Surgery (Austin & Northern Health) - Theses
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Item18F-fluorodeoxyglucose positron emission tomography as a biomarker for colorectal cancer liver metastases( 2017)Background: Colorectal cancer is the second most common cause of cancer-related death in Australia. The majority of patients with colorectal cancer develop liver metastases but only those amenable for surgical resection have a possibility of long term survival. Recent advances in achieving macroscopic resectability of colorectal liver metastases needs to be balanced urgently, by an ability to assess systemic micrometastatic disease. Tumour staging by 18F-fluorodeoxyglucose positron emission tomography (PET) is a non-invasive tool already in routine use. Aim: To explore metabolic characteristics assessed by PET as biomarkers for colorectal cancer liver metastases. Methods / Results: Four studies were performed, each addressing separate aspects regarding the utility of tumour metabolic assessment. The first three studies were performed on retrospective cohorts while the fourth study was a prospective study. The studies and main novel findings are summarized below: 1) The Prognostic Impact of Tumour Metabolism an a Single PET Scan after Preoperative Chemotherapy Various parameters that characterize and quantify tumour metabolism were assessed for their prognostic ability. These parameters were compared to clinical and pathological features as well as previously verified prognostic scoring systems. The metabolic parameters corresponding to metabolic tumour burden were found to be most prognostic on a single PET scan following preoperative chemotherapy. 2) The Prognostic Impact of Tumour Metabolic Response to Preoperative Chemotherapy The prognostic ability of metabolic response to preoperative chemotherapy was assessed using the serial assessment of various metabolic parameters. In comparison, tumour size shrinkage on computed tomography and pathological response, the current gold standards of chemotherapy response evaluation, were assessed. Metabolic response to preoperative chemotherapy was shown to be the best prognostic indicator. 3) Metabolic Response Correlated to Biological Mechanisms The biological mechanisms underlying the prognostic impact of metabolic response was explored. Immunohistochemical analysis of six tumour biomarkers showed an inverse correlation between metabolic response and the expression of Ki-67, a marker of cellular proliferation; and a direct correlation between metabolic response and the expression of p16, a tumour suppressor. 4) Early Metabolic Response Assessment The use of early tumour metabolic response after only the first cycle of preoperative chemotherapy was assessed for the ability to predict eventual metabolic response. Early tumour metabolic response after one cycle of chemotherapy did not predict eventual metabolic response or clinical outcome. Conclusion: This thesis showed tumour metabolism to be a powerful prognostic indicator for patients with colorectal cancer liver metastases. In particular, it reveals the burden of disease as well as the sensitivity of the metastases to systemic chemotherapy. PET assessment of tumour metabolic response to chemotherapy should be routinely performed, particularly in patients undergoing complex liver surgery.
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ItemRole of p21-activated kinases in pancreatic cancer( 2016)Pancreatic cancer remains one of the most lethal of all solid tumours with an overall 5-year survival rate of 7%. Management has not improved significantly over the last thirty years and based on current trends, is expected to become the second leading cause of cancer-related mortality by 2030. Treatment options are limited and gemcitabine-based chemotherapy remains the standard of care as a single agent. Furthermore, the presence of the dense stroma, characteristic of pancreatic cancer, contributes to therapeutic resistance and poor therapeutic response. Thus, a better understanding of the underlying genetic and molecular mechanisms is urgently required to find targeted and effective therapies. There is growing evidence that p21-activated kinases (PAKs) are involved in pancreatic carcinogenesis. The PAK family consist of six isoforms, two of which, PAK1 and PAK4, are upregulated and/or hyper-activated in pancreatic cancer. PAK1 can mediate many different cellular processes including the regulation of cytoskeletal dynamics and cell adhesion, the evasion of apoptosis, the promotion of cell survival, proliferation, migration and invasion, the fibrosis that constitutes the stroma, and the interplay between cancer cells and the stroma. PAK1’s role has not been fully elucidated in pancreatic cancer and has not been evaluated as a target for therapeutic