First-Line Venetoclax Combinations in Chronic Lymphocytic Leukemia.

BACKGROUND: Randomized trials of venetoclax plus anti-CD20 antibodies as first-line treatment in fit patients (i.e., those with a low burden of coexisting conditions) with advanced chronic lymphocytic leukemia (CLL) have been lacking. METHODS: In a phase 3, open-label trial, we randomly assigned, in a 1:1:1:1 ratio, fit patients with CLL who did not have TP53 aberrations to receive six cycles of chemoimmunotherapy (fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab) or 12 cycles of venetoclax-rituximab, venetoclax-obinutuzumab, or venetoclax-obinutuzumab-ibrutinib. Ibrutinib was discontinued after two consecutive measurements of undetectable minimal residual disease or could be extended. The primary end points were undetectable minimal residual disease (sensitivity, <10-4 [i.e., <1 CLL cell in 10,000 leukocytes]) as assessed by flow cytometry in peripheral blood at month 15 and progression-free survival. RESULTS: A total of 926 patients were assigned to one of the four treatment regimens (229 to chemoimmunotherapy, 237 to venetoclax-rituximab, 229 to venetoclax-obinutuzumab, and 231 to venetoclax-obinutuzumab-ibrutinib). At month 15, the percentage of patients with undetectable minimal residual disease was significantly higher in the venetoclax-obinutuzumab group (86.5%; 97.5% confidence interval [CI], 80.6 to 91.1) and the venetoclax-obinutuzumab-ibrutinib group (92.2%; 97.5% CI, 87.3 to 95.7) than in the chemoimmunotherapy group (52.0%; 97.5% CI, 44.4 to 59.5; P<0.001 for both comparisons), but it was not significantly higher in the venetoclax-rituximab group (57.0%; 97.5% CI, 49.5 to 64.2; P = 0.32). Three-year progression-free survival was 90.5% in the venetoclax-obinutuzumab-ibrutinib group and 75.5% in the chemoimmunotherapy group (hazard ratio for disease progression or death, 0.32; 97.5% CI, 0.19 to 0.54; P<0.001). Progression-free survival at 3 years was also higher with venetoclax-obinutuzumab (87.7%; hazard ratio for disease progression or death, 0.42; 97.5% CI, 0.26 to 0.68; P<0.001), but not with venetoclax-rituximab (80.8%; hazard ratio, 0.79; 97.5% CI, 0.53 to 1.18; P = 0.18). Grade 3 and grade 4 infections were more common with chemoimmunotherapy (18.5%) and venetoclax-obinutuzumab-ibrutinib (21.2%) than with venetoclax-rituximab (10.5%) or venetoclax-obinutuzumab (13.2%). CONCLUSIONS: Venetoclax-obinutuzumab with or without ibrutinib was superior to chemoimmunotherapy as first-line treatment in fit patients with CLL. (Funded by AbbVie and others; GAIA-CLL13 ClinicalTrials.gov number, NCT02950051; EudraCT number, 2015-004936-36.).

Acalabrutinib, venetoclax and obinutuzumab in relapsed CLL: Final efficacy and ctDNA analysis of the CLL2-BAAG trial.

The phase 2 CLL2-BAAG trial tested the measurable residual disease (MRD)-guided triple combination of acalabrutinib, venetoclax and obinutuzumab after an optional bendamustine debulking in 45 patients with relapsed/refractory CLL (one patient was excluded from the analysis due to a violation of exclusion criteria). MRD was measured by flow cytometry (FCM, undetectable MRD <10-4) in peripheral blood (PB) and circulating tumor DNA (ctDNA) by digital droplet PCR (ddPCR) of variable-diversity-joining (VDJ) rearrangements and CLL-related mutations in plasma. MRD recurrence was defined as detectable ctDNA and/or MRD ≥10-4 after achieving both uMRD/undetectable ctDNA. The median number of previous treatments was 1 (range 1-4), 18 patients (40%) had received a BTK inhibitor (BTKi) and/or venetoclax prior to inclusion, 14/44 (31.8%) had TP53 aberrations, 34 (75.6%) had unmutated IGHV. With a median observation time of 36.3 months and all patients off treatment for a median of 21.9 months, uMRD <10-4 in PB was achieved in 42/45 patients (93.3%) at any time point, including 17/18 (94.4%) previously exposed to venetoclax/BTKi and 13/14 (92.9%) with TP53 aberrations. The estimated three-year progression-free and overall survival rates were 85.0% and 93.8%. Overall 585 paired FCM/ctDNA samples were analyzed and 18 MRD recurrences (5 with and 13 without clinical progression) occurred after the end of treatment. Twelve were first detected by ctDNA, three by FCM and three synchronously. Patients with earlier detection by ctDNA appeared to have genetically higher risk disease. In conclusion, time-limited MRD-guided acalabrutinib, venetoclax and obinutuzumab achieved deep remissions in almost all patients with relapsed/refractory CLL. The addition of ctDNA-based analyses to FCM MRD assessment seems to improve early detection of relapses. ClinicalTrials.gov Identifier: NCT03787264.

