Adaptive radiotherapy (up to 74 Gy) or standard radiotherapy (66 Gy) for patients with stage III non-small-cell lung cancer, according to [18F]FDG-PET tumour residual uptake at 42 Gy (RTEP7-IFCT-1402): a multicentre, randomised, controlled phase 2 trial.

BACKGROUND: Thoracic radiation intensification is debated in patients with stage III non-small-cell lung cancer (NSCLC). We aimed to assess the activity and safety of a boost radiotherapy dose up to 74 Gy in a functional sub-volume given according to on-treatment [18F]fluorodeoxyglucose ([18F]FDG)-PET results. METHODS: In this multicentre, randomised, controlled non-comparative phase 2 trial, we recruited patients aged 18 years or older with inoperable stage III NSCLC without EGFR mutation or ALK rearrangement with an Eastern Cooperative Oncology Group performance status of 0-1, and who were affiliated with or a beneficiary of a social benefit system, with evaluable tumour or node lesions, preserved lung function, and who were amenable to curative-intent radiochemotherapy. Patients were randomly allocated using a central interactive web-response system in a non-masked method (1:1; minimisation method used [random factor of 0·8]; stratified by radiotherapy technique [intensity-modulated radiotherapy vs three-dimensional conformal radiotherapy] and by centre at which patients were treated) either to the experimental adaptive radiotherapy group A, in which only patients with positive residual metabolism on [18F]FDG-PET at 42 Gy received a boost radiotherapy (up to 74 Gy in 33 fractions), with all other patients receiving standard radiotherapy dosing (66 Gy in 33 fractions over 6·5 weeks), or to the standard radiotherapy group B (66 Gy in 33 fractions) over 6·5 weeks. All patients received two cycles of induction platinum-based chemotherapy cycles (paclitaxel 175 mg/m2 intravenously once every 3 weeks and carboplatin area under the curve [AUC]=6 once every 3 weeks, or cisplatin 80 mg/m2 intravenously once every 3 weeks and vinorelbine 30 mg/m2 intravenously on day 1 and 60 mg/m2 orally [or 30 mg/m2 intravenously] on day 8 once every 3 weeks). Then they concomitantly received radiochemotherapy with platinum-based chemotherapy (three cycles for 8 weeks, with once per week paclitaxel 40 mg/m2 intravenously and carboplatin AUC=2 or cisplatin 80 mg/m2 intravenously and vinorelbine 20 mg/m2 intravenously on day 1 and 40 mg/m2 orally (or 20 mg/m2 intravenously) on day 8 in 21-day cycles). The primary endpoint was the 15-month local control rate in the eligible patients who received at least one dose of concomitant radiochemotherapy. This RTEP7-IFCT-1402 trial is registered with ClinicalTrials.gov (NCT02473133), and is ongoing. FINDINGS: From Nov 12, 2015, to July 7, 2021, we randomly assigned 158 patients (47 [30%] women and 111 [70%] men) to either the boosted radiotherapy group A (81 [51%]) or to the standard radiotherapy group B (77 [49%)]. In group A, 80 (99%) patients received induction chemotherapy and 68 (84%) received radiochemotherapy, of whom 48 (71%) with residual uptake on [18F]FDG-PET after 42 Gy received a radiotherapy boost. In group B, all 77 patients received induction chemotherapy and 73 (95%) received radiochemotherapy. At the final analysis, the median follow-up for eligible patients who received radiochemotherapy (n=140) was 45·1 months (95% CI 39·3-48·3). The 15-month local control rate was 77·6% (95% CI 67·6-87·6%) in group A and 71·2% (95% CI 60·8-81·6%) in group B. Acute (within 90 days from radiochemotherapy initiation) grade 3-4 adverse events were observed in 20 (29%) of 68 patients in group A and 33 (45%) of 73 patients in group B, including serious adverse events in five (7%) patients in group A and ten (14%) patients in group B. The most common grade 3-4 adverse events were febrile neutropenia (seven [10%] of 68 in group A vs 16 [22%] of 73 in group B), and anaemia (five [7%] vs nine [12%]). In the acute phase, two deaths (3%) occurred in group B (one due to a septic shock related to chemotherapy, and the other due to haemotypsia not related to study treatment), and no deaths occurred in group A. After 90 days, one additional treatment-unrelated death occurred in group A and two deaths events occurred in group B (one radiation pneumonitis and one pneumonia unrelated to treatment). INTERPRETATION: A thoracic radiotherapy boost, based on interim [18F]FDG-PET, led to a meaningful local control rate with no difference in adverse events between the two groups in organs at risk, in contrast with previous attempts at thoracic radiation intensification, warranting a randomised phase 3 evaluation of such [18F]FDG-PET-guided radiotherapy dose adaptation in patients with stage III NSCLC. FUNDING: Programme Hospitalier de Recherche Clinique National 2014.

