Magnetic resonance T2 mapping and diffusion-weighted imaging for early detection of cystogenesis and response to therapy in a mouse model of polycystic kidney disease.

Polycystic kidney disease (PKD) is among the leading causes of end-stage renal disease. Increasing evidence exists that molecular therapeutic strategies targeted to cyst formation and growth might be more efficacious in early disease stages, highlighting the growing need for sensitive biomarkers. Here we apply quantitative magnetic resonance imaging techniques of T2 mapping and diffusion-weighted imaging in the jck mouse model for PKD using a clinical 3.0 T scanner. We tested whether kidney T2 values and the apparent diffusion coefficient (ADC) are superior to anatomical imaging parameters in the detection of early cystogenesis, as shown on macro- and histopathology. We also tested whether kidney T2 values and ADC have the potential to monitor early treatment effects of therapy with the V2 receptor antagonist Mozavaptane. Kidney T2 values and to a lesser degree ADC were found to be highly sensitive markers of early cystogenesis and superior to anatomical-based imaging parameters. Furthermore, kidney T2 values exhibited a nearly perfect correlation to the histological cystic index, allowing a clear separation of the two mouse genotypes. Additionally, kidney T2 values and ADC were able to monitor early treatment effects in the jck mouse model in a proof-of-principle experiment. Thus, given the superiority of kidney T2 values and ADC over anatomical-based imaging in mice, further studies are needed to evaluate the translational impact of these techniques in patients with PKD.

Characterization of a splice-site mutation in the tumor suppressor gene FLCN associated with renal cancer.

BACKGROUND: Renal cell carcinoma is among the most prevalent malignancies. It is generally sporadic. However, genetic studies of rare familial forms have led to the identification of mutations in causative genes such as VHL and FLCN. Mutations in the FLCN gene are the cause of Birt-Hogg-Dubé syndrome, a rare tumor syndrome which is characterized by the combination of renal cell carcinoma, pneumothorax and skin tumors. METHODS: Using Sanger sequencing we identify a heterozygous splice-site mutation in FLCN in lymphocyte DNA of a patient suffering from renal cell carcinoma. Furthermore, both tumor DNA and DNA from a metastasis are analyzed regarding this mutation. The pathogenic effect of the sequence alteration is confirmed by minigene assays and the biochemical consequences on the protein are examined using TALEN-mediated transgenesis in cultured cells. RESULTS: Here we describe an FLCN mutation in a 55-year-old patient who presented himself with progressive weight loss, bilateral kidney cysts and renal tumors. He and members of his family had a history of recurrent pneumothorax during the last few decades. Histology after tumor nephrectomy showed a mixed kidney cancer consisting of elements of a chromophobe renal cell carcinoma and dedifferentiated small cell carcinoma component. Subsequent FLCN sequencing identified an intronic c.1177-5_-3delCTC alteration that most likely affected the correct splicing of exon 11 of the FLCN gene. We demonstrate skipping of exon 11 to be the consequence of this mutation leading to a shift in the reading frame and the insertion of a premature stop codon. Interestingly, the truncated protein was still expressed both in cell culture and in tumor tissue, though it was strongly destabilized and its subcellular localization differed from wild-type FLCN. Both, altered protein stability and subcellular localization could be partly reversed by blocking proteasomal and lysosomal degradation. CONCLUSIONS: Identification of disease-causing mutations in BHD syndrome requires the analysis of intronic sequences. However, biochemical validation of the consecutive alterations of the resulting protein is especially important in these cases. Functional characterization of the disease-causing mutations in BHD syndrome may guide further research for the development of novel diagnostic and therapeutic strategies.

Mutations in NEK8 link multiple organ dysplasia with altered Hippo signalling and increased c-MYC expression.

