No association of malignant B-cell non-Hodgkin lymphomas with ipsilateral SARS-CoV-2 vaccination.

PURPOSE: SARS-CoV-2 vaccines cause acute ipsilateral lymph node swelling in an important proportion of vaccines. Thus far, no malignant lymphadenopathies have been reported in temporal context to vaccination in the ipsilateral draining lymph node areas. EXPERIMENTAL DESIGN: Prompted by two cases with unilateral axillary lymphomas that occurred ipsilaterally to prior SARS-CoV-2 vaccination, we systematically retrieved all B-cell non-Hodgkin lymphomas at two German University Medical Centers diagnosed before and after introduction of SARS-CoV-2 vaccines in Germany. Available lymphoma tissue (n=19) was subjected to next-generation immunosequencing of the IGH locus. Malignant clonotypes were mined in the CoVabDab database and published data sets from 342 uninfected individuals, 55 individuals 28 days after anti-SARS-CoV-2 vaccination and 139 individuals with acute COVID-19 together encompassing over 1 million CDR3 sequences in total. RESULTS: Of 313 newly diagnosed cases in the two centers and observation periods, 27 unilateral manifestations in the defined deltoid draining regions were identified. The majority thereof were diffuse large B-cell lymphomas (18 of 27 cases). Eleven unilateral cases were diagnosed in the era of SARS-CoV-2 vaccination and 16 in the control period before introduction of such vaccines. Of the 11 unilateral lymphomas that occurred during the vaccination period, ten had received a SARS-CoV-2 vaccine prior to lymphoma diagnosis. These cases were further evaluated. While left-sided were more frequent than right-sided lymphomas (19 vs 8 cases), no statistically significant association of vaccination site and laterality of the lymphoma manifestation was found. The unilateral lymphomas showed a normal range of B-cell receptors typically found in these lymphoma subtypes with no evidence for anti-SARS-CoV-2 sequences in the malignant clonotype. CONCLUSIONS: Together, we found no evidence that the current SARS-CoV-2 vaccines could serve as a trigger for lymphomagenesis in the draining lymph node areas of the deltoid region used for vaccination.

Divergent Effects of EZH1 and EZH2 Protein Expression on the Prognosis of Patients with T-Cell Lymphomas.

T-cell lymphomas are highly heterogeneous and their prognosis is poor under the currently available therapies. Enhancers of zeste homologue 1 and 2 (EZH1/2) are histone H3 lysine-27 trimethyltransferases (H3K27me3). Despite the rapid development of new drugs inhibiting EZH2 and/or EZH1, the molecular interplay of these proteins and the impact on disease progression and prognosis of patients with T-cell lymphomas remains insufficiently understood. In this study, EZH1/2 mutation status was evaluated in 33 monomorphic epitheliotropic intestinal T-cell lymphomas by next generation sequencing and EZH1/2 and H3K27me3 protein expression levels were detected by immunohistochemistry in 46 T-cell lymphomas. Correlations with clinicopathologic features were analyzed and survival curves generated. No EZH1 mutations and one (3%) EZH2 missense mutation were identified. In univariable analysis, high EZH1 expression was associated with an improved overall survival (OS) and progression-free survival (PFS) whereas high EZH2 and H3K27me3 expression were associated with poorer OS and PFS. Multivariable analysis revealed EZH1 (hazard ratio (HR) = 0.183; 95% confidence interval (CI): 0.044-0.767; p = 0.020;) and EZH2 (HR = 8.245; 95% CI: 1.898-35.826; p = 0.005) to be independent, divergent prognostic markers for OS. In conclusion, EZH1/2 protein expression had opposing effects on the prognosis of T-cell lymphoma patients.

RBMX Protein Expression in T-Cell Lymphomas Predicts Chemotherapy Response and Prognosis.

T-cell non-Hodgkin's lymphomas (T-NHL) are a heterogeneous group of lymphomas with a mature T-cell phenotype. While in some hematological diseases the prognosis improved over the last decades, T-NHL cases often relapse early or present with an initially refractory course. Recently, it has been shown that RNA binding proteins have a crucial role for malignant tumor initiation, progression and treatment response while contributing to chemotherapy resistance. Therefore, we investigated the protein expression of the RNA binding protein X (RBMX), which has been shown to be of great relevance in disease initiation and progression in hematological diseases in 53 T-NHL cases using conventional immunohistochemistry. Low RBMX expression was associated with better response to anthracycline-containing first-line treatment. Furthermore, low RBMX expression predicted an improved overall survival and progression-free survival in univariate analysis. Multivariable Cox regression revealed RBMX as an independent prognostic marker for overall survival (p = 0.007; hazard ratio (HR) = 0.204; 95% confidence interval (CI): 0.064-0.646) and progression-free survival (p = 0.006; HR = 0.235; 95% CI: 0.083-0.666). The study identifies low RBMX expression to predict better chemotherapy response, overall survival and progression-free survival in patients with T-cell non-Hodgkin's lymphomas. These results suggest that RBMX protein expression levels might be a contributing factor towards chemotherapy resistance and thus affect prognosis. Hence, RBMX may be a potential therapeutic target and prognostic marker in T-cell lymphomas.

