Prognostic risk score and index including the platelet-to-lymphocyte ratio and lactate dehydrogenase in patients with metastatic or unresectable urothelial carcinoma treated with immune checkpoint inhibitors.

BACKGROUND: Avelumab and pembrolizumab are administered after platinum-based chemotherapy for the treatment of metastatic urothelial carcinoma. We explored the prognostic factors and risk scores for predicting the outcomes of metastatic or unresectable urothelial carcinoma at the start of treatment with immune checkpoint inhibitors. METHODS: This retrospective study included patients with metastatic or unresectable urothelial carcinoma treated with avelumab or pembrolizumab after platinum-based chemotherapy between January 2017 and December 2022. Prognostic factors, including patient and tumor characteristics and blood data at the initiation of immune checkpoint inhibitor therapy, were examined. RESULTS: This study included 36 and 207 patients treated with avelumab and pembrolizumab, respectively, for metastatic or unresectable urothelial carcinoma. Eastern Cooperative Oncology Group performance status, presence of visceral metastases, platelet-to-lymphocyte ratio and lactate dehydrogenase levels were independent prognostic factors for predicting overall survival. The median overall survival of patients in the risk-score model was 58.5 months (score zero), 27.9 months (one), 13.1 months (two) and 3.9 months (three or higher). The C-index for overall survival was 0.718 for the newly developed risk score compared with 0.679 for the Bellmunt score and 0.703 for the Bellmunt-C-reactive protein score. Additionally, the C-index for overall survival using the immune prognostic index derived from lactate dehydrogenase and the platelet-to-lymphocyte ratio was 0.646 compared with 0.615 for the Lung Immune Prognostic Index. CONCLUSIONS: A risk score that includes the platelet-to-lymphocyte ratio and lactate dehydrogenase may serve as a useful model for predicting prognosis following the initiation of immune checkpoint inhibitors in patients with metastatic or unresectable urothelial carcinoma.

Comparative Efficacy of Avelumab Maintenance Therapy Versus Continued Chemotherapy Followed by Pembrolizumab in Metastatic Urothelial Carcinoma With No Progression After 4 Cycles of Chemotherapy: A Retrospective Study Using Propensity Score Matching.

INTRODUCTION: In cases of metastatic and unresectable urothelial carcinoma with no disease progression after 4 cycles of chemotherapy, including platinum agents, treatment options include continuation of chemotherapy or switching to maintenance therapy with avelumab. This study compared the treatment outcomes of avelumab maintenance therapy with those of pembrolizumab in urothelial carcinoma using propensity score matching. PATIENTS AND METHODS: Between January 2017 and December 2022, 243 patients with metastatic and unresectable urothelial carcinoma were treated with either avelumab or pembrolizumab at the Yamaguchi University Hospital and its affiliated institutions. We retrospectively compared the oncological outcomes and adverse events by aligning patient characteristics and treatment backgrounds using propensity score matching. RESULTS: The analysis compared 36 cases receiving avelumab maintenance therapy after chemotherapy to 49 cases where patients, after receiving 4 courses of chemotherapy including platinum-based agents without disease progression, were subsequently administered pembrolizumab as a second-line treatment following disease progression. Using propensity score matching, 27 cases from each group were selected for comparison. From the initiation of prechemotherapy to disease progression on immune checkpoint inhibitors, the median progression-free survival was 20.7 and 23.3 months in the avelumab and pembrolizumab groups, respectively, with no statistically significant difference observed (P = .358). However, avelumab tended to have a lower rate of high-dose glucocorticoid treatment compared to pembrolizumab. CONCLUSION: Progression-free survival was similar for avelumab maintenance therapy and the sequence of continued chemotherapy followed by pembrolizumab after no disease progression at four chemotherapy courses. Avelumab may require less high-dose glucocorticoid treatment, potentially enhancing safety.

[OVERALL SURVIVAL EVALUATION OF PROSTATE CANCER PATIENTS TREATED WITH ANDROGEN DEPRIVATION THERAPY BY ESTIMATING FLUCTUANT PATTERNS OF METABOLIC FACTOR SERUM LEVELS].

