Haematotoxicity during peptide receptor radionuclide therapy: Baseline parameters differences and effect on patient's therapy course.

BACKGROUND: Mainly severe (CTCAE grade 3-4) haematotoxicity during peptide receptor radionuclide therapy (PRRT) is reported in literature due to major clinical impact, however moderate (CTCAE grade 2) haematotoxicity is common and could affect therapy management. The aim of this study was to evaluate the haematotoxicity course during PRRT and to compare baseline parameters between haematotoxicity grades. METHODS: In this retrospective study, 100 patients with a neuroendocrine tumour treated with PRRT were included. Patients were treated with an aimed number of four cycles with 7.4 GBq [177Lu]Lu-DOTA-TATE administered every 10 weeks. Haematological assessment was performed at baseline and frequently up to 10 weeks after the fourth cycle. The lowest haematological value was graded according to CTCAE v5.0, and patients were classified using the highest observed grade. Differences in baseline parameters, including [68Ga]Ga-DOTA-TATE positive tumour volume, were evaluated between CTCAE grades. RESULTS: Four cycles were completed by 86/100 of patients, 4/100 patients discontinued due to haematotoxicity, and 10/100 patients due to progressive disease. The treatment course was adjusted due to haematotoxicity in 24/100 patients, including postponed next cycle (n = 17), reduced administered activity (n = 13), and both adjustments (n = 10). The most observed haematotoxicity grade was grade 0-1 in 54/100 patients, grade 2 in 38/100 and grade 3-4 in 8/100. Significant differences in baseline leucocyte, neutrophil and platelet counts were observed between grade 0-1 and grade 2. However, the correlation between baseline and lowest observed values was poor to moderate. No differences between haematotoxicity grades and baseline parameters or somatostatin receptor positive tumour volume was observed. CONCLUSIONS: The incidence of severe haematotoxicity was low with extensive screening and monitoring. The vast majority of patients (96/100) was not restricted in treatment continuation by haematotoxicity; therefore, our selection criteria appeared appropriate for safe PRRT treatment. Baseline parameters showed limited correlation with the degree of decline in haematological values.

177 Lutetium SPECT/CT: Evaluation of collimator, photopeak and scatter correction.

PURPOSE: The goal of this study was to find the optimal combination of collimator, photopeak and scatter correction for 177 Lutetium (177 Lu) SPECT/CT imaging. METHODS: Three experiments [sphere-to-background ratios (SBR) 50:1, 10:1, and 2:1] were performed with the NEMA Image Quality phantom filled with 177 Lu-trichloride. SPECT/CT acquisitions were performed with the medium-energy low-penetration (MELP) collimator and 99m Tc/Krypton collimator. For each acquisition six reconstructions, all with attenuation correction (AC), were made: the 113-keV photopeak only, the 208-keV photopeak only and both photopeaks combined, each with or without scatter correction (SC). Image quality was assessed using contrast-to-noise ratios (CNR), quantification accuracy by means of recovery coefficients (RCs) and the spatial resolution using line profiles. RESULTS: With SBR 50:1 and 10:1, both collimators met the Rose criterion (CNR > 5), whereas the MELP collimator showed a higher CNR for the 2:1 ratio. The RCmean was higher with the MELP collimator, most explicit after the 208-keV AC/SC reconstruction for all acquisitions. The line profiles showed a better spatial resolution for the MELP collimator and the 208-keV AC/SC reconstructions. CONCLUSION: 177 Lu SPECT/CT image quality and quantification was most optimal when acquired with the MELP collimator and reconstructed using the 208-keV photopeak, with AC and SC.

A head-to-head comparison between two commercial software packages for hybrid dosimetry after peptide receptor radionuclide therapy.