intervention. The work presented in this thesis investigates the role of PAK1 in pancreatic cancer and the effect of PAK1 inhibitors, alone and in combination with gemcitabine, on pancreatic cancer growth, metastasis, stroma, and survival. First, we investigated the effect of glaucarubinone, a known inhibitor that reduces the activity of PAK1 and PAK4, on pancreatic cancer growth, migration and murine survival. Using 4 human and 2 murine pancreatic cancer cell lines, PAK1 and PAK4 was expressed in all pancreatic cancer cell lines tested and proliferation and migration/invasion inhibited by treatment of glaucarubinone with reduction in PAK1 and PAK4 activity in vitro. Synergistic inhibition was observed when combined with gemcitabine with decrease in pancreatic cancer proliferation in vitro, decrease in pancreatic cancer growth in human xenograft tumours in vivo, and increase in murine survival in an orthotopic immunocompetent model in vivo. This was one of the first studies that showed clinical benefit of targeting and reducing PAK1 in pancreatic cancer. Using more direct methods of reducing PAK1 activity, shRNA knockdown systems, and a PAK1 selective inhibitor, FRAX597, were utilised. shRNA knockdown of PAK1 resulted in a reduction in pancreatic cancer cell proliferation and survival and sensitised cells to gemcitabine in vitro. PAK1 was also found to be key regulator of signalling pathways such as PI3K and HIF1α. FRAX597 treatment decreased pancreatic cancer cell proliferation and migration/invasion and synergised with gemcitabine to decrease cell proliferation in vitro. FRAX597, combined with gemcitabine, reduced pancreatic tumour volume and increased murine survival in preclinical orthotopic immunocompetent murine models in vivo. Although, further clinical validation is required, it illustrates the clinical potential of a PAK1 inhibitor, FRAX597, combined with gemcitabine to improve pancreatic cancer patient outcomes. PAK1’s role was investigated in pancreatic stellate cells (PSCs), which are primarily responsible for the fibrosis that constitutes the pancreatic cancer stroma. This was the first study to show the presence of PAK1 activity in isolated human PSCs. The treatment of the selective PAK1 inhibitor, FRAX597, on PSCs resulted in a reduction in their activation, proliferation, and increase in apoptosis in vitro. PAK1 knockout mice tumours had decreased expression and activity of PAK1, associated with increased murine survival, showing the effect of depleting host PAK1 in an orthotopic immunocompetent murine model in vivo. These results implicate PAK1 as a regulator of PSC activation, proliferation and apoptosis and targeting stromal PAK1 could increase therapeutic response and survival of patients with pancreatic cancer. Together, these results illustrate the importance of PAK1 signalling in pancreatic cancer and the possible therapeutic benefit of targeting PAK1 with gemcitabine on pancreatic cancer growth and the stroma to increase the survival of pancreatic cancer patients.
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ItemSelection and management of men for active surveillance in low risk prostate cancer( 2016)Aims: To investigate: 1. Selection of men for active surveillance of prostate cancer a. Validation of risk calculators b. Suitability for inclusion of Gleason 3+4 disease. 2. Performance of prostate biopsy during AS a. Differences in quality of diagnostic biopsy between academic and referral centres. b. Optimization of biopsy templates c. Examination of prognostic indicators for disease progression Methods: Data were obtained from several difference sources: • Men suitable for AS on prostate biopsy but undergoing upfront radical prostatectomy were pooled from 3 international academic institutions in Cambridge (UK), Toronto (Canada) and Melbourne (Australia). • Prospectively maintained AS prostate cancer database at Princess Margaret Cancer Centre (PMCC) (1997-2012). Analyses performed: • Four risk calculators were assessed for their ability to predict different definitions of insignificant prostate cancer by area under the curve (AUC) of receiver operating characteristic curves and Brier scores for discrimination, calibration curves and decision curve analysis. • Men with biopsy Gleason 3+4 disease, suitable according to modified Royal Marsden, Sunnybrook Toronto and PRIAS selection criteria, were assessed for presence of adverse pathology at upfront radical prostatectomy. • Patients on AS at a tertiary referral centre (PMCC) were dichotomized depending on where their diagnostic biopsy was performed (interval versus external). Multivariate logistic regression was performed to examine for predictors of re-classification at the second, or confirmatory, biopsy. • Mapping of all patients with pathological progression at PMCC for location