(Background) The effects of fluctuant patterns of serum alkaline phosphatase (ALP) and lactic acid dehydrogenase (LDH) levels on overall survival of patients with prostate cancer (PC) treated with androgen deprivation therapy (ADT) remain unclear. (Methods) We enrolled 236 patients with PC and divided into 3 cohorts by fluctuant patterns of serum levels of ALP and LDH between at baseline and at 1 year later, or at diagnosis of castration-resistant prostate cancer (CRPC): intermediate, within interquartile range (IQR) [I]; lower than IQR [L]; higher than IQR [H]. (Results) In the 1 year later ALP cohort, all parameters except age were significantly different. In the L cohort, 75% of patients had bone metastasis and > 50% developed CRPC or died. In the 1 year later LDH cohort, Eastern Cooperative Oncology Group-performance status (ECOG-PS) and clinical metastasis classification were significantly different among the cohorts. In the CRPC/ALP cohorts, baseline prostate-specific antigen values and clinical metastasis classification were significantly different among the cohorts, and all cases had metastasis in the L cohort. In the CRPC/LDH cohort, the L cohort had higher ECOG-PS and shorter time to CRPC. In the 1 year later ALP cohort, the hazard ratio (HR) for death of the L and H cohort to the I cohort was 3.77 and 2.27, respectively and both were significant. In the CRPC/LDH cohort, the HR for death of L cohort to I cohort was 1.99. (Conclusions) Larger fluctuations in serum ALP and LDH levels were a sign of poorer prognosis, especially for patients in the L cohort.

[ADVERSE EFFECTS OF ANDROGEN DEPRIVATION THERAPY ON PATIENTS WITH PROSTATE CANCER AND ITS EFFECT ON OVERALL SURVIVAL].

(Background) Patients with prostate cancer, which progresses slowly compared with other cancers, are generally older, and not a few are solely treated with androgen-deprivation therapy (ADT). The physical effects of ADT on bone health, body composition, and hematological parameters must be carefully considered. (Methods) We collected the clinical records of 185 men with pathologically diagnosed prostate cancer who were treated with ADT at our hospital. The primary aim of the study was to determine the prevalence and severity of adverse effects caused by ADT. The second aim was to analyze the effect of fluctuation in the rate of these adverse effects on overall survival (OS). (Results) The median age of patients was 75 years. After ADT for 1 or 2 years, evaluation of bone mineral density revealed median losses of 3% and 6%, respectively. After ADT for 1 year, body mass index was significantly increased by a median 2.1%, and total cholesterol and hemoglobin levels were significantly increased and decreased, respectively. The local and systemic symptoms of subcutaneous granuloma and hot flashes were experienced by 39% and 21.6% patients, respectively. Mono- and multivariate analysis revealed that significant fluctuation in the rate of adverse events after 1-year ADT did not affect OS. (Conclusion) Prevalence and severity of adverse effects caused by ADT were acceptable and almost all patients could be treated in the outpatient clinic, and significant fluctuation in the rate of adverse effects had no effect on OS.

[EFFECT OF NEW ANDROGEN RECEPTOR AXIS-TARGETED AGENTS ON SURVIVAL OF CASTRATION-RESISTANT PROSTATE CANCER].

