The REWRITE Study - REal-WoRld effectIveness of TrifluridinE/tipiracil in Patients with Previously Treated Metastatic Colorectal Cancer.

AIMS: In the pivotal RECOURSE trial, trifluridine/tipiracil improved survival outcomes in refractory metastatic colorectal cancer (mCRC), while demonstrating an acceptable toxicity profile. Routine clinical practice evidence is important to support the ongoing value of recently approved medicines. Our objective was to assess the utilisation patterns and real-world effectiveness of trifluridine/tipiracil in previously treated mCRC patients. MATERIALS AND METHODS: This was a retrospective observational study including consecutive patients who started trifluridine/tipiracil between 1 April 2018 and 30 September 2019 in the medical oncology departments of three major public hospitals in Portugal. The primary outcome measure was overall survival. Associations between overall survival and patient and tumour characteristics were assessed using multivariate Cox regression analyses. RESULTS: In total, 111 patients were included in the study, with a mean age of 64 years. From these, 45.9% received two prior lines of treatment, 47.8% had three or more previous lines of treatment and 83.6% had Eastern Cooperative Oncology Group (ECOG) performance status 0-1 at baseline. The median duration of trifluridine/tipiracil treatment was 3.7 cycles (95% confidence interval 3.4-4.1). Most patients (80.4%) remained on their planned dose throughout the trifluridine/tipiracil treatment period, fulfilling 100% relative dose intensity. The median overall survival in the total study cohort was 7.9 months (95% confidence interval 6.4-9.8) and the median progression-free survival was 3.4 months (95% confidence interval 3.2-3.9). The median overall survival was significantly higher in patients with a normal serum lactate dehydrogenase (LDH) level (median overall survival 11.2 months for [135, 205] IU/l LDH [95% confidence interval 8.2-NR] and 13.6 months for [205, 251] IU/l LDH [95% confidence interval 8.2-NR]) and in better fitted (ECOG = 0-1) patients (median overall survival 8.0 months; 95% confidence interval 6.7-10.0). The median time to worsening performance status was 6.2 months (95% confidence interval 5.0-8.0). Treatment discontinuation due to adverse events was low (3.1%). CONCLUSION: Our study confirms the effectiveness of trifluridine/tipiracil in real-life mCRC patients. Overall survival and progression-free survival outcomes are consistent with the efficacy profile reported in the earlier randomised RECOURSE clinical trial. Like other real-world studies, we found no additional safety concerns in the use of trifluridine/tipiracil.

Der p 23 sensitisation in patients with house dust mite respiratory allergy.

Summary: Background. The sensitization profile of patients allergic to house dust mites (HDM) and its molecular diagnosis may determine treatment and evolution of the disease. The present study investigates the prevalence of Der p 23 sensitization and its relation to asthma in a population of HDM-allergic patients. Methods. We conducted a cross-sectional study of 891 patients with HDM allergy with symptoms of rhinitis and 52.1% of them with asthma. Total and specific IgE (sIgE) was measured against Dermatophagoides pteronyssinus and its molecular components (Der p 1, Der p 2 and Der p 23) and the storage mite Lepidoglyphus destructor using ImmunoCAP. Prevalence of sensitization and levels of sIgE were analysed according to asthma diagnosis and asthma severity. Results. Der p 23 was the predominant allergen in this population (83.7%) but IgE levels were lower than those of sIgE to Der p 1 and Der p 2. A good correlation was found between sIgE to Der p 23 and the other allergens. A total of 8.2% patients were monosensitized to Der p 23. Asthma was more frequent in patients with positive sIgE against Der p 23 than in patients without this sensitization (52.8% vs 42.8%, p = 0.027). A tendency to increase both total IgE and sIgE was observed in relation to the severity of asthma from intermittent mild asthma to persistent moderate asthma but a substantial decrease in total IgE and sIgE was detected in more severe asthmatics. Conclusions. Der p 23 might be a prevalent allergen in regions with high rates of HDM exposure. Even though sIgE levels against this allergen are usually low, its presence could increase the risk of asthma.

