Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: primary results from the phase III MARIPOSA-2 study.

BACKGROUND: Amivantamab plus carboplatin-pemetrexed (chemotherapy) with and without lazertinib demonstrated antitumor activity in patients with refractory epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC) in phase I studies. These combinations were evaluated in a global phase III trial. PATIENTS AND METHODS: A total of 657 patients with EGFR-mutated (exon 19 deletions or L858R) locally advanced or metastatic NSCLC after disease progression on osimertinib were randomized 2 : 2 : 1 to receive amivantamab-lazertinib-chemotherapy, chemotherapy, or amivantamab-chemotherapy. The dual primary endpoints were progression-free survival (PFS) of amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy. During the study, hematologic toxicities observed in the amivantamab-lazertinib-chemotherapy arm necessitated a regimen change to start lazertinib after carboplatin completion. RESULTS: All baseline characteristics were well balanced across the three arms, including by history of brain metastases and prior brain radiation. PFS was significantly longer for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy [hazard ratio (HR) for disease progression or death 0.48 and 0.44, respectively; P < 0.001 for both; median of 6.3 and 8.3 versus 4.2 months, respectively]. Consistent PFS results were seen by investigator assessment (HR for disease progression or death 0.41 and 0.38 for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy, respectively; P < 0.001 for both; median of 8.2 and 8.3 versus 4.2 months, respectively). Objective response rate was significantly higher for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy (64% and 63% versus 36%, respectively; P < 0.001 for both). Median intracranial PFS was 12.5 and 12.8 versus 8.3 months for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy (HR for intracranial disease progression or death 0.55 and 0.58, respectively). Predominant adverse events (AEs) in the amivantamab-containing regimens were hematologic, EGFR-, and MET-related toxicities. Amivantamab-chemotherapy had lower rates of hematologic AEs than amivantamab-lazertinib-chemotherapy. CONCLUSIONS: Amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy improved PFS and intracranial PFS versus chemotherapy in a population with limited options after disease progression on osimertinib. Longer follow-up is needed for the modified amivantamab-lazertinib-chemotherapy regimen.

Analysis of apheresis outcomes in a cohort of Chilean patients treated with autologous stem cell transplantation: A single center real-world experience.

Adequate stem cell harvesting is required for autologous hematopoietic transplantation. In deficient mobilizer patients, the collection of stem cells can be challenging because of the impossibility of achieving satisfactory CD34 cell counts with GCSF + - chemotherapy. Plerixafor is a potent and expensive drug that promotes the release of stem cells from the medullary niche to the peripheral blood and allows satisfactory harvests. We performed a retrospective analysis of 370 patients with myeloma and lymphoma harvested at our institution. 99 % of patients achieved satisfactory apheresis using Plerixafor in 45 %. Satisfactory harvests were obtained in patients mobilized with GCSF or plerixafor. In patients who used plerixafor, it was necessary to perform fewer apheresis procedures (P = 0.05). In multivariate analysis, the only factor that predicted the need for plerixafor was the presence of less than 30,000 CD34 / ul on the day of apheresis (OR 0.3. p < 0.001). Since we adopted the plerixafor protocol guided by CD34 counts, the number of patients with harvest failure has decreased. In conclusion, the rational and standardized use of plerixafor favors satisfactory harvest in patients who require autologous transplantation in South-American patients.

Effect of female sex hormones on the developmental cycle of Chlamydia abortus compared to a penicillin-induced model of persistent infection.

