Penile cancer--Guideline adherence produces optimum results.

OBJECTIVE: To audit the management and outcome of penile cancer in a tertiary university teaching hospital, comparing our results to international best practice and published guidelines. METHODS: The Hospital Inpatient Enquiry database of the Mercy University Hospital was interrogated for penile cancer patients treated between 2001 and 2012. Data relating to presentation, local treatment, histology, lymph-node management, outcome and survival was recorded. Data were analysed using the Log Rank test, with significance defined as P ≤ 0.05. RESULTS: Twenty-five patients were identified with a median age of 61 years. The majority of cases at presentation were ≥ T2 (54%) and intermediate to high grade (76%). The median follow-up of patients was 3.75 years (range 9 months-10 years). Overall survival was 76% (n = 19), these patients are all disease free to date. Disease-specific survival was 85% at 10 years. Penile cancer related mortality was 8% (n = 2), 4 patients (16%) died of non-penile cancer related causes. Twenty-two patients (88%) had surgery and 3 patients (12%) had radiotherapy. Based on EAU guidelines inguinal lymph node dissection (ILND) was performed in 64% (n = 16) of cases with 44% (n = 7) of these patients requiring concurrent bilateral pelvic lymph node dissection. Fifty percent (n = 8) of ILNDs showed metastatic disease. Ten year disease-specific survival for node negative versus node positive disease is 100% versus 57%. Thirty-two percent (n = 8) of patients received chemotherapy. CONCLUSIONS: Penile cancer is a rare oncological condition that often requires bilateral inguinal ± pelvic lymph node dissection and should be managed according to published guidelines, in specialist centres in order to maximize outcomes.

Suitability of PSA-detected localised prostate cancers for focal therapy: experience from the ProtecT study.

BACKGROUND: Contemporary screening for prostate cancer frequently identifies small volume, low-grade lesions. Some clinicians have advocated focal prostatic ablation as an alternative to more aggressive interventions to manage these lesions. To identify which patients might benefit from focal ablative techniques, we analysed the surgical specimens of a large sample of population-detected men undergoing radical prostatectomy as part of a randomised clinical trial. METHODS: Surgical specimens from 525 men who underwent prostatectomy within the ProtecT study were analysed to determine tumour volume, location and grade. These findings were compared with information available in the biopsy specimen to examine whether focal therapy could be provided appropriately. RESULTS: Solitary cancers were found in prostatectomy specimens from 19% (100 out of 525) of men. In addition, 73 out of 425 (17%) men had multiple cancers with a solitary significant tumour focus. Thus, 173 out of 525 (33%) men had tumours potentially suitable for focal therapy. The majority of these were small, well-differentiated lesions that appeared to be pathologically insignificant (38-66%). Criteria used to select patients for focal prostatic ablation underestimated the cancer's significance in 26% (34 out of 130) of men and resulted in overtreatment in more than half. Only 18% (24 out of 130) of men presumed eligible for focal therapy, actually had significant solitary lesions. CONCLUSION: Focal therapy appears inappropriate for the majority of men presenting with prostate-specific antigen-detected localised prostate cancer. Unifocal prostate cancers suitable for focal ablation are difficult to identify pre-operatively using biopsy alone. Most lesions meeting criteria for focal ablation were either more aggressive than expected or posed little threat of progression.

Renal oncocytoma: CT features cannot reliably distinguish oncocytoma from other renal neoplasms.

AIM: To retrospectively review the computed tomography (CT) imaging features of a series of histologically confirmed renal oncocytomas and to determine whether imaging features are predictive of this subtype of benign renal epithelial tumour. MATERIALS AND METHODS: From May 2001 to October 2007, 21 patients with 28 renal masses, confirmed as renal oncocytoma on histological examination of the resection specimen, were identified from the pathology database at our institution. The preoperative imaging findings were retrospectively analysed to determine characteristic features, if any, to predict this rare subtype of benign renal tumour. RESULTS: There were 11 female and 10 male patients and the age at presentation ranged from 40-80 years (mean age 65.9 years). The size of the masses ranged from 1.2-12 cm in diameter (mean diameter 4.9 cm). All masses showed contrast enhancement. In 18 (64.3%) lesions the enhancement of the tumour was isodense to renal cortex. Ten (35.7%) lesions were hypodense to renal cortex. In three (10.7%) lesions, a well-defined stellate central scar was seen at CT and confirmed pathologically. In two (7.1%) lesions, a central scar was identified pathologically, but not seen on CT. The size of the central scars ranged from 10-29 mm diameter on CT. Twenty-two (78.6%) lesions did not demonstrate a scar on CT or pathologically. None of the patients had regional lymphadenopathy or distant metastasis. CONCLUSION: Renal oncocytoma is typically described as being hypervascular and homogeneous, with a characteristic central stellate scar on CT. The present study demonstrates that these imaging features are found in only a small proportion of these tumours. Therefore, imaging characteristics alone are unreliable when differentiating between oncocytoma and renal cell carcinoma, and histopathological diagnosis remains the reference standard.

