Personalizing adjuvant therapy for patients with colorectal cancer.

The current standard-of-care adjuvant treatment for patients with colorectal cancer (CRC) comprises a fluoropyrimidine (5-fluorouracil or capecitabine) as a single agent or in combination with oxaliplatin, for either 3 or 6 months. Selection of therapy depends on conventional histopathological staging procedures, which constitute a blunt tool for patient stratification. Given the relatively marginal survival benefits that patients can derive from adjuvant treatment, improving the safety of chemotherapy regimens and identifying patients most likely to benefit from them is an area of unmet need. Patient stratification should enable distinguishing those at low risk of recurrence and a high chance of cure by surgery from those at higher risk of recurrence who would derive greater absolute benefits from chemotherapy. To this end, genetic analyses have led to the discovery of germline determinants of toxicity from fluoropyrimidines, the identification of patients at high risk of life-threatening toxicity, and enabling dose modulation to improve safety. Thus far, results from analyses of resected tissue to identify mutational or transcriptomic signatures with value as prognostic biomarkers have been rather disappointing. In the past few years, the application of artificial intelligence-driven models to digital images of resected tissue has identified potentially useful algorithms that stratify patients into distinct prognostic groups. Similarly, liquid biopsy approaches involving measurements of circulating tumour DNA after surgery are additionally useful tools to identify patients at high and low risk of tumour recurrence. In this Perspective, we provide an overview of the current landscape of adjuvant therapy for patients with CRC and discuss how new technologies will enable better personalization of therapy in this setting.

Preclinical Testing of a Novel Niclosamide Stearate Prodrug Therapeutic (NSPT) Shows Efficacy Against Osteosarcoma.

Therapeutic advances for osteosarcoma have stagnated over the past several decades, leading to an unmet clinical need for patients. The purpose of this study was to develop a novel therapy for osteosarcoma by reformulating and validating niclosamide, an established anthelminthic agent, as a niclosamide stearate prodrug therapeutic (NSPT). We sought to improve the low and inefficient clinical bioavailability of oral dosing, especially for the relatively hydrophobic classes of anticancer drugs. Nanoparticles were fabricated by rapid solvent shifting and verified using dynamic light scattering and UV-vis spectrophotometry. NSPT efficacy was then studied in vitro for cell viability, cell proliferation, and intracellular signaling by Western blot analysis; ex vivo pulmonary metastatic assay model; and in vivo pharmacokinetic and lung mouse metastatic model of osteosarcoma. NSPT formulation stabilizes niclosamide stearate against hydrolysis and delays enzymolysis; increases circulation in vivo with t 1/2 approximately 5 hours; reduces cell viability and cell proliferation in human and canine osteosarcoma cells in vitro at 0.2-2 µmol/L IC50; inhibits recognized growth pathways and induces apoptosis at 20 µmol/L; eliminates metastatic lesions in the ex vivo lung metastatic model; and when injected intravenously at 50 mg/kg weekly, it prevents metastatic spread in the lungs in a mouse model of osteosarcoma over 30 days. In conclusion, niclosamide was optimized for preclinical drug delivery as a unique prodrug nanoparticle injected intravenously at 50 mg/kg (1.9 mmol/L). This increased bioavailability of niclosamide in the blood stream prevented metastatic disease in the mouse. This chemotherapeutic strategy is now ready for canine trials, and if successful, will be targeted for human trials in patients with osteosarcoma.

Diabetes Healthcare Professionals Use Multiple Continuous Glucose Monitoring Data Indicators to Assess Glucose Management.

BACKGROUND: Continuous glucose monitoring (CGM) offers multiple data features that can be leveraged to assess glucose management. However, how diabetes healthcare professionals (HCPs) actually assess CGM data and the extent to which they agree in assessing glycemic management are not well understood. METHODS: We asked HCPs to assess ten de-identified CGM datasets (each spanning seven days) and rank order each day by relative glycemic management (from "best" to "worst"). We also asked HCPs to endorse features of CGM data that were important in making such assessments. RESULTS: In the study, 57 HCPs (29 endocrinologists; 28 diabetes educators) participated. Hypoglycemia and glycemic variance were endorsed by nearly all HCPs to be important (91% and 88%, respectively). Time in range and daily lows and highs were endorsed more frequently by educators (all Ps < .05). On average, HCPs endorsed 3.7 of eight data features. Overall, HCPs demonstrated agreement in ranking days by relative glycemic control (Kendall's W = .52, P < .001). Rankings were similar between endocrinologists and educators (R2 = .90, Cohen's kappa = .95, mean absolute error = .4 [all Ps < .05]; Mann-Whitney U = 41, P = .53). CONCLUSIONS: Consensus in the endorsement of certain data features and agreement in assessing glycemic management were observed. While some practice-specific differences in feature endorsement were found, no differences between educators and endocrinologists were observed in assessing glycemic management. Overall, HCPs tended to consider CGM data holistically, in alignment with published recommendations, and made converging assessments regardless of practice.

