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With the approval of the antibody-drug conjugate enfortumab vedotin (EV), NECTIN4 has emerged as a bona fide therapeutic target in urothelial carcinoma (UC). Here, we report the development of a NECTIN4-directed chimeric antigen receptor (CAR) T cell, which exhibits reactivity across cells expressing a range of endogenous NECTIN4, with enhanced activity in high expressors. We demonstrate that the PPARγ pathway, critical for luminal differentiation, transcriptionally controls NECTIN4 , and that the PPARγ agonist rosiglitazone primes and augments NECTIN4 expression, thereby increasing sensitivity to NECTIN4-CAR T cell-mediated killing. NECTIN4-CAR T cells have potent anti-tumor activity even against EV resistant cells, which largely retain NECTIN4 expression, including in a post-EV biopsy cohort. Our results elucidate a therapeutically actionable mechanism that UC cells use to control NECTIN4 expression and suggest therapeutic approaches that leverage PPARγ agonists for rational combinations with NECTIN4-targeting agents in UC, as well as future potential treatment options for EV-refractory patients. Enfortumab vedotin (EV) is the current standard treatment for advanced bladder cancer, but resistance typically develops within a year, highlighting the need for new therapies. This study demonstrates that NECTIN4-targeting CAR T cells are effective against bladder cancer, including EV-resistant cells, and their potency can be further enhanced by using rosiglitazone to boost NECTIN4 expression.

Background: Web-based digital slide viewers for pathology commonly use OpenSlide and OpenSeadragon (OSD) to access, visualize, and navigate whole-slide images (WSI). Their standard settings represent WSI as deep zoom images (DZI), a generic image pyramid structure that differs from the proprietary pyramid structure in the WSI files. The transformation from WSI to DZI is an additional, time-consuming step when rendering digital slides in the viewer, and inefficiency of digital slide viewers is a major criticism for digital pathology. Aims: To increase efficiency of digital slide visualization by serving tiles directly from the native WSI pyramid, making the transformation from WSI to DZI obsolete. Methods: We implemented a new flexible tile source for OSD that accepts arbitrary native pyramid structures instead of DZI levels. We measured its performance on a data set of 8104 WSI reviewed by 207 pathologists over 40 days in a web-based digital slide viewer used for routine diagnostics. Results: The new FlexTileSource accelerates the display of a field of view in general by 67 ms and even by 117 ms if the block size of the WSI and the tile size of the viewer is increased to 1024 px. We provide the code of our open-source library freely on https://github.com/schuefflerlab/openseadragon. Conclusions: This is the first study to quantify visualization performance on a web-based slide viewer at scale, taking block size and tile size of digital slides into account. Quantifying performance will enable to compare and improve web-based viewers and therewith facilitate the adoption of digital pathology.

Giant cell tumor of the tendon sheath (GCT-TS) is a benign yet locally aggressive soft tissue neoplasm that typically arises in synovium-lined structures, including tendon sheaths, bursae, and joints. Also known as localized nodular tenosynovitis, this tumor primarily affects the hands and fingers but can occur in other anatomical locations. GCT-TS is histologically characterized by multinucleated giant cells within a background of mononuclear stromal cells. While it is generally nonmetastatic, the tumor carries a risk of local recurrence following surgical removal. Recognizing the clinical presentation, histopathological features, and appropriate management strategies is essential for effective treatment and recurrence prevention. Here, we present the case of a 34-year-old woman with a one-year history of pain in the infrapatellar region. Imaging revealed a well-defined soft tissue mass posterior to the patellar tendon, which was surgically excised. Histopathological examination confirmed the diagnosis of nodular-type GCT-TS. The patient's symptoms resolved completely postoperatively, and no recurrence was observed during a five-year follow-up period, highlighting the effectiveness of surgical excision in managing this rare tumor location.