Neoadjuvant gemcitabine plus carboplatin for locally advanced bladder cancer.

OBJECTIVE: Although cisplatin-based neoadjuvant chemotherapy followed by cystectomy was demonstrated to improve the survival among patients with locally advanced bladder cancer, its severe adverse events, including nephrotoxicity, are critical issues. We investigated the safety and activity of carboplatin, a mild nephrotoxic agent, combined with gemcitabine as a neoadjuvant chemotherapy compared with methotrexate, vinblastine, doxorubicin and cisplatin for patients with locally advanced bladder cancer. METHODS: We retrospectively evaluated 68 patients with locally advanced bladder cancer who received neoadjuvant methotrexate, vinblastine, doxorubicin and cisplatin (n = 34) or gemcitabine and carboplatin (n = 34) followed by cystectomy at our institute. The adverse events, chemotherapy delivery profile, rate of down-stage and recurrence-free survival were assessed for methotrexate, vinblastine, doxorubicin and cisplatin compared with gemcitabine and carboplatin. RESULTS: The mean cycles of methotrexate, vinblastine, doxorubicin and cisplatin, and gemcitabine and carboplatin, were 2.5 and 2.7, respectively. The hematologic adverse events of Grade 3 or 4 neutropenia, anemia and thrombocytopenia for methotrexate, vinblastine, doxorubicin and cisplatin were 15, 18 and 0%, respectively. The occurrences for gemcitabine and carboplatin were 53, 21 and 50%, respectively. Grade 3 or 4 non-hematologic toxicities for methotrexate, vinblastine, doxorubicin and cisplatin were nausea and vomiting in 24%, and were not observed for gemcitabine and carboplatin. The lowest median estimated glomerular filtration rate during methotrexate, vinblastine, doxorubicin, and cisplatin and gemcitabine and carboplatin was 55.8 and 70.6 ml/min/1.73 m(2), respectively (P = 0.002). The rate of down-stage to pT1 or less was 59% for methotrexate, vinblastine, doxorubicin and cisplatin, and 53% for gemcitabine and carboplatin (P = 0.624). The recurrence-free survival of methotrexate, vinblastine, doxorubicin and cisplatin, and gemcitabine and carboplatin, at 36 months from the diagnosis was 79 and 75%, respectively (P = 0.85). CONCLUSIONS: Neoadjuvant gemcitabine and carboplatin showed less non-hematologic toxicity than methotrexate, vinblastine, doxorubicin and cisplatin, and especially less nephrotoxicity was demonstrated for gemcitabine and carboplatin. Although observed during the short term, the recurrence-free survival for gemcitabine and carboplatin was comparable to that for methotrexate, vinblastine, doxorubicin and cisplatin.

Resveratrol suppresses growth of cancer stem-like cells by inhibiting fatty acid synthase.

Resveratrol is a natural polyphenolic compound and has been shown to exhibit cardio-protective as well as anti-neoplastic effects on various types of cancers. However, the exact mechanism of its anti-tumor effect is not clearly defined. Resveratrol has been shown to have strong hypolipidemic effect on normal adipocytes and as hyper-lipogenesis is a hallmark of cancer cell physiology, the effect of resveratrol on lipid synthesis in cancer stem-like cells (CD24(-)/CD44(+)/ESA(+)) that were isolated from both ER+ and ER- breast cancer cell lines was examined. The authors found that resveratrol significantly reduced the cell viability and mammosphere formation followed by inducing apoptosis in cancer stem-like cells. This inhibitory effect of resveratrol is accompanied by a significant reduction in lipid synthesis which is caused by the down-regulation of the fatty acid synthase (FAS) gene followed by up-regulation of pro-apoptotic genes, DAPK2 and BNIP3. The activation of apoptotic pathway in the cancer stem-like cells was suppressed by TOFA and by Fumonisin B1, suggesting that resveratrol-induced apoptosis is indeed through the modulation of FAS-mediated cell survival signaling. Importantly, resveratrol was able to significantly suppress the growth of cancer stem-like cells in an animal model of xenograft without showing apparental toxicity. Taken together, the results of this study indicate that resveratrol is capable of inducing apoptosis in the cancer stem-like cells through suppression of lipogenesis by modulating FAS expression, which highlights a novel mechanism of anti-tumor effect of resveratrol.