Reassessing the chronic lymphocytic leukemia International Prognostic Index in the era of targeted therapies.

ABSTRACT: We evaluated the chronic lymphocytic leukemia International Prognostic Index (CLL-IPI) in patients with CLL treated first line with targeted drugs (n = 991) or chemoimmunotherapy (n = 1256). With a median observation time of 40.5 months, the 3-year progression-free survival (PFS) rates for targeted drug-treated patients varied by CLL-IPI risk group: 96.5% (low), 87.6% (intermediate), 82.4% (high), and 78.7% (very high). Differences between consecutive CLL-IPI risk groups were observed for intermediate vs low and high vs intermediate, but not very high vs high. CLL-IPI factors ß2-microglobulin, immunoglobulin heavy variable (IGHV) status, and TP53 status each retained prognostic value for PFS. The 3-year overall survival (OS) rates by CLL-IPI risk groups were 100%, 96%, 93.9%, and 89.4%, respectively, with no differences between consecutive risk groups. Age, Binet stage, ß2-microglobulin, and TP53 status each retained prognostic value for OS. In chemoimmunotherapy patients (median observation time, 66.9 months), 3-year PFS rates for CLL-IPI risk groups were 78.1%, 51.4%, 40.1%, and 16.5%, respectively; corresponding 3-year OS rates were 97.4%, 93.1%, 81.8%, and 57.3%. In a matched-pair analysis, PFS differences in targeted therapies (n = 812) vs chemoimmunotherapy (n = 812) across all risk groups and OS differences in all but patients at low risk were demonstrated. The CLL-IPI maintains its prognostic value in predicting PFS outcomes with targeted drugs, but its impact in predicting survival appears diminished. Targeted therapies showed enhanced outcomes over chemoimmunotherapy, highlighting their effectiveness across various risk groups. Our findings support ongoing assessment of prognostic tools in CLL treatment evolution. These trials were registered at www.ClinicalTrials.gov as #NCT02345863, #NCT02401503, #NCT02689141, #NCT02445131, #NCT02758665, #NCT02950051, #NCT02242942, #NCT00262782, #NCT00281918, and #NCT01010061.

High karyotypic complexity is an independent prognostic factor in patients with CLL treated with venetoclax combinations.

Complex karyotypes have been associated with inferior outcomes in chronic lymphocytic leukemia (CLL) treated with chemoimmunotherapy (CIT), whereas their prognostic impact in the context of venetoclax-based treatments is still debated. In this prospective analysis on karyotype complexity in CLL, we evaluated the impact of complex (≥3 chromosomal aberrations [CAs], CKTs) and highly complex karyotypes (≥5 CAs; hCKTs) as well as specific aberrations in previously untreated patients without TP53 aberrations undergoing either CIT or time-limited venetoclax-based therapies in the phase 3 GAIA/CLL13 trial. Karyotype analyses were available for 895 of 926 patients (96.7%), of whom 153 (17%) had a CKT and 43 (5%) hCKT. In the CIT arm, CKT was associated with shorter progression-free survival (PFS) (hazard ratio [HR] 2.58; 95% confidence interval [95% CI], 1.54-4.32; P < .001) and overall survival (HR, 3.25; 95% CI, 1.03-10.26; P = .044). In the pooled venetoclax arms, a multivariable analysis identified hCKTs (HR, 1.96; 95% CI, 1.03-3.72; P = .041), but not CKTs, as independent adverse prognosticators for PFS. The presence of translocations (unbalanced and/or balanced) was also independently associated with shorter PFSs in the venetoclax arms. CIT led to the acquisition of additional CAs (mean CAs, 2.0-3.4; from baseline to CLL progression), whereas karyotype complexity remained stable after venetoclax-based treatments (2.0, both time points). This analysis establishes highly complex karyotypes and translocations as adverse prognostic factors in the context of venetoclax-based combination treatments. The findings of this study support the incorporation of karyotyping into the standard diagnostic workup of CLL, because it identifies patients at high risk of poor treatment outcomes and thereby improves prognostication. This trial was registered at www.clinicaltrials.gov as #NCT02950051.

