-PCA anastomotic branch.

Ad26.COV2.S Vaccine-Induced Thrombocytopenia Leading to Dural Sinus Thrombosis and Intracranial Hemorrhage Requiring Hemicraniectomy: A Case Report and Systematic Review.

The coronavirus disease 2019 (COVID-19) pandemic has claimed nearly 5.5 million lives worldwide. Adenovirus-based vaccines are safe and effective, but they are rarely associated with vaccine-induced thrombosis and thrombocytopenia (VITT) as well as cerebral venous sinus thrombosis (CVST). We conducted a systematic literature search of intracerebral hemorrhage (ICH) secondary to CVST associated with VITT from the Ad26.COV2.S vaccine, and we present the first case of this pathology in the reviewed literature of a patient who required neurosurgical decompression. The systematic literature review was completed on December 19, 2021, by searching PubMed and Ovid for articles with primary data on CVST associated with VITT following the Ad26.COV2.S vaccine. We also specifically searched for cases that required neurosurgical intervention. Articles were independently screened by two authors, and both secondary and tertiary searches were done as well. Descriptive statistics were collected and presented in table form. Nine studies were identified that met inclusion criteria. There were no cases identified of patients who underwent neurosurgical decompression after developing this pathology. We thus present the first case in the reviewed literature of a patient who developed ICH after receiving the Ad26.COV2.S vaccine and underwent decompressive hemicraniectomy. Despite severe thrombocytopenia and prolonged intensive care, the patient was discharged to neurorehabilitation. There is a much greater risk of CVST and ICH during COVID-19 infections than from the vaccines. However, as booster vaccines are approved and widely distributed, it is critical to make prompt, accurate diagnoses of this vaccine-related complication and consider neurosurgical decompression.

Safety of Contemporary Carotid Artery Stenting and Associated Risk Factors for Treatment of Carotid Artery Stenosis.

BACKGROUND: The prevalence of carotid artery atherosclerosis and stroke is increasing. Carotid artery stenting (CAS), which treats carotid artery stenosis and prevents strokes, has benefited from advances in techniques and technology. In this study, we aimed to identify significant risk factors for major complications following contemporary CAS. METHODS: Utilizing the National Surgical Quality Improvement Program registry, we investigated individuals who underwent CAS between the years 2015-2018. Multivariable logistic regression was performed to identify risk factors associated with stroke, myocardial infarction (MI), and death within 30 days of CAS. RESULTS: Of the 770 patients within the National Surgical Quality Improvement Program registry who met study criteria, 3.2% experienced strokes, 1.6% experienced MIs, and 2.2% died within 30 days of CAS. A total of 6.1% of patients experienced any of these major complications. Of the 395 asymptomatic patients, 3.5% suffered a stroke, 1.5% experienced an MI, and 1.0% died for a total of 5.6% patients suffering from any event. Of the 375 symptomatic patients, there were 2.9% strokes, 1.6% MIs, and 3.5% deaths with 6.7% suffering any event. Age, race, and hyponatremia were significantly associated with stroke, and hyponatremia was associated with MI. Age, anemia, hypoalbuminemia, international normalized ratio, and emergency case were associated with death. CONCLUSIONS: These results suggest that preoperative risk stratification of CAS patients may not be straightforward as each adverse event has its own risk factors, precluding a generalized CAS risk stratification scoring system from being created. This paper can aid in patient selection for CAS by highlighting risk factors in modern CAS.

The relationship between COVID-19 infection and intracranial hemorrhage: A systematic review.

INTRODUCTION: In addition to the deleterious effects Covid-19 has on the pulmonary and cardiovascular systems, COVID-19 can also result in damage to the nervous system. This review aims to explore current literature on the association between COVID-19 and intracranial hemorrhage (ICH). METHODS: We conducted a systematic review of PubMed for literature published on COVID-19 and ICH. Ninety-four of 295 screened papers met inclusion criteria. RESULTS: The literature addressed incidence and mortality of ICH associated with Covid-19. It also revealed cases of COVID-19 patients with subarachnoid hemorrhage, intraparenchymal hemorrhage, subdural hematomas, and hemorrhage secondary to cerebral venous thrombosis and ischemic stroke. ICH during COVID-19 infections was associated with increased morbidity and mortality. Risk factors for ICH appeared to be therapeutic anticoagulation, ECMO, and mechanical ventilation. Outcomes varied widely, depending on the severity of COVID-19 infection and neurologic injury. CONCLUSION: Although treatment for severe Covid-19 infections is often aimed at addressing acute respiratory distress syndrome, vasculopathy, and coagulopathy, neurologic injury can also occur. Evidence-based treatments that improve COVID-19 mortality may also increase risk for developing ICH. Providers should be aware of potential neurologic sequelae of COVID-19, diagnostic methods to rule out other causes of ICH, and treatment regimens.

