Patient-derived follicular lymphoma spheroids recapitulate lymph node signaling and immune profile uncovering galectin-9 as a novel immunotherapeutic target.

Follicular lymphoma (FL), the most common indolent non-Hodgkin lymphoma, constitutes a paradigm of immune tumor microenvironment (TME) contribution to disease onset, progression, and heterogenous clinical outcome. Here we present the first FL-Patient Derived Lymphoma Spheroid (FL-PDLS), including fundamental immune actors and features of TME in FL lymph nodes (LNs). FL-PDLS is organized in disc-shaped 3D structures composed of proliferating B and T cells, together with macrophages with an intermediate M1/M2 phenotype. FL-PDLS recapitulates the most relevant B-cell transcriptional pathways present in FL-LN (proliferation, epigenetic regulation, mTOR, adaptive immune system, among others). The T cell compartment in the FL-PDLS preserves CD4 subsets (follicular helper, regulatory, and follicular regulatory), also encompassing the spectrum of activation/exhaustion phenotypes in CD4 and CD8 populations. Moreover, this system is suitable for chemo and immunotherapy testing, recapitulating results obtained in the clinic. FL-PDLS allowed uncovering that soluble galectin-9 limits rituximab, rituximab, plus nivolumab/TIM-3 antitumoral activities. Blocking galectin-9 improves rituximab efficacy, highlighting galectin-9 as a novel immunotherapeutic target in FL. In conclusion, FL-PDLS maintains the crosstalk between malignant B cells and the immune LN-TME and constitutes a robust and multiplexed pre-clinical tool to perform drug screening in a patient-derived system, advancing toward personalized therapeutic approaches.

Sclerosing angiomatoid nodular transformation (SANT) of the spleen can be safely diagnosed by a core percutaneous ultrasound-guided biopsy.

Sclerosing angiomatoid nodular transformation (SANT) is a rare benign lesion of the spleen. SANT cannot be distinguished from other benign or malignant splenic tumors based on imaging findings. So, diagnosis relies on histopathologic examination. Although splenectomy is frequently considered as an option, core needle biopsy tissue analysis is safe and accurate to avoid surgery.

Safety and efficacy of parsaclisib in combination with rituximab, bendamustine + rituximab, or ibrutinib in patients with previously treated B-cell lymphoma: analysis of a phase 1 dose-finding study (CITADEL­112).

Parsaclisib, a potent and highly selective phosphoinositide 3-kinase δ inhibitor, has shown clinical activity in relapsed/refractory (R/R) B-cell lymphoma. The phase 1 CITADEL-112 (NCT03424122) study assessed safety and efficacy of parsaclisib in combination with investigator choice standard of care (SOC; rituximab [Treatment A], rituximab plus bendamustine [Treatment B], or ibrutinib [Treatment C]) in 50 patients with R/R B-cell lymphoma. The most common treatment-emergent adverse events included neutropenia (62.5%, 50.0%, and 50.0% of patients in Treatments A, B, and C, respectively); diarrhea (37.5%) and anemia (31.3%) in Treatment A; abdominal pain, asthenia, diarrhea, and nausea (each 33.3%) in Treatment B; and increased alanine and aspartate aminotransferase (each 37.5%) in Treatment C. Objective responses were observed in 13 patients (81.3%) in Treatment A, 10 (55.6%) in Treatment B, and 8 (50.0%) in Treatment C. Parsaclisib combined with SOC therapies had an expected safety profile and promising efficacy in patients with R/R B-cell lymphomas.

Bone metabolism and inflammatory biomarkers in radiographic and non-radiographic axial spondyloarthritis patients: a comprehensive evaluation.

