The neutrophil-lymphocyte ratio has a role in predicting the effectiveness of nivolumab in Japanese patients with metastatic renal cell carcinoma: a multi-institutional retrospective study.

BACKGROUND: The neutrophil-lymphocyte ratio (NLR) is a well-known prognostic marker in various cancers. However, its role as a predictive marker for the effectiveness of nivolumab in patients with metastatic RCC (mRCC) remains unclear. We evaluated the relationships between the NLR and progression-free survival (PFS) or overall survival (OS) in mRCC patients treated with nivolumab. METHODS: The data of 52 mRCC patients who received nivolumab therapy were collected from seven institutes and evaluated. The median follow-up period from treatment with nivolumab was 25.2 months (IQR 15.5-33.2). RESULTS: The median duration of nivolumab therapy was 7.1 months (IQR 2.9-24.4). The objective response rate was 25% and the 1- and 2-year PFS rates were 46.2 and 25.2%, respectively. The median NLR values at baseline and 4 weeks were 3.7 (IQR 2.7-5.1) and 3.3 (IQR 2.4-5.7), respectively. In the multivariate analysis, an NLR of ≥3 at 4 weeks was an independent predictor of PFS (P = 0.013) and OS (P = 0.034). The 1-year PFS of patients with an NLR of < 3 at 4 weeks was better than that of those with an NLR of ≥3 (75% versus 29%, P = 0.011). The 1-year OS of patients with an NLR of < 3 at 4 weeks was also better than that of those with an NLR of ≥3 (95% versus 71%, P = 0.020). CONCLUSIONS: Although the baseline NLR was not associated with PFS or OS, an NLR of ≥3 at 4 weeks after the initiation of therapy might be a robust predictor of poor PFS and OS in mRCC patients undergoing sequential treatment with nivolumab.

[A case report of ureteropelvic junction obstruction and multiple renal stones associated with nutcracker syndrome].

A 20 year-old man presented to emergency room with severe left-sided flank pain. Urinalysis showed hematuria and he was referred to the urology department. KUB, DIP and retrograde pyelography (RP) revealed multiple renal stones, left hydronephrosis (grade 2) and ureteropelvic junction obstruction (UPJO). Abdominal CT revealed shortened nutcracker distance and renal angiography showed left renal vein hypertension. From these findings, diagnosis of nutcracker syndrome was made. Transposition of the left renal vein, dismembered pyeloplasty and left pyelolithotomy were performed simultaneously. 2 months after the procedure, his symptom and hematuria disappeared. 3 months after the procedure, DIP revealed improvement of hydronephrosis (grade 1) and CT showed elongation of nutcracker distance. In 12 months follow-up, there was no recurrence of symptom and hydonephrosis. To the best our knowledge, there has been no report of UPJO associated with nutcracker syndrome and the simultaneous treatment for the both diseases.

Detection of sentinel node micrometastasis by step section and immunohistochemistry in patients with prostate cancer.

PURPOSE: The role of step section and immunohistochemistry for diagnosing sentinel node micrometastases and the sentinel node concept in patients with prostate cancer was investigated. In patients administered neoadjuvant hormone therapy its influence on the sentinel node concept and metastasis diagnosis was also investigated. MATERIALS AND METHODS: Of 62 patients without metastasis enrolled in our study 42 were eligible for analysis. The prostate was injected with the radioactive tracer (99m)technetium phytate 5 to 6 hours before surgery. A planar image and a fusion image with x-ray computerized tomography and single photon emission computerized tomography were obtained 3 hours after tracer injection. Extended lymph node dissection and lymphatic mapping were performed to verify the sentinel node concept. Lymph node metastasis was histologically confirmed by routine hematoxylin and eosin, and thereafter by immunohistochemistry using 250 mum step-sectioned slides. RESULTS: The mean number of dissected lymph nodes was 26.3 per patient. Hot nodes were noted in 41 of 42 patients. The sensitivity and specificity of hot node prediction of lymph node metastasis were 92.3% and 100%, respectively. On routine hematoxylin and eosin examination lymph node metastases were found in 4 of 27 patients with and in 4 of 15 without neoadjuvant hormone therapy. Step section and immunohistochemistry identified micrometastasis in 5 more patients with neoadjuvant hormone therapy. CONCLUSIONS: The validity of the sentinel node concept in conjunction with the detection of micrometastases was considered to be high. Furthermore, it was suggested that the efficacy of metastasis diagnosis may also be enhanced, especially in patients receiving neoadjuvant hormone therapy.