(Background)The real world's effect of new androgen receptor axis-targeted agents (ARATs) on survival of castration-resistant prostate cancer (CRPC) remains unclear in Japan. (Aims)The primary aim was to determine the clinical benefit of ARATs on survival of CRPC patients. The secondary aim was to evaluate predictive factors affecting the survival of CRPC patients. (Patients and results)Among 236 patients treated with androgen deprivation therapy (ADT), 68 patients developed CRPC; two groups of 34 patients were treated with ARATs (A cases) or conventional ADT (V cases). In a median follow-up of 61.5 months, 20 A and 22 V cases died of cancer. Median survival time (MST) from diagnosis was 99 and 66 months for A and V cases, respectively, and MST from CRPC to death were 50.5 and 44.5 months, respectively. There were no significant differences between both cases. The hazard ratio for death from diagnosis or CRPC progression of the A cases to V cases was 0.711; 95% confidence interval (CI), 0.371 to 1.362; P = 0.3037, or 0.805; 95% CI, 0.434 to 1.491; P=0.4899, respectively. Multivariable analysis revealed that a unique and significant independent prognostic factor from diagnosis was time to CRPC. (Conclusions)In this small retrospective study, we could not determine the clinical benefit of new ARATs compared with conventional ADT on survival of CRPC patients, and a unique and significant independent prognostic factor from diagnosis was time to CRPC. We need to validate these results in a future multi-institutional study.

Patient-reported outcomes and biochemical alterations during hormonal therapy in men with hypogonadotropic hypogonadism who have finished infertility treatment.

Male hypogonadotropic hypogonadism (MHH) is effectively treated by gonadotropins with a high rate of ejaculate sperm and paternity; however, there is no information regarding the appropriate management, including patient-reported outcomes (PROs), of men with MHH who have finished infertility treatment. To compare health-related quality of life, erectile function and biochemical alterations in men with MHH who were treated with testosterone replacement therapy (TRT) or human chorionic gonadotropin (hCG). Twenty-six MHH patients (mean age: 34 years) who needed to improve their androgen deficiency symptoms underwent either hCG therapy (n = 16, started with self-injection of 2,000-7,500 IU per week) or TRT (n = 10, testosterone enanthate 250 mg every 3 weeks). The 36-item Short Form Health Survey (SF-36) questionnaire, five-item International Index of Erectile Function (IIEF-5) and hormonal and biochemical analyses were assessed every 3 months. Changes and comparison of each treatment regarding these parameters were analyzed. Both hCG and TRT significantly improved all domains of the SF-36, except for bodily pain and social functioning. hCG significantly improved the general and mental health domains compared with TRT. Significant improvements in IIEF-5 were observed with both treatments, showing significant improvement with hCG compared to TRT. TRT caused progressive testicular atrophy. There were significant decreases in waist circumference and triglycerides in both treatment groups and significant elevations in prostate-specific antigen and hematocrit. Both hCG and TRT are effective and safe, with preferable PROs by hCG, for treating androgen deficiency in men with MHH who do not need infertility treatment.

[A STUDY OF MULTIPARAMETER ANALYSIS OF SERUM URIC ACID LEVELS -A STUDY IN APPARENTLY HEALTHY JAPANESE MEN AND WOMEN].

(Background) Hyperuricemia is associated with hypertension, vascular disease, cardiovascular events, and renal dysfunction. Several studies have reported the relationship between serum uric acid (UA) level and clinical outcome in the general population. However, most such studies have not quantitatively evaluated the association between UA and age, body mass index (BMI), and estimated glomerular filtration rate (eGFR). (Method) From April 2015 to March 2016, a total 10,133 healthy individuals underwent multiphasic screening at our medical checkup center. Among all participants, eGFR was evaluated in 1,684 men and 1,195 women. The data of this cohort were reviewed and analyzed. (Results) The median age of men and women was 51.0 and 50.0 years, respectively. Median serum UA was 6.1 mg/dL in men and 4.5 mg/dL in women. The prevalence of hyperuricemia was 23.9% in men and 8.5% in women. In all 10-year age groups, men had significantly higher serum UAs than women. In men, no significant differences of serum UA were observed among 10-year age groups. Menopause-associated increases in serum UA among women were observed. Men in their 20s to 50s and women in their 30s to 60s showed significant differences in serum UA between each BMI category in the same age decade. Both men and women in their 40s to 60s showed significant differences in serum UA between each eGFR category in the same age decade. We used the results of multiple regression analysis to derive equations to predict the associations among these variables, as follows: men, UA (mg/dL) = 5.637+0.065 × (BMI) - 0.014 × (eGFR) (R2 = 0.059, P < 0.0001); women < 50 years old, UA (mg/dL) = 4.068+0.065 × (BMI) - 0.014 × (eGFR) (R2 = 0.091, P < 0.0001) and women > 50 years old, UA (mg/dL) = 4.311+0.075 × (BMI) - 0.017 × (eGFR) (R2 = 0.116, P < 0.0001). (Conclusions) We present epidemiological evidence indicating that the levels of serum UA vary with BMI and eGFR in both sexes. In women, it should be recognized that menopause is independently associated with higher levels of UA.

