Comparison of the Perioperative and Postoperative Outcomes of Ileal Conduit and Cutaneous Ureterostomy: A Propensity Score-Matched Analysis.

INTRODUCTION: To compare perioperative and postoperative outcomes related to urinary diversion (UD) between ileal conduit and cutaneous ureterostomy following open radical cystectomy (ORC). METHODS: This retrospective study included 232 patients with bladder cancer who underwent ORC and subsequent UD (ileal conduit, n = 123; cutaneous ureterostomy, n = 109) at Kobe University and related hospitals between January 2007 and December 2016. A propensity score method was used to adjust the preoperative status of the two groups, and the perioperative and postoperative outcomes were compared between matched cohorts. In addition, we evaluated several factors predicting renal deterioration. RESULTS: In the matched cohorts, 87 patients were included in each group. While the operative time and postoperative fasting periods were significantly longer in patients with ileal conduit in comparison to those with cutaneous ureterostomy (both p < 0.001), there were no differences in blood loss or duration of hospitalization. Although the incidence of grade ≥III perioperative complications was similar between the two groups, the incidence of postoperative recurrent pyelonephritis in the cutaneous ureterostomy group was significantly higher than that in the ileal conduit group (25.3 and 11.4%, respectively; p = 0.030), and cutaneous ureterostomy was identified as a significant predictor of a decrease in the estimated glomerular filtration rate with an odds ratio of 2.13 (95% confidence interval, 1.19-3.85; p = 0.010). CONCLUSIONS: The perioperative safety of ileal conduit was comparable to that of cutaneous ureterostomy, and cutaneous ureterostomy was a significant risk factor for pyelonephritis and subsequent renal deterioration, suggesting that ileal conduit may be preferable to cutaneous ureterostomy.

Long-term changes in renal function outcomes following radical cystectomy and urinary diversion.

BACKGROUND: We analyzed long-term changes in the renal function of patients undergoing radical cystectomy and urinary diversion (UD). METHODS: This study included 169 patients who underwent radical cystectomy and UD (42, cutaneous ureterostomy; 40, ileal conduit; 87, neobladder substitution), and were followed for at least 60 months (median 106 months). Renal deterioration was defined as a >25 % decrease in the estimated glomerular filtration rate (eGFR) relative to that prior to surgery. We determined the associations between several parameters and postoperative renal deterioration. RESULTS: Despite the significantly younger age and more favorable renal function of patients with neobladder substitution than of those with other types of UD, no significant differences were observed in the remaining preoperative clinical parameters among the three different UD groups. The mean eGFR of the 169 patients decreased from 69.6 to 55.9 mL/min/1.73 m(2), and renal deterioration was observed in 24 (57.1 %), 20 (50.0 %) and 34 (39.0 %) patients in the cutaneous ureterostomy, ileal conduit and neobladder substitution groups, respectively. Multivariate analysis of several parameters identified the presence of baseline hypertension and an episode of acute pyelonephritis, but not the type of UD, as significant predictors of postoperative renal deterioration. CONCLUSIONS: The incidence of renal deterioration was comparatively high following radical cystectomy, irrespective of the type of UD. Special attention should be paid to the long-term preservation of renal function in these patients, particularly those with hypertension and/or episodes of acute pyelonephritis.

Impact of sorafenib on health-related quality of life in Japanese patients with metastatic renal cell carcinoma: a prospective evaluation.

