Exploring precision polymers to fine-tune magnetic resonance imaging properties of iron oxide nanoparticles.

The use of bio-polymers as stabilising agents for iron oxide-based negative magnetic resonance imaging (MRI) contrast agents has become popular in recent years, however the wide polydispersity of biologically-derived and commercially available polymers limits the ability to produce truly tuneable and reproducible behaviour, a major challenge in this area. In this work, stable colloids of iron oxide nanoparticles were prepared utilising precision-engineered bio-polymer mimics, poly(2-acrylamido-2-methylpropane sodium sulfonate) (P(AMPS)) polymers, with controlled narrow polydispersity molecular weights, as templating stabilisers. In addition to producing magnetic colloids with excellent MRI contrast capabilities (r2 values reaching 434.2 mM-1 s-1 at 25 °C and 23 MHz, several times higher than similar commercial analogues), variable field relaxometry provided unexpected important insights into the dynamic environment of the hydrated materials, and hence their exceptional MRI behaviour. Thanks to the polymer's templating backbone and flexible conformation in aqueous suspension, nanocomposites appear to behave as "multi-core" clustered species, enhancing interparticle interactions whilst retaining water diffusion, boosting relaxation properties at low frequency. This clustering behaviour, evidenced by small-angle X-ray scattering, and strong relaxometric response, was fine-tuned using the well-defined molecular weight polymer species with precise iron to polymer ratios. By also showing negligible haemolytic activity, these nanocomposites exhibit considerable potential for MRI diagnostics.

Sulfonated Copolymers as Heparin-Mimicking Stabilizer of Fibroblast Growth Factor: Size, Architecture, and Monomer Distribution Effects.

Fibroblast growth factors (FGF) are involved in a wide range of biological processes such as cell proliferation and differentiation. In living organisms, the binding of FGF to its receptors are mediated through electrostatic interactions between FGF and naturally occurring heparin. Despite its prevalent use in medicine, heparin carries notable limitations; namely, its extraction from natural sources (expensive, low yield and extensive purification), viral contamination, and batch-to-batch heterogeneity. In this work a range of synthetic homopolymers and copolymers of sodium 2-acrylamido-2-methylpropanesulfonate were evaluated as potential FGF stabilizers. This was studied by measuring the proliferation of BaF3-FR1c cells, as a model assay, and the results will be compared with the natural stabilization and activation of FGF by heparin. This study explores the structure-activity relationship of these polysulfonated polymers with a focus on the effect of molecular weight, comonomer type, charge dispersion, and polymer architecture on protein stabilization.

Heparin-Mimicking Sulfonated Polymer Nanoparticles via RAFT Polymerization-Induced Self-Assembly.

Heparin plays a significant role in wound healing and tissue regeneration applications, through stabilization of fibroblast growth factors (FGF). Risks associated with batch-to-batch variability and contamination from its biological sources have led to the development of synthetic, highly sulfonated polymers as promising heparin mimics. In this work, a systematic study of an aqueous polymerization-induced self-assembly (PISA) of styrene from poly(2-acrylamido-2-methylpropane sodium sulfonate) (P(AMPS)) macro reversible addition-fragmentation chain transfer (macro-RAFT) agents produced a variety of spherical heparin-mimicking nanoparticles, which were further characterized with light scattering and electron microscopy techniques. None of the nanoparticles tested showed toxicity against mammalian cells; however, significant hemolytic activity was observed. Nonetheless, the heparin-mimicking nanoparticles outperformed both heparin and linear P(AMPS) in cellular proliferation assays, suggesting increased bFGF stabilization efficiencies, possibly due to the high density of sulfonated moieties at the particle surface.

Is Radiotherapy Useful for Treating Pain in Mesothelioma?: A Phase II Trial.

