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Purpose: Established prognostic factors in localized prostate cancer explain only a moderate proportion of variation in outcome. We analyzed tumor expression of apoptotic markers with respect to outcome in men with localized prostate cancer in two randomized controlled trials of radiotherapy dose escalation. Methods and Materials: Between 1995 and 2001, 308 patients with localized prostate cancer received neoadjuvant androgen deprivation and radical radiotherapy at our institution in one of two dose-escalation trials. The biopsy specimens in 201 cases were used to make a biopsy tissue microarray. We evaluated tumor expression of Bcl-2, p53, and MDM2 by immunohistochemistry with respect to outcome. Results: Median follow-up was 7 years, and 5-year freedom from biochemical failure (FFBF) was 70.4% (95% CI, 63.5–76.3%). On univariate analysis, expression of Bcl-2 (p < 0.001) and p53 (p = 0.017), but not MDM2 (p = 0.224), was significantly associated with FFBF. Expression of Bcl-2 remained significantly associated with FFBF (p = 0.001) on multivariate analysis, independently of T stage, Gleason score, initial prostate-specific antigen level, and radiotherapy dose. Seven-year biochemical control was 61% vs. 41% (p = 0.0122) for 74 Gy vs. 64 Gy, respectively, among patients with Bcl-2–positive tumors and 87% vs. 81% (p = 0.423) for 74 Gy vs. 64 Gy, respectively, among patients with Bcl-2–negative tumors. There was no statistically significant interaction between dose and Bcl-2 expression. Conclusions: Bcl-2 expression was a significant, independent determinant of biochemical control after neoadjuvant androgen deprivation and radical radiotherapy for prostate cancer. These data generate the hypothesis that Bcl-2 expression could be used to inform the choice of radiotherapy dose in individual patients. [ABSTRACT FROM AUTHOR]

Summary: Background: Expression of intrinsic markers of tumour hypoxia and angiogenesis are important predictors of radiotherapeutic, and possibly surgical, outcome in several cancers. Extent of tumour hypoxia in localised prostate cancer is comparable to that in other cancers, but few data exist on the association of extent of tumour hypoxia with treatment outcome. We aimed to study the predictive value of intrinsic markers of tumour hypoxia and angiogenesis in localised prostate cancer, both in patients treated with radiotherapy and in those treated surgically. Methods: We applied a new, needle biopsy tissue microarray (TMA) technique to study diagnostic samples from men with localised, previously untreated prostate cancer treated in two randomised controlled trials of radiotherapy-dose escalation. Multivariate analysis by Cox proportional hazards was done to assess the association between clinical outcome, in terms of biochemical control, and immunohistochemical staining of hypoxia inducible factor-1 alpha (HIF-1 alpha), vascular endothelial growth factor (VEGF), and osteopontin expression. The analysis was repeated on an independent series of men with localised, previously untreated prostate cancer treated by radical prostatectomy. The main outcome was time to biochemical (ie, prostate-specific antigen [PSA]) failure. Findings: Between Oct 12, 1995, and Feb 5, 2002, 308 patients were identified from two prospective, randomised trials at the Royal Marsden Hospital, London and Sutton, UK, for the radiotherapy cohort and diagnostic biopsies were available for 201 of these patients. Between June 6, 1995, and Nov 4, 2005, 329 patients were identified from the Aarhus University Hospital, Skejby, Denmark, for the prostatectomy cohort; of these, 40 patients were excluded because the tumour was too small to sample (19 patients), because the paraffin block was too thin (19 patients), or because the blocks were missing (two patients), leaving 289 patients for analysis. For patients treated with radiotherapy, increased staining for VEGF (p=0·008) and HIF-1 alpha (p=0·02) expression, but not increased osteopontin expression (p=0·978), were significant predictors of a shorter time to biochemical failure on multivariate analysis, independent of clinical tumour stage, Gleason score, serum PSA concentration, and dose of radiotherapy. For patients treated with surgery, increased staining for VEGF (p<0·0001) and HIF-1 alpha (p<0·0001) expression, and increased osteopontin expression (p=0·0005) were each significantly associated with a shorter time to biochemical failure on multivariate analysis, independent of pathological tumour stage, Gleason score, serum PSA concentration, and margin status. Interpretation: 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. Funding: Prostate Cancer Research Foundation, London, UK; Danish Cancer Society, Copenhagen, Denmark; Cancer Research UK, London, UK; and National Cancer Research Institute South of England Prostate Cancer Collaborative, London, UK. [Copyright &y& Elsevier]

Classical renal tuberculosis is a well-known cause of urinary tract scarring and calcification, and sometimes renal dysfunction. In the past two decades there have been reports, particularly from the United Kingdom among immigrants from the Indian subcontinent, of a more insidiously progressive form of renal disease. Ultrasound shows small smooth kidneys, and histology reveals tubulointerstitial nephritis including granulomas but not acid-fast bacilli. Evidence is mounting that the underlying cause may be tuberculosis, but the mechanism remains obscure. [ABSTRACT FROM AUTHOR]

