[Interpretation of lymphoid proliferations and lymphomas associated with immune deficiency and dysregulation in the 5th edition WHO classification of haematolymphoid tumours].

The fifth edition of the World Health Organization (WHO) classification of lymphohematopoietic system tumors updated the terminology, types of lesions, diagnostic criteria, nomenclature, and other aspects of lymphoid proliferations and lymphomas associated with immune deficiency and dysregulation. The important updates and main changes in this section were briefly introduced, in order to guide the precise classification of lymphoid proliferations and lymphomas associated with immune deficiency and dysregulation, and standardize pathological reports.

[CAR T-cell therapy for malignant lymphoma].

Advances in understanding of the pathogenesis of B-cell lymphoma have led to development of various novel targeted therapies. Among them, CD19-targeted chimeric antigen receptor (CAR) T-cell therapies for relapsed and refractory B-cell lymphomas have shown remarkable efficacy in clinical trials, and three CAR T-cell products are now available in Japan. Real-world evidence (RWE) has shown that these products can provide comparable efficacy to clinical trials in clinical practice, where CAR T-cells were administered in patients with wider range of backgrounds. This finding will certainly broaden the role of CAR T-cell therapies in the treatment of B-cell lymphoma. However, since about half of the patients treated with CAR T-cell therapy progress thereafter, there is an urgent need for risk stratification and optimized management of refractory cases. Here, we review the results of clinical trials and RWE of CAR T-cell therapy in B-cell lymphoma.

[Cancer genomic panels for lymphoid malignancies].

Cancer precision medicine (genome-based individualized treatment for cancer patients) has already been introduced for solid tumors, and involves identifying driver genes in the development and progression of tumors and suggesting optimal treatments targeting those genes. So far, many patients have received this style of treatment. Meanwhile, preparations for cancer genomic medicine based on cancer gene panel testing are also underway for hematopoietic tumors. In this article, I would like to share fundamental information about the main genetic mutations in malignant lymphomas and their clinical significance, and discuss how this information should be utilized in cancer genomic medicine in the future.

The National Swedish Lymphoma Register - a systematic validation of data quality.

BACKGROUND AND PURPOSE: The Swedish Lymphoma Register (SLR) was initiated in the year 2000 with the aim to monitor quality of care in diagnostics, treatment and outcome of all lymphomas diagnosed nationally among adults. Here, we present the first systematic validation of SLR records as a basis for improved register quality and patient care. PATIENTS AND METHODS: We evaluated timeliness and completeness of register records among patients diagnosed with lymphoma in the SLR (n = 16,905) compared with the National Cancer Register for the period 2013-2020. Comparability was assessed through evaluation of coding routines against national and international guidelines. Accuracy of 42 variables was evaluated through re-abstraction of data from medical records among 600 randomly selected patients diagnosed in 2016-2017 and treated across all six Swedish healthcare regions.  Results: Completeness was high, >95% per year for the period 2013-2018, and >89% for 2019-2020 compared to the National Cancer Register. One in four patients was registered within 3 months, and 89.9% within 2 years of diagnosis. Registration instructions and coding procedures followed the prespecified guidelines. Missingness was generally low (<5%), but high for occasional variables, for example, those describing maintenance and consolidative treatment. Exact agreement of categorical variables was high overall (>80% for 24/34 variables), especially for treatment-related data (>80% for 17/19 variables). INTERPRETATION: Completeness and accuracy are high in the SLR, while timeliness could be improved. Finetuning of variable registration guided by this validation can further improve reliability of register reports and advance service to lymphoma patients and health care in the future.

Clinical, Pathological and Immunohistochemical Characteristics of Patients with Primary Testicular Lymphoma Undergoing Orchiectomy: A Systematic Review and Meta-Analysis.