OBJECTIVE: To characterize the impact of sorafenib treatment on health-related quality of life (HRQL) in Japanese patients with mRCC. PATIENTS AND METHODS: We performed a prospective observational study including 85 consecutive patients undergoing radical nephrectomy who were diagnosed as having mRCC refractory to cytokine therapy and subsequently treated with sorafenib for at least 3 months. HRQL in these patients was assessed using the Medical Outcomes Study 36-Item Short Form (SF-36). RESULTS: Before treatment all eight scores in the 85 patients were significantly inferior to those in the age-matched control population in Japan. Three months after sorafenib treatment, one score (mental health) in the 85 patients was significantly higher than what it was before treatment. Three scores (body pain, role limitations because of emotional problems, mental health) in patients who had some degree of tumour shrinkage were significantly better than those in the remaining patients, while there were no significant differences in all but one score (social function) between patients with and without severe AEs. Furthermore, there were no significant differences in any scores 3, 6 and 12 months after sorafenib treatment in 26 patients who could be followed for at least 12 months. CONCLUSIONS: Despite non-randomized study including a comparatively small number of patients, the findings of the present study suggest that sorafenib treatment may not impair HRQL in patients with mRCC, and HRQL in patients receiving sorafenib is likely to be affected by the efficacy rather than AEs during treatment.

Experience with various types of orthotopic neobladder in Japanese men: long-term follow-up.

INTRODUCTION: The objective of this study was to review the long-term outcomes of orthotopic neobladder (NB) creation. MATERIALS AND METHODS: This study included 235 Japanese men who underwent NB reconstruction after radical cystectomy and were followed for at least 3 years. The types of NB used in this series were Studer, Reddy, Hautmann and Mainz NB in 136, 51, 32 and 16, respectively. RESULTS: Early and late complications occurred in 70 and 33 men, respectively. Of the 235 men, 210 could void spontaneously, and day- and nighttime continence were achieved in 189 and 149, respectively. The mean maximal flow rate, voided volume and post-void residual were 15.9 ml/s, 209.6 and 38.0 ml, respectively. SF-36 survey for postoperative quality of life showed no significant differences in 7 of the 8 scale scores between the 235 men and an age-matched control population in Japan. The 5-year overall and cancer-specific survival rates were 71.2 and 75.7%, respectively. There were no significant differences in any parameters examined among the four groups except for post-void residual, which was significantly smaller in the Reddy group than in the other three groups. CONCLUSION: The orthotopic NB could generally provide satisfactory outcomes on long-term follow-up, irrespective of the types of NB.

Quantitative detection of micrometastases in pelvic lymph nodes in patients with clinically localized prostate cancer by real-time reverse transcriptase-PCR.

PURPOSE: Routine pathologic examination can miss micrometastatic tumor foci in the lymph nodes of patients with prostate cancer, resulting in confusion during tumor staging and clinical decision-making. The objective of this study was to clarify the significance of micrometastases in pelvic lymph nodes in patients who underwent radical prostatectomy for prostate cancer. EXPERIMENTAL DESIGN: The expression of prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA) in 2,215 lymph nodes isolated from 120 patients with clinically localized prostate cancer was assessed by a fully quantitative real-time reverse transcriptase-PCR. We regarded specimens in which either PSA or PSMA mRNAs were positive as proof of the "presence of micrometastasis." Immunohistochemical staining of lymph node specimens with an antibody against PSA was also done. RESULTS: Pathologic examinations detected tumor cells in 29 lymph nodes from 11 patients, and real-time reverse transcriptase-PCR further identified micrometastasis in 143 lymph nodes from 32 patients with no pathologic evidence of lymph node involvement. The presence of micrometastatic cancer cells was confirmed by immunohistochemical staining in 61 lymph nodes from 17 patients with pathologically negative lymph nodes. The presence of micrometastases was significantly associated with other conventional prognostic variables, including serum PSA value, pathologic stage, Gleason score, and tumor volume. Biochemical recurrence was detected in 32 patients, 17 of whom were negative for lymph node metastasis by pathologic examination (including 4 patients with pathologically organ-confined disease), but were diagnosed as having micrometastasis. Biochemical recurrence-free survival rate in patients without micrometastasis was significantly higher than in those with micrometastasis irrespective of the presence of pathologically positive nodes. Furthermore, only the presence of micrometastasis was independently associated with biochemical recurrence regardless of other factors examined. CONCLUSIONS: These findings suggest that approximately 30% of clinically localized prostate cancers shed cancer cells to the pelvic lymph nodes, and that biochemical recurrence after radical prostatectomy could be explained, at least in part, by micrometastases in pelvic lymph nodes.

