Amivantamab plus lazertinib versus osimertinib in first-line EGFR-mutant advanced non-small-cell lung cancer with biomarkers of high-risk disease: a secondary analysis from MARIPOSA.

BACKGROUND: Amivantamab-lazertinib significantly prolonged progression-free survival (PFS) versus osimertinib in patients with epidermal growth factor receptor (EGFR)-mutant advanced non-small-cell lung cancer [NSCLC; hazard ratio (HR) 0.70; P < 0.001], including those with a history of brain metastases (HR 0.69). Patients with TP53 co-mutations, detectable circulating tumor DNA (ctDNA), baseline liver metastases, and those without ctDNA clearance on treatment have poor prognoses. We evaluated outcomes in these high-risk subgroups. PATIENTS AND METHODS: This analysis included patients with treatment-naive, EGFR-mutant advanced NSCLC randomized to amivantamab-lazertinib (n = 429) or osimertinib (n = 429) in MARIPOSA. Pathogenic alterations were identified by next-generation sequencing (NGS) of baseline blood ctDNA with Guardant360 CDx. Ex19del and L858R ctDNA in blood was analyzed at baseline and cycle 3 day 1 (C3D1) with Biodesix droplet digital polymerase chain reaction (ddPCR). RESULTS: Baseline ctDNA for NGS of pathogenic alterations was available for 636 patients (amivantamab-lazertinib, n = 320; osimertinib, n = 316). Amivantamab-lazertinib improved median PFS (mPFS) versus osimertinib for patients with TP53 co-mutations {18.2 versus 12.9 months; HR 0.65 [95% confidence interval (CI) 0.48-0.87]; P = 0.003} and for patients with wild-type TP53 [22.1 versus 19.9 months; HR 0.75 (95% CI 0.52-1.07)]. In patients with EGFR-mutant, ddPCR-detectable baseline ctDNA, amivantamab-lazertinib significantly prolonged mPFS versus osimertinib [20.3 versus 14.8 months; HR 0.68 (95% CI 0.53-0.86); P = 0.002]. Amivantamab-lazertinib significantly improved mPFS versus osimertinib in patients without ctDNA clearance at C3D1 [16.5 versus 9.1 months; HR 0.49 (95% CI 0.27-0.87); P = 0.015] and with clearance [24.0 versus 16.5 months; HR 0.64 (95% CI 0.48-0.87); P = 0.004]. Amivantamab-lazertinib significantly prolonged mPFS versus osimertinib among randomized patients with [18.2 versus 11.0 months; HR 0.58 (95% CI 0.37-0.91); P = 0.017] and without baseline liver metastases [24.0 versus 18.3 months; HR 0.74 (95% CI 0.60-0.91); P = 0.004]. CONCLUSIONS: Amivantamab-lazertinib effectively overcomes the effect of high-risk features and represents a promising new standard of care for patients with EGFR-mutant advanced NSCLC.

Immune thrombotic thrombocytopenic purpura in older patients: Results from the Spanish TTP Registry (REPTT).

Immune thrombotic thrombocytopenic purpura (iTTP) is an ultra-rare disease that seldom occurs in the elderly. Few reports have studied the clinical course of iTTP in older patients. In this study, we have analysed the clinical characteristics at presentation and response to therapy in a series of 44 patients with iTTP ≥60 years at diagnosis from the Spanish TTP Registry and compared them with 209 patients with <60 years at diagnosis from the same Registry. Similar symptoms and laboratory results were described in both groups, except for a higher incidence of renal dysfunction among older patients (23% vs. 43.1%; p = 0.008). Front-line treatment in patients ≥60 years was like that administered in younger patients. Also, no evidence of a difference in clinical response and overall survival was seen in both groups. Of note, 14 and 25 patients ≥60 years received treatment with caplacizumab and rituximab, respectively, showing a favourable safety and efficacy profile, like that observed in patients <60 years.

Males and females with first episode psychosis present distinct profiles of social cognition and metacognition.

