Circulating alternative pathway complement cleavage factor Bb is associated with vascular lesions and outcomes in IgA nephropathy.

BACKGROUND: Complement alternative pathway (AP) activation is linked to immunoglobulin A nephropathy (IgAN) prognosis severity, but Bb fragment's role is unclear. We examined the relationship between serum Bb fragment concentration at IgAN diagnosis and disease activity and outcomes. METHODS: This retrospective study included 125 biopsy-proven IgAN patients [age 39.9 years, 75% male, estimated glomerular filtration rate (eGFR) 82 ml/min, proteinuria 0.5 g/day] enrolled from 1984 to 2010 and followed for a minimum of 18 months. Monitoring continued until the last follow-up, end-stage kidney disease (ESKD) or death. Serum Bb fragment was measured using an enzyme-linked immunosorbent assay at diagnosis. Oxford classification and global optical score (GOS) were utilized for pathology assessment. RESULTS: Patients were followed for a median of 16 years; 42% developed chronic kidney disease stage ≥3, 19% reached ESKD and 9% died. Serum Bb fragment concentration negatively correlated with eGFR values at the last follow-up and positively with vascular and tubular histopathological indices. In univariate Cox regression analyses, higher Bb fragment concentration was associated with ESKD alongside older age, increased body mass index, arterial hypertension, lower eGFR, higher proteinuria, E1, S1, T1-2, GOS and corticotherapy. Patients with Bb levels ≥14.3 µg/ml had shorter mean kidney survival time (19.5 versus 22.7 years, P = .07); after adjusting for progression risk factors, the association persisted [hazard ratio 4.76 (95% confidence interval 1.56-14.43)]. CONCLUSIONS: Serum Bb fragment concentration at diagnosis may predict long-term IgAN outcomes, potentially due to AP activation at the endothelial surface. Further research is needed to confirm these results and evaluate Bb fragment's role in IgAN management.

Validation of the international IgA nephropathy prediction tool in a French cohort beyond 10 years after diagnosis.

INTRODUCTION: The International IgA Nephropathy Network developed a tool (IINN-PT) for predicting the risk of end-stage renal disease (ESRD) or a 50% decline in the estimated glomerular filtration rate (eGFR). We aimed to validate this tool in a French cohort with longer follow-up than previously published validation studies. METHODS: The predicted survival of patients with biopsy-proven immunoglobulin A nephropathy (IgAN) from the Saint Etienne University Hospital cohort was computed with IINN-PT models with or without ethnicity. The primary outcome was the occurrence of either ESRD or a 50% decline in eGFR. The models' performances were evaluated through c-statistics, discrimination and calibration analysis. RESULTS: There were 473 patients with biopsy-proven IgAN, with a median follow-up of 12.4 years. Models with and without ethnicity showed areas under the curve (95% confidence interval) of 0.817 (0.765; 0.869) and 0.833 (0.791; 0.875) and R2D of 0.28 and 0.29, respectively, and an excellent discrimination of groups of increasing predicted risk (P < .001). The calibration analysis was good for both models up to 15 years after diagnosis. The model without ethnicity exhibited a mathematical issue of survival function after 15 years. DISCUSSION: The IINN-PT provided good performances even after 10 years post-biopsy as showed by our study based on a cohort with a longer follow-up than previous cohorts (12.4 versus <6 years). The model without ethnicity exhibited better performances up to 15 years but became aberrant beyond this point due to a mathematical issue affecting the survival function. Our study sheds light on the usefulness of integrating ethnicity as a covariable for prediction of IgAN course.

Convolutional neural networks for PET functional volume fully automatic segmentation: development and validation in a multi-center setting.

