Contribution of Genomic Imbalance in Prenatal Congenital Anomalies of the Kidney and Urinary Tract: A Multi-Center Cohort Study.

OBJECTIVES: To investigate the diagnostic utility of copy-number variant (CNV) detection by chromosomal microarray analysis (CMA) and genotype-phenotype associations in prenatal congenital anomalies of the kidney and urinary tract (CAKUT). METHODS: This is a retrospective multi-center study of CNV analysis in 457 fetuses with ultrasound-detected CAKUT and normal karyotypes. Cohorts from published studies were included for further pooled analyses (N = 2746). A literature review of single-nucleotide variant (SNV) and small insertions and deletions (Indel) analysis by whole-exome sequencing was performed to investigate monogenic causes. RESULTS: In our multi-center cohort, 5.3% (24/457) of fetuses had pathogenic CNVs (pCNV); 3.9% (14/359) and 10.2% (10/98) in isolated and non-isolated CAKUT, respectively. Fetuses with isolated hyperechogenic kidneys (HEK) had the highest incidence of having pCNVs. In the literature review, 6.6% (180/2746) of fetuses carried pCNVs; 6.1% and 7.5% in isolated and non-isolated CAKUT, respectively. SNV/Indel analysis provided at least 16.5% (63/381) additional diagnostic yield beyond CNV analysis; 12.8% and 23.8% in isolated and non-isolated CAKUT, respectively. CONCLUSION: pCNVs comprise a significant proportion of genetic diagnostic findings in prenatal CAKUT, most commonly detected in fetuses with isolated HEK, MCDK, renal agenesis, and non-isolated CAKUT. Monogenic causes should be considered when karyotyping and CMA are nondiagnostic.

Genome sequencing in the prenatal diagnosis of structural malformations in the fetus.

Prenatal genetic diagnosis has undergone two pivotal paradigm shifts, initially with the introduction of chromosomal microarray and subsequently with the advent of next-generation sequencing technologies (NGS). NGS technology has given rise to a multitude of applications, with gene panels, exome sequencing (ES), and genome sequencing (GS) emerging as highly promising tests for prenatal genetic investigations. These advanced approaches have demonstrated superior diagnostic rates when compared to conventional testing methods, showcasing the evolution and enhancement of prenatal genetic screening and diagnostic capabilities. With these ground-breaking innovations, NGS technologies have the potential to replace current standard practice in prenatal diagnosis. With the increasing use of prenatal sequencing, the need for better education and guidance on their applications grows. This chapter aims to illustrate the detection scope and feasibility of various NGS-based methods that are currently used in prenatal diagnosis.

Demonstrating the Efficacy of Dual Energy Computer Tomography with Gemstone Spectral Imaging Software to Determine Mixed and Single Composition ex vivo Urolithiasis.

Objective: To assess the capability of determining the mixed chemical composition of urinary stones using spectral imaging properties of Dual Energy Computed Tomography (DECT) Gemstone Spectral Imaging (GSI) software. Material and Methods: Twenty-six single and 24 mixed composition ex vivo urinary stones with known chemical composition determined by Fourier-transform infrared spectroscopy (FTIR) prior to this project were scanned with DECT imaging and GSI in vitro. The major components of the stones included Uric Acid (UA), Calcium Oxalate (CaOx), Calcium Phosphate (CaP), Magnesium Ammonium Phosphate (MAP), and Cystine (Cys). A histogram to display the distribution of the effective atomic number (Z-eff) of each pixel of the tested area, spectral curve (40-140 keV, with 10 keV interval) and Hounsfield Units (HU) of each stone scanned was provided with analysis of monochromatic images at 140 keV in the axial plane. Results: The overall pooled sensitivity, specificity, and accuracy of DECT for identifying major stone composition were 0.802, 0.831, and 0.807, respectively, with a 95% confidence interval. Accuracy was 100% for identifying UA and Cys stones. Conclusion: DECT is a superior imaging modality when compared to low dose computed tomography kidney ureter bladder scans. It allows for improved characterization of major components of urinary stones, in an accurate, non-invasive approach to pre-treatment. This can translate to urologists having greater confidence in determining patient suitability for medical or surgical management of their renal stones, in clinical practice.

