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.

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.

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.

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.

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.

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.

Analysis of splicing of four mouse JNK/SAPKalpha variants.

The JNK/SAPK (c-Jun NH2-terminal kinase/stress-activated protein kinase) cascade is activated by a variety of stress stimuli and by the inflammatory cytokines interleukin-I (IL-I) and tumor necrosis factor alpha (TNFalpha). Four splice variants of the mouse JNK/SAPKalpha isoform, which differ in a region located in subdomains IX-X of the protein, were previously identified. Analysis of the sequence of the central region of the mouse JNK/SAPKalpha gene indicates that splice variants I and II are generated by a typical alternative splicing mechanism, while splice variants III and IV are generated by a less common mechanism, where alternative 3' splice sites located inside an exon (cryptic sites) are selected. The major splice variants alphaI and all have a wide and similar distribution in hippocampus, cerebral cortex, caudate-putamen, amygdala and the granule cell layer of cerebellum, although their expression is specifically regulated in certain cell types.

[Lost opportunities for preventing tuberculosis and derived costs; comment]. / Oportunidades perdidas para prevenir la tuberculosis y costes derivados.

BACKGROUND: We determined the extent to which opportunities for prevention were missed among patients with tuberculosis and the costs derived from the lack of prevention. METHOD: Descriptive study of patients with active tuberculosis were studied in the hospital ward of tuberculosis at the A. Marcide-Novoa Santos Centre (Ferrol, Spain), from September of 1991 to August of 1995. Risk factors to develop tuberculosis, vaccination with BCG, previous tuberculin skin test and previous history of drug prophylaxis or tuberculosis therapy were determined. Then, we determined whether they had undergone prevention procedures in accordance with current recommendations of the American Thoracic Society. An evaluation of the direct and indirect derived costs was carried out in patients with any missed opportunity for tuberculosis prevention. RESULTS: Out of 433 studied patients, 167 (38.6%) got missed any opportunity for prevention. Out of 167, 29 patients (6.7%) did not complete a previous treatment; 9 (2.1%) did not complete drug prophylaxis; 12 (2.8%) with known previous positive tuberculin skin test and an indication for drug prophylaxis never received it, and 117 (27%) with known indications for screening never received a skin test. 62 patients (53%) with known exposure to active pulmonary tuberculosis, and 65 (55.6%) with predisposing medical conditions. From the missed opportunities for prevention we calculated some direct costs of 116,909,911 pesetas and some indirect costs derived from the absence to work (141.9 +/- 114.3 days) and from the death of 6 patients for tuberculosis. CONCLUSIONS: A large percentage of missed opportunities to prevent the disease was found among patients with tuberculosis. This means a considerable expense that could have been avoided.

[Resistance of Mycobacterium tuberculosis in Ferrol, Spain. Associated factors]. / Resistencias de Mycobacterium tuberculosis en Ferrol. Factores asociados.

OBJECTIVE: To know the frequency of resistances of Mycobacterium tuberculosis and the associated factors. PATIENTS AND METHODS: Prospective study of the sensitivity of Mycobacterium tuberculosis by means of the method of the proportions of Canetti in the Hospital Arquitecto Marcide-Profesor Novoa Santos (Ferrol, Spain) among 1991 and 1998. A descriptive and multiple regression analyses were performed. RESULTS: Were studied 355 strains. Primary resistance: Isoniazid 1.1%, Streptomycin 1.1%. Secondary resistance: Isoniazid 11.6%, in the 5.2% existed multidrug-resistance. The risk factors for drug-resistant tuberculosis were previous treatment (odds ratio [OR] = 10.9; 95% CI, 2.9-39.4) and age higher than 40 years (OR = 3.9; 95% CI, 1.1-14.5). CONCLUSIONS: A low frequency of resistance was observed. The factors associated with the resistances were previous treatment and age.

[Hepatotoxicity induced by cyanamide. A review of the anatomicopathological changes apropos a case]. / Hepatotoxicidad inducida por cianamida. Revisión de las alteraciones anatomopatológicas a propósito de un caso.