BACKGROUND: Chlamydia abortus, an obligate intracellular pathogen with an affinity for placenta, causes reproductive failure. In non-pregnant animals, an initial latent infection is established until the next gestation, when the microorganism is reactivated, causing abortion. The precise mechanisms that trigger the awakening of C. abortus are still unknown. Sexual hormones such as estradiol and progesterone have been shown to affect the outcome of infection in other species of the family Chlamydiaceae, while estrogens increase chlamydial infection, progesterone has the opposite effect. To try to establish whether there is a relationship between these events and the latency/ reactivation of C. abortus in the reproductive tract of small ruminants, ovine endometrial (LE) and trophoblastic (AH-1) cells were treated with estradiol or progesterone prior to their infection with C. abortus. The results are compared with those obtained for treatment with penicillin prior to infection, which is a well-established model for studying persistent infection in other chlamydial species. Cells were examined by transmission electron microscopy, and an mRNA expression analysis of 16 genes related to the chlamydial developmental cycle was made. RESULTS: The changes observed in this study by the action of sex hormones seem to depend on the type of cell where the infection develops. In addition, while the changes are morphologically similar to those induced by treatment with penicillin, the patterns of gene expression are different. Gene expression patterns therefore, seem to depend on the persistence induced models of C. abortus used. Hormone treatments induced aberrant forms in infected endometrial cells but did not affect the chlamydial morphology in trophoblast cells. At the genetic level, hormones did not induce significant changes in the expression of the studied genes. CONCLUSIONS: The results suggest that penicillin induces a state of persistence in in vitro cultured C. abortus with characteristic morphological features and gene transcriptional patterns. However, the influence of hormones on the C. abortus developmental cycle is mediated by changes in the host cell environment. Furthermore, a persistent state in C. abortus cannot be characterised by a single profile of gene expression pattern, but may change depending on the model used to induce persistence.

Reply to Comment by Zhang on "Exploring the Influence of Smallholders' Perceptions Regarding Water Availability on Crop Choice and Water Allocation Through Socio-hydrological Modeling".

Zhang (2019, https://doi.org/10.1002/wrcr.v54.4) criticizes several of the assumptions and parameter choices of the model of Kuil et al. (2018, https://doi.org/10.1002/2017WR021420) and claims that, due to an inconsistency in the irrigation equation, the key findings should be interpreted with much caution. We address each of the comments and show that the conclusions of Kuil et al. (2018, https://doi.org/10.1002/2017WR021420) remain fully valid.

Recommendations for the prevention and diagnosis of asthma in children: Evidence from international guidelines adapted for Mexico.

BACKGROUND: With the availability of high-quality asthma guidelines worldwide, one possible approach of developing a valid guideline, without re-working the evidence, already analysed by major guidelines, is the ADAPTE approach, as was used for the development of National Guidelines on asthma. METHODS: The guidelines development group (GDG) covered a broad range of experts from medical specialities, primary care physicians and methodologists. The core group of the GDG searched the literature for asthma guidelines 2005 onward, and analysed the 11 best guidelines with AGREE-II to select three mother guidelines. Key clinical questions were formulated covering each step of the asthma management. RESULTS: The selected mother guidelines are British Thoracic Society (BTS), GINA and GEMA 2015. Responses to the questions were formulated according to the evidence in the mother guidelines. Recommendations or suggestions were made for asthma treatment in Mexico by the core group, and adjusted during several rounds of a Delphi process, taking into account: 1. Evidence; 2. Safety; 3. Cost; 4. Patient preference - all these set against the background of the local reality. Here the detailed analysis of the evidence present in BTS/GINA/GEMA sections on prevention and diagnosis in paediatric asthma are presented for three age-groups: children with asthma ≤5 years, 6-11 years and ≥12 years. CONCLUSIONS: For the prevention and diagnosis sections, applying the AGREE-II method is useful to develop a scientifically-sustained document, adjusted to the local reality per country, as is the Mexican Guideline on Asthma.

National registry of hemoglobinopathies in Spain (REPHem).

BACKGROUND: Although highly prevalent throughout the world, the accurate prevalence of hemoglobinopathies in Spain is unknown. PROCEDURE: This study presents data on the national registry of hemoglobinopathies of patients with thalassemia major (TM), thalassemia intermedia (TI), and sickle cell disease (SCD) in Spain created in 2014. Fifty centers reported cases retrospectively. Data were registered from neonatal screening or from the first contact at diagnosis until last follow-up or death. RESULTS: Data of the 715 eligible patients were collected: 615 SCD (497 SS, 64 SC, 54 SBeta phenotypes), 73 thalassemia, 9 CC phenotype, and 18 other variants. Most of the SCD patients were born in Spain (65%), and 51% of these were diagnosed at newborn screening. Median age at the first diagnosis was 0.4 years for thalassemia and 1.0 years for SCD. The estimated incidence was 0.002 thalassemia cases and 0.03 SCD cases/1,000 live births. Median age was 8.9 years (0.2-33.7) for thalassemia and 8.1 years (0.2-32.8) for SCD patients. Stroke was registered in 16 SCD cases. Transplantation was performed in 43 TM and 23 SCD patients at a median age of 5.2 and 7.8 years, respectively. Twenty-one patients died (3 TM, 17 SCD, 1 CC) and 200 were lost to follow-up. Causes of death were related to transplantation in three patients with TM and three patients with SCD. Death did not seem to be associated with SCD in six patients, but nine patients died secondary to disease complications. Overall survival was 95% at 15 years of age. CONCLUSIONS: The registry provides data about the prevalence of hemoglobinopathies in Spain and will permit future cohort studies and the possibility of comparison with other registries.