Pterostilbene modifies triglyceride metabolism in hepatic steatosis induced by high-fat high-fructose feeding: a comparison with its analog resveratrol.

The use of phenolic compounds as a new therapeutic approach against NAFLD has emerged recently. In the present study, we aim to study the effect of pterostilbene in the prevention of liver steatosis developed as a consequence of high-fat (saturated) high-fructose feeding, by analysing the changes induced in metabolic pathways involved in triglyceride accumulation. Interestingly, a comparison with the anti-steatotic effect of its parent compound resveratrol will be made for the first time. Rats were distributed into 5 experimental groups and fed either a standard laboratory diet or a high-fat high-fructose diet supplemented with or without pterostilbene (15 or 30 mg per kg per d) or resveratrol (30 mg per kg per d) for 8 weeks. Serum triglyceride, cholesterol, NEFA and transaminase levels were quantified. Liver histological analysis was carried out by haematoxylin-eosin staining. Different pathways involved in liver triglyceride metabolism, including fatty acid synthesis, uptake and oxidation, triglyceride assembly and triglyceride release, were studied. Pterostilbene was shown to partially prevent high-fat high-fructose feeding induced liver steatosis in rats, demonstrating a dose-response pattern. In this dietary model, it acts mainly by reducing de novo lipogenesis and increasing triglyceride assembly and release. Improvement in mitochondrial functionality was also appreciated. At the same dose, the magnitude of pterostilbene and resveratrol induced effects, as well as the involved mechanisms of action, were similar.

Immunoglobulin G4-Related Disease: What an Allergist Should Know.

Immunoglobulin G4-related disease (IgG4-RD) is a fibroinflammatory disorder that begins in 1 or more organs as inflammatory tumors that progress toward fibrosis. It is often accompanied by elevated serum IgG4. IgG4-RD was first described in 2003 as a new concept encompassing a number of immunoallergic diseases that had previously been considered unrelated. IgG4-RD mainly affects middleaged and older men. It consists of upregulation and expansion of CD4+ cytotoxic T lymphocytes, oligoclonal plasmablasts, and other inflammatory cells that infiltrate affected tissues and induce inflammation, organ dysfunction, and fibrosis. Symptoms depend on the location, severity, and extent of the disease. Virtually any organ can be affected, including the pancreas, salivary glands, lacrimal glands, thyroid gland, retro-orbital tissue, lymph nodes, retroperitoneum, mediastinum, lung, kidney, aorta, serosal surfaces, and meninges. Patients with widespread disease may present general symptoms. At least 30%-40% of patients are atopic or display atopic traits such as eosinophilia and elevated serum IgE levels. Additional laboratory features include increased serum IgG4 concentrations, increased blood IgG4-plasmablasts, hypergammaglobulinemia, and hypocomplementemia. Diagnosis of IgG4-RD is based on a clinicopathological correlation. Lymphoplasmacytic infiltrate with abundant IgG4-positive plasma cells, storiform-type fibrosis, obliterative phlebitis, and tissue eosinophilia are the pathological hallmarks. Therapy for IgG4-RD is based primarily on corticosteroids but may include additional immunomodulatory drugs and monoclonal antibodies such as rituximab. In individuals with allergic features, IgG4-RD should be suspected when a history of unexplained swelling is observed in 1 or more organs, particularly if they respond to corticosteroids and the patients are men in the sixth decade of life and beyond.

Anaphylaxis to Vespa velutina nigrithorax: Pattern of Sensitization for an Emerging Problem in Western Countries.

