Target heterogeneity in oncology : the best predictor for differential response to radioligand therapy in neuroendocrine tumors and prostate cancer

Tumor or target heterogeneity (TH) implies presence of variable cellular populations having different genomic characteristics within the same tumor, or in different tumor sites of the same patient. The challenge is to identify this heterogeneity, as it has emerged as the most common cause of ‘treatment resistance’, to current therapeutic agents. We have focused our discussion on ‘Prostate Cancer’ and ‘Neuroendocrine Tumors’, and looked at the established methods for demonstrating heterogeneity, each with its advantages and drawbacks. Also, the available theranostic radiotracers targeting PSMA and somatostatin receptors combined with targeted systemic agents, have been described. Lu-177 labeled PSMA and DOTATATE are the ‘standard of care’ radionuclide therapeutic tracers for management of progressive treatment-resistant prostate cancer and NET. These approved therapies have shown reasonable benefit in treatment outcome, with improvement in quality of life parameters. Various biomarkers and predictors of response to radionuclide therapies targeting TH which are currently available and those which can be explored have been elaborated in details. Imaging-based features using artificial intelligence (AI) need to be developed to further predict the presence of TH. Also, novel theranostic tools binding to newer targets on surface of cancer cell should be explored to overcome the treatment resistance to current treatment regimens.http://www.mdpi.com/journal/cancerspm2021Nuclear Medicin

Target Heterogeneity in Oncology: The Best Predictor for Differential Response to Radioligand Therapy in Neuroendocrine Tumors and Prostate Cancer

Tumor or target heterogeneity (TH) implies presence of variable cellular populations having different genomic characteristics within the same tumor, or in different tumor sites of the same patient. The challenge is to identify this heterogeneity, as it has emerged as the most common cause of ‘treatment resistance’, to current therapeutic agents. We have focused our discussion on ‘Prostate Cancer’ and ‘Neuroendocrine Tumors’, and looked at the established methods for demonstrating heterogeneity, each with its advantages and drawbacks. Also, the available theranostic radiotracers targeting PSMA and somatostatin receptors combined with targeted systemic agents, have been described. Lu-177 labeled PSMA and DOTATATE are the ‘standard of care’ radionuclide therapeutic tracers for management of progressive treatment-resistant prostate cancer and NET. These approved therapies have shown reasonable benefit in treatment outcome, with improvement in quality of life parameters. Various biomarkers and predictors of response to radionuclide therapies targeting TH which are currently available and those which can be explored have been elaborated in details. Imaging-based features using artificial intelligence (AI) need to be developed to further predict the presence of TH. Also, novel theranostic tools binding to newer targets on surface of cancer cell should be explored to overcome the treatment resistance to current treatment regimens

Intense focal Fluoro-deoxyglucose uptake in the lungs with no corresponding computed tomography abnormality

Scenario such as uptake of Fluoro-deoxyglucose (FDG) with no corresponding abnormality on computed tomography (CT) is encountered in case of brown fat uptake. However, it is rarely encountered in the lung parenchyma. We report one such case of a focal FDG uptake in the lung parenchyma with no corresponding CT abnormality, in a treated case of hypopharyngeal cancer

PET reconstruction artifact can be minimized by using sinogram correction and filtered back-projection technique

Filtered Back-Projection (FBP) has become an outdated image reconstruction technique in new-generation positron emission tomography (PET)/computed tomography (CT) scanners. Iterative reconstruction used in all new-generation PET scanners is a much improved reconstruction technique. Though a well-calibrated PET system can only be used for clinical imaging in few situations like ours, when compromised PET scanner with one PET module bypassed was used for PET acquisition, FBP with sinogram correction proved to be a better reconstruction technique to minimize streak artifact present in the image reconstructed by the iterative technique

Performance characteristic evaluation of a bismuth germanate-based high-sensitivity 5-ring discovery image quality positron emission tomography/computed tomography system as per National Electrical Manufacturers Association NU 2-2012

