We investigated whether radiation-induced nontargeted effects are involved in the cytotoxic effects of anticell surface monoclonal antibodies labeled with Auger electron emitters, such as iodine 125 ...(monoclonal antibodies labeled with (125)I (125)I-mAbs).
We showed that the cytotoxicity of (125)I-mAbs targeting the cell membrane of p53(+/+) HCT116 colon cancer cells is mainly due to nontargeted effects. Targeted and nontargeted cytotoxicities were inhibited in vitro following lipid raft disruption with Methyl-β-cyclodextrin (MBCD) or filipin or use of radical oxygen species scavengers. (125)I-mAb efficacy was associated with acid sphingomyelinase activation and modulated through activation of the AKT, extracellular signal-related kinase ½ (ERK1/2), p38 kinase, c-Jun N-terminal kinase (JNK) signaling pathways, and also of phospholipase C-γ (PLC-γ), proline-rich tyrosine kinase 2 (PYK-2), and paxillin, involved in Ca(2+) fluxes. Moreover, the nontargeted response induced by directing 5-(125)Iiodo-2'-deoxyuridine to the nucleus was comparable to that of (125)I-mAb against cell surface receptors. In vivo, we found that the statistical significance of tumor growth delay induced by (125)I-mAb was removed after MBCD treatment and observed oxidative DNA damage beyond the expected Auger electron range. These results suggest the involvement of nontargeted effects in vivo also.
Low-energy Auger electrons, such as those emitted by (125)I, have a short tissue range and are usually targeted to the nucleus to maximize their cytotoxicity. In this study, we show that targeting the cancer cell surface with (125)I-mAbs produces a lipid raft-mediated nontargeted response that compensates for the inferior efficacy of non-nuclear targeting.
Our findings describe the mechanisms involved in the efficacy of (125)I-mAbs targeting the cancer cell surface. Antioxid. Redox Signal. 25, 467-484.
Features of resting brain metabolism in motor functional neurological disorder are poorly characterized. This study aimed to investigate the alterations of resting brain metabolism in a cohort of ...patients experiencing a first episode of motor functional neurological disorder with recent symptom onset, and their association with persistent disability after 3 months. Patients eligible for inclusion were diagnosed with first episode of motor functional neurological disorder, were free from bipolar disorder, substance use disorder, schizophrenia, psychogenic non-epileptic seizure or any chronic or acute organic neurological disorder. Exclusion criteria included current suicidal ideation, antipsychotic intake and previous history of functional neurological disorder. Nineteen patients were recruited in Psychiatry and Neurology departments from 2 hospitals. Resting brain metabolism measured with 18F-fluorodeoxyglucose positron emission computed tomography at baseline and 3 months was compared to 23 controls without neurological impairment. Disability was scored using Expanded Disability Status Scale and National Institutes of Health Stroke Scale score at baseline and 3 months. Correlations were calculated with Spearman correlation coefficient. Hypometabolism was found at baseline in bilateral frontal regions in patients versus controls, disappearing by 3 months. The patients with Expanded Disability Status Scale score improvement showed greater resting state activity of prefrontal dorsolateral cortex, right orbito-frontal cortex and bilateral frontopolar metabolism at 3 months versus other patients. The resting state metabolism of the right subgenual anterior cingular cortex at baseline was negatively correlated with improvement of motor disability (measured with Expanded Disability Status Scale) between inclusion and 3 months (r=-0.75, p = 0.0018) and with change in motor symptoms assessed with the National Institutes of Health Stroke Scale (r=-0.81, p= 0.0005). The resting state metabolism of the left subgenual anterior cingular cortex at baseline was negatively correlated with improvement in Expanded Disability Status Scale and National Institutes of Health Stroke Scale scores between inclusion and 3 months (r= -0.65, p = 0.01 and r= -0.75, p = 0.0021, respectively). The negative association between the brain metabolism of the right subgenual anterior cingular cortex at baseline and change in National Institutes of Health Stroke Scale score remained significant (r=-0.81, p= 0.0414) after correction for multiple comparisons. Our findings suggest the existence of metabolic "state markers" associated with motor disability and that brain markers are associated with motor recovery in functional neurological disorder patients.
During the last decades, new radionuclide-based targeted therapies have emerged as efficient tools for cancer treatment. Targeted radionuclide therapies (TRTs) are based on a multidisciplinary ...approach that involves the cooperation of specialists in several research fields. Among them, radiobiologists investigate the biological effects of ionizing radiation, specifically the molecular and cellular mechanisms involved in the radiation response. Most of the knowledge about radiation effects concerns external beam radiation therapy (EBRT) and radiobiology has then strongly contributed to the development of this therapeutic approach. Similarly, radiobiology and dosimetry are also assumed to be ways for improving TRT, in particular in the therapy of solid tumors, which are radioresistant. However, extrapolation of EBRT radiobiology to TRT is not straightforward. Indeed, the specific physical characteristics of TRT (heterogeneous and mixed irradiation, protracted exposure, and low absorbed dose rate) differ from those of conventional EBRT (homogeneous irradiation, short exposure, and high absorbed dose rate), and consequently the response of irradiated tissues might be different. Therefore, specific TRT radiobiology needs to be explored. Determining dose-effect correlation is also a prerequisite for rigorous preclinical radiobiology studies because dosimetry provides the necessary referential to all TRT situations. It is required too for developing patient-tailored TRT in the clinic in order to estimate the best dose for tumor control, while protecting the healthy tissues, thereby improving therapeutic efficacy. Finally, it will allow to determine the relative contribution of targeted effects (assumed to be dose-related) and non-targeted effects (assumed to be non-dose-related) of ionizing radiation. However, conversely to EBRT where it is routinely used, dosimetry is still challenging in TRT. Therefore, it constitutes with radiobiology, one of the main challenges of TRT in the future.