Radiotherapy boost in patients with hypoxic lesions identified by 18F-FMISO PET/CT in non-small-cell lung carcinoma: can we expect a better survival outcome without toxicity? [RTEP5 long-term follow-up].

PURPOSE: Chemoradiotherapy is the reference curative-intent treatment for nonresectable locally advanced non-small-cell lung carcinoma (NSCLC), with unsatisfactory survival, partially due to radiation resistance in hypoxic tissues. The objective was to update survival and toxicity at 3 years following radiotherapy boost to hypoxic tumours in NSCLC patients treated with curative-intent chemoradiotherapy. METHODS: This was an open-label, nonrandomized, multicentre, phase II clinical trial. 18F-Fluoromisonidazole (18F-FMISO) PET/CT was used to determine the hypoxic profile of the patients. 18F-FMISO-positive patients and those without organ-at-risk constraints received a radiotherapy boost (70-84 Gy); the others received standard radiotherapy (66 Gy). Overall survival (OS), progression-free survival (PFS) and safety were assessed. RESULTS: A total of 54 patients were evaluated. OS and PFS rates at 3 years were 48.5% and 28.8%, respectively. The median OS in the 18F-FMISO-positive patients was 25.8 months and was not reached in the 18F-FMISO-negative patients (p = 0.01). A difference between the groups was also observed for PFS (12 months vs. 26.2 months, p = 0.048). In 18F-FMISO-positive patients, no difference was observed in OS in relation to dose, probably because of the small sample size (p = 0.30). However, the median OS seemed to be in favour of patients who received the radiotherapy boost (26.5 vs. 15.3 months, p = 0.71). In patients who received the radiotherapy boost, no significant late toxicities were observed. CONCLUSION: 18F-FMISO uptake in NSCLC patients is strongly associated with features indicating a poor prognosis. In 18F-FMISO-positive patients, the radiotherapy boost seemed to improve the OS by 11.2 months. A further clinical trial is needed to investigate the efficacy of a radiotherapy boost in patients with hypoxic tumours.

Rapid Contour-based Segmentation for 18F-FDG PET Imaging of Lung Tumors by Using ITK-SNAP: Comparison to Expert-based Segmentation.

Purpose To assess the performance of the ITK-SNAP software for fluorodeoxyglucose (FDG) positron emission tomography (PET) segmentation of complex-shaped lung tumors compared with an optimized, expert-based manual reference standard. Materials and Methods Seventy-six FDG PET images of thoracic lesions were retrospectively segmented by using ITK-SNAP software. Each tumor was manually segmented by six raters to generate an optimized reference standard by using the simultaneous truth and performance level estimate algorithm. Four raters segmented 76 FDG PET images of lung tumors twice by using ITK-SNAP active contour algorithm. Accuracy of ITK-SNAP procedure was assessed by using Dice coefficient and Hausdorff metric. Interrater and intrarater reliability were estimated by using intraclass correlation coefficients of output volumes. Finally, the ITK-SNAP procedure was compared with currently recommended PET tumor delineation methods on the basis of thresholding at 41% volume of interest (VOI; VOI41) and 50% VOI (VOI50) of the tumor's maximal metabolism intensity. Results Accuracy estimates for the ITK-SNAP procedure indicated a Dice coefficient of 0.83 (95% confidence interval: 0.77, 0.89) and a Hausdorff distance of 12.6 mm (95% confidence interval: 9.82, 15.32). Interrater reliability was an intraclass correlation coefficient of 0.94 (95% confidence interval: 0.91, 0.96). The intrarater reliabilities were intraclass correlation coefficients above 0.97. Finally, VOI41 and VOI50 accuracy metrics were as follows: Dice coefficient, 0.48 (95% confidence interval: 0.44, 0.51) and 0.34 (95% confidence interval: 0.30, 0.38), respectively, and Hausdorff distance, 25.6 mm (95% confidence interval: 21.7, 31.4) and 31.3 mm (95% confidence interval: 26.8, 38.4), respectively. Conclusion ITK-SNAP is accurate and reliable for active-contour-based segmentation of heterogeneous thoracic PET tumors. ITK-SNAP surpassed the recommended PET methods compared with ground truth manual segmentation.

Effect of CRP value on 18F-FDG PET vascular positivity in Takayasu arteritis: a systematic review and per-patient based meta-analysis.

