Genetic factors contributing to late adverse musculoskeletal effects in childhood acute lymphoblastic leukemia survivors.

BACKGROUND: A substantial number of survivors of childhood acute lymphoblastic leukemia (ALL) suffer from treatment-related late adverse effects. While multiple studies have identified the effects of chemotherapeutics and radiation therapy on musculoskeletal outcomes, few have investigated their associations with genetic factors. METHODS: Here we analyzed musculoskeletal complications in relation to common and rare genetic variants derived through whole-exome sequencing of the PETALE cohort. Top-ranking associations were further assessed through stratified and multivariate analyses. RESULTS: DUOX2 variant was associated with skeletal muscle function deficit, as defined by peak muscle power Z score ≤ -2 SD (P = 4.5 × 10-5 for genotyping model). Upon risk stratification analysis, common variants in the APOL3, COL12A1, and LY75 genes were associated with Z score ≤ -2 SD at the cross-sectional area (CSA) at 4% radial length and lumbar bone mineral density (BMD) in high-risk patients (P ≤ 0.01). The modulation of the effect by risk group was driven by the interaction of the genotype with cumulative glucocorticoid dose. Identified variants remained significant throughout multivariate analyses incorporating non-genetic factors of the studied cohort. CONCLUSION: This exploratory study identified novel genetic variants associated with long-term musculoskeletal impairments in childhood ALL survivors. Replication in an independent cohort is needed to confirm the association found in this study.

What is the evidence for oxygenation during kidney preservation for transplantation in 2021? A scoping review.

PURPOSE: The main objective of static cold storage is to reduce cellular metabolic demands to extend the period of ischaemia prior to transplantation. Hypothermia does not halt metabolism and the absence of oxygen causes a cellular shift toward anaerobic respiratory pathways. There is emerging evidence that the introduction of oxygenation during organ preservation may help ameliorate the degree of ischaemia reperfusion injury and improve post-transplantation outcomes. This review aims to appraise and summarise all published literature that utilises oxygenation to improve kidney preservation for purposes of transplantation. METHODS: We performed a scoping review of the literature using the bibliographic databases Embase and MEDLINE. The final date for searches was 20 March 2021. All research studies included were those that reported oxygen delivery during kidney preservation as well as providing a description of the oxygenation technique. RESULTS: 17 human and 48 animal studies met the inclusion criteria. The oxygen delivery methods investigated included hypothermic oxygenated machine perfusion (HOPE), oxygen carriers, two-layer method, venous systemic persufflation, hyperbaric oxygenation, normothermic machine perfusion and sub-normothermic machine perfusion. The COMPARE trial was the only study carried out with the most methodological robustness being a randomised, double blind, controlled, phase III trial that investigated the efficacy of HOPE versus HMP. CONCLUSION: A variety of studies reflect the evolution of oxygenation with useful lessons and encouraging outcomes. The first in human studies investigating HOPE and oxygen carriers are most robustly investigated strategies for oxygenation during kidney preservation and are, therefore, the best clinical references.

Anatomical variations of the renal artery based on the surgeon's direct observation: A French perspective.

INTRODUCTION: Renal arterial vasculature presents a great anatomical variation. A good knowledge of this anatomy is essential in the field of kidney transplantation. The aim of this study is to describe the anatomical variations of the renal arterial vasculature based on the retrieved but not transplanted kidneys (RNTK) and their contralateral grafted kidneys (CGK), which anatomy is described by surgeons themselves after aortic dissection during multi-organ procurement (MOP). MATERIAL AND METHODS: Using the "Crystal" database of the French "Agence de la biomédecine" (ABM), all RNTK were retrospectively selected over one year. Then, the arterial anatomy of each RNTK and their CGK was studied using the surgical and the histopathological reports. The surgical report was completed by the surgeon at the end of the MOP from deceased donors. The qualitative variables were expressed in numbers (percentage of the population) and were compared by a Chi2 test or an exact Fisher test depending on the sample size. A P-value of less than 0.05 was considered statistically significant. RESULTS: In total, 356 kidneys were studied (241 RNTK - 115 CGK), 69% had a single artery and 31% had multiple arteries (26% with two arteries and 5% with three or more). The incidence of multiple arteries was similar between the right and left kidneys (32% vs. 30% respectively). A modal arrangement with 1 artery on each side was present in 51% of cases. Thus, 1 in 2 donors had at least 2 arteries on one side. Multiple arteries were bilateral in 12% of cases. The RNTK group presented more kidneys with multiple arteries than the CGK group (35% vs. 22%). CONCLUSION: Our study shows a higher incidence of multiple renal arteries than the literature (31% vs. 25%). Thus, MOP can be considered as an accurate and reliable method of describing renal arterial anatomy, especially that some small arteries may be missed when using radiological or cadaveric dissection techniques.

