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Vincristine-induced peripheral neuropathy (VIPN) is an adverse effect of regimens used for the treatment of aggressive B-cell non-Hodgkin lymphoma (B-NHL). A single-nucleotide polymorphism (SNP) in the promotor region of the CEP72 gene has been identified as risk factor for the development of VIPN in children. To validate these results in adults we aimed to determine the association of the high-risk CEP72 (rs924607 TT genotype) with the occurrence and severity of VIPN. Analysis of SNP rs924607 (TT, CC or CT) was performed in all enrolled patients with available blood samples with a TaqMan genotyping assay. Rates and grades of VIPN were assessed prospectively as part of the RICOVER-60 trial. CEP72 genotype could be assessed in 519 patients. VIPN data was available for 499/519 patients who were included in the final analysis. 286 (57%) patients developed VIPN of any grade during treatment. Grade 2-4 VIPN occurred in 33% (166/499) of patients. The high-risk CEP72 TT genotype at rs924607 was identified in 97/499 (19%) patients. The TT genotype was not correlated with VIPN in the overall study population compared to patients with either CC or CT genotypes (p = 0.748). However, in the subgroup of female patients, the TT genotype was associated with increased occurrence of any-grade VIPN as well as grade 2-4 VIPN as compared to patients with either CC or CT genotypes (p = 0.016 and p = 0.020, respectively). Thus, the SNP rs924607 in the CEP72 gene is associated with increased VIPN incidence in female patients with aggressive B-NHL treated with CHOP chemotherapy. Trial registration ClinicalTrials.gov identifier: NCT00052936, submission date: 2005-06-23, EudraCT Number: 2010-019587-36., (© 2024. The Author(s).)

Background: First-line treatment in patients with acute myeloid leukemia (AML) unfit for intensive therapy is the combination of a hypomethylating agent (HMA) with venetoclax (VEN). However, retrospective data confirming the benefits of this regimen outside of clinical trials have shown conflicting results., Methods: We performed a multicenter retrospective analysis of outcomes with first-line HMA-VEN versus HMA in AML patients unfit for intensive chemotherapy., Results: A total of 213 patients were included from three German hospitals (125 HMA-VEN, 88 HMA). Median overall survival in the HMA-VEN cohort was 7.9 months (95% confidence interval [CI], 5.1-14.7) versus 4.9 months (3.1-7.1) with HMA. After 1 year, 42% (95% CI, 33-54) and 19% (12-30) of patients were alive, respectively (hazard ratio [HR] for death, 0.64; 95% CI, 0.46-0.88). After adjusting for clinical and molecular baseline characteristics, treatment with HMA-VEN remained significantly associated with both prolonged survival (HR, 0.48; 95% CI, 0.29-0.77) and time to next treatment (HR, 0.63; 95% CI, 0.47-0.85). Patients who achieved recovery of peripheral blood counts had a favorable prognosis (HR for death, 0.52; 95% CI, 0.33-0.84)., Discussion: These data align with findings from the pivotal VIALE-A trial and support the use of HMA-VEN in patients unfit for intensive therapy., (© 2024 The Author(s). European Journal of Haematology published by John Wiley & Sons Ltd.)

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma entity, and its incidence increases with age. There is a paucity of data regarding use of biweekly R-CHOP (R-CHOP-14) in patients ≥80 years of age. We performed a retrospective cohort study of patients with DLBCL aged ≥80 years treated with R-CHOP-14 and R-miniCHOP in two academic tertiary centers in Germany between 01/01/2005 and 12/30/2019. Overall, 79 patients were included. Median age was 84 years (range 80-91). Despite higher CR rates with R-CHOP-14 (71.4% vs. 52.4%), no statistically significant difference could be found between patients treated with R-CHOP-14 and R-miniCHOP regarding overall survival (OS) (p = .88, HR 0.94, 95% CI = 0.47-1.90) and progression-free survival (PFS) (p = .26, HR 0.66, 95% CI = 0.32-1.36). At a median follow-up of 40 months, the 2-year OS rates were 56% with R-CHOP-14 and 53% with R-miniCHOP. Two-year PFS rates were 46% for R-CHOP-14 and 50% for R-mini-CHOP. Relative dose intensity of chemotherapy did not correlate with OS (p = .72). With the caveat of a retrospective cohort study, we conclude that lacking a difference in OS, R-miniCHOP should be preferred for most patients with untreated DLBCL aged ≥80 years., (© 2024 The Author(s). European Journal of Haematology published by John Wiley & Sons Ltd.)

Objective: Psoriatic arthritis (PsA) is known as a seronegative form of spondylarthropathy. The interleukin-36 cytokine family may have a major role in disease pathogenesis and particularly the related cutaneous manifestations. In light of our recent observations on (transient) autoantibody phenotypes neutralizing endogenous anti-inflammatory receptor antagonists (progranulin, IL-1Ra) in different inflammatory conditions, we set out to investigate the potential role of such antibodies targeting IL-36 cytokine family members in PsA and psoriasis without arthritic manifestations (Pso)., Methods: In the present study we screened for hypothetic autoantibodies against the anti-inflammatory mediators IL-36 receptor antagonist (IL-36Ra) and anti-inflammatory IL-38 in PsA, Pso and inflammatory and healthy controls. Serum samples of patients with PsA (n = 254), Pso (n = 100), systemic lupus erythematosus (SLE, n = 50), rheumatoid arthritis (RA, n = 100), ulcerative colitis (UC, n = 50), Crohn´s disease (CD, n = 50), and healthy controls (n = 237) were screened for autoantibodies against IL-36Ra and IL-38 as well as IL-36Ra levels by ELISA. Biochemical analysis for immune complexes and atypic protein isoforms as well as IL-36 signaling reporter assays were performed., Results: Anti-IL-36Ra antibodies were detected in five out of 100 (5.0 %) patients with Pso, in 12 of 254 (4.72 %) patients with PsA and in one of 50 (2 %) patients with CD, but in none of the other investigated inflammatory or healthy controls. The IL-36Ra autoantibodies belonged to the IgG1 subclass and their titers ranged between 1:200 to 1:1600. They resulted in immune-complex formation, depletion of serum IL-36Ra levels and were functional in terms of facilitating unrestricted IL-36 signaling., Conclusion: IL-36Ra autoantibodies were found in subgroups of patients with Pso and PsA and may drive respective pathology., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Lorenz Thurner reports financial support was provided by Saarland University. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Macrophages are one of the key mediators of the therapeutic effects exerted by monoclonal antibodies, such as the anti-CD19 antibody tafasitamab, approved in combination with lenalidomide for the treatment of relapsed or refractory (r/r) diffuse large B cell lymphoma (DLBCL). However, antibody-dependent cellular phagocytosis (ADCP) in the tumor microenvironment can be counteracted by increased expression of the inhibitory receptor SIRPα on macrophages and its ligand, the immune checkpoint molecule CD47 on tumor cells. The aim of this study was to investigate the impact of the CD47-SIRPα axis on tafasitamabmediated phagocytosis and explore the potential of anti-CD47 blockade to enhance its antitumor activity. Elevated expression of both SIRPα and CD47 was observed in DLBCL patient-derived lymph node biopsies compared to healthy controls. CRISPR-mediated CD47 overexpression impacted tafasitamab-mediated ADCP in vitro and increased expression of SIRPα on macrophages correlated with decreased ADCP activity of tafasitamab against DLBCL cell lines. Combination of tafasitamab and an anti-CD47 blocking antibody enhanced ADCP activity of in vitro generated macrophages. Importantly, tafasitamab-mediated phagocytosis was elevated in combination with CD47 blockade using primary DLBCL cells and patient-derived lymphoma-associated macrophages (LAMs) in an autologous setting. Furthermore, lymphoma cells with low CD19 expression were efficiently eliminated by the combination treatment. Finally, combined treatment of tafasitamab and an anti-CD47 antibody resulted in enhanced tumor volume reduction and survival benefit in lymphoma xenograft mouse models. These findings provide evidence that CD47 blockade can enhance the phagocytic potential of tumor targeting immunotherapies such as tafasitamab and suggest there is value in exploring the combination in the clinic.

