Vijay K Sangar

A potential role of heat shock proteins and nicotinamide N-methyl transferase in predicting response to radiation in bladder cancer

The use of definitive radiotherapy for treatment of invasive bladder cancer has the advantage of preserving bladder function, but tumour regression is only achieved in approximately 40–50% of patients. Knowledge of the molecular basis of sensitivity to ionizing radiation and identification of potential molecular predictors will provide useful information regarding patient response and thus help clinicians to individualize treatment. The recent application of cDNA expression array technology provides a useful tool to investigate hundreds or even thousands of genes in a single experiment. In our study, we have used the Atlas human stress cDNA array™ to investigate the expression profile of stress‐related and DNA repair genes in a radioresistant bladder carcinoma cell line (MGH‐U1) and its radiosensitive subclone (S40b). This provides an ideal situation to study genes related to radiation because the genotypes of both cell lines are basically similar and differential changes detected are likely to be related to the different radiosensitivity phenotype. Of 234 genes blotted on the array, 3 genes (Heat shock protein 90, Heat shock protein 27 and Nicotinamide N‐methyl transferase) showed consistent downregulation in the radiosensitive clone in 2 independent experiments. These results were further confirmed for HSP27 and NNMT using Sybr Green I‐based real‐time QRT‐PCR. The role of heat shock proteins (HSPs) in response to radiation remains to be determined; however, the results of our present work suggest a possible role of HSP27 in determining radiosensitivity. Our study also opens avenues for the investigation of genes, such as NNMT, which has not previously been linked to response to radiation.

Phase II Study of Conformal Hypofractionated Radiotherapy With Concurrent Gemcitabine in Muscle-Invasive Bladder Cancer

PURPOSE The aim of this prospective, phase II trial was to determine the response of muscle-invasive bladder cancer (MIBC) to concurrent chemoradiotherapy of weekly gemcitabine with 4 weeks of radiotherapy (RT; GemX). PATIENTS AND METHODS Fifty patients with transitional cell carcinoma, stage T2-3, N0, M0 after transurethral resection and magnetic resonance imaging, were recruited. Gemcitabine was given intravenously at 100 mg/m(2) on days 1, 8, 15, and 22 of a 28-day RT schedule that delivered 52.5 Gy in 20 fractions. Chemotherapy was stopped for Radiation Therapy Oncology Group (RTOG) grade 3 bladder or bowel toxicity. The primary end points were tumor response, toxicity, and survival. RESULTS All patients completed RT; 46 tolerated all four cycles of gemcitabine. Two patients stopped after two cycles, and two stopped after three cycles, because of bowel toxicity. Forty-seven patients had a post-treatment cystoscopy; 44 (88%) achieved a complete endoscopic response. At a median follow-up of 36 months (range, 15 to 62 months), 36 patients were alive, and 32 of these had a functional and intact bladder. Fourteen patients died; seven died as a result of metastatic MIBC, five died as a result of intercurrent disease, and two died as a result of treatment-associated deaths. Four patients underwent cystectomy; three because of recurrent disease and one because of toxicity. One patient required a bowel resection for late toxicity. By using Kaplan-Meier analyses, 3-year cancer-specific survival was 82%, and overall survival was 75%. CONCLUSION Concurrent gemcitabine-based chemoradiotherapy (ie, GemX) produces a high response rate in MIBC and has durable local control and acceptable toxicity, which allows patients to preserve their own bladder. This treatment modality warrants additional investigation in a phase III setting.

The differential effects of statins on the metastatic behaviour of prostate cancer.

Background:Although statins do not affect the incidence of prostate cancer (CaP), usage reduces the risk of clinical progression and mortality. Although statins are known to downregulate the mevalonate pathway, the mechanism by which statins reduce CaP progression is unknown.Methods:Bone marrow stroma (BMS) was isolated with ethical approval from consenting patients undergoing surgery for non-malignant disease. PC-3 binding, invasion and colony formation within BMS was assessed by standardised in vitro co-culture assays in the presence of different statins.Results:Statins act directly on PC-3 cells with atorvastatin, mevastatin, simvastatin (1 μM) and rosuvastatin (5 μM), but not pravastatin, significantly reducing invasion towards BMS by an average of 66.68% (range 53.93–77.04%; P<0.05) and significantly reducing both number (76.2±8.29 vs 122.9±2.48; P=0.0055) and size (0.2±0.0058 mm2 vs 0.27±0.012 mm2; P=0.0019) of colonies formed within BMS. Statin-treated colonies displayed a more compact morphology containing cells of a more epithelial phenotype, indicative of a reduction in the migrational ability of PC-3 cells. Normal PC-3 phenotype and invasive ability was recovered by the addition of geranylgeranyl pyrophosphate (GGPP).Conclusion:Lipophilic statins reduce the migration and colony formation of PC-3 cells in human BMS by inhibiting GGPP production, reducing the formation and the spread of metastatic prostate colonies.

Differential radiosensitisation by ZD1839 (Iressa), a highly selective epidermal growth factor receptor tyrosine kinase inhibitor in two related bladder cancer cell lines.