First-line venetoclax combinations versus chemoimmunotherapy in fit patients with chronic lymphocytic leukaemia (GAIA/CLL13): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: In the primary analysis report of the GAIA/CLL13 trial, we found that venetoclax-obinutuzumab and venetoclax-obinutuzumab-ibrutinib improved undetectable measurable residual disease (MRD) rates and progression-free survival compared with chemoimmunotherapy in patients with previously untreated chronic lymphocytic leukaemia. However, to our knowledge, no data on direct comparisons of different venetoclax-based combinations are available. METHODS: GAIA/CLL13 is an open-label, randomised, phase 3 study conducted at 159 sites in ten countries in Europe and the Middle East. Eligible patients were aged 18 years or older, with a life expectancy of at least 6 months, an Eastern Cooperative Oncology group performance status of 0-2, a cumulative illness rating scale score of 6 or lower or a single score of 4 or lower, and no TP53 aberrations. Patients were randomly assigned (1:1:1:1), with a computer-generated list stratified by age, Binet stage, and regional study group, to either chemoimmunotherapy, venetoclax-rituximab, venetoclax-obinutuzumab, or venetoclax-obinutuzumab-ibrutinib. All treatments were administered in 28-day cycles. Patients in the chemoimmunotherapy group received six cycles of treatment, with patients older than 65 years receiving intravenous bendamustine (90 mg/m2, days 1-2), whereas patients aged 65 years or younger received intravenous fludarabine (25 mg/m2, days 1-3) and intravenous cyclophosphamide (250 mg/m2, days 1-3). Intravenous rituximab (375 mg/m2, day 1 of cycle 1; 500 mg/m2, day 1 of cycles 2-6) was added to chemotherapy. In the experimental groups, patients received daily venetoclax (400 mg orally) for ten cycles after a 5-week ramp-up phase starting on day 22 of cycle 1. In the venetoclax-rituximab group, intravenous rituximab (375 mg/m2, day 1 of cycle 1; 500 mg/m2, day 1 of cycles 2-6) was added. In the obinutuzumab-containing groups, obinutuzumab was added (cycle 1: 100 mg on day 1, 900 mg on day 2, and 1000 mg on days 8 and 15; cycles 2-6: 1000 mg on day 1). In the venetoclax-obinutuzumab-ibrutinib group, daily ibrutinib (420 mg orally, from day 1 of cycle 1) was added until undetectable MRD was reached in two consecutive measurements (3 months apart) or until cycle 36. The planned treatment duration was six cycles in the chemoimmunotherapy group, 12 cycles in the venetoclax-rituximab and the venetoclax-obinutuzumab group and between 12 and 36 cycles in the venetoclax-obinutuzumab-ibrutinib group. Coprimary endpoints were the undetectable MRD rate in peripheral blood at month 15 for the comparison of venetoclax-obinutuzumab versus standard chemoimmunotherapy and investigator-assessed progression-free survival for the comparison of venetoclax-obinutuzumab-ibrutinib versus standard chemoimmunotherapy, both analysed in the intention-to-treat population (ie, all patients randomly assigned to treatment) with a split α of 0·025 for each coprimary endpoint. Both coprimary endpoints have been reported elsewhere. Here we report a post-hoc exploratory analysis of updated progression-free survival