Effect of mitomycin C on concentrations of vascular endothelial growth factor and its receptors in bladder cancer cells and in bladders of rats intravesically instilled with mitomycin C

What’s known on the subject? and What does the study add? Mitomycin C is widely used for treatment of bladder cancer, however disease progression after mitomycin C treatment is common. We found that intravesical mitomycin C treatment increases urinary vascular endothelial growth factor (VEGF) and bladder VEGF receptor‐2 protein and mRNA in rats. Mitomycin C also increases VEGF mRNA and VEGF receptor‐2 protein and mRNA levels in bladder cancer cells. Therefore, we speculate that mitomycin C may increase the angiogenic potential of both cancer and normal cells.

OBJECTIVES

• ? To examine, using in vitro and in vivo models, the largely unexamined effect of mitomycin C (MMC), an effective intravesical treatment for superficial bladder cancer and carcinoma in situ, on expression of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor‐2 (VEGFR‐2), which mediates many of the angiogenic properties of VEGF.
• ? To measure, as a positive control, concentrations of the inhibitor of apoptosis, survivin, as an assessment of MMC effectiveness.
• ? To measure MMC‐induced changes in proliferation in the presence and absence of VEGF‐A small interfering RNA (siRNA).

MATERIALS AND METHODS

• ? After treatment with increasing MMC concentrations (5–200 µg/mL), we measured proliferation, as well as VEGF, survivin, VEGF receptor‐1 (VEGFR‐1) and VEGFR‐2 concentrations in RT‐4 and T‐24 bladder cancer cells.
• ? The effect of pre‐treatment of VEGF siRNA and survivin siRNA on MMC‐induced decreases in proliferation was measured.
• ? Urinary VEGF concentrations and bladder and kidney concentrations of VEGF‐A, VEGFR‐1, VEGFR‐2 and interleukin‐6 (IL‐6) mRNA were measured in rats intravesically instilled with saline or MMC (200 µg/mL).

RESULTS

• ? Although MMC treatment inhibited cell proliferation and decreased survivin mRNA expression in T‐24 and RT4 cells, MMC (12–50 µg/mL) increased VEGF‐A mRNA and VEGFR‐2 mRNA and protein expression.
• ? Pre‐treatment with VEGF‐A siRNA or survivin siRNA before MMC treatment reduced proliferation more than MMC alone.
• ? MMC‐induced reductions in proliferation were reduced additively by pre‐treatment with survivin siRNA, but were potentiated by pre‐treatment with VEGF‐A siRNA.
• ? VEGFR‐2 mRNA and protein concentrations and urinary VEGF concentrations were increased in bladders of rats instilled with MMC.

CONCLUSIONS

• ? Intravesically instilled MMC increases urinary VEGF and bladder VEGFR‐2 protein and mRNA in rats.
• ? MMC increases VEGF mRNA and VEGFR‐2 protein and mRNA concentrations in bladder cancer cells. Therefore, we speculate that MMC could increase the angiogenic potential of both cancer and normal cells.
• ? In cancer cells this effect is largest at lower MMC concentrations.
• ? Combining MMC with agents that reduce EGF concentrations could be of value in treatment of transitional cell carcinoma of the bladder (TCC).

     

Dicoumarol enhances doxorubicin‐induced cytotoxicity in p53 wild‐type urothelial cancer cells through p38 activation

OBJECTIVE

To investigate the effectiveness of a combined treatment of 3–30‐methylene‐bis[4‐hydroxycoumarin] (dicoumarol) with doxorubicin for the treatment of urothelial cancer, as doxorubicin is a common chemotherapeutic agent but its therapeutic efficacy is limited.