Inter-software variability in post-implanted CT analysis for interstitial permanent brachytherapy for prostate cancer: differences in automatically detected seed location.

Purpose. The present study investigated inter-software variability in automatically detected seed location and dose volume histogram (DVH). Materials and methods. Image sets from computed tomography (CT) of 25 patients treated using interstitial permanent brachytherapy were examined. Interplant and Variseed were used as software for post-implanted CT analysis. Seed locations are automatically detected by Variseed and Interplant. Dose-volume histograms were calculated using seed locations as detected by the two programs. DVH parameters were compared between Variseed and Interplant. Results. Considerable differences in DVH parameters existed between Variseed and Interplant. For example, mean differences in dose to 90% of prostate volume (pD90) and dose to 5% of urethral volume (uD5) were 8.27 Gy and 20.18 Gy, respectively. The difference in uD5 was associated with prostate volume. Conclusion. Our results suggest that considerable inter-software variability exists in post-implanted CT analysis. DVH parameters from other software should be used with care.

[COMPLETE RESECTION OF URACHAL CARCINOMA WITH SIGMOID COLON INVASION AFTER FOLFOX CHEMOTHERAPY: A CASE REPORT].

A 45-years-old man presented discharge of abscess from the umbilicus with lower abdominal pain. CT scan showed huge tumor from the bladder to the umbilical part with sigmoid colon invasion. He was diagnosed as urachal carcinoma, which was confirmed by pathological examination. We started FOLFOX chemotherapy according to advanced colon cancer. Approximately 80% of reduction was accomplished after 11 courses of FOLFOX. We performed radical cystectomy with sigmoid colon resection. Pathological examination revealed complete resection with negative surgical margin. No recurrence and metastasis were observed after 30 months of surgery. Urachal carcinoma is often advanced cancer when diagnosed. Effective chemotherapy is not established well. FOLFOX chemotherapy demonstrated the well antitumor effect in this case.

Multi-institutional retrospective analysis of learning curves on dosimetry and operation time before and after introduction of intraoperatively built custom-linked seeds in prostate brachytherapy.

This multi-institutional retrospective analysis examined learning curves for dosimetric parameters and operation time after introduction of intraoperatively built custom-linked (IBCL) seeds. Data from consecutive patients treated with seed implantation before and after introduction of IBCL seeds (loose seed, n = 428; IBCL seed, n = 426) were collected from 13 centers. Dose-volume histogram parameters, operation times, and seed migration rates were compared before and after introduction of IBCL seeds. At the 1-month CT analysis, no significant differences were seen in dose to 90% of prostate volume between before and after IBCL seed introduction. No learning curve for dosimetry was seen. Prostate and rectal volume receiving at least 150% of prescription dose (V150 and RV150) were higher in the loose-seed group than in the IBCL-seed group. Operation time was extended by up to 10 min when IBCL seeds were used, although there was a short learning curve of about five patients. The percentage of patients with seed migration in the IBCL-seed group was one-tenth that in the loose-seed group. Our study revealed no dosimetric demerits, no learning curve for dosimetry, and a slightly extended operation time for IBCL seeds. A significant reduction in the rate of seed migration was identified in the IBCL-seed group.

[Refractory germ cell cancer of testis treated by salvage high-dose chemotherapy: report of three cases].

We reported three cases (42, 20 and 18-year-old men) of advanced nonseminomatous testicular germ cell cancer treated by salvage high-dose chemotherapy (HDC) supported by peripheral blood stem cell autotransplantation. Two cases which had been refractory to (B) EP (bleomycin, etoposide, cisplatin) and VIP (etoposide, ifosfmide, cisplatin) chemotherapies received one course of high-dose CEI (carboplatin 1,250 mg/m2, etoposide 1,500 mg/m2 and ifosfamide 7.5 g/m2), and the other case had been refractory to PVB (cisplatin, vinblastine, bleomycin) and VIP chemotherapies received one course of high-dose CEI and high-dose CCT (carboplatin 800 mg/m2, cyclophosphamide 6 g/m2 and thiotepa 720 mg/m2). Only one case achieved an incomplete remission by HDC, which was verified as a pathological complete response at the following salvage surgery, and has been alive with no evidence of disease for 68 months. The others achieved no change of disease following HDC and died from cancer progression. Hepatotoxicity, neurotoxicity and severe depression occurred, but not fatal in 2 cases.