Objectives: To compare the results of Gleason Grade Group (GGG) classification following central pathology review with previous local pathology assessment, and to examine the difference between using overall and worst GGG in a large patient cohort treated with radiotherapy and short‐course hormone therapy. Patients and Methods: Patients with low‐ to high‐risk localized prostate cancer were randomized into the multicentre CHHiP fractionation trial between 2002 and 2011. Patients received short‐course hormone therapy (≤6 month) and radical intensity‐modulated radiotherapy (IMRT). Of 2749 consented patients, 1875 had adequate diagnostic biopsy tissue for blinded central pathology review. The median follow‐up was 9.3 years. Agreement between local pathology and central pathology‐derived GGG and between central pathology‐derived overall and worst GGG was assessed using kappa (κ) statistics. Multivariate Cox regression and Kaplan–Meier methods were used to compare the biochemical/clinical failure (BCF) and distant metastases (DM) outcomes of patients with GGG 1–5. Results: There was poor agreement between local pathology‐ and central pathology‐derived GGG (κ = 0.19) but good agreement between overall and worst GGG on central pathology review (κ = 0.89). Central pathology‐derived GGG stratified BCF and DM outcomes better than local pathology, while overall and worst GGG on central pathology review performed similarly. GGG 3 segregated with GGG 4 for BCF, with BCF‐free rates of 90%, 82%, 74%, 71% and 58% for GGGs 1–5, respectively, at 8 years when assessed using overall GGG. There was a progressive decrease in DM‐free rates from 98%, 96%, 92%, 88% and 83% for GGGs 1–5, respectively, at 8 years with overall GGG. Patients (n = 57) who were upgraded from GGG 2–3 using worst GS had BCF‐free and DM‐free rates of 74% and 92% at 8 years. CHHiP eligibility criteria limit the interpretation of these results. Conclusion: Contemporary review of International Society of Urological Pathology GGG successfully stratified patients treated with short‐course hormone therapy and IMRT with regard to both BCF‐free and DM‐free outcomes. Patients upgraded from GGG 2 to GGG 3 using worst biopsy GS segregate with GGG 3 on long‐term follow‐up. We recommend that both overall and worst GS be used to derive GGG. [ABSTRACT FROM AUTHOR]

The author comments on a study published within the issue about centralized histopathological review in penile cancer. The experiences of the author in managing penile cancer patients at St. George's Hospital in South London, England are highlighted. The significance of a central review and expert second opinion service in the management of penile cancer is emphasized.

Objectives: Several clinical studies have indicated that the rates of invasive growth and metastatic disease in cancer depend on the degree of hypoxia, which is mediated by hypoxia-inducible factor 1 α (HIF-1α). To determine its potential role as a marker for prostate cancer (CaP) diagnosis, HIF-1α mRNA levels were measured in blood samples of patients diagnosed with different stages of prostatic disease. Methods: HIF-1α mRNA levels were measured by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and correlated with accurate clinicopathological data. Quantitative data were compared with serum prostate-specific antigen (PSA) measurements to determine variations in the accuracy of the CaP diagnosis. Results: HIF-1α mRNA levels were significantly upregulated in patients with localized CaP (LocCaP; n=63; p<0.0001), compared with patients with no evidence of malignancy (NEOM) and benign prostatic hyperplasia (BPH) (n=35 for both patient groups combined). Receiver operator characteristic (ROC) curve analysis demonstrated that HIF-1α specificity for the NEOM/BPH diagnosis was 88.6%. Sensitivity for LocCaP was 74.6% with an overall diagnostic efficiency of 79.6%. Specificity of the NEOM diagnosis at PSA levels of 4.0 ng ml-1 was 28.6% and sensitivity of the LocCap diagnosis was 65.1%, demonstrating a reduced overall diagnostic efficiency, compared with that given by HIF-1α measurements, of 52.0%. Levels of HIF-1α in patients with metastatic CaP (MetCaP; n=27)) were similar to those in the NEOM/BPH group. Conclusions: HIF-1α is upregulated early in CaP development with subsequent downregulation at later metastatic stages. This study demonstrates increased accuracy of early-stage disease diagnosis using HIF-1α qRT-PCR compared with serum PSA measurements. HIF-1α may therefore be a useful adjunct, together with other diagnostic markers used in relative qRT-PCR and current diagnostic techniques (including serum PSA and PSA velocity) to minimize unnecessary biopsies indicated by elevated serum PSA levels alone. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the significance of close surgical margins in organ‐sparing surgery (OSS) in the treatment of penile squamous cell carcinoma (pSCC) and clinicopathological factors that may influence local recurrence. Patients and Methods: At our tertiary referral centre, between March 2001 and September 2012, 332 patients treated with OSS for pSCC had clear surgical margins. As the focus was the impact of close clear margins on local recurrence, patients with positive margins were excluded for the purpose of this study. Our overall positive margin rate for OSS in penile cancer is 7.6% (42 patients). Analysis was carried out on an on‐going prospective database, including prospective accurate pathological recording of surgical margins. Patients underwent OSS after multidisciplinary team (MDT) discussion. Local recurrence was the primary outcome measured and Fisher's exact test and time‐to‐recurrence curves were used in the analysis. All local recurrences were scrutinised by the MDT and were categorised into: true recurrences or metachronous new occurrences (i.e. tumours arising from a background of penile intraepithelial neoplasia and forming on an epithelial surface not related to the site of initial resection). A multivariate analysis was also conducted to elucidate other factors influencing local recurrence. Results: In all, 64% of the patients had a <5 mm clear deep surgical margin, with 16% clear by <1 mm. Overall, 4% of patients had a true local recurrence, with a median time to recurrence of 6 months. In all, 53% were due to embolic spread, with residual occult local disease accounting for 47%. There was a statistically significant relationship between cavernosal involvement (P = 0.014) and lymphovascular invasion (LVI; P = 0.001) and local recurrence. Although multivariate analysis revealed that the extent of clear margin was not a predictor of disease (P = 0.405), we found an increased risk of local recurrence in the clear margin cohort of <1 mm compared to those of >1 mm (P < 0.001). Those patients considered to have metachronous tumours were scrutinised by our MDT, and eight patients (2.4%) were found to have new occurrences. Our overall proportion of patients therefore needing further treatment for either new occurrences or recurrent disease after OSS stands at 6.4%. Conclusions: Overall the presence of local recurrent disease in OSS in our experience is low (4%). We report an embolic mechanism of local recurrence, strongly suggested by the presence of cavernosal involvement and LVI. We conclude that a deep clear margin of >1 mm has a very low risk of local recurrence in penile OSS. [ABSTRACT FROM AUTHOR]