[Urothelial carcinoma in kidney transplant recipients and candidates: The French guidelines from CTAFU]. / Recommandations françaises du Comité de transplantation de l'association française d'urologie (CTAFU) : carcinome urothélial chez le patient transplanté rénal et le candidat à la transplantation rénale.

OBJECTIVE: To propose surgical recommendations for urothelial carcinoma management in kidney transplant recipients and candidates. METHOD: A review of the literature (Medline) following a systematic approcah was conducted by the CTAFU regarding the epidemiology, screening, diagnosis and treatment of urothelial carcinoma in kidney transplant recipients and candidates for renal transplantation. References were assessed according to a predefined process to propose recommendations with levels of evidence. RESULTS: Urothelial carcinomas occur in the renal transplant recipient population with a 3-fold increased incidence as compared with general population. While major risk factors for urothelial carcinomas are similar to those in the general population, aristolochic acid nephropathy and BK virus infection are more frequent risk factors in renal transplant recipients. As compared with general population, NMIBC in the renal transplant recipients are associated with earlier and higher recurrence rate. The safety and efficacy of adjuvant intravesical therapies have been reported in retrospective series. Treatment for localized MIBC in renal transplant recipients is based on radical cystectomy. In the candidate for a kidney transplant with a history of urothelial tumor, it is imperative to perform follow-up cystoscopies according to the recommended frequency, depending on the risk of recurrence and progression of NMIBC and to maintain this follow-up at least every six months up to transplantation whatever the level of risk of recurrence and progression. Based on current data, the present recommendations propose guidelines for waiting period before active wait-listing renal transplant candidates with a history of urothelial carcinoma. CONCLUSION: The french recommendations from CTAFU should contribute to improve the management of urothelial carcinoma in renal transplant patients and renal transplant candidates by integrating both oncologic objectives and access to transplantation.

[Localized Prostate cancer in candidates for renal transplantation and recipients of a kidney transplant: The French Guidelines from CTAFU]. / Recommandations françaises du Comité de transplantation de l'Association française d'urologie (CTAFU) : cancer de la prostate localisé chez le patient transplanté rénal ou en attente de transplantation.

OBJECTIVE: To define guidelines for the management of localized prostate cancer (PCa) in kidney transplant (KTx) candidates and recipients. METHOD: A systematic review (Medline) of the literature was conducted by the CTAFU to report prostate cancer epidemiology, screening, diagnosis and management in KTx candidates and recipients with the corresponding level of evidence. RESULTS: KTx recipients are at similar risk for PCa as general population. Thus, PCa screening in this setting is defined according to global French guidelines from CCAFU. Systematic screening is proposed in candidates for renal transplant over 50 y-o. PCa diagnosis is based on prostate biopsies performed after multiparametric MRI and preventive antibiotics. CCAFU guidelines remain applicable for PCa treatment in KTx recipients with some specificities, especially regarding lymph nodes management. Treatment options in candidates for KTx need to integrate waiting time and access to transplantation. Current data allows the CTAFU to propose mandatory waiting times after PCa treatment in KTx candidates with a weak level of evidence. CONCLUSION: These French recommendations should contribute to improve PCa management in KTx recipients and candidates, integrating oncological objectives with access to transplantation.