PURPOSE: In this work, we addressed fully automatic determination of tumor functional uptake from positron emission tomography (PET) images without relying on other image modalities or additional prior constraints, in the context of multicenter images with heterogeneous characteristics. METHODS: In cervical cancer, an additional challenge is the location of the tumor uptake near or even stuck to the bladder. PET datasets of 232 patients from five institutions were exploited. To avoid unreliable manual delineations, the ground truth was generated with a semi-automated approach: a volume containing the tumor and excluding the bladder was first manually determined, then a well-validated, semi-automated approach relying on the Fuzzy locally Adaptive Bayesian (FLAB) algorithm was applied to generate the ground truth. Our model built on the U-Net architecture incorporates residual blocks with concurrent spatial squeeze and excitation modules, as well as learnable non-linear downsampling and upsampling blocks. Experiments relied on cross-validation (four institutions for training and validation, and the fifth for testing). RESULTS: The model achieved good Dice similarity coefficient (DSC) with little variability across institutions (0.80 ± 0.03), with higher recall (0.90 ± 0.05) than precision (0.75 ± 0.05) and improved results over the standard U-Net (DSC 0.77 ± 0.05, recall 0.87 ± 0.02, precision 0.74 ± 0.08). Both vastly outperformed a fixed threshold at 40% of SUVmax (DSC 0.33 ± 0.15, recall 0.52 ± 0.17, precision 0.30 ± 0.16). In all cases, the model could determine the tumor uptake without including the bladder. Neither shape priors nor anatomical information was required to achieve efficient training. CONCLUSION: The proposed method could facilitate the deployment of a fully automated radiomics pipeline in such a challenging multicenter context.

Repeat renal biopsy improves the Oxford classification-based prediction of immunoglobulin A nephropathy outcome.

BACKGROUND: The prognosis of IgA nephropathy (IgAN) is very heterogeneous. Predicting the nature and the rate of the disease progression is crucial for refining patient treatment. The aim of this study was to evaluate the prognostic impact of an Oxford classification-based repeat kidney tissue evaluation to predict end-stage renal disease (ESRD). METHODS: Patients with biopsy-proven primary IgAN who underwent two renal biopsies at our centre were analyzed retrospectively. Renal biopsies were scored by two pathologists blinded to the clinical data and according to the updated Oxford classification. Cox models were generated to evaluate the prognostic impact considering the Oxford classification elementary lesions from the first (Model 1) or the second (Model 2) biopsy, adjusted on clinical data at time of reevaluation. The prognostic impacts of the dynamic evolution of each elementary lesion between biopsies were also assessed through univariate and multivariate evaluation. RESULTS: A total of 168 adult patients were included, with a median follow-up duration of 18 (range 11-24) years. The second biopsy was performed either systematically (n = 112) of for-cause (n = 56), after a median time of 5.4 years. The prognostic performances of Model 2 (second biopsy) were significantly better than Model 1 (first biopsy, analysis of deviance P < 0.0001). The dynamic changes of C and T lesions were significantly associated with the progression toward ESRD after adjustment on variables from Model 2. CONCLUSION: Both static and dynamic Oxford-based histological evaluation offered by a repeat biopsy improves the prediction of ESRD in patients with IgAN.

External validation of a combined PET and MRI radiomics model for prediction of recurrence in cervical cancer patients treated with chemoradiotherapy.

PURPOSE: The aim of this study was to validate previously developed radiomics models relying on just two radiomics features from 18F-fluorodeoxyglucose positron emission tomography (PET) and magnetic resonance imaging (MRI) images for prediction of disease free survival (DFS) and locoregional control (LRC) in locally advanced cervical cancer (LACC). METHODS: Patients with LACC receiving chemoradiotherapy were enrolled in two French and one Canadian center. Pre-treatment imaging was performed for each patient. Multicentric harmonization of the two radiomics features was performed with the ComBat method. The models for DFS (using the feature from apparent diffusion coefficient (ADC) MRI) and LRC (adding one PET feature to the DFS model) were tuned using one of the French cohorts (n = 112) and applied to the other French (n = 50) and the Canadian (n = 28) external validation cohorts. RESULTS: The DFS model reached an accuracy of 90% (95% CI [79-98%]) (sensitivity 92-93%, specificity 87-89%) in both the French and the Canadian cohorts. The LRC model reached an accuracy of 98% (95% CI [90-99%]) (sensitivity 86%, specificity 100%) in the French cohort and 96% (95% CI [80-99%]) (sensitivity 83%, specificity 100%) in the Canadian cohort. Accuracy was significantly lower without ComBat harmonization (82-85% and 71-86% for DFS and LRC, respectively). The best prediction using standard clinical variables was 56-60% only. CONCLUSIONS: The previously developed PET/MRI radiomics predictive models were successfully validated in two independent external cohorts. A proposed flowchart for improved management of patients based on these models should now be confirmed in future larger prospective studies.

Deletion Variants of CFHR1 and CFHR3 Associate with Mesangial Immune Deposits but Not with Progression of IgA Nephropathy.