Mutations affecting the integrity and function of cilia have been identified in various genes over the last decade accounting for a group of diseases called ciliopathies. Ciliopathies display a broad spectrum of phenotypes ranging from mild manifestations to lethal combinations of multiple severe symptoms and most of them share cystic kidneys as a common feature. Our starting point was a consanguineous pedigree with three affected fetuses showing an early embryonic phenotype with enlarged cystic kidneys, liver and pancreas and developmental heart disease. By genome-wide linkage analysis, we mapped the disease locus to chromosome 17q11 and identified a homozygous nonsense mutation in NEK8/NPHP9 that encodes a kinase involved in ciliary dynamics and cell cycle progression. Missense mutations in NEK8/NPHP9 have been identified in juvenile cystic kidney jck mice and in patients suffering from nephronophthisis (NPH), an autosomal-recessive cystic kidney disease. This work confirmed a complete loss of NEK8 expression in the affected fetuses due to nonsense-mediated decay. In cultured fibroblasts derived from these fetuses, the expression of prominent polycystic kidney disease genes (PKD1 and PKD2) was decreased, whereas the oncogene c-MYC was upregulated, providing potential explanations for the observed renal phenotype. We furthermore linked NEK8 with NPHP3, another NPH protein known to cause a very similar phenotype in case of null mutations. Both proteins interact and activate the Hippo effector TAZ. Taken together, our study demonstrates that NEK8 is essential for organ development and that the complete loss of NEK8 perturbs multiple signalling pathways resulting in a severe early embryonic phenotype.

The ciliopathy disease protein NPHP9 promotes nuclear delivery and activation of the oncogenic transcriptional regulator TAZ.

Nephronophthisis (NPH) is a genetically heterogenous kidney disease and represents the most common genetic cause for end-stage renal disease in children. It is caused by the mutation of genes encoding for the nephrocystin proteins (NPHPs) which localize to primary cilia or centrosomes, classifying this disease as a 'ciliopathy'. Recently, it has been shown that NPHP4 acts as a potent negative regulator of mammalian Hippo signalling by interacting with the Lats protein kinase and controlling the phosphorylation of the oncogenic transcriptional activator TAZ. Here, we demonstrate that NPHP9, another NPH family member, also controls TAZ activity by a distinct mechanism. NPHP9, which is also called NEK8, directly interacted with TAZ and induced nuclear translocation of the TAZ/NPHP9 protein complex. Binding of NPHP9 to TAZ was enhanced in a TAZ mutant that lost its ability to bind 14-3-3, suggesting that 14-3-3 and NPHP9 may compete for TAZ binding, with 14-3-3 favouring cytoplasmic retention and NPHP9 mediating nuclear delivery. Consistently, co-expression of NPHP4, which inhibits TAZ phosphorylation at the 14-3-3 binding site through the inhibition of Lats kinase activity, induced efficient nuclear delivery of the TAZ/NPHP9 protein pair. Consistent with a role for TAZ in controlling proliferation and tumorigenesis, the downregulation of NPHP9 inhibited the TAZ-dependent proliferation of hippo-responsive normal epithelial and also breast cancer cells. As NPHP9 has been shown to be upregulated in breast cancer, these data do not only support a critical role for TAZ/hippo signalling in the pathogenesis of NPH but may also imply a possible role for NPHP9 in TAZ-mediated tumorigenesis.

Thoracic type Ia endoleak: direct percutaneous coil embolization of the aortic arch at the blood entry site after TEVAR and double-chimney stent-grafts.

OBJECTIVES: To introduce a novel percutaneous technique to stop blood entry at the lesser aortic arch curvature by coil embolisation in type Ia endoleak after TEVAR. METHODS: A 61-year-old Marfan patient presented with type Ia endoleak of the aortic arch and a growing aortic arch pseudoaneurysm after TEVAR. Multiple preceding operations and interventions made an endovascular approach unsuccessful. Direct percutaneous puncture of the aneurysmal sac would have cured the sign, but not the cause of blood entry at the lesser curvature of the aortic arch. Direct CT-guided percutaneous puncture of the blood entry site in the aortic arch with fluoroscopically guided coil embolisation using detachable extra-long coils was successfully performed. RESULTS: Three weeks after the intervention, the patient developed fever because of superinfection of the pseudoaneurysm. The blood cultures and CT-guided mediastinal aspirate were sterile. After intravenous administration of antibiotics, the fever disappeared and the patient recovered. Six-month follow-up showed permanent closure of the endoleak and a shrinking aneurysmal sac. CONCLUSIONS: Direct percutaneous puncture of the aortic arch at the blood entry site of a thoracic type Ia endoleak after TEVAR and double-chimney stent-grafts with coil embolisation of the wedge-shaped space between the lesser aortic curvature and the stent-graft is possible. KEY POINTS: Endoleaks after thoracic endovascular aortic repair are common in 15-30 %. Most endoleaks can be treated by endovascular means. Direct percutaneous endoleak repair is described as a bail-out option. Direct percutaneous aortic arch coil embolisation of type 1a endoleak is possible. Antibiotic prophylaxis should be administered case by case, considering individual risk factors.