Deep learning for prediction of colorectal cancer outcome: a discovery and validation study.

BACKGROUND: Improved markers of prognosis are needed to stratify patients with early-stage colorectal cancer to refine selection of adjuvant therapy. The aim of the present study was to develop a biomarker of patient outcome after primary colorectal cancer resection by directly analysing scanned conventional haematoxylin and eosin stained sections using deep learning. METHODS: More than 12 000 000 image tiles from patients with a distinctly good or poor disease outcome from four cohorts were used to train a total of ten convolutional neural networks, purpose-built for classifying supersized heterogeneous images. A prognostic biomarker integrating the ten networks was determined using patients with a non-distinct outcome. The marker was tested on 920 patients with slides prepared in the UK, and then independently validated according to a predefined protocol in 1122 patients treated with single-agent capecitabine using slides prepared in Norway. All cohorts included only patients with resectable tumours, and a formalin-fixed, paraffin-embedded tumour tissue block available for analysis. The primary outcome was cancer-specific survival. FINDINGS: 828 patients from four cohorts had a distinct outcome and were used as a training cohort to obtain clear ground truth. 1645 patients had a non-distinct outcome and were used for tuning. The biomarker provided a hazard ratio for poor versus good prognosis of 3·84 (95% CI 2·72-5·43; p<0·0001) in the primary analysis of the validation cohort, and 3·04 (2·07-4·47; p<0·0001) after adjusting for established prognostic markers significant in univariable analyses of the same cohort, which were pN stage, pT stage, lymphatic invasion, and venous vascular invasion. INTERPRETATION: A clinically useful prognostic marker was developed using deep learning allied to digital scanning of conventional haematoxylin and eosin stained tumour tissue sections. The assay has been extensively evaluated in large, independent patient populations, correlates with and outperforms established molecular and morphological prognostic markers, and gives consistent results across tumour and nodal stage. The biomarker stratified stage II and III patients into sufficiently distinct prognostic groups that potentially could be used to guide selection of adjuvant treatment by avoiding therapy in very low risk groups and identifying patients who would benefit from more intensive treatment regimes. FUNDING: The Research Council of Norway.

Retrospective Clinical Study of Advanced Pancreatic Cancer Treated With Chemotherapy and Abdominal Hyperthermia.

PURPOSE: Hyperthermia is a mechanistically plausible partner with chemotherapy, although many of the underlying molecular mechanisms of this combination treatment are not yet properly understood. Preclinical studies suggest that there is potential synergy with gemcitabine and that provides the basis for retrospective analysis of a clinical series combining these treatment modalities for patients with advanced pancreatic cancer. PATIENTS AND METHODS: Twenty-nine chemotherapy-naive patients with locally advanced or metastatic pancreatic carcinoma with malignant ascites were treated with intraperitoneal cisplatin 30 mg/m2 and gemcitabine 800 to 1,000 mg/m2 intravenously on days 1, 8, and 15 every 28 days until tumor progression. Patients also received regional hyperthermia treatment (41 to 42°C) on the upper abdomen two times per week from days 1 to 21. RESULTS: In all, 83 cycles of chemotherapy were administered and were generally well tolerated. No patients had a complete response, 13 had a partial response, seven had stable disease, and 9 had progressive disease. Mean progression-free survival and overall survival were 119 ± 61days and 195 ± 98 days, respectively. CONCLUSION: This study provides preliminary evidence that the treatment approach of combined systemic and intraperitoneal chemotherapy plus hyperthermia is well tolerated, is active, and has an acceptable survival profile for patients with stage IV pancreatic cancer and ascites.

Intratumoral stromal morphometry predicts disease recurrence but not response to 5-fluorouracil-results from the QUASAR trial of colorectal cancer.