of disease progression enabled comparison of hypothetical biopsy templates (sextant and standard extended) to the institutional template used. • Men on AS at PMCC were evaluated for presence of disease progression at serial biopsy in the prostate transition zone (TZ). Multivariate Cox proportional hazards regression evaluated predictors of TZ progression. • At PMCC, men were dichotomized based on presence of cancer at their confirmatory biopsy. Pathological progression was investigated using a Cox proportional hazards regression model. Results: • All 4 models predicting presence of insignificant prostate cancer had weak discrimination at best (AUC 0.618-0.664). • Presence of Gleason 3+4 at biopsy, compared to 3+3 disease, increases risk of adverse pathology at radical prostatectomy if modified Sunnybrook Toronto criteria are used (19% versus 33%, p≤0.001). Using a stricter protocol such as PRIAS, there was no statistical difference between the groups. • External biopsy predicted both grade related re-classification (OR 4.14, C.I. 2.01-8.54, p<0.001) and volume related re-classification (OR 3.43, C.I. 1.87-6.25, p<0.001). • Sextant and standard extended biopsy templates were inferior to the institutional biopsy template in detecting presence of cancer (84% and 99% versus 100%), and pathological progression (47.9% and 81.9% versus 100%). • At each subsequent biopsy during AS, 2.7-6.7% of men had disease progression only in the TZ which would not have been detected if TZ biopsy was not performed. Predictors of TZ progression were maximum % single core (HR 1.99, C.I. 1.30-3.04, p=0.002), and MRI reporting cancer (HR 3.19, C.I. 1.23-8.27, p=0.02). • Men with no cancer at confirmatory biopsy were less likely to have pathological progression (HR 0.47, CI 0.29-0.77, p=0.003). Sub-analysis showed this was predictive of volume-related progression (HR=0.36, CI 0.20-0.62, p=0.0006) and not grade-related progression. Conclusions: • Utilization of models predicting suitability for AS should be used with caution as external validation in our cohort was weak. • If considering biopsy Gleason 3+4 disease for AS, a stricter protocol such as PRIAS must be utilized. • At PMCC, patients who had their initial diagnostic prostate biopsy for AS done externally, were more likely to have worse pathological features and re-classify on the second biopsy. • For men on AS, sextant and standard extended biopsy are less likely to detect prostate cancer or disease progression than the template used at PMCC. • TZ biopsy should be considered for all men having serial biopsy on AS, in particular those with high % core involvement or positive MRI findings. • Absence of cancer on B2 is associated with a significantly decreased risk of volume-related but not grade-related progression.
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ItemThe role of hypoxia inducible factor 1 alpha (HIF1α) in prostate cancer( 2016)Prostate cancer (PC) is one of the most prevalent cancers in men. Although many PCs are indolent, a significant proportion will metastasize and develop resistance to therapy. Contemporary screening tests lack the finesse to accurately differentiate aggressive PCs from indolent tumours, potentially leading to over-diagnosis and over-treatment. While cellular hypoxia often plays an integral role in carcinogenesis and tumour progression, this connection has been difficult to demonstrate in PC. However, a downstream marker of hypoxia, Hypoxia inducible factor 1α (HIF1α), which is a transcription factor that protects cells against noxious stimuli, is frequently over expressed in PC. Therefore, the role of HIF1α in PC was investigated in this thesis. The Castrate resistant PC (CRPC)-like human PC cell lines PC3 and DU145 were found to over-express HIF1α protein compared to an androgen-sensitive cell line LNCaP under normoxic conditions. Using HIF1α 5’UTR-luciferase constructs in PC3 cells, further experiments revealed that increased translation of HIF1α mRNA regulated by a 70bp GC-rich, secondary structure in the 5’UTR of the HIF1α promoter may be responsible for normoxic HIF1α overexpression. Cell proliferation assays revealed that PC3 cells over-expressing HIF1α were more resistant to destruction by cytotoxic agents (H2O2 and 5-fluorouracil) than androgen-dependent LNCaP cells. Reduction of HIF1α expression in PC3 cells using RNA interference decreased both the resistance towards cytotoxic agents and cell migration. Conversely, in the androgen-dependent LNCaP cells overexpression of HIF1α increased the resistance to cytotoxic agents. One hundred prostate tumours were then immune-stained for HIF1α and outcomes measured. On multivariate analysis HIF1α was an independent risk factor for progression to metastatic PC (Hazard ratio (HR) 9.8, p = 0.017) and development of CRPC (HR 10.0, p = 0.021) in patients on androgen-deprivation therapy (ADT). Notably the tumours that did not express HIF1α did not metastasise or develop CRPC. Next, the effects of non-specific HIF1α inhibitors (digoxin, metformin and angiotensin-2 receptor blockers) were investigated in ninety-eight patients who had continuous ADT as first line therapy and developed CRPC. The median CRPC-free survival was longer in men using HIF1α inhibitors compared to those not on inhibitors (6.7 yrs vs. 2.7yrs, p=0.01) and there was a 71% reduction in the risk of developing CRPC (p=0.02) and an 81% reduction in the risk of developing metastases (p=0.02) after adjustment for Gleason score, age and PSA. Finally, the effects of metformin were investigated in 2055 men treated for PC with external beam radiotherapy. Surprisingly, metformin did not result in any improvement in time to biochemical failure, time to metastases or overall survival in men undergoing radiotherapy, but there was an 1.5 fold increase in PC-specific deaths (p<0.05) in men on metformin who received ADT when adjusted for cancer risk and co-morbidities. In conclusion, the results presented in this thesis indicate that HIF1α is a promising marker in PC, which may be used for early identification of cancers that potentially will progress to metastases and develop resistance to ADT. HIF1α is likely to contribute to metastasis and chemo-resistance of CRPC, targeted reduction of HIF1α may improve outcomes of aggressive PC.
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ItemThromboembolism and neoadjuvant chemoradiation for rectal cancer( 2015)Thromboembolism (TE) is one of the leading causes of morbidity and mortality in cancer, is an independent predictor of reduced survival, and the overall rate of TE in cancer patients is increasing. Assessing the TE risk of an individual patient at a given time point and the benefit of thromboprophylaxis (TP) can be complex, involving widely variable TE rates according to tumour related factors (such as cancer subtype and disease stage), as well as patient and treatment related factors. Some, such as surgery and hospitalisation are well recognised and appropriately targeted with mechanical and pharmacological thromboprophylaxis (TP) strategies backed by Level I evidence. There is evidence that TP after hospital discharge following surgery (extended TP) is also beneficial. Recently, subgroups such as those with metastases receiving palliative chemotherapy have been shown to be at equally high risk, and also benefit from primary TP. Both chemotherapy and central venous access devices (CVAD) have been shown to be independently associated with development of TE. In addition, early studies examining neoadjuvant radiotherapy (nRT) in rectal cancer reported higher rates of TE however this finding was not repeated in subsequent studies using modern radiotherapy techniques. Extrapolating these findings raises the question of TE risk and the potential benefit of TP during neoadjuvant radiotherapy (nRT) or chemoradiotherapy (nCRT) for rectal cancer. This thesis explores the current evidence and contemporary guidelines concerning TE risk during nCRT, demonstrating considerable uncertainty and a lack of robust data. Randomised trials examining nCRT in rectal cancer are systematically reviewed to determine rates of TE, demonstrating a failure to capture TE events due to inadequate complication reporting frameworks. Existing attitudes and prescribing practices of specialist rectal cancer surgeons are surveyed, as well as barriers to TP prescribing. Issues of equipoise, ownership and logistical problems with outpatient TP prescribing were identified. The historical TE rate and epidemiology over a prolonged follow-up period in rectal cancer patients, as well as the relationship to nCRT is examined at both Peter MacCallum Cancer Centre in Australia and the Cleveland Clinic in the United States. These studies demonstrated that most TE events occurred in patients with metastatic disease receiving ambulatory palliative chemotherapy, and that the overall rate of TE in patients treated with nCRT was not elevated over those patients who had surgery alone. Finally, a prospective study of thrombogenic biomarkers in patients with rectal cancer was undertaken demonstrating significant coagulation abnormalities in colorectal cancer patients at baseline, but no major alteration during neoadjuvant chemoradiation. Marked and prolonged procoagluant abnormalities were demonstrated in the post-operative phase. Thus the current literature, attitudes of treating clinicians, historical rates, as well as candidate biomarkers for prospective TE risk were examined in nCRT for rectal cancer for the first time, identifying future potential research questions aimed at reducing this common complication of cancer care.