Donor-specific anti-human leukocyte antigen (HLA) antibodies represent a main cause of primary graft failure specifically in the setting of haploidentical stem cell transplantation. Newer therapy strategies including daratumumab could overcome some of these limitations. We describe the case of a patient with refractory acute myeloid leukemia. A haploidentical allogeneic stem cell transplantation was therefore initiated. HLA-antibodies testing revealed a high titer of donor-specific antibodies. First desensitization therapy failed, resulting in primary graft failure. A second desensitization regimen including plasmapheresis, intravenous gammaglobulins, and daratumumab resulted in good engraftment. Daratumumab is a promising and effective desensitization option in high-risk allo-sensitized patients undergoing haploidentical stem cell transplantation., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Abstract: We report an 18 F-FDG PET/CT scan of a 47-year-old man diagnosed with diffuse mast cell sarcoma with lymph node, bone, liver, spleen, and lung involvement. This interesting image should remind colleagues to consider mast cell sarcoma as a rare differential diagnosis in patients with multiple, intensely hypermetabolic lesions in various organs and lymph nodes., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Primary vitreoretinal lymphoma (PVRL) is a rare subtype of DLBCL and can progress into primary central nervous system lymphoma (PCNSL). To investigate the role of chronic antigenic stimulation in PVRL, we cloned and expressed B-cell receptors (BCR) from PVRL patients and tested for binding against human auto-antigens. SEL1L3, a protein with multiple glycosylation sites, was identified as the BCR target in 3/20 PVRL cases. SEL1L3 induces proliferation and BCR pathway activation in aggressive lymphoma cell lines. Moreover, SEL1L3 conjugated to a toxin killed exclusively lymphoma cells with respective BCR-reactivity. Western Blot analysis indicates the occurrence of hyper-N-glycosylation of SEL1L3 at aa 527 in PVRL patients with SEL1L3-reactive BCRs. The BCR of a PVRL patient with serum antibodies against SEL1L3 was cloned from a vitreous body biopsy at diagnosis and of a systemic manifestation at relapse. VH4-04*07 was used in both lymphoma manifestations with highly conserved CDR3 regions. Both BCRs showed binding to SEL1L3, suggesting continued dependence of lymphoma cells on antigen stimulation. These results indicate an important role of antigenic stimulation by post-translationally modified auto-antigens in the genesis of PVRL. They also provide the basis for a new treatment approach targeting unique lymphoma BCRs with ultimate specificity., (© 2024. The Author(s).)

Background: Adult-onset Still's disease (AOSD) and systemic juvenile idiopathic arthritis (sJIA) resemble a continuum of a rare, polygenic IL-1β-driven disease of unknown etiology., Objective: In the present study we sought to investigate a potential role of recently described autoantibodies neutralizing the interleukin-1(IL-1)-receptor antagonist (IL-1-Ra) in the pathogenesis of Still's disease., Methods: Serum or plasma samples from Still's disease patients (AOSD, n = 23; sJIA, n = 40) and autoimmune and/or inflammatory disease controls (n = 478) were analyzed for autoantibodies against progranulin (PGRN), IL-1Ra, IL-18 binding protein (IL-18BP), and IL-36Ra, as well as circulating IL-1Ra and IL-36Ra levels by ELISA. Biochemical analyses of plasma IL-1Ra were performed by native Western blots and isoelectric focusing. Functional activity of the autoantibodies was examined by an in vitro IL-1β-signaling reporter assay., Results: Anti-IL-1-Ra IgG were identified in 7 (27%) out of 29 Still's disease patients, including 4/23 with AOSD and 3/6 with sJIA and coincided with a hyperphosphorylated isoform of endogenous IL-1Ra. Anti-IL-36Ra antibodies were found in 2 AOSD patients. No anti-PGRN or anti-IL-18BP antibodies were detected. Selective testing for anti-IL-1Ra antibodies in an independent cohort (sJIA, n = 34) identified 5 of 34 (14.7%) as seropositive. Collectively, 8/12 antibody-positive Still's disease patients were either new-onset active disease or unresponsive to IL-1 blocking drugs. Autoantibody-seropositivity associated with decreased IL-1Ra plasma/serum levels. Seropositive plasma impaired in vitro IL-1Ra bioactivity, which could be reversed by anakinra or canakinumab treatment., Conclusion: Autoantibodies neutralizing IL-1Ra may represent a novel patho-mechanism in a subgroup of Still's disease patients, which is sensitive to high-dose IL-1 blocking therapy., (© 2024. The Author(s).)

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., (© 2023. The Author(s).)