AIMS: The biological importance of tumour-associated stroma is becoming increasingly apparent, but its clinical utility remains ill-defined. For stage II/Dukes B colorectal cancer (CRC), clinical biomarkers are urgently required to direct therapeutic options. We report here prognostic/predictive analyses, and molecular associations, of stromal morphometric quantification in the Quick and Simple and Reliable (QUASAR) trial of CRC. METHODS AND RESULTS: Relative proportions of tumour epithelium (PoT) or stroma (PoS) were morphometrically quantified on digitised haematoxylin and eosin (H&E) sections derived from 1800 patients enrolled in QUASAR, which randomised 3239 (91% stage II) CRC patients between adjuvant fluorouracil/folinic acid (FUFA) chemotherapy and observation. The prognostic and predictive values of PoT/PoS measurements were determined by the use of stratified log-rank analyses. A high proportion of tumour stroma (≥50%) was associated with an increased recurrence risk: 31.3% (143/457) recurrence for ≥50% versus 21.9% (294/1343) for <50% [rate ratio (RR) 1.62; 95% confidence interval (CI) 1.30-2.02; P < 0.0001]. Of patients with stromal proportions of ≥65%, 40% (46/115) had recurrent disease within 10 years. The adverse prognostic effect of a high stromal proportion was independent of established prognostic variables, and was maintained in stage II/Dukes B patients (RR 1.62; 95% CI 1.26-2.08; P = 0.0002). KRAS mutation in the presence of a high stromal proportion augmented recurrence risk (RR 2.93; 95% CI 1.87-4.59; P = 0.0005). Stromal morphometry did not predict response to FUFA chemotherapy. CONCLUSIONS: Simple digital morphometry applied to a single representative H&E section identifies CRC patients with a >50% higher risk of disease recurrence. This technique can reliably partition patients into subpopulations with different risks of tumour recurrence in a simple and cost-effective manner. Further prospective validation is warranted.

Associations between vitamin D levels and depressive symptoms in healthy young adult women.

There have been few studies of whether vitamin D insufficiency is linked with depression in healthy young women despite women׳s high rates of both problems. Female undergraduates (n=185) living in the Pacific Northwest during fall, winter, and spring academic terms completed the Center for Epidemiologic Studies Depression (CES-D) scale weekly for 4 weeks (W1-W5). We measured serum levels of vitamin D3 and C (ascorbate; as a control variable) in blood samples collected at W1 and W5. Vitamin D insufficiency (<30ng/mL) was common at W1 (42%) and W5 (46%), and rates of clinically significant depressive symptoms (CES-D≥16) were 34-42% at W1-W5. Lower W1 vitamin D3 predicted clinically significant depressive symptoms across W1-W5 (ß=-0.20, p<0.05), controlling for season, BMI, race/ethnicity, diet, exercise, and time outside. There was some evidence that lower levels of depressive symptoms in Fall participants (vs. Winter and Spring) were explained by their higher levels of vitamin D3. W1 depressive symptoms did not predict change in vitamin D3 levels from W1 to W5. Findings are consistent with a temporal association between low levels of vitamin D and clinically meaningful depressive symptoms. The preventive value of supplementation should be tested further.

Consensus pathways: evidence into practice.

HealthPathways is a website that provides general practice teams with guidance on clinical assessment and management of medical conditions, relevant to local services and resources. The website evolved in 2008 as part of changes towards an integrated healthcare system in the Canterbury region of New Zealand. The website differs from other clinical guidance websites as the clinical pathways are formulated by local healthcare professionals, health managers, and technical writers. This process is facilitated by a proactive group called the Canterbury Initiative. The website now contains over 570 clinical pathways, with access increasing seven-fold since 2009 (visits/mth; 1053 in 2009 vs. 7729 in 2014). HealthPathways has contributed to the delivery of more care in the community (e.g. primary care spirometry; 1443 measurements in 2014 representing one-quarter of the total number). Introduction of the website has been associated with an improvement in referral quality, more equitable referral triage, and more transparent management of demand for secondary care. Because the website provides relevant localised clinical information required during a patient consultation in an easy-to-use standardised format, it has overcome many of the barriers encountered by other online clinical guidance systems. The website has also acted as a change management tool by disseminating information required for successful integration of health services.

The predictive and prognostic value of sex in early-stage colon cancer: a pooled analysis of 33,345 patients from the ACCENT database.

