T-cell non-Hodgkin Lymphoma Research Articles

Tumour assessment of ROR1 levels in various adult leukaemia and lymphoma types.

Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a tumour target currently used for the development of novel therapeutic modalities, such as antibody-drug conjugates, chimeric antigen receptor T-cell therapies, and others. Success of these new drugs depends on the selection of relevant indications based on ROR1 tumour prevalence, staining heterogeneity, and subcellular localization, among other parameters. We investigated ROR1 immunophenotype using validated antibody clones for immunohistochemistry (IHC) and flow cytometry (FC), analyzing 292 tumour specimens from 7 haematological malignancies and triple negative breast cancer (TNBC) as a reference solid tumour indication. ROR1 prevalence varied significantly across distinct tumour types, showing 100% of ROR1 positivity in all chronic lymphocytic leukaemia (n = 48) and hairy cell leukaemia (n = 14) specimens analyzed via FC with ranges between 1.1-99.8% and 0.8-62.1%, respectively. Samples analysed via IHC showed ROR1 membrane/cytoplasmic positivity in 44% of mantle cell lymphoma tumour samples (n = 27; H-score range: 10-285 in positive cases); 30% in TNBC (n = 46; H-score range: 1-200); 15% in diffuse large B-cell lymphoma (n = 45; H-score: 40-250); and 11% in follicular lymphoma (n = 34; H-score: 2-300). Finally, all acute myeloid leukaemia (n = 52) and most T-cell non-Hodgkin lymphoma (n = 31/32) tested samples were negative for ROR1 via IHC. In conclusion, ROR1 shows a heterogeneous tumour cell expression profile across multiple leukaemias and lymphomas, making it a tumour target that would require different patient selection strategies to develop novel therapeutic modalities.

Efficacy of verdinexor for the treatment of naïve canine epitheliotropic cutaneous T-cell lymphoma: An open-label pilot study.

Verdinexor (Laverdia-CA1; Dechra Veterinary Products), a selective inhibitor of nuclear export, has been utilised for treatment of non-Hodgkin T-cell lymphoma in dogs. However, the efficacy of verdinexor has not been evaluated for cutaneous epitheliotropic T-cell lymphoma (CETL). To evaluate the efficacy of verdinexor for the treatment of CETL. Eight client-owned animals with CETL. Patients received between 1.28 and 1.45 mg/kg verdinexor per os twice weekly with a minimum of 72 h between doses until disease progression or voluntary withdrawal. Adjunctive therapy with lokivetmab or prednisone was permitted after Day (D)14. Assessment of clinical lesions (canine Response Evaluation Criteria in Solid Tumors [cRECIST v1.0] and novel Canine Epitheliotropic Lymphoma Extent and Severity Index [CELESI]), pruritus (Visual Analog Scale) and treatment efficacy (owner global assessment of treatment efficacy [OGATE]) were evaluated every 14 days for 3 months, then monthly thereafter (mean 70 ± 43.4 days). Seventy-five percent of patients achieved complete response, partial response or stable disease. The mean time to disease progression was 56 ± 41 days. There was a significant reduction (p = 0.026) in total CELESI score when the lowest score for each dog was compared to their score at D0. Verdinexor did not significantly reduce pruritus at any time point (p = 0.45), including when given as a monotherapy or concurrently with lokivetmab ± glucocorticoids. On D28, 75% of owners rated response to treatment as 'fair' to 'excellent'. The most common adverse effects included weight loss, inappetence, vomiting and lethargy. Verdinexor could be considered a safe, palliative treatment for canine CETL.

Conventional PCR-based versus next-generation sequencing-based approach for T-cell receptor γ gene clonality assessment in mature T-cell lymphomas: A phase 3 diagnostic accuracy study.