Three-dimensional summation of rectal doses in brachytherapy combined with external beam radiotherapy for prostate cancer.

BACKGROUND AND PURPOSE: To determine the dose constraints for rectal bleeding in brachytherapy (BRT) combined with external beam radiotherapy (EBRT). MATERIALS AND METHODS: Post-BRT, pelvic computed tomography images were used for subsequent EBRT planning and BRT postplans in 37 patients. The physical doses for each plan were converted to biologically effective doses, and corresponding voxel doses were integrated to plot the summed dose-volume histogram (sum-DVH). Between 5 patients with (bled-pts) and 32 without (spared-pts) grade 2 or 3 rectal bleeding, the differences in the mean minimal dose (rDn) covering the rectal volume of 0.5-10.0 cc and the rectal volume (rVn) receiving the calculated dose of 20-150Gy were compared. RESULTS: The differences in the summed-rDn were determined by BRT exposure, while those of the summed-rVn were determined in the low-dose range and superimposed in the high-dose range by EBRT exposure. Of the 13 patients with rV150 of >1.2 cc, 4 were bled-pts (30.8%). Of the 24 patients with rV150 of ≤ 1.2cc, 1 was a bled-pts (4.2%) (p=0.024; odds ratio, 10.2; CI (95%), 1.0-104.3). CONCLUSIONS: The mono-scale DVH analysis is a promising method for exploring the threshold for rectal bleeding in combined radiotherapy.

Narrow safety range of intraoperative rectal irradiation exposure volume for avoiding bleeding after seed implant brachytherapy.

BACKGROUND & PURPOSE: Rectal toxicity is less common after 125I seed implant brachytherapy for prostate cancer, and intraoperative rectal dose-volume constraints (the constraint) is still undetermined in pioneering studies. As our constraint failed to prevent grade 2 or 3 rectal bleeding (bled-pts) in 5.1% of patients, we retrospectively explored another constraint for the prevention of rectal bleeding. MATERIALS AND METHODS: The study population consisted of 197 patients treated with the brachytherapy as monotherapy using real-time intraoperative transrectal ultrasound (US)-guided treatment at a prescribed dose of 145 Gy. Post-implant dosimetry was performed on Day 1 and Day 30 after implantation using computed tomography (CT) imaging. Rectal bleeding toxicity was classified by CTC-AE ver. 3.0 during a mean 29-month (range, 12-48 months) period after implantation. The differences in rV100s were compared among intraoperative, Day 1 and Day 30 dosimetry, and between that of patients with grade 2 or 3 rectal bleeding (the bled-pts) and of the others (the spared-pts). All patients were divided into groups based on provisional rV100s that were increased stepwise in 0.1-cc increments from 0 to 1.0 cc. The difference in the ratios of the bled-pts to the spared-pts was tested by chi-square tests, and their odds ratios were calculated (bled-OR). All statistical analyses were performed by t-tests. RESULTS: The mean values of rV100us, rV100CT_1, and rV100CT_30 were 0.31 ± 0.43, 0.22 ± 0.36, and 0.59 ± 0.68 cc, respectively. These values temporarily decreased (p = 0.020) on Day 1 and increased (p = 0.000) on Day 30. There was no significant difference in rV100s between the bled-pts and spared-pts at any time of dosimetry. The maximum bled-OR was identified among patients with an rV100us value above 0.1 cc (p = 0.025; OR = 7.8; 95% CI, 1.4-145.8); an rV100CT_1 value above 0.3 cc (p = 0.014; OR = 16.2; 95% CI, 3.9-110.7), and an rV100CT_30 value above 0.5 cc (p = 0.019; OR = 6.3; 95% CI, 1.5-42.3). CONCLUSION: By retrospective analysis exploring rV100 as intraoperative rectal dose-volume thresholds in 125I seed implant brachytherapy for prostate cancer, it is proved that rV100 should be less than 0.1 cc for preventing rectal bleeding.

Matched-pair analysis and dosimetric variations of two types of software for interstitial permanent brachytherapy for prostate cancer.