Abstract
The prevalence of sarcopenia in patients with obesity varies according to the definition used. The purpose of our study was to: (i) determine the prevalence of sarcopenia in terms of lean ...tissue mass in older women with obesity using the current cut-offs, (ii) redefine a specific cut-off for low lean tissue mass (LLTM), and (iii) re-determine the prevalence of LLTM using this new cut-off. Appendicular lean mass (ALM) and the ALM index ALM/height
2
: ALMI(h
2
) and ALMI/body mass index ALMI(BMI) were determined in 791 women with or without obesity. LLMM prevalence was calculated using the current cut-offs: EWGSOP2: ALM < 15 kg and ALMI(h
2
) < 5.5 kg/m
2
; FNIH: ALM < 15.02 kg and ALMI(BMI) < 0.51; and IWGS: ALMI(h
2
) < 5.67 kg/m
2
and cut-offs newly determined from data provided from young women with obesity. ALM, ALMI(h
2
) and ALMI(BMI) were lower in older compared to young obese women. Using the current cut-offs, a wide distribution of LLTM prevalence (0 to 29.2%) was observed. When the newly determined cut-offs were applied – i.e., ALM < 18.51 kg; ALMI(h
2
) < 7.15 kg/m
2
, ALMI(BMI) < 0.483, and T-score: (ALMI(h
2
) measured)-(2.08 + 0.183*BMI)/0.72 − the LLTM mass prevalence was 17.37%; 8.47, 14.8 and 12.71%. respectively. This study showed that the current cut-offs for LLTM as criteria for sarcopenia diagnosis are not adapted to the obese population. Although the new “static” cut-offs appeared to be more adapted, a “dynamic” cut-off for ALMI(h
2
) that took into account the BMI and thus the obesity severity appeared even more relevant.
The purpose of this study was to compare a routine bone SPECT/CT protocol using CT reconstructed with filtered backprojection (FBP) with an optimized protocol using low-dose CT images reconstructed ...with adaptive statistical iterative reconstruction (ASiR).
In this prospective study, enrolled patients underwent bone SPECT/CT, with 1 SPECT acquisition followed by 2 randomized CT acquisitions: FBP CT (FBP; noise index, 25) and ASiR CT (70% ASiR; noise index, 40). The image quality of both attenuation-corrected SPECT and CT images was visually (5-point Likert scale, 2 interpreters) and quantitatively (contrast ratio CR and signal-to-noise ratio SNR) estimated. The CT dose index volume, dose-length product, and effective dose were compared.
Seventy-five patients were enrolled in the study. Quantitative attenuation-corrected SPECT evaluation showed no inferiority for contrast ratio and SNR issued from FBP CT or ASiR CT (respectively, 13.41 ± 7.83 vs. 13.45 ± 7.99 and 2.33 ± 0.83 vs. 2.32 ± 0.84). Qualitative image analysis showed no difference between attenuation-corrected SPECT images issued from FBP CT or ASiR CT for both interpreters (respectively, 3.5 ± 0.6 vs. 3.5 ± 0.6 and 3.6 ± 0.5 vs. 3.6 ± 0.5). Quantitative CT evaluation showed no inferiority for SNR between FBP and ASiR CT images (respectively, 0.93 ± 0.16 and 1.07 ± 0.17). Qualitative image analysis showed no quality difference between FBP and ASiR CT images for both interpreters (respectively, 3.8 ± 0.5 vs. 3.6 ± 0.5 and 4.0 ± 0.1 vs. 4.0 ± 0.2). Mean CT dose index volume, dose-length product, and effective dose for ASiR CT (3.0 ± 2.0 mGy, 148 ± 85 mGy⋅cm, and 2.2 ± 1.3 mSv) were significantly lower than for FBP CT (8.5 ± 3.7 mGy, 365 ± 160 mGy⋅cm, and 5.5 ± 2.4 mSv).
The use of 70% ASiR blending in bone SPECT/CT can reduce the CT radiation dose by 60%, with no sacrifice in attenuation-corrected SPECT and CT image quality, compared with the conventional protocol using FBP CT reconstruction technique.
