Introduction and Aims Pain is the most common symptom associated with hernias but there is little in the literature on its effects on an individual’s physical activity or quality of life. Up to one-third of patients with an inguinal hernia have no symptoms from the hernia. Repair of a ventral hernia is a common operation and increasing in frequency. Many operations for hernia are on patients with minimal symptoms but data on outcomes are lacking. The aims of the studies are to: assess the frequency of pain and its effects on physical activity and quality of life in patients with inguinal and ventral hernias; to determine the long term outcome of patients with a painless inguinal hernia randomised to observation or operation; to assess the long term outcomes of patients with an asymptomatic ventral hernia managed by a period of observation; and to examine the incidence of umbilical hernias in a general adult population and establish the long term outcome of patients with an umbilical hernia. Patients and Methods All patients undergoing operation for an elective inguinal or ventral hernia over a 16 month period were asked to complete a questionnaire recording data on baseline characteristics, a 4-point Verbal Rating Scale (VRS) and Visual Analogue Scale (VAS) of their pain. They also completed the short form Brief Pain Inventory (BPI) to assess pain severity and interference. 160 men aged 55 years or more with an asymptomatic inguinal hernia were randomised to observation or operation. Clinical follow up was undertaken at a median of 5 years and final follow up at a minimum of 6 years from randomisation. Ventral hernia patients presenting to a surgical clinic over a one year period were identified and those who were asymptomatic were followed up either by annual clinical examination or review of their electronic case records. All new patient referrals to a general surgical clinic over a year without a previous history of abdominal surgery were examined for clinical evidence of an umbilical hernia. All general practitioner referrals with an umbilical hernia were assessed for symptoms and both groups were followed up by review of their electronic case records. Results 124 patients (72 inguinal, 52 ventral), completed the pain questionnaire and 93 (75%) registered pain on the BPI. There was good correlation between VRS, VAS and BPI scores (Correlation Coefficient >0.8). Patients with a ventral hernia had more pain (P=0.037), interference with mood (P=0.027), sleep (P=0.004), relations with other people (P=0.019), and enjoyment of life (P=0.029) than their inguinal hernia counterparts. At a median follow up of 7•5 (range 6•2–8•2) years in patients with an asymptomatic inguinal hernia randomised to observation or operation, 46 of the 80 in the observation group had converted to an operation. The estimated conversion rate for the observation group using the Kaplan–Meier method was 16% (95 % confidence interval 9 to 26%) at 1 year, and 72% (59 to 84%) at 7•5 years. The main reason for conversion was pain in 33 men, and two presented with an acute hernia. Over a one year period 112 patients were identified with 115 ventral hernias. 62 (55%) had an asymptomatic hernia, 14 of whom opted for operation. 48 patients with 50 asymptomatic hernias participated in the study. At a median follow up of 6.2 years (IQR 5.8-6.9 years) 3 (6%) patients converted to operation due to pain. The incidence of umbilical hernia in the general population was 2.4% (15 or 622 patients) and all were asymptomatic with only 2 who were aware of their hernia. 36 patients were referred by their general practitioner for assessment of an umbilical hernia and 18 were asymptomatic. 28 of the 36 underwent operation of which 3 (Kaplan-Meier estimate 10% (95% CI 3% – 30%)) required re-operation for a recurrent hernia at a median follow-up of 6.1 years (IQR 5.8 – 6.2 years). Of the 15 patients with an incidental hernia, 2 (Kaplan-Meier estimate 15% (95% CI 3% – 44%)) required an operation for pain at a median follow-up of 6.1 years (IQR 5.9 – 6.4 years). Conclusions The BPI is an easy and effective way of assessing pain and its impact on physical activity and quality of life in patients with an inguinal or ventral hernia. Most patients with a painless inguinal hernia develop symptoms over time and will require an operation therefore surgical repair is recommended for medically fit patients with a painless inguinal hernia. In contrast, a policy of non-operation is a satisfactory alternative for patients with an asymptomatic ventral hernia although further studies in this area are required to confirm these outcomes. Umbilical hernias are common in the adult population and most cause no symptoms and are unlikely to become symptomatic. Clinical trials are necessary to assess the value of operation in patients with an asymptomatic umbilical hernia.