A case of toxic liver disease induced by cyanamide in a patient in treatment with this drug during 18 months, is presented. We reviewed the different liver cell alterations produced by a long-term treatment with cyanamide, which produces fibrosis and portal inflammation, as well as polished cells with different characteristic features. These alterations forced the establishing of close controls of patients in treatment with this type of anti-alcoholism drug, as well as the reduction of the duration of therapy, this questioning the efficacy of the treatment of chronic alcoholism with this aversive drug.

Hidromorfona: una alternativa en el tratamiento del dolor / Hydromorphone: an option in the treatment of pain

Los analgésicos opioides constituyen uno de los pilares fundamentales en el tratamiento farmacológico del dolor moderado-grave, especialmente en el dolor agudo y el crónico oncológico. La molécula de hidromorfona es estructuralmente muy similar a la morfina, se puede administrar tanto por vía enteral como por vía parenteral, y se une principal-mente a los receptores opioides μ y en menor grado a los receptores δ. La unión a receptores tipo u es la causa del efecto analgésico, así como de los efectos secundarios. La hidromorfona se encuentra disponible en presentaciones de liberación inmediata y prolongada durante 12 o 24 horas. Recientemente, se ha comercializado en España una preparación de liberación sostenida durante 24 horas que utilizan el sistema OROS Puhs-Pull®. En el tratamiento del dolor agudo, la evidencia clínica demuestra que la hidromorfona presenta una equivalencia analgésica similar a otros opiodes. Respecto al tratamiento del dolor oncológico, se ha evaluado respecto a otros opioides y con diferentes formulaciones, y se ha observado que es un fármaco equivalente a la morfina en cuanto a eficacia analgésica y efectos secundarios. En el tratamiento del dolor crónico no oncológico, no hay ensayos clínicos controlados que otorguen evidencia científica a la hidromorfona en estos pacientes. Como conclusión, la hidromorfona presenta un perfil farmacológico, propiedades analgésicas y efectos secundarios similares a la morfina, todavía persisten ciertas controversias en lo referente a las dosis equianalgésicas entre la hidromorfona y la morfina y entre la dosis oral y la parenteral (AU)

The analgesics opioids are one of the fundamental props in the pharmacological treatment of the moderate and severe pain, particularly in chronic oncology pain. The hydromorphone molecule is structurally very similar to morphine and it may be administered enterally or parenterally. It binds mainly to μ opioid receptors and to a lesser extent to δ receptors. The binding to the μ receptor is responsible for the analgesic effect as well as for the appearance of side effects. Hydromorphone is available in 12-hour and 24-hour slow-release presentations. A 24-hour sustained release preparation has recently come available on the market in Spain which uses the OROS push-pull system. In the treatment of the acute pain, the clinical evidence demonstrates that hydromorphone has similar analgesic equivalence to other opioids. Treatment of oncological pain has been evaluated compared to other opioids and with different formulations, demonstrating it to be a drug equivalent to morphine as regards its analgesic effectiveness and side effects. There are no controlled clinical trials on the use of hydromorphone in the treatment of chronic nononcological pain. Conclusions, hydromorphone has a pharmacological profile, analgesic properties and side effects similar to morphine, but there is still controversy as regards hydromorphone-morphine equivalent doses and the oral-parenteral dose (AU)

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.

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.

Celiac plexus block as treatment for refractory pain related to sclerosing cholangitis in AIDS patients.

Sclerosing cholangitis may be a cause of refractory pain in patients infected with the human immunodeficiency virus. We performed celiac plexus block in three such patients with sever pain from sclerosing cholangitis and a poor response to conventional analgesia. The pain had been centered in the epigastrium and/or upper-right quadrant of the abdomen for 2, 10, and 15 weeks, respectively. Computed tomography-guided celiac plexus block with absolute alcohol and bupivacaine was performed. All three patients reported complete disappearance of the pain immediately after the procedure in two cases and 3 days later in the remaining patient. All patients were discharged free of pain and without analgesics and were followed up for 2, 8, and 11 months, respectively, without recurrence of pain. Celiac plexus block deserves further trial for the treatment of severe pain associated with sclerosing cholangitis in patients with acquired immunodeficiency syndrome. The quality of life of our three patients was considerably improved with this relatively simple procedure.