A randomised phase II study of osimertinib and bevacizumab versus osimertinib alone as second-line targeted treatment in advanced NSCLC with confirmed EGFR and acquired T790M mutations: the European Thoracic Oncology Platform (ETOP 10-16) BOOSTER trial.

BACKGROUND: While osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is the standard treatment in patients with advanced non-small-cell lung cancer (NSCLC) with sensitising EGFR and acquired T790M mutations, progression inevitably occurs. The angiogenic pathway is implicated in EGFR TKI resistance. PATIENTS AND METHODS: BOOSTER is an open-label randomised phase II trial investigating the efficacy and safety of combined osimertinib 80 mg daily and bevacizumab 15 mg/kg every 3 weeks, versus osimertinib alone, in patients with EGFR-mutant advanced NSCLC and acquired T790M mutations after failure on previous EGFR TKI therapy. Primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints were overall survival (OS), objective response rate (ORR) and adverse events (AEs). RESULTS: Between May 2017 and February 2019, 155 patients were randomised (combination: 78; osimertinib: 77). At data cut-off of 22 February 2021, median follow-up was 33.8 months [interquartile range (IQR): 26.5-37.6 months] and 129 (83.2%) PFS events were reported in the intention-to-treat population. There was no difference in median PFS between the combination [15.4 months; 95% confidence interval (CI) 9.2-18.0 months] and osimertinib arm (12.3 months; 95% CI 6.2-17.2 months; stratified log-rank P = 0.83), [hazard ratio (HR) = 0.96; 95% CI 0.68-1.37]. Median OS was 24.0 months (95% CI 17.8-32.1 months) in the combination arm and 24.3 months (95% CI 16.9-37.0 months) in the osimertinib arm (stratified log-rank P = 0.91), (HR = 1.03; 95% CI 0.67-1.56). Exploratory analysis revealed a significant interaction of smoking history with treatment for PFS (adjusted P = 0.0052) with a HR of 0.52 (95% CI 0.30-0.90) for smokers, and 1.47 (95% CI 0.92-2.33) for never smokers. ORR was 55% in both arms and the median time to treatment failure was significantly shorter in the combination than in the osimertinib arm, 8.2 months versus 10.8 months, respectively (P = 0.0074). Safety of osimertinib and bevacizumab was consistent with previous reports with grade ≥3 treatment-related AEs (TRAEs) reported in 47% and 18% of patients on combination and osimertinib alone, respectively. CONCLUSIONS: No difference in PFS was observed between osimertinib plus bevacizumab and osimertinib alone. Grade ≥3 TRAEs were more common in patients on combination.

Removal of contaminants of emerging concern by continuous flow solar photo-Fenton process at neutral pH in open reactors.

For the first time, the operational feasibility of the solar photo-Fenton process at neutral pH in continuous flow has been tested for three consecutive days. The aim of the treatment was to remove of contaminants of emerging concern (CECs) from wastewater treatment plant secondary effluents. To this end, a 5 cm-deep raceway pond reactor was run in continuous flow mode and the degradation of the CECs present in real secondary effluents was monitored at their natural concentrations. To keep dissolved iron at neutral pH, ethylenediamine-N,N'-disuccinic acid (EDDS) was used to form the complex Fe(III):EDDS as an iron source for the photo-Fenton reactions. At pilot scale the effects of the Fe(III):EDDS molar ratio (1:1 and 1:2) and hydraulic residence time (HRT) (20 and 40 min) on CEC removal were studied. The best operating condition was 20 min of HRT, giving rise to a treatment capacity of 900 L m-2 d-1 with CEC removal percentages of around 60%. The reactant concentrations were 0.1 mM Fe(III):EDDS at a 1:1 M ratio and 0.88 mM H2O2. Under these operating conditions, the short-term stability of the process was also demonstrated, thus pointing out the potential of this solar technology as a tertiary treatment.

The updated Charlson comorbidity index is a useful predictor of mortality in patients with Staphylococcus aureus bacteraemia.

