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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.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.In all, 64% of the patients had a5 mm clear deep surgical margin, with 16% clear by1 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 of1 mm compared to those of1 mm (P0.001). 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%.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 of1 mm has a very low risk of local recurrence in penile OSS.

The publication of each successive edition of the TNM staging classification by the International Union Against Cancer (UICC) is widely anticipated, as the staging system is accepted and utilized internationally. Late in 2016 the eighth edition of the TNM classification (UICC 8)1 was released but unfortunately, and despite the passage of six years since the publication of the seventh edition of the staging classification, the new edition incorporates little new data. In addition to this there are a number of differences between the staging recommendations of UICC 8 and those recently published as part of the 8th edition of the American Joint Committee for Cancer (AJCC 8). This article is protected by copyright. All rights reserved.

Penile cancer is a rare malignancy estimated to affect 26,000 men globally each year. The association with penile cancer, in particular non-invasive disease, and human papilloma virus (HPV) is well known. Ninety-five percent of cases of penile cancer are squamous cell carcinoma (SCC), which are staged using the TNM staging system. Terminology describing the histological appearance of non-invasive penile cancer has changed with all cases grouped under the umbrella term of penile intraepithelial neoplasia (PeIN); either undifferentiated or differentiated. This replaces previous terms such as carcinoma in situ (CIS) and eponymous names such as Bowen's disease. This change is recognised by the World Health Organisation (WHO). The topical treatments most commonly used for PeIN are 5-fluorouracil (5-FU) and imiquimod (IQ). Other treatments such as photodynamic therapy (PDT) are used but to a lesser degree. The evidence for all of these treatments is heterogenous with no randomised data available. Overall up to 57% complete response has been reported with a low number of serious adverse events. In this article, we aim to review the available evidence for the topical treatment of non-invasive penile cancer specifically regarding its efficacy and toxicity.

Glans resurfacing is a recently described technique in the management of precancerous lesions and superficial invasive tumours of the glans penis as well as cases of indolent persistent lichen sclerosus. The technique is complex and is usually only practiced in specialist centres with combined urological and plastic surgical expertise. Cosmetic and functional results are better than in more extensive penile surgery, such as glansectomy, for such cases, cancer cure and control is comparable. Knowledge of the technique used and the spectrum of disease are vital for appropriate specimen handling and pathological reporting of these complex cases to aid further management and avoid over reporting of positive margins.

Distal urethral carcinomas are very rare and are similar in their pathology and behaviour to tumours of the glans penis and foreskin. Similarly they are associated with penile intraepithelial neoplasia (PeIN) of both differentiated and undifferentiated types. Current management is mainly surgical, but increasingly involves specialist penile-preserving techniques. Handling and dissection of the specimens is broadly the same as other primary penile tumours. The prognosis of distal urethral lesions is believed to be worse than penile tumours and better than prostatic urethral tumours, but the evidence is sparse. The staging system for urethral tumours does not distinguish between proximal and distal, apart from prostatic urethra, and has led to much confusion in the literature. Although the subtypes of tumours seen in the distal urethra are the same as those on the glans and foreskin, there is an increased proportion of basaloid squamous carcinoma and malignant melanoma whereas the majority of tumours seen in the proximal and prostatic urethra are of urothelial origin. In future, distal urethral tumours should be separately designated with site-specific staging/TNM and reporting system and pathologically classified in the same way as penile and foreskin tumours. Ultimately, this will improve the quality of data and produce evidence to inform management.