PURPOSE: The aim of this study was to quantify the association between the CRP value and 18F-FDG PET vascular positivity in Takayasu arteritis (TAK) through a structured dedicated systematic review and meta-analysis. METHODS: From January 2000 to December 2016, the PubMed/MEDLINE database was searched for articles specifically dealing with the assessment of vascular inflammation using 18F-FDG PET and CRP biomarkers in TAK. Inclusion criteria for the qualitative analysis were (1) 18F-FDG PET used to assess the disease activity, (2) The use of the ACR criteria for the diagnosis of TAK, (3) No case mixed vasculitis (i.e., no giant cell arteritis), and (4) CRP concentration and clinical disease activity available. For the meta-analysis, PET-positive and PET-negative subgroups with the corresponding CRP concentrations were generated based on per patient data. The standard mean difference, which represents the effect of the CRP concentrations on the 18F-FDG PET vascular uptake, was computed for all studies, and then the results were pooled together. RESULTS: Among the 33 initial citations, nine complete articles including 210 patients fulfilled the inclusion criteria. Five studies found a significant correlation between the 18F-FDG PET and CRP concentration, one provided a trend towards association and three did not find any association between the two biomarkers. Six studies found a significant association between 18F-FDG PET and clinical disease activity, one found a trend towards association and the last two studies did not evaluate this correlation. The meta-analysis (121 patients) provided the following results: Standard Mean Deviation = 0.54 [0.15;0.92]; Chi2 = 3.35; I2 = 0%; Test for overall effect: Z = 2.70 (P = 0.007). CONCLUSION: The CRP concentration only moderately reflects the 18F-FDG PET vascular positivity in TAK, suggesting dissociated information. Standardized longitudinal prospective studies are necessary to assess the value of 18F-FDG PET as an independent biomarker for subtle vascular wall inflammation detection.

Contribution of (18)F-FDG PET in the diagnostic assessment of fever of unknown origin (FUO): a stratification-based meta-analysis.

PURPOSE: The aim of this study was to quantify the contribution of FDG PET to the diagnostic assessment of fever of unknown origin (FUO), taking into account the diagnostic limitations resulting from the composite nature of this entity. METHODS: The PubMed/MEDLINE database was searched from 2000 to September 2015. Original articles fulfilling the following criteria were included: (1) FUO as the initial diagnosis, (2) no immunosuppressed or nosocomial condition, (3) final diagnosis not based on PET, (4) a follow-up period specified, (5) adult population, and (6) availability of adapted data for calculation of odds ratios (ORs). ORs were computed for each study and then pooled using a random effects model. Stratification-based sensitivity analyses were finally performed using the following prespecified criteria: (a) study design, (b) PET device, (c) geographic area, and (d) follow-up period. RESULTS: A meta-analysis of the 14 included studies showed that normal PET findings led to an increase in the absolute final diagnostic rate of 36 % abnormal PET findings to an increase of 83 %, corresponding to a pooled OR of 8.94 (95 % CI 4.18 - 19.12, Z = 5.65; p < 0.00001). The design of the studies influenced the results (OR 2.92, 95 % CI 1.00 - 8.53 for prospective studies; OR 18,57, 95 % CI 7.57 - 45.59 for retrospective studies; p = 0.01), whereas devices (dedicated or hybrid), geographic area and follow-up period did not. CONCLUSION: Abnormal PET findings are associated with a substantially increased final diagnostic rate in FUO. Consequently, FDG PET could be considered for inclusion in the first-line diagnostic work-up of FUO. Further randomized prospective studies with standardized FDG PET procedures are warranted to confirm this first-line position.

Threshold levels of visual field and acuity loss related to significant decreases in the quality of life and emotional states of patients with retinitis pigmentosa.

INTRODUCTION: Retinitis pigmentosa (RP) is an inherited retinal disorder, characterized by photoreceptor degeneration inducing progressive vision loss. This study evaluates its impact on quality of life (QOL) and emotional states of patients affected by RP. METHODS: A cross-sectional study was conducted on 60 RP patients diagnosed with rod-cone dystrophy and on 20 control subjects. The RP population has been divided into 3 groups according to visual field (VF) and visual acuity (VA) impairments. Concurrently, scores of self-reported QOL (25-item National Eye Institute Visual Functioning Questionnaire) and of the Hospital Anxiety and Depression Scale for anxiety/depression assessments were collected. RESULTS: For the QOL composite score, we noticed consistent differences between all VF and VA affected groups and their control group. We also found significant differences between both the most affected VF group (VF1: ØVF <20°) and VA group (VA1: VA <0.3) compared to other VF and VA groups. For anxiety/depression scores, consistent differences have been found between the control group and VF1 and VA1, respectively. CONCLUSIONS: This work determines that, for RP patients, a significant QOL and emotional state deterioration correlates with a residual VF diameter below 20° and a VA lower than 0.3. It introduces, for the first time, thresholds to be used in visual restoration or visual preservation therapies to improve QOL of RP patients.

Chronic urinary obstruction: evaluation of dynamic contrast-enhanced MR urography for measurement of split renal function.