MATERIALS AND METHODS

The synergistic effect of dicoumarol with chemotherapeutic agents such as cisplatin, doxorubicin and paclitaxel was evaluated in RT112 urothelial cancer cells. Then, dicoumarol‐mediated enhancement of doxorubicin‐induced cytotoxicity was screened in urothelial cancer cell lines with different p53 statuses or RT112 stable transfectants with a dominant‐negative mutant of p53 (p53DN). To clarify the importance of the modification of p53 function by dicoumarol to enhance doxorubicin toxicity, the change in the p53‐p21 pathway and mitogen‐activated protein kinase (MAPK)‐mitochondria pathway by the combined treatment were elucidated by Western blot analysis. Finally, the effect of p21 knockdown in the susceptibility to doxorubicin was examined with RT112 stable transfectants with short hairpin RNA (shRNA) of p21.

RESULTS

Dicoumarol significantly increased the susceptibility of RT112 cells to cisplatin and doxorubicin, but not to paclitaxel in RT112 cells. Dicoumarol (100 µm ) also enhanced the cytotoxicity of doxorubicin in other bladder cancer cell lines with wild‐type p53 (wt‐p53; three times in 253J and 13 times in KK47), but not in those with mutant‐type p53 (TCCsup, J82 and EJ) or in RT112 p53DN. The combined treatment with dicoumarol suppressed p53/p21 induction by doxorubicin and resulted in sequential p38 MAPK activation, myeloid cell leukaemia 1 suppression and caspase cleavage. The synergistic effect of doxorubicin/dicoumarol was suppressed by the p38 MAPK inhibitor SB202190 and, furthermore, p21 knockdown with shRNA transfection made RT112 cells six times more susceptible to doxorubicin with p38 MAPK activation.

CONCLUSION

These results suggest that concomitant use of dicoumarol could enhance the cytotoxicity of doxorubicin in urothelial cancer cells with wt‐p53 through the p53/p21/p38 MAPK pathways. This combined treatment may provide a new therapeutic option to overcome chemoresistance in bladder cancer.     

Favourable outcomes of patients with clinical stage T3N0M0 bladder cancer treated with induction low‐dose chemo‐radiotherapy plus partial or radical cystectomy vs immediate radical cystectomy: a single‐institutional retrospective comparative study

OBJECTIVES

To address the role of neoadjuvant concurrent chemo‐radiotherapy (CRT) in muscle‐invasive bladder cancer, by comparing retrospectively the oncological outcomes between a low‐dose CRT (LCRT) plus partial cystectomy (PC) or radical cystectomy (RC) protocol and an immediate RC protocol.

PATIENTS AND METHODS

From 1997 to 2007, 119 patients with clinical stage T2–4aN0M0 bladder cancer received LCRT consisting of RT of 40 Gy in 4 weeks concurrently with two cycles of chemotherapy with cisplatin (20 mg/day for 5 days) during the first and fourth week of RT. Subsequently, 24 (20%) and 65 patients (55%) had PC and RC, respectively, while 30 (25%) had no curative surgery; the median follow‐up was 36 months. From 1983 to 1997, 73 patients had an immediate RC; 29 (41%) received cisplatin‐based adjuvant chemotherapy, and the median follow‐up was 46 months. Oncological outcomes were compared retrospectively between these groups.

RESULTS

The cancer‐specific survival (CSS) rate at 5 years was 75% and 61% for the LCRT protocol and immediate RC protocol, respectively (P = 0.11). In patients with clinical stage T3N0M0 the LCRT protocol gave significantly better survival rates than the immediate RC protocol, with 5‐year CSS rates of 62% vs 27% (P = 0.006), while being comparable in those with clinical stage T2N0M0 disease (89% vs 88%, P = 0.84). In patients with clinical stage T3N0M0 the LCRT protocol provided a lower 5‐year recurrence rate at distant sites than the immediate RC protocol (31% vs 62%, P = 0.09).

CONCLUSIONS

The LCRT plus PC or RC protocol gave significantly better survival rates than the historical, immediate RC protocol in patients with clinical stage T3N0M0 bladder cancer, suggesting that neoadjuvant CRT possibly has survival benefits for such patients.     

Paclitaxel and cisplatin as intravesical agents against non-muscle-invasive bladder cancer

OBJECTIVES

To investigate the effects of cisplatin and paclitaxel against human bladder cancer cells in vitro, and to obtain both pharmacokinetic and pharmacodynamic data after intravesical administration in mice.

