Ibrutinib combined with immunochemotherapy with or without autologous stem-cell transplantation versus immunochemotherapy and autologous stem-cell transplantation in previously untreated patients with mantle cell lymphoma (TRIANGLE): a three-arm, randomised, open-label, phase 3 superiority trial of the European Mantle Cell Lymphoma Network.

BACKGROUND: Adding ibrutinib to standard immunochemotherapy might improve outcomes and challenge autologous stem-cell transplantation (ASCT) in younger (aged 65 years or younger) mantle cell lymphoma patients. This trial aimed to investigate whether the addition of ibrutinib results in a superior clinical outcome compared with the pre-trial immunochemotherapy standard with ASCT or an ibrutinib-containing treatment without ASCT. We also investigated whether standard treatment with ASCT is superior to a treatment adding ibrutinib but without ASCT. METHODS: The open-label, randomised, three-arm, parallel-group, superiority TRIANGLE trial was performed in 165 secondary or tertiary clinical centres in 13 European countries and Israel. Patients with previously untreated, stage II-IV mantle cell lymphoma, aged 18-65 years and suitable for ASCT were randomly assigned 1:1:1 to control group A or experimental groups A+I or I, stratified by study group and mantle cell lymphoma international prognostic index risk groups. Treatment in group A consisted of six alternating cycles of R-CHOP (intravenous rituximab 375 mg/m2 on day 0 or 1, intravenous cyclophosphamide 750 mg/m2 on day 1, intravenous doxorubicin 50 mg/m2 on day 1, intravenous vincristine 1·4 mg/m2 on day 1, and oral prednisone 100 mg on days 1-5) and R-DHAP (or R-DHAOx, intravenous rituximab 375 mg/m2 on day 0 or 1, intravenous or oral dexamethasone 40 mg on days 1-4, intravenous cytarabine 2 × 2 g/m2 for 3 h every 12 h on day 2, and intravenous cisplatin 100 mg/m2 over 24 h on day 1 or alternatively intravenous oxaliplatin 130 mg/m2 on day 1) followed by ASCT. In group A+I, ibrutinib (560 mg orally each day) was added on days 1-19 of R-CHOP cycles and as fixed-duration maintenance (560 mg orally each day for 2 years) after ASCT. In group I, ibrutinib was given the same way as in group A+I, but ASCT was omitted. Three pairwise one-sided log-rank tests for the primary outcome of failure-free survival were statistically monitored. The primary analysis was done by intention-to-treat. Adverse events were evaluated by treatment period among patients who started the respective treatment. This ongoing trial is registered with ClinicalTrials.gov, NCT02858258. FINDINGS: Between July 29, 2016 and Dec 28, 2020, 870 patients (662 men, 208 women) were randomly assigned to group A (n=288), group A+I (n=292), and group I (n=290). After 31 months median follow-up, group A+I was superior to group A with 3-year failure-free survival of 88% (95% CI 84-92) versus 72% (67-79; hazard ratio 0·52 [one-sided 98·3% CI 0-0·86]; one-sided p=0·0008). Superiority of group A over group I was not shown with 3-year failure-free survival 72% (67-79) versus 86% (82-91; hazard ratio 1·77 [one-sided 98·3% CI 0-3·76]; one-sided p=0·9979). The comparison of group A+I versus group I is ongoing. There were no relevant differences in grade 3-5 adverse events during induction or ASCT between patients treated with R-CHOP/R-DHAP or ibrutinib combined with R-CHOP/R-DHAP. During maintenance or follow-up, substantially more grade 3-5 haematological adverse events and infections were reported after ASCT plus ibrutinib (group A+I; haematological: 114 [50%] of 231 patients; infections: 58 [25%] of 231; fatal infections: two [1%] of 231) compared with ibrutinib only (group I; haematological: 74 [28%] of 269; infections: 52 [19%] of 269; fatal infections: two [1%] of 269) or after ASCT (group A; haematological: 51 [21%] of 238; infections: 32 [13%] of 238; fatal infections: three [1%] of 238). INTERPRETATION: Adding ibrutinib to first-line treatment resulted in superior efficacy in younger mantle cell lymphoma patients with increased toxicity when given after ASCT. Adding ibrutinib during induction and as maintenance should be part of first-line treatment of younger mantle cell lymphoma patients. Whether ASCT adds to an ibrutinib-containing regimen is not yet determined. FUNDING: Janssen and Leukemia & Lymphoma Society.

Predictive value of pre-infusion tumor growth rate for the occurrence and severity of CRS and ICANS in lymphoma under CAR T-cell therapy.