Durability of working channel in flexible ureteroscopes when inserting ureteroscopic devices.

PURPOSE: We studied the physical damage to the working channel of flexible ureteroscopes caused by insertion of various accessories. A procedure was developed to avoid channel damage. MATERIALS AND METHODS: An experimental model representing a flexible ureteroscope was prepared, and damage to its working channel was evaluated by inserting instruments through it. Deflection angles of the channel were changed from 0 degrees to 120 degrees, and each device was inserted and removed 100 times for each selected angle of the channel. Any induced pinholes were identified by an air-leak test. Also, the inside of the channel was inspected with an extremely fine fiberscope. RESULTS: Insertions of 3F biopsy forceps or a 2.4F Nitinol stone-retrieval device caused only slight damage to the model channel, even when the deflection angle was 120 degrees. However, the tips of 200- or 250-microm holmium laser fibers shaved the inner surface of the channel at 60 degrees of deflection, and at 120 degrees, the laser fiber either penetrated the channel or could not be advanced because of resistance by the channel wall. When the laser fiber was inserted within a protective tube, the channel was never damaged, even when the deflection angle was 120 degrees. CONCLUSIONS: When devices are inserted into the working channel of a flexible ureteroscope, damage to the wall depends on the kind of device and deflection angle. Harm could be avoided by inserting the devices, especially laser probes, within a protective tube.

Fusion of SPECT and multidetector CT images for accurate localization of pelvic sentinel lymph nodes in prostate cancer patients.

OBJECTIVE: The present study was performed to investigate the feasibility of fusion of images obtained by SPECT and multidetector CT (MDCT) for the accurate localization of sentinel lymph nodes in prostate cancer patients. METHODS: To facilitate the fusion of both SPECT and CT images, a pelvic MDCT scan was performed with 3 markers of small plastic bullets attached to the skin over the bilateral iliac crests and the ventral midline at the same height. SPECT was performed after the same locations were marked with needle caps containing (99m)Tc-pertechnetate. The images were superimposed by use of free software (MRIcro). The results of hot lymph node detection with fusion images were compared with those of surgery. RESULTS: The images could be successfully superimposed for all 11 patients examined. Surgeons accurately confirmed 27 (87.1%) of 31 regional lymph nodes on fusion images. CONCLUSION: Fusion of SPECT and MDCT images is useful for the precise localization of sentinel lymph nodes in prostate cancer patients.

[Sentinel lymph node concept in prostate cancer].

A sentinel node (SN) validation study using a radioactive tracer and back-up extended pelvic lymph node (LN) dissection was performed in 40 patients with non-metastatic prostate cancer (PCa). The results of the study were favorable with sensitivity, specificity, and accuracy of SN biopsies revealed 90%, 100% and 97.5%, respectively. Based on our promising results to date, we examined the utility of SN navigation surgery (SNNS) in patients with LN metastasis probability of 10% or less on Partin tables. Endoscopic mini-laparotomy surgery was applied to our SN biopsies in 9 patients with clinically localized PCa. SNs were successfully resected in 7 of these patients. Endoscopic minilaparotomy SNNS is a less invasive form of radical surgery for prostate cancer with accurate diagnosis of LN status.

[Application of sentinel node navigation surgery to prostate cancer].

