Neoplasms

All Conditions

Immune System Diseases

Symptoms and General Pathology

Rare Diseases

Glioblastoma

Hypersensitivity

Body Weight

Astrocytoma

Glioma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Temozolomide

Standard of care glioblastoma resection with standard of care adjuvant therapy (temozolomide + radiation therapy)

CEST MRI Based Resection of glioblastoma with standard of care adjuvant therpay (temozolomide + radiation therapy)

Using pre-operative amine chemical exchange saturation transfer pH weighted MRI, regions of interest that correspond to infiltrating glioblastoma will be identified and via intraoperative neuronavigation, guide resection of glioblastoma

CEST PH MRI based resection of glioblastoma

Kunal S Patel, MD

Standard of care therapy and all FDA approved adjuvant therapy for glioblastoma continue to provide \< 12-month progression free survival (PFS) and \< 24-month overall survival (OS). Standard of care therapy continues to be defined by the volume of tumor that enhances with gadolinium on standard magnetic resonance imaging (MRI). The investigators have identified a significant tumor burden in non-enhancing (NE) regions beyond the contrast-enhancing (CE) portion of tumor. Furthermore, the investigators have adapted a pH-sensitive technique called amine chemical exchange saturation transfer (CEST) MRI to identify tumor cells in NE regions with high sensitivity and specificity. This study is a randomized trial of CEST based resections versus standard of care in newly diagnosed glioblastoma with primary endpoint of progression free survival and secondary endpoints of overall survival and quality of life metrics. The hypothesis being tested is whether surgical resection of infiltrating tumor cells visualized by CEST MRI contributes to survival in glioblastoma patients.

The investigators have previously addressed the difficulty in identifying tumor in non-enhancing (NE) T2 hyperintense regions surrounding the contrast-enhancing bulk of tumor. The investigators have applied pH sensitive amine chemical exchange saturation transfer echo planar imaging (CEST-EPI) to patients with glioblastoma. CEST imaging can utilize detection of fast-exchanging amine protons to obtain an imaging contrast that is dependent on tissue acidity. Bulk water protons undergo chemical exchange with amine protons. CEST imaging detects the attenuation of bulk water magnetization following a saturation pulse, which can vary by concentration of amine protons. This contrast can be quantitated as the asymmetry in the magnetization transfer ratio (MTRasym) relative to water proton resonance frequency. Tumor cells are known to produce elevated levels of extracellular hydrogen, given 1) a higher metabolic rate secondary to increased cell turnover and 2) an affinity for anaerobic glycolysis - the Warburg Effect. The investigators have shown active tumor burden and active replication occurring in infiltrating glioblastoma cells. and thus leveraged CEST imaging to visualize infiltrating tumor cells. 19 In newly diagnosed and recurrent glioblastoma, higher median MTRasym at 3ppm within CEST+ NE regions p=0.007; p=0.0326\] and higher volumes of CEST+ NE tumor \[p=0.020; p\<0.001\] were associated with decreased PFS. Prospective MRI guided biopsies of CEST+ NE regions showed a correlation with presence of cell density and %Ki-67 positivity \[p\<0.001, p\<0.001\]. Furthermore, using pathological diagnosis as the gold standard, the investigators saw a threshold of MTRasym \> 1.50% as able to identify tumor cells with a sensitivity of 100% and specificity of 71.4%. In unpublished data with additional samples only from newly diagnosed WHO IV glioblastoma, the calculated sensitivity and specificity was 100% when using neuro-pathological review as the gold standard. Additionally, when using single cell RNA sequencing (scRNAseq) detection of tumor cells via copy number variation analysis as the gold standard, from 17 biopsies in CEST+ NE regions, the same threshold of 1.50% identified tumor cells with a sensitivity of 93% and specificity of 100%. Given the strong correlation between tumor cells and CEST+ NE regions, the investigators have preliminary conducted CEST+ NE resections on 5 patients with newly diagnosed WHO IV glioblastoma. In this preliminary data, the investigators found no significant post-operative complications with the larger resections. All patients received standard of care adjuvant therapy (temozolomide + radiotherapy) and none of the patients have experienced progression (median PFS 13 months). With this data, the investigators hypothesize that maximal safe resection of CEST+ NE regions will minimize the post-surgical tumor cell burden and allow for increased survival.

