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The oncogene PIM2 is upregulated in several malignancies but has never been investigated in mycosis fungoides (MF), the most common type of cutaneous T‐cell lymphoma (CTCL). PIM2 is a well‐known oncogene and is regulated by cell signaling pathways like the JAK/STAT‐ and NF‐kB‐pathway, key regulators in the pathogenesis of CTCL. The aim of this study was to examine the role of PIM2 in MF. PIM2 gene expression was measured in 81 formalin‐fixed paraffin‐embedded skin biopsies from patients with MF and 46 control biopsies from healthy skin (HS) and benign inflammatory skin disease (BID). Validation of PIM2 protein expression was performed on selected biopsies with immunohistochemical staining. We found a significant difference in gene expression levels between both early stage MF and HS (p < 0.0001), and BID (p < 0.0001). In addition, the PIM2 gene expression was higher in advanced‐stage MF compared to early stage disease (p = 0.0001). No significant difference in gene expression levels was found between patients with and without disease progression. In conclusion, we found PIM2 expression is significantly increased in MF compared to controls, and in advanced‐stage MF compared to early stage MF. These findings could potentially have diagnostic value in discriminating early stage MF from BID. [ABSTRACT FROM AUTHOR]

Next-generation sequencing (NGS) affords comprehensive insights into the genomic landscape of lymphomas. We examined the mutational pattern in patients with Waldenström macroglobulinemia (WM) or lymphoplasmacytic lymphoma (LPL) as well as the diagnostic and clinical utility of a tailored NGS lymphoma panel. A consecutive series of 45 patients was reviewed and NGS analysis was performed as part of a routine diagnostic setup. The custom designed NGS panel assayed all coding sequences of 59 genes of known clinical significance in lymphoid neoplasms. The most frequently mutated genes were MYD88, CXCR4, BIRC3, CD79B, and ARID1A. Additional somatic mutations were detected in 17 genes with four mutations categorized as pathogenic or likely pathogenic. BIRC3 and TP53 mutations were associated with adverse clinical phenotypes. NGS performance for the MYD88L265P variant was 96% when compared to qPCR. In conclusion, targeted NGS provided important diagnostic and prognostic information in a routine clinical setting. [ABSTRACT FROM AUTHOR]

Our objective was to investigate the effects of topically applied neuropeptide Y (NPY) on ischemic wounds. Initially, the animal model for ischemic wound healing was validated using 16 male Sprague Dawley albino rats. In the intervention study, an additional 28 rats were divided into three groups: NPY (0.025%), the positive control insulin-like growth factor-I (IGF-I, 0.0025%), and the hydrogel carrier alone (control). The hydrogel was selected due to its capacity to prolong NPY release (p < 0.001), as demonstrated in a Franz diffusion cell. In the animals, an 8 mm full-thickness wound was made in a pedunculated dorsal ischemic skin flap. Wounds were then treated and assessed for 14 days and collected at the end of the experiment for in situ hybridization analysis (RNAscope®) targeting NPY receptor Y2R and for meticulous histologic examination. Wound healing rates, specifically the percentage changes in wound area, did not show an increase with NPY (p = 0.907), but there was an increase with rhIGF-I (p = 0.039) compared to the control. Y2R mRNA was not detected in the wounds or adjacent skin but was identified in the rat brain (used as a positive control). Light microscopic examination revealed trends of increased angiogenesis and enhanced inflammatory cell infiltration with NPY compared to control. An interesting secondary discovery was the presence of melanophages in the wounds. Our findings suggest the potential of NPY to enhance neovascularization under ischemic wound healing conditions, but further optimization of the carrier and dosage is necessary. The mechanism remains elusive but likely involves NPY receptor subtypes other than Y2R. [ABSTRACT FROM AUTHOR]