PURPOSE: To compare long-term outcomes between men and women in a large cohort of clinical trial participants with early-stage colon cancer, specifically by examining whether the prognostic effect of sex varies based on age, stage of disease, and type of adjuvant therapy received. METHODS: A pooled analysis of individual patient data from 33,345 patients with colon cancer enrolled in 24 phase III studies of various adjuvant systemic therapies was conducted. Chemotherapy consisted of (1) fluorouracil (5-FU), (2) 5-FU variations, (3) 5-FU plus oxaliplatin, (4) 5-FU plus irinotecan, or (5) oral fluoropyrimidine-based regimens. The primary endpoint was disease-free survival; secondary endpoints included overall survival and time to recurrence. Stratified Cox models were used to assess the effect of sex on outcomes. Multivariate models were used to assess adjusted effects and to explore the interaction among sex and other factors. RESULTS: A total of 18,244 (55%) men and 15,101 (45%) women were included. In the entire cohort, the median age was 61 years; 91% (24,868) were white; 31% (10,347) and 69% (22,964) had stage I/II and III disease, respectively. Overall, men had inferior prognoses when compared with women for time to recurrence (hazard ratio [HR] 1.05 [95% CI, 1.01-1.09]) and other endpoints after adjusting for age, stage, and treatment. Sex was not a predictive factor of treatment efficacy (P for interaction between sex and treatment when adjusting for age and stage were .40, .67, and .77 for disease-free survival, overall survival, and time to recurrence, respectively). In exploratory analyses, worse outcomes in men were more prominent in the older patients when adjusting for stage and treatment (HR 1.08 in age ≤ 65 years vs. HR 1.18 in age > 65 years; interaction P = .016 for disease-free survival). The stage of disease and type of adjuvant regimen did not modify the prognostic value of sex. CONCLUSIONS: Sex is a modest independent prognostic marker for patients with early-stage colon cancer, particularly in older patients.

Young Adult Outcomes Associated with Teen Pregnancy Among High-Risk Girls in an RCT of Multidimensional Treatment Foster Care.

Teen pregnancy is associated with a host of deleterious outcomes for girls such as drug use and poor parenting. Thus, reducing teen pregnancy rates could improve long-term developmental outcomes for girls, improving adjustment during young adulthood. Based on the positive effects of Multidimensional Treatment Foster Care (MTFC) relative to group care (GC) in a study of adolescent girls-significantly fewer pregnancies reported in the 2-year follow-up for MTFC girls-the present study followed this sample into young adulthood (approximately 7 years postbaseline) to examine the effects of adolescent pregnancy on young adult substance use and pregnancy-related outcomes. All participants were randomly assigned to MTFC (n = 81) or GC (n = 85) as adolescents as part of two RCTs. Results from logistic regression analyses indicated that becoming pregnant during the 2-year follow-up was significantly related to illicit drug use, miscarriage from a new pregnancy, and child welfare involvement at 7 years postbaseline. In addition, baseline marijuana use predicted marijuana use at 7 years postbaseline.

Delivering affordable cancer care in high-income countries.

The burden of cancer is growing, and the disease is becoming a major economic expenditure for all developed countries. In 2008, the worldwide cost of cancer due to premature death and disability (not including direct medical costs) was estimated to be US$895 billion. This is not simply due to an increase in absolute numbers, but also the rate of increase of expenditure on cancer. What are the drivers and solutions to the so-called cancer-cost curve in developed countries? How are we going to afford to deliver high quality and equitable care? Here, expert opinion from health-care professionals, policy makers, and cancer survivors has been gathered to address the barriers and solutions to delivering affordable cancer care. Although many of the drivers and themes are specific to a particular field-eg, the huge development costs for cancer medicines-there is strong concordance running through each contribution. Several drivers of cost, such as over-use, rapid expansion, and shortening life cycles of cancer technologies (such as medicines and imaging modalities), and the lack of suitable clinical research and integrated health economic studies, have converged with more defensive medical practice, a less informed regulatory system, a lack of evidence-based sociopolitical debate, and a declining degree of fairness for all patients with cancer. Urgent solutions range from re-engineering of the macroeconomic basis of cancer costs (eg, value-based approaches to bend the cost curve and allow cost-saving technologies), greater education of policy makers, and an informed and transparent regulatory system. A radical shift in cancer policy is also required. Political toleration of unfairness in access to affordable cancer treatment is unacceptable. The cancer profession and industry should take responsibility and not accept a substandard evidence base and an ethos of very small benefit at whatever cost; rather, we need delivery of fair prices and real value from new technologies.

Value of mismatch repair, KRAS, and BRAF mutations in predicting recurrence and benefits from chemotherapy in colorectal cancer.