BACKGROUND: Primary testicular lymphoma (PTL) is a rare and aggressive malignant tumour with no specific clinical symptoms. Large-scale evidence-based medical evidence to guide preoperative diagnosis is lacking at present. This study aimed to analyse the clinical, pathological and immunohistochemical characteristics of patients with PTL undergoing testicular resection surgery. METHODS: Literature on the clinical characteristics of patients with PTL undergoing orchiectomy was retrieved from databases, including PubMed, Web of Science, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI) and Wanfang Data. The search covered all available records from the inception of these databases until December 31, 2023. Data extraction was followed by a meta-analysis using Stata 15.0 software. RESULTS: A total of 22 articles and 475 cases of PTL were included. The meta-analysis revealed that 58.1% of patients with PTL undergoing orchiectomy were under 60 years old, and 41.9% were 60 years or older. The lesion is mostly located on the right side (55.1%). Common symptoms included testicular swelling and falling swelling (91.3%), hydrocele testis (31.0%) and testicular pain (23.0%). Ann Arbor stages I-IV accounted for 53.3%, 16.7%, 14.8% and 15.7%, respectively. Diffuse large B-cell lymphoma (DLBCL) cases were higher at 95.5% than NK/T-cell lymphoma cases at 8.2%. Amongst DLBCL cases, 69.3% were non-germinal centre B-cell (GCB) subtype, and 27.6% were GCB subtype. Immunohistochemistry markers showed 95.9% CD3 negative, 94.9% CD10 negative, 94.4% CD20 positive, 88.4% multiple myeloma oncogene-1 (MUM-1) negative, 73.6% B-cell lymphoma-6 (BCL-6) negative and 66.5% BCL-2 positive. Laboratory findings indicated that 70.4% of patients had a tumour proliferating cell nuclear antigen (Ki67) index of ≥80%, 36.0% had increased serum lactate dehydrogenase level and 22.9% had increased serum ß2-microglobulin level. CONCLUSIONS: PTL is rare, and it often occurs in elderly male patients. Common symptoms include testicular swelling and falling swelling, and the common histological type is DLBCL. Diagnosis should be based on histopathological characteristics and immunohistochemical examination.

Mitigating the impact of image processing variations on tumour [18F]-FDG-PET radiomic feature robustness.

Radiomics analysis of [18F]-fluorodeoxyglucose ([18F]-FDG) PET images could be leveraged for personalised cancer medicine. However, the inherent sensitivity of radiomic features to intensity discretisation and voxel interpolation complicates its clinical translation. In this work, we evaluated the robustness of tumour [18F]-FDG-PET radiomic features to 174 different variations in intensity resolution or voxel size, and determined whether implementing parameter range conditions or dependency corrections could improve their robustness. Using 485 patient images spanning three cancer types: non-small cell lung cancer (NSCLC), melanoma, and lymphoma, we observed features were more sensitive to intensity discretisation than voxel interpolation, especially texture features. In most of our investigations, the majority of non-robust features could be made robust by applying parameter range conditions. Correctable features, which were generally fewer than conditionally robust, showed systematic dependence on bin configuration or voxel size that could be minimised by applying corrections based on simple mathematical equations. Melanoma images exhibited limited robustness and correctability relative to NSCLC and lymphoma. Our study provides an in-depth characterisation of the sensitivity of [18F]-FDG-PET features to image processing variations and reinforces the need for careful selection of imaging biomarkers prior to any clinical application.

Computed tomography-based radiomics combined with machine learning allows differentiation between primary intestinal lymphoma and Crohn's disease.

BACKGROUND: Due to similar clinical manifestations and imaging signs, differential diagnosis of primary intestinal lymphoma (PIL) and Crohn's disease (CD) is a challenge in clinical practice. AIM: To investigate the ability of radiomics combined with machine learning methods to differentiate PIL from CD. METHODS: We collected contrast-enhanced computed tomography (CECT) and clinical data from 120 patients form center 1. A total of 944 features were extracted single-phase images of CECT scans. Using the last absolute shrinkage and selection operator model, the best predictive radiographic features and clinical indications were screened. Data from 54 patients were collected at center 2 as an external validation set to verify the robustness of the model. The area under the receiver operating characteristic curve, accuracy, sensitivity and specificity were used for evaluation. RESULTS: A total of five machine learning models were built to distinguish PIL from CD. Based on the results from the test group, most models performed well with a large area under the curve (AUC) (> 0.850) and high accuracy (> 0.900). The combined clinical and radiomics model (AUC = 1.000, accuracy = 1.000) was the best model among all models. CONCLUSION: Based on machine learning, a model combining clinical data with radiologic features was constructed that can effectively differentiate PIL from CD.

Tethered IL15-IL15Rα augments antitumor activity of CD19 CAR-T cells but displays long-term toxicity in an immunocompetent lymphoma mouse model.