Background: Melanoma is widely recognized to be an immunogenic tumor that often contains tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment. During cancer progression, expression of ligands that bind immune checkpoint (IC) proteins, such as PD-1, expressed on the surface of TILs, hinder them from exerting their antitumor functions. TILs consist of a heterogenous group of immune cells and their presence is associated with an improved overall survival in melanoma patients. Introduction of IC inhibitors has revolutionized management and prognosis of advanced melanoma. Unfortunately, the response rates have continued to be limited, resulting in growing interest in characterizing novel IC proteins, and developing combination therapy that includes inhibitors against multiple IC proteins. Methods: In a regional cohort of 166 patients diagnosed with cutaneous superficial spreading melanoma with different degree of TILs, we investigated the tumor immune-associated gene expression profile using NanoString Technology. We used multiplex immunofluorescence (mIF) staining in a subset of tumors (N = 7), combining IC proteins T-cell immunoglobulin and ITIM domain (TIGIT) and LAG3 with a melanoma cell marker (SOX10) and immune cell markers (CD8 [cytotoxic T cells], CD4 [T helper cells], FOXP3 [regulatory T cells/Tregs], PAX5 [B cells], and CD56 [NK/NKT cells]) and IC protein PD-1. Results: We found upregulation of 91 differentially expressed genes, including IC proteins, LAG3 and TIGIT in melanomas with brisk TILs compared to tumors where TILs were absent. mIF staining revealed LAG3 and TIGIT expression in the majority of CD8+ T cells. Only few Tregs and CD4+ T cells expressed LAG3, whereas majority of them expressed TIGIT. LAG3 and TIGIT were expressed in a small fraction of the NK/NKT cells and lacked in the B cells. The majority of PD-1+ cells co-localized with LAG3 and TIGIT. Conclusion: We report a variable expression of LAG3 and TIGIT on TILs subtypes and a coeval occurrence with PD-1. This knowledge places LAG3 and TIGIT in spatial and cellular context in melanoma. The data suggest that targeting multiple IC proteins might help overcome the current challenges with IC therapies. [ABSTRACT FROM AUTHOR]

We investigated the impact of synthetic nucleic acid antigens on the autoantibody profiles in patients with localized scleroderma, an autoimmune skin disease. Anti-DNA antibodies, including double-stranded DNA (dsDNA) and single-stranded DNA (ssDNA), are common among autoimmune diseases, such as systemic lupus erythematosus and localized scleroderma. Based on recent studies, we hypothesized that the sequence of nucleic acid antigens has an impact on the autoimmune reactions in localized scleroderma. To test our hypothesis, we synthesized a panel of DNA and RNA antigens and used them for autoantibody profiling of 70 children with localized scleroderma compared with the healthy controls and patients with pediatric systemic lupus erythematosus (as a disease control). Among the tested antigens, dsD4, which contains the sequence of the human oncogene BRAF, showed a particularly strong presence in localized scleroderma but not systemic lupus erythematosus. Disease activity in patients was significantly associated with dsD4 autoantibody levels. We confirmed this result in vivo by using a bleomycin-induced mouse model of localized scleroderma. When administered intraperitoneally, dsD4 promoted an active polyclonal response in the mouse model. Our study highlights sequence specificity for nucleic acid antigens in localized scleroderma that could potentially lead to developing novel early-stage diagnostic tools. [ABSTRACT FROM AUTHOR]

Our understanding of the regulatory processes of reepithelialization during wound healing is incomplete. In an attempt to map the genes involved in epidermal regeneration and differentiation, we measured gene expression in formalin-fixed, paraffin-embedded standardized epidermal wounds induced by the suction-blister technique with associated nonwounded skin using NanoString technology. The transcripts of 139 selected genes involved in clotting, immune response to tissue injury, signaling pathways, cell adhesion and proliferation, extracellular matrix remodeling, zinc transport and keratinocyte differentiation were evaluated. We identified 22 upregulated differentially expressed genes (DEGs) in descending order of fold change (MMP1, MMP3, IL6, CXCL8, SERPINE1, IL1B, PTGS2, HBEGF, CXCL5, CXCL2, TIMP1, CYR61, CXCL1, MMP12, MMP9, HGF, CTGF, ITGB3, MT2A, FGF7, COL4A1 and PLAUR). The expression of the most upregulated gene, MMP1, correlated strongly with MMP3 followed by IL6 and IL1B. rhIL-1β, but not rhIL-6, exposure of cultured normal human epidermal keratinocytes and normal human dermal fibroblasts increased both MMP1 mRNA and MMP-1 protein levels, as well as TIMP1 mRNA levels. The increased TIMP1 in wounds was validated by immunohistochemistry. The six downregulated DEGs (COL7A1, MMP28, SLC39A2, FLG1, KRT10 and FLG2) were associated with epidermal maturation. KLK8 showed the strongest correlation with MKI67 mRNA levels and is a potential biomarker for keratinocyte proliferation. The observed gene expression changes correlate well with the current knowledge of physiological reepithelialization. Thus, the gene expression panel described in this paper could be used in patients with impaired healing to identify possible therapeutic targets. [ABSTRACT FROM AUTHOR]