The objective was to compare the performance of the updated Charlson comorbidity index (uCCI) and classical CCI (cCCI) in predicting 30-day mortality in patients with Staphylococcus aureus bacteraemia (SAB). All cases of SAB in patients aged ⩾14 years identified at the Microbiology Unit were included prospectively and followed. Comorbidity was evaluated using the cCCI and uCCI. Relevant variables associated with SAB-related mortality, along with cCCI or uCCI scores, were entered into multivariate logistic regression models. Global model fit, model calibration and predictive validity of each model were evaluated and compared. In total, 257 episodes of SAB in 239 patients were included (mean age 74 years; 65% were male). The mean cCCI and uCCI scores were 3.6 (standard deviation, 2.4) and 2.9 (2.3), respectively; 161 (63%) cases had cCCI score ⩾3 and 89 (35%) cases had uCCI score ⩾4. Sixty-five (25%) patients died within 30 days. The cCCI score was not related to mortality in any model, but uCCI score ⩾4 was an independent factor of 30-day mortality (odds ratio, 1.98; 95% confidence interval, 1.05-3.74). The uCCI is a more up-to-date, refined and parsimonious prognostic mortality score than the cCCI; it may thus serve better than the latter in the identification of patients with SAB with worse prognoses.

Low cost UVA-LED as a radiation source for the photo-Fenton process: a new approach for micropollutant removal from urban wastewater.

Light Emitting Diode (LED) technology has matured sufficiently to be considered as an alternative UVA radiation source in photoreactors. Currently, low energy consuming LEDs with a wide range of wavelengths and radiant flux are readily available. In this study, UVA-LEDs were used as a radiation source for the photo-Fenton process as tertiary treatment. The water matrix used was a simulated secondary effluent doped with 200 µg L-1 of the pesticide acetamiprid (ACTM) due to its recalcitrant nature. All experiments were carried out in a LED-box reactor at pH 2.8. The main purpose of this research was to gain some insight into the relationships among energy supply, LED consumption, UVA irradiance and reaction rate. The effect of LED wavelength on energy efficiency for ACTM degradation was studied by varying the iron concentration and liquid depth. Three wavelengths (365, 385 and 400 nm) and two iron concentrations (5 and 11 mg L-1) for two different liquid depths (5 and 15 cm) were evaluated in order to obtain more energy efficient conditions. The results suggest that while the wavelength of 365 nm with 11 mg Fe2+ L-1 was the best condition for ACTM degradation, the wavelength of 385 nm had slower kinetics, but higher energy efficiency.

Insulin polymers in the plasma of obese subjects are associated with elevated levels of carbonyl groups and are decreased by (-)-epicatechin.

We investigated whether oxidative damage and insulin polymerization at a systemic level are associated with the insulin resistance (IR) observed in obese subjects. We evaluated 3 groups (n=16/each) divided according to body mass index (BMI): Normal weight (NW) with a BMI of 18.5-24.9, obese 1 (O1) 30-34.9, and obese 3 (O3)>40 kg/m(2). IR and oxidative damage status of the groups were established by HOMA value and the analysis of biomarkers of oxidative stress in plasma. Insulin polymers in systemic circulation were detected using an antibody specific coupled to magnetic beads, which were incubated in plasma from the study groups. Analysis of magnetic beads by electrophoresis on polyacrylamide gel and silver stain assessed the presence of insulin polymers. The inhibition of polymers formation was studied by the presence of (-)-epicatechin. We demonstrated that O1 and O3 subjects with IR showed higher oxidative damage to their plasma lipids and proteins than NW subjects. This oxidative damage was associated with the presence of insulin polymers in the plasma of the O1 and O3 subjects. This polymer showed a high concentration of carbonyl groups by Western blot, suggesting the participation of oxidative damage in the generation of the polymer. The antioxidant (-)-epicatechin decreased the formation of the insulin polymer, indicating that the prevention of oxidative damage can inhibit insulin polymerization. Our study revealed an association between the presence of carbonyl stress, IR, and insulin polymer formation in obese subjects. This study also demonstrates that the antioxidant (-)-epicatechin inhibits insulin polymerization.