results after a 4-year follow-up of our study population. Safety analyses included all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT02950051, recruitment is complete, and all patients are off study treatment. FINDINGS: Between Dec 13, 2016, and Oct 13, 2019, 1080 patients were screened and 926 were randomly assigned to treatment (chemoimmunotherapy group n=229; venetoclax-rituximab group n=237; venetoclax-obinutuzumab group n=229; and venetoclax-obinutuzumab-ibrutinib group n=231); mean age 60·8 years (SD 10·2), 259 (28%) of 926 patients were female, and 667 (72%) were male (data on race and ethnicity are not reported). At data cutoff for this exploratory follow-up analysis (Jan 31, 2023; median follow-up 50·7 months [IQR 44·6-57·9]), patients in the venetoclax-obinutuzumab group had significantly longer progression-free survival than those in the chemoimmunotherapy group (hazard ratio [HR] 0·47 [97·5% CI 0·32-0·69], p<0·0001) and the venetoclax-rituximab group (0·57 [0·38-0·84], p=0·0011). The venetoclax-obinutuzumab-ibrutinib group also had a significantly longer progression-free survival than the chemoimmunotherapy group (0·30 [0·19-0·47]; p<0·0001) and the venetoclax-rituximab group (0·38 [0·24-0·59]; p<0·0001). There was no difference in progression-free survival between the venetoclax-obinutuzumab-ibrutinib and venetoclax-obinutuzumab groups (0·63 [0·39-1·02]; p=0·031), and the proportional hazards assumption was not met for the comparison between the venetoclax-rituximab group versus the chemoimmunotherapy group (log-rank p=0·10). The estimated 4-year progression-free survival rate was 85·5% (97·5% CI 79·9-91·1; 37 [16%] events) in the venetoclax-obinutuzumab-ibrutinib group, 81·8% (75·8-87·8; 55 [24%] events) in the venetoclax-obinutuzumab group, 70·1% (63·0-77·3; 84 [35%] events) in the venetoclax-rituximab group, and 62·0% (54·4-69·7; 90 [39%] events) in the chemoimmunotherapy group. The most common grade 3 or worse treatment-related adverse event was neutropenia (114 [53%] of 216 patients in the chemoimmunotherapy group, 109 [46%] of 237 in the venetoclax-rituximab group, 127 [56%] of 228 in the venetoclax-obinutuzumab group, and 112 [48%] of 231 in the venetoclax-obinutuzumab-ibrutinib group). Deaths determined to be associated with study treatment by the investigator occurred in three (1%) patients in the chemoimmunotherapy group (n=1 due to each of sepsis, metastatic squamous cell carcinoma, and Richter's syndrome), none in the venetoclax-rituximab and venetoclax-obinutuzumab groups, and four (2%) in the venetoclax-obinutuzumab-ibrutinib group (n=1 due to each of acute myeloid leukaemia, fungal encephalitis, small-cell lung cancer, and toxic leukoencephalopathy). INTERPRETATION: With more than 4 years of follow-up, venetoclax-obinutuzumab and venetoclax-obinutuzumab-ibrutinib significantly extended progression-free survival compared with both chemoimmunotherapy and venetoclax-rituximab in previously untreated, fit patients with chronic lymphocytic leukaemia, thereby supporting their use and further evaluation in this patient group, while still considering the higher toxicities observed with the triple combination. FUNDING: AbbVie, Janssen, and F Hoffmann-La Roche.