Introduction: Axial spondyloarthritis (axSpA) is a heterogeneous disease that can be represented by radiographic axSpA (r-axSpA) and non-radiographic axSpA (nr-axSpA). This study aimed to evaluate the relationship between the markers of inflammation and bone turnover in r-axSpA patients and nr-axSpA patients. Methods: A cross-sectional study included 29 r-axSpA patients, 10 nr-axSpA patients, and 20 controls matched for age and sex. Plasma markers related to bone remodeling such as human procollagen type 1 N-terminal propeptide (P1NP), sclerostin, tartrate-resistant acid phosphatase 5b (TRACP5b), receptor activator of nuclear factor kappa B ligand (RANKL), and osteoprotegerin (OPG) were measured by an ELISA kit. A panel of 92 inflammatory molecules was analyzed by proximity extension assay. Results: R-axSpA patients had decreased plasma levels of P1NP, a marker of bone formation, compared to controls. In addition, r-axSpA patients exhibited decreased plasma levels of sclerostin, an anti-anabolic bone hormone, which would not explain the co-existence of decreased plasma P1NP concentration; however, sclerostin levels could also be influenced by inflammatory processes. Plasma markers of osteoclast activity were similar in all groups. Regarding inflammation-related molecules, nr-axSpA patients showed increased levels of serum interleukin 13 (IL13) as compared with both r-axSpA patients and controls, which may participate in the prevention of inflammation. On the other hand, r-axSpA patients had higher levels of pro-inflammatory molecules compared to controls (i.e., IL6, Oncostatin M, and TNF receptor superfamily member 9). Correlation analysis showed that sclerostin was inversely associated with IL6 and Oncostatin M among others. Conclusion: Altogether, different inflammatory profiles may play a role in the development of the skeletal features in axSpA patients particularly related to decreased bone formation. The relationship between sclerostin and inflammation and the protective actions of IL13 could be of relevance in the axSpA pathology, which is a topic for further investigation.

Long-term surveillance of the feline leukemia virus in the endangered Iberian lynx (Lynx pardinus) in Andalusia, Spain (2008-2021).

Feline leukemia virus (FeLV) infection is considered one of the most serious disease threats for the endangered Iberian lynx (Lynx pardinus) Over 14 years (2008-2021), we investigated FeLV infection using point-of-care antigen test and quantitative real-time TaqMan qPCR for provirus detection in blood and tissues in lynxes from Andalusia (Southern Spain). A total of 776 samples from 586 individuals were included in this study. The overall prevalence for FeLV antigen in blood/serum samples was 1.4% (5/360) (95% CI: 0.2-2.6), FeLV proviral DNA prevalence in blood samples was 6.2% (31/503) (95% CI: 4.1-8.6), and FeLV proviral DNA in tissues samples was 10.2% (34/333) (95% CI: 7-13.5). From a subset of 129 longitudinally sampled individuals, 9.3% (12/129) PCR-converted during the study period. Our results suggest that FeLV infection in the Andalusian population is enzootic, with circulation of the virus at low levels in almost all the sampling years. Moreover, since only one viremic individual succumbed to the infection, this study suggests that lynxes may therefore control the infection decreasing the possibility of developing a more aggressive outcome. Although our results indicate that the FeLV infection in the Iberian lynx from Andalusia tends to stay within the regressive stage, continuous FeLV surveillance is paramount to predict potential outbreaks and ensure the survival of this population.

Pain as a disease in the new International Classification of Diseases (ICD-11): Latin American expert consensus.

Aims: Pain diagnoses in the 10th version of the International Classification of Diseases (ICD-10) did not adequately support the current management of pain. Therefore, we aimed to review the new 11th revision (ICD-11) in order to analyze its usefulness for the management, coding, research and education of chronic pain from a Latin American perspective. Methods: The Latin American Federation of Associations for the Study of Pain convened a meeting of pain experts in Lima, Peru. Pain specialists from 14 Latin American countries attended the consensus meeting. Results: In ICD-11, chronic pain is defined as pain that persists or recurs longer than 3 months and is subdivided into seven categories: chronic primary pain and six types of chronic secondary pain. Chronic primary pain is now considered a disease in itself, and not a mere symptom of an underlying disease. Conclusion: The novel definition and classification of chronic pain in ICD-11 is helpful for better medical care, research and health statistics. ICD-11 will improve chronic pain management in Latin American countries, for both the pain specialist and the primary care physician.

