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Advanced solid tumors are exposed to hypoxic conditions over longer periods of time as they grow. Tumor hypoxia is a major factor that induces malignant progression, but most previous studies on tumor hypoxia were performed under short-term hypoxia for up to 72 hours and few studies have focused on tumor response to chronic hypoxic conditions. Here we show a molecular mechanism by which chronic hypoxia promotes invasive behavior in prostate cancer cells. We found that an epithelial-mesenchymal transition (EMT)-driving transcription factor, slug, is specifically upregulated under chronic hypoxia and promotes tumor cell migration and invasion. Unexpectedly, processes associated with EMT, such as loss of E-cadherin, are not observed under chronic hypoxia. Instead, expression of ephrin-B1, a ligand of Eph-related receptor tyrosine kinases, is markedly induced by slug through E-box motifs and promotes cell migration and invasion. Furthermore, slug and ephrin-B1 are highly coexpressed in chronic hypoxic cells of human prostate adenocarcinoma tissues after androgen deprivation, which is known to cause tumor hypoxia. Taken together, these results indicate that chronic hypoxia-induced slug promotes invasive behavior of prostate cancer cells by activating the expression of ephrin-B1. In addition, ephrin-B1 may be a novel therapeutic target in combination with androgen deprivation therapy for aggressive prostate cancer.

We performed Pfannenstiel laparoendoscopic reduced-port bilateral radical nephrectomy on a patient with renal cell carcinoma undergoing hemodialysis. A 4-cm Pfannenstiel incision was made, and a GelPOINT access was inserted. Three trocars were placed through the access platform, and additional 5- and 3-mm trocars were inserted in the umbilicus and paraumbilical area, respectively. After left nephrectomy, right nephrectomy was successfully completed in 401 min, with an estimated blood loss of 70 mL. There were no intraoperative or postoperative complications, and the patient was discharged 10 days postoperatively. The umbilical scar was concealed within the umbilical fold, and the scar from the 3-mm trocar was almost invisible. The Pfannenstiel scar was minimal and concealed by the patient's underwear. Pfannenstiel laparoendoscopic reduced-port simultaneous bilateral radical nephrectomy is a safe and technically feasible procedure that offers great cosmesis for patients with bilateral renal tumors and end-stage renal disease.

Introduction Laparoendoscopic single-site surgery is a recently innovated urologic surgical procedure. Transumbilical laparoendoscopic single-site adrenalectomy (LESS-A) is technically safe and feasible in patients with benign adrenal tumors. To improve patient counseling and informed consent, we evaluated patient-reported postoperative pain, body image, and cosmetic satisfaction after transumbilical LESS-A. Methods We reviewed 24 patients who underwent transumbilical LESS-A and assessed their operative and esthetic outcomes and incisional pain. Incisional pain was evaluated using a 10-point visual analog scale, and the body image and cosmetic satisfaction were measured using a questionnaire that included a body image scale (range, 5–20 points) and a cosmetic scale (range, 3–24 points). Results Pure LESS-A was performed on 10 patients using a multichannel port; an additional 5-mm trocar was used in two obese patients. Supplementary to the single-incision approach, one or two 3-mm ports were used in 12 patients. The mean operative time was 203 min; the mean blood loss was 41 mL. The mean pain visual analog scale scores on postoperative days 1, 3, and 7 were 3.5, 2.2 (P = 0.012), and 1.5 points (P = 0.018), respectively. The mean body image scale and cosmetic scale scores indicating wound satisfaction 1 month after the surgery were 20 and 22 points, respectively. Although one patient had liver injury during surgery, the postoperative course during the 3-month follow-up was uneventful. Conclusion Transumbilical LESS-A confers less postoperative pain and better cosmetic satisfaction than conventional laparoscopic adrenalectomy. Therefore, this procedure could potentially become a standard treatment option for benign adrenal tumors.

Angiopoietin-like protein 4 (ANGPTL4) is a multifunctional protein, playing roles in glucose and lipid metabolism, inflammation, angiogenesis, and tumorigenesis. Recent research suggests that ANGPTL4 is induced by hypoxia and is a useful diagnostic or prognostic marker for various cancers. However, it remains unclear whether ANGPTL4 expression influences prostate cancer. Here we examined the biological and clinical relevance of ANGPTL4 expression in prostate cancer. Firstly we examined ANGPTL4 expression in the prostate cancer cell lines LNCaP and LNCaP/CH incubated at 1% O2 for at least 6 months. We compared cellular proliferation, migration, and ANGPTL4 secretion in a culture medium between these cell lines. In addition, we investigated the effect of various concentrations of recombinant ANGPTL4 protein (rANGPTL4) on cellular proliferation and intracellular signaling pathways. Moreover, we used ANGPTL4 knockdown by RNA interference to investigate the influence of ANGPTL4 expression on these cell lines. Finally, we investigated the correlation between ANGPTL4 expression in prostate cancer specimens and clinicopathological parameters using immunohistochemistry. Our data suggested that the expression of ANGPTL4 in hypoxic conditions was 14.4-fold higher than that in normoxic condition. ANGPTL4 secretion in the culture medium increased 7.0-fold. In addition, rANGPTL4 increased cellular proliferation 1.72-fold via Akt activation. Moreover, ANGPTL4 knockdown decreased cell growth and its secretion by 25.7 and 41.4%, respectively, compared with the control. A multivariate analysis showed that positive ANGPTL4 expression in the resected specimens was an independent prognostic indicator of biochemical recurrence (P=0.03, hazard ratio = 2.02). Our results show that ANGPTL4 is induced by hypoxia and promotes cancer progression via the activated PI3K/Akt pathway. Moreover, ANGPTL4 can be used as a prognostic marker for prostate cancer patients undergoing radical prostatectomy.

Multiple endocrine neoplasia type 2 (MEN2) is an autosomal-dominant cancer syndrome with major components of medullary thyroid carcinoma, pheochromocytoma, and hyperparathyroidism. MEN2B is the most aggressive and rarest of the MEN2 variants. Pheochromocytoma in MEN2 is virtually always located in the adrenal medulla, but MEN2-associated extra-adrenal pheochromocytomas (paraganglioma) are rare. A 59-year-old man who has been diagnosed with MEN2B consulted our hospital for surgical treatment of a 10-mm left adrenal mass and a 30-mm retroperitoneal mass. He had paroxysmal elevations in blood pressure and in urinary metanephrine and vanillylmandelic acid values. Laparoscopic excision of the left adrenal gland and retroperitoneal mass was performed. We experienced an extremely rare case of composite paraganglioma-ganglioneuroma concomitant with adrenal metastasis of medullary thyroid carcinoma in a patient with MEN2B.

We have previously reported that Salvador homologue 1 (SAV1), a component of the Hippo pathway, is significantly down-regulated in high-grade clear cell renal cell carcinoma (ccRCC) due to 14q copy number loss, and that this down-regulation contributes to the proliferation and survival of renal tubular epithelial cells through activation of Yes-associated protein 1 (YAP1), a downstream target of the Hippo pathway. However, the impact of SAV1 loss on the proliferation and survival of kidney cells in vivo remained to be determined. To address this issue, we generated kidney-specific Sav1-knockout (Cdh16-Cre;Sav1(fl/fl) ) mice. Sav1 deficiency enhanced the proliferation of renal tubular epithelial cells in Cdh16-Cre;Sav1(fl/fl) mice, accompanied by nuclear localization of Yap1, suggesting suppression of the Hippo pathway. Sav1 deficiency in renal tubules also caused structural and cellular abnormalities of the epithelial cells, including significant enlargement of their nuclei. Furthermore, Cdh16-Cre;Sav1(fl/fl) mice developed both glomerular and tubular cysts. Although lining cells of the glomerular cysts showed no atypia, those of the tubular cysts showed variations in cell size and nuclear shape, which became more severe as the mice aged. In aged Cdh16-Cre;Sav1(fl/fl) mice, we observed focal disruption of proximal tubules and perivascular lymphocytic infiltration. In conclusion, Sav1 is required for the maintenance of growth, nuclear size and structure of renal tubules under physiological conditions, and its deficiency leads to the acquisition of enhanced proliferation of renal epithelial cells through suppression of Hippo signalling.