A diagnostic challenge-First case of chronic lymphatic leukemia-associated necrotizing sweet syndrome.

Sweet syndrome, also known as acute febrile neutrophilic dermatosis, is a rare disorder typically characterized by the clinical triad including a sudden onset of fever, painful skin lesions, and neutrophilia. The histopathological findings are a dense neutrophilic infiltrate and oedema of the dermis and epidermis without evidence of a vasculitis. Besides treatment of the underlying cause, sweet syndrome is typically treated with high-dose corticosteroids leading to a relapse-free response in 70% of patients. However, if left unrecognized or untreated, the condition may lead to serious complications. Here, we report on the case of a 38-year-old patient in whom, under the assumption of the presence of necrotizing fasciitis, exarticulation of the right arm was performed. In the absence of pathogen detection and insufficient response to anti-infective therapies, the diagnosis of a sweet syndrome was assumed and, later, confirmed by an excellent response to high-dose administration of systematic glucocorticoids. The case emphasizes the need to be aware of this rare syndrome, which can be easily misdiagnosed due to its close resemblance to infection and stresses the need of further research to define distinct diagnostic tools.

Marked hyperferritinemia in critically ill cancer patients.

OBJECTIVES: To investigate characteristics and outcomes of critically ill cancer patients with marked hyperferritinemia. METHODS: A single-center retrospective analysis comprising cancer patients with a ferritin level >10.000 µg/L treated in the intensive care unit (ICU) between 2012 and 2022 was conducted. RESULTS: A total of 117 patients were included in the analysis. The median age was 59 years (range: 15-86 years). Females accounted for 48% of cases. 90% of patients had a hematologic malignancy. The median maximum ferritin level was 27.349 µg/L (range: 10.300-426.073 µg/L). The diagnostic criteria of septic shock were fulfilled in 51% of cases; 31% of patients had hemophagocytic lymphohistiocytosis (HLH) according to the HLH-2004 criteria. Mechanical ventilation, renal replacement therapy and the use of vasopressors were necessary in 59%, 35% and 70% of cases, respectively. The ICU, hospital, 90-day and 1-year survival rates were 33.3%, 23.1%, 23.7% and 11.7%. Patients with septic shock had a worse survival than those without septic shock (p = .001); the survival of patients who fulfilled the HLH-2004 criteria did not differ from those who did not (p = .88). CONCLUSION: Critically ill cancer patients with marked hyperferritinemia have poor outcomes. The present data may help to make informed decisions for this patient group.

Noninvasive minimal residual disease assessment in relapsed/refractory large B-cell lymphoma using digital droplet PCR.

Although several promising approaches for the treatment of relapsed/refractory diffuse large B-cell lymphoma (rrDLBCL) have been approved recently, it remains unclear which patients will ultimately achieve long-term responses. Circulating tumor (ct)DNA sequencing has emerged as a valuable tool to assess minimal residual disease (MRD). Correlations between MRD and outcomes have been shown in previously untreated DLBCL, but data on the repeated assessment of MRD in the dynamic course of rrDLBCL is limited. Here, we present an approach leveraging cost- and time-sensitivity of digital droplet (dd)PCR to repeatedly assess MRD in rrDLBCL and present proof-of-principle for its ability to predict outcomes.

Precise excision of HTLV-1 provirus with a designer-recombinase.

The human T cell leukemia virus type 1 (HTLV-1) is a pathogenic retrovirus that persists as a provirus in the genome of infected cells and can lead to adult T cell leukemia (ATL). Worldwide, more than 10 million people are infected and approximately 5% of these individuals will develop ATL, a highly aggressive cancer that is currently incurable. In the last years, genome editing tools have emerged as promising antiviral agents. In this proof-of-concept study, we use substrate-linked directed evolution (SLiDE) to engineer Cre-derived site-specific recombinases to excise the HTLV-1 proviral genome from infected cells. We identified a conserved loxP-like sequence (loxHTLV) present in the long terminal repeats of the majority of virus isolates. After 181 cycles of SLiDE, we isolated a designer-recombinase (designated RecHTLV), which efficiently recombines the loxHTLV sequence in bacteria and human cells with high specificity. Expression of RecHTLV in human Jurkat T cells resulted in antiviral activity when challenged with an HTLV-1 infection. Moreover, expression of RecHTLV in chronically infected SP cells led to the excision of HTLV-1 proviral DNA. Our data suggest that recombinase-mediated excision of the HTLV-1 provirus represents a promising approach to reduce proviral load in HTLV-1-infected individuals, potentially preventing the development of HTLV-1-associated diseases.

Characteristics and outcomes of patients undergoing high-dose chemotherapy and autologous stem cell transplantation admitted to the intensive care unit: a single-center retrospective analysis.

High-dose chemotherapy and autologous stem cell transplantation (ASCT) can be associated with adverse events necessitating treatment on the intensive care unit (ICU). Data focusing on patients admitted to the ICU during hospitalization for high-dose chemotherapy and ASCT are scarce. We thus conducted a single-center retrospective analysis comprising 79 individuals who had high-dose chemotherapy and ASCT between 2014 and 2020 and were admitted to the ICU between the initiation of conditioning therapy and day 30 after ASCT. The median age was 57 years (range: 20-82 years); 38% of patients were female. B-cell non-Hodgkin lymphoma (34%) and plasma cell disorders (28%) were the most common indications for high-dose chemotherapy and ASCT. Sepsis represented the major cause for ICU admission (68%). Twenty-nine percent of patients required mechanical ventilation (MV), 5% had renal replacement therapy, and 44% needed vasopressors. The ICU, hospital, 90-day, and 1-year survival rates were 77.2%, 77.2%, 72.2%, and 60.3%, respectively. Stable disease or disease progression prior to the initiation of high-dose chemotherapy (p = 0.0028) and MV (p < 0.0001) were associated with an impaired survival. A total of 36 patients died during observation. The most frequent causes of death were the underlying malignancy (44%) and sepsis (39%). Taken together, the present analysis indicates a favorable overall outcome for patients admitted to the ICU during hospitalization for high-dose chemotherapy and ASCT. Thus, this patient group should not be denied admission and treatment on the ICU.

