Synthesis and biological evaluation of modified laminin peptide (N2S2-KDP) with enhanced affinity for neuronal growth and targeted molecular imaging (SPECT).

An analog of γ1 laminin (RDIAEIIKDI) decapeptide has been used to augment neuronal survival and regeneration after injuries, during aging and other CNS disorder. As a prime synthetic peptide, KDI, is responsible for the neurite outgrowth of human embryonic neurons. In this study, we have designed, modified a KDI derivative and synthesized by replacing isoleucine (I) with Pro (P) amino acid at C-terminal to enhance its potency towards neurite growth. -Cys-Gly-Cys (-CGC) N2S2 motif was also incorporated in the present design for peptide radiolabeling. The modified peptide showed a better binding with the desired 3T1M receptor for neurite growth. The peptide was synthesized using solid phase peptide synthesis and Fmoc-strategy with more than 80% yield. The receptor binding studies of 99mTc-N2S2-KDP in Neuro2A cell lines showed Kd value in 31 nM range and the complex showed appreciable brain uptake in mice. The results on human SH-SY5Y indicate that the unlabeled N2S2-KDP may perhaps be useful for neurite growth in neurodegenerative disorder.

Estimation of radiation dose to patients from (18) FDG whole body PET/CT investigations using dynamic PET scan protocol.

BACKGROUND & OBJECTIVES: There is a growing concern over the radiation exposure of patients from undergoing 18FDG PET/CT (18F-fluorodeoxyglucose positron emission tomography/computed tomography) whole body investigations. The aim of the present study was to study the kinetics of 18FDG distributions and estimate the radiation dose received by patients undergoing 18FDG whole body PET/CT investigations. METHODS: Dynamic PET scans in different regions of the body were performed in 49 patients so as to measure percentage uptake of 18FDG in brain, liver, spleen, adrenals, kidneys and stomach. The residence time in these organs was calculated and radiation dose was estimated using OLINDA software. The radiation dose from the CT component was computed using the software CT-Expo and measured using computed tomography dose index (CTDI) phantom and ionization chamber. As per the clinical protocol, the patients were refrained from eating and drinking for a minimum period of 4 h prior to the study. RESULTS: The estimated residence time in males was 0.196 h (brain), 0.09 h (liver), 0.007 h (spleen), 0.0006 h (adrenals), 0.013 h (kidneys) and 0.005 h (stomach) whereas it was 0.189 h (brain), 0.11 h (liver), 0.01 h (spleen), 0.0007 h (adrenals), 0.02 h (kidneys) and 0.004 h (stomach) in females. The effective dose was found to be 0.020 mSv/MBq in males and 0.025 mSv/MBq in females from internally administered 18FDG and 6.8 mSv in males and 7.9 mSv in females from the CT component. For an administered activity of 370 MBq of 18FDG, the effective dose from PET/CT investigations was estimated to be 14.2 mSv in males and 17.2 mSv in females. INTERPRETATION & CONCLUSIONS: The present results did not demonstrate significant difference in the kinetics of 18FDG distribution in male and female patients. The estimated PET/CT doses were found to be higher than many other conventional diagnostic radiology examinations suggesting that all efforts should be made to clinically justify and carefully weigh the risk-benefit ratios prior to every 18FDG whole body PET/CT scan.

Synthesis and evaluation of curcumin reduced and capped gold nanoparticles as a green diagnostic probe with therapeutic potential.

Curcumin, a compound in turmeric, shows promise for its anti-cancer properties. In this study, we successfully synthesised curcumin-reduced and capped gold nanoparticles. Most evaluations have been limited to in-vitro studies for these nanoparticles; our study takes a step further by highlighting the in-vivo assessment of these curcumin-reduced and capped gold nanoparticles (GNPCs) using non-invasive imaging (SPECT and optical) and possible therapeutic potential. The GNPCs showed an average hydrodynamic diameter of 58 nm and a PDI of 0.336. The synthesised and fully characterised GNPCs showed ex-vivo hemolysis value of ≤ 1.74 % and serum stability of ≥ 95 % over 24 h. Using in-vivo non-invasive (SPECT and optical Imaging), prolonged circulation and enhanced bioavailability of GNPCs were seen. The biodistribution studies after radiolabelling GNPCs with 99 mTc complemented the optical imaging. The SPECT images showed higher uptake of the GNPCs at the tumour site, viz the contralateral muscle and the native Curcumin, resulting in a high target-to-non-target ratio that differentiated the tumour sufficiently and enhanced the diagnostics. Other organs also accumulate radiolabeled GNPCs in systemic circulation; bio dosimetry is performed. It was found that the dose received by the different organs was safe for use, and the in-vivo toxicity studies in rats indicated negligible toxicity over 30 days. The tumour growth was also reduced in mice models treated with GNPCs compared to the control. These significant findings demonstrate that GNPC shows synergistic activity in vivo, indicating its ability as a green diagnostic probe that has the potential for therapy.

