R-miniCHOP versus R-CHOP in elderly patients with diffuse large B-cell lymphoma: A propensity matched population-based study.

For elderly frail patients with diffuse large B-cell lymphoma (DLBCL), an attenuated chemo-immunotherapy strategy of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-miniCHOP) was introduced as a treatment option as from 2014 onward in the Netherlands. Although R-miniCHOP is more tolerable, reduction of chemotherapy could negatively affect survival compared to R-CHOP. The aim of this analysis was to assess survival of patients treated with R-miniCHOP compared to R-CHOP. DLBCL patients ≥65 years, newly diagnosed in 2014-2020, who received ≥1 cycle of R-miniCHOP or R-CHOP were identified in the Netherlands Cancer Registry, with survival follow-up through 2022. Patients were propensity-score-matched for baseline characteristics. Main endpoints were progression-free survival (PFS), overall survival (OS), and relative survival (RS). The use of R-miniCHOP in DLBCL increased from 2% in 2014 to 15% in 2020. In total, 384 patients treated with R-miniCHOP and 384 patients treated with R-CHOP were included for comparison (median age; 81 years, stage 3-4; 68%). The median number of R-(mini)CHOP cycles was 6 (range, 1-8). The 2-year PFS, OS and RS were inferior for patients treated with R-miniCHOP compared to R-CHOP (PFS 51% vs. 68%, p < .01; OS 60% vs. 75%, p < .01; RS 69% vs. 86%, p < .01). In multivariable analysis, patients treated with R-miniCHOP had higher risk of all-cause mortality compared to patients treated with R-CHOP (HR 1.73; 95%CI, 1.39-2.17). R-miniCHOP is effective for most elderly patients. Although survival is inferior compared to R-CHOP, the use of R-miniCHOP as initial treatment is increasing. Therefore, fitness needs to be carefully weighed in treatment selection.

Semi-Quantitative Characterization of Post-Transplant Lymphoproliferative Disorder Morphological Subtypes with [18F]FDG PET/CT.

Background: Post-transplant lymphoproliferative disorder (PTLD) is a complication of organ transplantation classified according to the WHO as nondestructive, polymorphic, monomorphic, and classic Hodgkin Lymphoma subtypes. In this retrospective study, we investigated the potential of semi-quantitative 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) PET/computed tomography (CT)-based parameters to differentiate between the PTLD morphological subtypes. Methods: 96 patients with histopathologically confirmed PTLD and baseline [18F]FDG PET/CT between 2009 and 2019 were included. Extracted semi-quantitative measurements included: Maximum, peak, and mean standardized uptake value (SUVmax, SUVpeak, and SUVmean). Results: Median SUVs were highest for monomorphic PTLD followed by polymorphic and nondestructive subtypes. The median SUVpeak at the biopsy site was significantly higher in monomorphic PTLD (17.8, interquartile range (IQR):16) than in polymorphic subtypes (9.8, IQR:13.4) and nondestructive (4.1, IQR:6.1) (p = 0.04 and p ≤ 0.01, respectively). An SUVpeak ≥ 24.8 was always indicative of a monomorphic PTLD in our dataset. Nevertheless, there was a considerable overlap in SUV across the different morphologies. Conclusion: The median SUVpeak at the biopsy site was significantly higher in monomorphic PTLD than polymorphic and nondestructive subtypes. However, due to significant SUV overlap across the different subtypes, these values may only serve as an indication of PTLD morphology, and SUV-based parameters cannot replace histopathological classification.

Diagnostic performance of FDG-PET/CT of post-transplant lymphoproliferative disorder and factors affecting diagnostic yield.