Deficits in social cognition and metacognition impact the course of psychosis. Sex differences in social cognition and metacognition could explain heterogeneity in psychosis. 174 (58 females) patients with first-episode psychosis completed a clinical, neuropsychological, social cognitive, and metacognitive assessment. Subsequent latent profile analysis split by sex yielded two clusters common to both sexes (a Homogeneous group, 53% and 79.3%, and an Indecisive group, 18.3% and 8.6% of males and females, respectively), a specific male profile characterized by presenting jumping to conclusions (28.7%) and a specific female profile characterized by cognitive biases (12.1%). Males and females in the homogeneous profile seem to have a more benign course of illness. Males with jumping to conclusions had more clinical symptoms and more neuropsychological deficits. Females with cognitive biases were younger and had lower self-esteem. These results suggest that males and females may benefit from specific targeted treatment and highlights the need to consider sex when planning interventions.

Controlling selectivity in N-heterocycle directed borylation of indoles.

Electrophilic borylation of indoles with BX3 (X = Cl or Br) using directing groups installed at N1 can proceed at the C2 or the C7 position. The six membered heterocycle directing groups utilised herein, pyridines and pyrimidine, result in indole C2 borylation being the dominant outcome (in the absence of a C2-substituent). In contrast, C7 borylation was achieved using five membered heterocycle directing groups, such as thiazole and benzoxazole. Calculations on the borylation of indole substituted with a five (thiazole) and a six (pyrimidine) membered heterocycle directing group indicated that borylation proceeds via borenium cations with arenium cation formation having the highest barrier in both cases. The C7 borylated isomer was calculated to be the thermodynamically favoured product with both five and six membered heterocycle directing groups, but for pyrimidine directed indole borylation the C2 product was calculated to be the kinetic product. This is in contrast to thiazole directed indole borylation with BCl3 where the C7 borylated isomer is the kinetic product too. Thus, heterocycle ring size is a useful way to control C2 vs. C7 selectivity in N-heterocycle directed indole C-H borylation.

Randomized control trial to assess the efficacy of metacognitive training compared with a psycho-educational group in people with a recent-onset psychosis.

BACKGROUND: Aims were to assess the efficacy of metacognitive training (MCT) in people with a recent onset of psychosis in terms of symptoms as a primary outcome and metacognitive variables as a secondary outcome. METHOD: A multicenter, randomized, controlled clinical trial was performed. A total of 126 patients were randomized to an MCT or a psycho-educational intervention with cognitive-behavioral elements. The sample was composed of people with a recent onset of psychosis, recruited from nine public centers in Spain. The treatment consisted of eight weekly sessions for both groups. Patients were assessed at three time-points: baseline, post-treatment, and at 6 months follow-up. The evaluator was blinded to the condition of the patient. Symptoms were assessed with the PANSS and metacognition was assessed with a battery of questionnaires of cognitive biases and social cognition. RESULTS: Both MCT and psycho-educational groups had improved symptoms post-treatment and at follow-up, with greater improvements in the MCT group. The MCT group was superior to the psycho-educational group on the Beck Cognitive Insight Scale (BCIS) total (p = 0.026) and self-certainty (p = 0.035) and dependence self-subscale of irrational beliefs, comparing baseline and post-treatment. Moreover, comparing baseline and follow-up, the MCT group was better than the psycho-educational group in self-reflectiveness on the BCIS (p = 0.047), total BCIS (p = 0.045), and intolerance to frustration (p = 0.014). Jumping to Conclusions (JTC) improved more in the MCT group than the psycho-educational group (p = 0.021). Regarding the comparison within each group, Theory of Mind (ToM), Personalizing Bias, and other subscales of irrational beliefs improved in the MCT group but not the psycho-educational group (p < 0.001-0.032). CONCLUSIONS: MCT could be an effective psychological intervention for people with recent onset of psychosis in order to improve cognitive insight, JTC, and tolerance to frustration. It seems that MCT could be useful to improve symptoms, ToM, and personalizing bias.

Prevention of transfusion-associated graft-versus-host disease with pathogen-reduced platelets with amotosalen and ultraviolet A light: a review.

BACKGROUND AND OBJECTIVES: Transfusion-associated graft-versus-host disease (TA-GVHD) is a serious complication of blood component transfusion therapy, caused by donor T lymphocytes. γ-Irradiation or pathogen inactivation methods, capable of inactivating proliferating T cells in blood components, should be selected to prevent TA-GVHD. This review summarizes the published evidence to support the use of pathogen-reduced platelets with amotosalen (150 µm) and ultraviolet A light (UVA, 320-400 nm, 3 J/cm2 ) for preventing TA-GVHD. MATERIALS AND METHODS: Available literature on the use of pathogen-reduced platelets to prevent TA-GVHD was reviewed. RESULTS: Observational studies, animal models, in vitro studies and mechanistic studies of pathogen-reduced platelets with amotosalen and UVA light showed that inactivation of T cells are equal or even superior to γ-irradiation. CONCLUSION: Pathogen-reduced platelets with amotosalen and UVA light can be used as a measure to prevent TA-GVHD.