[99mTc]Tc-DTPA-Bis(cholineethylamine) as an Oncologic Tracer for the Detection of Choline Transporter (ChT) and Choline Kinase (ChK) Expression in Cancer.

OBJECTIVE: The elevated choline transporters (ChT), choline kinase (ChK), choline uptake, and phosphorylation in certain tumor cells have influenced the development of radiolabeled choline derivatives as diagnostic probes for imaging cell membrane proliferation. We, therefore, aimed to develop a choline-based moiety for imaging choline kinase-overexpressed tumors by single-photon emission tomography (SPECT). A novel choline-based diagnostic probe was synthesized and evaluated preclinically in various ChT- and ChK-overexpressed tumor models for SPECT imaging applications. METHODS: The synthesis of diethylenetriaminepentaacetic acid-bis-choline ethylamine [DTPA-bis(ChoEA)] featured the conjugation of dimethylaminoethanol to a bifunctional chelator DTPA anhydride. [99mTc]Tc-DTPA-bis(ChoEA) was prepared, and its in vivo characteristics were evaluated in BALB/c mice and tumor-xenografted PC3, A549, and HCT116 athymic mouse models. The in vitro parameters, including cell binding and cytotoxicity, were assessed in PC3, A549, and HCT116 cell lines. To evaluate the specificity of the radioprobe, competitive binding studies were performed. Small-animal SPECT/CT diagnostic imaging was performed for in vivo evaluation. The mouse biodistribution data was further investigated to estimate the radiation dose in humans. RESULTS: In silico studies suggested high binding with enhanced specificity. A standard radiolabeling procedure using stannous chloride as a reducing agent showed a labeling yield of 99.5 ± 0.5%. The in silico studies suggested high binding with enhanced specificity. [99mTc]Tc-DTPA-bis(ChoEA) showed high in vitro stability and specificity. The pharmacokinetic studies of [99mTc]Tc-DTPA-bis(ChoEA) in mice showed an increased tumor-to-background ratio after few minutes of intravenous administration. The first-in-human trial was also conducted. The effective dose was estimated to be 0.00467 mSv/MBq (4.67 mSv/GBq), resulting in a radiation dose of up to 1.73 mSv for the 370 MBq injection of [99mTc]Tc-DTPA-bis(ChoEA). CONCLUSIONS: The synthesized radioprobe [99mTc]Tc-DTPA-bis(ChoEA) accumulates specifically in choline kinase-overexpressed tumors with a high signal-to-noise ratio. The preclinical and first-in-man data suggested that [99mTc]Tc-DTPA-bis(ChoEA) could potentially be used as a diagnostic SPECT tracer in the monitoring and staging of cancer.

Does the initial chest radiograph severity in COVID-19 impact the short- and long-term outcome? - a perspective from India.

PURPOSE: The chest radiograph (CXR) is among the most widely used investigations in coronavirus disease 2019 (COVID-19) patients. Little is known about its predictive role on the long-term outcome. The purpose of this study was to explore its association with the short and long-term outcome in COVID-19 patients. METHODS: A total of 1530 patients were assessed for the presence, radiographic pattern and distribution of lung lesions observed on baseline chest radiographs obtained at admission. The Brixia scoring system was applied for semiquantitative assessment of lesion severity. Short-term outcome was determined by clinical severity, duration of hospitalization and mortality. The 1415 survivors in this group were assessed after 5-6 months for the presence of residual symptoms. RESULTS: About 67% patients had an abnormal baseline CXR. Bilateral involvement with a basal preponderance was observed and ground-glass opacification was the most frequent finding. The Brixia score ranged from 0 to 16, median 2, interquartile range (IQR) [0-6]. About 36% patients were symptomatic on 5-6-month follow-up, with fatigability being the commonest symptom. A good correlation was observed between the CXR score and disease severity as well as duration of hospitalization. On multivariate analysis, the CXR score was found to be a significant independent predictor of in-patient mortality as well as presence of long-term residual symptoms in survivors. CONCLUSIONS: Disease severity as seen on the chest radiograph appears to play an important role in driving the short and long-term consequences of COVID-19 and could serve as a prognostic indicator, which influences short-term management and long-term follow-up.