Introduction: The DIEP flap is a popular choice for breast reconstruction, though selection of which perforating blood vessel(s) to supply the flap is still largely based on surgeon preference, with little evidence to support numbers or location of perforators. In addition, many surgeons routinely discard zone IV of the flap, limiting the size of transferrable tissue. The aim of this research was to investigate the effect of number and location of perforators within a DIEP flap, on the total pedicle flow and perfusion of zone IV fat and skin. Methods: This research comprised of two studies; an animal model and a patient study: 1) 20 cranially-based abdominal epigastric perforator flaps were raised in Wistar rats on two perforators. The perforators were sequentially clamped and released in a randomised order and total pedicle flow (measured using microvascular flow-probes) and skin perfusion (measured using laser Doppler Flowmetry) was recorded on the following perforator combinations: • P1 (superior perforator) • P2 (inferior perforator) • P1+2 (both perforators) In addition, half of the animal flaps were randomised to receive a single (15 minute) period of pedicle-clamped ischaemic preconditioning after raising, with all measurements repeated to observe any effect. 2) 13 DIEP flaps were raised in post-mastectomy patients requiring breast reconstruction on two perforators. These were clamped and released as before to assess perfusion of fat and skin in zone IV using SPY Indocyanine-green-fluorescence-angiography scans on the same perforator combinations as in our animal study, listed above. Results: All data were analysed using non-parametric analyses and revealed that in our animal model, total pedicle flow was significantly (p<0.001) greater on a single perforator compared to two but no significant differences were identified in the flap skin perfusion. In our clinical study a single superior perforator supplied zone IV significantly (p=0.039) better than both peroforators, though this was not observed with the single inferior perforator. No significant differences were seen in zone IV skin perfusion. A single period of ischaemic preconditioning significantly (p<0.05) increased the total pedicle flow, but not the skin perfusion in our rat model. Conclusions: Possible reasons for these observed differences could be related to the flow dynamics and resistances specific to perforator flap anatomy and physiology and the possibility of vessel shunting in the subcutis.

Chronic wounds are difficult to heal and exhibit physiological features including prolonged inflammatory phase, mixed bacterial flora resistance and formation of biofilms, ineffectiveness of topical antimicrobials and high volumes of wound exudate. Polymeric gels of Polyox (POL) and blends of POL with carrageenan (CAR), chitosan (CS), hydroxypropylmethylcellulose (HPMC) and sodium alginate (SA) in different weight ratios were used to prepare films by the solvent casting technique and evaluated using scanning electron microscopy (SEM), X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and Fourier transform spectroscopy (FTIR). The same gels were analysed using DSC to develop an optimum lyophilisation cycle with or without an annealing step to obtain freeze dried wafers of POL-CAR and POL-SA. Films prepared from POL were non-transparent and showed spherulitic crystallisation, however POL blends with CAR and SA (75/25 and 50/50 weight ratios respectively) showed improved flexibility and transparency with reduced spherulitic crystallisation (i.e. homogeneous surface) through hydrogen bonding between POL and/or CAR and SA. Addition of annealing step -25°C resulted in formulations with porous surface morphology for both POL-CAR and POL-SA wafers. Annealing (wafers) and addition of glycerol (GLY) (films) resulted in improved mechanical properties expected to withstand the mechanical stresses occurring during day-to-day