Robot-assisted nephroureterectomy for upper tract urothelial carcinoma-feasibility and complications: a single center experience.

BACKGROUND: Robot-assisted nephroureterectomy (RANU) is the primary treatment for upper tract urothelial carcinoma (UTUC) at our hospital for patients with clinical stage less than T2, and for patients with invasive tumours, but unfit for major surgery. OBJECTIVE: To assess peri-operative conditions and outcomes of RANU at our unit, and to evaluate the safety of the procedure. METHODS: The medical records of all 166 patients undergoing RANU for suspected UTUC and followed for more than three months in a large university hospital in Sweden were reviewed retrospectively. After the exclusion of twenty patients because of previous cystectomy, simultaneous surgical procedure, or other tumour types than UTUC in the pathological report, 146 patients remained for the analyses. The primary endpoint was complication rate according to Clavien-Dindo at 90 days. Secondary endpoints were perioperative bleeding, violation of oncological surgical principles, hospital stay, and re-admission within 90 days. RESULTS: The median age was 75 [(Inter Quartile Range) IQR 70-80] years and 57% of the patients had an ASA score above 2. According to Clavien-Dindo, one patient had a grade 3 complication, and no patient had a grade 4-5 complication. The median blood loss was 50 (IQR 20-100) ml and the median hospital stay was 6 (IQR 5-7) days. Twelve patients were re-admitted to the hospital within 90 days (eight with urinary tract infection/haematuria, one with hematoma, and three with other diseases). CONCLUSION: Robot-assisted nephroureterectomy is a safe procedure for patients with upper tract urothelial carcinoma, with a low risk of major surgical complications.

Macrophage and dendritic cell subsets in IBD: ALDH+ cells are reduced in colon tissue of patients with ulcerative colitis regardless of inflammation.

Disruption of the homeostatic balance of intestinal dendritic cells (DCs) and macrophages (MQs) may contribute to inflammatory bowel disease. We characterized DC and MQ populations, including their ability to produce retinoic acid, in clinical material encompassing Crohn's ileitis, Crohn's colitis and ulcerative colitis (UC) as well as mesenteric lymph nodes (MLNs) draining these sites. Increased CD14(+)DR(int) MQs characterized inflamed intestinal mucosa while total CD141(+) or CD1c(+) DCs numbers were unchanged. However, CD103(+) DCs, including CD141(+)CD103(+) and CD1c(+)CD103(+) DCs, were reduced in inflamed intestine. In MLNs, two CD14(-) DC populations were identified: CD11c(int)HLADR(hi) and CD11c(hi)HLADR(int) cells. A marked increase of CD11c(hi)HLADR(int) DC, particularly DR(int)CD1c(+) DCs, characterized MLNs draining inflamed intestine. The fraction of DC and MQ populations expressing aldehyde dehydrogenase (ALDH) activity, reflecting retinoic acid synthesis, in UC colon, both in active disease and remission, were reduced compared to controls and inflamed Crohn's colon. In contrast, no difference in the frequency of ALDH(+) cells among blood precursors was detected between UC patients and non-inflamed controls. This suggests that ALDH activity in myeloid cells in the colon of UC patients, regardless of whether the disease is active or in remission, is influenced by the intestinal environment.

A major population of mucosal memory CD4+ T cells, coexpressing IL-18Rα and DR3, display innate lymphocyte functionality.

Mucosal tissues contain large numbers of memory CD4(+) T cells that, through T-cell receptor-dependent interactions with antigen-presenting cells, are believed to have a key role in barrier defense and maintenance of tissue integrity. Here we identify a major subset of memory CD4(+) T cells at barrier surfaces that coexpress interleukin-18 receptor alpha (IL-18Rα) and death receptor-3 (DR3), and display innate lymphocyte functionality. The cytokines IL-15 or the DR3 ligand tumor necrosis factor (TNF)-like cytokine 1A (TL1a) induced memory IL-18Rα(+)DR3(+)CD4(+) T cells to produce interferon-γ, TNF-α, IL-6, IL-5, IL-13, granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-22 in the presence of IL-12/IL-18. TL1a synergized with IL-15 to enhance this response, while suppressing IL-15-induced IL-10 production. TL1a- and IL-15-mediated cytokine induction required the presence of IL-18, whereas induction of IL-5, IL-13, GM-CSF, and IL-22 was IL-12 independent. IL-18Rα(+)DR3(+)CD4(+) T cells with similar functionality were present in human skin, nasal polyps, and, in particular, the intestine, where in chronic inflammation they localized with IL-18-producing cells in lymphoid aggregates. Collectively, these results suggest that human memory IL-18Rα(+)DR3(+) CD4(+) T cells may contribute to antigen-independent innate responses at barrier surfaces.

Resident and pro-inflammatory macrophages in the colon represent alternative context-dependent fates of the same Ly6Chi monocyte precursors.

Macrophages (mφ) are essential for intestinal homeostasis and the pathology of inflammatory bowel disease (IBD), but it is unclear whether discrete mφ populations carry out these distinct functions or if resident mφ change during inflammation. We show here that most resident mφ in resting mouse colon express very high levels of CX3CR1, are avidly phagocytic and MHCII(hi), but are resistant to Toll-like receptor (TLR) stimulation, produce interleukin 10 constitutively, and express CD163 and CD206. A smaller population of CX3CR1(int) cells is present in resting colon and it expands during experimental colitis. Ly6C(hi)CCR2(+) monocytes can give rise to all mφ subsets in both healthy and inflamed colon and we show that the CX3CR1(int) pool represents a continuum in which newly arrived, recently divided monocytes develop into resident CX3CR1(hi) mφ. This process is arrested during experimental colitis, resulting in the accumulation of TLR-responsive pro-inflammatory mφ. Phenotypic analysis of human intestinal mφ indicates that analogous processes occur in the normal and Crohn's disease ileum. These studies show for the first time that resident and inflammatory mφ in the intestine represent alternative differentiation outcomes of the same precursor and targeting these events could offer routes for therapeutic intervention in IBD.

Molecular characterization of early-stage bladder carcinomas by expression profiles, FGFR3 mutation status, and loss of 9q.

We used gene expression profiling, mutation analyses of FGFR3 and TP53, and LOH analyses of chromosome 9 and the TP53 region on chromosome arm 17p, to molecularly characterize 75 Ta and T1 bladder carcinomas. We identified four major cellular processes related to cell cycle, protein synthesis, immune response, and extra cellular components that contribute to the expressional heterogeneity of early-stage urothelial cell carcinoma (UCC). Activating FGFR3 mutations were found at the highest frequency in G1 tumors (80%), and showed a strong correlation with FGFR3 expression. In contrast, G3 tumors displayed mutations in less than 10% of the cases and a low level of FGFR3 expression. Even though LOH on chromosome 9 was not associated with any specific expression pattern, our data indicate that loss of chromosome 9 is associated with tumor development rather than initiation. The combined analyses suggest the existence of two types of UCC tumors, one which is characterized by FGFR3 mutation or expression, high expression of protein synthesis genes, and low expression of cell cycle genes. Furthermore, the presented data underscore FGFR3 receptor involvement in urothelial cell transformation as the presence of FGFR3 mutations has a major impact on the global gene expression profile of bladder carcinomas.