Background: Colonic stent is recommended as a bridge to elective surgery for malignant obstruction to improve short-term clinical outcomes for patients with colorectal cancer. However, since the oncological outcomes remain controversial, this study aimed to investigate the impact of self-expandable metallic stent (SEMS) on the tumor microenvironment. Methods: Patients treated with colonic stent as a bridge to surgery from 2010 to 2015 were identified from hospital records. Tumor biopsies and resected tumor samples of the eligible patients were retrieved retrospectively. Gene expression analysis was performed using the NanoString nCounter PanCancer IO 360 gene expression panel. Results: Of the 164 patients identified, this study included 21 who underwent colonic stent placement as a bridge to elective surgery. Gene expression analysis revealed 82 differentially expressed genes between pre- and post-intervention specimens, of which 72 were upregulated and 10 downregulated. Among the significantly upregulated genes, 46 are known to have protumor functions, of which 26 are specifically known to induce tumorigenic mechanisms such as proliferation, migration, invasion, angiogenesis, and inflammation. In addition, ten differentially expressed genes were identified that are known to promote antitumor functions. Conclusion: SEMS induces gene expressional changes in the tumor microenvironment that are associated with tumor progression in colorectal cancer and may potentiate a more aggressive phenotype. Future studies are warranted to establish optimal timing of surgery after SEMS insertion in patients with obstructive colorectal cancer. [ABSTRACT FROM AUTHOR]

Most patients cannot be included in randomized clinical trials. We report real-world outcomes of all Danish patients with multiple myeloma (MM) treated with daratumumab-based regimens until 1 January 2019. Methods: Information of 635 patients treated with daratumumab was collected retrospectively and included lines of therapy (LOT), hematologic responses according to the International Myeloma Working Group recommendations, time to next treatment (TNT) and the cause of discontinuation of treatment. Baseline characteristics were acquired from the validated Danish Multiple Myeloma Registry (DMMR). Results: Daratumumab was administrated as monotherapy (Da-mono) in 27.7%, in combination with immunomodulatory drugs (Da-IMiD) in 57.3%, in combination with proteasome inhibitors (Da-PI) in 11.2% and in other combinations (Da-other) in 3.8% of patients. The median number of lines of therapy given before daratumumab was 5 for Da-mono, 3 for Da-IMiD, 4 for Da-PI, and 2 for Da-other. In Da-mono, overall response rate (ORR) was 44.9% and median time to next treatment (mTNT) was 4.9 months. In Da-IMiD, ORR was 80.5%, and mTNT was 16.1 months. In Da-PI, OOR was 60.6% and mTNT was 5.3 months. In patients treated with Da-other, OOR was 54,2% and mTNT was 5.6 months. The use of daratumumab in early LOT was associated with longer TNT (p<0.0001). Patients with amplification 1q had outcome comparable to standard risk patients, while patients with t(4;14), t(14;16) or del17p had worse outcome (p = 0.0001). Multivariate analysis indicated that timing of treatment (timing of daratumumab in the sequence of all LOT that the patients received throughout the course of their disease) was the most important factor for outcome (p<0.0001). Conclusion: The real-world outcomes of multiple myeloma patients treated with daratumumab are worse than the results of clinical trials. Outcomes achieved with daratumumab were best when daratumumab was used in combination with IMIDs and in early LOT. Patients with high-risk CA had worse outcomes, but patients with amp1q had similar outcomes to standard-risk patients. [ABSTRACT FROM AUTHOR]