Level of agreement and biopsy correlation using two- and three-tier systems to grade cervical dyskaryosis.

At present, a three-tier system is used to grade cervical dyskaryosis in the UK, although the two-tier Bethesda system is used in the United States, and the British Society for Clinical Cytology has recommended that a two-tier system be implemented here. In this study, we have retrospectively re-graded 117 conventional cervical smears using both systems to determine the intra- and interobserver variation and compare the cytology grading in both systems with the final histology. The intra and interobserver agreement was moderate using both grading systems, but the agreement between cytology grade and final histology was poor in both the two- and three-tier systems, and slightly worse using two-tier grading. However, when each of the three histological categories is considered separately the two-tier system appears to work better. Therefore, changing the way in which cervical dyskaryosis is graded in the UK may result in poorer agreement between the cervical smear result and the final histological diagnosis if introduced without proper training, monitoring and assessment.

SV40 Tag DNA sequences, present in a small proportion of human hepatocellular carcinomas, are associated with reduced survival.

AIMS: To study the association between simian virus 40 (SV40) and human hepatocarcinogenesis. METHODS: Polymerase chain reaction (PCR) to detect SV40 large T antigen (Tag) DNA was performed on: 50 human hepatocellular carcinoma (HCCs) diagnosed between 1978 and 1989 (cohort A); 20 cases of alcoholic liver cirrhosis from the same period; and 20 HCCs diagnosed after 1997 (cohort B). PCR to detect SV40 regulatory sequence and SV40 Tag immunohistochemistry were performed on selected cases from cohorts A and B. Amplified products were directly sequenced. Immunohistochemistry for p53 and pRb and clinicopathological analyses were performed on selected cases from cohorts A and B. Complete survival data were collected for cohort A. RESULT: SV40 Tag DNA was found in five cohort A HCCs but not in alcoholic liver cirrhosis cases or cohort B HCCs. Neither SV40 regulatory sequence nor SV40 Tag protein were demonstrated in Tag DNA positive HCCs. No clinicopathological differences existed between Tag DNA positive and negative HCCs, but the presence of Tag DNA was associated with reduced disease specific survival. Relatively fewer Tag DNA positive than negative HCCs expressed p53, but loss of pRb expression was similar in the two groups. Patients with Tag DNA positive HCCs were unlikely to have received SV40 contaminated poliovirus vaccine. CONCLUSIONS: SV40 Tag DNA is present in a small proportion of historical HCCs and may contribute to their pathogenesis and influence their outcome. The source of the virus is uncertain and more recent HCCs show no evidence of SV40.

Association of the D allele of the angiotensin I converting enzyme polymorphism with malignant vascular injury.

AIMS: To determine whether there is an association between the insertion/deletion (I/D) polymorphism of the human angiotensin I converting enzyme (ACE) gene and malignant vascular injury (MVI). METHODS: The polymerase chain reaction was used to genotype DNA extracted from archival, paraffin wax embedded renal biopsy material from 48 patients with MVI, made up from cases of malignant hypertension (n = 23), scleroderma (n = 10), and haemolytic uraemic syndrome (n = 15), and from whole blood samples from 191 healthy controls. RESULTS: The D allele was found more frequently in cases of MVI than in healthy controls, (65% v 52%). Both the DD and I/D genotypes occurred significantly more frequently in patients with MVI than did the II genotype (chi(2) = 7.26, p = 0.007; and chi(2) = 4.06, p = 0.04, respectively). CONCLUSIONS: Possession of at least one copy of the D allele is associated with an increased risk of developing MVI. Our data support a dominant mode of effect for the D allele. Use of the I/D polymorphism as a genetic marker for MVI may be of value clinically in identifying at risk individuals before the development of target end organ damage. Furthermore, those at risk may benefit from early ACE inhibition.

Immunohistochemical assessment of Ki67 and p53 expression assists the diagnosis and grading of ulcerative colitis-related dysplasia.