Chimeric antigen receptor T-cell therapy (CART) can be administered outpatient yet requires management of potential side effects such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The pre-infusion tumor burden is associated with CRS, yet there is no data on the relevance of pre-infusion tumor growth rate (TGR). Our objective was to investigate TGR for the occurrence and severity of CRS and ICANS. Consecutive patients with available pre-baseline and baseline (BL) imaging before CART were included. TGR was determined as both absolute (abs) and percentage change (%) of Lugano criteria-based tumor burden in relation to days between exams. CRS and ICANS were graded according to ASTCT consensus criteria. Clinical metadata was collected including the international prognostic index (IPI), patient age, ECOG performance status, and LDH. Sixty-two patients were included (median age: 62 years, 40% female). The median pre-BL TGR [abs] and pre-BL TGR [%] was 7.5 mm2/d and 30.9%/d. Pre-BL TGR [abs] and pre-BL TGR [%] displayed a very weak positive correlation with the grade of CRS (r[abs] = 0.14 and r[%] = 0.13) and no correlation with ICANS (r[abs] = - 0.06 and r[%] = - 0.07). There was a weak positive correlation between grade of CRS and grade of ICANS (r = 0.35; p = 0.005) whereas there was no significant correlation of CRS or ICANS to any other of the examined parameters. The pre-infusion TGR before CART was weakly associated with the occurrence of CRS, but not the severity, whereas there were no significant differences in the prediction of ICANS. There was no added information when compared to pre-infusion tumor burden alone. Outpatient planning and toxicity management should not be influenced by the pre-infusion TGR.

Rituximab, gemcitabine and oxaliplatin in relapsed or refractory indolent and mantle cell lymphoma: results of a multicenter phase I/II-study of the German Low Grade Lymphoma Study Group.

Rituximab, gemcitabine and oxaliplatin (R-GemOx) has demonstrated to be effective and safe in lymphoma patients. We aimed to determine the maximum tolerated dose (MTD) of oxaliplatin in combination with rituximab and gemcitabine and to explore the efficacy and safety of R-GemOx in relapsed or refractory (r/r) indolent and mantle cell lymphoma (MCL). In this single-arm, phase I/II trial, we enrolled 55 patients with r/r indolent lymphoma and MCL not suitable for autologous stem-cell transplantation. Patients received 4 cycles of R-GemOx. In the dose escalation group, 70 mg/m2 of oxaliplatin was applied and interindividually increased by 10 mg/m2 until the MTD was reached together with fixed doses of rituximab and gemcitabine. At the oxaliplatin MTD, an extension cohort was opened. Primary aim was to detect an overall response rate (ORR) greater than 65% (α = 0.05). Oxaliplatin 70 mg/m2 (MTD) was chosen for the extension cohort after 3 of 6 patients experienced a DLT at 80 mg/m2. Among 46 patients evaluable for the efficacy analysis ORR was 72% (33/46), missing the primary aim of the study (p = 0.21). After a median follow-up of 7.9 years, median PFS and OS were 1.0 and 2.1 years. Most frequent grade ≥ 3 adverse events were cytopenias. R-GemOx induces decent response rates in r/r indolent lymphoma and MCL, though novel targeted therapies have largely replaced chemotherapy in the relapse setting. Particularly in MCL, R-GemOx might be an alternative option in late relapses or as bridging to CAR-T-cells. This study was registered with ClinicalTrials.gov on Aug 4th, 2009, number NCT00954005.

A practical guide to bioimaging research data management in core facilities.

Bioimage data are generated in diverse research fields throughout the life and biomedical sciences. Its potential for advancing scientific progress via modern, data-driven discovery approaches reaches beyond disciplinary borders. To fully exploit this potential, it is necessary to make bioimaging data, in general, multidimensional microscopy images and image series, FAIR, that is, findable, accessible, interoperable and reusable. These FAIR principles for research data management are now widely accepted in the scientific community and have been adopted by funding agencies, policymakers and publishers. To remain competitive and at the forefront of research, implementing the FAIR principles into daily routines is an essential but challenging task for researchers and research infrastructures. Imaging core facilities, well-established providers of access to imaging equipment and expertise, are in an excellent position to lead this transformation in bioimaging research data management. They are positioned at the intersection of research groups, IT infrastructure providers, the institution´s administration, and microscope vendors. In the frame of German BioImaging - Society for Microscopy and Image Analysis (GerBI-GMB), cross-institutional working groups and third-party funded projects were initiated in recent years to advance the bioimaging community's capability and capacity for FAIR bioimage data management. Here, we provide an imaging-core-facility-centric perspective outlining the experience and current strategies in Germany to facilitate the practical adoption of the FAIR principles closely aligned with the international bioimaging community. We highlight which tools and services are ready to be implemented and what the future directions for FAIR bioimage data have to offer.

The virtual reference radiologist: comprehensive AI assistance for clinical image reading and interpretation.

