Comparing R-Bendamustine vs. R-CHOP Plus Maintenance Therapy as First-Line Systemic Treatment in Follicular Lymphoma: A Multicenter Retrospective GELTAMO Study.

Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and R-bendamustine (R-B) are the most common frontline treatment strategies for advanced-stage follicular lymphoma (FL). After R-CHOP induction therapy, using rituximab for maintenance therapy notably improves outcomes; however, whether this can be achieved by using the same approach after R-B therapy is still being determined. This retrospective analysis compared 476 FL patients from 17 GELTAMO centers who received R-based regimens followed by rituximab maintenance therapy for untreated advanced-stage FL. The complete response rate at the end of induction was higher with R-B and relapses were more frequent with R-CHOP. During induction, cytopenias were significantly more frequent with R-CHOP and so was the use of colony-stimulating factors. During maintenance therapy, R-B showed more neutropenia and infectious toxicity. After a median follow-up of 81 months (95% CI: 77-86), the 6-year rates of progression-free survival (PFS) were 79% (95% CI: 72-86) for R-bendamustine vs. 67% (95% CI: 61-73) for R-CHOP (p = 0.046), and 6-year overall survival (OS) values were 91% (95% CI: 86-96) for R-B vs. 91% (95% CI: 87-94) for R-CHOP (p = 0.49). In conclusion, R-B followed by rituximab maintenance therapy in patients with previously untreated FL resulted in significantly longer PFS than R-CHOP, with older patients also benefiting from this treatment without further toxicity. Adverse events during maintenance were more frequent with R-B without impacting mortality.

Association of Cytogenetics Aberrations and IGHV Mutations with Outcome in Chronic Lymphocytic Leukemia Patients in a Real-World Clinical Setting.

Immunoglobulin heavy chain variable ( IGHV ) region mutations, TP53 mutation, fluorescence in situ hybridization (FISH), and cytogenetic analysis are the most important prognostic biomarkers used in chronic lymphocytic leukemia (CLL) patients in our daily practice. In real-life environment, there are scarce studies that analyze the correlation of these factors with outcome, mainly referred to time to first treatment (TTFT) and overall survival (OS). This study aimed to typify IGHV mutation status, family usage, FISH aberrations, and complex karyotype (CK) and to analyze the prognostic impact in TTFT and OS in retrospective study of 375 CLL patients from a Spanish cohort. We found unmutated CLL (U-CLL) was associated with more aggressive disease, shorter TTFT (48 vs. 133 months, p < 0.0001), and shorter OS (112 vs. 246 months, p < 0.0001) than the mutated CLL. IGHV3 was the most frequently used IGHV family (46%), followed by IGHV1 (30%) and IGHV4 (16%). IGHV5-51 and IGHV1-69 subfamilies were associated with poor prognosis, while IGHV4 and IGHV2 showed the best outcomes. The prevalence of CK was 15% and was significantly associated with U-CLL. In the multivariable analysis, IGHV2 gene usage and del13q were associated with longer TTFT, while VH1-02, +12, del11q, del17p, and U-CLL with shorter TTFT. Moreover, VH1-69 usage, del11q, del17p, and U-CLL were significantly associated with shorter OS. A comprehensive analysis of genetic prognostic factors provides a more precise information on the outcome of CLL patients. In addition to FISH cytogenetic aberrations, IGHV and TP53 mutations, IGHV gene families, and CK information could help clinicians in the decision-making process.

Outcomes and Management of the SARS-CoV2 Omicron Variant in Recipients of Hematopoietic Cell Transplantation and Chimeric Antigen Receptor T Cell Therapy.

