Survival outcomes of patients with diffuse large B-cell lymphoma undergoing autologous stem cell transplantation in Germany: real-world evidence from an administrative database between 2010 and 2019.

Background: Limited real-world evidence is available for patients with diffuse large B-cell lymphoma (DLBCL) who received an autologous stem cell transplantation (ASCT) in Germany. Objectives: This study aims to describe the real-world survival outcomes of patients with DLBCL who received ASCT in Germany after diagnosis. Design: This study is a retrospective database analysis covering the period between 2010 and 2019. Methods: Unadjusted overall survival (OS) was plotted using the Kaplan-Meier estimator for the overall population and stratified by relapse status. A Cox regression was run to identify factors that influence OS. Results: A total of 112 patients received an ASCT, with the average time from first-line treatment to ASCT being 11.7 months. The median OS estimated by Kaplan-Meier was 83.4 months for the entire cohort. The only variable that significantly reduced the OS was the presence of subsequent treatment after ASCT in a time-dependent model. Conclusion: OS after ASCT for DLBCL patients in Germany is higher than previously reported and may still be considered a valid option for carefully selected patients with relapsed/refractory DLBCL.

A dimeric holin/antiholin complex controls lysis by phage T4.

Lytic phages control the timepoint of host cell lysis by timing the holin-mediated release of cell wall-degrading endolysins. In phage T4, the antiholin RI inhibits the holin T, thereby preventing the early release of the T4 endolysin and lysis. The antiholin achieves lysis inhibition (LIN) in response to phage superinfections, thereby increasing the chance for lysis in an environment with a lower phage concentration. The holin T consists of a small N-terminal cytoplasmic domain, a transmembrane helix, and a periplasmic C-terminal domain. The antiholin is targeted to the periplasm by a cleavable signal peptide. Recently, the periplasmic soluble domains of the holin and the antiholin were found to form T2/RI2 tetramers in crystals. To investigate the functional relevance of this complex, we reconstituted LIN in a phage-free system, using only RI, T, and endolysin, and combined targeted mutagenesis with functional analyses. Inactivation of the RI signal peptide cleavage site did not abolish LIN, indicating that RI can function in a membrane-bound state, which argued against the tetramer. This led to analyses showing that only one of the two T/RI interfaces in the tetramer is physiologically relevant, which is also the only interaction site predicted by AlphaFold2. Some holin mutations at this interaction site prevented lysis, suggesting that the RI interaction likely acts by blocking the holin oligomerization required for hole formation. We conclude that LIN is mediated by a dimeric T/RI complex that, unlike the tetramer, can be easily formed when both partners are membrane-anchored.

Circulating Tumor DNA Sequencing for Biologic Classification and Individualized Risk Stratification in Patients With Hodgkin Lymphoma.

PURPOSE: Current clinical challenges in Hodgkin lymphoma (HL) include difficult-to-treat relapsed/refractory disease and considerable long-term toxicities of treatment. Since clinical risk factors lack discriminatory power, intensity of therapy is mainly based on tumor burden. Exploring HL genetics and tumor microenvironment (TME) might provide valuable insights for improved risk stratification. MATERIALS AND METHODS: In this study, we applied circulating tumor DNA sequencing to 243 patients obtained from pivotal German Hodgkin Study Group trials to identify subtypes of HL. Independent validation of the subtypes was performed in 96 patients treated in the EuroNet-PHL-C2 study. Outcome differences of subtypes were assessed in an event-enriched clinical validation cohort comprising 72 patients from the HD21 trial, using a refined, validated, and clinically feasible assay. RESULTS: We propose a biologic classification of HL consisting of three distinct subtypes: inflammatory immune escape HL is characterized by frequent copy-number variations including immune escape variants such as high-level amplifications of the PD-L1 locus and an inflammatory TME. Virally-driven HL is associated with Epstein-Barr virus and/or human herpesvirus 6 and an inflammatory TME with neutrophils and macrophages, while the tumor mutational burden (TMB) is low. Oncogene-driven HL is defined by a high TMB, recurrent mutations in oncogenic drivers such as TNFAIP3, ITPKB, and SOCS1, and a cold TME. A refined and validated assay version aiming at clinically feasible risk stratification showed significant progression-free survival differences between subtypes. In addition, assessment of minimal residual disease (MRD) allowed for the detection of patients at very high risk of relapse within the subtypes. CONCLUSION: We propose a clinically feasible, noninvasive method for individualized risk stratification and MRD monitoring in patients with HL on the basis of circulating tumor DNA sequencing.