Mycosis fungoides is the most common type of cutaneous T-cell lymphoma. The inflammatory microenvironment in mycosis fungoides is complex. There is accumulating evidence that the neoplastic T-cells take control of the microenvironment and thereby promote their own expansion by suppressing cellular immunity. B-cells have proved to be upregulated in large-cell transformed mycosis fungoides, and could potentially play a role in disease progression. To investigate the presence of B-cells in mycosis fungoides compared with controls, this study analysed 85 formalin-fixed and paraffin-embedded mycosis fungoides biopsies. MS4A1 gene expression was significantly upregulated in mycosis fungoides compared with controls (p < 0.0001) and further upregulated in disease progression, (p = 0.001). Digital quantification of PAX5+/CD20+ cells confirmed the increased presence of Bcells in mycosis fungoides compared with controls. No co-labelling of CD3/CD20 was observed in the neoplastic T-cells. This study found a significantly increased presence of B-cells in the tumour-associated microenvironment in mycosis fungoides. These findings could potentially lead to new treatment strategies for mycosis fungoides. [ABSTRACT FROM AUTHOR]

Background: The calreticulin (CALR) exon 9 mutations that are identified in 20% of patients with Philadelphia chromosome negative chronic myeloproliferative neoplasms (MPN) generate immunogenic antigens. Thus, therapeutic cancer vaccination against mutant CALR could be a new treatment modality in CALR -mutant MPN. Methods: The safety and efficacy of vaccination with the peptide CALRLong36 derived from the CALR exon 9 mutations was tested in a phase I clinical vaccination trial with montanide as adjuvant. Ten patients with CALR mut MPN were included in the trial and received 15 vaccines over the course of one year. The primary end point was evaluation of safety and toxicity of the vaccine. Secondary endpoint was assessment of the immune response to the vaccination epitope (www.clinicaltrials.gov identifier NCT03566446). Results: Patients had a median age of 59.5 years and a median disease duration of 6.5 years. All patients received the intended 15 vaccines, and the vaccines were deemed safe and tolerable as only two grade three AE were detected, and none of these were considered to be related to the vaccine. A decline in platelet counts relative to the platelets counts at baseline was detected during the first 100 days, however this did not translate into neither a clinical nor a molecular response in any of the patients. Immunomonitoring revealed that four of 10 patients had an in vitro interferon (IFN)-γ ELISPOT response to the CALRLong36 peptide at baseline, and four additional patients displayed a response in ELISPOT upon receiving three or more vaccines. The amplitude of the immune response increased during the entire vaccination schedule for patients with essential thrombocythemia. In contrast, the immune response in patients with primary myelofibrosis did not increase after three vaccines. Conclusion: Therapeutic cancer vaccination with peptide vaccines derived from mutant CALR with montanide as an adjuvant, is safe and tolerable. The vaccines did not induce any clinical responses. However, the majority of patients displayed a marked T-cell response to the vaccine upon completion of the trial. This suggests that vaccines directed against mutant CALR may be used with other cancer therapeutic modalities to enhance the anti-tumor immune response. [ABSTRACT FROM AUTHOR]

Diagnosis of mycosis fungoides and Sézary syndrome can be very challenging. Clinical and histopathological data for patients with mycosis fungoides and Sézary syndrome in Denmark are limited. A retrospective study was performed in Region Zealand, Denmark from 1990 to 2016. A total of 43 patients with mycosis fungoides or Sézary syndrome were identified during the period. At the time of diagnosis the patients' mean age was 64.3 years and 74.5% had early-stage (≤IIA) disease. The mean time from onset of skin disease to diagnosis was 4.4 years. Surprisingly, 43% progressed to a higher disease stage, and risk of disease progression was higher for stage IB than IA (p = 0.01). All cases displayed some degree of epidermotropism and the infiltrates consisted of pleomorphic lymphocytes with a T-helper (CD4+/CD8-) phenotype. This study describes, for the first time, all aspects of clinical and histopathological findings in patients with mycosis fungoides and Sézary syndrome in a well-characterized Danish cohort. [ABSTRACT FROM AUTHOR]