PURPOSE: To evaluate if measurement of split renal function ( SRF split renal function ) with dynamic contrast material-enhanced ( DCE dynamic contrast enhanced ) magnetic resonance (MR) urography is equivalent to that with renal scintigraphy ( RS renal scintigraphy ) in patients suspected of having chronic urinary obstruction. MATERIALS AND METHODS: The study protocol was approved by the institutional ethics committee of the coordinating center on behalf of all participating centers. Informed consent was obtained from all adult patients or both parents of children. This prospective, comparative study included 369 pediatric and adult patients from 14 university hospitals who were suspected of having chronic or intermittent urinary obstruction, and data from 295 patients with complete data were used for analysis. SRF split renal function was measured by using the area under the curve and the Patlak-Rutland methods, including successive review by a senior and an expert reviewer and measurement of intra- and interobserver agreement for each technique. An equivalence test for mean SRF split renal function was conducted with an α of 5%. RESULTS: Reproducibility was substantial to almost perfect for both methods. Equivalence of DCE dynamic contrast enhanced MR urography and RS renal scintigraphy for measurement of SRF split renal function was shown in patients with moderately dilated kidneys (P < .001 with the Patlak-Rutland method). However, in severely dilated kidneys, the mean SRF split renal function measurement was underestimated by 4% when DCE dynamic contrast enhanced MR urography was used compared with that when RS renal scintigraphy was used. Age and type of MR imaging device had no significant effect. CONCLUSION: For moderately dilated kidneys, equivalence of DCE dynamic contrast enhanced MR urography to RS renal scintigraphy was shown, with a standard deviation of approximately 12% between the techniques, making substitution of DCE dynamic contrast enhanced MR urography for RS renal scintigraphy acceptable. For severely dilated kidneys, a mean underestimation of SRF split renal function of 4% should be expected with DCE dynamic contrast enhanced MR urography, making substitution questionable.

Development and Validation of a Novel Mobility Test for Rod-Cone Dystrophies: From Reality to Virtual Reality.

PURPOSE: To validate a novel mobility test (MOST, MObility Standardized Test) and performance outcomes in real (RL) and virtual (VR) environments to be used for interventional clinical studies in order to characterize vision impairment in rod-cone dystrophies, also known as retinitis pigmentosa (RP). DESIGN: Prospective, interventional, noninvasive, reliability and validity analysis. METHODS: We designed MOST to be used in both VR and RL and conducted 3 experimental studies with 89 participants to (1) validate the difficulty of the mobility courses (15 controls), (2) determine the optimal number of light levels and training trials (14 participants with RP), and (3) validate the reproducibility (test-retest), reliability (VR/RL), sensitivity, and construct/content validity of the test (30 participants with RP and 30 controls). A comprehensive ophthalmologic examination was performed in all subjects. Outcomes of interest included MOST performance score, visual acuity, contrast sensitivity, dark adaptation thresholds, visual field parameters, and correlation between the performance score and visual function. RESULTS: The mobility courses exhibited statistically similar difficulty, and 5 trials are sufficient to control for the learning effect. MOST is highly reproducible (test-retest correlations >0.98) and reliable (correlations VR/RL = 0.98). MOST achieved a discrimination between participants with RP and controls (accuracy >95%) and between early and late stages of the disease (82.3% accuracy). The performance score is correlated with visual function parameter (0.57-0.94). CONCLUSION: MOST is a validated mobility test, with the controlled learning effect, excellent reproducibility, and high agreement between RL and VR conditions, as well as sensitivity and specificity to measure disease progression and therapeutic benefit in rod-cone dystrophies.

Metabolically healthy obesity in adults with X-linked hypophosphatemia.

OBJECTIVES: X-linked hypophosphatemia (XLH) is characterized by increased concentrations of circulating fibroblast growth factor 23 (FGF-23) resulting in phosphate wasting, hypophosphatemia, atypical growth plate and bone matrix mineralization. Epidemiologic studies suggest a relationship between FGF-23, obesity, and metabolic dysfunction. The prevalence of overweight and obesity is high in children with XLH. We aimed to evaluate the prevalence of obesity and metabolic complications in adults with XLH. METHODS: We conducted a prospective cohort study in adult XLH patients from a single tertiary referral center. The proportion of patients with a BMI >25 kg/m2 was the main outcome measure. Body fat mass percentage (FM%) and adipose tissue surfaces were secondary outcome measures. Glucose homeostasis (plasma glucose and insulin concentrations after fasting and 2 hours after an oral glucose tolerance test) was explored in a subgroup of patients and compared with age-, sex-, and BMI-matched healthy controls. RESULTS: Among 113 evaluated patients, 85 (75%) were female and 110 (97%) carried a PHEX mutation. Sixty-three (56%) patients were overweight or obese, with a median BMI of 25.3 [IQR, 22.7; 29.2] kg/m2. BMI was correlated with FM%, abdominal and thigh subcutaneous and intra-abdominal adipose tissue surfaces. The prevalence of impaired fasting glucose, impaired glucose tolerance, and diabetes was not different between XLH patients and matched controls. CONCLUSION: The prevalence of overweight and obesity is high among XLH patients and is associated with excess fat mass. However, the prevalence of glucose homeostasis abnormalities is not increased in patients compared to healthy controls, suggesting that metabolically healthy overweight or obesity predominates.