Hematopoietic cell transplantation (HCT) and chimeric antigen receptor T cell therapy (CAR-T) recipients who develop Coronavirus disease 2019 (COVID-19) can have decreased overall survival (OS), likely due to disease-inherent and therapy-related immunodeficiency. The availability of COVID-19-directed therapies and vaccines have improved COVID-19-related outcomes, but immunocompromised individuals remain vulnerable. Specifically, the effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant infections, including Omicron and its sublineages, particularly in HCT recipients, remain to be defined. The aim of this study was to compare the impact of SARS-CoV-2 Omicron infections in HCT/CAR-T recipients with outcomes previously reported for ancestral SARS-CoV-2 infections early in the pandemic (March to June 2020). This was a retrospective analysis of adult HCT/CAR-T recipients diagnosed with COVID-19 at Memorial Sloan Kettering Cancer Center between July 2021 and July 2022. We identified 353 patients (172 autologous HCT recipients [49%], 152 allogeneic HCT recipients [43%], and 29 CAR-T recipients [8%]), with a median time from HCT/CAR-T to SARS-CoV-2 infection of 1010 days (interquartile range, 300 to 2046 days). Forty-one patients (12%) were diagnosed with COVID-19 during the delta wave, and 312 patients (88%) were diagnosed during the Omicron wave. Risk factors associated with increased odds of COVID-19-related hospitalization were the presence of 2 or more comorbidities (odds ratio [OR], 4.9; 95% confidence interval [CI], 2.4 to 10.7; P < .001), CAR-T therapy compared to allogeneic HCT (OR, 7.7; 95% CI, 3.0 to 20.0; P < .001), hypogammaglobulinemia (OR, 2.71; 95% CI, 1.06 to 6.40; P = .027), and age at COVID-19 diagnosis (OR, 1.03; 95% CI, 1.0 to 1.05; P = .04). In contrast, infection during the Omicron variant BA5/BA4-dominant period compared to variant BA1 (OR, .21; 95% CI, .03 to .73; P = .037) and more than 3 years from HCT/CAR-T therapy to COVID-19 diagnosis compared to early infection at <100 days (OR, .31; 95% CI, .12 to .79; P = .011) were associated with a decreased odds for hospitalization. The OS at 12 months from COVID-19 diagnosis was 89% (95% CI, 84% to 94%), with 6 of 26 deaths attributable to COVID-19. Patients with the ancestral strain of SAR-CoV-2 had a lower OS at 12 months, with 73% (95% CI, 62% to 84%) versus 89% (95% CI, 84% to 94%; P < .001) in the Omicron cohort. Specific COVID-19 treatment was administered in 62% of patients, and 84% were vaccinated with mRNA COVID-19 vaccines. Vaccinated patients had significantly better OS than unvaccinated patients (90% [95% CI, 86% to 95%] versus 82% [95% CI, 72% to 94%] at 12 months; P = .003). No significant difference in OS was observed in patients infected with the Omicron and those infected with the Delta variant (P = .4) or treated with specific COVID-19 treatments compared with those not treated (P = .2). We observed higher OS in HCT and CAR-T recipients infected with the Omicron variants compared to those infected with the ancestral strain of SARS-CoV2. The use of COVID-19 antivirals, mAbs, and vaccines might have contributed to the improved outcomes.

Low-risk HPLLs/ABC score patients with splenic marginal zone lymphoma can be safely managed without treatment: Results from a prospective Spanish study.

The aims of our study were to analyse compliance with the 2014 GELTAMO SMZL Guidelines, in patients with splenic marginal zone lymphoma (SMZL), and to evaluate the outcome according to the HPLLs/ABC-adapted therapeutic strategy. Observational prospective multicenter study of 181 SMZL patients diagnosed between 2014 and 2020. Lymphoma-specific survival (LSS), composite event-free survival (CEFS) and response rates were assessed. 57% of the 168 patients included in the analysis followed the Guidelines. The overall response rate was higher in the rituximab chemotherapy and in the rituximab arms compared with the splenectomy arm (p < 0.001). The 5-year overall survival was 77% and the 5-year LSS of 93%. There were no differences in the 5-year LSS according to the treatment received (p = 0.68). The 5-year CEFS in the overall series was 45%, and there were significant differences between scores A and B (p = 0.036). There were no significant differences when comparing LSS and progression-free survival in patients treated with rituximab or rituximab chemotherapy at diagnosis or after observation. Our data support HPLLs/ABC score as a practical tool for the management of SMZL, observation as the best approach for patients in group A and rituximab as the best treatment for group B.

A pilot screening for cognitive impairment through voice technology (WAY2AGE).

