Prognostic value of pre-treatment risk stratification and post-treatment neutrophil/lymphocyte ratio change for pembrolizumab in patients with advanced urothelial carcinoma.

BACKGROUND: Pembrolizumab is effective in a limited number of patients with advanced urothelial carcinoma (UC). Therefore, we evaluated the prognostic value of clinical biomarkers following pembrolizumab treatment in patients with advanced UC. METHODS: We retrospectively reviewed the medical records of 121 patients with platinum-refractory advanced UC who received pembrolizumab. Inflammation-based prognostic scores before and 6 weeks after the treatment were recorded. The categorical variables influencing overall survival (OS) and objective response rate (ORR) were analyzed. RESULTS: Multivariate analyses showed that pretreatment Eastern Cooperative Oncology Group (ECOG) performance score (PS), presence of only lymph node metastasis (only LN mets), C-reactive protein (CRP), and neutrophil/lymphocyte ratio (NLR) were independent prognostic factors for OS (P = 0.0077; RR = 2.42, P = 0.0049; RR = 0.36, P = 0.0047; RR = 2.53, and P = 0.0079; RR = 2.33, respectively). The pretreatment risk stratification using ECOG PS, only LN mets, CRP, and NLR was used for estimating the OS (P < 0.0001) and ORR (P < 0.0001). Furthermore, changes in NLR in response to pembrolizumab were significantly associated with the OS (P = 0.0002) and ORR (P = 0.0023). This change was also significantly correlated with OS even in the high-risk group stratified by this pretreatment risk stratification (P = 0.0069). CONCLUSIONS: This pretreatment risk stratification may be used for estimating the OS and ORR of patients with advanced UC treated with pembrolizumab. If changes in NLR in response to pembrolizumab treatment improve, pembrolizumab should be continued.

Identification of curable high-risk prostate cancer using radical prostatectomy alone: who are the good candidates for undergoing radical prostatectomy among patients with high-risk prostate cancer?

BACKGROUND: Currently, there is no consensus regarding which patients with high-risk prostate cancer (PCa) would benefit the most by radical prostatectomy (RP). We aimed to identify patients with high-risk PCa who are treatable by RP alone. METHODS: We retrospectively reviewed data on 315 patients with D'Amico high-risk PCa who were treated using RP without neoadjuvant or adjuvant therapy at the institutions of the Yamaguchi Uro-Oncology Group between 2009 and 2013. The primary endpoint was biochemical progression-free survival (bPFS) after RP. Risk factors for biochemical progression were extracted using the Cox proportional hazard model. We stratified the patients with high-risk PCa into 3 subgroups based on bPFS after RP using the risk factors. RESULTS: At a median follow-up of 49.9 months, biochemical progression was observed in 20.5% of the patients. The 2- and 5-year bPFS after RP were 89.4 and 70.0%, respectively. On multivariate analysis, Gleason score (GS) at biopsy (≥ 8, HR 1.92, p < 0.05) and % positive core (≥ 30%, HR 2.85, p < 0.005) were independent predictors of biochemical progression. Patients were stratified into favorable- (0 risk factor; 117 patients), intermediate- (1 risk factor; 127 patients), and poor- (2 risk factors; 57 patients) risk groups, based on the number of predictive factors. On the Cox proportional hazard model, this risk classification model could significantly predict biochemical progression after RP (favorable-risk, HR 1.0; intermediate-risk, HR 2.26; high-risk, HR 5.03; p < 0.0001). CONCLUSION: The risk of biochemical progression of high-risk PCa after RP could be stratified by GS at biopsy (≥ 8) and % positive core (≥ 30%).

Use of preoperative performance status and hemoglobin concentration to predict overall survival for patients aged ≥ 75 years after radical cystectomy for treatment of bladder cancer.