A sentinel node (SN) validation study using a radioactive tracer and back-up extended pelvic lymph node (LN) dissection was performed in 40 patients with non-metastatic prostate cancer (PCa). The results of the study were favorable, with sensitivity, specificity, and accuracy of SN biopsies revealed 90%, 100%, and 97.5%, respectively. Although 1 patient had false negative LNs, the SN concept was still validated because extensive LN metastasis disrupted the physiological lymphatic flow in this case. Based on our promising results to date, we examined the utility of SN navigation surgery (SNNS) in patients with LN metastasis probability of 10% or less on Partin tables. Endoscopic minilaparotomy surgery, established by Kihara et al., was applied to our SN biopsies in 9 patients with clinically localized PCa. SNs were successfully resected in 7 of these patients. Limited pelvic LN dissection was performed in 3 patients, including 1 patient with LN metastasis. SN biopsy and radical prostatectomy were performed via a 5-cm lower abdominal incision. In summary, endoscopic minilaparotomy SNNS is a less invasive form of radical surgery for PCa that offers accurate diagnosis of LN status.

In vitro chemosensitivity test for human genito-urinary tumors using collagen gel matrix.

BACKGROUND: Although the aim of chemosensitivity tests is to predict the efficacy of anticancer agents for individual patients, no generally accepted assay has been established. METHODS: A chemosensitivity test was conducted for solid tumors with an organ culture system using collagen gel matrix (CGM). Seventy-five samples of transitional cell carcinoma (TCC), 20 of germ cell tumor (GCT) and 13 of renal cell carcinoma (RCC) were used for the chemosensitivity test, and 20 patients were treated with anticancer drugs on the basis of the test results. RESULTS: Positive rates of anticancer drugs for the 75 TCC samples were 64.9% for carboplatin, 63.4% for cisplatin, 32.1% for etoposide, 19.7% for THP-adriamycin, 16.7% for vinblastine, and 12.3% for methotrexate, indicating that positive rates of the latter three agents consisting of an MVAC regimen were unexpectedly low. The GCT had higher positive rates than the other cancers while RCC had the lowest. In 20 eligible patients (seven patients with bladder tumors and 13 with GCT), the true positive and true negative rates were 42% (5/12) and 75% (6/8), respectively, and the sensitivity and specificity were 71% (5/7) and 46% (6/13), resulting in a 55% (11/20) accurate predictive value. CONCLUSION: Although predictive accuracy was moderate when combination chemotherapy was used, information about chemosensitivity may have some beneficial effect on the treatment of patients with invasive bladder cancer or advanced GCT, because insensitive drugs detected by the test could be deleted or replaced with more sensitive ones.

Inverse correlation of microvessel density with metastasis and prognosis in renal cell carcinoma.

BACKGROUND: Although a correlation between microvessel density (MVD) and tumor aggressiveness has been established for several malignancies, the data for renal cell carcinoma (RCC) is conflicting. In order to clarify the significance of MVD, we investigated the relationships between MVD and tumor stage, grade, size, occurrence of metastasis and patient survival. METHODS: Tumor specimens from 70 patients with primary renal cell carcinoma were examined by immunohistochemical staining for CD34. RESULTS: There was a tendency for MVD to decrease from G1 to G3 tumors or from stage T1 to T3 tumors, although this was not statistically significant. However, the MVD for 56 non-metastatic and 14 metastatic tumors were significantly different (P = 0.005) at 109 +/- 67 and 58 +/- 35 per x400 field (mean +/- SD), respectively. Microvessel density for 36 large and 34 small tumors was also significantly different (P < 0.0001) at 48 +/- 22 and 142 +/- 54 per x400 field, respectively. The survival rate of patients with small, low grade and hypervascular tumors was significantly higher than that of patients with large (P = 0.0015), high grade (P = 0.05) or low MVD (P = 0.039) tumors. Cox proportional hazards regression analysis showed that tumor grade and size emerged as independent prognostic factors. CONCLUSION: High MVD in RCC was inversely associated with tumor aggressiveness, but MVD was not the independent prognostic factor.