Clonality assessment is currently the major molecular analysis utilized to support the diagnosis of suspicious lymphoid malignancies. Clonal rearrangements of the V-J segments of T-cell receptor G chain locus (TCRγ or TRG) have been observed in almost all types of T neoplasms, such as T-cell-related non-Hodgkin lymphomas and leukemias. At present, the gold standard for clonality evaluation is multiplex polymerase chain reaction (PCR), plus subsequent capillary electrophoresis/heteroduplex analyses, and/or Sanger sequencing. This approach overcomes the problem with the conventional Southern blot hybridization and is more efficient, simple, fast, and reproducible. In the recent years, the new next-generation sequencing (NGS) technologies provided alternative techniques for the analysis of antigen receptors genes, which presented several advantages, such as increased efficiency, specificity (SP), sensitivity (ST), resolution, and objectivity of the results, leading to a better classification, stratification, and monitoring of lymphoid malignancies. Nonetheless, these technologies are still far from being the new gold standard since further studies are warranted to prove their utility. The present study aimed to assess the diagnostic accuracy of these two methods by comparing a commercial NGS-based assay for the evaluation of TRG locus with the gold standard PCR-based one, to fulfill the requirements of a phase 3 diagnostic accuracy study. We assessed the TRG gene rearrangements in 72 cases using the conventional and highly-validated PCR-based assay proposed by EuroClonality consortium, an alternative commercial PCR-based assay, namely, IdentiClone® TCR Gamma Gene Rearrangement Assay 2.0, and a commercial NGS-based assay, that is, Invivoscribe LymphoTrack® Dx MiSeq® (both by Invivoscribe Technologies Inc., San Diego, CA, USA), to determine the diagnostic accuracy of the latter, and compare them with reference diagnoses made based on observation of clinical manifestations, cytohistological, and immunohistochemical analyses. Statistical values were calculated using the Oxford CATmaker software package. Using standardized criteria of interpretation, the obtained results showed a diagnostic accuracy of 90.3% (correspondence in 65 out of 72 cases) of the test under investigation, with a ST of 86%, a SP of 95%, a positive predicting value of 94%, and a negative predicting value of 88%, demonstrating that it had high efficiency and reliability in detecting clonal TRG gene rearrangements in T-cell non-Hodgkin lymphomas. This diagnostic accuracy study yielded comparable results using a validated PCR-based approach and a new NGS-based one. Subsequent studies and cost-effectiveness evaluation are needed to put the NGS-based clonality assessment into routine diagnostic practice.

Health-related quality of life profile of newly diagnosed patients with Hodgkin and non-Hodgkin lymphomas: A real-world study including 3922 patients from the French REALYSA cohort

IntroductionConsidering the notable advances made in the treatment of lymphoma, assessment of health-related quality of life (HRQoL) of lymphoma patients has become a critical aspect to consider both in clinical research and routine practice. However, there is paucity of information about lymphoma specific HRQoL profile at diagnosis. Patients and methodsHRQoL at diagnosis was assessed for 3922 adult patients with newly diagnosed high-grade (HG) (n = 1994), low-grade (LG) (n = 1053) non-Hodgkin (NHL) and Hodgkin (HL) (n = 875) lymphomas included in REal world dAta in LYmphoma and Survival in Adults (REALYSA, NCT03869619), a prospective non-interventional multicentric cohort in France. Disease-specific HRQoL aspects were assessed with three validated EORTC questionnaires, namely, the QLQ‐NHL‐HG29, the QLQ-NHL-LG20 and the QLQ-HL27, for patients with NHL-HG, NHL-LG and HL, respectively. ResultsWe confirmed the high-level of completion of these questionnaires in REALYSA cohort, ranging from 84 % for QLQ-HG29 to 88 % for QLQ-HL27. The proportion of patients with impaired global health status was as follows: T-cell NHL, 67 %; diffuse large B-cell (DLBCL), 62 %; Burkitt, 61 %; HL, 53 %; marginal zone, 49 %; mantle cell, 48 %; follicular, 47 %. Multivariable regression analyses for DLBCL, follicular and HL showed that gender, performance status and B symptoms were independently associated with all HRQoL dimensions. However, a variable effect of age and stage were observed among these three subtypes. ConclusionsA comprehensive analysis was made describing the HRQoL profile of newly diagnosed patients with different types of lymphomas. Our data may help to enhance the interpretation of HRQoL results in future studies using the recently validated EORTC lymphoma specific questionnaires.

Impact of military deployment on non-Hodgkin lymphoma subtype.