Front microrheology of the non-Newtonian behaviour of blood: scaling theory of erythrocyte aggregation by aging.

We introduce a new framework to study the non-Newtonian behaviour of fluids at the microscale based on the analysis of front advancement. We apply this methodology to study the non-linear rheology of blood in microchannels. We carry out experiments in which the non-linear viscosity of blood samples is quantified at different haematocrits and ages. Under these conditions, blood exhibits a power-law dependence on the shear rate. In order to analyse our experimental data, we put forward a scaling theory which allows us to define an adhesion scaling number. This theory yields a scaling behaviour of the viscosity expressed as a function of the adhesion capillary number. By applying this scaling theory to samples of different ages, we are able to quantify how the characteristic adhesion energy varies as time progresses. This connection between microscopic and mesoscopic properties allows us to estimate quantitatively the change in the cell-cell adhesion energies as the sample ages.

Pediatric and neonatal transport in Spain, Portugal and Latin America. / Transporte pediátrico y neonatal en España, Portugal y Latinoamérica.

OBJECTIVE: To study the organization of inter-hospital transport of pediatric and neonatal patients in Spain, Portugal and Latin America. DESIGN: An observational study was performed. An on-line survey was sent by email including questions about characteristics of national, regional and local health transport systems, vehicles, material, and composition of the transport team and their training. SETTING: Hospital pediatric healthcare professionals treating children in Spain, Portugal and Latin America RESULTS: A total of 117 surveys from 15 countries were analyzed. Of them, 55 (47%) come from 15 regions of Spain and the rest from Portugal and 13 Latin American countries. The inter-hospital transport of pediatric patients is unified only in the Spanish regions of Baleares and Cataluña and in Portugal. Chile has a mixed unified transport system for pediatric and adult patients. Only 51.4% of responders have an educational program for the transport personnel, and only in 36.4% of them the educational program is specific for pediatric patients. In Spain and Portugal the transport is executed mostly by public entities, while in Latin America public and private systems coexist. Specific pediatric equipment is more frequent in the transport teams in the Iberian Peninsula than in Latin American teams. The specific pediatric transport training is less frequent for teams in Latin America than on Spain and Portugal. CONCLUSIONS: There is a great variation in the organization of children transport in each country and region. Most of countries and cities do not have unified and specific teams of pediatric transport, with pediatric qualified personnel and specific material.

Coagulation profile after plasma exchange using albumin as a replacement solution measured by thromboelastometry.

BACKGROUND: Significant decrease in fibrinogen and other coagulation proteins is observed after plasma exchange when albumin is used as a replacement fluid. Little is known about how those changes impact on thromboelastometry (TEM). The aim of this study was to describe the changes in TEM after performing plasma exchange procedures using 5% albumin as a replacement fluid and its correlation with the standard coagulation tests. STUDY DESIGN AND METHODS: Consecutive patients treated with plasma exchange were prospectively recorded. We performed laboratory and TEM assays extrinsec patway [EXTEM and fibrin-based TEM (fibTEM)] from patient's blood sampled immediately before starting and immediately after finishing each procedure. Bleeding events during and after the procedure were monitored. Mann-Whitney U-test and Spearman's correlation test were used when needed. RESULTS: After plasma exchange, all TEM parameters decreased under normal limits, especially the clotting time (CT): 62% reduction (range: 35-84%) and the fibTEM: 50% (range: 62-27%); maximum clot firmness (MCF) decreased to a lesser extent, 23% (range: 29-21%). Main TEM parameters showed a strong correlation with fibrinogen values: CT, r = -0·81; MCF, r = 0·85; and fibTEM, r = 0·79. No bleeding complications were observed. CONCLUSION: A profound derangement of TEM parameters was observed after PE, evidenced by delay in the clot formation and reduction in the clot firmness. More studies are warranted to elucidate the clinical implications of derangement in TEM parameters in patients without concomitant coagulopathy.