Activation of complement through the alternative pathway has a key role in the pathogenesis of IgA nephropathy (IgAN). Large, international, genome-wide association studies have shown that deletion of complement factor H-related genes 1 and 3 (CFHR3,1Δ) is associated with a reduced risk of developing IgAN, although the prognostic value of these deletions in IgAN remains unknown. Here, we compared the renal outcomes of patients with IgAN according to their CFHR3,1Δ genotype. This retrospective, monocentric cohort study included 639 white patients with biopsy-proven IgAN since 1979 (mean age at diagnosis, 40.1 years; median follow-up, 132 months). We determined the number of CFHR3 and CFHR1 gene copies by quantitative PCR and collected clinical and biologic data by reviewing the patients' medical records. In all, 30.5% of the patients were heterozygous and 4% were homozygous for CFHR3,1Δ We did not detect an association between CFHR3,1Δ and age, eGFR, urinary protein excretion rate, or the presence of hypertension or hematuria at the time of diagnosis. The mean intensities of immune IgA, IgG, and C3 deposits were lower in the group with heterozygous or homozygous gene deletions than in those with no deletion. However, CFHR3,1Δ did not associate with progression to stage 3 CKD or renal death. In conclusion, the CFHR3,1Δ genotype did not associate with progression toward CKD stages 3 and 5 in our white population of patients with IgAN, although it did associate with a reduced level of glomerular immune deposits.

Protein A-Based Immunoadsorption Is More Efficient Than Conventional Plasma Exchange to Remove Circulating Anti-HLA Antibodies.

We retrospectively evaluated the ability of protein-A immunoadsorption (IA) as compared to that of conventional plasma exchanges (PE) in reducing the mean fluorescence intensity (MFI) of anti-HLA antibodies assessed by the single antigen assay in sensitized renal transplant recipients. Change in MFI of 441 anti-HLA antibodies was measured after 1 single session of IA or after 3 consecutive daily PE sessions. While both strategies were able to significantly lower the amount of anti-HLA antibodies, the relative reduction in MFI was higher after IA as compared to PE (-69 vs. -58%, respectively, p = 0.003). This better efficacy of IA was observed despite a lower total volume of treated plasma (105 ± 6 vs. 160 ± 16 ml/kg after IA and after PE, respectively). Our data suggest a higher efficiency of IA over conventional PE sessions to remove anti-HLA antibodies and call for a larger evaluation of IA to confirm its potential added value in desensitization protocols.

Serum cystatin C is a determinant of central pressure augmentation index measured by oscillometric method in renal transplant recipients.

BACKGROUND: Serum cystatin C (ScysC) may help predicting cardiovascular outcome not only through its ability to detect renal dysfunction but also through its potential connection to others factors that are directly related to cardiovascular diseases. We explored the potential association of ScysC with arterial stiffness--a major contributor to cardiovascular disease--in renal transplant recipients (RTR). METHODS: Traditional and non-traditional cardio-vascular risk factors were collected from 215 stable RTR whom arterial stiffness was evaluated by the measure of the augmentation index of central pressure (AIx) determined by the arteriograph device. Serum creatinine and ScysC were measured the same day using standardized methods. Association between ScysC and AIx was examined in univariate and multivariate linear regression analysis. RESULTS: In univariate analysis, ScysC was strongly associated with AIx. This relationship was not confounded by age, gender, length of time spent on dialysis and transplantation vintage. Adjustment on the level of GFR estimated by the MDRD Study equation attenuated but did not abolish the association between ScysC and AIx. CONCLUSIONS: In conclusion, ScysC is an independent predictor of AIx in RTR. Our data suggest that arterial stiffness may partially mediate the association between ScysC and cardiovascular risk in renal transplantation.

Prospective results for 5-year survival and toxicity of moderately hypofractionated radiotherapy with simultaneous integrated boost (SIB) in (very) high-risk prostate cancer.