Patients with diffuse large cell lymphoma who have an adequate vitamin D supply derive significantly more benefit from immuno-chemotherapy with rituximab than patients with vitamin D deficiency; this is especially true for female patients. We have already been able to show that vitamin D increases the antibody-dependent cytotoxicity (ADCC) of NK cells in a sex-dependent manner, but it is unclear how vitamin D makes NK cells more efficient., Methods: Healthy individuals with vitamin D deficiency were supplemented with vitamin D to sufficient levels. NK cells were isolated from blood samples before and after vitamin D saturation. For transcriptome analysis, we used the Affymetrix Gene-Chip 2.0™. Gene expression analysis as well as supervised and unsupervised pathway analysis were performed., Results: Among others the "NK cell-associated cytotoxicity pathway" increased after vitamin D substitution. Five IFN-α subtypes (2, 4, 6, 7 and 10) and IFN-κ were more highly expressed and are mainly responsible in these pathways. In contrast, the pathway "interferon-gamma response", as well as other sets in cytokine production and chemotaxis showed a reduction. Toll-like receptor genes (TLR-8, TLR-7, TLR-2) were downregulated and, therefore, are responsible for the decline of these pathways. The same could be shown for the "ubiquitin-ligase" pathway., Conclusions: Increased expression of several IFN-α subtypes may explain the increased ADCC of NK cells in vitamin D-replenished and otherwise healthy subjects. Other regulators of interferon production and ADCC are compensatory upregulated in compensation, such as Toll-like receptors and those of the ubiquitin ligase, and normalize after vitamin D substitution.

Despite recent advances in the therapy of diffuse large B-cell lymphoma, not otherwise specified (DLBCL), around 30% of patients develop refractory disease or relapse after first-line treatment. Recently, Ars2 was reported as the auto-antigenic target of the B-cell receptor (BCR) in approximately 25% of activated B-cell DLBCL cases. Ars2 could be used to specifically target B cells expressing Ars2-reactive BCRs. However, the optimal therapeutic format to integrate Ars2 into has yet to be determined. To mimic therapeutic antibody formats, Ars2-containing bispecific and IgG1-like constructs (BCR antigens for reverse [BAR]-bodies) were developed. Two bispecific BAR-bodies connecting single-chain antibodies against CD16 or CD3 to the BCR-binding epitope of Ars2 were constructed. Both constructs showed strong binding to U2932 cells and induced effector cell-dependent and selective cytotoxicity against U2932 cells of up to 44% at concentrations of 20 μg/ml. Additionally, IgG1-format Ars2 BAR-bodies were constructed by replacing the variable heavy- and light-chain regions of a full-length antibody with the Ars2 epitope. IgG1-format Ars2 BAR-bodies also bound selectively to U2932 and OCI-Ly3 cells and induced selective cytotoxicity of up to 60% at 10 μg/ml. In conclusion, Ars2-containing bispecific and IgG1-format BAR-bodies both are new therapeutic formats to target DLBCL cells., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: Patients with cancer and autoimmune diseases are at higher risk of severe COVID-19. They may not develop protective immune responses following vaccination. We investigated patients' cellular and humoral immune response after two COVID-19 vaccine doses., Research Design and Methods: Subjects were stratified into subgroups according to therapy and grade of immunosuppression at time of vaccination., Results: Antibody titers were compared to healthy controls. 32/122 (26%) did not develop detectable antibody titers. Of these, 22 (66.6%) had active therapy. Patients showed significant lower antibody titers compared to controls (median 790 vs. 3923 AU/mL, p = 0.026). Patients with active therapy had significant lower antibody titers compared to those without (median 302 vs. 3952 U/L P < 0.001). B-cell count was lower in the group without antibody titers (median 29.97 vs. 152.8; p = 0.002). 100% of patients under anti-CD20 therapy had no detectable antibody titer, followed by anti-TNF (66%), BTK inhibitors (50%), ruxolitinib (35.5%), TKI (14.2%), and lenalidomide (12.5%). Anti-CD20 therapy, ruxolitinib, BTK inhibitors, and anti-CD38 therapy presented significant lower antibody titers compared to controls., Conclusions: Patients undergoing therapy for cancer or autoimmune diseases are at higher risk of insufficient humoral immune response following COVID-19 vaccination. Furthermore, alterations in the B-cell compartment correlate with lower antibody titers.

Background: Patients suffering from refractory aggressive B-cell lymphoma not responding to salvage chemotherapy have a dismal prognosis. CAR T-cells or allogeneic stem cell transplantation (SCT) are potentially curative approaches. However, obtaining a remission, and lowering tumor burden before consolidation seems crucial for long-term efficacy of both treatment modalities., Materials and Methods: In this retrospective analysis, we reviewed patients with chemoresistant aggressive B-cell lymphoma, defined as being refractory or progressive to at least second line salvage chemotherapy including the regimen immediately preceding autologous stem cell transplantation (ASCT), treated at 2 tertiary centers, who were eligible for intensive treatment using single agent high-dose (HD) melphalan to obtain a remission before consolidating therapy., Results: We identified 36 patients that received single agent HD melphalan and ASCT as remission induction followed by CAR T-cells or allogeneic stem cell transplantation (SCT). Thirteen of the evaluable patients (39.4%) achieved a partial remission and 9 patients (27.73%) a complete remission, resulting in an overall response rate (ORR) of 66.7%. High remission rates were seen across all subgroups including patients with primary refractory lymphoma (ORR 58.3%), uncontrolled disease and high tumor burden as indicated by increased LDH levels (ORR 66.7% for patients with elevated LDH above 2 times upper limit of norm). 22 patients proceeded to allogeneic SCT and 5 to CAR T-cell therapy. Treatment related mortality of ASCT was 5.5% (2 patients, both due to infections). Two-year overall survival of all patients was 15.8%, primarily due to a high non-relapse mortality (45.5%) of allogeneic SCT patients treated with myeloablative conditioning chemotherapy., Conclusion: Single agent HD melphalan produces high remission rates in patients with chemoresistant, uncontrolled aggressive B-cell lymphoma and provides a window of opportunity for consolidation therapy., Microabstract: Patient with refractory/relapsed aggressive B-cell lymphoma after salvage therapy are an unmet medical need because of their very poor prognosis. In our retrospective analysis of 36 patients we showed that single agent high-dose melphalan can achieve high response rates (ORR 66.7%) even in uncontrolled disease enabling consolidation therapy e.g. with allogeneic stem cell transplantation or CAR T-cell therapy., (Copyright © 2022. Published by Elsevier Inc.)