OBJECTIVE: To define the sensitization pattern of patients with anaphylaxis to Vespa velutina nigrithorax (VVN). METHODS: We studied 100 consecutive Spanish patients with anaphylaxis to Hymenoptera venom and systematically determined specific IgE (sIgE) to whole venoms (Vespula species, Polistes dominula, Apis mellifera, Vespa crabro, and Dolichovespula maculata) and their molecular components (rApi m 1, rApi m 5, rApi m 10, rVes v 1, rVes v 5, rPol d 5, and cross-reactive carbohydrates). Specific IgE to VVN venom and its antigen 5 (nVesp v 5) were measured in a subsample. RESULTS: Seventy-seven patients had anaphylaxis to VVN. Of these, only 16 (20.8%) reported previous VVN stings, but were stung by other Hymenoptera. Positive sIgE (>0.35 kUA/L) to each of the whole venoms was detected in >70% of patients (Vespula species in 100%). The components showing >50% positivity were rApi m 5 (51.4%), rPol d 5 (80.0%), and rVes v 5 (98.7%). This pattern was similar to that of Vespula species anaphylaxis (n=11) but different from that of A mellifera anaphylaxis (n=10). Specific IgE to nVesp v 5 was positive in all patients (n=15) with VVN anaphylaxis and was correlated with sIgE to both rVes v 5 (R=0.931) and rPol d 5 (R=0.887). CONCLUSIONS: VVN has become the commonest cause of Hymenoptera anaphylaxis in our area. Most cases report no previous VVN stings. Their sensitization pattern is similar to that of patients with anaphylaxis to other Vespidae. Specific IgE to antigen-5 from VVN, Vespula species, and P dominula are strongly correlated in patients with VVN anaphylaxis.

Effects of resveratrol and its derivative pterostilbene on brown adipose tissue thermogenic activation and on white adipose tissue browning process.

The main function of brown adipose tissue (BAT) is thermogenesis, a process mediated by uncoupling protein 1 (UCP1), which is located in the inner mitochondrial membrane and acts uncoupling oxidative phosphorylation from ATP production, thereby dissipating energy as heat. White adipose tissue can also express UCP1 positive cells due to a process known as browning. This phenomenon could also increase the thermogenic effect in the classical brown adipose depots. BAT thermogenesis depends, among other factors on both, nutritional conditions and food availability. Indeed, some studies have found that BAT recruitment and function are enhanced by some food components. The present study focuses on the effects of resveratrol and pterostilbene, two phenolic compounds belonging to the stilbene group, on BAT thermogenic activation and white adipose tissue browning process. The reported studies, carried out in cell cultures and animal models, show that both resveratrol and pterostilbene induce thermogenic capacity in interscapular BAT by increasing mitochondriogenesis, as well as enhancing fatty acid oxidation and glucose disposal. In addition, resveratrol seems to promote browning by activating peroxisome proliferator-activated receptor (PPAR), while the lack of changes in mitochondrial biogenesis suggests that probably the browning process occurs by direct resveratrol-mediated upregulation of ucp1 mRNA expression.

Assessing the relationship between markers of glycemic control through flexible copula regression models.

Glycated haemoglobin (HbA1c) is a sensitive marker of blood glucose in patients with diabetes. However, levels can vary considerably, even amongst individuals with similar mean blood glucose concentrations. Other glycated proteins, such as fructosamine, can also act as blood sugar markers, but estimating HbA1c and fructosamine via independent models may lead to errors of interpretation regarding disease severity. From a clinical standpoint, it would be of great interest to know the factors that affect the mean concentration of both HbA1c and fructosamine, which influence the variability in the concentrations of these glycated markers and cause HbA1c/fructosamine discordance. Flexible models are required to illustrate the behaviour of these variables as well as the association between them. This work reviews existing models that might serve in this regard. Flexible copula regression models using splines were used to provide a better understanding of the behaviour of both glycated proteins and the relationship between them under the possible influence of different covariates. This work shows the usefulness of this type of models in practise and provides a basis for their clinical interpretation by means of an understandable case study. Ultimately, to better understand the effects of each continuous covariate, they are represented at the true scale of the response variables.

False-Positive Results of Serological Tests for Allergy in Alcoholic Patients.