Next-Generation Sequencing-Optimal Sequencing of Therapies in Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL).

PURPOSE OF REVIEW: This research paper aims to provide an overview of evidence-based sequencing of therapies in relapsed/refractory chronic lymphocytic leukemia (CLL) in the era of targeted drugs. RECENT FINDINGS: In the absence of data from randomized clinical trials comparing novel agents head-to-head, growing evidence suggests that patients with late relapse (> 2 years) after fixed-duration therapies benefit from identical retreatment, whereas a class switch is favorable in those with short-lived remissions or progressive disease on continuous drug intake. Treatment of patients previously exposed to both covalent inhibitors of BTK and BCL2 remains an unmet medical need. Novel drugs, in particular noncovalent BTKI, show promising efficacy in this difficult-to-treat subgroup in early clinical trials. The optimal sequencing of therapies in CLL requires consideration of individual patient factors and disease characteristics. Double-refractory disease continuous to pose a clinical challenge with a focus on participation in clinical trials whenever possible.

Experimental Atherosclerosis Research on Large and Small Animal Models in Vascular Surgery.

Animal models have significantly advanced our understanding of the mechanisms of atherosclerosis formation and the evaluation of therapeutic options. The current focus of research is on preventive strategies and includes pharmacologic and biologic interventions directed primarily against smooth-muscle cell proliferation, endovascular devices for recanalization and/or drug delivery, and an integrated approach using both devices and pharmacobiologic agents. The experience over many decades with animal models in vascular research has established that a single, ideal, naturally available model for atherosclerosis does not exist. The spectrum ranges from large animals such as pigs to small animal experiments with genetically modified rodents such as the ApoE-/- mouse with correspondingly differently pronounced changes in their lipid and lipoprotein levels. The development of transgenic variants of currently available models, e.g., an ApoE-deficient rabbit line, has widened our options. Nevertheless, an appreciation of the individual features of natural or stimulated disease in each species is of importance for the proper design and execution of relevant experiments.

Impact of timing and precision of histopathological diagnosis on outcomes of patients with Burkitt lymphoma and high-grade B-cell lymphoma.

BACKGROUND: Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) are aggressive B-cell non-Hodgkin lymphomas (B-NHL) with a generally favorable prognosis after immunochemotherapy. The outcome of BL is superior to DLBCL. In 2016, a distinct group of lymphomas displaying characteristics of both BL and DLBCL (high grade B-cell lymphoma, HGBL) was introduced into the WHO classification. Histopathological discrimination of BL, DLBCL, and HGBL may be challenging. Data on the frequency of histopathological difficulties resulting in revision of the final diagnosis of BL/DLBCL/HGBL and its impact on the prognosis are limited. METHODS: We assessed histopathological features and clinical outcomes of 66 patients with suspected diagnosis of BL at the reporting institution between 2010 and 2020. RESULTS: The median age was 51 years (range 19-82) and final histopathological diagnosis revealed BL (n = 40), DLBCL (n = 12), or HGBL (n = 14). Patients with DLBCL and HGBL were either treated with DLBCL-directed (83.3% and 35.7%) or BL-directed (16.7% and 64.3%) protocols. Patients in whom diagnosis was revised from DLBCL to BL after initiation of DLBCL-directed treatment had a significantly inferior progression-free survival (PFS) than patients initially diagnosed with BL (p = 0.045), thus resembling rather the prognosis of DLBCL/HGBL. There was no difference between patients with DLBCL and HGBL, respectively, regarding PFS and OS (p = 0.38 and p = 0.27). CONCLUSION: These results suggest that timely and precise histopathological diagnosis as well as reference histopathological review of the underlying lymphoma is critical to determine up-front treatment strategies. Consequently, selection of more aggressive treatment protocols in case of difficulties with discrimination between DLBCL/HGBL/BL may be a reasonable approach.

Onset of Adverse Abdominal Events Due to Intestinal Ischemia-Reperfusion Injury after Aortic Cross-Clamping Is Associated with Elevated HSP70 Serum Levels in the Early Postoperative Phase.