Previously, we reported that genomic loss of 14q occurs more frequently in high‐grade than in low‐grade clear cell renal cell carcinomas (ccRCCs), and has a significant impact on the levels of expression of genes located in this region, suggesting that such genes may be involved in the malignant transformation of ccRCCs. Here, we found that six of the genes located in the minimal common region of 14q loss were significantly downregulated in high‐grade ccRCCs due to copy number loss. Using a dataset from The Cancer Genome Atlas Research Network, we found that downregulation of one of these six genes, WDR20, was significantly associated with poorer outcome in patients with ccRCC, suggesting that WDR20 downregulation may be involved in the malignant transformation of ccRCCs. In functional assays, exogenous WDR20 significantly inhibited the growth of RCC cell lines and induced apoptosis. Interestingly, the phosphorylation levels of ERK and protein kinase B/AKT, which reportedly contribute to the malignant phenotype of RCC cells, were clearly reduced by exogenous expression of WDR20. Thus, our data suggest that downregulation of WDR20 due to 14q loss may be involved in the malignant transformation of ccRCCs, in part through activation of the ERK and protein kinase B/AKT pathways.

This study was conducted to clarify the genomic profiles of metastatic clear cell renal cell carcinomas (ccRCCs) and identify the genes responsible for development of metastasis. We analyzed the genomic profiles of 20 cases of primary ccRCC and their corresponding metastases using array-based comparative genomic hybridization, and identified 32 chromosomal regions in which gene copy number alterations were detected more frequently in metastases than in the primary tumors. Among these 32 regions, 9p24.1-p13.3 loss was the most statistically significant alteration. Furthermore, we found that patients with 9p24.1-p13.3 loss in primary tumors exhibited significantly lower rates of recurrence-free and cancer-specific survival, suggesting that 9p loss in the primary tumor is a potential biomarker predicting early recurrence of metastasis. Interestingly, the genomic profiles of primary tumors with 9p loss resembled those of their corresponding metastases, though 9p loss was accumulated in the metastases derived from the primary tumors without 9p loss. Comparison of the mRNA expression levels revealed that 2 of 58 genes located at 9p24.1-p13.3 were downregulated due to gene copy number loss in ccRCCs. An overexpression study of these two genes in ccRCC cell lines revealed that downregulation of NDUFB6 due to loss at 9p24.1-p13.3 may confer a growth advantage on metastatic ccRCC cells. These results were confirmed by analyzing the data of 405 cases of ccRCC obtained from The Cancer Genome Atlas (TCGA). On the basis of our present data, we propose that NDUFB6 is a possible tumor suppressor of metastatic ccRCCs.

Heat shock proteins (HSPs), which are molecular chaperones that stabilize numerous vital proteins, may be attractive targets for cancer therapy. The aim of the present study was to investigate the possible anticancer effect of single or dual targeting of HSP90 and HSP70 and the combination treatment with HSP inhibitors and chemotherapeutic agents in bladder cancer cells. The expression of HSP90 and the anticancer effect of the HSP90 inhibitor 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) coupled with cisplatin, docetaxel, or gemcitabine were examined using immunohistochemistry, quantitative real-time PCR, cell growth, flow cytometry, immunoblots and caspase-3/7 assays. The expression of HSP70 under HSP90 inhibition and the additive effect of HSP70 inhibitor pifithrin-μ (PFT-μ) were examined by the same assays and transmission electron microscopy. HSP90 was highly expressed in bladder cancer tissues and cell lines. 17-AAG enhanced the antiproliferative and apoptotic effects of each chemotherapeutic agent. 17-AAG also suppressed Akt activity but induced the upregulation of HSP70. PFT-μ enhanced the effect of 17-AAG or chemotherapeutic agents; the triple combination of 17-AAG, PFT-μ and a chemotherapeutic agent showed the most significant anticancer effect on the T24 cell line. The combination of 17-AAG and PFT-μ markedly suppressed Akt and Bad activities. With HSP90 suppression, HSP70 overexpression possibly contributes to the avoidance of cell death and HSP70 may be a key molecule for overcoming resistance to the HSP90 inhibitor. The dual targeting of these two chaperones and the combination with conventional anticancer drugs could be a promising therapeutic option for patients with advanced bladder cancer.

β2-microglobulin (β2-m) has become the focus of intense scrutiny since the discovery of its undesirable roles promoting osteomimicry and cancer progression. β2-m is a well-known housekeeping protein that forms complexes with the heavy chain of major histocompatibility complex class I molecules, which are heterodimeric cell surface proteins that present antigenic peptides to cytotoxic T cells. On recognition of foreign peptide antigens on cell surfaces, T cells actively bind and lyse antigen-presenting cancer cells. In addition to its roles in tumor immunity, β2-m has two different functions in cancer cells, either tumor promoting or tumor suppressing, in cancer cell context-dependent manner. Our studies have demonstrated that β2-m is involved extensively in the functional regulation of growth, survival, apoptosis, and even metastasis of cancer cells. We found that β2-m is a soluble growth factor and a pleiotropic signaling molecule which interacts with its receptor, hemochromatosis protein, to modulate epithelial-to-mesenchymal transition (EMT) through iron-responsive pathways. Specific antibodies against β2-m have remarkable tumoricidal activity in cancer, through β2-m action on iron flux, alterations of intracellular reactive oxygen species, DNA damage and repair enzyme activities, β-catenin activation and cadherin switching, and tumor responsiveness to hypoxia. These novel functions of β2-m and β2-m signaling may be common to several solid tumors including human lung, breast, renal, and prostate cancers. Our experimental results could lead to the development of a novel class of antibody-based pharmaceutical agents for cancer growth control. In this review, we briefly summarize the recent data regarding β2-m as a promising new cancer therapeutic target and discuss antagonizing this therapeutic target with antibody therapy for the treatment of localized and disseminated cancers.