Photocoagulation or sham laser in addition to conventional anti-VEGF therapy in macular edema associated with TelCaps due to diabetic macular edema or retinal vein occlusion (TalaDME): a study protocol for a multicentric, French, two-group, non-commercial, active-control, observer-masked, non-inferiority, randomized controlled clinical trial.

BACKGROUND: Macular edema (ME) results from hyperpermeability of retinal vessels, leading to chronic extravasation of plasma components into the retina and hence potentially severe visual acuity loss. Current standard of care consists in using intravitreal injections (IVI), which results in a significant medical and economic burden. During diabetic retinopathy (DR) or retinal vein occlusion (RVO), it has recently been shown that focal vascular anomalies (capillary macro-aneurysms, also termed TelCaps) for telangiectatic capillaries may play a central role in the onset, early recurrence, and/or persistence of ME. Since targeted photocoagulation of TelCaps may improve vision, identification, and photocoagulation of TelCaps, it may represent a way to improve management of ME. OBJECTIVE: The Targeted Laser in (Diabetic) Macular Edema (TalaDME) study aims to evaluate whether ICG-guided targeted laser (IGTL), in association with standard of care by IVI, allows reducing the number of injections during the first year of treatment compared with IVI only, while remaining non-inferior for visual acuity. METHODS: TalaDME is a French, multicentric, two-arms, randomized, sham laser-controlled, double-masked trial evaluating the effect of photocoagulation of TelCaps combined to IVI in patients with ME associated with TelCaps. Patients with vision loss related to center involved ME secondary to RVO or DR and presenting TelCaps are eligible. Two hundred and seventy eyes of 270 patients are randomized in a 1:1 ratio to standard care, i.e., IVI of anti-VEGF solely (control group) or combined with IGTL therapy (experimental group). Stratification is done on the cause of ME (i.e., RVO versus diabetes). Anti-VEGF IVI are administered to both groups monthly for 3 months (loading dose) and then with a pro re nata regimen with a monthly follow-up for 12 months. The primary endpoint will be the number of IVI and the change in visual acuity from baseline to 12 months. Secondary endpoints will be the changes in central macular thickness, impact on quality of life, cost of treatment, and incremental cost-utility ratio in each groups. KEY SAFETY: Rare but severe AE linked to the use of IVI and laser, and previously described, are expected. In the sham group, rescue laser photocoagulation may be administered by the unmasked investigator if deemed necessary at month 3. DISCUSSION: The best management of ME associated with TelCaps is debated, and there have been no randomized study designed to answer this question. Given the fact that TelCaps may affect 30 to 60% of patients with chronic ME due to DR or RVO, a large number of patients could benefit from a specific management of TelCaps. TalaDME aims to establish the clinical and medico-economic benefits of additional targeted laser. The results of TalaDME may raise new recommendations for managing ME and impact healthcare costs. TRIAL REGISTRATION: EudraCT: 2018-A00800-55/ NCT03751501. Registration date: Nov. 23, 2018.

Incidence and characteristics of rhegmatogenous retinal detachment during coronavirus-19 pandemic: A French study.

PURPOSE: To assess the impact of the Covid-19 pandemic and subsequent lockdown on the number and clinical characteristics of patients with retinal detachment (RD) in a French public university eye hospital. METHODS: Single-center, retrospective non-interventional study. Patients consulting at the emergency room (ER) of Quinze-Vingts Hospital (France) for rhegmatogenous RD before and after instauration of the lockdown were reviewed. We compared the characteristics of patients with RD between the containment period (March17th - April27th,2020) and the period preceding the lockdown (February18th - March16th,2020). We compared the number of RD surgeries performed between the first month of lockdown (March17th - April19th,2020) and the corresponding period of 2019. Number of cases, delay between diagnosis and surgery, visual acuity was measured. RESULTS: During the first month of lockdown, 59 RDs were operated on, compared to 107 in the corresponding period in 2019 (-44,8%). Mean time from first symptoms to surgery was significantly higher during the lockdown 12.7 (11.3) days vs 7.6 (7.8) days (p = 0.031) before. During the lockdown, the mean BCVA was lower albeit the difference did not reach statistical significance (1.16 (0.9) during pre-containment vs 1.5 (0.9) during containment; p = 0.09). Reasonsfor delayed consultation were: fear of Covid-19 (31%; p = 0.0001), absence of referral doctor (31%; p = 0.003) and difficulties in getting to public transport (10.3%;p = 0.859). CONCLUSION: Despite maintaining accessto emergency eye care facilitiesin our hospital, the lockdown affected visual health. Should the lockdown be reinstated, we postulate that a better information about eye care access for non-Covid emergencies may attenuate its effect on visual health.