Factors Impacting Microwave Ablation Zone Sizes: A Retrospective Analysis.

PURPOSE: Evaluation of the influence of intrinsic and extrinsic conditions on ablation zone volumes (AZV) after microwave ablation (MWA). METHODS: Retrospective analysis of 38 MWAs of therapy-naïve liver tumours performed with the NeuWave PR probe. Ablations were performed either in the 'standard mode' (65 W, 10 min) or in the 'surgical mode' (95 W, 1 min, then 65 W, 10 min). AZV measurements were obtained from contrast-enhanced computed tomography immediately post-ablation. RESULTS: AZVs in the 'standard mode' were smaller than predicted by the manufacturer (length 3.6 ± 0.6 cm, 23% below 4.7 cm; width 2.7 ± 0.6, 23% below 3.5 cm). Ablation zone past the tip was limited to 6 mm in 28/32 ablations. Differences in AZV between the 'surgical mode' and 'standard mode' were not significant (15.6 ± 7.8 mL vs. 13.9 ± 8.8 mL, p = 0.6). AZVs were significantly larger in case of hepatocellular carcinomas (HCCs) (n = 19) compared to metastasis (n = 19; 17.8 ± 9.9 mL vs. 10.1 ± 5.1 mL, p = 0.01) and in non-perivascular tumour location (n = 14) compared to perivascular location (n = 24, 18.7 ± 10.4 mL vs. 11.7 ± 6.1 mL, p = 0.012), with both factors remaining significant in two-way analysis of variance (HCC vs. metastasis: p = 0.02; perivascular vs. non-perivascular tumour location: p = 0.044). CONCLUSION: Larger AZVs can be expected in cases of HCCs compared with metastases and in non-perivascular locations. Using the 'surgical mode' does not increase AZV significantly.

The status of academic interventional radiologists in Germany with focus on gender disparity: how can we do better?

PURPOSE: The aim was to characterize the framework conditions in academic interventional radiology (IR) in Germany with focus on differences between genders. MATERIALS AND METHODS: After IRB approval, all members of The German Society for Interventional Radiology and Minimally Invasive Therapy (n = 1,632) were invited to an online survey on work and research. Statistical comparisons were undertaken with the Fisher's exact test, Wilcoxon rank sum test or Pearson's Chi-squared test. RESULTS: From 267 available questionnaires (general response rate 16.4%), 200 were fully completed. 40% of these (78/200) were involved in research (71% men vs. 29% women, p < 0.01) and eligible for further analysis. Of these, 6% worked part-time (2% vs. 17%, p < 0.05). 90% of the respondents spent less than 25% of their research during their paid working hours, and 41% performed more than 75% of their research during. leisure time. 28% received exemption for research. 88% were (rather) satisfied with their career. One in two participants successfully applied for funding, with higher success rates among male applicants (90% vs. 75%) and respondents with protected research time (93% vs. 80%). Compared to men, women rated their entrance in research as harder (p < 0.05), their research career as more important (p < 0.05), felt less noticed at congresses (93% vs. 53%, p < 0.01), less confident (98% vs. 71%, p < 0.01), and not well connected (77% vs. 36%, p < 0.01).  CONCLUSION: Women and men did research under the same circumstances; however, women were underrepresented. Future programs should generally focus on protected research time and gather female mentors to advance academic IR in Germany.