INTRODUCTION AND OBJECTIVES: There are more than 200,000 cases of renal cell carcinoma (RCC) each year in the world, accounting for approximately 2% of all cancers. RCC clear cell type (ccRCC) is the most common subtype of RCC and accounts for 75 to 80% of the cases with highest rates of local invasion, development of metastasis and mortality. New target therapy is based on antiangiogenic antibodies and molecules, changing the course of the disease, but the results so far are disappointing. Our aim is to study miRNAs and their target genes related to angiogenesis in ccRCC trying to bring some new knowledge to the molecular pathways related to the disease METHODS: The expression levels of miRNAs miR-99a, 99b, 100; 199a; 106a; 106b; 29a; 29b; 29c; 126; 200a, 200b and their respective target genes: mTOR, HIF1-a, VHL, PDGF, VEGF, VEGFR1 and VEGFR2 were evaluated using qRT-PCR.in snap-frozen tumor tissue samples from 56 patients diagnosed with ccRCC and 5 samples of benign renal tissue as control. The results were related to tumor size, Fuhrman nuclear grade and microvascular invasion, considering the risk criteria proposed by Dall’Oglio et al. (2007). RESULTS: We found an underexpression of the most genes except the VEGFA and PDGF, while the analysis of miRNAs showed underexpression only the miR 199a, 100 and 126. We compared the expression of genes with their possible regulatory miRNAs, and we found that mTOR was underexpressed while miR99a was overexpressed in most samples. This relationship also occurs between VEGFA and miR126 and between miRNAs 106a, 106b, and their target gene VHL. Considering the risk groups the overexpression of miR200b was associated with high-risk patients (p 1⁄4 0.01) and the overexpression of miR126 was associated with lower Fuhrman grade (I-II) (p 1⁄4 0.03). CONCLUSIONS: Our results show that in ccRCC there is an unbalance in the expression of genes and miRNAs related to angiogenesis and cell proliferation and survival. Furthermore with our findings we can speculate the role of miR200b and miR126 in the prognostic of ccRCC. We believe that the relationship between miRNAs and their respective genes should be more profoundly searched as markers and possible therapeutic agents in this neoplasia.

Bone metastasis is one of the predominant causes of cancer lethality. This study demonstrates for the first time how β2-microglobulin (β2-M) supports lethal metastasis in vivo in human prostate, breast, lung, and renal cancer cells. β2-M mediates this process by activating epithelial to mesenchymal transition (EMT) to promote lethal bone and soft tissue metastases in host mice. β2-M interacts with its receptor, hemochromatosis (HFE) protein, to modulate iron responsive pathways in cancer cells. Inhibition of either β2-M or HFE results in reversion of EMT. These results demonstrate the role of β2-M in cancer metastasis and lethality. Thus, β2-M and its downstream signaling pathways are promising prognostic markers of cancer metastases and novel therapeutic targets for cancer therapy. Cancer Res; 71(7); 2600–10. ©2011 AACR.

Background: ST-segment elevation in a structurally normal heart is observed in Brugada- and early repolarization syndrome. The incidence of both syndromes is much higher in males than females. Clinical and basic studies suggest that testosterone plays an important role in ventricular repolarization. Methods and Results: Standard surface 12-lead electrocardiograms recorded in 640 healthy subjects were studied (310 males, 330 females ranging in age from 5 to 89 years) (Study 1). The 3 ST levels (ST-J, -M, and -E) were measured in leads V2 and V5, which are representative of the right and left ventricles, respectively. The effect of androgen-deprivation therapy on the ST segment was also evaluated in 21 prostate cancer patients (Study 2). In both leads, the 3 ST levels were significantly higher in adult males than females (P

A multicenter randomized controlled study was undertaken in order to determine whether epoetin beta (EPO) ameliorates the anemia in aplastic anemia (AA) patients treated with granulocyte colony-stimulating factor (G-CSF). Enrolled patients were randomized into 3 groups: group C receiving G-CSF alone as the control; group L receiving G-CSF and 200 IU/kg of EPO; group H receiving G-CSF and 400 IU/kg of EPO. Throughout the study, the dose and the administration interval of G-CSF were adjusted to maintain neutrophil counts between 1000 and 5000 microliters EPO was administered subcutaneously for 12 wk as the first step in treatment and when favorable effects were observed over this period, treatment was continued for another 12 wk as the second step in treatment. Significant erythroid responses were defined as increases in untransfused hemoglobin values > 1.0 g/dl or > 50% decreases in RBC transfusion requirements over the treatment period. Of 131 patients enrolled, 88 patients allocated to groups L and H were evaluated for toxicity to EPO and 110 were evaluated for erythroid responses. Four of the 31 patients (12.9%) in group C, 6 of the 41 patients (14.6%) of group L, and 14 of the 38 patients (36.8%) of group H showed erythroid responses in the first step in treatment. The erythroid responses of group H were significantly higher than those of the other 2 groups (p < 0.05). The significant effects of EPO were due to erythroid responses in non-severe AA. Responding patients were significantly different from non-responders with regard to disease severity, hemoglobin concentration, reticulocyte count, serum endogenous erythropoietin levels and serum transferrin receptors; non-severe AA patients were more likely to respond to EPO, and responding patients had lower serum EPO and higher hemoglobin concentration, reticulocyte count and serum transferrin receptors than non-responders. The response rate increased in the second step in treatment, suggesting that long-term treatment improved the efficacy of EPO. No serious side-effects were observed. From these results, we conclude that EPO given in combination with G-CSF is a safe and effective alternative for the treatment of anemia of a subset of AA patients.

Solitary fibrous tumor (SFT) is a rare spindle cell neoplasm mainly originated in the pleural cavity. We report here an unusual case of a large SFT in the retroperitoneum. A 27-year-old female complaining of a palpable mass in the right flank with dull pain was admitted to our hospital with the diagnosis of right retroperitoneal tumor. Computed tomography (CT) and magnetic resonance imaging (MRI) showed a large retroperitoneal tumor arising from latissimus dorsi muscle. Surgical findings revealed a partly encapsulated tumor and complete resection of tumor concomitantly with right kidney, 11th and 12th ribs, and diaphragm was performed. Pathological examination demonstrated the tumor to be composed of increased mitotic activity and cellularity of spindle cells with a collagenous matrix. Immunohistochemical staining was positive for CD34, vimentin, and basic fibroblast growth factor (bFGF) and negative for CD31, cytokeratin, desmin, S-100p, smooth muscle actin, Bc1-2, and insulin-like growth factor (IGF) with Ki-67 labeling index of 0.1%. Based on pathological features, diagnosis of SFT in the retroperitoneum was confirmed. To our knowledge, this is the first report of an SFT arising from latissimus dorsi muscle and it is important to include SFT in the differential diagnosis of retroperitoneal tumors that caused considerable diagnostic problems due to its unusual site of origin.

Purpose: β2-Microglobulin (β2M) has been shown to promote osteomimicry and the proliferation of human prostate cancer cells. The objective of this study is to determine the mechanism by which targeting β2M using anti-β2M antibody inhibited growth and induced apoptosis in prostate cancer cells.Experimental Design: Polyclonal and monoclonal β2M antibodies were used to interrupt β2M signaling in human prostate cancer cell lines and the growth of prostate tumors in mice. The effects of the β2M antibody on a survival factor, androgen receptor (AR), and its target gene, prostate-specific antigen (PSA) expression, were investigated in cultured cells and in tumor xenografts.Results: The β2M antibody inhibited growth and promoted apoptosis in both AR-positive and PSA-positive, and AR-negative and PSA-negative, prostate cancer cells via the down-regulation of the AR in AR-positive prostate cancer cells and directly caused apoptosis in AR-negative prostate cancer cells in vitro and in tumor xenografts. The β2M antibody had no effect on AR expression or the growth of normal prostate cells.Conclusions: β2M downstream signaling regulates AR and PSA expression directly in AR-positive prostate cancer cells. In both AR-positive and AR-negative prostate cancer cells, interrupting β2M signaling with the β2M antibody inhibited cancer cell growth and induced its apoptosis. The β2M antibody is a novel and promising therapeutic agent for the treatment of human prostate cancers.

