Trabectedin Enhances Oncolytic Virotherapy by Reducing Barriers to Virus Spread and Cytotoxic Immunity in Preclinical Pediatric Bone Sarcoma.

We previously reported that the DNA alkylator and transcriptional-blocking chemotherapeutic agent trabectedin enhances oncolytic herpes simplex viroimmunotherapy in human sarcoma xenograft models, though the mechanism remained to be elucidated. Here we report trabectedin disrupts the intrinsic cellular anti-viral response which increases viral transcript spread throughout the human tumor cells. We also extended our synergy findings to syngeneic murine sarcoma models, which are poorly susceptible to virus infection. In the absence of robust virus replication, we found trabectedin enhanced viroimmunotherapy efficacy by reducing immunosuppressive macrophages and stimulating granzyme expression in infiltrating T and NK cells to cause immune-mediated tumor regressions. Thus, trabectedin enhances both the direct virus-mediated killing of tumor cells and the viral-induced activation of cytotoxic effector lymphocytes to cause tumor regressions across models. Our data provide a strong rationale for clinical translation as both mechanisms should be simultaneously active in human patients.

Kidney Biopsy Corner: Amyloidosis.

Amyloidosis is an infiltrative disease caused by misfolded proteins depositing in tissues. Amyloid infiltrates the kidney in several patterns. There are, as currently described by the International Society of Amyloidosis, 14 types of amyloid that can involve the kidney, and these types may have different locations or clinical settings. Herein we report a case of AA amyloidosis occurring in a 24-year-old male with a history of intravenous drug abuse and provide a comprehensive review of different types of amyloids involving the kidney.

Acute Interstitial Nephritis in the Pediatric Population: A Review of Etiologic Associations, Histologic Findings, and Clinical Outcome.

BACKGROUND: Acute interstitial nephritis (AIN) is an infrequent cause of acute kidney injury in the pediatric population with a broad range of etiologies. This retrospective review attempts to characterize AIN in the pediatric population, delineate etiologic factors, histologic features, and clinical outcome. MATERIALS AND METHODS: Institutional pathology reports were queried for a diagnosis of AIN between 1/2010 and 10/2021. Archived slides and reports and clinical records were reviewed. RESULTS: Twenty-four patients were identified whose ages ranged from 5 to 20 years. A 8 cases (37.5%) were characterized as tubulointerstitial nephritis and uveitis (TINU), 4 cases (16.7%) were associated with an autoimmune disease, 4 cases (16.7%) were likely drug induced, and 8 cases (37.5%) had unclear etiology. DISCUSSION: Although all cases of drug induced interstitial nephritis contained eosinophils they were not exclusive to drug induced interstitial nephritis. A prominent plasma cell infiltrate was seen in both cases of Sjögren's associated interstitial nephritis. The vast majority (n = 18, 75%) showed an improved serum creatinine (<1 mg/dL) 1 year post diagnosis/at last follow-up. In this pediatric series of AIN, TINU contributed to a large subset of cases with known etiologies. On follow up, majority of the cases demonstrated recovery of renal function.

Clinical Significance of Renal Allograft Urothelial Thickening Identified by Ultrasound.

OBJECTIVES: To assess the etiology and clinical implications of ultrasound (US)-diagnosed urothelial thickening (UT) in renal transplants. METHODS: Patients with renal transplants who had UT diagnosed by US from January 2000 to December 2018 were retrospectively identified and compared to patients with transplants without UT scanned during the study period. Medical records were reviewed for demographics, US findings, pathologic results, laboratory values, and clinical outcomes and compared between groups by Fisher exact and t tests. RESULTS: A total of 143 patients with UT and 128 controls comprised our cohorts. The patient age in the UT group versus controls (mean ± SD, 50.2 ± 16.5 versus 51.2 ± 15.3 years) and the time since transplant (2.9 ± 4.2 versus 2.4 ± 5.8 years) were similar. Patients with UT were more likely to be female than controls (76 of 143 [53.1%] versus 53 of 128 [41.4%]; P = .07), but the difference was not statistically significant, and patients with UT were more likely to have indwelling stents (31 of 143 [21.7%] versus 9 of 128 [7.0%]; P = .001) and hydronephrosis (25 of 143 [17.4%] versus 11 of 128 [8.6%]; P = .03). At biopsy, rejection and vascular sclerosis were more likely in patients with UT compared to controls (24 of 25 [49.0%] versus 11 of 43 [25.6%]; P = .031; 42 of 49 [85.7%] versus 22 of 43 [51.2%]; P = .0005, respectively), whereas acute tubular necrosis was similar. The sensitivity (50.0%) and specificity (74.4%) of UT for rejection were low. CONCLUSIONS: Urothelial thickening correlates with US findings of urinary obstruction and indwelling stents, suggesting a possible mechanical component to UT's etiology. Although transplant rejection and vascular sclerosis were more frequent at biopsy in the UT group than controls, UT had low sensitivity and specificity for rejection.