Patients with diffuse large B-cell lymphoma (DLBCL) treated with the R-CHOP regime receive a high cumulative dose of prednisone. We used computer tomography-ascertained Hounsfield units (HU) as a surrogate parameter for bone mineral density (BMD) in three different locations of the L3 vertebral body at baseline and post-treatment. HU were measured in 50 patients with DLBCL of the previously published FLYER-trial which compared four cycles of R-CHOP + 2 × rituximab infusion to six cycles of R-CHOP in young, favorable DLBCL patients. In total, median loss was 26.8 HU in all patients over time. The median HU loss was significantly lower in the four cycles arm (21.3 HU vs. 41.3 HU, p  = 0.023). In conclusion, young patients with DLBCL receiving R-CHOP have significant HU/BMD loss under treatment with R-CHOP. Patients receiving four cycles of R-CHOP had less HU/BMD loss than patients receiving six cycles.

Background: The addition of rituximab to chemotherapy has substantially improved outcomes for patients with B-cell malignancies. The mechanisms of action of rituximab include activation of natural killer cells. Killer-cell immunoglobulin-like receptors (KIRs) mediate natural killer cell function through interaction with HLA. We evaluated the clinical impact of KIR-HLA genotypes on rituximab-containing therapy., Methods: For this post-hoc analysis, we used data from the RICOVER-60 trial (NCT00052936) as the discovery cohort and the CLL8 trial (NCT00281918) as the validation cohort. RICOVER-60 included patients aged 61-80 years with aggressive B-cell lymphoma treated with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) with or without rituximab. CLL8 included patients aged 30-81 years with chronic lymphocytic leukaemia treated with chemotherapy (fludarabine and cyclophosphamide; FC) with or without rituximab. We evaluated the KIR and HLA-C status of 519 patients with available blood samples in the RICOVER-60 trial and the KIR2DS1 and HLA-C status of 549 patients with available blood samples in the CLL8 trial, and evaluated their associations with event-free survival (RICOVER-60), progression-free survival, and overall survival (RICOVER-60 and CLL8)., Findings: In the RICOVER-60 trial, 201 (39%) patients were positive for KIR2DS1, 79 (15%) were homozygous for HLA-C2, and 36 (7%) were positive for KIR2DS1 and homozygous for HLA-C2. In the CLL8 trial, 206 (38%) patients were positive for KIR2DS1, 75 (14%) were homozygous for HLA-C2, and 26 (5%) were positive for KIR2DS1 and homozygous for HLA-C2. In the RICOVER-60 trial, both KIR2DS1 and HLA-C status were identified as independent risk factors for survival. KIR2DS1 positivity, homozygosity for HLA-C2, and subsequent KIR2DS1-HLA-C status were associated with adverse clinical outcome in patients receiving rituximab-containing therapy (event-free survival for patients with KIR2DS1-HLA-C2/C2 vs all other patients, HR 2·6 [95% CI 1·4-4·7], p=0·0015; progression-free survival, 2·7 [1·5-5·1], p=0·0013; overall survival, 2·8 [1·5-5·4], p=0·0016) but not in patients receiving CHOP chemotherapy only (event-free survival, 0·9 [0·5-1·7], p=0·85; progression-free survival, 1·1 [0·6-2·0], p=0·81; overall survival, 1·2 [0·6-2·4], p=0·53). A significant interaction between KIR2DS1-HLA-C status and rituximab was observed (p=0·018 for event-free survival and p=0·034 for progression-free survival). In contrast to all other patients, those positive for KIR2DS1 and homozygous for HLA-C2 did not benefit from adding rituximab to CHOP chemotherapy (event-free survival, 1·9 [0·8-4·6], p=0·16; progression-free survival, 1·4 [0·6-3·4], p=0·48; overall survival, 1·6 [0·6-4·3], p=0·33). In the CLL8 trial, KIR2DS1-HLA-C status was confirmed as a predictive marker for benefit from rituximab therapy (p=0·024 for the interaction of KIR2DS1-HLA-C status and rituximab regarding progression-free survival). In contrast to all other patients, those positive for KIR2DS1 and homozygous for HLA-C2 did not benefit from adding rituximab to FC chemotherapy (progression-free survival, 2·1 [0·9-4·9], p=0·094; overall survival, 2·6 [0·5-12·7], p=0·21)., Interpretation: Assessment of KIR2DS1 and HLA-C genotype might identify patients who would not benefit from rituximab, thereby allowing alternative therapies to be given. Further validation of these findings in prospective clinical trials is needed., Funding: F Hoffman La Roche., Competing Interests: Declaration of interests DK-M reports personal fees, grants, and non-financial support from Novartis, ViiV Healthcare, and Gilead. SS reports personal fees, grants, and non-financial support from AbbVie, Amgen, AstraZeneca, BeiGene, Bristol Myers Squibb, Celgene, Gilead, GlaxoSmithKline, Roche, Janssen, Novartis, and Sunesis. KF reports personal fees from AbbVie and Roche, outside the submitted work. VP reports non-financial support from Abbvie, Amgen, Bristol Myers Squibb, and Roche. JTB reports personal fees from Merck Sharp & Dohme and Incyte Pharmaceutical, and non-financial support from Gilead. LTh reports grants from the non-profit Wilhelm Sander Foundation, personal fees from EUSA Pharma and AstraZeneca, and non-financial support from AbbVie, EUSA Pharma, and Janssen. MB reports grants from the non-profit Deutsche José-Carreras Leukaemie Stiftung. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Precision cancer medicine (PCM) is an emerging paradigm in oncology, which includes tumour comprehensive genomic profiling (CGP) to enable molecularly guided therapy. However, cost-effectiveness analyses of PCM are faced with several challenges and, thus, its cost-effectiveness remains unclear. Early trials using only molecularly guided therapy were faced with the challenge of providing adequate measures of outcome, which probably explains the modest treatment benefits demonstrated. Endpoints like the progression-free survival (PFS)2/PFS1 ratio may assist in overcoming this issue. Moreover, specific tumour subtypes appear to benefit more from PCM. Costs associated with next-generation sequencing (NGS) for CGP are decreasing, but targeted therapy itself represents a major cost driver. CGP not only enables prediction of response to treatment, but also resistance, and could thus prevent administration of unnecessary (and costly) therapies. In clinical practice, the presence of clinical frameworks, such as the Recommendations for the Use of NGS for Patients with Metastatic Cancers from the ESMO Precision Medicine Working Group, and the ESMO Scale for Clinical Actionability of Molecular Targets, are essential in appropriately identifying situations where PCM is clinically meaningful, thereby improving its cost-effectiveness., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2020, Spandidos Publications.)