[LOCAL REACTIONS OF LUTEINIZING HORMONE-RELEASING HORMONE AGENTS AND ITS EFFECTS ON CLINICAL OUTCOMES IN PROSTATE CANCER PATIENTS].

(Background) Currently, luteinizing hormone-releasing hormone (LH-RH) agonists and antagonists are used for androgen-deprivation therapy (ADT). However, they are associated with subcutaneous granuloma, rubor, dolor, calor, and eventual ulcer and/or abscess formation. The prevalence of these adverse effects, causes and mechanisms, and effects on serum testosterone levels and clinical outcomes are poorly understood. (Method) We collected the clinical records of men with pathologically diagnosed prostate cancer who were followed in our hospital. The primary aim of the study was to determine the prevalence of granuloma formation, its causes, and the mechanisms involved. The secondary aim was to analyze the effects of subcutaneous induration on serum testosterone levels and clinical outcomes. (Results) Overall, 185 men using leuprorelin (n=161; median age, 75 years), degarelix (n=21; median age, 76), or goserelin (n=3; median age, 76) were analyzed. In the leuprorelin cohort, 51 patients (33.5%) had subjective and/or objective subcutaneous induration and 2 (1.2%) had a large lesion (diameter > 3.0 cm). In the degarelix cohort, 18 patients (85.7%) developed induration and 8 (38%) had a large lesion. One month after the start of ADT, patients in the leuprorelin and degarelix cohorts had median serum testosterone levels that reached the same level as that after castration. There was no significant difference in the overall survival rate between the leuprorelin and degarelix cohorts. There was no significant difference in the serum testosterone level or overall survival rate between patients with or without induration. (Conclusions) The local adverse effects of LH-RH agents are prevalent, but we can regulate the adverse effects by understanding the mechanism involved. The formation of subcutaneous induration did not affect the serum testosterone level or clinical outcome.

Transperitoneal versus retroperitoneal laparoscopic adrenalectomy for large pheochromocytoma: Comparative outcomes.

OBJECTIVES: To evaluate operative and oncological outcomes of laparoscopic adrenalectomy through a transperitoneal approach and retroperitoneal approach for large (>5 cm in diameter) pheochromocytomas. METHODS: We retrospectively compared the results of a transperitoneal approach with those of a retroperitoneal approach in 22 patients (mean age 57.5 years, range 38-76 years) with unilateral large pheochromocytomas (12 right, 10 left). The mean body mass index, operation time, pneumoperitoneum time, estimated blood loss, fluctuation in blood pressure and complication rate were compared between the two approaches. RESULTS: The mean tumor diameter (range) was 7.0 cm (range 5.2-15.5 cm), and no significant differences were observed between the transperitoneal approach and retroperitoneal approach in any baseline clinical parameter. For right-sided procedures, significant differences were found for operation time (113 vs 85 min), pneumoperitoneum time (93 vs 64 min) and estimated blood loss (96 vs 23 mL; P < 0.05, transperitoneal approach and retroperitoneal approach, respectively). No open conversion or recurrence was reported, but one right transperitoneal approach case required blood transfusion. No difference in these parameters was noted on the left side. CONCLUSIONS: For right side procedures, the retroperitoneal approach is feasible, safer and faster than the transperitoneal approach for large pheochromocytomas. Early transection of the feeding artery is beneficial for managing the tumor and reducing the risk of bleeding.

Human chorionic gonadotrophin treatment prior to microdissection testicular sperm extraction in non-obstructive azoospermia.