Purpose: High-risk (HR) prostate cancer patients usually receive high-dose radiotherapy (RT) using a two-phase sequential technique, but data on a simultaneous integrated boost (SIB) technique are lacking. We prospectively evaluated the long-term results of urinary (GU) and digestive (GI) toxicity and survival data for high-dose RT using a SIB technique in HR and very high-risk (VHR) prostate cancer. Methods: Patients were treated using an SIB technique in 34 fractions, at a dose of 54.4 Gy to the pelvis and seminal vesicles and 74.8 Gy to the prostate, combined with 36 months of androgen-depriving therapy in a prospective multicenter study. Acute and late GU and GI toxicity data were collected. Overall survival (OS), biochemical-relapse-free survival (bRFS), loco-regional-relapse-free survival (LRRFS), metastasis-free-survival (MFS) and disease-free-survival (DFS) were assessed. Results: We recruited 114 patients. After a median follow-up of 62 months, very few patients experienced acute (M0-M3) (G3-4 GU = 3.7 %; G3-4 GI = 0.9 %) or late (M6-M60) severe toxicity (G3-4 GU = 5.6 %; G3-4 GI = 2.8 %). The occurrence of acute G2 + GU or GI toxicity was significantly related to the consequential late G2 + toxicity (p < 0.01 for both GU and GI). Medians of OS, bRFS, LRRFS, MFS and DFS were not reached. At 60 months, OS, bRFS, LRRFS, MFS and DFS were 88.2 % [82.1; 94.7], 86.0 % [79.4 %;93.2 %], 95.8 % [91.8 %;99.9 %], 87.2 % [80.9 %;94.0 %] and 84.1 % [77.2 %;91.6 %] respectively. Conclusion: SIB RT at a dose of 54.4 Gy to the pelvis and 74.8 Gy to the prostate is feasible, leading to satisfying tumor control and reasonable toxicity in HR and VHR prostate cancer.

GFR estimation using standardized cystatin C in kidney transplant recipients.

BACKGROUND: The utility of serum cystatin C (SCysC) as a filtration marker in kidney transplantation is uncertain. We took advantage of the recent validation of a reference calibrator for SCysC and of newly developed CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equations (2012) expressed for use with standardized SCysC level to reassess the performance of SCysC as a filtration marker in kidney transplant recipients. STUDY DESIGN: Study of diagnostic test accuracy. SETTING & PARTICIPANTS: 670 kidney transplant recipients from 3 centers undergoing glomerular filtration rate (GFR) measurements from December 2006 to November 2012. INDEX TEST: Estimated GFR (eGFR) using the 2012 SCysC-based and serum creatinine (SCr)/SCysC-based CKD-EPI equations (eGFR(cys) and eGFR(cr-cys), respectively) and the 2009 SCr-based CKD-EPI equation (eGFR(cr)), with SCysC and SCr measured at a single laboratory between April 2011 and June 2011. REFERENCE TEST: Measured GFR (mGFR) using urinary clearance of inulin. RESULTS: Bias (the difference between mGFR and eGFR) was significantly smaller for eGFR(cys) and eGFR(cr-cys) versus eGFR(cr) (-2.82 and -0.54 vs +4.4 mL/min/1.73 m(2), respectively; P < 0.001). Precision (standard deviation of the mean bias) also was better for eGFR(cys) and eGFR(cr-cys) versus eGFR(cr) (12 and 11 vs 13 mL/min/1.73 m(2) [P < 0.001 for both comparisons]). Accuracy (percentage of GFR estimates within 30% of mGFR) was greater for eGFR(cys) and eGFR(cr-cys) versus eGFR(cr) (81% and 86% vs 75%, respectively [P = 0.004 and P < 0.001]). Net reclassification index with respect to mGFR of 30 mL/min/1.73 m(2) for eGFR(cr-cys) and eGFR(cys) versus eGFR(cr) was 18.8% [95% CI, 8.6%-28.9%] and 22.5% [95% CI, 10.2%-34.9%]. LIMITATIONS: Patients were exclusively of European descent; association with transplant outcome was not evaluated. CONCLUSIONS: Our data validate the use of both the newly developed SCysC-based and SCr/SCysC-based CKD-EPI equations (2012) in kidney transplant recipients. Both equations perform better than the SCr-based CKD-EPI equation (2009).

Sexual Structure Sparing for Prostate Cancer Radiotherapy: A Systematic Review.

