小児異所性尿管瘤に対して施行した後腹膜鏡下半腎摘出術の1例

5歳女児.1歳2ヵ月より尿路感染症を繰り返し, 右異所性尿管瘤と診断され保存的に経過観察されていた.IVP, DMSA腎シンチで瘤所属右上半腎は無機能で下半腎に国際分類III度の膀胱尿管逆流症を認めた.1998年8月13日, 右後腹膜鏡下半腎摘出術及び瘤切除, 右下半腎逆流防止術を施行した.術後経過は良好で, 術後3ヵ月目のVCGでも逆流は消失し, 腎機能も良好であった.小児における腹腔鏡下半腎摘出術は現在迄に15例の報告があるが, 後腹膜アプローチは本症例が初めてであるA 5-year-old girl with a history of recurrent urinary tract infection since the age of 14 months was diagnosed as having a right duplicated urinary collecting system with the upper ureter ectopically opening in the urethra. She underwent retroperitoneoscopic heminephrectomy for a right dysplastic kidney and open ureterocelectomy and reimplantation of the refluxing lower ureter via Pfannenstiel incision. She survived the procedure without serious complications and resumed normal daily activities by day 6. To the best of our knowledge, this case is the 16th case of laparoscopic heminephrectomy for pediatric patients and the first case treated by the retroperitoneal approach in the English literature

Tranilast inhibits hormone refractory prostate cancer cell proliferation and suppresses transforming growth factor Β1-associated osteoblastic changes

BACKGROUND Tranilast is a therapeutic agent used in treatment of allergic diseases, although it has been reported to show anti-tumor effects on some cancer cells. To elucidate the effects of tranilast on prostate cancer, we investigated the mechanisms of its anti-tumor effect on prostate cancer. METHODS The anti-tumor effects and related mechanisms of tranilast were investigated both in vitro on prostate cancer cell lines and bone-derived stromal cells, and in vivo on severe combined immunodeficient (SCID) mice. We verified its clinical effect in patients with advanced hormone refractory prostate cancer (HRPC). RESULTS Tranilast inhibited the proliferation of LNCaP, LNCaP-SF, and PC-3 cells in a dose-dependent manner and growth of the tumor formed by inoculation of LNCaP-SF in the dorsal subcutis and in the tibia of castrated SCID mice. Flow cytometry and TUNEL assay revealed induction of cell cycle arrest and apoptosis by tranilast. Tranilast increased expression of proteins involved in induction of cell cycle arrest and apoptosis. Coculture with bone-derived stromal cells induced proliferation of LNCaP-SF cells. Tranilast also suppressed secretion of transforming growth factor Β1 (TGF-Β1) from bone-derived stromal cells, which induced their differentiation. Moreover, tranilast inhibited TGF-Β1-mediated differentiation of bone-derived stromal cells and LNCaP-SF cell migration induced by osteopontin. In the clinical investigation, PSA progression was inhibited in 4 of 16 patients with advanced HRPC. CONCLUSIONS These observations suggest that tranilast may be a useful therapeutic agent for treatment of HRPC via the direct inhibitory effect on cancer cells and suppression of TGF-Β1-associated osteoblastic changes in bone metastasis. Prostate 69:1222–1234, 2009. © 2009 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63038/1/20975_ftp.pd

The Role of RANK-Ligand Inhibition in Cancer: The Story of Denosumab

The bone is a very common site of metastasis in patients with advanced cancer. Skeletal metastases are most common in breast and prostate cancer, but virtually any advanced cancer may disseminate to the bone. On the basis of recent advances in the understanding of bone remodeling processes, denosumab, a fully human monoclonal antibody against RANK-L, has been developed. Phase III clinical trials have demonstrated that denosumab is well tolerated and effective in the treatment of bone loss and prevention of skeletal-related events in patients with bone metastases

RANKL acts directly on RANK-expressing prostate tumor cells and mediates migration and expression of tumor metastasis genes