Integration of an online application to optimise multi-disciplinary meetings: a retrospective analysis.

BACKGROUND: Multi-disciplinary Meetings (MDM) play a crucial role in complex patient care, involving input from various specialties to formulate evidence-based management plans. However, traditional unidirectional approaches and reliance on manual processes have led to inefficiencies in the MDM pathway. AIMS: This study identified and aimed to improve four critical moments where Information Communication Technologies (ICTs) could enhance the MDM process. Initial referral, information synthesis, meeting presentation and the creation of actionable/auditable items. METHODS: Microsoft Office Forms, a customisable survey platform, was implemented to streamline MDM processes. Forms were created to gather patient information, develop agendas, and track outcomes. Automation through Excel scripting further optimised data organisation and agenda creation. RESULTS: Referrals using Forms takes an average of 7 min and 21 s. Over 15 months the submission time has reduced and is trending towards under 5 min for each referral. The system's scalability has allowed 1744 cases to be discussed over a 15-month period. Active departments using Forms is expanding to seven from two prior to the pilot. CONCLUSION(S): Microsoft Office Forms proved to be a valuable and adaptable tool for MDMs, offering benefits such as streamlined information gathering, real-time collaboration, and scalability. The study highlights the potential of existing tools within Microsoft licenses for healthcare process optimisation, providing a cost-effective and customisable solution for MDM agendas. While recognising some limitations, the study concludes that leveraging Microsoft Office Forms can significantly improve system efficiency in a multi-disciplinary setting.

Are systematic prostate biopsy still necessary in biopsy naive men?

PURPOSE: Multiparametric MRI and the transperineal approach have become standard in the diagnostic pathway for suspected prostate cancer. Targeting of MRI lesions is performed at most centers, but the routine use of systematic cores is controversial. We aim to assess the value of obtaining systematic cores in patients undergoing cognitive fusion targeted double-freehand transperineal prostate biopsy. MATERIALS AND METHODS: Patients who underwent a cognitive fusion, freehand TPB at a single tertiary urology service (Perth, Australia) between November 2020 and November 2021 were retrospectively reviewed. Patients were included if they were biopsy naive and had a clinical suspicion of prostate cancer, based on their mpMRI results. Both targeted and systematic cores were taken at the time of their biopsy. RESULTS: One hundred forty patients suited the selection criteria. Clinically significant cancer was identified in 63% of patients. Of those that had clinically significant cancer, the target lesion identified 91% of the disease, missing 9% of patients whom the target biopsy detected non-clinically significant cancer but was identified in the systematic cores. Higher PI-RADS category patients were also found to be associated with an increasing likelihood of identifying clinically significant cancer within the target. CONCLUSIONS: In patients with PI-RADS 3 and higher, the target biopsy can miss up to 9% of clinically significant cancer. Systematic cores can add value as they can also change management by identifying a high-risk disease where only intermediate cancer was identified in the target. A combination of targeted and systematic cores is still required to detect cancer.

Radiological Density, Atomic Numbers, and Stone Fragmentation of Bego Stones Used for Research in Endourology: Comparison to Real Urinary Stones.

Objective: The aim of the study was to characterize artificial stones used for research in endourology in terms of radiological properties and hardness, based on stone fragmentation, and to compare them with real stones. Materials and Methods: We built artificial stones using BegoStone Plus™ powder (BEGO, Lincoln, RI), with powder (g)-water (mL) ratios ranging from 15:03 to 15:12. The CT Gemstone Spectral Imaging Software® (GE Medical Systems, LLC, Waukesha, WI) was used to evaluate the radiological density in HU and spectral properties. Stone fragmentation was assessed in an in vitro experimental setting. These properties of artificial stones were compared with real urinary calculi. Results: Regarding radiological density in terms of HUs, 15:03 artificial calculi showed similar results when compared with real stones comprising calcium oxalate and calcium phosphate. The 15:03 and 15:04 artificial stones showed similar spectral property results to calcium pyrophosphate stones. The 15:11 artificial stones showed similar stone fragmentation results to real stones comprising uric acid, and 15:03 artificial calculi showed similar results to apatite and cystine stones. Conclusions: Artificial stones are useful for research in endourology. Stones with a powder (g)-water (mL) ratio of 15:03 proved to mimic real hard stones in terms of HUs, atomic number, and stone fragmentation in our study and could be used as artificial hard stones, and 15:11 stones showed similar stone fragmentation to uric acid stones. Our study might suggest that standard Bego stones are useful to investigate different areas in endourology, but not radiological properties because radiological homogeneity is not ensured unless more sophisticated mixing methods are used.