Characteristics, outcomes and health care utilization of patients with acute myeloid leukemia aged 70 years or older: A single-center retrospective analysis.

The overall prognosis of older patients with acute myeloid leukemia (AML) is dismal. Only a small subgroup experiences long-term survival. The discrimination between patients who are candidates for potentially curative approaches and those who are not is crucial since - in addition to differences in terms of AML-directed treatment - different policies concerning intensive care unit (ICU) admission and involvement of specialized palliative care (SPC) seem obvious. To shed more light on characteristics, outcomes and health care utilization of older individuals with AML, we conducted an analysis comprising 107 consecutive patients with newly diagnosed AML aged ≥70 years treated at an academic tertiary care center in Germany between 1 January 2015, and 31 December 2020. Median age was 75 years (range: 70-87 years); 45% of patients were female. The proportion of patients receiving intensive induction chemotherapy was 35%, 55% had low-intensity treatment and 10% did not receive AML-directed treatment or follow-up ended before treatment initiation. At least one ICU admission was documented for 47% of patients; SPC was involved in 43% of cases. Median follow-up was 199 days. The median overall survival (OS) was 2.5 months; the 1-year OS rate was 16%. Among patients who died during observation, the median proportion of time spent in the hospital between AML diagnosis and death was 56%. The most common places of death were normal wards (31%) and the ICU (28%). Patients less frequently died in a palliative care unit (14%) or at home (12%). In summary, results of the present analysis confirm the unfavorable prognosis of older patients with AML despite intensive health care utilization. Future efforts in this patient group should aim at optimizing the balance between appropriate AML-directed treatment on the one hand and health care utilization including ICU stays on the other hand.

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.

Entirely noninvasive outcome prediction in central nervous system lymphomas using circulating tumor DNA.

ABSTRACT: State-of-the-art response assessment of central nervous system lymphoma (CNSL) by magnetic resonance imaging is challenging and an insufficient predictor of treatment outcomes. Accordingly, the development of novel risk stratification strategies in CNSL is a high unmet medical need. We applied ultrasensitive circulating tumor DNA (ctDNA) sequencing to 146 plasma and cerebrospinal fluid (CSF) samples from 67 patients, aiming to develop an entirely noninvasive dynamic risk model considering clinical and molecular features of CNSL. Our ultrasensitive method allowed for the detection of CNSL-derived mutations in plasma ctDNA with high concordance to CSF and tumor tissue. Undetectable plasma ctDNA at baseline was associated with favorable outcomes. We tracked tumor-specific mutations in plasma-derived ctDNA over time and developed a novel CNSL biomarker based on this information: peripheral residual disease (PRD). Persistence of PRD after treatment was highly predictive of relapse. Integrating established baseline clinical risk factors with assessment of radiographic response and PRD during treatment resulted in the development and independent validation of a novel tool for risk stratification: molecular prognostic index for CNSL (MOP-C). MOP-C proved to be highly predictive of outcomes in patients with CNSL (failure-free survival hazard ratio per risk group of 6.60; 95% confidence interval, 3.12-13.97; P < .0001) and is publicly available at www.mop-c.com. Our results highlight the role of ctDNA sequencing in CNSL. MOP-C has the potential to improve the current standard of clinical risk stratification and radiographic response assessment in patients with CNSL, ultimately paving the way toward individualized treatment.

Multicenter development of a PET-based risk assessment tool for product-specific outcome prediction in large B-cell lymphoma patients undergoing CAR T-cell therapy.

PURPOSE: The emergence of chimeric antigen receptor (CAR) T-cell therapy fundamentally changed the management of individuals with relapsed and refractory large B-cell lymphoma (LBCL). However, real-world data have shown divergent outcomes for the approved products. The present study therefore set out to evaluate potential risk factors in a larger cohort. METHODS: Our analysis set included 88 patients, treated in four German university hospitals and one Italian center, who had undergone 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography (PET) before CAR T-cell therapy with tisagenlecleucel or axicabtagene ciloleucel. We first determined the predictive value of conventional risk factors, treatment lines, and response to bridging therapy for progression-free survival (PFS) through forward selection based on Cox regression. In a second step, the additive potential of two common PET parameters was assessed. Their optimal dichotomizing thresholds were calculated individually for each CAR T-cell product. RESULTS: Extra-nodal involvement emerged as the most relevant of the conventional tumor and patient characteristics. Moreover, we found that inclusion of metabolic tumor volume (MTV) further improves outcome prediction. The hazard ratio for a PFS event was 1.68 per unit increase of our proposed risk score (95% confidence interval [1.20, 2.35], P = 0.003), which comprised both extra-nodal disease and lymphoma burden. While the most suitable MTV cut-off among patients receiving tisagenlecleucel was 11 mL, a markedly higher threshold of 259 mL showed optimal predictive performance in those undergoing axicabtagene ciloleucel treatment. CONCLUSION: Our analysis demonstrates that the presence of more than one extra-nodal lesion and higher MTV in LBCL are associated with inferior outcome after CAR T-cell treatment. Based on an assessment tool including these two factors, patients can be assigned to one of three risk groups. Importantly, as shown by our study, metabolic tumor burden might facilitate CAR T-cell product selection and reflect the individual need for bridging therapy.

