Circulating Transcript Analysis (NETest) in GEP-NETs Treated With Somatostatin Analogs Defines Therapy

Context: Early and precise delineation of therapeutic responses are key issues in neuroendocrine neoplasm/tumor management. Imaging is currently used but exhibits limitations in sensitivity and specificity. The utility of biomarkers is unclear. Objective, Setting, and Design: This prospective cohort study (11 mo) sought to determine whether measurements of circulating neuroendocrine tumor transcripts (NETest) predict responses to somatostatin analogs (SSAs). Patients: The test set consisted of 35 SSA-treated gastroenteropancreatic-NETs (RECISTevaluated). The prospective set consisted of 28 SSA-treated Grade 1–Grade 2 GEP-NETs. Intervention(s): Whole blood for transcript analysis (NETest) and plasma for Chromogranin A (CgA) (baseline), were collected every 4 weeks (prior to SSA injection). Morphologic (multidetector computed tomography/MRI) and functional imaging (99mTc-[HYNIC, Tyr3]-Octreotide) was undertaken at entry and 6-month intervals until progression (RECIST 1.0). Main Outcome Measure(s): Treatment response. Results: Test set: NETest (≥80%; scale, 0–100%) differentiated stable (SD) and progressive (PD) disease (P < .0001). Prospective set: 28 patients (26/28 SD) undergoing standard SSA. Grading: 12 G1, 16 G2. SSA Response: progression-free survival: 315 days: 14 (50%) SD, 14 (50%) PD. NETest: Twenty had elevated (≥80%) values; 14 developed PD; six, SD. CgA: Twelve of 28 exhibited elevated baseline values and/or subsequent >25% increase; eight developed PD; four, SD. NETest (P = .002) and grade (P = .054) were the only factors associated with treatment response. Multiple regression analysis established that the NETest could predict disease progression (P = .0002). NETest changes occurred significantly earlier (146 d prior to progression vs 56 d CgA; P < .0001; χ2 = 19) and in more patients (100 vs 57%; P < .02). Conclusions: NETest values (80–100%) were more accurate and occurred at a significantly earlier time point than CgA and predicted SSA treatment response

Peptide Receptor Radionuclide Therapy for Advanced Neuroendocrine Tumors

No abstract availabl

A Deblurring/Denoising Corrected Scintigraphic Planar Image Reconstruction Model for Targeted Alpha Theory

Scintigraphy is a common nuclear medicine method to image molecular target’s bio-distribution and pharmacokinetics through the use of radiotracers and gamma cameras. The patient’s images are obtained by using a pair of opposing large flat gamma ray detectors equipped with parallel-hole lead or tungsten collimators that preferentially detect gamma-rays that are emitted perpendicular to the plane of the detector. The resulting images form an anterior/posterior (A/P) planar image pairs. The obtained images are contaminated by noise and contain artifacts caused by gamma-ray attenuation, collimator penetration, scatter and other detrimental factors. Post-filtering of the images can reduce the noise, but at the cost of spatial resolution loss, and cannot remove any of the aforementioned artifacts. In this study, we introduced a new image reconstruction-based method to recover a single corrected planar scintigraphic patient image corrected for attenuation, system spatial resolution and collimator penetration, using the A/P image pair (two conjugated views) as data. To accomplish this task, we used a system model based on the gamma camera detectors physical properties and applied regularization method based on sparse image representation to control noise while preserving spatial resolution. In this proof-of-concept study, we evaluated the proposed approach using simple numerical phantoms. The images were evaluated for simulated lesions images contrast and background variability. Our initial results indicate that the proposed method outperforms the conventional methods. We conclude, that the proposed approach is a promising methodology for improved planar scintigraphic image quality and warrants further exploration

imaging and biomarkers in gastroenteropancreatic neuroendocrine tumor disease management

The complexity of the clinical management of neuroendocrine neoplasia (NEN) is exacerbated by limitations in imaging modalities and a paucity of clinically useful biomarkers. Limitations in currently available imaging modalities reflect difficulties in measuring an intrinsically indolent disease, resolution inadequacies and inter-/intra-facility device variability and that RECIST (Response Evaluation Criteria in Solid Tumors) criteria are not optimal for NEN. Limitations of currently used biomarkers are that they are secretory biomarkers (chromogranin A, serotonin, neuron-specific enolase and pancreastatin); monoanalyte measurements; and lack sensitivity, specificity and predictive capacity. None of them meet the NIH metrics for clinical usage. A multinational, multidisciplinary Delphi consensus meeting of NEN experts (n = 33) assessed current imaging strategies and biomarkers in NEN management. Consensus (>75%) was achieved for 78% of the 142 questions. The panel concluded that morphological imaging has a diagnostic value. However, both imaging and current single-analyte biomarkers exhibit substantial limitations in measuring the disease status and predicting the therapeutic efficacy. RECIST remains suboptimal as a metric. A critical unmet need is the development of a clinico-biological tool to provide enhanced information regarding precise disease status and treatment response. The group considered that circulating RNA was better than current general NEN biomarkers and preliminary clinical data were considered promising. It was resolved that circulating multianalyte mRNA (NETest) had clinical utility in both diagnosis and monitoring disease status and therapeutic efficacy. Overall, it was concluded that a combination of tumor spatial and functional imaging with circulating transcripts (mRNA) would represent the future strategy for real- time monitoring of disease progress and therapeutic efficacy