Lymphomas encompass a diverse group of malignant lymphoid neoplasms. Over recent years much scientific effort has been undertaken to identify and understand molecular changes in lymphomas, resulting in a wide range of genetic alterations that have been reported across all types of lymphomas. As many of these changes are now incorporated into the World Health Organization's defined criteria for the diagnostic evaluation of patients with lymphoid neoplasms, their accurate identification is crucial. Even if many alterations are not routinely evaluated in daily clinical practice, they may still have implications in risk stratification, treatment, prognosis or disease monitoring. Moreover, some alterations can be used for targeted treatment. Therefore, these advances in lymphoma molecular diagnostics in some cases have led to changes in treatment algorithms. Here, we give an overview of and discuss advances in molecular techniques in current clinical practice, as well as highlight some of them in a clinical context.

Peptide receptor radionuclide therapy (PRRT) of metastatic neuroendocrine tumors (NET) can be successfully repeated but may eventually be dose-limited. Since 177 Lu-DOTATATE dose limitation may come from hematological rather than renal function, hematological peripheral blood stem cell backup might be desirable. Here, we report our initial experience of peripheral blood stem-cell collection (PBSC) in patients with treatment-related cytopenia and therefore high risk of bone-marrow failure. Five patients with diffuse bone-marrow infiltration of NET and relevant myelosuppression (≥grade 2) received PBSC before one PRRT cycle with 177 Lu-DOTATATE (7.6 ± 0.8 GBq/cycle). Standard stem-cell mobilization with Granulocyte-colony stimulating factor (G-CSF) was applied, and successful PBSC was defined as a collection of >2 × 10 6 /kg CD34+ cells. In case of initial failure, Plerixafor was administered in addition to G-CSF prior to apheresis. PBSC was successfully performed in all patients with no adverse events. Median cumulative activity was 44.8 GBq (range, 21.3-62.4). Three patients had been previously treated with PRRT, two of which needed the addition of Plerixafor for stem-cell mobilization. Only one of five patients required autologous peripheral blood stem-cell transplantation during the median follow up time of 28 months. PBSC collection seems to be feasible in NET with bone-marrow involvement and might be worth considering as a backup strategy prior to PRRT, in order to overcome dose-limiting bone-marrow toxicity.

Mantle cell lymphoma (MCL) accounts for 5%-10% of all lymphomas. The disease's genetic hallmark is the t(11; 14)(q13; q32) translocation. In younger patients, the first-line treatment is chemoimmunotherapy followed by autologous stem cell transplantation. Upon disease progression, novel and targeted agents such as the BTK inhibitor ibrutinib, the BCL-2 inhibitor venetoclax, or the combination of both are increasingly used, but even after allogeneic stem cell transplantation or CAR T-cell therapy, MCL remains incurable for most patients. Chronic antigenic stimulation of the B-cell receptor (BCR) is thought to be essential for the pathogenesis of many B-cell lymphomas. LRPAP1 has been identified as the autoantigenic BCR target in about 1/3 of all MCLs. Thus, LRPAP1 could be used to target MCL cells, however, there is currently no optimal therapeutic format to integrate LRPAP1. We have therefore integrated LRPAP1 into a concept termed BAR, for B-cell receptor antigens for reverse targeting. A bispecific BAR body was synthesized consisting of the lymphoma-BCR binding epitope of LRPAP1 and a single chain fragment targeting CD3 or CD16 to recruit/engage T or NK cells. In addition, a BAR body consisting of an IgG1 antibody and the lymphoma-BCR binding epitope of LRPAP1 replacing the variable regions was synthesized. Both BAR bodies mediated highly specific cytotoxic effects against MCL cells in a dose-dependent manner at 1-20 µg/mL. In conclusion, LRPAP1 can substitute variable antibody regions in different formats to function in a new therapeutic approach to treat MCL., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

Low-density lipoprotein (LDL) receptor-related protein-associated protein 1 (LRPAP1) had been identified by B-cell receptor (BCR) expression cloning and subsequent protein array screening as a frequent and proliferation-inducing autoantigen of mantle cell lymphoma (MCL). Of interest, high-titered and light chain-restricted LRPAP1 autoantibodies were detected in 8 of 28 patients with MCL. In the present study, LRPAP1 autoantibodies in sera of patients treated within the Younger and Elderly trials of the European MCL Network were analyzed regarding frequency, association with disease characteristics, and prognostic impact. LRPAP1 autoantibodies were detected in 41 (13%) of 312 evaluable patients with MCL. These LRPAP1 autoantibodies belonged predominantly to the immunoglobulin G (IgG) class and were clonally light chain restricted (27 with κ light chains, 14 patients with λ light chains). Titers ranged between 1:400 and 1:3200. The presence of LRPAP1 autoantibodies was not significantly associated with any baseline clinical characteristic, however, it was associated with a superior 5-year probability for failure-free survival (FFS) of 70% (95% confidence interval [CI], 57% to 87%) vs 51% (95% CI, 44% to 58%), P = .0052; and for overall survival (OS) of 93% (95% CI, 85% to 100%) vs 68% (95% CI, 62% to 74%), P = .0142. LRPAP1-seropositive patients had a Mantle Cell Lymphoma International Prognostic Index-adjusted hazard ratio for FFS of 0.48 (95% CI 0.27-0.83, P = .0083) and for OS of 0.47 (95% CI 0.24-0.94, P = .032). LRPAP1 autoantibodies were frequently detected in a large cohort of MCL patients treated within prospective multicenter clinical trials. Our results suggest better outcomes for LRPAP1-autoantibody seropositive patients., (© 2021 by The American Society of Hematology.)

