Osimertinib treatment based on plasma T790M monitoring in patients with EGFR-mutant non-small-cell lung cancer (NSCLC): EORTC Lung Cancer Group 1613 APPLE phase II randomized clinical trial.

BACKGROUND: The APPLE trial aimed to evaluate the feasibility of longitudinal plasma epidermal growth factor receptor (EGFR) T790M monitoring for the best sequencing strategy of gefitinib and osimertinib. METHODS: APPLE is a randomized, non-comparative, phase II study in patients with common EGFR-mutant, treatment-naive non-small-cell lung cancer including three arms: arm A (osimertinib upfront until RECIST progression, PD), arm B [gefitinib until emergence of circulating tumor DNA (ctDNA) EGFR T790M mutation by cobas EGFR test v2 or RECIST PD], and arm C (gefitinib until RECIST PD), and then switch to osimertinib in both arms. The primary endpoint is the progression-free survival (PFS) rate 'on osimertinib' at 18 months (PFSR-OSI-18) after randomization in arm B (H0: PFSR-OSI-18 of ≤40%). Secondary endpoints include response rate, overall survival (OS), and brain PFS. We report the results of arms B and C. RESULTS: From November 2017 to February 2020, 52 and 51 patients were randomized into arms B and C, respectively. Most patients were females (70%) and had EGFR Del19 (65%); one-third had baseline brain metastases. In arm B, 17% of patients (8/47) switched to osimertinib based on the emergence of ctDNA T790M mutation before RECIST PD, with a median time to molecular PD of 266 days. The study met its primary endpoint of PFSR-OSI-18 of 67.2% (84% confidence interval 56.4% to 75.9%) in arm B versus 53.5% (84% confidence interval 42.3% to 63.5%) in arm C, with a median PFS of 22.0 months versus 20.2 months, respectively. The median OS was not reached in arm B versus 42.8 months in arm C. Median brain PFS in arms B and C was 24.4 and 21.4 months, respectively. CONCLUSIONS: The serial monitoring of ctDNA T790M status in advanced EGFR-mutant non-small-cell lung cancer during treatment with first-generation EGFR inhibitors was feasible, and a molecular progression before RECIST PD led to an earlier switch to osimertinib in 17% of patients with satisfactory PFS and OS outcomes.

The factors associated with the trend in incidence of Bacteraemia and associated mortality over 30 years.

BACKGROUND: Studies have reported increased incidence of BSI over the past decades and indicate that it is necessary to investigate the causes. The aim of this study was to determine the factors affecting trends in the incidence of bacteraemias and associated mortality. METHODS: We conducted a retrospective cohort study assessing prospectively collected data of all clinically significant bacteraemias between 1991 and 2020 in a 450-bed hospital. We determined the evolution of bacteraemia-associated incidence, adjusted 30-day mortality and performed multivariable logistic regression to compare the evolution of variables associated with mortality between 5-year periods. RESULTS: 6777 episodes were included, 59.7% males, age 66.5 ± 18.2, 39.4% ≥ 75 years. The incidence total increased: 43.8/100,000/year in 1991-1995 to 205 in 2016-2020; community-acquired bacteraemia (24.9 to 139) and hospital-acquired (0.36/1000 inpatients-days to 1.09). Bacteraemia with source in vascular catheter, urinary and biliary tract increased. The 30-day mortality rate of patients was 1179/6777 (17.4%) in the whole series and population-adjusted mortality incidence increased from 11.4/100,000 in 1991-1996 to 28.4 in 2016-2020 (RR 2.49, 95% CI 2.01-3.08). Mortality was higher in men (18.2% vs 16.3%) and those over 74 years (22.2% vs 14.3%). Appropriate empirical antimicrobial treatment improved (66.5% to 73.1%), 30-day mortality of patients decreased from 26.1 to 13.9%. When comparing the evolution of the factors associated with mortality between 1991 and 1996 vs 2016-2020, the frequency of some variables associated with higher mortality increased: male sex (OR 1.38, 95% CI 1.10-1,74), age (OR 1.02, 1.01-10.3), immunosuppressive treatment (OR 3.1, 2.09-4.6), polymicrobial bacteraemia (OR 1.76, 1.12-2.79), and others decreased: severe sepsis/septic shock (OR 0.70, 0.52-0.93), spontaneous bacterial peritonitis in cirrhosis (OR 0.06, 0.02-0.23), endocarditis (OR 0.54, 0.35-0.83); on the other hand, the frequency of factors associated with lower mortality increased: urinary (OR 1.67, 95% CI 1.23-2.27) and bile tract source (OR 1.59, 1.04-2.43), and adequate empirical treatment (OR 1.42, 95% CI 1.10-1.83). CONCLUSIONS: The incidence of bacteraemia increased due to more elderly, co-morbid patients undergoing procedures and more device related bacteraemia. The percentage of mortality decreased because adequate empirical treatment improved, decreased spontaneous bacterial peritonitis in cirrhosis and endocarditis, and increased bacteraemia of urinary and biliary tract source.