BACKGROUND Metastases to bone are a frequent complication of human prostate cancer and result in the development of osteoblastic lesions that include an underlying osteoclastic component. Previous studies in rodent models of breast and prostate cancer have established that receptor activator of NF-ΚB ligand (RANKL) inhibition decreases bone lesion development and tumor growth in bone. RANK is essential for osteoclast differentiation, activation, and survival via its expression on osteoclasts and their precursors. RANK expression has also been observed in some tumor cell types such as breast and colon, suggesting that RANKL may play a direct role on tumor cells. METHODS Male CB17 severe combined immunodeficient (SCID) mice were injected with PC3 cells intratibially and treated with either PBS or human osteprotegerin (OPG)-Fc, a RANKL antagonist. The formation of osteolytic lesions was analyzed by X-ray, and local and systemic levels of RANKL and OPG were analyzed. RANK mRNA and protein expression were assessed on multiple prostate cancer cell lines, and events downstream of RANK activation were studied in PC3 cells in vitro. RESULTS OPG-Fc treatment of PC3 tumor-bearing mice decreased lesion formation and tumor burden. Systemic and local levels of RANKL expression were increased in PC3 tumor bearing mice. PC3 cells responded to RANKL by activating multiple signaling pathways which resulted in significant changes in expression of genes involved in osteolysis and migration. RANK activation via RANKL resulted in increased invasion of PC3 cells through a collagen matrix. CONCLUSION These data demonstrate that host stromal RANKL is induced systemically and locally as a result of PC3 prostate tumor growth within the skeleton. RANK is expressed on prostate cancer cells and promotes invasion in a RANKL-dependent manner. Prostate 68: 92–104, 2008. © 2007 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/57344/1/20678_ftp.pd

Osteoprotegerin inhibits bone resorption and prevents tumor development in a xenogenic model of Ewing's sarcoma by inhibiting RANKL

Ewing's sarcoma (ES) associated with high osyeolytic lesions typically arises in the bones of children and adolescents. The development of multi-disciplinary therapy has increased current long-term survival rates to greater than 50% but only 20% for high risk group patients (relapse, metastases, etc.). Among new therapeutic approaches, osteoprotegerin (OPG), an anti-bone resorption molecule may represent a promising candidate to inhibit RANKL-mediated osteolytic component of ES and consequently to limit the tumor development. Xenogenic orthotopic models of Ewing's sarcoma were induced by intra-osseous injection of human TC-71 ES cells. OPG was administered in vivo by non-viral gene transfer using an amphiphilic non ionic block copolymer. ES bearing mice were assigned to controls (no treatment, synthetic vector alone or F68/empty pcDNA3.1 plasmid) and hOPG treated groups. A substantial but not significant inhibition of tumor development was observed in the hOPG group as compared to control groups. Marked bone lesions were revealed by micro-computed tomography analyses in control groups whereas a normal bone microarchitecture was preserved in the hOPG treated group. RANKL over-expressed in ES animal model was expressed by tumor cells rather than by host cells. However, TRAIL present in the tumor microenvironment may interfere with OPG effect on tumor development and bone remodeling via RANKL inhibition. In conclusion, the use of a xenogenic model of Ewing's sarcoma allowed discriminating between the tumor and host cells responsible for the elevation of RANKL production observed in this tumor and demonstrated the relevance of blocking RANKL by OPG as a promising therapy in ES

In vivo real-time imaging of TGF-Β-induced transcriptional activation of the RANK ligand gene promoter in intraosseous prostate cancer

BACKGROUND Current animal models of prostate cancer (CaP) bone metastasis do not allow measurement of either tumor growth in bone over time or activation of gene promoters in intraosseous tumors. To develop these methods, we used bioluminescent imaging (BLI) to determine if expression of receptor activator of NF-ΚB ligand (RANKL), a pro-osteoclastogenic factor that promotes CaP bone metastases, is modulated by the bone matrix protein transforming growth factor-Β (TGF-Β) in vivo. METHODS C4-2B human CaP cells were treated with TGF-Β in vitro and RANKL mRNA and protein production were measured by polymerase chain reaction (PCR) and ELISA, respectively. Then C4-2B cells stably transfected with the RANKL promoter driving luciferase (lux) were injected intra-tibially into severe combined immundeficient (SCID) mice. Tumors were subjected to BLI every 2 weeks for 6 weeks and serum prostate specific antigen (PSA) was measured using ELISA. Vehicle (V), 1,25 dihydroxyvitamin D (VitD), or TGF-Β was administered to mice with established tumors and BLI to measure RANKL promoter activity was performed. Tumors were then subjected to immunohistochemistry for lux and assayed for RANKL mRNA levels. RESULTS TGF-Β induced RANKL protein and mRNA expression and activated the RANKL promoter activity in a dose-dependent manner in vitro. BLI demonstrated an increase in intraosseous tumor size over time, which correlated with serum PSA levels. Administration of TGF-Β and VitD to mice with established intraosseous tumors increased lux activity compared to V. Intratibial tumor RANKL mRNA expression paralleled the increased promoter activity. Immunohistochemistry confirmed the presence of lux in the intraosseous tumors. CONCLUSIONS These results demonstrate the ability to measure intraosseous tumor growth over time and gene promoter activation in an established intraosseous tumor in vivo and also demonstrate that TGF-Β induces activates the RANKL promoter. These results provide a novel method to explore the biology of CaP bone metastases. © 2004 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/34765/1/20019_ftp.pd

