Optimising the therapeutic ratio of radioimmunotherapy; an investigation of the roles of chimerisation, fractionation and radiation dosimetry

Radioimmunotherapy (RIT) is a targeted form of treatment for cancer which uses tumour-associated antibodies to selectively deliver a therapeutic radionuclide to sites of disease. In lymphoma, radioimmunotherapy has proved a remarkably effective agent due to the high radiosensitivity of the tumour and its propensity to undergo apoptosis following irradiation. However, success in the treatment of the more radioresistant common solid tumours has been less successful, and for these patients RIT remains investigative. The effectiveness of RIT is limited by non-specific irradiation of normal tissues whilst antibody remains in the circulation, in particular bone marrow, and also by immunogenicity of antibody which does not allow for repeated therapy. In the first chapter I have hypothesised that lymphomas expressing the interleukin-2 receptor might be effectively treated using a radiolabeled antibody to this receptor. In a phase I/II clinical study, 131I labelled CHT-25, a chimeric antibody against the IL-2Ra chain, has shown encouraging evidence of efficacy in the 9 patients with multiply- relapsed lymphomas treated so far. In addition, use of this antibody has been associated with low immunogenicity allowing for repeated therapies to be given. In the second chapter I have hypothesised that dosimetry led, individual patient therapy, might further optimise 1311 CHT-25 treatment. To investigate this I have used marrow toxicity as a biological assay of absorbed dose and shown that simple, but individual, patient biodistribution indices correlate better with observed toxicity than the population-based dose estimates currently employed. I have proposed that adoption of individual patient dosimetry using tracer studies is worthy of further investigation for the future development of 131I- CHT-25. In the third chapter I have hypothesised that dose fractionation might improve the therapeutic ratio of RIT. This has been investigated in a pre-clinical human colorectal xenograft model in nude mice using 131I-A5B7, a murine antibody against CEA. In this setting fractionation neither reduces normal tissue toxicity nor increases the effectiveness of therapy. This thesis demonstrates, using both pre-clinical and clinical data, how the therapeutic ratio of RIT might be improved through antibody design, leading to reduced immunogenicity, dose fractionation and radiation dosimetry, and proposes how these approaches might be used to optimise the effectiveness of RIT in the clinic

Altered stress hormone response following acute exercise during prostate cancer treatment

Exercise training reduces the side effects of cancer treatments; however, the stress hormone response to acute exercise during prostate cancer (PCa) treatment is unclear. The study purpose was to examine the effects of acute exercise on circulating cortisol, epinephrine (Epi), and norepinephrine (NE) concentrations during PCa treatment with and without androgen deprivation therapy (ADT). Men with PCa (n = 11), with PCa on ADT (n = 11), and with non-cancer controls (n = 8) had blood samples for stress hormones collected before and immediately (0 hour), 2 hours, and 24 hours after 45 minutes of intermittent cycling at 60% of peak wattage. NE increased by 385% (P < .001) at 0 hour and remained elevated at 2 hours (P < .05) with no group differences. Overall, cortisol significantly increased at 0 hour (36%, P < .012) and then significantly decreased below baseline at 2 hours (-24%, P < .001) before returning to resting levels at 24 hours. Cortisol levels during ADT were 32% lower than PCa (P = .006) with no differences vs controls. Epi increased immediately after exercise more in controls (817%, P < .001) than with ADT (700%) and PCa (333%) patients, and both cancer groups' absolute levels were attenuated relative to controls (ADT: -54%, PCa: -52%, P = .004). Compared with age-matched controls, PCa and ADT patients exhibited similar stress hormone responses with acute exercise for NE and cortisol but an attenuated EPI response that suggests altered adrenal function. Future studies should examine the physical stress of multiple exercise bouts to verify these findings and to explore the functional hormonal effects, such as immune and metabolic responses, during cancer treatment

Bed net use and associated factors in a rice farming community in Central Kenya

<p>Abstract</p> <p>Background</p> <p>Use of insecticide-treated nets (ITNs) continues to offer potential strategy for malaria prevention in endemic areas. However their effectiveness, sustainability and massive scale up remain a factor of socio-economic and cultural variables of the local community which are indispensable during design and implementation stages.</p> <p>Methods</p> <p>An ethnographic household survey was conducted in four study villages which were purposefully selected to represent socio-economic and geographical diversity. In total, 400 households were randomly selected from the four study villages. Quantitative and qualitative information of the respondents were collected by use of semi-structured questionnaires and focus group discussions.</p> <p>Results</p> <p>Malaria was reported the most frequently occurring disease in the area (93%) and its aetiology was attributed to other non-biomedical causes like stagnant water (16%), and long rains (13%). Factors which significantly caused variation in bed net use were occupant relationship to household head (χ²= 105.705; df 14; P = 0.000), Age (χ²= 74.483; df 14; P = 0.000), village (χ²= 150.325; df 6; P = 0.000), occupation (χ²= 7.955; df 3; P = 0.047), gender (χ²= 4.254; df 1; P = 0.039) and education levels of the household head or spouse (χ²= 33.622; df 6; P = 0.000). The same variables determined access and conditions of bed nets at household level. Protection against mosquito bite (95%) was the main reason cited for using bed nets in most households while protection against malaria came second (54%). Colour, shape and affordability were some of the key potential factors which determined choice, use and acceptance of bed nets in the study area.</p> <p>Conclusion</p> <p>The study highlights potential social and economic variables important for effective and sustainable implementation of bed nets-related programmes in Sub-Saharan Africa.</p