Vacuum-Assisted Suction Drainage as a Successful Treatment Option for Postoperative Symptomatic Lymphoceles.

PURPOSE: Lymphoceles often occur within several weeks or even months after surgery. Mostly asymptomatic and therefore undiagnosed, they may be self-healing without any treatment. A small percentage of postoperative lymphoceles are symptomatic with significant pain, infection, or compression of vital structures, thus requiring intervention. Many different treatment options are described in the literature, like drainage with or without sclerotherapy, embolization of lymph vessels, and surgical approaches with laparoscopy or laparotomy. Inspired by reports stating that postoperative suction drainage can prevent the formation of lymphoceles, we developed a simple protocol for vacuum-assisted drainage of symptomatic lymphoceles, which proved to be successful and which we would therefore like to present. MATERIALS AND METHOD: Between 2008 and 2020, 35 patients with symptomatic postoperative lymphoceles were treated with vacuum-assisted suction drainage (in total 39 lymphoceles). The surgery that caused lymphocele formation had been performed between 8 and 572 days before. All lymphoceles were diagnosed based on biochemical and cytologic findings in aspirated fluid. The clinical and imaging data were collected and retrospectively analyzed. RESULTS: In total, 43 suction drainage catheters were inserted under CT guidance. The technical success rate was 100 %. One patient died of severe preexisting pulmonary embolism, sepsis, and poor conditions (non-procedure-related death). In 94.8 % of symptomatic lymphoceles, healing and total disappearance could be achieved. 4 lymphoceles had a relapse or dislocation of the drainage catheter and needed a second drainage procedure. Two lymphoceles needed further surgery. The complication rate of the procedure was 4.6 % (2/43, minor complications). The median indwelling time of a suction drainage catheter was 8-9 days (range: 1-30 days). CONCLUSION: The positive effects of negative pressure therapy in local wound therapy have been investigated for a long time. These positive effects also seem to have an impact on suction drainage of symptomatic lymphoceles with a high cure rate. KEY POINTS: · Suction drainage of lymphoceles is an easy and successful method to cure symptomatic lymphoceles at various locations.. · We believe this to be due to the induction of cavity collapse and surface adherence.. · In most cases rapid clinical improvement could be obtained.. CITATION FORMAT: · Franke M, Saager C, Kröger J et al. Vacuum-Assisted Suction Drainage as a Successful Treatment Option for Postoperative Symptomatic Lymphoceles. Fortschr Röntgenstr 2022; 194: 384 - 390.

Leiomyosarcoma of the Nasal Cavity.

Leiomyosarcoma (LMS) in the sinonasal tract (SNT) is a rarity that has been firstly described in 1958. Since then, there have been only a few articles about this entity. Most of the data available about LMS in the SNT is derived from case reports. We believe that our case will support the data set and help guiding the management of this rare condition. A 84-year-old female presented with nasal airway obstruction on the left side. She experienced several episodes of epistaxis from her left nostril, what made her to seek medical care. A rhinoscopy revealed an obstructing mass in the left nasal cavity. Computed tomography (CT) scan of the paranasal sinuses revealed a homogenous mass occupying the left nasal cavity, bone destruction of the left middle, and inferior nasal turbinates. An infiltration of the left nasolacrimal duct was also present. The patient refused to undergo open surgery and the mass was removed during an endoscopic approach. The histopathological analysis combined with immunohistochemistry was consistent with LMS. The resection margins were positive for tumor cells. A staging with CT-neck-thorax, abdomen ultrasound, and MRI of the head ruled out metastases. She underwent a second endoscopic tumor resection surgery with positive resection margins and obtained adjuvant radiotherapy. On 9 months of follow-up, there was no recurrence or metastases.

Not All Embolizations Are Created Equally in the Management of Posterior Epistaxis: Discussion of Safety Measures Avoiding Neurological Complications.