The aim of the present study was to describe a rare case of orbital precursor B-lymphoblastic lymphoma (B-LBL) in an adult. A 56-year-old male in complete remission of a gastric precursor B-LBL was referred to our orbital clinic due to rapid development of left-sided painless periorbital swelling, diplopia, and proptosis. Complete ophthalmoplegia was observed. Notably, magnetic resonance imaging showed swelling of the medial and inferior rectus muscles in the left orbit and biopsies were performed. Following histological diagnosis of precursor B-LBL, the patient was treated with radiotherapy (2Gy × 20) and chemotherapy according to the NOPHO ALL 2008 protocol. The disease progressed and the patient succumbed after 5 months. Histomorphologically, a lymphoblastic infiltrate was observed within the skeletal muscle tissue. The tumor cells were small and immature, and stained strongly for cluster of differentiating (CD)10, CD79a, paired box 5 and B cell lymphoma-2. The Ki-67 proliferative index was 90%. Multiplex ligation-dependent probe amplification and array comparative genomic hybridization detected whole chromosomal gain of X and 12, and both hemizygous and homozygous deletion on 9p comprising cyclin dependent kinase inhibitor 2A/B. Furthermore, array comparative genomic hybridization detected copy number imbalances consisting of focal or smaller deletions on chromosomes 1, 9, 10, 11 and 20. The final diagnosis was precursor B-LBL relapse in the extraocular muscles. Orbital precursor B-LBL is extremely rare in adults, and the diagnosis may be challenging to make. It is recommended to obtain material for cytogenetic and molecular analyses. [ABSTRACT FROM AUTHOR]

Peripheral T-cell lymphomas (PTLs) represent an area of high medical need. Previously, we demonstrated high expression of Notch, a known oncogene, in primary cutaneous anaplastic large cell lymphoma (ALCL). In this study, we performed immunohistochemical staining for Notch1 in lymph nodes from PTL not otherwise specified (PTL-NOS) and systemic ALCL (ALK+ and ALK−) and report a similar distribution among the three subgroups: Negative, moderate and strong expression was, respectively, 18%, 27% and 55% for PTL-NOS (33 cases), 20%, 0% and 80% for ALCL ALK+ (10 cases) and 45%, 22% and 33% for ALCL ALK− (nine cases) ( p > 0.05). In the ALK+ ALCL cell line, Karpas-299, pharmacological inhibition of Notch with γ-secretase inhibitor (GSI) I was far more potent than with GSI IX, XX and XXI with regard to cell viability and apoptosis. In conclusion, PTL tumor cells have prominent Notch1 expression and treatment with Notch inhibitors has cytotoxic effects. [ABSTRACT FROM AUTHOR]

Background: HIV-infected controllers control viral replication and maintain normal CD4+ T cell counts. Long Term Non-Progressors (LTNP) also maintain normal CD4+ T cell counts, but have on-going viral replication. We hypothesized that different immunological mechanisms are responsible for preserved CD4+ T cell counts in controllers and LTNP. Methods: 25 HIV-infected controllers and 14 LTNP were included in this cross-sectional study. For comparison, 25 progressors and 34 healthy controls were included. Production and destruction of T cells were addressed by determination of T cell receptor excision circles (TREC), recent thymic emigrants, naïve cells, immune activation, senescence and apoptosis. Furthermore, telomere length was determined, and the amount of lymphoid tissue in tonsil biopsies was quantified. Results: Controllers presented with partly preserved thymic output, preserved expression of the IL-7 receptor and IL-7 receptor density, and lower levels of destruction of cells than progressors resembling HIV-negative healthy controls. In contrast, LTNP appeared much like progressors, and different from controllers in immune activation, senescence, and apoptosis. Interestingly, CD8+ RTE, TREC and telomere length were partly preserved. Finally, both controllers and LTNP displayed decreased amounts of lymphoid tissue compared to healthy controls. Conclusions: Controllers presented with an immunological profile different from LTNP. While controllers resembled healthy controls, LTNP were similar to progressors, suggesting different immunological mechanisms to be responsible for preserved CD4+ T cell counts in LTNP and controllers. However, both controllers and LTNP presented with reduced amounts of lymphoid tissue despite preserved CD4+ T cell counts, indicating HIV to cause damage even in non-progressors. [ABSTRACT FROM AUTHOR]