BACKGROUND: Adoptive cell therapy using genetically modified T cells to express chimeric antigen receptors (CAR-T) has shown encouraging results, particularly in certain blood cancers. Nevertheless, over 40% of B cell malignancy patients experience a relapse after CAR-T therapy, likely due to inadequate persistence of the modified T cells in the body. IL15, known for its pro-survival and proliferative properties, has been suggested for incorporation into the fourth generation of CAR-T cells to enhance their persistence. However, the potential systemic toxicity associated with this cytokine warrants further evaluation. METHODS: We analyzed the persistence, antitumor efficacy and potential toxicity of anti-mouse CD19 CAR-T cells which express a membrane-bound IL15-IL15Rα chimeric protein (CD19/mbIL15q CAR-T), in BALB/c mice challenged with A20 tumor cells as well as in NSG mice. RESULTS: Conventional CD19 CAR-T cells showed low persistence and poor efficacy in BALB/c mice treated with mild lymphodepletion regimens (total body irradiation (TBI) of 1 Gy). CD19/mbIL15q CAR-T exhibits prolonged persistence and enhanced in vivo efficacy, effectively eliminating established A20 B cell lymphoma. However, this CD19/mbIL15q CAR-T displays important long-term toxicities, with marked splenomegaly, weight loss, transaminase elevations, and significant inflammatory findings in some tissues. Mice survival is highly compromised after CD19/mbIL15q CAR-T cell transfer, particularly if a high TBI regimen is applied before CAR-T cell transfer. CONCLUSION: Tethered IL15-IL15Rα augments the antitumor activity of CD19 CAR-T cells but displays long-term toxicity in immunocompetent mice. Inducible systems to regulate IL15-IL15Rα expression could be considered to control this toxicity.

Gonadotropic Axis, Bone Mass, and Sarcopenia Assessment After Autologous Hematopoietic Stem Cell Transplantation for Lymphoma.

Gonadal dysfunction, the most frequent endocrine complication in both sexes after autologous hematopoietic cell transplant (HCT) could increase bone loss and sarcopenia, a disease characterized by reduced muscle strength and mass. Sarcopenia is associated with worse survival, lower remission rates, and progression-free survival in patients with lymphoma after HCT. Low bone mass affected approximately 20% of the transplanted patients within 2 years and harms quality of life. This study was conducted in a single center and identified a strong relationship with patients transplanted more recently by LEC (lomustine, etoposide, and cyclophosphamide) conditioning regimen with sarcopenia. Peripheral neuropathy and bone mass changes were also associated with sarcopenia as well, suggesting a relationship with muscle strength loss.

Early progression during or after cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy indicates poor outcome with rescue protocols in dogs with multicentric lymphoma.

BACKGROUND: Dogs with lymphoma that fail cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy (CHOP) before completion of their protocol are commonly thought to have poor long-term outcome, but no previous studies have evaluated the effect of early relapse on progression-free interval (PFI) or overall survival time (OST) for patients undergoing rescue chemotherapy. OBJECTIVE: Correlate rescue treatment outcomes in dogs with multicentric lymphoma with outcomes after 1st-line CHOP chemotherapy. METHODS: Data were collected from 6 previous retrospective or prospective studies in 187 dogs with multicentric lymphoma that received 1st-line CHOP chemotherapy and then received either lomustine (CCNU), L-asparaginase and prednisone (LAP), or rabacfosadine (RAB, Tanovea), with or without prednisone or L-asparaginase. RESULTS: The PFI after initiation of CHOP chemotherapy was significantly associated with response rate postprogression, PFI, and postrescue survival time (ST) for both rescue protocols. Immunophenotype (B- vs T-cell) was not significantly associated with response, PFI or OST for LAP but was significantly associated with response and PFI for RAB. CONCLUSION: Dogs that experience short PFI during or after 1st-line CHOP chemotherapy had lower response rates to rescue treatment, with shorter PFI and ST. Immunophenotype did not significantly affect outcome with LAP but was associated with PFI for RAB.

ETS1 Function in Leukemia and Lymphoma.

