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Lymph cancer, also known as lymphoma, refers to the uncontrolled proliferation of the body's defensive cells, resulting in their transformation into cancerous cells. Lymphoma belongs to the group of blood cancers and exhibits a higher incidence compared to other cancers within this category. Early and accurate diagnosis plays a crucial role in managing this disease. In this particular investigation, an expert support system was developed employing histopathological images of lymph cancer. The data set comprised images of various lymphomas, including chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), and mantle cell lymphoma (MCL). The initial approach involved utilizing the GLCM method to extract features from these images, while subsequent approaches adopted transfer learning architectures. Additionally, principal component analysis was employed for feature selection and dimension reduction. For the classification stage, a combination of machine learning algorithms such as random forests, k-nearest neighbors (KNN), naive Bayes, and decision trees, as well as deep learning methods including VGG16, ResNet50, and DenseNet201 architectures were employed. The models were trained separately for double and triple classes, and their performance was evaluated. The highest accuracy values in binary classification are: 94% for CLL and FL, 92% for FL and MCL, and 82% for MCL and CLL. In triple classification, the highest accuracy rate is 82%. The lowest accuracy values in binary classification are: 52% for CLL and FL, 57% for FL and MCL, and 49% for MCL and CLL. The methods by which these accuracy values were obtained are stated in "Results" section. However, due to the difficulty in distinguishing between MCL- and CLL-type lymphomas, the classification accuracy for these lymphomas was lower compared to the other classifications. On the other hand, the classification accuracy for FL was higher, as it exhibits more distinctive features than the other two lymphomas. The lowest success in the study was achieved at 36% as a result of the use of the KNN algorithm in triple classification. Notably, the DenseNet201 method achieved the highest success in the study, accurately classifying FL and CLL with a 94% accuracy rate. [ABSTRACT FROM AUTHOR]

Summary: Autologous chimeric antigen receptor (CAR) T‐cell therapy has revolutionized the treatment of lymphoid malignancies, leading to the approval of CD19‐CAR T cells for B‐cell lymphomas and acute leukaemia, and more recently, B‐cell maturation antigen‐CAR T cells for multiple myeloma. The long‐term follow‐up of patients treated in the early clinical trials demonstrates the possibility for long‐term remission, suggesting a cure. This is associated with a low incidence of significant long‐term side effects and a rapid improvement in the quality of life for responders. In contrast, other types of immunotherapies require prolonged treatments or carry the risk of long‐term side effects impairing the quality of life. Despite impressive results, some patients still experience treatment failure or ultimately relapse, underscoring the imperative to improve CAR T‐cell therapies and gain a better understanding of their determinants of efficacy to maximize positive outcomes. While the next‐generation of CAR T cells will undoubtingly be more potent, there are already opportunities for optimization when utilizing the currently available CAR T cells. This review article aims to summarize the current evidence from clinical, translational and fundamental research, providing clinicians with insights to enhance their understanding and use of CAR T cells. [ABSTRACT FROM AUTHOR]

This study used COTA de-identified data (2010–2021) of patients in the US to explore outcomes of novel therapies in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) in real-world settings. Demographics, clinical characteristics, and clinical outcomes of patients with R/R DLBCL who received novel treatments including chimeric antigen receptor T-cell (CAR T) therapy and tafasitamab- or polatuzumab-based therapies were evaluated. Overall, 175 patients with R/R DLBCL were analyzed; 73, 69, and 27 received CAR T therapy, polatuzumab-based regimens, and tafasitamab-based regimens, respectively. In patients who had ≥1 prior lines of therapy (i.e. starting second-line or later therapy; 2 L+), CAR T, polatuzumab-based regimens, and tafasitamab-based regimens achieved a median overall survival of 26.5, 7.8, and 6.3 months, respectively. Outcomes were particularly poor for patients with relapse following CAR T, indicating that polatuzumab- and tafasitamab-based regimens in 2 L + R/R DLBCL have suboptimal outcomes in the real world. Additional treatment options are needed. [ABSTRACT FROM AUTHOR]

The prevalence of frailty in clinical trials of lymphoma is unknown. We conducted a secondary analysis of the phase III LY.12 trial in which patients with relapsed aggressive non-Hodgkin lymphoma were randomized to different salvage regimens before autologous stem cell transplant. The primary objective was to construct a lymphoma clinical trials-specific frailty index (LyFI) using previously described methods. The secondary objective was to describe the association of frailty withover all and event-free survival (OS, EFS). The LyFI was constructed using 619 patients, and11% (N = 70) were classified as frail. Frailty was associated with EFS (HR 1.94, 95%CI 1.53–2.46) and OS (HR 2.01, 95%CI 1.57–2.58) in univariable analysis, but was only significant as a continuous (not binary) variable in multivariable analysis controlling for prognostic score, suggesting limitations of a FI in this trial population. Future work could validate the FI using clinical assessments and/or apply it to an older trial population. [ABSTRACT FROM AUTHOR]

Pediatric ALK-positive anaplastic large cell lymphoma is a rare subtype of non-Hodgkin lymphoma, and approximately 30% of patients relapse following treatment with conventional chemotherapy. Alectinib monotherapy has demonstrated excellent activity in relapsed and refractory ALCL, but its role as a maintenance therapy after hematopoietic cell transplantation is unclear. We experienced a relapse case of pediatric ALK-positive ALCL with central nervous system involvement treated with alectinib maintenance therapy following cord blood transplantation. The patient has maintained complete remission for more than 3 years after transplantation. There were no remarkable adverse effects that led to discontinuation of alectinib. [ABSTRACT FROM AUTHOR]

Unlike small molecule drugs and generic products, the active component of biologics and biosimilars are not identical chemical entities. Despite bioequivalence, there is limited evidence in clinical practice (i.e. Phase IV post-marketing surveillance) regarding the safety of biosimilar rituximab and even less so for "switching therapy" with respect to safety. Drug substitution by switching aims to realise cost savings by changing therapy involving a reference (biologic) product to a biosimilar. A retrospective analysis of safety outcomes including treatment-emergent adverse effects (TEAEs), rates of death and discontinuation of therapy, for all patients that received switching therapy (from reference to biosimilar rituximab, n = 33) was compared to patients who did not did not switch therapy (received biosimilar rituximab only, n = 18) at an Australian metropolitan cancer centre, over a six-month period. There was no statistical significant differences for any safety outcomes examined. Switching therapy for patients receiving rituximab does not lead to poorer safety outcomes. [ABSTRACT FROM AUTHOR]

Diffuse large B-cell lymphoma (DLBCL), the most common non-Hodgkin's lymphoma (NHL), is substantially heterogeneous. Approximately 5–10% of DLBCLs express CD5, which makes CD5+ DLBCL a rare subgroup. Different studies have shown that CD5+ DLBCL patients are often older and female and have higher lactate dehydrogenase levels, an Eastern Cooperative Oncology Group (ECOG) performance status > 1, and higher International Prognostic Index (IPI) scores. Moreover, patients often have advanced stage disease with a high incidence of central nervous system (CNS) relapse and bone marrow involvement. CD5+ DLBCL cells are more likely to express MYC, BCL-2, and MUM-1, less likely to express CD10, and most belong to the activated B-cell-like (ABC) subtype. The potential mechanisms underlying the poor prognosis of CD5+ DLBCL patients may be related to CD5-mediated B-cell receptor (BCR)-dependent and -independent pathways. The efficacy of the traditional rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) regimen is unsatisfactory in CD5+ DLBCL patients. Despite supporting evidence from retrospective studies, it is currently unclear whether dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus rituximab (DA-EPOCH-R) can improve outcomes in this population. Several new drugs, such as Bruton tyrosine kinase inhibitors (BTKi), BCL-2 inhibitors, and CXCR4 antagonists, as well as immunotherapy, may help to improve the prognosis of CD5+ DLBCL patients, but additional clinical explorations are needed to determine the optimal therapeutic strategy for this disease. [ABSTRACT FROM AUTHOR]

Vincristine-induced peripheral neuropathy (VIPN) is an adverse effect of regimens used for the treatment of aggressive B-cell non-Hodgkin lymphoma (B-NHL). A single-nucleotide polymorphism (SNP) in the promotor region of the CEP72 gene has been identified as risk factor for the development of VIPN in children. To validate these results in adults we aimed to determine the association of the high-risk CEP72 (rs924607 TT genotype) with the occurrence and severity of VIPN. Analysis of SNP rs924607 (TT, CC or CT) was performed in all enrolled patients with available blood samples with a TaqMan genotyping assay. Rates and grades of VIPN were assessed prospectively as part of the RICOVER-60 trial. CEP72 genotype could be assessed in 519 patients. VIPN data was available for 499/519 patients who were included in the final analysis. 286 (57%) patients developed VIPN of any grade during treatment. Grade 2–4 VIPN occurred in 33% (166/499) of patients. The high-risk CEP72 TT genotype at rs924607 was identified in 97/499 (19%) patients. The TT genotype was not correlated with VIPN in the overall study population compared to patients with either CC or CT genotypes (p = 0.748). However, in the subgroup of female patients, the TT genotype was associated with increased occurrence of any-grade VIPN as well as grade 2–4 VIPN as compared to patients with either CC or CT genotypes (p = 0.016 and p = 0.020, respectively). Thus, the SNP rs924607 in the CEP72 gene is associated with increased VIPN incidence in female patients with aggressive B-NHL treated with CHOP chemotherapy. Trial registration ClinicalTrials.gov identifier: NCT00052936, submission date: 2005-06-23, EudraCT Number: 2010-019587-36. [ABSTRACT FROM AUTHOR]