BACKGROUND: The standard of care for treatment of localized muscle-invasive bladder cancer (MIBC) is radical cystectomy (RC). The patient's condition may affect management of MIBC, especially for elderly patients with more comorbid conditions and lower performance status. We retrospectively evaluated the association between clinicopathological data and outcomes for patients with bladder cancer (BCa) treated by RC. We particularly focused on elderly patients (age ≥75 years) with BCa. METHODS: We enrolled 254 patients with BCa who underwent RC and urinary diversion with or without pelvic lymph node dissection. We assessed perioperative complications and clinicopathological data affecting overall survival (OS) after RC. RESULTS: The incidence of complications was 34.3 %, and that of severe complications (Grade 3-5) was 16.5 %. The elderly group experienced more severe complications (P = 0.042). Median follow-up was 43.0 months (range 1.0-155.6). Five-year OS after RC was 62.7 %. OS after RC was no different for patients aged ≥75 and <75 years (P = 0.983). Multivariate analysis revealed that Eastern Cooperative Oncology Group performance status (ECOG PS) and hemoglobin (Hb) concentration were associated with all-cause mortality. Hb concentration of <12.6 g/dl was an independent predictor of a poor prognosis among elderly patients after RC for BCa. ECOG PS >1 tended to affect OS after RC in this group. CONCLUSION: ECOG PS and preoperative Hb concentration were useful for prediction of clinical outcome after RC for elderly patients. This information may aid decision-making in the treatment of elderly patients with MIBC.

Impact of variant histology on disease aggressiveness and outcome after nephroureterectomy in Japanese patients with upper tract urothelial carcinoma.

BACKGROUND: Patients with urinary bladder urothelial carcinoma (UC) with variant histology have features of more advanced disease and a likelihood of poorer survival than those with pure UC. We investigated the impact of variant histology on disease aggressiveness and clinical outcome after radical nephroureterectomy (RNU) in Japanese patients with upper tract UC (UTUC). Information on variant histology might guide appropriate patient selection for adjuvant therapy after RNU. METHODS: We enrolled 502 UTUC patients treated with RNU in this retrospective cohort study, and analyzed associations of variant histology with clinicopathological variables and disease-specific survival. RESULTS: The median follow-up was 41.4 months. A total of 60 (12.0 %) UTUC patients had variant histology. UTUC with variant histology was significantly associated with advanced pathological T stage (pT ≥ 3), higher tumor grade (G3), and more lymphovascular invasion (P < 0.0001). Variant histology in all patients was significantly associated with worse disease-specific survival after RNU on univariate analysis (P = 0.0004), but this effect did not remain significant on multivariate analysis. However, variant histology was a significantly independent predictor for disease-specific survival in patients with pT ≥ 3 tumors (P = 0.0095). CONCLUSIONS: UTUC with variant histology might be a phenotype of high-grade, locally aggressive advanced tumors rather than of systemic disease. Variant histology may be useful for selection of patients with pT ≥ 3 UTUC for adjuvant therapy. Prospective studies in a larger number of patients with a centralized pathological review are needed to confirm our results.

Risk group stratification based on preoperative factors to predict survival after nephroureterectomy in patients with upper urinary tract urothelial carcinoma.

BACKGROUND: After radical nephroureterectomy (RNU), substantial numbers of patients with upper urinary tract urothelial carcinoma (UUT-UC) are ineligible for adjuvant chemotherapy owing to diminished renal function. Accurate preoperative prediction of survival is considered important because neoadjuvant chemotherapy may be as effective for high-risk UUT-UC as for muscle-invasive bladder cancer. We performed risk group stratification to predict survival based on specific preoperative factors. METHODS: We enrolled 536 UUT-UC patients treated with RNU in this retrospective cohort study and assessed preoperative clinical and laboratory variables influencing disease-specific survival. RESULTS: The median follow-up was 40.9 months. Using univariate analysis, tumor location; number of tumors; hydronephrosis; clinical T stage; clinical N category; voided urine cytology; neoadjuvant chemotherapy; hemoglobin; white blood cell (WBC) counts; and C-reactive protein had a significant influence on disease-specific survival (P < 0.05). Multivariate analysis revealed that clinical T stage, voided urine cytology, and WBC were independent predictors (P = 0.041, P = 0.020, and P = 0.017, respectively). We divided patients into three risk groups based on the number of the three independent predictors: 0, low risk; 1, intermediate risk; 2 and 3, high risk. Significant differences in disease-specific survival were found among these risk groups (P ≤ 0.0047). CONCLUSIONS: Our results suggest that risk group stratification based on preoperative clinical T stage, voided urine cytology, and WBC counts may be useful for selection of UUT-UC patients for neoadjuvant chemotherapy. Prospective studies with larger numbers of patients and a longer follow-up period are needed to confirm our results.