Impact of bone marrow involvement on outcome in relapsed and refractory transplant eligible diffuse large B-cell lymphoma and transformed indolent lymphoma.

In front-line treatment of diffuse large B-cell lymphoma (DLBCL), prior studies suggest that concordant but not discordant involvement of the bone marrow (BM) portends a poor prognosis. The prognostic impact of bone marrow infiltration (BMI) in recurrent or refractory DLBCL (r/rDLBCL) and transformed indolent lymphoma (r/rTRIL) patients is less clear. Thus, we examined the prognostic significance of the infiltration of bone marrow (BMI) by concordant, large B-cells (conBMI) and discordant, small B-cells (disBMI) in this patient group. We performed a single center retrospective analysis of the prognostic impact of BMI diagnosed before start of second-line treatment as well as multiple clinicopathologic variables in 82 patients with r/rDLBCL or r/rTRIL intended to treat with autologous SCT. Twenty-five of 82 patients (30.5%) had BMI. Out of these, 19 (76%) had conBMI and 6 (24%) had disBMI. In patients with conBMI but not disBMI, uni- and multivariate analysis revealed inferior progression free survival (PFS) and overall survival (OS) compared to patients without BMI (median PFS, 9.2 vs 17.45 months, log rank: p = 0.049; Hazard Ratio, 2.34 (Confidence Interval, 1.24-4.44), p = 0.009; median OS 14.72 vs 28.91 months, log rank: p = 0.017; Hazard Ratio, 2.76 (Confidence Interval, 1.43-5.31), p = 0.002). ConBMI was strongly associated with nonGCB subtype as classified by the Hans algorithm (82.4% vs 17.6%, p = 0.01). ConBMI comprised an independent predictor of poor prognosis in primary and secondary r/rDLBCL. Incorporating conBMI in the pretherapeutic risk assessment for r/rDLBCL and r/rTRIL patients may be useful for prognostication, for stratification in clinical trials, and to assess new therapies for this high-risk patient subset that might not benefit from SCT in second-line treatment.

Nivolumab maintenance after salvage autologous stem cell transplantation results in long-term remission in multiple relapsed primary CNS lymphoma.

Recurrence of primary central nervous system lymphoma (PCNSL) after high-dose chemotherapy with autologous stem cell transplantation (ASCT) usually has a poor overall prognosis with limited treatment options. Data on repeated ASCT are sparse. Checkpoint inhibitor maintenance therapy has also not been reported in PCNSL. Here, we report the first documented case of a successful third ASCT in second relapse of PCNSL. Whole-exome sequencing identified a hypermutated tumor genotype. Additionally, immunohistochemistry on pretreatment tumor tissue revealed infiltrates of PD-1+ cytolytic T cells. These alterations provided a rationale for subsequent nivolumab maintenance treatment. Therapy led to a long-term, ongoing complete remission. In eligible patients with recurrent MTX-sensitive PCNSL, multiple long-term remissions can be induced by repetition of high-dose MTX-based chemotherapy followed by autologous retransplantation. Subsequent immune checkpoint inhibitor maintenance therapy might be able to prolong or maintain remission.

Ultrastructural morphometric findings of cardiomyocytes in patients with impaired ventricular function--a comparative clinicopathological study.

AIM: The present study aims to analyze the differences in ultrastructural changes between right ventricular myocardium in clinically determined grades of heart failure (HF) [New York Heart Association (NYHA) classes I-IV] and their value in the routine diagnostic setting. METHODS: We investigated consecutive right ventricular endomyocardial biopsies of 12 patients presenting with HF (49±11.2years; male=10) by light microscopy and ultrastructural morphometric analysis. The patients were divided into four groups according to their NYHA classes (NYHA I: n=1, II: n=2, III: n=8, IV: n=1). We used a stereological point counting method on electron micrographs to determine the volume, surface, and numerical density of cardiomyocyte myofibrils; z-lines; mitochondria; and cristae as required. Further, secondary parameters were calculated. RESULTS: Myofibrillar parameters increased between NYHA class I and II (P<.01), which matched with more pronounced cardiomyocyte hypertrophy on the light microscopic level. In NYHA classes III and IV, the myofibrillar parameters dropped, while parameters concerning the mitochondria and their cristae rose (P<.01). This resulted in an elevated mitochondria to myofibril ratio (P<.05) and correlated with histologically evident atrophic cardiomyocytes, perinuclear loss of myofibrils and dot-like perinuclear staining positive on peroxide acid shift. CONCLUSION: In this present study, right ventricular myocardial ultrastructure differed between patients diagnosed with HF of different degrees in distinct subcellular changes. These findings suggest that ultrastructural analysis, while correlated with histopathological features, adds to the diagnosis in the routine diagnostic setting, specifically in lower NYHA grades, in which only minor changes are observed histologically.