The purpose of this study was to determine whether identical dosimetric results could be achieved using different planning software for permanent interstitial brachytherapy for prostate cancer. Data from 492 patients treated with brachytherapy were used for matched-pair analysis. Interplant and Variseed were used as software for ultrasound-based treatment planning. Institution, neoadjuvant hormonal therapy, prostate volume, and source strength were used for factors to match the 2 groups. The study population comprised of 126 patients with treatment planning using Interplant software and 127 matched patients using Variseed software. Dosimetric results were compared between the 2 groups. The Variseed group showed significantly higher values for dose covering 90% of prostate volume (pD90), prostate volume covered by 150% of prescription dose (pV150), and dose covering 30% of the urethra (uD30) compared with the Interplant group. Our results showed that use of different software could lead to different dosimetric results, which might affect the clinical outcomes.

Effects of ellipsoid prostate deformation on dose delivery during permanent interstitial brachytherapy.

PURPOSE: To elucidate the potential effects of prostate deformation on dose distribution during Iodine-125 ((125)I) seed implantation brachytherapy for prostate cancer. METHODS AND MATERIALS: A retrospective analysis of 245 patients who underwent only transperineal brachytherapy for low-risk prostate adenocarcinoma was performed. The maximum diameters of the prostate were measured before treatment by transrectal ultrasound volumetry along right to left (RL), anterior to posterior (AP), and apex to base (Length) directions. The seeds were inserted by the modified peripheral loading method using real-time ultrasound-guided seed placement. The ellipsoid deformation rates in the axial plane (E(ax)) and in the sagittal plane (E(sag)) were defined as [RL-AP]/RL and [Length-AP]/Length, respectively. The correlation between them and the dose-volume histogram parameters at 30 days after the operation was evaluated. A simulation test was additionally performed to ascertain the change in dose distribution among virtual volumes built in a radiotherapy planning device that corresponds to prostates with increased Eax or Esag. RESULTS: The mean Esag and Eax of patients were 0.313 (range, -0.28 to 0.844) and 0.261 (range, -0.02 to 0.54), respectively. Esag showed a positive correlation with dose (Gy) covering 90% of the prostate volume (pD(90)), prostate volume (%) covered by 100% of the prescribed dose (pV(100)), the rectal volume (cc) irradiated by 100% of the prescribed dose (rV(100)), and the rectal volume (cc) irradiated by 150% of the prescribed dose (rV(150)), whereas Eax showed a positive correlation with prostate volume (%) covered by 150% of the prescribed dose (pV(150)) and the urethral dose (Gy) delivered to 5% of its volume (uD(5)). The simulation test suggested that the prescribed dose resulted in the best coverage in patients with increased E(sag), and that patients with increased E(ax) exhibited poor urethral sparing from overdosage. CONCLUSION: In the seed implantation method, ellipsoid deformation of the prostate causes higher rectal dose exposure or dose delivery to the urethra.

Differences between intraoperative ultrasound-based dosimetry and postoperative computed tomography-based dosimetry for permanent interstitial prostate brachytherapy.

PURPOSE: To compare the results of intraoperative ultrasound (US)-based dosimetry with those of postimplant computed tomography (CT)-based dosimetry after (125)I prostate brachytherapy. METHODS AND MATERIALS: Subjects comprised 160 patients who underwent prostate brachytherapy using (125)I seed implants. Prescribed dose was set as 145 Gy to the periphery of the prostate. Implantation was performed using an intraoperative interactive technique. Postimplant dosimetry was performed on Days 1 and 30 after implantation using CT. Dosimetric results for the prostate, urethra, and rectum were compared among intraoperative US and CT on Day 1 (CT(1)) and Day 30 (CT(30)). RESULTS: Mean minimal dose received by 90% of prostate volume was 133.7%, 115.6%, and 125.8% of the prescribed dose on US, CT(1), and CT(30), respectively: This value temporarily decreased on Day 1 and increased on Day 30. Other parameters for the prostate and urethra showed similar trends. Conversely, mean rectal volume receiving 100% of the prescribed dose was 0.69, 0.46, and 1.02 mL on US, CT(1), and CT(30), respectively. Rectal parameters tended to be underestimated on US relative to CT(30)-based dosimetry. A positive linear relationship was identified between US and CT observations for every prostate parameter and the dose covering 30% of the urethra. CONCLUSIONS: Our results demonstrate significant differences between dosimetric parameters obtained by US, CT(1), and CT(30). However, significant correlations also exist between US and CT, at least in prostate and urethral parameters. Clarification of the degrees of difference might make US planning more feasible.