Today, there are still no uniform guidelines for the treatment of epistaxis. Furthermore, it is widely debated whether embolization or surgical approaches should be the first choice of treatment for intractable posterior epistaxis after conservative measures have failed. In several meta-analyses, it is reported that endoscopic sphenopalatine artery ligation and embolization have similar success rates, but embolization was associated with more severe neurological complications. Regarding existing literature, there are many comparative analyses of surgical methods but none for embolization protocols. Against this backdrop of a lack of uniform standards in embolization techniques, we present a retrospective evaluation of what has emerged to be best procedural practice for endovascular treatment of epistaxis in our department using microsphere particles and microcoils, in particular regarding precaution measures to avoid neurological complications. In our retrospective data analysis of 141 procedures in 123 patients, performed between 2008 and 2019, we find success rates very similar to those reported in other studies (95.1% immediate-stop-of-bleeding success and 90.2% overall embolization success) but did not encounter any major neurological complication opposed to other reports. We suggest some aspects of our protocol as precaution measure to avoid neurological complications. More generally and perhaps even more importantly, we make a strong case for standardization for embolization techniques to the level of details in surgical procedure standardization to enable an apples to apples comparison of embolization techniques to each other and of intervention vs. surgery.

Targeted deletion of the AAA-ATPase Ruvbl1 in mice disrupts ciliary integrity and causes renal disease and hydrocephalus.

Ciliopathies comprise a large number of hereditary human diseases and syndromes caused by mutations resulting in dysfunction of either primary or motile cilia. Both types of cilia share a similar architecture. While primary cilia are present on most cell types, expression of motile cilia is limited to specialized tissues utilizing ciliary motility. We characterized protein complexes of ciliopathy proteins and identified the conserved AAA-ATPase Ruvbl1 as a common novel component. Here, we demonstrate that Ruvbl1 is crucial for the development and maintenance of renal tubular epithelium in mice: both constitutive and inducible deletion in tubular epithelial cells result in renal failure with tubular dilatations and fewer ciliated cells. Moreover, inducible deletion of Ruvbl1 in cells carrying motile cilia results in hydrocephalus, suggesting functional relevance in both primary and motile cilia. Cilia of Ruvbl1-negative cells lack crucial proteins, consistent with the concept of Ruvbl1-dependent cytoplasmic pre-assembly of ciliary protein complexes.

Computed Tomography Volumetry in Preoperative Living Kidney Donor Assessment for Prediction of Split Renal Function.

BACKGROUND: Transplant centers commonly evaluate split renal function (SRF) with Tc-99m-mercapto-acetyltriglycin (MAG3) scintigraphy in living kidney donation. Alternatively, the kidney volume can be measured based on predonation CT scans. The aim of this study was to identify the most accurate CT volumetry technique for SRF and the prediction of postdonation kidney function (PDKF). METHODS: Three CT volumetry techniques (modified ellipsoid volume [MELV], smart region of interest [ROI] volume, renal cortex volume [RCV]) were performed in 101 living kidney donors. Preoperation CT volumetric SRF was determined and compared with MAG3-SRF, postoperation donor kidney function, and graft function. RESULTS: The correlation between donors predonation total kidney volume and predonation kidney function was the highest for RCV (0.58 with creatine clearance, 0.54 with estimated glomerular filtration rate-Cockcroft-Gault). The predonation volume of the preserved kidney was (ROI, MELV, RCV) 148.0 ± 29.1 cm, 151.2 ± 35.4 and 93.9 ± 25.2 (P < 0.005 MELV vs RCV and ROI vs RCV). Bland-Altman analysis showed agreement between CT volumetry SRF and MAG3-SRF (bias, 95% limits of agreement: ROI vs MAG3 0.4%, -7.7% to 8.6%; MELV vs MAG3 0.4%, -8.9% to 9.7%; RCV vs MAG3 0.8%, -9.1% to 10.7%). The correlation between predonation CT volumetric SRF of the preserved kidney and PDKF at day 3 was r = 0.85 to 0.88, between MAG3-SRF and PDKF (r = 0.84). The difference of predonation SRF between preserved and donated kidney was the lowest for ROI and RCV (median, 3% and 4%; 95th percentile, 9% and 13%). CONCLUSIONS: Overall renal cortex volumetry seems to be the most accurate technique for the evaluation of predonation SRF and allows a reliable prediction of donor's PDKF.