Computed Tomography-Guided Prostate Sampling and Fiducial Marker Insertion in Patients With Absent Rectums.

OBJECTIVES: We aimed to present our experience and the outcomes of a novel technique, computed tomography (CT)-guided prostate biopsy and fiducial marker insertion in patients with absent rectums. METHODS: Patients who underwent CT-guided prostate biopsy at a single institution from November 2010 to November 2022 were retrospectively reviewed. Patients were included if they had a clinical suspicion of prostate cancer and had absent rectums from previous surgical resection. Contrast-enhanced CT scan was used to perform transgluteal prostate biopsy. Patient demographics, multiparametric magnetic resonance imaging, and biopsy details were recorded. RESULTS: Thirteen biopsy procedures and 1 CT-guided fiducial marker insertion were performed on 12 unique patients. The reasons for the absence of rectums included surgical resection for rectal cancer (n = 10) and surgical resection for inflammatory bowel disease (n = 2). Clinically significant cancer was found in 7 of 13 biopsy results (52.8%), clinically insignificant cancer in 3 of 13 (23.1%), and benign cancer in 3 of 13 (23.1%). No complications were recorded. CONCLUSIONS: Our data support CT-guided prostate biopsy as an accurate and effective technique for investigating prostate cancer that requires tissue sampling in patients with absent rectums.

The Use of Prophylactic Ureteric Stents in Major Abdomino-Pelvic Sarcoma Surgery: Risks, Benefits, and Potential Complications.

Here we present two cases of post-operative obstructive renal failure following major abdomino-pelvic sarcoma surgery. In both cases, prophylactic ureteric stents were inserted to aid the identification and protection of the ureters during resection of these complex retroperitoneal masses. In case one, obstructive renal failure occurred following ureteric stent removal on day 0 post-operatively. In case two, obstructive renal failure developed on day 1 post-operatively despite having a ureteric stent in situ. Here we propose that a combination of reflex anuria/ureteric edema and papillary sloughing led to the obstructive renal failure in both cases. Re-insertion of bilateral ureteric stents in case one, and replacement of a right ureteric stent in case two saw prompt excretion of urine and sloughy debris with rapid improvement of renal function. This article presents these cases in detail and further reviews the use of prophylactic ureteric stents in major abdomino-pelvic surgery along with the current guidelines for their usage.

The Utility of Renal Mass Biopsy in Large Renal Masses.

Objectives: The role of needle core renal biopsy in large renal masses, defined as lesions larger than 4 cm, is debatable, as larger renal masses are associated with malignant histology. We aim to review the safety and impact of renal biopsy on the management of large renal masses. Methods: A retrospective, single-center review of all renal biopsies performed between January 2011 and December 2020 at Royal Perth Hospital was conducted. Indications for biopsy, complications and final management plans were correlated to assess the value of biopsies in large renal masses. Results: In total, 126 biopsies were performed. Indeterminate imaging findings and comorbidities were the main indications for biopsies. We identified 116 (92.1%) diagnostic biopsies and 10 (8.0%) non-diagnostic biopsies due to insufficient samples or inflammatory tissue. Of the diagnostic biopsies, 99 (78.6%) were malignant and 17 (13.5%) were benign. Unnecessary extirpative surgery was avoided in 17 patients. Histology included renal cell carcinoma (96%) and other malignancies such as urothelial carcinoma (3%) and non-Hodgkin's lymphoma (1%). Benign biopsies identified histology including angiomyolipoma (35.3%) and oncocytoma (52.5%). The median follow-up time was 68 months (range 19-132 months). Conclusion: Renal biopsies in large renal masses may aid in preventing unnecessary surgery, especially in situations where imaging findings are equivocal or in patients with many comorbidities.

