Publications by authors named "Gunilla Enblad"

124 Publications

Prior antithymocyte globulin therapy and survival in post-transplant lymphoproliferative disorders.

Acta Oncol 2021 Apr 1:1-8. Epub 2021 Apr 1.

Experimental and Clinical Oncology, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.

Treatment with antithymocyte globulin (ATG) is a well-recognized risk factor for the development of post-transplant lymphoproliferative disorders (PTLD) after solid organ transplantation, but it is unknown how its use affects overall survival after PTLD. A total of 114 patients with PTLD and available data on immunosuppressive regimen were included from a nation-wide case series of solid organ transplant recipients in Sweden. Prior use of ATG was correlated to clinical features, PTLD subtype, and survival. A total of 47 (41%) patients had received ATG prior to the diagnosis of PTLD. The ATG-treated patients were more likely to be recipients of hearts or lungs, and less likely of kidneys ( < 0.01). They had experienced more acute rejections ( = 0.02). The PTLDs arose earlier, median 2.0 vs. 6.6 years post-transplant ( = 0.002) and were more often situated in the allograft (32% vs. 7%,  < 0.001) in patients with prior ATG vs. no ATG treatment. The PTLDs in the ATG group were more often Epstein-Barr virus-positive (80% vs. 40%,  < 0.001). There were more polymorphic PTLDs (17% vs. 1.5%,  = 0.004) and less T-cell PTLDs (4% vs. 19%,  = 0.02) in the ATG group than in the no ATG group. Diffuse large B-cell lymphoma was equally common in patients with and without prior ATG therapy, but the non-germinal center subtype was more frequent in the ATG group ( = 0.001). In an adjusted Cox proportional hazards regression model, prior ATG treatment and better performance status were associated with superior overall survival, whereas older age, T-cell subtype of PTLD, presence of B symptoms, and elevated lactate dehydrogenase were associated with inferior overall survival. Patients receiving ATG solely as rejection therapy had superior overall survival compared with those receiving ATG as induction therapy or both ( = 0.03). ATG therapy, especially rejection therapy, prior to PTLD development is an independent prognostic factor for superior overall survival after PTLD diagnosis.
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http://dx.doi.org/10.1080/0284186X.2021.1904520DOI Listing
April 2021

Prognostic impact of soluble CD163 in patients with diffuse large Bcell lymphoma.

Haematologica 2021 Mar 25. Epub 2021 Mar 25.

Research Program Unit, Applied Tumor Genomics, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Department of Oncology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland; iCAN Digital Precision Cancer Medicine Flagship, Helsinki.

Not available.
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http://dx.doi.org/10.3324/haematol.2020.278182DOI Listing
March 2021

Revisiting IL-6 expression in the tumor microenvironment of classical Hodgkin lymphoma.

Blood Adv 2021 Mar;5(6):1671-1681

Experimental and Clinical Oncology, Department of Immunology, Genetics and Pathology, and.

Interleukin-6 (IL-6) can induce therapeutic resistance for several cancer agents currently used to treat classical Hodgkin lymphoma (cHL). We aimed to investigate whether the presence of IL-6+ leukocytes and IL-6+ Hodgkin-Reed-Sternberg (HRS) cells in the tumor microenvironment (TME) was associated with adverse survival outcomes, expression of other immune markers, and serum IL-6 levels. We used a contemporarily treated cohort (n = 136), with a median follow-up of 13.8 years (range, 0.59-15.9 years). We performed immunohistochemistry with an IL-6 antibody on tissue microarrays from diagnostic biopsies of cHL patients. Patients with IL-6+ leukocytes ≥1% (n = 54 of 136) had inferior event-free survival (hazard ratio [HR] = 3.58; 95% confidence interval [CI], 1.80-7.15) and overall survival (HR = 6.71; 95% CI, 2.51-17.99). The adverse survival was maintained in multivariate Cox regression and propensity score-matched analyses, adjusting for well-known poor-prognostic covariates. The presence of IL-6+ HRS cells and high serum IL-6 levels were not associated with survival. IL-6+ leukocytes correlated with increased proportions of IL-6+ HRS cells (P < .01), CD138+ plasma cells (P < .01), CD68+ macrophages (P = .02), and tryptase-positive mast cells (P < .01). IL-6+ HRS cells correlated with increased proportions of CD68+ macrophages (P = .03), programmed death-ligand 1-positive (PD-L1+) leukocytes (P = .04), and PD-L1+ HRS cells (P < .01). Serum-IL-6 lacked correlation with IL-6 expression in the TME. This is the first study highlighting the adverse prognostic impact of IL-6+ leukocytes in the TME in a cohort of contemporarily treated adult patients with cHL.
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http://dx.doi.org/10.1182/bloodadvances.2020003664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993098PMC
March 2021

Boosting CAR T-cell responses in lymphoma by simultaneous targeting of CD40/4-1BB using oncolytic viral gene therapy.

Cancer Immunol Immunother 2021 Mar 5. Epub 2021 Mar 5.

Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory C11, Dag Hammarskjölds Väg 20, 75185, Uppsala, Sweden.

Pretreatment of B-cell lymphoma patients with immunostimulatory gene therapy using armed oncolytic viruses may prime tumor lesions for subsequent chimeric antigen receptor (CAR) T-cell therapy, thereby enhancing CAR T-cell functionality and possibly increasing response rates in patients. LOAd703 (delolimogene mupadenorepvec) is an oncolytic adenovirus (serotype 5/35) that encodes for the transgenes CD40L and 4-1BBL, which activate both antigen-presenting cells and T cells. Many adenoviruses failed to demonstrate efficacy in B-cell malignancies, but LOAd703 infect cells via CD46, which enables B cell infection. Herein, we investigated the therapeutic potential of LOAd703 in human B-cell lymphoma models, alone or in combination with CAR T-cell therapy. LOAd703 could infect and replicate in B-cell lymphoma cell lines (BC-3, Karpas422, Daudi, DG-75, U-698) and induced an overall enhanced immunogenic profile with upregulation of co-stimulatory molecules CD80, CD86, CD70, MHC molecules, death receptor Fas and adhesion molecule ICAM-1. Further, CAR T-cell functionality was boosted by stimulation with lymphoma cells infected with LOAd703. This was demonstrated by an augmented release of IFN-γ and granzyme B, increased expression of the degranulation marker CD107a, fewer PD-1 + TIM-3+ CAR T cells in vitro and enhanced lymphoma cell killing both in in vitro and in vivo xenograft models. In addition, LOAd703-infected lymphoma cells upregulated the secretion of several chemokines (CXCL10, CCL17, CCL22, CCL3, CCL4) essential for immune cell homing, leading to enhanced CAR T-cell migration. In conclusion, immunostimulatory LOAd703 therapy is an intriguing approach to induce anti-lymphoma immune responses and to improve CAR T-cell therapy in B-cell lymphoma.
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http://dx.doi.org/10.1007/s00262-021-02895-7DOI Listing
March 2021

PD-L1 and IDO1 are potential targets for treatment in patients with primary diffuse large B-cell lymphoma of the CNS.