Prognostic significance of adjuvant cisplatin-based combination chemotherapy following radical cystectomy in patients with invasive bladder cancer.

OBJECTIVES: The objectives of this study were to retrospectively examine the outcomes of adjuvant cisplatin-based combination chemotherapy following radical cystectomy in patients with invasive bladder cancer in order to identify parameters predicting the prognosis of these patients. METHODS: This study included a total of 51 patients with muscle invasive bladder cancer who underwent radical cystectomy between January 1995 and December 2004, and subsequently received at least two cycles of either MVAC (methotrexate, vinblastine, doxorubicin and cisplatin) or MVP-CAB (methotrexate, doxorubicin, vincristine, cyclophosphamide, bleomycin and cisplatin) chemotherapy in an adjuvant setting because of the presence of diseases corresponding to pT3/4 and/or pN1/2 without clinical evidence of metastasis. The significance of several clinicopathological factors as predictors of disease recurrence and cancer-specific death was evaluated using univariate and multivariate analyses. RESULTS: During the observation period of this study (median, 26.5 months), disease-recurrence and cancer-specific death were observed in 21 and 16 patients, respectively. The 5-year recurrence-free and cancer-specific survival rates were 48.6% and 54.1%, respectively. Among several factors examined in this series, lymph node metastasis and concomitant carcinoma in situ (CIS) were identified as significant predictors of both disease-recurrence and cancer-specific death, and these were also independently associated with disease-recurrence and cancer-specific death. CONCLUSIONS: Adjuvant cisplatin-based combination chemotherapy for patients with extravesically extended bladder cancer following radical cystectomy resulted in comparatively unsatisfactory outcome concerning cancer-control; accordingly, it would be necessary to develop a more efficacious therapeutic strategy for such patients, particularly for those with lymph node metastasis and/or concomitant CIS.

Surgical margin status of open versus laparoscopic radical prostatectomy specimens.

OBJECTIVES: To compare the surgical margin (SM) status between open and laparoscopic radical prostatectomy (RRP and LRP, respectively) specimens. METHODS: Surgical specimens from 137 patients undergoing LRP and 220 patients undergoing RRP for clinically localized prostate cancer were included in the analysis. SM status in each resected specimen, including the number of positive SM as well as their location, was examined. RESULTS: The incidence of positive SM in the LRP group was significantly greater than that in the RRP group. Despite the lack of significant difference in the proportion of solitary positive SM between these two groups, the proportion of multiple positive SM in the LRP group was significantly greater than that in the RRP group. There was no significant difference in the incidence of anterior positive SM between the two groups, while the incidences of positive SM at the apex, posterior site and bladder neck in the LRP group were significantly greater than those in the RRP group. Furthermore, there were no significant preoperative parameters predicting positive SM in the LRP group. On the other hand, the biopsy Gleason score and clinical T stage were identified as significant predictors of positive SM in the RRP group, of which the biopsy Gleason score was independently related to the presence of positive SM. CONCLUSIONS: Clinical T stage and Gleason score could be useful predictors of SM status following RRP, while positive SM in LRP specimens were detected irrespective of preoperative parameters, suggesting the need for an effort for further refining the LRP procedure.

Significance of radical cystectomy for bladder cancer in patients over 80 years old.

OBJECTIVES: The objective of this study was to evaluate the usefulness of radical cystectomy for bladder cancer in elderly patients. MATERIALS AND METHODS: This study included 72 patients aged > or =80 years (group A) who underwent radical cystectomy and urinary diversion between January 1995 and December 2003, and the clinical outcome of these patients were compared with those of 557 patients aged <80 years (group B) undergoing radical cystectomy during the same period as group A. RESULTS: As the procedure for urinary diversion, ureterocutaneostomy was most frequently performed in group A (87.5%), while neobladder creation was most common in group B (43.8%). Despite the absence of significant differences in tumor grade and incidence of lymph node metastasis between these two groups, pathological stage in group A was significantly greater than that in group B. The perioperative mortality rate in group A was significantly higher than that in group B, whereas the incidences of both early and late postoperative complications in group A were similar to those in group B. Cancer-specific survival in group A was significantly lower than that in group B; however, among patients with disease < or =pT2, there was no significant difference in cancer-specific survival between these two groups. CONCLUSIONS: These findings suggest that an aggressive surgical approach may be an optimal therapeutic strategy for properly selected elderly patients who require definitive therapy for locally invasive bladder cancer, particularly in those with disease < or =pT2.