Low-Pass Genome Sequencing-Based Detection of Paternity: Validation in Clinical Cytogenetics.

Submission of a non-biological parent together with a proband for genetic diagnosis would cause a misattributed parentage (MP), possibly leading to misinterpretation of the pathogenicity of genomic variants. Therefore, a rapid and cost-effective paternity/maternity test is warranted before genetic testing. Although low-pass genome sequencing (GS) has been widely used for the clinical diagnosis of germline structural variants, it is limited in paternity/maternity tests due to the inadequate read coverage for genotyping. Herein, we developed rapid paternity/maternity testing based on low-pass GS with trio-based and duo-based analytical modes provided. The optimal read-depth was determined as 1-fold per case regardless of sequencing read lengths, modes, and library construction methods by using 10 trios with confirmed genetic relationships. In addition, low-pass GS with different library construction methods and 1-fold read-depths were performed for 120 prenatal trios prospectively collected, and 1 trio was identified as non-maternity, providing a rate of MP of 0.83% (1/120). All results were further confirmed via quantitative florescent PCR. Overall, we developed a rapid, cost-effective, and sequencing platform-neutral paternity/maternity test based on low-pass GS and demonstrated the feasibility of its clinical use in confirming the parentage for genetic diagnosis.

A pilot investigation of low-pass genome sequencing identifying site-specific variation in chromosomal mosaicisms by a multiple site sampling approach in first-trimester miscarriages.

STUDY QUESTION: Can multiple-site low-pass genome sequencing (GS) of products of conception (POCs) improve the detection of genetic abnormalities, especially heterogeneously distributed mosaicism and homogeneously distributed mosaicism in first-trimester miscarriage? SUMMARY ANSWER: Multiple-site sampling combined with low-pass GS significantly increased genetic diagnostic yield (77.0%, 127/165) of first-trimester miscarriages, with mosaicisms accounting for 17.0% (28/165), especially heterogeneously distributed mosaicisms (75%, 21/28) that are currently underappreciated. WHAT IS KNOWN ALREADY: Aneuploidies are well known to cause first-trimester miscarriage, which are detectable by conventional karyotyping and next-generation sequencing (NGS) on a single-site sampling basis. However, there are limited studies demonstrating the implications of mosaic genetic abnormalities in first-trimester miscarriages, especially when genetic heterogeneity is present in POCs. STUDY DESIGN, SIZE, DURATION: This is a cross-sectional cohort study carried out at a university-affiliated public hospital. One hundred seventy-four patients diagnosed with first-trimester miscarriage from December 2018 to November 2021 were offered ultrasound-guided manual vacuum aspiration (USG-MVA) treatment. Products of conception were subjected to multiple-site low-pass GS for the detection of chromosomal imbalances. PARTICIPANTS/MATERIALS, SETTING, METHODS: For each POC, multiple sites of villi (three sites on average) were biopsied for low-pass GS. Samples with maternal cell contamination (MCC) and polyploidy were excluded based on the quantitative fluorescence polymerase chain reaction (QF-PCR) results. The spectrum of chromosomal abnormalities, including mosaicism (heterogeneously distributed and homogeneously distributed) and constitutional abnormalities was investigated. Chromosomal microarray analysis and additional DNA fingerprinting were used for validation and MCC exclusion. A cross-platform comparison between conventional karyotyping and our multiple-site approach was also performed. MAIN RESULTS AND THE ROLE OF CHANCE: One hundred sixty-five POCs (corresponding to 490 DNA samples) were subjected to low-pass GS. Genetic abnormalities were detected in 77.0% (127/165) of POCs by our novel approach. Specifically, 17.0% (28/165) of cases had either heterogeneously distributed mosaicism (12.7%, 21/165) or homogeneously distributed mosaicism (6.1%, 10/165) (three cases had both types of mosaicism). The remaining 60.0% (99/165) of cases had constitutional abnormalities. In addition, in the 71 cases with karyotyping performed in parallel, 26.8% (19/71) of the results could be revised by our approach. LIMITATIONS, REASONS FOR CAUTION: Lack of a normal gestational week-matched cohort might hinder the establishment of a causative link between mosaicisms and first-trimester miscarriage. WIDER IMPLICATIONS OF THE FINDINGS: Low-pass GS with multiple-site sampling increased the detection of chromosomal mosaicisms in first-trimester miscarriage POCs. This innovative multiple-site low-pass GS approach enabled the novel discovery of heterogeneously distributed mosaicism, which was prevalent in first-trimester miscarriage POCs and frequently observed in preimplantation embryos, but is currently unappreciated by conventional single-site cytogenetic investigations. STUDY FUNDING/COMPETING INTEREST(S): This work was supported partly by Research Grant Council Collaborative Research Fund (C4062-21GF to K.W.C), Science and Technology Projects in Guangzhou (202102010005 to K.W.C), Guangdong-Hong Kong Technology Cooperation Funding Scheme (TCFS), Innovation and Technology Fund (GHP/117/19GD to K.W.C), HKOG Direct Grant (2019.050 to J.P.W.C), and Hong Kong Health and Medical Research Fund (05160406 to J.P.W.C). The authors have no competing interests to declare. TRIAL REGISTRATION NUMBER: N/A.