Acta Oncol 2021 Apr 12;60(4):531-538. Epub 2021 Feb 12.

Clinical and Experimental Pathology, Department of Immunology, Genetics and Pathology, Uppsala University and University Hospital, Uppsala, Sweden.

Background: Programmed cell death 1 (PD-1) and its ligands PD-L1 and PD-L2, as well as Indoleamine 2,3-deoxygenase (IDO1) can be expressed both by tumor and microenvironmental cells and are crucial for tumor immune escape. We aimed to evaluate the role of PD-1, its ligands and IDO1 in a cohort of patients with primary diffuse large B-cell lymphoma of the CNS (PCNSL).

Material And Methods: Tissue microarrays (TMAs) were constructed in 45 PCNSL cases. RNA extraction from whole tissue sections and RNA sequencing were successfully performed in 33 cases. Immunohistochemical stainings for PD-1, PD-L1/paired box protein 5 (PAX-5), PD-L2/PAX-5 and IDO1, and Epstein-Barr virus encoding RNA (EBER) hybridization were analyzed.

Results: High proportions of PD-L1 and PD-L2 positive tumor cells were observed in 11% and 9% of cases, respectively. High proportions of PD-L1 and PD-L2 positive leukocytes were observed in 55% and 51% of cases, respectively. RNA sequencing revealed that gene expression of was high in patients with high proportion of PD-L1 positive leukocytes ( = .01). Protein expression of IDO1 in leukocytes was detected in 14/45 cases, in 79% of these cases a high proportion of PD-L1 positive leukocytes was observed. Gene expression of was high in EBER-positive cases ( = .0009) and protein expression of IDO1 was detected in five of six EBER-positive cases.

Conclusion: Our study shows a significant association between gene and protein expression of IDO1 and protein expression of PD-L1 in the tumor microenvironment of PCNSL, possibly of importance for prediction of response to immunotherapies.
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http://dx.doi.org/10.1080/0284186X.2021.1881161DOI Listing
April 2021

Plasma proteome profiling of cardiotoxicity in patients with diffuse large B-cell lymphoma.

Cardiooncology 2021 Feb 3;7(1). Epub 2021 Feb 3.

Department of Immunology, Genetics & Pathology, Uppsala University, Rudbecklaboratoriet, 75185, Uppsala, Sweden.

Background: Cardiovascular toxicity is a notorious complication of doxorubicin (DXR) therapy for diffuse large B-cell lymphoma (DLBCL). Although surveillance of well-known biological markers for cardiovascular disease (CVD) as NTproBNP and Troponins may be helpful, there are no established markers to monitor for evolving CVD during treatment. New possibilities have arisen with the emergence of newer techniques allowing for analysis of plasma proteins that can be associated with cardiovascular disease. Proximity Extension Assay is one of them.

Objectives: We aimed to illustrate the incidence of CVD in DLBCL patients treated with DXR and to establish whether there are plasma proteins associated with pre-existing or emerging CVD.

Methods: In 95 patients, 182 different proteins from OLINK panels, NTproBNP, Troponin I and CRP were assessed prior to, during and after treatment. For comparison, samples from controls were analyzed.

Results: In the DLBCL cohort, 33.3% had pre-treatment CVD compared to 5.0% in the controls and 23.2% developed new CVD. Of the 32.6% who died during follow up, CVD was the cause in 4 patients. Spondin-1 (SPON-1) correlated to pre-treatment CVD (1.22 fold change, 95% CI 1.10-1.35, p = 0.00025, q = 0.045). Interleukin-1 receptor type 1 (IL-1RT1) was associated to emerging CVD (1.24 fold change, 95% CI 1.10-1.39, p = 0.00044, q = 0.082).

Conclusion: We observed a higher prevalence of CVD in DLBCL patients compared to controls prior to DXR therapy. Two proteins, SPON-1 and IL-1RT1, were related to pre-existing and emerging CVD in DXR treated patients. If confirmed in larger cohorts, IL-1RT1 may emerge as a reliable biomarker for unfolding CVD in DLBCL.
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http://dx.doi.org/10.1186/s40959-021-00092-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856776PMC
February 2021

Incidence of relapsed/refractory diffuse large B-cell lymphoma (DLBCL) including CNS relapse in a population-based cohort of 4243 patients in Sweden.

Blood Cancer J 2021 Jan 7;11(1). Epub 2021 Jan 7.

Division of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.

We performed a national population-based study of all patients diagnosed with diffuse large B-cell lymphoma (DLBCL) in Sweden in 2007-2014 to assess treatment intent and risk of relapsed/refractory disease, including central nervous system (CNS) relapse, in the presence of competing risks. Overall, 84% of patients started treatment with curative intent (anthracycline-based) (n = 3550, median age 69 years), whereas 14% did not (n = 594, median age 84 years) (for 2% the intent was uncertain). Patients treated with curative intent had a 5-year OS of 65.3% (95% CI: 63.7-66.9). The median OS among non-curatively treated patients was 2.9 months. The 5-year cumulative incidence of relapsed/refractory disease in curative patients was 23.1% (95% CI: 21.7-24.6, n = 847). The 2-year cumulative incidence of CNS relapse was 3.0% (95% CI: 2.5-3.6, n = 118) overall, and 8.0% (95% CI: 6.0-10.6, n = 48) among patients with high CNS-IPI (4-6), when considering other relapse locations and death as competing events. The incidence of relapsed/refractory DLBCL overall and in the CNS was lower than in previous reports, still one in seven patients was not considered fit enough to start standard immunochemotherapy at diagnosis. These results are important for quantification of groups of DLBCL patients with poor prognosis requiring completely different types of interventions.
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http://dx.doi.org/10.1038/s41408-020-00403-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791057PMC
January 2021

Relative and absolute cancer risks among Nordic kidney transplant recipients-a population-based study.

Transpl Int 2020 12 25;33(12):1700-1710. Epub 2020 Sep 25.

Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.