Stankiewicz E, Prowse D M, Ktori E, Cuzick J, Ambroisine L, Zhang X, Kudahetti S, Watkin N, Corbishley C & Berney D M (2011) Histopathology58, 433–439 The retinoblastoma protein/p16INK4Apathway but not p53 is disrupted by human papillomavirus in penile squamous cell carcinoma Aims: 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, p16INK4A and retinoblastoma (RB) protein. Methods and results: One hundred and forty-eight PSCC samples were examined immunohistochemically for RB, p16INK4A, 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

98 Background: A uniform fractionation schedule is used to deliver external beam RT for localised prostate tumours Individualising fractionation according to tumour biology may improve outcomes. In addition recurrence rates after RT vary considerably and better prognostic markers are needed to guide treatment choices. This study aims to identify if the cell proliferation marker Ki67 predicts response to RT fractionation in CHHiP, a randomised trial of 3 RT fractionation schedules. It also aims to identify if Ki67 predicts prognosis. Methods: A matched case:control study design was used, patients with biochemical or clinical failure > 2 years after RT (BCR) were matched to patients without recurrence according to established prognostic factors (Gleason score, PSA, Tumour-stage) and fractionation schedule. Immunohistochemical (IHC) staining of diagnostic biopsy sections was carried out using the MIB1 Ki67 antibody. Two independent investigators scored Ki67 using the unweighted global method (1) to derive a mean and maximum percentage of cells staining positive (mean Ki67 and maximum Ki67 respectively). Conditional logistic regression models were fitted with interaction terms between the biomarker and the fractionation schedules to determine whether Ki67 predicted BCR according to fractionation. Secondly models were fitted using the entire case:control study sample to estimate the prognostic value of Ki67 on risk of BCR. Results: Ki67 results were available for 173 matched pairs. The interaction terms between Ki67 and the fractionation schedules were not significant. However mean and maximum Ki67 were significant prognostic markers for BCR in a model adjusted for established prognostic factors. Conditioning on matching variables and age, the odds of BCR is estimated to increase by 9% per 1 point increase in mean Ki67 (OR = 1.09, 95%CI:1.04–1.15, p = 0.001). Conclusions: Ki67 did not predict BCR according to fractionation schedule in CHHiP, however it did predict prognosis independently of established prognostic factors. Additional IHC biomarkers are under evaluation.

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 low-risk, 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.

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.

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.

Premalignant penile lesions are a difficult group of disorders to accurately differentiate from benign dermatoses. There is often a history of self-management or management in non-specialist centres leading to a delay in diagnosis. Early recognition and treatment of these lesions may prevent progression to invasive cancer thereby reducing the need for more traumatic interventions. It is important to note that penile cancer is a relatively rare malignancy affecting approximately 1 in 100,000 men per year in Europe and the USA, with premalignant lesions forming a small proportion of new cases. Therefore, the knowledge base relating to the management of premalignant lesions is often from small series or case reports.

INTRODUCTION AND OBJECTIVES: Glans resurfacing involves excision of the glans and subcoronal epithelial and subepithelial tissues followed by partial thickness skin grafting to the denuded corpus spongiosum. We have extended the use of this technique from benign and premalignant penile disease to the treatment of selected superficially invasive squamous cell carcinomas (SCC). METHODS: Between April 2002 and October 2010, 64 patients had glans resurfacing at our unit for penile neoplasia. 36 men had the procedure for superficially invasive hyperkeratotic penile SCC and 28 for confirmed pre-malignant lesions. Data was recorded prospectively in a database and outcome measures of positive margin rate, early revision rate and local recurrence rate were determined from the database, patient notes and histopathology records. RESULTS: Of the 36 men treated for SCC, preoperative biopsy was accurate in only 34% of cases. However, 78% had low / intermediate grade SCC (T1 G1/2) on final histology. 4 men had focal positive margins (11%) 2 had a small nodular recurrence excised completely and remain disease free at 12 and 33 months follow-up (recurrence rate 6%). The remaining 2 men are recurrence free at 12 and 26 months. 3 had T2 positive margins and had an early revision with a glansectomy (8%). There were no recurrences in patients with negative margins at a median follow up of 21 months (7-69). Except 1 man, grafts took well with good cosmetic results. 6 men had penile cancer diagnosed unexpectedly having undergone glans resurfacing for preoperative biopsy proven pre-malignant lesions. CONCLUSIONS: This is a novel way of managing superficially invasive hyperkeratotic penile cancer. With experience case selection should become tighter reducing the early revision and recurrence rates. Glans resurfacing provides the optimal cosmetic and functional result currently available in penile cancer surgery.

