Cystic Disease Research Articles

Surgical management of hydatid cyst disease of the liver: An improvement from our previous experience?

Hydatid liver disease remains an important issue in endemic areas, which may require immediate surgery. Although laparoscopic surgery is on the rise, the presence of certain complications may require conversion to the open approach. To compare the results of laparoscopic treatment and the open approach in the context of a 12-year single institution experience, and to perform a further comparison between results from the current study and those from a previous study. Between January 2009 and December 2020, 247 patients underwent surgery for hydatic disease of the liver in our department. Of the 247 patients, 70 underwent laparoscopic treatment. A retrospective analysis between the two groups was performed, as well as a comparison between current and previous laparoscopic experience (1999-2008). There were statistically significant differences between the laparoscopic and open approaches regarding the cyst dimension, location, and presence of cystobiliary fistula. There were no intraoperative complications in the laparoscopic group. The cutoff value for the cyst size regarding the presence of cystobiliary fistula was 6.85 cm (P = 0.001). Laparoscopic surgery still plays an important role in the treatment of hydatid disease of the liver, with an increase in its usage over the course of years that has shown benefits regarding the postoperative recovery with a decreased rate of intraoperative complications. Although experienced surgeons can perform laparoscopic surgery in the most difficult conditions, there are some selection criteria that need to be maintained for higher quality results.

The role of shear viscosity as a biomarker for improving chronic kidney disease detection using shear wave elastography: A computational study using a validated finite element model

The application of ultrasound shear wave elastography for detecting chronic kidney disease, namely renal fibrosis, has been widely studied. A good correlation between tissue Young’s modulus and the degree of renal impairment has been established. However, the current limitation of this imaging modality pertains to the linear elastic assumption used in quantifying the stiffness of renal tissue in commercial shear wave elastography systems. As such, when underlying medical conditions such as acquired cystic kidney disease, which may potentially influence the viscous component of renal tissue, is present concurrently with renal fibrosis, the accuracy of the imaging modality in detecting chronic kidney disease may be affected. The findings in this study demonstrate that quantifying the stiffness of linear viscoelastic tissue using an approach similar to those implemented in commercial shear wave elastography systems led to percentage errors as high as 87%. The findings presented indicate that use of shear viscosity to detect changes in renal impairment led to a reduction in percentage error to values as low as 0.3%. For cases in which renal tissue was affected by multiple medical conditions, shear viscosity was found to be a good indicator in gauging the reliability of the Young’s modulus (quantified through a shear wave dispersion analysis) in detecting chronic kidney disease. The findings show that percentage error in stiffness quantification can be reduced to as low as 0.6%. The present study demonstrates the potential use of renal shear viscosity as a biomarker to improve the detection of chronic kidney disease.

Cx3cr1 controls kidney resident macrophage heterogeneity.

Kidney macrophages are comprised of both monocyte-derived and tissue resident populations; however, the heterogeneity of kidney macrophages and factors that regulate their heterogeneity are poorly understood. Herein, we performed single cell RNA sequencing (scRNAseq), fate mapping, and parabiosis to define the cellular heterogeneity of kidney macrophages in healthy mice. Our data indicate that healthy mouse kidneys contain four major subsets of monocytes and two major subsets of kidney resident macrophages (KRM) including a population with enriched Ccr2 expression, suggesting monocyte origin. Surprisingly, fate mapping data using the newly developed Ms4a3Cre Rosa Stopf/f TdT model indicate that less than 50% of Ccr2+ KRM are derived from Ly6chi monocytes. Instead, we find that Ccr2 expression in KRM reflects their spatial distribution as this cell population is almost exclusively found in the kidney cortex. We also identified Cx3cr1 as a gene that governs cortex specific accumulation of Ccr2+ KRM and show that loss of Ccr2+ KRM reduces the severity of cystic kidney disease in a mouse model where cysts are mainly localized to the kidney cortex. Collectively, our data indicate that Cx3cr1 regulates KRM heterogeneity and niche-specific disease progression.

