Differential presentation of hypersensitivity reactions to carboplatin and oxaliplatin: Phenotypes, endotypes, and management with desensitization.

BACKGROUND: Drug hypersensitivity reactions (DHRs) to platinum-based drugs are heterogenous and restrict their access, and drug desensitization (DD) has provided a ground-breaking procedure for their re-introduction, although the response is heterogeneous. We aimed to identify the phenotypes, endotypes, and biomarkers of reactions to carboplatin and oxaliplatin and their response to DD. METHODS: Seventy-nine patients presenting with DHRs to oxaliplatin (N = 46) and carboplatin (N = 33) were evaluated at the Allergy Departments of two tertiary care hospitals in Spain. Patient symptoms, skin testing, biomarkers, and outcomes of 267 DDs were retrospectively analyzed. RESULTS: Oxaliplatin-reactive patients presented with type I (74%), cytokine release reaction (CRR) (11%), and mixed (Mx) (15%) phenotypes. In contrast, carboplatin reactive patients presented with predominantly type I (85%) and Mx (15%) but no CRRs. Out of 267 DDs, breakthrough reactions (BTRs) to oxaliplatin occurred twice as frequently as carboplatin (32% vs. 15%; p < .05). Phenotype switching from type I to another phenotype was observed in 46% of oxaliplatin DDs compared to 21% of carboplatin DDs. Tryptase was elevated in type I and Mx reactions, and IL-6 in CRR and Mx, indicating different mechanisms and endotypes. CONCLUSION: Carboplatin and oxaliplatin induced three different types of reactions with defined phenotypes and endotypes amendable to DD. Although most of the initial reactions for both were type I, oxaliplatin presented with unique CRR reactions. During DD, carboplatin reactive patients presented mostly type I BTR, while oxaliplatin-reactive patients frequently switched from type I to CRR, providing a critical difference and the need for personalized DD protocols.

Skin Testing With Peach Peel Extract Versus Serum IgE to Pru p 3 as a Stronger Predictor of Peach-Induced Anaphylaxis.

The most important peach fruit allergen is Pru p 3, followed by Pru p 1, Pru p 4, and Pru p 7. We aimed to assess their role in subjects with peach fruit-induced allergy (anaphylaxis and OAS) and compare skin prick tests (SPT) vs. specific immunoglobulin E (sIgE) for predicting anaphylaxis. We also selected a control group. SPT included prevalent inhalant and plant food allergens plus peach peel extract. The sIgE to Pru p 1, Pru p 3, Pru p 4, and Pru p 7 were quantified. Compared with controls (n = 42), cases (n = 41) were younger (P = 0.003), more frequently female (P < 0.05) and had higher SPT positivity to peach peel (44% vs. 2.4%, P < 0.0001). There were significant differences in sensitization to several pollens: Olea europaea, Artemisia vulgaris, Prunus persica, Platanus acerifolia (all P < 0.001); and fruits: apple (P < 0.04), peanut (P < 0.002), tomato (P < 0.005), and melon (P < 0.05). Pru p 3 sIgE was detected in 61% of all cases (85% anaphylaxis and 38% OAS; P < 0.01 each) and 5% of controls (P < 0.001). Pru p 4 sIgE was present in 19% of cases and 7% of controls. The sIgE to Pru p 1 and Pru p 7 were not found. The odds ratio to predict anaphylaxis for peach peel SPT was 113 (confidence interval [CI], 20-613; P < 0.0001); for sIgE to Pru p 3, 22 (CI, 5.3-93; P < 0.0001); and for SPT positivity to selected plant food allergens, 5 (CI, 1-19; P < 0.05). In our study group, SPT with peel peach extract was a better predictor of anaphylaxis than Pru p 3 sIgE or other variables considered. The role of sIgE to Pru p 1, Pru p 4, and Pru p 7 seemed negligible.

Subjects develop tolerance to Pru p 3 but respiratory allergy to Pru p 9: A large study group from a peach exposed population.

Peach tree allergens are present in fruit, pollen, branches, and leaves, and can induce systemic, respiratory, cutaneous, and gastrointestinal symptoms. We studied the capacity of peach fruit/Pru p 1, Pru p 3, Pru p 4, Pru p 7 and peach pollen/Pru p 9 for inducing symptoms following oral or respiratory exposure in a large group of subjects. We included 716 adults (aged 21 to 83 y.o.) exposed to peach tree pollen and fruit intake in the study population. Participants completed a questionnaire and were skin tested with a panel of inhalant and food allergens, including peach tree pollen, Pru p 9 and peach fruit skin extract. Immunoglobulin E antibodies (SIgE) to Pru p 1, Pru p 3, Pru p 4 and Pru p 7 were quantified. Sensitised subjects underwent oral food challenge with peach fruit and nasal provocation test with peach tree pollen and Pru p 9. The prevalence of sensitisation to peach fruit was 5% and most of these had SIgE to Pru p 3, with a very low proportion to Pru p 4 SIgE and no SIgE to Pru p 1 and Pru p 7. In only 1.8%, anaphylaxis was the clinical entity induced. Cases with positive skin tests to peach and SIgE to Pru p 3 presented a good tolerance after oral challenge with peach fruit. The prevalence of skin sensitisation to peach tree pollen was 22%, with almost half recognising Pru p 9. This induced respiratory symptoms in those evaluated by nasal provocation. In a large population group exposed to peach fruit and peach tree pollen, most individuals were tolerant, even in those with SIgE to Pru p 3. A positive response to Pru p 9 was associated with respiratory allergy.