CONTEXT: Erectile dysfunction represents a major side effect of prostate cancer (PCa) treatment, negatively impacting men's quality of life. While radiation therapy (RT) advances have enabled the mitigation of both genitourinary and gastrointestinal toxicities, no significant improvement has been showed in sexual quality of life over time. OBJECTIVE: The primary aim of this review was to assess sexual structures' dose-volume parameters associated with the onset of erectile dysfunction. EVIDENCE ACQUISITION: We searched the PubMed database and ClinicalTrials.gov until January 4, 2023. Studies reporting the impact of the dose delivered to sexual structures on sexual function or the feasibility of innovative sexual structure-sparing approaches were deemed eligible. EVIDENCE SYNTHESIS: Sexual-sparing strategies have involved four sexual organs. The mean penile bulb doses exceeding 20 Gy are predictive of erectile dysfunction in modern PCa RT trial. Maintaining a D100% of ≤36 Gy on the internal pudendal arteries showed preservation of erectile function in 88% of patients at 5 yr. Neurovascular bundle sparing appears feasible with magnetic resonance-guided radiation therapy, yet its clinical impact remains unanswered. Doses delivered to the testicles during PCa RT usually remain <2 Gy and generate a decrease in testosterone levels ranging from -4.6% to -17%, unlikely to have any clinical impact. CONCLUSIONS: Current data highlight the technical feasibility of sexual sparing for PCa RT. The proportion of erectile dysfunction attributable to the dose delivered to sexual structures is still largely unknown. While the ability to maintain sexual function over time is impacted by factors such as age or comorbidities, only selected patients are likely to benefit from sexual-sparing RT. PATIENT SUMMARY: Technical advances in radiation therapy (RT) made it possible to significantly lower the dose delivered to sexual structures. While sexual function is known to decline with age, the preservation of sexual structures for prostate cancer RT is likely to be beneficial only in selected patients.

Race-free estimated glomerular filtration rate equation in kidney transplant recipients: development and validation study.

OBJECTIVE: To compare the performance of a newly developed race-free kidney recipient specific glomerular filtration rate (GFR) equation with the three current main equations for measuring GFR in kidney transplant recipients. DESIGN: Development and validation study SETTING: 17 cohorts in Europe, the United States, and Australia (14 transplant centres, three clinical trials). PARTICIPANTS: 15 489 adults (3622 in development cohort (Necker, Saint Louis, and Toulouse hospitals, France), 11 867 in multiple external validation cohorts) who received kidney transplants between 1 January 2000 and 1 January 2021. MAIN OUTCOME MEASURE: The main outcome measure was GFR, measured according to local practice. Performance of the GFR equations was assessed using P30 (proportion of estimated GFR (eGFR) within 30% of measured GFR (mGFR)) and correct classification (agreement between eGFR and mGFR according to GFR stages). The race-free equation, based on creatinine level, age, and sex, was developed using additive and multiplicative linear regressions, and its performance was compared with the three current main GFR equations: Modification of Diet in Renal Disease (MDRD) equation, Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2009 equation, and race-free CKD-EPI 2021 equation. RESULTS: The study included 15 489 participants, with 50 464 mGFR and eGFR values. The mean GFR was 53.18 mL/min/1.73m2 (SD 17.23) in the development cohort and 55.90 mL/min/1.73m2 (19.69) in the external validation cohorts. Among the current GFR equations, the race-free CKD-EPI 2021 equation showed the lowest performance compared with the MDRD and CKD-EPI 2009 equations. When race was included in the kidney recipient specific GFR equation, performance did not increase. The race-free kidney recipient specific GFR equation showed significantly improved performance compared with the race-free CKD-EPI 2021 equation and performed well in the external validation cohorts (P30 ranging from 73.0% to 91.3%). The race-free kidney recipient specific GFR equation performed well in several subpopulations of kidney transplant recipients stratified by race (P30 73.0-91.3%), sex (72.7-91.4%), age (70.3-92.0%), body mass index (64.5-100%), donor type (58.5-92.9%), donor age (68.3-94.3%), treatment (78.5-85.2%), creatinine level (72.8-91.3%), GFR measurement method (73.0-91.3%), and timing of GFR measurement post-transplant (72.9-95.5%). An online application was developed that estimates GFR based on recipient's creatinine level, age, and sex (https://transplant-prediction-system.shinyapps.io/eGFR_equation_KTX/). CONCLUSION: A new race-free kidney recipient specific GFR equation was developed and validated using multiple, large, international cohorts of kidney transplant recipients. The equation showed high accuracy and outperformed the race-free CKD-EPI 2021 equation that was developed in individuals with native kidneys. TRIAL REGISTRATION: ClinicalTrials.gov NCT05229939.

Single nucleotidic polymorphism 844 A->G of FCAR is not associated with IgA nephropathy in Caucasians.