Kidney cystosis — hereditary, congenital and acquired

Renal cysts can be both an independent nosological entity, and a clinical manifestation, or a complication of a severe diseases. Understanding the epidemiology, pathogenesis and diversity of causes of cystic kidney disease contributes to the timely diagnosis and selection of reasonable treatment and prevention tactics. The presented literature review describes the most common processes that contribute to the development of this pathology, as well as genetic diseases and rare causes, the clinical manifestation of which is the formation of cystic cavities. The article presents the main diagnostic algorithms and modern classifications of the disease for practical assistance to the doctor. The review contains up-to-date information on the modern staging of cystic kidney disease according to the Bosniak classification, and also presents the risk of malignancy, according to the statistical data presented in the literature.

Frequent apocrine changes in pleomorphic adenoma with malignant transformation: a possible pre-malignant step in ductal carcinoma ex pleomorphic adenoma.

The most common type of carcinoma ex pleomorphic adenoma (CPA) is histologically equivalent to salivary duct carcinoma, which has an apocrine phenotype. Invasive CPA is often accompanied by non-invasive or in situ carcinoma, an observation that suggests the presence of precursor lesions. The aim of this study was to identify candidate precursor lesions of CPA within pleomorphic adenoma (PA). Eleven resected cases of CPA with residual PA and 17 cases of PA with atypical changes were subjected to immunohistochemistry (IHC) for p53, human epidermal growth factor receptor 2 (HER2), androgen receptor (AR), pleomorphic adenoma gene 1, gross cystic disease fluid protein-15 (GCDFP-15), and anti-mitochondrial antibody. Invasive or in situ carcinoma cells in all CPAs were positive for AR, GCDFP-15, and HER2. Atypical foci in PAs corresponded to either apocrine or oncocytic changes on the basis of their reactivity to AR, GCDFP-15, and anti-mitochondrial antibody. Atypical cells in PAs surrounding CPAs had an apocrine phenotype without HER2 expression. Our study identified frequent apocrine changes in residual PAs in CPA cases, suggesting a possible precursor role of apocrine changes. We recommend the use of HER2 IHC in atypical PAs, and that clinicians take HER2 positivity into serious consideration.

Association of Hypoalbuminemia with Risk of Death in Pediatric Patients with End Stage Renal Disease undergoing Hemodialysis: A Tertiary Care Experience in Pakistan

Background: One of the most important and common feature of chronic kidney disease is Hypoalbuminemia and is considered a poor prognostic factor. Low levels of Serum albumin are a predictor of growth failure and are strongly associated with increase death rate in pediatric patients undergoing hemodialysis with End Stage Renal Disease (ESRD), especially a challenge in underdeveloped countries. Aim: To evaluate the association of serum albumin level with hospitalization and rate of death in ESRD hemodialyzed pediatric patients. Study Design: Cohort study Place and Duration of Study: Department of Pediatric Nephrology, University of Child Health Sciences, Lahore from 1st January 2018 to 31st January 2022 Methodology: Ninety two children on hemodialysis and aged 5-16 years were included. Data including patient demographics, anthropometry, date of dialysis initiation, diagnosis, systolic and diastolic blood pressure, dialysis access (HD line/AV fistula), laboratory parameters, compliance to dialysis prescription, and frequency of hospitalization and combined duration of hospital stay was recorded. Results: The mean age at dialysis was 10.6±2.7 years with male to female ratio of 1.3:1. The mean duration on dialysis was 2.03±0.9 years. In our study, CAKUT (42.4%) was the most commonly occurring underlying etiology of end stage renal disease, followed by cystic renal disease (27.2%) and glomerular disease (15.2%) respectively. Regarding the systolic hypertension 22.9% were hypertensive and 35.8% were pre-hypertensive (BP 90th to 95th percentile). For diastolic hypertension, 18.5% were hypertensive and 42.4%were noted as pre-hypertensive. Majority of patients (87%) had hypoalbuminemia (serum albumin < 3.5 gm/dl) at dialysis initiation. In our study the value of serum albumin has inverse relationship with \risk of mortality in ESRD hemodialyzed patients even after adjustment to other factors. There is a 70% higher risk of death with each 1gm/dl decline in serum albumin value (hazard ratio=0.300(0.122-0.740) P<0.009). In addition, AVF access group has a significantly lower risk of death compared to the catheter group (hazard ratio=0.444 (0.246-0.801), P = 0.007). On generation of ROC curves, AUC obtained for serum albumin was statistically significant (AUC=0.838, 95% CI 0.758–0.918). In our study, no correlation was found between hypoalbuminemia and annual frequency of hospitalization (P<0.812) and total duration of stay (P<0.997).For mortality prediction, our study demonstrated a cut off value of albumin of 3g/dl with sensitivity of 80% and specificity of 68.7%. Conclusion: The independent prognostic value of serum albumin in mortality prediction at a cut off value of 3g/dl. In the final model even after adjustment of other covariates, hypoalbuminemia at dialysis initiation and type of vascular access continued to be vital indicator of risk of death in pediatric ESRD patients. However, no statistically significant association was observed between hypoalbuminemia and hospitalization in dialysis patients. Keywords: ESRD, Hypoalbuminemia, Growth failure, Haemodialysis