Voice technology has grown exponentially, offering an opportunity to different fields, such as the health area. Considering that language can be a sign of cognitive impairment and most screening tools are based on speech measures, these devices are of interest. The aim of this work was to examine a screening tool for Mild Cognitive Impairment (MCI) through voice technology. For this reason, the WAY2AGE voice Bot was tested across Mini-Mental (MMSE) scores. The main results depict a strong relationship between MMSE and WAY2AGE scores, as well as a good AUC value to discriminate between no cognitive impairment (NCI) and MCI groups. However, a relationship between age and WAY2AGE scores, but not between age and MMSE scores, was found. This would indicate that, even if WAY2AGE seems sensitive to detect MCI, the voice tool is age-sensitive and not as robust as the traditional MMSE scale. Future lines of research should look more deeply into parameters that distinguish developmental changes. As a screening tool, these results are of interest for the health area and for at-risk older adults.

Extranodal natural killer/T-cell lymphoma nasal type in a western population: Molecular profiling identifies new therapeutic targets.

(A) Correlation matrix of unsupervised co-regulated genes, based on the 208 genes included in the NanoString platform. Some of the clusters of co-regulated genes corresponded to the following: Inflammatory cells; Epstein-Barr virus; B-cells; Cytotoxic T-cells; T-cells; and Proliferation. (B) Analysis of genomic alterations by targeted sequencing. Distribution of mutations in the 62 analyzed genes. Rows correspond to sequenced genes, columns represent individual patients. Color coding: green, missense; blue, synonymous; pink, frameshift; violet, Indel; red, stop gained; yellow, UTR.

Psychometric Properties of the Subjective Cognitive Decline Questionnaire (SCD-Q) and Its Invariance across Age Groups.

Considering that a good sense of subjective cognitive decline seems to be crucial to prevent decline before clinical impairment, the interest in examining tools on this front were raised in the last decade. The aim of the present study is to examine the psychometric properties of the Subjective Cognitive Decline Questionnaire (SCD-Q) across age in its Spanish adaptation. It should be noted that two constructs were proposed in this context: mnestic processes and executive function factors. For this reason, a sample of 750 individuals aged from 18 to 82 years participated in the study. They were divided into three different groups: young, middle, and older adults. A confirmatory factor analysis (CFA) and invariance analysis were carried out. Moreover, a logistic regression was employed to address the role of age. The results support a good goodness of fit for both uni- and bifactorial models. The invariance analysis reached the structural covariances levels. Last, age did not predict the recognition of cognitive decline in the last two years, while the SCD-Q bifactorial model did. These results are of interest both on a theoretical level, to provide more information on models of cognitive impairment, and on a practical level, for screening.

B-cell malignancies treated with targeted drugs and SARS-CoV-2 infection: A European Hematology Association Survey (EPICOVIDEHA).

Patients with lymphoproliferative diseases (LPD) are vulnerable to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Here, we describe and analyze the outcome of 366 adult patients with chronic lymphocytic leukemia (CLL) or non-Hodgkin Lymphoma (NHL) treated with targeted drugs and laboratory-confirmed COVID-19 diagnosed between February 2020 and January 2022. Median follow-up was 70.5 days (IQR 0-609). Most used targeted drugs were Bruton-kinase inhibitors (BKIs) (N= 201, 55%), anti-CD20 other than rituximab (N=61, 16%), BCL2 inhibitors (N=33, 9%) and lenalidomide (N=28, 8%).Only 16.2% of the patients were vaccinated with 2 or more doses of vaccine at the onset of COVID-19. Mortality was 24% (89/366) on day 30 and 36%(134/366) on the last day of follow-up. Age >75 years (p<0.001, HR 1.036), active malignancy (p<0.001, HR 2.215), severe COVID-19 (p=0.017, HR 2.270) and admission to ICU (p<0.001, HR 5.751) were risk factors for mortality at last day of follow up. There was no difference in OS rates in NHL vs CLL patients (p=0.306), nor in patients treated with or without BKIs (p=0.151). Mortality in ICU was 66% (CLL 61%, NHL 76%). Overall mortality rate decreased according to vaccination status, being 39% in unvaccinated patients, 32% and 26% in those having received one or two doses, respectively, and 20% in patients with a booster dose (p=0.245). Overall mortality rate dropped from 41% during the first semester of 2020 to 25% at the last semester of 2021. These results show increased severity and mortality from COVID-19 in LPDs patients treated with targeted drugs.