A 45-year-old man on long-term hemodialysis (HD) was incidentally discovered to have a pheochromocytoma and underwent successful resection. This patient was normotensive, and had no symptoms suggesting pheochromocytoma. The plasma concentrations of total adrenomedullin (AM-T) and mature AM (AM-m) were higher than those in normal controls. To elucidate the source of AM, we measured plasma AM levels by immunoradiometric assay before and 3 weeks after surgery in addition to plasma adrenaline, noradrenaline and dopamine. AM expression was also assessed by immunoblot and immunohistochemical analyses on normal adrenal and tumor tissues. After surgery, elevated plasma adrenaline levels returned to the normal range; however, the levels of AM-T and AM-m remained almost the same as the preoperative values. Furthermore, although AM was expressed in both normal adrenal and tumor tissues, the AM expression level was less in tumor. In this case, it was suggested that elevation in plasma AM level might be a factor associated with normotensive blood pressure; however, adrenal pheochromocytoma was not a major source of circulating AM. To our knowledge, this is the first case of pheochromocytoma in patient with HD associated with AM in the literature.

Introduction: The purpose of the present study was to compare the incidence of inguinal hernias after conventional and minilaparotomy (minilap) radical retropubic prostatectomy (RRP). Patients and Methods: In this retrospective study, we review our experience with 70 consecutive patients with prostate cancer who underwent prostatectomy from April 1995 through March 2001. Of these, 35 patients had conventional RRP, and 35 patients had minilap RRP. Results: Conventional RRP and minilap RRP groups were similar in body mass index (mean 24.4 and 23.5), operative time (mean 260 and 241 min), previous lower abdominal operation record (mean 37.1 and 25.7%), and post-prostatectomy anastomotic strictures (mean 11.4 and 14.3%). The volume of the estimated blood loss was significantly less for minilap RRP (mean 1,220 ml) than for conventional RRP (mean 1,666 ml; p = 0.0194). The incidence of postoperative inguinal hernias was 17.1% (6 of 35), 2.9% (1 of 35), and 3.2% (1 of 31) in conventional RRP, minilap RRP, and unoperated groups, respectively. The incidence of inguinal hernias after minilap RRP was significantly lower than after conventional RRP (p = 0.0464). Seven patients with postoperative inguinal hernias had a high incidence of postoperative strictures (42.9%), while 63 patients without hernia had a low incidence (9.5%). There was a significant difference in developing postoperative strictures between patients with hernia and those without (p = 0.0124). While postoperative stricture and operative technique were different in the hernia and hernia-free groups on univariate analysis, multivariate logistic analysis revealed that the operative technique was an independent factor for the occurrence of inguinal hernias (p = 0.0419). Conclusion: Minilap RRP compares favorably with conventional RRP in view of the postoperative inguinal hernia development.

Lymphoepithelioma-like carcinoma (LELC) in the bladder is uncommon with a reported incidence of 0.4%–1.3% of all bladder carcinomas. In Japan, some occurrences of LELC have been reported in the renal pelvis and ureter but only two in the bladder. A bladder tumor was identified in a 70-year-old man suffering from macroscopic hematuria for 2 months. Sections of the transurethral tumor resection showed invasive high-grade urothelial carcinoma. The patient was diagnosed with local invasive bladder tumor, and cystectomy with ileal conduit formation was performed. The final pathological evaluation was predominant LELC with urothelial carcinoma. We present a new case of LELC in the bladder and performed a review of all published cases of LELC in the urinary tract to obtain its characteristics and prognostic guide.

A 64-year-old Japanese man suffering from IgD lambda myeloma and renal failure requiring chronic hemodialysis was treated with thalidomide. Serum IgD concentration was 4,050 mg/dl and myeloma cells constituted 95.6% of nucleated cells in bone marrow at the start of treatment. These parameters improved markedly to 1,590 mg/dl and 22.0%, respectively, in the 4 months immediately prior to his death due to pneumonia. Thalidomide caused peripheral neuropathy and constipation at a dose of 100 mg daily in the first week of treatment, but adverse effects resolved upon dose reduction. Thalidomide represents a valid therapeutic option for some myeloma patients receiving hemodialysis.

Lower pole renal stones are well known to show a poor stone clearance rate after extracorporeal shock wave lithotripsy (ESWL) (Dornier Medical Systems, Marietta, Georgia). In the current study we analyzed several anatomical factors as predictors of lower pole stone clearance that may be used to indicate the usefulness of ESWL in such patients.Between January 1993 and October 2000, 63 patients with a unilateral single lower pole stone of 2 cm. or less were included in the study. Excretory urography was done to determine the lower infundibulopelvic angle, caliceal pelvic height, lower infundibular length and diameter, lower infundibular length-to-diameter ratio and number of lower pole minor calices. Stone-free status was assessed by x-ray.The overall stone clearance rate was 54% (34 of 63 patients). While caliceal pelvic height, lower infundibular diameter, length, length-to-diameter ratio and number of minor calices were different in the stone-free and residual stone groups on univariate analysis, multivariate logistic analysis revealed that the lower infundibular length-to-diameter ratio, diameter and number of minor calices were independent predictors of successful stone clearance. The 13 patients (20.6%) who showed all 3 favorable anatomical factors (lower infundibular length-to-diameter ratio less than 7, diameter greater than 4 mm. and a single minor calix) achieved an impressive 84.6% stone clearance rate. In patients with only 1 or 2 favorable factors the stone clearance rate was still greater than 60%. In contrast, the stone clearance rate was only 6.7% in the 15 patients who showed none of these factors.From this study it is apparent that successful ESWL is highly sensitive to the anatomy of the lower pole of the kidney. If a patient with a lower pole stone has at least 1 of the favorable factors identified in this study, ESWL may be advocated as first line therapy with a greater than 60% prospect of a successful outcome. Other treatment options should be considered in those without any of these predictive factors.

Summary. To investigate the efficacy and safety of granulocyte colony-stimulating factor (G-CSF) in patients with acute myelogenous leukaemia, a multicentre randomized study was performed. From October 1993 to September 1996, 270 patients with newly diagnosed acute myelogenous leukaemia were randomized to G-CSF or control groups after remission induction therapy. The G-CSF group received G-CSF (Filgrastim) from 48 h after the completing chemotherapy until the absolute neutrophil count exceeded 1·5 × 109/l. The control group did not receive G-CSF unless severe infection occurred. There were 245 evaluable patients (120 and 125 in the G-CSF and control groups respectively). The complete remission rate was similar in the G-CSF and control groups (80·8% versus 76·8%), as was the 5-year probability of disease-free survival (34·5% versus 33·6%) and overall survival (42·7% versus 35·6%). Neutrophil recovery was significantly faster in the G-CSF group than in the control group (12 d versus 18 d, P = 0·0001). The median duration of febrile neutropenia was significantly shorter in the G-CSF group than in the control group (3 d versus 4 d, P = 0·0001). In conclusion, prophylactic administration of G-CSF after remission induction therapy for acute myelogenous leukaemia is safe and useful even in patients without infection on completing chemotherapy.