activities and whilst flexible enough to prevent potential damage to newly formed tissue. Tough and flexible films were obtained by the addition of 9%w/w and 20% w/w GLY in POL-SA and POL-CAR respectively. Further, the POL-CAR and POL-SA films and wafers were loaded with 5-15%w/w of diclofenac (DLF) and 15-30% w/w of streptomycin (STP). Furthermore POL-CAR and POL-SA blank (BLK) and drug loaded (DL) films and wafers were analysed for swelling, mucoadhesion (in presence of normal and viscous simulated wound fluid), in vitro drug dissolution and anti-bacterial activity and compared against marketed medicated wound dressings. Addition of drug (STP and DLF) resulted in fair transparency of films and decreased porosity of wafers with existence of sodium sulphate which affected general performance of the films and wafers in terms of swelling, mucoadhesion, and antimicrobial activity. BLK plasticised (GLY) films and BLK annealed wafers showed higher swelling capacities compared to DL films and wafers. Neither DL films nor wafers showed 100 % release of the incorporated STP and DLF due to the formation of sodium sulphate which reduced hydration. Findings also showed that POL-SA films and wafers were effective against normal exudate whereas POL-CAR films and wafers were effective for viscous exudate to achieve better bioavailability and prolonged retention time. Multivariate data analysis of mucoadhesion showed slower rate of mucin diffusion into POL-CAR films and wafers compared to POL-SA films and wafers. The formulated films, wafers and marketed dressing showed antibacterial efficacy against 105 CFU/ml of S. aureus, P. aeruginosa and E. coli. STP and DLF present in both films and wafers acted synergistically and showed better antimicrobial activity than marketed dressings. Film dressing allows ease of application and due to fair transparency and flexibility whereas wafer dressings are useful to control exudate and both can maintain a moist environment. Combination of STP and DLF within a single dressing is expected to help to treat and prevent wound infections whereas DLF can help to relieve pain and inflammation associated with injury.

The hip is a ball and socket joint in which the femoral head (the ball) articulates with the acetabulum (the socket). In a condition called femoroacetabular impingement (FAI) the hip has a shape abnormality and is no longer perfectly spherical. The hip shape abnormality FAI provokes premature impingement between the femoral head and rim of the acetabulum leading to pain and in the longer term osteoarthritis. Slipped capital femoral epiphysis (SCFE), an adolescent hip disease, is thought to be one cause of FAI. However, a cohort study of patients with SCFE presented in this thesis found no evidence of an association between worsening hip shape, function and pain. Factors other than abnormal hip shape may therefore have an important role in the development of hip symptoms in both SCFE and FAI. Systematic reviews presented in this thesis highlight that surgery or physical therapy can be used to treat FAI but the true clinical effectiveness of either treatment is not known. At least 100 surgeons undertook 2399 surgical procedures in the year 2011/12 in the UK National Health Service for FAI of which 80% were done arthroscopically. A qualitative interview study amongst 14 of these surgeons showed that many would like to engage in a RCT measuring the clinical effectiveness of their surgery. To test recruitment to such a RCT a pilot RCT comparing hip arthroscopy versus nonoperative care for FAI was undertaken. Forty-two out of 60 (recruitment 70%) eligible patients were recruited. Twenty one patients were allocated to nonoperative care, and 81% received per protocol treatment, with no evidence of serious adverse events. The work in this thesis should now facilitate a RCT to be undertaken in an area (treatment for FAI) where no RCTs have previously been conducted.

