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Immunotherapy-based combinations including pembrolizumab plus lenvatinib are the standard of care for patients with first-line clear-cell renal cell carcinoma, but these combinations are not well characterised in non-clear-cell renal cell carcinoma. We aimed to assess the activity and safety of pembrolizumab plus lenvatinib as a first-line treatment for patients with advanced non-clear-cell renal cell carcinoma. KEYNOTE-B61 is a single-arm, phase 2 trial being conducted at 48 sites (hospitals and cancer centres) in 14 countries (Australia, Canada, France, Hungary, Ireland, Italy, Poland, South Korea, Russia, Spain, Türkiye, Ukraine, the UK, and the USA). Adult patients (aged ≥18 years) with previously untreated stage IV non-clear-cell renal cell carcinoma and a Karnofsky performance status of 70% or higher were eligible for enrolment. All enrolled patients received pembrolizumab 400 mg intravenously every 6 weeks for up to 18 cycles (2 years) plus lenvatinib 20 mg orally once daily or until disease progression, unacceptable toxicity, or withdrawal; lenvatinib could be continued beyond 2 years. The primary endpoint was the proportion of patients with a confirmed objective response as per adjusted Response Evaluation Criteria in Solid Tumours (version 1.1) assessed by independent central review. Activity and safety were analysed in all patients who received at least one dose of study treatment (the as-treated population). This trial is registered with ClinicalTrials.gov (NCT04704219) and is no longer recruiting participants but is ongoing. Between Feb 23, 2021, and Jan 21, 2022, 215 patients were screened; 158 were enrolled and received treatment. Median age at baseline was 60 years (IQR 52–69), 112 (71%) of 158 patients were male, 46 (29%) were female, 128 (81%) were White, 12 (8%) were Asian, three (2%) were Black or African American, and 15 (9%) were missing data on race. As of data cutoff (Nov 7, 2022), median study follow-up was 14·9 months (IQR 11·1–17·4). 78 of 158 patients had a confirmed objective response (49%; 95% CI 41–57), including nine (6%) patients with a confirmed complete response and 69 (44%) with a confirmed partial response. Grade 3–4 treatment-related adverse events occurred in 81 (51%) of 158 patients, the most common of which were hypertension (37 [23%] of 158), proteinuria (seven [4%]), and stomatitis (six [4%]). Serious treatment-related adverse events occurred in 31 (20%) of 158 patients. Eight (5%) patients died due to adverse events, none of which was considered related to the treatment by the investigators (one each of cardiac failure, peritonitis, pneumonia, sepsis, cerebrovascular accident, suicide, pneumothorax, and pulmonary embolism). Pembrolizumab plus lenvatinib has durable antitumour activity in patients with previously untreated advanced non-clear-cell renal cell carcinoma, with a safety profile consistent with that of previous studies. Results from KEYNOTE-B61 support the use of pembrolizumab plus lenvatinib as a first-line treatment option for these patients. Merck Sharp & Dohme (a subsidiary of Merck & Co, NJ, USA), and Eisai.

A subset of patients with metastatic renal-cell carcinoma show indolent growth of metastases. Because of the toxicity and non-curative nature of systemic therapy, some of these patients could benefit from initial active surveillance. We aimed to characterise the time to initiation of systemic therapy in patients with metastatic renal-cell carcinoma under active surveillance. In this prospective phase 2 trial, we enrolled patients with treatment-naive, asymptomatic, metastatic renal-cell carcinoma from five hospitals in the USA, Spain, and the UK. Patients were radiographically assessed at baseline, every 3 months for year 1, every 4 months for year 2, then every 6 months thereafter. Patients continued on observation until initiation of systemic therapy for metastatic renal-cell carcinoma; a decision that was made at the discretion of the treating physician and patient. The primary endpoint of the study was time to initiation of systemic therapy in the per-protocol population. The follow-up of patients is ongoing. Between Aug 21, 2008, and June 7, 2013, we enrolled 52 patients. Median follow-up of patients in the study was 38·1 months (IQR 29·4–48·9). In the 48 patients included in analysis, median time on surveillance from registration on study until initiation of systemic therapy was 14·9 months (95% CI 10·6–25·0). Multivariate analysis showed that higher numbers of International Metastatic Database Consortium (IMDC) adverse risk factors (p=0·0403) and higher numbers of metastatic disease sites (p=0·0414) were associated with a shorter surveillance period. 22 (46%) patients died during the study period, all from metastatic renal-cell carcinoma. A subset of patients with metastatic renal-cell carcinoma can safely undergo surveillance before starting systemic therapy. Additional investigation is required to further define the benefits and risks of this approach. None.