Retrospective study on stage B prostate cancer in the Hokuriku District, Japan.

BACKGROUND: The present study was conducted to investigate how patients with clinically localized prostate cancer were treated in the Hokuriku District, Japan. METHODS: Medical records of 536 patients with stage B prostate cancer were retrospectively reviewed. The patients were diagnosed and treated at four university hospitals and 32 collaborating hospitals in the Hokuriku District. RESULTS: Because their medical records were incomplete and/or they not available for follow up, 79 cases were excluded from this study. Conservative treatment with hormone therapy was used for 248 cases. Radical prostatectomy was performed in 199 cases, only 27 of whom underwent surgical monotherapy. There was no significant difference in disease-specific survival rates between the hormone (69.0%) and surgery group (83.2%) after 110 months. Results of the analysis of disease-specific survival rates according to histologic grade showed that patients with poorly differentiated cancers treated with hormone therapy were the only subset with significant differences when compared against the other patients. CONCLUSION: The value of prostatectomy alone or added was marginal in terms of survival. Only patients with poorly differentiated cancer might benefit from prostatectomy.

Bilateral epididymal sarcoidosis presenting without radiographic evidence of intrathoracic lesion: Review of sarcoidosis involving the male reproductive tract.

Sarcoidosis is a multisystem disorder that rarely involves the genitourinary tract. To date, only 59 cases of histologically proven sarcoidosis involving the male reproductive tract have been reported in the literature. We present here a case of bilateral epididymal sarcoidosis without radiographic evidence of intrathoracic lesion. A 46-year-old man presented with a one-week history of painless bilateral scrotal swellings. Physical examination detected multiple elastic firm nodules on both sides of the scrotum which showed no tenderness. The nodules seemed to involve the entire bilateral epididymides. Some irregularly shaped hypoechoic masses in the bilateral epididymides were identified on gray scale ultrasonography. On magnetic resonance images, the bilateral epididymides were seen to be enlarged, heterogeneous and nodular without any signs of testicular involvement. The lesion showed a slightly high signal intensity on the T2-weighted image. Pathological evaluation following bilateral epididymectomy found non-caseating epithelioid cell granulomas with giant cells in epididymal tissue, thus confirming a diagnosis of sarcoidosis. Gallium-67 scanning showed additional small hot spots in the anterior chest wall and extremities. Open biopsy of a superficial papular lesion in the dermis of the right upper arm was performed and pathological findings indicated sarcoid granulomas. This report also includes a review of the literature pertaining to sarcoidosis of the male reproductive tract.

Validity of sentinel lymph node concept for patients with prostate cancer.

PURPOSE: We investigated the feasibility and validity of the sentinel lymph node concept for patients with prostate cancer. MATERIALS AND METHODS: A total of 24 patients (mean age 68.1 years) with prostate cancer but without detectable distant metastases were enrolled in this study. Radioactive tracer (technetium labeled phytate) was injected into the prostate 5 to 6 hours before surgery. Preoperative lymphoscintigraphy was viewed, and in vivo and ex vivo gamma probing was performed during the surgery, which included backup extended lymph node dissection. Radioactivity of the excised lymph nodes was measured and validated with an autowell scintillation counter. RESULTS: Radioactive positive (hot) nodes were identified in 17 of the 24 (70.8%) patients by lymphoscintigraphy, in 21 of 24 (87.5%) patients by in vivo probing and in 23 of 24 (95.8%) patients by ex vivo probing. On an individual basis the numbers of hot nodes identified by lymphoscintigraphy and in vivo probing were low (40% and 36%, respectively) compared to the high detection rate for ex vivo probing (91%). CONCLUSIONS: Although sentinel lymph nodes can be used for prostate cancer, detailed lymph node mapping and extended dissection backup are currently needed. It is also important to establish novel procedures for accurate and complete removal of all hot nodes.