Kidney transplant recipients (KTRs) have an increased cancer risk compared to the general population, but absolute risks that better reflect the clinical impact of cancer are seldom estimated. All KTRs in Sweden, Norway, Denmark, and Finland, with a first transplantation between 1995 and 2011, were identified through national registries. Post-transplantation cancer occurrence was assessed through linkage with cancer registries. We estimated standardized incidence ratios (SIR), absolute excess risks (AER), and cumulative incidence of cancer in the presence of competing risks. Overall, 12 984 KTRs developed 2215 cancers. The incidence rate of cancer overall was threefold increased (SIR 3.3, 95% confidence interval [CI]: 3.2-3.4). The AER of any cancer was 1560 cases (95% CI: 1468-1656) per 100 000 person-years. The highest AERs were observed for nonmelanoma skin cancer (838, 95% CI: 778-901), non-Hodgkin lymphoma (145, 95% CI: 119-174), lung cancer (126, 95% CI: 98.2-149), and kidney cancer (122, 95% CI: 98.0-149). The five- and ten-year cumulative incidence of any cancer was 8.1% (95% CI: 7.6-8.6%) and 16.8% (95% CI: 16.0-17.6%), respectively. Excess cancer risks were observed among Nordic KTRs for a wide range of cancers. Overall, 1 in 6 patients developed cancer within ten years, supporting extensive post-transplantation cancer vigilance.
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http://dx.doi.org/10.1111/tri.13734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756726PMC
December 2020

Clonal hematopoiesis in patients with high-grade B-cell lymphoma is associated with inferior outcome.

Am J Hematol 2020 Jul 6. Epub 2020 Jul 6.

Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.

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http://dx.doi.org/10.1002/ajh.25927DOI Listing
July 2020

The ProBio trial: molecular biomarkers for advancing personalized treatment decision in patients with metastatic castration-resistant prostate cancer.

Trials 2020 Jun 26;21(1):579. Epub 2020 Jun 26.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Background: Multiple therapies exist for patients with metastatic castration-resistant prostate cancer (mCRPC). However, their improvement on progression-free survival (PFS) remains modest, potentially explained by tumor molecular heterogeneity. Several prognostic molecular biomarkers have been identified for mCRPC that may have predictive potential to guide treatment selection and prolong PFS. We designed a platform trial to test this hypothesis.

Methods: The Prostate-Biomarker (ProBio) study is a multi-center, outcome-adaptive, multi-arm, biomarker-driven platform trial for tailoring treatment decisions for men with mCRPC. Treatment decisions in the experimental arms are based on biomarker signatures defined as mutations in certain genes/pathways suggested in the scientific literature to be important for treatment response in mCRPC. The biomarker signatures are determined by targeted sequencing of circulating tumor and germline DNA using a panel specifically designed for mCRPC.

Discussion: Patients are stratified based on the sequencing results and randomized to either current clinical practice (control), where the treating physician decides treatment, or to molecularly driven treatment selection based on the biomarker profile. Outcome-adaptive randomization is implemented to early identify promising treatments for a biomarker signature. Biomarker signature-treatment combinations graduate from the platform when they demonstrate 85% probability of improving PFS compared to the control arm. Graduated combinations are further evaluated in a seamless confirmatory trial with fixed randomization. The platform design allows for new drugs and biomarkers to be introduced in the study.

Conclusions: The ProBio design allows promising treatment-biomarker combinations to quickly graduate from the platform and be confirmed for rapid implementation in clinical care.

Trial Registration: ClinicalTrials.gov Identifier NCT03903835. Date of registration: April 4, 2019. Status: Recruiting.
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http://dx.doi.org/10.1186/s13063-020-04515-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318749PMC
June 2020

Tumor endothelial ELTD1 as a predictive marker for treatment of renal cancer patients with sunitinib.

BMC Cancer 2020 Apr 22;20(1):339. Epub 2020 Apr 22.

Department of Immunology, Genetics and Pathology, Uppsala University, 75185, Uppsala, Sweden.

Background: Patients with metastatic renal cell cancer (mRCC) are commonly treated with the tyrosine kinase inhibitor sunitinib, which blocks signalling from vascular endothelial growth factor (VEGF) - and platelet-derived growth factor-receptors, inhibiting development of new blood vessels. There are currently no predictive markers available to select patients who will gain from this treatment. Epidermal growth factor, latrophilin and seven transmembrane domain-containing protein 1 (ELTD1) is up-regulated in tumor endothelial cells in many types of cancer and may be a putative predictive biomarker due to its association with ongoing angiogenesis.

Methods: ELTD1, CD34 and VEGF receptor 2 (VEGFR2) expressions were analysed in tumor vessels of renal cancer tissues from 139 patients with mRCC using immunohistochemistry. Ninety-nine patients were treated with sunitinib as the first or second-line therapy. Early toxicity, leading to the termination of the treatment, eliminated 22 patients from the analyses. The remaining (n = 77) patients were included in the current study. In an additional analysis, 53 sorafenib treated patients were evaluated.

Results: Patients with high ELTD1 expression in the tumor vasculature experienced a significantly better progression free survival (PFS) with sunitinib treatment as compared to patients with low ELTD1 expression (8 versus 5.5 months, respectively). The expression level of CD34 and VEGFR2 showed no correlation to sunitinib response. In sorafenib treated patients, no association with ELTD1 expression and PFS/OS was found.

Conclusions: Our results identify tumor vessel ELTD1 expression as a positive predictive marker for sunitinib-treatment in patients suffering from mRCC. The negative results in the sorafenib treated group supports ELTD1 being a pure predictive and not a prognostic marker for sunitinib therapy.
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http://dx.doi.org/10.1186/s12885-020-06770-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7179003PMC
April 2020

Outcome and determinants of failure to complete primary R-CHOP treatment for reasons other than non-response among patients with diffuse large B-cell lymphoma.

Am J Hematol 2020 07 3;95(7):740-748. Epub 2020 Apr 3.

Division of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.