In the primary analysis of CheckMate 9ER, nivolumab plus cabozantinib showed superior progression-free survival, overall survival, and objective response over sunitinib in patients with previously untreated advanced renal cell carcinoma (median follow-up of 18·1 months). Here, we report extended follow-up of overall survival and updated efficacy and safety. This open-label, randomised, phase 3 trial was done in 125 hospitals and cancer centres across 18 countries. We included patients aged 18 years or older with previously untreated advanced or metastatic clear-cell renal cell carcinoma, a Karnofsky performance status of 70% or higher, measurable disease according to Response Evaluation Criteria in Solid Tumors version 1.1 assessed by the investigator, any International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic risk category, and available tumour tissue for PD-L1 testing. Patients were randomly assigned (1:1) to nivolumab (240 mg) intravenously every 2 weeks plus cabozantinib (40 mg) orally once daily or sunitinib (50 mg orally) once daily (4 weeks per 6-week cycle). Randomisation, stratified by IMDC risk status, tumour PD-L1 expression, and geographical region, was done by permuted block within each stratum using a block size of four, via an interactive response system. The primary endpoint was progression-free survival by blinded independent central review. Overall survival was a secondary endpoint (reported here as the preplanned final analysis according to the protocol). Efficacy was assessed in all randomly assigned patients; safety was assessed in all patients who received at least one dose of any study drug. This ongoing study, closed to recruitment, is registered with ClinicalTrials.gov, NCT03141177. Between Sept 11, 2017, and May 14, 2019, 323 patients were randomly assigned to the nivolumab plus cabozantinib group and 328 to the sunitinib group. With an extended follow-up (data cutoff of June 24, 2021; median 32·9 months [IQR 30·4–35·9]), median overall survival was 37·7 months (95% CI 35·5–not estimable) in the nivolumab plus cabozantinib group and 34·3 months (29·0–not estimable) in the sunitinib group (hazard ratio [HR] 0·70 [95% CI 0·55–0·90], p=0·0043) and updated median progression-free survival was 16·6 months (12·8–19·8) versus 8·3 months (7·0–9·7; HR 0·56 [95% CI 0·46−0·68], p<0·0001). Grade 3–4 treatment-related adverse events occurred in 208 (65%) of 320 patients with nivolumab plus cabozantinib versus 172 (54%) of 320 with sunitinib. The most common grade 3–4 treatment-related adverse events were hypertension (40 [13%] of 320 patients in the nivolumab plus cabozantinib group vs 39 [12%] of 320 in the sunitinib group), palmar–plantar erythrodysaesthesia (25 [8%] vs 26 [8%]), and diarrhoea (22 [7%] vs 15 [5%]). Grade 3–4 treatment-related serious adverse events occurred in 70 (22%) of 320 patients in the nivolumab plus cabozantinib group and 31 (10%) of 320 in the sunitinib group. One additional treatment-related death occurred with sunitinib (sudden death). With extended follow-up and preplanned final overall survival analysis per protocol, nivolumab plus cabozantinib demonstrated improved efficacy versus sunitinib, further supporting the combination in the first-line treatment of advanced renal cell carcinoma. Bristol Myers Squibb and Ono Pharmaceutical.