Eleven-year experience with the avidin-biotin pretargeting system in glioblastoma: Toxicity, efficacy and survival

Background: The 3-step avidin-biotin pretargeting approach is applied in patients with recurrent glioblastoma (GBM), using biotinylated anti-tenascin monoclonal antibody as the first step of pretargeting followed by avidin and 90Ybiotin. Methods: The present study reviews objective response and overall survival rates in 502 glioblastoma patients treated with 3-step radioimmunotherapy in our institute from December 1994 to December 2005. Patients underwent standard treatment before receiving Pretargeted Antibody-Guided Radionuclide Therapy with 90Y-biotin (PAGRIT ®). Results: Of the 502 patients, 272 (54%) were evaluable for response and 375 (75%) for overall survival. 174 patients (64%) continued to progress after PAGRIT ®, 77 (28%) obtained disease stabilization, and 21 (8%) showed objective tumor regression. Survival of the 375 evaluable patients was 98.4% at 6 months, 79.2% at 12 months, 51.7% at 18 months, and 30.7% at 24 months after the first cycle of PAGRIT ®. All 375 received 3-step PAGRIT ® at recurrence of GBM. The median survival time from diagnosis was 19 months. Conclusion: The results from this retrospective analysis suggest that 90Y-biotin PAGRIT ® interferes with the progression of glioblastoma, prolonging survival in a larger number of patients. Our analysis forms the basis for further prospective trials, where radioimmunotherapy, which is known to be more effective in minimal residual disease, could be offered immediately after surgery. © Grana et al.; Licensee Bentham Open

Impact of liver tumour burden, alkaline phosphatase elevation, and target lesion size on treatment outcomes with 177Lu-Dotatate: an analysis of the NETTER-1 study

Purpose: To assess the impact of baseline liver tumour burden, alkaline phosphatase (ALP) elevation, and target lesion size on treatment outcomes with 177Lu-Dotatate. Methods: In the phase 3 NETTER-1 trial, patients with advanced, progressive midgut neuroendocrine tumours (NET) were randomised to 177Lu-Dotatate (every 8 weeks, four cycles) plus octreotide long-acting release (LAR) or to octreotide LAR 60 mg. Primary endpoint was progression-free survival (PFS). Analyses of PFS by baseline factors, including liver tumour burden, ALP elevation, and target lesion size, were performed using Kaplan-Meier estimates; hazard ratios (HRs) with corresponding 95% CIs were estimated using Cox regression. Results: Significantly prolonged median PFS occurred with 177Lu-Dotatate versus octreotide LAR 60 mg in patients with low ( 50%) liver tumour burden (HR 0.187, 0.216, 0.145), and normal or elevated ALP (HR 0.153, 0.177), and in the presence or absence of a large target lesion (diameter > 30 mm; HR, 0.213, 0.063). Within the 177Lu-Dotatate arm, no significant difference in PFS was observed amongst patients with low/moderate/high liver tumour burden (P = 0.7225) or with normal/elevated baseline ALP (P = 0.3532), but absence of a large target lesion was associated with improved PFS (P = 0.0222). Grade 3 and 4 liver function abnormalities were rare and did not appear to be associated with high baseline liver tumour burden. Conclusions: 177Lu-Dotatate demonstrated significant prolongation in PFS versus high-dose octreotide LAR in patients with advanced, progressive midgut NET, regardless of baseline liver tumour burden, elevated ALP, or the presence of a large target lesion. Clinicaltrials.gov : NCT01578239, EudraCT: 2011-005049-11

Impact of liver tumour burden, alkaline phosphatase elevation, and target lesion size on treatment outcomes with 177Lu-Dotatate: an analysis of the NETTER-1 study

Purpose: To assess the impact of baseline liver tumour burden, alkaline phosphatase (ALP) elevation, and target lesion size on treatment outcomes with 177Lu-Dotatate. Methods: In the phase 3 NETTER-1 trial, patients with advanced, progressive midgut neuroendocrine tumours (NET) were randomised to 177Lu-Dotatate (every 8 weeks, four cycles) plus octreotide long-acting release (LAR) or to octreotide LAR 60 mg. Primary endpoint was progression-free survival (PFS). Analyses of PFS by baseline factors, including liver tumour burden, ALP elevation, and target lesion size, were performed using Kaplan-Meier estimates; hazard ratios (HRs) with corresponding 95% CIs were estimated using Cox regression. Results: Significantly prolonged median PFS occurred with 177Lu-Dotatate versus octreotide LAR 60 mg in patients with low ( 50%) liver tumour burden (HR 0.187, 0.216, 0.145), and normal or elevated ALP (HR 0.153, 0.177), and in the presence or absence of a large target lesion (diameter > 30 mm; HR, 0.213, 0.063). Within the 177Lu-Dotatate arm, no significant difference in PFS was observed amongst patients with low/moderate/high liver tumour burden (P = 0.7225) or with normal/elevated baseline ALP (P = 0.3532), but absence of a large target lesion was associated with improved PFS (P = 0.0222). Grade 3 and 4 liver function abnormalities were rare and did not appear to be associated with high baseline liver tumour burden. Conclusions: 177Lu-Dotatate demonstrated significant prolongation in PFS versus high-dose octreotide LAR in patients with advanced, progressive midgut NET, regardless of baseline liver tumour burden, elevated ALP, or the presence of a large target lesion. Clinicaltrials.gov: NCT01578239, EudraCT: 2011-005049-11