PulseRider Treated Aneurysm with Significant Artifact on Postoperative Magnetic Resonance Angiography: A Case Report and Literature Review.

The PulseRider is a neuroendovascular adjunct for wide-necked intracranial aneurysms. The decreased metal burden of the PulseRider theoretically reduces artifact on radiologic imaging. However, we report here on a case of a patient who underwent PulseRider-assisted stent-coiling of a basilar tip aneurysm. He returned 19 months later for intermittent diplopia and darkening of vision but was neurologically intact on exam. Both contrast-enhanced and time-of-flight magnetic resonance angiography (MRA) demonstrated absence of signal in the basilar artery in the proximal anchors of the PulseRider. Given his lack of reproducible symptoms and high functional status, it is presumed that the imaging reflected artifact and not thrombosis/stenosis. Although the PulseRider is a useful treatment option for wide-necked intracranial aneurysms, the clinician should be aware that even contrast-enhanced MRA can produce artifact that resembles thrombosis/stenosis. Non-angiogram radiologic imaging modalities may be appropriate for evaluation for residual aneurysm but not patency of the parent artery.

Opioid Utilization in Geriatric Patients After Operation for Degenerative Spine Disease.

BACKGROUND: Few studies have investigated opioid utilization by geriatric patients after spinal surgery, a population in whom degenerative spine disease (DSD) is highly prevalent. We aimed to quantify rates of chronic, continuous opioid utilization by geriatric patients following spine surgery for DSD-related diagnoses. MATERIALS AND METHODS: Utilizing a national 5% Medicare sample database, we investigated individuals aged above 66 years who underwent spinal surgery for a DSD-related diagnosis between the years of 2008 and 2014. The outcomes of interest were the rate of and risk factors for continuous opioid utilization at 1-year following anterior cervical discectomy and fusion, posterior cervical fusion, 360-degree cervical fusion, lumbar microdiscectomy, lumbar laminectomy, posterior lumbar fusion, anterior lumbar fusion, or 360-degree lumbar fusion for a DSD-related diagnosis. RESULTS: Of the 14,583 Medicare enrollees who met study criteria, 6.0% continuously utilized opioids 1-year after spinal surgery. When stratified by preoperative opioid utilization (with the prior year divided into 4 quarters), the rates of continuous utilization at 1-year postsurgery were 0.3% of opioid-naive patients and 23.6% of patients with opioid use in all 4 quarters before surgery. Anxiety, benzodiazepine use within the year before surgery, and Medicaid dual-eligibility were associated with prolonged opioid utilization. CONCLUSIONS: Of opioid-naive geriatric patients who underwent surgery for DSD, 0.3% developed chronic, continuous opioid use. Preoperative opioid use was the strongest predictor of prolonged utilization, which may represent suboptimal use of nonopioid alternatives, pre-existing opioid use disorders, delayed referral for surgical evaluation, or over-prescription of opioids for noncancer pain.

Effect of an additional neurosurgical resident on procedure length, operating room time, estimated blood loss, and post-operative length-of-stay.