Abstract Objective Our goal in this multicentric prospective study was 2-fold: first, to test the diagnostic accuracy of ultrasound, color Doppler imaging (CDI), and contrast-enhanced ultrasound (CEUS) in identifying disease activity in patients with Crohn’s disease (CD) compared with endoscopy as the reference standard; and, second, to construct a sonographic score that allows disease activity to be detected. Materials and methods Seventy-two patients with CD from 3 hospitals underwent within a 30-day period both colonoscopy and ultrasound (US), including mural thickness, CDI, and CEUS, prospectively as part of clinical care. A multivariate analysis was carried out to assess the influence of each of the ultrasound variables in predicting endoscopic activity. We then developed a predictive ultrasound score for disease activity, and a receiver operating characteristic (ROC) curve was constructed to determine the area under the ROC curve (AUC) and the best cut-off score value to discriminate between active and inactive disease. Results Sonographic findings that were independent predictors of the presence of active disease at endoscopy were wall thickness, color grade, and contrast parameters. A score based on those variables showed high accuracy in predicting active disease, with an area under the ROC curve of 0.972. A simpler index, without contrast parameters, also showed high accuracy in detecting disease activity (AUC, 0.923). Conclusion A score based on wall thickness, color Doppler grade, and contrast parameters showed high accuracy in predicting active disease. A score without including the use of contrast agent had practically similar results and is easier to use in monitoring response to treatment. Wall thickness, color Doppler grade, and contrast parameters are independent predictors of active disease at endoscopy. A score based on those variables is highly accurate in predicting active disease and may provide an objective measure of the therapeutic response.

We analyze, using the micro data of the Household Financial Survey (HFS) of the Bank of Spain, the consumption consequences of the household balance sheets and debt accumulation during the real estate bubble of 2002–2005, the Great Recession (2008–2011) and the subsequent economic recovery phase (2014–2017). Using quantile regression models, we find heterogeneity in household consumption behavior with respect to income and net worth levels, and in response to changes in household net worth in the last two periods. During the considered real estate bubble period, this heterogeneity in behavior is diminished, and only occurs in relation to the level of net wealth, in line with Hyman Minsky’s Paradox of Tranquility. These findings favor the post-Keynesian theory on consumption. The greater inequality leads to a higher propensity of certain households to consume in response to changes in housing and financial net worth. This is compatible with the relative income hypothesis extended in expenditure cascades models. Otherwise, households will be willing to take on more risk during economic boom periods associated with a real estate bubble, which translates into debt-financed consumption that virtually makes such heterogeneity practically disappear.

Abstract Background Limited data are available on the outcome of inflammatory bowel disease (IBD) in patients with solid organ transplantation (SOT). We describe the natural history of pre-existing IBD and de novo IBD after SOT. Methods This was a retrospective, multicenter study that included patients with pre-existing IBD at the time of SOT and patients with de novo IBD after SOT. The primary outcome was IBD progression, defined by escalation of medical treatment, surgical therapy, or hospitalization due to refractory IBD. Risk factors were identified using multivariate Cox proportional hazard analysis. Results A total of 177 patients (106 pre-existing IBD and 71 de novo IBD) were included. Most patients with pre-existing IBD (92.5%) were in remission before SOT. During follow-up, 32% of patients with pre-existing IBD had disease progression, with a median time between SOT and IBD progression of 2.2 (interquartile range, 1.3-4.6) years. In the de novo cohort, 55% of patients had disease progression with a median time to flare of 1.9 (interquartile range, 0.8-3.9) years after diagnosis. In the pre-existing IBD cohort, active IBD at the time of SOT (hazard ratio, 1.80; 95% confidence interval, 1.14-2.84; P = .012) and the presence of extraintestinal manifestations (hazard ratio, 3.10; 95% confidence interval, 1.47-6.54; P = .003) were predictive factors for IBD progression. Conclusions One-third of patients with pre-existing IBD and about half of patients with de novo IBD have disease progression after SOT. Active IBD at the time of SOT and the presence of extraintestinal manifestations were identified as risk factors for IBD progression.

A bstract There has been substantial progress in applying machine learning techniques to classification problems in collider and jet physics. But as these techniques grow in sophistication, they are becoming more sensitive to subtle features of jets that may not be well modeled in simulation. Therefore, relying on simulations for training will lead to sub-optimal performance in data, but the lack of true class labels makes it difficult to train on real data. To address this challenge we introduce a new approach, called Tag N’ Train (TNT), that can be applied to unlabeled data that has two distinct sub-objects. The technique uses a weak classifier for one of the objects to tag signal-rich and background-rich samples. These samples are then used to train a stronger classifier for the other object. We demonstrate the power of this method by applying it to a dijet resonance search. By starting with autoencoders trained directly on data as the weak classifiers, we use TNT to train substantially improved classifiers. We show that Tag N’ Train can be a powerful tool in model-agnostic searches and discuss other potential applications.