The adrenal androgen androstenediol is present in prostate cancer tissue after androgen deprivation therapy and activates mutated androgen receptor.

Despite an initial response to androgen deprivation therapy, prostate cancer (PCa) progresses eventually from an androgen-dependent to an androgen-independent phenotype. One of the mechanisms of relapse is antiandrogen withdrawal phenomenon caused by mutation of 877th amino acid of androgen receptor (AR). In the present study, we established a method to measure the concentration of androstenediol (adiol) in prostate tissue. We found that adiol maintains a high concentration in PCa tissue even after androgen deprivation therapy. Furthermore, adiol is a stronger activator of mutant AR in LNCaP PCa cells and induces more cell proliferation, prostate-specific antigen (PSA) mRNA expression, and PSA promoter than dihydrotestosterone (DHT). Because antiandrogen, bicalutamide, blocked adiol activity in LNCaP cells, it was suggested that adiol effect was mediated through AR. However, high concentration of bicalutamide was necessary to block completely adiol activity. These effects were specific to LNCaP cells because adiol had less effect in PC-3 PCa cells transfected with wild-type AR than DHT and had similar effect in PC-3 cells transfected with mutant AR. The mechanism that adiol activates mutant AR in LNCaP cells did not result from the increased affinity to mutant AR or from AR's association with coactivator ARA70. However, low concentration of adiol induced more AR nuclear translocation than DHT in LNCaP cells and not PC-3 cells transfected with AR. These results indicate that adiol may cause the progression of PCa even after hormone therapy.

Comparison of two in vivo models for prostate cancer: orthotopic and intratesticular inoculation of LNCaP or PC-3 cells.

BACKGROUND: The critical events in the clinical course of prostate cancer are the occurrence of metastasis and the induction of the hormone-refractory status of the disease. In order to investigate the factors responsible for these events, we need appropriate in vivo models. MATERIALS AND METHODS: Orthotopic and intratesticular models were created by the injection of LNCaP cells or PC-3 cells into the prostate or testis of severe combined immunodeficient mice. RESULTS: LNCaP cells in the intratesticular model showed a higher incidence of tumor formation and lymph node metastasis when compared with those in the orthotopic model, while PC-3 cells were highly tumorigenic and metastastic in both models. A high concentration of androgens might play a role in tumor aggressiveness of LNCaP cells, given that enhanced mRNA expressions of integrin alphaV and vascular endothelial growth factor was induced by dehydrotestosterone administration in vitro. The high expression of metastasis-related genes, including the urokinase plasminogen activator system, metalloproteinases and vascular endothelial growth factor-C, might be attributed to the high metastatic potential in both models. Interestingly, testicular xenografts of LNCaP cells were able to survive on the subcutis back of castrated male mice as well female mice. CONCLUSIONS: Intratesticular models of prostate cancer appear to be suitable for studying the mechanisms of metastasis and for evaluating various treatment strategies.

New targets for therapy in prostate cancer: modulation of stromal-epithelial interactions.

Changes in genomic and phenotypic expression of progressing prostate tumors and their stroma occur in a dynamic fashion based on bidirectional signaling from stromal-epithelial interactions. These interactions may underlie the ability of prostate cancer cells to survive and proliferate in the prostate and bone. By investigating the phenotypic and genotypic changes of stromal cells adjacent to cancer cells and the reciprocal changes of cancer cells, novel molecular markers may be developed to diagnose cancer earlier before pathologic appearance of cancer cells at the primary site. Attacking epithelial and stromal elements together is a unique approach to both localized and metastatic prostate cancer therapy. Co-targeting both tumor cells and stroma requires identifying a reliable tumor and tissue-specific cis-DNA element, such as osteocalcin (OC) promoter. OC expression is elevated in prostate tumor cells and in prostate and bone stromal cells interdigitating with both localized and metastatic prostate epithelium. We have previously designed an adenovirus-based therapeutic gene vehicle and demonstrated that a replication-competent adenoviral vector (Ad vector) is highly efficient in blocking the growth of cancer cells in culture, including cells without androgen receptor as well as cells that do or do not make prostate-specific antigen. In vivo, intravenous administration of an Ad-OC vector was effective against preexisting human prostate cancer subcutaneous and bone xenografts. The addition of vitamin D(3) enhanced further viral replication at target sites. Co-targeting tumor cells and stroma using systemic Ad vector is a viable and promising option for treatment of both localized and metastatic prostate cancer.