Single versus tandem autologous stem-cell transplantation in patients with newly diagnosed multiple myeloma and high-risk cytogenetics. A retrospective, open-label study of the PETHEMA/Spanish Myeloma Group (GEM).

Tandem ASCT has been suggested as a valid approach to improve the prognosis of patients with MM and HR cytogenetic. In this observational, retrospective study, 213 patients with newly diagnosed MM and HR cytogenetic in 35 hospitals from the Spanish Myeloma Group underwent single or tandem ASCT between January 2015 and December 2019 after induction with VTD/VRD. HR cytogenetic was defined as having ≥1 of the following: del17p, t(4;14), t(14;16) or gain 1q21. More patients in the tandem group had R-ISS 3 and >1 cytogenetic abnormality at diagnosis. With a median follow-up of 31 months (range, 10-82), PFS after single ASCT was 41 months versus 48 months with tandem ASCT (p = 0.33). PFS in patients with del17p undergoing single ASCT was 41 months, while 52% of patients undergoing tandem ASCT were alive and disease free at 48 months. In conclusion, tandem ASCT partly overcomes the bad prognosis of HR cytogenetic.

Role of Epstein-Barr Virus and Human Papilloma Virus in the Development of Oropharyngeal Cancer: A Literature Review.

The aim of this review was to describe the association and related mechanisms between HPV, EBV, and the development of oral and oropharyngeal cancer. A search for scientific evidence was carried out in electronic databases (MEDLINE/PubMed, SciELO). It was found that, among the carcinogenic mechanisms of HPV, E6 and E7 proteins are responsible for the malignization process, inhibiting tumor suppressors p53 and pRb. As to EBV, it was noted that its "hit and run" phenomenon manipulates the host epigenetic mechanism, triggering the tumor process without the virus being currently present; a "cellular reprogramming" is essentially generated, causing heritable changes in gene expression without DNA mutation. In conclusion, there is an association between oropharyngeal carcinogenesis and HPV and also between the former and EBV. Further studies are required to clarify the causal mechanisms and impact of both viruses on cancer development and to obtain biomarkers of greater specificity in the case of EBV.

Reading digital- versus print-easy texts: a study with university students who prefer digital sources.

The transition from on-paper to on-screen reading seems to make it necessary to raise some considerations, as a greater attentional effort has been claimed for print texts than digital ones. Not surprisingly, most university students prefer this digital medium. This research aims to examine reading times by contextualizing this phenomenon into two processes: namely, word recognition and reading comprehension task on paper and on screen. Thus, two different tasks-counterbalanced into digital and print mediums-were carried out per each participant with a preference for a digital medium: a reading comprehension task (RCT) and a lexical decision task (LDT) after reading a specific story. Participants were slower reading print texts and no statistically significant differences were found in RCT accuracy. This result suggests that the task required more cognitive resources under the print medium for those with a worse comprehension performance in reading, and a more conservative pattern in digital RCT for those with a better performance.

Metal effects on germination and seedling development in closely-related halophyte species inhabiting different elevations along the intertidal gradient.

Seed germination and seedling establishment are very sensitive plant stages to metal pollution. Many halophyte species colonizing salt marshes are able to germinate and establish in highly contaminated habitats and low marsh halophyte species seem to show higher tolerance to metals than high marsh species. We analyzed the effects of copper, zinc and nickel in concentrations up to 2000 µM on seed germination and seedling growth in two closely related species of Sarcocornia, S. perennis, a low marsh species, and S. fruticosa, a high marsh species. Germination of both halophytes was not affected by any metal concentration, and their seedling growth, mainly radicle length, was reduced by increasing metal concentrations. Seedlings of S. perennis showed higher tolerance to the three metals than those of S. fruticosa. Our results are useful for designing ecotoxicological bioassays and planning phytoremediation projects in salt marshes.

Identification of Type VI Secretion Systems Effector Proteins That Contribute to Interbacterial Competition in Salmonella Dublin.