[Similarities and differences among patients with symptomatic atherosclerosis affecting several territories. The AIRVAG cohort (Integral Attention to Global VAscular Risk)]. / Similitudes y diferencias entre los pacientes con aterosclerosis sintomática de distintos territorios. Cohorte AIRVAG (Atención Integral al Riesgo VAscular Global).

BACKGROUND AND OBJECTIVE: Even though atherosclerosis is a systemic disease, few prospective studies have evaluated in a thorough and systematic manner the whole vascular tree in patients with clinical damage of different territories. PATIENTS AND METHOD: Prospective protocolized study of 269 consecutive patients younger than 70, attended because of symptomatic arteriosclerosis of any territory -53% coronary (CHD), 32% cerebrovascular (CVD), 15% peripheral (PVD)-. Patients underwent evaluation of risk factors and their control, systematic non-invasive study of the vascular tree (Doppler-ultrasound) and comparison between groups according to the index territory. RESULTS: Even though all risk factors were represented in the 3 groups, male sex, smoking and diabetes were more frequent in PVD and dyslipemia was more common in CHD (p < 0.05) Abdominal aortic diameter and carotid intima-media thickness were similar for all groups, while the number of carotid plaques was higher in PVD. CHD patients more often presented left ventricular hypertrophy and reduced ejection fraction. PVD patients showed a marked reduction of the ankle-brachial index as well as increased C-reactive protein and homocysteine (p < 0.05). Severe unsuspected vascular lesions were found in 13% of cases (95% confidence interval, 9.5-17.6%). Risk factor control was better for CHD, followed by CVD and PVD, but was globally poor. CONCLUSIONS: The systematic evaluation of the vascular tree detects generalized atherosclerotic lesions, in some cases severe and clinically unsuspected. New markers to identify patients at very high risk are necessary. Peripheral vascular disease identifies a group of patients of particular risk. Risk factor control is deficient, particularly among PVD patients.

Endocannabinoid regulation of amyloid-induced neuroinflammation.

The modulation of endocannabinoid (EC) levels and the activation of cannabinoid receptors are seen as promising therapeutic strategies in a variety of diseases, including Alzheimer's disease (AD). We aimed to evaluate the effect of the pharmacologic and genetic inhibition of anandamide-degrading enzyme in a mouse model of AD (5xFAD). Pharmacologic inhibition of the fatty acid amide hydrolase (FAAH) had little impact on the expression of key enzymes and cytokines and also on the cognitive impairment, plaque deposition, and gliosis in 5xFAD mice. CB1 blockade exacerbated inflammation in this transgenic mouse model of AD. The genetic inactivation of FAAH led to increases in the expression of inflammatory cytokines. At the same time, FAAH-null 5xFAD mice exhibited a behavioral improvement in spatial memory that was independent of the level of anxiety and was not CB1 mediated. Finally, mice lacking FAAH showed diminished soluble amyloid levels, neuritic plaques, and gliosis. These data reinforce the notion of a role for the EC system in neuroinflammation and open new perspectives on the relevance of modulating EC levels in the inflamed brain.

ß-Amyloid exacerbates inflammation in astrocytes lacking fatty acid amide hydrolase through a mechanism involving PPAR-α, PPAR-γ and TRPV1, but not CB1 or CB2 receptors.