Bendamustine in combination with rituximab (BR) or with rituximab and cytarabine (R-BAC) is the standard first-line immunochemotherapy in mantle cell lymphoma (MCL) for elderly patients and patients ineligible for intensive regimens or autologous transplantation. As bendamustine causes prolonged lymphopenia and the literature lacks evidence of its persistence in patients with MCL, this retrospective analysis aims to estimate the lymphocyte recovery time, also in view of potential immunotherapy with CAR-T cells. Data were collected from 44 consecutive MCL patients who received bendamustine (BR or R-BAC) as first-line therapy at the Hematology Unit of Sapienza University Hospital between May 2011 and April 2022. Twenty patients (45%) were treated with R-BAC and 24 (55%) with BR. At baseline, the median lymphocyte count was 1795/µl (range: 370–11730/µL). One month after the end of therapy, it was 450/µl (range: 50–3300/µl) and 3 months after 768/µl (range: 260–1650/µl). After 6 and 9 months, we observed a gradual increase in median lymphocyte count of 900/µl (range: 370–2560/µl and 130–2770/µl, respectively). After 12 months median lymphocyte count was 1256/µl (range: 240–4140/µl). Median lymphocyte count at 1, 3, 6, and 9 months post-treatment was significantly lower than baseline but showed recovery by the 12 months. This finding is crucial for MCL patients considering CAR-T cell therapy, suggesting a minimum 9-month interval between bendamustine administration and leukapheresis. [ABSTRACT FROM AUTHOR]

BACKGROUND. Most GWAS of plasma proteomics have focused on White individuals of European ancestry, limiting biological insight from other ancestry-enriched protein quantitative loci (pQTL). METHODS. We conducted a discovery GWAS of approximately 3,000 plasma proteins measured by the antibody-based Olink platform in 1,054 Black adults from the Jackson Heart Study (JHS) and validated our findings in the Multi-Ethnic Study of Atherosclerosis (MESA). The genetic architecture of identified pQTLs was further explored through fine mapping and admixture association analysis. Finally, using our pQTL findings, we performed a phenome-wide association study (PheWAS) across 2 large multiethnic electronic health record (EHR) systems in All of Us and BioMe. RESULTS. We identified 1,002 pQTLs for 925 protein assays. Fine mapping and admixture analyses suggested allelic heterogeneity of the plasma proteome across diverse populations. We identified associations for variants enriched in African ancestry, many in diseases that lack precise biomarkers, including cis-pQTLs for cathepsin L (CTSL) and Siglec-9, which were linked with sarcoidosis and non-Hodgkin's lymphoma, respectively. We found concordant associations across clinical diagnoses and laboratory measurements, elucidating disease pathways, including a cis-pQTL associated with circulating CD58, WBC count, and multiple sclerosis. CONCLUSIONS. Our findings emphasize the value of leveraging diverse populations to enhance biological insights from proteomics GWAS, and we have made this resource readily available as an interactive web portal. FUNDING. NIH K08 HL161445-01A1; 5T32HL160522-03; HHSN268201600034I; HL133870. [ABSTRACT FROM AUTHOR]

The phosphatidylinositol 3‑kinase/protein kinase B (PI3K/AKT) signaling pathway is critically active in many cell types, both normal and neoplastic. Many small-molecule inhibitors targeting different levels of the PI3K/AKT pathway have been developed for cancer therapy, but their efficacy is reduced by compensatory pathway re-activation mechanisms, and their tolerability by toxic side effects. We studied this problem using cell lines representing diffuse large B-cell lymphoma (SUDHL-4 and OCI-Ly7), a genetically-encoded live-cell reporter of AKT activity, and 3 small-molecule inhibitors targeting different levels of the pathway: idelalisib (PI3Kδ), GSK2334470 (PDPK1), and ipatasertib (AKT). Half-maximal (IC50) concentrations of these inhibitors for AKT activity inhibition at 1 h, when used individually, were much lower than their IC50 values for reduction of viable cell number after 4 days. Time-course studies explained this discrepancy: AKT activity in the continuous presence of the inhibitors returned to normal after 24 h, and was supranormal after inhibitor removal. Combining all 3 inhibitors produced sustained inhibition of AKT activity, was broadly synergistic at reducing viable cell number, enabled substantially lower doses of each inhibitor to be used, and was enhanced further by the mTOR inhibitor rapamycin. Moreover, combined PDPK1 and AKT inhibition showed synergy with multiple different PI3K inhibitors. In a syngeneic mouse cell line model of lymphoma (A20), the triple combination showed antitumor activity and no evidence of toxicity. Our findings provide proof of concept suggesting further study of the safety and efficacy of low-dose multilevel PI3K/AKT pathway inhibition, for lymphoma and perhaps other cancers. [ABSTRACT FROM AUTHOR]

Odronextamab, a CD20×CD3 bispecific antibody that engages cytotoxic T cells to destroy malignant B cells, has demonstrated encouraging activity across multiple subtypes of relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma. This phase II study (ELM-2; NCT03888105) evaluated odronextamab in patients with R/R follicular lymphoma after two or more lines of systemic therapy. Patients received intravenous odronextamab in 21-day cycles, with step-up dosing in cycle 1 to help mitigate the risk of cytokine release syndrome, until disease progression or unacceptable toxicity. The primary endpoint was objective response rate by independent central review. Among 128 patients evaluated, 95% completed cycle 1, and 85% completed four or more cycles. At 20.1 months' efficacy follow-up, objective response rate was 80.0% and complete response rate was 73.4%. Median duration of complete response was 25.1 months. Median progression-free survival was 20.7 months, and median overall survival was not reached. Discontinuation of odronextamab due to adverse events occurred in 16% of patients. The most common treatment-emergent adverse events were cytokine release syndrome [56%; grade ≥3 1.7% (1/60) with 0.7/4/20 mg step-up], neutropenia (39%), and pyrexia (38%). Odronextamab achieved high complete response rates with generally manageable safety in patients with heavily pretreated R/R follicular lymphoma. • Outcomes for patients with follicular lymphoma (FL) worsen with each relapse, representing a clear medical unmet need. • Odronextamab achieved high rates of deep response with durability in R/R FL, with 73% of patients attaining complete response. • Grade ≥3 cytokine release syndrome was seen in one patient with the optimized step-up regimen, and safety was generally manageable with odronextamab treatment. [ABSTRACT FROM AUTHOR]

Background Urticaria has been tentatively linked to cancer, but epidemiological evidence supporting this link is sparse and conflicting. We conducted a population-based cohort study using healthcare databases covering the Danish population (January 1980–December 2022). We followed 87 507 people for a median of 10.1 years after their first hospital contact for urticaria. Objectives To examine associations of a hospital diagnosis of urticaria with incident cancer. Methods We computed the absolute risk of cancer and standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) standardized to Danish national cancer rates. In a cross-sectional analysis, we examined whether the extent of cancer spread differed between people with vs. without a previous urticaria diagnosis. Results The overall SIR for all types of cancer was 1.09 (95% CI 1.06–1.11) based on 7788 observed vs. 7161 expected cases. The risk for any cancer was 0.7% (95% CI 0.6–0.7) for the first year of follow-up. Cancer was diagnosed in 588 people with urticaria during the first year of follow-up (SIR 1.49, 95% CI 1.38–1.62) and in 7200 people thereafter (SIR 1.06, 95% CI 1.04–1.09). During the first year of follow-up, we found strong associations with haematological cancers (e.g. non-Hodgkin lymphoma; SIR 2.91, 95% CI 1.92–4.23). Cancer stage was similar in people with vs. without a previous urticaria diagnosis. Conclusions At the time of urticaria diagnosis, or in the first year afterward, we found a large increase in the risk of cancer. In subsequent years, a persistent 6% increase in risk remained. Diagnostic efforts may partly explain the elevated short-term risk, but occult cancer may promote urticaria, or cancer and urticaria share common risk factors. [ABSTRACT FROM AUTHOR]

