To our knowledge, this is the largest study of intrinsic markers of hypoxia and angiogenesis in relation to the outcome of radical treatment of localised prostate cancer. Increased expression of VEGF, HIF-1 alpha, and, for patients treated with surgery, osteopontin, identifies patients at high risk of biochemical failure who would be suitable for enrolment into trials of treatment intensification.

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Primary extrapulmonary tumors with histologic features indistinguishable from bronchogenic oat cell carcinoma are appearing with increasing frequency in the literature. These tumors have been described in the esophagus, stomach, pancreas, larynx, hypopharynx, salivary glands, nasal cavity and paranasal sinuses, thymus, small and large bowel, uterine cervix, endometrium, breast, prostate, urinary bladder, and skin. It is now widely believed that oat cell carcinoma is a poorly differentiated counterpart of carcinoid tumor and that both originate from an endocrine cell system. In this article, the authors review all cases of extrapulmonary oat cell carcinomas, which they were able to find in the English literature, and report personally studied examples of these tumors, occurring in the esophagus, stomach and urinary bladder. A closely related, if not identical, tumor arising in the skin is also described. It is emphasized that a wider recognition of these tumors is likely to lead to their more frequent diagnosis and possible treatment.

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Penile verrucous carcinoma is a rare disease and little is known of its aetiology or pathogenesis. In this study we examined cell-cycle proteins expression and correlation with human papillomavirus infection in a series of 15 pure penile verrucous carcinomas from a single centre. Of 148 penile tumours, 15 (10%) were diagnosed as pure verrucous carcinomas. The expression of the cell-cycle-associated proteins p53, p21, RB, p16 INK4A and Ki67 were examined by immunohistochemistry. Human papillomavirus infection was determined by polymerase chain reaction to identify a wide range of virus types. The expression of p16 INK4A and Ki67 was significantly lower in verrucous carcinoma than in usual type squamous cell carcinoma, whereas the expression of p53, p21 and RB was not significantly different. p53 showed basal expression in contrast to usual type squamous cell carcinoma. Human papillomavirus infection was present in only 3 out of 13 verrucous carcinomas. Unique lowrisk, high-risk and mixed viral infections were observed in each of the three cases. In conclusion, lower levels of p16 INK4A and Ki67 expressions differentiate penile verrucous carcinoma from usual type squamous cell carcinoma. The low Ki67 index reflects the slow-growing nature of verrucous tumours. The low level of p16 INK4A expression and human papillomavirus detection suggests that penile verrucous carcinoma pathogenesis is unrelated to human papillomavirus infection and the oncogenes and tumour suppressor genes classically altered by virus infection.

BackgroundThe pathogenesis of penile squamous cell carcinoma (PSCC) is not well understood, though risk factors include human papillomavirus (HPV). Disruption of HER/PTEN/Akt pathway is present in many cancers; however there is little information on its function in PSCC. We investigated HER family receptors and phosphatase and tension homolog (PTEN) in HPV-positive and negative PSCC and its impact on Akt activation using immunohistochemistry and fluorescent in situ hybridisation (FISH).Methodology/Principal Findings148 PSCCs were microarrayed and immunostained for phosphorylated EGFR (pEGFR), HER2, HER3, HER4, phosphorylated Akt (pAkt), Akt1 and PTEN proteins. EGFR and PTEN gene status were also evaluated using FISH. HPV presence was assessed by PCR. pEGFR expression was detected significantly less frequently in HPV-positive than HPV-negative tumours (p = 0.0143). Conversely, HER3 expression was significantly more common in HPV-positive cases (p = 0.0128). HER4, pAkt, Akt and PTEN protein expression were not related to HPV. HER3 (p = 0.0054) and HER4 (p = 0.0002) receptors significantly correlated with cytoplasmic Akt1 immunostaining. All three proteins positively correlated with tumour grade (HER3, p = 0.0029; HER4, p = 0.0118; Akt1, p = 0.0001). pEGFR expression correlated with pAkt but not with tumour grade or stage. There was no EGFR gene amplification. HER2 was not detected. PTEN protein expression was reduced or absent in 62% of tumours but PTEN gene copy loss was present only in 4% of PSCCs.Conclusions/SignificanceEGFR, HER3 and HER4 but not HER2 are associated with penile carcinogenesis. HPV-negative tumours tend to express significantly more pEGFR than HPV-positive cancers and this expression correlates with pAkt protein, indicating EGFR as an upstream regulator of Akt signalling in PSCC. Conversely, HER3 expression is significantly more common in HPV-positive cases and positively correlates with cytoplasmic Akt1 expression. HER4 and PTEN protein expression are not related to HPV infection. Our results suggest that PSCC patients could benefit from therapies developed to target HER receptors.

OBJECTIVETo assess the feasibility, toxicity and immunogenicity of dendritic cell (DC)‐based immunotherapy in patients with advanced urological cancers.PATIENTS AND METHODSPatients with hormone‐refractory prostate cancer (11) and metastatic renal cell carcinoma (five) received 1–3 × 106 intradermal allogeneic tumour lystate‐pulsed DCs fortnightly for six vaccinations then monthly until disease progression. Intradermal keyhole limpet haemocyanin was injected near the DCs as the adjuvant. DC vaccine was prepared from buffy coats, then lysate‐pulsed, cryopreserved in aliquots, and tested for phenotypic expression and activity in an allogeneic mixed lymphocyte reaction before clinical use.RESULTSThere was no evidence of significant toxicity from vaccine or adjuvant. Delayed‐type hypersensitivity skin testing and biopsy revealed a cellular infiltrate to intradermal re‐challenge to tumour lysate and adjuvant in almost all patients. In addition, there was increased expression of T helper type 1 cytokines, interferon‐γ‐expressing T cell by ELISPOT analysis, but also interleukin‐10 in a few patients. Vaccination resulted in a reduction in the level of prostate‐specific antigen (PSA) in one patient, a reduction in PSA velocity in a further man and an increased PSA doubling time in six. Two of five patients with renal cell carcinoma had stabilization of disease.CONCLUSIONThe cryopreservation and repeated administration of DC vaccine was feasible and not toxic. There was evidence of induction of both humoral and cellular immunity to vaccine and adjuvant in most patients. The use of sequential aliquots of identical cryopreserved vaccine will ensure quality control and greatly facilitate future clinical studies in terms of consistency of vaccine administered and the provision of primed DCs for in vitro assessment of response.

Needle biopsies are taken as standard diagnostic specimens for many cancers, but no technique exists for the high-throughput analysis of multiple individual immunohistochemical (IHC) markers using these samples. Here we present a simple and highly reliable technique for constructing tissue microarrays (TMAs) from prostatic needle biopsies. Serial sectioning of the TMAs, called 'Checkerboard TMAs', facilitated expression analysis of multiple proteins using IHC markers. In total, 100% of the analysed biopsies within the TMA both preserved their antigenicity and maintained their morphology. Checkerboard TMAs will allow the use of needle biopsies (i) alongside other tissue specimens (trans-urethral resection of prostates and prostatectomies in the case of prostate cancer) in clinical correlation studies when searching for new prognostic markers, and (ii) in a diagnostic context for assessing expression of multiple proteins in cancers from patients prior to treatment.