Kidney transcriptome and cystic kidney disease genes in zebrafish.

Introduction: Polycystic kidney disease (PKD) is a condition where fluid filled cysts form on the kidney which leads to overall renal failure. Zebrafish has been recently adapted to study polycystic kidney disease, because of its powerful embryology and genetics. However, there are concerns on the conservation of this lower vertebrate in modeling polycystic kidney disease. Methods: Here, we aim to assess the molecular conservation of zebrafish by searching homologues polycystic kidney disease genes and carrying transcriptome studies in this animal. Results and Discussion: We found that out of 82 human cystic kidney disease genes, 81 have corresponding zebrafish homologs. While 75 of the genes have a single homologue, only 6 of these genes have two homologs. Comparison of the expression level of the transcripts enabled us to identify one homolog over the other homolog with >70% predominance, which would be prioritized for future experimental studies. Prompted by sexual dimorphism in human and rodent kidneys, we studied transcriptome between different sexes and noted significant differences in male vs. female zebrafish, indicating that sex dimorphism also occurs in zebrafish. Comparison between zebrafish and mouse identified 10% shared genes and 38% shared signaling pathways. String analysis revealed a cluster of genes differentially expressed in male vs. female zebrafish kidneys. In summary, this report demonstrated remarkable molecular conservation, supporting zebrafish as a useful animal model for cystic kidney disease.

Research note changes in the number of outpatient visits in Japan during the COVID-19 pandemic

ObjectiveThis study aimed to determine the change in the number of outpatient visits in Japan since the beginning of the COVID-19 pandemic, using data on the outpatient claims submitted by medical institutions to insurers in 2019 and 2020, from the National Database of Health Insurance Claims and Specific Health Check-ups. We calculated the total number of outpatient visits, and number of visits for individual diseases according to the International Classification of Diseases-10 codes on the claim form.ResultsThe number of outpatient visits per million people decreased by 9.98% in 2020 compared to 2019. Of the diseases included in the analysis, 71 showed a decrease in the number of visits by ≥ 1%. There were significant decreases in the number of visits related to infectious diseases (influenza, acute bronchitis, and acute laryngitis, etc.), and chronic diseases (hemorrhoids, cystic kidney disease, dyspepsia, and chronic sinusitis, etc.). The observed decreased rate of outpatient visit might have been due to, a decrease in the incidence of disease, a decreased frequency of visit by patients with the disease, or both. Our analysis method using actual health insurance claim data can be applied worldwide, where researchers have access to national information on health insurance claims.