Analysis of mismatch repair (MMR) proteins expression in a series of malignant pleural mesothelioma (MPM) patients.

BACKGROUND: Promising results have been reported with immune checkpoint inhibitors (ICI) in a small proportion of MPM patients. MMR deficiency (dMMR) has been well described in several malignancies and was approved as a biomarker for anti-PD-1 inhibitors. Next generation sequencing (NGS) data demonstrated that 2% of MPM harbor microsatellite instability. The aim of this study is to characterize MMR by immunohistochemistry (IHC) in a series of MPM including a subset of patients treated with immunotherapy. METHODS: Tumors of 159 MPM p diagnosed between 2002 and 2017 were reviewed. Formalin-fixed, paraffin-embedded tissue was stained for MLH1, MSH2, MSH6 and PMS2 and tumors were classified as dMMR (MMR protein expression negative) and MMR intact (all MMR proteins positively expressed). We retrospectively collected clinical outcomes under standard chemotherapy and experimental immunotherapy in the entire cohort. RESULTS: MMR protein expression was analyzed in 158 samples with enough tissue and was positive in all of the cases. Twenty two patients received ICI with anti-CTLA4 or anti-PD-1 blockade in clinical trials, 58% had a response or stable disease for more than 6 m, with median progression-free survival (PFS) of 5.7 m (2.1-26.1 m). The median overall survival (mOS) in all population was 15 months (m) (13.5-18.8 m). In a multivariable model factors associated to improved mOS were PS 0, neutrophil-lymphocyte ratio (NLR) < 5 and epithelioid histology (p < 0.001). CONCLUSIONS: In our series we were unable to identify any MPM patient with dMMR by IHC. Further studies are needed to elucidate potential predictive biomarkers of ICI benefit in MPM.

Long-term efficacy of 6-month therapy with isoniazid and rifampin compared with isoniazid, rifampin, and pyrazinamide treatment for pleural tuberculosis.

Research into anti-tuberculosis treatment has mainly focused on pulmonary tuberculosis (TB), with few studies on pleural-TB. The aim of the study is to compare the long-term efficacy of a 6-month treatment regimen with isoniazid and rifampicin (6HR) with treatment regimen of isoniazid, rifampicin, and pyrazinamide (6HR2Z) for pleural-TB. A case-control study of 200 HIV-negative patients with pleural-TB prospectively followed in our TB-unit from 1995 to 2018. The primary resistance to isoniazid is < 4% in our geographic area. Pleural-TB diagnosis was based on a positive culture for M. tuberculosis (84 patients), presence of caseating granulomas in pleural biopsy (28), or characteristics of pleural fluid (88). A comparative study of demographic and clinical characteristics between the treatment groups was carried out. Out of the 200 patients followed, (112 males, 88 females; mean age 32.9 ± 18.4 years), 99 patients were treated with 6HR regimen and 101 with 6HR2Z. The groups were comparable, except the 6HR2Z had larger size of pleural effusion. All patients completed the treatment. The group treated with 6HR presented fewer adverse effects (15.3%) than 6HR2Z group (33%), p = 0.005, and lower frequency of severe hepatic toxicity (5% vs 10.9%). Four patients died from causes other than TB during treatment with 6HR2Z, and all other patients were cured during a monitoring period for 8.4 years (IQRs, 3.3-14.3). Six patients in 6HR and 10 in 6HR2Z developed residual pachypleuritis. 6HR is as effective as 6HR2Z treatment for pleural-TB, with fewer adverse effects.

Quality of life improvement with allergen immunotherapy treatment in patients with rhinoconjunctivitis in real life conditions. Results of an observational prospective study (ÍCARA).

Summary: Objectives. Evaluate the changes in quality of life of patients with allergic rhinoconjunctivitis (AR), with or without asthma, after one-year treatment with allergen immunotherapy. Methods. This was an observational prospective multicenter study. RQLQ questionnaire and VAS scale to assess treatment satisfaction were used. Impact on AR and asthma was also analyzed. Any adverse reaction was recorded. Results. 127 patients were recruited. Mean values in RQLQ decreased from 2.61 to 1.34 points, reflecting a statistically and clinically significant improvement (p minor 0.01). The percentage of asthmatic patients decreased significantly (p minor 0.01). Mean value of patients' satisfaction was 7.24 (SD = 1.90). Only 11 patients presented systemic reactions (9.17%), none of them serious. Conclusions. One-year AIT treatment significantly increases QoL in patients with AR. Moreover, high patients' satisfaction values were reported, together with an adequate safety profile.