AIMS: To assess whether Ki67 and p53 immunostaining may assist the diagnosis and grading of ulcerative colitis-related dysplasia. METHODS AND RESULTS: Location of Ki67 staining and location and intensity of p53 staining were assessed in ulcerative colitis (UC) cases showing the features of high-grade dysplasia (HGD, n = 14), low-grade dysplasia (LGD, n = 22), 'indefinite for dysplasia' (n = 12), or regenerative atypia (RA, n = 22). Good intra- and inter-observer reproducibilities were demonstrated in the performance of these assessments. All the dysplasia cases showed extension of Ki67 staining above the basal third of the crypt. Moderate intensity p53 staining was seen in 10/22 RA cases, but strong intensity p53 staining was seen only in cases of dysplasia. All the cases of HGD showed extension of Ki67 and p53 staining above the basal two thirds of the crypt. CONCLUSIONS: Restriction of Ki67 staining to the basal third of the crypt appears to exclude a diagnosis of dysplasia whereas strong intensity p53 staining suggests a diagnosis of dysplasia. Restriction of Ki67 or p53 staining to the basal two-thirds of the crypt appears to exclude a diagnosis of HGD.

Molecular and cellular prospects for repair, augmentation, and replacement of the failing heart.

Molecular and cellular biology offer the promise of new approaches to the treatment of heart failure. This article discusses the basic science background, the current state of investigation, and the potential for therapeutic application of these new sciences. It also emphasizes the limitations and unknowns in this frontier. Three approaches are presented: First, increasing the number of myocytes in the heart, previously held to be untenable because postnatal cardiomyocytes do not divide, may be possible by regulating the cell cycle to reinduce cardiac growth. Also, nonmyocytes extant in the heart may be coaxed into differentiating into cardiomyocytes, or exogenous muscle cells may be grafted into the myocardium. Second, cardiac function may be augmented by molecular therapies that increase contractile protein function or regulate beta-adrenergic receptors or Ca++ channels. Third, improved prospects for transplantation of the failed heart may occur by genetic modification of a xenograft donor heart that reduces the chance of immune rejection by the human recipient. The formulation for the successful application of any of these therapies depends on not only the creativity of scientists but also the wisdom of physicians.

The molecular and cellular biology of heart failure.

We review recent publications that use molecular and cellular biology to explore the diagnosis and treatment of cardiovascular diseases that have relevance to heart failure. Familial hypertrophic cardiomyopathy has now been shown to be due to mutations not only in the previously described beta myosin heavy chain gene, but also in the troponin T and alpha-tropomyosin genes, thus providing some symmetry to the idea that this is a molecular disease of the sarcomere. The basis for a type of familial dilated cardiomyopathy without substantial skeletal muscle involvement, caused by a mutation in the dystrophin gene, has been explored. However, by-and-large, the disease basis for most patients with dilated cardiomyopathy remains a molecular mystery. The role of a polymorphism in the angiotensin-converting enzyme gene was examined as a risk factor for a number of cardiovascular diseases. In animal models, the hypothesis that the devolution from hypertrophy to heart failure includes alterations in the molecular direction of extracellular matrix production gained some support. The experimental foundation was laid this year for the concept of and approach to cardiomyocytoplasty--the molecular and cellular treatment of heart failure by augmentation, repair, or replacement of cardiac myocytes--by experiments in cardiac gene transfer and transgenic animals. Gene causes and cures for restenosis after angioplasty garnered considerable attention. As we gain greater understanding of the molecular basis for disease, we will also have to increase our wisdom in the application of genetic testing.

Developmental changes of the 26 S proteasome in abdominal intersegmental muscles of Manduca sexta during programmed cell death.

cDNA clone MS73 codes for an ATPase that is a regulatory subunit of the 26 S proteasome. Reverse transcriptase polymerase chain reaction analysis demonstrates that the expression of the gene dramatically increases in the pre-eclosion period. Western analyses show increases in other related. ATPases including MS73, MSS1, and mts2 but not TBP1. A similar increase in the 30-kDa subunit of the 20 S proteasome occurs. There are accompanying large changes in the peptidase activities of the 26 S proteasome. Relative to the 30-kDa subunit, there is no change in MSS1 and MS73, a 3-fold increase in mts2, and a 5-fold decline in TBP1. A large increase in the concentration of 26 S proteasomes together with extensive regulatory reprogramming may facilitate rapid muscular proteolysis.