National Electrical Manufacturers Association (NEMA) provides guidelines to assess the performance of Positron Emission Tomography (PET). A PET/CT scanner, Discovery IQ, GE Medical systems, Milwaukee, USA was installed in our department which has high a sensitivity PET component. We have performed the NEMA NU-2 2012 quality control tests to evaluate this system on site before clinical use. Performance measurements of the PET scanner were made using the NEMA NU2-2012 procedures for spatial resolution, scatter fraction, sensitivity, count rate loss and random coincidence estimation, Noise Equivalent Count Rate (NECR) and image quality. As per NU2 2012, spatial resolution was measured at 1 cm, 10 cm and 20 cm vertically from the centre and at each of these points resolution was measured at tangential, radial and axial directions. Sensitivity was measured at centre and 10 cm off center vertically from the center. The system sensitivity is reported as an average of the two measured values. Scatter fraction and NECR measurements, Image quality test was also performed. The tangential, radial and axial FWHM were 4.99 mm, 4.20 mm and 4.79 mm at 1 cm off centre, 5.49 mm, 4.69 mm and 4.81 mm at 10 cm off centre and 7.99 mm, 5.07 mm and 4.95 mm at 20 cm off centre respectively. The absolute sensitivity of this scanner was found to be 20.1 cps/kBq. The scatter fraction calculated from the decay method was 37.94% and NECR was 125 kcps. The peak NECR was achieved at activity concentration of 8.7 KBq/ml and the count loss below the peak NECR was found to be 0.68%. Image quality test for, contrast recovery, background variability and lung error residual mean met all specifications. Overall PET performance of Discovery IQ whole-body scanner was satisfactory and the scanner met all the performance specifications required by NEMA 2012.</p

Development of a [lu-177]bpamd labeling kit and an automated synthesis module for routine bone targeted endoradiotherapy

Painful bone lesions, both benign and metastatic, are often managed using conventional analgesics. However, the treatment response is not immediate and is often associated with side-effects. Radionuclide therapy is used for pain palliation in bone metastases as well as some benign neoplasms. Endoradiotherapy has direct impact on the pain-producing bone elements, and hence, response is significant, with minimal or no side-effects. A new potential compound for endoradiotherapy is [Lu-177]BPAMD. It combines a highly affine bisphosphonate, covalently bridged with DOTA through an amide bond, with the low-energy beta(-) emitting therapeutic radiolanthanide Lu-177. For routine chemical application, an automated synthesis of this radiopharmaceutical and a Kit-type labeling procedure appears to be a basic requirement for its good manufacturing practice (GMP) based production. A Kit formulation combining BPAMD, acetate buffer, and ethanol resulted in almost quantitative labeling yields. The use of ethanol and ascorbic acid as quenchers prevented radiolysis over 48 hours. An automated synthesis unit was designed for the production of therapeutic doses of [Lu-177]BPAMD up to 5 GBq. The procedure was successfully applied for patient treatments

Reverse swing-M, phase 1 study of repurposing mebendazole in recurrent high-grade glioma

BackgroundRelapsed high-grade glioma has dismal outcomes. Mebendazole has shown promising activity against glioma in in-vitro and in-vivo studies. Hence, we undertook a phase 1 study to repurpose mebendazole in the treatment of glioblastoma.MethodsWe conducted a phase 1 study (accelerated titrated design 4) of mebendazole in patients with recurrent glioblastoma (GBM). Patients eligible for re-irradiation were enrolled in arm A1 (radiation with concurrent temozolomide 75 mg/m2 daily during the course of radiation+mebendazole) while patients who were ineligible were enrolled in either arm B1 (CCNU 110 mg/m2 day 1, every 6 weekly + mebendazole) or arm C1 (temozolomide 200 mg/m2 day 1-5, every 4 weekly + mebendazole). The primary endpoint of phase 1 was to identify the MTD of mebendazole in each combination.Findings11 patients were enrolled in the whole study. MTD of mebendazole was not reached in arm A1 and C1 and hence the recommended dose for phase 2 was 1600 mg TDS (4800 mg) per day. The MTD of mebendazole in combination with CCNU was 1600 mg TDS (4800 mg) per day and the dose recommended for phase 2 was 800 mg TDS (2400 mg) per day. The three most common adverse events seen in the study were anemia (n = 9, 81.8%), nausea (n = 7, 63.6%), and fatigue (n = 6, 55.5%).InterpretationThe recommended phase 2 dose of mebendazole is 1600 mg TDS with temozolomide and temozolomide-radiation combination while the dose of 800 mg TDS needs to be used with single-agent CCNU