Intraductal carcinoma of the prostate in an Irish prostate cancer patient cohort-an aggressive pathology and a strong familial link.

BACKGROUND: The prevalence of intraductal carcinoma of the prostate (IDC-P) is poorly studied in the Irish population. This study investigated the incidence and clinicopathologic characteristics of IDC-P in an Irish prostate cancer (PCa) patient cohort. The study also discusses the rationale for genetic counseling and screening in Irish patients with familial risk factors for IDC-P. MATERIALS AND METHODS: This study investigated patients diagnosed with IDC-P on prostate biopsy from 2012 to 2016. Primary outcome measurements were incidence, management, and clinical outcomes after follow-up in patients with IDC-P. The secondary outcome measurement was to identify a familial link for IDC-P. RESULTS: A total of 1,143 patients were diagnosed with PCa on needle biopsy, of which 30 (2.3%) had concomitant IDC-P. Mean age and prostate-specific antigen at diagnosis were 68.6 ± 10.5 years (range 53-85 years) and 9.15 ± 8.65 ng/mL (range 2.1-166 ng/mL), respectively. In total, 17 of 30 patients (57%) were diagnosed with concomitant high-grade (i.e., ≥Gleason score 8) PCa. Eight patients (27%) were treated with radical prostatectomy; of which five had biochemical recurrence (BCR) after 10.55 ± 25.9 months. Eleven patients (37%) received radical radiotherapy; of which one had BCR after 36 months. Eleven patients (37%) presented with advanced PCa and were managed with androgen deprivation therapy ± chemotherapy. A family history for PCa in first-degree relatives was found in eight patients (27%). CONCLUSIONS: IDC-P is associated with more aggressive clinicopathologic features and an increased risk of BCR after treatment. In Ireland, clinical guidelines and a genetic screening pathway are required to provide early detection and appropriate multimodal management of patients with IDC-P.

Ex vivo reconstruction of the donor renal artery in renal transplantation: a case-control study.

Transplantation of renal allografts with anatomic variability or injured vasculature poses a challenge to the transplanting surgeon but can be salvaged for transplantation with ex vivo bench reconstruction of the vasculature. We investigated whether renal allograft function is impaired in these reconstructed allografts; compared to the donor-matched, un-reconstructed allograft. Reconstructed allografts were transplanted into 60 patients at our institution between 1986 and 2012. A control group was selected from the matched pair of the recipient in deceased donor transplantation. We found no significant difference in the overall graft and patient survival rates (P = 1.0, P = 0.178). Serum creatinine levels were not significantly higher in the study group at 1, 3 and 12 months postoperatively. There were two cases of vascular thrombosis in the study group that were not related to the ex vivo reconstruction. A significantly greater proportion of reconstructed patients were investigated with a colour duplex ultrasound postoperatively (0.007). Although we have demonstrated a higher index of suspicion of transplant failure in patients with a reconstructed allograft, this practice has proven to be a safe and useful technique with equivocal outcome when compared to normal grafts; increasing the organ pool available for transplantation.

Outcome of deceased donor renal transplantation in patients with an ileal conduit.

Renal transplantation in recipients with an ileal conduit is uncommon and occasionally controversial as it has been associated with high morbidity and mortality rates. We report on 17 patients with an ileal conduit who received a deceased donor renal transplant at our institution between January 1986 and December 2012. We retrospectively reviewed their allograft and surgical outcome. There were four mortalities at five, five, 39, and 66 months post-transplant. Sixteen of 17 grafts functioned immediately; one patient had primary non-function secondary to vascular thrombosis. Thirteen of 17 (76.5%) grafts were functioning at a mean follow-up period of 105 months. The mean serum creatinine at follow-up was 111 µM (±38.62). Five patients had seven episodes of urosepsis requiring hospital admission, and five patients received treatment for renal stone disease. We conclude that given improvements in immunosuppression, surgical technique, infection treatment, and selection criteria, we believe that renal transplantation in the patient with an ileal conduit yields excellent graft survival, although there is a high morbidity rate in this cohort of patients in the long term.

Neuroendocrine responses mediate macrophage function after trauma.