Elevated urinary cytokine levels in patients undergoing ileal neobladder replacement compared with sigmoid neobladder replacement.

OBJECTIVES: The objective of this study was to examine the urinary cytokine levels for assessment of inflammatory conditions in patients with orthotopic neobladder. MATERIALS AND METHODS: Urinary levels of IL-1beta, IL-6, and IL-8 were measured in 20 and 22 patients who underwent orthotopic neobladder replacement using ileum and sigmoid colon, respectively, and all cytokine levels greater than 5 pg/ml were defined as elevated. The outcomes were compared with respect to several parameters. RESULTS: The proportions of patients positive for urinary culture, pyuria, and bacteriuria in the ileal neobladder group were higher than those in the sigmoid neobladder group, but these differences were not significant. Urinary levels of IL-1beta, IL-6, and IL-8 in the ileal neobladder group were significantly greater than those in the sigmoid neobladder group. Furthermore, the incidences of elevated urinary levels of IL-1beta, IL-6, and IL-8 in both groups were not affected by age, postoperative period, residual urine volume or pyuria; however, the incidences of elevated urinary IL-6 levels significantly differed between patients with and without bacteriuria in the ileal neobladder group, while there was a significant difference in the incidences of elevated urinary IL-8 levels between patients with and without bacteriuria in the sigmoid neobladder group. CONCLUSIONS: These findings suggest that chronic inflammation was more frequently observed in patients with ileal neobladder than in those with sigmoid neobladder, and that IL-6 and IL-8 were involved in persistent bacteriuria in patients with ileal and sigmoid neobladder, respectively.

Clinical symptoms in localized renal cell carcinoma reflect its invasive potential: comparative study between incidentally detected and symptomatic diseases.

The objectives of this study were to analyze the association of clinical symptoms with several parameters in patients with organ-confined renal cell carcinoma (RCC), and investigate the difference in biologic characteristics between incidentally detected and symptomatic RCCs. This study included 132 patients who were pathologically diagnosed with organ-confined RCC after radical surgery, and their clinicopathologic features were compared to those in patients with incidentally detected and symptomatic diseases. In this series, 91 patients were incidentally diagnosed with RCC, while the remaining 41 had some clinical symptoms. The cause-specific survival in patients with incidental RCC was significantly higher than that in patients with symptomatic RCC, and the presence of clinical symptoms could be an independent predictor of cause-specific survival in these patients. Immunohistochemical staining of resected specimens from these patients were then performed with Ki-67, Bcl-2, matrix metalloproteinase (MMP)-2, MMP-9, and vascular endothelial growth factor antibodies. Despite the lack of differences in Ki-67, Bcl-2, and vascular endothelial growth factor expression between these 2 groups, significantly increased expressions of MMP-2 and MMP-9 in symptomatic RCCs were observed compared with those in incidental RCCs. Moreover, the presence of clinical symptoms in organ-confined RCC was significantly correlated with immunoreactivities of MMP-2 and MMP-9. These findings suggest that clinical symptoms have a significant impact on the prognosis of patients with organ-confined RCC and that the appearance of clinical symptoms may reflect the increased invasive potentials characterized by overexpression of MMPs.

Oncologic Outcome of Radical Prostatectomy as Monotherapy for Men with High-risk Prostate Cancer.

