An Ex Vivo Human Kidney Perfusion Model Confirms Larger Microwave Ablation Dimensions After Transarterial Embolization.

PURPOSE: To utilize a novel ex vivo perfused human renal model and quantify microwave ablation (MWA) size differences in renal tissue when combining MWA with transarterial embolization (TAE). MATERIALS AND METHODS: Human kidneys (n = 5) declined for transplantation were obtained and connected to a fluoroscopic-compatible ex vivo perfusion system. Two ablations-1 standard MWA, 1 TAE-MWA-were performed in each kidney for 2 minutes at 100 Watts using a MWA system (Solero Angiodynamics). MWA alone was performed in the upper pole. In the lower pole, MWA was performed after TAE with M0 LUMI microspheres (Boston Scientific) to achieve angiographic stasis. Ablation zones of coagulative necrosis were sectioned along the long axis and segmented for maximal short axis diameter (SAD) and long axis diameter (LAD) measurements. RESULTS: A total of 10 ablations (5 MWA, 5 TAE-MWA) were performed in five human kidneys. TAE-MWA resulted in significantly increased SAD, LAD, volume, and sphericity compared to standard MWA + SD with mean measurements as follows (5 standard MWA + SD vs 5 TAE-MWA, two-tailed t-test): SAD, 1.8 ± 0.1 cm vs 2.5 ± 0.1 cm (p < 0.001); LAD, 2.9 ± 0.3 cm vs 3.2 ± 0.1 cm (p = 0.039); volume, 5.0 ± 0.5 mL vs 11.0 ± 0.7 mL (p < 0.001); sphericity, 0.4 ± 0.2 vs 0.6 ± 0.1 (p = 0.049). Histology demonstrated no differences in TAE-MWA other than concentrated microspheres. CONCLUSION: This study utilized a novel ex vivo human kidney perfusion model to confirm combined MWA-TAE significantly increases ablation size and spherical shape.

Histological variants of non-muscle invasive bladder cancer: Survival outcomes of radical cystectomy vs. bladder preservation therapy.

BACKGROUND: To compare the overall survival (OS) outcomes of non-muscle invasive bladder cancer (NMIBC) patients with variant histology who underwent radical cystectomy (RC) vs. bladder preservation therapy (BPT). METHODS: We investigated the National Cancer Database for NMIBC patients with variant histological features. Patients diagnosed with micropapillary, sarcomatoid, neuroendocrine, squamous, and glandular variants were identified. Inverse probability weighting (IPW)-adjusted Kaplan Meier survival curves and Cox proportional hazard models were utilized to compare OS in the setting of RC versus BPT. RESULTS: A total of 8,920 (2.7%) NMIBC patients presented with variant histology, of whom 2,450 (27.5%) underwent RC, while 6,470 (72.5%) had BPT. When compared with BPT, patients who underwent RC had significantly higher 5-year OS rates for sarcomatoid (31.9% vs. 23.3%, P < 0.001) neuroendocrine (31% vs. 21.7%, P < 0.001), glandular (44% vs. 41%, P = 0.04) and squamous variants (39.7% vs 19.9%, P < 0.001). This OS benefit was not observed with micropapillary variant (43.9% vs. 53.2% P = 0.14). IPW-adjusted log-rank analysis identified RC as an independent predictor of OS for patients with sarcomatoid (hazards ratio [HR] 0.78, confidence interval [CI] 0.71-0.85, P < 0.001), squamous (HR 0.56, CI 0.53-0.59, P < 0.001), and neuroendocrine variants (HR 0.83, CI 0.76-0.91, P < 0.001), but not for micropapillary variant (HR 1.45, CI 1.24-1.7, P < 0.001). CONCLUSIONS: Among NMIBC patients presenting with variant histologies, RC was associated with better OS for sarcomatoid, squamous, glandular, and neuroendocrine variants when compared to BPT. This OS survival benefit was not observed in patients with micropapillary variant suggesting a potential role for bladder preservation in such population.

IgA-dominant infection-associated glomerulonephritis in the pediatric population.

BACKGROUND: IgA-dominant infection-associated glomerulonephritis is well-documented in adults but has not been studied in depth in children. We assessed the incidence of pediatric IgA-dominant infection-associated glomerulonephritis and clinical and kidney biopsy findings. METHODS: Pediatric native kidney biopsies over a 10-year period with IgA dominance, strong C3, and findings indicative of infection-associated etiology were identified. RESULTS: We identified 9 cases of IgA-dominant infection-associated glomerulonephritis, 0.8% of pediatric native kidney biopsies. Seven patients presented with elevated creatinine. All had hematuria and proteinuria. Eight patients had clinical evidence of infection: one each with central port infection by methicillin-sensitive Staphylococcus aureus, recurrent streptococcal pharyngitis and recent otitis media, streptococcal pharyngitis demonstrated 8 months after biopsy, suspected streptococcal scalded skin syndrome, and viral gastroenteritis, and three with serologic evidence of Streptococcal infection but no identified site of infection. All but one patient experienced short-term normalization of creatinine and resolution of proteinuria, though two eventually progressed to kidney failure: one 3 years later due to progressive disease and one 11 years later due to focal segmental glomerulosclerosis without concurrent immune deposits. CONCLUSIONS: Pediatric IgA-dominant infection-associated glomerulonephritis is rare, and generally has a favorable prognosis, contrasting that seen in adults with severe comorbidities. A higher resolution version of the Graphical abstract is available as Supplementary.