The effect of osteoprotegerin administration on the intra-tibial growth of the osteoblastic LuCaP 23.1 prostate cancer xenograft

Osteoprotegerin (OPG) plays a central role in controlling bone resorption. Exogenous administration of OPG has been shown to be effective in preventing osteolysis and limiting the growth of osteolytic metastasis. The objective of this study was to investigate the effects of OPG on osteoblastic prostate cancer (CaP) metastases in an animal model. LuCaP 23.1 cells were injected intra-tibially and Fc-OPG (6.0 mg/kg) was administered subcutaneously three times a week starting either 24 hours prior to cell injection (prevention regimen) or at 4 weeks post-injection (treatment regimen). Changes in bone mineral density at the tumor site were determined by dual x-ray absorptiometry. Tumor growth was monitored by evaluating serum prostate specific antigen (PSA). Fc-OPG did not inhibit establishment of osteoblastic bone lesions of LuCaP 23.1, but it decreased growth of the tumor cells, as determined by decreases in serum PSA levels of 73.0 ± 44.3% ( P < 0.001) and 78.3 ± 25.3% ( P < 0.001) under the treatment and prevention regimens, respectively, compared to the untreated tumor-bearing animals. Administration of Fc-OPG decreased the proliferative index by 35.0% ( P = 0.1838) in the treatment group, and 75.2% ( P = 0.0358) in the prevention group. The results of this study suggest a potential role for OPG in the treatment of established osteoblastic CaP bone metastases.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/42587/1/10585_2004_Article_2869.pd

腎摘除術後の対側腎の代償性肥大と腎機能の変移

腎摘除術後の対側腎の体積と腎機能の変移を検討した.対象は腎細胞癌で腎摘除術を受け, 対側腎に明らかな異常がなく, 当院で少なくとも2年以上経過観察している25例であった.25例中12例で毎年CT検査を受けていた.腎の体積は造影CT上の腎の3方向の径を測定し楕円体体積の公式に当てはめて求めた。対側腎の体積は術後3年目まで増加し, 術前体積(100%)に比べて2～7年後の平均最終体積は120%であった.対側腎の腎摘前の体積と術後の最終体積の間に有意な相関はなかったが, 術前に小さい腎は腎摘後の最終体積比率が大きい傾向にあった.血清クレアチニン値は術後1年目に有意に増加したが, 1年目の値に比べてその後数年の経過で有意に低下した.つまり, 代償性腎肥大と腎機能の改善は術後数年以内に完成されるものの, 腎肥大に比べて血清クレアチニン値の改善は遅れた.この理由として, 術後早期の腎血漿流量の増加に伴って代償性腎肥大は起こるが, 糸球体濾過率の上昇は2-一一3年遅れるため, 上昇していた血清クレアチニン値の低下も遅れたことが考えられた.We studied the changes in the serum creatinine level and the volume of the remaining kidney following nephrectomy using contrast-enhanced compounded tomogram (CT) scans. Twenty-five patients undergoing nephrectomy for renal cell carcinoma without obvious disease in the remaining kidney were carefully followed for a period of at least two years at our hospital. Twelve patients received follow-up CT scans each year after nephrectomy. The ellipsoid volume of the kidney was calculated by measuring the 3-dimensional size on CT scans. The mean relative volume (%) of the remaining kidney increased up to year 3 postoperatively, and the final mean relative volume at varying periods from years 2 to 7 was 120%. Kidneys that were smaller prior to nephrectomy showed a tendency to have a larger final relative volume after nephrectomy, although there was no significant correlation between the kidney volume prior to nephrectomy and at final measurement. The mean serum creatinine level was significantly increased at one year after nephrectomy, but it decreased significantly over time. Therefore, both compensatory renal hypertrophy and improved renal function seemed to be established within several years after nephrectomy. However, the improvement of serum creatinine was delayed compared with the increase of kidney volume. That is, renal plasma flow might be increased early by compensatory renal hypertrophy, followed within a few years by an increase in glomerular filtration and a decrease of serum creatinine