Gene therapy for prostate cancer using the cytosine deaminase/uracil phosphoribosyltransferase suicide system.

BACKGROUND: Cytosine deaminase (CD) activates prodrug 5-FC to 5-FU and is used for suicide gene therapy (the CD/5-FC system). E. coli uracil phosphoribosyltransferase (UPRT) is a pyrimidine salvage enzyme that directly converts 5-FU into 5-fluorouridine monophosphate and improves the antitumoral effect of 5-FU. This study demonstrates the effectiveness of transduction of the UPRT gene in addition to CD/5-FC cancer suicide gene therapy. METHODS: We investigated a combined suicide gene transduction therapy for human hormone independent prostate cancer cell line DU145 using two separate adenovirus vectors expressing the E. coli CD and E. coli UPRT genes and systemic 5-FC administration (the CD+UPRT/5-FC system). RESULTS: Cells transfected with AdCA-UPRT showed approximately 57 times lower IC50 to 5-FU compared with those transfected with AdCA-LacZ. Furthermore, cells transfected with AdCA-CD and AdCA-UPRT proved to be more sensitive to 5-FC compared with those transfected with AdCA-CD. Intratumoral injection of AdCA-CD and AdCA-UPRT drastically suppressed the growth of tumors which had generated from DU145 cells inoculated into athymic (nude) mice compared with those injected with AdCA-LacZ or AdCA-LacZ and AdCA-CD. CONCLUSIONS: These results suggest that the CD+UPRT/5-FC system could be a powerful factor in human prostate cancer suicide gene therapy.

Antitumor effect of reduction of 150-kDa oxygen-regulated protein expression on human prostate cancer cells.

BACKGROUND: The 150-kDa oxygen-regulated protein ORP150, a new member of the heat shock protein family that functions as a molecular chaperone in the endoplasmic reticulum, was found to increase in infiltrating cancer cells. Since enhancement of ORP150 expression and the presence of vascular endothelial growth factor (VEGF) in human prostate cancer glands were immunohistochemically demonstrated, we examined whether transduced antisense ORP150 cDNA can reduce angiogenicity and tumorigenicity through suppression of VEGF secretion. METHODS: Human prostate cancer specimens were immunohistochemically stained with fluorescein isothiocyanate (FITC) for ORP150 or vascular endothelial growth factor (VEGF). An adenovirus vector (Ad) carrying antisense ORP150 cDNA (AdCA-Antisense ORP150) was constructed and infected to prostate cancer DU145 cells. Expression of ORP150 in the cells was analyzed with western blotting and secretion of VEGF into the supernatant with an enzyme-linked immunoabsorbent assay (ELISA). Angiogenicity was evaluated by chorioallantoic membrane (CAM) assay. A nude mouse xenograft model was used to examine tumorigenicity. RESULTS: Immunohistochemical study proved that the expression of ORP150 and VEGF was enhanced in the cytoplasm of prostate cancer cells. The Ad showed 100% transduction efficiency and minimum cytotoxicity when the cells were infected at a multiplicity of infection (MOI) of 20 for 24 h. Expression of ORP150 was substantially reduced by the antisense treatment. Secretion of VEGF into the culture supernatant was reduced to 30%. Consequently, the CAM assay showed relatively low angiogenicity, while marked suppression of tumor formation was observed in the xenograft model. CONCLUSION: Adenoviral-mediated antisense ORP150 cDNA transfer is well worth considering as an option for prostate cancer gene therapy.