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TCL1 mice are the most commonly used preclinical model for chronic lymphocytic leukemia (CLL), a B-cell malignancy characterized by clonal CD5 + B-lymphocyte accumulation. B-cell receptor (BCR) sequencing identifies two important risk markers, immunoglobulin heavy chain variable region (IGHV) mutational status and receptor stereotypy. Despite its clinical relevance in patients, comprehensive examinations of endogenous BCR repertoires in TCL1 mice remain limited. We analysed BCR repertoires of 85 TCL1 mice, primarily comprising CLL clones using IGHV1 and IGHV11 (27.3 and 49.1% of CLL clones, respectively). Interestingly, TCL1 mice with dominant IGHV1 CLL clones showed significantly higher levels of CD4 + T-cells, and increased exhaustion levels (PD-1) on splenic CD8 + T-cells compared to IGHV11 CLL clones. Cancer related pathways (p53, MTORC and KRAS) were distinctly regulated in IGHV1 CLL clones. These clones occurred more frequently in female mice, characterized by short survival times (hazard ratio 2.6). Additionally, mice with dominant IGHV1 CLL clones displayed an almost twofold inguinal lymph node enlargement. In conclusion, we identified molecular, phenotypical and immunological differences between IGHV1 and IGHV11 CLL clones, which are key to consider for preclinical studies using the TCL1 mouse model. Furthermore, our data suggests that IGHV1 CLL clones model the nodal form of human CLL.

Cytidine to uridine (C-to-U) as well as adenosine to inosine (A-to-I) RNA editing denotes the posttranscriptional modification of RNA by specialized RNA deaminases. As RNA editing alters the sequence of the RNA, it can affect splicing, stability, miRNA binding and may also lead to recoding of the translated protein. Recently, we analysed recoding A-to-I RNA editing in chronic lymphocytic leukaemia (CLL) and could define prognostically relevant editing patterns. However, disease relevant C-to-U RNA editing in CLL remained unexplored. In this study, we examined C-to-U RNA editing in CLL and discovered a recoding RNA editing site within the MFN1 gene (hg38; chr3:179,375,230), which has recently been described as RNA editing site in brain samples. We found that MFN1 editing was not only present in CLL samples but also in naive B cell subsets, primarily occurred at unspliced RNA and correlated with intron retention. We further identified catalytically active ADARB1 as an essential regulator for MFN1 editing. Finally, MFN1 editing correlated with prolonged time to treatment and overall survival in CLL patients. Summarizing, we identified a novel ADARB1 function as C to U editing regulator, which regulates MFN1 splicing and MFN1 S329L recoding with pathogenic relevance in CLL.

Impaired apoptosis is now recognized to be central to tumor development. Bcl2, activated by chromosomal translocation in human follicular lymphoma, promotes oncogenesis by inhibiting apoptosis. Bim, a distant proapoptotic relative, is emerging as a major physiologic antagonist of Bcl2. Here, we show that loss of Bim is oncogenic. Bim protein levels were elevated in the apoptosis-prone B lymphoid cells of Eμ-Myc-transgenic mice, and Bim-mutant Eμ-Myc mice had increased numbers of IgM-bearing B cells. Eμ-Myc-expressing B lymphoid cells deficient in Bim were refractory to apoptosis induced in vitro by cytokine deprivation or antigen receptor cross-linking. Thus, Bim is induced by Myc in B cells and mediates apoptosis. Remarkably, inactivation of even a single allele of Bim accelerated Myc-induced development of tumors, particularly acute B cell leukemia. None of the primary tumors from Bim+/- Eμ-Myc mice displayed loss of the second allele of Bim. These findings indicate that Bim is a tumor suppressor, at least in B lymphocytes, and is haploinsufficient. Whereas the p19Arf/p53 pathway is frequently mutated in tumors arising in Bim+/+ Eμ-Myc mice, it was unaffected in most Bim-deficient tumors, indicating that Bim reduction is an effective alternative to loss of p53 function.