MATERIALS AND METHODS

Six bladder cancer cell lines (J82, KU7, RT4, SW780, T24, UMUC3) were treated with various combined doses of both drugs and cell proliferation was evaluated 3 days later. In vivo, solutions of cisplatin and micellar paclitaxel were instilled transurethrally in female mice and pharmacokinetic data were acquired using high‐performance liquid chromatography‐mass spectrometry and atomic absorption methods. To obtain efficacy data, mice with orthotopic KU7‐luc tumours were administered cisplatin and/or micellar paclitaxel intravesically, and the tumour burden quantified using bioluminescence imaging.

RESULTS

In vitro, both cisplatin and paclitaxel potently decreased the proliferation of all cell lines tested, and in combination had an additive but not a synergistic effect. After intravesical instillation, mouse serum concentrations of cisplatin and paclitaxel were in the low microgram/millilitre range and bladder tissue concentrations achieved were 82 and 241 µg/g, respectively. Similar drug levels were reached using combined therapy. In vivo, all chemotherapeutic agents significantly inhibited bladder tumour growth, with the best results for combined therapy and micellar paclitaxel alone. However, there was toxicity in the combined treatment arm.

CONCLUSIONS

Both cisplatin and paclitaxel were absorbed at effective amounts into bladder tissues. As intravesical agents, paclitaxel had slightly stronger anticancer potency than cisplatin. Due to increased adverse events, caution should be exercised when combining both cisplatin and paclitaxel intravesically.     

Enhanced S100 calcium‐binding protein P expression sensitizes human bladder cancer cells to cisplatin

What’s known on the subject? and What does the study add? So far, several molecules have been reported to be involved in cisplatin resistance. This study revealed that a decreased expression of S100P is implicated in cisplatin resistance. In addition, S100P overexpression rendered bladder cancer cells sensitive to cisplatin.

OBJECTIVE

• ? To investigate the role of S100 calcium‐binding protein P (S100P) in the gain of cis‐diamminedichloroplatinum (II) (cisplatin) resistance in bladder cancer, having previously found, with cDNA microarrays using two pairs of parental (T24, KK47) and their cisplatin‐resistant bladder cancer cell lines (T24/DDP10, KK47/DDP20), that S100P mRNA expression was significantly reduced in cisplatin‐resistant cells.

MATERIALS AND METHODS

• ? S100P mRNA and protein expression levels were investigated by northern and western blot analyses, respectively.
• ? Intracellular S100P localization was examined by immunocytochemistry and immunohistochemistry.
• ? S100P over‐expression, obtained by transfection with S100P expression plasmid, was used to investigate whether or not S100P affected cellular resistance to cisplatin.

RESULTS

• ? S100P mRNA showed increased expression by cisplatin stimulation in parental cell lines.
• ? On the other hand, S100P mRNA and protein expression levels were markedly reduced in cisplatin‐resistant cells.
• ? The over‐expression of S100P in resistant cells resulted in an increased sensitivity to cisplatin.

CONCLUSIONS

• ? In bladder cancer cells, S100P was expressed and localized mainly in the nucleus.
• ? S100P expression was also involved in cisplatin sensitivity.
• ? S100P might thus represent a molecular marker predicting cisplatin sensitivity and a molecular therapeutic target for cisplatin‐based chemotherapy.

     

Long‐term results of a combination of paclitaxel,cisplatin and gemcitabine for salvage therapy in male germ‐cell tumours

OBJECTIVE

To retrospectively review the long‐term activity, efficacy and toxicity of the combination of paclitaxel, cisplatin and gemcitabine (TPG) as third‐ or further‐line chemotherapy in patients with germ‐cell tumours (GCTs) who are not cured after at least two courses of standard‐dose chemotherapy, high‐dose chemotherapy or both.