The pathogenesis of autoimmune complications triggered by SARS-CoV2 has not been completely elucidated. Here, we performed an analysis of the cellular immune status, cell ratios, and monocyte populations of patients with COVID-19 treated in the intensive care unit (ICU) (cohort 1, N = 23) and normal care unit (NCU) (cohort 2, n = 10) compared with control groups: patients treated in ICU for noninfectious reasons (cohort 3, n = 30) and patients treated in NCU for infections other than COVID-19 (cohort 4, n = 21). Patients in cohort 1 presented significant differences in comparison with the other cohorts, including reduced frequencies of lymphocytes, reduced CD8+T-cell count, reduced percentage of activated and intermediate monocytes and an increased B/T8 cell ratio. Over time, patients in cohort 1 who died presented with lower counts of B, T, CD4 + T, CD8 + T-lymphocytes, NK cells, and activated monocytes. The B/T8 ratio was significantly lower in the group of survivors. In cohort 1, significantly higher levels of IgG1 and IgG3 were found, whereas cohort 3 presented higher levels of IgG3 compared to controls. Among many immune changes, an elevated B/T8-cell ratio and a reduced rate of activated monocytes were mainly observed in patients with severe COVID-19. Both parameters were associated with death in cohort 1., (© 2021 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.)

Invasive infections caused by carbapenemase-producing bacteria are associated with excess mortality. We applied a rapid diagnostic test (RDT) on clinical samples with an elevated likelihood of carbapenemase-producing bacteria and documented its impact on antibiotic treatment decisions. Among 38 patients, twelve tested positive for infections caused by carbapenemase-producing bacteria (31.6%), mainly in blood cultures. KPC (n = 10) was more frequent than OXA-48 (n = 2). RDT-based carbapenemase detection led to a treatment modification to ceftazidime/avibactam-containing regimens in all patients before detailed antibiotic testing results became available. Eleven patients (92%) survived the acute infection, whereas one patient with a ceftazidime/avibactam- and colistin-resistant OXA-48-positive isolate died.

Purpose: Previous published data showed an impact of single-nucleotide polymorphisms in the VEGF A and VEGFR2 genes on the survival of patients with various malignancies, among others diffuse large B-cell lymphoma (DLBCL)., Patients and Methods: We investigated the role of four VEGF-A and two VEGFR-2 gene polymorphisms on the outcome of 273 patients with diffuse large B-cell lymphoma who were treated with R-CHOP within a prospective, randomized trial of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL). The genomic DNA samples were analyzed using commercial DNA Probes (Applied Biosystems, USA) to detect single-nucleotide polymorphisms in the VEGF A rs699947, rs1570360, rs2010963, rs3025039 and rs1870377, and rs2305948 in the VEGFR2 receptor. Hundred healthy blood donors served as a control., Results: There was no difference between the SNP allele frequencies in lymphoma patients compared to the control group for all investigated SNPs. None of the investigated SNPs was significantly associated with EFS or OS. After adjusting for the International Prognostic Index risk factors in a multivariate analysis, these results could be confirmed., Conclusion: Single-nucleotide polymorphisms of the VEGF and VEGFR2 were not associated with a worse outcome in Caucasian patients with DLBCL., (© 2020 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Patients undergoing intensive chemotherapy are usually in need for central venous catheters (CVC). Due to contradictory study results, relation of insertion site and CVC-associated complication rate in these patients is not clear. We therefore retrospectively analyzed CVC-related data of all patients undergoing intensive chemotherapy with high risk of febrile neutropenia according to NCCN criteria, who received a CVC at our bone marrow transplantation unit between May 2016 and December 2019. In total, 210 patients received 281 CVC. CVC were placed via either the subclavian-vein (SCV, n = 58; 20%) or the internal-jugular-vein (IJV, n = 223; 80%). Median duration of CVC-lifetime and neutropenic days per CVC were comparable between the two groups (IJV vs SCV: 23 days vs 21 days (p = 0.16) and 12 days vs 11 days (p = 0.65)). Both, time to CVC removal due to local inflammation and time to central line-associated bloodstream infection was significantly shorter in patients with SCV catheters (p = 0.013 and p = 0.045). CVC placed in the IJV were associated with significantly less catheter-related infectious events compared with CVC placed in the SCV. This difference was consistent across different subgroups including 88 patients undergoing allogeneic stem cell transplantation.

With an infection rate of 60-90%, the human cytomegalovirus (HCMV) is very common among adults but normally causes no symptoms. When T cell-mediated immunity is compromised, HCMV reactivation can lead to increased morbidity and mortality. HCMV antigens are processed and presented as peptides on the cell surface via HLA I complexes to the T cell receptor (TCR) of T cells. The generation of antibodies against HCMV peptides presented on HLA complexes (TCR-like antibodies) has been described, but is without therapeutic applications to date due to the polygenic and polymorphic nature of HLA genes. We set out to obtain antibodies specific for HLA/HCMV-peptides, covering the majority of HLA alleles present in European populations. Using phage display technology, we selected 10 Fabs, able to bind to HCMV-peptides presented in the 6 different HLA class I alleles A*0101, A*0201, A*2402, B*0702, B*0801 and B*3501. We demonstrate specific binding of all selected Fabs to HLA-typed lymphoblastoid cell lines (EBV-transformed B cells) and lymphocytes loaded with HCMV-peptides. After infection with HCMV, 4/10 tetramerized Fabs restricted to the alleles HLA-A*0101, HLA-A*0201 and HLA-B*0702 showed binding to infected primary fibroblasts. When linked to the pseudomonas exotoxin A, these Fab antibodies induce highly specific cytotoxicity in HLA matched cell lines loaded with HCMV peptides. TCR-like antibody repertoires therefore represent a promising new treatment modality for viral infections and may also have applications in the treatment of cancers.

Information regarding the curative role of allogeneic stem cell transplantation (allo-HCT) in systemic anaplastic large cell lymphoma (sALCL) is scarce. We analyzed the results of allo-HCT in patients with relapsed/refractory sALCL with special emphasis on the role of brentuximab vedotin (BV) as a bridge to allo-HCT. Forty-four patients (24 females, median age 38 years) with sALCL were included. Twenty-three patients (52%) received BV before allo-HCT; BV-treated patients were more heavily pretreated (≥3 lines of therapy in 74% vs. 38%, p = 0.04). Twenty-three patients (52%) were in complete remission (CR) at allo-HCT. Three-year nonrelapse mortality and incidence of relapse (IR) after allo-HCT were 7% and 40%, respectively. With a median follow-up of 39 (12-69) months for survivors, 3-year progression-free survival (PFS) and overall survival were 53% and 74%, respectively. Univariate analysis showed that heavily pretreated patients and those not in CR had a higher IR and a lower PFS. The use of BV before transplant did not impact on any of the outcomes. Allo-HCT is a curative therapeutic strategy in a significant proportion of patients with relapsed/refractory sALCL; BV does not seem to modify transplant-related outcomes but might be able to render more patients candidates for this curative treatment.