[Lower urinary tract symptoms and urinary incontinence in renal transplant recipients and candidates: The French guidelines from CTAFU]. / Recommandations françaises du Comité de transplantation de l'association française d'urologie (CTAFU) : symptômes du bas appareil urinaire et incontinence urinaire chez le patient transplanté ou en attente de transplantation rénale.

OBJECTIVE: To propose surgical recommendations for the management of lower urinary tract symptoms (LUTS) and urinary incontinence in kidney transplant recipients and candidates. METHOD: Following a systematic approach, a review of the literature (Medline) was conducted by the CTAFU focusing on medical and surgical treatment of LUTS and urinary incontinence in kidney transplant recipients and candidates. References were assessed according to a predefined process to propose recommendations with levels of evidence. RESULTS: Functional bladder capacity and bladder compliance are impaired during dialysis. LUTS, related to pre-kidney transplantion alterations, frequently improve spontaneously after kidney transplantation. LUTS secondary to benign prostatic hyperplasia (BPH) may be underestimated before kidney transplantation due to oliguria, low bladder compliance and low bladder capacity. In LUTS associated with BPH, anticholinergics require dosage adjustment with creatinine clearance. If surgery is indicated after kidney transplantation, procedure can be safely performed in the early post-transplant course after removal of ureteral stent. Surgical management of urinary incontinence does not seem to be associated with an icreased risk for infectious complications in kidney transplant recipients. Particular attention should be paid to the management of postvoid residual and bladder pressures in case of neurological bladder disease. Optimal care of neurological bladder should be provided prior to transplantation: with a cautious management, and despite an increased occurrence of febrile urinary tract infections, transplant survival is not compromised. CONCLUSION: These recommendations must contribute to improve the management of lower urinary tract symptoms and urinary incontinence in kidney transplant patients and kidney transplant candidates.

[Living donor nephrectomy: The French guidelines from CTAFU]. / Recommandations françaises du Comité de transplantation de l'Association française d'urologie (CTAFU) : néphrectomie pour don de rein.

OBJECTIVE: To propose surgical recommendations for living donor nephrectomy. METHOD: Following a systematic approach, a review of the literature (Medline) was conducted by the CTAFU regarding functional and anatomical assessment of kidney donors, including which side the kidney should be harvested from. Distinct surgical techniques and approaches were evaluated. References were considered with a predefined process to propose recommendations with the corresponding levels of evidence. RESULTS: The recommendations clarify the legal and regulatory framework for kidney donation in France. A rigorous assessment of the donor is one of the essential prerequisites for donor safety. The impact of nephrectomy on kidney function needs to be anticipated. In case of modal vascularization of both kidneys without a relative difference in function or urologic abnormality, removal of the left kidney is the preferred choice to favor a longer vein. Mini-invasive approaches for nephrectomy provide faster donor recovery, less donor pain and shorter hospital stay than open surgery. CONCLUSION: These French recommendations must contribute to improving surgical management of candidates for kidney donation.

[Urinary stones in renal transplant recipients and donors: The French guidelines from CTAFU]. / Recommandations françaises du Comité de transplantation de l'association française d'urologie (CTAFU) : lithiase urinaire chez le receveur ou le donneur en transplantation rénale.