Clear Cell Adenocarcinoma in Men: A Series of 15 Cases.

Clear cell adenocarcinoma (CCA) is a rare tumor in the genitourinary tract with female predominance and few reports in men. We identified 15 cases of CCA in men evaluated at our institution. Five arose in the bladder, 7 in the prostate or prostatic urethra, 2 in the membranous urethra (1 multifocal in the prostatic and membranous urethra), 1 periprostatic (likely from an embryologic remnant), and 1 between rectum and bladder (likely in a prostatic utricle cyst). No cases showed associated Müllerian structures. One case showed separate foci of nephrogenic adenoma at diagnosis, and 1 case showed urothelial carcinoma in situ on a later follow-up biopsy. Four tumors extended into other organs (prostate to seminal vesicle and periprostatic soft tissue, periprostatic soft tissue to prostate, prostatic urethra to bladder and rectum, and prostate to bladder neck). One tumor showed extraprostatic extension alone. Four tumors metastasized to lymph nodes, with 3 also metastasizing to other sites (bladder, lung and adrenal, and right flank). Eleven patients underwent resection, including 3 transurethral resections. Seven underwent other treatments, including radiation (5 [1 for recurrence]), chemotherapy (3), hormonal therapy (3), immunotherapy with nivolumab (1), and targeted therapy with gefitinib (1). The mean follow-up was 35 months (range: 1 to 138 mo). At the last follow-up, 7 patients showed no evident disease and 3 were alive with disease. Four died with the cause of death unknown, with 2 cases having confirmed disease at the time of death and the remaining 2 dying less than a year after diagnosis. The mean time to death was 16 months (range: 6 to 39 mo). No follow-up was available on 1 patient. All patients who died in this series had CCA of the prostate or prostatic urethra. Pathologists need to be attuned to CCA occurring in males, given that the literature emphasizes its occurrence in females. In addition to established sites such as bladder and urethra, our series demonstrates that tumor may present in unusual adjacent sites, such as in periprostatic embryologic remnants or prostatic utricle.

Principles of Membrane Adaptation Revealed through Environmentally Induced Bacterial Lipidome Remodeling.

Cells, from microbes to mammals, adapt their membrane lipid composition in response to environmental changes to maintain optimal properties. Global patterns of lipidome remodeling are poorly understood, particularly in organisms with simple lipid compositions that can provide insight into fundamental principles of membrane adaptation. Using shotgun lipidomics, we examine the simple yet, as we show here, adaptive lipidome of the plant-associated Gram-negative bacterium Methylobacterium extorquens. We observe that minimally 11 lipids account for 90% of total variability, thus constraining the upper limit of variable lipids required for an adaptive living membrane. Through lipid features analysis, we reveal that acyl chain remodeling is not evenly distributed across lipid classes, resulting in headgroup-specific effects of acyl chain variability on membrane properties. Results herein implicate headgroup-specific acyl chain remodeling as a mechanism for fine-tuning the membrane's physical state and provide a resource for using M. extorquens to explore the design principles of living membranes.

Histomorphologic features of lung adenocarcinomas exhibiting ALK gene rearrangement.

With the advent of tyrosine kinase inhibitors, the identification of tumors with alterations in tyrosine kinase genes has become important to guide treatment. Lung adenocarcinomas harboring ALK translocations may be targeted with drugs such as crizotinib. We undertook a retrospective review of our institution's pathology records from January 2015 through September 2017 and identified 10 lung adenocarcinomas with ALK rearrangements. We reviewed the histomorphologic features and immunohistochemical results from these 10 cases. Morphologic features included patterns such as acinar, papillary, micropapillary, and solid, as well as features such as cribriform, signet ring, and extracellular mucin. Acinar (including simple and cribriform) was the most common pattern, followed by papillary. Solid and signet ring features were the least common. These findings were consistent with prior histomorphologic studies of ALK-positive lung adenocarcinomas. Certain histomorphologic patterns are associated with ALK positivity. However, histomorphologic features are neither absolutely sensitive nor absolutely specific in suggesting ALK rearrangement. Thus, identification of lung adenocarcinomas that may benefit from treatment with tyrosine kinase inhibitors requires comprehensive molecular testing.

DEL-1 promotes macrophage efferocytosis and clearance of inflammation.