Patients with diffuse large B-cell lymphoma (DLBCL) who fail to complete planned treatment with R-CHOP due to toxicity are sparsely described. We investigated the extent of failure to complete treatment (six cycles or more, or three cycles + RT for patients with stage I disease) with R-CHOP for reasons unrelated to non-response, the determinants of such failure and the outcome among these patients. Three thousand one hundred and forty nine adult DLBCL patients who started primary treatment with R-CHOP were identified through the Swedish lymphoma register 2007-2014. Of these, 147 (5%) stopped prematurely after 1-3 cycles of R-CHOP for reasons unrelated to non-response, 168 (5%) after 4-5 cycles and 2639 patients (84%) completed planned treatment. Additionally, 195 (6%) patients did not complete treatment due to non-response or death before treatment end. In a multivariable logistic regression model, age > 75 years, poor performance status, extranodal disease and Charlson Comorbidity Index ≥1 were significantly associated with failure to complete planned R-CHOP treatment for other reasons than non-response. Non-completion of treatment strongly correlated with survival. Five-year overall survival for patients who received 1-3 cycles was 26% (95% CI: 19%-33%), 49% (95% CI: 41%-57%) for 4-5 cycles and 76% (74%-77%) for patients who completed treatment. Failure to complete planned R-CHOP treatment is an important clinical issue associated with inferior survival. Old age and poor performance status most strongly predict such failure. These results indicate a need for improved treatment tailoring for patients with certain baseline demographics to improve tolerability and chance for treatment completion.
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http://dx.doi.org/10.1002/ajh.25789DOI Listing
July 2020

CD30 expression and survival in posttransplant lymphoproliferative disorders.

Acta Oncol 2020 Jun 27;59(6):673-680. Epub 2020 Feb 27.

Experimental and Clinical Oncology, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.

Post-transplant lymphoproliferative disorder (PTLD) is a rare but life-threatening complication of transplantation. For refractory and relapsed PTLD new therapies are needed, such as the antibody-drug conjugate brentuximab vedotin that targets CD30. There is limited knowledge of CD30 expression in various subtypes of PTLD and its correlation to clinicopathological features. Therefore, we studied the expression of CD30 in PTLD following solid organ transplantation and correlated CD30 expression to PTLD subtype, Epstein-Barr virus (EBV)-status, intratumoral regulatory T-cells (Tregs), clinical features, and outcome. We included 50 cases of PTLD from a nation-wide study of PTLDs following solid organ transplantation in Sweden. The tumor biopsies were reevaluated, and clinical data were collected. CD30 expression on tumor cells was analyzed by immunohistochemistry with the clone Ber-H2. Thirty-one cases were stained with clone 236 A/E7 for detection of forkhead box protein 3 (FoxP3, a Treg biomarker). The case series consisted of 6% polymorphic, 88% monomorphic, and 6% Hodgkin lymphoma-like PTLDs and 53% of the cases were EBV+. Overall, 70% (35/50) of the PTLDs were CD30+ (≥1% CD30+ tumor cells) and 30% (15/50) were CD30-. All polymorphic PTLDs ( = 3) and Hodgkin lymphomas ( = 3), 88% (14/16) of non-germinal center type of diffuse large B-cell lymphoma (DLBCL), and 75% (9/12) of T-cell PTLDs were CD30+ whereas all germinal center-type of DLBCL ( = 5) and Burkitt type PTLD ( = 2) were CD30-. CD30+ PTLD tended to be EBV+ more frequently ( = .07) and occurred earlier posttransplant (2.1 vs. 8.2 years,  = .01) than CD30- PTLD. Type of transplant and localization of the tumor did not differ between the groups except that CNS engagement was more common in CD30- PTLD ( = .02). CD30-status was not associated with presence of intratumoral Tregs or overall survival. Expression of CD30 varied with PTLD subtype. There was no association between CD30 and survival, regardless of subtype.
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http://dx.doi.org/10.1080/0284186X.2020.1731924DOI Listing
June 2020

Precursor cells and implications of a T-cell inflamed immune response in the pre-malignant setting in Hodgkin lymphoma.

Immunobiology 2020 01 25;225(1):151872. Epub 2019 Nov 25.

Experimental and Clinical Oncology, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.

The etiology of classical Hodgkin lymphoma (cHL) is largely unknown. High serum CD30-levels are associated with increased risk of cHL. Epstein-Barr virus (EBV) is detectable in the tumor cells in 1/3 of cHL cases in the Western world. The PD-1 pathway (T-cell inflamed immune response) might contribute to the pathogenesis by enabling pre-malignant CD30+ or EBV + cells to evade immune surveillance. We aimed to investigate if high infiltrations of CD30+, PD-1+, PD-L1+ and EBV + cells in benign lymph nodes from patients that later develop cHL (cases) (n = 15) were associated with risk of cHL compared to controls (n = 45) with benign lymph nodes from patients that did not develop cHL. Pathology registries including 3500 cH L patients were screened. Lymph nodes were stained with immunohistochemistry and in situ hybridization and the risk for cHL calculated with logistic regression. High CD30-expression by B- and T-cells was associated with a decreased risk of cHL [(OR = 0.10, 95 % CI:0.03-0.39) and (OR = 0.13, 95 % CI:0.01-0.71), respectively], which remained significant for CD30 + B-cells (OR = 0.15, 95 % CI:0.03-0.60) in multivariate analyses. Amount of PD-1+, PD-L1+ and EBV + cells were not statistically significantly associated with risk of cHL. However, the amount of PD-L1+ leukocytes tended to be higher in cases later developing cHL (OR = 2.84, 95 % CI:0.61-12.61). High proportions of potential precursors to cHL, i.e. CD30 + B-cells in benign lymph nodes are not associated with an increased risk of cHL, while a tendency for a T-cell inflamed immune response, i.e. abundant PD-L1+ cells, was observed in biopsies taken prior to the cHL diagnosis.
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http://dx.doi.org/10.1016/j.imbio.2019.11.007DOI Listing
January 2020

Prognostic impact of abdominal lymph node involvement in diffuse large B-cell lymphoma.

Eur J Haematol 2020 Mar 20;104(3):207-213. Epub 2019 Dec 20.

Clinical and Experimental Pathology, Department of Immunology, Genetics and Pathology, Uppsala University and University Hospital, Uppsala, Sweden.

Objective: The prognostic value of site of nodal involvement in diffuse large B-cell lymphomas (DLBCL) is mainly unknown. We aimed to determine the prognostic significance of nodal abdominal involvement in relation to tumour cell markers and clinical characteristics of 249 DLBCL patients in a retrospective single-centre study.

Methods: Contrast-enhanced computed tomography (CT) of the abdomen and thorax revealed pathologically enlarged abdominal lymph nodes in 156 patients, while in 93 patients there were no pathologically enlarged lymph nodes in the abdomen. In 81 cases, the diagnosis of DLBCL was verified by histopathological biopsy obtained from abdominal lymph node.

