Natural History and Genomic Landscape of Chemotherapy-Resistant Muscle-Invasive Bladder Cancer.

PURPOSE: Patients with residual invasive bladder cancer after neoadjuvant chemotherapy (NAC) and radical cystectomy have a poor prognosis. Data on adjuvant therapy for these patients are conflicting. We sought to evaluate the natural history and genomic landscape of chemotherapy-resistant bladder cancer to inform patient management and clinical trials. METHODS: Data were collected on patients with clinically localized muscle-invasive urothelial bladder cancer treated with NAC and cystectomy at our institution between May 15, 2001, and August 15, 2019, and completed four cycles of gemcitabine and cisplatin NAC, excluding those treated with adjuvant therapies. Survival was estimated using the Kaplan-Meier method, and multivariable Cox proportional hazards models were used to identify predictors of recurrence-free survival (RFS). Genomic alterations were identified in targeted exome sequencing (Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets) data from post-NAC specimens from a subset of patients. RESULTS: Lymphovascular invasion (LVI) was the strongest predictor of RFS (hazard ratio, 2.15 [95% CI, 1.37 to 3.39]) on multivariable analysis. Patients with ypT2N0 disease without LVI had a significantly prolonged RFS compared with those with LVI (70% RFS at 5 years). Lymph node yield did not affect RFS. Among patients with sequencing data (n = 101), chemotherapy-resistant tumors had fewer alterations in DNA damage response genes compared with tumors from a publicly available chemotherapy-naïve cohort (15% v 29%; P = .021). Alterations in CDKN2A/B were associated with shorter RFS. PIK3CA alterations were associated with LVI. Potentially actionable alterations were identified in more than 75% of tumors. CONCLUSION: Although chemotherapy-resistant bladder cancer generally portends a poor prognosis, patients with organ-confined disease without LVI may be candidates for close observation without adjuvant therapy. The genomic landscape of chemotherapy-resistant tumors is similar to chemotherapy-naïve tumors. Therapeutic opportunities exist for targeted therapies as adjuvant treatment in chemotherapy-resistant disease.

New Advancements in Inflatable Penile Prosthesis.

INTRODUCTION: Inflatable penile prosthesis (IPP) technology is a mainstay in the treatment of erectile dysfunction refractory to medical management. Technological advancements in the design of 3-piece IPPs have been improved to optimize concealability and surgical placement since the 1980s. Recent advancements over the past 10 years include pump, reservoir, tubing, and cylinder updates. OBJECTIVES: This review examines the latest updates in IPP technology, reviews recent relevant research, and is based on over 32 years of experience performing IPP surgery in addition to concurrent postoperative management. METHODS: A literature review was conducted for studies published over the last 10 years through March 2020 with an emphasis on technical updates of IPP, specifically the pump, reservoir, tubing, and cylinder, and their functional outcomes. Anti-infective coating and transgender innovations, in addition to postoperative management, are also reviewed. RESULTS: Technological advancements include a flat reservoir designed for improved discreteness and a prosthesis with optimized tubing length, a one-touch deflatable 3-piece system, narrow-base cylinders, a 0° angle design between the cylinders and tubing to aid in cylinder placement, a soft molding cylinder tip redesign that better mimics human anatomy, and a 3-piece IPP specifically designed for neophallus use. Furthermore, the Food and Drug Administration approved the submuscular reservoir placement. CONCLUSION: Penile prosthesis has evolved over time to improve functional outcomes, ease of use, and minimize postoperative complications and pain. Penile prosthesis implantation continues to be a life-changing procedure for patients and it is imperative for surgeons to be up-to-date on the latest developments and research in order to provide the best functional outcomes for those they take care of. Dinerman BF, Telis L, Eid JF. New Advancements in Inflatable Penile Prosthesis. Sex Med Rev 2021;9:507-514.

Robotic Assisted Laparoscopic Prostatectomy after High Intensity Focused Ultrasound Failure.