Purpose: To assess whether the cellular proliferation marker Ki67 provides prognostic information and predicts response to radiation therapy fractionation in patients with localized prostate tumors participating in a randomized trial of 3 radiation therapy fractionation schedules (74 Gy/37 fractions vs 60 Gy/20 fractions vs 57 Gy/19 fractions).Methods and Materials: A matched case-control study design was used; patients with biochemical/clinical failure >2 years after radiation therapy (BCR) were matched 1:1 to patients without recurrence using established prognostic factors (Gleason score, prostate-specific antigen, tumor stage) and fractionation schedule. Immunohistochemistry was used to stain diagnostic biopsy specimens for Ki67, which were scored using the unweighted global method. Conditional logistic regression models estimated the prognostic value of mean and maximum Ki67 scores on BCR risk. Biomarker-fractionation interaction terms determined whether Ki67 was predictive of BCR by fractionation.Results: Using 173 matched pairs, the median for mean and maximum Ki67 scores were 6.6% (interquartile range, 3.9%-9.8%) and 11.0% (interquartile range, 7.0%-15.0%) respectively. Both scores were significant predictors of BCR in models adjusted for established prognostic factors. Conditioning on matching variables and age, the odds of BCR were estimated to increase by 9% per 1% increase in mean Ki67 score (odds ratio 1.09; 95% confidence interval 1.04-1.15, P = .001). Interaction terms between Ki67 and fractionation schedules were not statistically significant.Conclusions: Diagnostic Ki67 did not predict BCR according to fractionation schedule in CHHiP; however, it was a strong independent prognostic factor for BCR. [ABSTRACT FROM AUTHOR]

The article discusses the difference between 8th edition of the TNM classification (UICC 8) and 8th edition of the American Joint Committee for Cancer (AJCC 8). Topics discussed include UICC 8 classification does not take into account the clear evidence like lack of agreement relating to staging criteria for testicular tumors; AJCC 8 consists lack of comparability between treatment centres; and lack of guidance regarding how tumors added into World Health Organization 2016 classification.