Results: Patients with abdominal nodal disease had inferior lymphoma-specific survival (P = .04) and presented with higher age-adjusted IPI (P < .001), lactate dehydrogenase (P < .001) and more often advanced stage (P < .001), bulky disease (P < .001), B symptoms (P < .001), and double expression of MYC and BCL2 (P = .02) compared to patients without nodal abdominal involvement, but less often extranodal involvement (P < .02). The worst outcome was observed in those where the abdominal nodal involvement was verified by histopathological biopsy.

Conclusion: Diffuse large B-cell lymphomas patients with abdominal nodal disease had inferior outcome and more aggressive behaviour, reflected both in clinical and biological characteristics.
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http://dx.doi.org/10.1111/ejh.13361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065091PMC
March 2020

Cell-of-origin determined by both gene expression profiling and immunohistochemistry is the strongest predictor of survival in patients with diffuse large B-cell lymphoma.

Am J Hematol 2020 01 7;95(1):57-67. Epub 2019 Nov 7.

Clinical and Experimental Pathology, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.

The tumor cells in diffuse large B-cell lymphomas (DLBCL) are considered to originate from germinal center derived B-cells (GCB) or activated B-cells (ABC). Gene expression profiling (GEP) is preferably used to determine the cell of origin (COO). However, GEP is not widely applied in clinical practice and consequently, several algorithms based on immunohistochemistry (IHC) have been developed. Our aim was to evaluate the concordance of COO assignment between the Lymph2Cx GEP assay and the IHC-based Hans algorithm, to decide which model is the best survival predictor. Both GEP and IHC were performed in 359 homogenously treated Swedish and Danish DLBCL patients, in a retrospective multicenter cohort. The overall concordance between GEP and IHC algorithm was 72%; GEP classified 85% of cases assigned as GCB by IHC, as GCB, while 58% classified as non-GCB by IHC, were categorized as ABC by GEP. There were significant survival differences (overall survival and progression-free survival) if cases were classified by GEP, whereas if cases were categorized by IHC only progression-free survival differed significantly. Importantly, patients assigned as non-GCB/ABC both by IHC and GEP had the worst prognosis, which was also significant in multivariate analyses. Double expression of MYC and BCL2 was more common in ABC cases and was associated with a dismal outcome. In conclusion, to determine COO both by IHC and GEP is the strongest outcome predictor to identify DLBCL patients with the worst outcome.
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http://dx.doi.org/10.1002/ajh.25666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6916573PMC
January 2020

No excess long-term mortality in stage I-IIA Hodgkin lymphoma patients treated with ABVD and limited field radiotherapy.

Br J Haematol 2020 03 14;188(5):685-691. Epub 2019 Oct 14.

Experimental and Clinical Oncology, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.

When treating limited stage classical Hodgkin lymphoma (cHL), balancing treatment efficacy and toxicity is important. Toxicities after extended-field radiotherapy are well documented. Investigators have aimed at reducing toxicity without compromising efficacy, mainly by using combined modality treatment (CMT), i.e. chemotherapy and limited-field radiotherapy. In some clinical trials, radiotherapy has been omitted. We evaluated 364 patients with stage I-IIA cHL treated between 1999 and 2005. Patients were treated with two or four cycles of doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) according to presence of risk factors, followed by 30 Gy limited-field (reduced compared to involved-field) radiotherapy. After a median follow-up of 16 years for survival, freedom from progression at five and ten years was 93% and overall survival at 5 and 10 years was 98% and 96%, respectively. Only two relapses, out of 27, occurred after more than 5 years. There was no excess mortality compared to the general population. Of the analysed subgroups, only patients with progression within five years showed significant excess mortality. The absence of excess mortality questions the concept of omitting radiotherapy after short-term chemotherapy, a strategy that has been associated with an elevated risk of relapse but not yet with a proven reduced long-term excess mortality.
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http://dx.doi.org/10.1111/bjh.16232DOI Listing
March 2020

Malignant lymphoma in granulomatosis with polyangiitis: subtypes, clinical characteristics and prognosis.

Acta Oncol 2019 Nov 13;58(11):1655-1659. Epub 2019 Aug 13.

Department of Medical Sciences, Section of Rheumatology, Uppsala University, Uppsala, Sweden.

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http://dx.doi.org/10.1080/0284186X.2019.1634833DOI Listing
November 2019

Tumoral Pyruvate Kinase L/R as a Predictive Marker for the Treatment of Renal Cancer Patients with Sunitinib and Sorafenib.

J Cancer 2019 2;10(14):3224-3231. Epub 2019 Jun 2.

Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.

: Treatment with tyrosine kinase inhibitors (TKI) like sunitinib and sorafenib has improved the prognosis of patients with metastatic renal cell cancer (mRCC). No predictive marker is available to select patients who will gain from these treatments. Tumoral pyruvate kinase L/R (PKLR) is a membrane protein with highly specific expression in the renal tubule. We have previously shown that the tumoral expression of cubilin (CUBN) is associated with progression free survival (PFS) in mRCC patients treated with sunitinib and sorafenib. The aim of the present study was to investigate if PKLR can predict response in these patients, alone and/or in combination with CUBN. : A tissue microarray (TMA) was constructed of tumor samples from 139 mRCC patients. One hundred and thirty-six of these patients had been treated with sunitinib or sorafenib in the first or second-line setting. Thirty patients suffered from early severe toxicity leading to the termination of treatment. The remaining patients (n=106) were selected for the current study. : Fifty-five (52%) of the tumors expressed membranous PKLR. Patients with PKLR tumor expression experienced a significantly longer PFS compared to patients with no expression (eight versus five months, p = 0.019). Overall survival (OS) was also significantly better for patients with PKLR expression. In addition, the combined expression of PKLR and CUBN resulted in a higher predictive value than either marker alone. : In this real world study we show that tumoral PKLR membrane expression is a positive predictive biomarker for sunitinib and sorafenib treatment in patients suffering from mRCC. Our results also indicate that the combined expression with cubilin more accurately than PKLR alone can select patients with no benefit from treatment.
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http://dx.doi.org/10.7150/jca.30130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6603390PMC
June 2019

Autoimmune disease in patients with diffuse large B-cell lymphoma: occurrence and impact on outcome.

Acta Oncol 2019 Aug 25;58(8):1170-1177. Epub 2019 May 25.

b Experimental and Clinical Oncology, Department of Immunology, Genetics, and Pathology , Uppsala University , Uppsala , Sweden.