Chronic pain is one of the most frequent reasons for medical consultation in Latin America. In the tenth revision of the International Classification of Diseases and Related Health Problems (ICD-10), chronic pain was not adequately defined and individual pain diagnoses were poorly defined. For the first time in Latin America, a meeting of pain experts analyzed and reviewed the 11th version of the International Classification of Diseases (ICD-11), when the Latin America Federation of Associations for the Study of Pain organized a meeting of experts from 14 Latin American countries. In ICD-11, chronic pain is recognized as a biopsychosocial phenomenon and defined as pain that continues or returns for more than 3 months. It is split into seven types: chronic primary pain and six types of chronic secondary pain. In ICD-11, chronic primary pain is now considered a disease in itself, not a mere manifestation of other disease. Our article is the first to address the problems, challenges and benefits of using ICD-11 from a Latin American perspective. It will help to facilitate and disseminate the use of this new classification of chronic pain. This will improve chronic pain treatment, statistics, research and development of better health strategies for pain management in Latin America.

An Approach to Establishing Diagnostic Reference Levels in Interventional Pediatric Cardiology from Different Regions of Brazil.

Diagnostic reference levels (DRLs) are a pivotal strategy to be implemented since pediatric interventional cardiology procedures are increasing. This work aimed to propose an initial set of Brazilian DRLs for pediatric interventional diagnostic and therapeutic (D&T) procedures. A retrospective study was carried out in four Brazilian states, distributed across the three regions of the country. Data were collected from pediatric patients undergoing cardiac interventional procedures (CIPs), including their age and anthropometric characteristics, and at least four parameters (number of images, exposure time, air kerma-area product-PKA, and cumulative air kerma). Data from 279 patients undergoing CIPs were gathered (147 diagnostic and 132 therapeutic procedures). There were no significant differences in exposure time and the number of images between the D&T procedures. A wide range of PKA was observed when the therapeutic procedures were compared to diagnostics for all age groups. There were significant differences between the D&T procedures, whether grouping data by patient weight or age. In terms of cumulative air kerma, it was noted that no value exceeded the level to trigger a monitoring process for patients. This study shows that it is possible to adopt them as the first proposal to establish national DRLs considering pediatric patient groups.

A rare case of Salmonella-associated acute pancreatitis in a patient with ulcerative colitis.

Inflammatory bowel disease is a known risk factor for enteric infections such as Salmonella. This infection can affect almost all major organs. Acute Salmonella pancreatitis is a rare complication. This is the case of a 61-year-old man with ulcerative colitis who developed acute pancreatitis complicating Salmonella infection.

Impact of tumor microenvironment on efficacy of anti-CD19 CAR T cell therapy or chemotherapy and transplant in large B cell lymphoma.

The phase 3 ZUMA-7 trial in second-line large B cell lymphoma demonstrated superiority of anti-CD19 CAR T cell therapy (axicabtagene ciloleucel (axi-cel)) over standard of care (SOC; salvage chemotherapy followed by hematopoietic transplantation) ( NCT03391466 ). Here, we present a prespecified exploratory analysis examining the association between pretreatment tumor characteristics and the efficacy of axi-cel versus SOC. B cell gene expression signature (GES) and CD19 expression associated significantly with improved event-free survival for axi-cel (P = 0.0002 for B cell GES; P = 0.0165 for CD19 expression) but not SOC (P = 0.9374 for B cell GES; P = 0.5526 for CD19 expression). Axi-cel showed superior event-free survival over SOC irrespective of B cell GES and CD19 expression (P = 8.56 × 10-9 for B cell GES high; P = 0.0019 for B cell GES low; P = 3.85 × 10-9 for CD19 gene high; P = 0.0017 for CD19 gene low). Low CD19 expression in malignant cells correlated with a tumor GES consisting of immune-suppressive stromal and myeloid genes, highlighting the inter-relation between malignant cell features and immune contexture substantially impacting axi-cel outcomes. Tumor burden, lactate dehydrogenase and cell-of-origin impacted SOC more than axi-cel outcomes. T cell activation and B cell GES, which are associated with improved axi-cel outcome, decreased with increasing lines of therapy. These data highlight differences in resistance mechanisms to axi-cel and SOC and support earlier intervention with axi-cel.

A low total metabolic tumor volume independently predicts for a longer time to first treatment in initially observed, low tumor burden follicular lymphoma.