e19070 Background: Approximately 3.5 million activity duty service members (ADSM) have deployed to Afghanistan or Iraq from 2001-2022. During deployments, ADSMs are potentially exposed to deployment-related toxins and carcinogens, which could theoretically alter cancer biology. In terms of non-Hodgkin lymphoma (NHL), it is unclear whether deployment affects NHL subtype or cancer-specific survival. Methods: Deployment and occupation data from the Defense Manpower Data Center was merged with data from the Department of Defense Tumor Registry. Documented cases of NHL diagnosed from 2001-2022 were identified. ADSMs and retirees were included; dependents and those under the age of 18 were excluded. Differences in NHL subtype (aggressive B-cell, indolent B-cell, T-cell) and cancer-specific survival were assessed by deployment status (previously deployed vs. never deployed). Occupation was assessed among those who deployed. Propensity score matching (2:1) for age at diagnosis, year of diagnosis, and gender was performed to minimize confounding. All data were carried out using SAS and Jump statistical software. This study was approved by the IRB. Results: There were 2,599 ADSMs and retirees diagnosed with NHL between 2001-2022. Approximately 15% had previously deployed (n=398). Compared with never deployed, military personnel who had previously deployed were more likely to have aggressive B-cell NHL (45% vs. 34%) and less likely to have indolent B-cell NHL (50% vs. 54%) or T-cell NHL (6% vs. 12%), p<0.001. Deployment to Iraq or Afghanistan did not impact NHL subtype. During deployment, occupations of Infantry, Engineering and Healthcare did not impact NHL subtype, whereas occupations of Pilot/Aircrew and Intelligence did, with less T-cell lymphoma diagnosed (0 vs. 7%, and 3% vs. 8%, respectively). When evaluating NHL subtype by race, it was noted that in comparison to White, Asian, Pacific Islander and Other Race, Black Race was associated with more T-cell NHL (21%), largely comprised of cutaneous T-cell lymphoma. Conclusions: After propensity score matching, prior deployment was associated with more aggressive B-cell lymphoma than military personnel who had never deployed. Deployment occupation affected NHL subtype diagnosed, with Pilots/Aircrew and Intelligence personnel being less likely to have T-cell lymphoma, whereas Black Race was associated with a higher likelihood of having T-cell lymphoma. This study sheds insights into the impact of deployment on cancer subtype. Ongoing investigations are assessing mortality differences by deployment as well as causes of death.

A20 promoted the phagocytosis of lymphoma cells by dendritic cells from activated B-cell-like non-Hodgkin lymphoma.

Non-Hodgkin lymphoma (NHL) is a lymphoproliferative disorder derived from either B or T lymphocytes. Among NHL, activated B-cell-like (ABC) diffuse large B-cell lymphoma (DLBCL) and T cell non-Hodgkin lymphomas (T-NHL) are poor prognosis and aggressive subtypes. Macrophages are professional phagocytic cells and dendritic cells (DCs) are professional antigen-presenting cells in immune system. Doxorubicin (Dox) and Etoposide (ET) are the most effective anti-cancer drugs. A20 and CYLD are negative regulators of NF-κB-dependent functions in many cell types. Little is known about the roles of A20 and CYLD in regulating functions of DCs and macrophages from NHL. The present study, therefore, explored whether A20/CYLD expression contributes to functions of DCs and macrophages from NHL. To this end, blood samples of seventy-nine patients with ABC DLBCL and T-NHL were examined. Gene expression profile was determined by quantitative RT-PCR and immunophenotype, cell apoptosis and phagocytosis by flow cytometry. As a result, immunophenotypic analysis showed that the numbers of CD13+CD117-, CD56+CD40+ and CD23+CD40+ expressing cells were significantly elevated in ABC DLBCL cases compared to healthy individuals and T-NHL patients. Interestingly, upon treatment of Dox and ET, the phagocytosis of lymphoma cells was significantly reduced by CD11c+CD123- DCs and the percentage of CD56+ mature DCs was significantly enhanced in ABC DLBCL patients only in the presence of A20 siRNA, but not CYLD siRNA. In conclusion, ABC DLBCL patients with low A20 expression were defective in elimination of lymphoma cells by DCs and linked to killer DC expansion in circulation.

Analysis of hepatitis B virus infection in 1424 patients with different pathological types of lymphoma (2018-2022): A real-world, retrospective study.

Recent studies have found a high prevalence of hepatitis B virus (HBV) infection in patients with non-Hodgkin's lymphoma (NHL), especially B-cell non-Hodgkin's lymphoma (B-NHL). However, most studies did not classify it and analyze the correlation between HBV and its various subtypes. The authors retrospectively analyzed 1424 patients with lymphoma. Differences in the prevalence of HBV infection in patients with different pathological types of lymphoma were analyzed. The clinical characteristics, progression-free survival (PFS), and overall survival (OS) of HBV-positive and negative B-NHL subtypes were compared according to HBV infection. The HBV infection rate in NHL patients was 7.65%, which was higher than that in HL patients (2.59%, p < 0.05). The HBV infection rate in the B-NHL was higher than that in the T-cell non-Hodgkin's lymphoma (T-NHL) (8.14% vs. 4.95%). The HBV infection rate in the aggressive B-NHL was similar to that of the indolent B-NHL (8.30% vs. 7.88%), and the highest HBV infection rates were found in diffuse large B-cell lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma, but no significant differences in clinical characteristics, PFS, and OS were seen between HBV-positive and negative patients in the two subtypes. There was an association between HBV infection and the development of NHL and HBV infection may play a role in the pathogenesis of B-NHL, but not T-NHL.