Kistik Fibrozisli Çocuklarda Karaciğer Tutulumunun Shear-Wave Elastografi ile Non-invaziv Değerlendirilmesi

Objectives: Hepatobiliary complications commonly occur in cystic fibrosis with increasing prevalence due to longer life expectancies and widespread screening efforts. Shear-wave elastography is a novel noninvasive method that involves application of local mechanical compression on soft tissue using focused ultrasonography and acquiring strain images that show tissue response. We aimed to compare abdominal ultrasonography and Shear-wave elastography and also clinical and laboratory findings of children with cystic fibrosis prospectively. Methods: This study is a prospective study conducted in 13 cystic fibrosis patients followed between February 2018 and March 2019. The severity of cystic fibrosis-related liver disease was categorized according to international criteria. Elastography measurement was performed in the same session with the evaluation of the liver by abdominal ultrasonography in the patients. The liver stiffness measurements were compared with clinical data, biochemistry parameters and ultrasound findings. Results: Measurements were performed in 13 cystic fibrosis children (3 boys, 10 girls). The mean kiloPascal values of liver stiffness measurements with shear-wave elastography were 8.68 (4.1-20.2). The median liver stiffness measurement in subjects without cystic fibrosis-related liver disease was 7.79 kiloPascals (n=5); The median liver stiffness measurement in subjects with cystic fibrosis-related liver disease was 9.23 kiloPascals. Conclusion: Cystic fibrosis-related liver disease has a significantly varying disease burden, its prevalence is increasing, and its early recognition is crucial for treatment and follow-up. Although there are no clear range values determined for children in tissue stiffness measurements in Shear-wave elastography, clinical and other laboratory and imaging methods and follow-up and evaluation are important.

Furin as a therapeutic target in cystic fibrosis airways disease.

Clinical management of cystic fibrosis (CF) has been greatly improved by the development of small molecule modulators of the CF transmembrane conductance regulator (CFTR). These drugs help to address some of the basic genetic defects of CFTR; however, no suitable CFTR modulators exist for 10% of people with CF (PWCF). An alternative, mutation-agnostic therapeutic approach is therefore still required. In CF airways, elevated levels of the proprotein convertase furin contribute to the dysregulation of key processes that drive disease pathogenesis. Furin plays a critical role in the proteolytic activation of the epithelial sodium channel; hyperactivity of which causes airways dehydration and loss of effective mucociliary clearance. Furin is also responsible for the processing of transforming growth factor-β, which is increased in bronchoalveolar lavage fluid from PWCF and is associated with neutrophilic inflammation and reduced pulmonary function. Pathogenic substrates of furin include Pseudomonas exotoxin A, a major toxic product associated with Pseudomonas aeruginosa infection and the spike glycoprotein of severe acute respiratory syndrome coronavirus 2, the causative pathogen for coronavirus disease 2019. In this review we discuss the importance of furin substrates in the progression of CF airways disease and highlight selective furin inhibition as a therapeutic strategy to provide clinical benefit to all PWCF.

Afectación renal en las enfermedades raras genéticas

Rare diseases are defined as those which affect fewer than 65 of every 100,000 individuals. Genetic diseases which affect the kidney mostly belong to this group and represent a significant percentage of patients in renal replacement treatment, especially at young ages. Together with cystic diseases, tubulopathies, or complement gene mutations with renal involvement, there are genetic renal diseases which affect different aspects. Some of them target the glomerulus, such as Alport syndrome (which affects the proteins that form type IV collagen, progressing with proteinuria, microscopic hematuria, and visual and auditory abnormalities), hereditary amyloidosis (which progress with AL amyloidosis and is responsible for 10% of all cases), and steroid-resistant nephrotic syndrome which arises from various mutations and is resistant to immunosuppression. Fabry disease causes the accumulation of glycosphingolipids, producing multisystemic involvement with cardiac and renal mortality. Primary hyperoxaluria is notable due to recurrent urolithiasis and nephrocalcinosis with multisystemic involvement when there is end-stage renal failure. Finally, CAKUT comprises a heterogeneous set of mutations in the genes responsible for the embryonic development of the kidney and urinary tract.