BACKGROUND: The objective of this study was to review our experience with radical prostatectomy (RP) as monotherapy for men with high-risk prostate cancer (PCa). PATIENTS AND METHODS: This study included 382 consecutive patients who were diagnosed with high-risk PCa according to the D'Amico definition and subsequently underwent RP without neoadjuvant therapy. Biochemical recurrence (BR) was defined as a serum prostate-specific antigen (PSA) level ≥ 0.2 ng/ml on two consecutive measurements, and none of the patients received any adjuvant therapies until their serum PSA levels reached ≥ 0.4 ng/ml. RESULTS: The median preoperative serum PSA level in these 382 patients was 15.9 ng/ml. Pathological stages ≥ pT2c and Gleason scores ≥ 8 were observed in 288 and 194 patients, respectively. During the observation period (median, 48.0 months), BR occurred in 134 patients, and the 5-year BR-free survival rate was 60.1%; however, no patient died of cancer progression. Multivariate analysis identified capsular invasion, seminal vesicle invasion, and surgical margin status as independent predictors of BR. CONCLUSIONS: Comparatively favorable cancer control could be achieved using RP as monotherapy for men with high-risk PCa; however, RP alone may be insufficient for patients with capsular invasion, seminal vesicle invasion, and/or surgical margin positivity.

Oncological Outcomes in Japanese Men Undergoing Orchiectomy for Stage I Testicular Germ Cell Tumor.

BACKGROUND: The objective of this study was to retrospectively review oncological outcomes in patients with stage I testicular germ cell tumor (GCT). PATIENTS AND METHODS: This study included 265 consecutive Japanese men undergoing orchiectomy for stage I testicular GCT, and a retrospective review of their records was performed. RESULTS: Of these 265 patients, 192 and 73 were pathologically classified with seminoma and nonseminoma, respectively. Prophylactic radiation and chemotherapy were performed in 62 patients with seminoma and 6 with nonseminoma, respectively. Disease recurrence occurred in 12 seminoma patients, of whom 11 had not received prophylactic radiation therapy; however, all 12 achieved a complete response to bleomycin, etoposide and cisplatin therapy. Of the nonseminoma patients, 19 experienced disease recurrence and were then treated with bleomycin, etoposide and cisplatin followed additionally by the surgical resection of residual tumors and salvage chemotherapy in 7 and 4, respectively. There was no cancer-specific death in the 265 patients, and 5-year recurrence-free survival rates in patients with seminoma and nonseminoma were 92.6 and 72.8%, respectively. Furthermore, following factors appeared to be significantly associated with recurrence-free survival in these patients: age, T classification, microvascular invasion and adjuvant therapy for those with seminoma, and microvascular invasion for those with nonseminoma. CONCLUSIONS: Despite a generally favorable prognosis in Japanese men with stage I testicular GCT, intensive follow-up or prophylactic therapy should be considered for men with possible risk factors of disease recurrence.

Prognostic outcome in patients treated with tyrosine kinase inhibitors as first-line molecular-targeted therapy for metastatic renal cell carcinoma: Experience in real-world clinical practice in Japan.

The aim of this study was to evaluate the oncological efficacy of tyrosine kinase inhibitors (TKIs) as first-line molecular-targeted therapy for Japanese patients with metastatic renal cell carcinoma (mRCC) in a routine clinical setting. This study included a total of 271 consecutive Japanese patients with TKI-naive mRCC, including 172 patients who received sorafenib and 99 who received sunitinib for ≥2 months as a first-line molecular-targeted agent. The prognostic outcomes of these patients were retrospectively assessed. During the observation period (median, 19 months), 126 patients (46.5%) succumbed to the disease and the median overall survival (OS) for the entire cohort was 33.1 months. The univariate analysis identified the Memorial Sloan-Kettering Cancer Center (MSKCC) classification, C-reactive protein (CRP) level, lymph node metastasis, bone metastasis, liver metastasis, histological subtype and sarcomatoid characteristics as significant predictors of OS. Of these factors, only the MSKCC classification, CRP level and liver metastasis were found to be independently associated with OS in the multivariate analysis. Furthermore, there were significant differences in OS according to the positivity for these 3 independent risk factors (i.e., negative for all factors vs. positive for a single factor vs. positive for 2 or 3 factors). These findings suggest that the introduction of TKIs as first-line molecular-targeted agents resulted in favorable cancer control outcomes in Japanese mRCC patients and that the prognosis of these patients may be stratified by 3 potential parameters, including the MSKCC classification, CRP level and liver metastasis.