Modeling type 2 diabetes in rats by administering tacrolimus.

The prevalence of diabetes is rapidly increasing. The current number of diagnosed cases is ~422 million, expected to reach ~640 million by 2040. Type 2 diabetes, which constitutes ~95% of the cases, is characterized by insulin resistance and a progressive loss of ß-cell function. Despite intense research efforts, no treatments are yet able to cure the disease or halt its progression. Since all existing animal models of type 2 diabetes have serious drawbacks, one is needed that represents the complete pathogenesis, is low cost and non-obese, and can be developed relatively quickly. The aim of this study was to evaluate a low-cost, non-obese model of type 2 diabetes engendered by administering a daily high dose of tacrolimus (an immunosuppressant) to Wistar rats for 4 weeks. The biochemical and antioxidant markers were measured at basal and after the 4-week tacrolimus treatment. At week 4, the values of these parameters closely resembled those observed in human type 2 diabetes, including fasting blood glucose at 141.5 mg/dL, blood glucose greater than 200 mg/dL at 120 min of the glucose tolerance test, blood glucose at varied levels in the insulin tolerance test, and elevated levels of cholesterol and triglyceride. The tacrolimus treatment produced hypoinsulinemia and sustained hyperglycemia, probably explained by the alteration found in pancreatic ß-cell function and morphology. This model should certainly be instrumental for evaluating possible type 2 diabetes treatments, and for designing new immunosuppressants that do not cause pancreatic damage, type 2 diabetes, or new-onset diabetes after transplantation (NODAT).

Selection of patients for percutaneous closure in nonlacunar cryptogenic stroke associated with patent foramen ovale. Data from the NORDICTUS cooperative registry.

INTRODUCTION: There is an extending use of percutaneous closure of patent foramen ovale (PFO) as therapy for PFO-associated cryptogenic strokes. The aim of our study was to investigate the clinical practice of percutaneous closure of PFO and to analyse the variables for decision-making on the selection of patients for this procedure. METHOD: A prospective observational multicentric survey was conducted using all the cases of cryptogenic stroke/transient ischaemic attack associated with PFO recorded in the NORDICTUS hospital registry during the period 2018-2021. Clinical data, radiological patterns, echocardiogram data and factors related to PFO-associated stroke (thromboembolic disease and paradoxical embolism criteria) were recorded. The indication for closure was analysed according to age (≤/> 60 years) and the characteristics of the PFO. RESULTS: In the group ≤ 60 years (n = 488), 143 patients (29.3%) underwent PFO closure. The most influential variables for this therapy were detection of a high-risk PFO (OR 4.11; IC 2.6-6.5, P < .001), criteria for paradoxical embolism (OR 2.61; IC 1.28-5.28; P = .008) and previous use of antithrombotics (OR 2.67; IC 1.38-5.18; P = .009). In the > 60 years group (n = 124), 24 patients had PFO closure (19%). The variables related to this option were history of pulmonary thromboembolism, predisposition to thromboembolic disease, paradoxical embolism criteria, and high-risk PFO. CONCLUSIONS: The detection of a high-risk PFO (large shunt, shunt with associated aneurysm) is the main criterion for a percutaneous closure-based therapy. Other conditions to consider in the eligibility of patients are the history of thromboembolic disease, paradoxical embolism criteria or the previous use of antithrombotics.

Oxidative stress present in the blood from obese patients modifies the structure and function of insulin.

Obesity and its associated disorders constitute a growing epidemic across the world. Numerous studies have demonstrated the presence of systemic oxidative stress in patients with obesity. In this study, we show the effects of oxidative stress present in the blood from obese patients on recombinant human insulin. Insulin was incubated with whole blood (WB) from overweight subjects (OW), obese 1 patients (O1), or normal weight volunteers (NW) (n=16 for each group). Whole blood from OW and O1, unlike WB from NW, increased the carbonyl content of insulin; however, only whole blood from O1 patients increased the amount of formazan present in the hormone. Interestingly, the incubation of insulin with WB from O1 provoked a decrease in the hypoglycemic activity of the hormone (18%), an effect due to insulin polymerization. In addition, we showed that the formation of the insulin polymer generated the formation of new epitopes and the development of a new immunogenicity. These observations show that oxidative stress present in the WB of O1 patients can result in abolition of the biological activity of insulin and contribute to the development of an immune response to the hormone.