PATIENTS AND METHODS

We evaluated 22 consecutive men treated between April 1999 and December 2000. Half of them were classified as absolutely refractory to cisplatin and a further two as refractory. The median (range) number of previous courses of chemotherapy was 8 (5–11). Treatment consisted of paclitaxel 80 mg/m², cisplatin 50 mg/m² and gemcitabine 800 mg/m² on days 1 and 8, every 3 weeks for four courses, followed by surgery of actual residual resectable masses.

RESULTS

The follow‐up was updated at August 2007. There were no deaths from toxicity and only one patient needed suspension of therapy for toxicity. There was both grade 3–4 thrombocytopenia and neutropenia in 15 patients (68%), and anaemia in nine (41%). There were partial remissions in eight (36%) patients. Six (27%) patients were rendered disease‐free with surgical removal of a residual mass after chemotherapy (two still containing viable cancer). Four (18%) patients are long‐term survivors at more than 80, 81, 94 and 99 months. The median (range) overall survival of the whole series was 13.5 (1–>99) months.

CONCLUSION

This combination had a toxicity profile that was acceptable and comparable with other third‐line regimens. There were eight (36%) major responses. After a 6‐year minimum follow‐up, four (18%) patients were long‐term disease‐free survivors.     

A phase II trial of neoadjuvant erlotinib in patients with muscle‐invasive bladder cancer undergoing radical cystectomy: clinical and pathological results

Study Type – Therapy (cohort)
Level of Evidence 2b

OBJECTIVE

To evaluate the clinicopathological efficacy of neoadjuvant erlotinib (an epidermal growth factor receptor, EGFR, inhibitor) for invasive bladder cancer in patients undergoing radical cystectomy (RC) as despite definitive surgical therapy, only half of patients undergoing RC will have long‐term disease‐free survival, and effective adjunctive therapies, especially using agents with lower toxicity, would be a significant advance in the treatment of invasive bladder cancer.

PATIENTS AND METHODS

The primary endpoint of this phase II trial is to determine the effect of neoadjuvant erlotinib (150 mg once daily for 4 weeks) before RC on the pathological complete response rate (pT0 rate) in RC specimens. In addition, the safety of therapy with erlotinib was also evaluated. Patients selected for study included those with histologically confirmed muscle‐invasive bladder cancer who had undergone initial transurethral resection.

RESULTS

In all, 20 patients with clinical stage T2 disease had neoadjuvant erlotinib therapy followed by RC. On surgical pathology, five patients (25%) were pT0; in addition, seven (35%) were clinically down‐staged (≤pT1) and 15 (75%) had organ‐confined disease at surgical pathology. At a mean follow‐up of 24.8 months, 10 patients remain alive and with no evidence of disease, four with organ‐confined disease had progression and nine died, including six from disease and three from other causes. Erlotinib was tolerated in all patients, with drug rash being the most common side‐effect, in 15 patients (75%). Interestingly, all pT0 and pTis/T1 patients had a rash.

CONCLUSIONS

The EGFR inhibitor erlotinib, when administered in the neoadjuvant setting, can have beneficial effects in terms of surgical pathology and short‐term clinical outcomes in patients undergoing RC for invasive bladder cancer. Analyses are underway to examine the molecular correlates of the apparent clinical effect of neoadjuvant therapy in these patients.     

The role of surveillance in the treatment of patients with muscle‐invasive bladder cancer after chemotherapy

Study Type – Prognosis (case series)
Level of Evidence 4

OBJECTIVE

To determine the survival of patients at our institution who were clinically tumour‐free (cT0) on re‐staging transurethral resection (TUR) after treatment with chemotherapy for muscle‐invasive bladder cancer.

PATIENTS AND METHODS

In all, 55 patients with muscle‐invasive, organ‐confined transitional cell carcinoma of the bladder were treated with TUR followed by systemic chemotherapy, over a 10‐year period. Patients were separated into two groups, those who were clinically T0 and those who showed persistent disease (>cT0) on re‐biopsy after chemotherapy. Overall and disease‐specific survival rates were calculated for the two groups. The cT0 group was further followed for tumour recurrence and clinical outcomes.