Angiopoietin-like proteins (ANGPTLs), which comprise 7 members (ANGPTL1-ANGPTL7), structurally resemble angiopoietins. We investigated the roles of ANGPTLs in the acquisition of androgen independence and the malignant behavior of human prostate cancer cells. Expression of ANGPTL messenger RNA (mRNA) and proteins were ascertained using RT-qPCR and western blot analysis in human prostate cancer cell lines. Androgen-dependent LNCaP and androgen-independent LNCaP/AI cells, respectively, were cultured in fetal bovine and charcoal-stripped medium. Cell proliferation, androgen dependence, migration and invasion, respectively, were examined under the overexpression and knockdown of ANGPTL2 by transfection of ANGPTL2 cDNA and its small-interfering RNA (siRNA). The effects of exogenous ANGPTL2 and blocking of its receptor, integrin α5β1, were also investigated. Human prostate cancer cell lines predominantly expressed ANGPTL2 among the members. Interrupting ANGPTL2 expression with siRNA suppressed the proliferation, migration and invasion of LNCaP cells. LNCaP/AI cells showed a higher ANGPTL2 expression than that of LNCaP cells. Furthermore, siRNA led to apoptosis of LNCaP/AI cells. The ANGPTL2-overexpressing LNCaP cells markedly increased proliferation, epithelial-to-mesenchymal transition (EMT) and malignant behavior in androgen-deprived medium. The migration rates were increased depending on the concentration of ANGPTL2 recombinant protein and were inhibited by anti-integrin α5β1 antibodies. To the best of our knowledge, this is the first study to elucidate the expression of ANGPTL2 in human prostate cancer cells. ANGPTL2 may be important in the acquisition of androgen independency and tumor progression of prostate cancer in an autocrine and/or paracrine manner via the integrin α5β1 receptor. Targeting ANGPTL2 may therefore be an efficacious therapeutic modality for prostate cancer.

Previously, it has been demonstrated that the neurotrophins and their receptors are present in human prostate tissue, but neither their functional role nor localization is clearly understood. We studied the expression of neurotrophins and their receptors in prostate cancer. Between 1990 and 1999, 48 prostate cancer specimens were obtained from patients undergoing radical prostatectomy, of whom 25 received neoadjuvant hormonal therapy (NHT) and 23 were untreated. The specimens were analyzed immunohistochemically for neurotrophins (nerve growth factor, brain derived neurotrophic factor, neurotrophin 3, neurotrophin 4/5) and their receptors (TrkA, TrkB, TrkC, p75NTR). Immunohistochemical studies revealed that both benign and malignant prostate gland epithelial cells expressed the neurotrophins and their receptors to various degrees, but no obvious immunopositive reaction was observed in stromal cells. In benign epithelial cells, the neurotrophins were localized to secretory cells and the receptors were localized to basal cells. The neurotrophins, TrkA and TrkC were expressed to a similar extent in prostate cancer specimens obtained from patients both with and without NHT. In contrast, the expression of TrkB was down-regulated and the expression of p75NTR was up-regulated in prostate cancer after hormonal therapy. These findings suggest that neurotrophins are secreted by prostate cancer cells in an autocrine fashion. Neurotrophins may be involved, through their receptors, in the escape mechanism from cell death after androgen depletion found in prostate cancer.

Background: We determined the tumor-associated macrophage (TAM) count to investigate its importance in predicting clinical outcome or prognosis in patients with bladder cancer. Methods: The TAM count and microvessel count (MVC) were determined immunohistochemically in 63 patients with bladder cancer, including 40 superficial bladder cancers and 23 invasive bladder cancers. To examine the relationship between TAM count and clinical outcome or prognosis in bladder cancer, cystectomy rates, distant metastasis rates, vascular invasion rates and 5 year survival rates were compared between patients with low (< 67) and high (≥ 67) TAM counts. Results: The TAM count in invasive bladder cancers (154.22 ± 11.98) was significantly higher than in superficial bladder cancers (49.05 ± 7.76; P < 0.0001). The MVC in invasive bladder cancers (71.55 ± 10.44) was also significantly higher than in superficial bladder cancers (47.02 ± 5.57; P < 0.05). There was a positive correlation between TAM count and MVC (r = 0.30; P = 0.02). Immunohistochemical staining using CD68/horseradish peroxidase monoclonal antibody showed more infiltrating cells in invasive than superficial bladder cancers. Patients with a high TAM count (≥ 67) showed significantly higher rates of cystectomy, distant metastasis and vascular invasion than those with a lower TAM count (< 67). The 5 year survival rate estimated using the Kaplan– Meier method was significantly lower in patients with a high TAM count than in those with a low TAM count (P < 0.0001). Conclusions: Our results suggest that determination of TAM count in bladder cancer tissues is of value to predict the clinical outcome or prognosis and to select appropriate treatment strategies in patients with bladder cancer.

In acute leukemia (AL) with a late-appearing Philadelphia (la-Ph) translocation, it is unclear whether these translocations arise from the same molecular event as classical Ph translocations. In order to elucidate the molecular events of la-Ph and subsequent translocations of la-Ph leukemia, we performed molecular analysis on the complex rearrangements, in a cell line, MY, which was established from bone marrow mononuclear cells of a patient with a la-Ph acute biphenotypic leukemia. This la-Ph, expressing an acute lymphoblastic leukemia (ALL)-type BCR/ABL transcript, produces a novel P180BCR/ABL fusion protein reflecting deletion of 174 bases (58 amino acids) encoded by the a2 exon of the ABL gene. An immune complex kinase assay showed that this protein had autophosphorylation activity. Fluorescence in situ hybridization (FISH) in conjunction with G-banding analysis revealed that the initial der(9)t(9;22)(q34;q11) progressed to a der(9)(9pter-->9q34::22q11-->22q13::5q11.2 -->5q15:: 10q23-->10qter) by, first, a three-way translocation among the der(9)t(9;22)(q34;q11), chromosome 5, and the normal chromosome 22, and then a subsequent translocation with chromosome 10. Moreover, both the end-stage leukemic cells of the patient and the MY cell line had another translocation, t(X;12)(p11.2;p13). The 12p breakpoint was located near the ETV6 gene by analysis of pulsed-field gel electrophoresis, but transcription of ETV6 was unaffected. Tumorigenicity analysis indicated that an additional translocation, t(2;3)(p16;q29), may have caused a more malignant clone, because only MY cells with the t(2;3)(p16;q29) were capable of growing subcutaneously in nude mice within 40 days. The molecular events of leukemogenesis and leukemic progression in the present la-Ph AL occurred by accumulation of unique translocations. This cell line, MY, expressing a novel variant P180BCR/ABL protein with a deletion of the a2 exon of the ABL gene, may be useful for elucidating the pathophysiology of this fusion protein and for studying ETV6-related leukemogenesis and t(2;3), as well as the molecular mechanisms of the complex translocations.

The cure rate of acute myeloid leukemia might increase if G-CSF were given concurrently with repeated postremission chemotherapy. However, this therapy might cause severe complications, including depletion of normal hematopoietic progenitors as a long-term toxicity. Thus, we conducted a pilot study of this strategy. Twenty-six acute myeloid leukemia patients in a first complete remission (CR) were treated with two courses of consolidation chemotherapy (10-day BHAC-DMP, consisting of behenoyl cytosine arabinoside, daunorubicin, 6-mercaptopurine and prednisolone) and repeated maintenance-intensification therapy including eight cycles of six-day BHAC-DMP. G-CSF (filgrastim) was administered concurrently with these BHAC-DMP therapies. Toxicity during the therapeutic period was not significant in the study group compared with the historical control, treated with the same regimen without G-CSF. Neutrophil recovery after the consolidation therapy was more rapid in the study group than in the historical control (p = 0.066 and 0.024 for the first and second consolidation courses, respectively). Long-term toxicity, such as cytopenia, has not been seen in eight patients who have remained in CR for a long period (range: 39-58 months). At a median follow-up of 39 months, the predicted rate of 42-month CR duration for these 26 patients was 50% (95% confidence limits: 30% to 71%). We conclude that G-CSF-combined repeated BHAC-DMP postremission therapy is feasible. Full elucidation of the clinical benefit of this strategy will require further study.