BACKGROUND: Dosimetry after peptide receptor radionuclide therapy (PRRT) is increasing; however, comparing or pooling of dosimetric results can be challenging since different approaches are used. The aim of this study was to perform a head-to-head comparison of post-PRRT curve fitting and dosimetry obtained from two commercial software Hybrid Viewer Dosimetry and PLANET Dose. METHODS: Post-therapy imaging included planar scintigraphy at 0.5, 4, 24 and 72 h post-injection of [177Lu]Lu-DOTA-TATE for kinetics and SPECT/CT at 24 h for quantification. On planar imaging, 2 cm regions-of-interest were positioned within the inferior pole of the kidneys and kidney cortex was segmented on low-dose CT. On both planar and SPECT/CT, 2 cm spheres were positioned in the proximal humerus (red marrow equivalent) and in the region with the highest uptake in tumour lesions. TACs were estimated with mono- and bi-exponential fits in both software systems, after which tissue absorbed (kidney, red marrow, tumour) and biological effective doses (kidney) were calculated. Agreement-ICC, Spearman correlation and Bland-Altman plots were used to compare results. RESULTS: Mono-exponential fits showed the most comparable correlation between the measured and fitted data between both software. The ICC between absorbed dose outcomes was > 0.7 in tumour lesions and kidneys, but negative for the red marrow. Spearman correlation was > 0.9 for mono-exponential fits in kidneys and tumour lesions, and -0.7 in red marrow. Bi-exponential fits resulted in lower correlations and agreement values. Concordance between both software packages concerning the number of PRRT cycles with 7.4 GBq was observed based on a biological effective dose limit of 27 Gy to the kidneys. CONCLUSION: [177Lu]Lu-DOTA-TATE dosimetry results of two software packages were comparable in the same dataset, despite the limited number of imaging time-points. However, these results should be verified in a larger cohort before pooling of clinical data, as the obtained results will depend on acquisition protocol, timing and lesions definition.

Multicentre quantitative 68Ga PET/CT performance harmonisation.

PURPOSE: Performance standards for quantitative 18F-FDG PET/CT studies are provided by the EANM Research Ltd. (EARL) to enable comparability of quantitative PET in multicentre studies. Yet, such specifications are not available for 68Ga. Therefore, our aim was to evaluate 68Ga-PET/CT quantification variability in a multicentre setting. METHODS: A survey across Dutch hospitals was performed to evaluate differences in clinical 68Ga PET/CT study protocols. 68Ga and 18F phantom acquisitions were performed by 8 centres with 13 different PET/CT systems according to EARL protocol. The cylindrical phantom and NEMA image quality (IQ) phantom were used to assess image noise and to identify recovery coefficients (RCs) for quantitative analysis. Both phantoms were used to evaluate cross-calibration between the PET/CT system and local dose calibrator. RESULTS: The survey across Dutch hospitals showed a large variation in clinical 68Ga PET/CT acquisition and reconstruction protocols. 68Ga PET/CT image noise was below 10%. Cross-calibration was within 10% deviation, except for one system to overestimate 18F and two systems to underestimate the 68Ga activity concentration. RC-curves for 18F and 68Ga were within and on the lower limit of current EARL standards, respectively. After correction for local 68Ga/18F cross-calibration, mean 68Ga performance was 5% below mean EARL performance specifications. CONCLUSIONS: 68Ga PET/CT quantification performs on the lower limits of the current EARL RC standards for 18F. Correction for local 68Ga/18F cross-calibration mismatch is advised, while maintaining the EARL reconstruction protocol thereby avoiding multiple EARL protocols.

Tumor heterogeneity on (18)F-FDG-PET/CT for response monitoring in non-small cell lung cancer treated with erlotinib.

Response monitoring using fluorodeoxyglucose positron emission tomography acquired together with low dose computed tomography (FDG-PET/CT) textural features has potential in targeted treatment with erlotinib in non-small cell lung cancer (NSCLC) patients. Patients with substantial decrease of metabolic activity during erlotinib treatment will probably benefit from continued treatment. However, various aspects of the method (quantification tools, cut-off values, etc.) need to be standardized before the software becomes widely available in a similar manner as standardized uptake value (SUV) measurements. Heterogeneity on FDG-PET/CT opened an additional window for innovation but simultaneously a new challenge for molecular hybrid imaging.

Pleural pressure swing and lung expansion after malignant pleural effusion drainage: the benefits of high-temporal resolution pleural manometry.

