Penile cancer in Ireland - A national review.

OBJECTIVE: Penile cancer is a rare malignancy, with a reported incidence of 1.5/100,000 males in the Republic of Ireland in 2015. The aim of this study was to perform the first national review and to evaluate clinicopathological factors affecting survival. SUBJECTS AND METHODS: All cases of penile cancer in Ireland between 1995 and 2010 were identified through the National Cancer Registry Ireland (NCRI) and analysed to identify factors affecting survival. RESULTS: 360 cases of penile cancer were identified, with a mean age at diagnosis of 65.5 years and 88% (n = 315) of cases occurred in those over 50. 91% (n = 328) of cases were squamous cell carcinomas (SCC). The majority of patients were treated surgically (n = 289), with 57% (n = 206) and 24% (n = 87) undergoing partial penectomy and total penectomy respectively. Only 18% (n = 65) received radiotherapy, and 8% (n = 27) received chemotherapy. Mean overall survival (OS) was 113 months, and five year disease specific survival (DSS) was 70% (95%CI: 59.1-77.8%). Age at diagnosis, nodal status and presence of metastatic disease were independent prognostic markers on multivariate analysis. CONCLUSION: This study represents the first national review of penile cancer in Ireland. The annual incidence and survival rates are comparable to European figures, though superior DSS has previously been reported from our institution, highlighting the role for centralisation of care in Ireland. LEVEL OF EVIDENCE: 2b.

Assessment of referral patterns for boys with suspected undescended testes and identification of risk factors to aid diagnosis.

INTRODUCTION: Undescended testis (UDT) is a clinical diagnosis and a common reason for referral to paediatric urology outpatients. Our aim was to assess current referral patterns at our unit and to identify predictive factors that may better aid primary care physicians (PCP) in diagnosing UDT based on history and physical exam. METHODS: A retrospective analysis of referrals to outpatients from 2014 to 2016 was performed to assess current referral patterns including referral source, age, reason for referral and outcome following assessment by a single consultant paediatric urologist.A prospective analysis of new referrals was performed to identify predictive factors which may aid in the diagnosis of UDT including gestational age, presence of scrotal asymmetry and previously obtained imaging. RESULTS: From 2014 to 2016, 259 boys were referred with suspected UDT. The majority of referrals were received from PCPs (62%) followed by Neonatology (29%), Paediatrics (8%) and general surgery (1%). Median age at time of assessment was 29 (5-180) months. One hundred and eight (41.7%) boys were diagnosed with UDT.There were 74 boys assessed prospectively. Median age at assessment was 24.5 (6-171) months. We identified 3 predictors of a diagnosis of UDT; history of prematurity (p = 0.001), UDT mentioned to the parents at birth (p = 0.027) and scrotal asymmetry on examination (p < 0.001). Greatest diagnostic inaccuracy was found in boys referred beyond one year of age (27.7%). In this cohort, the absence of all three risk factors was associated with a negative predictive value of 94.1%. CONCLUSION: The majority of boys with suspected UDT are referred beyond the age recommended for orchidopexy (6-12 months). The majority of boys referred for assessment did not have UDT. We have identified three predictive factors that may aid referring physicians when assessing boys, particularly those older than 1 year.

Research misconduct: time for a re-think?

The incidence of research misconduct appears to be increasing, drawing attention in the general media and academic literature. Concerns have been expressed about probable under-reporting, harms arising, lack of an agreed international definition, welfare of whistleblowers and the adequacy of the investigation processes and any subsequent sanctions. A fully satisfactory approach to prevention, detection, investigation and adjudication has yet to emerge. While the definition of research misconduct contained in the Australian Code for the Responsible Conduct of Research is comprehensive, universities and other research institutions at times struggle in their task of investigating and adjudicating allegations of research misconduct. A more centralised, independent process of oversight and monitoring of this role played by the universities and institutions would help support those institutions and help maintain community confidence in the research endeavour.