Tissue injury of the viscera during open thoracoabdominal aortic (TAA) reconstructions has been reported as the aftermath of the ischemia-reperfusion mechanism following supracoeliac aortic cross-clamping. Abdominal complications after open aortic reconstructions, although rare through the intraoperative implementation of selective visceral artery blood perfusion, are associated with high rates of reinterventions and a poor prognosis. Recent animal experiments demonstrated that provoking mesenteric ischemia in rats induces the leukocyte-mediated transcription of heat-shock protein 70 (HSP70), a chaperone belonging to the danger-associated molecular pattern proteins (DAMPs). Translating these findings clinically, we investigated the serum levels of HSP70 in patients undergoing open aortic reconstructions with supracoeliac clamping. We postoperatively observed a relevant induction of HSP70, which remained significantly elevated in cases of postoperative abdominal complications (paralytic ileus, abdominal compartment syndrome, and visceral malperfusion). The receiver-operator curve analysis revealed the reliable prognostic accuracy of HSP70 as a biomarker for these complications as soon as 12 h post-operation (AUC 0.908, sensitivity 88.9%, specificity 83.3%). In conclusion, measuring HSP70 serum levels in the early postoperative phase may serve as a further adjutant in the diagnostic decision making for both the vascular surgeon and intensivist for the timely detection and management of abdominal complications following open TAA surgery.

Spinal Stroke: Outcome Attenuation by Erythropoietin and Carbamylated Erythropoietin and Its Prediction by Sphingosine-1-Phosphate Serum Levels in Mice.

Spinal strokes may be associated with tremendous spinal cord injury. Erythropoietin (EPO) improves the neurological outcome of animals after spinal cord ischemia (SCI) and its effects on ischemia-induced endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) are considered possible molecular mechanisms. Furthermore, sphingosin-1-phosphate (S1P) is suggested to correlate with SCI. In this study, the effect of recombinant human EPO (rhEPO) and carbamylated EPO (cEPO-Fc) on the outcome of mice after SCI and a prognostic value of S1P were investigated. SCI was induced in 12-month-old male mice by thoracic aortal cross-clamping after administration of rhEPO, cEPO-Fc, or a control. The locomotory behavior of mice was evaluated by the Basso mouse scale and S1P serum levels were measured by liquid chromatography-tandem mass spectrometry. The spinal cord was examined histologically and the expressions of key UPR proteins (ATF6, PERK, and IRE1a, caspase-12) were analyzed utilizing immunohistochemistry and real-time quantitative polymerase chain reaction. RhEPO and cEPO-Fc significantly improved outcomes after SCI. The expression of caspase-12 significantly increased in the control group within the first 24 h of reperfusion. Animals with better locomotory behavior had significantly higher serum levels of S1P. Our data indicate that rhEPO and cEPO-Fc have protective effects on the clinical outcome and neuronal tissue of mice after SCI and that the ER is involved in the molecular mechanisms. Moreover, serum S1P may predict the severity of impairment after SCI.

Treatment patterns and disease course of previously untreated Primary Central Nervous System Lymphoma: Feasibility of MTX-based regimens in clinical routine.

BACKGROUND: Primary central nervous system lymphoma (PCNSL) is a rare type of aggressive lymphoma of the central nervous system. Treatment strategies improved significantly over the past decades differ regionally but mainly consist of rituximab and high-dosed methotrexate (MTX)-based therapies. METHODS: We assessed clinical outcomes of 100 patients with newly diagnosed PCNSL between 2010-2020 at the University Hospital of Cologne, Germany. RESULTS: Patients were 23-88 years of age and either treated with MTX-based regimens (PRIMAIN, MARTA, MATRix), individual regimens, or best supportive care, respectively. Overall response rates were generally high (66,7-83,8%), but different organ toxicities required dose adjustments in most groups. Two-year overall survival rates were 57,9% (PRIMAIN), 63,6% (MARTA), 65,4% (MATRix), and 37,5% (Other), respectively. Out of 9 patients suffering from relapse >12 months from primary diagnosis, 7 patients (77,8%) received methotrexate-based salvage therapy with 2-year overall survival of 4/6 patients (66,7%). CONCLUSION: Although a relevant proportion of patients are not eligible for clinical trials due to age, performance status, or comorbidities, these results prove feasibility of different MTX-based treatment strategies in clinical routine. Even elderly patients displayed surprisingly favorable outcomes. However, with compromising organ toxicities, reduction of intensity should be part of strategies in future clinical trials.

Modeling Approach to Predict the Impact of Inflammation on the Pharmacokinetics of CYP2C19 and CYP3A4 Substrates.