Assessment of health-related quality of life in Japanese patients with metastatic renal cell carcinoma during treatment with tyrosine kinase inhibitors.

The objective of this study was to comprehensively analyze the health-related quality of life (HRQOL) in Japanese patients with metastatic renal cell carcinoma (mRCC) during treatment with tyrosine kinase inhibitors (TKIs). This study included 240 Japanese mRCC patients treated with TKIs. We conducted a total of 305 surveys assessing the HRQOL before and 3 months after the introduction of TKIs, including 150, 95 and 60 during treatment with sorafenib, sunitinib and axitinib, respectively, using the Medical Outcomes Study 36-Item Short Form, consisting of eight multi-item scales measuring the health status. There were no significant differences in any of the eight scale scores between these 305 surveys conducted before and 3 months after TKI treatment. Two scores in the surveys during axitinib treatment were significantly superior to those during sorafenib treatment; however, no significant differences were noted in any of the remaining scale scores among the surveys during treatment with the three TKIs. Multivariate analyses, which were performed to evaluate the contribution of several factors to each scale score, revealed that the therapeutic efficacy had independent impacts on two scale scores, despite the lack of an independent association between any scores and the remaining factors, including the age, gender, introduced TKI, timing of TKI introduction and degree of adverse events. Collectively, these findings suggest that treatment with TKIs did not result in a significant impairment of the HRQOL in Japanese patients with mRCC; however, patients with unfavorable disease control appeared to fail to achieve a satisfactory HRQOL during treatment with TKIs.

Prognostic significance of primary Gleason pattern in Japanese men with Gleason score 7 prostate cancer treated with radical prostatectomy.

OBJECTIVES: To evaluate the significance of the primary Gleason pattern in patients with Gleason score (GS) 7 prostate cancer treated with radical prostatectomy. MATERIALS AND METHODS: This study included 959 consecutive Japanese men who underwent radical prostatectomy without neoadjuvant therapies and were subsequently diagnosed as having GS 7 prostate cancer based on the modified International Society of Urological Pathology (ISUP) 2005 Gleason grading system. RESULTS: Of these 959 patients, 666 (69.4%) and 293 (30.6%) had GS 3+4 and GS 4+3 tumors, respectively. There were significant differences in the prostate-specific antigen (PSA) level, biopsy GS, pathologic T stage, lymphatic invasion, microvenous invasion, and perineural invasion between these 2 groups. During the mean observation of 48.9 months, biochemical recurrence occurred in 211 patients (22.0%), and there was a significant difference in the biochemical recurrence-free survival between patients with GS 3+4 tumors and those with GS 4+3 tumors. Of several factors examined, biochemical recurrence-free survival was significantly associated with the PSA level, biopsy Gleason score, capsular penetration, seminal vesicle invasion, surgical margin status, lymphatic invasion, microvenous invasion, perineural invasion, and primary Gleason pattern, among which the PSA level, capsular penetration, seminal vesicle invasion, and surgical margin status, but not primary Gleason pattern, appeared to be independent predictors of biochemical recurrence. CONCLUSIONS: Despite the lack of an independent significance, primary Gleason pattern based on the modified ISUP 2005 Gleason grading system is shown to be significantly associated with the biochemical outcome of Japanese men with GS 7 prostate cancer.

Orthotopic sigmoid vs. ileal neobladders in Japanese patients: a comparative assessment of complications, functional outcomes, and quality of life.