OBJECTIVES: Large language models (LLMs) have shown potential in radiology, but their ability to aid radiologists in interpreting imaging studies remains unexplored. We investigated the effects of a state-of-the-art LLM (GPT-4) on the radiologists' diagnostic workflow. MATERIALS AND METHODS: In this retrospective study, six radiologists of different experience levels read 40 selected radiographic [n = 10], CT [n = 10], MRI [n = 10], and angiographic [n = 10] studies unassisted (session one) and assisted by GPT-4 (session two). Each imaging study was presented with demographic data, the chief complaint, and associated symptoms, and diagnoses were registered using an online survey tool. The impact of Artificial Intelligence (AI) on diagnostic accuracy, confidence, user experience, input prompts, and generated responses was assessed. False information was registered. Linear mixed-effect models were used to quantify the factors (fixed: experience, modality, AI assistance; random: radiologist) influencing diagnostic accuracy and confidence. RESULTS: When assessing if the correct diagnosis was among the top-3 differential diagnoses, diagnostic accuracy improved slightly from 181/240 (75.4%, unassisted) to 188/240 (78.3%, AI-assisted). Similar improvements were found when only the top differential diagnosis was considered. AI assistance was used in 77.5% of the readings. Three hundred nine prompts were generated, primarily involving differential diagnoses (59.1%) and imaging features of specific conditions (27.5%). Diagnostic confidence was significantly higher when readings were AI-assisted (p > 0.001). Twenty-three responses (7.4%) were classified as hallucinations, while two (0.6%) were misinterpretations. CONCLUSION: Integrating GPT-4 in the diagnostic process improved diagnostic accuracy slightly and diagnostic confidence significantly. Potentially harmful hallucinations and misinterpretations call for caution and highlight the need for further safeguarding measures. CLINICAL RELEVANCE STATEMENT: Using GPT-4 as a virtual assistant when reading images made six radiologists of different experience levels feel more confident and provide more accurate diagnoses; yet, GPT-4 gave factually incorrect and potentially harmful information in 7.4% of its responses.

Investigation of TGF-α-overexpressing mouse hepatocytes (TAMH) cultured as spheroids for use in hepatotoxicity screening of drug candidates.

The immortalized mouse liver cell line TAMH has been described as a valuable tool for studying hepatotoxic mechanisms, but until now, it has only been reported to grow as a monolayer in culture. However, culturing hepatocytes as three-dimensional (3D) spheroids has been shown to result in improved liver-specific functions (e.g., metabolic capacity) by better mimicking the in vivo environment. This approach may lead to more reliable detection of drug-induced liver injury (DILI) in the early phase of drug discovery, preventing post-marketing drug withdrawals. Here, we investigated the cultivation of TAMH as 3D spheroids, characterizing them with optical and transmission electron microscopy as well as analyzing their gene expression at mRNA level (especially drug-metabolizing enzymes) compared to TAMH monolayer. In addition, comparisons were made with spheroids grown from the human hepatoblastoma cell line HepG2, another current spheroid model. The results indicate that TAMH spheroids express hepatic structures and show elevated levels of some of the key phase I and II drug-metabolizing enzymes, in contrast to TAMH monolayer. The in vitro hepatotoxic potencies of the drugs acetaminophen and flupirtine maleate were found to be very similar between TAMH spheroidal and the monolayer cultures. Both the advantages and disadvantages of TAMH spheroids as an in vitro hepatotoxicity model compared to monolayer model are discussed.

Do preoperative scapular fractures affect long-term outcomes after reverse shoulder arthroplasty?

BACKGROUND: Postoperative scapular stress fractures (SSFs) are a formidable problem after reverse shoulder arthroplasty (RSA). Less is known about patients who have these fractures preoperatively. The primary aim of this study was to examine postoperative satisfaction in patients undergoing primary RSA who have preoperative SSF and compared to a matched cohort without preoperative fracture. The secondary aim was to examine the differences in patient-reported outcomes between and within study cohorts. METHODS: A retrospective chart review of primary RSAs performed by a single surgeon from 2000 to 2020 was conducted. Patients diagnosed with cuff tear arthropathy (CTA), massive cuff tear (MCT), or rheumatoid arthritis (RA) were included. Five hundred twenty-five shoulders met inclusion criteria. Fractures identified on preoperative computed tomography scans were divided into 3 groups: (1) os acromiale, (2) multifragments (MFs), and (3) Levy types. Seventy-two shoulders had an occurrence of SSF. The remaining 453 shoulders were separated into a nonfractured cohort. American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES) and visual analog scale (VAS) scores were compared pre- and postoperatively in the total fracture group and the nonfractured group cohort. The multifragment subgroup was also compared to the pooled Os/Levy subgroup. RESULTS: The total incidence of SSF in all shoulders was 13.7%. There was a difference in satisfaction scores at all time points between the nonfracture (7.9 ± 2.8) and total fracture group (5.4 ± 3.6, P < .001, at last visit). There was also a greater ASES total score in the nonfractured group vs the total fracture group at the final visit (69.4 ± 23.4 and 62.1 ± 24.2; P = .02). The MF group had worse ASES functional or VAS functional scores than the Os/Levy group at all time points: at 1 year, ASES function: MF 24.2 ± 14.5 and Os/Levy 30.7 ± 14.2 (P = .045); at 2 years, ASES function: MF 21.4 ± 14.4 and Os/Levy 35.5 ± 10.6 (P < .001); and at last follow-up, VAS function: MF 4.8 ± 2.8 and Os/Levy 6.4 ± 3.2 (P = .023). DISCUSSION: Scapular fractures were proportionally most common in patients diagnosed with CTA (16.3%) compared with a 9.2% and 8.6% incidence in patients diagnosed with MCT and RA, respectively. Patients with preoperative SSF still see an improvement in ASES scores after RSA but do have lower satisfaction scores compared with the nonfractured cohort. The multifragment fracture group has lower functional and satisfaction scores at all postoperative time points compared with both the nonfracture and the Os/Levy fracture group.