BACKGROUND: Despite the improved success rate of sperm retrieval by microdissection testicular sperm extraction (micro-TESE), methods to stimulate spermatogenesis in men with non-obstructive azoospermia (NOA) remain unexplored. The aim of this study was to evaluate the effects of hCG-based hormonal stimulation in men with NOA on the success of sperm retrieval by micro-TESE. METHODS: Forty-eight men with NOA who had negative sperm retrieval results by the micro-TESE procedure were included. A second micro-TESE was subsequently performed on these men: 20 were not treated by any hormonal therapy, and 28 subjects received daily subcutaneous injections of hCG for 4-5 months prior to the second micro-TESE. Recombinant FSH was added if endogenous gonadotrophin levels decreased during the hCG stimulation. The sperm retrieval rate at the second micro-TESE; the levels of gonadotrophins, testosterone and estradiol; and the effects of hormonal therapy on testicular histology were evaluated. RESULTS: Among the 28 men with hCG stimulation, 15 (54%) showed decreased LH and FSH levels (0.67 ± 0.10 and 0.96 ± 0.14 mIU, mean ± SEM, respectively) due to elevated serum testosterone (9.5 ng/dl). Sperm were obtained at the second micro-TESE from six men who had received hormonal therapy (21%), whereas no sperm were retrieved from untreated men (P < 0.05). Success at the second micro-TESE was more likely if histology at the first micro-TESE showed hypospermatogenesis. CONCLUSIONS: The Leydig cells of the testis can respond positively to exogenous hCG even under hypergonadotropic conditions. HCG-based hormonal therapy prior to a second micro-TESE attempt is effective in men with hypospermatogenesis.

Preoperative erythrocyte sedimentation rate is an independent prognostic factor in Japanese patients with localized clear cell renal cell carcinoma.

INTRODUCTION: Few studies have examined the prognostic significance of common laboratory variables in Japanese patients with localized clear cell renal cell carcinoma (CCRCC). We evaluate the prognostic significance of preoperative laboratory variables in Japanese patients with localized CCRCC. PATIENTS AND METHODS: The study included 110 Japanese patients who were pathologically confirmed as nonmetastatic CCRCC (pT1-3 N0M0) after radical nephrectomy at our institution. We assessed the clinical (including laboratory measurements) and pathological findings, with the survival rates after surgery. RESULTS: Tumor stage and erythrocyte sedimentation rate (ESR) were identified as significant independent prognostic factors of progression-free survival in multivariate analysis. As for the prognostic factors for disease-specific survival, tumor stage and ESR had prognostic significance both in univariate and multivariate analyses. When the analysis was limited to pT1, multivariate analysis showed that only ESR was an independent prognostic factor for disease-specific survival. CONCLUSIONS: Preoperative ESR is an independent prognostic factor in Japanese patients with localized CCRCC, especially in patients with pT1.

Risk of concomitant carcinoma in situ determining biopsy candidates among primary non-muscle-invasive bladder cancer patients: retrospective analysis of 173 Japanese cases.

OBJECTIVES: To determine candidates for bladder biopsies among Japanese primary non-muscle-invasive bladder cancer patients according to the risk of concomitant carcinoma in situ (CIS). METHODS: Between January 1992 and August 2006, 173 primary non-muscle-invasive bladder cancer cases underwent transurethral resection of the bladder tumor with bladder biopsies for the detection of CIS. Correlations between biopsy results and preoperative/pathological features were retrospectively analyzed. RESULTS: Positive cytology was statistically associated with the presence of concomitant CIS in multivariate analysis (P < 0.01). Abnormal cystoscopic appearance outside the tumor almost achieved statistical significance in multivariate analysis among preoperative factors (P = 0.06). In our series, one (12.5%) of eight low-risk, 18 (24.7%) of 73 intermediate-risk and 41 (59.4%) of 69 high-risk cases had CIS in normal-looking sites, respectively. In cases with a single papillary tumor and negative cytology, one of 16 (6.3%) had concomitant CIS in their biopsy specimens at the normal-looking sites. CONCLUSIONS: All non-muscle-invasive bladder cancer patients with positive cytology are candidates for additional random biopsies. Targeted biopsies should be performed for all suspicious areas in the bladder mucosa. Random biopsies should be considered in cases with the macroscopic types of cancer for predicting intermediate- and high-risk cancer.