Resolution of inflammation is essential for tissue homeostasis and represents a promising approach to inflammatory disorders. Here we found that developmental endothelial locus-1 (DEL-1), a secreted protein that inhibits leukocyte-endothelial adhesion and inflammation initiation, also functions as a non-redundant downstream effector in inflammation clearance. In human and mouse periodontitis, waning of inflammation was correlated with DEL-1 upregulation, whereas resolution of experimental periodontitis failed in DEL-1 deficiency. This concept was mechanistically substantiated in acute monosodium-urate-crystal-induced inflammation, where the pro-resolution function of DEL-1 was attributed to effective apoptotic neutrophil clearance (efferocytosis). DEL-1-mediated efferocytosis induced liver X receptor-dependent macrophage reprogramming to a pro-resolving phenotype and was required for optimal production of at least certain specific pro-resolving mediators. Experiments in transgenic mice with cell-specific overexpression of DEL-1 linked its anti-leukocyte-recruitment action to endothelial cell-derived DEL-1 and its efferocytic/pro-resolving action to macrophage-derived DEL-1. Thus, the compartmentalized expression of DEL-1 facilitates distinct homeostatic functions in an appropriate context that can be harnessed therapeutically.

Secondary involvement of the gastrointestinal tract by renal cell carcinoma.

Secondary involvement of the gastrointestinal (GI) tract by renal cell carcinoma is rare. We undertook a retrospective review of our institution's pathology records from January 2006 to July 2017 and identified eight cases of GI tract involvement by renal cell carcinoma. Sites of involvement included stomach, duodenum, jejunum, ileum, and cecum. Pertinent clinical information was obtained from electronic medical records. The interval from primary resection to identification of GI involvement was often prolonged, averaging 6 years, and mimicked primary GI tract malignancies, with presentations including GI bleeding, abdominal pain, and obstruction. One case presented asymptomatically on follow-up imaging. Histologic patterns of involvement varied from classic clear cell to purely sarcomatoid or complex unclassifiable morphology. Two patients with tumors exhibiting sarcomatoid morphology died within 2 years of primary resection and <1 year of GI involvement. The remaining patients survived a mean of 9 years (range, 5 to 22 years) at their last available follow-up.

Clinical uptake of antimicrobial stewardship recommendations following Nanosphere Verigene Blood Culture Gram-negative reporting.

We performed a retrospective chart review of patients to determine if the Verigene Gram-negative blood culture (BC-GN) results would lead to earlier deescalation of empiric therapy for inpatients with GN bacteremia with Citrobacter spp., Enterobacter spp., Klebsiella spp., and Escherichia coli to appropriate targeted coverage. A total of 899 records were reviewed from April 2014 to February 2016 from three institutions within the Baylor Scott & White Health network. The cases were reviewed for initial antibiotic coverage, timing of Verigene results, change in antibiotic coverage, and how these changes related to the timing of Verigene results. The lab reported the BC-GN results and final conventional susceptibility results within 2.5 ± 1.3 and 73.6 ± 40.0 hours from the Gram stain, respectively. Overall, 29.1% of patients were transitioned from empiric to targeted therapy at 12.2 ± 13.5 hours in response to BC-GN results, which was significantly earlier (P < 0.001) than results by conventional methods. After accounting for patients already on targeted therapy, polymicrobial infections, and patients deceased or lost to follow-up, we identified antibiotic stewardship opportunities in ∼28% of GN infections. Further subanalysis demonstrated site-specific differences in the uptake of stewardship recommendations, whereby 32.4%, 50.5%, and 15.0% of cases at different hospitals demonstrated the expected change in antibiotics. These results suggest that Verigene had the expected impact in a third of the cases and the results reporting algorithm minimized the real-time involvement of the pharmacist while maintaining optimal patient management. However, this impact varied substantially by clinical site and was tempered by variable initial antibiotic coverage and clinician response.

Hopanoids as functional analogues of cholesterol in bacterial membranes.

The functionality of cellular membranes relies on the molecular order imparted by lipids. In eukaryotes, sterols such as cholesterol modulate membrane order, yet they are not typically found in prokaryotes. The structurally similar bacterial hopanoids exhibit similar ordering properties as sterols in vitro, but their exact physiological role in living bacteria is relatively uncharted. We present evidence that hopanoids interact with glycolipids in bacterial outer membranes to form a highly ordered bilayer in a manner analogous to the interaction of sterols with sphingolipids in eukaryotic plasma membranes. Furthermore, multidrug transport is impaired in a hopanoid-deficient mutant of the gram-negative Methylobacterium extorquens, which introduces a link between membrane order and an energy-dependent, membrane-associated function in prokaryotes. Thus, we reveal a convergence in the architecture of bacterial and eukaryotic membranes and implicate the biosynthetic pathways of hopanoids and other order-modulating lipids as potential targets to fight pathogenic multidrug resistance.