Variation in Dosimeter Calibration Factor (NDW) Over a Period of 20 Years.

Long delays in renewal of calibration of secondary standards radiation dosimeters in radiation oncology centers due to the COVID19 pandemic have aroused concerns regarding accuracy in dose delivery to patients. The concerns are mainly due to the uncertainty in the absorbed dose to water calibration factor (NDW) over a period of time. In this study, the NDWfactor for two ion chambers, thimble type (Farmer) and parallel plate type (Markus), used in most of the radiotherapy centers, were retrospectively reviewed for 20 years. The calibration on all occasions except once was carried out at the Secondary Standards Dosimetry Laboratory, Bhabha Atomic Research Centre, Mumbai. The change in the NDWfactor over this period was < ±3%. We, therefore, believe that a dosimeter with no history of repairs showed reasonable stability in the NDWfactor over a long period.

A SIMPLE AND NOVEL APPROACH TO STUDY KINETICS AND ESTIMATE RADIATION DOSES FROM INTERNALLY ADMINISTERED RADIOPHARMACEUTICALS USING AN EXTERNAL DOSE MEASUREMENT SYSTEM.

Various methods have been reported to study radiotracer kinetics and make internal dosimetry feasible in the routine clinical nuclear medicine practice. The aim of the present study was to quantify cumulative activity and organ doses using an indigenously designed and fabricated external dose measurement system. The measurement was demonstrated on patients undergoing whole-body (WB) 18F-FDG (Fluorine-18-fluorodeoxyglucose) direct positron emission tomography/computed tomography investigations. An external dose measurement system comprising of an ionisation chamber-survey meter and the movable focussing collimator was used to quantify the uptake of 18F-FDG in liver and brain. Cumulative activity and normalised cumulative activity in these organs were calculated. The results were validated by performing measurements on a phantom uniformly filled with known activity of 18F-FDG.The difference in the absorbed dose estimated with and without collimator was statistically significant (p < 0.05). The external dose measurement technique is relatively novel, convenient and reliable for the assessment of internal absorbed dose of organs.

Simplifying Tumor Volume Estimation from Linear Dimensions for Intra-Cranial Lesions Treated with Stereotactic Radiosurgery.

AIMS: This study aims to derive simple yet robust formula(s) for the calculation of cranial tumor volume using linear tumor dimensions in anterioposterior (AP), mediolateral (ML) and craniocaudal (CC) directions and also propose a reproducible methodology for tumor dimension measurements. MATERIALS AND METHODS: Magnetic resonance images (MRI) of 337 patients planned for Gammaknife Stereotactic Radiosurgery for different types of brain tumors were analyzed using Leksell Gamma Plan (LGP) software. Tumor volume in three dimensional was outlined and maximum tumor diameters were measured in three orthogonal directions AP, ML, and CC on the MRI. Formulas were derived to calculate tumor volume from AP, ML, and CC diameters using linear regression technique. An agreement between the calculated volume and standard volume observed from LGP software was determined using Bland Altman (B-A) plot. A comparison was made between the volume calculated using traditionally used formula of ellipsoid, standard volume obtained from LGP software and volume calculated from formulas derived in the present study. RESULTS: The tumors were divided into two categories based on their size for better volume prediction. The tumors having product of their diameters in the range 0-2.5cc were called "small tumors" and the formula proposed for their volume estimation (V = 1.513) × (AP × ML × CC) + 0.047 ) was found to predict the tumor volume with an average bias of 0.0005cc. For "large tumors," having product of diameters in the range 2.5-36cc, the proposed formula (V = 0.444 × (AP × ML × CC) + 0.339 ) predicted the tumor volume with an average bias of 0.007cc. CONCLUSIONS: The two formulas proposed in the study are more accurate as compared to the commonly used formula that considers the tumors as ellipsoids. The methodology proposed in the study for measurement of linear tumor dimensions is simple and reproducible.

Quantification of DNA damage in patients undergoing non-contrast and contrast enhanced whole body PET/CT investigations using comet assay and micronucleus assay.