Meropenem antimicrobial stewardship program: clinical, economic, and antibiotic resistance impact.

There are few prospective studies with sufficient duration in time to evaluate clinical and antibiotic resistance impact of antibiotic stewardship programs (ASP). This is a descriptive study between January 2012 and December 2017, pre-post intervention. A meropenem ASP was initiated in January 2015; in patients who started treatment with meropenem, an infectious disease physician performed treatment recommendations to prescribers. Prospective information was collected to evaluate adequacy of meropenem prescription to local guidelines and to compare results between cases with accepted or rejected intervention. Analysis was performed to verify variables associated with intervention acceptance and with any significant change in meropenem consumption, hospital-acquired multidrug-resistant (MDR) bloodstream infections (BSIs), and 30-day all-cause crude death in MDR BSIs. Adequacy of meropenem prescription and de-escalation from meropenem treatment to narrower-spectrum antibiotic improved progressively over time, after ASP implementation (p < 0.001). Interventions on prescription were performed in 330 (38.7%) patients without meropenem justified treatment; in 269, intervention was accepted and in 61 not. Intervention acceptance was associated with shorter duration of treatment, cost, and inpatient days (p < 0.05); intervention rejection was not associated with severity of patient. During the period 2015-2017, meropenem consumption decreased compared with 2012-2014 (rate ratio [RR] 0.67; 95% CI 0.58-0.77, p < 0.001). Also decreased were hospital-acquired MDR BSI rate (RR 0.63; 95% CI 0.38-1.02, p = 0,048) and 30-day all-cause crude death in MDR BSIs (RR 0.45; 95% CI 0.14-1.24, p = 0.096), coinciding in time with ASP start-up. The decrease and better use of meropenem achieved had a sustained clinical, economic, and ecological impact, reducing costs and mortality of hospital-acquired MDR BSIs.

Anisakis simplex allergy after eating chicken meat.

BACKGROUND: Allergic reactions to food can be produced by contaminants that induce sensitization. Among these, Anisakis simplex can cause seafood infestation, and allergic symptoms (urticaria-angioedema, anaphylaxis, and asthma) can follow the eating or handling of affected fish. Although seafood is the principal source of human infections by this parasite, we have found allergic symptoms in 8 patients previously diagnosed as having A simplex sensitization after they ate chicken meat. Chicken feed usually has a high proportion of fishmeal, which might possibly be contaminated by this nematode. OBJECTIVE: The aim of our study was to determine whether parasite proteins present in chicken meat could be responsible for the symptoms reported by these subjects. METHODS: We carried out in vivo tests (prick, bronchial challenge, and double-blind placebo-controlled challenge with meat chicken) in these 8 patients. We performed immunoblotting using the sera from the 8 patients and controls in order to detect A simplex sensitization. We also investigated the presence of A simplex proteins in sera from chickens fed with fishmeal and in other sera from chickens fed only with cereals. We excluded sensitization to other chicken nematodes by serologic methods. RESULTS: All 8 patients presented positive prick and challenges to A simplex. When we used serum from chickens fed with fishmeal as the antigen in blotting, patients 3, 4, 5, 6, 7, and 8 recognized a band of 16 kd, also obtained when using pools of fish-shellfish and A simplex larva. No detection was observed with sera from chickens fed with only cereals. CONCLUSION: We provide evidence, based on in vivo and in vitro tests, that subjects highly sensitized to A simplex can detect the presence of Anisakis species allergens in chicken meat.

Cereal-induced anaphylaxis in an adult after eating a baby cereal formula.

Ingestion of infant cereal formula as a cause of anaphylaxis has been exclusively described in children. We report the case of a man who experienced an anaphylactic reaction after eating his son's cereal formula. We believe that cereals constitute a rising problem and a hidden allergen that can cause severe reactions. Although these reactions are not fully understood, they may possibly be a life-long event.

Living in towers as risk factor of pollen allergy.