Targeted therapies in the management of malignant lymphoma - is the end of conventional chemotherapy near?

Advances in the understanding of the biology of malignant lymphoma has facilitated the development of numerous molecularly targeted therapies. The incorporation of these precision therapeutics has produced more effective and often less-toxic treatment regimens leading to a significant improvement of treatment outcomes for individuals with lymphoid malignancies.In relapsed diseases, molecularly targeted therapeutic approaches have demonstrated superior outcomes compared to conventional chemotherapy, leading to a growing number of patients being treated entirely chemotherapy-free. This review outlines the current landscape of targeted therapies for both B-cell (B-NHL) and T-cell non-Hodgkin lymphomas (T-NHL) and provides an overview of targeted agents currently approved for the treatment of malignant lymphoma.

Anaplastic lymphoma kinase-negative anaplastic large-cell lymphoma

Anaplastic large-cell lymphoma (ALCL) is a non-Hodgkin T-cell lymphoma characterized by persistent expression of CD 30 antigen that represents 2–3% of non-Hodgkin lymphoma (NHL). ALCL may present as a primary cutaneous disease or systemic disease with secondary cutaneous involvement. World Health Organization (WHO) classifies ALCL into ALK-positive and ALK-negative ALCL. ALK-negative ALCL shows poor response on treatment and has a bad prognosis. We report locally aggressive and metastasizing primary cutaneous anaplastic lymphoma kinase-negative anaplastic large-cell lymphoma in a 58-year-old female, due to its paucity of literature.

Abstract 4320: Interrogation of autophagy inhibition in anaplastic large cell lymphoma (ALCL)

Abstract The objectives of this study are to evaluate if anaplastic lymphoma kinase (ALK) inhibition activates autophagy in ALK+ ALCL cells and to determine if that activation can be mitigated using autophagy inhibition. ALCL is an aggressive T-cell non-Hodgkin lymphoma that often presents as advanced stage disease. With the addition of crizotinib or brentuximab vedotin to the ALCL99 chemotherapy backbone, the recently reported Children’s Oncology Group ANHL12P1 study demonstrated a 2-year event-free survival for ALCL patients of 79%. Thus, even with multi-agent chemotherapy combined with targeted therapy, improved therapeutic efficacy is needed. Autophagy is activated when mTORC1 is inhibited, and as ALK signaling is known to promote mTORC1 activity, ALK inhibition is hypothesized to activate autophagy. If present, ALK inhibitor-induced autophagy activation would represent a novel therapeutic opportunity targetable with emerging autophagy inhibitors. An ALK+ ALCL cell line, Karpas 299, was treated with drug combinations for 3 hours, lysates prepared, and proteins separated by molecular weight using standard procedures. ALK inhibitor target engagement was assessed by western blot using phospho-ALKY1604 intensity in 9-point dose response curves. Target engagement of autophagy inhibition (ULK-101 directed against ULK1/2 and hydroxychloroquine (HCQ) targeting the lysosome) was assessed by western blot using phospho-ATG14S29 and LC3B-II intensity in 6-point dose response curves. Cell viability was evaluated using a luminescent CellTiter-Glo assay. Karpas299 cells resistant to crizotinib at 50nM (KCrizR50) were generated by gradually increasing crizotinib concentration in the media until cells grew at a rate similar to parental cells. Crizotinib, ceritinib, and lorlatinib all effectively inhibit ALK phosphorylation in Karpas 299 cells with low nanomolar potency. ULK-101 effectively inhibited pATG14S29 at 5 µM and HCQ effectively inhibited autophagic flux, as evidenced by increased LC3B-II intensity, at 20 µM. When treated with the lowest ALK inhibitor dose needed to achieve complete pALK inhibition (IC99), pATG14 intensity increased representing increased autophagic activity. When combined with ALK inhibition, ULK-101 effectively decreased pATG14S29, blocking the ALK inhibitor-induced autophagy activation. Decreased viability in Karpas 299 cells was observed after crizotinib, ceritinib and lorlatinib treatments with nanomolar potency. KCrizR50 cells had a potency higher than parental Karpas 299 cells for all three ALK inhibitors. ALK inhibition activates autophagy in ALCL cells and autophagy activation is effectively mitigated through concurrent autophagy inhibition. ALK inhibitor resistance in Karpas 299 cells will be further evaluated to determine whether autophagy contributes to the resistant phenotype. Citation Format: Katie L. Buelow, Stephanie Celano, Gregory Poole, Katie Martin, Jeffrey MacKeigan, David J. Hoogstra. Interrogation of autophagy inhibition in anaplastic large cell lymphoma (ALCL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4320.

