Androgen receptor phosphorylation status at serine 578 predicts poor outcome in prostate cancer patients

Purpose: Prostate cancer growth is dependent upon androgen receptor (AR) activation, regulated via phosphorylation. Protein kinase C (PKC) is one kinase that can mediate AR phosphorylation. This study aimed to establish if AR phosphorylation by PKC is of prognostic significance. Methods: Immunohistochemistry for AR, AR phosphorylated at Ser-81 (pARS81), AR phosphorylated at Ser-578 (pARS578), PKC and phosphorylated PKC (pPKC) was performed on 90 hormone-naïve prostate cancer specimens. Protein expression was quantified using the weighted histoscore method and examined with regard to clinico-pathological factors and outcome measures; time to biochemical relapse, survival from biochemical relapse and disease-specific survival. Results: Nuclear PKC expression strongly correlated with nuclear pARS578 (c.c. 0.469, p=0.001) and cytoplasmic pARS578 (c.c. 0.426 p=0.002). High cytoplasmic and nuclear pARS578 were associated with disease-specific survival (p<0.001 and p=0.036 respectively). High nuclear PKC was associated with lower disease-specific survival when combined with high pARS578 in the cytoplasm (p=0.001) and nucleus (p=0.038). Combined high total pARS81 and total pARS578 was associated with decreased disease-specific survival (p=0.005) Conclusions: pARS578 expression is associated with poor outcome and is a potential independent prognostic marker in hormone-naïve prostate cancer. Furthermore, PKC driven AR phosphorylation may promote prostate cancer progression and provide a novel therapeutic target

Right ventricular dysfunction in patients with COVID-19 pneumonitis whose lungs are mechanically ventilated: a multicentre prospective cohort study

Cardiovascular complications due to COVID-19, such as right ventricular dysfunction, are common. The combination of acute respiratory distress syndrome, invasive mechanical ventilation, thromboembolic disease and direct myocardial injury creates conditions where right ventricular dysfunction is likely to occur. We undertook a prospective, multicentre cohort study in 10 Scottish intensive care units of patients with COVID-19 pneumonitis whose lungs were mechanically ventilated. Right ventricular dysfunction was defined as the presence of severe right ventricular dilation and interventricular septal flattening. To explore the role of myocardial injury, high-sensitivity troponin and N-terminal pro B-type natriuretic peptide plasma levels were measured in all patients. We recruited 121 patients and 118 (98%) underwent imaging. It was possible to determine the primary outcome in 112 (91%). Severe right ventricular dilation was present in 31 (28%), with interventricular septal flattening present in nine (8%). Right ventricular dysfunction (the combination of these two parameters) was present in seven (6%, 95%CI 3–13%). Thirty-day mortality was 86% in those with right ventricular dysfunction as compared with 45% in those without (p = 0.051). Patients with right ventricular dysfunction were more likely to have: pulmonary thromboembolism (p < 0.001); higher plateau airway pressure (p = 0.048); lower dynamic compliance (p = 0.031); higher plasma N-terminal pro B-type natriuretic peptide levels (p = 0.006); and raised plasma troponin levels (p = 0.048). Our results demonstrate a prevalence of right ventricular dysfunction of 6%, which was associated with increased mortality (86%). Associations were also observed between right ventricular dysfunction and aetiological domains of: acute respiratory distress syndrome; ventilation; thromboembolic disease; and direct myocardial injury, implying a complex multifactorial pathophysiology

Same day discharge, surgical training and early complications after open and laparoscopic repair of primary paraumbilical hernia

AIMS: The aims of this study were to compare same day discharges and early complications after open and laparoscopic primary paraumbilical hernia (PUH) repair, including the procedures performed by surgical trainees (STs).<p></p> METHODS: All patients who had open (suture or mesh) and laparoscopic repair of primary PUH in the Day Surgery Unit (DSU) between January 2007 and June 2009 were identified from the hospital database. The database was questioned regarding the grade of operating surgeon, type of surgical repair, day of admission and discharge from the DSU, and a patient's return to surgical services. Data were stored in Microsoft Excel(®) (TM 2007). Statistical significance was determined using Fisher's exact test.<p></p> RESULTS: PUH was repaired in 337 patients: 252/337 (74.8 %) had open and 85/337 (25.2 %) had laparoscopic repair. Significantly, more patients were discharged home on the day of surgery after an open repair compared to the laparoscopic repair: open repair 187/252 (74.2 %), laparoscopic repair 35/85 (41.17 %), P = 0.0001. Overall early complications such as wound complications and hospital re-visits were similar in both groups: open repair 6.3 % (16/252), laparoscopic repair 11.7 % (10/85), P = 0.1554. STs performed 142/337 (42.1 %) of the PUH repairs with similar same day discharges from the DSU: STs 64.7 % (92/142), consultant surgeons 66.7 % (130/195), P = 0.7285. The difference in hernia recurrence between open repair 7/252 (2.78 %) and laparoscopic group 0/85 was not significant (P = 0.1985).<p></p> CONCLUSION: Patients with PUH repair were more likely to go home on the day of surgery after open than after laparoscopic repair. This was not affected by the grade of the operating surgeon. Early complications were similar following open and laparoscopic repair of primary PUH.<p></p&gt