Background. Prostate cancer is the most common cancer diagnosed in men. As new focal therapies become more popular in treatment of prostate cancer, failure cases requiring salvage therapy with either surgical or other techniques are being reported. Objective. To report the options in treatment of prostate cancer after recurrence or failure of the primary treatment modality. Methods. We report a salvage robotic assisted laparoscopic radical prostatectomy (RALP) for prostate cancer recurrence following high intensity focused ultrasound treatment (HIFU) in the United States. Results. A 67-year-old man who underwent HIFU treatment for prostate adenocarcinoma 2 years prior was presented with a rising prostate specific antigen of 6.1 ng/mL to our clinic. A biopsy proven recurrent disease in the area of previous treatment documented the failure of treatment. The patient elected to undergo a salvage RALP. The operation time was 159 minutes. The patient was discharged from the hospital on postoperative day 1 with no complications. The catheter was removed on post-op day 10. The patient reserved sexual function and urinary continence. The PSA levels on 6 months' follow-up are undetectable. Conclusions. Salvage RALP is an effective and safe treatment choice for recurrent prostate adenocarcinoma following failed HIFU treatment if operated by an experienced surgeon.

Hematopoietic stem cell origin of BRAFV600E mutations in hairy cell leukemia.

Hairy cell leukemia (HCL) is a chronic lymphoproliferative disorder characterized by somatic BRAFV600E mutations. The malignant cell in HCL has immunophenotypic features of a mature B cell, but no normal counterpart along the continuum of developing B lymphocytes has been delineated as the cell of origin. We find that the BRAFV600E mutation is present in hematopoietic stem cells (HSCs) in HCL patients, and that these patients exhibit marked alterations in hematopoietic stem/progenitor cell (HSPC) frequencies. Quantitative sequencing analysis revealed a mean BRAFV600E-mutant allele frequency of 4.97% in HSCs from HCL patients. Moreover, transplantation of BRAFV600E-mutant HSCs from an HCL patient into immunodeficient mice resulted in stable engraftment of BRAFV600E-mutant human hematopoietic cells, revealing the functional self-renewal capacity of HCL HSCs. Consistent with the human genetic data, expression of BRafV600E in murine HSPCs resulted in a lethal hematopoietic disorder characterized by splenomegaly, anemia, thrombocytopenia, increased circulating soluble CD25, and increased clonogenic capacity of B lineage cells-all classic features of human HCL. In contrast, restricting expression of BRafV600E to the mature B cell compartment did not result in disease. Treatment of HCL patients with vemurafenib, an inhibitor of mutated BRAF, resulted in normalization of HSPC frequencies and increased myeloid and erythroid output from HSPCs. These findings link the pathogenesis of HCL to somatic mutations that arise in HSPCs and further suggest that chronic lymphoid malignancies may be initiated by aberrant HSCs.

Deletion of Asxl1 results in myelodysplasia and severe developmental defects in vivo.

Somatic Addition of Sex Combs Like 1 (ASXL1) mutations occur in 10-30% of patients with myeloid malignancies, most commonly in myelodysplastic syndromes (MDSs), and are associated with adverse outcome. Germline ASXL1 mutations occur in patients with Bohring-Opitz syndrome. Here, we show that constitutive loss of Asxl1 results in developmental abnormalities, including anophthalmia, microcephaly, cleft palates, and mandibular malformations. In contrast, hematopoietic-specific deletion of Asxl1 results in progressive, multilineage cytopenias and dysplasia in the context of increased numbers of hematopoietic stem/progenitor cells, characteristic features of human MDS. Serial transplantation of Asxl1-null hematopoietic cells results in a lethal myeloid disorder at a shorter latency than primary Asxl1 knockout (KO) mice. Asxl1 deletion reduces hematopoietic stem cell self-renewal, which is restored by concomitant deletion of Tet2, a gene commonly co-mutated with ASXL1 in MDS patients. Moreover, compound Asxl1/Tet2 deletion results in an MDS phenotype with hastened death compared with single-gene KO mice. Asxl1 loss results in a global reduction of H3K27 trimethylation and dysregulated expression of known regulators of hematopoiesis. RNA-Seq/ChIP-Seq analyses of Asxl1 in hematopoietic cells identify a subset of differentially expressed genes as direct targets of Asxl1. These findings underscore the importance of Asxl1 in Polycomb group function, development, and hematopoiesis.