PURPOSE: It is uncertain whether modest benefits from adjuvant chemotherapy in stage II colorectal cancer justify the toxicity, cost, and inconvenience. We investigated the usefulness of defective mismatch repair (dMMR), BRAF, and KRAS mutations in predicting tumor recurrence and sensitivity to chemotherapy. PATIENTS AND METHODS: Immunohistochemistry for dMMR and pyrosequencing for KRAS/BRAF were performed for 1,913 patients randomly assigned between fluorouracil and folinic acid chemotherapy and no chemotherapy in the Quick and Simple and Reliable (QUASAR) trial. RESULTS: Twenty-six percent of 695 right-sided colon, 3% of 685 left-sided colon, and 1% of 407 rectal tumors were dMMR. Similarly, 17% of right colon, 2% of left colon, and 2% of rectal tumors were BRAF mutant. KRAS mutant tumors were more evenly distributed: 40% right colon, 28% left colon, and 36% rectal tumors. Recurrence rate for dMMR tumors was half that for MMR-proficient tumors (11% [25 of 218] v 26% [438 of 1,695] recurred; risk ratio [RR], 0.53; 95% CI, 0.40 to 0.70; P < .001). Risk of recurrence was also significantly higher for KRAS mutant than KRAS wild-type tumors (28% [150 of 542] v 21% [219 of 1,041]; RR, 1.40; 95% CI, 1.12 to 1.74; P = .002) but did not differ significantly between BRAF mutant and wild-type tumors (P = .36). No marker predicted benefit from chemotherapy with efficacy not differing significantly by MMR, KRAS, or BRAF status. The prognostic value of MMR and KRAS was similar in the presence and absence of chemotherapy. CONCLUSION: MMR assays identify patients with a low risk of recurrence. KRAS mutational analysis provides useful additional risk stratification to guide use of chemotherapy.

Roles of tetrahydrobiopterin in promoting tumor angiogenesis.

Nitric oxide (NO), which is derived from endothelial NO synthase (eNOS), provides crucial signals for angiogenesis in the tumor microenvironment. Tetrahydrobiopterin (BH4) is an absolute requirement for eNOS activity. In this study, we investigated whether this activation is both maintained by a wild-type Ras/phosphatidylinositol 3-kinase (PI3K)/Akt-positive feedback loop in endothelial cells and affects tumor angiogenesis. We found that supplementation of BH4 (via the pterin salvage pathway with Sep) increased Akt/eNOS phosphorylation in both human eNOS-transfected COS-7 cells and endothelial cells concomitant with increases in NO production, cell proliferation, migration, and tube formation. This augmentation was abrogated by a PI3K inhibitor. Sepiapterin (Sep) also increased GTP-bound wild-type Ras and PI3K/Akt/eNOS activation, which was prevented by the eNOS inhibitor, Nω-Nitro-L-arginine methyl ester (L-NAME). Furthermore, expression of GTP cyclohydrolase I (the rate-limiting enzyme in de novo BH4 synthesis) under doxycycline control potentiated in vivo tumorigenesis, tumor cell proliferation, as well as angiogenesis. Conversely, both switching off GTP cyclohydrolase I expression as well as inhibiting its enzymatic activity significantly decreased eNOS expression and tumor vascularization. This study demonstrates an important role for BH4 synthesis in angiogenesis by the activation of eNOS for NO production, which is maintained by a PI3K/Akt-positive feedback loop through effects on wild-type Ras in endothelial cells. Our findings suggest that BH4 synthesis may be a rational target for antiangiogenesis therapy for tumors.

What is the role and impact of molecular markers on treatment decisions for colorectal cancer in the adjuvant setting?

The new mantra for delivering optimal cancer treatment is "personalized care." This extends beyond the holistic to using germline and somatic tumoral mutations to link a specific therapy to some prognostic or predictive factor which defines a particularly responsive patient subgroup who might benefit most from treatment. Furthermore, inherited polymorphisms have the potential to greatly modulate the side effects of treatment, especially for chemotherapy which has a notoriously narrow therapeutic window.

Raltitrexed (Tomudex) versus standard leucovorin-modulated bolus 5-fluorouracil: Results from the randomised phase III Pan-European Trial in Adjuvant Colon Cancer 01 (PETACC-1).