Can docetaxel therapy improve overall survival from primary therapy compared with androgen-deprivation therapy alone in Japanese patients with castration-resistant prostate cancer? A multi-institutional cooperative study.

BACKGROUND: To verify the actual clinical benefit of docetaxel (DOC) therapy and to explore the prognostic factors that may predict overall survival in Japanese patients with castration-resistant prostate cancer (CRPC). METHODS: Baseline characteristics-matched CRPC patients who received conventional androgen-deprivation therapy (ADT) or ADT plus DOC were compared retrospectively. The primary endpoint was overall survival (OS) from primary therapy. Secondary endpoints were response of tumor(s), prostate-specific antigen (PSA) levels, and toxicity. RESULTS: Median OS was significantly longer in the DOC group (n = 117) than the control group (n = 118) (94.0 vs. 70.0 months, P = 0.0077) and the corresponding hazard ratio (HR) for death in DOC group was 0.566 [95% confidence interval (95%CI) 0.370-0.867; P = 0.0088]. Effective DOC groups [medium dose (50-69 mg/m(2)) and high dose (≥70 mg/m(2))] had significantly longer median OS than control even when survival times were calculated from the start of castration-resistant events (151 vs. 36 months; P = 0.0173) and the corresponding HR for death in the DOC group was 0.515 (95%CI 0.293-0.903; P = 0.0205). In multivariate analysis, statistically significant prognostic indicators were Gleason score, time to CRPC events, and receipt of DOC therapy. Response rate of both measurable lesion and PSA was not significantly different between each DOC dose group. Grade 3 or 4 adverse events associated with low- [30-49 mg/m(2)], medium-, and high-dose DOC were 21.9, 35.7, and 90.7%, respectively. No death due to DOC therapy was reported. CONCLUSION: Treatment with DOC improves OS from primary therapy compared with conventional ADT alone in Japanese patients with CRPC.

Risk group stratification to predict recurrence after transurethral resection in Japanese patients with stage Ta and T1 bladder tumours: validation study on the European Association of Urology guidelines.

OBJECTIVE: • To validate the European Association of Urology (EAU) guidelines on risk group stratification to predict recurrence in Japanese patients with stage Ta and T1 bladder tumours. PATIENTS AND METHODS: • A cohort of 592 Japanese patients who were treated with transurethral resection (TUR) and histopathologically diagnosed with Ta and T1 urothelial carcinoma of the bladder were enrolled in this retrospective study. • The primary endpoint of the present study was recurrence-free survival, and the median follow-up duration was 37 months in recurrence-free survivors. RESULTS: • Multivariate Cox proportional hazards regression analysis showed that the Eastern Cooperative Oncology Group performance status (ECOG PS), prior recurrence rate, number of tumours and T category were independent predictors of time to recurrence (P < 0.05). According to the EAU guidelines for predicting recurrence, the vast majority of Japanese patients were classified into intermediate risk. • The intermediate-risk patients were further divided into intermediate-low-risk and intermediate-high-risk subgroups based on the European Organization for Research and Treatment of Cancer risk table, and a significant difference in the recurrence-free survival rates was found between these subgroups (P < 0.001). • It was also found that patients with high risk combined with intermediate-high risk had significantly poorer recurrence-free survival rates than those with low risk combined with intermediate-low risk (P < 0.001). CONCLUSIONS: • This is the first report on the ECOG PS as a potentially useful predictor for bladder tumour recurrence. • The risk group stratification of the EAU guidelines for recurrence might not be applicable to Japanese patients with Ta and T1 bladder tumours, but the subgroup classification of intermediate risk could be appropriate.

Haploinsufficiency of 8p22 may influence cancer-specific survival in prostate cancer.