Land use change impacts on floods at the catchment scale: Challenges and opportunities for future research.

Research gaps in understanding flood changes at the catchment scale caused by changes in forest management, agricultural practices, artificial drainage, and terracing are identified. Potential strategies in addressing these gaps are proposed, such as complex systems approaches to link processes across time scales, long-term experiments on physical-chemical-biological process interactions, and a focus on connectivity and patterns across spatial scales. It is suggested that these strategies will stimulate new research that coherently addresses the issues across hydrology, soil and agricultural sciences, forest engineering, forest ecology, and geomorphology.

Detection of hotspots and rapid determination of methane emissions from landfills via a ground-surface method.

We present a method for the rapid determination of methane emissions from landfills based on atmospheric dispersion theory, which suggests that the methane concentration, at a small distance from the soil/atmosphere interface, is proportional to its flux. Thus, after suitable calibration, the determination of methane concentrations close to the ground allows for flux determination in a shorter time than with standard enclosure techniques. This concept was tested using a surface probe in direct contact with the ground. The probe extracts a continuous sample of the air at the probe/ground interface and transports it to a portable methane analyzer. It was observed that stable methane concentrations were measured 30 s after the probe was positioned at the measurement point. These concentrations correlated well with the fluxes measured by standard static chambers. The method was used to determine the fluxes at 217 points within a 90,000 m(2) landfill. These measurements facilitated mapping of the CH4 emissions and the localization of hotspots. We conclude that the method is simple, effective, and relatively quick, compared to existing standard methods.

Consensus update on the therapeutic approach to patients with neurogenic detrusor overactivity.

INTRODUCTION AND OBJECTIVES: A Consensus document on the management of patients with neurogenic detrusor overactivity (NDO) was published in 2018. The present document aims to update its recommendations regarding treatment considering the new evidence available, and to contribute to the standardization of the management of this disorder. METHODS: The methodology used was based on a systematic review and the Nominal Group Technique. The clinical coordinator (CC) and the Consensus update group (CUG) defined the questions to be updated and carried out a systematic review to identify the new available evidence. After being evaluated by the expert panel, the relevant recommendations were updated and agreed in a consensus meeting. RESULTS: A total of 3210 publications were identified and 26 publications that met the inclusion criteria were included. The CUG updated 18 recommendations on the therapeutic approach to NDO. Unanimous consensus was reached on all of them. CONCLUSIONS: Previous recommendations need to be revised due to the availability of new drugs, the increasing evidence on the use of botulinum toxin or neuromodulation procedures, and new surgical options.

Risk management of radioiodine treatment in differentiated thyroid cancer.

INTRODUCTION: Patient safety is paramount in providing quality healthcare and constitutes a global concern for healthcare systems. Radioiodine treatment to patients with well-differentiated thyroid cancer is not without risks. The aim of this study is to identify, evaluate and mitigate the risks associated with this procedure. MATERIALS AND METHODS: A single-centre descriptive study was conducted in which risk management was carried out by establishing a risk map using FMEA methodology. RESULTS: Based on the process map 6 sub-processes and 23 failure modes in the three phases of the treatment process were analysed. According to risk priority number (RPN), the sub-process with the highest risk was administrative management (RPN 82), followed by treatment per se and post-treatment imaging (both with RPN 70). An overall process RPN of 300 (156 pre-treatment, 74 treatment and 70 post-treatment) was obtained. Failures directly related to the patient pose a high risk. The implementation of verification systems, performing tasks earlier and providing quality medical information are the most relevant preventive measures to be implemented. CONCLUSIONS: The application of the FMEA methodology in the risk management for radioiodine treatment is a valuable tool for improving the quality and safety of this process. The risk map has been able to identify failures at different stages, assess their causes and effects, prioritise the risks identified and implement preventive and corrective measures that can be monitored, ensuring the effectiveness of the actions taken.