Hyperleukocytosis in patients with acute myeloid leukemia admitted to the intensive care unit: a single-center retrospective analysis.

A relevant proportion of patients with acute myeloid leukemia (AML) presenting with hyperleukocytosis are admitted to the intensive care unit (ICU). However, data on characteristics and outcomes of these patients are limited. We therefore conducted a single-center retrospective analysis including 69 consecutive AML patients with a white blood cell (WBC) count > 100.000/µl who had been treated on the ICU between 2011 and 2020. The median age was 63 years (range: 14-87 years). Males accounted for the majority of cases (n = 43; 62.3%). Mechanical ventilation (MV), renal replacement therapy and the use of vasopressors were necessary in 34.8%, 8.7% and 40.6% of patients, respectively. Cardiopulmonary resuscitation was performed in 15.9% of patients. The ICU, hospital, 90-day and 1-year survival rates were 53.6%, 43.5%, 42% and 30.4%, respectively. Age (p = 0.002), SOFA score (p < 0.001) and MV (p < 0.001) were independently associated with a reduced survival probability. A score comprising the factors age > 70 years, lactate dehydrogenase level > 1500 U/l, WBC count > 150.000/µl, elevated lactate level and SOFA score > 7 allowed the discrimination of 3 distinct risk groups (low-risk: 0-1 points, intermediate-risk: 2 points, high-risk: 3-5 points) with regard to survival (p < 0.0001). Taken together, the present analysis indicates that more than two-thirds of AML patients with hyperleukocytosis treated on the ICU die within 1 year. However, outcomes vary considerably depending on the presence of risk factors.

Clinical applications of circulating tumor DNA in Hodgkin lymphoma.

Hodgkin lymphoma is a B-cell lymphoma often affecting young adults. Outcomes following intensive chemo- and radiotherapy are generally favourable but leave patients at high risk for early and late toxicities frequently reducing quality of life. Relapsed/refractory disease is regularly difficult to treat and ultimately results in death in a relevant subset of patients. Current strategies for risk stratification and response evaluation rely on clinical features and imaging only, and lack discriminatory power to detect patients at risk for disease progression. Here, we explore how circulating tumor DNA sequencing might help to overcome these shortcomings. We provide an overview over recent technical and methodological developments and suggest potential use cases for different clinical situations. Circulating tumor DNA sequencing offers the potential to significantly augment current risk stratification strategies with the ultimate goal of further individualizing treatment strategies for patients with HL.

Survival outcomes of patients newly diagnosed with diffuse large B-cell lymphoma: real-world evidence from a German claims database.

PURPOSE: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma with increasing incidence. Although the burden of disease is high, only limited current real-world data on survival analysis, especially survival time, of German patients with DLBCL are available. This retrospective claims-based analysis was conducted to describe real-world survival evidence and treatment patterns of patients with DLBCL in Germany. METHODS: Using a large claims database of the German statutory health insurance with 6.7 million enrollees, we identified patients between 2010 and 2019 who were newly diagnosed with DLBCL (index date) and had no other cancer co-morbidity. Overall survival (OS) from index date and from the end of each treatment line was plotted by means of the Kaplan-Meier estimator, both for the overall cohort and stratified by treatment regimen. Treatment lines were identified based on a predefined set of medications categorized by established DLBCL treatment recommendations. RESULTS: 2495 incident DLBCL patients were eligible for the study. After index date, 1991 patients started a first-line, 868 a second-line, and 354 a third-line therapy. In first line, 79.5% of patients received a Rituximab-based therapy. 5.0% of the of the 2495 patients received a stem cell transplantation. Overall, median OS after index was 96.0 months. CONCLUSION: DLBCL-associated mortality is still high, especially in relapsed patients and in the elderly. Therefore, there is a high medical need for new effective treatments that can improve survival outcomes in DLBCL patients.