BACKGROUND AND OBJECTIVE: Alcohol consumption is associated with enhanced TH2 immune responses. Objective: To investigate the frequency of false-positive results in serological tests for allergy in alcoholic patients. METHODS: A total of 138 alcoholic patients consecutively admitted to hospital underwent a panel of allergy tests that included serum total IgE, a multiallergen IgE test (UniCAP Phadiatop), and skin prick tests to relevant aeroallergens in the area, which were considered the standard reference for atopy. In selected cases with positive specific IgE (sIgE) to cross-reactive carbohydrate determinants (CCDs) on ImmunoCAP, we determined sIgE to hymenoptera venom components (ADVIA Centaur) and a microarray of 103 allergen components (ISAC). RESULTS: Increased serum total IgE (>170 IU/mL) was observed in 59/110 (54%) of nonatopic (skin prick test-negative) patients. The result of the multiallergen IgE test was positive in 46 nonatopic patients (42%). This finding was closely associated with high serum concentrations of total IgE and sIgE to CCDs. The vast majority of patients with positive CCD-sIgE showed positivity to glycosylated plant and hymenoptera allergen components on ISAC and ADVIA Centaur. Only 1 out of 26 patients with positive sIgE to CCD and hymenoptera venom developed honeybee venom allergy after a median follow-up of 166 months. Correlations between measurements of sIgE to CCD markers on ImmunoCAP, ADVIA Centaur, and ISAC were imperfect. CONCLUSIONS: Serological tests for allergy should be interpreted with caution in alcoholic patients, who frequently have increased levels of total IgE and CCD-sIgE and subsequent positivity of sIgE to glycosylated allergen components, irrespective of the method used.

Beyond second-line therapy in patients with metastatic colorectal cancer: a systematic review.

Background: The optimal chemotherapeutic regimen for use beyond the second line for patients with metastatic colorectal cancer (mCRC) remains unclear. Materials and methods: We systematically searched the Cochrane Database of Systematic Reviews, EMBASE and Medline for records published between January 2002 and May 2017, and cancer congress databases for records published between January 2014 and June 2017. Eligible studies evaluated the efficacy, safety and patient-reported outcomes of monotherapies or combination therapies at any dose and number of treatment cycles for use beyond the second line in patients with mCRC. Studies were assessed for design and quality, and a qualitative data synthesis was conducted to understand the impact of treatment on overall survival and other relevant cancer-related outcomes. Results: The search yielded 938 references of which 68 were included for qualitative synthesis. There was limited evidence to support rechallenge with chemotherapy, targeted therapy or both. Compared with placebo, an overall survival benefit for trifluridine/tipiracil (also known as TAS-102) or regorafenib has been shown for patients previously treated with conventional chemotherapy and targeted therapy. There was no evidence to suggest a difference in efficacy between these treatments. Patient choice and quality of life at this stage of treatment should also be considered when choosing an appropriate therapy. Conclusions: These findings support the introduction of an approved agent such as trifluridine/tipiracil or regorafenib beyond the second line before any rechallenge in patients with mCRC who have failed second-line treatment.

Factors Influencing Serum Concentrations of Immunoglobulin D in the Adult Population: An Observational Study in Spain.

Immunoglobulin D (IgD) is the least studied of immunoglobulin classes. This study sought to investigate the potential relationship between demographic, metabolic, lifestyle and immunological factors, and serum IgD concentrations in a general adult population. We measured serum IgD concentrations by means of a commercial turbidimetric assay in 413 individuals (median age, 55 years; 45% males), randomly selected from the adult population of a Spanish municipality. Serum IgD concentrations displayed considerable variation in the population, ranging from undetectable (<6.7 mg/l) to 878 mg/l. Serum IgD concentrations were undetectable in 78 cases (18.9%) and >100 mg/l in 39 cases (9.4%). Median IgD was 21.9 mg/l. Serum IgD concentrations were negatively associated with age and positively associated with smoking, after adjustment for potential confounders. Overweight individuals showed lower concentrations of IgD than did normal-weight individuals. Atopy (positivity of skin tests to aeroallergens) was not significantly associated with IgD concentrations, although non-symptomatic atopics showed higher IgD concentrations. No consistent association was observed between serum IgD concentrations and gender, metabolic syndrome, or alcohol consumption. No significant association was found between baseline IgD concentrations and development of either allergic or immune disease after a median 11.4 years of follow-up. In conclusion, serum IgD concentrations in adults show a wide variation in the population and may be influenced by common factors, particularly age and smoking habit. These factors should be taken into account when defining reference ranges for serum IgD concentrations.