Objectives: The aim of the study was to examine the incidence, baseline characteristics, and outcomes of Chimeric Antigen Receptor T-cell (CAR-T) therapy admissions in individuals who developed acute respiratory failure (ARF). The study utilized the National Inpatient Sample (NIS) database for the years 2017 to 2020. Methods: The study identified CAR-T cell therapy hospitalizations through the International Classification of Diseases, Tenth Revision, Procedure Coding System (ICD-10-PCS) codes. Patients with acute respiratory failure (ARF) were further classified using specific International Classification of Disease, Tenth Revision, Clinical Modification (ICD-10-CM) codes. Descriptive statistics were performed to analyze baseline characteristics, comorbidities, complications, and outcomes. Results: Analysis of the NIS Database identified 5545 CAR-T therapy admissions between 2017 and 2020, revealing a rising trend over time. In our study, we found that hypertension (39%), dyslipidemia (21.7%), and venous thromboembolism (13%) were the most frequently observed comorbidities in CAR-T cell therapy admissions. Acute respiratory failure (ARF) was reported in 7.1% of admissions, and they had higher all-cause in-hospital mortality than CAR-T cell therapy admissions without ARF (32.9% vs 1.3%, P < 0.001). ARF admissions that required invasive mechanical ventilation (IMV) also had higher all-cause in-hospital mortality compared to admissions not requiring IMV (48.9% vs 11.8%, P = 0.001). There was no difference in the mortality rate among admissions with non-Hodgkin's Lymphoma, Multiple Myeloma, and Leukemia that utilized CAR-T therapy. Conclusions: In this largest study to date, we illuminate the incidence and outcomes of CAR-T cell therapy admissions with ARF. Higher mortality rates were observed in CAR-T cell therapy admissions with ARF. The study emphasizes the crucial role of interdisciplinary collaboration in CAR-T patient management and calls for additional research to clarify ARF's etiology and inform effective management strategies. [ABSTRACT FROM AUTHOR]

Background: Common Variable Immunodeficiency (CVID) represents a heterogenic group of primary immunodeficiencies (PID) characterized by impaired antibody production and susceptibility to infections. Non-infectious complications, such as autoimmune diseases, lymphoproliferative disorders, and malignancies, now significantly impact prognosis. Moreover, both hematologic and solid organ malignancies are more frequently observed in CVID patients compared to other PIDs. The risk factors for carcinogenesis in CVID remain largely unknown. Objective: This multicenter study aims to characterize the clinical profile of cancer in CVID patients in Spain and to identify independent risk factors associated with malignancy development, focusing on the role of immune dysregulation. Methods: A nationwide, cross-sectional study was conducted from November 2019 to May 2022, involving 17 hospitals treating PID patients in Spain. Data were collected systematically on demographics, infectious and non-infectious comorbidities, immunological parameters, and treatment. Statistical analysis, including multivariate logistic regression, was performed to identify risk factors associated to malignancy. Results: Of 250 CVID patients, 38 (15.26%) were diagnosed with cancer, predominantly non-Hodgkin lymphoma, gastric cancer, and lung adenocarcinoma. Cancer patients were significantly older (mean age 60.70 vs. 49.36 years, p<0.001) and had higher rates of immune dysregulation (81.58% vs. 59.7%, p=0.01). Immune dysregulation was an independent risk factor for cancer (OR 2.19, p=0.04), alongside previous immunosuppressant therapy (OR 2, p=0.031), higher IgM levels (OR 1.008 per SD, p=0.012), older age (OR 1.04, p<0.001), and lower CD4 cell counts at diagnosis (OR 0.997, p<0.001). Conclusions: This study highlights the increased cancer risk in CVID patients, with immune dysregulation, prior immunosuppressant use, elevated IgM levels, and lower CD4 cell counts as conjointly associated. These findings underscore the need for vigilant cancer screening and tailored management strategies in CVID patients to improve outcomes. Future research should focus on elucidating the molecular mechanisms linking immune dysregulation and malignancy in CVID. [ABSTRACT FROM AUTHOR]

AbstractIn the absence of head-to-head randomized trials, unanchored matching-adjusted indirect comparisons were conducted to estimate the relative efficacy of zanubrutinib versus ibrutinib and zanubrutinib versus rituximab in relapsed or refractory marginal zone lymphoma (MZL). Logistic propensity score models were used to estimate weights for the patient-level data from two phase II single-arm trials, MAGNOLIA and BGB-3111-AU-003, such that their characteristics matched the ibrutinib and rituximab aggregate-level data from PCYC-1121 and CHRONOS-3, respectively. The base case model for each comparison incorporated four key prognostic factors: prior lines of therapy, MZL subtype, response to prior therapy, and age. A sensitivity analysis incorporating additional prognostic factors was also conducted for the ibrutinib comparison. The impact of each covariate was explored via a leave-one-out analysis. Compared with ibrutinib and rituximab, zanubrutinib demonstrated significant benefits in terms of both overall response and progression-free survival in patients with previously treated MZL. [ABSTRACT FROM AUTHOR]

Background: The coexistence of non-Hodgkin's lymphoma of the stomach and multiple primary lung adenocarcinomas with pulmonary cryptococcosis has rarely been reported. Case presentation: We herein present a 75-year-old man who was admitted to our hospital due to hematemesis. Gastroscopy and imaging revealed extensive stomach wall thickening and multiple lung lesions, including nodules and cavernous lesion. The patient was diagnosed with primary diffuse large B-cell lymphoma via gastroscopy and bilateral lung primary adenocarcinoma with cryptococcal infection via percutaneous CT-guided puncture biopsy. He subsequently underwent six cycles of R-CHOP regimen for gastric lymphoma, along with CT-guided radiofrequency ablation for the upper lobe of the right lung primary adenocarcinoma and radioactive particle implantation was performed on the lower lobe of the left lung primary adenocarcinoma, supplemented with antifungal therapy. After a definite diagnosis and systemic treatment, the patient was followed up for twenty-seven months with no tumor recurrence, progression or metastasis. Conclusion: To the best of our knowledge, the complex combination of multiple primary malignancies and pulmonary cryptococcal infection is extremely rare. The diagnosis is been confusing and challenging. CT-guided needle biopsy can help achieve pathological diagnosis, elucidate the type and stage of the tumor, and even change the clinical treatment strategy, which is necessary and beneficial. [ABSTRACT FROM AUTHOR]

Background: Asparaginase-associated pancreatitis (AAP) is a major challenge for continuing asparaginase therapy. We aimed to investigate the acute and longterm complications and survival rates related to first and second AAP episodes in Chinese children with haematological malignancies. Methods: We retrospectively analysed clinical data of children with pancreatitis who received asparaginase chemotherapy for acute lymphoblastic leukaemia (ALL), acute mixed cell leukaemia, and non-Hodgkin's lymphoma at Shanghai Children's Medical Center from November 2013 to November 2023. Results: Of the 76 children included in the study, 12 had local complications (15.79%), with no deaths recorded. Systemic complications manifested in 28 patients (36.84%), resulting in 3 deaths (3.95%). Four patients (5.26%) developed long-term complications (chronic pancreatitis or insulin-dependent diabetes mellitus). No significant differences in local or long-term complications were recorded between children in the asparaginase re-exposed (n=39) and non-reexposed (n=45) groups. Among the re-exposed patients, eight (25.81%) experienced a second attack without fatalities or complications. Survival analysis of intermediate-to high-risk patients revealed a significantly higher event-free survival (EFS) rate for the re-exposed group than for the non-reexposed group. The second AAP episode's occurrence and severity had no relation to the first AAP episode's severity, and the second AAP episode was significantly less severe than the first (p<0.001). Conclusions: The second AAP episode's occurrence is unrelated to the first AAP episode's severity, and the second AAP episode's severity is significantly lower than that of the first. Further, asparaginase therapy could improve EFS in children with intermediate and high-risk ALL. [ABSTRACT FROM AUTHOR]

The document discusses the occurrence of indolent relapse after initial aggressive B-cell lymphoma treatment, focusing on the transformation of lymphoma types and the clinical outcomes of patients. It highlights the rarity of indolent relapse following initial aggressive lymphoma and the challenges in managing such cases. The study found that patients with indolent relapse had favorable outcomes, with a 10-year overall survival rate of 60%, and suggests the inclusion of these patients in clinical trials for relapsed/refractory indolent lymphomas. [Extracted from the article]