Cytogenetic analysis of false-positive mucosa by photodynamic diagnosis using 5-aminolevulinic acid - possible existence of premalignant genomic alterations examined by in vitro experiment.

OBJECTIVE: Although photodynamic diagnosis is a powerful tool for the detection of flat urothelial tumors, false-positive fluorescent mucosa still requires further elucidation. Thus, we aimed to study the significance of nonmalignant fluorescent mucosa by a cytogenetic approach. METHODS: Sixty specimens of bladder mucosa were collected from 20 patients who were suspected of having carcinoma in situ by fluorescence cystoscopy with 5-aminolevulinic acid. To detect the copy number aberrations, the multi-color fluorescence in situ hybridization technique was performed, and the variant fractions (total fractions other than those of the modal copy number) of chromosomes 7, 9 and 17 and the chromosomal instability were determined. To delineate the relevant gene to the fluorescent mucosa, a comparative genomic hybridization technique was applied for 8 established bladder cancer cell lines, and these results were compared with the in vitro fluorescent expression experiment. RESULTS: Fluorescent mucosa was detected in 33 of the 34 malignant tissue specimens (16 carcinoma in situ, 18 other transitional cell carcinomas) and in 11 of the 26 nonmalignant tissue specimens (6 dysplasia, 20 normal mucosa), with a false-positive rate of 42.3%. The variant fraction of chromosome 9 was significantly higher in fluorescent than in non-fluorescent mucosa, not only for all tissues (33 vs. 17%; p = 0.0069), but also for nonmalignant tissues (28 vs. 15%; p = 0.0225). There was no alteration in chromosome 9 in 1 cell line without fluorescent mucosa, while 5 of the 7 cell lines with fluorescent mucosa had a common deleted region on 9q24.1. CONCLUSION: These data suggest that a substantial portion of nonmalignant fluorescent mucosa harbors alterations in chromosome 9.

Discrepancies between cytology, cystoscopy and biopsy in bladder cancer detection after Bacille Calmette-Guerin intravesical therapy.

OBJECTIVES: To evaluate discrepancies in the detection of Bacille Calmette-Guerin (BCG)-resistant bladder cancer by cystoscopy, bladder biopsy and urinary cytology. METHODS: Between January 1992 and August 2006, 127 bladder cancer patients underwent a cycle of eight weekly BCG instillations. Four weeks after the last BCG instillation, urinary cytological analysis and cystoscopy with targeted biopsy in addition to eight-nine selected-site biopsies were performed. RESULTS: Biopsy-proven cancer was found in 11/27 (40.7%), 5/42 (11.9%), and 11/58 (19.0%) of positive, suspicious, and negative cytology cases, respectively. Abnormal and normal cystoscopic findings correlated with a biopsy-proven cancer in 13/53 (24.5%) and 14/74 (18.9%) cases, respectively. The combination of a macroscopic cystoscopic suspicion and a positive cytology missed malignant cases in 15.9% of the cases. In 100 cases without biopsy-proven cancer, the rates of denuded urothelium at biopsy in the cases with positive and non-positive cytology were 7/16 (43.8%) and 16/84 (19.0%), respectively. CONCLUSIONS: According to our study, routine biopsy is recommended in the evaluation of BCG treatment, even if the timing, limitations and disadvantages of the procedure should be taken into account.

Clinical significance of lymphovascular invasion in upper urinary tract urothelial cancer.