BACKGROUND AND PURPOSE: The endocannabinoid system may regulate glial cell functions and their responses to pathological stimuli, specifically, Alzheimer's disease. One experimental approach is the enhancement of endocannabinoid tone by blocking the activity of degradative enzymes, such as fatty acid amide hydrolase (FAAH). EXPERIMENTAL APPROACH: We examined the role of FAAH in the response of astrocytes to the pathologic form of ß-amyloid (Aß). Astrocytes from wild-type mice (WT) and from mice lacking FAAH (FAAH-KO) were incubated with Aß for 8, 24 and 48 h, and their inflammatory responses were quantified by elisa, western-blotting and real-time quantitative-PCR. KEY RESULTS: FAAH-KO astrocytes were significantly more responsive to Aß than WT astrocytes, as shown by the higher production of pro-inflammatory cytokines. Expression of COX-2, inducible NOS and TNF-α was also increased in Aß-exposed KO astrocytes compared with that in WTs. These effects were accompanied by a differential pattern of activation of signalling cascades involved in mediating inflammatory responses, such as ERK1/2, p38MAPK and NFκB. PPAR-α and PPAR-γ as well as transient receptor potential vanilloid-1 (TRPV1), but not cannabinoid CB1 or CB2 receptors, mediate some of the differential changes observed in Aß-exposed FAAH-KO astrocytes. The pharmacological blockade of FAAH did not render astrocytes more sensitive to Aß. In contrast, exogenous addition of several acylethanolamides (anandamide, palmitoylethanolamide and oleoylethanolamide) induced an antiinflammatory response. CONCLUSIONS: The genetic deletion of FAAH in astrocytes exacerbated their inflammatory phenotype against Aß in a process involving PPAR-α, PPAR-γ and TRPV1 receptors.

Similitudes y diferencias entre los pacientes con aterosclerosis sintomática de distintos territorios. Cohorte AIRVAG (Atención Integral al Riesgo Vascular Global) / Similarities and differences among patients with symptomatic atherosclerosis affecting several territories. The AIRVAG cohort (Integral Attention to Global Vascular Risk)

Fundamento y objetivo: Aunque la aterosclerosis es una enfermedad generalizada del árbol vascular, existen escasos estudios prospectivos que evalúen transversalmente de modo extenso a pacientes con afectación clínica de diferentes territorios. Pacientes y método: Se ha realizado un estudio prospectivo protocolizado de 269 pacientes consecutivos menores de 70 años atendidos por aterosclerosis sintomática de cualquier territorio ­en un 53% coronario (CI), en un 32% cerebral (VC) y en un 15% periférico (VP)­. Se evaluaron los factores de riesgo y su control, y se realizó un estudio sistemático no invasivo del árbol vascular (ecografía Doppler) con una comparación entre los grupos según el territorio índice. Resultados: Aunque todos los factores de riesgo estaban representados en los 3 grupos, el sexo masculino, el tabaquismo y la diabetes fueron más frecuentes en VP y la dislipemia en CI (p < 0,05). El diámetro de la aorta abdominal y el grosor carotídeo mediointimal fueron similares en los 3 grupos, si bien el número de placas carotídeas fue superior en VP. CI presentó más frecuentemente hipertrofia ventricular y disminución de la fracción de eyección. VP presentó un índice tobillo-brazo notablemente inferior, junto con valores más elevados de proteína C reactiva y homocisteína (p < 0,05). Se descubrieron lesiones vasculares graves no sospechadas en un 13% de los pacientes (intervalo de confianza del 95%, 9,5-17,6%). El control de los factores de riesgo fue mejor en CI, seguido por VC y VP, si bien globalmente fue deficiente. Conclusiones: El estudio sistemático del árbol vascular detecta lesiones aterosclerosas generalizadas, no sospechadas clínicamente, en algunos casos graves. Son necesarios marcadores que permitan identificar a los pacientes de muy alto riesgo. La enfermedad vascular periférica identifica a un grupo de pacientes de especial riesgo vascular. El grado de control de los factores de riesgo es deficiente, especialmente en VP

Background and objective: Even though atherosclerosis is a systemic disease, few prospective studies have evaluated in a thorough and systematic manner the whole vascular tree in patients with clinical damage of different territories. Patients and method: Prospective protocolized study of 269 consecutive patients younger than 70, attended because of symptomatic arteriosclerosis of any territory ­53% coronary (CHD), 32% cerebrovascular (CVD), 15% peripheral (PVD)­. Patients underwent evaluation of risk factors and their control, systematic non-invasive study of the vascular tree (Doppler-ultrasound) and comparison between groups according to the index territory. Results: Even though all risk factors were represented in the 3 groups, male sex, smoking and diabetes were more frequent in PVD and dyslipemia was more common in CHD (p < 0.05) Abdominal aortic diameter and carotid intima-media thickness were similar for all groups, while the number of carotid plaques was higher in PVD. CHD patients more often presented left ventricular hypertrophy and reduced ejection fraction. PVD patients showed a marked reduction of the ankle-brachial index as well as increased C-reactive protein and homocysteine (p < 0.05). Severe unsuspected vascular lesions were found in 13% of cases (95% confidence interval, 9.5-17.6%). Risk factor control was better for CHD, followed by CVD and PVD, but was globally poor. Conclusions: The systematic evaluation of the vascular tree detects generalized atherosclerotic lesions, in some cases severe and clinically unsuspected. New markers to identify patients at very high risk are necessary. Peripheral vascular disease identifies a group of patients of particular risk. Risk factor control is deficient, particularly among PVD patients