Not long ago, the place of the autopsy in medical practice seemed to be primarily the concern of the medical profession. Then the issue of organ retention came to public attention in the UK following the Bristol Royal Infirmary and Alder Hey Inquiries1,2, and the whole question of keeping organs and other samples from autopsies suddenly became the focus of intense media attention, generally negative, in which the British government was involved3,4. In consequence, there is debate about the future role of the autopsy. Several government-sponsored reviews of the conduct of the medical profession in regard to autopsies have been proposed. Some of these are currently out to consultation and include national standardized autopsy consent forms, a code of practice for bereavement services4, a review of the removal and retention of human organs (including a code of practice for museums, archives and collections of human organs and tissue)5 and a Home Office-led review of death certification and the coronial system in England and Wales6. A comprehensive review of the Human Tissue Act (1961) is planned. These measures will undoubtedly regulate all aspects of autopsy practice and its contribution to research, education and audit. The National Confidential Enquiry into Perioperative Deaths (NCEPOD) stands to be much affected by such changes but must continue to play a part in informing the debate.

Surface hydrophobicity of the gastric mucosa is reduced in peptic ulcer disease and Helicobacter pylori infection. This abnormality may be caused by H. pylori or may be an inherent defect. The aim of the present study was to clarify the relationship between H. pylori infection and mucosal hydrophobicity by examining the effect of eradication of the organism. H. pylori-positive patients with (n = 42) or without (n = 42) duodenal ulcer were randomized to receive ranitidine, bismuth, or bismuth plus antibiotics. Surface hydrophobicity of gastric mucosa was assessed by measurement of plateau-advancing contact angle. Measurements were performed at presentation, end of treatment, and 1 month later. Contact angle was unchanged after ranitidine (55 degrees vs. 56 degrees) but increased with bismuth (57 degrees-62 degrees; P < 0.05) and bismuth plus antibiotics (56 degrees-67 degrees; P < 0.0001). One month after treatment ended, contact angles in patients in whom H. pylori was not eradicated were not different from those before treatment (56 degrees vs. 56 degrees) but increased to a value similar to H. pylori-negative controls in patients in whom H. pylori was eradicated (56 degrees-69 degrees; P < 0.0001). It is concluded that reduced mucosal hydrophobicity in peptic ulcer disease is secondary to H. pylori infection and that this impaired mucosal defense provides a possible mechanism whereby H. pylori infection predisposes to acid/peptic digestion.

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 alpha (HIF-1alpha). To determine its potential role as a marker for prostate cancer (CaP) diagnosis, HIF-1alpha mRNA levels were measured in blood samples of patients diagnosed with different stages of prostatic disease.HIF-1alpha 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.HIF-1alpha mRNA levels were significantly upregulated in patients with localized CaP (LocCaP; n=63; p0.0001), 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-1alpha 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-1alpha measurements, of 52.0%. Levels of HIF-1alpha in patients with metastatic CaP (MetCaP; n=27)) were similar to those in the NEOM/BPH group.HIF-1alpha 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-1alpha qRT-PCR compared with serum PSA measurements. HIF-1alpha 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.

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.

OBJECTIVE To assess the feasibility, toxicity and immunogenicity of dendritic cell (DC)-based immunotherapy in patients with advanced urological cancers. PATIENTS AND METHODS 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. RESULTS 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. CONCLUSION 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.