Patients with certain autoimmune diseases (AID) have an increased risk of developing diffuse large B-cell lymphoma (DLBCL). However, the occurrence of AID in patients with DLBCL as well as the impact of AID on outcome has not been extensively studied. The main purpose of this study was to establish the occurrence of AIDs in a population-based cohort of DLBCL patients and to compare outcomes in patients with or without AID treated with rituximab(R)-CHOP/CHOP-like treatment. We also aimed to analyse gender differences and the potential role of different AIDs on outcome and the frequency of treatment-associated neutropenic fever. All adult patients treated 2000-2013 with R-CHOP/CHOP-like treatment for DLBCL in four counties of Sweden were included ( = 612). Lymphoma characteristics, outcome and the presence of AID were obtained through medical records. The number of patients with AID was 106 (17.3%). Thyroid disease dominated ( = 33, 31.1%) followed by rheumatoid arthritis (RA) ( = 24, 22.6%). The proportion of AID was significantly higher in females (59/254, 23.2%) vs. in males (47/358, 13.1%) ( = .001). In the whole cohort there was no difference in event free survival (EFS) or overall survival (OS) between patients with or without AID. However, patients with an AID primarily mediated by B-cell responses (thyroid disorders excluded) had a worse OS ( = .037), which seemed to affect only women. The AID group more often had neutropenic fever after first treatment (16.0% vs 8.7%,  = .034 and those with neutropenic fever had a worse OS ( = .026) in Kaplan-Meier analyses. There is a high prevalence of AID among patients with DLBCL. AIDs categorized as primarily B-cell mediated (in this study mainly RA, systemic lupus erythematosus and Sjögren's syndrome) may be associated with inferior OS. AID patients may be more prone to neutropenic fever compared to patients without concomitant AID.
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http://dx.doi.org/10.1080/0284186X.2019.1619936DOI Listing
August 2019

Focal skeletal FDG uptake indicates poor prognosis in cHL regardless of extent and first-line chemotherapy.

Br J Haematol 2019 08 22;186(3):431-439. Epub 2019 May 22.

Department of Haematology, Aarhus University Hospital, Aarhus N, Denmark.

F-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (FDG-PET/CT) is used for staging classical Hodgkin lymphoma (cHL) with high sensitivity for skeletal involvement. However, it is unclear whether a single bone lesion carries the same adverse prognosis as multifocal lesions and if this is affected by type of chemotherapy [ABVD (adriamycin, bleomycin, vincristine, dacarbazine) versus BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, prednisone)]. We reviewed the clinico-pathological and outcome data from 209 patients with newly diagnosed cHL staged by FDG-PET/CT. Patterns of skeletal/bone marrow uptake (BMU) were divided into 'low' and 'high' diffuse BMU (i.e. without focal lesions), and unifocal or multifocal lesions. Additional separate survival analysis was performed, taking type of chemotherapy into account. Forty patients (19·2%) had skeletal lesions (20 unifocal, 20 multifocal). The 3-year progression-free-survival (PFS) was 80% for patients with 'low BMU', 87% for 'high BMU', 69% for 'unifocal' and 51% for 'multifocal' lesions; median follow-up was 38 months. The presence of bone lesions, both uni- and multifocal, was associated with significantly inferior PFS (log rank P = 0·0001), independent of chemotherapy type. Thus, increased diffuse BMU should not be considered as a risk factor in cHL, whereas unifocal or multifocal bone lesions should be regarded as important predictors of adverse outcome, irrespective of the chemotherapy regimen used.
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http://dx.doi.org/10.1111/bjh.15933DOI Listing
August 2019

High tumour plasma cell infiltration reflects an important microenvironmental component in classic Hodgkin lymphoma linked to presence of B-symptoms.

Br J Haematol 2019 01 2;184(2):192-201. Epub 2018 Dec 2.

Experimental and Clinical Oncology, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.

Plasma cells are important prognostic actors in different malignancies. The tumour microenvironmental composition in classic Hodgkin lymphoma (cHL) is a major prognostic key element; however, clinicopathological studies regarding plasma cells in cHL are lacking. The aim of this study was to investigate CD138+ (also termed SDC1+) plasma cell and IgG4 producing (IgG4+) plasma cells infiltration in the microenvironment of cHL. Immunohistochemistry with anti-CD138 and IgG4 antibodies was performed on diagnostic tumour biopsies from 124 patients with cHL, on tissue micro array (TMA). In 120 cases, CD138+ plasma cell-infiltration was associated with the presence of B-symptoms (P = 0·028) and advanced stage, IIB-IVB (P = 0·009). In multivariate analysis, CD138+ plasma cells correlated with eosinophil infiltration (P = 0·013). The subgroup of IgG4+ plasma cells was analysed in 122 cases and only correlated to CD138+ plasma cells (P = 0·004). Patients with high proportion of tumour infiltrating CD138+ plasma cells (defined as ≥10%), had a more inferior event-free survival (P = 0·007) and overall survival (P = 0·004) than patients with a low proportion of infiltrating CD138+ plasma cells (<10%), although significance was not maintained in multivariate analysis. In summary, a high proportion of tumour-associated plasma cells in cHL reflect an important component in the microenvironment of cHL.
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http://dx.doi.org/10.1111/bjh.15703DOI Listing
January 2019

Expression of PD-1 and PD-L1 increase in consecutive biopsies in patients with classical Hodgkin lymphoma.

PLoS One 2018 27;13(9):e0204870. Epub 2018 Sep 27.

Experimental and Clinical Oncology, Department of Immunology, Genetics and Pathology; Uppsala University, Uppsala, Sweden.

High expression of programmed death receptor 1 (PD-1) and its ligand (PD-L1) by leukocytes in primary classical Hodgkin lymphoma (cHL) is associated with inferior outcome. However, it is unclear how expression varies during disease progression, and in the event of relapse. Our aim was to study PD-1 and PD-L1 in consecutive biopsies from untreated and treated cHL patients. We screened pathology registries from 3500 cHL patients. Eleven patients had a diagnostic cHL biopsy and a previous benign lymph node biopsy reclassified as cHL when reviewed and designated as the untreated. Thirty patients had a primary and a relapse biopsy, designated as the treated. Biopsies were immunostained to detect PD-1+ and PD-L1+ leukocytes, and PD-L1+ tumor cells. In the untreated, none of the markers were statistically significantly different when biopsies 1 and 2 were compared. In the treated, 19, 22, and 18 of 30 cases had increased proportions of PD-1+ leukocytes, PD-L1+ leukocytes and PD-L1+ tumor cells, respectively, and were all statistically significantly increased when primary and relapse biopsies were compared. PD-1 and PD-L1 most likely increase due to primary treatment with chemotherapy and radiotherapy, which could have implications regarding treatment with PD-1 inhibitors.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0204870PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160169PMC
March 2019

A Phase I/IIa Trial Using CD19-Targeted Third-Generation CAR T Cells for Lymphoma and Leukemia.