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ItemConsiderations for surgical intervention in metastatic cancer to the spine: evaluation of risk factors for pathologic fracture and spinal cord compression, and analysis of pre-operative scoring systems for the prognostication and treatment of patients with spinal metastases( 2014)The spine has structural load bearing and neural-protective functions, and tumour growth and bony destruction caused by spinal metastases results in pathologic fracture and cord compression, causing pain, neurological deficit, impaired function and quality of life. Surgery is the only method to immediately stabilise the spine and decompress the spinal cord. Survival prognosis is one of the key factors in selecting patients for surgery, and there are a number of scoring systems aimed at prognostication and treatment decision making for patients with spinal metastases, however these differ in the parameters assessed and prognostic value. The ability to predict those patients with spinal metastases most likely to progress to pathological fracture or develop spinal cord compression may simplify the surgical decision-making process and enable earlier surgical intervention, with the potential to prevent permanent neurological deficit and disability and maintain function and quality of life for the remainder of the patient's life. This thesis considers the complexities of treatment decision making for patients with spinal metastases, with two major aims: 1) An evaluation of patient risk factors and radiological parameters associated with pathological fracture and metastatic epidural spinal cord compression, and 2) Validation of survival prognostication of current pre-operative prognostic scoring systems, in order to optimise the treatment decision-making process. The methodology involved retrospective assessment of clinical and radiological parameters of 72 patients with spinal metastases who had undergone decompressive and/or stabilisation surgery for pathological fracture and/or metastatic epidural spinal cord compression or nerve root compression. The items assessed for association with pathological fracture or metastatic epidural spinal cord compression were: tumour size, location, type and lesion morphology, disease burden, pain and function. Pre-operative scores were calculated for each patient, and the prognostic value of each scoring system evaluated by comparison of predicted and actual survival. The results showed that tumour size within the vertebral body, vertebral endplate and three-column involvement, tumour growth rate, multiple vertebral metastases, and pain were associated with increased risk for pathological fracture. Vertebral posterior element and costovertebral joint involvement by tumour, primary tumour growth rate and presence of visceral metastases were associated with metastatic epidural spinal cord or nerve root compression. All patients with pathological fracture had at least one of three risk factors – pain; >25% tumour occupancy of vertebral body; and endplate or 3-column involvement – and incidence of pathological fracture increased with higher number of risk factors. The Revised Tokuhashi, Bauer, Modified Bauer, and Tomita scoring systems were the most reliable for survival prediction. It is concluded that these risk factors should be considered in the decision-making process for surgery for spinal metastases. Patients with spinal metastases causing pain, greater than 25% occupancy of the vertebral body and involving the vertebral endplate or all three columns should be considered for prophylactic or therapeutic decompressive and stabilization surgery. As a component of comprehensive treatment planning, we recommend the use of Revised Tokuhashi, Modified Bauer, and Tomita scoring systems due to their favourable survival prognostic accuracy and clearly outline of treatment strategy according to prognostic group.