Potential synergy between radiotherapy and CAR T-cells - a multicentric analysis of the role of radiotherapy in the combination of CAR T cell therapy.

BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy has improved the limited overall survival (OS) of patients with intensively pretreated diffuse large B-cell lymphoma (DLBCL). However, the potentially life-threatening toxicities of CAR T-cells and early relapses remain a challenge. As suggested by smaller monocentric analyses, radiotherapy (RT) in combination with CAR T-cells may have an immunomodulatory effect. METHOD/ RESULTS: In this multicentric retrospective analysis, we investigated potentially synergistic effects of RT and CAR T-cells. Of 78 patients from four centers who received CAR T-cell therapy for DLBCL, 37 patients underwent bridging RT or received salvage RT. RTs (median 36 gray) were well tolerated. Therapy response and disease control of CAR T-cell therapy were comparable after bridging RT or bridging systemic therapy. High-grade neurotoxicity tended to occur less frequently after bridging RT. After further disease progression, patients with localized relapses showed better outcomes, compared to those in advanced stage. In the subgroup with localized relapse, patients receiving salvage RT had an increased OS, vs. those without salvage RT (1-year OS rate 89% vs. 38%, p = 0.03). CONCLUSION: Our analysis demonstrated that RT in combination with CAR T-cells led neither to high-grade toxicities, nor to a decreased response rate. We observed better outcomes of salvage therapies in patients with localized relapses vs. those with advanced stage relapses. Especially the patients who received salvage RTs for localized relapses seem to benefit more. Further analyses are necessary to clarify whether specific synergistic effects exist, such as an enhanced anti-tumor effect of CAR T-cells from RT sensitizing.

Outcome Prediction in Patients With Large B-cell Lymphoma Undergoing Chimeric Antigen Receptor T-cell Therapy.

The introduction of chimeric antigen receptor (CAR) T-cell therapy has led to a fundamental shift in the management of relapsed and refractory large B-cell lymphoma. However, our understanding of risk factors associated with non-response is still insufficient and the search for predictive biomarkers continues. Some parameters measurable on 18F-fluorodeoxyglucose positron emission tomography (PET) may be of additional value in this context. A total of 47 individuals from three German university centers who underwent re-staging with PET prior to CAR T-cell therapy were enrolled into the present study. After multivariable analysis considering tumor characteristics and patient factors that might affect progression-free survival (PFS), we investigated whether metabolic tumor volume (MTV) or maximum standardized uptake value (SUVmax) further improve risk stratification. Their most suitable cut-offs were determined by Cox and logistic regression. Forward selection identified extra-nodal disease as the most predictive factor of those routinely available, and we found it to be associated with significantly inferior overall survival after CAR T-cell treatment (P = 0.012). Furthermore, patients with MTV and SUVmax higher than the optimal threshold of 11 mL and 16.7, respectively, experienced shorter PFS (P = 0.016 and 0.002, respectively). Hence, these risk factors might be useful for selection of individuals likely to benefit from CAR T-cell therapy and their management.

Healthcare Resource Utilization and Associated Costs of German Patients with Diffuse Large B-Cell Lymphoma: A Retrospective Health Claims Data Analysis.

INTRODUCTION: Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin's lymphoma with increasing prevalence. Although the disease burden associated with DLBCL is high, only limited data on healthcare resource utilization (HCRU) and associated costs of German patients with DLBCL is available. METHODS: Using a large claims database of the German statutory health insurance with 6.7 million enrollees, we identified patients who were newly diagnosed with DLBCL between 2011 and 2018 (index date). Treatment lines were identified based on a predefined set of medication. HCRU and related costs were collected for the entire post index period and per treatment line. RESULTS: A total of 2495 incident DLBCL patients were eligible for the analysis. The average follow-up time after index was 41.7 months. During follow-up, 1991 patients started a first-line treatment, 868 a second-line treatment, and 354 a third-line treatment. Overall, patients spent on average (SD) 5.24 (6.17) days per month in hospital after index. While on anti-cancer treatment, this number increased to nine (10.9) in first-line, 8.7 (13.7) in second-line, and 9.4 (15.8) in third-line treatments. Overall costs per patient per month (PPPM) increased from €421 (875.70) before to €3695 (4652) after index. While on a treatment line, PPPM costs were €17,170 (10,246) in first-line, €13,362 (12,685) in second-line, and €12,112 (16,173) in third-line treatments. Time-unadjusted absolute costs sum up to €59,868 (43,331), €35,870 (37,387), and €28,832 (40,540) during first-line, second-line, and third-line treatments, respectively. The main cost drivers were hospitalizations (71% of total costs) and drug acquisition costs (18% of total costs). CONCLUSIONS: The financial burden of DLBCL in Germany is high, mainly due to hospitalization and drug costs. Therefore, there is a high medical need for new cost-effective therapeutic options that can lower the disease burden and remain financially viable to support the growing number of patients with this aggressive disease.