The Type VI Secretion System (T6SS) is a multiprotein device that has emerged as an important fitness and virulence factor for many Gram-negative bacteria through the injection of effector proteins into prokaryotic or eukaryotic cells via a contractile mechanism. While some effector proteins specifically target bacterial or eukaryotic cells, others can target both types of cells (trans-kingdom effectors). In Salmonella, five T6SS gene clusters have been identified within pathogenicity islands SPI-6, SPI-19, SPI-20, SPI-21, and SPI-22, which are differentially distributed among serotypes. Salmonella enterica serotype Dublin (S. Dublin) is a cattle-adapted pathogen that harbors both T6SSSPI-6 and T6SSSPI-19. Interestingly, while both systems have been linked to virulence and host colonization in S. Dublin, an antibacterial activity has not been detected for T6SSSPI-6 in this serotype. In addition, there is limited information regarding the repertoire of effector proteins encoded within T6SSSPI-6 and T6SSSPI-19 gene clusters in S. Dublin. In the present study, we demonstrate that T6SSSPI-6 and T6SSSPI-19 of S. Dublin CT_02021853 contribute to interbacterial competition. Bioinformatic and comparative genomic analyses allowed us to identify genes encoding three candidate antibacterial effectors located within SPI-6 and two candidate effectors located within SPI-19. Each antibacterial effector gene is located upstream of a gene encoding a hypothetic immunity protein, thus conforming an effector/immunity (E/I) module. Of note, the genes encoding these effectors and immunity proteins are widely distributed in Salmonella genomes, suggesting a relevant role in interbacterial competition and virulence. Finally, we demonstrate that E/I modules SED_RS01930/SED_RS01935 (encoded in SPI-6), SED_RS06235/SED_RS06230, and SED_RS06335/SED_RS06340 (both encoded in SPI-19) contribute to interbacterial competition in S. Dublin CT_02021853.

The Effect of Corrective Feedback in Basic Cognitive Tasks: A Study in Early Childhood.

The aim of this study was to examine the effect of trial-by-trial corrective feedback in a go-no-go task for children. A sample of 40 preschool students, divided into 4- and 5-year-olds, participated in the study, as well as a group of 20 university students. All the groups performed the task in a counterbalanced design of blocks with and without corrective feedback. Reaction time and accuracy rate were measured as dependent variables. Moreover, reaction time was also analyzed through an ex-Gaussian fit. Children were slightly more accurate and slower under the presence of corrective feedback, suggesting a more conservative pattern. University students were faster, but corrective feedback did not reach the statistical level. Regarding reaction time components, a reduction of the distribution tails, depicted by the τ parameter, was found for both groups under the corrective feedback condition. This suggests that parameterization of reaction time can be considered as a strategy for a more detailed analysis to examine the effect of corrective feedback, even at early ages. In this way, corrective feedback depicted beneficial effects in the τ parameter at early ages, suggesting its use in basic cognitive tasks based on go-no-go but not for older groups.

Reading digital- versus print-easy texts: a study with university students who prefer digital sources

The transition from on-paper to on-screen reading seems to make it necessary to raise some considerations, as a greater attentional efort has been claimed for print texts than digital ones. Not surprisingly, most university students prefer this digital medium. This research aims to examine reading times by contextualizing this phenomenon into two processes: namely, word recognition and reading comprehension task on paper and on screen. Thus, two diferent tasks­counterbalanced into digital and print mediums­were carried out per each participant with a preference for a digital medium: a reading comprehension task (RCT) and a lexical decision task (LDT) after reading a specifc story. Participants were slower reading print texts and no statistically signifcant diferences were found in RCT accuracy. This result suggests that the task required more cognitive resources under the print medium for those with a worse comprehension performance in reading, and a more conservative pattern in digital RCT for those with a better performance.

Hypermetabolic abdominal and cervical lymph nodes mimicking Hodgkin lymphoma relapse on FDG PET/CT after adenovirus-vectored COVID-19 vaccine.

Vaccine-associated hypermetabolic lymphadenopathy (VAHL) has been reported as a common post-vaccination side effect, especially with mRNA-based COVID-19 vaccines. Most VAHL cases present normal or enlarged regional lymph nodes close to the injection site, usually with mild-moderate FDG (18 F-Fluorodeoxyglucose) uptake on FDG positron emission tomography (PET)/CT. Here, we describe the case of a 33-year-old woman with past history of Classic Hodgkin Lymphoma (CHL) who underwent follow-up FDG PET/CT 3 days (d) after the first dose of the adenovirus-vectored Oxford-AstraZeneca COVID-19 vaccine. FDG PET/CT showed unexpected small hypermetabolic cervical and abdominal lymph nodes in the same location as at the onset of the disease, suggesting radiological relapse. Considering temporal relationship and other cases of VAHL, a new image was performed 2 months later, which revealed decreased lymph nodes and normalization of FDG uptake. This case illustrates that the possibility of a false-positive should always be considered by physicians in this new context, even when hypermetabolic lymph nodes appear far from the vaccination site.