Despite advances in medical science, dialysis treatment for end stage renal disease remains fraught with complications and severely limits the quality and longevity of life in these patients. Renal transplantation allows for an enhanced length and quality of life. Unfortunately the demand for kidneys outstrips the supply and nephrologists have taken to performing transplantation in conditions that were previously thought impossible. Human leucocyte antigen (HLA) antibody incompatible transplantation, a process of transplanting kidneys into recipients who have antibodies against HLA antigen on the donor kidney, has recently become an acceptable mode of transplanting patients who would have previously died whilst on dialysis. Although increasingly successful, the Achilles’ heel of this form of transplantation remains acute antibody mediated rejection (AMR), a particularly severe form of rejection. It is generally accepted that the complement system is intricately involved in the process of acute AMR and, indeed, C4d, a split product of complement factor C4, when detected on renal biopsies in the correct context, is considered by the BANFF classification (an internationally accepted method of classifying renal transplant rejection) to be a hallmark feature of acute AMR. The sensitivity and specificity of this test, however, is increasingly debated and requires an interventional diagnostic test that is not without risk. A “blood” test to detect or predict the onset of acute AMR is not available. In addition, although the complement system is known to be involved in acute AMR, characterisation of the three complement pathways and the degree of their systemic activation has not been fully described. Although the liver is the main source of complement factors in the body, other organs such as the kidney, are capable of synthesizing complement. It is unknown whether the complement factors involved in acute AMR following renal transplantation are of systemic or local origin. It is also not known which renal cell, if any, is responsible for this. Importantly, the first cells to encounter antibodies against antigen on their surfaces, the renal microvascular endothelial cells, have not so far been shown to be able to produce complement factors. This thesis briefly examines changes in antibody levels during the process of HLA antibody incompatible transplantation, histological features associated with subsequent graft dysfunction and possible serum markers (soluble CD27 and Cd30) that could indicate onset of AMR. Whilst anti-HLA antibody monitoring was found to be useful in the management of patients it was not possible to use levels to predict rejection or accommodation of the graft. No correlation was found between soluble factors CD27 and CD30 and AMR. The thesis then examines the effect of HLA antibody incompatible renal transplantation on the complement pathways and on the levels of complement factors C3a and C4a. There was no systemic pathway activation in the presence of rejection. Systemic levels of C3a and C4a did not rise with a simultaneous increased level of HLA antibodies or with rejection episodes. Indeed, in patients who did not have an episode of rejection and in those with rejection but no evidence of C4d on renal biopsy, mean C4a levels were significantly lower at 4-6 weeks when compared to those who did have C4d-postive AMR. This points to a role for inhibitory mechanisms in these patients. The thesis also demonstrates the ability of microvascular endothelial cells (including of glomerular origin for the first time) to produce complement C4 on stimulation with gamma interferon and with antibodies against the cell HLA type. Finally, the thesis briefly examines the possible use of a complement inhibitor in the treatment of AMR.

Mesenchymal Stem Cells (MSC’s) have shown promise as a cell-based therapy for myocardial repair. However, MSC’s have a finite replicative lifespan and lose proliferative and differentiation capacity during expansion in vitro. Therefore, understanding the molecular mechanisms that regulate ageing and senescence of MSC’s should enhance our ability to use these cells in cell-based approaches and give insight into mechanisms of tissue ageing. We established MSC cultures from the sternal bone marrow of eight donors undergoing coronary artery bypass surgery. After thirty population doublings (nine passages) MSC’s displayed morphological abnormalities, expression of senescence associated β-galactosidase, telomere erosion and decreased adipogenic and osteogenic differentiation capacity. Using serial analysis of gene expression (SAGE) we identified 243 known genes differentially expressed between MSC’s at passages two and nine. Analysis of known direct interactions between genes revealed a regulatory signaling network centered on down-regulation of the transcription factor, activator protein 1 (AP-1). Transcriptional changes in MSC’s at passage nine included genes associated with inflammation, regulation of cell cycle, metabolism and extracellular matrix re-modelling. The validation studies corroborated the SAGE results and eighteen genes were identified as differentially expressed in late passage MSC’s from multiple donors. Furthermore, caveolin 1, cyclin D1, tissue plasminogen activator and olfactomedin-like 3 were able to discriminate MSC’s of different culture age. In addition, we show evidence that the p38 MAPK signalling pathway contributes to the decline in proliferation and differentiation of MSC’s during expansion and is critical for the maintenance of genomic stability. The results provide further evidence that MSC’s senesce prematurely in response to undefined culture stresses. Our studies have provided novel markers that identify MSC ageing in vitro and suggest that identifying factors that activate p38 MAPK signalling should enhance our ability to use MSC’s in cell-based therapies.