Is there a role for the development of a supra-regional network for the management of penile cancer in the Republic of Ireland?

INTRODUCTION: There is an average of 25 cases of penile cancer in the Republic of Ireland each year. Due to the low volume of cases, the National Institute for Clinical Excellence recommends that treatment is centralised to allow the best standardised treatment for primary tumours and nodal disease. OBJECTIVES: To determine whether outcomes for patients with penile cancer differed significantly between secondary and tertiary referral centres in the Republic of Ireland. METHODS: Between 2001 and 2014, 36 patients were treated in the Mercy University Hospital (MUH) with penile cancer. Twenty patients were treated primarily in MUH and 16 patients underwent initial management in a secondary referral centre (SRC) with subsequent referral to the MUH. A retrospective matched case-control study was performed on this patient cohort. RESULTS: There were no significant differences in length of follow-up or risk factors for the development of penile cancer between both groups (p = 0.6 and p = 0.5 respectively) Ultimately, the incidence of high risk disease, nodal metasases, high grade disease and pelvic lymph node dissection were significantly greater in patients that were initially managed in a SRC (p = 0.02, p = 0.03, p = 0.004 and p = 0.028 respectively). Patients undergoing initial treatment in a SRC had a non-significantly reduced rate of cancer specific survival (88 Vs 66%, MUH Vs SRCs, p = 0.495) and recurrence free survival (85 Vs 46%, MUH Vs SRCs, p = 0.24). CONCLUSION: Our findings suggest that managing penile cancer in special interest centres may improve oncological outcome.

Endothelial and platelet microparticles in patients with antiphospholipid antibodies.

BACKGROUND: The antiphospholipid syndrome (APS) is the association of thrombosis and recurrent pregnancy loss and/or pregnancy morbidity with persistent antiphospholipid antibodies (aPL). Previous studies of microparticles in patients with APS/aPL have mainly been small and findings, contradictory. OBJECTIVES: To quantify endothelial and platelet microparticle levels in patients with isolated antiphospholipid antibodies or primary antiphospholipid syndrome (PAPS). PATIENTS/METHODS: We measured endothelial and platelet microparticle levels by flow cytometry in 66 aPL/PAPS patients and 18 healthy controls. RESULTS: Levels of circulating platelet (CD41 and CD61) and endothelial microparticles (CD51 and CD105) were significantly increased in patients with PAPS and aPL compared to healthy controls. There were correlations between platelet and endothelial microparticles levels in all patients with aPL. CONCLUSIONS: Platelet and endothelial microparticles are increased in all patient groups within this cohort of patients aPL. Whether they may have a role in the pathogenesis of APS merits further study.

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.

The detrimental impact of the implementation of the European working time directive (EWTD) on surgical senior house officer (SHO) operative experience.

BACKGROUND: Concerns have been voiced regarding the impact of the European Working Time Directive (EWTD) on surgical training. Following its introduction (August 2009) in Wexford General Hospital, Ireland Surgical Senior House Officers (SSHOs) are required to leave the hospital at 10 a.m. the morning after on-call duty. This study investigates the consequences of this practice on operative experience gained by six SSHOs in comparison to their predecessors. METHODS: A prospectively maintained database of surgical procedures was interrogated. Operative experience of SSHOs over a 5-month period (August-December 2009) was compared with that of colleagues 1 year earlier. The primary endpoint was overall operative volume of SSHOs. Subgroup analysis was performed of cases by primary operator versus assistant, intermediate versus minor procedures and by team. Comparison was made of operative volume between Group 1 (pre-EWTD) and Group 2 (post-EWTD). RESULTS: Operative volume for Group 1 (pre-EWTD) was 461 cases. Group 2 (post-EWTD) was involved in a total of 349 operations, showing a decrease of 24% (P=0.006). SSHOs in Group 1 (pre-EWTD) had been the primary operator in 109 cases compared to 87 in Group 2 (post-EWTD), demonstrating a reduction of 20% (P=0.06). Most worryingly, there was a reduction of 63% (P=0.04) in the intermediate cases performed as operating surgeon in Group 2 (post-EWTD). CONCLUSIONS: The present data set demonstrates a significant reduction in operative experience gained by SSHOs after local implementation of the EWTD. A major challenge facing Irish surgical training over the next decade is reduced operative exposure in the clinical setting.