Abstract 7015: Crosstalk between histone and DNA methylation in the development and progression of ALK+ ALCL

Abstract ALK-positive anaplastic large cell lymphoma (ALK+ ALCL) is a T-cell non-Hodgkin lymphoma characterized by the presence of the fusion oncogene nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). Tumor cells control the expression of key genes in different manners: mutations, translocations or epigenetically. Our group have shown that in this tumor a plethora of genes are silenced by NPM-ALK through DNA methylation. However, recent evidence showed that some of the genes downregulated by DNA methylation might have already been silenced prior to the appearance of DNA methylation. Herein, we investigate the possible role of histone methylation in the silencing of genes and its relationship to DNA methylation. To better understand the possible players in the silencing of genes in ALK+ ALCL we used T-cell transformed with NPM-ALK and recorded over time the changing in gene expression, DNA methylation and histone marks. Using RNAseq comparing transformed cells at different time points, we noticed that downregulated genes in ALK+ ALCL became gradually silenced also in our system. Next, we investigated the DNA methylation (meDNA) on their promoters, and we confirmed a progressive increase of meDNA but clearly slower compared to the silencing of the genes, or if compared to the meDNA status of established ALK+ ALCL cell lines. Finally, we explored the presence of silencing histone marks on the promoter of the silenced genes using qPCR-ChIP. Among the repressive histone marks evaluated, H3K27me3 stood up as possible candidate for the gene silencing. Therefore, we look at the different gene expression changes after the inhibition of either meDNA, using a DNMT1 inhibitor (GSK3685032), or histone methylation, by EZH2 inhibitor (EPZ6438). RNAseq data showed the re-expression of downregulated genes after EZH2 and/or DNMT1 inhibition providing clear insights on their epigenetic regulation. The co-presence of H3K27me3 and meDNA on the promoters of those genes points towards a crosstalk between DNA and histone methylation machineries. Despite it is clear how NPM-ALK regulates DNA methylation, nothing is known about NPM-ALK and EZH2. To investigate their relationship, we treated ALK+ cells with ALK inhibitor, and we observed a decrease of EZH2 expression at protein and mRNA level. STAT3 inhibition, through napabucasin or by STAT3 silencing using Crispr-cas9 technology, resulted, likewise, in the downregulation of EZH2. Moreover, ChIPseq showed STAT3 presence on EZH2 promoter, further confirming this mechanism. Altogether, those data showed that NPM-ALK regulates EZH2 expression through STAT3. In conclusion, we provide, not only novel information on the mechanism in the downregulation of genes in ALK+ ALCL, but also new insight on the understanding of the epigenetics machinery and the crosstalk between histone and DNA methylation, for long time considered two mutually exclusive mechanisms, or even antagonist. Citation Format: Cosimo Lobello, Shengchun Wang, Shilpa Rao, Jan Pawlicki, Nashwa Mansoor, James L. Riley, Reza Nejati, Wasik A. Mariusz. Crosstalk between histone and DNA methylation in the development and progression of ALK+ ALCL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7015.

Abstract P32: CAR-NK Specific Targeting of Clonal TCRVβ Chain to Treat T-cell Non-Hodgkin's Lymphoma

Abstract P32: CAR-NK Specific Targeting of Clonal TCRVβ Chain to Treat T-cell Non-Hodgkin's Lymphoma

T-cell non-Hodgkin lymphoma of lymphoblastic type revealed by a chronic swollen testicle managed in the urology department of Laquintinie Hospital in Douala, Cameroon