Introduction: Neurosurgical residency training is costly, with expenses largely borne by the academic institutions that train residents. One expense is increased operative duration, which leads to poorer patient outcomes. Although other studies have assessed the effect of one resident assisting, none have investigated two residents; thus, we sought to investigate if two residents versus one scrubbed-in impacted operative time, estimated blood loss (EBL), and length-of-stay (LOS).Methods: In this retrospective review of patients who underwent a neurosurgical procedure involving one or two residents between January 2013 and April 2016, we performed multivariable linear regression to determine if there was an association between resident participation and case length, operating room time, EBL, and LOS. We also included patient demographics, attending surgeon, day of the week, start time, pre-operative LOS, procedure performed, and other variables in our model. Only procedures performed at least 40 times during the study period were analyzed.Results: Of 860 procedures that met study criteria, 492 operations were one of six procedures performed at least 40 times, which were anterior cervical discectomy and fusion, cerebrospinal fluid (CSF) shunt insertion, CSF shunt revision, lumbar laminectomy, intracranial hematoma evacuation, and non-skull base, supratentorial parenchymal brain tumor resection. An additional resident was associated with a 35.1-min decrease (p = .01) in operative duration for lumbar laminectomies. However, for intracranial hematoma evacuations, an extra resident was associated with a 24.1 min increase (p = .03) in procedural length. There were no significant differences observed in the other four surgeries.Conclusion: An additional resident may lengthen duration of intracranial hematoma evacuations. However, two residents scrubbed-in were associated with decreased lumbar laminectomy duration. Overall, an extra resident does not increase procedural duration, total operating room utilization, EBL, or post-operative LOS. Allowing two residents to scrub in may be a safe and cost-effective method of educating neurosurgical residents.

A Systematic Review of Ion Radiotherapy in Maintaining Local Control Regarding Atypical and Anaplastic Meningiomas.

OBJECTIVE: Atypical and anaplastic meningiomas, unlike their benign counterparts, are highly aggressive, locally destructive, and likely to recur after treatment. These diseases are difficult to definitively treat with traditional radiotherapy without injuring adjacent brain parenchyma. The physical properties of ion radiotherapy allows for treatment plans that avoid damaging critical neural structures. The objectives of this systematic review were to evaluate the use and efficacy of ion radiotherapy in the treatment of atypical and anaplastic meningiomas. METHODS: We performed a systematic review of the literature by querying the PubMed and Ovid databases to identify and examine literature addressing the efficacy of ion radiotherapy in maintaining long-term local tumor control for patients with atypical or anaplastic meningiomas. The outcome of interest was rate of local tumor control at 5 years after ion radiotherapy. RESULTS: Across the included studies, proton therapy delivered a mean local control rate of 59.62% after 5 years. Carbon ion radiotherapy studies showed local control rates of 95% and 63% at 2 years for grade II and III meningiomas, respectively. In contrast, carbon ion radiotherapy studies that failed to differentiate between atypical and anaplastic meningiomas produced a local control rate of 33% at 2 years. CONCLUSIONS: Proton and carbon ion radiotherapy maintain comparable rates of local control to conventional photon therapy and allow for more targeted treatment plans that may limit excess radiation damage. Although additional prospective trials are needed, ion therapy represents a burgeoning field in the treatment of atypical and anaplastic meningiomas.

Cefazolin versus vancomycin for neurosurgical operative prophylaxis - A single institution retrospective cohort study.

OBJECTIVES: Cefazolin and vancomycin are common choices for neurosurgical antimicrobial prophylaxis. Cefazolin is typically first-line due to its lower toxicity profile and specificity for gram-positives such as skin commensals, while vancomycin is often reserved for patients with cephalosporin or penicillin allergies. However, one randomized clinical trial demonstrated superiority of vancomycin for cerebrospinal fluid (CSF) shunt insertions at a hospital with a high prevalence of methicillin-resistance Staphylococcus aureus (MRSA). We aimed to evaluate the association of prophylaxis choice and incidence of surgical site infection (SSI) at our own institution. PATIENTS AND METHODS: This was a retrospective cohort study of patients who underwent a neurosurgical operation from January 2013 to April 2016 at one particular hospital belonging to our institution. We included patients who received either only cefazolin or only vancomycin as their pre-incisional prophylaxis. Vancomycin was substituted for cefazolin in patients with known penicillin or cephalosporin allergy. Procedures requiring multiple attending surgeons were excluded. We defined a SSI as a confirmed culture isolated from the wound, implant (if pertinent), or CSF (if pertinent) within a year of surgery. Multivariable logistic regression was performed with consideration of antibiotic, operation performed, wound class, and procedure length. RESULTS: A total of 859 operations met study criteria; 664 patients received Cefazolin, and 195 received Vancomycin. We identified 22 SSIs, with 14 in the cefazolin (2.2%) and 8 in the vancomycin (4.1%) group. Upon logistic regression, there was no significant association of vancomycin substitution with incidence of SSIs between the two groups (odds ratio, 1.59; 95% CI, 0.42-6.00, p = .49). In the cefazolin group, 8/14 cultures were positive for S. aureus compared to 1/8 of the vancomycin group. CONCLUSIONS: There was no significant difference in neurosurgical site infection incidence when vancomycin prophylaxis was substituted for cefazolin. S. aureus was isolated from patients who received cefazolin at a higher rate although this was not statistically significant. At our institution, S. aureus makes up 36% of isolated organisms from inpatient and intensive care units. Institutions should consider their own investigations into local antibiograms, SSI rates, and choice of prophylaxis.