Objectives The two-fold aim of this study was: (i) to determine the effects of undernutrition on the myokines in patients with restrictive anorexia nervosa (AN) and (ii) to examine the potential link ...between myokines and bone parameters. Methods In this study, 42 young women with restrictive AN and 42 age-matched controls (CON) (mean age, 18.5 ± 4.2 years and 18.6 ± 4.2 years, respectively) were enrolled. aBMD and body composition were determined with DXA. Resting energy expenditure (REEm), a marker of energy status, was indirectly assessed by calorimetry. Bone turnover markers and myokines (follistatin, myostatin and irisin) were concomitantly evaluated. Results AN patients presented low aBMD at all bone sites. REEm, bone formation markers, myostatin and IGF-1 were significantly lower, whereas the bone resorption marker and follistatin were higher in AN compared with controls. No difference was observed between groups for irisin levels. When the whole population was studied, among myokines, only myostatin was positively correlated with aBMD at all bone sites. However, multiple regression analyses showed that in the AN group, the independent variables for aBMD were principally amenorrhoea duration, lean tissue mass (LTM) and procollagen type I N-terminal propeptide (PINP). For CON, the independent variables for aBMD were principally LTM, age and PINP. Whatever the group analysed, none of the myokines appeared as explicative independent variables of aBMD. Conclusion This study demonstrated that despite the altered myokine levels in patients with AN, their direct effect on aBMD loss and bone turnover alteration seems limited in comparison with other well-known disease-related factors such as oestrogen deprivation.
We assessed the contribution of antibody internalization in the efficacy and toxicity of intraperitoneal α-radioimmunotherapy (RIT) of small volume carcinomatosis using (212)Pb-labeled monoclonal ...antibodies (mAbs) that target HER2 (internalizing) or CEA (non-internalizing) receptors.
Athymic nude mice bearing 2-3 mm intraperitoneal tumor xenografts were intraperitoneally injected with similar activities (370, 740 and 1480 kBq; 37 MBq/mg) of (212)Pb-labeled 35A7 (anti-CEA), trastuzumab (anti-HER2) or PX (non-specific) mAbs, or with equivalent amounts of unlabeled mAbs, or with NaCl. Tumor volume was monitored by bioluminescence and survival was reported. Hematologic toxicity and body weight were assessed. Biodistribution of (212)Pb-labeled mAbs and absorbed dose-effect relationships using MIRD formalism were established.
Transient hematological toxicity, as revealed by white blood cells and platelets numbering, was reported in mice treated with the highest activities of (212)Pb-labeled mAbs. The median survival (MS) was significantly higher in mice injected with 1.48 MBq of (212)Pb-35A7 (non-internalizing mAbs) (MS = 94 days) than in animals treated with the same activity of (212)Pb-PX mAbs or with NaCl (MS = 18 days). MS was even not reached after 130 days when follow-up was discontinued in mice treated with 1.48 MBq of (212)Pb-trastuzumab. The later efficacy was unexpected since final absorbed dose resulting from injection of 1.48 MBq, was higher for (212)Pb-35A7 (35.5 Gy) than for (212)Pb-trastuzumab (27.6 Gy). These results also highlight the lack of absorbed dose-effect relationship when mean absorbed dose was calculated using MIRD formalism and the requirement to perform small-scale dosimetry.
These data indicate that it might be an advantage of using internalizing anti-HER2 compared with non-internalizing anti-CEA (212)Pb-labeled mAbs in the therapy of small volume xenograft tumors. They support clinical investigations of (212)Pb-mAbs RIT as an adjuvant treatment after cytoreductive surgery in patients with peritoneal carcinomatosis.
The objective of the study was to assess the agreement between the Stratos (DMS) and QDR 4500A (Hologic) DXAs in determining whole body and regional aBMD, as well as whole body composition. ...Fifty-five individuals (46 women: 84%) with a mean age of 41 ± 13.0 years (range: 20 to 64) and a mean BMI of 31.9 ± 10 kg/m² (range: 12.2 to 49.5) were consecutively scanned on the same day using the two devices. Predictive equations for areal bone mineral density (aBMD) and whole body composition (WBC) were derived from linear regression of the data. The two DXAs were highly correlated (p<0.001 for all parameters) with a correlation coefficient (r) ranging from 0.89 to 0.99 for aBMD (r=0.89 for whole body, r=0.92 for radius, r=0.95 for femoral neck, r=0.96 for total hip, and r=0.99 for L1-L4). For WBC, the r value was 0.98 for lean tissue mass (LTM) and 1.0 for fat mass (FM). Paired t-tests indicated a statistically significant bias between the two DXAs for the majority of measurements, requiring the determination of specific cross-calibration equations. Compared to QDR 4500A, Stratos underestimated whole body aBMD and LTM and overestimated neck and hip aBMD and whole body FM. Conversely, no significant bias was demonstrated for mean aBMD at L1-L4 and radius. For whole body aBMD and FM, the concordance between the two DXAs was influenced by BMI. Despite a high concordance between the two DXAs, the systematic bias for aBMD and WBC measurements illustrates the need to define cross-calibration equations to compare data across systems.
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