Despite modern chemotherapy regimens, survival of pancreatic cancer patients remains dismal. Toxicity is a major concern and it is a challenge to upfront identify patients with the highest benefit from aggressive polychemotherapy. We aimed to evaluate ORR and side effects of the FOLFIRINOX regimen, highlighting dose modification and to explore possible prognostic response factors as a clinical tool. This retrospective study includes 123 patients with metastatic PC that were treated with FOLFIRINOX between the years 2007 to 2016 in a single academic institution. Survival rates were analysed using the Kaplan-Meier method. Prognostic models including laboratory and clinical parameters were calculated using Cox proportional models in univariate and multivariate analyses. Median age at diagnosis was 64 years (47-78 years), 71 (57, 7%) were male and the majority had an ECOG performance status of 0 or 1 (63 patients; 83.7%). After a median follow up of 17.8 months, median progression free survival (PFS) and overall survival (OS) were 5.7 (4.55-6.84; 95%CI) and 11.8 months (9.35-14.24; 95%CI) respectively. Overall response rate with FOLFIRINOX was 34.9% and stable disease rate was 21.9%. Regarding Grade 3/4 side effects, 62 events, were reported in 37 patients. Looking at risk factors e.g. patient characteristics, tumor marker, inflammatory markers and body composition multivariate analyses proved CEA >4 elevation and BMI > 25 at the time point before palliative chemotherapy to be independent negative prognostic factors for OS. Grouping patients with no risk factor, one or two of these risk factors we analyzed a median OS of 17.4 moths, 9.6 months and 6.7 months (p<0.001) respectively. In addition we identified thrombocytosis and low BMI as predictors of early toxicity. This study identifies two easily available factors influencing overall survival with FOLFIRINOX therapy. By combining these two factors to create a score for OS, we propose a prognostic tool for physicians to identify patients, who are unlikely to benefit more from FOLFIRINOX or likely to experience toxicity.

Despite modern treatment approaches, survival of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) remains low and it is difficult to identify patients who derive optimal benefit from treatment. We therefore analyzed which commonly available laboratory and clinical parameters may help improve the prognostication in this patient group. This retrospective monocenter analysis includes 128 patients with recurrent or metastatic SCCHN treated with cetuximab alone or in combination with polychemotherapy as first line therapy. Factors with independent prognostic power in the multivariate analysis were used to build up a score separating patient groups with different survival. Patients had a median age of 61 years and 103 patients were treated with polychemotherapy plus cetuximab. An ECOG score above 1, high CRP and leukocyte levels, less intensive treatment and a time below 12 months from primary diagnosis to relapse remained as independent negative prognostic factors in multivariate analysis. Patients with 0 to 1 risk factors had a median OS of 13.6 months compared to a median OS of less than one month for patients 4 to 5 risk factors (p<0.001). This study identifies 5 clinical and serum values that influence survival of patients with recurrent or metastatic SCCHN treated with cetuximab. By combining these factors to create a score for OS, it is possible to distinguish a group of patients with significantly improved survival and define those most likely to have no benefit from cetuximab treatment.

Aims COVID‐19, a respiratory viral disease causing severe pneumonia, also affects the heart and other organs. Whether its cardiac involvement is a specific feature consisting of myocarditis, or simply due to microvascular injury and systemic inflammation, is yet unclear and presently debated. Because myocardial injury is also common in other kinds of pneumonias, we investigated and compared such occurrence in severe pneumonias due to COVID‐19 and other causes. Methods and results We analysed data from 156 critically ill patients requiring mechanical ventilation in four European tertiary hospitals, including all n = 76 COVID‐19 patients with severe disease course requiring at least ventilatory support, matched to n = 76 from a retrospective consecutive patient cohort of severe pneumonias of other origin (matched for age, gender, and type of ventilator therapy). When compared to the non‐COVID‐19, mortality (COVID‐19 = 38.2% vs. non‐COVID‐19 = 51.3%, P = 0.142) and impairment of systolic function were not significantly different. Surprisingly, myocardial injury was even more frequent in non‐COVID‐19 (96.4% vs. 78.1% P = 0.004). Although inflammatory activity [C‐reactive protein (CRP) and interleukin‐6] was indifferent, d‐dimer and thromboembolic incidence (COVID‐19 = 23.7% vs. non‐COVID‐19 = 5.3%, P = 0.002) driven by pulmonary embolism rates (COVID‐19 = 17.1% vs. non‐COVID‐19 = 2.6%, P = 0.005) were higher. Conclusions Myocardial injury was frequent in severe COVID‐19 requiring mechanical ventilation, but still less frequent than in similarly severe pneumonias of other origin, indicating that cardiac involvement may not be a specific feature of COVID‐19. While mortality was also similar, COVID‐19 is characterized with increased thrombogenicity and high pulmonary embolism rates.