Simple Summary: This study examines the immune differences in follicular lymphoma (FL) and particularly focuses on the transformation into an aggressive disease, a major cause of FL-related deaths. We analyzed gene expression in diagnostic samples from 70 FL patients, categorized as either non-transforming FL (nt-FL) and subsequently transforming FL (st-FL) using NanoString technology. We identified 164 significantly differentially expressed genes between nt-FL and nt-FL samples, with st-FL showing an increased expression of B cell-related and immunosuppressive genes. Particularly, immune cell analysis revealed differences in macrophage and neutrophil fractions between nt-FL and st-FL, with higher levels of these cells linked to shorter transformation-free survival. Meanwhile, tFL samples had fewer T follicular helper cells and more immunosuppressive macrophages and neutrophils. The findings highlight the critical role of the immune microenvironment in FL transformation and patient outcomes. Background: Follicular lymphoma (FL) presents significant clinical heterogeneity, with some patients experiencing transformation into an aggressive disease, a key contributor to FL-related mortality. Based on gene expression profiles, this study aimed to provide insights into immunological differences associated with transformation. Methods: Gene expression analysis using the NanoString nCounter Tumor Signaling 360 Panel was performed on diagnostic lymphoma samples from 70 FL patients diagnosed in the rituximab era, either non-transforming FL (nt-FL, n = 34) or subsequently transforming FL (st-FL, n = 36), with paired high-grade transformed FL (tFL, n = 36) samples available. In silico immunophenotyping was performed to infer immune cell infiltration using the CIBERSORTx algorithm. Results: The gene expression analysis revealed 164 significantly differentially expressed genes, distinguishing st-FL from nt-FL and generally presenting an upregulation of B cell-related genes (CD40, IRF4, RELB), immunosuppressive molecules (IL10, SOCS3), and immune checkpoint molecules (CD276, TIM3). Analysis of immune cell proportions indicated significant differences in infiltrates of M1-like macrophages (p = 0.007) and neutrophils (p = 0.012) in nt-FL versus st-FL samples. Transformation-free survival (TFS) was associated with high numbers of both these cellular subsets (p = 0.006 and 0 = 0.002, respectively). This was even more evident when combined with inferior TFS in lymphomas with high infiltrates of both cell types (p < 0.001). After transformation, tFL samples showed a reduction in T follicular helper cells (p = 0.008) and an increase in immunosuppressive M2-like macrophages and neutrophils (p < 0.001 and p = 0.028, respectively). Conclusion: By elucidating the distinct molecular and immune landscapes of FL at the time of diagnosis and transformation, this study underscores the importance of immune microenvironment in FL transformation and patient outcome. [ABSTRACT FROM AUTHOR]

Simple Summary: Bruton's tyrosine kinase inhibitors (BTKi) have revolutionized the treatment of various B-cell lymphoid malignancies. However, acquisition of resistance to BTKi has emerged as an important clinical challenge. Herein, we provide a detailed review, describing the clinical trials that led to the FDA approval of the BTK inhibitors for management of Chronic Lymphocytic Leukemia (CLL), Mantle Cell Lymphoma, Marginal Zone Lymphoma (MZL), Follicular Lymphoma (FL) and Waldenstrom Macroglobulinemia (WM). We describe the mechanism of intrinsic and extrinsic resistance to the BTKi with main emphasis on the functional description of BTK mutations in CLL. Finally, we review the latest updates of the PROTACs BTK degraders, an evolving treatment modality for the management of the BTKi refractory B-cell malignancies. B-cell lymphoid malignancies are a heterogeneous group of hematologic cancers, where Bruton's tyrosine kinase (BTK) inhibitors have received FDA approval for several subtypes. The first-in-class covalent BTK inhibitor, Ibrutinib, binds to the C481 amino acid residue to block the BTK enzyme and prevent the downstream signaling. Resistance to covalent BTK inhibitors (BTKi) can occur through mutations at the BTK binding site (C481S) but also other BTK sites and the phospholipase C gamma 2 (PLCγ2) resulting in downstream signaling. To bypass the C481S mutation, non-covalent BTKi, such as Pirtobrutinib, were developed and are active against both wild-type and the C481S mutation. In this review, we discuss the molecular and genetic mechanisms which contribute to acquisition of resistance to covalent and non-covalent BTKi. In addition, we discuss the new emerging class of BTK degraders, which utilize the evolution of proteolysis-targeting chimeras (PROTACs) to degrade the BTK protein and constitute an important avenue of overcoming resistance. The moving landscape of resistance to BTKi and the development of new therapeutic strategies highlight the ongoing advances being made towards the pursuit of a cure for B-cell lymphoid malignancies. [ABSTRACT FROM AUTHOR]

Background/Objectives: Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease caused by an autoimmune attack on hepatocytes. The first-line treatment for AIH comprises two core components: glucocorticoids and thiopurine analog inhibitors and mycophenolate mofetil (MMF). Numerous studies have suggested an increased risk for lymphoma among patients with either rheumatoid arthritis or inflammatory bowel disease (IBD) who are treated with azathioprine/6-mercaptopurine (6-MP). The relative risk of non-Hodgkin lymphoma (NHL) among autoimmune hepatitis patients treated with these immunosuppressive drugs remains unclear. We aimed at investigating the risk of NHL across a large retrospective AIH cohort after a long-term follow-up. Methods: This retrospective, population-based study comprised approximately 2.7 million adults over two decades. It included adult patients aged 20 years or older at the time of autoimmune hepatitis diagnosis who had initiated treatment with azathioprine, 6-MP, or MMF. The primary outcome was the development of non-Hodgkin lymphoma. Results: The study initially included 834 patients diagnosed with AIH. A total of 685 patients remained in the research cohort after matching the data to the local cancer registry. Compared to the predicted NHL rate in the general population, NHL incidence was considerably higher in AIH patients (Standardized Incidence Ratio, SIR = 36.5). Subgroup studies showed that lymphoma mainly affected patients 45 years of age and over and was detected primarily during the first seven years following the AIH diagnosis. No correlation was found between the incidence of NHL and the treatment drug used. Conclusions: Patients with AIH exhibit a markedly higher risk of NHL compared to the general population. [ABSTRACT FROM AUTHOR]

Introduction. Non-Hodgkin lymphomas (NHL) are a heterogeneous group of lymphoproliferative disorders originating from B, T or natural killer (NK) lymphocytes. Clinical scoring systems have been developed to better stratify the patients' risk and help select therapeutic strategies. Materials and methods. Clinical and prognostic stratification scores were applied to 99 patients with extranodal aggressive NHL. The diagnosis was confirmed morphologically by tumor biopsy and immunohistochemistry. Results. IPI is an independent prognostic factor for progression-free survival. In addition, it facilitates the investigation of the independent impact of other prognostic biomarkers through adjusted analyses. Calculating International Prognostic Index (IPI), we obtained the following results: IPI 0 - 25% and IPI1 - 23.2% with a low risk and 5-year survival of 73%, IPI2 - 18.1% with low intermediate risk and 5-year survival of 51%, IPI3 - 17.1% with high intermediate risk and 5-year survival of 43%, IPI4 - 12.1% and IPI 5 - 4.5% with high risk and 5-year survival of 26%. Conclusions. Clinical scoring systems allow better risk stratification of patients and selection of appropriate therapeutic strategies. The IPI is a clinical tool developed to help predict the prognosis of patients with aggressive NHL. RIPI is a clinically useful prognostic index that allows guiding treatment planning in patients with DLBCL. [ABSTRACT FROM AUTHOR]

Background: Diffuse large B-cell lymphoma (DLBCL) is an aggressive non-Hodgkin lymphoma and is characterized by heterogeneity in biology and clinical behavior. Mutations in the myeloid differentiation primary response 88 (MYD88) are found in different lymphoproliferative disorders and are associated with variable clinical and prognostic impact. Aim: To investigate the frequency of MYD88 L265P mutation and its clinical impact in a cohort of Egyptian DLBCL patients. Methods: FFPE lymph node samples from 87 DLBCL patients (46 males / 41 females; median age, 58 years) were included and analyzed for MYD88 L265P by an allele-specific PCR. Results: MYD88 L265P mutations were found in 52 patients (59.8%) out of 87 DLBCL cases. Patients with L265 mutation were significantly younger than non-mutated patients (p = 0.022). None of the patients with the L265P mutation showed a significant association with the clinical parameters of DLBCL. Interestingly, MYD88 L265 mutated patients were found to be significantly correlated with HCV infection (p = 0.037). The median follow-up time across the entire cohort was 26 months. Univariate analysis showed that overall survival (OS) was affected by gender, LDH level, and CNS-IPI scoring (p = 0.048, 0.008, and 0.046, respectively), while disease-free survival (DFS) was affected by B symptoms and LDH level (p = < 0.000 and 0.02, respectively). However, the MYD88 mutation status and other prognostic factors showed no association with OS or DFS. Conclusions: Our findings indicate a high frequency of MYD88 L265P mutations in our study population and not associated with prognostic markers or the outcome of the disease. [ABSTRACT FROM AUTHOR]