Sporadic cases have developed pulmonary toxicity after receiving chemotherapy and granulocyte colony-stimulating factor (G-CSF). However, because such cases received chemotherapy that alone frequently causes pulmonary toxicity, the role of G-CSF in this toxicity has been unclear. CHOP therapy (cyclophosphamide, doxorubicin, vincristine and prednisolone) only slightly induces pulmonary toxicity. However, we observed a considerable incidence of this toxicity in non-Hodgkin's lymphoma subjects receiving CHOP therapy and G-CSF (6 out of 52 subjects, 11.5%). In this cohort, among various characteristics, including the dose and interval of CHOP therapy, only the mean peak leucocyte count (MPLC) with each therapy cycle was associated with development of this toxicity (MPLC > or = 23.0 x 10(9) l(-1), 6 out of 29 cases; MPLC < 23.0 x 10(9) l(-1), 0 out of 23 cases; P = 0.020). These findings suggest that the effect of G-CSF is the main determinant of the pulmonary toxicity in these cases. Because the toxicity was associated with a large MPLC and did not recur in cases readministered G-CSF, an idiosyncratic reaction to G-CSF is unlikely to be the pathogenesis of this toxicity. Thus, lowering the G-CSF dose seems to be useful in the prevention of this toxicity. In all six cases, the time course of manifestation of the toxicity was the same, and early application of high-dose corticosteroid led to cure. This knowledge will be helpful in the care of similar cases. Images Figure 2

症例: 66歳女性. 1967年子宮全摘除. 1987年血液透析導入. 1996年7月下旬頃より右腰部痛, 下腹部痛, 発熱を認め, 腹部CTで右腎に腫瘤性病変を指摘され7月30日当科入院となった. 尿閉, 尿路感染を認め, 抗生物質投与および間歇導尿・膀胱洗浄を続け全身状態の改善を待って右腎摘出術を予定していたが, 8月8日38℃を超える発熱を認めたため膿腎症の診断で経皮的腎瘻術施行. 腎瘻術後は解熱傾向となり全身状態も改善した. 本症例は子宮全摘除術の合併症として神経因性膀胱を生じ, 尿閉, 尿路感染症を合併し, 腎盂腎炎, 膿腎症へと進展したと考えられた.長期透析患者での発熱の原因として尿路感染症を見逃してはならず, また膿腎症を発症した場合には, 経皮的腎瘻術による尿ドレナージを完全に行えば保存的に治療可能と考えられた.

Chronological changes in hematological findings were analyzed in 225 patients with myelodysplastic syndromes (MDS). They were diagnosed between 1990 and 1992. Their hematological findings, i.e. hemoglobin levels, leukocyte and platelet counts, proportions of peripheral blood (PB) blasts and monocytes, and proportion of blasts in bone marrow (BM), were recorded for up to 42 months after diagnosis, when available. BM was examined regularly in only a few patients. Therefore, it was impractical to use the French-American-British Cooperative Group criteria for subtype classification during the disease course. Thus, we used the percentage of PB blasts as the only indicator of stage evolution. We classified the disease into four stages: stage 1, less than 1% PB blasts; stage 2, 1-5% PB blasts; stage 3, 5-30% PB blasts; and stage 4, 30% or more PB blasts. There were 171 patients initially in stage 1, 37 initially in stage 2, and 17 initially in stage 3. Less than half (45%) of the patients initially in stage 1 progressed to stage 2, while 91% of the patients initially in stage 2 and all of the patients initially in stage 3 showed stage evolution. Eight variables, i.e. BM blasts 5% or more, male sex, karyotypic abnormalities, micromegakaryocytes, mononuclear large megakaryocytes, platelet counts 50 x 10(9)/l or higher, abnormal nucleus of granulocytes, and abnormal granules of granulocytes, were found to be significant risk factors for evolution from stage 1 to 2. Evolution from stage 1 to a higher stage within 15 months of diagnosis was associated with impending poor prognosis in most patients. However, of the 67 patients initially in stage 1 who died, 30 did not show stage evolution. Evolution from stage 2 to a higher stage and from stage 3 to stage 4 was also associated with impending poor prognosis. Higher levels of cytopenia were not associated with poorer prognosis in the stage 1 patients. In conclusion, our grading system proved to be useful in evaluating the chronological changes in MDS patients.

A recto-peritoneal fistula is an extremely rare complication after prostate biopsy. We report herein on a peritonitis arising from a recto-peritoneal fistula 5 days after undergoing prostate biopsy. To our knowledge, this is the first case of recto-peritoneal fistula following transperineal needle biopsy of the prostate in the published literature.

There is a paucity of definitive evidence that supports the use of enoxaparin to prevent venous thromboembolism (VTE) after urologic laparoscopic surgery. The purpose of this study was to evaluate the efficacy and safety of postoperative subcutaneous enoxaparin injection in patients who underwent urologic laparoscopic surgery. A total of 63 patients were evaluated from June 2010 to December 2012. All patients received postoperative prophylaxis with enoxaparin (2000 IU twice daily for 5 days). None of the patients treated with enoxaparin developed symptomatic VTE, but two cases (3.2%) of pulmonary embolism were noted before initial enoxaparin administration. Statistically significant differences were observed between the prothrombin time (PT) and activated partial thromboplastin time (APTT) values and D-dimer levels obtained at baseline and on day 7 after surgery; however, the PT and APTT values did not exceed the normal range. In addition, signs of any adverse events were not encountered in any of the patients treated with enoxaparin. The use of enoxaparin immediately after a surgery may confer valuable thromboprophylaxis benefits for urologic laparoscopic surgery.

INTRODUCTION AND OBJECTIVES: Although it is well known that deregulation of VHL-HIF1 pathway is responsible for the carcinogenesis of clear cell renal cell carcinoma (ccRCC), molecular mechanisms responsible for the development of metastasis are still poorly investigated. The first aim of this study is to identify copy number alteration (CNA) that is specifically detected in metastasis but not in primary lesion. The second aim is to identify a gene whose deregulation is responsible for the development of metastasis. METHODS: For the array comparative genomic hybridization (CGH) analysis, genomic DNAs were extracted from the formalin-fixed, paraffin-embedded tissues. Twenty cases of primary ccRCCs and their corresponding metastases were analyzed using 4x44K oligonucleotide CGH array (Agilent Inc.). For the gene expression analysis, total RNA was extracted from frozen samples of 30 primary ccRCCs. Expression levels of the 58 genes were analyzed by qRT-PCR. To investigate the biologic function of candidate genes, RCC cell lines, 786-O and 769-P were used. Cell proliferation, invasiveness and apoptosis were analyzed before and after the infection of lenti-virus encoding candidate genes to the RCC cell lines. RESULTS: By comparing CNAs of primary ccRCCs with their corresponding metastases, we found that gene copy number loss at 9p24.1-p13.3 was more frequently found in metastases than in primary lesions. Out of 58 genes located at 9p24.1-p13.3, we identified 2 genes, NDUFB6 and LRRC19, both of which were down-regulated due to copy number loss. Next, using lenti-virus encoding each gene, we introduced the two genes into 786-O and 769-P cells in which both the 2 genes were down-regulated. We found that, when NDUFB6 was overexpressed in both cell lines, cell proliferation was significantly suppressed (figure shown below), although apoptotic activity and invasion activity were unchanged. CONCLUSIONS: Down-regulation of NDUFB6 caused by gene copy number loss at 9p24.1-p13.3 may bring about growth advantage to metastatic ccRCC cells. We propose that NDUFB6 is a new candidate for a tumor suppressor and that its down-regulation may play an important role in the development of metastasis of ccRCC.