Objective: To quantify DNA damage in patients undergoing non-contrast and contrast-enhanced 18F-FDG PET/CT whole body positron emission tomography/computed tomography (WB PET/CT) investigations using comet assay technique and micronucleus assay, and to study the effect of other baseline parameters of patients on DNA damage. Methodology: Eighty-four patients referred for 18F-FDG PET/CT investigation were included in the study of which 44 patients underwent contrast-enhanced WB PET/CT and 40 patients underwent non-contrast WB PET/CT investigations. The investigations were performed on Discovery 690 PET/CT. For contrast-enhanced investigation, Omnipaque300 was injected intravenously based on the patient body weight. Absorbed dose resulting from the intravenous administration of 18F-FDG was estimated using the ICRP 106 dose coefficients. Radiation dose from the acquisition of CT scans was estimated using CT dose index and dose-length product. Blood samples were collected from the patients for DNA damage analysis. Comet assay and MN assay was used to assess the DNA damage. The Differences in the comet TM (Tail Moment) and MNBC % in both groups were calculated. Result: The radiation dose received by the study population during 18F-FDG WB PET/CT examination was 27.03 ± 2.33 mSv. Comet TM and percentage frequency of MNBC % was 65.22 ± 35.42 and 18.55 ± 10.14, respectively in the patients injected with contrast and 42.49 ± 28.52 and 13.76 ± 7.52 for non-contrast group. Significant increase in DNA damage was observed in the contrast group as compared to non-contrast group. Significant association was observed between patient weight, contrast volume and TM and MNBC%. Baseline parameters of the patients did not show significant correlation with TM and MNBC%. Conclusion: The patients undergoing contrast-enhanced WB PET/CT investigations have demonstrated higher DNA damage. The DNA damage was also observed to be more in heavier patients. The other baseline parameters of patients like age, sex, CBG, serum creatinine did not show any correlation with DNA damage.

Role of 99mTc-Tetrofosmin delayed scintigraphy and color Doppler sonography in characterization of solitary thyroid nodules.

OBJECTIVES: A study was undertaken to evaluate the diagnostic efficiency of Tc-Tetrofosmin scan and color Doppler in the characterization of benign and malignant solitary thyroid nodules. METHODS: Fifty-two patients found to have a cold solitary thyroid nodule on Tc-pertechnetate scintigraphy were included in this study. All patients underwent a single-injection dual-phase (30 min and 120 min) Tc-Tetrofosmin scan. The intranodular vascularity was measured using color Doppler sonography. Fine-needle aspiration cytology was performed on all the patients. In the following days and weeks all patients underwent surgery. RESULTS: Thirteen out of 15 patients with thyroid cancer showed delayed retention of radiotracer (on 120 min images as compared to the initial 30 min image). Thirty-six out of 37 patients harboring benign solitary nodules showed significant washout of tracer on delayed images. Sensitivity, specificity, positive predictive value and negative predictive value of delayed Tc-Tetrofosmin scintigraphy were found to be 86.6, 97.2, 92.8 and 94.7%, respectively. The Doppler study was able to demonstrate increased vascularity in the center of 8 of the 15 malignant nodules. Thirty-two patients harboring a benign solitary nodule showed normal or increased peripheral vascularity on Doppler study. Sensitivity, specificity, positive predictive value and negative predictive value of color Doppler were found to be 53.5, 86.4, 61.5 and 82%, respectively. CONCLUSION: Delayed Tc-Tetrofosmin scintigraphy is a highly sensitive and specific method for characterizing solitary thyroid nodules, while color Doppler has a low sensitivity but relatively high specificity in differentiating benign from malignant thyroid lesions.

The phenomenon of drop in output at larger field sizes for telecobalt units.

It is known that the output factors (OPFs) for external-beam radiotherapy units increase with field size due to increased scattered radiation from the collimator system. Saturation in the OPF value is generally reported beyond approximately 30 × 30 cm(2). For the first time, to the best of our knowledge, we report on a drop in OPF values, although marginal, measured for a telecobalt machine beyond the 38 × 38 cm(2) field size. We believe that reporting and explaining the results will lead to a better understanding of the scatter composition of the radiation from telecobalt machines. This also has the potential to impact the estimation of low dose regions in patients, in addition to being a purely scientific inquiry. We used Monte Carlo (MC) simulations to validate the measured values. The MC data showed that the decrease in OPF was due to decreased scatter from the machine head.