Tuberculosis of the kidney and urinary tract is, like other forms of the disease, caused by members of the Mycobacte- rium tuberculosis complex. By far the most common causative organism is the human tubercle bacillus, M. tuberculosis, but the bovine tubercle bacillus, M. bovis, occasionally can be responsible. The vaccine strain, Bacille Calmette-Guerin (BCG), also has been the cause of renal lesions as a compli- cation of intravesical instillation of BCG for the treatment of superficial bladder cancer. The members of the M. tuberculosis complex are obligate pathogens and, together with M. leprae, differ from the many other species within the genus Mycobacterium, which are free-living environmental saprophytes and are commonly found in water, including piped water supplies. Some of these so-called environmental mycobacteria occasionally cause hu- man disease, particularly in immunosuppressed individuals, including recipients of renal transplants (1). The kidney may be involved when environmental mycobacteria cause dissemi- nated disease, such as that caused by M. avium in AIDS patients. Renal disease caused by environmental mycobacteria in nonimmunosuppressed individuals is exceedingly rare (2). However, because they occur in water, environmental myco- bacteria readily contaminate the lower urethra and external genitalia and, thus, often are isolated from urine samples. Globally, tuberculosis is a common disease, with 8 to 10 million new cases annually and a rising incidence, particularly in regions with a high incidence of HIV infection. Most often the lung is affected, but, after lymphadenopathy, the most common form of nonpulmonary tuberculosis is genitourinary disease, accounting for 27% (range, 14 to 41%) of nonpulmo- nary cases in several surveys in the United States, Canada, and United Kingdom (3). In developed countries, nonpulmonary tuberculosis is rela- tively more common in patients from ethnic minority groups, the exception being genitourinary tuberculosis, which is un- common in these groups. In the United Kingdom, the latter accounts for 5% of cases of nonpulmonary tuberculosis in ethnic minorities, mostly those of Indian subcontinent ethnic origin, compared with 27% of such cases in the European (white) population. This is, to some extent, age related: when patients of white and of Indian subcontinent ethnic origin were stratified by age, the incidence of genitourinary tuberculosis was similar in the two groups in each age band (4). Tuberculosis caused by M. bovis is now uncommon in industrially developed nations, accounting for fewer than 1% of all cases of tuberculosis. It is usually due to reactivation of old, dormant disease, although cases have occurred in younger, HIV-positive patients (5). In approximately 25% of cases caused by reactivation in older persons, the genitourinary sys- tem is involved (6). Such disease has a somewhat bizarre veterinary health significance because a number of farmers have infected cattle by urinating on hay in cowsheds (7).

4640 Background: Dynamic sentinel node biopsy (DSNB) in combination with ultrasound scan (USS) has been the technique of choice at our centre since 2004 for the assessment of non palpable inguinal lymph nodes in patients with squamous cell carcinoma of the penis (SCCp). Sensitivity/false-negative rates may vary depending on whether results are reported per patient or per node basin and with and without USS. The purpose of this study was to determine the long-term outcome of DSNB and ultrasound-guided fine needle aspiration cytology (FNAC) in our cohort of newly diagnosed patients and to analyse any variation in sensitivity of the procedure. Methods: A prospective cohort study over 6 years (2004 to 2010). Inclusion criteria: New diagnosis SCCp, T1G2 or greater definitive histology, non-palpable nodes in inguinal basin. Exclusion: patient with persistent/untreated local disease. Sensitivity of the procedure was calculated, per node basin, per patient, DSNB alone, USS/DSNB combined. Minimum follow up 12 months. Results: 500 inguinal basins in 264 patients underwent USS+/-FNAC and DSNB. 70 (14%) positive inguinal basins in 57(22%) patients were identified. 9 (2%) inguinal basins had no tracer uptake. 2 inguinal basins were confirmed false negative at 8 and 12 months. 2 inguinal basins had positive USS+FNAC and negative DSNB. Overall sensitivity of the technique is reported in the table. Conclusions: DSNB in combination with USS has excellent performance characteristics to stage patients with clinically node-negative penile cancer with a 3% false negative rate. USS improves performance by 4% over DSNB alone. There is no difference in performance of the combined technique if it is reported per node basin or per patient. [Table: see text]