Although Knudson's two-hit hypothesis with functional loss of a tumor suppressor gene has been widely accepted, accumulating evidence suggests that several genes are regulated by the quantity of their product in a dose-dependent manner (gene dosage effect). The study was designed to identify the influence of gene dosage effect of 8p22 on patient prognosis. With a median age of 71 years, 40 patients with prostate cancer (11 organ-confined, 13 capsular penetrating, and 16 nodal and/or distant metastatic) were followed for a median of 68.5 months. A fluorescence in situ hybridization (FISH) technique was applied using a region-specific cosmid probe combined with centromeric probe. Allelic losses of 8p22, 8p21.3, 8p21.1 approximately 2, and 8p12 were found in 23, 22, 14, and 9 patients, respectively. A Cox proportional hazard model revealed that decreased fraction (i.e., the fraction of nuclei with a lesser number of cosmid signals than of centromeric probe signals) of 8p22 proved to be the sole independent prognostic factor predicting cancer-specific death, as well as disease progression--but allelic loss of 8p22 was not predictive. Cytogenetic estimation of 8p22 by FISH can yield quantitative evaluation of relevant gene dosage, which may become a useful biomolecular marker predicting poor patient prognosis.

Smoking may cause genetic alterations at 5q22.2 approximately q23.1 in clear-cell renal cell carcinoma.

The aim of this study was to examine the relationship between allelic imbalance (AI) on chromosome 5q and clinico-pathologic parameters, including cigarette smoking. We examined the AI on chromosome 5q in 119 clear-cell renal cell carcinomas (CRCC) by a fluorescent polymerase chain reaction technique using nine microsatellite markers. AI of one or more loci was found in 43 cases (36.1%). The most frequent AI was observed at chromosome 5q23.1 (D5S467), where the LOX gene is located. The minimally involved region ranged from 5q22.1 to 5q23.2, with a possible breakpoint between 5q22 and 5q22.1. Regarding the relationships between the frequency of AI and the clinico-pathologic and environmental backgrounds, smokers had a significantly higher frequency of AI of 5q22.2 approximately q22.3 (D5S471) than nonsmokers (P = 0.013). No other significant associations were found between AI of specific loci and other parameters. Our results suggest that AI at 5q plays an important role in the genesis of CRCC. In addition, smoking may cause genetic alterations at 5q22.2 approximately q23.1, where the LOX gene is located.

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.

Allelic loss of 3p25 associated with alterations of 5q22.3 approximately q23.2 may affect the prognosis of conventional renal cell carcinoma.

Little is known about the clinical significance at the frequent association of 3p loss with 5q gain/loss in conventional renal cell carcinoma (RCC). We analyzed the clinical significance of copy number gain and loss at 5q21 approximately q23 combined with allelic loss of 3p25 (including the VHL gene). Fifty RCCs were examined by dual-color fluorescence in situ hybridization with DNA probes for D3Z1 (3cen), cCI3-865 (3p25.1 approximately p25.3), D5S23 (5p15.2), cCI5-243 (5q21.2 approximately q21.3), and cCI5-215 (5q22.3 approximately q23.2). In patients who had 3p loss, there was a significant association of loss at 5q22.3 approximately q23.2 with large tumors (>7 cm) and high-grade tumors (both P < 0.05), whereas gain at 5q22.3 approximately q23.2 was associated with low-grade tumors (P < 0.05). There was also a significant association loss at 5q21.2 approximately q21.3 high-grade tumors in patients with 3p loss (P < 0.05). Patients with 3p loss and gain at 5q22.3 approximately q23.2 had a significantly better disease-specific survival than those who had 3p loss without such gain (P < 0.05). Allelic loss of 3p25 including the VHL gene is thought to be an immediate event in the development of conventional RCC. Copy number gains or losses of 5q21 approximately q23 are thought to be events that lead to tumor progression although the clinical significance of either gains or losses is not well known.

Centrosome hyperamplification predicts progression and tumor recurrence in bladder cancer.