OBJECTIVES: To compare the clinical outcomes of sigmoid and ileal neobladders (NBs) created following radical cystectomy. MATERIALS AND METHODS: This study included 90 and 144 Japanese patients undergoing radical cystectomy and orthotopic NB reconstruction with a sigmoid and ileal segment, respectively. Postoperative clinical outcomes between the sigmoid and ileal NB groups (SNBG and INBG) were compared. RESULTS: In this series, 110 early and 51 late complications occurred in 71 and 41 patients, respectively; however, there was no significant difference in the incidence of complications between SNBG and INBG. At 1 year postoperatively, there were no significant differences in the proportion of spontaneous voiders and the continence status between these 2 groups; however, despite the lack of significant differences in the maximal flow rate and voided volume, the post-void residual in SNBG was significantly smaller than that in INBG. Voiding functional outcomes at 5 years postoperatively were also obtained from 28 and 49 in SNBG and INBG, respectively. Although there were no significant changes in the functional outcomes in SNBG, the proportion of spontaneous voiders and post-void residual in INBG at 5 years postoperatively were significantly poorer than those at 1 year postoperatively. Furthermore, the postoperative health-related quality of life assessed by a Short-Form 36 survey did not show any significant differences in all 8 scores between these 2 groups. CONCLUSIONS: Both types of NB reconstruction resulted in comparatively satisfactory outcomes; however, the voiding function, particularly that on long-term follow-up, in SNBG appeared to be more favorable than that in INBG.

Prognostic prediction in patients with metastatic renal cell carcinoma treated with sorafenib based on expression levels of potential molecular markers in radical nephrectomy specimens.

OBJECTIVES: To investigate the expression levels of multiple molecular markers in radical nephrectomy specimens from patients with metastatic renal cell carcinoma (RCC) treated with sorafenib in order to identify factors predicting susceptibility to this agent. MATERIALS AND METHODS: This study included 45 consecutive patients undergoing radical nephrectomy for clear cell RCC who were diagnosed as having metastatic diseases refractory to cytokine therapy and subsequently treated with sorafenib. Expression levels of 19 molecular markers involved in the regulation of apoptosis, cell cycle, signal transduction, and angiogenesis in primary RCC specimens were measured by immunohistochemical staining. RESULTS: There was no molecular marker having significant impact on the prediction of response to sorafenib. However, progression-free survival (PFS) was significantly associated with the expression levels of Bcl-xL and platelet-derived growth factor receptor (PDGFR)-α in addition to the presence of bone metastasis and C-reactive protein level on univariate analysis. Of these significant factors, PDGFR-α expression and the presence of bone metastasis appeared to be independently related to PFS by multivariate analysis. Furthermore, there were significant differences in PFS according to positive numbers of these 2 independent risk factors; that is, disease progression occurred in 2 of 7 patients who were negative for risk factor, 19 of 34 positive for a single risk factor, and 6 of 6 positive for both risk factors. CONCLUSIONS: Collectively, these findings suggest that it would be useful to consider expression levels of potential molecular markers, particularly PDGFR-α, as well as clinical parameters to select metastatic RCC patients likely to benefit from treatment with sorafenib.

Abnormalities of thyroid function in Japanese patients with metastatic renal cell carcinoma treated with sorafenib: a prospective evaluation.

The objective of this study was to characterize features of thyroid dysfunction in Japanese patients with metastatic renal cell carcinoma (RCC) who were treated with sorafenib. We performed a prospective observational study including 69 Japanese patients who were diagnosed as having metastatic RCC refractory to cytokine therapy and subsequently treated with sorafenib for at least 12 weeks. Thyroid function was assessed before and every 4 weeks after the initiation of sorafenib treatment. Of the 69 patients, 23 (33.3%) did not show any biochemical thyroid abnormality, while the remaining 46 (67.7%) developed hypothyroidism. However, 11 (23.9%) of these 46 hypothyroid patients initially had a suppressed thyroid-stimulating hormone (TSH) value accompanying the increase in free triiodothyronine (T3) and/or free thyroxine (T4) before developing hypothyroidism, suggesting sorafenib-induced thyroiditis. During the observation period of this study, 4 patients (5.8%) demonstrated severe clinical symptoms caused by hypothyroidism and received thyroid hormone replacement. Among several factors examined, only age was significantly associated with the risk for hypothyroidism. These findings suggest that although the incidence of clinically significant hypothyroidism requiring thyroid hormone replacement therapy was not very high, biochemical thyroid abnormality was frequently observed in Japanese RCC patients treated with sorafenib. Accordingly, regular surveillance of thyroid function by the measurement of TSH, free T3, and T4 is warranted during sorafenib treatment in Japanese RCC patients.