TJ-137 administered to patients with chronic ITP increased the platelet count "slightly" or more in 31.7% of the patients and showed a clinical effect in 40.9% with a rating of "modestly effective" or better. With a low incidence of adverse reactions, TJ-137 is ex pected to be a new drug for the treatment of ITP.

To assess the hypothesis that the plasma soluble interleukin-2 receptor (sIL-2R) level may have predictive value for morbidity/mortality in patients with myelodysplastic syndromes (MDS), we determined in plasma sIL-2R level of 80 MDS patients and examined their subsequent clinical course. Compared with low-risk MDS (refractory anaemia (RA) and RA with ringed sideroblasts) patients and normal subjects, the plasma sIL-2R level was significantly elevated in high-risk MDS (three other MDS subtypes and acute leukaemia following MDS) patients (high-risk MDS versus low-risk MDS, P0.01; high-risk MDS versus normal subjects, P0.01). 14/40 low-risk MDS patients developed at least one of the following during the follow-up period: erythrocyte transfusion dependence, infections requiring hospitalization, disease progression or MDS-related death. The plasma sIL-2R level was higher in these eventful subjects than in event-free low-risk subjects (P0.0001), and all of 10 low-risk subjects with a plasma sIL-2R level540 U/ml experience at least one event. By logistic regression analysis of various parameters in these 40 low-risk subjects, the plasma sIL-2R level was identified as the strongest independent parameter for predicting eventful subjects (P0.0047). The plasma sIL-2R level did not show a predictive value in high-risk MDS. This study revealed that the plasma sIL-2R level is significantly elevated in high-risk MDS and suggested that the plasma sIL-2R level is a valuable predictive factors for the clinical outcome in low-risk MDS.

The efficacy of recombinant human interferon alpha-2b (rh IFN alpha-2b) in the treatment of steroid resistant idiopathic thrombocytopenic purpura (ITP) was studied in 50 cases. Forty-one patients treated with rh IFN alpha-2b three times a week, six of 18 (33.3%) in the low dose group (150 x 10(4)IU: 3 MIU) and four of 20 (20.0%) in the high dose group (300 x 10(4)IU: 3 MIU) responded with platelet counts increasing to above 50 x 10(9)/L. Because of the exacerbation of thrombocytopenia and nasal bleeding, treatment was discontinued within 2 weeks in three patients out of 41 cases. On the other hand, six of nine patients (66.7%) treated with 3 MIU of IFN alpha-2b once a week for 8 weeks showed satisfactory response. Treatment with either administration schedule did not result in sustaining platelet counts above 50 x 10(9)/L for a long time after treatment. The results indicate that once a week administration schedule of rh IFN alpha-2b is more efficacious for platelet counts increasing for short period in patients who failed to respond to steroid and other medications than other schedules. The maintenance of this treatment schedule will allow sustained increased platelet levels, resulting in relief of bleeding tendency, while also being cost effective in comparison with other IFN treatment schedules and achieving better patient compliance without flu-like symptoms.

A 75-year-old Japanese woman with polycythemia vera was admitted to our hospital in January 2003 with suspected pulmonary thromboembolism. After administration of heparin, platelet count decreased from 1,694 x 10(9)/l on admission to 60 x 10(9)/l on hospital day 14. The patient developed acute limb embolism and transient cerebral ischemic attack on days 17 and 25, respectively. Signs and symptoms mimicked those of disseminated intravascular coagulation. Antibodies against heparin and platelet factor 4 complexes were detected in serum, and a diagnosis of heparin-induced thrombocytopenia and thrombosis was made. Argatroban treatment improved thrombocytopenia and hypercoagulable state.

The characteristics of Japanese (JPN) patients with myelodysplastic syndromes (MDS) were investigated in 838 retrospectively collected cases. The median age of the JPN patients was 60 years, about 10 years younger than that in most of the reports based on Western patients. Median survivals were 65 months for refractory anemia (RA), 58 months for RA with ring sideroblasts (RARS), 16 months for RA with an excess of blasts (RAEB), 10 months for RAEB in transformation (RAEBT), and 20 months for chronic myelomonocytic leukemia (CMML). Cumulative leukemia-free rates at final observation were 73% for RA, 79% for RARS, 24% for RAEB, 20% for RAEBT, and 53% for CMML. When low-risk (RA and RARS) patients were divided into two groups, those 40 years of age and older, and those under 40, the cumulative leukemia-free rate was 94% for the younger patients (n = 101), compared with 66% for the older patients (n = 318). The prognostic factors for survival were different from those in Western reports, i.e., variables representing quantitative abnormalities (hemoglobin levels, granulocyte, and platelet counts) were not major prognostic factors, while variables representing qualitative abnormalities (morphological abnormalities in granulocytic and megakaryocytic series cells) were highly significant. Two scoring systems for overall survival and for leukemic transformation were developed, based on multivariate prognostic factor analysis. Neither system included variables representing the degree of cytopenia. Whatever the reason for the different prognostic factors in JPN and Western MDS patients, the use of a scoring system based on Western patients for clinical decision-making in a JPN patient could be misleading, and vice versa.

We report here a case of "splenic lymphoma with villous lymphocytes" (SLVL) which exhibited both B- and T-cell phenotypes and genotypes. The patient was a 73-year-old man. Physical examination revealed splenomegaly and lymphadenopathy. The white blood cell count was 55.2 x 10(9)/L with 70.5% atypical lymphocytes, having cytoplasmic villi, characteristic of SLVL. The atypical cells infiltrated both the red and white pulps. Immunological analysis of the peripheral leukocytes showed both B- and T-cell phenotypes (CD5,CD11c,CD19,CD20,HLA-DR, SmIgM and lambda positive). DNA analysis revealed a dual rearrangement of the immunoglobulin heavy chain gene and T-cell receptor beta gene. SLVL has been identified as a B-cell leukemia with a relatively benign clinical course. This case had both B- and T-cell pheno- and genotypes with a progressive course. To the best of our knowledge, no case of SLVL with dual genotypes has ever been reported.

A 74-year-old woman presenting with bilateral ureteral stricture was referred to our hospital. She had undergone radical hysterectomy and adjuvant irradiation therapy for cervical cancer in 2000. Double-J stents were inserted in both the ureters and replaced at regular intervals. Eighteen months after ureteral stenting, she complained of gross hematuria and was managed with hemostatic agents. During a routine replacement of the right double-J stent, massive bleeding was observed from the urethra which continued intermittently. The source of bleeding was not identified on computed tomography and angiography. We kept her at rest, which reduced the bleeding. However, she required intermittent transfusions. Angiography was performed at the time of bleeding on March 5, 2011. A uretero-internal pudendal artery fistula was found, and coil embolization was performed. Thereafter, hematuria did not recur up to the last followup in July 2011.