Background: The 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 Findings: 148 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/Significance: EGFR, 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. [ABSTRACT FROM AUTHOR]

Stankiewicz E, Prowse D M, Ktori E, Cuzick J, Ambroisine L, Zhang X, Kudahetti S, Watkin N, Corbishley C & Berney D M (2011) Histopathology, 433-439 The pathogenesis of penile squamous cell carcinoma (PSCC) is not well understood. Human papillomavirus (HPV) may be involved in carcinogenesis, but few studies have compared cell-cycle protein expression in HPV positive and negative cancers. The aim was to determine the extent of HPV infection in different histological subtypes of PSCC and its impact on the expression of key cell-cycle proteins: p53, p21, p16 and retinoblastoma (RB) protein. One hundred and forty-eight PSCC samples were examined immunohistochemically for RB, p16, p53 and p21 protein expression. One hundred and two cases were typed for HPV by PCR. HPV DNA was detected in 56% of tumours, with HPV16 present in 81%. Basaloid tumours were related strongly to HPV infection (10 of 13), while verrucous were not (three of 13). Fifty-nine per cent (38 of 64) of usual type SCCs had HPV infection. RB protein correlated negatively ( P < 0.0001) and p16 ( P < 0.0001) and p21 ( P = 0.0002) correlated positively with HPV infection. p53 did not correlate with HPV infection. HPV infection is present in more than half of penile cancers and it is responsible for RB pathway disruption. However, no link between HPV and p53 immunodetection was found. Only basaloid and half of usual-type PSSCs correlate with HPV infection, confirming possible separate aetiologies for those tumours. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: We present medium-term outcome data for patients with invasive penile cancer treated with glansectomy and reconstruction with a split-thickness skin graft. Methods: A series of consecutive patients referred with penile malignancies over a 6-yr period were analyzed prospectively. A dedicated histopathologist reviewed all the specimens. After clinical staging, patients with tumours confined to the glans were offered glansectomy. Results: A total of 72 patients (32% of patients, 31% of procedures) underwent glansectomy for penile carcinoma. Of these, 65 patients were new diagnoses and seven were recurrences after radiotherapy. The mean follow-up period was 27 mo (range: 4–68 mo). There have been three late local recurrences (4%). Conclusion: Glansectomy appears to be an oncologically safe and effective procedure for patients with glans-confined squamous cell tumours. It preserves maximum phallic length and results in a very satisfactory cosmetic penile appearance after reconstruction. [Copyright &y& Elsevier]

OBJECTIVES To investigate, in a retrospective study, the expression of erythropoietin (Epo) in human renal cell carcinoma (RCC) and its correlation with overall survival, as Epo (an haematopoietic cytokine that regulates the production of red blood cells), with its receptor, was recently localized in non-haematopoietic tissues, e.g. liver, uterus, central nervous system, vascular endothelial cells and solid tumours. PATIENTS AND METHODS We used data from 113 patients who had radical nephrectomy for RCC between 1990 and 2000, taking sections from formalin-fixed and paraffin wax-embedded tissue blocks. The association between Epo staining and the patients’ characteristics was assessed by either chi-squared tests (for categorical variables) or two-sample independent t-tests (for continuous variables). RESULTS Tissue from 37 patients (33%) was positive for cytoplasmic Epo expression; 76 (67%) samples were negative. Univariate hazard ratio analysis confirmed that those with positive Epo staining were more than twice as likely to die as those with negative staining (hazard ratio 2.34, 95% confidence interval 1.27–4.3). CONCLUSION This study shows that the expression of Epo in RCC is adversely associated with overall survival. This is the first report of such an association, and might be explained by the loss of Von Hippel-Lindau protein function in clear cell RCC. The expression of Epo might have potential use in clinical trials when stratifying high-risk patients for adjuvant therapy after nephrectomy. [ABSTRACT FROM AUTHOR]

OBJECTIVE To evaluate medium-term outcome data from patients with distal urethral cancers treated with penile-preserving surgery. PATIENTS AND METHODS We analysed prospectively 18 consecutive men referred for the management of urethral carcinoma. All had a specialist review in a supra-regional multidisciplinary team meeting, where the histology findings were reviewed by one pathology consultant. Tumours were staged according to the Tumour-Node-Metastasis classification and the patients offered penile-preserving surgery when tumours were limited to the glanular or penile urethra. RESULTS All 18 patients were suitable for penile-preserving surgery; the procedures were: three hypospadias formation with or without topical chemotherapy; four buccal mucosa urethroplasty; three glansectomy and reconstruction; six glansectomy, distal corporectomy, reconstruction and hypospadias formation; two urethrectomy with or with no excision of adjacent tunica albuginea. The mean (median, range) follow-up was 26 (20.5, 9–58) months. There were no local recurrences; four patients with regional nodal disease progressed and of these, two died from metastatic disease, and one died from an unrelated condition. CONCLUSION Medium-term data show that penile-preserving surgery is a feasible treatment for men with distal urethral carcinoma, providing excellent local control without prejudicing survival; a longer follow-up is needed. [ABSTRACT FROM AUTHOR]

To assess the feasibility, toxicity and immunogenicity of dendritic cell (DC)-based immunotherapy in patients with advanced urological cancers. Patients 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. There 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. The 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. [ABSTRACT FROM AUTHOR]

Presents several letters concerning medicine. Usefulness of electron microscopy for morphological diagnosis; Prevalence of sexual abuse of children; Examination of the mianserin-induced agranulocytosis.