PURPOSE: Recent studies have reported that centrosome hyperamplification (CH) is closely related to chromosomal instability in bladder cancer. In this study, we investigated whether CH could be used as a prognostic biomarker for patients with bladder cancer. EXPERIMENTAL DESIGN: CH was evaluated by immunohistochemistry in 50 bladder cancers (< or =pT1: 43; > or =pT2: 7). In addition, numerical aberrations of chromosomes 7, 9, and 17 and gain of 20q13, on which the Aurora-A gene is located, were evaluated by fluorescence in situ hybridization, and DNA ploidy was assessed. Preliminary experiments on eight bladder cancer cell lines found that six had over 5% of CH cells associated with a gain of 20q13 and overexpression of Aurora-A; therefore, CH-positive cases (CH+) were defined as those having over 5% of cells with > or =3 centrosomes per cell. RESULTS: CH+, 20q13 gain, chromosomal instability, and DNA aneuploidy were detected in 30 (60%), 18 (36%), 22 (44%), and 19 (38%) patients, respectively. There were significant differences in tumor number, grade, recurrence, and progression between the CH+ and CH- groups. The later had significantly higher recurrence-free and progression-free survivals than the former (P = 0.0028 and P = 0.0070, respectively, log-rank test). Multivariate analysis revealed that CH+ was the strongest predictor for tumor recurrence in nonmuscle invasive (pTa and pT1) bladder cancer (hazard ratio, 1.882; 95% confidence interval, 1.161-3.325; P = 0.0094). CONCLUSIONS: Detection of CH may provide crucial prognostic information about tumor recurrence in bladder cancer.

Renal cell carcinoma: allelic loss at chromosome 9 using the fluorescent multiplex-polymerase chain reaction technique.

Loss of tumor-suppressor genes on both arms of chromosome 9 appears to be common in many types of cancer. Chromosome 9q is often partially deleted in bladder cancer, lung cancer, and basal cell carcinoma. However, little data are available on allelic loss on chromosome 9 in renal cell carcinoma (RCC). One hundred and nine nonpapillary RCCs were studied for loss of heterozygosity (LOH) at 13 loci on chromosome 9 by using the fluorescent multiplex-polymerase chain reaction method to compare DNA from tumor samples and peripheral blood lymphocytes. At the loci tested, LOH was found in from 2.3% (9q31, D9S938) to 17% (9q22, 1AJL) of informative cases, and 27 (24.8%) of the 109 RCCs had LOH at 1 or more loci of chromosome 9. LOH was more often detected at 9q22 within the PTCH gene (17%) when compared with LOH at the other 12 loci (P = 0.0172). Regarding the relationship with clinical parameters, however, there were no statistically significant associations between this LOH and tumor stage or grade. Among the 109 tumors, 6 (5.5%) showed replication errors. Our results suggest that LOH of the PTCH gene may be related to the development of nonpapillary RCC, although the clinical relevance has not been not clarified.

Numerical aberrations of chromosome 9 in bladder cancer. A possible prognostic marker for early tumor recurrence.

To investigate whether nonrandom aberrations of chromosomal numbers could predict tumor recurrence in patients with bladder cancer, archival urine cytology specimens (Giemsa-stained) from patients previously treated for transitional cell carcinoma of the urinary bladder were studied retrospectively by fluorescence in situ hybridization. A total of 48 patients (pTis, 6; pTa, 2: pT1, 32; and pT2-4, 8) were consecutively enrolled in this study, and numerical aberrations of chromosomes 9 and 17 were investigated. Cytology was diagnosed as negative for malignancy in 18 patients and positive in 30 patients. Twenty-seven of the 48 patients (56%) had one or more chromosomal aberrations. The frequency of numerical aberrations of chromosome 17 was correlated with increasing stage and grade, whereas loss of copies of chromosome 9 (monosomy) was frequently observed at a lower stage and grade. Chromosomal aberrations were detected in 9 (50%) of 18 patients with negative or equivocal cytology (class I, II, or III) by the Papanicolaou classification. Of eight patients with negative or equivocal cytology who developed tumor recurrence, four (50%) showed monosomy 9 and one (14%) showed a numerical aberration of chromosome 17. All six patients who showed monosomy of chromosome 9 developed tumor recurrence within 12 months, whereas four of the nine patients who did not show monosomy of this chromosome developed recurrence within 12 months (P<0.05, Fisher test). These results suggest that monosomy of chromosome 9 might be a prognostic marker for early tumor recurrence in patients with negative or equivocal cytology specimens.