OBJECTIVES: PETACC-1 assessed if raltitrexed is non-inferior to 5-fluorouracil and leucovorin for relapse-free survival (RFS) and overall survival (OS) in adjuvant stage III colon cancer. METHODS: Non-inferiority required both HR for RFS and OS<1.25 at 1-sided alpha=0.05. Patients (1921) were randomised to six cycles of 5-FU/LV (n=969) or eight cycles of raltitrexed (n=952). We report the final results in 993 eligible patients who started and completed the allocated treatment (489 5-FU/LV and n=504 Raltitrexed) of whom respectively 146 and 148 died, respectively. RESULTS: The trial closed prematurely when 17 (1.9%) raltitrexed-related deaths were reported. Haematological and gastrointestinal toxicities were more frequent with 5-FU/LV, liver toxicities with raltitrexed. Raltitrexed was stopped for toxicity in 13.2% and 5-FU/LV in 8.5%. Sixty-day mortality was 9% versus 7%. With 4.1 years median follow-up, the HR for RFS was 1.16 (90% CI 0.99-1.37) and that for OS was 1.01 (90% CI 0.84-1.23). CONCLUSION: The trial failed to demonstrate non-inferiority of raltitrexed. FUNDING: Free drugs and financial support from AstraZeneca.

Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study.

BACKGROUND: The aim of the QUASAR trial was to determine the size and duration of any survival benefit from adjuvant chemotherapy for patients with colorectal cancer at low risk of recurrence, for whom the indication for such treatment is unclear. METHODS: After apparently curative resections of colon or rectal cancer, 3239 patients (2963 [91%] with stage II [node negative] disease, 2291 [71%] with colon cancer, median age 63 [IQR 56-68] years) enrolled between May, 1994, and December, 2003, from 150 centres in 19 countries were randomly assigned to receive chemotherapy with fluorouracil and folinic acid (n=1622) or to observation (with chemotherapy considered on recurrence; n=1617). Chemotherapy was delivered as six 5-day courses every 4 weeks or as 30 once-weekly courses of intravenous fluorouracil (370 mg/m2) with high-dose (175 mg) L-folinic acid or low-dose (25 mg) L-folinic acid. Until 1997, levamisole (12 courses of 450 mg over 3 days repeated every 2 weeks) or placebo was added. After 1997, patients who were assigned to receive chemotherapy were given fluorouracil and low-dose folinic acid only. The primary outcome was all-cause mortality. Analyses were done by intention to treat. This trial is registered with the International Clinical Trial Registry, number ISRCTN82375386. FINDINGS: At the time of analysis, 61 (3.8%) patients in the chemotherapy group and 50 (3.1%) in the observation group had missing follow-up. After a median follow-up of 5.5 (range 0-10.6) years, there were 311 deaths in the chemotherapy group and 370 in the observation group; the relative risk of death from any cause with chemotherapy versus observation alone was 0.82 (95% CI 0.70-0.95; p=0.008). There were 293 recurrences in the chemotherapy group and 359 in the observation group; the relative risk of recurrence with chemotherapy versus observation alone was 0.78 (0.67-0.91; p=0.001). Treatment efficacy did not differ significantly by tumour site, stage, sex, age, or chemotherapy schedule. Eight (0.5%) patients in the chemotherapy group and four (0.25%) in the observation group died from non-colorectal cancer causes within 30 weeks of randomisation; only one of these deaths was deemed to be possibly chemotherapy related. INTERPRETATION: Chemotherapy with fluorouracil and folinic acid could improve survival of patients with stage II colorectal cancer, although the absolute improvements are small: assuming 5-year mortality without chemotherapy is 20%, the relative risk of death seen here translates into an absolute improvement in survival of 3.6% (95% CI 1.0-6.0).

Influence of caffeine on heart rate variability in patients with long-standing type 1 diabetes.

OBJECTIVE: The effect of caffeine on cardiovascular health remains controversial. Patients with long-standing type 1 diabetes are at risk of autonomic failure and sudden cardiac death. We investigated the effects of caffeine on autonomic dysfunction (as assessed by heart rate variability [HRV]) in this high-risk group and in a control population. RESEARCH DESIGN AND METHODS: Using a randomized blinded, placebo-controlled, crossover design trial, we examined 2 weeks of caffeine consumption (250 mg twice daily) on HRV in 20 type 1 diabetic patients and 10 matched healthy volunteers. RESULTS: Baseline HRV was blunted in the diabetic patients (P < 0.0005 vs. control subjects) and markedly increased by caffeine in both groups (+103% in the group with diabetes [P = 0.009] and +38% in control subjects [P = 0.002]). The caffeine-associated increase in HRV was not statistically different between the control and the type 1 diabetes groups (P = 0.16). CONCLUSIONS: Modest amounts of caffeine improved autonomic function in diabetic patients and healthy volunteers. For individuals with abnormal HRV, regular caffeine use may have the potential to reduce the risk of cardiovascular events.