Can Virtual Assistants Perform Cognitive Assessment in Older Adults? A Review.

Community-dwelling older adults have raised the scientific community's interest during the COVID-19 era as their chronic conditions might be aggravated by the consequences of confinement. Digital devices in this field to monitor cognitive impairment are an emerging reality of an innovative nature. However, some groups may not have benefited from these developments as much as, for example, younger people. The aim of this manuscript is to carry out a review on the development of digital devices, and specifically virtual assistants, for the detection of cognitive impairment in older adults. After a screening process, eight studies were found under the given criteria, and this number was even smaller for those using virtual assistants. Given the opportunities offered by virtual assistants through techniques such as natural language processing, it seems imperative to take advantage of this opportunity for groups such as older adults.

Síndrome de Hirata, causa poco frecuente de hipoglucemia / Hirata syndrome, a rare cause of hypoglycemia

Mujer de 32 años, asmática en tratamiento irregular con prednisona (ultima dosis hace 1 mes), Enfermedad de Graves Basedow desde hace 3 años, reiniciótratamiento hace 3 meses (metimazol 40 mg/día), antecedente de aborto dos semanas previas al ingreso. Acude por pérdida del conocimiento, constatándose hipoglucemia. Al persistir el cuadro de hipoglucemia a pesar del tratamiento instaurado y descartadas otras causas etiológicas, la evaluación endocrinológica confirma hipoglucemia autoinmune, niveles de autoanticuerpos contra la insulina e insulina extremadamente elevados.

A 32-year-old woman, asthmatic on irregular treatment with prednisone (last dose 1 month ago), Graves Basedow's disease for 3 years, restartedtreatment 3 months before(methimazole 40 mg / day).History of abortion two weeks prior to admission. She came for loss of consciousness, finding hypoglycemia. As hypoglycemia persists despite the treatment instituted and other etiological causes ruled out, the endocrinological evaluation confirms autoimmune hypoglycemia,autoantibody levelsagainst insulinandextremely high insulin.

Severe infections in patients with lymphoproliferative diseases treated with new targeted drugs: A multicentric real-world study.

BACKGROUND: Lymphoid neoplasms treatment has recently been renewed to increase antitumor efficacy and conventional chemotherapies toxicities. Limited data have been published about the infection risk associated with these new drugs, therefore this study analyzes the infectious complications in patients with lymphoproliferative diseases (LPD) treated with monoclonal antibodies (obinutuzumab, ofatumumab, brentuximab, nivolumab, or pembrolizumab), BTK inhibitors (ibrutinib and acalabrutinib), PI3K inhibitors (idelalisib) and BCL2 inhibitors (venetoclax). METHODS: Multicenter retrospective study of 458 LPD patients treated with targeted therapies in real-life setting, in 18 Spanish institutions, from the time of their commercial availability to August 2020. RESULTS: Severe infections incidence was 23% during 17-month median follow-up; cumulative incidence was higher in the first 3-6 months of targeted drug treatment and then decreased. The most frequent etiology was bacterial (54%). Nine (6%) Invasive fungal infections (IFI) were observed, in its majority in chronic lymphocytic leukemia (CLL) patients treated predominantly with ibrutinib. Significant risk factors for severe infection were: severe lymphopenia (p = 0.009, OR 4.7, range 1.3-1.7), combined targeted treatment vs single agent treatment (p = 0.014 OR 2.2 range 1.1-4.2) and previous rituximab (p = 0.03 OR 1.8, range 1.05-3.3). Infection-related mortality was 6%. In 22% of patients with severe infections, definitive discontinuation of the targeted drug was observed. CONCLUSION: A high proportion of patients presented severe infections during follow-up, with non-negligible attributable mortality, but infection incidence is not superior to the one observed during the chemotherapy era. In selected cases with specific risk factors for infection, antimicrobial prophylaxis should be considered.