Background: Non-Hodgkin T-cell lymphomas typically develop in lymph node territories, and primary extra nodal locations are rare. The clinical presentation is nonspecific, dominated by signs of compression. Imaging aids in suspicion, and histology confirms the diagnosis. Clinical Observation: A 61-year-old patient initially hospitalized for the management of upper gastrointestinal bleeding six months ago was referred to the urology outpatient clinic due to a chronic swollen testicle persisting for a year. A non-contributory testicular ultrasound showed peri scrotal lymphedema with inguinal lymphadenopathy, right orchid epididymitis, and left epididymitis. Blood tests were normal. Despite antibiotic therapy, there was no improvement in the clinical condition. Physical examination revealed painless and mobile cervical, axillary, and inguinal lymph nodes. Pelvic MRI suspected a probable lymphoma. A lymph node biopsy in the left groin confirmed a non-Hodgkin T-cell lymphoma of lymphoblastic type infiltrating the capsule. The patient was transferred to haematology for further management. Conclusion: T-cell lymphoblastic lymphoma is primarily characterized by nodal involvement. There is a diagnostic delay that is anatomopathological in nature. Management involves polychemotherapy.

Cell-Free DNA as a Biomarker at Diagnosis and Follow-Up in 256 B and T-Cell Lymphomas.

Cell-free DNA (cfDNA) analysis has become a promising tool for the diagnosis, prognosis, and monitoring of lymphoma cases. Until now, research in this area has mainly focused on aggressive lymphomas, with scanty information from other lymphoma subtypes. We selected 256 patients diagnosed with lymphomas, including a large variety of B-cell and T-cell non-Hodgkin and Hodgkin lymphomas, and quantified cfDNA from plasma at the time of diagnosis. We further selected 49 large B-cell lymphomas (LBCL) and analyzed cfDNA levels at diagnosis (pre-therapy) and after therapy. In addition, we performed NGS on cfDNA and tissue in this cohort of LBCL. Lymphoma patients showed a statistically significant higher cfDNA concentration than healthy controls (mean 53.0 ng/mL vs. 5.6 ng/mL, p < 0.001). The cfDNA concentration was correlated with lymphoma subtype, lactate dehydrogenase, the International Prognostic Index (IPI) score, Ann Arbor (AA), and B-symptoms. In 49 LBCL cases, the cfDNA concentration decreased after therapy in cases who achieved complete response (CR) and increased in non-responders. The median cfDNA at diagnosis of patients who achieved CR and later relapsed was higher (81.5 ng/mL) compared with levels of those who did not (38.6 ng/mL). A concordance of 84% was observed between NGS results in tumor and cfDNA samples. Higher VAF in cfDNA is correlated with advanced stage and bulky disease. cfDNA analysis can be easily performed in almost all lymphoma cases. The cfDNA concentration correlated with the characteristics of the aggressiveness of the lymphomas and, in LBCL, with the response achieved after therapy. These results support the utility of cfDNA analysis as a complementary tool in the management of lymphoma patients.

Higher tumor mutational burden and PD-L1 expression correlate with shorter survival in hematologic malignancies.

The prognostic implications of tumor mutational burden (TMB) and programmed death ligand 1 (PD-L1) expression are poorly studied in hematologic malignancies. This study aimed to better understand the characteristics and prognostic value of TMB and PD-1/PD-L1 in hematologic malignancies. This real-world study was conducted among patients with hematologic malignancies who had next-generation sequencing (NGS) (Foundation Medicine) at the University of California San Diego Moores Cancer Center (2014-2018). TMB was measured by NGS. PD-L1 expression (tumor proportion score, TPS) was measured by immunohistochemistry (classified as high (⩾50%), low (1-49%), and negative (<1%)). Data was curated from the electronic medical records. In 388 evaluable patients, the most common diagnoses were B-cell non-Hodgkin lymphoma (NHL) (35%) and Philadelphia chromosome-negative myeloproliferative disorders (16%). Median TMB was 1.6 mutations/Mb (range, 0-46.83). Forty-eight patients (12%) had TMB ⩾10 mutations/Mb, 90% of which were B-cell or T-cell NHL. In 85 samples with available PD-L1 scores, 11 were high; 26, low; and 48, no tumor cell expression. PD-L1 TPS positive (⩾1%) was most common in T-cell NHL (7/9 (77%) cases) followed by B-cell NHL (21/51 (41%) cases). TMB ⩾4 mutations/Mb and PD-L1 score ⩾1% were significantly associated with shorter overall survival (OS) from diagnosis, with hazard ratio (HR) = 1.46 (p = 0.02, 95% confidence interval (CI) 1.05-2.03) and HR = 2.11 (p = 0.04, 95% CI 1.04-4.30), respectively; the relationship was more pronounced when PD-L1 ⩾50% versus <50% was used (HR = 2.80, p = 0.02, 95% CI 1.19-6.59). Higher TMB and higher PD-L1 positivity correlation were significant but weak (Pearson correlation coefficient R 2 = 0.04, p = 0.04). TMB ⩾4 mutations/Mb and positive PD-L1 TPS are poor prognostic factors, correlating with shorter OS across hematologic malignancies. ClinicalTrials.gov NCT02478931.