Patterns of relapse and treatment outcome after active surveillance or adjuvant carboplatin for stage I seminoma: a retrospective study of the Spanish Germ Cell Cancer Group.

PURPOSE: Active surveillance (AS) and adjuvant chemotherapy (AC) with carboplatin are valid alternatives for managing stage I seminoma, and most relapses can be cured with cisplatin-based chemotherapy. However, some reports suggest that AC may modify the classical pattern of recurrences. METHODS: We analyzed all relapses observed in a series of 879 patients with stage I seminoma included in 4 consecutive studies of the Spanish Germ Cell Cancer Group. After a median follow-up of 67 months, recurrences were detected in 56/467 (12%) low-risk cases on AS and 13/412 (3%) high-risk cases after AC (p < 0.001). The objective was to describe clinical features, treatment and outcome. Univariate comparisons were performed between both groups. RESULTS: No significant differences were found between relapses on AS and those after AC in terms of time to relapse (13 vs 17 months), size (26 vs 27 mm), location (retroperitoneum in 88% vs 85%), and method of detection (computed tomography in 77% vs 69%). Treatment consisted of chemotherapy (etoposide + cisplatin ± bleomycin) in 89% and 92%, respectively. Late relapses (after > 3 years) were seen in 11% vs 7.7% (p = NS) and second or successive recurrences in 1.8 vs 23% (p < 0.05). With a median follow-up of 130 moths, two patients died of seminoma-unrelated causes (AS group) and the rest are alive and disease-free. CONCLUSION: In the setting of a risk-adapted treatment of stage I seminoma, the administration of two courses of AC in patients with tumor size > 4 cm and/or rete testis invasion is associated with a higher incidence of second recurrences but does not significantly modify the pattern of relapses or their outcome.

[Clinical implications of the genus Mycoplasma]. / Implicaciones clínicas de las especies del género Mycoplasma.

Within Mycoplasma genus, M. pneumoniae, M. genitalium, M. hominis or U. urealyticum are the main species that have been traditionally linked to infectious processes. However, there are many other species involved in these conditions and that are, frequently, unfamiliar to healthcare professionals. The aim of this review is to identify all Mycoplasma genus species that have been isolated in human beings and to determine their involvement in infectious pathology.

Neutral or acidic pH for the removal of contaminants of emerging concern in wastewater by solar photo-Fenton? A techno-economic assessment of continuous raceway pond reactors.

As far as the authors know, no in-depth comparison has been made between the different performances of the solar photo-Fenton process for the removal of contaminants of emerging concern (CECs) as a function of pH. To this end, real WWTP secondary effluents were treated in continuous flow mode at pilot plant scale. The effect of hydraulic residence time (HRT), liquid depth and percentage of CEC removal on treatment capacity was studied. At acidic pH (2.8), the iron source was FeSO4 and at neutral pH (7.0), it was Fe(III)-EDDS. At both pH values, 2250 L m-2 d-1 can be treated in 15-cm deep raceway pond reactors at 30 min HRT with 0.1 mM iron and 0.88 mM H2O2 in order to achieve 80% CEC removal. Treatment costs were 0.25 € m-3 and 0.56 € m-3 at acidic and neutral pH, respectively. This study paves the way for the solar photo-Fenton process to be employed on a commercial scale.

[Choroidal metastasis from a breast carcinoma. Diagnosis and follow-up with optical coherence tomography and fluorescein angiography and autofluorescence with HRA-II (Heidelberg Retina Angiograph)]. / Metástasis coroideas de carcinoma de mama. Diagnóstico y seguimiento mediante tomografía de coherencia óptica y angiofluoresceingrafía y autofluorescencia con HRA-II (Heidelberg Retina Angiograph).