Machine learning applications for the differentiation of primary central nervous system lymphoma from glioblastoma on imaging: a systematic review and meta-analysis.

OBJECTIVEGlioblastoma (GBM) and primary central nervous system lymphoma (PCNSL) are common intracranial pathologies encountered by neurosurgeons. They often may have similar radiological findings, making diagnosis difficult without surgical biopsy; however, management is quite different between these two entities. Recently, predictive analytics, including machine learning (ML), have garnered attention for their potential to aid in the diagnostic assessment of a variety of pathologies. Several ML algorithms have recently been designed to differentiate GBM from PCNSL radiologically with a high sensitivity and specificity. The objective of this systematic review and meta-analysis was to evaluate the implementation of ML algorithms in differentiating GBM and PCNSL.METHODSThe authors performed a systematic review of the literature using PubMed in accordance with PRISMA guidelines to select and evaluate studies that included themes of ML and brain tumors. These studies were further narrowed down to focus on works published between January 2008 and May 2018 addressing the use of ML in training models to distinguish between GBM and PCNSL on radiological imaging. Outcomes assessed were test characteristics such as accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve (AUC).RESULTSEight studies were identified addressing use of ML in training classifiers to distinguish between GBM and PCNSL on radiological imaging. ML performed well with the lowest reported AUC being 0.878. In studies in which ML was directly compared with radiologists, ML performed better than or as well as the radiologists. However, when ML was applied to an external data set, it performed more poorly.CONCLUSIONSFew studies have applied ML to solve the problem of differentiating GBM from PCNSL using imaging alone. Of the currently published studies, ML algorithms have demonstrated promising results and certainly have the potential to aid radiologists with difficult cases, which could expedite the neurosurgical decision-making process. It is likely that ML algorithms will help to optimize neurosurgical patient outcomes as well as the cost-effectiveness of neurosurgical care if the problem of overfitting can be overcome.

Invasive colon cancer, but not non-invasive adenomas induce a gradient effect of Wnt pathway receptor frizzled 1 (Fz1) expression in the tumor microenvironment.

BACKGROUND: Wnt signaling in the colon cancer tumor microenvironment (TME) may affect cancer biologic properties including invasion and metastatic dissemination. Prior reports have suggested that the expression of select frizzled (Fz) receptors may be altered in cancers and in the TME. METHODS: Colon cancer, colonic adenoma and normal colonic mucosal specimens were obtained under institutional review board approval and analyzed for the expression of Fz1 and Fz2 by confocal fluorescent immunohistochemistry and Wnt-specific membrane array. In vitro, the effect of Wnt3a on Fz1 expression was examined in normal-derived NCM460 cells by qRT-PCR and immunohistochemistry. RESULTS: Fz1 was expressed in colon cancer and villous adenomas but not in more benign tubular adenomas. Fz1 expression was seen in normal colonic mucosa in close proximity to colon cancer, but not villous or tubular adenomas. Normal colonic mucosa distant from colon cancer did not express Fz1. Fz2 was expressed ubiquitously in cancer, adenomas and normal colonic mucosa. Fz1 expression was induced by Wnt3a in a normal colon mucosa-derived cell line in vitro. CONCLUSIONS: Fz1 is a Wnt responsive gene in colon-derived tissues. Fz1 expression exhibited increased expression in normal mucosa only in close proximity to colon cancer. This field effect was not seen with pre-malignant adenomas and may be due to Wnt/ß-catenin signaling within the TME. Fz1 may represent a new TME-directed therapeutic target for patients with colon cancer.

Differentiation of tubular and villous adenomas based on Wnt pathway-related gene expression profiles.