A prospective, active haemovigilance study with combined cohort analysis of 19,175 transfusions of platelet components prepared with amotosalen-UVA photochemical treatment.

BACKGROUND AND OBJECTIVES: A photochemical treatment process (PCT) utilizing amotosalen and UVA light (INTERCEPT(™) Blood System) has been developed for inactivation of viruses, bacteria, parasites and leucocytes that can contaminate blood components intended for transfusion. The objective of this study was to further characterize the safety profile of INTERCEPT-treated platelet components (PCT-PLT) administered across a broad patient population. MATERIALS AND METHODS: This open-label, observational haemovigilance programme of PCT-PLT transfusions was conducted in 21 centres in 11 countries. All transfusions were monitored for adverse events within 24 h post-transfusion and for serious adverse events (SAEs) up to 7 days post-transfusion. All adverse events were assessed for severity (Grade 0-4), and causal relationship to PCT-PLT transfusion. RESULTS: Over the course of 7 years in the study centres, 4067 patients received 19,175 PCT-PLT transfusions. Adverse events were infrequent, and most were of Grade 1 severity. On a per-transfusion basis, 123 (0.6%) were classified an acute transfusion reaction (ATR) defined as an adverse event related to the transfusion. Among these ATRs, the most common were chills (77, 0.4%) and urticaria (41, 0.2%). Fourteen SAEs were reported, of which 2 were attributed to platelet transfusion (<0.1%). No case of transfusion-related acute lung injury, transfusion-associated graft-versus-host disease, transfusion-transmitted infection or death was attributed to the transfusion of PCT-PLT. CONCLUSION: This longitudinal haemovigilance safety programme to monitor PCT-PLT transfusions demonstrated a low rate of ATRs, and a safety profile consistent with that previously reported for conventional platelet components.

Automation of blood component preparation from whole blood collections.

BACKGROUND AND OBJECTIVES: Automation of blood component preparation (BCP) from whole blood (WB) collections is increasingly being widespread implemented. This review summarizes the quality of blood components obtained with new automated devices. MATERIALS AND METHODS: We reviewed available literature on the quality of blood components obtained with new automated devices developed in the 2000s. RESULTS: Blood components obtained with the new devices met European standards. Of note, compared with platelet concentrates obtained with manual methods, automation of BCP improved the consistency of the final products. CONCLUSION: The complete automation of BCP from WB collections is still in development and it represents a huge change in paradigm.

Counting platelets at transfusion threshold levels: impact on the decision to transfuse. A BEST Collaborative - UK NEQAS(H) International Exercise.

BACKGROUND AND OBJECTIVES: Obtaining accurate and precise platelet enumeration in automatic platelet analysers at low platelet counts is a challenge. To explore the performance of current haematology analysers in counting platelet concentrations usually used as platelet transfusion threshold. MATERIAL AND METHODS: An international exercise where four blood samples with platelet levels near usual platelet transfusion thresholds was prepared and distributed. RESULTS: The samples shipped had a platelet count of 6·3, 13·3, 21·6 and 53·0 × 10(9) /l according to the international reference method. We received 82 sets of results from nine countries. Instruments from six different manufacturers were represented. Although the mean count for each of the four samples was very similar to the values, according to the reference method (9·0, 16·2, 23·0 and 57·6 × 10(9) /l), significant variability in the results was found. Assuming that these were patient samples and the result of the count used to indicate a prophylactic platelet transfusion, undertransfusion would have occurred for 24·5% of the LP1 samples at a transfusion threshold of 10 × 10(9) /l and, at a threshold of 20 × 10(9) /l, undertransfusion would have occurred for 7·2% of the LP1 and 16·2% of the LP2 samples and overtransfusion would have occurred with 23·1% of the LP3 samples. CONCLUSION: The results suggest that significant inaccuracy exists in counting low levels of platelets and that this inaccuracy might have a significant impact in under- and overtransfusion of platelet concentrates to patients.

Morbimortality associated to acute kidney injury in patients admitted to pediatric intensive care units.