PURPOSE: Post-transplant lymphoproliferative disorder (PTLD) is a serious complication after solid organ and hematopoietic stem cell transplantation, requiring a timely and accurate diagnosis. In this study, we evaluated the diagnostic performance of FDG-PET/CT in patients with suspected PTLD and examined if lactate dehydrogenase (LDH) levels, Epstein-Barr virus (EBV) load, or timing of FDG-PET/CT relate to detection performance of FDG-PET/CT. METHODS: This retrospective study included 91 consecutive patients with clinical suspicion of PTLD and a total of 97 FDG-PET/CT scans within an 8-year period. Pathology reports and a 2-year follow-up were used as the reference standard. Diagnostic performance of FDG-PET/CT for detection of PTLD as well as logistic regression analysis for factors expected to affect diagnostic yield were assessed. RESULTS: The diagnosis of PTLD was established in 34 patients (35%). Fifty-seven FDG-PET/CT scans (59%) were true negative, 29 (30%) were true positive, 6 (6%) false positive, and 5 (5%) false negative. Sensitivity of FDG-PET/CT for the detection of PTLD was 85%, specificity 90%, positive predictive value 83%, and negative predictive value 92%, with good inter-observer variability (k = 0.78). Of the parameters hypothesized to be associated with a true positive FDG-PET/CT result for the diagnosis of PTLD, only LDH was statistically significant (OR 1.03, p = 0.04). CONCLUSION: FDG-PET/CT has a good diagnostic performance in patients suspected of PTLD, with a good inter-observer agreement. Only LDH levels seemed to influence the detection performance of FDG-PET/CT. EBV-DNA load and timing of FDG-PET/CT after transplantation did not affect FDG-PET/CT diagnostic yield.

Relationship between semiquantitative 18F-fluorodeoxyglucose positron emission tomography metrics and necrosis in classical Hodgkin lymphoma.

Semiquantitative 18F-fluoro-2-deoxy-D-glucose positron emission tomography (18F-FDG PET) parameters have been proposed as prognostic markers in classical Hodgkin lymphoma (cHL). In non-Hodgkin lymphoma necrosis as assessed by 18F-FDG PET or computed tomography (CT) (necrosisvisual) correlates with an adverse prognosis. We investigated whether semiquantitative 18F-FDG PET metrics correlate with necrosisvisual, determined the incidence of necrosisvisual and explored the prognostic impact of these factors in cHL. From 87 cHL cases treated with ABVD, (escalated) BEACOPP or CHOP chemotherapy between 2010 and 2017, 71 had both a NEDPAS/EARL accredited 18F-FDG PET and a contrast enhanced CT scan. Semiquantitative 18F-FDG PET parameters were determined using Hermes Hybrid 3D software. Necrosisvisual, defined by photopenic tumor areas on 18F-FDG PET and attenuation values between 10 and 30 Hounsfield units (HUs) on CT, was assessed blinded to outcome. Univariate Cox regression survival analyses of progression free survival (PFS) were performed. Necrosisvisual was observed in 18.3% of cHL patients. Bulky disease (tumor mass >10 cm in any direction) (P = 0.002) and TLG (P = 0.041) but no other semiquantitative parameters were significantly associated with necrosisvisual. In exploratory univariate survival analysis for PFS the covariates IPS, bulky disease, MTV and TLG were prognostic, while necrosisvisual was not.

The microenvironment of classical Hodgkin lymphoma: heterogeneity by Epstein-Barr virus presence and location within the tumor.

This corrects the article DOI: 10.1038/bcj.2016.26.

Emerging roles for long noncoding RNAs in B-cell development and malignancy.

Long noncoding (lnc)RNAs have emerged as essential mediators of cellular biology, differentiation and malignant transformation. LncRNAs have a broad range of possible functions at the transcriptional, posttranscriptional and protein level and their aberrant expression significantly contributes to the hallmarks of cancer cell biology. In addition, their high tissue- and cell-type specificity makes lncRNAs especially interesting as biomarkers, prognostic factors or specific therapeutic targets. Here, we review current knowledge on lncRNA expression changes during normal B-cell development, indicating essential functions in the differentiation process. In addition we address lncRNA deregulation in B-cell malignancies, the putative prognostic value of this as well as the molecular functions of multiple deregulated lncRNAs. Altogether, the discussed work indicates major roles for lncRNAs in normal and malignant B cells affecting oncogenic pathways as well as the response to common therapeutics.