Factors affecting risk of recurrence with periprosthetic infection in shoulder arthroplasty.

BACKGROUND: The goal of treating periprosthetic infection, besides its eradication, is to avoid recurrence. The purpose of this study was to evaluate the impact of increasing Infection Severity (IS) score (based on the 2018 International Consensus Meeting on Orthopedic Infections statement), single-stage revision, and pathogenicity of the infective organism on the risk of infection recurrence. METHODS: A database of 790 revisions performed by a single surgeon from 2004-2020 was reviewed for patients with minimum 2-year follow-up and ≥1 positive culture finding and/or pathology result from the revision surgical procedure. In total, 157 cases performed in 144 patients met the inclusion criteria. These cases were then categorized by infection probability (IS score) according to the 2018 consensus statement. Of 157 cases, 46 (29%) were classified as definitely or probably infected; 25 (16%), possibly infected; and 86 (55%), unlikely to be infected. Additionally, patients were grouped by single-stage surgery and pathogenicity of the infective organism. RESULTS: A recurrence in this study was classified as the growth of the same organism in any patient requiring revision surgery. The 86 cases in the group with unlikely infection showed a recurrence rate of 2.3%. The 25 cases in the group with possible infection showed a recurrence rate of 12%. The 46 cases in the group with definite or probable infection showed a recurrence rate of 17.4%. Patients in the definite/probable infection group had a higher rate of recurrence than those in the groups with possible infection and unlikely infection (P = .009). The IS score was higher in the recurrence group than the non-recurrence group (7.5 ± 4.3 vs. 3.9 ± 3.4, P < .001). Overall, patients who underwent 1-stage revision had a 5.0% recurrence rate, but among the 34 patients with an infection classification of definite or probable who underwent 1-stage revision, the recurrence rate was 5.9%. Cases of highly virulent methicillin-resistant Staphylococcus aureus also showed a recurrence rate of 30.8% compared with 4.0% and 5.9% for Cutibacterium acnes and coagulase-negative staphylococci, respectively (P = .005). CONCLUSION: Recurrent infection after treatment of a periprosthetic infection is associated with increasing severity scores, as defined in the 2018 consensus statement, and more aggressive microorganisms. However, a single-stage surgical procedure, even in patients with higher IS scores, did not impart a significantly increased risk of recurrence.

A New Way to Restrict Free Leg Movement During Unilateral Vertical Jump Test.

The purpose of this investigation was (1) to test the effect of movement restriction of the free leg during unilateral vertical jump on performance and power output comparing 2 different jump techniques: flexed (Classic technique) and straight (FC Luzern technique) free leg, and (2) to test the correlation between performance and power output obtained using these 2 techniques. Twenty elite soccer players performed squat (SJ) and countermovement (CMJ) jumps on each leg. The jump height and peak power output were compared between the 2 techniques for both legs. The jump height and peak power were significantly higher for the classic test for SJ and CMJ (P < .001) with no side effects or interactions. The angular range of motion of the free leg was higher for the Classic test than for the FC Lucerne test (P < .001), with no difference in the angular range of motion of the trunk. A moderate correlation was found between the 2 techniques on peak power (SJ: r = .626; CMJ: r = .649) and jump height (SJ: r = .742; CMJ: r = .891). Consequently, FC Lucerne technique, limiting the contribution of the free leg, is more appropriate to assess lower limb strength capacities during unilateral jump test.

Single High-Sensitivity Point-of-Care Whole-Blood Cardiac Troponin I Measurement to Rule Out Acute Myocardial Infarction at Low Risk.