Clin Cancer Res 2018 12 10;24(24):6185-6194. Epub 2018 Aug 10.

Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory C11, Uppsala, Sweden.

Purpose: The chimeric antigen receptor (CAR) T-cell therapy has been effective for patients with CD19 B-cell malignancies. Most studies have investigated the second-generation CARs with either CD28 or 4-1BB costimulatory domains in the CAR receptor. Here, we describe the first clinical phase I/IIa trial using third-generation CAR T cells targeting CD19 to evaluate safety and efficacy.

Patients And Methods: Fifteen patients with B-cell lymphoma or leukemia were treated with CAR T cells. The patients with lymphoma received chemotherapy during CAR manufacture and 11 of 15 were given low-dose cyclophosphamide and fludarabine conditioning prior to CAR infusion. Peripheral blood was sampled before and at multiple time points after CAR infusion to evaluate the persistence of CAR T cells and for immune profiling, using quantitative PCR, flow cytometry, and a proteomic array.

Results: Treatment with third-generation CAR T cells was generally safe with 4 patients requiring hospitalization due to adverse reactions. Six of the 15 patients had initial complete responses [4/11 lymphoma and 2/4 acute lymphoblastic leukemia (ALL)], and 3 of the patients with lymphoma were in remission at 3 months. Two patients are still alive. Best predictor of response was a good immune status prior to CAR infusion with high IL12, DC-Lamp, Fas ligand, and TRAIL. Responding patients had low monocytic myeloid-derived suppressor cells (MDSCs; CD14CD33HLADR) and low levels of IL6, IL8, NAP3, sPDL1, and sPDL2.

Conclusions: Third-generation CARs may be efficient in patients with advanced B-cell lymphoproliferative malignancy with only modest toxicity. Immune profiling pre- and posttreatment can be used to find response biomarkers.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-0426DOI Listing
December 2018

Does the omission of vincristine in patients with diffuse large B cell lymphoma affect treatment outcome?

Ann Hematol 2018 Nov 8;97(11):2129-2135. Epub 2018 Aug 8.

Department of Immunology, Genetics, and Pathology, Experimental and Clinical Oncology, Uppsala University, Uppsala, Sweden.

The standard treatment for diffuse large B cell lymphoma (DLBCL) is rituximab with CHOP (cyclophosphamide, doxorubicin, vincristine (VCR), and prednisone). Maintaining high dose intensity of cytotoxic treatment has been associated with better outcome but little is known about the role of maintaining VCR. This study aimed to answer whether the omission of vincristine due to neurotoxicity affects patient outcome. A Swedish cohort of patients primarily treated with curative intent for DLBCL or high-grade malignant B cell lymphoma was retrospectively analyzed. In total, 541 patients treated between 2000 and 2013 were included. Omission of VCR was decided in 95 (17.6%) patients and was more often decided during the last three cycles (n = 86, 90.5%). The omission of VCR did not affect disease-free or overall survival neither in the whole cohort nor in elderly patients. On the contrary, the relative dose intensity of doxorubicin was associated with overall survival (p = 0.014). Kidney or adrenal involvement (p = 0.014) as well as bulky disease (p = 0.037) was found to be associated with worse overall survival. According to our results, clinicians can safely decide to omit VCR in case of severe neurotoxicity due to VCR but should be aware of the importance of giving adequate doses of doxorubicin during treatment given the growing body of evidence on the role of dose intensity on survival. Considering the association of bulky disease and kidney/adrenal manifestation of lymphoma on survival, further studies should focus on whether the treatment options for these subgroups need to be individualized.
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http://dx.doi.org/10.1007/s00277-018-3437-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6182738PMC
November 2018

Expression of PD-1, PD-L1, and PD-L2 in posttransplant lymphoproliferative disorder after solid organ transplantation.

Leuk Lymphoma 2019 02 22;60(2):376-384. Epub 2018 Jul 22.

e Experimental and Clinical Oncology, Department of Immunology, Genetics and Pathology , Uppsala University , Uppsala , Sweden.

We studied the expression of programed death 1 (PD-1) receptor and its ligands (PD-L1/-L2) by immunohistochemistry and its association with clinicopathological features in 81 posttransplant lymphoproliferative disorders (PTLDs) following solid organ transplantation. Overall, 67% (54/81) of the PTLDs were positive in any of the three immunostainings. PD-1 was detected on tumor-infiltrating cells in 41% (33/81) of the PTLDs. PD-L1 was expressed on ≥5% of the tumor cells in 50% (40/80) and PD-L2 in 32% (23/72) of the PTLDs. All Burkitt lymphomas were PD-L1 negative. Expression of PD-L1 tended to be associated with non-germinal center-type of diffuse large B-cell lymphoma (63% vs. 33% in GC-type, p = .14) and latent membrane protein-1+ PTLD (76% vs. 44% in LPM1-, p = .09). Heart recipients had more frequent PTLDs with PD-1+ microenvironment (p = .01). The frequent expression of PD-1 or -L1/-L2 in PTLD warrants further clinical evaluation of the efficacy and safety of PD-(L)1 inhibitors for refractory PTLD.
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http://dx.doi.org/10.1080/10428194.2018.1480767DOI Listing
February 2019

Long-term survival and loss in expectancy of life in a population-based cohort of 7114 patients with diffuse large B-cell lymphoma.

Am J Hematol 2018 May 17. Epub 2018 May 17.

Division of Clinical Epidemiology, Department of Medicin Solna, Karolinska Institutet, Stockholm, Sweden.