Association Between Asthma and Sensitization to Allergens of Dermatophagoides pteronyssinus.

BACKGROUND AND OBJECTIVE: Little is known about the role of molecular diagnosis in house dust mite (HDM) allergy. In this study, we investigated the association between the sensitization profile of adolescent and adult HDM-allergic patients and asthma in a region with high rates of exposure to HDM. METHODS: We conducted a cross-sectional study of 384 HDM-allergic patients (38.5%, males; median age, 28 years). A total of 368 patients (95.8%) had rhinitis, and 175 (45.6%) had asthma. Specific IgE (sIgE) to Dermatophagoides pteronyssinus, nDer p 1, rDer p 2, and rPen a 1 was measured in all patients. sIgE to Lepidoglyphus destructor was measured in patients (n=301) with a positive skin test result. RESULTS: Significantly higher concentrations of sIgE to Der p 1 and sIgE to Der p 2 were observed in patients with asthma than in those without asthma. The proportion of asthmatic patients was higher among individuals who reacted (≥0.35 kUA/L) to both Der p 1 and Der p 2 (147/291, 50.5%) than among those who reacted to only 1 allergen (either Der p 1 or Der p 2, 18/55, 32.7%) or neither allergen (10/38, 26.3%, P=.002). Reactivity to both allergens was associated with asthma after adjusting for age and sex (OR, 2.87; 95%CI, 1.32-6.20). Higher concentrations of sIgE to L destructor were observed in patients with asthma than in patients without asthma. Tropomyosin sIgE ≥0.35 kUA/L was detected in only 6 individuals (1.6%). CONCLUSIONS: L destructor may be a relevant allergen in high-exposure areas. Dual sensitization (ie, IgE to both Der p 1 and Der p 2) may help to identify HDM-allergic patients who are at risk of asthma.

MicroRNAs involved in the browning process of adipocytes.

The present review focuses on the role of miRNAs in the control of white adipose tissue browning, a process which describes the recruitment of adipocytes showing features of brown adipocytes in white adipose tissue. MicroRNAs (miRNAs) are a class of short non-coding RNAs (19-22 nucleotides) involved in gene regulation. Although the main effect of miRNAs is the inhibition of the translational machinery, thereby preventing the production of the protein product, the activation of protein translation has also been described in the literature. In addition to modifying translation, miRNAs binding to its target mRNAs also trigger the recruitment and association of mRNA decay factors, leading to mRNA destabilization, degradation, and thus to the decrease in expression levels. Although a great number of miRNAs have been reported to potentially regulate genes that play important roles in the browning process, only a reduced number of studies have demonstrated experimentally an effect on this process associated to changes in miRNA expressions, so far. These studies have shown, by using either primary adipocyte cultures or experimental models of mice (KO mice, mice overexpressing a specific miRNA), that miR-196a, miR-26, and miR-30 are needed for browning process development. By contrast, miR-155, miR-133, miR-27b, and miR-34 act as negative regulators of this process [corrected]. Further studies are needed to fully describe the miRNA network-involved white adipose tissue browning regulation.

Suggestive evidence of a role of HLA-DRB4 mismatches in the outcome of allogeneic hematopoietic stem cell transplantation with HLA-10/10-matched unrelated donors: a French-Swiss retrospective study.