Watchful waiting is an acceptable management strategy for advanced-stage, low tumor burden (LTB) patients with follicular lymphoma (FL). However, the prediction of how long this treatment-free observation period will last remains imperfect. We explored whether total metabolic tumor volume (TMTV) and other positron emission tomography parameters were predictive of time to first treatment (TTFT). We analyzed 97 grade 1-3A advanced-stage LTB FL patients and found that a high TMTV was associated with other tumor burden features at diagnosis. Patients with a TMTV above our established cutoff of 50 mL had a significantly shorter median duration of observation (2.6 vs. 8.8 years; p = 0.001). At 5 years, 77% of patients with a high TMTV and 46% of patients with a low TMTV required treatment. In the multivariable analysis, a high TMTV was the only independent factor predicting TTFT (hazard ratio = 2.09; p = 0.017). Overall, TMTV is a strong predictor of the duration of observation in LTB FL patients. Upon validation of our cutoff in external series and standardization of the methodology, the TMTV could become an additional factor to consider deferring or initiating treatment in otherwise LTB patients.

Hyperthyroidism and cardiovascular disease: an association study using big data analytics.

BACKGROUND: The cardiovascular (CV) system is profoundly affected by thyroid hormones. Both hypo- and hyperthyroidism can increase the risk of severe CV complications. OBJECTIVE: To assess the association of hyperthyroidism with major CV risk factors (CVRFs) and CV diseases (CVDs) using a big data methodology with the Savana Manager platform. MATERIAL AND METHODS: This was an observational and retrospective study. The data were obtained from the electronic medical records of the University Hospital Puerta de Hierro Majadahonda (Spain). Artificial intelligence techniques were used to extract the information from the electronic health records and Savana Manager 3.0 software was used for analysis. RESULTS: Of a total of 540,939 patients studied (53.62% females; mean age 42.2 ± 8.7 years), 5504 patients (1.02%; 69.9% women) had a diagnosis of hyperthyroidism. Patients with this diagnosis had a significantly (p < 0.0001) higher frequency of CVRFs than that found in non-hyperthyroid subjects. The higher frequency of CVRFs in patients with hyperthyroidism was observed in both women and men and in patients younger and older than 65 years of age. The total frequency of CVDs was also significantly (p < 0.0001) higher in patients diagnosed with hyperthyroidism than that found in patients without this diagnosis. The highest odds ratio values obtained were 6.40 (4.27-9.61) for embolic stroke followed by 5.99 (5.62-6.38) for atrial fibrillation. The frequency of all CVDs evaluated in patients with a diagnosis of hyperthyroidism was significantly higher in both women and men, as well as in those younger and older than 65 years, compared to subjects without this diagnosis. A multivariate regression analysis showed that hyperthyroidism was significantly and independently associated with all the CVDs evaluated except for embolic stroke. CONCLUSION: The data from this hospital cohort suggest that there is a significant association between the diagnosis of hyperthyroidism and the main CVRFs and CVDs in our population, regardless of the age and gender of the patients. Our study, in addition to confirming this association, provides useful information for understanding the applicability of artificial intelligence techniques to "real-world data and information".

The academic point-of-care anti-CD19 chimeric antigen receptor T-cell product varnimcabtagene autoleucel (ARI-0001 cells) shows efficacy and safety in the treatment of relapsed/refractory B-cell non-Hodgkin lymphoma.

Varnimcabtagene autoleucel (var-cel) is an academic anti-CD19 chimeric antigen receptor (CAR) product used for the treatment of non-Hodgkin lymphoma (NHL) in the CART19-BE-01 trial. Here we report updated outcomes of patients with NHL treated with var-cel. B-cell recovery was compared with patients with acute lymphoblastic leukaemia (ALL). Forty-five patients with NHL were treated. Cytokine release syndrome (any grade) occurred in 84% of patients (4% grade ≥3) and neurotoxicity in 7% (2% grade ≥3). The objective response rate was 73% at Day +100, and the 3-year duration of response was 56%. The 3-year progression-free and overall survival were 40% and 52% respectively. High lactate dehydrogenase was the only covariate with an impact on progression-free survival. The 3-year incidence of B-cell recovery was lower in patients with NHL compared to ALL (25% vs. 60%). In conclusion, in patients with NHL, the toxicity of var-cel was manageable, while B-cell recovery was significantly prolonged compared to ALL. This trial was registered as NCT03144583.

Foamy Macrophages in a Case of Mononucleosis With Amoxicillin-Induced Rash, Hyperlipidemia, and Hemophagocytic Lymphohistiocytosis.