RESULTS

Thirty‐one patients (56%) were clinically T0 on TUR after chemotherapy; of these patients, 22 (71%) either died from other causes (with no disease recurrence) or are alive and with no evidence of disease at a mean follow‐up of 53 months. Twenty of the 31 patients (65%) have retained their bladder with no evidence of cancer recurrence at a mean follow‐up of 46 months. Disease‐free status (cT0) at the time of TUR after chemotherapy was associated with significantly higher overall and cancer‐specific survival (hazard ratio 3.40, P = 0.003; and 8.63, P = 0.001, respectively).

CONCLUSION

Previous studies suggest that surveillance can be a reasonable option for patients with muscle‐invasive transitional cell carcinoma of the bladder who show no evidence of disease on TUR after chemotherapy. Patients with persistent bladder cancer on re‐biopsy after chemotherapy tend to fare poorly even with immediate cystectomy.     

Combined treatment with a β3‐adrenergic receptor agonist and a muscarinic receptor antagonist inhibits detrusor overactivity induced by cold stress in spontaneously hypertensive rats

Aims

This study determined if combined treatment with the muscarinic receptor (MR) antagonist solifenacin and the β₃‐adrenergic receptor (AR) agonist mirabegron could inhibit detrusor overactivity induced by cold stress in spontaneously hypertensive rats (SHRs).

Methods

Thirty‐two female 10‐week‐old SHRs were fed an 8% NaCl‐supplemented diet for 4 weeks. Cystometric measurements of the unanesthetized, unrestricted rats were performed at room temperature (RT, 27 ± 2°C) for 20 min. The rats were then intravenously administered vehicle, 0.1 mg/kg solifenacin alone, 0.1 mg/kg mirabegron alone, or the combination of 0.1 mg/kg mirabegron and 0.1 mg/kg solifenacin (n = 8 each group). Five minutes later, the treated rats were exposed to low temperature (LT, 4 ± 2°C) for 40 min. Finally, the rats were returned to RT. After the cystometric investigations, the β₃‐ARs and M₃‐MRs expressed within the urinary bladders were analyzed.

Results

Just after transfer from RT to LT, vehicle‐, solifenacin‐, and mirabegron‐treated SHRs exhibited detrusor overactivity that significantly decreased voiding interval and bladder capacity. However, treatment with the combination of solifenacin and mirabegron partially inhibited the cold stress‐induced detrusor overactivity patterns. The decreases of voiding interval and bladder capacity in the combination‐treated rats were significantly inhibited compared to other groups. Within the urinary bladders, there were no differences between expression levels of M₃‐MR and β₃‐AR mRNA. The tissue distribution of M₃‐MRs was similar to that of the β₃‐ARs.

Conclusions

This study suggested that the combination of solifenacin and mirabegron act synergistically to inhibit the cold stress‐induced detrusor overactivity in SHRs. Neurourol. Urodynam. 36:1026–1033, 2017. © 2016 The Authors. Neurourology and Urodynamics Published by Wiley Periodicals, Inc.     

The lymphatic system and its specific growth factor vascular endothelial growth factor C in kidney tissue and in renal cell carcinoma

OBJECTIVE

To determine the role of vascular endothelial growth factor C (VEGF‐C) and the quantitative extent of the lymphatic system in renal cell carcinoma (RCC) to analyse a possible correlation with the metastatic spread of cancer cells.

PATIENTS AND METHODS

In all, 44 patients with clear cell RCC and 12 with papillary or chromophobe RCC were included in an immunohistochemical study. The lymphatic vessel density (LVD) was assessed in the tumour body, the tumour capsule and the tumour‐free adherent renal tissue. The expression of VEGF‐C was semiquantitatively assessed by the percentage of positive epithelial and cancer cells. Data were analysed for any correlation with the clinicopathological variables.