Vitamin D receptor gene polymorphisms are associated with increased risk and progression of renal cell carcinoma in a Japanese population.

AIM: Biological and epidemiologic data suggest that 1 alpha, 25 dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) levels may influence development of renal cell carcinoma. The vitamin D receptor (VDR) is a crucial mediator for the cellular effects of 1,25(OH)(2)D(3) and additionally interacts with other cell signaling pathways that influence cancer progression. VDR gene polymorphisms may play an important role in risk of incidence for various malignant tumors. This study investigated whether VDR gene polymorphisms were associated with increased risk and prognosis of renal cell carcinoma (RCC) in a Japanese population. METHODS: To analyze risk of RCC depending on VDR polymorphism, a case-control association study was performed. The VDR gene polymorphisms at three locations, BsmI, ApaI and TaqI, were genotyped in 135 RCC patients and 150 controls in a Japanese population. Logistic regression models were used to assess the genetic effects on prognosis. RESULTS: Significant differences in the ApaI genotype were observed between RCC patients and controls (chi(2) = 6.90, P = 0.032). No statistical significant difference was found in the BsmI and TaqI polymorphisms. The frequency of the AA genotype in the ApaI polymorphism was significantly higher in the RCC patients than in the controls (odds ratio, 2.59; 95% confidence intervals, 1.21-5.55; P = 0.012). Multivariate regression analysis showed that the AA genotype was an independent prognostic factor for cause-specific survival (relative risk 3.3; P = 0.038). CONCLUSION: The AA genotype at the ApaI site of the VDR gene may be a risk of incidence and poor prognosis factor for RCC in the Japanese population. Additional studies with a large sample size and investigation of the functional significance of the ApaI polymorphism in RCC cells are warranted.

Eight year experience with Studer ileal neobladder.

BACKGROUND: We reviewed our experience with orthotopic continent urinary reconstruction after radical cystectomy to assess the feasibility of Studer ileal neobladder for patients who are relatively advanced in age. METHODS: Between June 1997 and January 2005, 31 consecutive male patients (mean age: 64 years) underwent lower urinary tract reconstruction after radical cystoprostatectomy. Perioperative and late complications, functional outcome of the neobladder, urinary continence, upper urinary tract status and renal function with the metabolic balance were evaluated in all patients. RESULTS: There was no perioperative death, and perioperative and late complication rates were 22.8% and 3.3%, respectively. All 31 patients were able to void urine. Although the mean maximal functional capacity of the neobladder was 122 ml at 1 month after surgery, the mean capacities were increased to 247 ml at 6 months and 321 ml at 1 year after the operation. Urodynamic results at 3 years showed unchanged characteristics as to micturition pattern and volume of residual urine and neobladder pressure remained low. Of 31 patients, 29 (93.5%) showed excellent or good continent status during the daytime and 9 (29%) were completely dry at night in 6 months after surgery. Even at 3 years after the operation, only 1 patient out of 21 evaluated required single pad during nighttime. In a subgroup of five patients (24%) older than 70 years, the status of continence was satisfactory at 3 years after the reconstruction, and only one patient required a pad during the night at that point. Renal function levels and metabolic status were comparable before surgery and 3 years after surgery. Moreover, pyelography revealed normal condition of the upper urinary tract 1 month postoperatively in almost all cases. CONCLUSIONS: These data provide evidence that Studer ileal neobladder is a satisfactory surgical technique for selected patients at our institute. Even for patients older than 70 years, this urinary diversion procedure is safe in terms of morbidity and efficacious as indicated by functional outcome.

Perinephric angiomyolipoma: a unique development pattern surrounding the kidney.

We report a case of a 31-year-old man with extrarenal angiomyolipoma of the perinephric space. He presented with asymptomatic macrohematuria. Computed tomography of the abdomen revealed a large perinephric mass which was separated from the right kidney and its unique growth appeared to have surrounded the kidney. Extrarenal angiomyolipomas of the perinephric fat are rare and they should be considered in the differential diagnosis of a retroperitoneal mass where asymptomatic macrohematuria was presented at the onset.