Lymphoma is a malignant tumour of the lymphatic system with an incidence rate of about 6.6 per 100,000 people. Among the many lymphoma types, the most common is non-Hodgkin’s lymphoma. Lymphomas are common in the gastrointestinal tract, breast, neck, etc., while those in female genital tracts are rare. In this article, we report four cases of primary female genital system lymphoid malignancies diagnosed and treated at our hospital from 2018 to 2023, with a systematic review. [ABSTRACT FROM AUTHOR]

Background: Metastatic bone disease (MBD) and its complications have a significant impact on patients' quality of life. Pathological fractures are a particular problem as they affect patient mobility and pose a high risk of non-union. The pelvis is frequently affected by MBD and its fixation is challenging. We present a case series of three pathological sacral fractures treated with a new minimally invasive bilateral fixed angle locking system. Case presentation: Case 1 and 2 suffered a pathological transforaminal sacral fracture without adequate trauma in stage 4 carcinomas (gastric cancer and breast cancer). Both were initially treated with non-surgical treatment, which had only a limited effect and led to imminent immobility. Both were operated on with fluoroscopic navigation and underwent transsacral SACRONAIL® stabilisation according to CT morphology (S1 + S2 and S1 respectively). Immediately after the operation, pain decreased and mobilisation improved. Case 3 had a pathological transalar sacral fracture during the 2nd cycle of chemotherapy due to non-Hodgkin's lymphoma. He soon became immobile and could only move in a wheelchair. The operation was performed with CT navigation due to the very small corridors and an implant was inserted in S1 and S2. The patient reported immediate pain relief and his ability to walk improved over the following months. Despite continued chemotherapy, no wound complications occurred. Conclusions: The cases show the advantages of the minimally invasive bilateral fixed angle locking system SACRONAIL® in the treatment of patients with pathological sacral fractures. It allows immediate full weight bearing and the risk of secondary surgical complications is low. All cases showed an improvement in pain scores and mobility. [ABSTRACT FROM AUTHOR]

Introduction: Statins reduce the cancer risk; however, non-Hodgkin lymphoma (NHL) evidence remains controversial. Therefore, we aimed to evaluate the relationship between statin consumption and NHL risk using a systematic review and meta-analysis. Materials and Methods: In this systematic review and meta-analysis, international databases, including Scopus, PubMed, Web of Science, Cochrane, and Google Scholar search engines, were searched without a time limit up to September 21, 2023. Data analysis was performed using STATA 14 software, and the significance level was considered P<0.05. Results: The results of combining 13 studies (9 case-control studies and 4 cohort studies) with a total sample size of 1 142 740 subjects showed that statin consumption could reduce NHL risk by 22% (RR: 0.78; 95% CI: 0.69, 0.88). Statin consumption in cohort studies reduced NHL risk by 14% (RR: 0.86; 95% CI: 0.77, 0.95), but in case-control studies, it reduced NHL risk by 26% (RR: 0.74; 95% CI: 0.62, 0.90). Furthermore, statin consumption reduced diffuse large B-cell lymphoma risk by 24% (RR: 0.76; 95% CI: 0.67, 0.87) and marginal zone risk by 26% (RR: 0.74; 95% CI: 0.59, 0.93). However, it did not affect reducing the risk of chronic lymphocytic leukemia/small lymphocytic lymphoma (RR: 0.94; 95% CI: 0.85, 1.05), follicular (RR: 0.96; 95% CI: 0.83, 1.10), plasma cell neoplasms (RR: 0.97; 95% CI: 0.70, 1.33), T cell lymphoma (RR: 0.81; 95% CI: 0.55, 1.19) and B cell lymphoma (RR: 0.94; 95% CI: 0.44, 2.01). Conclusion: Statin consumption significantly reduced the risk of NHL, diffuse large B-cell lymphoma, and marginal zone but did not affect other NHL types. Registration: This study has been compiled based on the PRISMA checklist, and its protocol was registered on the PROSPERO (CRD42023469126) and Research Registry (UIN: reviewregistry1732) website. [ABSTRACT FROM AUTHOR]

Signet ring cell lymphoma (SRCL) is a non-Hodgkin's lymphoma with a very rare variant. Although this morphology is frequently seen in follicular lymphoma, it can also be observed in the group of diffuse large B-cell lymphomas. A seventy-six year old woman with known diagnosis of gastric adenocarcinoma, tubular type, moderately differentiate presented with a mesenteric lymphadenopathy with high FDG uptake (SUVmax: 21.3) in PET/CT during follow-up. A tru-cut biopsy was performed for histopathological diagnosis. Diffuse infiltrative singet ring neoplastic cells showed negativity for PanCK, CK7, CK20, S100, SMA, calretinin and vimentin. The panel was then expanded to include SRCL, a rare variant of lymphoma. Additional immunohistochemical evaluation revealed positivity for CD20, CD19, PAX-5 and Bcl-2. Ki-67 proliferation index was about 80%. CD3, CD30, Myc, Bcl-6, ALK, Cyclin-D1, CD23, CD10, CD21, and MUM-1 were negative. EBER was also negative by chromogen in situ hybridization (CISH). Based on these data, diffuse large B-cell lymphoma (DLBCL) was considered. We herein reported a case of signet ring cell lymphoma discussed its clinical and morphological features with regard to the literature. [ABSTRACT FROM AUTHOR]

Purpose: The risk stratification of pediatric anaplastic large cell lymphoma (ALCL) has not been standardized. In this study, new risk factors were included to establish a new risk stratification system for ALCL, and its feasibility in clinical practice was explored. Materials and Methods: On the basis of the non-Hodgkin's lymphoma Berlin–Frankfurt–Munster 95 (NHL-BFM-95) protocol, patients with minimal disseminated disease (MDD), high-risk tumor site (multiple bone, skin, liver, and lung involvement), and small cell/lymphohistiocytic (SC/LH) pathological subtype were enrolled in risk stratification. Patients were treated with a modified NHL-BFM-95 protocol combined with an anaplastic lymphoma kinase inhibitor or vinblastine (VBL). Results: A total of 136 patients were enrolled in this study. The median age was 8.8 years. The 3-year event-free survival (EFS) and overall survival of the entire cohort were 77.7% (95% confidence interval [CI], 69.0% to 83.9%) and 92.3% (95% CI, 86.1% to 95.8%), respectively. The 3-year EFS rates of low-risk group (R1), intermediate-risk group (R2), and high-risk group (R3) patients were 100%, 89.5% (95% CI, 76.5% to 95.5%), and 67.9% (95% CI, 55.4% to 77.6%), respectively. The prognosis of patients with MDD (+), stage IV cancer, SC/LH lymphoma, and high-risk sites was poor, and the 3-year EFS rates were 45.3% (95% CI, 68.6% to 19.0%), 65.7% (95% CI, 47.6% to 78.9%), 55.7% (95% CI, 26.2% to 77.5%), and 70.7% (95% CI, 48.6% to 84.6%), respectively. At the end of follow-up, one of the five patients who received maintenance therapy with VBL relapsed, and seven patients receiving anaplastic lymphoma kinase inhibitor maintenance therapy did not experience relapse. Conclusion: This study has confirmed the poor prognostic of MDD (+), high-risk site and SC/LH, but patients with SC/LH lymphoma and MDD (+) at diagnosis still need to receive better treatment (ClinicalTrials.gov number, NCT03971305). [ABSTRACT FROM AUTHOR]

Non-Hodgkin's Lymphoma (NHL) is the most common subtype of lymphoma. The incidence of venous thromboembolism (VTE) in aggressive NHL was estimated recently to be 11%. Several risk assessment scores and factors are available to help identify cancer patients at risk for developing VTE. Patients with a pathologically confirmed diagnosis of NHL were identified at the Oncology Center of Mansoura University. The study included 777 patients: 719 with DLBCL-NOS, 26 with Anaplastic-B-cell, and 32 with T-cell-rich-NHL. Data were retrospectively collected from electronic medical records, including clinical, radiological, and laboratory information related to VTE and NHL. The median age at NHL diagnosis was 53 years, (range: 18–98). There was a male predominance, 51.4% of the cases. At initial lymphoma diagnosis, VTE was identified in 46 (5.9%) patients, and 61 (7.9%) patients experienced VTE while undergoing chemotherapy. According to logistic regression analysis, a PS (performance status) ≥ 2, bulky lesions, and mediastinal masses were significant predictors of VTE at presentation, with P-values of 0.022, 0.002, and < 0.001, respectively. Meanwhile, NHL patients who developed VTE during chemotherapy had significantly poorer PS, higher absolute neutrophilic counts (ANC), neutrophil/lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR) and lactate dehydrogenase (LDH) levels than lymphoma patients without VTE, with P-values of 0.003, 0.034, 0.049, 0.01 and 0.007, respectively, as determined by multivariate analysis. The ROC curve identified the cut-off values of 4.875 × 109/L for ANC, 2.985 for NLR, 144.85 for PLR, and 417.5 U/L for LDH as potential markers for predicting VTE in NHL patients. Patients with a PS ≥ 2 and values exceeding these cut-offs for ANC, NLR, and PLR experienced significantly higher incidences of VTE than other groups, with P-values of 0.003, < 0.001, < 0.001, and < 0.001, respectively. At the end of the follow-up, the overall survival was significantly shortened by VTE occurring during chemotherapy, hypoalbuminemia, intermediate-high and high international prognostic index (IPI) scores (intermediate-high and high), responses other than CR and relapse, all with P-values < 0.05. ECOG PS and Inflammatory markers such as NLR, PLR, and neutrophilic count could serve as predictors of the development of thrombotic events in patients with NHL-DLBCL. Additionally, the occurrence of VTE during chemotherapy is an independent poor prognostic marker for overall survival (OS). [ABSTRACT FROM AUTHOR]