RESULTS

The clear and papillary cell RCC contained no lymphatic vessels (0.2, sd 0.8). Chromophobe RCC specimens showed scattered obliterated vessels (0.0–7.7). Several lymphatic vessels were found in the normal renal tissue, mainly associated with blood vessels (2.9, sd 1.9). The highest mean (sd ) LVD was in the tumour capsule, of 6.9 (3.4). There was no statistical correlation between the LVD and VEGF‐C. In clear cell RCC the expression of VEGF‐C was correlated with the size of the tumour (P = 0.042).

CONCLUSIONS

RCC does not promote the growth of its own lymphatic vessels. The role of a high LVD in the tumour capsule needs to be determined. The VEGF‐C staining pattern in normal kidney tissue hints at functions other than lymphangiogenesis.     

Glucose-regulated protein 78 silencing down-regulates vascular endothelial growth factor/vascular endothelial growth factor receptor 2 pathway to suppress human colon cancer tumor growth

Background

Up to 20% of colorectal cancer (CRC) is diagnosed with distant metastasis. The combination of chemotherapy with anti-vascular endothelial growth factor (VEGF) antibody can improve patient survival. Glucose-regulated protein 78 (GRP78) has an important role in cancer progression, but little is known about its role in VEGF production in CRC. The aim of this study was to explore the mechanism of GRP78 in two human colon cancer cell lines.

Methods

We first checked the expression of GRP78 in human normal and colon cancer tissues and two colon cancer cell lines. Glucose-regulated protein 78 was knocked down using GRP78 small interfering RNA (siRNA) in HT29 and DLD-1 cells. We examined knockdown cells by the cell growth kinetics in vitro and tumor growth rate in vivo, respectively. We also investigated the effect of GRP78 siRNA on the expression of hypoxia inducible factor (HIF-1α), VEGF, and VEGF receptor 2 (VEGFR2).

Results

Compared with their adjacent normal tissue, we detected high expression levels of GRP78 of surgically removed colon cancer tissues. Using GRP78 siRNA, we reduced the expression of GRP78 in HT29 and DLD-1 cells. The GRP78 knockdown cells had a lower proliferation rate with fewer colony-forming units in vitro and produced smaller tumors in vivo. In dissecting the mechanism underlying the reduced cell growth, we found that the down-regulation of GRP78 decreased the production of HIF-1α, VEGF, and VEGFR2 and suppressed angiogenesis.

Conclusions

Silencing GRP78 not only inhibits tumor, but also decreases the expression of VEGF and VEGFR2. Collectively, therapy targeting for GRP78 may inhibit the formation of colon cancer tumors via the HIF-1α/VEGF/VEGFR2 pathway.     

A Whole-genome CRISPR Screen Identifies a Role of MSH2 in Cisplatin-mediated Cell Death in Muscle-invasive Bladder Cancer

Background

The response to first-line, platinum-based treatment of muscle-invasive bladder cancer has not improved in 3 decades.

High neutrophil‐to‐lymphocyte ratio predicts worse overall survival in patients with advanced/metastatic urothelial bladder cancer

Objectives

To study the role of the neutrophil‐to‐lymphocyte ratio in predicting survival outcomes for patients with advanced bladder cancer.

Methods

We retrospectively reviewed 150 patients diagnosed with advanced or metastatic bladder cancer between January 2004 and June 2014. The neutrophil‐to‐lymphocyte ratio was computed on diagnosis and after the first cycle of chemotherapy. A neutrophil‐to‐lymphocyte ratio cut‐off of 3.0 was determined, with a concordance index of 0.89. Kaplan–Meier curves, log–rank tests, Cox proportional hazards and logistic regression models were used to predict the association of the neutrophil‐to‐lymphocyte ratio with survival outcomes.

