An image-based notion for therapeuticplanar organ activity dosimetry in a developing country: Masterdose software.

OBJECTIVE: Planar dosimetry is often performed in developing countries due to its simplicity during basic quantitative dosimetry. The geometric mean method is often used during planar dosimetry and imaging counts can be corrected for background, attenuation and scatter. The aim of our study was to develop computerized software called Masterdose that may be used for therapeutic isotope planar organ personalized dosimetry. MATERIALS AND METHODS: Masterdose software uses various methods to correct for background, scatter and attenuation.We also introduced a method to convert imaging counts to activity on the software,which is Java based and runs on Windows, Linux and Macintosh platforms. RESULTS: Three user interfaces named image processing, quantification and dosimetry were developed for the software. Masterdose could quantify kidney and liver doses of lutetium-177-DOTA-0-Tyr3-octreotate (177Lu-DOTATATE) patients. The software was validated throughcalculation of the kidney and liver doses of ten neuroendocrine tumour patients (NET) treated with 177Lu-DOTATATE. CONCLUSION: Masterdose presents an option for planar quantification that can be used as a quality control tool to verify imaging counts and perform dosimetry in particular organs.

Lung and blood early biomarkers for host-directed tuberculosis therapies: Secondary outcome measures from a randomized controlled trial.

BACKGROUND: Current tuberculosis treatments leave most patients with bronchiectasis and fibrosis, permanent conditions that impair lung function and increase all-cause post-TB mortality. Host-directed therapies (HDTs) may reduce lung inflammation and hasten eradication of infection. Biomarkers can accelerate tuberculosis regimen development, but no studies have yet examined early biomarkers of TB-HDTs. METHODS: Biomarkers of inflammation and microbicidal activity were evaluated as a part of a recent phase-2 randomized controlled trial of four HDTs in 200 patients with pulmonary tuberculosis and baseline predictors of poor outcome, including CC-11050 (PDE4i), everolimus (mTORi), auranofin (oral gold salt), and ergocalciferol (vitamin D). Two of the 4 arms (CC-11050 and everolimus) showed superior recovery of lung function at day 180 compared to control; none showed accelerated eradication of MTB infection. Patients underwent 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) on entry and day 56. PET signals were analyzed according to total, maximal, and peak glycolytic activity; CT was analyzed according to total modified Hounsfield units to assess radiodensity. Mycobactericidal activity in ex vivo whole blood culture was measured on days 42, 84, and 140. C-reactive protein (CRP) was measured at multiple time points. RESULTS: All PET/CT parameters showed highly significant reductions from baseline to day 56; however, only maximal or peak glycolytic activity showed further experimental reduction compared to controls, and only in everolimus recipients. CRP dropped precipitously during early treatment, but did so equally in all arms; over the entire period of treatment, the rate of decline of CRP tended to be greater in CC-11050 recipients than in controls but this fell short of statistical significance. Whole blood mycobactericidal activity in ex-vivo culture was enhanced by auranofin compared to controls, but not by other HDTs. CONCLUSIONS: None of these early biomarkers correctly predicted HDT effects on inflammation or infection across all four experimental arms. Instead, they each appear to show highly specific responses related to HDT mechanisms of action.

Adjunctive host-directed therapies for pulmonary tuberculosis: a prospective, open-label, phase 2, randomised controlled trial.

