Primary localized amyloidosis of the ureter with osseous metaplasia presenting as a suspicious ureteral mass.

Primary amyloidosis of the ureter is a rare disease that is difficult to distinguish from urothelial carcinoma. Only 50 cases of primary ureter amyloidosis have been reported since it was first described in 1937. Of these, only five cases of ureter amyloidosis with osseous metaplasia were reported. In this study, we report the clinical presentation of ureter primary amyloidosis that presented as a mass with osseous metaplasia. The aim of this study is to provide clinicians with knowledge about the clinical/radiologic manifestation that raise the suspicion of amyloidosis, bearing in mind the importance of differentiating it from other "malignant" processes.

Two separate synchronous primary genitourinary tumors.

A 54-year-old man presented to the office with gross painless hematuria, dysuria, and urinary frequency. He was diagnosed with renal cell carcinoma of the kidney and transitional cell carcinoma of the bladder. The article reviews the presentation, radiology, pathology, and intervention of an uncommon case of synchronous primary carcinomas, and aims to show the importance of continued clinical suspicion for multiple genitourinary primary neoplasms.

Prostate tumor microenvironment alters immune cells and prevents long-term survival in an orthotopic mouse model following flt3-ligand/CD40-ligand immunotherapy.

A novel orthotopic metastatic model of mouse prostate cancer was developed using MHC-negative TRAMP-C1P3 (transgenic adenocarcinoma of mouse prostate) cells derived by serial passage of the parental TRAMP-C1 line in mouse prostate glands. TRAMP-C1P3 cells grew efficiently in mouse prostate glands and reproducibly metastasized to draining lymph nodes. Using this model, we show that Fms-like tyrosine kinase-3 ligand (flt3-L) dramatically inhibited growth of preexisting orthotopic TRAMP-C1P3 tumors and the development of metastatic disease. Mice remained in remission for several months following termination of flt3-L treatment but eventually relapsed and died of progressive disease. flt3-ligand treatment induced a pronounced mixed inflammatory cell infiltrate that consisted of CD8alpha-CD4- dendritic cells (CD11c+), macrophages, granulocytes (Gr-1+) and to a lesser extent T cells (CD4+ and CD8+). Dendritic cells isolated from TRAMP-C1P3 tumors were phenotypically immature (CD11c+ B7.2-I-A-CD40-), and this phenotype was also predominant in peripheral organs of mice treated with flt3-L alone or in combination with the DC maturation factor, CD40-L. Diminished expression of TCR-beta, CD3-epsilon, and CD3-zeta was also observed on intratumoral T cells, although these signaling proteins were reexpressed following in vitro culture with IL-2. The TCR/CD3 complex remained intact on peripheral T cells except in mice treated with flt3-L where CD3-zeta loss was observed. In contrast to alphabeta-T cells, tumor-infiltrating gammadelta-T cells maintained expression of their antigen receptors but not CD3epsilon. Thus, TRAMP-C1P3 tumors quickly establish a microenvironment that profoundly diminishes expression of molecules critical for normal dendritic cell and T cell function, thus limiting the efficacy of flt3-L and CD40-L immunotherapy. Overall, these data suggest that long-term cures of established MHC-negative tumors may not be achieved until therapeutic interventions are engineered to overcome this immunosuppressive microenvironment.

Impact of the tumor microenvironment on host infiltrating cells and the efficacy of flt3-ligand combination immunotherapy evaluated in a treatment model of mouse prostate cancer.

We have previously reported that Fms-like tyrosine kinase-3 ligand (flt3-L) induced tumor stabilization and regression of palpable ectopic prostate tumors (TRAMP-C1). Although some mice remained "tumor free" for several months following termination of therapy, tumors invariably reappeared and grew progressively in all animals. The lack of a curative response suggests that TRAMP-C1 tumors may inhibit the development of a flt3-L-induced anti-tumor immune response. Consistent with this view, we demonstrate herein that TRAMP-C1 tumors isolated from flt3-L treated animals contained a marked dendritic cell (DC) infiltrate that was temporally correlated with tumor regression. However, tumor-associated DCs, especially in a flt3-L setting, progressively lost MHC class II antigen expression during tumor growth. Treatment with the DC maturation factor trimeric CD40 ligand (CD40-L) either alone or in combination with fl3-L neither prevented loss of DC class II antigens nor disease relapse. Because loss of class II antigens would prevent CD4+ helper T (Th) cell development, we treated tumor-bearing mice with agonistic anti-4-1BB antibody (Ab), which can promote cytotoxic T lymphocyte (CTL) development independent of Th cell function. However, anti-4-1BB Ab alone did not alter TRAMP-C1 growth kinetics, and, when used in combination, was no more effective than flt3-L alone. The inability of the 4-1BB co-stimulatory signal to promote tumor regression may have been related to two additional features of TRAMP-C1 tumors. First, tumor-associated T cells, but not splenic T cells from tumor-bearing animals, were profoundly deficient in expression of CD3-epsilon (CD3epsilon) and T cell receptor-beta chain (TCRbeta). Second, CTLs required 24 h to efficiently kill TRAMP-C1 target cells even after up-regulation of MHC class I antigens by interferon-gamma. This rate of tumor cell destruction by CTLs may not be sufficient to prevent tumor progression. Taken together, these data reveal several important immunosuppressive characteristics of the prostate tumor microenvironment (TME) that immunotherapeutic interventions must first overcome to achieve longterm cures. These data also highlight the importance of utilizing treatment versus vaccination models in the evaluation of immunotherapeutic modalities.

Orthotopic treatment model of prostate cancer and metastasis in the immunocompetent mouse: efficacy of flt3 ligand immunotherapy.

We established an orthotopic treatment model of prostate cancer to generate reproducible primary and metastatic carcinoma in immunocompetent C57BL/6 mice. Using an in vivo selection scheme of intraprostatic implantation of TRAMP-C1 cells, primary prostate tumors were cultured and recycled three times by intraprostatic injection resulting in the selection and establishment of the recycled cell line TRAMP-C1P3. Prostate tumors were detected approximately 30 days post-implantation with periaortic lymph node metastasis in 19/20 (95%) of mice. Tissue culture amplification, DNA ploidy and PCR amplification of the SV40 transgene were used to detect metastatic TRAMP-C1P3 in lymph node specimens. Tissue culture amplification and DNA ploidy were as sensitive as SV40 transgene amplification by PCR in detection of early metastatic disease in draining lymph nodes. To establish the use of the orthotopic model of prostate cancer for immunotherapy, mice were injected orthotopically with TRAMP-C1P3 cells and 7 days post-implantation treated daily for 28 days with either flt3L or carrier control. Carrier-treated mice had clinically detectable prostate tumors, lymph node metastasis and were moribund at 29-35 days, whereas flt3L therapy markedly suppressed primary TRAMP-C1P3 growth and lymph node metastasis, and prolonged survival. In summary, we have established a reproducible and clinically relevant orthotopic treatment model of prostate cancer in immunocompetent mice with application to a variety of therapeutic strategies. We demonstrate that flt3L treatment suppressed orthotopic prostate tumor growth and lymph node metastasis reinforcing a role for flt3L as an immunotherapeutic strategy for prostate cancer.