ETS proto-oncogene 1 (ETS1) is a transcription factor (TF) critically involved in lymphoid cell development and function. ETS1 expression is tightly regulated throughout differentiation and activation in T-cells, natural killer (NK) cells, and B-cells. It has also been described as an oncogene in a range of solid and hematologic cancer types. Among hematologic malignancies, its role has been best studied in T-cell acute lymphoblastic leukemia (T-ALL), adult T-cell leukemia/lymphoma (ATLL), and diffuse large B-cell lymphoma (DLBCL). Aberrant expression of ETS1 in these malignancies is driven primarily by chromosomal amplification and enhancer-driven transcriptional regulation, promoting the ETS1 transcriptional program. ETS1 also facilitates aberrantly expressed or activated transcriptional complexes to drive oncogenic pathways. Collectively, ETS1 functions to regulate cell growth, differentiation, signaling, response to stimuli, and viral interactions in these malignancies. A tumor suppressor role has also been indicated for ETS1 in select lymphoma types, emphasizing the importance of cellular context in ETS1 function. Research is ongoing to further characterize the clinical implications of ETS1 dysregulation in hematologic malignancies, to further resolve binding complexes and transcriptional targets, and to identify effective therapeutic targeting approaches.

Engraftment Syndrome in Autologous Hematopoietic Stem Cell Transplant Patients: Incidence, Associated Risk Factors, Features, and Outcomes.

BACKGROUND Autologous stem cell transplantation (ASCT) is the standard treatment for multiple myeloma (MM) and refractory/relapsed (R/R) lymphoma patients. Engraftment syndrome (ES) is a non-infectious febrile syndrome during ASCT. This study focused on the incidence, risk factors, manifestations, and outcomes of patients with ES receiving ASCT. MATERIAL AND METHODS This retrospective cohort study included MM and R/R lymphoma patients who underwent ASCT at Chiang Mai University Hospital from January 2014 to September 2020. ES was diagnosed by the consensus of independent reviewers based on clinical manifestations, laboratory, and radiological findings. RESULTS We included 124 patients, of whom 67 (54.1%) had lymphoma. The mean age was 48.0±12.3 years. The incidence of ES was 36.3%. The ES group had a significantly higher proportion of patients with fever, elevated liver enzymes, elevated bilirubin, hypoalbuminemia, and weight gain compared to the non-ES group. TNC more than 10×108 cells/kg was an independent risk factor for ES (odds ratio 2.94 with a 95% confidence interval of 1.15-7.50, P=0.024). ES was associated with longer length of stay (22.5±8.2 vs 16.9±6.4 days, P<0.001) but was not associated with overall survival (OS). CONCLUSIONS The incidence of ES in this cohort was 36.3%. Features observed in ES patients were fever, elevated liver enzymes, elevated bilirubin, and hypoalbuminemia. TNC of more than 10×108 cells/kg was an independent risk factor. ES was associated with longer length of stay but not survival outcomes.

THE MANAGEMENT OF LYMPHOPROLIFERATIVE NEOPLASIA IN FOUR NORTHERN SEA OTTERS (ENHYDRA LUTRIS KENYONI).

Lymphoproliferative neoplasia has been reported in both free-ranging sea otters and those in managed care, but little information is available on the management of this neoplastic disease in this species. This case series describes clinical lymphoma in four northern sea otters (Enhydra lutris kenyoni) in managed care. Two otters presented with Stage 5 lymphoma with evidence of hematologic spread resulting in leukemia. Two additional otters presented with Stage 3 disease. Immunophenotypes in these cases included disseminated large B-cell lymphoma and lymphoblastic lymphoma of potential T-cell origin. Cases were managed with multiagent chemotherapy protocols including prednisone, L-asparaginase, cyclophosphamide, vincristine, cytosine arabinoside, lomustine, and doxorubicin. Unique approaches included the use of a vascular access port in one case and development of an autologous vaccine in another. Survival time ranged from 81 to 409 days. Diagnosis, staging, and treatment with multiagent protocols is recommended for the management of lymphoma in sea otters.

Development and validation of nomograms to predict survival of primary cervical lymphoma: A surveillance, epidemiology, and end results (SEER) database analysis.

