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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]

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]

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]

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]

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]

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.)

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.

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.