VLA-4 and CD38 predict a poor clinical outcome in chronic lymphocytic leukemia (CLL). We used CLL samples with discordant VLA-4/CD38 risk to address their individual roles in human bone marrow infiltration (BM), CLL cell homing to murine BM, and in supportive CLL cell-stromal cell interactions. VLA-4, CD38, and Ki-67 expression was measured in CLL cells from peripheral blood (PB) and bone marrow (BM) aspirates. CLL BM infiltration rates, routinely determined by Pathology, were correlated to VLA-4 and CD38 expression. Short-term homing capacity of CLL cells was evaluated by adoptive transfer experiments. CLL cell viability and adhesion in stromal cell co-culture was determined. About 20% of CLL samples in our cohort displayed discordant VLA-4 and CD38 risk, with either high VLA-4 and low CD38 risk or vice versa. Using particularly such samples, we observed that VLA-4, and not CD38, was responsible for recirculation of CLL cells to murine BM. Human BM infiltration was also significantly higher in patients with high VLA-4 risk but not high CD38 risk. However, both molecules acted as independent prognostic markers. While both VLA-4 and CD38 expression were increased in BM-derived CLL cells, and VLA-4+ and CD38+ subpopulations showed enriched Ki-67 expression, VLA-4 did not contribute to CLL cell protection by stromal cells in vitro. Our data argue for a prominent role of VLA-4 but not CD38 expression in the homing of CLL cells to BM niches and in human BM infiltration, but only a limited role in their protection by stromal cells.

High-sensitive real-time PCR assays are routinely used to monitor HIV-1 infected subjects. Inter-assay discrepancies have been described at the low viral load (VL) end, where clinical decisions regarding possible virological rebound are based. A retrospective study was performed to analyze frequencies of viral blips after transition to the COBAS Ampliprep/COBAS TaqMan v2.0 HIV-1 assay (Taqman v2.0) in patients with prior undetectable VLs as measured with the Roche Cobas Ampliprep Amplicor HIV-1 Monitor Test, v1.5 (Amplicor) and was evaluated in comparison to a group of patients monitored with the Abbott Real-time HIV-1 assay (Abbott RT) during the same period of time. 85 of 373 patients with VLs below the limit of quantification with Amplicor had VLs >50 copies/mL after transition to the TaqMan v2.0 assay. Among these 74.1% had VLs ranging from 50-499 copies/mL, 22.9% had VLs >500 copies/mL. From 22 patients with initial Taqman v2.0 based VLs exceeding 500 copies/mL, 6 patients had VLs <20 copies/mL after novel VL measurement on a next visit. In our control group with VL quantification using the Abbott RT assay, only 1 patient became detectable and showed a VL of <40 copies/mL after new measurement. Transition to the Taqman v2.0 assay was accompanied by an increase of quantifiable HIV-1 VLs in patients with long term viral suppression under antiretroviral therapy that might be attributed to technical shortcomings of the Taqman v2.0 assay. A high test variability at the low VL end but also beyond was observed, making meaningful clinical interpretation of viral blips derived from different assays difficult.

Understanding the impact of induction and maintenance therapy on patients’ quality of life (QoL) is important for treatment selection. This study aims to compare patient‐reported QoL between patients treated with KTd or KRd induction therapy and K maintenance therapy or observation. QoL was assessed using the EORTC QOL‐C 30 and QOL‐MY20 questionnaires in the AGMT‐02 study, in which 123 patients with newly diagnosed transplant ineligible multiple myeloma were randomized to nine cycles of either KTd or KRd induction therapy, followed by 12 cycles of K maintenance therapy, or observation. Longitudinal assessments showed statistically significant improvements in global health‐related QoL, various disease symptoms and pain for both treatment regimens. KTd improved insomnia and fatigue, and KRd improved physical functioning. Cross‐sectional comparisons indicated a “slight” superiority of KTd over KRd in several scales, with the exception of higher neuropathy scores with KTd. During maintenance, longitudinal comparisons showed no statistically significant changes. Cross‐sectional comparisons revealed a “slight” improvement in cognitive functioning during carfilzomib therapy, but a worsening in most other QoL scales. Induction therapy led to improvements in most QoL items, while maintenance therapy with K maintenance was associated with “slight” or “moderate” impairments in several QoL scales compared with the observation group.

A survey of hospitals on three continents was performed to assess their infection control preparedness and measures, and their infection rate in hospital health care workers during the COVID-19 pandemic. All surveyed hospitals used similar PPE but differences in preparedness, PPE shortages, and infection rates were reported.