The relationship between cytomegalovirus (CMV) infection and cardiac allograft rejection is controversial, some authors reporting a significant association, others not, on the basis of the results of conventional virological diagnosis by culture or serology. This problem was reinvesti-gated in 88 patients using a semi-quantitative nest polymerase chain reaction (PCR) procedure for detecting CMV DNA in endomyocardial biopsy specimens. Significantly more positive biopsies were obtained from patients with moderate (grade 2; P = 0.02) or severe (grade 3a-4; P = 0.03) rejection than with no or mild (grade 0-1 b) rejection, whereas there was no significant association between rejection and CMV as diagnosed by virus isolation from urine, throat or blood, or by the detection of CMV-IgM. PCR-positive biopsies originated most frequently from CMV-antibody positive recipients (R+) of hearts from seropositive donors (D+), in association with moderate or severe rejection rather than with mild or no rejection The detection of CMV in the heart thus seemed to be related more to R+D+ serological status than to severity of rejection, that is, to circumstances that favoured co-infection with strains of CMV from both donor and recipient. Studies on sequential biopsy specimens from selected patients also provided evidence that CMV infection and rejection were not always related events. The PCR was able to differentiate latent from active CMV infection; moreover, some seroneg-ative individuals gave repeatedly positive biopsies, thereby supporting the work of others that some patients undergo CMV infection without mounting a detectable antibody response. The use of the PCR provided additional and more definitive information linking CMV and post-transplantation cardiac rejection when compared to conventional methods of viral diagnosis which were less suitable as correlates of deep seated focal infection. © 1994 Wiley-Liss, inc.

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.

Summary— Twenty-one patients with post-operative retention following unassociated surgery and requiring transurethral resection of the prostate were compared with patients with acute retention (control group). Histological evidence of acute prostatic infarction was significantly increased in the post-operative retention group. Prolonged operative hypotension was associated with acute prostatic infarction, as were smoking and pre-existing cardiovascular disease.

The expression of the estrogen-regulated breast-cancer-associated pS2 gene was examined in 75 stomach resections taken from 45 patients. The 600-base pS2 mRNA was found in all of the 47 non-neoplastic samples at varying levels: in the histologically normal group we observed a Poisson-type distribution, whereas 79% of the tissues exhibiting dysplastic features expressed high levels of transcript. Tumour samples expressed relatively lower pS2 mRNA, with only 18% having high levels and 43% with no detectable expression. These differences were not correlated to tumour grading, stage or site. No amplification or rearrangement of the pS2 gene was found. Immunohistochemical analysis of formalin-fixed paraffin sections, using a polyclonal antibody against pS2 protein, showed specific staining of both cytoplasm and membrane of epithelial cells in the neck region of antral and body glands as well as in luminal secretions. Immunoreactivity was observed in the sub-nuclear region of foveolar cells, with specialized gland and goblet cells in atrophic gastritis being negative. Heterogeneous but strong focal cytoplasmic staining was seen in tumour cells as well as in dysplastic epithelium. Two gastric cell lines, KATO III and MKN-45, derived from poorly differentiated adenocarcinomas also expressed pS2, whereas 3 other lines from well differentiated parental tumours did not. Genomic analysis revealed a BamHI polymorphism in Kato III cells and in the non-expressing MKN-28 cells. Immunostaining to pS2 protein was also demonstrated in the cytoplasm of KATO III cells, but neither these nor any of 30 tissues examined showed any positivity with a monoclonal antibody (MAb) to estrogen receptor. Our results suggest that pS2 is normally expressed in human stomach, possibly in association with secretory activity, and becomes down-regulated during malignancy.

Limiting dilution analysis showed that the frequency of precursor donor-lytic cytolytic lymphocytes increased dramatically within the leucocyte population recovered by broncho-alveolar lavage in dogs after unilateral lung transplantation. The increases for animals experiencing acute pulmonary rejection (11.5–24.8 times pre-operative level) and for those receiving long-term ciclosporin A therapy (5.4–17.6 times pre-operative level) were similar. Therefore, it appears that ciclosporin A does not prevent the sequestration of precursor donor-lytic cytotoxic cells within lung allograft tissue.