Loss of signal transducer and activator of transcription 1 is associated with prostate cancer recurrence.

STAT1 loss has previously been implicated in cell line studies to modify prostate cancer cell growth and survival, however the clinical significance of this has not previously been established. This study investigated if STAT1 loss was associated with patient outcome measures and the phenotypic consequence of STAT1 silencing. STAT1 expression was assessed in two patient cohorts with localised (n = 78) and advanced prostate cancer at initial diagnosis (n = 39) by immunohistochemistry (IHC). Impact of STAT1 silencing on prostate cancer cells lines was assessed using Cell Death detection ELISA, TLDA gene signature apoptosis arrays, WST-1 assay, xCELLigence system, clonogenic assay, and wound healing assay. In the localised patient cohort, low expression of STAT1 was associated with shorter time to disease recurrence (3.8 vs 7.3 years, P = 0.02) and disease specific survival (6.6 vs 9.3 years, P = 0.05). In the advanced patient cohort, low expression was associated with shorter time to disease recurrence (2.0 vs 3.9 years, P = 0.001). When STAT1 was silenced in PC3 cells (AR negative) and LNCaP cells (AR positive) silencing did not influence levels of apoptosis in either cell line and had little effect on cell viability in the LNCaP cells. In contrast, STAT1 silencing in the PC3 cells resulted in a pronounced increase in cell viability (WST-1 assay: mock silenced vs STAT1 silenced, P < 0.001), clonagenicity (clonogenic assay: mock silenced vs STAT1 silenced, P < 0.001), and migration (wound healing: mock silenced vs STAT1 silenced, P < 0.001). In conclusion, loss of STAT1 may promote prostate cancer recurrence in AR negative patients via increasing cell viability. © 2015 Wiley Periodicals, Inc.

Androgen receptor phosphorylation at serine 308 and serine 791 predicts enhanced survival in castrate resistant prostate cancer patients.

We previously reported that AR phosphorylation at serine 213 was associated with poor outcome and may contribute to prostate cancer development and progression. This study investigates if specific AR phosphorylation sites have differing roles in the progression of hormone naïve prostate cancer (HNPC) to castrate resistant disease (CRPC). A panel of phosphospecific antibodies were employed to study AR phosphorylation in 84 matched HNPC and CRPC tumours. Immunohistochemistry measured Androgen receptor expression phosphorylated at serine residues 94 (pAR94), 308 (pAR308), 650(pAR650) and 791 (pAR791). No correlations with clinical parameters were observed for pAR94 or pAR650 in HNPC or CRPC tumours. In contrast to our previous observation with serine 213, high pAR308 is significantly associated with a longer time to disease specific death (p = 0.011) and high pAR791 expression significantly associated with a longer time to disease recurrence (p = 0.018) in HNPC tumours and longer time to death from disease recurrence (p = 0.040) in CRPC tumours. This observation in CRPC tumours was attenuated in high apoptotic tumours (p = 0.022) and low proliferating tumours (p = 0.004). These results demonstrate that understanding the differing roles of AR phosphorylation is necessary before this can be exploited as a target for castrate resistant prostate cancer.

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.

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

INTRODUCTION: 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), 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.

Pathological Correlation between Number of Biopsies and Radical Surgery: Does It Make a Difference to Final Pathology?

AIMS: To evaluate whether the number of biopsies performed via transrectal ultrasound (TRUS) accurately predicts pathological parameters such as Gleason sum, prostatic intraepithelial neoplasia and perineural invasion of the final prostatectomy specimen. MATERIALS AND METHODS: The cohort consisted of 99 patients whom had undergone radical prostatectomy. Comparisons were made between the number of biopsies utilised and the presence of the pathological parameters from tissue at time of diagnosis and tissue from the final prostatectomy. RESULTS: A significant difference was noted between Gleason sum, prostatic intraepithelial neoplasia and perineural invasion from tissue at time of diagnosis irrespective of the number of biopsies utilised and tissue from the radical specimen (p < 0.001, p < 0.001, p < 0.001 respectively). No difference was noted in the mean Gleason sum when 11-14 biopsies were utilised at TRUS and the Gleason sum from the radical specimen. CONCLUSION: We have demonstrated that the number of biopsies utilised at time of TRUS for diagnosis predicts the accuracy of pathological parameters in the final radical prostatectomy specimen. We believe that 11-14 biopsies should be utilised at time of TRUS as this allows a higher accuracy in the Gleason sum and therefore allows optimum treatment plans to be devised.

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.