BACKGROUND: The effects of fluctuations in pollen counts have important implications for health services. Little research on the clinical implications of the vertical distribution of pollen in allergy symptoms has been carried out. METHODS: We have investigated the allergic symptoms of a population of 17 171 patients coming from our health area (Valladolid, Spain) and living in the city and villages. We compared the prevalence of sensitization to different pollens: Graminae, trees and shrub in relation with the floor of the building where they were living. RESULTS: Relative risk of pollen sensitization (confidence index, CI 95%) was higher in patients who were living at high floors than in those patients who were living in lower floors or at street level, independently of rural or urban conditions The chi-square showed a lineal trend in this relationship in the case of sensitization to grass pollen: chi(2): 1794, P > 0.00001 CONCLUSIONS: On the basis of our local investigations, natural pollen sensitization appears to increase with height where the patient lives. This paper reports clinical results on the influence of vertical pollen distribution in pollen allergy.

Enhancement of tomato allergenicity after treatment with plant hormones.

BACKGROUND: Practical applications to enhance the productivity of agriculture by using plants with improved resistance to pathogens are expected to increase in the near future. Although tomato has been widely investigated for breeding purposes, there have been no studies on tomato allergenicity after plant hormones treatments. METHODS: Prick by prick tests were carried out with different tomato samples (fruits grown under biological conditions without addition of chemical products, and treated with ethylene and salicylic acid) in eight patients with ages between 12 and 27 years who suffered from anaphylaxis episodes after eating raw tomatoes. An immunoblot experiment with the different tomato extracts was performed using sera from these eight patients and controls. RESULTS: The wheals obtained in prick tests were significantly higher with the extracts of tomato treated with ethylene and SAA (chi(2) = 31.3, p < 0.0001) and the patients who presented higher wheal diameters in skin tests were those who had more severe episodes of anaphylaxis. Neither the protein stain nor the IgE immunodetection patterns clearly varied between the untreated and the hormone-treated samples. CONCLUSIONS: In the case of anaphylaxis induced by tomato, the treatment with plant hormones induced a higher cutaneous response than with non-treated tomato, but the "in vitro" response was similar.

Is Lolium pollen from an urban environment more allergenic than rural pollen?

BACKGROUND: Allergy to grass pollen is a highly prevalent allergic disease. Hay fever is more predominant in urban than in rural areas, despite the increasingly smaller areas of surrounding grassland. The effect of vehicle exhaust pollutants, mainly diesel particles, and other industrial sources of atmospheric pollution leading to plant damage has been implicated in this phenomenon. OBJECTIVE: This study compared the in vivo and in vitro allergenicity of pooled samples of Lolium perenne grass pollen harvested from 10 different urban areas with that of samples of the same pollen from 10 neighboring rural areas. METHODS: Lolium perenne pollen from different parts of a city and from a nearby rural area was harvested in 1999 and 2000 during the peak pollination period. Protein composition was compared by SDS-PAGE and in vivo and in vitro IgE-binding capacity was compared by skin-prick tests, RAST-inhibition and measurement of the major allergen, Lol p 5. RESULTS: In the two years under study, urban samples contained approximately twice the protein content of the rural samples. Biological activity and Lol p 5 content was higher in urban pollen than in rural pollen and showed differences in the two years under study. CONCLUSIONS: The protein content and allergenicity of Lolium perenne pollen was higher in urban areas than in rural areas. These differences might explain why allergy to grass pollen is more prevalent in urban areas. This finding should be taken into account in diagnosis, preventive measures and specific immunotherapy.

Allergy after ingestion or inhalation of cereals involves similar allergens in different ages.

BACKGROUND: Cereals are among the major foods that account for food hypersensitivity reactions. Salt-soluble proteins appear to be the most important allergens contributing to the asthmatic response. In contrast, very limited information is available regarding cereal allergens responsible for allergic reactions after ingestion of cereal proteins. OBJECTIVE: The aim of this study was to evaluate the allergenic reactivity of ingested and inhaled cereal allergens in different ages, in order to investigate if the response to different allergens would depend on the sensitization route. METHODS: We included 66 patients in three groups. Group 1: 40 children aged 3 to 6 months who suffered from diarrhoea, vomiting, eczema or weight loss after the introduction of cereal formula in their diet and in which a possibility of coeliac disease was discarded. Group 2: 18 adults with food allergy due to cereals tested by prick tests, specific IgE and food challenge. Group 3: eight patients previously diagnosed as having baker's asthma. Sera pool samples were collected from each group of patients and IgE immunoblotting was performed. RESULTS: We found an important sensitization to cereal in the 40 children. The most important allergens were wheat followed by barley and rye. Among the adults with cereal allergy, sensitization to other allergens was common, especially to Lolium perenne (rye grass) pollen. Immunoblotting showed similar allergenic detection in the three groups. CONCLUSION: Clinically significant reactivity to cereal may be observed in early life. Inhalation and ingestion routes causing cereal allergy seem to involve similar allergens. The diet control was more effective in children. The possibility of cereal allergy after the introduction of cereal formula during the lactation period should not be underestimated.