AIM: To describe the morbimortality associated to the development of acute kidney injury (AKI) defined by the pediatric adaptation of the RIFLE criteria in a Pediatric Intensive Care Unit (PICU). DESIGN: A retrospective cohort study was carried out. SETTING: Children admitted to a PICU in a tertiary care hospital. Patients or participants A total of 320 children admitted to a tertiary care hospital PICU during the year 2011. Neonates and renal transplant patients were excluded. Primary endpoints AKI was defined and classified according to the pediatric adaptation to the RIFLE criteria. PICU and hospital stays, use of mechanical ventilation and mortality were used to evaluate morbimortality. RESULTS: A total of 315 children met the inclusion criteria, with a median age of 19 months (range 6-72). Of these patients, 128 presented AKI (73 reached the Risk category and 55 reached the Injury and Failure categories). Children with AKI presented a longer PICU stay (6.0 [4.0-12.5] vs. 3.5 [2.0-7.0] days) and hospital stay (17 [10-32] vs. 10 [7-15] days), and a greater need for mechanical ventilation (61.7 vs. 36.9%). The development of AKI was an independent factor of morbidity, associated with a longer PICU and hospital stay, and with a need for longer mechanical ventilation, with a proportional relationship between increasing morbidity and the severity of AKI. CONCLUSION: The development of AKI in critically ill children is associated with increased morbimortality, which is proportional to the severity of renal injury.

Clinical application of midtrimester non-invasive fetal RHD genotyping and identification of RHD variants in a mixed-ethnic population.

OBJECTIVE: This study aims to assess the suitability of non-invasive prenatal RHD genotyping in non-immunized midtrimester pregnant women from a mixed ethnic population, to prevent unnecessary anti-D immunoglobulin prophylaxis and to identify RHD variants METHODS: Rhesus D-negative pregnant women were offered fetal RHD genotyping at 24 gestational weeks. A total of 284 samples were tested for RHD status using multiplex rt-PCR amplification of exons 5 and 7 of the RHD gene and exons 6 and 10 in selected cases. Women carrying RHD-negative fetuses were counseled about their option to avoid routine antenatal anti-D immunoglobulin administration. Diagnostic accuracy of RHD genotyping was compared with postnatal Rhesus D serotyping. RESULTS: A total of 184 positives (65%), 91 negatives (32%) and 7 cases (2.5%) compatibles with RHD variants were detected by RHD genotyping. No false negative results were found, and a single false positive was observed in a twin pregnancy. Genotyping was accepted when offered by 94% of women (284/302), and anti-D immunoglobulin was avoided in 95% (90/95) of RHD-negative fetuses. CONCLUSIONS: Non-invasive routine antenatal RHD genotyping at 24 weeks of pregnancy is a highly accurate method, resulting in the avoidance of 95% of unnecessary administrations of anti-D immunoglobulin, with no false negative results.

Therapeutic efficacy of platelet components treated with amotosalen and ultraviolet A pathogen inactivation method: results of a meta-analysis of randomized controlled trials.

BACKGROUND AND OBJECTIVES: There are conflicting data regarding the therapeutic efficacy of platelets inactivated using amotosalen and ultraviolet A light. We have performed a meta-analysis to summarize the results of different randomized controlled trials (RCT). MATERIALS AND METHODS: Five RCTs reported through March 2011 met the criteria for meta-analysis. Weighted mean difference (WMD) in corrected count increment (CCI) at 1 h, CCI-24 h, and transfusion interval (days) and summary odds ratio (OR) of bleeding in inactivated platelet (I-P) group vs. noninactivated platelet (C-P) group were calculated across studies. RESULTS: Randomized controlled trials were statistically homogeneous when we analysed CCI-24 h, and the transfusion of C-P was associated with a higher CCI-24 h when compared with the transfusion of I-P (WMD, 3×10(3); 95% CI, 2·32×10(3)-3·69×10(3); P<0·00001). RCTs were statistically heterogeneous when we analysed CCI-1 h, transfusion interval and OR of bleeding. Regarding the OR of bleeding in the I-P and C-P groups, it varied by as much as a multiple of four among the trials, from 0·66 to 2·66. When we combined double-blinded and high methodologic quality score RCTs, the use of I-P was not statistically associated with an increase in the OR of bleeding when compared with the use of C-P (OR, 0·97; 95% CI, 0·75-1·27; P=0·84). CONCLUSION: Although the transfusion of I-P was associated with lower CCI-24 h when compared with the transfusion of C-P, this was not associated with differences in the OR of bleeding between I-P and C-P.