Nephrotic syndrome due to lupus-like glomerulonephritis in an HIV-positive patient.

Lupus nephritis, a well-known complication in systemic lupus erythematosus, is characterised by a proliferative glomerulonephritis or membranous nephropathy along with a full-house immunofluorescence pattern on renal biopsy. There are very few exceptions in which similar histopathological findings are present, but case reports show that an increasing number of HIV-positive patients (mostly black Africans, but also white patients) have HIV-immune complex disease (HIVICK), which can mimic lupus nephritis. Lupus-like HIVICK is treated differently than 'true' lupus nephritis, so distinction is warranted.

Novel treatment concepts in Hodgkin lymphoma.

Treatment of classical Hodgkin's lymphoma (HL) has been a success story, with cure of localized disease with radiotherapy in the 1930s, cure of advanced stages with combination chemotherapy with/without radiotherapy in the mid-1960s and continuous improvements since then. Nonetheless, at present approximately 2% of patients with classical HL are primarily refractory to conventional therapy with only 50% becoming long-term survivors. Another 13% of patients relapse, with only 60% being alive 10 years postrecurrence (as exemplified in this review in a Swedish cohort of 18- to 65-year-old patients diagnosed during the period 1992-2009). Recently, novel targeted drugs were approved for refractory/relapsed HL and here we review results of trials that form the basis for these approvals as well as new trials. In summary, brentuximab vedotin can be used in refractory patients (i) as a complement to high-dose chemotherapy with autologous stem cell transplantation (SCT) improving the chances of being able to proceed to an allogenic SCT and cure, (ii) as consolidation after autologous SCT and (iii) as palliative life-prolonging treatment. However, we have yet to determine whether this drug provides the greatest benefit in first- or second-line treatment, as consolidation or in refractory disease or relapse. Trials of immune checkpoint inhibitors, such as those targeting programmed death 1 (nivolumab and pembrolizumab), and thus not primarily the tumour cells, have shown overall response rates of >65%. Long-term results and data from Phase III trials are still lacking, but nivolumab recently gained approval in refractory patients already treated with brentuximab vedotin and autologous SCT. Other novel treatments of interest include T cells with a chimeric antigen receptor and combination therapies with histone deacetylase inhibitors.

CD58 mutations are common in Hodgkin lymphoma cell lines and loss of CD58 expression in tumor cells occurs in Hodgkin lymphoma patients who relapse.

CD58 is involved in immune recognition of tumor cells via binding of the CD2 receptor expressed on cytotoxic T cells. In diffuse large B-cell lymphoma, mutations of the CD58 gene are reported to contribute to immune evasion of the tumor cells. We previously showed CD58 mutations in three Hodgkin lymphoma (HL) cell lines by whole-exome sequencing. In this study, we confirmed the mutations by Sanger sequencing at the DNA and RNA level and showed low levels or total loss of CD58 mRNA expression in two of the three cell lines. CD58 protein expression as determined by flow cytometry, western blotting and immunohistochemistry was absent in all three mutated HL cell lines. In primary tissue samples, loss of CD58 expression was observed in 11% of the patients who relapse. These data suggest that loss of CD58 is a potential immune escape mechanism of HL tumor cells, especially in clinically aggressive disease.

A meta-analysis of Hodgkin lymphoma reveals 19p13.3 TCF3 as a novel susceptibility locus.

Recent genome-wide association studies (GWAS) of Hodgkin lymphoma (HL) have identified associations with genetic variation at both HLA and non-HLA loci; however, much of heritable HL susceptibility remains unexplained. Here we perform a meta-analysis of three HL GWAS totaling 1,816 cases and 7,877 controls followed by replication in an independent set of 1,281 cases and 3,218 controls to find novel risk loci. We identify a novel variant at 19p13.3 associated with HL (rs1860661; odds ratio (OR)=0.81, 95% confidence interval (95% CI) = 0.76-0.86, P(combined) = 3.5 × 10(-10)), located in intron 2 of TCF3 (also known as E2A), a regulator of B- and T-cell lineage commitment known to be involved in HL pathogenesis. This meta-analysis also notes associations between previously published loci at 2p16, 5q31, 6p31, 8q24 and 10p14 and HL subtypes. We conclude that our data suggest a link between the 19p13.3 locus, including TCF3, and HL risk.