Colorectal cancer remains the second commonest cause of cancer death in Western Europe and North America. Each year in the UK, there are approximately 35,000 new cases and 16,000 deaths attributable to the disease. Despite a trend towards earlier presentation and improvements in the quality of surgery many patients still die of their disease. Overall about a third of patients undergoing surgery for potentially curative disease will die within five years. Recent work has meant that it is now recognised that it is not only the tumour characteristics that are responsible for cancer specific survival but also the host immune response. Part of this host response is the non-specific systemic inflammatory response. There is now a body of work examining the relationship between the systemic inflammatory response and cancer specific survival. Indeed, there is evidence that the systemic inflammatory response, as evidenced by an elevated C-reactive protein, predicts overall and cancer specific survival independent of tumour stage in a number of solid tumours including colorectal cancer. The aim of this thesis was to investigate the following in patients undergoing potentially curative surgery for colorectal cancer: 1. To establish the prognostic value of the pre-operative compared with the post-operative systemic inflammatory response in patients undergoing potentially curative surgery for colorectal cancer. 2. To examine the pre-operative inflammatory response in patients undergoing potentially curative surgery for colorectal cancer. 3. To examine the utility of the systemic inflammatory response as a guide to treatment in patient undergoing potentially curative surgery for colorectal cancer. Chapter 3 examines the relationship between the systemic inflammatory response in the preoperative period and the immediate post operative period. This chapter confirmed that an elevated C-reactive protein concentration, prior to but not immediately after surgery, was associated with poor cancer specific survival in patients undergoing curative open resection for colorectal cancer. This might suggest that approaches that focus on reducing the magnitude of the immediate post-operative systemic inflammatory response are unlikely to improve long term outcomes. Chapter 4 examines the relationship between the tumour size and the systemic inflammatory response. This chapter shows that the maximal tumour diameter is associated with an elevated pre-operative C-reactive protein concentration but not survival in patients with primary operable colorectal cancer. This would suggest that the direct relationship between CRP and tumour diameter may be due to a compromised immune response promoting tumour growth. Chapter 5 examines how the patients presented for their surgery. The results of this study suggest that as well as being prognostic in patients undergoing elective surgery C-reactive protein and the modified Glasgow prognostic score (mGPS) are prognostic in patients who present as an emergency which is the first time this has been shown. Chapter 6 examines the relationship between the systemic inflammatory response, interleukin-6 and 10 and lymphocyte subpopulations in patients with colorectal cancer. The results of this study suggest that the presence of a systemic inflammatory response is associated with upregulation of immunomodulatory cytokines but not with down regulation of lymphocyte derived immune status. Chapter 7 examines the relationship between the systemic inflammatory response and outcome in those patients receiving post-operative adjuvant chemotherapy. This shows that the presence of a systemic inflammatory response appears to be an independent predictor of poor outcome in patients receiving adjuvant 5FU-based chemotherapy following potentially curative resection for colorectal cancer. Chapter 8 is a pilot study examining the relationship between node negative colon cancer patients and the systemic inflammatory response. This chapter suggests that an elevated C-Reactive protein might predict cancer specific survival, independent of recommended pathological criteria, in patients undergoing resection for node negative colon cancer. However this does need a further, much larger study to confirm this trend. Taken together, the studies in the present thesis would indicate that an elevated pre-operative systemic inflammatory response is a prognostic factor independent of stage of disease.