ABSTRACT: A 38-year-old man presented with fever, cough, and jaundice. Four days before, he had started taking amoxicillin/clavulanic acid. He subsequently developed a morbilliform rash, and, according to clinical features and blood analyses, a diagnosis of mononucleosis with Epstein-Barr virus-associated antibiotic-induced exanthema and secondary hemophagocytic lymphohistiocytosis was made. A skin biopsy revealed a superficial perivascular lymphohistiocytic infiltrate with interface dermatitis and many foamy macrophages in the papillary dermis and around the vessels of the superficial dermal plexus. A blood lipid test uncovered marked hypercholesterolemia and hypertriglyceridemia. After treatment with dexamethasone and immunoglobulin, the skin rash, liver function, and lipid profile progressively improved. Xanthomatous cells have been observed in skin biopsies of acute graft-versus-host disease with liver involvement, and these cells have been suggested to represent a clue to the presence of hepatic disease. In our case, underlying cholestatic hepatopathy with hyperlipidemia was present. We believe that the incidental finding of foamy cells in graft-versus-host disease cases and in our case are likely related to the presence of severe liver disease with cholestatic hepatopathy and secondary hyperlipidemia in different background conditions.

Multiple rhabdomyomatous mesenchymal hamartomas in a patient with mosaic Barber-Say syndrome.

Barber-Say syndrome (BSS) is a rare congenital ectodermal dysplasia with few cases reported in the literature. We describe a 9-year-old boy with congenital generalized hypertrichosis and multiple rhabdomyomatous mesenchymal hamartomas (RMHs) on his nose and periocular region. Next-generation sequencing, performed in DNA from a blood sample, and RMH tissue, revealed a pathogenic variant in the TWIST2 gene, which was not detected in a salivary sample of the patient, nor in his parents. Therefore, we consider this variant as de novo mosaicism. To our knowledge, this is the first case of multiple RMHs associated with BSS.

Primary Hyperparathyroidism and Cardiovascular Disease: An Association Study Using Clinical Natural Language Processing Systems and Big Data Analytics.

Primary hyperparathyroidism (PHPT) seems to be associated with different cardiovascular diseases (CVDs). We evaluated the association of PHPT with major CV risk factors (CVRFs) and CVDs by using artificial intelligence (AI) tools. An observational and retrospective study was conducted using data from the electronic health records (EHRs) of the Hospital Universitario Puerta de Hierro Majadahonda (Spain). Of a total of 699,157 patients over 18 years of age studied (54.7% females), 6515 patients (0.9%; 65.4% women; mean age 67.6 ± 15.9 years) had a diagnosis of PHPT. The overall frequencies of hypertension, dyslipidemia, diabetes mellitus, and smoking habit in the cohort of patients with PTHP were all significantly (p < 0.001) higher than those found in patients without a diagnosis of PTHP. The total frequency of stroke, ischemic heart disease, atrial fibrillation, deep vein thrombosis, and pulmonary embolism in the cohort of PHPT patients were significantly (p < 0.001) higher than that found in patients without the diagnosis of PHPT. A multivariate regression analysis showed that PHPT was significantly (p < 0.001) and independently associated with all the CVDs evaluated. Our data show that there is a significant association between the diagnosis of PHPT and the main CVRFs and CVDs in our hospital population.

Systemic lupus erythematosus in pediatric patients: Pulmonary manifestations.

The pulmonary manifestations of Systemic Lupus Erythematosus (SLE) in pediatric patients are poorly understood and the pulmonary manifestations reported from the adult population are generally extrapolated to the pediatric population. In the present work, the review of 228 files was carried out, in which the pulmonary manifestations, symptoms and antibody levels of the patients treated at the Hospital Regional de Alta Especialidad de Ixtapaluca (HRAEI), State of Mexico, Mexico, were identified. Statistical significance between groups was estimated using the Chi-square and Mann-Whitney U test. The main pulmonary manifestations identified were pleurisy (14 %), pulmonary hemorrhage (3.9 %), pulmonary thromboembolism (0.9 %), acute lupus pneumonitis (0.4 %), pulmonary arterial hypertension (0.4 %), and small lung syndrome (0.4 %). While the initial symptomatology was dyspnea with an incidence of 9.6 %, the mean oxygen saturation in the population was 96.87 %. Pleural effusion was identified as the most frequent pulmonary manifestation in radiographic changes. No statistically significant difference was found in antibody levels when comparing the groups. The most common pulmonary manifestation associated with SLE is pleurisy, however, the range of pulmonary manifestations in this type of patient can be very varied, as well as the presentation of each of them.