BACKGROUND: High-sensitivity cardiac troponin (hs-cTn) laboratory assays are used to rule out myocardial infarction (MI) on presentation, but prolonged result turnaround times can delay patient management. Our primary aim was to identify patients at low risk of index MI using a rapid point-of-care (POC) whole-blood hs-cTnI assay at presentation with potential early patient discharge. METHODS: Consecutive patients presenting to the emergency department from 2 prospective observational studies with suspected acute coronary syndrome were enrolled. A POC hs-cTnI assay (Atellica VTLi) threshold using whole blood at presentation, which resulted in a negative predictive value of ≥99.5% and sensitivity of >99% for index MI, was derived (SEIGE [Safe Emergency Department Discharge Rate]) and validated with plasma (SAMIE [Suspected Acute Myocardial Infarction in Emergency]). Event adjudications were established with hs-cTnI assay results from routine clinical care. The primary outcome was MI at 30 days. RESULTS: A total of 1086 patients (8.1% with MI) were enrolled in a US derivation cohort (SEIGE) and 1486 (5.5% MI) in an Australian validation cohort (SAMIE). A derivation whole-blood POC hs-cTnI concentration of <4 ng/L provided a sensitivity of 98.9% (95% CI, 93.8%-100%) and negative predictive value of 99.5% (95% CI, 97.2%-100%) for ruling out MI. In the validation cohort, the sensitivity was 98.8% (95% CI, 93.3%-100%), and negative predictive value was 99.8% (95% CI, 99.1%-100%); 17.8% and 41.8%, respectively, were defined as low risk for discharge. The 30-day adverse cardiac events were 0.1% (n=1) for SEIGE and 0.8% (n=5) for SAMIE. CONCLUSIONS: A POC whole-blood hs-cTnI assay permits accessible, rapid, and safe exclusion of MI and may expedite discharge from the emergency department. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04772157. URL: https://www.australianclinicaltrials.gov.au/anzctr_feed/form; Unique identifier: 12621000053820.

Nuclear import of BCL11B is mediated by a classical nuclear localization signal and not the Krüppel-like zinc fingers.

The Krüppel-like transcription factor (KLF) BCL11B is characterized by a wide tissue distribution and crucial functions in key developmental and cellular processes, as well as in various pathologies including cancer and HIV infection. Although the basics of BCL11B activity and relevant interactions with other proteins have been uncovered, how this exclusively nuclear protein localizes to its compartment remained unclear. Here, we demonstrate that unlike other KLFs, BCL11B does not require the C-terminal DNA-binding domain to pass through the nuclear envelope but has an independent, previously unidentified, nuclear localization signal (NLS), which is located distantly from the zinc finger domains and fulfills the essential criteria of being an autonomous NLS. First, it can redirect a heterologous cytoplasmic protein to the nucleus. Second, its mutation causes aberrant localization of the protein of origin. Finally, we provide experimental and in silico evidences of the direct interaction with importin-α. The relative conservation of this motif allows formulating a consensus sequence (K/R)K-X13-14-KR+K++ ('+' indicates amino acids with similar chemical properties), which can be found in all BCL11B orthologs among vertebrates and in the closely related protein BCL11A.

CAR-HEMATOTOX: a model for CAR T-cell-related hematologic toxicity in relapsed/refractory large B-cell lymphoma.

Hematotoxicity represents a frequent chimeric antigen receptor (CAR) T-cell-related adverse event and remains poorly understood. In this multicenter analysis, we studied patterns of hematopoietic reconstitution and evaluated potential predictive markers in 258 patients receiving axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) for relapsed/refractory large B-cell lymphoma. We observed profound (absolute neutrophil count [ANC] <100 cells per µL) neutropenia in 72% of patients and prolonged (21 days or longer) neutropenia in 64% of patients. The median duration of severe neutropenia (ANC < 500 cells per µL) was 9 days. We aimed to identify predictive biomarkers of hematotoxicity using the duration of severe neutropenia until day +60 as the primary end point. In the training cohort (n = 58), we observed a significant correlation with baseline thrombocytopenia (r = -0.43; P = .001) and hyperferritinemia (r = 0.54; P < .0001) on univariate and multivariate analysis. Incidence and severity of cytokine-release syndrome, immune effector cell-associated neurotoxicity syndrome, and peak cytokine levels were not associated with the primary end point. We created the CAR-HEMATOTOX model, which included markers associated with hematopoietic reserve (eg, platelet count, hemoglobin, and ANC) and baseline inflammation (eg, C-reactive protein and ferritin). This model was validated in independent cohorts, one from Europe (n = 91) and one from the United States (n = 109) and discriminated patients with severe neutropenia ≥14 days to <14 days (pooled validation: area under the curve, 0.89; sensitivity, 89%; specificity, 68%). A high CAR-HEMATOTOX score resulted in a longer duration of neutropenia (12 vs 5.5 days; P < .001) and a higher incidence of severe thrombocytopenia (87% vs 34%; P < .001) and anemia (96% vs 40%; P < .001). The score implicates bone marrow reserve and inflammation prior to CAR T-cell therapy as key features associated with delayed cytopenia and will be useful for risk-adapted management of hematotoxicity.

Prognostic value of pre-infusion tumor growth rate for patients with lymphoma receiving chimeric antigen receptor T-cell therapy.