Cutaneous T-cell lymphoma (CTCL) represents a heterogeneous group of potentially devastating primary skin malignancies. Despite decades of intense research efforts, the pathogenesis is still not fully understood. In the early stages, both clinical and histopathological diagnosis is often difficult due to the ability of CTCL to masquerade as benign skin inflammatory dermatoses. Due to a lack of reliable biomarkers, it is also difficult to predict which patients will respond to therapy or progress towards severe recalcitrant disease. In this review, we discuss recent discoveries concerning dysregulated microRNA (miR) expression and putative pathological roles of oncogenic and tumor suppressive miRs in CTCL. We also focus on the interplay between miRs, histone deacetylase inhibitors, and oncogenic signaling pathways in malignant T cells as well as the impact of miRs in shaping the inflammatory tumor microenvironment. We highlight the potential use of miRs as diagnostic and prognostic markers, as well as their potential as therapeutic targets. Finally, we propose that the combined use of miR-modulating compounds with epigenetic drugs may provide a novel avenue for boosting the clinical efficacy of existing anti-cancer therapies in CTCL. [ABSTRACT FROM AUTHOR]

Reepithelialisation is fundamental to wound healing, but our current understanding largely relies on cellular and animal studies. The aim of the present randomised double-blind three-arm controlled trial was to correlate genuine epidermal wound healing with key proteins and topical zinc treatment in humans. Sixty wounds were produced using deroofed suction blisters in 30 healthy volunteers and randomised to topical zinc sulphate (n = 20), placebo (n = 20), or control (n = 20) treatment for 4 days. All wounds with perilesional skin were processed for automatic immunostaining of paraffin tissue sections with monoclonal antibodies against Ki-67, metallothionein (MT) and matrix metalloproteinase (MMP)-1. Protein expression was quantified by automated digital image analysis. Epidermal Ki-67 and MT labelling indices were increased in keratinocytes in the neoepidermis (∼1.1 mm) and at the wound edge (0.5 mm) compared to normal skin. Increased MMP-1 immunostaining was restricted to the neoepidermis. MT was robustly upregulated in the upper dermis of the wounds. Zinc treatment enhanced MMP-1 expression beneath the neoepidermis via paracrine mechanisms and MT under the neoepidermis and in the nonepithelialised wound bed via direct actions of zinc as indicated by the induction of MT2A mRNA but not MMP-1 mRNA in cultured normal human dermal fibroblasts by zinc sulphate. The present human study demonstrates that quantitative immunohistochemistry can identify proteins involved in reepithelialisation and actions of external compounds. Increased dermal MT expression may contribute to the anti-inflammatory activities of zinc and increased MMP-1 levels to promote keratinocyte migration. [ABSTRACT FROM AUTHOR]

We report the two-year end-of-study results from the phase 2 COMBI II clinical trial (#EudraCT2018-004150-13) investigating the combination treatment of ruxolitinib and low-dose pegylated interferon-α2a in patients with newly diagnosed polycythemia vera. The primary outcome was safety and key secondary endpoints were efficacy, based on hematological parameters, quality of life measurements, and JAK2V617F variant allele frequency (VAF). We used the 2013 ELN and IWG-MRT remission criteria. The remission criteria included remissions in symptoms, splenomegaly, peripheral blood counts, and bone marrow. We included 25 patients with PV with a median age of 70 years; 5 of those had prior thromboembolic events and three had CT-verified splenomegaly. Two patients stopped both study drugs, one of these due to progression to post-PV myelofibrosis; only that patient had a grade 3 infection. No events of herpes zoster infections were observed. No patients discontinued treatment due to psychiatric symptoms. The peripheral blood cell count remission rate was 92% at 24 months. Using the 2013 ELN and IWG-MRT remission criteria, 14 (56%) achieved remission at 24 months; 3 (12%) achieved complete remission, and 11 (44%) achieved partial remission. The following items from the Myeloproliferative Neoplasm Symptom Total Symptom Score were significantly reduced: abdominal discomfort, night sweats, itching, and bone pain. The median JAK2V617F VAF decreased from 47% (95%CI, 35-59%) to 7% (95%CI, 3-15%), and 60% of patients achieved molecular remission. In conclusion, combination treatment improved cell counts; bone marrow cellularity, and fibrosis; and decreased JAK2V617F VAF; with acceptable toxicity in patients with polycythemia vera. EudraCT2018-004150-13., (Copyright © 2024 American Society of Hematology.)