CLINICAL CASE: A 69-year-old woman developed choroidal metastasis from a breast carcinoma 2 years after the initial diagnosis, surgery and chemotherapy. After treatment with palliative chemotherapy and external radiotherapy, we used fluorescein angiography (FA) and optical coherence tomography (OCT) to evaluate the resolution of the serous retinal detachment, as well as a later relapse in the optic nerve. DISCUSSION: OCT is useful in the follow-up of choroidal metastasis after treatment. However, OCT imaging is limited by the initial choroidal location of metastasis. The autofluorescence can detect exudative tumoral activity even without obvious changes in OCT or FA.

Increasing resolution of airborne pollen forecasting at a discrete sampled area in the southwest Mediterranean Basin.

Daily fluctuations of the airborne pollen concentrations produce variations on symptomatology in allergic population. Such fluctuations are influenced by local vegetal coverage, flowering phenology, geography and climatology. Since 1991, airborne pollen of Malaga province (southern Spain) has been monitored in 7 different locations. Malaga station has been kept operational uninterruptedly throughout the studied period, while the rest of the stations only worked in periods of 2-4 years. Weekly, its pollen information is updated online to inform the population in order to prevent allergic diseases. Increasing the spatial resolution of pollen information would be very useful for allergic population living at unsampled locations. Due to the impossibility of keeping operational a high number of pollen stations covering the whole province of Malaga, the aim of this study is to create spatial models to extrapolate and forecast the pollen concentrations to Malaga province by using the concentrations registered at the capital as unique input. To do so, the relationships obtained between the airborne pollen concentrations detected at Malaga city and those detected at the other stations have been used to elaborate models for the main pollen types registered at the province. These models were spatially interpolated all over the province by using co-kriging techniques and the Compensated Thermicity Index as covariable. As result of this work, pollen distribution of the 8 most prevalent taxa has been depicted all over the whole Malaga province and an allergy alert system has been set up to extrapolate pollen information from Malaga to the whole province.

Short-term anatomic effect of ranibizumab for polypoidal choroidal vasculopathy.

PURPOSE: To assess the short-term anatomic effect of intravitreal ranibizumab for polypoidal choroidal vasculopathy. METHODS: All patients had undergone a full ophthalmic examination. A monthly injection of ranibizumab was performed for 3 months. Indocyanine angiography (ICG) and optical coherence tomography (OCT) were performed 1 month after the third-month ranibizumab injection. RESULTS: Polyps disappeared on ICG angiography in 9 out of 13 lesions (69.2%). Retinal thickness diminished significantly on OCT (p=0.02). In our series we noticed a significant reduction of the percentage of patients presenting with subretinal fluid (p=0.02) and pigment epithelium detachment between the initial and final visits (0.016). In addition, we noticed that BCVA increased significantly (p 0.02). CONCLUSIONS: Monthly intravitreal injection of ranibizumab for 3 months has a short-term beneficial anatomic effect.

Angle-closure glaucoma after piggyback intraocular lens implantation.

PURPOSE: To report a case of angle closure glaucoma after piggyback intraocular lens implantation and its treatment. METHODS: The authors present the case of a 75-year-old woman who was seen in the emergency department with angle closure glaucoma. Two years before she had undergone piggyback intraocular lens (IOL) implantation in order to correct a refractive error after cataract surgery. Ultrasound biomicroscopy revealed a closed angle with synechiae in 360 degrees as well as the presence of two IOLs: one in the capsular bag and the other in the ciliary sulcus. Extraction of the anterior IOL was precluded due to the poor endothelial count. Peripheral iridotomy and trabeculectomy were ineffective to lower the intraocular pressure (IOP); the authors decided to implant with an Ahmed valve and to place the valve's tube between the two IOLs to protect the endothelium. RESULTS: After Ahmed valve implantation, IOP maintains stable around 10-12 mmHg without medical treatment. CONCLUSIONS: Ahmed valve implantation is a good option in angle closure glaucoma due to piggyback. The placement of the valve's tube between the two IOLs is a good option to protect corneal endothelium.

