Autologous tumor lysate/Bacillus Calmette-Guérin immunotherapy as an adjuvant to conventional breast cancer therapy

Introduction. Autologous tumor cell vaccines rely on the concept of preserving an individual’s own tumorigenic makeup, expressing its unique set of tumor-associated antigens as well as antigenic elements from the surrounding stroma. These autologous tumor characteristics are usually presented with an immune adjuvant in the hopes of enhancing an immune response. Methods. The autologous vaccine we used was composed of tumor cells combined with BCG and formalin. Animal safety and toxicity were evaluated using mice tumors for the immunotherapy. A small number of patients with advanced stage breast cancer were recruited for an uncontrolled study, using the vaccine solely or combined with chemotherapy/radiotherapy. Results. The immunotherapy had shown to be safe in mice and humans. Upon a 5-year follow-up, the survival rate was 60 % for the combined treatment. Conclusions. The data suggest that the combined treatment could be a feasible and safe therapeutic strategy. However, further controlled studies should be conducted (AU)

No disponible

Autologous tumor lysate/Bacillus Calmette-Guérin immunotherapy as an adjuvant to conventional breast cancer therapy.

INTRODUCTION: Autologous tumor cell vaccines rely on the concept of preserving an individual's own tumorigenic makeup, expressing its unique set of tumor-associated antigens as well as antigenic elements from the surrounding stroma. These autologous tumor characteristics are usually presented with an immune adjuvant in the hopes of enhancing an immune response. METHODS: The autologous vaccine we used was composed of tumor cells combined with BCG and formalin. Animal safety and toxicity were evaluated using mice tumors for the immunotherapy. A small number of patients with advanced stage breast cancer were recruited for an uncontrolled study, using the vaccine solely or combined with chemotherapy/radiotherapy. RESULTS: The immunotherapy had shown to be safe in mice and humans. Upon a 5-year follow-up, the survival rate was 60 % for the combined treatment. CONCLUSIONS: The data suggest that the combined treatment could be a feasible and safe therapeutic strategy. However, further controlled studies should be conducted.

Cerebral white matter and retinal arterial health in hypertension and type 2 diabetes mellitus.

We examined 33 hypertensive (22 with comorbid type 2 diabetes mellitus (T2DM)) and 29 normotensive (8 with T2DM) middle-aged and elderly adults, comparable in age and education. Relative to normotensive participants, those with hypertension, in addition to a higher prevalence of periventricular white matter (WM) lesions, had significantly lower WM microstructural integrity of major fiber tracts as seen with MRI-based diffusion tensor imaging. Among participants with hypertension, those with co-morbid T2DM (n = 22) had more widespread WM pathology than those without T2DM (n = 11). Furthermore and consistent with previous research, both hypertension and T2DM were related to decreased retinal arterial diameter. Further exploratory analysis demonstrated that the observed retinal arteriolar narrowing among individual with hypertension was associated with widespread subclinical losses in WM microstructural integrity and these associations were present predominantly in the frontal lobe. We found that T2DM adds to the damaging effects of hypertension on cerebral WM, and notably these effects were independent of age and body mass index. Given that the decrease in retinal arteriolar diameter may be a biomarker for parallel pathology in cerebral arterioles, our data suggest that the frontal lobe may be particularly vulnerable to microvascular damage in the presence of hypertension and T2DM.

Systematic differences between lean and obese adolescents in brain spin-lattice relaxation time: a quantitative study.

BACKGROUND AND PURPOSE: Emerging evidence suggests that obese adolescents show changes in brain structure compared with lean adolescents. In addition, obesity impacts body development during adolescence. We tested a hypothesis that T1, a marker of brain maturation, can show brain differences associated with obesity. MATERIALS AND METHODS: Adolescents similar in sex, family income, and school grade were recruited by using strict entry criteria. We measured brain T1 in 48 obese and 31 lean adolescents by quantitative MR imaging at 1.5T. We combined MPRAGE and inversion-recovery sequences with normalization to standard space and automated skull stripping to obtain T1 maps with a symmetric voxel volume of 1 mm(3). RESULTS: Sex, income, triglycerides, total cholesterol, and fasting glucose did not differ between groups, but obese adolescents had significantly lower HDL, higher LDL, and higher fasting insulin levels than lean adolescents. Intracranial vault volume did not differ between groups, but obese adolescents had smaller intracranial vault-adjusted brain parenchymal volumes. Obese adolescents had 4 clusters (>100 contiguous voxels) of T1 relaxation that were significantly different (P < .005) from those in lean adolescents. Three of these clusters had longer T1s in obese adolescents (in the orbitofrontal and parietal regions), and 1 cluster had shorter T1s, compared with lean adolescents. CONCLUSIONS: Our results suggest that obesity may have a significant impact on brain development, especially in the frontal and parietal lobes. It is unclear if these changes persist into adulthood or whether they indicate that obese subjects follow a different developmental trajectory during adolescence.

Abnormal Cholesterol is Associated with Prefrontal White Matter Abnormalities among Obese Adults: a Diffusion Tensor Imaging Study.