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ItemThe Effect of Co-stimulation Blockade on Survival of Xenogeneic Pancreatic Beta-cells( 2014)Diabetes mellitus is a chronic disease affecting millions of people worldwide. Currently, the only potential cure is through pancreatic transplantation, either as whole organ or with pancreatic islet cells. However, the morbidity associated with immunosuppression and the scarcity of donor organs do not support the common practice of pancreatic transplantation. Both these factors can potentially be addressed by xenotransplantation of genetically modified cells that are capable of attenuating the immune system. The costimulation pathway of the immune system was the focus of this project, in particular blockade of the ICOS (inducible costimulation molecule) and CTLA-4 (cytotoxic T lymphocyte associated antigen 4) pathways to prolong xenograft survival. To address the problem of diabetes as well as investigate the efficacy of costimulation blockade on xenograft survival, rat insulinoma (beta) cell lines (INS-1E) stably expressing either ICOS-Ig or CTLA4-Ig were generated. The secreted proteins were demonstrated to be biologically active in xenogeneic mixed lymphocyte reactions by their ability to inhibit lymphocyte proliferation. Unfortunately, the in vivo effect of these transgenic INS-1E cells on xenograft survival was unable to be determined because of their failure to establish as tumours due to the slow growth rate of these cells following subcutaneous injection into BALB/c mice. The aim of the second part of this project was to assess the effect of rationally mutated ICOS-Ig on xenograft survival. PIEC (pig iliac endothelial cells) stably expressing ICOS-Ig with single (K52/S and S76/E) and combined (K52/S + S76/E) amino acid mutations were generated. In vitro, compared to wild type ICOS-Ig, the mutants with single amino acid substitutions showed stronger binding avidity to ICOS ligand. This increase in binding avidity however did not translate into superior inhibition of lymphocyte proliferation compared to wild type ICOS-Ig in xenogeneic mixed lymphocyte reactions. Similarly in vivo, the PIECs secreting mutated forms of ICOS-Ig did not prolong xenograft survival after subcutaneous injection of these cells into BALB/c mice. These data suggest that despite their higher avidity, the ICOS-Ig mutants are not biologically more superior than wild type ICOS-Ig both in vitro and in vivo.
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ItemGastrin-mediated adaptive responses to hypoxia in colorectal cancer( 2014)Over the past two decades the potential biological activities exerted by gastrin precursors on colorectal tumourigenesis have gradually widened to include mitogenesis, apoptosis resistance, stimulation of angiogenesis and promotion of cell migration and invasion. However, the molecular mechanisms underlying this plethora of biological effects are unclear. Furthermore, the interplay between gastrin precursors and the colorectal tumour microenvironment has been a relatively neglected area of gastrin research. This thesis investigates these two important areas of gastrin biology and is the first study to report that hypoxia-inducible gastrin gene expression in colorectal cancer cells mediates resistance against hypoxia-inducible cell death in vitro and in vivo and may contribute to the development of distant metastatic disease.
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ItemIntravenous lignocaine followed by a 24-hour postoperative subcutaneous infusion shortens length of hospital stay after open radical retropubic prostatectomy: a blinded, randomised, placebo-controlled multicentre trial( 2014)Introduction: An alternative method of administering lignocaine for its beneficial anti-inflammatory and analgesic effects to improve and accelerate postoperative recovery is to administer the local anaesthetic solution by a continuous intravenous infusion. However, in patients undergoing major abdominal surgery, intravenous lignocaine combined with a 24-hour continuous subcutaneous infusion has not been systematically examined for efficacy and safety. A subcutaneous infusion of lignocaine may be an effective strategy to continue systemic lignocaine into the early postoperative period. Subcutaneous delivery may be more advantageous than an intravenous infusion, being technically easier to deliver, safer and cost-effective. Drug tolerance may also be less likely to develop. A significant advantage of subcutaneous infusions over intravenous drug delivery methods is that plasma levels are more stable, and symptom control may be achieved without the toxic effects of peaks and troughs resulting from episodic drug administration or a prolonged continuous intravenous infusion. However, it is unknown whether this intervention will impact clinically on important postoperative outcomes, such as length of hospital stay and accelerated postoperative rehabilitation. Before a combination of intravenous lignocaine and subcutaneous lignocaine is adopted as a feasible and efficacious technique for patients undergoing major abdominal surgery, it needs to be investigated in a randomised controlled clinical trial to measure its benefits and harm, and to better define its role in therapy. Study aims: The aims of this study are to evaluate whether a combination of intravenous lignocaine followed by a postoperative 24-hour subcutaneous