A Rare Case of Primary Bone Lymphoma Masquerading as Langerhans Cell Histiocytosis

Anaplastic Large Cell Lymphoma (ALCL) is an uncommon type of Non Hodgkin Lymphoma (NHL). It commonly arises in lymph nodes and can also involve extranodal sites such as the skin, soft tissues, lungs, bones, and liver. Here, a case of Anaplastic Lymphoma Kinase (ALK)-positive ALCL in a 17-year-old male patient who presented with swelling in the frontal and occipital bones is presented. The patient was clinically and radiologically diagnosed with Langerhans Cell Histiocytosis (LCH), and excision of the occipital lesion was performed. Preoperatively, lymphoma was not considered a differential diagnosis. Detailed histopathological examination, immunohistochemistry, and Positron Emission Tomography (PET) scan confirmed the diagnosis of primary bone ALK-positive ALCL. This T-cell NHL is composed of large lymphoid cells with abundant cytoplasm and pleomorphic horseshoe or kidney-shaped nuclei, with characteristic ALK and CD30 positivity. An isolated presentation of ALCL as a primary lesion in the bone is extremely rare. Clinicians and pathologists should be aware of this rare presentation, as prompt diagnosis and proper treatment can lead to favourable outcomes.

Epstein-Barr virus-associated lymphomas decoded.

Epstein-Barr virus (EBV)-associated lymphomas cover a range of histological B- and T-cell non-Hodgkin and Hodgkin lymphoma subtypes. The role of EBV on B-cell malignant pathogenesis and its impact on the tumour microenvironment are intriguing but incompletely understood. Both the International Consensus Classification (ICC) and 5th Edition of the World Health Organization (WHO-HAEM5) proposals give prominence to the distinct clinical, prognostic, genetic and tumour microenvironmental features of EBV in lymphoproliferative disorders. There have been major advances in our biological understanding, in how to harness features of EBV and its host immune response for targeted therapy, and in using EBV as a method to monitor disease response. In this article, we showcase the latest developments and how they may be integrated to stimulate new and innovative approaches for further lines of investigation and therapy.

Особливості клінічного перебігу анапластичної крупноклітинної лімфоми в дітей. Клінічний випадок

Anaplastic large cell lymphoma (ALCL) is a rare type of T-cell non-Hodgkin lymphoma with a characteristic primary localized, mainly extra-bone marrow tumor growth of lymphoid tissue, the clinical picture of which includes lesions of peripheral lymph nodes and extranodal organs, such as bones, skin, lungs, liver, muscles which tissues and bone marrow. Purpose - to acquaint practicing doctors with the features of clinical manifestations, differential diagnosis and course of ALCL in children. Features of the clinical course of ALCL in a child are described. The main diagnostic value of the anamnesis, clinical picture, laboratory, instrumental, immunohistochemical and microscopic research methods, in particular trepan biopsy of this tumor, is highlighted. Microscopic examination of the tissue trepanbioptate show that in half of the cells of the bone marrow, its normal structure is revealed, hematopoietic bone marrow is present with the preservation of all sprouts, with a slightly increased number of megakaryocytes. Half of the cells are filled with solid layers of sharply atypical lymphocyte-like cells with a moderate amount of eosinophilic cytoplasm, the nuclei of tumor cells are large, vesicular, with the formation of 1-2 basophilic nuclei. In the tumor cells there are figures of mitosis, including atypical ones. Single hematopoietic cells of various germs are found between these cells. The conducted immunohistochemical study of tumor cells show that they are positive for common leukocyte antigen (CD4), negative for common cytokeratins, S-100, myogenin, MuoD1, which indicates their hematopoietic origin. Upon further examination, the tumor cells were positive for CD 30, negative for CD3, CD20, CD 43, CD 68, CD11c, tdt, myeloperoxidase, CD 1a. Staining for CD246 reveals a granular cytoplasmic reaction in tumor cells. The histological pattern and immunophenotype of tumor cells correspond to ALCL. The research was carried out in accordance with the principles of the Helsinki Declaration. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the authors.