MALAT1 expression is associated with aggressive behavior in indolent B-cell neoplasms.

MALAT1 long non-coding RNA has oncogenic roles but has been poorly studied in indolent B-cell neoplasms. Here, MALAT1 expression was analyzed using RNA-seq, microarrays or qRT-PCR in primary samples from clinico-biological subtypes of chronic lymphocytic leukemia (CLL, n = 266), paired Richter transformation (RT, n = 6) and follicular lymphoma (FL, n = 61). In peripheral blood (PB) CLL samples, high MALAT1 expression was associated with a significantly shorter time to treatment independently from other known prognostic factors. Coding genes expressed in association with MALAT1 in CLL were predominantly related to oncogenic pathways stimulated in the lymph node (LN) microenvironment. In RT paired samples, MALAT1 levels were lower, concordant with their acquired increased independency of external signals. Moreover, MALAT1 levels in paired PB/LN CLLs were similar, suggesting that the prognostic value of MALAT1 expression in PB is mirroring expression differences already present in LN. Similarly, high MALAT1 expression in FL predicted for a shorter progression-free survival, in association with expression pathways promoting FL pathogenesis. In summary, MALAT1 expression is related to pathophysiology and more aggressive clinical behavior of indolent B-cell neoplasms. Particularly in CLL, its levels could be a surrogate marker of the microenvironment stimulation and may contribute to refine the clinical management of these patients.

Survival of skyrmions along granular racetracks at room temperature.

Skyrmions can be envisioned as bits of information that can be transported along nanoracetracks. However, temperature, defects, and/or granularity can produce diffusion, pinning, and, in general, modification in their dynamics. These effects may cause undesired errors in information transport. We present simulations of a realistic system where both the (room) temperature and sample granularity are taken into account. Key feasibility magnitudes, such as the success probability of a skyrmion traveling a given distance along the racetrack, are calculated. The results are evaluated in terms of the eventual loss of skyrmions by pinning, destruction at the edges, or excessive delay due to granularity. The model proposed is based on the Fokker-Planck equation resulting from Thiele's rigid model for skyrmions. The results could serve to establish error detection criteria and, in general, to discern the dynamics of skyrmions in realistic situations.

Insularity determines nestling sex ratio variation in Egyptian vulture populations.

Variation in offspring sex ratio, particularly in birds, has been frequently studied over the last century, although seldom using long-term monitoring data. In raptors, the cost of raising males and females is not equal, and several variables have been found to have significant effects on sex ratio, including food availability, parental age, and hatching order. Sex ratio differences between island populations and their mainland counterparts have been poorly documented, despite broad scientific literature on the island syndrome reporting substantial differences in population demography and ecology. Here, we assessed individual and environmental factors potentially affecting the secondary sex ratio of the long-lived Egyptian vulture Neophron percnopterus. We used data collected from Spanish mainland and island populations over a ca. 30-year period (1995-2021) to assess the effects of insularity, parental age, breeding phenology, brood size, hatching order, type of breeding unit (pairs vs. trios), and spatial and temporal variability on offspring sex ratio. No sex bias was found at the population level, but two opposite trends were observed between mainland and island populations consistent with the island syndrome. Offspring sex ratio was nonsignificantly female-biased in mainland Spain (0.47, n = 1112) but significantly male-biased in the Canary Islands (0.55, n = 499), where a male-biased mortality among immatures could be compensating for offspring biases and maintaining a paired adult sex ratio. Temporal and spatial variation in food availability might also have some influence on sex ratio, although the difficulties in quantifying them preclude us from determining the magnitude of such influence. This study shows that insularity influences the offspring sex ratio of the Egyptian vulture through several processes that can affect island and mainland populations differentially. Our research contributes to improving our understanding of sex allocation theory by investigating whether sex ratio deviations from parity are possible as a response to changing environments comprised by multiple and complexly interrelated factors.