BackgroundThe outbreak of COVID-19 has rapidly evolved into a pandemic that has represented a challenge to health systems worldwide. Inflammatory bowel disease (IBD) units have been forced to change their practices to address the disease and to ensure the quality of care.MethodsWe conducted a national survey among IBD gastroenterologist members of the Spanish Working Group on Crohn’s Disease and Colitis regarding changes of practice, IBD treatments, and diagnosis and treatment of COVID-19.ResultsWe received 54 answers from Spanish hospitals. One hundred percent of the IBD units rescheduled onsite visits to telematic consultation, and elective endoscopic and surgical procedures were delayed. Protective measures were also taken in the infusion units (100% of health centers) and hospital pharmacies, with 40.7% sending subcutaneous medications to patients. No switching between intravenous and subcutaneous anti-tumor necrosis factor drugs were made. We also found that 96.1% of IBD units advised their patients to maintain treatment if they were asymptomatic for COVID-19. For patients with COVID-19 symptoms, 92.6% of IBD units referred them to primary care or the emergency department. In addition, 7.5% of IBD units made a COVID-19 diagnosis through polymerase chain reaction and/or chest x-ray.Modifications in IBD treatment and treatment recommended for COVID-19 are also discussed.ConclusionsWe report a representative national survey of changes made in the structure, diagnosis of COVID-19, and modifications in IBD treatments within IBD units.Because of the COVID-19 pandemic, IBD units have been forced to adapt their practices to address the disease. A nationwide questionnaire was conducted among IBD units regarding measures taken in terms of organization, IBD treatment, and management of patients with COVID-19 symptoms.

Monitoring avocado (Persea americana Mill., cv. Semil-34) in tropical mountain landscapes of Cambita, San Cristóbal, Dominican Republic is inherently complex due to the pronounced topographical and climatic heterogeneity that modulates the crop’s ecophysiological responses, specifically vegetative vigor, carbon allocation, and the synchronization of reproductive flushes. This study integrates 5-year (2020–2025) Sentinel-2 time series, ERA5-Land climatic variables (air temperature, total precipitation, and radiation), and geomorphometric covariates to explain variability in yield and fruit quality. Multispectral indices, including the Normalized Difference Vegetation Index (NDVI), Enhanced Vegetation Index (EVI), Normalized Difference Red Edge (NDRE), and Normalized Difference Moisture Index (NDMI), were analyzed using Partial Least Squares Regression (PLSR) to characterize phenological dynamics and rank dominant predictors. The results revealed coherent spectral phenological trajectories; however, a significant inverse relationship was detected between canopy vigor and yield during reproductive phases. High vegetation index values were significantly and negatively associated with lower production (r = −0.58, p < 0.0021), reflecting a potential source–sink imbalance. Topography functioned as a structural filter, regulating root drainage and productive stability across the landscape. While yield variability was partially explainable (R2 = 0.38), internal fruit quality, measured as dry matter content, exhibited comparatively high environmental stability. A central contribution of this research lies in identifying the “vigor paradox” in cv. Semil-34 and the suggestion that topography may exert a stronger influence than direct spectral signals under tropical hillside conditions. These findings provide an exploratory framework for anticipating yield and fruit quality through satellite remote sensing or UAVs, supporting site-specific management decisions in mountain agricultural systems.

This paper examines the perceptions of firms in April 2020, one month after the Spanish Government declared the state of alarm, about how the COVID-19 pandemic will affect their business activity in the following months, and what employment decisions they expect to make in response. The data for the study was collected by the Government of the region of Aragon (Spain) through a survey of a non-randomly selected sample of firms located in the region. In addition to prospects and intended actions, firms were asked whether or not they had applied for ERTE aid (the Spanish job retention scheme to contain the pandemic crisis). We find that firms participating (voluntarily and anonymously) in the survey anticipated rather well the severity of the effects of the pandemic in the following months. The ERTE aid helped firms to maintain the jobs of their inactive employees, while firms that did not ask for aid responded by laying off employees. Further, the ERTE aid helped to maintain the jobs of furloughed employees, but the firms receiving ERTE aid expected to lay off the same proportion of employees as firms without that aid, controlling for the different anticipated effects of the pandemic in the two groups of firms.