Purpose: The Danish Pathology Life Course (PATHOLIFE) cohort was established to facilitate epidemiological research relating histological and cytological features extracted from patient tissue specimens to the rich life course histories, including both prior and future register data, of the entire Danish population. Research results may increase quality of diagnosis, prognosis and stratification of patient subtypes, possibly identifying novel routes of treatment., Participants: All Danish residents from 1 January 1986 to 31 December 2019, totalling 8 593 421 individuals., Findings to Date: We provide an overview of the subpopulation of Danish residents who have had a tissue specimen investigated within the Danish healthcare system, including both the primary sector and hospitals. We demonstrate heterogeneity in sociodemographic and prognostic factors between the general Danish population and the above mentioned subpopulation, and also between the general Danish population and subpopulations of patients with tissue specimens from selected anatomical sites. Results demonstrate the potential of the PATHOLIFE cohort for integrating many different factors into identification and selection of the most valuable tissue blocks for studies of specific diseases and their progression. Broadly, we find that living with a partner, having higher education and income associates with having a biopsy overall. However, this association varies across different tissue and patient types, which also display differences in time-to-death and causes of death., Future Plans: The PATHOLIFE cohort may be used to study specified patient groups and link health related events from several national health registries, and to sample patient groups, for which stored tissue specimens are available for further research investigations. The PATHOLIFE cohort thereby provides a unique opportunity to prospectively follow people that were characterised and sampled in the past., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Mantle cell lymphoma (MCL) is an incurable disease with a highly variable clinical course. The prognosis after relapse is generally poor, and no standard of care exists. We investigated the postrelapse outcomes of 149 patients who were initially treated in the Nordic Lymphoma Group trials, MCL2 or MCL3, both representing intensive cytarabine-containing frontline regimens including autologous stem cell transplant. Patients with progression of disease before 24 months (POD24, n = 51, 34%) displayed a median overall survival of 6.6 months compared with 46 months for patients with later POD (n = 98, 66%; P < 0.001). MCL international prognostic index, cell proliferation marker, blastoid morphology, and TP53 mutations showed independent prognostic value irrespective of POD24, and in a combined, exploratory risk score, patients with 0, 1, 2-3, or 4-5 high-risk markers, respectively, displayed a 5-year overall survival of 62%, 39%, 31%, and 0%. By a comparison of median progression-free survival of the different salvage therapies in the relapse setting, bendamustine-rituximab was superior to all other combination chemotherapy regimens; however, it was also associated with longer responses to last line of therapy. Collectively, we confirm the prognostic impact of POD24 and highlight the relevance of other biomarkers, and we emphasize the importance of novel therapies for patients with high-risk features at first POD., Competing Interests: IG has received IG Honoraria from Janssen. CUN has received consultancy fees and/or travel grants from Janssen, Abbvie, Novartis, Roche, Sunesis, Gilead, AstraZeneca, and CSL Behring, and research funding from Novo Nordisk Foundation, grant NNF16OC0019302, Abbvie, AstraZeneca and Janssen, outside this project. All the other authors have no conflicts of interest to disclose., (Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

While performing the screening programme for colorectal cancer in Denmark, some cases of adenomas have been found. By histological analysis they were shown to be lymphomas. In this case report, two such cases are described. Screening is the subject of much debate. These cases are relevant because they showthat malignant diseases, which the program was not designed to identify, were found. When debating screening it should be taken into consideration, that secondary diseases, with the potential for earlier diagnostics and potentially better prognosis may be detected.