Applying patient personalized organoid model system to understand complex GI manifestations in cystic fibrosis disease

Background: Stem cell-derived organotypic culture has become a revolutionary tool in transforming care for patients with multiple GI-disorders. Cystic fibrosis is a deadly genetic disorder with multiple GI complications, such as Distal intestinal obstruction syndrome (DIOS), chronic constipation, Gastroesophageal reflux disease (GERD), and in some cases pancreatitis, caused by loss of function mutations in the gene that encodes for the cystic fibrosis transmembrane conductance regulator (CFTR) chloride/bicarbonate ion channel. Due to genetic and environmental influences, CF patients exhibit large phenotypic variation. These factors make clinical trials difficult and largely impractical due to limited and heterogenous patient pools, and additionally, the benefit of approved small-molecule CF therapy in a large number of rare mutation patients is not known. Moreover, critical questions of whether CFTR contributes to the development of intestine and how it contributes to GI-related issues remain unanswered. Results: In this study, we performed a comprehensive bench-side study using in vitro patient enteroids and in vivo mice implanted Human Intestinal Organoids (HIOs) to test highly effective CFTR modulators -Ivacaftor response for a rare CF mutation patient. Based on the positive Ivacaftor response in the enteroids, the patient was enrolled in N=1 clinical trial and showed improved GI outcomes upon Ivacaftor treatment. HIO implantation model allowed in vivo modulator dosing and provided an elegant human organ-based demonstration of bench-to-bedside testing of modulator effects. Additionally, using the CF HIO model the role of CFTR function in the maturation of human intestine was reported for the first time. In HIOs derived from a stop mutation CF patient and CFTR-corrected HIOs as control, we performed single cell RNAseq analysis to generate a molecular map of GI-cell type specific transcriptomic alterations and identify key targetable pathways relevant to stop mutations in CFTR for which currently there is no small molecule therapy. Conclusion: In all, we demonstrate that these models effectively serve to translate data from the lab to the clinic and back so that patient specific therapies could be validated, or new therapies be devised. Additionally, single-cell RNA sequencing in patient HIOs will provide useful insights into cell population specific and transcriptomic level alterations that are associated with abnormalities in GI function in CF. Nothing to disclose This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Human epididymis protein 4 (HE4) plasma concentration inversely correlates with the improvement of cystic fibrosis lung disease in p.Phe508del-CFTR homozygous cases treated with the CFTR modulator lumacaftor/ivacaftor combination

BackgroundWe previously documented that elevated HE4 plasma concentration decreased in people with CF (pwCF) bearing the p.Gly551Asp-CFTR variant in response to CFTR modulator (CFTRm) ivacaftor (IVA), and this level was inversely correlated with the FEV1% predicted values (ppFEV1). Although the effectiveness of lumacaftor (LUM)/IVA in pwCF homozygous for the p.Phe508del-CFTR variant has been evaluated, plasma biomarkers were not used to monitor treatment efficacy thus far. MethodsPlasma HE4 concentration was examined in 68 pwCF drawn from the PROSPECT study who were homozygous for the p.Phe508del-CFTR variant before treatment and at 1, 3, 6 and 12 months after administration of LUM/IVA therapy. Plasma HE4 was correlated with ppFEV1 using their absolute and delta values. The discriminatory power of delta HE4 was evaluated for the detection of lung function improvements based on ROC-AUC analysis and multiple regression test. ResultsHE4 plasma concentration was significantly reduced below baseline following LUM/IVA administration during the entire study period. The mean change of ppFEV1 was 2.6% (95% CI, 0.6 to 4.5) by 6 months of therapy in this sub-cohort. A significant inverse correlation between delta values of HE4 and ppFEV1 was observed especially in children with CF (r=-0.7053; p<0.0001). Delta HE4 predicted a 2.6% mean change in ppFEV1 (AUC: 0.7898 [95% CI 0.6823–0.8972]; P < 0.0001) at a cut-off value of -10.7 pmol/L. Moreover, delta HE4 independently represented the likelihood of being a responder with ≥ 5% delta ppFEV1 at 6 months (OR: 0.89, 95% CI: 0.82–0.95; P = 0.001). ConclusionsPlasma HE4 level negatively correlates with lung function improvement assessed by ppFEV1 in pwCF undergoing LUM/IVA CFTRm treatment.