Isolated first rib fracture with minimal trauma.

BACKGROUND: The traditional teaching states that upper rib fractures are associated with severe trauma and a high risk of neurovascular insult. MATERIAL AND METHODS: We present the case of an 18-year-old male who sustained an isolated, uncomplicated fracture of the first rib by falling on his elbow during a soccer match. CONCLUSION: This case illustrates that an uncomplicated upper rib fracture can occur with minor trauma. The term "rebound" fracture is proposed for this type of rib injury.

Difficult physician-patient encounters.

Consultant physicians encounter patients, and families and carers of patients, who leave us feeling helpless, frustrated, irritated and even angry. There are limited opportunities for trainees and physicians to discuss how to recognize, manage, learn from and prevent these difficult physician-patient encounters. This paper addresses factors, including physician factors, that may contribute to making encounters difficult, categorizes the types of difficult encounters and provides generic and specific suggestions (based in part on published literature and in part on our personal experience) about prevention and management of many of them.

The amyloidogenic potential and behavioral correlates of stress.

Observations of elevated basal cortisol levels in Alzheimer's disease (AD) patients prompted the hypothesis that stress and glucocorticoids (GC) may contribute to the development and/or maintenance of AD. Consistent with that hypothesis, we show that stress and GC provoke misprocessing of amyloid precursor peptide in the rat hippocampus and prefrontal cortex, resulting in increased levels of the peptide C-terminal fragment 99 (C99), whose further proteolytic cleavage results in the generation of amyloid-beta (Abeta). We also show that exogenous Abeta can reproduce the effects of stress and GC on C99 production and that a history of stress strikingly potentiates the C99-inducing effects of Abeta and GC. Previous work has indicated a role for Abeta in disruption of synaptic function and cognitive behaviors, and AD patients reportedly show signs of heightened anxiety. Here, behavioral analysis revealed that like stress and GC, Abeta administration causes spatial memory deficits that are exacerbated by stress and GC; additionally, Abeta, stress and GC induced a state of hyperanxiety. Given that the intrinsic properties of C99 and Abeta include neuroendangerment and behavioral impairment, our findings suggest a causal role for stress and GC in the etiopathogenesis of AD, and demonstrate that stressful life events and GC therapy can have a cumulative impact on the course of AD development and progression.

Estradiol enables cortisol to act directly upon the pituitary to suppress pituitary responsiveness to GnRH in sheep.

We have shown that cortisol infusion reduced the luteinizing hormone (LH) response to fixed hourly GnRH injections in ovariectomized ewes treated with estradiol during the non-breeding season (pituitary-clamp model). In contrast, cortisol did not affect the response to 2 hourly invariant GnRH injections in hypothalamo-pituitary disconnected ovariectomized ewes during the breeding season. To understand the differing results in these animal models and to determine if cortisol can act directly at the pituitary to suppress responsiveness to GnRH, we investigated the importance of the frequency of GnRH stimulus, the presence of estradiol and stage of the circannual breeding season. In experiment 1, during the non-breeding season, ovariectomized ewes were treated with estradiol, and pulsatile LH secretion was restored with i.v. GnRH injections either hourly or 2 hourly in the presence or absence of exogenous cortisol. Experiments 2 and 3 were conducted in hypothalamo-pituitary disconnected ovariectomized ewes in which GnRH was injected i.v. every 2 h. Experiment 2 was conducted during the non-breeding season and saline or cortisol was infused for 30 h in a cross-over design. Experiment 3 was conducted during the non-breeding and breeding seasons and saline or cortisol was infused for 30 h in the absence and presence of estradiol using a cross-over design. Samples were taken from all animals to measure plasma LH. LH pulse amplitude was reduced by cortisol in the pituitary clamp model with no difference between the hourly and 2-hourly GnRH pulse mode. In the absence of estradiol, there was no effect of cortisol on LH pulse amplitude in GnRH-replaced ovariectomized hypothalamo-pituitary disconnected ewes in either season. The LH pulse amplitude was reduced in both seasons in experiment 3 when cortisol was infused during estradiol treatment. We conclude that the ability of cortisol to reduce LH secretion does not depend upon the frequency of GnRH stimulus and that estradiol enables cortisol to act directly on the pituitary of ovariectomized hypothalamo-pituitary disconnected ewes to suppress the responsiveness to GnRH; this effect occurs in the breeding and non-breeding seasons.