BACKGROUND: IgA nephropathy is characterized by a high heterogeneity of clinical expression with 10-30% of patients progressing to end-stage renal failure. The gene of the FcαRI or CD89 presents a single-nucleotide polymorphism responsible for a proinflammatory phenotype of neutrophils in vitro and ex vivo. The aim of our study was to assess whether this CD89 polymorphism 844 A->G is (i) a marker of disease susceptibility and/or (ii) associated with a more severe prognosis. METHODS: All patients diagnosed with IgA nephropathy and for whom DNA frozen sample was available were included in this European monocentric retrospective analysis and compared to a cohort of healthy volunteers. Allelic discrimination was performed by real-time quantitative polymerase chain reaction (Applied Biosystems™). We first compared the distribution of A and G alleles between patients and volunteers and then studied the relationships between alleles and renal survival, histological score, proteinuria and renal function at diagnosis. RESULTS: Seven hundred and twenty-six patients were analyzed for the study of susceptibility and 425 in the association study. The presence of the G allele was not associated with the occurrence of IgA nephropathy (χ(2) test 0.57, ns). Likewise, renal survival and the criteria for disease activity at time of diagnosis were not affected by the presence of the G allele. CONCLUSIONS: No significant association between 844 A->G CD89 polymorphism and the expression of the IgA nephropathy in Caucasians exists. This result does, however, not preclude the implication of other CD89 polymorphisms neither the possibility for a role of CD89 in the pathogenesis of IgA nephropathy.

The New 2021 CKD-EPI Equation Without Race in a European Cohort of Renal Transplanted Patients.

BACKGROUND: Whether the new chronic kidney disease-epidemiology (CKD-EPI) equation without the race variable remains accurate enough for glomerular filtration rate (GFR) estimation in non-US kidney transplant recipients (KTRs) is unclear. We sought to compare the predictive performance between this equation and the classical CKD-EPI equation in a French cohort of KTRs. We also evaluated the performance of the European Kidney Function Consortium (EKFC) equation, an estimate that has proved very accurate in nontransplant patients and that does not include race variable. METHODS: We retrospectively selected 489 KTRs for whom GFR was measured by inulin clearance. Performances of GFR equations were compared according to median bias, imprecision, and accuracy within 30% (P30) and 20% (P20). Differences in P20/P30 were tested using the exact McNemar test. RESULTS: Although the 4 equations exhibited a similar level of imprecision, the bias of the new CKD-EPI equation was +5.5 (4.0; 6.6) mL/min/1.73 m², much higher than the bias of the classical CKD-EPI, EKFC, and Modified Diet in Renal Diseases (MDRD) equation (2.4 [1.7;3.5], 2.2 [1.1;3.1], and -0.5 [-1.5; 1.0] mL/min/1.73 m², respectively). The new CKD-EPI equation was significantly less accurate with a P30 of 68.3% as compared with 74.2%, 75.3%, and 77.1% for the classical CKD-EPI, EKFC, and MDRD equation, respectively. The EKFC equation outperformed both versions of the CKD-EPI equation in terms of P20. CONCLUSIONS: The new CKD-EPI equation is suboptimal for the care and follow-up of European transplanted patients. The EKFC equation shows at least a similar performance to the MDRD and the classical CKD-EPI equation. Further validation of the EKFC equation in KTRs from a diverse ethnic background is needed.

A transfer learning approach to facilitate ComBat-based harmonization of multicentre radiomic features in new datasets.

PURPOSE: To facilitate the demonstration of the prognostic value of radiomics, multicenter radiomics studies are needed. Pooling radiomic features of such data in a statistical analysis is however challenging, as they are sensitive to the variability in scanner models, acquisition protocols and reconstruction settings, which is often unavoidable in a multicentre retrospective analysis. A statistical harmonization strategy called ComBat was utilized in radiomics studies to deal with the "center-effect". The goal of the present work was to integrate a transfer learning (TL) technique within ComBat-and recently developed alternate versions of ComBat with improved flexibility (M-ComBat) and robustness (B-ComBat)-to allow the use of a previously determined harmonization transform to the radiomic feature values of new patients from an already known center. MATERIAL AND METHODS: The proposed TL approach were incorporated in the four versions of ComBat (standard, B, M, and B-M ComBat). The proposed approach was evaluated using a dataset of 189 locally advanced cervical cancer patients from 3 centers, with magnetic resonance imaging (MRI) and positron emission tomography (PET) images, with the clinical endpoint of predicting local failure. The impact performance of the TL approach was evaluated by comparing the harmonization achieved using only parts of the data to the reference (harmonization achieved using all the available data). It was performed through three different machine learning pipelines. RESULTS: The proposed TL technique was successful in harmonizing features of new patients from a known center in all versions of ComBat, leading to predictive models reaching similar performance as the ones developed using the features harmonized with all the data available. CONCLUSION: The proposed TL approach enables applying a previously determined ComBat transform to new, previously unseen data.