OBJECTIVE: To define guidelines for the management of kidney stones in kidney transplant (KTx) donor or recipients. METHOD: Following a systematic approach, a review of the literature (Medline) was conducted by the CTAFU to report kidney stone epidemiology, diagnosis and management in KTx donors and recipients with the corresponding level of evidence. RESULTS: Prevalence of kidney stones in deceased donor is unknown but reaches 9.3% in living donors in industrialized countries. Except in Maastrich 2 donors, diagnosis is done on systematic pre-donation CT scan according to standard french procedure. No prospective study has compared therapeutic strategies available for the management of kidney stones in KTx donor: ureteroscopy or an extra corporeal lithotripsy in case of living donor prior to donation, ex vivo approach (pyelotomy or ureteroscopy), ureterocopy in the KTx recipient or surveillance. De novo kidney stones result from a lithogenesis process to be identified and treated in order to avoid recurrences. The context of solitary functional kidney renders the prevention of recurrence of great importance. Diagnosis is suspected when identification of a renal graft dysfunction, hematuria or urinary tract infection with renal pelvis dilatation. Stone size and location are determined by computed tomography. There are no prospective, controlled studies on kidney stone management in the KTx. The therapeutic strategies are similar to standard management in general population. CONCLUSION: These French recommendations should contribute to improve kidney stones management in KTx donor and recipients.

History of transplantation: Nothing is ever written. Part I.

The history of the first transplants is an ideal model for analyzing the different stages of disruptive innovation in surgery. Pioneers have often taken paths that were strewn with pitfalls, mistakes or failures. Sometimes victory, brilliant or more modest, lies at the end of this path. We propose to re-explore the extraordinary pathways that led to the first transplantations of the kidney, liver, lung and heart. That these first transplants should one day become possible required the concurrence of several factors: basic research, laboratory work to perfect the surgical techniques, a favorable legislative and societal context, and, above all, pioneering surgeons who would dare to apply their expertise to human subjects. Initial failures were not technical but immunological. Not everything would be perfect, especially ethical questions in some cases. Furthermore, initial results often humbled the greatest surgeons. Even though the historical and legislative contexts have evolved considerably as have science, society and the organization of the health system, this analysis of the past is rich in lessons for the modern surgeon who wishes to embark today along innovative pathways in the face of a still unresolved problem. Because nothing is ever carved in stone.

History of first transplantations: Nothing is ever written. Part II.

The history of the first transplants is an ideal model for analyzing the different stages of disruptive innovation in surgery. Pioneers have often taken paths that were strewn with pitfalls, mistakes or failures. Sometimes victory, brilliant or more modest, lies at the end of this path. We propose to re-explore the extraordinary pathways that led to the first transplantations of the kidney, liver, lung and heart. That these first transplants should one day become possible required the concurrence of several factors: basic research, laboratory work to perfect the surgical techniques, a favorable legislative and societal context, and, above all, pioneering surgeons who would dare to apply their expertise to human subjects. Initial failures were not technical but immunological. Not everything would be perfect, especially ethical questions in some cases. Furthermore, initial results often humbled the greatest surgeons. Even though the historical and legislative contexts have evolved considerably as have science, society and the organization of the health system, this analysis of the past is rich in lessons for the modern surgeon who wishes to embark today along innovative pathways in the face of a still unresolved problem. Because nothing is ever carved in stone.

Is there a relationship between vitamin D nutritional status and metabolic syndrome in childhood acute lymphoblastic leukemia survivors? A PETALE study.

BACKGROUND: Treatment of childhood acute lymphoblastic leukemia (cALL) has reached unprecedented success leading to survival rates reaching 90%. This is regrettably linked to increased risk of developing long-term health-related sequels into early adulthood. OBJECTIVE: This study aims at assessing the relationship between the vitamin D status and metabolic biomarkers in PETALE, a well-characterized cohort of cALL survivors. RESULTS: We demonstrate that 15.9% of the study participants exhibited 3 or more metabolic syndrome (MetS) risk factors. We also show a direct relationship between s25OHD3 and plasma HDL-Cholesterol concentrations in female but not male participants. CONCLUSION: Our data, from a metabolically well-described cohort, support a modest role for vitamin D in lipid metabolism in childhood leukemia survivors. The major outcome of this study is the strong association between HDL-Cholesterol concentration and s25OHD3 only in female subjects, thereby conveying vitamin D a gender-specific cardio-protective effect. cALL survivors represent a population at higher risk for secondary diseases. For this reason thorough nutritional evaluation, including vitamin D should be part of the regular follow-up.

Vitamin D nutritional status and bone turnover markers in childhood acute lymphoblastic leukemia survivors: A PETALE study.