BACKGROUND: Current tuberculosis treatments leave patients with clinically significant lung injury and increased all-cause mortality post-cure. Adjunctive host-directed therapies could protect the lungs, improve long-term survival, and shorten treatment duration; however, few have been tested clinically. Therefore, we aimed to assess the safety and preliminary efficacy of four host-directed therapies for tuberculosis. METHODS: In this prospective, open-label, phase 2, randomised controlled trial, patients with pulmonary tuberculosis were recruited at three clinical sites in South Africa. Eligible patients were aged 18-65 years, HIV-1-negative, and had rifampicin-susceptible Mycobacterium tuberculosis, a sputum Xpert cycle threshold of less than 20, and moderately advanced or far advanced disease on chest radiography. By use of numbers generated in blocks of ten and stratification by site, eligible patients were randomly assigned (1:1:1:1:1) to receive one of the four oral host-directed treatments plus standard tuberculosis treatment or standard treatment alone (the control group). Host-directed treatments were: CC-11050 (200 mg twice daily, taken with food; day 1-112); everolimus (0·5 mg/day; day 1-112); auranofin (3 mg/day for seven doses, then 6 mg/day; day 1-112); and ergocalciferol (5 mg on day 1, then 2·5 mg on day 28 and day 56). All study participants received oral rifabutin-substituted standard tuberculosis treatment for 180 days. Patients and clinicians were not masked to treatment assignment. Spirometry and sputum culture with solid and liquid media were done at baseline and up to 180 days at specified intervals throughout treatment. The primary endpoint was safety and tolerability up to day 210. Secondary preliminary efficacy endpoints were treatment effects on sputum microbiology (culture status at day 56 and the hazard ratio for stable culture conversion up to day 180) and lung function (FEV1 and forced vital capacity [FVC]) measured by spirometry at day 56, day 180, and day 540. Safety was analysed in the intention-to-treat population and preliminary efficacy primarily in the per-protocol population. The trial is registered at ClinicalTrials.gov, NCT02968927. Post-treatment follow-up was completed in 2020. FINDINGS: Between Nov 18, 2016, and Sept 27, 2018, 200 patients were screened and randomly assigned to different treatment groups (n=40 per group, apart from n=39 in the everolimus group after one patient withdrew consent). 11 treatment-emergent serious adverse events occurred either during treatment or within 30 days after treatment discontinuation, of which three were attributable to a host-directed treatment. Life-threatening thrombocytopenia occurred in an auranofin recipient; apparent intra-abdominal sepsis leading to death occurred in another auranofin recipient and was classified as a suspected unexpected serious adverse reaction. Tuberculous spondylitis occurred as an apparent paradoxical reaction in a patient receiving ergocalciferol. Two patients in the control group had life-threatening, treatment-attributable liver injury. No treatment-emergent, treatment-attributable serious adverse events occurred in patients receiving CC-11050 or everolimus. Mean FEV1 in the control group was 61·7% of predicted (95% CI 56·3-67·1) at baseline and 69·1% (62·3-75·8) at day 180. Patients treated with CC-11050 and everolimus had increased recovery of FEV1 at day 180 relative to the control group (mean difference from control group 6·30%, 95% CI 0·06-12·54; p=0·048; and 6·56%, 0·18-12·95; p=0·044, respectively), whereas auranofin and ergocalciferol recipients did not. None of the treatments had an effect on FVC during 180 days of follow-up or on measures of sputum culture status over the course of the study. INTERPRETATION: CC-11050 and everolimus were safe and reasonably well tolerated as adjunctive therapies for tuberculosis, and analysis of preliminary efficacy suggests they might also enhance the recovery of FEV1, a key measure of lung function and predictor of all-cause mortality. Further studies of these candidates are warranted. FUNDING: The Bill & Melinda Gates Foundation and the South African Medical Research Council.

Evaluation of technetium-99m metastable nanocolloid as an imaging agent for performing milk scans.

OBJECTIVE: The aim of this study was to determine whether technetium-99m (Tc) nanocolloid was a suitable alternative tracer for carrying out milk scan studies in pediatric patients. PARTICIPANTS AND METHODS: Twenty-seven milk scans performed with Tc nanocolloid were retrospectively assessed for identification of significant esophageal hold-up, gastroesophageal reflux, pulmonary aspiration, and gastric emptying (GE). Scans were also assessed for liver, spleen, and bone marrow uptake. GE results were compared with those of 27 randomly selected normal GE studies carried out using Tc tin colloid. RESULTS: None of the studies had liver, spleen, or bone marrow uptake, and all studies were interpretable. Significant esophageal hold-up and gastroesophageal reflux was observed in 11 and 48% of the patients, respectively. Only one patient had evidence of pulmonary aspiration, and all patients had normal GE at 2 h after radiolabeled milk ingestion. The average rate of GE at 2 h was faster in the Tc nanocolloid group compared with the Tc tin colloid group (8.85% retained±8.96% vs. 15.48% retained±10.52%, P=0.016). CONCLUSION: Our findings show that Tc nanocolloid is technically a suitable alternative to Tc sulfur colloid for performing milk scans. However, we could not conclude with certainty on the comparison of the GE rates of Tc nanocolloid and Tc tin colloid. This was because of the variability in the two population groups as well as the fact that the milk that was used in each patient was individualized to the patient and was not standardized.

A prospective study comparing 99mTc-MIBI and 99mTc-MDP with 99mTc-DTPA for lung ventilation scintigraphy in pulmonary thromboembolism.

OBJECTIVE: The aim of the study was to assess the efficacy of technetium 99m-methyl diphosphonate (Tc-MDP) and technetium 99m-methoxyisobutylisonitrile (Tc-MIBI) as radioaerosol alternatives to technetium 99m-diethylenetriaminepentacetate (Tc-DTPA) in the evaluation of pulmonary thromboembolism, as the direct consequence of the possible outcome could be cost saving. PATIENTS AND METHODS: Patients referred to our institution from August 2015 to July 2017 for a ventilation-perfusion scan who fulfilled the inclusion criteria were enrolled into the study as participants. Each ventilation agent was used to ventilate 43 participants, making a total of 129 participants in the study. Images were assessed for quality and alveolar clearance qualitatively and semiquantitatively correspondingly by a nuclear medicine physician blinded to the agent used. RESULTS: Tc-MIBI had higher count rates than Tc-DTPA and Tc-MDP, with a statistically significant difference when compared with Tc-DTPA (P=0.021). Tc-MIBI clearly showed slower alveolar clearance when compared with the clearance of Tc-DTPA (P≤0.0001) and Tc-MDP (P≤0.001). In terms of image quality, Tc-MIBI generally had better quality images as compared with the other two radioaerosols, with a statistically significant difference when compared with Tc-DTPA (P=0.001). CONCLUSION: Tc-MIBI had superior image quality and slower alveolar clearance when compared with Tc-DTPA. Alongside Tc-MDP, these agents can replace Tc-DTPA whenever clinically and economically applicable.