Statistical harmonization can improve the development of a multicenter CT-based radiomic model predictive of nonresponse to induction chemotherapy in laryngeal cancers.

PURPOSE: To develop a radiomic model predicting nonresponse to induction chemotherapy in laryngeal cancers, from multicenter pretherapeutic contrast-enhanced computed tomography (CE-CT) and evaluate the benefit of feature harmonization in such a context. METHODS: Patients (n = 104) eligible for laryngeal preservation chemotherapy were included in five centers. Primary tumor was manually delineated on the CE-CT images. The following radiomic features were extracted with an in-house software (MIRAS v1.1, LaTIM UMR 1101): intensity, shape, and textural features derived from Gray-Level Co-occurrence Matrix (GLCM), Neighborhood Gray Tone Difference Matrix (NGTDM), Gray-Level Run Length Matrix (GLRLM), and Gray-Level Size Zone Matrix (GLSZM). Harmonization was performed using ComBat after unsupervised hierarchical clustering, used to determine labels automatically, given the high heterogeneity of imaging characteristics across and within centers. Patients with similar feature distributions were grouped with unsupervised clustering into an optimal number of clusters (2) determined with "silhouette scoring." Statistical harmonization was then carried out with ComBat on these 2 identified clusters. The cohort was split into training/validation (n = 66) and testing (n = 32) sets. Area under the receiver operating characteristics curves (AUC) were used to evaluate the ability of radiomic features (before and after harmonization) to predict nonresponse to chemotherapy, and specificity (Sp) and sensitivity (Se) were used to quantify their performance in the testing set. RESULTS: Without harmonization, none of the features identified as predictive in the training set remained significant in the testing set. After ComBat, one textural feature identified in the training set keeps a predictive trend in the testing set-Zone Percentage, derived from the GLSZM, was predictive of nonresponse in the training set (AUC = 0.62, Se = 70%, Sp = 64%, P = 0.04) and obtained a satisfactory performance in the testing set (Se = 80%, Sp = 67%, P = 0.03), although significance was limited by the size of the testing set. These results are consistent with previously published findings in head and neck cancers. CONCLUSIONS: Radiomic features from CE-CT could help in the selection of patients for induction chemotherapy in laryngeal cancers, with relatively good sensitivity and specificity in predicting lack of response. Statistical harmonization with ComBat and unsupervised clustering seems to improve the predictive value of features extracted in such a heterogeneous multicenter setting.

Cost and Toxicity Comparisons of Two IMRT Techniques for Prostate Cancer: A Micro-Costing Study and Weighted Propensity Score Analysis Based on a Prospective Study.

BACKGROUND: Intensity modulated radiation therapy (IMRT) combined with androgen deprivation therapy (ADT) has become the standard treatment for patients with high-risk prostate cancer. Two techniques of rotational IMRT are commonly used in this indication: Volumetric Modulated Arc Therapy (VMAT) and helical tomotherapy (HT). To the best of our knowledge, no study has compared their related costs and clinical effectiveness and/or toxicity in prostate cancer. We aimed to assess differences in costs and toxicity between VMAT and HT in patients with high-risk prostate cancer with pelvic irradiation. MATERIAL AND METHODS: We used data from the "RCMI pelvis" prospective multicenter study (NCT01325961) including 155 patients. We used a micro-costing methodology to identify cost differences between VMAT and HT. To assess the effects of the two techniques on total actual costs per patient and on toxicity we used stabilized inverse probability of treatment weighting. RESULTS: The mean total cost for HT, €2019 3,069 (95% CI, 2,885-3,285) was significantly higher than the mean cost for VMAT €2019 2,544 (95% CI, 2,443-2,651) (p <.0001). The mean ± SD labor and accelerator cost for HT was €2880 (± 583) and €1978 (± 475) for VMAT, with 81 and 76% for accelerator, respectively. Acute GI and GU toxicity were more frequent in VMAT than in HT (p = .021 and p = .042, respectively). Late toxicity no longer differed between the two groups up to 24 months after completion of treatment. CONCLUSION: Use of VMAT was associated with lower costs for IMRT planning and treatment than HT. Similar stabilized long-term toxicity was reported in both groups after higher acute GI and GU toxicity in VMAT. The estimates provided can benefit future modeling work like cost-effectiveness analysis.