PURPOSE: For decades, inflammation has been considered a cause of pharmacokinetic variability, mainly in relation to the inhibitory effect of pro-inflammatory cytokines on the expression level and activity of cytochrome P450 (CYP). In vitro and clinical studies have shown that two major CYPs, CYP2C19 and CYP3A4, are both impaired. The objective of the present study was to quantify the impact of the inflammatory response on the activity of both CYPs in order to predict the pharmacokinetic profile of their substrates according to systemic C-reactive protein (CRP). METHODS: The relationships between CRP concentration and both CYPs activities were estimated and validated using clinical data first on midazolam then on voriconazole. Finally, clinical data on omeprazole were used to validate the findings. For each substrate, a physiologically based pharmacokinetics model was built using a bottom-up approach, and the relationships between CRP level and CYP activities were estimated by a top-down approach. After incorporating the respective relationships, we compared the predictions and observed drug concentrations. RESULTS: Changes in pharmacokinetic profiles and parameters induced by inflammation seem to be captured accurately by the models. CONCLUSIONS: These findings suggest that the pharmacokinetics of CYP2C19 and CYP3A4 substrates can be predicted depending on the CRP concentration.

Decision Making in Phagocytosis.

Dictyostelium cells are professional phagocytes that are capable of handling particles of variable shapes and sizes. Here we offer long bacteria that challenge the uptake mechanism to its limits and report on the responses of the phagocytes if they are unable to engulf the particle by closing the phagocytic cup. Reasons for failure may be a length of the particle much larger than the phagocyte's diameter, or competition with another phagocyte. A cell may simultaneously release a particle and engulf another one. The final phase of release can be fast, causing the phagosome membrane to turn inside-out and to form a bleb. Myosin-II may be involved in the release by generating tension at the plasma membrane, it does however not accumulate on the phagosome to act there directly in expelling the particle. Labeling with GFP-2FYVE indicates that processing of the phagosome with phosphatidylinositol 3-phosphate begins at the base of a long phagosome already before closure of the cup. The decision of releasing the particle can be made even at the stage of the processed phagosome.

[Diagnosis and treatment of external otitis]. / Diagnostik und Behandlung der Otitis externa.

External otitis is one of the most common infections in the head and neck region, as about 10% of all people suffer from it at least once during their life. It is an infection of the cutis and subcutis of the outer ear canal caused by bacteria, viruses, and fungus as well as allergens or degenerative toxic substances. A concomitant infection of the eardrum (myringitis) may develop. Patients typically present with unilateral, rarely bilateral, earache (otalgia), with accompanying hearing loss and sometimes discharge from the ear (otorrhea). In general, otalgia is one of the most common reasons for consulting a general practitioner in Germany (4.2-7.7%), especially for children up to 14 years.

Structure-activity relationship study: Mechanism of cyto-genotoxicity of Nitropyrazole-derived high energy density materials family.

Stringent toxicological tests have to be performed prior to the industrial development of alternative chemicals particularly high energy dense materials (HEDMs) such as explosives. The properties (e.g., power, stability) of these compounds are constantly being improved, the current axis of research being the nitration of nitrogen heterocycles leading to HEDMs such as nitropyrazole-derived molecules. However, except for 3,4,5-trinitropyrazole (3,4,5-TNP), which was shown to be highly toxic in mice, the toxicological impact of these HEDMs has so far not been investigated. Furthermore, as industrials are strongly advised to develop alternative safety testing assays to in vivo experiments, we herein focused on determining the cytotoxic and genotoxic effects of seven Nitropyrazole-derived HEDMs on three rodent cell lines (mouse embryonic BALB/3T3 clone A31 cells, Chinese hamster ovary cells CHO-K1 and mouse lymphoma L5178Y TK +/- clone (3.7.2C) cells), two human fibroblast lines (CRC05, PFS04062) and on the human hepatic HepaRG model (both in proliferative and differentiated cells). A stronger cytotoxic effect was observed for 1,3-dinitropyrazole (1, 3-DNP) and 3,4,5-TNP in all cell lines, though differentiated HepaRG cells clearly displayed fewer likely due to the metabolism and elimination of these molecules by their functional biotransformation pathways. At the mechanistic level, the sub-chronic cytotoxic and genotoxic effects were linked to ROS/RNS production (experimental assays), HA2.X and to transcriptomic data highlighting the increase in DNA repair mechanisms.