Histopathological Study Of Various Neoplastic And Non-neoplastic Lesions Of Small Intestine At Tertiary Care Centre Of South Gujarat

Introduction: Small intestine, the longest part of digestive tract, makes up about 75% of the total length and can be affected by various developmental, inflammatory or neoplastic conditions. Non neoplastic lesions like abdominal tuberculosis are frequently seen in small intestine. Although small intestine is an uncommon site for tumour nearly twothirds of these tumours are malignant, with most of them being adenocarcinoma. To study the histopat Objective: hology of various neoplastic and non-neoplastic lesions of small intestine and to evaluate their frequency and pattern with respect to age, sex, anatomical sites and clinical findings. This observational cross-sectional Materials and Methods: study was conducted on a total of 101 small intestinal specimens including biopsies and surgically resected specimen received for histopathological examination over a period of two years in the Department of Pathology affiliated with tertiary care hospital. In addition to Haematoxylin and Eosin staining, Immunohistochemistry and special stains were also done in required cases. This study showed a male is to female ratio of 1.97:1. Peak incidence of Results: cases was seen in the 31-40 years age group. Out of total 101 pathological lesions 87 cases were non -neoplastic that included Infective lesions like tuberculous enteritis, Inflammatory lesions like Non-specific Enteritis, Necrotising Enteritis and Congenital lesions like Meckel's diverticulum, Enteric Duplication cyst and Celiac disease while only 14 cases were neoplastic that included benign neoplastic lesions like various types of polyps and malignant neoplastic lesions like adenocarcinoma, GIST, neuroendocrine tumour and B cell NHL. This study showed a characteristic Conclusion: distribution of cases in the three different parts of small intestine and highlighted the clinical importance of timely detection of intestinal pathology by the means of detailed clinical study combined with radiological and histopathological examination.

Cystic kidney diseases in children

Cystic kidney disease comprises a broad group of heterogeneous diseases, which differ greatly in age at onset, disease manifestation, systemic involvement, disease progression, and long-term prognosis. As our understanding of these diseases continues to evolve and new treatment strategies continue to emerge, correctly differentiating and diagnosing these diseases becomes increasingly important. In this review, we aim to highlight the key features of the most relevant cystic kidney diseases, underscore important diagnostic characteristics of each disease, and present specific management options if applicable.

Simple Kidney Cysts: Sclerotherapy versus Laparoscopy

Introduction: The simple kidney cyst is part of a heterogeneous family of cystic kidney disease, and is the most common entity. It is admitted that these cysts are, except for a few anecdotic cases, all benign. Aim: The aim of this work is to compare the efficiency of sclerotherapy and laparoscopy in the treatment of simple kidney cysts. Material and Methods: This was prospective study of 30 simple kidney cysts cases. We split patients into 2 arms. In arm A, 15 patients were treated by sclerotherapy under local anesthesia and in arm B, 15 patients were treated by laparoscopy under general anesthesia. Results: Average operative time was significantly lower in arm A (15 min vs 45 min, p &lt;0.001). No postoperative complication was noted in arm A, whereas conversion was required in arm B (0% vs. 6.7%, p = 1). The average length of stay was not significant, 3.2 days versus 2.8 days (p = 0.52). The overall radiological success rate was 80% for arm A and 87.5% for arm B. Conclusion: This shows that sclerotherapy offers a shorter operative time, and a lower postoperative pain. Although, laparoscopic results are better than sclerotherapy’s. We cannot statistically conclude the superiority of one method over the other.