INTRODUCTION: Radiotherapy is often used to treat pain in malignant pleural mesothelioma (MPM), although there is limited evidence to support this. The aim of this trial was to assess the role of radiotherapy for the treatment of pain in MPM. METHODS: A multicentre, single arm phase II trial was conducted. Eligible patients fulfilled the following criteria: pathological or radiological diagnosis of MPM; pain secondary to MPM; radiotherapy indicated for pain control; and more than 18 years of age. Patients had assessments of pain and other symptoms at baseline and then received 20 Gy in five daily fractions. Key follow-up points were 5 and 12 weeks posttreatment. The primary end point measure was assessment of pain at the site of radiotherapy at 5 weeks. Secondary end points included effects on quality of life, breathlessness, fatigue, mood, toxicity, and the radiological response. RESULTS: Forty patients were recruited from three UK oncology centers. Fourteen patients had a clinically meaningful improvement in their pain 5 weeks post radiotherapy (intention to treat), with five patients having a complete improvement. On the basis of a complete case analysis of the 30 patients assessable at week 5, 47% (confidence intervals, 28.3-65.7) of patients alive at week 5 had an improvement in their pain. There was no improvement in other key symptoms or quality of life. CONCLUSIONS: Radiotherapy for pain control in MPM is an effective treatment in a proportion of patients. Future studies examining differing radiotherapy regimens with a view to improving response rates are warranted.

Loading dose ibandronate versus standard oral ibandronate in patients with bone metastases from breast cancer.

INTRODUCTION: In this phase II trial, the efficacy and safety of loading-dose I.V. ibandronate in patients with breast cancer with bone metastases were evaluated. PATIENTS AND METHODS: Thirty-four patients were randomized to receive a loading dose of 12 mg I.V. ibandronate on day 1 then oral ibandronate 50 mg daily (arm A), or standard oral therapy of 50 mg ibandronate daily from day 1 (arm B). The primary end point was percentage change in serum C-terminal crosslinking telopeptide of type I collagen (S-CTX) from baseline by day 5 of study. Secondary/exploratory end points included percentage change in other bone turnover markers (N-terminal cross-linking telopeptides of type I collagen [NTX], procollagen type I N propeptide, bone alkaline phosphatase) and change in average bone pain score. RESULTS: There was a significantly greater reduction in S-CTX at day 5 in arm A compared with arm B (median difference, 15.82%; P = .005). There was also a significantly greater reduction in urine NTX/creatinine at day 5 (P = .009) and at the end of weeks 1 to 8 (averaged; P = .006). Average bone pain score was lower in arm A at the end of 8 weeks (P = .012). There were no additional adverse events after administration of 12 mg I.V. loading dose of ibandronate. CONCLUSION: A 12-mg dose of I.V. ibandronate rapidly reduced markers of bone turnover and can be administered without additional toxicity.

Prognostication in advanced cancer: a study examining an inflammation-based score.

CONTEXT: Prognostication in advanced cancer is challenging. Biomarkers of systemic inflammation (C-reactive protein and albumin) combined in the modified Glasgow Prognostic Score (mGPS) have been used to assist prognostication in various cancer types. OBJECTIVES: The aim of this study was to examine whether an inflammation-based prognostic score (mGPS) is useful in prognostication in advanced cancer patients. METHODS: Cancer patients who had biomarkers (C-reactive protein and albumin) recorded were allocated an mGPS ranging from 0-2. Groups were compared using Jonckheere-Terpstra and Chi-squared tests. Survival analyses were carried out using Kaplan-Meier and multivariate Cox regression models. RESULTS: A total of 296 patients were included, and a representative subgroup of 102 had biomarkers recorded. The mGPS was predictive of death (P=0.014) adjusted for sex, cancer site, age, hemoglobin, and white cell count. Patients with an mGPS of 2 had 2.7 times the risk of death of those with an mGPS of 0 (P=0.011). Patients with an mGPS less than 2 had an 86.1% and 74.3% chance of being alive at two and four weeks, respectively. CONCLUSION: A role for the mGPS in prognostication near the end of life is suggested. Biomarkers (e.g., mGPS) may assist clinical decisions as to whether intensive treatments are appropriate and may facilitate end-of-life care planning.

Explaining the effects of socio-economic deprivation on survival in a national prospective cohort study of 1909 patients with head and neck cancers.