HLA-G protein expression as a potential immune escape mechanism in classical Hodgkin's lymphoma.

Classical Hodgkin's lymphoma (cHL) is characterized by the presence of an abundant reactive infiltrate, lacking effective cytotoxic responses. Especially in Epstein-Barr virus (EBV)-negative cHL, the neoplastic Hodgkin-Reed-Sternberg (HRS) cells have lost protein expression of major histocompatibility complex (MHC) class I, enabling escape from cytotoxic T lymphocyte (CTL) responses. However, downregulation of MHC class I generally induces natural killer (NK) cell activation. The paucity of NK cells in the reactive infiltrate of cHL and the systemic NK cell deficiency observed in cHL patients led us to investigate the expression of human leukocyte antigen (HLA)-G, which is known to inhibit NK-cell- and CTL-mediated cytotoxicity. By immunohistochemistry, HLA-G protein was expressed by HRS cells in 54% (95/175) of cHL cases. This expression was associated with absence of MHC class I on the cell surface of HRS cells (P < 0.001) and EBV-negative status (P < 0.001). Previously, genetic markers located in the proximity of the HLA-A and HLA-G genes had been shown to be associated with susceptibility to EBV-positive cHL. In the present study, these markers associated with MHC class I protein expression but not with presence of HLA-G. Our results suggest that induction of HLA-G protein expression in HRS cells contributes to the modulation of immune responses observed in cHL.

Genetic susceptibility to Hodgkin's lymphoma associated with the human leukocyte antigen region.

Based on the presence of an abundant inflammatory infiltrate, expression of a broad spectrum of cytokines and the professional antigen presenting phenotype of Hodgkin Reed-Sternberg cells it can be anticipated that immunological mechanisms play a major role in the pathogenesis of Hodgkin's lymphoma (HL). Genetic susceptibility to HL probably relates to functionality of the immune system and the large number of associations with the human leukocyte antigen (HLA) region in family and population-based studies supports this relation. In Epstein-Barr virus (EBV) positive HL cases, which usually demonstrate HLA class I expression, HRS cells should be able to present EBV derived antigenic peptides and trigger the immune system. This process depends on the affinity of the HLA binding groove for binding immunogenic peptides and thus on the HLA alleles. It can be anticipated that certain combinations of alleles predispose to or protect from the development of EBV positive HL. In EBV negative HL cases other antigenic peptides, related to malignant transformation, in combination with other HLA alleles may be involved. In addition, differential attraction and activation of inflammatory cells may influence HL subtype. In this article, possible roles of HLA in HL pathogenesis are explored and genetic associations of HLA with HL are reviewed and commented on.

Association with HLA class I in Epstein-Barr-virus-positive and with HLA class III in Epstein-Barr-virus-negative Hodgkin's lymphoma.