Molecular genetic diagnosis of kidney ciliopathies: Lessons from interpreting genomic sequencing data and the requirement for accurate phenotypic data.

Massively parallel sequencing (MPS) techniques have made a major impact on the identification of the genetic basis of inherited kidney diseases such as the ciliopathy autosomal dominant polycystic kidney disease (ADPKD). Great care must be taken when analysing MPS data in isolation from accurate phenotypic information, as this can cause misdiagnosis. Here, we describe a family trio, recruited to the Genomics England 100,000 Genomes Project, labelled as having cystic kidney disease, who were genetically unsolved following routine data analysis pipelines. We performed a bespoke reanalysis of Whole Genome Sequencing (WGS) data and coupled this with revised phenotypic data and targeted PCR and Sanger sequencing to provide a precise molecular genetic diagnosis. We detected a heterozygous PKD1 frameshift variant within the WGS data which segregated with the redefined ADPKD phenotypes. An additional heterozygous exon deletion in ALG8 was also found in affected and unaffected individuals, but its precise clinical significance remains unclear. This case illustrates that reanalysis of WGS data in unsolved cases of cystic kidney disease is valuable. Clinical phenotypes must be reassessed as these may have been incorrectly recorded and evolve over time. Undertaking additional studies including genotype-phenotype correlation in wider family members provides useful diagnostic information.

Estradiol Augments Tumor-Induced Neutrophil Production to Promote Tumor Cell Actions in Lymphangioleiomyomatosis Models.

Lymphangioleiomyomatosis (LAM) is a rare cystic lung disease caused by smooth muscle cell-like tumors containing tuberous sclerosis (TSC) gene mutations and found almost exclusively in females. Patient studies suggest LAM progression is estrogen dependent, an observation supported by in vivo mouse models. However, in vitro data using TSC-null cell lines demonstrate modest estradiol (E2) responses, suggesting E2 effects in vivo may involve pathways independent of direct tumor stimulation. We previously reported tumor-dependent neutrophil expansion and promotion of TSC2-null tumor growth in an E2-sensitive LAM mouse model. We therefore hypothesized that E2 stimulates tumor growth in part by promoting neutrophil production. Here we report that E2-enhanced lung colonization of TSC2-null cells is indeed dependent on neutrophils. We demonstrate that E2 induces granulopoiesis via estrogen receptor α in male and female bone marrow cultures. With our novel TSC2-null mouse myometrial cell line, we show that factors released from these cells drive E2-sensitive neutrophil production. Last, we analyzed single-cell RNA sequencing data from LAM patients and demonstrate the presence of tumor-activated neutrophils. Our data suggest a powerful positive feedback loop whereby E2 and tumor factors induce neutrophil expansion, which in turn intensifies tumor growth and production of neutrophil-stimulating factors, resulting in continued TSC2-null tumor growth.

Heterogeneous liver on research ultrasound identifies children with cystic fibrosis at high risk of advanced liver disease

BackgroundThis study examines whether heterogeneous (HTG) pattern on liver ultrasound (US) identifies children at risk for advanced cystic fibrosis liver disease (aCFLD). MethodsProspective 6-year multicenter case-controlled cohort study. Children with pancreatic insufficient cystic fibrosis (CF) aged 3–12 years without known cirrhosis underwent screening US. Participants with HTG were matched (by age, Pseudomonas infection status and center) 1:2 with participants with normal (NL) US pattern. Clinical status and laboratory data were obtained annually and US bi-annually for 6 years. Primary endpoint was development of nodular (NOD) US pattern consistent with aCFLD. Results722 participants underwent screening US, with 65 HTG and 592 NL. Final cohort included 55 HTG and 116 NL with ≥ 1 follow-up US. ALT, AST, GGTP, FIB-4, GPR and APRI were higher, and platelets were lower in HTG compared to NL. HTG had a 9.5-fold increased incidence (95% confidence interval [CI]:3.4, 26.7, p<0.0001, 32.7% vs 3.4%) of NOD versus NL. HTG had a sensitivity of 82% and specificity of 75% for subsequent NOD. Negative predictive value of a NL US for subsequent NOD was 96%. Multivariate logistic prediction model that included baseline US, age, and log(GPR) improved the C-index to 0.90 compared to only baseline US (C-index 0.78). Based on survival analysis, 50% of HTG develop NOD after 8 years. ConclusionsResearch US finding of HTG identifies children with CF with a 30–50% risk for aCFLD. A score based on US pattern, age and GPR may refine the identification of individuals at high risk for aCFLD. Clinical Trial RegistrationProspective Study of Ultrasound to Predict Hepatic Cirrhosis in CF: NCT 01,144,507 (observational study, no consort checklist)