Results

Just five patients were alive at the end of the study; the rest died from metastatic bladder cancer. On multivariate analysis, higher Eastern Cooperative Oncology Group status, lymphadenopathy, visceral metastases and neutrophil‐to‐lymphocyte ratio ≥3.0 were associated with poorer overall survival (hazard ratio 1.67, P = 0.03; hazard ratio 1.97, P = <0.01; hazard ratio 2.02, P = <0.01; hazard ratio 5.06, P = <0.01), whereas chemotherapy conferred better overall survival (hazard ratio 0.546, P = 0.01). Furthermore, the role of chemotherapy prolonged survival longer in patients with a neutrophil‐to‐lymphocyte ratio <3.0 (median overall survival 13.0 vs 22.0 months, hazard ratio 0.273, P = 0.008) compared with a neutrophil‐to‐lymphocyte ratio ≥3.0 (median overall survival 4.0 vs 7.0 months, hazard ratio 0.452, P = 0.020). More importantly, when dichotomized to the four different pre‐ and post‐chemotherapy groups, patients with a pre‐ and post‐chemotherapy neutrophil‐to‐lymphocyte ratio <3.0 had the best additional median overall survival of 19.0 months compared with patients with a pre‐ and post‐chemotherapy neutrophil‐to‐lymphocyte ratio ≥3.0 (3.0 months).

Conclusions

Elevated neutrophil‐to‐lymphocyte ratio is independently associated with poorer chemotherapeutic response and overall survival in patients with advanced or metastatic bladder cancer. The neutrophil‐to‐lymphocyte ratio can be an inexpensive novel factor in prognosticating disease progression and providing better patient counseling.     

Chemotherapy for metastatic testicular cancer: The first nationwide multi‐institutional study by the Cancer Registration Committee of the Japanese Urological Association

Objectives

To assess clinicopathological data and oncological outcomes focused on metastatic testicular cancer patients, who received chemotherapy as the initial treatment, in the nationwide multi‐institutional study by the Cancer Registration Committee of the Japanese Urological Association.

Methods

A testicular cancer survey was carried out by the Japanese Urological Association in 2011 to register newly diagnosed testicular cancers in 2005 and 2008. Among 1121 registered patients, 278 patients with metastases who received chemotherapy as the initial treatment and could be categorized by the Japanese Urological Association classification were eligible for the analysis.

Results

As first‐line chemotherapy, bleomycin, etoposide and cisplatin, and etoposide and cisplatin therapies were chosen for 260 patients (93.5%). As second‐line therapy, vinblastine, ifosfamide and cisplatin/etoposide, ifosfamide and cisplatin; and paclitaxel, ifosfamide and cisplatin/paclitaxel, ifosfamide and nedaplatin therapies were carried out in 23 out of 63 (36.5%) and 29 out of 63 (46.0%) patients, respectively. The response rate and serum tumor marker normalization rate were 93.4% and 81.3% at first line, 75.4% and 60.7% at second line, and 41.7% and 16.7% at third line, respectively. The Japanese Urological Association classification (≥IIIB2 vs ≤IIIB1) and choriocarcinoma component in primary histology were independent prognostic factors of overall survival before starting chemotherapy. Furthermore, in patients with non‐seminomatous germ cell tumors, serum tumor marker normalization was an independent factor that was associated with better outcome of overall survival after completion of the initial series of chemotherapies.

Conclusions

The initial accurate diagnosis and risk stratification is an important prognostic factor to achieve better oncological outcomes. In patients with non‐seminomatous germ cell tumors, aiming for serum tumor marker normalization with continuous sequential chemotherapy could improve overall survival.

     

Regulation of growth factors in hormone‐ and drug‐resistant prostate cancer cells by synergistic combination of docetaxel and octreotide

OBJECTIVE

To evaluate the effects of combined treatment with docetaxel and octreotide, a somatostatin analogue, on human hormone‐ and drug‐refractory prostate cancer cell lines, PC‐3 and DU‐145, and on some growth factors related to tumour growth and angiogenesis in prostate cancer.

MATERIALS AND METHODS

A cell proliferation assay was used to assess the cytotoxicity of the drugs. To verify apoptosis, both DNA fragmentation (by enzyme‐linked immunosorbent assay) and caspase 3/7 activity were measured. We also investigated the effect of combined docetaxel and octreotide on growth factors secreted from prostate cancer cells using a human growth factor antibody array.

