Retroperitoneal lymph node dissection (RPLND) for malignant phenotype Leydig cell tumours of the testis: a 10-year experience.

Retroperitoneal lymph node dissection (RPLND) is a prognostic, palliative, and potentially therapeutic procedure for patients with malignant phenotype Leydig cell tumours of the testis. We reviewed the records of patients diagnosed with malignant phenotype Leydig cell tumours of the testis treated by RPLND. Modified template dissection was performed in all cases with extra-template excision of tumour mass in Stage II disease. Routine clinico-radiological follow-up was performed. Six open RPLNDs (1 re-do procedure) were performed on 5 patients diagnosed with Stage I (n = 3) and Stage II (n = 2) malignant phenotype Leydig cell tumour of the testis. Median age = 63 years (range = 55-72). Median peri-operative blood loss = 1500 ml (range = 500-1500 ml). Median operating time = 6 h (range = 4.5-6.5). Two patients with Stage II disease developed post-operative complications of acute kidney injury (n = 1) and pneumonia (n = 1). Median length of stay was 8 days (range = 6-11). RPLND specimens from patients with Stage I were tumour-free, whilst patients with Stage II disease had evidence of metastatic tumour. At latest follow-up (median = 13 months, range = 7-22), no patient with Stage I disease had radiological evidence of recurrence, however the two patients with Stage II disease had died due to tumour recurrence at 13 months and 36 months. RPLND for malignant phenotype Leydig cell testicular tumours appears to be well tolerated. Despite surgery, overall outcomes for Stage II appear to be poor due to the disease phenotype. Larger prospective multi-centre studies are required to determine the definitive criteria for surgery in Stage I disease

The significance of proline-rich tyrosine kinase2 (Pyk2) on hepatocellular carcinoma progression and recurrence

Understanding the precise molecular mechanisms that trigger liver cancer cell migration and invasion could develop novel therapeutic strategies targeting cancer cell invasion to increase the sensitivity to current treatment modalities. In the current study, 49 patients with hepatocellular carcinoma (HCC) were included prospectively. Liver tumour and adjacent non-tumour tissues were detected for the expression of Proline-rich tyrosine kinase 2 (Pyk2), focal adhesion kinase (FAK), ezrin and fibronectin at protein and/or gene levels. Correlation between the expressions of Pyk2/FAK with the clinical pathological data was analysed. Protein expression of Pyk2 was also examined in a nude mice orthotopic liver tumour model with higher metastatic potential. There were 59% (29 out of 49) and 57% (28 out of 49) of HCC patients with higher levels of Pyk2 and FAK protein/gene expression, respectively. We observed a positive correlation between the protein and gene expression levels of Pyk2 and FAK (P=0.000, r=0.875). Overexpression of Pyk2 and FAK was significantly correlated with shorter disease-free survival. Patients with higher levels of Pyk2/FAK had larger tumour size and advanced Edmonson grading. In the animal studies, Pyk2 overexpression was found in infiltrative tumour cells and lung metastatic nodules. In conclusion, overexpression of Pyk2 and FAK was found in nearly 60% of HCC patients and was significantly correlated with poor prognosis. The significance of Pyk2 in HCC invasiveness was confirmed by animal studies. © 2007 Cancer Research UK.published_or_final_versio

Biomechanical considerations in the pathogenesis of osteoarthritis of the knee

Osteoarthritis is the most common joint disease and a major cause of disability. The knee is the large joint most affected. While chronological age is the single most important risk factor of osteoarthritis, the pathogenesis of knee osteoarthritis in the young patient is predominantly related to an unfavorable biomechanical environment at the joint. This results in mechanical demand that exceeds the ability of a joint to repair and maintain itself, predisposing the articular cartilage to premature degeneration. This review examines the available basic science, preclinical and clinical evidence regarding several such unfavorable biomechanical conditions about the knee: malalignment, loss of meniscal tissue, cartilage defects and joint instability or laxity

Chondroprotection by urocortin involves blockade of the mechanosensitive ion channel Piezo1

Osteoarthritis (OA) is characterised by progressive destruction of articular cartilage and chondrocyte cell death. Here, we show the expression of the endogenous peptide urocortin1 (Ucn1) and two receptor subtypes, CRF-R1 and CRF-R2, in primary human articular chondrocytes (AC) and demonstrate its role as an autocrine/paracrine pro-survival factor. This effect could only be removed using the CRF-R1 selective antagonist CP-154526, suggesting Ucn1 acts through CRF-R1 when promoting chondrocyte survival. This cell death was characterised by an increase in p53 expression, and cleavage of caspase 9 and 3. Antagonism of CRF-R1 with CP-154526 caused an accumulation of intracellular calcium (Ca2+) over time and cell death. These effects could be prevented with the non-selective cation channel blocker Gadolinium (Gd3+). Therefore, opening of a non-selective cation channel causes cell death and Ucn1 maintains this channel in a closed conformation. This channel was identified to be the mechanosensitive channel Piezo1. We go on to determine that this channel inhibition by Ucn1 is mediated initially by an increase in cyclic adenosine monophosphate (cAMP) and a subsequent inactivation of phospholipase A2 (PLA2), whose metabolites are known to modulate ion channels. Knowledge of these novel pathways may present opportunities for interventions that could abrogate the progression of OA