BACKGROUND: Socio-economic differences in survival from head and neck cancers are among the largest of any malignancies. Population-based data have been unable to explain these differences. AIMS: To describe survival from head and neck cancers in a large cohort of patients for whom a range of socio-economic, demographic, behavioural and casemix data was available. METHODS: Prospective cohort study using data from the Scottish Head and Neck Audit on all patients diagnosed with a head and neck cancer in Scotland between 1st September 1999 and 31st August 2001 linked to General Register Office for Scotland death records to 30th June 2006. Cox proportional hazards models were produced to describe adjusted hazards of death according to socio-economic circumstances, using validated area-based DEPCAT scores. RESULTS: Data on 1909 patients were analysed. 71.0% were male and mean age was 64.3 (SD 12.2) years. Overall 5-year survival was 45.6% (95% CI: 43.4-47.8%). In order of strength of association in univariate regression, World Health Organisation Performance Status, disease stage, patient age, tumour site, smoking status, alcohol use, tumour differentiation, and deprivation were significant predictors of all-cause mortality but after multiple adjustment, deprivation was no longer an independent predictor of survival. CONCLUSIONS: Socio-economic differentials in survival from head and neck cancers are determined by a mixture of risk factors, some of which may be amenable to targeted earlier detection methods and lifestyle interventions. However, further research is needed to understand the impacts of performance status in more deprived patients.

Socio-economic deprivation and survival of non-Hodgkin lymphoma in Scotland.

Socio-economic deprivation is known to be associated with poorer survival from non-Hodgkin lymphoma (NHL) but routine data have not been able to determine whether this can be explained by differences in disease severity at presentation. We examined survival in all patients diagnosed with NHL in Scotland between 1979 and 1996 and between 1994 and 1996 used Scotland and Newcastle Lymphoma Group data, which include detailed clinical staging information. Compared with individuals from the most affluent areas, survival is 10% poorer in intermediate, and 19% poorer in patients living in the most deprived areas. Deprivation is associated with more B symptoms and poorer performance status but not with other indicators of more advanced disease, suggesting that the disease may be more aggressive or immunocompetence poorer among more deprived populations. We also noted improvements in relative survival from NHL over time.

Changes in the incidence of cutaneous melanoma in the west of Scotland and Queensland, Australia: hope for health promotion?

We compared trends in melanoma incidence by body site in two populations exposed to different levels of sunlight and different approaches to melanoma prevention. We analysed site-specific melanoma incidence during the period 1982-2001 in Queensland, Australia (n=28 862 invasive melanomas; 2536 lentigo maligna melanomas) and the west of Scotland (n=4278 invasive melanomas; 525 lentigo maligna melanomas). Analyses were stratified by sex and age group (<40 years, 40-59 years, >/=60 years). We estimated annual percentage change (APC) in melanoma incidence by regressing the logarithms of the rates and exponentiating the coefficients. Among men, overall melanoma incidence increased log-linearly in both settings, but significantly more rapidly in the west of Scotland (APC 2.8%) than Queensland (APC 1.4%). Rates of increase among Scottish men were higher for every body site and all ages than among Queensland men. Among women, overall melanoma incidence increased more rapidly among Scottish (APC 1.8%) than Queensland women (APC 0.7%). Most discrepant were trends in upper limb melanomas, which underwent large annual increases among Scottish women, but declined among younger Queensland women. Melanoma incidence continues to rise rapidly in all age groups in Scotland and among older people in Queensland. Rates of melanoma in younger people in Queensland are stabilizing, as might be expected if primary prevention campaigns were effective in reducing solar exposure. Variations in rates of change at different body sites warrant further monitoring.

A comparison of the anatomic distribution of cutaneous melanoma in two populations with different levels of sunlight: the west of Scotland and Queensland, Australia 1982-2001.