BACKGROUND: The remarkable progress in the treatment of childhood acute lymphoblastic leukemia (cALL) has led to a survival rate reaching 90%. This success story is unfortunately linked to increased risk of impaired skeletal mass accumulation during childhood and adolescence, predisposing the patients to osteoporosis and pathological fractures at adulthood. OBJECTIVE: This study aims at characterizing the vitamin D status and bone health biomarkers in a well-characterized cohort of cALL survivors. RESULTS: Food frequency questionnaires reveal that (i) the total vitamin D intake varies greatly (44-2132 IU/d), (ii) only 16.8% of the participants consume vitamin D supplements, and (iii) 74% of survivors' intakes are below the Recommended Daily Intakes (400 IU/d). For the 42 participants taking vitamin D supplements, the median (2.5-97.5%iles) intake is 600 IU/d (21.2-1972 IU/d). Sixteen participants are vitamin D deficient (<30 nM) and 66 insufficient (≥30 - <50 nM). Serum 24,25(OH)2D3 concentrations are directly related to those of 25OHD3, and those of 3-epi-25OHD3 below the Lower Limit of Quantification in most samples. The participants' serum concentrations of cross-linked C-telopeptide of type-I collagen and intact amino-terminal pro-peptide of type-I collagen decrease steadily with age, leveling at adulthood, and are at all times higher in males. CONCLUSION: The present study shows that the prevalence of vitamin D insufficiency or deficiency is not greater in cALL survivors compared to the general Canadian population despite low vitamin D food and supplement intakes. Furthermore, there seem to be no overt imbalance in the gender- and age-adjusted serum bone turnover marker concentrations.

Transition zone and anterior stromal prostate cancers: Evaluation of discriminant location criteria using multiparametric fusion-guided biopsy.

PURPOSE: The purpose of this study was to evaluate precise location criteria on magnetic resonance imaging (MRI) to improve detection of transition zone (TZ) and anterior stroma (AS) prostate cancers using targeted MRI/transrectal ultrasound fusion biopsies as a reference standard. MATERIAL AND METHODS: Ninety-six men (mean age: 65 years±7.7 [SD] [range: 46-83 years]) with an elevated prostate-specific antigen (PSA) (PSA≥4ng/mL) who underwent standard and targeted biopsies on a TZ/AS suspicious lesion were included. The database was reviewed to assess topographical and morphological features of each suspicious lesion on MR images (T2-weighted anatomical images on 1.5T MRI or 3T) including PI-RADS score assessed by a senior radiologist. Histopathological examination of MRI-transrectal ultrasound fusion biopsy specimens was used as the reference standard. RESULTS: Ninety patients had a positive targeted biopsy with a median [IQR] lesion size of 16mm [13-20mm]. Homogeneous hypointensity on T2-weighted mages, lenticular shape, lack of capsule and indistinct margins were present in 77/90 (85%) patients. All TZ/AS prostate cancers were located in the anterior half of the prostate: 3% at the base, 69% in the mid gland and 28% at the apex. Lesions were mainly located close to or within the AS (74%) and more rarely laterally compressed close to the peripheral anterior horn. CONCLUSION: Our results suggest that specific topographic criteria of TZ and AS prostate cancers could add independent information to the usual diagnostic criteria in prostate MRI. Transrectal ultrasound fusion-targeted biopsies based on these specific criteria improve volume estimation of prostate cancers with substantial impact for prognosis and treatment planning.

Unique case report of a chromomycosis and Listeria in soft tissue and cerebellar abscesses after kidney transplantation.