Accuracy of an array comparative genomic hybridization (CGH) technique in detecting DNA copy number aberrations: comparison with conventional CGH and loss of heterozygosity analysis in prostate cancer.

Although genomic DNA microarray (array comparative genomic hybridization [CGH]) technique is a rapid and powerful diagnostic tool for the comprehensive analysis of detailed chromosomal alterations of DNA copy numbers, its accuracy has not been well demonstrated. To clarify the accuracy of this technique, we applied array CGH spotted with 283 specific genes to 11 clinical prostate cancers, and the results were compared with comparative genomic hybridization (conventional CGH) and loss of heterozygosity (LOH) analysis using microsatellite DNA markers. The overall rate of correspondence between array CGH and conventional CGH with respect to the loss of DNA sequences was 94.5%. When the results of both CGH techniques were compared with those of LOH analysis, the correspondence rate of array CGH was significantly higher than that of conventional CGH (93.4% vs. 72.2%, P<0.05). In conclusion, the accuracy of array CGH was higher than that of conventional CGH in detecting losses of the DNA sequences. Array CGH is shown to be a promising tool for screening to identify unknown genes involved in tumorigenesis in prostate cancer.

Clinical significance of allelic loss of chromosome region 5q22.3 approximately q23.2 in nonpapillary renal cell carcinoma.

To analyze the clinical significance of copy number gain and loss at chromosome region 5q21 approximately q23, 105 nonpapillary renal cell carcinomas (RCC) were examined by interphase cytogenetic analysis using the dual-color fluorescence in situ hybridization (FISH) technique. DNA probes for D5S23 (5p15.2), cCI5-243 (5q21.2 approximately q21.3), and cCI5-215 (5q22.3 approximately q23.2) were used, and the signals for cCI5-243 and cCI5-215 were compared with those for D5S23 as the numerical control. Aneusomy (three or more copies) of chromosome 5 was found in 22 tumors (21.0%). Aneusomy was significantly correlated with loss at 5q21 approximately q23, while disomy with gain at 5q21 approximately q23 (P<0.05). Aneusomy was also significantly related to poor disease-specific survival (P<0.01). Gain and loss at cCI5-243 were seen in 34 (32.4%) and 59 (56.2%) tumors, respectively, while gain and loss at cCI5-215 occurred in 55 (52.4%) and 45 (42.9%) cases, respectively. The frequency of gain at cCI5-215 was significantly correlated with a smaller tumor diameter (7 cm or less, P<0.05), while loss with a larger one (>7 cm, P<0.05). Both loss at cCI5-215 and aneusomy of chromosome 5 were significantly related to poor disease-specific survival (P<0.05). In conclusion, alterations of chromosome 5 (including allelic loss of 5q22.3 approximately q23.2) could be a useful genetic marker for predicting the patient prognosis of RCC.

DNA sequence copy number aberrations in prostate cancers: a comparison of comparative genomic hybridization data between Japan and European countries.

Incidence of prostate cancer in Japan and resultant mortality rates are lower than in Western countries. To elucidate the reasons behind this, the genetic characteristics of prostate cancer in Japanese patients were investigated. Comparative genomic hybridization was applied in 27 cases of prostate cancers in Japanese patients. Frequent gains were found at Xq, 8q, Xp, and 7q and frequent losses at 8p, 6q, 2q, 16q, and 17p (in decreasing order of frequency). Loss of 6q was frequently detected in both early and advanced tumors. Gains of 7q and 8q and loss of 8p were more frequent in advanced than early tumors. The frequency of 13q loss in primary tumors was significantly lower in patients in Japan than in European countries. These data suggest that a loss of 6q is associated with the development of prostate cancer, and that gains of 7q and 8q and a loss of 8p are linked with cancer progression. The frequency of 13q loss may imply differences in biological behavior of prostate cancer between Japan and Western countries.

Clinical significance of lymph node dissection in renal cell carcinoma.