BACKGROUND: Clearly understanding the interactions between macrophage (M phi)-generated inflammatory mediators and the neuroendocrine system in regulating immune function after traumatic injury may aid in reversing trauma-mediated immune dysfunction and diminish the incidence and severity of infection in the traumatized patient. METHODS: Trauma consisted of an open femur fracture and 40% retro-orbital hemorrhage (Trauma) or anesthesia alone (Control). Female Balb/C mice (6-8 weeks) with intact adrenal glands (Intact) or a bilateral adrenalectomy (ADX) were used. For glucocorticoid studies, corticosterone or a vehicle was administered via intraperitoneal (ip) injection 2 hours before the trauma. Splenic M phis were harvested and prostaglandin E(2) (PGE(2)) and interleukin-6 (IL-6) production, and mRNA, cyclooxygenase-2 (COX-2) protein, and nuclear factor kappa B (NF-kappa B) activity were measured. RESULTS: M phi, PGE(2) and IL-6 production in Trauma+Intact mice was significantly increased compared with Control+Intact mice. Adrenalectomy decreased these levels to Control levels. Similar changes were observed for COX-2 and IL-6 expression. M phi nuclear NF-kappa B levels were increased in Trauma+Intact mice compared with controls. Adrenalectomy abrogated this increase. Treating Trauma+Intact mice with RU-486 did not restore PGE(2) and IL-6 production or COX-2 and IL-6 messenger RNA to control levels. Administering exogenous glucocorticoid to Intact mice did not increase PGE(2) and IL-6 production or COX-2 and IL-6 mRNA to Trauma levels. CONCLUSIONS: The neuroendocrine system upregulates certain M phi inflammatory mediators, including PGE(2), IL-6, and NF-kappa B, after trauma. This upregulation does not seem to be mediated via glucocorticoids and possibly may be mediated via catecholamines. Elucidation of the interactions between the neuroendocrine system, the immune system, and inflammatory mediator secretion might provide novel therapeutic strategies for the injured patient.

Altered cyclooxygenase-2 expression and nitric oxide metabolism following major elective surgery.

BACKGROUND AND AIMS: Postoperative variation in immune function leads to increased susceptibility to infections. Cyclooxygenase-2 (COX-2)-generated Prostaglandin-E(2) (PGE(2)), which signals through the PGE(2) receptor (EP receptor), as well as nitric oxide metabolites (NOx), appear to be important in postoperative immune dysfunction. It is unclear, however, how these substrates and receptors change over time. This study was conducted to evaluate postoperative changes in inflammatory mediator production and monocyte COX-2 and EP receptor expression. MATERIALS AND METHODS: Nineteen patients had blood drawn preoperatively and up to 1 week postoperatively. Plasma NOx levels were measured. Peripheral blood mononuclear cell (PBMC) COX-2 and EP receptor mRNA expression were analyzed by reverse transcription-polymerase chain reaction (RT-PCR). PBMC PGE(2), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), and IL-10 productions were evaluated by enzyme-linked immunosorbent assay (ELISA) kits. Statistical analyses were by ANOVA and Student's t tests. RESULTS: Postoperatively, PBMC mean PGE(2) and IL-6 productions were significantly increased at all time points. Mean TNF-alpha production was maximal on postoperative day 2, while mean IL-10 production was unchanged. Mean circulating NOx levels demonstrated a biphasic response decreasing early postoperatively and normalizing at postoperative day (POD) 7. PBMC COX-2 enzyme and EP receptor mRNA expression were unchanged. CONCLUSIONS: Altered PBMC PGE(2) production and plasma NOx levels support a role for altered macrophage activity, which may contribute to immune dysfunction in the postoperative period.

Glucocorticoid pretreatment induces cytokine overexpression and nuclear factor-kappaB activation in macrophages.