BACKGROUND: Chromomycosis is a rare mycotic infection encountered in tropical and subtropical regions. The disease presents as a slowly-evolving nodule that can become infected with bacteria. Here, we describe a unique association of abscesses caused by a chromomycosis and Listeria monocytogenes in a kidney transplant recipient, and didactically expose how the appropriate diagnosis was reached. CASE PRESENTATION: A 49-year old male originating from the Caribbean presented a scalp lesion which was surgically removed in his hometown where it was misdiagnosed as a sporotrichosis on histology, 3 years after he received a kidney transplant. He received no additional treatment and the scalp lesion healed. One year later, an abscess of each thigh due to both F. pedrosoi and L. monocytogenes was diagnosed in our institution. A contemporary asymptomatic cerebellar abscess was also found by systematic MRI. An association of amoxicillin and posaconazole allowed a complete cure of the patient without recurring to surgery. Histological slides from the scalp lesion were re-examined in our institution and we retrospectively concluded to a first localisation of the chromomycosis. We discuss the possible pathophysiology of this very unusual association. CONCLUSION: In this case of disseminated listeriosis and chromomycosis, complete cure of the patients could be reached with oral anti-infectious treatment only.

[Local analgesia during flexible cystoscopy in male patients: A non-inferiority study comparing Xylocaine® gel to Instillagel® Lido]. / Anesthésie locale pour fibroscopie chez l'homme : étude de non-infériorité comparant le Xylocaine® gel à l'Instillagel® Lido.

INTRODUCTION: Local anesthesia using urethral gel has been proven to reduce discomfort of male patients during flexible cystoscopy. This study was a non-inferiority study between two lidocain-containing urethral gel (Instillagel® Lido and Xylocaine® gel). METHODS: A prospective single center study was conducted between June 2014 and November 2014. Male patients seen in the office and in whom a flexible cystoscopy was planned were included in the present study and received urethral instillation of either Xylocaine® gel or Instillagel® Lido at least 5minutes before flexible cystoscopy. No other anesthetic agent was used. Primary endpoint was pain during the procedure, assessed through visual analog scale (VAS) from 0 to 10. RESULTS: Four hundred and sixty-one men were included: 233 in the Instillagel® Lido group and 228 in the Xylocaine® gel group. Indications of flexible cystoscopy non-muscle invasive bladder cancer follow-up in 44 % of cases, hematuria work-up in 21 % of cases and lower urinary tract symptoms work-up in 35 %. Patients' age was comparable betwwen both groups: 64.5 years (±1.1) in the Instillagel® Lido group and 66.2 years (±1.1) in the Xylocaine® gel group (P=0.29). The mean VAS was 0.8 (±0.1) in the Instillagel® Lido group and 0.6 (±0.1) in the Xylocaine® gel group (P=0.10). The non-inferiority criterion was reached (P<0.001) as the average difference in VAS between the two groups was 0.2 with a confidence interval not comprising 1 (CI 97.5 %: -0.47; 0.07). CONCLUSION: In this prospective study, Instillagel® Lido was not inferior to Xylocaine® gel for local analgesia during flexible cystoscopy in male patients. LEVEL OF EVIDENCE: 4.

Polymorphisms of ABCC5 and NOS3 genes influence doxorubicin cardiotoxicity in survivors of childhood acute lymphoblastic leukemia.

Anthracyclines are efficient chemotherapy agents. However, their use is limited by anthracycline-induced cardiotoxicity (CT). We investigated the influence of polymorphisms in doxorubicin metabolic and functional pathways on late-onset CT as estimated by echocardiography in 251 childhood acute lymphoblastic leukemia (cALL) patients. Association analyses revealed a modulating effect of two variants: A-1629 T in ABCC5, an ATP-binding cassette transporter, and G894T in the NOS3 endothelial nitric oxide synthase gene. Individuals with the ABCC5 TT-1629 genotype had an average of 8-12% reduction of ejection (EF) and shortening fractions (SF; EF: P<0.0001, and SF: P=0.001, respectively). A protective effect of the NOS3 TT894 genotype on EF was seen in high-risk patients (P=0.02), especially in those who did not receive dexrazoxane (P=0.002). Analysis of an additional cohort of 44 cALL patients replicated the ABCC5 association but was underpowered for NOS3. In summary, we identified two biomarkers that may contribute to cALL anthracycline CT risk stratification.