Incidental Bystander or Essential Culprit: A Systematic Review of Bacterial Significance in the Pathogenesis of Breast Implant-Associated Anaplastic Large Cell Lymphoma.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a distinct subtype of T-cell non-Hodgkin lymphoma that arises in the context of prolonged exposure to textured breast implants. The intent of this manuscript is to explore whether the bacterial presence in biofilms on these implants is a mere incidental finding or plays a pivotal role in the pathogenesis of BIA-ALCL. Our goal is to delineate the extent of bacterial involvement, offering insights into potential underlying mechanisms, and establishing future research priorities aimed at resolving the remaining uncertainties surrounding this complex association. A comprehensive systematic review of several databases was performed. The search strategy was designed and conducted by an experienced librarian using controlled vocabulary with keywords. The electronic search identified 442 publications. After evaluation, six studies from 2015 to 2021 were included, encompassing 201 female patients aged 23 to 75. The diagnosis span post-implantation ranged from 53 to 135.6 months. Studies consistently found bacteria near breast implants in both BIA-ALCL cases and controls, with varied microbial findings. Both BIA-ALCL cases and controls exhibited the presence of specific bacteria, including Pseudomonas aeruginosa, Klebsiella oxytoca, Staphylococcus aureus, and Ralstonia spp., without any statistically significant differences between groups. The use of antiseptic and antimicrobial agents during implant insertion did not demonstrate any impact on reducing or altering the risk of developing BIA-ALCL. Our systematic review reveals that the current evidence is inadequate to link bacterial etiology as a central factor in the development of BIA-ALCL. The limitations in the existing data prevent a complete dismissal of the role of biofilms in its pathogenesis. The observed gap in knowledge underscores the need for more focused and comprehensive research, which should be structured in a multi-faceted approach. Initially, this involves the utilization of sophisticated genomic and proteomic methods. Following this, it is crucial to delve into the study of immunological reactions specifically induced by biofilms. Finally, this research should incorporate extended observational studies, meticulously tracking the evolution of biofilm development and its correlation with the emergence of BIA-ALCL. In light of the inconclusive nature of current findings, further investigation is not only justified but urgently needed to clarify these unresolved issues.

Intraoperative pathologic diagnosis of central nervous system lymphomas: A comparison of frozen and permanent section diagnoses, and the significance of preoperative imaging

BackgroundCentral nervous system (CNS) lymphomas, either primary or secondary in origin, are rare malignant tumors affecting the brain, spinal cord, or leptomeninges. Diagnosis of CNS lymphomas is complicated by their diverse clinical presentations, radiological features, and histopathological characteristics. Although frozen section (FS) analysis is commonly employed for various CNS tumors, its role and accuracy in CNS lymphoma diagnosis are less explored. In this study, we conducted a comparative analysis to assess the impact of knowledge of preoperative imaging on enhancing the accuracy of FS diagnosis in CNS lymphomas. MethodsData collection involved a retrospective review of CNS lymphoma patients from January 2009 to August 2021. Patients who underwent intraoperative consultation were included, excluding those with prior cortisone treatment. The dataset incorporated patient demographics, classification as primary or secondary lymphoma, radiological preliminary diagnoses, FS diagnosis, and permanent section diagnosis. We employed various archived materials, including FSs, touch imprint slides, crush cytology slides, H&E-stained sections, and immunohistochemical stains, and re-evaluated all slides for diagnostic validation. ResultsOur study included 25 patients, of whom 60 % were female and had a mean age of 56.5 years. Preoperative radiology data were available for 80 % of cases, with preliminary diagnoses commonly including lymphoma and/or metastasis. Intraoperative consultation results indicated lymphoma in 18 (72 %) patients, with discordance observed in 28 % of cases when compared to permanent section diagnoses. Most permanent section diagnoses were diffuse large B-cell lymphomas (92 %), with the remainder being T-cell non-Hodgkin lymphoma (4 %) and follicular lymphoma (4 %). Intraoperative misdiagnoses were significantly associated with the absence of knowledge of preoperative imaging. ConclusionOur study demonstrates the reliability of FS diagnosis for CNS lymphomas during surgery, with a favorable complete concordance rate of 72 % when compared to permanent diagnoses. Importantly, lack of knowledge of preoperative imaging significantly impaired diagnostic accuracy in FS, emphasizing the need for close collaboration between pathologists and radiologists.