To explore whether the anatomic distribution of melanoma differs with ambient sunlight levels, we compared age- and site-specific melanoma incidence in two genetically similar populations from different geographic regions. We ascertained all new cases of invasive cutaneous melanoma in the west of Scotland and Queensland 1982-2001. Melanoma incidence was calculated for four anatomic regions (head and neck, trunk, upper and lower limbs), standardized to the European population and adjusted for relative surface area of each site. Highest rates among males aged <40 years and 40-59 years were observed on the trunk, but on the upper limbs among Queensland females and lower limbs among Scottish females. After age 60, melanoma rates were highest on the head and neck in both sexes. In both sexes and at all ages, lower limb melanomas were more common in Scotland than expected from the Queensland population. These analyses indicate that while the overall distribution of melanoma is similar in populations with different levels of ambient sunlight, important differences remain. Identifying the causes of these differences is likely to provide better understanding of how sunlight causes melanoma.

Value of sentinel node status as a prognostic factor in melanoma: prospective observational study.

OBJECTIVE: To establish the prognostic value of knowledge of sentinel node status in melanoma. DESIGN: Single centre prospective observational study, with sentinel nodes identified by lymphoscintigraphy, gamma probe, and intraoperative blue dye and examined by both conventional histopathology and immunopathology. SETTING: Specialist surgical service in west of Scotland. PARTICIPANTS: 482 patients with melanoma who consented to sentinel node biopsy in 1996-2003. MAIN OUTCOME MEASURE: Time to recurrence of or death from melanoma. RESULTS: Of 472 patients who consented to sentinel node biopsy and in whom at least one sentinel node was identified, 367 (78%) had no tumour in the sentinel node. At mean follow-up of 42 months, 299 (82%) of this group were alive and free from disease, 24 were alive with melanoma recurrence, and 31 had died of melanoma. Of 105 patients with a positive sentinel node biopsy, 44 (42%) were alive and disease free, 12 were alive with recurrence, and 46 had died of melanoma. The survival difference between patients who were negative and those who were positive for tumour in the sentinel node was highly significant at all thickness levels over 1.0 mm (P < 0.001). Multivariate analysis showed that sentinel node status was independent of tumour thickness and ulceration. 71/105 (68%) patients with a positive sentinel node had a negative completion lymphadenectomy, and 44/71 (62%) were alive and disease free at follow-up; 34 patients with a positive sentinel node had further nodes involved, and only 4 (12%) were disease free (P < 0.001). 16 patients (13 sentinel node biopsy positive; 3 negative) died of other causes. CONCLUSION: Sentinel node status is a highly significant predictor of prognosis in melanoma and should be considered in adjuvant studies. However, it should not be regarded as a standard of care until mature data from ongoing randomised trials are available.

Incidence of and survival from malignant melanoma in Scotland: an epidemiological study.

BACKGROUND: We aimed to assess the incidence and survival for all patients with invasive primary cutaneous malignant melanoma diagnosed in Scotland, UK, during 1979-98. METHODS: The Scottish Melanoma Group obtained data for 8830 patients (3301 male and 5529 female) first diagnosed with invasive cutaneous malignant melanoma. FINDINGS: Age-standardised incidence rose from 3.5 in 1979 to 10.6 per 10(5) population in 1998 for men, and from 7.0 to 13.1 for women, a rise of 303% and 187%, respectively. After 1995, the rate of increase levelled in women younger than 65 years at diagnosis. Melanoma incidence increased most in men on the trunk, head, and neck and in women on the leg. 5-year survival rose from 58% to 80% for men diagnosed in 1979 and 1993, respectively, and from 74% to 85% for women; improvements of 38% (p<0.001) and 15% (p<0.001), respectively. Most improvement was attributable to a higher proportion of thinner tumours. Male mortality from melanoma was 1.9/10(5) population per year at the start and end of the study, whereas mortality for men younger than 65 years at diagnosis rose from 1.2 to 1.35 (p=0.24). For all women, mortality fell slightly from 1.9 to 1.85/10(5) population per year (p=0.61), whereas for women younger than 65 years at diagnosis, mortality fell from 1.3 to 1.15 (p=0.62). INTERPRETATION: Interventions aimed at both primary and secondary prevention of melanoma are justified. Specialist tumour registers for entire countries can be used to plan and monitor public health interventions.