Abstract 6066: Genomic analysis of end-stage renal disease

Abstract Background: Chronic kidney disease is frequently associated with persistent inflammation, which results in fibrosis in the stroma, a reduced number of renal tubules, the formation of multiple cystic lesions, ultimately terminating in renal failure and hemodialysis. Given the high incidence of renal cell carcinoma (RCC) in hemodialysis patients, suggesting a relationship between tissue remodeling by chronic inflammation and carcinogenesis. However, little is known about the genetic background of cancer development from remaining tubules and cystic lesions in hemodialysis patients. Method: We enrolled 5 patients under hemodialysis who were accompanied by acquired cystic kidney disease and underwent radical nephrectomy for RCC. Surgical specimens were fixed with alcohol-based solution and paraffin-embedded, and after H&amp;E staining, subjected to laser capture microdissection (LCM) to collect remaining tubules and cysts containing approximately 200 cells. DNA was extracted and analyzed for somatic mutations and copy number alteration by whole-exome sequencing. Result: In total, we collected 161 LCM samples, including 118 from proximal tubules, 17 from collecting ducts, and 26 from cysts. Median variant allele frequencies of detected mutations were 0.237 in proximal tubules, 0.133 in collecting duct, and 0.381 in cysts, indicating larger clonal expansion in proximal tubules and cysts than in collecting ducts. Proximal tubules and cysts contained recurrent mutations in FAT1 (11% and 8%, respectively), STAG2 (5% and 8%), and PTEN (3% and 4%), whereas no recurrent driver mutations were identified in collecting ducts. In copy number analysis, 26% of proximal tubules, 35% of collecting ducts, and 80% of cysts had copy number alterations. Of note, samples from cysts had more copy number alterations compared to remaining tubules (on average, 2.3 vs. 1.1). Proximal tubules had recurrent copy number gains of chromosomes 3, 7, 10, 18, and 20, and loss of chromosome 22 and samples from collecting ducts showed gains of chromosome 7 and loss of chromosome 18. In cysts, gains of chromosomes 2, 3, 7, 10, 12, and 16 and loss of chromosomes 15, 16, 21, and 22 were frequently observed. Copy number profile in cysts was similar to that of papillary RCC and acquired cystic disease-associated RCC. Conclusion: In the end-stage cystic kidney, proximal tubules and cysts showed an enrichment of driver mutations commonly found in papillary RCC and RCC with acquired cystic disease, reflecting the fact that the incidence of these two types of RCC increases as the duration of dialysis becomes longer. In addition, clear cell RCC drivers, such as VHL mutation and loss of chromosome 3, were not observed, possibly explaining the rare occurrence of clear cell RCC in hemodialysis patients. Since cysts had more frequent copy number alterations than remaining tubules, cysts in the end-stage kidney might be precursor lesions of RCC. Citation Format: Kosuke Ieiri, Nobuyuki Kakiuchi, Tomonori Hirano, Tomomi Nishimura, Koichi Watanabe, Hiroko Tanaka, Satoru Miyano, Dai Takamatsu, Keisuke Monji, Eiji Kashiwagi, Masaki Shiota, Junichi Inokuchi, Masatoshi Eto, Seishi Ogawa. Genomic analysis of end-stage renal disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6066.