BACKGROUND AIMS: Chimeric antigen receptor T-cell therapy (CART) prolongs survival for patients with refractory or relapsed lymphoma, yet its efficacy is affected by the tumor burden. The relevance of tumor kinetics before infusion is unknown. We aimed to study the prognostic value of the pre-infusion tumor growth rate (TGRpre-BL) for progression-free (PFS) and overall survival (OS). METHODS: Consecutive patients with available pre-baseline (pre-BL) and baseline (BL) computed tomography or positron emission tomography/computed tomography scan before CART were included. TGR was determined as change of Lugano criteria-based tumor burden between pre-BL, BL and follow-up examinations (FU) in relation to days between imaging exams. Overall response rate (ORR), depth or response (DoR) and PFS were determined based on Lugano criteria. Multivariate regression analysis studied association of TGR with ORR and DoR. Proportional Cox regression analysis studied association of TGR with PFS and OS. RESULTS: In total, 62 patients met the inclusion criteria. The median TGRpre-BL was 7.5 mm2/d (interquartile range -14.6 mm2/d to 48.7 mm2/d); TGRpre-BL was positive (TGRpre-BL POS) in 58% of patients and negative (TGRpre-BL NEG, indicating tumor shrinkage) in 42% of patients. Patients who were TGRpre-BL POS had a 90-day (FU2) ORR of 62%, a DoR of -86% and a median PFS of 124 days. Patients who were TGRpre-BL NEG had a 90-day ORR of 44%, DoR of -47% and a median PFS of 105 days. ORR and DoR were not associated with slower TGR (P = 0.751, P = 0.198). Patients with an increase of TGR from pre-BL over BL to 30-day FU (FU1) ≥100% (TGRpre-BL-to-FU1≥100%) showed a significant association with shorter median PFS (31 days versus 343 days, P = 0.002) and shorter median OS after CART (93 days versus not reached, P < 0.001), compared with patients with TGRpre-BL-to-FU1<100%. CONCLUSIONS: In the context of CART, differences in pre-infusion tumor kinetics showed minor differences in ORR, DoR, PFS and OS, whereas the change of the TGR from pre-BL to 30-day FU significantly stratified PFS and OS. In this patient population of refractory or relapsed lymphomas, TGR is readily available based on pre-BL imaging, and its change throughout CART should be explored as a potential novel imaging biomarker of early response.

Prognostic value of the International Metabolic Prognostic Index for lymphoma patients receiving chimeric antigen receptor T-cell therapy.

PURPOSE: Chimeric antigen receptor T-cell therapy (CART) prolongs survival for patients with relapsed/refractory B-cell non-Hodgkin's lymphoma. The recently introduced International Metabolic Prognostic Index (IMPI) was shown to improve prognostication in the first-line treatment of large B-cell lymphoma. Here, we investigate the prognostic value of the IMPI for progression-free (PFS) and overall survival (OS) in the setting of CD19 CART. METHODS: Consecutively treated patients with baseline 18F-FDG PET/CT imaging and follow-up imaging at 30 days after CART were included. IMPI is composed of age, stage, and metabolic tumor volume (MTV) at baseline and was compared with the International Prognostic Index (IPI). Both indices were grouped into quartiles, as previously described for IPI. In addition, the continuous IMPI was subdivided into tertiaries for better separation of risk groups. Overall response rate (ORR), depth of response (DoR), and PFS were determined based on Lugano criteria. Proportional Cox regression analysis studied association of IMPI and IPI with PFS and OS. RESULTS: Thirty-nine patients were included. The IPI was 1 in 23%, 2 in 21%, 3 in 26%, 4 in 21%, and 5 in 10% of the patients. IMPIlow risk, IMPIintermediate risk, and IMPIhigh risk patients had 30-day ORR of 69%, 62%, and 62% and 30-day DoR of - 67%, - 66%, and - 54% with a PFS of 187 days, 97 days, and 87 days, respectively. ORR and DoR showed no correlation with lower IMPI (r = 0.065, p = 0.697). Dividing patients into three risk groups showed a significant trend for PFS stratification (p = 0.030), while IPI did not (p = 0.133). Neither IPI nor IMPI yielded a significant association with OS after CART (both p > 0.05). CONCLUSION: In the context of CART, the IMPI yielded prognostic value regarding PFS estimation. In contrast with IMPI in the first-line DLBCL setting, we did not observe a significant association of IMPI at baseline with OS after CART.

The addition of rituximab to chemotherapy improves overall survival in mantle cell lymphoma-a pooled trials analysis.