Flow-cytometry (FC) is a powerful tool that can assist in lymphoma diagnosis in lymph node (LN) specimens. Although lymphoma diagnosis and classification are mainly based on tumor cell characteristics, surrounding cells are less employed in this process. We retrospectively investigated alterations in the ploidy status, proliferative cell fraction (PF) and the percentages of surrounding immune cells in 62 consecutive LN specimens with B-Cell Non-Hodgkin Lymphoma (B-NHL) that were submitted for FC evaluation between 2019–2022. Compared with indolent B-NHLs, aggressive B-NHLs show increased DNA aneuploidy and PF, increased monocytes, immature-granulocytes, mature granulocytes, CD8+ T-cells, Double-Negative-T-cells and Double-Positive-T-cells, and decreased total CD45+ cells, total lymphocytes, CD4+ T-cells and CD4/CD8 ratio. Receiver operating characteristic analysis determined PF > 6.8% and immature-granulocytes > 0.9% as optimal cutoffs with highest specificity and sensitivity in differentiating aggressive and indolent B-NHLs. These findings further strength the diagnostic value of DNA content analysis by FC and suggest the utilization of tumor surrounding immune cells in NHL diagnosis and classification. [ABSTRACT FROM AUTHOR]

The article discusses the impact of total lesion glycolysis (TLG) in predicting the response of follicular lymphoma (FL) to rituximab. FL is a common type of non-Hodgkin lymphoma characterized by the (14;18) translocation. The study evaluates whether early rituximab monotherapy could delay chemotherapy in FL patients with low tumor burden. Results suggest that patients with FL should be evaluated using 18F-FDG PET scan and stratified based on TMTV and TLG thresholds to guide treatment decisions. [Extracted from the article]

We present the case of a 43-year-old Caucasian man who developed visceral leishmaniasis (VL) following treatment with a combination of brentuximab vedotin and doxorubicin, vinblastine, and dacarbazine (A+AVD) for advanced-stage classical Hodgkin's lymphoma (cHL). The patient initially showed a favorable response to the treatment, but shortly after completing six cycles, he experienced recurrent fever, splenomegaly, and severe anemia. Extensive infectious disease evaluations led to a diagnosis of VL, confirmed by PCR testing. The patient was treated with amphotericin B, resulting in full clinical recovery. In addition to presenting this rare case, we conducted a full review of the literature on VL in the context of hematological disorders, including non-Hodgkin's lymphoma, splenic marginal zone lymphoma, and other lymphoproliferative diseases. This review highlights the increasing prevalence of VL in immunocompromised individuals, particularly those undergoing treatments like chemotherapy or immunotherapy, and underscores the importance of considering VL in differential diagnoses when such patients present with persistent fever and splenomegaly. [ABSTRACT FROM AUTHOR]

Simple Summary: This study analyzes the use of rituximab (RTX) in the daily clinical practice of several Italian oncohematology centers, with a particular focus on the adoption of biosimilars. The results show that only a minority of patients (22%) switched between different biosimilars, while the majority continued treatment with the biosimilars Rixathon and Truxima. This finding suggests that the proactive sharing of guidelines between regulators and prescribers, from the outset, may be an effective strategy to further promote the adoption of biosimilars. This approach could be particularly useful in those areas where the use of biosimilars is still lower than the national average, helping to free up economic resources that could be redirected towards other healthcare opportunities. The clinical safety and efficacy of rituximab biosimilars compared to the reference rituximab (Mabthera) have been well established in randomized trials. However, concerns persist regarding the safety of changing from the reference product to biosimilars, and particularly between different biosimilars. This prospective multicenter observational study was conducted in 13 oncohematology units of eight Italian regions. The study included 800 patients with non-Hodgkin lymphoma (NHL) or chronic lymphocytic leukemia (CLL) who received rituximab between March 2018 and June 2022. To minimize survivorship bias, only newly diagnosed patients (i.e., those without prior rituximab treatment) were included in the analysis of adverse drug reactions (ADRs). Thus, this study focused on 505 incident cases (79.8% of the initial cohort) from 13 centers. A total of 3681 rituximab infusions were administered, and 16.8% of the patients experienced at least one ADR. These were observed most frequently during the first infusion (44 patients, 52%) and the second infusion (17 patients, 20%). The most frequent reactions were general disorders and administration site conditions (n. 50, 8% serious). These findings support the clinical safety of rituximab biosimilars and suggest that switching between biosimilars does not increase the risk of adverse events. This evidence may alleviate concerns about biosimilar use, potentially leading to broader acceptance and reduced healthcare costs. [ABSTRACT FROM AUTHOR]

Simple Summary: Cutaneous T-cell lymphomas (CTCLs) represent a heterogeneous group of rare extranodal non-Hodgkin lymphomas with variable clinical presentation. In the Middle East and North Africa (MENA region), where darker skin colors are more common than in the West, CTCL generally presents at a younger age and with distinct clinical features that necessitate special expertise and management across disciplines: rare forms of CTCL are more common (hypo- and hyperpigmented mycosis fungoides (MF)) and a higher prevalence of pediatric MF is noticed. The high cancer burden in the Middle East and North Africa (MENA region) is coupled with an increasing cancer incidence. While the MENA region constitutes 6% of the world's population, it remains underrepresented in clinical trials. Cutaneous T-cell lymphomas (CTCLs) represent a heterogeneous group of rare extranodal non-Hodgkin lymphomas with variable clinical presentation. In the MENA region, where darker skin colors are more common than in the West, CTCL generally presents at a younger age and with distinct clinical features that necessitate special expertise and management across disciplines: rare forms of CTCL are more common (hypo- and hyperpigmented MF) and a higher prevalence of pediatric MF is noticed. The multidisciplinary approach to cancer management is growing worldwide and is necessary for the comprehensive management of CTCL. The MENA CTCL group was established with the aim of creating a collaborative environment for the diagnosis and treatment of CTCL in the region. Its first meeting was held in May 2023. The group plans to increase the global representation of the MENA region and establish CTCL registries and patient advocacy groups in the region. [ABSTRACT FROM AUTHOR]

Simple Summary: This research aims to identify new protein markers that can help predict the risk of disease progression in patients with follicular lymphoma (FL) at the time of diagnosis. By analyzing a large number of proteins in FL samples, the study found significant differences in protein composition among patients, which may help distinguish those at higher risk of disease progression. These findings could improve our understanding of FL biology and lead to the discovery of new biomarkers or treatment targets, potentially allowing for more personalized and effective treatment strategies for FL patients, improving their outcomes. Background: Follicular lymphoma (FL) is characterized by an indolent nature and generally favorable prognosis, yet poses a particular clinical challenge, since disease progression is observed in a notable subset of patients. Currently, it is not possible to anticipate which patients will be at risk of progression, highlighting the need for reliable predictive biomarkers that can be detected early in the disease. Methods: We applied tandem-mass-tag labelled nano-liquid chromatography tandem mass spectrometry (nLC-MS/MS) on 48 diagnostic formalin-fixed, paraffin-embedded tumor samples from patients with advanced-stage FL. Of these, 17 experienced subsequent progression (subsequently-progressing, sp-FL) while 31 did not (non-progressing, np-FL). Results: We identified 99 proteins that were significantly differentially expressed between sp-FL samples and np-FL samples (p < 0.05; log2-fold changes between 0.2 and −1.3). Based on this subset of proteins, we classified patients into high-risk and low-risk subgroups using unsupervised machine learning techniques. Pathway analyses of the identified proteins revealed aberrancies within the immune system and cellular energy metabolism. In addition, two proteins were selected for immunohistochemical evaluation, namely stimulator of interferon genes 1 (STING1) and isocitrate dehydrogenase 2 (IDH2). Notably, IDH2 retained significantly lower expression levels in sp-FL samples compared with np-FL samples (p = 0.034). Low IDH2 expression correlated with shorter progression-free survival (PFS, p = 0.020). Conclusions: This study provides evidence for some of the biological mechanisms likely to be involved in FL progression and, importantly, identifies potential predictive biomarkers for improvement of risk stratification up-front at time of FL diagnosis. [ABSTRACT FROM AUTHOR]