Agreement between slit lamp examination and optical coherence tomography in estimating cup-disc ratios.

PURPOSE: To compare optical coherence tomography (OCT) cup-disc ratio measurements with those estimated by two independent examiners using the slit lamp in an evaluation of the optic nerve head (ONH). METHODS: In 47 eyes each of 47 patients with glaucoma and 47 healthy subjects, the ONH was examined using the slit lamp with a 78 D lens. Two examiners subjectively determined the cup-disc area ratio (A-CDR), the horizontal cup-disc ratio (H-CDR), and the vertical cup-disc ratio (V-CDR). These measurements were compared to objective OCT readings obtained by a third examiner blind to the slit lamp results. RESULTS: For the three variables determined, correlation indices between the OCT readings and the two sets of slit lamp measurements were significantly higher for the glaucoma group than the control group. In the patients with glaucoma, the OCT tended to underestimate A-CDR and overestimate H-CDR. For both these variables, Bland-Altmann analysis revealed significant differences between the two methods that persisted across the whole range of CDRs examined. In contrast, differences in V-CDR varied with disc size. CONCLUSIONS: The OCT is a diagnostic tool that provides a complete automatic evaluation of the ONH. However, its measurements vary significantly from those obtained in subjective evaluations performed by experienced ophthalmologists.

Ocular inflammatory signs observed in a cohort of Spanish patients with Behçet disease and ocular inflammation.

PURPOSE: To study the clinical characteristics of a cohort of Spanish patients diagnosed with Behcet disease and who also presented ocular inflammation. METHODS: Thirty cases of Behçet disease were studied retrospectively. The authors studied age distribution, distribution by sex, clinical course, laterality, type of uveitis, secondary glaucoma, corneal involvement, hypopyon, iris-lens synechiae, secondary cataract, cystoid macular edema (CME), and papillitis (optic neuritis). RESULTS: Fourteen of the patients were men and 16 were women (ratio 0.875:1). The mean age of the patients was 35.24 years (+/-10.917; 21-61 years). In 23 patients, the disease course was recurrent. In 9 patients, the disease manifested unilaterally. In 5 patients showing unilateral onset, the contralateral eye became affected. In 2 of the 30 patients, uveitis exclusively affected the anterior segment. In 8 patients, uveitis was solely posterior. There was one case of intermediate uveitis. The remaining 19 patients showed panuveitis. Three had focal chorioretinitis. One had diffuse chorioretinitis. Fifteen showed signs of diffuse vasculitis. Eight patients showed focal vasculitis. CONCLUSIONS: Women were slightly more affected than men, although the authors found no significant correlation between sex and the clinical variables examined. Apart from one unexpected case of intermediate uveitis, the observations are similar to those reported for other patient series.

Degradation of alachlor and pyrimethanil by combined photo-Fenton and biological oxidation.

Biodegradability of aqueous solutions of the herbicide alachlor and the fungicide pyrimethanil, partly treated by photo-Fenton, and the effect of photoreaction intermediates on growth and DOC removal kinetics of the bacteria Pseudomonas putida CECT 324 are demonstrated. Toxicity of 30-120 mg L(-1) alachlor and pyrimethanil has been assayed in P. putida. The biodegradability of photocatalytic intermediates found at different photo-treatment times was evaluated for each pesticide. At a selected time during batch-mode phototreatment, larger-scale biodegradation kinetics were analysed in a 12 L bubble column bioreactor. Both alachlor and pyrimethanil are non-toxic for P. putida CECT 324 at the test concentrations, but they are not biodegradable. A approximately 100 min photo-Fenton pre-treatment was enough to enhance biodegradability, the biological oxidation response being dependent on the pesticide tested. The different alachlor and pyrimethanil respiration and carbon uptake rates in pre-treated solutions are related to change in the growth kinetics of P. putida. Reproducible results have shown that P. putida could be a suitable microorganism for determining photo-Fenton pre-treatment time.