Mantle cell lymphoma (MCL) is a distinct subtype of B-cell lymphoma and commonly used induction immunochemotherapies include the anti-CD20 antibody rituximab. However, efficacy data for rituximab regarding overall survival (OS) in first line MCL therapy remain conflicting.We report long-term outcomes of a pooled trials analysis comparing Cyclophosphamide, Doxorubicine, Vincristine, Prednisone (CHOP) to R-CHOP in MCL to confirm efficacy on failure free survival (FFS) and OS in relevant subgroups. Untreated, adult MCL patients of two prospective trials assigned to CHOP or R-CHOP were included. Primary endpoints were FFS and OS, secondary endpoints included duration of response (DOR), secondary malignancies and OS after relapse. Between 1996 and 2003, 385 MCL patients were assigned to CHOP (201) or R-CHOP (184). After a median follow-up of 13.4 years, the addition of Rituximab significantly improved FFS (1.36 vs. 2.07 years, HR 0.62 (0.50-0.77)), OS (4.84 vs. 5.81 years, HR 0.78 (0.61-0.99)) and DOR (1.48 vs. 2.08 years, HR 0.67 (0.53-0.86)). Furthermore, Rituximab improved survival across different MCL risk groups. In a post-hoc analysis of OS after relapse comparing patients receiving chemotherapy with / without rituximab, rituximab maintained efficacy with a median OS of 3.10 vs. 2.11 years (HR 0.70, 0.54-0.91). The rate of secondary malignancies was 0.5 and 3.9% for hematological and 7 and 8% for non-hematological malignancies for CHOP and R-CHOP patients, respectively. We present mature results of a pooled MCL cohort, demonstrating prolonged FFS, OS and DOR for the combined immuno-chemotherapy, confirming the standard of care in first line treatment.

Frequency and outcomes of STEMI patients presenting between 12 and 24 h after symptom onset: Late-presenting STEMI.

OBJECTIVES: To assess the characteristics and prognosis of ST-elevation myocardial infarction (STEMI) patients, presenting between 12 and 24 h after symptom onset, in contemporary regional STEMI systems of care in the United States. BACKGROUND: Previous observational studies have been inconsistent regarding the benefit of primary percutaneous coronary intervention (PCI) compared with conservative management for late-presenting STEMI patients and the majority of randomized trials are from the fibrinolytic era. METHODS: Using a two-center registry-based cohort from March 2003 to December 2020, we evaluated the frequency, clinical characteristics, and outcomes of STEMI patients, stratified by symptom onset to balloon time: <3, 3-6, 6-12, and 12-24 h (late presenters). RESULTS: Among 5427 STEMI patients with available symptom onset time, 6.2% were late presenters, which increased to 11% during the early phase of the Covid-19 pandemic. As symptom onset to balloon time increased, patients were more likely to be older, female, and have a history of hypertension and diabetes mellitus. Late presenters with an identifiable culprit lesion were less likely to be revascularized with PCI (96%, 96%, 95%, and 92%; p for trend = 0.004) and had a longer median door-to-balloon time (82, 109, 107, and 117 min; p for trend < 0.001). In-hospital and 1-year death risks were comparable between late and earlier presenters. CONCLUSION: Despite the unfavorable risk profile and longer door-to-balloon time, clinical outcomes of late presenters were similar to those presenting within 12 h of symptom onset.

Renal impairment and mortality in patients with STEMI and cardiogenic shock/cardiac arrest.

OBJECTIVES: We sought to study the association of renal impairment (RI) with mortality in ST-segment elevation myocardial infarction (STEMI) complicated by cardiogenic shock and/or cardiac arrest (CS/CA). METHODS: Patients with RI (estimated glomerular filtration rate <60 mL/min/1.73 m2 ) were identified from the Midwest STEMI consortium, a prospective registry of four large regional programs comprising consecutive patients over 17 years. Primary outcome was in-hospital and 1-year mortality stratified by RI status and presence of CS/CA among patients with STEMI referred for coronary angiography. RESULTS: In a cohort of 13,463 STEMI patients, 13% (n = 1754) had CS/CA, 30% (n = 4085) had RI. Overall, in-hospital mortality was 5% (12% RI vs. 2% no-RI, p < 0.001) and 1-year mortality 9% (21% RI vs. 4% no-RI, p < 0.001). Among uncomplicated STEMI, in-hospital mortality was 2% (4% RI vs. 1% no-RI, p < 0.001) and 1-year mortality 6% (13% RI vs. 3% no-RI, p < 0.001). In STEMI with CS/CA, in-hospital mortality was 29% (43% RI vs. 15% no-RI, p < 0.001) and 1-year mortality 33% (50% RI vs. 16% no-RI, p < 0.001). Using Cox proportional hazards, RI was an independent predictor of in-hospital mortality in STEMI with CS/CA (odds ratio [OR]: 3.86; confidence interval [CI]: 2.6, 5.8). CONCLUSIONS: The association of RI with in-hospital and 1-year mortality is disproportionately greater in those with CS/CA compared to uncomplicated STEMI presentations. Factors predisposing RI patients to higher risk STEMI presentations and pathways to promote earlier recognition in the chain of survival need further investigation.

Pediatric multi-drug-resistant tuberculosis in Germany - diagnostic and therapeutic challenges of an "orphan disease".