infusion is beneficial in decreasing length of hospital stays, improving analgesia, and reducing opioid consumption compared to placebo. This study will also quantify the safety of this technique in a perioperative setting. The study was designed to test the hypothesis that perioperative systemic lignocaine infusion in this combination enhances recovery and shortens length of hospital stay after an open radical retropubic prostatectomy. Methods: The Austin and Box Hill Human Research Ethics Committees approved this study. This was a blinded, randomised, placebo-controlled, multicentre trial at two university teaching hospitals. Patients undergoing open radical retropubic prostatectomy were randomised to receive intravenous lignocaine (bolus injection 1.5 mg/kg), then an intravenous infusion (1.5 mg/kg/hr) during surgery, followed by iv subcutaneous infusion for 24 hours (1.5 mg/kg/hr) (Lignocaine group), or a Placebo group who received an equal volume of normal saline delivered at the same infusion rates and over the same time period. General anaesthesia, including the use intraoperative opioids, was standardized, and no patient received regional analgesia or anaesthesia, surgical wound catheters, or infiltration of the surgical wound with local anaesthetic solutions. All patients received morphine patient-controlled analgesia postoperatively in a standardized dosing regime. The primary aim of this study is to evaluate whether a combination of intravenous lignocaine followed by a postoperative 24-hour subcutaneous infusion is beneficial in decreasing the length of hospital stay compared to placebo. Important secondary outcomes included comparing intraoperative haemodynamics (heart rate, blood pressure), Bispectral index (BIS), and end-tidal sevoflurane concentrations required to maintain 1 MAC of anaesthesia. In addition, postoperative pain using a Visual Analogue Scale at the incision site measured at rest and with coughing, morphine and rescue analgesia consumption, need for rescue anti-emetic therapy, and patient satisfaction were also evaluated. Opioid-related and lignocaine-related side effects were critically examined including the measurement of plasma lignocaine levels performed in the immediate postoperative period and at 24 hours prior to the discontinuation of the lignocaine subcutaneous infusion. Results: The Lignocaine group had 37 patients and the control group had 38 patients. Patient demographics were similar between groups. The mean duration for surgery was 155.7 minutes (SD: 34.2) for the Lignocaine group and 141.6 minutes (SD: 44.6) for the Placebo group (estimated difference: 14.1 minutes, 95% CI: -4.27 to 32.47, p = 0.13). In the Lignocaine group, the mean highest heart rate recorded was 97.5 beats/minute vs. 103.8 beats/minute in the Placebo group (estimated difference: 6.3 beats/minute; 95% CI: 2.4 to 10.3 beats/minute, p = 0.001). Intraoperatively, the Lignocaine group had lower heart rates [52.1 beats/minute vs. 59.0 beats/minute; estimated difference: 6.8 beats/minute; 95% CI: 3.3 to 10.3 beats/minute, p = 0.001]. The mean BIS is the Lignocaine group was lower than that in the Placebo group (43.4% vs. 49.8%; estimated difference 6.3%, 95% CI: 3.0% to 9.7%, p = 0.001). Despite the BIS being lower in the Lignocaine group, the average concentration of sevoflurane required to maintain 1 MAC of anaesthesia was lower in the Lignocaine group [1.49% vs. 1.89%; estimated difference 0.39%, 95% CI: 0.26% to 0.5%, p = 0.001]. The Lignocaine group had a shorter length of hospital stay [3.3 days (SD: 0.8) vs. 4.7 days (SD: 3.2), estimated difference 1.3 days; 95% CI: 0.2 to 2.4, p = 0.02]. The Lignocaine group required less morphine during the first 24 hours [mean 38 mg (SD: 24) vs. 52 mg (SD: 27); estimated difference 14 mg; 95% CI 2 to 26 mg, p = 0.02]. The mean Visual Analogue Scores for pain at rest one hour postoperatively were 3.73 units for the Placebo group and 1.93 units for the Lignocaine group. On average, the Placebo group scored 1.80 units higher than the Lignocaine group at this time point (95% CI: 0.73 to 2.88, p = 0.001). There was no difference in rest pain at 24 hours. There were also no significant differences in pain on movement over the 24-hour period. Among secondary endpoints, the time taken to tolerate free fluids and a light ward diet were shorter in the Lignocaine group. Time to mobilize was also shorter in the Lignocaine group. Other secondary endpoints were similar. In the Lignocaine group, the mean plasma lignocaine level after surgery was 1.36 mcg/mL (SD: 0.48), range 0.5 mcg/mL to 2.19 mcg/mL; and at 24 hours postoperatively was 3.1 mcg/mL (SD: 0.95); range 1.1 mcg/mL to 4.96 mcg/mL. Lignocaine levels in the Placebo group were always less than 0.5 mcg/mL. No patient experienced complications associated with lignocaine infusion. Conclusions: Intravenous lignocaine followed by a 24-hour subcutaneous infusion resulted in a shorter length of hospital stay and accelerated acute rehabilitation after open radical retropubic prostatectomy. Furthermore, subcutaneous infusion of lignocaine was an effective strategy to continue systemic lignocaine into the early postoperative period. To date, this is the first randomised clinical trial evaluating the use of subcutaneous lignocaine in this setting, and therefore adds to the growing body of literature supporting the use of lignocaine via this route for open abdominal surgery.