We have conducted a retrospective study on 251 patients from three centers in France and Switzerland between 2004 and 2010 with the goal to evaluate the impact of HLA-DRB3/B4/B5 allele mismatching after HLA-10/10-matched unrelated allogeneic hematopoietic stem cell transplantation (HSCT). Fourteen (5.5%) patients receiving HSCT from an HLA-10/10-matched unrelated donor had a mismatched DRB4 donor, 23 (9.5%) patients had a mismatched DRB3 donor and 214 (85%) had a fully matched unrelated donor (HLA-10/10) without DRB3- or DRB4-mismatched donor. We compared the outcomes of 37 patients with a DRB3 or DRB4 mismatch with the rest of the population. The median survival for a patient without DRB3/4 mismatch was 18 months (95% confidence interval (CI), 13-29), for DRB3-mismatched patients 32 months (95% CI, 13-NR) and for DRB4-mismatched patients 7 months (95% CI, 3-NR). The multivariate analysis showed a significant impact of DRB4 mismatching on survival (Hazards ratio (HR)=2.1 (95% CI, 1.01-4.67), P=0.045), acute GvHD (HR=2.66 (95% CI, 0.99-7.09) P=0.05) and on transplant-related mortality (HR=2.8; (95% CI, 1.7-4.4) P=0.024). In the view of an impact of DRB4 locus mismatch on clinical outcome, it would be important to confirm this observation in a prospective study as it may be worth considering DRB4 in the unrelated donor selection.

Sensitization pattern of crustacean-allergic individuals can indicate allergy to molluscs.

This study investigated the sensitization pattern of crustacean-allergic patients according to tolerance to molluscs. Thirty-one patients with anaphylaxis to crustaceans (14 with mollusc allergy and 17 with mollusc tolerance) were studied using skin prick tests (SPTs), specific IgEs (sIgEs) and SDS-PAGE immunoblotting. IgE-reactive shrimp proteins were identified by proteomic analyses. Patients with mollusc allergy presented more frequently SPTs positive to molluscs and higher sIgE titres in response to both molluscs and crustaceans. Shrimp-sIgE and rPen a1-sIgE values of 1.57 kUA /l and 4.38 kUA /l, respectively, showed positive likelihood ratios of 4.3 and 10.9 for the identification of mollusc allergy. Patients with mollusc allergy reacted more frequently to tropomyosin in immunoblots than did patients without it (93% vs 35%, respectively, P = 0.004). Reactivity to proteins other than tropomyosin (n = 14) was not different between the two groups. Among patients with crustacean anaphylaxis, patients with mollusc allergy and mollusc tolerance show a different pattern of sensitization, something that may help identify them.

The impact of poor psychosocial work environment on non-work-related sickness absence.

PURPOSE: We aimed to analyse the impact of psychosocial work environment on non-work-related sickness absence (NWRSA) among a prospective cohort study, stratified using a random sampling technique. METHODS: Psychosocial variables were assessed among 15,643 healthy workers using a brief version of the Spanish adaptation of Copenhagen Psychosocial Questionnaire. A one year follow-up assessed the total count of NWRSA days. Zero-inflated negative binomial regression was used for multivariate analyses. RESULTS: After adjusting for covariates, low levels of job control and possibilities for development (Odds Ratio [OR]: 1.17; 95% CI: 1.01-1.36 [men]; OR: 1.39 95% CI: 1.09-1.77 [women]), poor social support and quality of leadership (OR: 1.29; 95% CI: 1.11-1.50 [men]; OR: 1.28; 95% CI: 1.01-1.63 [women]), and poor rewards (OR: 1.34; 95% CI: 1.14-1.57 [men]; OR: 1.30; 95% CI: 1.01-1.66 [women]) predicted a total count of sickness absence greater than zero, in both men and women. Double presence was also significantly associated with NWRSA different than 0, but only among women (OR: 1.40; 95% CI: 1.08-1.81). Analyses found no association between psychosocial risk factors at work and the total count (i.e., number of days) of sickness absences. CONCLUSIONS: The results suggest that work-related psychosocial factors may increase the likelihood of initiating an NWRSA episode, but were not associated with the length of the sickness absence episode. Among our large cohort we observed that some associations were gender-dependent, suggesting that future research should consider gender when designing psychosocial interventions aimed at decreasing sickness absences.