The brain is the most cholesterol-rich organ in the body. Although most of the cholesterol in the brain is produced endogenously, some studies suggest that systemic cholesterol may be able to enter the brain. We investigated whether abnormal cholesterol profiles correlated with diffusion-tensor-imaging-based estimates of white matter microstructural integrity of lean and overweight/obese (o/o) adults. Twenty-two lean and 39 obese adults underwent magnetic resonance imaging, kept a three-day food diary, and had a standardized assessment of fasting blood lipids. The lean group ate less cholesterol-rich food than o/o although both groups ate equivalent servings of food per day. Voxelwise correlational analyses controlling for age, diabetes, and white matter hyperintensities, resulted in two significant clusters of negative associations between abnormal cholesterol profile and fractional anisotropy, located in the left and right prefrontal lobes. When the groups were split, the lean subjects showed no associations, whereas the o/o group expanded the association to three significant clusters, still in the frontal lobes. These findings suggest that cholesterol profile abnormalities may explain some of the reductions in white matter microstructural integrity that are reported in obesity.

Preliminary evidence for brain complications in obese adolescents with type 2 diabetes mellitus.

AIMS/HYPOTHESIS: Central nervous system abnormalities, including cognitive and brain impairments, have been documented in adults with type 2 diabetes who also have multiple co-morbid disorders that could contribute to these observations. Assessing adolescents with type 2 diabetes will allow the evaluation of whether diabetes per se may adversely affect brain function and structure years before clinically significant vascular disease develops. METHODS: Eighteen obese adolescents with type 2 diabetes and 18 obese controls without evidence of marked insulin resistance, matched on age, sex, school grade, ethnicity, socioeconomic status, body mass index and waist circumference, completed MRI and neuropsychological evaluations. RESULTS: Adolescents with type 2 diabetes performed consistently worse in all cognitive domains assessed, with the difference reaching statistical significance for estimated intellectual functioning, verbal memory and psychomotor efficiency. There were statistical trends for executive function, reading and spelling. MRI-based automated brain structural analyses revealed both reduced white matter volume and enlarged cerebrospinal fluid space in the whole brain and the frontal lobe in particular, but there was no obvious grey matter volume reduction. In addition, assessments using diffusion tensor imaging revealed reduced white and grey matter microstructural integrity. CONCLUSIONS/INTERPRETATION: This is the first report documenting possible brain abnormalities among obese adolescents with type 2 diabetes relative to obese adolescent controls. These abnormalities are not likely to result from education or socioeconomic bias and may result from a combination of subtle vascular changes, glucose and lipid metabolism abnormalities and subtle differences in adiposity in the absence of clinically significant vascular disease. Future efforts are needed to elucidate the underlying pathophysiological mechanisms.

Cognitive impairment in nondiabetic middle-aged and older adults is associated with insulin resistance.

To determine whether the cognitive impairments observed in adults with type 2 diabetes mellitus (T2DM) exist in preclinical disease, we compared 38 adult participants with evidence of insulin resistance (IR) to 54 age-, gender-, and education-matched control participants on a battery of neuropsychological tests. We found that participants with IR had performance reductions in declarative memory and executive functioning. When we examined IR simultaneously with other biomedical indicators with which it co-occurs, only IR itself was associated with declarative memory, and hemoglobin A1c (HbA1c) was associated with executive functioning and working memory. We conclude that individuals with insulin resistance already demonstrate similar reductions in cognitive performance as those described in T2DM.

C-reactive protein is linked to lower cognitive performance in overweight and obese women.

Our objective was to ascertain the nature of the associations between C-reactive protein (CRP) and cognition, and to examine how they are affected by gender and obesity. We evaluated 62 females and 63 males between 42 and 82 years of age. There were 20 lean females with a body mass index (BMI) of <25 kg/m2 and 42 overweight or obese females, with BMIs > or =25 kg/m2. There were 14 lean males and 49 with BMIs >/=25 kg/m2. CRP was associated with lower scores on cognitive tests of frontal lobe function among females and these associations were driven by the overweight/obese female group. In these data no associations between CRP and cognition were found among males. Obesity-associated inflammation is much more prominent in females and it appears to be associated with cognitive dysfunction, particularly of frontal lobe tasks.

Hippocampal damage and memory impairments as possible early brain complications of type 2 diabetes.

AIMS/HYPOTHESIS: There is evidence that type 2 diabetes mellitus is associated with cognitive impairment. Most studies investigating this association have evaluated elderly individuals, after many years of diabetes, who generally have poor glycaemic control and significant vascular disease. The aim of the current study was to investigate the early cognitive consequences and associated brain correlates of type 2 diabetes. MATERIALS AND METHODS: With regard to cognition and brain measures, we compared 23 age-, sex- and education-matched control subjects with 23 mostly middle-aged individuals with relatively well-controlled diabetes of less than 10 years from the time of diagnosis. RESULTS: We found deficits in hippocampal-based memory performance and preservation of other cognitive domains. Relative to control subjects, individuals with diabetes had reductions in brain volumes that were restricted to the hippocampus. There was an inverse relationship between glycaemic control and hippocampal volume; in multivariate regression analysis, HbA(1c) was the only significant predictor of hippocampal volume, accounting for 33% of the observed variance. Other variables commonly associated with type 2 diabetes, such as elevated BMI, hypertension or dyslipidaemia, did not independently contribute to the variance in hippocampal volume. CONCLUSIONS/INTERPRETATION: These results suggest that the medial temporal lobe may be the first brain site affected by type 2 diabetes and that individuals in poorer metabolic control may be affected to a greater extent.