This study was undertaken to define whether differences in the expression of Wnt pathway components are present between normal colonic mucosa, early (tubular) adenomas and villous adenomas which have a higher malignant potential. Normal mucosa, tubular adenomas and villous adenomas were obtained from twelve patients. RNA was isolated and utilized for Wnt pathway-specific membrane array expression analysis. Quantitative real-time polymerase chain reaction (qRT-PCR) and fluorescent immunohistochemistry (IHC) were utilized for confirmatory analyses. Fifteen Wnt pathway-related genes showed differential expression between villous adenomas and normal mucosa and villous and tubular adenomas at a significance level of p<0.01. Genes involved in canonical Wnt (beta-catenin) signaling with increased expression in villous adenomas included wnt1, fz2, csnk2A2, pygo2, pygo1, frat2 and myc, the latter confirmed by qRT-PCR and IHC. Myc protein expression was confined primarily to stromal components of villous adenomas. Genes involved in non-canonical Wnt signaling with increased expression in villous adenomas included rho-u, daam1, damm2, cxxc4 and nlk. Successive increases in the expression of ctnnb1 (beta-catenin) from normal to tubular adenomas to villous adenomas was seen. The Wnt pathway gene expression profile can differentiate between tubular and villous adenomas. These data suggest that Wnt signaling regulation changes during the progression from normal mucosa to tubular adenomas to villous adenomas. Expression of Myc in adenoma stroma suggests a dynamic signaling network within adenomas between mucosal and stromal elements. Inhibition of the Wnt pathway may provide a novel approach for cancer prevention in patients with benign tubular adenomas.

Results of a phase I pilot clinical trial examining the effect of plant-derived resveratrol and grape powder on Wnt pathway target gene expression in colonic mucosa and colon cancer.

CONTEXT: Resveratrol exhibits colon cancer prevention activity in animal models; it is purported to have this activity in humans and inhibit a key signaling pathway involved in colon cancer initiation, the Wnt pathway, in vitro. DESIGN: A phase I pilot study in patients with colon cancer was performed to evaluate the effects of a low dose of plant-derived resveratrol formulation and resveratrol-containing freeze-dried grape powder (GP) on Wnt signaling in the colon. Eight patients were enrolled and normal colonic mucosa and colon cancer tissue were evaluated by Wnt pathway-specific microarray and quantitative real-time polymerase chain reaction (qRT-PCR) pre- and post-exposure to resveratrol/GP. RESULTS: Based on the expression of a panel of Wnt target genes, resveratrol/GP did not inhibit the Wnt pathway in colon cancer but had significant (p < 0.03) activity in inhibiting Wnt target gene expression in normal colonic mucosa. The greatest effect on Wnt target gene expression was seen following ingestion of 80 g of GP per day (p < 0.001). These results were confirmed with qRT-PCR of cyclinD1 and axinII. The inhibitory effect of GP on Wnt signal throughput was confirmed in vitro with a normal colonic mucosa-derived cell line. CONCLUSIONS: These data suggest that GP, which contains low dosages of resveratrol in combination with other bioactive components, can inhibit the Wnt pathway in vivo and that this effect is confined to the normal colonic mucosa. Further study of dietary supplementation with resveratrol-containing foods such as whole grapes or GP as a potential colon cancer preventive strategy is warranted. TRIAL REGISTRATION: NCT00256334.

Wnt pathway-related gene expression in inflammatory bowel disease.

The purpose of this study was to examine the expression of Wnt pathway-related genes in patients with ulcerative colitis (UC). RNA from colonoscopic biopsies from noninflammatory bowel disease (non-IBD) subjects and UC patients were obtained and examined with a Wnt-specific microarray for the expression of Wnt pathway-related genes. Paired samples from uninflamed and inflamed areas of the colon were obtained for the UC patients. WNT2B, WNT3A, WNT5B, WNT6, WNT7A, WNT9A, and WNT11 exhibited significantly increased expression in UC compared to non-IBD patients. Frizzled 3 (FZD3) and FZD4 exhibited significantly increased expression, and FZD1 and FZD5 exhibited significantly decreased expression in UC patients. Genes with increased expression in inflamed mucosa included DKK4, DVL2, SOX17, and COL1A1. There was no difference in the expression of a panel of Wnt target genes. The expression of inducible nitric oxide synthase (INOS) was variably influenced by inflammation. Significant differences in extracellular and cell-surface components of the Wnt pathway exist in the colonic mucosa of patients with UC compared with non-IBD patients, which may influence the strength or specificity of Wnt signaling. In inflammation, inhibitory components of the Wnt pathway exhibit increased expression, but no changes in Wnt pathway target gene expression are seen. The role and complex regulation of Sox17 and iNOS in IBD warrant further investigation.