BACKGROUND: Associations of Hodgkin's lymphoma with HLA have been reported for many years. In 20-40% of patients with this disorder, Epstein-Barr virus (EBV) is present in the neoplastic cells. Because presentation of EBV antigenic peptides can elicit vigorous immune responses, we investigated associations of the HLA region with EBV-positive and EBV-negative Hodgkin's lymphoma. METHODS: In a retrospective, population-based study, patients with Hodgkin's lymphoma were reclassified according to the WHO classification, and EBV status was assessed by in-situ hybridisation of EBV-encoded small RNAs. Germline DNA was isolated from 200 patients diagnosed between 1987 and 2000 and from their first-degree relatives. Genotyping was done with 33 microsatellite markers spanning the entire HLA region and two single-nucleotide polymorphisms in the genes for tumour necrosis factor alpha and beta. Classic association analysis and the haplotype sharing statistic were used to compare patients with controls. FINDINGS: Classic association analysis (but not the haplotype sharing statistic) showed an association of consecutive markers D6S265 and D6S510 (p=0.0002 and 0.0003), located in the HLA class I region, with EBV-positive lymphomas. The haplotype sharing statistic (but not classic association analysis) showed a significant difference in mean haplotype sharing between patients and controls surrounding marker D6S273 (p=0.00003), located in HLA class III. INTERPRETATION: Areas within the HLA class I and class III regions are associated with susceptibility to Hodgkin's lymphoma, the association with class I being specific for EBV-positive disease. This finding strongly suggests that antigenic presentation of EBV-derived peptides is involved in the pathogenesis of EBV-involved Hodgkin's lymphoma. RELEVANCE TO PRACTICE: Polymorphisms in the HLA region could explain ethnic variation in the incidence of Hodgkin's lymphoma. The association of EBV-positive Hodgkin's lymphoma with HLA class I suggests that this polymorphism might affect the proper presentation of EBV antigens to cytotoxic T lymphocytes.

High expression of Mcl-1 in ALK positive and negative anaplastic large cell lymphoma.

AIM: To gain more insight into the genes involved in the aetiology and pathogenesis of anaplastic large cell lymphoma (ALCL). METHODS: Serial analysis of gene expression (SAGE) was undertaken on the CD4+ALK+ (anaplastic lymphoma kinase positive) ALCL derived cell line Karpas299 and as comparison on CD4+ T cells. Quantitative reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry were performed on five ALCL derived cell lines and 32 tissue samples to confirm the SAGE data. RESULTS: High expression of Mcl-1 was seen in the Karpas299 cell line, whereas the two other antiapoptotic Bcl-2 family members, Bcl-2 and Bcl-X(L), were not detected in the SAGE library. Quantitative RT-PCR confirmed the high expression of Mcl-1 mRNA and low expression of Bcl-2 and Bcl-X(L) in Karpas299 and in four other ALCL cell lines. To expand on these initial observations, primary tissue samples were analysed for Mcl-1, Bcl-X(L), and Bcl-2 by immunohistochemistry. All 23 ALK+ and nine ALK- ALCL cases were positive for Mcl-1. Bcl-2 and Bcl-X(L) were expressed infrequently in ALK+ ALCL cases, but were present in a higher proportion of ALK- ALCL cases. CONCLUSION: The consistent high expression of Mcl-1 in ALK+ and ALK- ALCL suggests that Mcl-1 is the main antiapoptotic protein in this disease. The high frequency of Mcl-1, Bcl-2, and Bcl-X(L) positive ALCL cases in the ALK- group compared with the ALK+ group indicates that ALK induced STAT3 activation is not the main regulatory pathway in ALCL.

Chemokines, cytokines and their receptors in Hodgkin's lymphoma cell lines and tissues.

BACKGROUND: Hodgkin's lymphoma (HL) is characterized by a minority of neoplastic cells, the so-called Reed-Sternberg (RS) cells, and an admixture of reactive cells including lymphocytes, plasma cells, eosinophils and histiocytes. Cytokines produced in HL, either by RS or infiltrating cells, might explain the presence and maintenance of an impaired immune response. Chemokines (cytokines with chemoattractant properties) produced by RS cells play a major role in leukocyte trafficking. These molecules with specific receptor affinities contribute, for example by attracting TH2-like T cells, to the maintenance of a favorable environment for survival of RS cells. RESULTS AND DISCUSSION: Cross-talk between RS cells and reactive elements involves several cytokine/chemokines that process proliferative [interleukin (IL)-13 and IL-17], immunosuppressive (IL-10 and transforming growth factor-beta) and background formation (IL-5, TARC, MDC, IP-10, RANTES, Mig and others) messages. These autocrine and paracrine interactions lead to an environment where RS cells are able to proliferate, escape from apoptosis and survive host anti-tumor defense. CONCLUSIONS: The proper modulation of these complex pathways may allow the development of new strategies in HL therapy.