Experimental Approach. The investigators will carry out a prospective, randomized controlled trial of surgical resection of glioblastoma with pH sensitive amine CEST-EPI. Patients will be enrolled by me at the UCLA Ronald Reagan Medical Center. The UCLA department of neurosurgery brain tumor program is a high-volume neuro-oncology center. The investigators will recruit patients with imaging consistent with WHO grade IV glioblastoma. 51 I will directly provide informed consent for participating in the trial along with informed consent for the surgery itself. Prior to randomization, all patients will undergo pre-operative medical clearance and standard pre-operative medication administration (levetiracetam 100mg BID and dexamethasone 4mg TID). All patients will undergo pre-operative standard anatomic MRI 52 within 1 week of surgery (3T Siemens Prisma, Siemens Healthcare, Erlangen, Germany). MRI sequences will include: 1mm 3D inversion-recover gradient recalled echo images prior to and after injection of gadolinium contrast (Gd-DTPA, 0.1 mmol/kg), and dual-echo proton density T2-weighted turbo spin echo images. pH-weighted amine CEST echo planar MRI27 will be obtained (field of view: 256 x 256 mm2, matrix size: 128 x 128, slice thickness 4mm, scan time: approximately 5 minutes).

Imaging data will be downloaded from the PACS server onto lab servers for post-processing and analysis (Figure 7). This will consist of affine motion correction (mcflirt; FSL, FMRIB, Oxford, UK) and registration to anatomic T1 with contrast images. MTRasym will be calculated for all voxels of CEST sequences. All further image analysis will be carried out on AFNI (Software for analysis and visualization of functional magnetic resonance neuroimages). 53 To obtain regions of interest based on MTRasym abnormality, the investigators will first identify CE tumor by a voxel-by-voxel subtraction of image intensity of T1 without contrast from T1 with contrast. 16 Using an intensity threshold, CE will be segmented and for tumors with necrotic or cystic core, these will be filled to obtain CE tumor regions of interest (ROI). This ROI will be expanded volumetrically to obtain NE ROI. The NE ROI will be co-registered to MTRasym maps and filtered by minimum value 1.5 which has been shown to predict presence of tumor cells with high sensitivity and specificity. 19 Lastly, the CE ROI will be subtracted from NE ROI filtered for abnormal MTRasym values to yield a CEST+ NE region of tumor (Figure 7). Prior to surgery, the subjects will be randomized. Patients randomized to the experimental arm will have CEST+ NE segmentations uploaded to intraoperative objects using our intraoperative neuronavigation software (BrainLab Surgical Navigation System, Munich, Germany). Patients randomized to the standard-of-care arm will have standard MRI w/wo contrast sequences uploaded to the intraoperative neuronavigation software. During surgery, I will carry out standard of care resection of the contrast-enhancing portion of tumor (standard-of-care arm) or standard of care resection plus maximal safe surgical resection of CEST+NE regions (experimental arm). Maximal safe surgical resection includes complete avoidance of eloquent (motor, language) tissue. Standard post-operative care will be carried out in all patients. Adjuvant therapy will include standard-of-care synchronous oral temozolomide (6 weeks) and radiation therapy 60 Gy over 30 fractions to the resection cavity. Standard MRI with and without contrast will be used as surveillance imaging and RANO criteria will be used to determine recurrence. Primary endpoint will be progression free survival and secondary endpoints will be overall survival, surgical complication rate, and quality of life differences as measured by pre- and post-operative karnofsky performance scale scores.

Statistical Plan. Using our preliminary data on CEST+ NE resections and median PFS (6 months) for our larger 10-year cohort of patients with newly diagnosed glioblastoma, the investigators calculated a sample size of 60 to provide a power of 95% to detect a meaningful 6 month difference in PFS at a 0.05 significance level. Clinical characteristics associated with survival (age, pre-operative KPS) will be compared using independent sample t-tests to assess for bias despite randomization. Multivariate cox and log rank tests will be used to compare survival outcomes. Independent sample chi squared tests will be used to compare differences in surgical complication rate and post-operative karnofsky performance scale changes.