OBJECTIVE: To identify the role of lymph node dissection in renal cell carcinoma (RCC). MATERIAL AND METHODS: A total of 100 patients (66 males, 34 females) were enrolled in the study. The mean age and tumor size were 61.4 years and 5.8 cm, respectively. A total of 41 patients (41%) had tumors <4 cm in diameter. The pathological status was pT1, pT2 and pT3 in 60, 11 and 29 patients, respectively. RESULTS: In total, lymph node metastases were found in seven cases (7%). Of 40 patients with pT1a tumors (tumor size <4 cm), one (2.5%) had lymph node metastasis. Patients with lymph node metastases had significantly larger tumors than those without (8.9 vs 5.5 cm; p<0.05). Regarding patient outcome, 33 (33%) had tumor progression (alive with disease, n=14; disease-specific death, n=19) after a median follow-up period of 54.0 months. In univariate analysis, 15/18 prognostic markers [tumor size, tumor grade, pT, pN and M categories, stage, microscopic venous invasion (V category), microscopic lymphatic invasion (Ly category), pathological tumor infiltration pattern (INF category), plasma fibrinogen, C-reactive protein, immunosuppressive acidic protein, alpha-2 globulin and erythrocyte sedimentation rates at 1 and 2 h] were common significant predictors of tumor progression. A Cox hazard model revealed tumor size, tumor grade and pathological stage to be independent prognostic factors. CONCLUSIONS: Tumor size is a crucial prognostic factor for tumor progression, and lymph node dissection may be omitted in T1a tumors.

Bax to Bcl-2 ratio and Ki-67 index are useful predictors of neoadjuvant chemoradiation therapy in bladder cancer.

OBJECTIVE: In this study, locally advanced bladder cancer was treated by radiation combined with cisplatin therapy and a retrospective analysis was conducted to predict the clinical response to chemoradiotherapy (CRT) based on the immunohistochemistry of apoptosis-related proteins. METHODS: Sixty-two patients (median age, 68 years; range, 45-89 years) with transitional cell carcinoma of the bladder (pT1G3-pT4M0) treated with CRT (median dose: 40.5 Gy of radiation and 230 mg of cisplatin) were studied. Mucosal biopsy was performed before and after CRT. Paraffin-embedded tumor specimens were examined with TUNEL and were immunostained for Ki-67, p53, Bcl-2 and Bax; the Bax/Bcl-2 ratio and apoptosis index (AI) were calculated. Clinical features of the patients and response to CRT were compared with data obtained from examination of the tumors. RESULTS: The 62 patients had a median follow-up period of 34 months (range, 3-84 months). Responses to CRT were as follows: CR, 34%; PR, 45%; NC, 21%. The survival rate of patients with Ki-67-positive tumors was significantly lower than those of patients with Ki-67-negative tumors (P < 0.05). No significant correlation was observed between the expression of any protein, the AI and the clinical response. However, the Bax/Bcl-2 ratio showed a significant association with the CR rate (P = 0.0289). CONCLUSIONS: The results of this study suggest that the combined assessment of Bcl-2 and Bax protein expression may be used to predict a clinical response to CRT based on the Bax/Bcl-2 ratio determined before therapy. The Ki-67 index may be a useful predictor of prognosis in patients treated by CRT.

A single nucleotide polymorphism in the matrix metalloproteinase-1 promoter is associated with conventional renal cell carcinoma.

Matrix metalloproteinase (MMP)-1 is associated with tumor cell invasion and metastasis, and its promoter polymorphism has been shown to influence the transcriptional level. Our study explored the association between this polymorphism and renal cell carcinoma in a Japanese population. DNA was extracted from peripheral blood and normal tissue of 119 patients with conventional renal cell carcinoma (RCC) and from 210 age- and sex-matched healthy volunteers. Genotyping was carried out using direct sequencing. In the MMP-1 gene promoter polymorphism, it was demonstrated that the frequency of the 2G/2G genotype, which is associated with higher enzyme activity, was significantly higher in patients with RCC than in controls (p = 0.0015; OR = 2.082; 95% CI 1.317-3.293). When stratified for gender, only men showed a significant association of the polymorphism with RCC (p = 0.0028; OR = 2.307; 95% CI 1.333-3.990). However, no significant association was observed between the 2G/2G genotype and clinicopathologic parameters including age, gender, tumor grade and pathologic stage. Our present data suggest that the MMP-1 promoter polymorphism may be linked to susceptibility for conventional RCC.