Hypomorphic Rag1 mutations alter the preimmune repertoire at early stages of lymphoid development.

Hypomorphic RAG1 mutations allowing residual T- and B-cell development have been found in patients presenting with delayed-onset combined immune deficiency with granulomas and/or autoimmunity (CID-G/AI) and abnormalities of the peripheral T- and B-cell repertoire. To examine how hypomorphic Rag1 mutations affect the earliest stages of lymphocyte development, we used CRISPR/Cas9 to generate mouse models with mutations equivalent to those found in patients with CID-G/AI. Immunological characterization showed partial development of T and B lymphocytes, with persistence of naïve cells and preserved serum immunoglobulin but impaired antibody responses and presence of autoantibodies, thereby recapitulating the phenotype seen in patients with CID-G/AI. By using high-throughput sequencing, we identified marked skewing of Igh V and Trb V gene usage in early progenitors, with a bias for productive Igh and Trb rearrangements after selection occurred and increased apoptosis of B-cell progenitors. Rearrangement at the Igk locus was impaired, and polyreactive immunoglobulin M antibodies were detected. This study provides novel insights into how hypomorphic Rag1 mutations alter the primary repertoire of T and B cells, setting the stage for immune dysregulation frequently seen in patients.

The natural history of papillary transitional cell carcinoma of the bladder and its treatment in an unselected population on the basis of histologic grading.

Between 1950 and 1965, 365 patients were treated for transitional cancer of the bladder at our hospitals. A retrospective study was done, using clinical records and a histopathologic review to determine the long-term natural history of this population when treated conservatively. The natural history of 3 separate patient populations was discovered, based solely on the grading of the transurethrally resected fragments. Based on the grade on initial presentation these patients were divided into grades I, II and III. Of the patients 5 per cent in grade I, 16 per cent in grade II, 28 to 35 per cent in grade III not involving muscle and 83 per cent in grade III involving muscle died of bladder cancer. Ninety-seven patients (26 per cent) died of bladder cancer, 110 (31 per cent) died of other causes and 158 (43 per cent) have been alive more than 5 years (104 more than 10 years). Grade I tumors that progressed to a higher grade did so within 2 years of the initial diagnosis. Of the bladder cancer deaths 83 per cent occurred within 2 years of the initial diagnosis. Of 64 patients dying more than 5 years after presentation only 7 died of bladder cancer.

Renal vein leiomyosarcoma.

The third reported case of renal vein leiomyosarcoma is presented. Diagnosis was not made until exploratory celiotomy revealed a tumor originating from the left renal vein. The tumor was resected with margins of normal vein, and the patient was alive without recurrence 12 months after operation. Review of 65 cases of leiomyosarcoma originating in other retroperitoneal structures revealed a two-year survival rate of 20%. Therefore, we recommend consideration of postoperative adjunctive chemotherapy for renal vein leiomyosarcomas.