Pancreatic cancer is a devastating disease with a five year survival of only 2-3%. Only 10-15% of patients have resectable disease at presentation and the only potential cure is major surgery with adjuvant chemotherapy. The outcomes of surgery are disappointing with a median survival of only15-17 months and operative mortality and morbidity figures of 5-10% and 40% respectively. This abysmal prognosis is likely due to the highly aggressive nature of the tumour, its resistance to adjuvant therapy, its late presentation and the likely presence of micro-metastases not detectable at staging or surgery. A pre-operative systemic inflammatory response (as measured by CRP) is known to be associated with a poor prognosis in a number of cancers including pancreatic cancer. The reasons behind this poor prognosis are not yet known. The main driver of plasma CRP levels is the cytokine IL-6, known to be elevated in the plasma of patients with pancreatic cancer. This thesis hypothesises that upregulation of two IL-6-dependent pathways, the JAK STAT and MAPK pathways is responsible for the poor prognosis associated with an inflammatory response in pancreatic cancer. Both of these pathways are known to be involved in cellular growth, differentiation and apoptosis and when activated they may confer a growth or survival advantage to tumour cells. The aims of this thesis were to establish the prognostic role of a systemic inflammatory response in resectable pancreatic cancer in both a retrospective and prospective cohort and establish whether increased protein expression in either the JAK STAT or MAPK pathways is associated with a poor prognosis in the same retrospective cohort. A retrospective database of 148 patients who had undergone Whipple resection for either pancreatic cancer (PC) or non-pancreatic peri-ampullary cancer (NPPC) was created with pre-operative CRP values and survival data. The author then created tissue micro-arrays (TMA’s) with both tumour and normal pancreatic duct tissue from each of the 148 patients in the retrospective cohort and carried out immunohistochemistry on 12 antibodies known to be crucial in IL-6 signalling (6 in the JAK STAT and 6 in the MAPK pathways). Following staining the author scored each of the antibodies using the weighted histoscore to allow analysis of antigen expression. During the period of research the author also created a prospective database of 36 patients who underwent surgery for either PC or NPPC. Plasma was stored pre-operatively from each of the patients and this was later thawed and using an ELISA kit another research fellow (JL) was able to establish plasma levels of IL-6 in the prospective cohort. On univariate analysis a raised pre-operative CRP was associated with poorer survival, 374 days versus 618 days (p=0.0001) in the retrospective PC group only. On multivariate analysis, only pre-operative CRP retained statistical significance amongst those factors shown to be significant on univariate analysis (P=0.009). In the prospective group, patients with low levels of IL-6 had a median survival of 799 days, against a median survival of 537 days in those with high plasma IL-6 levels (P=0.002) when all 36 patients were analysed together. On analysis of protein expression, no significant relationship between increased expression and poor survival was seen for any of the 12 proteins analysed. The results from this thesis confirm that a pre-operative inflammatory response is associated with poor survival in patients with resectable pancreatic cancer. Raised plasma levels of IL-6 are also associated with poorer survival in similar patients. However, the poor prognosis appears to be via a JAK STAT/ MAPK independent mechanism. Other possible explanations for this poor prognosis including the connection between inflammation and cachexia and other important inflammatory proteins such as NF-κB and SOCS are explored in the discussion of this thesis.

The subject matter for this research work is the area of perioperative recovery for patients undergoing major abdominal surgery. During clinical studies we have investigated some of the factors influencing postoperative recovery as well as suggesting strategies to improve patient care. The main focus of the scientific work of this thesis is the role of intravenous fluids in the perioperative management of patients undergoing abdominal surgery. We found that restriction of intravenous fluid in the postoperative period does not significantly improve recovery in terms of gastrointestinal function (4.2 (3.2-6.9) versus 4.7 (3.7-6.1) days; p=0.80) or hospital stay (5.9 (4.0-7.9) versus 5.8 (4.1-7.3) days; p=0.90). Analysing our findings in the context of what is already known suggests that the immediate perioperative period when the effect of the metabolic-endocrine response is at its greatest is the most important period for fluid management. During this period fluid optimisation has an important role in patient recovery but following this period the body’s own homeostatic mechanisms are more able to cope with any fluid excess. We also found that using a ‘fast-track’ regime we could reduce hospital stay to levels comparable with other studies in the published literature. Our work using a multi-modal rehabilitation regime in association with both laparoscopic and open surgery suggests that it is the postoperative care package which has the more major influence on recovery. Our findings are in agreement with other small sized studies beginning to appear in the literature and indicate that further large scale studies are required to determine the role of laparoscopic surgery and any potential benefits. One of the most significant causes of morbidity for patients undergoing abdominal surgery is postoperative ileus. During the course of our studies we found that the extent of surgery and particularly handling and exposure of the intestines seems to have little effect on the duration of postoperative ileus. These findings add to the previously contradictory findings of other groups. Our experience with ‘fast-track’ postoperative programmes was also applied to liver surgery, an area where it has not previously been reported, to show that a variety of abdominal procedures may benefit from this approach. By comparing our results with series published in the medical literature we found that hospital stay can be significantly reduced (4 versus 5-8 days).