Synthesis and application of lactosylated, 99mTc chelating albumin for measurement of liver function.

Neogalactosylated and neolactosylated albumins are currently used as radiopharmaceutical agents for imaging the liver asialoglycoprotein receptors, which allows the quantification of hepatic liver function in various diseases and also in healthy liver transplant donors. We developed an original process for synthesizing a chelating neolactosylated human albumin using maleimidopropyl-lactose and maleimidopropyl-diethylene triamine pentaacetic acid (DTPA) derivatives. The lactosylated protein (LACTAL) conjugate showed excellent liver uptake compared to nonlactosylated protein and a very high signal-to-noise ratio, based on functional assessment of biodistribution in mice using (99m)Tc-scintigraphy.

Carbon dioxide is largely responsible for the acute inflammatory effects of tobacco smoke.

Tobacco smoking is responsible for a vast array of diseases, particularly chronic bronchitis and lung cancer. It is still unclear which constituent(s) of the smoke is responsible for its toxicity. The authors decided to focus on carbon dioxide, since its level of concentration in mainstream cigarette smoke is about 200 times higher than in the atmosphere. The authors previously demonstrated that inhalation of carbon dioxide concentrations above 5% has a deleterious effect on lungs. In this study, the authors assessed the inflammatory potential of carbon dioxide contained in cigarette smoke. Mice were exposed to cigarette smoke containing a high or reduced CO(2) level by filtration through a potassium hydroxyde solution. The inflammatory response was evaluated by histological analysis, protein phosphatase 2 A (PP2A) and nuclear factor (NF)-kappaB activation, and proinflammatory cytokine secretion measurements. The data show that the toxicity of cigarette smoke may be largely due to its high level of CO(2). Pulmonary injuries consequent to tobacco smoke inhalation observed by histology were greatly diminished when CO(2) was removed. Cigarette smoke exposure causes an inflammatory response characterized by PP2A and NF-kappaB activation followed by proinflammatory cytokine secretion. This inflammatory response was reduced when the cigarette smoke was filtered through a potassium hydroxide column, and reestablished when CO(2) was injected downstream from the filtration column.Given that there is an extensive literature linking a chronic inflammatory response to the major smoking-related diseases, these data suggest that carbon dioxide may play a key role in the causation of these diseases by tobacco smoking.

Hyperparathyroidism in Patients With X-Linked Hypophosphatemia.

X-linked hypophosphatemia (XLH) is characterized by increased activity of circulating FGF23 resulting in renal phosphate wasting and abnormal bone mineralization. Hyperparathyroidism may develop in XLH patients; however, its prevalence, pathogenesis, and clinical presentation are not documented. This observational study (CNIL 171036 v 0) recruited XLH adult patients in a single tertiary referral center. Each patient was explored in standardized conditions and compared with two healthy volunteers, matched for sex, age, and 25-OH vitamin D concentrations. The primary endpoint was the proportion of patients with hyperparathyroidism. The secondary endpoints were the factors influencing serum parathyroid hormone (PTH) concentrations and the prevalence of hypercalcemic hyperparathyroidism. Sixty-eight patients (51 women, 17 men) were enrolled and matched with 136 healthy volunteers. Patients had higher PTH concentrations compared with healthy controls (53.5 ng/L, interquartile range [IQR] 36.7-72.7 versus 36.0 ng/L, IQR 27.7-44.0, p < .0001). Hyperparathyroidism was observed in 17 patients of 68 (25%). In patients, a positive relationship between PTH and calcium concentrations and a negative relationship between PTH and phosphate concentrations were observed. Seven (10%) patients (3 premenopausal women, 1 postmenopausal woman, and 3 men) were diagnosed with hypercalcemic hyperparathyroidism. All underwent parathyroid surgery, with consecutive normalization of calcium and PTH concentrations. Hyperparathyroidism is a frequent complication in XLH adult patients. Disruption of the physiological regulation of PTH secretion contributes to parathyroid disease. Early-onset hypercalcemic hyperparathyroidism can be effectively and safely cured by surgical resection. © 2020 American Society for Bone and Mineral Research.

Biliary leak in a child after liver transplant and value of delayed images.