We report the final 2-year end-of-study results from the first clinical trial investigating combination treatment with ruxolitinib and low-dose pegylated interferon-α2 (PEG-IFNα2). The study included 32 patients with polycythemia vera and 18 with primary or secondary myelofibrosis; 46 patients were previously intolerant of or refractory to PEGIFNα2. The primary outcome was efficacy, based on hematologic parameters, quality of life measurements, and JAK2 V617F allele burden. We used the 2013 European LeukemiaNet and International Working Group- Myeloproliferative Neoplasms Research and Treatment response criteria, including response in symptoms, splenomegaly, peripheral blood counts, and bone marrow. Of 32 patients with polycythemia vera, ten (31%) achieved a remission which was a complete remission in three (9%) cases. Of 18 patients with myelofibrosis, eight (44%) achieved a remission; five (28%) were complete remissions. The cumulative incidence of peripheral blood count remission was 0.85 and 0.75 for patients with polycythemia vera and myelofibrosis, respectively. The Myeloproliferative Neoplasm Symptom Assessment Form total symptom score decreased from 22 [95% confidence interval (95% CI):, 16-29] at baseline to 15 (95% CI: 10-22) after 2 years. The median JAK2 V617F allele burden decreased from 47% (95% CI: 33-61%) to 12% (95% CI: 6-22%), and 41% of patients achieved a molecular response. The drop-out rate was 6% among patients with polycythemia vera and 32% among those with myelofibrosis. Of 36 patients previously intolerant of PEG-IFNα2, 31 (86%) completed the study, and 24 (67%) of these received PEG-IFNα2 throughout the study. In conclusion, combination treatment improved cell counts, reduced bone marrow cellularity and fibrosis, decreased JAK2 V617F burden, and reduced symptom burden with acceptable toxicity in several patients with polycythemia vera or myelofibrosis. #EudraCT2013-003295-12.

The voltage-gated potassium channel Kv1.3 (KCNA3) is expressed by a subset of chronically activated memory T cells and plays an important role in their activation and proliferation. Here, we show that primary malignant T cells isolated from patients with Sézary syndrome (SS) express Kv1.3 and are sensitive to potent Kv1.3 inhibitors ShK and Vm24, but not sensitive to a less potent inhibitor [N17A/F32T]-AnTx. Kv1.3 blockade inhibits CD3/CD28-induced proliferation and IL-9 expression by SS cells in a concentration-dependent manner. In parallel, CD3/CD28-mediated CD25 induction is inhibited, whereas Kv1.3 blockade has no effect on apoptosis or cell death as judged by Annexin V and PI staining. In conclusion, we provide the first evidence that malignant T cells in SS express functional Kv1.3 channels and that Kv1.3 blockade inhibits activation-induced proliferation as well as cytokine and cytokine receptor expression in malignant T cells, suggesting that Kv1.3 is a potential target for therapy in SS., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

Treatment of advanced cutaneous T-cell lymphomas (CTCL) is challenging because they are resistant to conventional chemotherapy. USP2 has been shown to promote resistance to chemotherapeutic agents in several cancer models.We show here USP2 is expressed in quiescent and activated T-cells and its expression is 50% lower in CTCL cell lines (MyLa2000, SeAx and Hut-78) than in normal T-cells. USP2 is expressed in neoplastic cells in early, plaque-stage mycosis fungoides (MF) and is downregulated in advanced tumor stages. Upon treatment with psoralen with UVA (PUVA) or a p53 activator, nutlin3a, USP2 expression is significantly increased in MyLa2000 (p53wt/wt), but not in SeAx (p53mut) or Hut-78 (p53-/-). USP2 knockdown decreases MyLa2000 cell viability after PUVA by 50% but not Hut-78, suggesting that the function of USP2 in CTCL cells is p53-dependent. Furthermore, USP2 knockdown results in a decreased Mdm2 expression and upregulation of p53. Taken together, our findings suggest that USP2 stabilizes Mdm2 which antagonizes pro-apoptotic activity of p53 and possibly contributes to therapeutic resistance in CTCL., Competing Interests: No conflicts of interest.