The global cancer divide: relationships between national healthcare resources and cancer outcomes in high-income vs. middle- and low-income countries.

BACKGROUND: Cancer continues to rise as a contributor to premature death in the developing world. Despite this, little is known about whether cancer outcomes are related to a country's income level, and what aspects of national healthcare systems are associated with improved cancer outcomes. METHODS: The most recent estimates of cancer incidence and mortality were used to calculate mortality-to-incidence ratio (MIR) for the 85 countries with reliable data. Countries were categorized according to high-income (Gross Domestic Product (GDP)>$15,000) or middle/low-income (GDP<$15,000), and a multivariate linear regression model was used to determine the association between healthcare system indicators and cancer MIR. Indicators study included per capita GDP, overall total healthcare expenditure (THE), THE as a proportion of GDP, total external beam radiotherapy devices (TEBD) per capita, physician density, and the year 2000 WHO healthcare system rankings. RESULTS: Cancer MIR in high-income countries (0.47) was significantly lower than that of middle/low-income countries (0.64), with a p<0.001. In high-income countries, GDP, health expenditure and TEBD showed significant inverse correlations with overall cancer MIR. A $3040 increase in GDP (p=0.004), a $379 increase in THE (p<0.001), or an increase of 0.59 TEBD per 100,000 population (p=0.027) were all associated with a 0.01 decrease in cancer MIR. In middle/low-income countries, only WHO scores correlated with decreased cancer MIR (p=0.022); 12 specific cancer types also showed similar significant correlations (p<0.05) as overall cancer MIR. CONCLUSIONS: The analysis of this study suggested that cancer MIR is greater in middle/low-income countries. Furthermore, the WHO healthcare score was associated with improved cancer outcomes in middle/low-income countries while absolute levels of financial resources and infrastructure played a more important role in high-income countries.

Malignant melanoma and radiotherapy: past myths, excellent local control in 146 studied lesions at Georgetown University, and improving future management.

INTRODUCTION: Once thought to be radioresistant, emerging cellular and clinical evidence now suggests melanoma can respond to large radiation doses per fraction. MATERIALS AND METHODS: We conducted a retrospective study of all patients treated with stereotactic radiosurgery and stereotactic body radiotherapy at Georgetown University Hospital from May 2002 through November 2008 and studied the classic extrapolated total dose corrected for volume (ETD(vol)) model for predicting melanoma tumor response. Region-specific tumor outcomes were categorized by RECIST criteria and local control curves were estimated and analyzed when stratified by ETD(vol) thresholds by use of the Kaplan-Meier method. RESULTS: Follow-up information was available for 78 lesions (49 intracranial, 8 spinal, and 21 body) with mean follow-up period of 9.2 (range, 2-36) months. 1-year local control rates for intracranial, spinal, and body tumors were 84, 100, and 72%, respectively. Treatments in general were well-tolerated. Increased ETD(vol) (p < 0.001) among intracranial sites resulted from larger (p < 0.001) doses per fraction combined with smaller (p < 0.001) tumor diameters. Intracranial 6-, 12-, and 24-month local control rates when treated above ETD(vol) threshold of 230 Gy were all 90 vs. 89, 80, and 53% below this threshold. Body 6- and 12-month local control rates when treated above ETD(vol) threshold of 100 Gy were 100 and 80% vs. 74 and 59% below this threshold. DISCUSSION: By tailoring to melanoma's unique radiobiology with large radiation doses per fraction, favorable local control was safely achieved. The ETD(vol) model combines the important factor of dose per fraction in melanoma treatment with a volume correction factor to predict tumor response. Although limited sample size may have prevented reaching statistical significance for local control improvements using ETD(vol) thresholds, optimal thresholds may exist to improve future tumor responses and further research is required.

Evidence that low-grade systemic inflammation can induce islet dysfunction as measured by impaired calcium handling.

In obesity and the early stages of type 2 diabetes (T2D), proinflammatory cytokines are mildly elevated in the systemic circulation. This low-grade systemic inflammation exposes pancreatic islets to these circulating cytokines at much lower levels than seen within the islet during insulitis. These low-dose effects have not been well described. We examined mouse islets treated overnight with a low-dose cytokine combination commonly associated with inflammation (TNF-alpha, IL-1 beta, and IFN-gamma). We then examined islet function primarily using intracellular calcium ([Ca(2+)](i)), a key component of insulin secretion and cytokine signaling. Cytokine-treated islets demonstrated several features that suggested dysfunction including excess [Ca(2+)](i) in low physiological glucose (3mM), reduced responses to glucose stimulation, and disrupted [Ca(2+)](i) oscillations. Interestingly, islets taken from young db/db mice showed similar disruptions in [Ca(2+)](i) dynamics as cytokine-treated islets. Additional studies of control islets showed that the cytokine-induced elevation in basal [Ca(2+)](i) was due to both greater calcium influx through L-type-calcium-channels and reduced endoplasmic reticulum (ER) calcium storage. Many of these cytokine-induced disruptions could be reproduced by SERCA blockade. Our data suggest that chronic low-grade inflammation produces circulating cytokine levels that are sufficient to induce beta-cell dysfunction and may play a contributing role in beta-cell failure in early T2D.

Evidence of diminished glucose stimulation and endoplasmic reticulum function in nonoscillatory pancreatic islets.

Pulsatility is a fundamental feature of pancreatic islets and a hallmark of hormone secretion. Isolated pancreatic islets endogenously generate rhythms in secretion, metabolic activity, and intracellular calcium ([Ca(2+)](i)) that are important to normal physiological function. Few studies have directly compared oscillatory and nonoscillatory islets to identify possible differences in function. We investigated the hypothesis that the loss of these oscillations is a leading indicator of islet dysfunction by comparing oscillatory and nonoscillatory mouse islets for multiple parameters of function. Nonoscillatory islets displayed elevated basal [Ca(2+)](i) and diminished [Ca(2+)](i) response and insulin secretory response to 3-28 mm glucose stimulation compared with oscillatory islets, suggesting diminished glucose sensitivity. We investigated several possible mechanisms to explain these differences. No differences were observed in mitochondrial membrane potential, estimated ATP-sensitive potassium channel and L-type calcium channel activity, or cell death rates. Nonoscillatory islets, however, showed a reduced response to the sarco(endo)plasmic reticulum calcium ATPase inhibitor thapsigargin, suggesting a disruption in calcium homeostasis in the endoplasmic reticulum (ER) compared with oscillatory islets. The diminished ER calcium homeostasis among nonoscillatory islets was also consistent with the higher cytosolic calcium levels observed in 3 mm glucose. Inducing mild damage with low-dose proinflammatory cytokines reduced islet oscillatory capacity and produced similar effects on glucose-stimulated [Ca(2+)](i), basal [Ca(2+)](i), and thapsigargin response observed among untreated nonoscillatory islets. Our data suggest the loss of oscillatory capacity may be an early indicator of diminished islet glucose sensitivity and ER dysfunction, suggesting targets to improve islet assessment.