Survival has improved among patients with diffuse large B-cell lymphoma (DLBCL) with the addition of anti-CD20 antibody therapy. We aimed to quantify trends and remaining loss in expectation of life (LEL) due to DLBCL at a national population-based level. Patients diagnosed with DLBCL 2000-2013 (N = 7114) were identified through the Swedish Lymphoma Registry and classified according to the age-adjusted International Prognostic Index (aaIPI). The novel measure LEL is the difference between remaining life years among patients and the general population and was predicted using flexible parametric models from diagnosis and among 2-year survivors, by age and sex. Median age at DLBCL-diagnosis was 70 (18-105) years and 54.8% presented with stage III-IV disease. On average, LEL due to DLBCL decreased from 8.0 (95% CI: 7.7-8.3) to 4.6 (95% CI: 4.5-4.6) years over the study period. By risk group, LEL was most reduced among patients with aaIPI ≥2 aged 50-60 years. However, these patients were still estimated to lose >8 years in 2013 (eg, LEL 8.6 years (95% CI: 5.0-12.3)). Among 2-year survivors, LEL was reduced from 6.1 years (95% CI: 5.6-6.5) (aaIPI ≥ 2) and 3.8 years (95% CI: 3.6-4.1) (aaIPI < 2) to 1.1 (95% CI: 1.1-1.2) and 1.0 year (95% CI: 0.8-1.1), respectively. The reduction was observed across all ages. Results for females were similar. By using LEL we illustrate the improvement of DLBCL survival over time. Despite adequate immunochemotherapy, substantial LEL among patients with IPI ≥ 2 points to remaining unmet medical needs. We speculate that observed reduced losses among 2-year survivors indicate a reduction of late relapses.
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http://dx.doi.org/10.1002/ajh.25147DOI Listing
May 2018

Expression of ribosomal and actin network proteins and immunochemotherapy resistance in diffuse large B cell lymphoma patients.

Br J Haematol 2018 06 16;181(6):770-781. Epub 2018 May 16.

Section of Haematology, Department of Medicine, South Älvsborg Hospital, Borås, Sweden.

Diffuse large B cell lymphoma (DLBCL) patients with early relapse or refractory disease have a very poor outcome. Immunochemotherapy resistance will probably, also in the era of targeted drugs, remain the major cause of treatment failure. We used proteomic mass spectrometry to analyse the global protein expression of micro-dissected formalin-fixed paraffin-embedded tumour tissues from 97 DLBCL patients: 44 with primary refractory disease or relapse within 1 year from diagnosis (REF/REL), and 53 who were progression-free more than 5 years after diagnosis (CURED). We identified 2127 proteins: 442 were found in all patients and 102 were differentially expressed. Sixty-five proteins were overexpressed in REF/REL patients, of which 46 were ribosomal proteins (RPs) compared with 2 of the 37 overexpressed proteins in CURED patients (P = 7·6 × 10 ). Twenty of 37 overexpressed proteins in CURED patients were associated with actin regulation, compared with 1 of 65 in REF/REL patients (P = 1·4 × 10 ). Immunohistochemical staining showed higher expression of RPS5 and RPL17 in REF/REL patients while MARCKS-like protein, belonging to the actin network, was more highly expressed in CURED patients. Even though functional studies aimed at individual proteins and protein interactions to evaluate potential clinical effect are needed, our findings suggest new mechanisms behind immunochemotherapy resistance in DLBCL.
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http://dx.doi.org/10.1111/bjh.15259DOI Listing
June 2018

High proportions of PD-1 and PD-L1 leukocytes in classical Hodgkin lymphoma microenvironment are associated with inferior outcome.

Blood Adv 2017 Aug 8;1(18):1427-1439. Epub 2017 Aug 8.

Experimental and Clinical Oncology, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.

Immune checkpoint inhibition targeting the programmed death receptor (PD)-1 pathway is a novel treatment approach in relapsed and refractory classical Hodgkin lymphoma (cHL). Identifying patients with a high risk of treatment failure could support the use of PD-1 inhibitors as front-line treatment. Our aim was to investigate the prognostic impact of PD-1, programmed death-ligand 1 (PD-L1), and PD-L2 in the tumor microenvironment in diagnostic biopsies of patients with cHL. Patients from Denmark and Sweden, diagnosed between 1990 and 2007 and ages 15 to 86 years, were included. Tissue microarray samples were available from 387 patients. Immunohistochemistry was used to detect PD-1, PD-L1, and PD-L2, and the proportions of positive cells were calculated. Event-free survival (EFS; time to treatment failure) and overall survival (OS) were analyzed using Cox proportional hazards regression. High proportions of both PD-1 (hazard ratio [HR], 1.77; 95% confidence interval [CI], 1.10-2.86) and PD-L1 (HR = 1.89; 95% CI, 1.08-3.30) leukocytes in the microenvironment were associated with inferior EFS in a multivariate analysis (adjusted for white blood cell count >15 × 10/L, hemoglobin <105 g/L, albumin <40 g/L, B symptoms, extranodal involvement, stage, bulky tumor, nodular sclerosis subtype, Epstein-Barr virus status, lymphocyte count <0.6 × 10/L, sex, and country). A high proportion of PD-L1 leukocytes was also associated with inferior OS in a multivariate analysis (HR, 3.46; 95% CI, 1.15-10.37). This is the first study to show a correlation after multivariate analysis between inferior outcome in cHL and a high proportion of both PD-1 and PD-L1 leukocytes in the tumor microenvironment.
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http://dx.doi.org/10.1182/bloodadvances.2017006346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727849PMC
August 2017

Tumoral ANXA1 Is a Predictive Marker for Sunitinib Treatment of Renal Cancer Patients.

J Cancer 2017 23;8(19):3975-3983. Epub 2017 Oct 23.

Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.

There is no established predictive marker for the treatment of renal cancer. Metastatic renal cell carcinoma (mRCC) patients are often treated with sunitinib, a tyrosine kinase inhibitor. Sunitinibs anti-cancer effect is at least partly mediated through interfering with angiogenesis. Our aim with the current study was to assess annexin A1 (ANXA1), which stimulates angiogenesis, as a predictive marker for sunitinib therapy in mRCC patients. Since previous studies have indicated a predictive potential for cubilin, we also investigated the predictivity of ANXA1 combined with cubilin. ANXA1 expression was analysed in tumor tissue from a cohort of patients with advanced RCC (n=139) using immunohistochemistry. Ninety-nine of the patients were treated with sunitinib in the first or second-line setting. Twenty-two of these were censored because of toxicity leading to the termination of treatment and the remaining (n=77) were selected for the present study. Twenty-five (32%) out of seventy-seven of the tumors lacked ANXA1 in the cytoplasm. On statistical analyses using Kaplan-Meier method, aNXA1 negative tumors were significantly associated with a longer treatment benefit in terms of progression free survival (PFS). Overall survival was also significantly better for patients with ANXA1 negative tumors. The combined ANXA1 positive and cubilin negative expression could more accurately than ANXA1 alone define the group not benefitting from treatment. Our results indicate that cytoplasmic expression of ANXA1 is a negative predictive marker for sunitinib therapy in mRCC patients. A possible explanation for this finding is that sunitinibs anti-angiogenic effect cannot overcome the pro-angiogenic drive from many ANXA1 proteins.
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http://dx.doi.org/10.7150/jca.20889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705999PMC
October 2017