Delay in diagnosing multidrug-resistant tuberculosis (MDR-pTB) in children prolongs time to effective treatment. Data on risk factors for pediatric MDR from low-incidence countries are scarce. Retrospective nationwide case-control study to analyze MDR-pTB cases in Germany between 2010 and 2020 in comparison to a drug-susceptible (DS)-pTB group. We included 52 MDR cases (24 tuberculosis (TB), 28 TB infection (TBI); mean age 7.3 years) and 56 DS cases (31 TB, 26 TBI; mean age 7.9 years). Groups were similar for sex, household size, and migration background. Compared to the DS group, more children with MDR were born in the Commonwealth of Independent States (CIS) (22% MDR-pTB vs. 13% DS-pTB, n.s.) and had more MDR index cases (94% MDR-pTB, 5% DS-pTB, p < 0.001). The interval between first healthcare contact and initiation of effective therapy was significantly longer in MDR-pTB (47 days) than in DS-pTB (11 days, p < 0.001), correlating with disease progression. Treatment for MDR-pTB was successful in 74%, but 22% experienced long-term adverse effects (e.g., hepatopathy, hearing loss). CONCLUSIONS: Close contact to MDR cases or birth in MDR-TB-high-incidence countries are risk factors for MDR-pTB. Early identification of potential MDR index cases by contact investigation, and susceptibility testing in children from high-burden MDR-TB countries are essential for timely diagnosis and treatment, reducing the severity of disease and treatment side effects. TRIAL REGISTRATION: Deutsches Register Klinischer Studien ( https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00023817 ), DRKS00023817, 2020-09-08. WHAT IS KNOWN: •Management of children with MDR-TB remains challenging due to difficulties in diagnosing MDR-TB (lack of information on MDR index case, lack of microbiological confirmation in paucibacillary disease). •Choice of treatment regimen and monitoring of side effects. WHAT IS NEW: •Children with an MDR-TB index or born in a MDR-TB-high-incidence country are at higher risk of developing MDR-TB in a low incidence country. •The time lag to initiate treatment in MDR-TB is longer than in DS-TB and MDR-TB treatment involves a higher risk of adverse effects in longer treatment regimens especially with injectables.

Highly infectious prions are not directly neurotoxic.

Prions are infectious agents which cause rapidly lethal neurodegenerative diseases in humans and animals following long, clinically silent incubation periods. They are composed of multichain assemblies of misfolded cellular prion protein. While it has long been assumed that prions are themselves neurotoxic, recent development of methods to obtain exceptionally pure prions from mouse brain with maintained strain characteristics, and in which defined structures-paired rod-like double helical fibers-can be definitively correlated with infectivity, allowed a direct test of this assertion. Here we report that while brain homogenates from symptomatic prion-infected mice are highly toxic to cultured neurons, exceptionally pure intact high-titer infectious prions are not directly neurotoxic. We further show that treatment of brain homogenates from prion-infected mice with sodium lauroylsarcosine destroys toxicity without diminishing infectivity. This is consistent with models in which prion propagation and toxicity can be mechanistically uncoupled.

FAIRness through automation: development of an automated medical data integration infrastructure for FAIR health data in a maximum care university hospital.

BACKGROUND: Secondary use of routine medical data is key to large-scale clinical and health services research. In a maximum care hospital, the volume of data generated exceeds the limits of big data on a daily basis. This so-called "real world data" are essential to complement knowledge and results from clinical trials. Furthermore, big data may help in establishing precision medicine. However, manual data extraction and annotation workflows to transfer routine data into research data would be complex and inefficient. Generally, best practices for managing research data focus on data output rather than the entire data journey from primary sources to analysis. To eventually make routinely collected data usable and available for research, many hurdles have to be overcome. In this work, we present the implementation of an automated framework for timely processing of clinical care data including free texts and genetic data (non-structured data) and centralized storage as Findable, Accessible, Interoperable, Reusable (FAIR) research data in a maximum care university hospital. METHODS: We identify data processing workflows necessary to operate a medical research data service unit in a maximum care hospital. We decompose structurally equal tasks into elementary sub-processes and propose a framework for general data processing. We base our processes on open-source software-components and, where necessary, custom-built generic tools. RESULTS: We demonstrate the application of our proposed framework in practice by describing its use in our Medical Data Integration Center (MeDIC). Our microservices-based and fully open-source data processing automation framework incorporates a complete recording of data management and manipulation activities. The prototype implementation also includes a metadata schema for data provenance and a process validation concept. All requirements of a MeDIC are orchestrated within the proposed framework: Data input from many heterogeneous sources, pseudonymization and harmonization, integration in a data warehouse and finally possibilities for extraction or aggregation of data for research purposes according to data protection requirements. CONCLUSION: Though the framework is not a panacea for bringing routine-based research data into compliance with FAIR principles, it provides a much-needed possibility to process data in a fully automated, traceable, and reproducible manner.