Prostate cancer is the most common cancer in men and the second leading cause of cancer-related death in western world. Typically, the treatment of advanced and metastatic prostate cancer consists of castration therapy, which suppresses the development of the disease for 2 years in average. Virtually all patients, undergoing androgen deprivation therapy eventually develop castration-resistant prostate cancer. Currently, only taxane class of drugs has been proven to provide short survival advantage in patients with castration-resistant prostate cancer. This form of the disease is the cause of significant morbidity, resulting in long periods of gradual deterioration of patients’ condition, pain related to local extension of the tumour and distant metastases, renal failure due to the invasion into the ureters etc. Castration resistance allows prostate tumours to progress despite androgen deprivation. Several mechanisms have been described, outlining the nature of molecular pathways, employed by prostate cancer cells in order to proliferate and migrate in low androgen environment. Hormone-sensitive prostate cancer cells rely on androgens for their growth needs with androgens acting through the androgen receptor (AR). In castration-resistant prostate cancer AR can be activated by reduced concentrations of androgens, AR antagonists, protein kinases or bypassed altogether. Detailed knowledge of these processes should allow better understanding of molecular patterns, driving the progression of prostate cancer and, ultimately, could lead to the development of novel molecular targeted therapies. Molecular pathways, implicated in the development of castration-resistant prostate cancer frequently show cross-talk, resulting in the ability of cancer cells to adapt to changing microenvironment. Inhibiting the proteins, facilitating these cross-talks provides an attractive targeting mechanism. Src family of non-receptor tyrosine kinases (SFK) represent proteins involved in the development of various solid malignancies, including prostate cancer. These proteins are often found on the cross-roads of intracellular pathways, integrating molecular systems into complex signalling networks. SFK interact with receptor tyrosine kinases, G-protein coupled receptors, motility and adhesion factors and, thus, influence multiple cell functions. In prostate cancer, SFK have been demonstrated to form complexes with AR, activating AR by means of tyrosine phosphorylation. SFK inhibitory compounds have been developed and are now in Phase II clinical trial in patients with castration-resistant prostate cancer. However, there is considerable lack of data regarding the role of SFK expression and activation in prostate cancer in clinical settings. In this thesis, we studied the role of SFK in prostate cancer using matched paired prostate cancer samples, taken from patients prior to castration therapy being administered and following the development of castration resistance. Using paired tissue specimens allows following molecular changes through the natural history of the disease and correlating these changes with various clinical parameters. We also conducted in vitro experiments, employing hormone-sensitive LNCaP cell line and its counterpart, castration-resistant LNCaP-SDM cell line, developed by gradual withdrawal of androgens from the culture medium. Our main finding is that in a subgroup of prostate cancer patients, the increase in SFK activity in the transition of prostate cancer from hormone-sensitive to castration-resistant state is associated with significant decrease in survival (p<0.0001). Furthermore, the presence of bone metastases in patients with castration-resistant prostate cancer was associated with higher SFK activity in prostate tissue specimens. Our in vitro experiments have demonstrated that in prostate cancer the relationship between SFK and AR are important as androgen deprivation resulted in significant reduction in SFK activity. Using SFK inhibitor dasatinib, we have shown that in prostate cancer cell lines, SFK activity was inhibited at low nanomolar concentrations. Inhibition of SFK activity was accompanied by the inhibition of downstream protein FAK at Src-specific phsophorylation site. Although the treatment with SFK inhibitor suppressed migration of both LNCaP and LNCaP-SDM cell lines, only proliferation of LNCaP-SDM cell was affected by dasatinib. Taken together, our date suggests that SFK inhibitors may have a role in the treatment of castration-resistant prostate cancer. However, important considerations should be given to the molecular heterogeneity of prostate cancer in order to improve the outcomes of clinical trials and the response to treatment. There is considerable evidence that SFK inhibitors suppress prostate cancer cells migration and future studies will hopefully further clarify their role in cancer cells proliferation.