Clinical outcome of combined immunotherapy with interferon-alpha and low-dose interleukine-2 for Japanese patients with metastatic renal cell carcinoma.

The objective of this study was to retrospectively investigate clinical outcomes of combined immunotherapy with interferon-alpha (IFN-alpha) and low-dose interleukin-2 (IL-2) in Japanese patients with metastatic renal cell carcinoma (RCC). This study included a total of 52 patients with metastatic RCC who were treated by combined immunotherapy with IFN-alpha and low-dose IL-2 following radical nephrectomy. These patients received a subcutaneous injection of IFN-alpha (5 to 6 million U/d) three times per week and intravenous injection of IL-2 (1.4 million U/d) twice per week. Tumor response was evaluated every 16 weeks, and as a rule, this weekly regimen was repeated 50 times in patients with evidence of objective response or stable disease. In this series, complete response and partial response were achieved in 1 and 11 patients, respectively; however, the remaining 20 and 20 patients were diagnosed as showing stable disease and progressive disease, respectively. Of several parameters examined, presence of metastases at diagnosis and C-reactive protein (CRP) level were significantly associated with response to this combined therapy. The 1-, 3-, and 5-year cancer-specific survival rates of these 52 patients were 80.4%, 51.7%, and 38.8%, respectively. Furthermore, cancer-specific survival was significantly associated with performance status, presence of metastases at diagnosis, metastatic organ and CRP level on univariate analysis; however, only performance status and presence of metastases at diagnosis appeared to be independent predictors of cancer-specific death by multivariate analysis. Toxicities related to this therapy were generally mild and tolerable, limited to World Health Organization (WHO) grade 1 or 2 in the majority of patients. Collectively, these findings suggest that combined immunotherapy with IFN-alpha and low-dose IL-2 could achieve comparatively acceptable oncological outcomes in patients with metastatic RCC; however, other therapeutic options should be considered in patients with unfavorable performance status and/or those positive for metastatic diseases at diagnosis.

Additional sampling of dorsal apex on systematic prostate biopsy: impact on early detection of prostate cancer.

OBJECTIVES: To evaluate the significance of additional routine biopsies targeting the dorsal apex (DA) in men undergoing transrectal ultrasound (TRUS)-guided biopsies. METHODS: This study included 429 patients undergoing TRUS-guided biopsy of the prostate. As a rule, 12 cores were taken from each patient, with 8 cores taken from the peripheral zones, 2 cores from the transition zones, and 2 additional cores from the DA. RESULTS: Cancer was detected in 150 patients, of whom 97 had positive cores in the DA. Furthermore, cancer was detected only in the DA in 14 patients; that is, the increase in the cancer detection rate by additional sampling from the DA was 9.3%. Significant differences were found in the prostate-specific antigen level, prostate-specific antigen density, digital rectal examination findings, TRUS findings, clinical T stage, and percentage of positive biopsy cores among the 14 men with positive cores in the DA alone (group 1), 83 in the DA and other regions (group 2), and 53 in regions except for the DA (group 3). Of these, radical prostatectomy was performed in 6, 41, and 26 in groups 1, 2, and 3, respectively. No significant differences were found in the several pathologic factors among these groups, and 5 of the 6 patients in group 1 had a tumor volume greater than 0.5 cm3. CONCLUSIONS: Additional sampling of biopsy cores from the DA significantly improved the cancer detection rate, particularly for early disease; however, this method does not appear to increase the detection of insignificant cancer. Accordingly, we recommend performing systematic biopsy routinely targeting the DA.