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ItemPrognostic factors in urological malignancies( 2014)BACKGROUND: The management of urologic cancers relies heavily on the implicit or explicit application of prognostic models. This may range from the appropriate selection of diagnostic tests based upon the pre-test probability of a positive finding, to an informed decision on choice of treatment modality or enrolment in suitable clinical trials. While some prognostic factors such as stage and grade are time-tested, others such as molecular and immunohistochemical markers or surgical approach are new and evolving. Furthermore, the literature abounds with nomograms, models, risk tables or groups which utilize varying combinations of predictor variables to prognosticate on myriad outcomes of interest. The aim of this body of work was to enhance our understanding of prognostication in urologic malignancies, particularly prostate cancer, renal cancer and urothelial cancer of the bladder, in various clinical settings. METHODS: Details of methodology vary – specifics are outlined in the relevant chapters. In general terms, an appropriate study population was defined based upon the hypothesis. Variables of interest were extracted from suitable database and / or clinical records, or assessed in the laboratory. Associations between predictors and outcomes were analysed using univariate and (where suitable) multivariate regression techniques. PRINCIPAL RESULTS: • PSA kinetics provide important prognostic information in various clinical settings, including prior to surgical treatment and after hormonal therapy • A persistently detectable PSA following radical prostatectomy is associated with a greater risk of progression and death, but with a long natural history • Younger patients with prostate cancer have less aggressive features, but a proportionately greater risk of progression and death despite curative surgical treatment • Obese patients with prostate cancer have more adverse pathologic features, but similar oncological outcomes compared to those of normal weight • A positive family history is associated with an increased risk of developing prostate cancer, but similar oncologic outcomes following surgical treatment • Gleason scoring has evolved over time, with consequent changes in the prognostic implications thereof • So-called “insignificant” prostate cancer has similar oncological outcomes to low-risk cancers overall, following surgical treatment • Patient suitability for brachytherapy as a single modality can be judged based on the clinically assessed risk of lymph node or seminal vesicle involvement • Clinical factors can predict the risk of nodal metastasis, thus allowing the rational selection of patients for pelvic lymphadenectomy at the time of radical prostatectomy • RALRP is associated with a lower rate of +SM compared to ORP, even after adjusting for known clinical and pathological risk factors • Renal cancers in solitary kidneys associated with vena caval extension may be treated by nephron-sparing surgery where technically suitable, although a high risk of disease progression and death remains • The pre-operative erythrocyte sedimentation rate provides independent prognostic information in patients with renal cancer • Renal lesions with low nephrometry score as measured using the R.E.N.A.L. have a greater likelihood of having benign or indolent histology • Histologic coagulative tumour necrosis within renal cancers is associated with poorer oncological outcomes after surgical treatment • Expression of the oncogene c-kit is rare within high-grade or sarcomatoid renal cancers • Muscle invasive urothelial cancers of the bladder are often infiltrated by profuse numbers of lymphocytes with a variety of phenotypes, although they appear not to impact on the risk of progression or death after surgical treatment • Peri-operative chemotherapy has been increasing in its use over recent years, and appears to reduce the risk of recurrence after surgical treatment of urothelial cancer of the bladder CONCLUSIONS: Many of the findings summarized above have had important implications for practice. For instance: • PSA kinetics are now in widespread use at various stages of prostate cancer management • Gleason scores from patients treated some time ago are often re-interpreted according to revised criteria