OBJECTIVES: To clarify the significance of lymphovascular invasion (LVI) in patients with pT3N0M0 upper urinary tract (UUT) urothelial carcinoma (UC) relative to prognosis in terms of disease-specific survival, as LVI, which implies both blood vessel and lymph vessel involvement, is reportedly a poor prognostic factor in patients with UUT-UC. PATIENTS AND METHODS: The clinical records of 90 patients who had surgery for UUT-UC were reviewed retrospectively. The median patient age was 71 years and the median follow-up was 42 months. The prognostic significances of LVI (with vs without), T stage (< 1 vs 2-4), grade (1-2 vs 3), N stage (0 vs 1-2), age (< or = 70 vs > 70 years), gender and tumour location (renal pelvis vs ureter) for survival time were evaluated. RESULTS: LVI of UUT-UC was found in 34 patients (37.8%). There were significantly higher frequencies of LVI with advancing stage and lymph node metastasis. Kaplan-Meier analysis showed that LVI was strongly associated with disease-specific survival in all patients (P < 0.001) and in patients with pT3N0M0 disease (P < 0.001). Univariate analyses showed that LVI, T stage, N stage and tumour grade were significantly related to disease-specific survival in all patients (P < 0.001, < 0.001, 0.003 and 0.007, respectively). Multivariate analysis using Cox proportional hazards model showed that LVI was the only prognostic factor with independent significance for disease-specific survival (P < 0.001). CONCLUSIONS: LVI appears to be an important and independent prognostic factor for UUT-UC in patients treated by nephroureterectomy. Our data suggest that the LVI status might be a predictive marker for disease-specific survival in patients with T3N0M0 UTT-UC.

DNA repair gene polymorphisms may be associated with prognosis of upper urinary tract transitional cell carcinoma.

Upper urinary tract transitional cell carcinoma (UUT-TCC) is quite an uncommon disease, and its prognosis differs among individuals irrespective of tumor stage. DNA repair gene polymorphisms are reported to result in the modulation of the repair capacity and might influence the prognosis of UUT-TCC. We examined the associations between functional polymorphisms in five DNA repair genes, and the prognosis of UUT-TCC in 103 UUT-TCC patients. Variant alleles in xeroderma pigmentosum complementation group C, more than three total variant alleles in all DNA repair genes studied and more than two total variant alleles in three nucleotide excision repair genes were independently associated with improved overall and disease-specific survival of UUT-TCC patients in multivariate analysis (P = .0063 and P = .0005 for xeroderma pigmentosum complementation group C, P = .016 and P = .0016 for all genes, and P = .0053 and P = .018 for nucleotide excision repair genes, respectively). These results suggest that some DNA repair gene polymorphisms may preoperatively be valuable as prognostic factors for UUT-TCC beyond tumor stage and grade, helping to provide optimal treatment strategies for individual patients.

Overexpression of polo-like kinase 1 (PLK1) and chromosomal instability in bladder cancer.

Polo-like kinase 1 (PLK1) participates in bipolar spindle formation and entry into mitosis. Chromosomal instability (CIN) is caused by abnormalities in spindle formation and chromosome segregation. In this study, we investigated the relationship of PLK1 overexpression to CIN, and compared the PLK1 status with clinicopathological parameters in 101 human urothelial carcinomas of the urinary bladder. Expression of PLK1 and the number of centrosomes were assessed by immunohistochemistry. Numerical aberrations of chromosomes 7, 9 and 17 spots that allowed estimation of CIN were evaluated by fluorescence in situ hybridization, and DNA ploidy was assessed by laser scanning cytometry. Cancers with a large intercellular variation in centromere copy number were defined as CIN cancers. Tumors with PLK1 overexpression were associated more frequently with CIN (p < 0.0001), DNA aneuploidy (p = 0.0007) and centrosome amplification (p = 0.0013) than those without. Overexpression of PLK1 was significantly related to higher pathological grade (p = 0.0024), multiple tumors (p = 0.0241) and positive urine cytology (p = 0.0192). These data suggest that a high level expression of PLK1 confers tumor progression advantages to urothelial cancer cells, although other factors are also involved.

Identification of genes linked to gefitinib treatment in prostate cancer cell lines with or without resistance to androgen: a clue to application of gefitinib to hormone-resistant prostate cancer.