The epidermal growth factor receptor (EGFR) is expressed in a wide variety of epithelial tumours including carcinoma of the bladder. Stimulation of the EGFR pathway is blocked by ZD1839 (Iressa), a highly selective EGFR tyrosine kinase inhibitor. Radical radiotherapy is an established organ sparing treatment option for muscle invasive bladder cancer and this study has explored the possibility for the use of ZD1839 as a radiosensitiser in this scenario. The effect of combination treatment with ZD1839 (0.01 μM) and ionising radiation in the established bladder cancer cell lines MGH-U1 and its radiosensitive mutant clone S40b was measured by clonogenic assays. A highly significant radiosensitising effect was seen in both cell lines (P<0.001 for MGH-U1 and S40b cell lines). This effect was independent of the concentration of the drug and the duration of exposure prior to treatment with ionising radiation. Cell cycle kinetics of both cell lines was not significantly altered with ZD1839 (0.01 μM) as a single agent. A modest induction of apoptosis was observed with ZD1839 (0.01 μM) as a single agent, but a marked induction was observed with the combination treatment of ZD1839 and ionising radiation. These results suggest a potentially important role for ZD1839 in combination with radiotherapy in the treatment of muscle invasive bladder cancer.

An evaluation of gemcitabines differential radiosensitising effect in related bladder cancer cell lines.

The aim of this study was to establish the radiosensitising properties of gemcitabine in a pair of related bladder tumour cell lines with differential radiosensitivity. The radioresistant bladder tumour cell line MGH-U1 and its radiosensitive mutant clone, S40b (both p53 mutant), had SF2 values (surviving fraction at 2 Gy) of 0.98 and 0.64, respectively (P<0.001). Colony-forming assays showed that at 0.01 μM gemcitabine radiosensitisation occurred only in the S40b cell line (dose-modifying factor (DMF)=1.4). At 0.3 μM (killing 50% of cells), both cell lines were radiosensitised; DMF=2.25 and 1.2 for MGH-U1 and S40b, respectively. These data suggest that gemcitabine is an effective radiosensitiser in bladder cancer cell lines, with greater sensitisation in the radioresistant parental line–a feature that should be useful in a clinical setting.

Dynamic sentinel lymph node biopsy for penile cancer: a comparison between 1- and 2-day protocols

To determine the outcome of clinically negative node (cN0) patients with penile cancer undergoing dynamic sentinel node biopsy (DSNB), comparing the results of a 1‐ and 2‐day protocol that can be used as a minimal invasive procedure for staging of penile cancer.

The treatment of penile carcinoma in situ (CIS) within a UK supra-regional network.

To review outcomes of the treatment of carcinoma in situ (CIS) of the penis at a large supra‐regional penile cancer network, where centralisation has permitted greater experience with treatment outcomes, and suggest treatment strategies.

Should centralized histopathological review in penile cancer be the global standard

To assess the role of centralized pathological review in penile cancer management.

Should molecular technology replace urine cytology

Patients presenting with haematuria continue to form a significant proportion of the workload of urological departments. It is known that > 26% of patients will have a significant pathological cause for their haematuria [1]. Urine cytology is amongst the many investigations used; in some centres it is used as ‘primary screening’ whilst in others it is used as a last attempt at reassurance that no malignant or premalignant condition exists. In other centres it has been abandoned. Nonetheless its use continues despite its variable sensitivity and specificity. For superficial disease, urine cytology has a sensitivity and specificity of 21% and 99%, respectively [2]. In addition, it involves the transport of specimens to laboratories, specimen preparation and laboratory personnel time, and analysis and reporting time, as well as secretarial time. The cost of 1000 tests at current National tariffs is £65 000.

A rare presentation of hidradenocarcinoma within the penis

Penile carcinoma is a rare malignancy representing 1% of male cancers. Squamous cell carcinoma accounts for 95% of all penile cancers.1 Cutaneous adnexal tumours can be benign or malignant lesions and tend to present on the head, neck and extremities. Cutaneous adnexal tumours of the penis are extremely rare and have only been reported once in the literature.2 To our knowledge, metastatic spread from these tumours on the penis has never been reported before. We present a case of a malignant cutaneous adnexal tumour of the penis with progressive metastatic spread. Case presentation A 46-year-old man presented with a cystic mass on the shaft of his penis. He had no significant co-morbidities. On examination, there was a mobile nodule over the left side of the distal shaft of the penis, proximal to the coronal sulcus near the frenulum, measuring 8mm in diameter. There was no palpable groin lymphadenopathy. He underwent a wide local excision of the lesion. Histological examination revealed a multi-nodular, solid-cystic and poorly differentiated carcinoma located within the dermis, measuring 15mm by 10mm with a margin of less than 5mm. On closer evaluation, the tumour resembled a high-grade and malignant cutaneous adnexal tumour of hidradenocarcinoma sub-type. It was characterised by large lobulated islands of basaloid cells, an abundance of mitotic figures and multiple foci of necrosis. Lymphovascular invasion was present but perineal invasion was not (Fig. 1, Fig. 2). Open in a separate window Fig. 1 HE (b) primary lesion seen on high power view; (c) primary lesion demonstratin lymphovascular invasion; (d) recurrent lesion presenting with corpora cavernosa.