A multicentre longitudinal observational study of changes in self reported health status in people with Parkinson's disease left untreated at diagnosis.

BACKGROUND: The issue of when to start treatment in Parkinson's disease (PD) remains controversial. Some favour treatment at diagnosis while others opt for a "wait and watch" policy. The effect of the latter policy on the self reported health status of people with PD is unknown. AIMS: To record self reported health status through longitudinal use of a validated PD specific questionnaire (PDQ-39) in untreated PD patients in multiple centres in the UK. To compare patients who were left untreated with those who were offered treatment during follow-up. METHODS: A multicentre, prospective, "real life" observational audit based study addressing patient reported outcomes in relation to self reported health status and other sociodemographic details. RESULTS: 198 untreated PD were assessed over a mean period of 18 months. During two follow-up assessments, the self reported health status scores in all eight domains of the PDQ-39 and the overall PDQ-39 summary index worsened significantly (p<0.01) in patients left untreated. In a comparative group in whom treatment was initiated at or soon after diagnosis, there was a trend towards improvement in self reported health status scores after treatment was started. CONCLUSIONS: This study addresses for the first time self reported health status, an indicator of health related quality of life, in untreated PD. The findings may strengthen the call for re-evaluation of the policy to delay treatment in newly diagnosed patients with PD.

The over-expression of the wild type or mutant forms of the presenilin-1 protein alters glycoprotein processing in a human neuroblastoma cell line.

Mutations in the presenilin proteins (PS1 and PS2) are responsible for more than 70% of the cases of the familial form of Alzheimer's disease (FAD). The proteins are expressed in the cell at a low level, primarily in the endoplasmic reticulum and cis Golgi, where they have been proposed to play a role in protein processing. As protein glycosylation is a key post-translational event that occurs within the Golgi, we have investigated the effect of altered PS1 expression levels on the protein glycosylation pattern using the SH-SY5Y human neuroblastoma cell line. In cells over-expressing either the wild type or mutant (M146L) PS1-FAD proteins, there was a decrease in the expression levels of protein-bound alpha2,3-linked sialic acid residues at the level of the cell membrane. This was particularly manifest as a significant decrease in the expression of the polysialic acid chain that is linked to the core oligosaccharide of the neural cell adhesion molecule in an alpha2,3 bond. These results suggest that the over-expression of either the wild type or mutant PS1 disturbs glycoprotein processing within the Golgi.

Misconduct in medical research: whose responsibility?

Abstract Examples of many types of misconduct in medical research continue to be reported. The true incidence is unknown because there is strong evidence of under-reporting as well as suggestions of increased detection. Risks to research participants may also be increasing, with contributing factors such as increased pressure on researchers to publish and to produce commercialization of their research. Institutions are perceived to typically respond slowly and inadequately to allegations of research misconduct. More could be done to try to prevent such mis-conduct, such as: (i) educating researchers about research ethics, (ii) assisting and protecting whistleblowers and (iii) instituting processes to adequately and promptly investigate and deal with allegations. In addition, a debate needs to take place as to whether research misconduct allegations should be dealt with at the institutional level or at a national level and whether medical boards should be routinely involved in the more serious breaches of ethical standards by medical practitioners engaged in research.