BACKGROUND: Malignant pleural effusion is a common complication in end-stage cancer patients and can cause severe dyspnea. Therapeutic thoracentesis is often limited to 1 to 1.5 L. Pleural manometry can be used to recognize a not-expanded lung. METHODS: Interval pleural pressure measurements with a high temporal resolution were performed after each removal of 200 mL of fluid to observe pleural pressure swings. Pleural elastance was defined as the difference in pleural pressure divided by the change in volume. Chest x-rays were performed to evaluate lung expansion, reexpansion pulmonary edema, and fluid residue. RESULTS: Thirty-four procedures in 30 patients were eligible for analysis. Four patients had incomplete lung expansion after drainage. No reexpansion pulmonary edema was observed. Pleural pressure swing after 200 mL drainage was higher when the lung did not expand. Pleural elastance after removal of 500 mL was higher in the not-expanded subgroup. CONCLUSIONS: We demonstrated that a high pleural pressure swing after removal of only 200 mL was related to incomplete lung expansion. We confirmed the association between pleural elastance and lung expansion.

Potential value of color-coded dynamic breast-specific gamma-imaging; comparing (99m)Tc-(V)-DMSA, (99m)Tc-MIBI, and (99m)Tc-HDP in a mouse mammary tumor model.

Using a mouse mammary tumor model based on orthotopic transplantation of luciferase-expressing mouse ILC cells (KEP1-Luc cells), we evaluated the diagnostic value of three clinically applied tracers: (99m)Tc-(V)-DMSA, (99m)Tc-MIBI, and (99m)Tc-HDP. Uptake of the tracers is compared using static and dynamic imaging procedures. We found that dynamic imaging in combination with pixel-by-pixel color coding has an added value over (high resolution) static imaging procedures. Such dynamic imaging procedures could enhance the potential of breast-specific gamma-imaging.

Influence of breathing resistance of heat and moisture exchangers on tracheal climate and breathing pattern in laryngectomized individuals.

BACKGROUND: The aim of this study was to determine the influence of breathing resistance of heat and moisture exchangers (HMEs) on endotracheal climate and breathing pattern. METHODS: Endotracheal temperature and humidity and tidal volumes were measured in 11 laryngectomized patients with a regularly used HME with "standard" breathing resistance (Provox Normal HME; R-HME), a low breathing-resistance HME (Provox HiFlow HME; L-HME), and without HME. RESULTS: Both R-HME and L-HME increased end-inspiratory humidity (+5.8 and 4.7 mgH(2)O/L, respectively), decreased end-inspiratory temperature (-1.6 and -1.0 degrees C, respectively), and prolonged the exhalation breath length to approximately 0.5 seconds. The R-HME significantly enlarged tidal volumes (0.07 L; p < .05). CONCLUSIONS: Both HMEs significantly improve tracheal climate. The R-HME has better moistening properties and a small but significant positive effect on tidal volume. Therefore, if the higher resistance is tolerated, the R-HME is the preferred pulmonary rehabilitation device. The L-HME is indicated if lower breathing resistance is required.

The influence of a heat and moisture exchanger on tracheal climate in a cold environment.

OBJECTIVE: The incidence of pulmonary complaints, severe tracheitis and lung function deterioration is increased during wintertime in laryngectomized individuals. We analyzed how a heat and moisture exchanger (HME) performs in cold and dry ambient circumstances, and how its efficiency in this environmental climate might be improved. STUDY DESIGN: Randomized crossover. METHODS: Intra-tracheal temperature and humidity were measured in 10 laryngectomized patients with and without HME, in a cold (mean, 4.7 degrees C) and dry (mean, 4.5 mgH2O/L) room. RESULTS: Presence of an HME causes the intra-tracheal mean humidity minima and maxima to increase with 4.2 mgH2O/L (95%CI: 3.3-5.0 mgH2O/L; p<0.001) and 2.4 mgH2O/L (95%CI: 1.7-3.1 mgH2O/L; p<0.001), respectively. The intra-tracheal mean temperature minima and maxima increased with 3.9 degrees C (95%CI: 2.7-5.1 degrees C; p<0.001) and 1.2 degrees C (95%CI: 0.8-1.2 degrees C; p<0.001), respectively. In the majority of patients, the calculated relative humidity values appear to reach well above 100% during inspiration. CONCLUSION: In a cold environment, presence of an HME significantly increases both inspiratory and expiratory temperature and humidity values. Relative humidity calculations suggest the formation of condense droplets during inspiration. To further increase its effectiveness, improvement of the HME's thermal capacity should be aimed for.