Autologous hematopoietic stem cell transplantation (auto-HSCT) is the standard of care for patients with diffuse large B-cell lymphoma (DLBCL) who relapse/progress after first line chemoimmunotherapy. Long-term outcome of those who relapse after transplant is poor. We present the results of a retrospective study of 256 adult patients reported to the EBMT registry with DLBCL who relapsed after auto-HSCT performed between 2003 and 2013, and who received active salvage strategies. One hundred and fifty-four (60%) were male; median age was 53 years. Median time to relapse was 7 months, 65% relapsed during the first year. Overall response rate after salvage therapy was 46%. Median follow-up after first salvage therapy was 40 months (IQR 23-63 months). Overall survival (OS) at 3 years was 27% (95% CI 22-33). OS at 3 years of patients relapsing longer than 1 year after auto-HSCT was 41% (95% CI 31-53) compared with 20% (95% CI 14-24) in those who relapsed in less than 1 year. Eighty-two patients (32%) had a second HSCT, an allogeneic HSCT (allo-HSCT) in 69 cases, at a median time of 6.5 months after relapse. OS at 3 years after allo-HSCT was 36% (95% CI 25-51). In conclusion, the prognosis of patients with DLBCL that relapse after auto-HSCT is dismal. Patients who relapse in less than 1 year remain an unmet need, and should be considered for CAR T cell therapy or clinical trials. Patients who relapse after 1 year can be rescued with salvage therapies and a second HSCT. These results provide a benchmark to compare data of new prospective studies.

Objectives: Previously we discovered antibodies against progranulin (PGRN-abs) in a protein array-based screening of sera from various rheumatic diseases. Here we conducted a study to evaluate the prevalence of PGRN-abs in seropositive and seronegative rheumatoid arthritis (RA)., Methods: PGRN-abs were determined in the sera from 257 RA patients being seropositive for RF-IgM and/or ACPA-IgG and from 224 seronegative RA patients who were prospectively included in this study (total RA cohort n=481). All serum samples from the included participants were tested for RF-IgM as well as for ACPA-IgG, and PGRN-abs were determined using a previously described ELISA. Statistics was performed using the χ2 test for evaluating differences in clinical data; to evaluate independent statistical effects on the frequency of PGRN-abs status a logistic regression model with Wald-test was performed., Results: PGRN-abs were detected in 25.3% from seropositive RA and in 21.0% from RF- and ACPA-negative RA resulting in a prevalence of 23.7% for both cohorts together. Comparing mean DAS28 values in the PGRN-abs positive cohort with the PGRN-abs negative cohort, the DAS28 value was significantly higher in PGRN-abs positive RA patients (3.81 vs. 3.50, p=0.038). A trend for higher frequencies of PGRN-abs in sera of RA patients with unfavourable characteristics such as erosive disease or requiring TNFi medication was observed., Conclusions: These data suggest that the determination of PGRN-abs in seronegative RA patients may reduce their seronegative status. Further studies are required to evaluate PGRN-abs as a potential diagnostic marker in RA.

Intensive chemotherapy, with or without following autologous or allogeneic stem cell transplantation (HSCT), is often the only curative treatment option for patients with hematological malignancies and leave many survivors physically and psychologically impaired. Electrical muscle stimulation (EMS) is a proven tool to improve physical performance in seniors and patients with chronic diseases. We therefore investigated the safety and feasibility of EMS in 45 patients undergoing autologous HSCT (n = 13), allogeneic HSCT (n = 11) and intensive chemotherapy (n = 21). Furthermore, physical (assessed by 6-min walking distance (6MWD) and short physical performance battery (SPPB)) and psychological performance (assessed by multidimensional fatigue inventory (MFI) and the EORTC QOL-C30 questionnaire) were measured before chemotherapy (T1) and at discharge from hospital (T2). Four patients died due to septic shock, two withdrew consent before the start of EMS training and five stopped EMS training during the study because of chemotherapy-related complications, loss of motivation or loss of ability to use EMS autonomously. Thirty-four out of 45 (76%) patients used EMS throughout the study period and participated in physical and psychological tests at time points 1 and 2. EMS-related adverse events were hematoma (n = 1) and muscle pain (n = 2). No bleeding events > 1 according to the WHO bleeding scale occurred. Decline in 6MWD from T1 to T2 was 24 m. The SPPB score stayed the same with 11 points at T1 and T2. Most MFI subscales showed stable fatigue levels and quality of life (QoL) did not decrease significantly throughout therapy. EMS is feasible and safe in patients undergoing intensive chemotherapy. Trial registration: NCT03467087.

Aims: It is unknown whether different training modalities exert differential cellular effects. Telomeres and telomere-associated proteins play a major role in cellular aging with implications for global health. This prospective training study examines the effects of endurance training, interval training (IT), and resistance training (RT) on telomerase activity and telomere length (TL)., Methods and Results: One hundred and twenty-four healthy previously inactive individuals completed the 6 months study. Participants were randomized to three different interventions or the control condition (no change in lifestyle): aerobic endurance training (AET, continuous running), high-intensive IT (4 × 4 method), or RT (circle training on 8 devices), each intervention consisting of three 45 min training sessions per week. Maximum oxygen uptake (VO2max) was increased by all three training modalities. Telomerase activity in blood mononuclear cells was up-regulated by two- to three-fold in both endurance exercise groups (AET, IT), but not with RT. In parallel, lymphocyte, granulocyte, and leucocyte TL increased in the endurance-trained groups but not in the RT group. Magnet-activated cell sorting with telomerase repeat-ampliflication protocol (MACS-TRAP) assays revealed that a single bout of endurance training-but not RT-acutely increased telomerase activity in CD14+ and in CD34+ leucocytes., Conclusion: This randomized controlled trial shows that endurance training, IT, and RT protocols induce specific cellular pathways in circulating leucocytes. Endurance training and IT, but not RT, increased telomerase activity and TL which are important for cellular senescence, regenerative capacity, and thus, healthy aging.