Understanding the molecular action of gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, might allow us to perform more effective therapies for hormone-independent advanced prostate cancer. A DNA microarray study was undertaken to comprehensively analyze the alteration of levels of 1,081 genes after gefitinib treatment in androgen-independent PC3 and DU145 cells and androgen-dependent LNCaP cells. The proliferation of PC3, DU145 and LNCaP cells was significantly inhibited by 50.2%, 83.8% and 55.2%, respectively, 6 days after 10 microM gefitinib administration. Of the above 1,081 genes, we identified 23, 13 and 33 genes with significantly different expression in PC3, DU145 and LNCaP cells, respectively, 24 h after 10 microM-gefitinib exposure. Among the identified genes, only Quiescin Q6, a negative cell cycle regulator, was increased after gefitinib treatment in all three cell lines regardless of gefitinib sensitivity. Except for Quiescin Q6, there were no overlapping genes between PC3 and DU145 cells. However, levels of several oncogenes or proliferation-related genes were changed after gefitinib treatment in the 2 androgen-independent cell lines. We also identified 7 unique genes [glycyl-tRNA synthetase, interferon, alpha-inducible protein, stratifin, nuclear factor of kappa light polypeptide gene enhancer in B-cells 1, dual specificity phosphatase 9, guanine nucleotide binding protein (G protein) beta polypeptide 2, neural retina leucine zipper] whose levels were altered exclusively after gefitinib administration in gefitinib-resistant PC3 and LNCaP cells, but not in DU145 cells, suggesting that these 7 genes could be targets for overcoming gefitinib resistance. Collectively, our molecular profiling data will serve as a framework for understanding the molecular action of gefitinib for prostate cancer.

Association between DNA repair gene polymorphisms and p53 alterations in Japanese patients with muscle-invasive bladder cancer.

OBJECTIVE: DNA repair enzymes play a vital role in protecting the genome from carcinogens, several of which can cause mutations in the TP53 gene in bladder cancer. Some single nucleotide polymorphisms (SNPs) in DNA repair genes reportedly modulate the repair capacity. This study aimed to clarify the effect of these functional SNPs on the alteration of p53 in muscle-invasive bladder cancer. METHODS: We investigated the association between SNPs in xeroderma pigmentosum complementation groups C (XPC), D and G and X-ray repair cross-complementing group 1 and 3 genes, and p53 expression and allelic imbalance at the TP53 locus in Japanese patients with muscle-invasive bladder cancer. p53 expression and the allelic imbalance were evaluated using immunohistochemistry and a microsatellite marker, respectively. RESULTS: Positive p53 expression was significantly less frequent in patients with the CC genotype of the XPC gene than in those with the AA or AC genotype (p = 0.0005). C alleles of the XPC gene were also less frequent in patients with positive p53 expression (p = 0.01). CONCLUSION: Our results suggested that the XPC polymorphism might affect p53 alteration and the molecular pathway defined by the p53 alteration in the development of muscle-invasive bladder cancer.

Deletion mapping of 18q in conventional renal cell carcinoma.

Loss of heterozygosity (LOH) is frequently associated with the inactivation of tumor suppressor genes. 18q LOH has been frequently reported in colorectal cancer and lung cancer; however, allelic loss on 18q has not been investigated in renal cell carcinoma (RCC). We evaluated LOH on 18q using nine microsatellite markers in 126 with conventional RCC (cRCC). LOH was observed in more than one 18q microsatellite locus in 24 cRCC (19%). We found the highest frequency of LOH (13.5%) at 18q21.3, where the DCC gene is located. We also assessed the relationship between LOH frequency and patient clinical parameters. Patients with a family history of cancer had a significantly higher frequency of 18q LOH than those without such a history (P=0.0017). No associations were found with other parameters, including gender, tumor grade, tumor stage, smoking status, and body mass index. The results suggest that inactivation of tumor suppressor genes at 18q21.3, including DCC and SMAD4 as candidates, may be involved in the tumorigenesis of some conventional RCCs.