Due to the rarity of primary cervical lymphoma (PCL), the long-term survival of patients with cervical lymphoma and factors influencing survival are unknown. This study aimed to compare the survivals of patients with PCL and those with other cervical tumors and construct a clinical prediction model to assess the prognosis of patients with PCL. Patients with PCL from the Surveillance, Epidemiology, and End Results database were allocated randomly in a 7:3 ratio to the training and validation sets. Cox proportional hazard and Fine-Gray models were used to verify independent factors influencing overall survival (OS) and disease-specific survival (DSS), and nomograms were constructed. Receiver operating characteristic curve analysis and decision curve analysis (DCA) were used to test the performance and clinical utility of the models, respectively. We included 206 patients with PCL. The areas under the curves (AUCs) and DCA showed that all models had clinical benefits; The models constructed in this study had a predictive performance for patients with PCL. It can guide clinicians to rationalize the treatment plan for patients.

Non-neoplastic B-cell predominant lymphoid proliferations at the organs exposed to external environment mimicking lymphoma: A potential diagnostic pitfall.

Background: Typically, lymphatic tissue proliferative lesions include either benign lesions or lymphoma. However, not all lymphatic lesions can currently be accurately classified into one category, particularly in mucosal areas that are in contact with the external environment.Aims: To explore the morphology, immunophenotype, and molecular changes of Non-neoplastic B-cell predominant lymphoid proliferations (NBPLP) in pathological areas that are exposed to external surroundings which mimicked lymphoma.Methods and Results: 18 cases of Atypical lymphoid hyperplasia (AtLP)  were retrieved in this study. The biopsy samples were mucosal samples obtained from areas exposed to external surroundings, including intestines, urethra, cervix, tonsils, and tongue. Microscopically, there is a different level of B cell hyperplasia accompanied by morphological atypia. We categorized the morphology into 4 groups: type A (7/18), type B (3/18), type C (3/18), type D (5/18). Part of the AtLP was found positive for BCR gene rearrangement (6/15), and TCR gene rearrangement (1/4). The follow-up period ranged from 14.2 to 70 months. No evidence of lymphoma was found. Therefore, we diagnosed all of the presented cases as NBPLP. We illustrated the key differential points and provided valuable diagnostic experience on each subtype.Conclusions: Areas exposed to the external environment are commonly exposed to antigen and easily present with AtLP of NBPLP, accompanying with positive IGH rearrangement. Therefore, a comprehensive evaluation of macroscopic, morphology, immunophenotype, and molecular diagnostics is required to prevent the overdiagnosis of lymphoma.

A case of equine multicentric lymphoma: Clinical, microscopical, and molecular findings.

Background: Although relatively uncommon, lymphoma is the most prevalent haematopoietic neoplasia in horses, and multicentric lymphoma remains the most common presentation of the disease. The pathogenesis of equine lymphoma is still poorly understood and the diagnosis is usually confirmed at an advanced stage of the disease, compromising the prognosis. This study investigated the clinical, pathological, and molecular features of a case of equine multicentric lymphoma. Case Description: An apparently healthy 5-year-old crossbreed mare hospitalized at the Centre of Animal Reproduction of Vairão, Portugal, suddenly presented clinical signs of supraorbital oedema and mandibular lymph node enlargement, developing fever, facial oedema, and generalized lymphadenopathy. The mare ended up dying twenty-four days after the first clinical signs due to multisystem organ failure. Haematological and biochemical analyses, necropsy, and microscopic and molecular evaluation of affected tissues were performed. At necropsy, the main findings were multiple multinodular lesions, distributed along the serous surface of oropharynx, trachea, pericardium, gastrointestinal tract, and mesentery. Microscopically, these consisted of solid proliferations of neoplastic round cells that exhibited immunopositivity for CD3 (T cells). Based on these findings, a medium-grade multicentric T-cell lymphoma was diagnosed. Conclusion: There is still very little research regarding the molecular characterization of lymphoma in horses. As an entity itself is quite heterogeneous, it is important to describe the interspecies particularities to understand its development and behaviour.

Lymphoma for the acute physician: diagnostic challenges and initial treatment decisions.

Prompt diagnosis of lymphoma facilitates early treatment and improves outcomes for patients. For non-haemato-oncologists, it is important to have an understanding of how lymphoma can present and the initial work-up. This review is intended to provide clinicians with background to aid clinical decisional making at presentation and when managing treatment related complications. There will be particular emphasis on emergency presentations (tumour lysis syndrome, management of patients with a mediastinal mass, infections in lymphoma patients) and novel treatment options which have unique toxicities often requiring multi-specialty expertise.