Macrophages are key mediators of the therapeutic effects exerted by monoclonal antibodies, such as the anti-CD38 antibody MOR202, currently introduced in multiple myeloma (MM) therapy. Therefore, it is important to understand how antibody-mediated effector functions of myeloma-associated macrophages (MAMs) are regulated. Here, we focused on the effects of vitamin D, a known regulator of macrophage effector functions. Consequently, it was the aim of this study to assess whether modulation of the vitamin D pathway alters the tumoricidal activity of MAMs. Here, we demonstrate that MAMs display a defective vitamin D pathway with reduced expression level of CYP27B1 and limited tumoricidal activity which can be restored by the IMiD lenalidomide in vitro. Furthermore, our data indicate that the vitamin D pathway of MAMs from MM patients does recover during an IMiD-containing therapy shown by an improved MOR202-mediated cytotoxic activity of these MAMs against primary MM cells ex vivo. Here, the ex vivo cytotoxic activity could be further enhanced by vitamin D supplementation. These data suggest that vitamin D holds a key role for the effector functions of MAMs and that vitamin D supplementation in IMiD combination trials could further increase the therapeutic efficacy of anti-CD38 antibodies such as MOR202, which remains to be investigated in clinical studies.

Vitamin D3 (25-OH-D3) deficiency impairs rituximab-dependent cellular cytotoxicity and the outcome of patients with diffuse large B-cell and follicular lymphomas (DLBCL). Since the optimum 25-OH-D3 serum levels for NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) are unknown, we determined the 25-OH-D3 serum levels associated with maximum NK cell-mediated ADCC. CD20 antibody-loaded CD20 + B-cell lymphoma cell lines were cultured with NK cells and ADCC activity was determined by lactate dehydrogenase release assays. Using a newly developed formula, pre-defined 25-OH-D3 serum levels were achieved with high individual precision over a wide range. NK cells from 20 healthy individuals killed antibody-treated CD20 + lymphoma cells in a concentration- and E:T ratio-dependent manner with obinutuzumab displaying a stronger ADCC activity than rituximab. Maximum NK-cell activity and ADCC were observed at 65 ng/ml 25-OH-D3, the middle of the normal range (30-100 ng/ml). 25-OH-D3 serum levels around this range should be the target in interventional trials aiming at improving NK cell-mediated ADCC by 25-OH-D3 substitution. Lower levels do not provide significant ADCC improvements in individuals with 25-OH-D3 deficiency or insufficiency and might result in the failure of interventions with 25-OH-D3.

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Vitamin D deficiency is frequently observed in human cancer patients and a prognostic relevance could be shown for some entities. Additionally, it is known that vitamin D can stimulate the patients' antitumor immunity. However, valid epidemiological data for head and neck squamous cell carcinoma (HNSCC) patients are sparse and functional studies on a possible connection between vitamin D and the patients' immune system are missing. 25-OH vitamin D serum levels were analyzed in 231 HNSCC patients and 232 healthy controls and correlated with clinical data and patient survival. Intra- and peritumoral infiltration with T-cell, NK-cell and macrophage populations was analyzed in 102 HNSCC patients by immunohistochemistry. In 11 HNSCC patients, NK-cells were isolated before and after vitamin D substitution and analyzed for their cytotoxic activity directed against a HNSCC cell line. Vitamin D serum levels were significantly lower in HNSCC patients compared with healthy controls. Low vitamin D levels were associated with lymphatic metastasis and a negative HPV status and were a significant predictor of poor overall survival. HNSCC patients with severe vitamin D deficiency showed significantly altered intra- and peritumoral immune cell infiltrate levels. After vitamin D substitution, the patients' NK cells showed a significant rise in cytotoxic activity. Taken together, we could show that Vitamin D deficiency is highly prevalent in HNSCC patients and is a predictor of poor survival. Vitamin D substitution used as an adjuvant in immune therapies such as cetuximab and nivolumab treatment could support antitumorigenic immune responses, thus contributing to the improvement of the patients' prognosis in the context of a multimodal therapy.

Various systemic inflammatory diseases, such as rheumatoid arthritis (RA), Sjögren's syndrome and systemic lupus erythematosus (SLE) are associated with an increased risk for the development of lymphomas. Studies on patients with RA and Sjögren's syndrome have shown that there is a clear association of the incidence of lymphoma with the severity and activity of the disease and lymphomas in particular are diseases which preferentially occur in immunosuppressed patients; therefore, knowledge of the different lymphoma subtypes, their prognosis and treatment options are important for rheumatologists. Currently, there is no evidence for an increased risk of lymphoma with the available conventional basis therapies or biologic disease-modifying antirheumatic drugs (DMARDs). The decision on how to treat a patient with previous lymphoma who requires antirheumatic treatment is more difficult as patients with previous malignancies are not included in clinical studies and in registries a bias with respect to patient selection must be taken into consideration. Decisions on the treatment approach, therefore need to be individualized and interdisciplinary management together with the treating hematologist is warranted.

Infiltration by macrophages represents a characteristic morphological hallmark in high-grade lymphatic malignancies such as Burkitt's lymphoma (BL). Although macrophages can, in principle, target neoplastic cells and mediate antibody-dependent cellular cytotoxicity (ADCC), tumor-associated macrophages (TAMs) regularly fail to exert direct cytotoxic functions. The underlying mechanisms responsible for this observation remain unclear. We demonstrate that inflammatory M1 macrophages kill proliferating high-grade B cell lymphoma cells by releasing the antimicrobial peptide cathelicidin in a vitamin D-dependent fashion. We show that cathelicidin directly induces cell death by targeting mitochondria of BL cells. In contrast, anti-inflammatory M2 macrophages and M2-like TAMs in BL exhibit an altered vitamin D metabolism, resulting in a reduced production of cathelicidin and consequently in inability to lyse BL cells. However, treatment of M2 macrophages with the bioactive form of vitamin D, 1,25D3, or a vitamin D receptor agonist effectively induces cathelicidin production and triggers tumoricidal activity against BL cells. Furthermore, rituximab-mediated cytotoxicity of vitamin D-treated M2 macrophages is cathelicidin-dependent. Finally, vitamin D treatment of 25-hydroxyvitamin D (25D)-deficient volunteers in vivo or primary TAMs in vitro improves rituximab-mediated ADCC against B cell lymphoma cells. These data indicate that activation of the vitamin D signaling pathway activates antitumor activity of TAMs and improves the efficacy of ADCC., (Copyright © 2015, American Association for the Advancement of Science.)