RESULTS

The combination of docetaxel and octreotide resulted in significant synergistic cytotoxic activity and apoptosis, which was dose‐ and time‐dependent. The combined treatment also resulted in significantly less secretion of stem cell factor and platelet‐derived growth factor‐AB in PC‐3 cells, and transforming growth factor‐β and basic fibroblast growth factor in DU‐145 cells, than in untreated controls.

CONCLUSION

Octreotide, a somatostatin analogue, combined with docetaxel might provide a rationale treatment option for hormone‐refractory prostate cancer cells, not only by direct inhibition of cell proliferation but also by inhibiting the secretion of growth factors.     

A chemosensitivity test to individualize intravesical treatment for non‐muscle‐invasive bladder cancer

OBJECTIVE

To describe the design of a new chemosensitivity assay based on the expression of genes involved in the resistance to standard intravesical regimens, to allow individualization of therapy for high‐risk non‐muscle‐invasive bladder cancer.

PATIENTS AND METHODS

To date, 35 patients with high‐risk no‐nmuscle‐invasive bladder cancer have been enrolled, all candidates for transurethral resection of the bladder (TURB) followed by intravesical treatment. The intravesical regimen was chosen according to the risk profile of each patient. All patients were evaluated by cystoscopy 3 and 6 months after TURB. According to the molecular characterization of each tumour, our team of molecular oncologists determined for each patient a molecular profile of chemosensitivity to BCG, mitomycin c, anthracyclines and gemcitabine. This profile was then correlated to the response to intravesical therapy 6 months after TURB.

RESULTS

This chemosensitivity test was able to predict response to treatment in 96% of patients. The assay is easy to perform, inexpensive and quick.

CONCLUSION

Our results, although preliminary, are encouraging for the future of an individualized therapeutic approach, with the aim to provide a higher treatment success rate while sparing patients unnecessary toxicity from drugs that are not suited for their tumours.     

Infiltrative lamina propria invasion pattern as an independent predictor for cancer‐specific and overall survival of instillation treatment‐naïve stage T1 high‐grade urothelial bladder cancer

Objectives

To investigate established prognostic factors and relatively new histopathological tumor characteristics including metric substage and lamina propria invasion patterns in a large series of T1 high‐grade non‐muscle‐invasive bladder cancer.

Methods

Between 1989 and 2012, 322 patients with initial stage T1 high‐grade bladder cancer underwent transurethral resection, followed by re‐transurethral resection and a conservative approach with follow‐up regime alone or instillation treatment. Transurethral resection specimens were reassessed by two experienced urological pathologists for tumor grade according to the World Health Organization 1973 classification, metric T1 substage, lamina propria invasion pattern and associated carcinoma in situ. The median follow‐up period was 42 months (interquartile range 25–72 months). In addition to Kaplan–Meier analyses, uni‐ and multivariable Cox regression analyses were used to compare progression‐free survival, cancer‐specific survival and overall survival for the studied parameters comparing two subcohorts.

Results

While in patients after instillation treatment no examined feature was shown as an independent predictor for prognosis, there were predictive histopathological features in multivariable Cox regression analyses in instillation treatment‐naïve patients: associated carcinoma in situ (hazard ratio 2.278, 95% confidence interval 1.119–4.634, P = 0.023) and World Health Organization 1973 grade 3 (hazard ratio 2.950, 95% confidence interval 1.021–8.536, P = 0.046) for worse progression‐free survival, infiltrative lamina propria tumor pattern for worse cancer‐specific survival (hazard ratio 2.369, 95% confidence interval 1.034–5.429, P = 0.042) and overall survival (hazard ratio 1.049, 95% confidence interval 1.024–1.075, P = 0.001).

Conclusions

The results of the present T1 high‐grade bladder cancer series suggest that lamina propria invasion pattern is a promising parameter to predict the prognosis of T1 high‐grade bladder cancer in an instillation treatment‐naïve subcohort. Prospective multicenter evaluations are warranted. The need for instillation treatment in T1 high‐grade bladder cancer is clearly demanded.