Assessment of tracheal temperature and humidity in laryngectomized individuals and the influence of a heat and moisture exchanger on tracheal climate.

BACKGROUND: The beneficial function of heat and moisture exchangers (HMEs) is undisputed, but knowledge of their effects on intra-airway temperature and humidity is scarce. The aim of this study was to evaluate the clinical applicability of a new airway climate explorer (ACE) and to assess the HME's influence on tracheal climate. METHODS: Intratracheal temperature and humidity were measured with and without HME in 10 laryngectomized patients. RESULTS: An HME causes the intratracheal mean humidity minima to increase with 3.2 mg H(2)O/L (95% CI: 1.5-4.8 mg H(2)O/L; p <.001), from 21.4 to 24.6 mg H(2)O/L, and the mean temperature minima to decrease with 1.6 degrees C (95% CI: 0.9-2.4 degrees C; p <.001) from 28.5 degrees C to 26.9 degrees C. Relative humidity values suggest that the tested HME keeps inspired air (nearly) fully saturated during the full course of inspiration. CONCLUSION: Assessment of intratracheal temperature and humidity, and evaluation of HME effectiveness is feasible with the ACE. The tested HME significantly increases the intratracheal humidity, but decreases the intratracheal temperature. Relative humidity calculations suggest that increasing the thermal capacity of this rehabilitation device can further increase the heat and moisture exchange efficiency.

Application of PET/CT in the development of novel anticancer drugs.

Combined positron emission tomography/computed tomography (PET/CT) is a relatively new imaging modality, combining the functional images of PET with the anatomical information of CT. Since its commercial introduction about 5 years ago, PET/CT has become an important tool in oncology. Currently, the technique is used for primary staging and restaging of cancer patients, as well as for surgery and radiation therapy planning. The abilities of PET/CT to measure early treatment response as well as drug distribution within the body make this technique very useful in the development of novel anticancer drugs. In this paper, the recent literature on the current role of PET/CT in drug development is reviewed.

Influence of heat and moisture exchanger respiratory load on transcutaneous oxygenation in laryngectomized individuals: a randomized crossover study.

BACKGROUND: High-resistance heat and moisture exchangers (HMEs) have been reported to increase transcutaneous oxygenation (tcpO(2)) values in laryngectomized individuals and to negatively influence patient compliance. The goal of the present study was to validate earlier published results on short-term transcutaneous oxygenation changes by high-resistance HMEs. METHODS: We conducted a randomized crossover study, monitoring the influence of an HME on tcpO(2) over a 2-hour time interval in 20 subjects. RESULTS: No evidence of an immediate HME effect (95% CI: -14.9-13.3 mm Hg, p = .91), or a time-dependent HME effect (95% CI: -.121 - .172 mm Hg/minute, p = .74), on tcpO(2) was found. After fitting the statistical model without time dependency, again no evidence of HME presence was seen (95% CI: -.5 mm Hg - 3.6 mm Hg, p = .15). CONCLUSION: In contrast to earlier suggestions, there is no evidence of increased tcpO(2) levels by high-resistance HMEs in laryngectomized individuals. Thus, using such HMEs has no added clinical value in this respect.

Mitochondrial PO2 measured by delayed fluorescence of endogenous protoporphyrin IX.

Molecular oxygen is the primary oxidant in biological systems. The ultimate destination of oxygen in vivo is the mitochondria where it is used in oxidative phosphorylation. The ability of this process to produce an amount of high-energy phosphates adequate to sustain life highly depends on the available amount of oxygen. Despite a vast array of techniques to measure oxygen, major (patho)physiological questions remain unanswered because of the unavailability of quantitative techniques to measure mitochondrial oxygen in situ. Here we demonstrate that mitochondrial PO(2) can be directly measured in living cells by harnessing the delayed fluorescence of endogenous protoporphyrin IX (PpIX), thereby providing a technique with the potential for a wide variety of applications. We applied this technique to different cell lines (V-79 Chinese hamster lung fibroblasts, HeLa cells and IMR 32-K1 neuroblastoma cells) and present the first direct measurements of the oxygen gradient between the mitochondria and the extracellular volume.