Estimation of patient dose in (18)F-FDG and (18)F-FDOPA PET/CT examinations.

PURPOSE: To estimate specific organ and effective doses to patients resulting from the (18)F-FDG ((18)F-2-deoxy-D-glucose) and (18)F-FDOPA (6-fluoro-((18)F)-L-3, 4-dihydroxyphenylalanine) PET/CT examinations for whole body and brain. MATERIALS AND METHODS: Three protocols for whole body and three for brain PET/CT were used. The CTDI values were measured using standard head and body CT phantoms and also computed using a software CT-Expo for dose evaluation from the CT component. OLINDA software based on MIRD method was used for estimating doses from the PET component of the PET/CT examination. RESULTS: The organ doses from (18)F-FDG and (18)F-FDOPA whole body and brain PET/CT studies were estimated. The total effective dose from a typical protocol of whole body PET/CT examination was 14.4 mSv for females and 11.8 mSv for male patients from (18)F-FDG, whereas it was 11 mSv for female and 9.1 mSv for male patients from (18)F-FDOPA. The total effective doses from a typical protocol for PET/CT studies of brain was 6.5 mSv for females and 5.1 mSv for males from (18)F-FDG whereas it was 3.7 mSv for females and 2.8 mSv for males from (18)F-FDOPA. CONCLUSIONS: The effective radiation doses from whole body PET/CT examination was approximately 4-8 times higher than the background radiation dose from both (18)F-FDG and (18)F-FDOPA scans, while it was 1-3 times the background radiation dose from PET/CT scans of brain.

Correlation of physical parameters during radiochemical synthesis of (18)F positron emission tomography radiopharmaceuticals.

Positron emission tomography is a highly specialized imaging technique using short-lived radiolabel substances to produce extremely high resolution images of the body's biological function. The (18)F(-) ion is produced via the (18)O(p,n)(18)F reaction using a silver target cell filled with 1.4 mL of enriched [(18)O] water. On a typical run, the target is irradiated for 45 minutes with 16.5 MeV protons (on target) and an average beam current of 5-45 mA. When the same reaction takes place with [(16)O] water [(13)N] Ammonia is produced as the primary product by the abstraction of hydrogen from water. This study investigated the physical parameters of medical cyclotron during the radiochemical process with induced radioactivity flux and mutual correlation of physical parameters for 16.5 MeV medical cyclotron at the INMAS Delhi, India. It is observed that by getting farther from the target, the relative number of low-energy neutrons increases while the overall flux of neutrons decreases. This is due to multiple scattering of high-energy neutrons in the walls and eventually absorption of low-energy neutrons. The other parameters are also linked with each other which are correlatable.

Spectrum of neurocognitive dysfunction in Indian population on FDG PET/CT imaging.

BACKGROUND: A variety of neurodegenerative disorders produce significant abnormal brain function which can be detected using fluorodeoxyglucose positron emission tomography (FDG PET) scan even when structural changes are not detected on CT or MRI Scan. A study was undertaken at our institute to evaluate the FDG PET/CT findings in Indian population suffering from mild cognitive impairment (MCI), Alzheimer's disease (AD), fronto-temporal dementia (FTD), dementia with lewy body disease (DLBD) and other miscellaneous causes of dementia. MATERIALS AND METHODS: 117 subjects having neurocognitive deficits and 36 normals were included in our study. All patients underwent a detailed history and clinical examination. This was followed by a mini mental state examination. Subsequently an FDG brain PET scan and an MRI were done. RESULTS: In the patient population included in our study group 36 were normal, 39 had MCI, 40 had AD, 14 had FTD, and 13 had DLBD and 11 dementia due to other miscellaneous causes. MCI patients showed primarily reduced tracer uptake in the mesio-temporal cortex. AD patients showed reduced tracer concentration in temporo-parietal lobes, while patients with advanced diseases showed frontal lobe disease additionally. In subjects of FTD, reduced radiotracer uptake in the fronto-temporal lobes was noted. In addition, FTD patients also showed basal ganglia defects. In contrast the DLBD patients showed globally reduced FDG uptake including severely affecting the occipital cortices. CONCLUSION: In the current study the F18-FDG PET scans have been shown to be highly useful in the diagnosis of various neurocognitive disorders of the brain. AD was found to be the most common dementia in the Indian population followed by MCI. Diffuse Lewy body disease, FTD and other miscellaneous categories of dementia had a near similar incidence.