Attenuation of Resting but Not Load-Mediated Protein Synthesis in Prostate Cancer Patients on Androgen Deprivation

Context: Androgen deprivation therapy (ADT) is a common prostate cancer (PCa) treatment but results in muscular atrophy. Periodic increases in muscle protein synthesis (MPS) that occur after resistance exercise or protein intake may ameliorate this muscle loss, but the impact of these anabolic stimuli during ADT is unclear. Objective: To determine the acute MPS response to whey protein supplementation with and without resistance exercise during ADT. Design: Acute response in PCa patients vs age-matched controls (CON). Setting: Academic laboratory setting. Participants: PCa patients on ADT (N = 8) and CON (N = 10). Intervention: A standardized diet was consumed for 2 days prior to performing unilateral knee extension resistance exercise followed by ingestion of 40 g of whey protein. Main Outcome Measures: Bilateral biopsies and stable isotope infusions were used to determine MPS rates at rest after protein ingestion with and without resistance exercise. Results: Baseline MPS during ADT was suppressed relative to CON (P = 0.01). Protein consumption stimulated MPS in both groups (approximate twofold increase, both P < 0.001), but to a greater extent in CON (P = 0.003). Protein plus resistance exercise increased MPS (∼3.4-fold increase, both P < 0.001) to a greater extent than did protein alone (P < 0.001), but with no difference between groups (P = 0.380). Conclusions: ADT reduces basal and protein feeding-induced rises in MPS; however, combined protein ingestion with resistance exercise stimulated MPS to a similar degree as CON. Testosterone appears to play a role in maintaining muscle mass but is not necessary to initiate a robust response in MPS following resistance exercise when combined with protein ingestion

Diagnostic accuracy of magnetic resonance angiography for internal carotid artery disease: a systematic review and meta-analysis

BACKGROUND AND PURPOSE: Accurate diagnosis of the degree of internal carotid artery (ICA) stenosis is needed for decisions regarding optimal stroke prevention. Noninvasive magnetic resonance angiography (MRA) is being proposed and used as a replacement for the gold standard, intra-arterial angiography. Our purpose was to perform a systematic review and diagnostic meta-analysis to determine the sensitivity and specificity of time-of-flight (TOF) MRA and contrast-enhanced (CE) MRA for the detection of (1) high-grade (> or = 70% to 99%) ICA stenoses; (2) ICA occlusions; (3) moderately severe (50% to 69%) ICA stenoses; and (4) compare the overall accuracy of the 2 MRA techniques. METHODS: The medical literature on MRA and the diagnosis of ICA steno-occlusive disease was reviewed through the PubMed, EMBASE, and SCOPUS databases. All publication years were included through to November 2006. Studies were eligible for inclusion if they compared the accuracy of TOF or CE MRA for the detection of ICA disease against intra-arterial angiography and reported sufficient data. RESULTS: The overall sensitivity of TOF MRA for the detection of > or = 70% to 99% ICA stenoses was 91.2% (95% CI: 88.9% to 93.1%) with a specificity of 88.3% (86.7% to 89.7%), whereas the sensitivity of CE MRA was 94.6% (92.4% to 96.4%) with a specificity of 91.9% (90.3% to 93.4%). For the detection of ICA occlusions, the sensitivity of TOF MRA was 94.5% (91.2% to 96.8%) and the specificity was 99.3% (98.9% to 99.6%), whereas the sensitivity and specificity values for CE MRA were 99.4% (96.8% to 100%) and 99.6% (99.2% to 99.9%), respectively. For moderately severe (50% to 69%) stenoses, TOF MRA had a sensitivity of only 37.9% (29.3% to 47.1%) and a specificity of 92.1% (89.6% to 94.1%); for CE MRA, the pooled sensitivity value was somewhat better at 65.9% (57.0% to 74.0%), whereas the specificity was 93.5% (91.3% to 95.3%). CONCLUSIONS: TOF MRA and CE MRA showed high accuracy for the detection of high-grade ICA stenoses and occlusions with CE MRA having the edge over TOF MRA, but had only poor (TOF MRA) to fair (CE MRA) sensitivity for the detection of moderately severe stenoses