Toru Inoue*, Keiko Matsuura, Chisato Nakada, Takeo Nomura, Fuminori Sato, Yufu, Japan; Yoji Nagashima, Yokohama, Japan; Chikara Ohyama, Hirosaki, Japan; Tomonori Habuchi, Akita, Japan; Yasuhiko Tomita, Yamagata, Japan; Satoru Takahashi, Tokyo, Japan; Osamu Ogawa, Kyoto, Japan; Norio Nonomura, Osaka, Japan; Akio Matsubara, Hiroshima, Japan; Masayuki Nakagawa, Kagoshima, Japan; Masatsugu Moriyama, Hiromitsu Mimata, Yufu, Japan

A widespread screening with prostate-specific antigen (PSA) has led increased diagnosis of localized prostate cancer along with a reduction in the proportion of advanced-stage disease at diagnosis. Over the past decade, interest in focal therapy as a less morbid option for the treatment of localized low-risk prostate cancer has recently been renewed due to downward stage migration. Focal therapy stands midway between active surveillance and radical treatments, combining minimal morbidity with cancer control. Several techniques of focal therapy have potential for isolated ablation of a tumor focus with sparing of uninvolved surround tissue demonstrating excellent short-term cancer control and a favorable patient’s quality of life. However, to date, tissue ablation has mostly used for near-whole prostate gland ablation without taking advantage of accompanying the technological capabilities. The available ablative technologies include cryotherapy, high-intensity focused ultrasound (HIFU), and vascular-targeted photodynamic therapy (VTP). Despite the interest in focal therapy, this technology has not yet been a well-established procedure nor provided sufficient data, because of the lack of randomized trial comparing the efficacy and morbidity of the standard treatment options. In this paper we briefly summarize the recent data regarding focal therapy for prostate cancer and these new therapeutic modalities.

The plasma soluble interleukin 2 receptor (sIL-2R) level and its relationships with haematologic and immunologic data were examined in 40 patients with myelodysplastic syndromes (MDS). The plasma sIL-2R level was significantly higher in the high-risk MDS group (refractory anaemia with excess blasts (RAEB), RAEB in transformation and chronic myelomonocytic leukaemia) than in the low-risk MDS group (refractory anaemia (RA) and RA with ringed sideroblasts) or in normal subjects, although there was considerable variation in the plasma sIL-2R level within each MDS group. The plasma sIL-2R level correlated positively with the bone marrow cellularity and bone marrow blast mass, but not with the absolute number of CD25+ lymphocytes. This may support the idea that plasma sIL-2R is derived from malignant MDS cells in the bone marrow. The plasma sIL-2R level correlated negatively with the absolute numbers of the CD8+, CD3-CD16+, and CD3-CD56+ cell populations in freshly isolated lymphocytes, the percentage of CD3-CD56+ cells in lymphokine (interleukin 2)-activated killer (LAK) cells, and the cytotoxicity of LAK cells. We conclude that MDS patients having a high plasma sIL-2R level often have a defect in natural killer and CD8+ T-cells.

Summary. The therapeutic potential of interleukin 2 (IL-2) for myelodsplastic syndromes (MDS) was evaluated in vitro, IL-2-induced lymphokine-activated killer (LAK) cells were prepared from 38 MDS patients and 20 normal subjects. The cytotoxicity of LAK cells against K562 and Raji cell lines and MDS blasts was significantly reduced in high-risk MDS (refractory anaemia with excess blasts (RAEB). RAEB in transformation, and leukaemic transformation of MDS), but was relatively well-preserved in low-risk MDS (refractory anaemia (RA) and RA with ringed sideroblasts). Examination of the immunophenotypes of freshly-isolated lymphocytes showed that the percentage of CD4+ cells in low-risk MDS and the percentage of CD3+, CD4+ and CD8+ cell populations in high-risk MDS was significantly reduced compared with these populations in normal subjects. After cultivation with IL-2, these three cell populations were still reduced in the corresponding MDS groups and the percentage of CD3-CD56+ cells were significantly reduced in high-risk MDS. There was a positive correlation between the percentage of K562 cells lysed by MDS LAK cells and the percentage of CD3-CD56+ lymphocytes in MDS LAK cells. These aberrant lymphocyte subpopulations appeared to explain, at least in part, the reduced LAK cell cytotoxicity in MDS. These results present a possibility that IL-2 and LAK therapies are ineffective for most high-risk MDS patients, whereas they have potential value for low-risk MDS patients whose lymphocyte cytotoxicity is usually preserved.

Inactivation of the deleted in colorectal carcinoma (DCC) tumor suppressor gene has been reported not only in colorectal carcinoma but also in other human malignancies. In order to evaluate the role of the DCC gene in leukemogenesis, we examined DCC expression using the reverse transcriptase-polymerase chain reaction (RT-PCR) method. Expression of the DCC gene was reduced or absent in 10 of 39 (26%) patients with acute myelogenous leukemia (AML), three of 14 (29%) patients with acute lymphocytic leukemia (ALL), seven of 33 (21%) patients with chronic myelogenous leukemia (CML), three of 39 (8%) patients with myelodysplastic syndromes (MDS), and five of nine (56%) patients with overt leukemia progressed from MDS. These findings suggest that inactivation of the DCC gene contributes to some instances of leukemogenesis.

We present here the patient undergoing laparoendoscopic single-site (LESS) retroperitoneal radical nephrectomy while receiving hemodialysis. An 81-year-old man under hemodialysis for 6 years was incidentally discovered to have two left renal masses with acquired cystic disease of the kidney (ACDK). A 4-cm flank incision for GelPort was made. Three trocars were inserted into the retroperitoneum through GelPort. After division of the renal vessels and ureter, the kidney was placed into the extraction bag and was retrieved through flank incision without any extra skin incision. There were no intraoperative and postoperative complications. This procedure offers an effective, minimally invasive therapeutic alternative to the standard laparoscopic technique in high-risk end-stage renal disease patients.

INTRODUCTION AND OBJECTIVES: Distant metastasis is one of the most important prognostic factors of clear cell renal cell carcinoma (ccRCC). To identify genomic copy number alterations (CNAs) responsible for metastasis, we compared genomic profiles between primary lesions of ccRCC and corresponding metastatic lesions using array comparative genomic hybridization (array CGH). METHODS: Genomic DNAs for samples were extracted from formalin fixed paraffin embedded tissues of 19 primary ccRCCs and corresponding metastases. Genomic DNAs for controls were from normal renal cortexes of the same patients. Array CGH was performed using Agilent Whole Human Genome 4x44K Oligo Micro Array. RESULTS: To identify CNAs correlated with metastasis of ccRCC, we compared CNAs of 19 primary lesions and corresponding metastatic lesions. In 9 cases, loss at 9p24.1-p13.3 was detected in both primary and metastatic lesions. While, in 8 of the remaining 10 cases without 9p24.1-p13.3 loss at primary lesions, 9p24.1-p13.3 loss was detected at metastatic lesions. In the remaining 2 of the 10 cases, 9p24.1-p13.3 loss was detected in neither primary nor metastatic lesions. Similar results were detected in terms of 8p12-p11.23 loss. These results indicate that frequencies of losses at 8p12-p11.23 and 9p24.1-p13.3 were significantly higher in metastatic lesions than in primary lesions (p 0.01), leading us to speculate that these CNAs may be added in the process of metastasis. Next, we investigated whether these CNAs are useful to predict metastasis. In primary lesions of 15 cases that were free of metastasis at first diagnosis, 9p24.1-p13.3 loss was detected in 5 cases but undetected in the other 10 cases. Between the 2 groups, we compared the recurrence free survival rate. We found that, in cases with 9p24.1-p13.3 loss at primary lesion, metastasis tends to occur earlier than those without 9p24.1-p13.3 loss at primary lesions (p 0.05). While, there was no significant difference in terms of 8p12-p11.23 loss. These results suggest that the presence of 9p24.1p13.3 loss at primary lesion may be a predictive indicator of metastasis. CONCLUSIONS: Genomic losses at 8p12-p11.23 and 9p24.1p13.3 are correlated with metastases of ccRCCs. Investigation of the presence or absence of loss at 9p24.1-p13.3 may be useful as an indicator to predict metastasis of ccRCC.