[Team-specific impacts of the corona pandemic on intensive care medicine personnel of a maximum care hospital]. / Teamspezifische Auswirkungen der Corona-Pandemie auf Mitarbeiter:innen der Internistischen Intensivmedizin eines Krankenhauses der Maximalversorgung.

The ongoing strain on personnel in the healthcare system during the COVID-19 pandemic is considerable and poses major emotional and psychological challenges for the personnel. In a team evaluation (physicians and nurses), team-specific stress, possible relief strategies, positive and negative experiences, and wishes for improvement of the situation in an intensive care unit were collected. While both occupational groups perceived equally high emotional stress intensities, nursing additionally perceived high stress intensities in the organizational and physical areas. Thus, the occupational group of nurses proves to be the most stressed by the COVID-19 pandemic. The findings presented here can be used to derive instructions for future actions.

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.

JAK inhibition with ruxolitinib in relapsed or refractory classical Hodgkin lymphoma: Final results of a phase II, open label, multicentre clinical trial (JeRiCHO).

OBJECTIVES: Patients with classical Hodgkin lymphoma (cHL) relapsing after second-line therapy have a dismal prognosis and novel approaches are required for this patient group. Based on promising (pre-)clinical data and the favourable toxicity profile, we performed a phase II clinical trial with the JAK inhibitor ruxolitinib in patients with relapsed or refractory cHL (r/r cHL). METHODS: Patients ≥18 years with histologically confirmed r/r cHL who failed second-line treatment were included. Ruxolitinib was given orally at a dose of 25 mg twice daily in continuous 28-day cycles until progression or unacceptable toxicity. Primary endpoint was the PET/CT-based overall response rate (ORR; complete response (CR) or partial response (PR)) after 2 cycles; secondary endpoints included progression-free (PFS) and overall survival (OS) as well as feasibility. The Jericho Trial adopted a 2-stage phase 2 design (Simon 1989). RESULTS: Among the 12 included patients in stage 1, 2 had a PR, 3 had a stable disease (SD) and 6 had progressive disease (PD) after two treatment cycles (ORR: 2/12 evaluable patients, 16.7%). Median PFS was 3.6 months, the 1-year OS estimate was 50.6% (median not reached). The toxicity profile was favourable with only one grade IV adverse event (7.1%) reported. CONCLUSION: Ruxolitinib exhibited a favourable side effect profile but modest activity in r/r cHL. Although the formal stopping criterion after stage 1 was not met, the trial did not continue to stage 2 due to the low response and PFS rates observed in stage 1.

Nucleome programming is required for the foundation of totipotency in mammalian germline development.

Germ cells are unique in engendering totipotency, yet the mechanisms underlying this capacity remain elusive. Here, we perform comprehensive and in-depth nucleome analysis of mouse germ-cell development in vitro, encompassing pluripotent precursors, primordial germ cells (PGCs) before and after epigenetic reprogramming, and spermatogonia/spermatogonial stem cells (SSCs). Although epigenetic reprogramming, including genome-wide DNA de-methylation, creates broadly open chromatin with abundant enhancer-like signatures, the augmented chromatin insulation safeguards transcriptional fidelity. These insulatory constraints are then erased en masse for spermatogonial development. Notably, despite distinguishing epigenetic programming, including global DNA re-methylation, the PGCs-to-spermatogonia/SSCs development entails further euchromatization. This accompanies substantial erasure of lamina-associated domains, generating spermatogonia/SSCs with a minimal peripheral attachment of chromatin except for pericentromeres-an architecture conserved in primates. Accordingly, faulty nucleome maturation, including persistent insulation and improper euchromatization, leads to impaired spermatogenic potential. Given that PGCs after epigenetic reprogramming serve as oogenic progenitors as well, our findings elucidate a principle for the nucleome programming that creates gametogenic progenitors in both sexes, defining a basis for nuclear totipotency.

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.