Randomized, non-blinded trial of intervention versus standard of care, with all further treatment and follow up in parallel

The principal investigator is the surgeon and so cannot be blinded from the type of surgical procedure carried out (interventional or standard of care).

PH Sensitive MRI Based Resections of Glioblastoma

PH Weighted Chemical Exchange Saturation Transfer Based Surgical Resections of Glioblastoma

Follow up MRI based progression free survival based on RANO criteria

Karnofsky Performance Scale is a quality of life and independence metric. It is scored from 0-100 with higher being more independence and greater quality of life.

University of California, Los Angeles

Assistant Professor Department of Neurosurgery

Colonic Polyps

Polyps

Pathological Conditions, Anatomical

Intestinal Polyps

Herbal and Botanical

Cola

Brian P Saunders, MD

Prospective study of accuracy of colonic polyp characterisation in vivo using high resolution white light endoscopy, narrow band imaging and chromoendoscopy.

Discard:Characterisation of Colonic Polyps in Vivo

Characterisation of Small Colonic Polyps in Vivo

Imperial College London

Digestive System Diseases

Recurrence

Cicatrix

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Disease Attributes

Assessment of endoscopic images prior to a learning tool about scars and recurrence

Assessment of endoscopic images after a learning tool about scars and recurrence

Video based learning tool about detection of endoscopic resection scars and recurrence.

Learning tool

David J trate, PhD

Sander Smeets, MD

David J Tate, PhD

Colorectal cancer is prevented by colonoscopy and polypectomy. Failure to recognize the endoscopic resection scar after Endoscopic Mucosal Resection (EMR) risks unrecognized recurrent or residual adenoma (RRA), which may propagate into post-colonoscopy colorectal cancer. Expert series suggest scar recognition and interrogation is well performed with a high negative predictive value of endoscopic imaging vs histopathology. In this study the authors will investigate the performance of endoscopic imaging in detecting RRA at an endoscopic resection scar amongst general endoscopist and the impact of a learning intervention on recognition of RRA.

Colorectal cancer is prevented by polypectomy. Failure to recognize the scar after EMR risks unrecognized recurrent or residual adenoma (RRA), which may propagate into post-colonoscopy colorectal cancer. Expert series suggest scar recognition and interrogation is well performed with a high negative predictive value of endoscopic imaging vs histopathology.

In this study the authors will investigate the performance of endoscopic imaging in detecting RRA at an endoscopic resection scar amongst general endoscopist and the impact of a learning intervention on recognition of RRA.

A survey containing 15 High Definition - White Light (HD-WL) and Narrow Band Imaging (NBI) images, a learning intervention on detection of RRA (LT), then another set of 15 images was circulated to a mailing list of the GIEQs (Gastrointestinal Endoscopy Quality and Safety) foundation. Each image contained the same questions: Is this a resection scar? Is there RRA? What is your level of confidence? Information on the participant was obtained: number of EMRs performed, grade (consultant vs trainee) and years of experience. Comparisons were made to expert opinion derived at a consensus meeting of the senior authors regarding the appearances of the scars using the approach set out in Desomer et al. 2017.

Detection of Endoscopic Resection Scars and Delineation of Recurrence is Trainable

Detection of Endoscopic Resection Scars and Delineation of Recurrence Amongst Non-experts is Less Accurate Than Experts But Trainable in a Short Learning Intervention

Individual participant data will not be made available to other researchers

Performance of detecting a recurrence at an endoscopic resection scar.

Performance of a learning tool in improving detection of recurrence at an endoscopic resection scar

Difference in performance of detecting a recurrence at an endoscopic resection scar between endoscopists with different experience level

Performance of a learning tool in improving detection of recurrence at an endoscopic resection scar compared between endoscopists with different experience level

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
PH Sensitive MRI Based Resections of Glioblastoma	NCT06176066	Glioblastoma	CEST PH MRI bas...	18 Years -	University of California, Los Angeles
Discard:Characterisation of Colonic Polyps in Vivo	NCT00888771	Colorectal Poly...		18 Years -	Imperial College London
Detection of Endoscopic Resection Scars and Delineation of Recurrence is Trainable	NCT06193356	Colorectal Poly... Colorectal Canc...	Learning tool	18 Years -	University Hospital, Ghent

Spots Global Cancer Trial Database for advanced imaging