BACKGROUND: Glucocorticoids are widely used in treating inflammatory diseases. The contribution of adrenal glucocorticoids to inflammatory regulation is unknown. Endogenous glucocorticoids, as distinct from synthetic analogues, not only suppress but also enhance immune functions. Elevated circulating cortisol levels are characteristic of injured patients. In a model of trauma, an early glucocorticoid surge occurs concomitantly with decreased cellular cytokine responses. Cytokine production elevated late after injury is associated with increased mortality. We hypothesized that this glucocorticoid surge mediates the later heightened macrophage responses. MATERIALS AND METHODS: The murine macrophage like cells RAW 264.7 were incubated with corticosterone (35 ng/mL), or vehicle control, for 1 h, after which the cells were washed and corticosterone-free medium added. At 0, 3, 6, 12, and 24 h after removal of the corticosterone, the cells were stimulated with lipopolysaccharide (LPS) and interferon-gamma. Supernatant tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and nitrite levels were measured. In separate experiments the effect of pretreatment with corticosterone on TNF-alpha, IL-6, and nitrite mRNA expression as well as nuclear factor-kappaB and glucocorticoid receptor activity was determined. CD14 receptor expression was determined by flow cytometry. RESULTS: Glucocorticoid pretreatment caused significantly increased RAW 264.7 cell production of nitrite, IL-6 and TNF-alpha. mRNA for these inflammatory mediators was induced 6 h after the corticosterone pretreatment, and was associated with activation of nuclear factor-kappaB in the presence of activated glucocorticoid receptor. Cell surface-expression of CD14 was likewise increased. CONCLUSIONS: The results of this study demonstrate a novel role for glucocorticoids and provide a mechanism for the late upregulation in macrophage function after injury.

Renal cell carcinoma induces prostaglandin E2 and T-helper type 2 cytokine production in peripheral blood mononuclear cells.

BACKGROUND: Patients with renal cell carcinoma (RCC) do not develop an effective antitumor immune response, despite significant infiltration by lymphocytes. Tumor production of immunosuppressive factors may account for this failure. The object of this study was to investigate the production of immunosuppressive mediators, especially prostaglandin E(2) (PGE(2)), by RCC. METHODS: Peripheral blood mononuclear cells (PBMC) were cocultured with conditioned medium (CM) from human RCC cell lines in the presence or absence of NS-398, a selective cyclooxygenase 2 (COX-2) inhibitor. Supernatants were analyzed for levels of PGE(2), interleukin (IL)-10, IL-6, IL-2, interferon-gamma, and IL-12. The effects of RCC CM on PBMC proliferation were also examined. The expression of basal and stimulated COX-2 messenger RNA in the cell lines was assessed by reverse transcriptase-polymerase chain reaction. RESULTS: RCC CM significantly increased PGE(2) production by PBMC. T-helper type 2 (Th2) cytokine production was also significantly increased. Th1 cytokines were unchanged or decreased. RCC CM increased proliferation of PBMC. Coculture with NS-398 reduced PBMC PGE(2) production to below control levels and significantly decreased IL-6 production and PBMC proliferation. NS-398 had no effect on cellular production of IL-10 or Th1 cytokines. CONCLUSIONS: Human RCC inhibits the host antitumor immune response by promoting PGE(2) production and Th2 cytokines in PBMC. Selective inhibition of COX-2 may have a role in abrogating this effect.

Cyclooxygenase-2 inhibition improves macrophage function in melanoma and increases the antineoplastic activity of interferon gamma.

BACKGROUND: Melanoma inhibits macrophage tumoricidal activity and increases the expression of cyclooxygenase-2 (COX-2). In this study, we sought to determine whether inhibition of COX-2 could restore macrophage function and hence maximize the antitumor activity of the immune stimulant interferon gamma (IFN gamma). METHODS: Peritoneal macrophages were exposed to B16 melanoma-conditioned medium for 24 hours with or without the COX-2 inhibitor NS-398 and then were stimulated with lipopolysaccharide and IFN gamma. Cytotoxic activity, nitrite production, and cytokine production by the stimulated macrophages were measured. In addition, B16 melanoma cells were implanted intradermally into mice treated with IFN gamma (14,000 U on alternate days) alone or with a combination of IFN gamma and a COX-2 inhibitor (NS-398 or nimesulide). Mice were assessed for tumor growth and survival. RESULTS: Macrophage cytotoxicity and nitrite production were significantly suppressed by melanoma-conditioned medium (P <.01). This was prevented by 200 micro M of NS-398 (P <.05). In vivo, combined treatment with IFN gamma and a COX-2 inhibitor caused a significant inhibition of tumor growth (P <.01) and improved survival (P =.02) compared with controls. CONCLUSIONS: COX-2 inhibition reversed melanoma-induced suppression of macrophage function, and combined treatment of IFN gamma plus a COX-2 inhibitor was maximally effective in reducing tumor growth and improving survival.