A unique case of an alpha-fetoprotein-producing lung cancer with testicular metastasis

Alpha-fetoprotein (AFP)-producing primary lung tumours are rare; we present the first case of an AFP-producing lung tumour with metastasis to testes. The patient, a 72-year-old man, presented with a history of flu-like symptoms and abdominal pain. On examination he had a hard, tender left scrotal mass. Imaging showed a 4.4-cm right lower lobe lung mass and the serum-AFP was raised (1189 ng/mL). Left orchidectomy excised a necrotic tumour. Microscopy showed complete hemorrhagic infarction and immunohistochemistry showed a lack of staining for AFP. Serum-AFP rose 3 days post-orchidectomy to 1466 ng/mL. The patient subsequently developed melaena and died. Autopsy revealed a 9 × 5-cm necrotic right lower lobe lung tumour. Immunohistochemistry showed the tumour cells reacted with a pan-cytokeratin antibody and less than 5% expressed AFP. Bilateral adrenal tumour deposits were also identified in addition to those in the bowel and spleen. The expression of AFP solely in the lung lesion and lack of expression in both testes, together with a rise in serum-AFP post-orchidectomy and the bilateral adrenal metastases, is overwhelming evidence for the reversal of the usual situation: a poorly differentiated AFP-secreting metastatic lung adenocarcinoma

The prognostic use of inflammation and tissue necrosis in benign prostatic hyperplasia

Introduction: Evidence for the role of inflammation in benign prostatic hyperplasia (BPH) is conflicting. Establishing the prognostic significance of local and systemic inflammation and tissue necrosis scoring systems in BPH may elucidate the potential of inflammatory pathways as a target of therapeutic intervention in these patients. Patients and Methods: Consecutive patients with histological BPH diagnosed between 1996 and 2005 were identified. Systemic inflammation was assessed by the modified Glasgow prognostic score (mGPS), local inflammation by the Klintrup-Makinen criteria and tissue necrosis was evaluated by an extent-based classification. Results: In 392 BPH patients, there was a trend for increased local inflammation and tissue necrosis to be associated with shorter time to failure of pre-operative medical treatment of BPH (p = 0.096 and 0.088, respectively). High modified Glasgow prognostic score was associated with older age (p = 0.002) and higher levels of deprivation (measured by the Scottish Index of Multiple Deprivation) (p = 0.021). Conclusions: The prognostic use of established scoring systems of systemic and local inflammation and tissue necrosis in BPH requires further investigation. It remains unclear as to whether targeting inflammation in BPH has therapeutic potential.</p

Body mass index predicts failure of surgical management in benign prostatic hyperplasia

Inflammation is postulated to link obesity and benign prostatic hyperplasia (BPH). The role of inflammation and the prognostic significance of body mass index (BMI) was investigated in BPH patients. Subjects and Methods: Consecutive patients with histological BPH were identified from 1996 to 2005. Systemic inflammation was assessed by modified Glasgow Prognostic Score (mGPS) and local inflammation by Klintrup-Makinen criteria. Results: In 392 patients, BMI was associated with cardiovascular disease (p = 0.033), type 2 diabetes mellitus (p = 4.45 × 10(-8)), aspirin usage (p = 0.018) and failure of surgical treatment (p = 0.001). mGPS and Klintrup-Makinen scores were not associated with clinical variables or outcome measures. On multivariate analysis BMI was an independent predictor of time to failure of surgical management of BPH, HR 1.56 (95% CI 1.11-2.19), p = 0.010. Conclusions: The mGPS and Klintrup-Makinen scores were not associated with BMI in BPH patients. High BMI is associated with failure of surgical management of BPH. Preoperative weight loss should be strongly encouraged in these patients