Bilateral renal papillary hyperplasia: A rare cause of visible haematuria conservatively managed.

Visible haematuria is a common presentation for investigation. Haematuria should be investigated thoroughly to exclude malignancy. Renal papillary hyperplasia is a rare, benign condition that can cause problematic haematuria. There are no currently management guidelines, as there are only few cases reported. We report a case of NSAID induced visible haematuria due to bilateral renal papillary hyperplasia and managed conservatively.

Lymph node assessment technique matters in radical cystectomy for bladder cancer.

BACKGROUND: For patients undergoing radical cystectomy with pelvic lymph node dissection for urothelial cancer, a lymph node count of at least 16 is associated with improved cancer-specific and overall survival. Lymph node yield is presumed to relate directly to extent of dissection and surgical quality, however limited studies have reviewed the impact of the pathological assessment process of lymph nodes on lymph node yield. METHOD: A retrospective assessment of 139 patients who had radical cystectomy for urothelial cancer between March 2015 and July 2021 from Fiona Stanley Hospital (Perth, Australia) by a single surgeon was assessed. A change in pathological assessment process from assessment of only palpable lymph nodes to microscopic assessment of the entire submitted specimens occurred in August 2018. Patients were divided into two groups accordingly and other relevant demographic and pathological data was recorded. The impact of pathological processing technique on lymph node yield was assessed using the Student T test and logistical regression was used to assess the impact of other demographic variables. RESULTS: The mean lymph node yield was 16.2 nodes (IQR 12-23) in 54 patients in the pre-process change group compared to 22.4 nodes (IQR 15-28.4) in 85 patients in the post-process change group (P < 0.0001). 53.7% had 16 or more nodes in the pre-process change group compared to 71.3% in the post-process change group (P = 0.04). Age, BMI, and gender were not significant predictors of lymph node yield. CONCLUSION: The current study demonstrates that the microscopic assessment of all lymph node tissue detects significantly more lymph nodes than only examining palpably abnormal tissue. Pathologic assessment protocols should be standardized to this technique to ensure the utility of lymph node yield as a quality metric.

Renal mucormycosis in post-COVID patients in Australia.

Renal mucormycosis is a rare entity that has been described with significant associated morbidity and mortality. It is an opportunistic infection affecting immunocompromised patients. With the pandemic of COVID-19, we report the first case of renal mucormycosis in Australia secondary to COVID-19 and its management.

TEDD: a database of temporal gene expression patterns during multiple developmental periods in human and model organisms.