Background: Thrombocytopenia is a common side effect of cytotoxic chemotherapies, which is often dose-limiting. Predicting an individual’s risk is of high clinical importance, as otherwise, a small subgroup of patients limits dosages for the overall population for safety reasons. Methods: We aim to predict individual platelet dynamics using non-linear auto-regressive networks with exogenous inputs (NARX). We consider different architectures of the NARX networks, namely feed-forward networks (FNN) and gated recurrent units (GRU). To cope with the relative sparsity of individual patient data, we employ transfer learning (TL) approaches based on a semi-mechanistic model of hematotoxicity. We use a large data set of patients with high-grade non-Hodgkin’s lymphoma to learn the respective models on an individual scale and to compare prediction performances with that of the semi-mechanistic model. Results: Of the examined network models, the NARX with GRU architecture performs best. In comparison to the semi-mechanistic model, the network model can result in a substantial improvement of prediction accuracy for patients with irregular dynamics, given well-spaced measurements. TL improves individual prediction performances. Conclusion: NARX networks can be utilized to predict an individual’s thrombotoxic response to cytotoxic chemotherapy treatment. For reasonable model learning, we recommend at least three well-spaced measurements per cycle: at baseline, during the nadir phase and during the recovery phase. We aim at generalizing our approach to other treatment scenarios and blood lineages in the future. [ABSTRACT FROM AUTHOR]

This study aimed to describe the prevalence of high‐risk human papillomavirus (HR‐HPV) types in the anal canal in a cohort of people living with HIV (PLWHIV) with a history of malignancy. Setting: Referral tertiary care hospital for adult patients with cancer. Methods: We reviewed data of patients from the AIDS Cancer Clinic on antiretroviral therapy in chronic control who were consecutively referred for high‐resolution anoscopy (HRA), where they underwent anal evaluation, collection of specimens for anal cytology and anal human papillomavirus (HPV) followed by HRA with directed biopsy if needed. Results: A total of 155 patients were included; 149 (96.1%) were men, all of them men who have sex with men (MSM); the median age was 39 (IQR 32‐47) years; 105 (67.7%) with Kaposi sarcoma, 40 (25.8%) with non‐Hodgkin lymphoma and 10 (6.4%) with other neoplasms; only 7 (4.5%) had active cancer. The prevalence of HR‐HPV infection was 89% (n=138) (95% CI 83–93) with at least one HR‐HPV infection, and 62% (96) had coinfection with at least two types; the median HR‐HPV types of coinfection were 3 (IQR 2–4). The number of patients infected with HPV 16 was 64 (41.3%, 95% CI 33.8–49.3), HPV 18 was 74 (47.7%, 95% CI 39.9–55.7) and with both 35 (22.6%). Some 59 patients (38%) had high‐grade squamous intraepithelial lesions (HSIL) and 49 (31.6%) had low‐grade squamous intraepithelial lesions (LSIL). The prevalence of HR‐HPV and HSIL among patients aged ≤35 and >35 years was the same. Conclusions: In this cohort of PLWHIV with a history of malignancy we found a high prevalence of HR‐HPV 16 and 18 and anal HSIL, even in persons aged ≤35 years. These data highlight the importance of anal cancer screening in PLWHIV and history of malignancy. [ABSTRACT FROM AUTHOR]

Routine histopathology of tonsillectomy specimens is not standard practice due to cost and resource constraints. This study aimed to evaluate the prevalence of abnormal histopathologies in tonsillectomy specimens to determine the necessity of routine histopathology. A prospective observational study was conducted from January 2014 to August 2016 at a general tertiary care center after approval of Institutional Ethics Committee (IEC). Patients scheduled for tonsillectomy surgery as per the AAOHNS 2011 criteria were included in the study. All tonsillectomy specimens were sent for histopathology, and abnormal findings were documented. Statistical analysis was performed. A total of 111 patients were enrolled in this study, and 222 tonsillectomy specimens were analyzed. The most common finding was chronic tonsillitis, which justified the selection criteria in 91.89% of patients. Two patients with chronic tonsillitis were also found to have actinomycosis present on the surface without parenchymal tissue reaction. Abnormal histopathological findings were observed in 9 (8.10%) of patients, leading to further investigations or treatment in 8 cases. These abnormalities included chronic granuloma, non-Hodgkin's lymphoma, early squamous cell carcinoma, and one choristoma. Tonsillar asymmetry, recent onset of symptoms and older age were found to be significantly correlated with abnormal histopathology and malignancy. Routine histopathology in tonsillectomy specimens helps to identify important findings that may require additional treatment. Based on the study we strongly recommend routine histopathology of tonsillectomy specimen. When significant cost constraints exist, risk-based approach can be adopted. Factors such as older age, asymmetry of tonsils, referred otalgia, duration of symptoms (recent onset) and a history of addiction should be considered for proceeding with histopathology. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma (MCL) is a rare subtype of B-cell non-Hodgkin's lymphoma (NHL), which generally has an aggressive course. Its pathophysiology seems to be related with the malignant transformation of B-cell mantle zone lymphocytes due to the CCND1 rearrangement. The occurrence of MCL in the oral cavity is especially rare. In this report, we present an exceptional case of oral MCL diagnosed in the palate in a 56-year-old male patient, highlighting its distinct morphological and immunohistochemical features that may assist in the accurate diagnosis. [ABSTRACT FROM AUTHOR]

Summary The clinical and prognostic implications of nodal involvement (NI) in Waldenström macroglobulinaemia (WM) are largely unknown. In this study, we explored the impact of NI on clinical presentation and outcome in a population‐based cohort of 469 patients with WM, consecutively diagnosed between 2000 and 2022. NI was detected in 34% of patients and was associated with symptomatic disease, adverse prognostic factors, an increased risk of transformation, and lymphoma‐related death. Our findings indicate that NI is of prognostic significance in WM, suggesting a need for enhanced surveillance in these patients. [ABSTRACT FROM AUTHOR]

The concept of time toxicity in oncology refers to the presence of frequent healthcare-related interactions that can interfere with patient well-being. In this review, we examine several manifestations of time toxicity in non-Hodgkin lymphoma and multiple myeloma and discuss their impact on decision-making with patients. For example, time toxicity may influence the choice of chemoimmunotherapy versus lenalidomide-rituximab in follicular lymphoma. In myeloma, it may inform the optimal dosing schedule for proteasome inhibitors and bisphosphonates. In both malignancies, varying time toxicity profiles are a key distinction between chimeric antigen receptor T-cell therapies and bispecific antibodies. We outline the challenges with measuring time toxicity as a trial endpoint but discuss its importance as a consideration for patient care, both in standard-of-care settings and in clinical trials. Throughout the review, we highlight strategies to lower the time toxicity of therapies in lymphoma and myeloma without compromising their efficacy or patient safety. [ABSTRACT FROM AUTHOR]

New immunotherapy drugs, such as bispecific T-cell engager antibodies, checkpoint inhibitors and antibody–drug conjugates, are commonly used as salvage therapy for patients with non-Hodgkin lymphoma relapsing after chimeric antigen receptor (CAR) T-cell therapy. Nevertheless, their potential long-term effects on the outcome of allogeneic stem cell transplantation (Allo-SCT) are not well known. We retrospectively analyzed the outcomes of 27 relapsed/refractory non-Hodgkin lymphoma patients receiving Allo-SCT after immunotherapy in the pre-CAR T-cell therapy era and compared them with a historical cohort of 28 subjects undergoing Allo-SCT after conventional therapy. The two cohorts had similar outcomes in terms of graft-versus-host disease/relapse-free survival (4 years, 59% versus 46%), overall survival (4 years, 77% versus 44%), non-relapse mortality (4 years, 19% versus 22%) and acute (6 months, 15% versus 21%) and chronic (4 years, 18% versus 24%) graft-versus-host disease. Of note, the cumulative incidence of relapse was lower after immunotherapy (4 years, 4% versus 14%), although significance was not reached. The cumulative incidence of cytomegalovirus and fungal infection did not differ among the two cohorts. Consolidation with Allo-SCT is a safe and curative option for patients achieving disease response after new immunotherapy drugs that could represent a desirable salvage strategy for patients relapsing after CAR T-cell therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Introduction: Diffuse large B-cell lymphoma (DLBCL), a prevalent non-Hodgkin lymphoma subtype, displays diverse clinical outcomes with persistently high mortality and relapse rates, despite treatment advancements. Notably, the Hispanic demographic lacks consideration in existing prognostic indices for DLBCL. Methods: A retrospective cohort study encompassing 112 DLBCL patients diagnosed between 2010 and 2020 was conducted at our institution. Patient data, including overall survival (OS), treatment response, and relapse, were analysed. Results: With a median age of 65 years and a predominant male population (60.7%), both the International Prognostic Index (IPI) and revised IPI correlated with OS. In multivariate analysis, patients with ki-67 ≥ 60% exhibited higher mortality risk (Hazard Ratio: 2.35, 95% confidence intervals (CI) 1.05-5.27, p = 0.039), even when controlled by IPI category and B2-microglobulin levels. The absence of B symptoms served as a protective factor for relapse (p < 0.01, OR: 0.147, 95% CI 0.058-0.376) when controlling for ki-67, CD5, and IPI. Conclusion: Our cohort demonstrated a 5-year OS rate comparable to high-income countries, highlighting the need for tailored prognostic models for Hispanic DLBCL patients. This study identifies easily accessible parameters aligning with regional resource constraints, providing insights into additional prognostic factors for DLBCL in the Hispanic population. [ABSTRACT FROM AUTHOR]