A 2-year-old child underwent liver transplant and was referred for postsurgical abdominal pain. Hepatobiliary scintigraphy with Tc-99m iminodiacetic acid (IDA) was performed and with the help of 24-hour delayed images, the diagnosis of biliary leak at the site of anastomosis was made possible. This case report confirms the value of delayed images to facilitate the diagnosis in unequivocal situations and reminds us of the usefulness of this noninvasive method, especially in pediatrics.

Reproducibility of differential renal function measurement using technetium-99m-ethylenedicysteine dynamic renal scintigraphy: a French prospective multicentre study.

OBJECTIVE: Dynamic renal scintigraphy remains the gold standard for assessing differential renal function (DRF). Recently, technetium-99m-ethylenedicysteine (Tc-EC) was shown to be valuable and had similar quality images as technetium-99m-mercaptoacetyltriglycine (Tc-MAG3). However, its reproducibility has never been confirmed. The aim of this study was to perform the first evaluation of Tc-EC reproducibility for assessing DRF in children who were referred for hydronephrosis or urinary tract dilatation. PATIENTS AND METHODS: A total of 109 patients from three French nuclear medicine departments prospectively underwent dynamic renal scintigraphy with Tc-EC. DRF reproducibility was assessed by different pairs of raters using a multilevel design that integrated local and centralized predefined procedures. RESULTS: Both local and centralized procedures yielded near-excellent inter-rater agreements, with all of the intraclass correlation coefficient values over 0.998. Bland-Altman plots showed a systematic bias of less than 1%, with the corresponding limits of agreements not exceeding the 5% threshold cut-off value that corresponds to the clinical definition of acceptable limits for this purpose. Intrarater agreements were also good to excellent. CONCLUSION: This prospective multicentre study showed that Tc-EC is highly reproducible for assessing DRF in a standard paediatric population, thus validating its use as an alternative to Tc-MAG3 in this setting.

Validation of a standardized normalization template for statistical parametric mapping analysis of 123I-FP-CIT images.

UNLABELLED: (123)I-FP-CIT ((123)I-N-omega-fluoropropyl-2beta-carbomethoxy-3beta-(4-iodophenyl)nortropane) is a SPECT dopamine transporter (DAT) tracer that probes dopaminergic cell loss in Parkinson's disease (PD). Quantification of (123)I-FP-CIT images is performed at equilibrium using a ratio (BR) of specific (striatal) to nonspecific (occipital) uptake with values obtained from regions of interest drawn manually over these structures. Statistical parametric mapping (SPM) is a fully automated voxel-based statistical approach that has great potential in the context of DAT imaging. However, the accuracy of the spatial normalization provided by SPM has not been validated for (123)I-FP-CIT images. Our first aim was to create an (123)I-FP-CIT template that does not require the acquisition of patient-specific MRI and to validate the spatial normalization procedure. Next, we hypothesized that this customized template could be used by different SPECT centers without affecting the outcomes of imaging analyses. METHODS: The spatial normalization to the customized template created with SPM (template A1) was validated using (123)I-FP-CIT images obtained from 6 subjects with essential tremor (ET) with normal DAT status and 6 PD patients. Variability in BR values due to the normalization was evaluated using striatal volume of interest (VOI). To determine whether different SPECT centers could use a unique (123)I-FP-CIT template, we generated 3 other (123)I-FP-CIT templates using different subjects and image-processing schemes. The interchangeability of these templates was assessed using (a) putamen BR values analyzed with the intraclass correlation coefficient (ICC) and the Bland-Altman graphical analysis, and (b) SPM analysis comparing the results of group comparisons-that is, ET versus PD, obtained after normalization to each of the 4 templates. RESULTS: There was no significant difference between pre- and post-normalization striatal BR values in our study. The mean variability calculated with putamen VOI values after normalization to each template was <10%, with the lowest ICC of 98%. Intergroup analyses performed with VOI and SPM approaches provided similar results independently of the template used. CONCLUSION: SPM normalization was accurate even in subjects with low striatal (123)I-FP-CIT uptake, making it a promising approach for automatic analysis of (123)I-FP-CIT images using a single customized template at different centers.

Clinical Validation of a Pixon-Based Reconstruction Method Allowing a Twofold Reduction in Planar Images Time of 111In-Pentetreotide Somatostatin Receptor Scintigraphy.