Characterization of the specific expression and chromatin profiles of genes enables understanding how they contribute to tissue/organ development and the mechanisms leading to diseases. Whilst the number of single-cell sequencing studies is increasing dramatically; however, data mining and reanalysis remains challenging. Herein, we systematically curated the up-to-date and most comprehensive datasets of sequencing data originating from 2760 bulk samples and over 5.1 million single-cells from multiple developmental periods from humans and multiple model organisms. With unified and systematic analysis, we profiled the gene expression and chromatin accessibility among 481 cell-types, 79 tissue-types and 92 timepoints, and pinpointed cells with the co-expression of target genes. We also enabled the detection of gene(s) with a temporal and cell-type specific expression profile that is similar to or distinct from that of a target gene. Additionally, we illustrated the potential upstream and downstream gene-gene regulation interactions, particularly under the same biological process(es) or KEGG pathway(s). Thus, TEDD (Temporal Expression during Development Database), a value-added database with a user-friendly interface, not only enables researchers to identify cell-type/tissue-type specific and temporal gene expression and chromatin profiles but also facilitates the association of genes with undefined biological functions in development and diseases. The database URL is https://TEDD.obg.cuhk.edu.hk/.

Isolated, PSMA-negative penile metastasis from castration resistant prostate adenocarcinoma, identified by FDG-PET.

Penile metastases are a rare entity and are associated with widespread metastatic disease. It is associated with significant morbidity with a poor prognosis. There have been few case reports about metastatic prostate adenocarcinoma to the penis. Diagnosis is often clinical, however, the use of PSMA PET has a high sensitivity. We report the first case of metastatic castration resistant prostate cancer with an isolated penile metastatic site. This was not identified on conventional staging or PSMA PET, but using FDG PET. A radical penectomy was performed with ongoing survival.

Mate-pair genome sequencing reveals structural variants for idiopathic male infertility.

Currently, routine genetic investigation for male infertility includes karyotyping analysis and PCR for Y chromosomal microdeletions to provide prognostic information such as sperm retrieval success rate. However, over 85% of male infertility remain idiopathic. We assessed 101 male patients with primary infertility in a retrospective cohort analysis who have previously received negative results from standard-of-care tests. Mate-pair genome sequencing (large-insert size library), an alternative long-DNA sequencing method, was performed to detect clinically significant structural variants (SVs) and copy-number neutral absence of heterozygosity (AOH). Candidate SVs were filtered against our in-house cohort of 1077 fertile men. Genes disrupted by potentially clinically significant variants were correlated with single-cell gene expression profiles of human fetal and postnatal testicular developmental lineages and adult germ cells. Follow-up studies were conducted for each patient with clinically relevant finding(s). Molecular diagnoses were made in 11.1% (7/63) of patients with non-obstructive azoospermia and 13.2% (5/38) of patients with severe oligozoospermia. Among them, 12 clinically significant SVs were identified in 12 cases, including five known syndromes, one inversion, and six SVs with direct disruption of genes by intragenic rearrangements or complex insertions. Importantly, a genetic defect related to intracytoplasmic sperm injection (ICSI) failure was identified in a patient with non-obstructive azoospermia, illustrating the additional value of an etiologic diagnosis in addition to determining sperm retrieval rate. Our study reveals a landscape of various genomic variants in 101 males with idiopathic infertility, not only advancing understanding of the underlying mechanisms of male infertility, but also impacting clinical management.

Ureteral embolisation for the management of persistent uretero-ileal anastomotic leak.

Ureteral embolisation has been described in the use of complete occlusion of the ureter to manage urinary leaks, haematuria, and fistulas. This is usually a management option of last resort in patients who have many co-morbidities, poor surgical candidates, or previous pelvic surgery. We report the use of vascular coils and glue to manage a uretero-ileal anastomotic leak following radical cystoprostatectomy.

The Burden and Benefits of Knowledge: Ethical Considerations Surrounding Population-Based Newborn Genome Screening for Hearing.

Recent advances in genomic sequencing technologies have expanded practitioners' utilization of genetic information in a timely and efficient manner for an accurate diagnosis. With an ever-increasing resource of genomic data from progress in the interpretation of genome sequences, clinicians face decisions about how and when genomic information should be presented to families, and at what potential expense. Presently, there is limited knowledge or experience in establishing the value of implementing genome sequencing into newborn screening. Herein we provide insight into the complexities and the burden and benefits of knowledge resulting from genome sequencing of newborns.