Report of a unique case of gemcitabine-induced radiation recall myelitis following spinal cord irradiation.

Radiation recall is a rare phenomenon, defined as an acute inflammatory reaction in a previously irradiated area, after administration of anti-tumor agents, including chemotherapy. It is most commonly reported to trigger skin reactions but internal organ involvement is possible, particularly with gemcitabine. We report here a unique case of a gemcitabine-induced radiation recall myelitis following spinal irradiation. A 53-year-old patient received analgesic irradiation of the seventh thoracic vertebra (T7) in the context of metastatic non-small cell lung cancer, at conventional radiotherapy dose and fractionation. She was subsequently treated with gemcitabine and developed myelitis whose chronology is compatible with a radiation recall reaction. Spinal MRI confirmed a T6-T7 spinal cord enhancement, with an associated spinal cord oedema. Corticosteroids and supportive care did not improve myelitis symptoms. The patient died within a year of the radiation recall, due to a metastatic progression of lung cancer. This is, to our knowledge, the first reported case of gemcitabine-induced radiation recall myelitis and only the third case involving the spinal cord. Radiation recall is a rare and poorly understood phenomenon and all cases should be reported.

Pretreatment 18F-FDG PET/CT Radiomics Predict Local Recurrence in Patients Treated with Stereotactic Body Radiotherapy for Early-Stage Non-Small Cell Lung Cancer: A Multicentric Study.

The aim of this retrospective multicentric study was to develop and evaluate a prognostic 18F-FDG PET/CT radiomic signature in early-stage non-small cell lung cancer patients treated with stereotactic body radiotherapy (SBRT). Methods: Patients from 3 different centers (n = 27, 29, and 8) were pooled to constitute the training set, whereas the patients from a fourth center (n = 23) were used as the testing set. The primary endpoint was local control. The primary tumor was semiautomatically delineated in the PET images using the fuzzy locally adaptive Bayesian algorithm, and manually in the low-dose CT images. In total, 184 Image Biomarkers Standardization Initiative-compliant radiomic features were extracted. Seven clinical and treatment parameters were included. We used ComBat to harmonize radiomic features extracted from the 4 institutions relying on different PET/CT scanners. In the training set, variables found significant in the univariate analysis were fed into a multivariate regression model, and models were built by combining independent prognostic factors. Results: Median follow-up was 21.1 mo (range, 1.7-63.4 mo) and 25.5 mo (range, 7.7-57.8 mo) in training and testing sets, respectively. In univariate analysis, none of the clinical variables, 2 PET features, and 2 CT features were significantly predictive of local control. The best predictive models in the training set were obtained by combining one feature from PET (Information Correlation 2) and one feature from CT (flatness), reaching a sensitivity of 100% and a specificity of 96%. Another model combining 2 PET features (Information Correlation 2 and strength) reached sensitivity of 100% and specificity of 88%, both with an undefined hazard ratio (P < 0.001). The latter model obtained an accuracy of 0.91 (sensitivity, 100%; specificity, 81%), with a hazard ratio undefined (P = 0.023) in the testing set; however, other models relying on CT radiomic features only or the combination of PET and CT features failed to validate in the testing set. Conclusion: We showed that 2 radiomic features derived from 18F-FDG PET were independently associated with local control in patients with non-small cell lung cancer undergoing SBRT and could be combined in an accurate predictive model. This model could provide local relapse-related information and could be helpful in clinical decision making.

MRI-derived radiomics: methodology and clinical applications in the field of pelvic oncology.

Personalized medicine aims at offering optimized treatment options and improved survival for cancer patients based on individual variability. The success of precision medicine depends on robust biomarkers. Recently, the requirement for improved non-biologic biomarkers that reflect tumor biology has emerged and there has been a growing interest in the automatic extraction of quantitative features from medical images, denoted as radiomics. Radiomics as a methodological approach can be applied to any image and most studies have focused on PET, CT, ultrasound, and MRI. Here, we aim to present an overview of the radiomics workflow as well as the major challenges with special emphasis on the use of multiparametric MRI datasets. We then reviewed recent studies on radiomics in the field of pelvic oncology including prostate, cervical, and colorectal cancer.