Discordant lymphoma (DL) is an uncommon condition in which two or more histologically different types of lymphomas are present at distinct anatomical sites in the same patient. Here, we report a case of a pediatric patient under 10 years old presenting with symptoms of general sickness with cervical lymphadenopathy, abdominal distension and an abdominal mass. Upon conducting investigations, classic Hodgkin lymphoma (CHL) was detected in the cervical lymph nodes, and high-grade B-cell non-Hodgkin lymphoma was detected in the bone marrow and abdominal mass. The patient was therefore diagnosed with DL. The boy was initially diagnosed with CHL but proceeded to have aggressive disease progression, due to which further workup was done. In the past, literature reports have been published for adult cases of DL, and currently, research is being conducted to formulate treatment protocols for it. However pediatric cases of DL remain widely undiscussed. Since we are dealing with a rare or widely underreported condition, we found it significant to elaborate on its clinical presentation, treatment plan, complications and prognosis. [ABSTRACT FROM AUTHOR]

The most difficult diagnostic challenge in neck imaging is the differentiation between benign and malignant neoplasms. The purpose of this work was to study the role of the ADC (apparent diffusion coefficient) value in discriminating benign from malignant neck neoplastic lesions. The study was conducted on 53 patients with different neck pathologies (35 malignant and 18 benign/inflammatory). In all of the subjects, conventional MRI (magnetic resonance imaging) sequences were performed apart from DWI (diffusion-weighted imaging). The mean ADC values in the benign and malignant groups were compared using the Mann–Whitney test. The ADCs of malignant lesions (mean 0.86 ± 0.28) were significantly lower than the benign lesions (mean 1.43 ± 0.57), and the mean ADC values of the inflammatory lesions (1.19 ± 0.75) were significantly lower than those of the benign lesions. The cutoff value of 1.1 mm2/s effectively differentiated benign and malignant lesions with a 97.14% sensitivity, a 77.78% specificity, and an 86.2% accuracy. There were also statistically significant differences between the ADC values of different malignant tumors of the neck (p, 0.001). NHL (0.59 ± 0.09) revealed significantly lower ADC values than SCC (0.93 ± 0.15). An ADC cutoff point of 0.7 mm2/s was the best for differentiating NHL (non-Hodgkin lymphoma) from SCC (squamous cell carcinoma); it provided a diagnostic ability of 100.0% sensitivity and 89.47% specificity. ADC mapping may be an effective MRI tool for the differentiation of benign and inflammatory lesions from malignant tumors in the neck. [ABSTRACT FROM AUTHOR]

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Lung transplantation (LTx) is a well-known treatment for end-stage lung disease. This study aimed to report the incidence of cancer after LTx and long-term outcome among lung transplant recipients with a pretransplant diagnosis of cancer. Patients who underwent LTx between 1990–2016 were included in the study. Detection of cancer was obtained by cross-checking the study population with the Swedish Cancer Registry and the Cause-of-Death registry. A total of 614 patients were followed for a median of 5.1 years. In all, 159 malignancies were diagnosed. The excess risk of cancer or standardized incidence ratio (SIR) following LTx was 5.6-fold compared to the general Swedish population. The most common malignancies were non-melanoma skin cancer (NMSC) (SIR 76.5 (95%CI 61.7–94.8); non-Hodgkin lymphoma (SIR 23.5, 95%CI 14.8–37.2); and lung cancer (SIR 8.89, 95%CI 5.67–13.9). There was no significant difference in overall survival between those with and without a history of cancer before LTx (p = 0.56). In total, 159 malignancies were identified after LTx, which was a 5.6-fold higher relative to the general population. A history of previous cancer yields similar survival in selected recipients, compared to those without cancer prior to LTx. [ABSTRACT FROM AUTHOR]

People living with HIV (PLWH) are at higher risk of developing lymphoma. In this study, we performed cytometry by time-of-flight (CyTOF) on peripheral blood mononuclear cells of cART-naïve HIV+ individuals and cART-naïve HIV+ individuals prior to AIDS-associated non-Hodgkin lymphoma (pre-NHL) diagnosis. Participants were enrolled in the Los Angeles site of the MACS/WIHS Combined Cohort Study (MWCCS). Uniform Manifold Approximation and Projection (UMAP) and unsupervised clustering analysis were performed to identify differences in the expression of B-cell activation markers and/or oncogenic markers associated with lymphomagenesis. CD10+CD27- B cells, CD20+CD27- B cells, and B-cell populations with aberrant features (CD20+CD27+CXCR4+CD71+ B cells and CD20+CXCR4+cMYC+ B cells) were significantly elevated in HIV+ cART-naïve compared to HIV-negative samples. CD20+CD27+CD24+CXCR4+CXCR5+ B cells, CD20+CD27+CD10+CD24+CXCR4+cMYC+ B cells, and a cluster of CD20+CXCR4hiCD27-CD24+CXCR5+CD40+CD4+AICDA+ B cells were significantly elevated in HIV+ pre-NHL (cART-naïve) compared to HIV+ cARTnaïve samples. A potentially clonal cluster of CD20+CXCR4+CXCR5+cMYC+AICDA+ B cells and a cluster of germinal center B-cell-like cells (CD19-CD20+CXCR4+Bcl- 6+PD-L1+cMYC+) were also found in the circulation of HIV+ pre-NHL (cART-naïve) samples. Moreover, significantly elevated clusters of CD19+CD24hiCD38hi cMYC+ AICDA+ B regulatory cells were identified in HIV+ pre-NHL (cART-naïve) compared to HIV+ cART-naïve samples. The present study identifies unique B-cell subsets in PLWH with potential pre-malignant features that may contribute to the development of pre-tumor B cells in PLWH and that may play a role in lymphomagenesis. [ABSTRACT FROM AUTHOR]

Background: The non-viral production of CAR-T cells through electroporation of transposon DNA plasmids is an alternative approach to lentiviral/retroviral methods. This method is particularly suitable for early-phase clinical trials involving novel types of CAR-T cells. The primary disadvantage of non-viral methods is the lower production efficiency compared to viral-based methods, which becomes a limiting factor for CAR-T production, especially in chemotherapy-pretreated lymphopenic patients. Methods: We describe a good manufacturing practice (GMP)-compliant protocol for producing CD19 and CD123-specific CAR-T cells based on the electroporation of transposon vectors. The lymphocytes were purified from the blood of patients undergoing chemotherapy for B-NHL or AML and were electroporated with piggyBac transposon encoding CAR19 or CAR123, respectively. Electroporated cells were then polyclonally activated by anti-CD3/CD28 antibodies and a combination of cytokines (IL-4, IL-7, IL-21). The expansion was carried out in the presence of irradiated allogeneic blood-derived mononuclear cells (i.e., the feeder) for up to 21 days. Results: Expansion in the presence of the feeder enhanced CAR-T production yield (4.5-fold in CAR19 and 9.3-fold in CAR123). Detailed flow-cytometric analysis revealed the persistence of early-memory CAR-T cells and a low vector-copy number after production in the presence of the feeder, with no negative impact on the cytotoxicity of feeder-produced CAR19 and CAR123 T cells. Furthermore, large-scale manufacturing of CAR19 carried out under GMP condi tions using PBMCs obtained from B-NHL patients (starting number=200x10e6 cells) enabled the production of >50x10e6 CAR19 in 7 out of 8 cases in the presence of the feeder while only in 2 out of 8 cases without the feeder. Conclusions: The described approach enables GMP-compatible production of sufficient numbers of CAR19 and CAR123 T cells for clinical application and provides the basis for non-viral manufacturing of novel experimental CAR-T cells that can be tested in early-phase clinical trials. This manufacturing approach can complement and advance novel experimental immunotherapeutic strategies against human hematologic malignancies. [ABSTRACT FROM AUTHOR]