OBJECTIVE: The objective of this study was to evaluate the diagnostic efficacy of Pixon-based reconstruction method on planar somatostatin receptor scintigraphy (SRS). METHODS: All patients with neuroendocrine tumors (NETs) disease who were referred for SRS to our department during 1-year period from January to December 2015 were consecutively included. Three nuclear physicians independently reviewed all the data sets of images which included conventional images (CI; 15 min/view) and processed images (PI) obtained by reconstructing the first 450 s extracted data using Oncoflash® software package. Image analysis using a 3-point rating scale for abnormal uptake of 111 Indium-DTPA-Phe-octreotide in any lesion or organ was interpreted as positive, uncertain, or negative for the evidence of NET disease. A maximum grade uptake of the radiotracer in the lesion was assessed by the Krenning scale method. The results of image interpretation by the two methods were considered significantly discordant when the difference in organ involvement assessment was negative vs. positive or in lesion uptake was ≥2 grades. Agreement between the results of two methods and by different scan observers was evaluated using Cohen κ coefficients. RESULTS: There was no significant (p = 0.403) correlation between data acquisition protocol and quality image. The rates of significant discrepancies for exam interpretation and organs involvement assessment were 2.8 and 2.6%, respectively. Mean κ values revealed a good agreement for concordance between CI and PI interpretation without difference of agreement for inter/intra-observer analysis. CONCLUSION: Our results suggest the feasibility to use a Pixon-based reconstruction method for SRS planar images allowing a twofold reduction of acquisition time and without significant alteration of image quality or on image interpretation.

Impact of Retinitis Pigmentosa on Quality of Life, Mental Health, and Employment Among Young Adults.

PURPOSE: To determine the relationship between visual function and quality of life, education, mental health, and employment among young adults with retinitis pigmentosa (RP). DESIGN: Cross-sectional study. METHODS: Inclusion of 148 patients (mean age 38.2 ± 7.1 years) diagnosed with RP, living in France. Quality of life was assessed using the National Eye Institute Visual Function Questionnaire (VFQ-25), mental state with the Hospital and Anxiety and Depression Scale (HADS), and employment with a specifically designed questionnaire. RESULTS: Limited visual impairment was noted in 22.3%, low vision in 29.7%, and legal blindness in 48.0%. There was a correlation between quality-of-life scores and residual visual field (P < .0001). Mental health scores were suggestive of anxiety in 36.5% and depression in 15.5%. The rates did not increase with disability level (P = .738, P = .134). The percentage of subjects with higher education did not significantly decrease with disability level (P = .113). The employment rate did not significantly decrease with disability level (P = .276). It was lower in subjects reporting depression (P = .0414). Self-rated impact of RP on employment increased with disability level (P = .02642). CONCLUSIONS: Our results differ from previous results showing lower education rates and employment rates in young adults with RP. Further research is warranted focusing on the impact of mental health, education, workplace conditions, and employment aids on employment rate vs age- and education-matched normally sighted controls to guide visual disability strategies in RP.

Phase II Study of a Radiotherapy Total Dose Increase in Hypoxic Lesions Identified by 18F-Misonidazole PET/CT in Patients with Non-Small Cell Lung Carcinoma (RTEP5 Study).

See an invited perspective on this article on page 1043.This multicenter phase II study investigated a selective radiotherapy dose increase to tumor areas with significant 18F-misonidazole (18F-FMISO) uptake in patients with non-small cell lung carcinoma (NSCLC). Methods: Eligible patients had locally advanced NSCLC and no contraindication to concomitant chemoradiotherapy. The 18F-FMISO uptake on PET/CT was assessed by trained experts. If there was no uptake, 66 Gy were delivered. In 18F-FMISO-positive patients, the contours of the hypoxic area were transferred to the radiation oncologist. It was necessary for the radiotherapy dose to be as high as possible while fulfilling dose-limiting constraints for the spinal cord and lungs. The primary endpoint was tumor response (complete response plus partial response) at 3 mo. The secondary endpoints were toxicity, disease-free survival (DFS), and overall survival at 1 y. The target sample size was set to demonstrate a response rate of 40% or more (bilateral α = 0.05, power 1-ß = 0.95). Results: Seventy-nine patients were preincluded, 54 were included, and 34 were 18F-FMISO-positive, 24 of whom received escalated doses of up to 86 Gy. The response rate at 3 mo was 31 of 54 (57%; 95% confidence interval [CI], 43%-71%) using RECIST 1.1 (17/34 responders in the 18F-FMISO-positive group). DFS and overall survival at 1 y were 0.86 (95% CI, 0.77-0.96) and 0.63 (95% CI, 0.49-0.74), respectively. DFS was longer in the 18F-FMISO-negative patients (P = 0.004). The radiotherapy dose was not associated with DFS when adjusting for the 18F-FMISO status. One toxic death (66 Gy) and 1 case of grade 4 pneumonitis (>66 Gy) were reported. Conclusion: Our approach results in a response rate of 40% or more, with acceptable toxicity. 18F-FMISO uptake in NSCLC patients is strongly associated with poor prognosis features that could not be reversed by radiotherapy doses up to 86 Gy.