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Role of Artificial Intelligence and Machine Learning in Prediction, Diagnosis, and Prognosis of Cancer. | Cancer is one of the most devastating, fatal, dangerous, and unpredictable ailments. To reduce the risk of fatality in this disease, we need some ways to predict the disease, diagnose it faster and precisely, and predict the prognosis accurately. The incorporation of artificial intelligence (AI), machine learning (ML), and deep learning (DL) algorithms into the healthcare system has already proven to work wonders for patients. Artificial intelligence is a simulation of intelligence that uses data, rules, and information programmed in it to make predictions. The science of machine learning (ML) uses data to enhance performance in a variety of activities and tasks. A bigger family of machine learning techniques built on artificial neural networks and representation learning is deep learning (DL). To clarify, we require AI, ML, and DL to predict cancer risk, survival chances, cancer recurrence, cancer diagnosis, and cancer prognosis. All of these are required to improve patient's quality of life, increase their survival rates, decrease anxiety and fear to some extent, and make a proper personalized treatment plan for the suffering patient. The survival rates of people with diffuse large B-cell lymphoma (DLBCL) can be forecasted. Both solid and non-solid tumors can be diagnosed precisely with the help of AI and ML algorithms. The prognosis of the disease can also be forecasted with AI and its approaches like deep learning. This improvement in cancer care is a turning point in advanced healthcare and will deeply impact patient's life for good. |
Epstein-Barr Virus-Positive Primary Diffuse Large B-cell Lymphoma of the Colon in a Patient With Human Immunodeficiency Virus. | Colorectal lymphomas of primary origin are rare neoplasms accounting for 3% of all lymphomas involving the gastrointestinal (GI) tract, and of that 3%, 0.1-0.5% involve the colorectal region. Among the types of non-Hodgkin's lymphomas involving the GI tract, diffuse large B-cell lymphoma (DLBCL) is the most common type. While extranodal involvement of DLBCL in the GI is common, DLBCL of the colon with Epstein-Barr virus positivity is a rare entity with only a few cases reported in the literature. Here, we present a rare case of a 53-year-old female with human immunodeficiency virus (HIV) who presented with generalized abdominal pain, weight loss, night sweats, and fevers. A computed tomography scan of the abdomen and pelvis showed a mass on the right side of the colon with associated retroperitoneal and right inguinal lymphadenopathy. She later underwent a colonoscopy with a biopsy. Histopathology showed DLBCL of the ascending colon and chemotherapy was initiated. |
SLP76 Mutation Associated with Combined Immunodeficiency and EBV-Related Lymphoma. | Increased susceptibility to develop severe forms of Epstein-Barr virus (EBV) infection in early age is a significant hallmark of an underlying primary immunodeficiency (PID). Here, we present immunologic and genetic evaluations of a 3-year-old child who was born to first-cousins parents and presented with recurrent infections, failure to thrive, and severe EBV-related infection and proliferation. A diagnosis of diffuse large B cell lymphoma was made and the immunological workup was suggestive of T cell immunodeficiency. Unfortunately, the patient succumbed to EBV-related lymphoma. Whole-exome sequencing revealed a novel homozygous mutation, c.991del.C; p. Q331Sfs*6 in the SLP76 gene. The SLP76 protein, a TCR signaling molecule, was recently linked to a human disease of the immune system. In order to examine the effect of this new SLP76 mutation on T cell signaling, a SLP76-deficient Jurkat-derived T cell line was transduced either with wild-type (WT), or with the specific SLP76 mutant, or with a mock vector. Downstream TCR signaling events, including ERK1/2 phosphorylation, CD69 expression, and Ca2 + mobilization, were reduced in cells harboring the reported mutation, linking this novel mutation to the expected immunological outcome. SLP76 deficiency should be added to the growing list of monogenetic diseases that predispose affected individuals to acquire severe and uncontrolled EBV infections and to develop substantial complications. This case further links mutations in the SLP76 gene to a significant human immunodeficiency and extends its clinical phenotype. |
Milk consumption and risk of twelve cancers: A large-scale observational and Mendelian randomisation study. | Milk consumption is a modifiable lifestyle factor that has been associated with several cancer types in observational studies. Limited evidence exists regarding the causality of these relationships. Using a genetic variant (rs4988235) near the lactase gene (LCT) locus that proxies milk consumption, we conducted a comprehensive survey to assess potential causal relationships between milk consumption and 12 types of cancer.
Our analyses were conducted using white British participants of the UK Biobank (n = up to 255,196), the FinnGen cohort (up to 260,405), and available cancer consortia. We included cancers with previous evidence of an association with milk consumption in observational studies, as well as cancers common in both UK Biobank and FinnGen populations (>1000 cases). We evaluated phenotypic associations of milk intake and cancer incidence in the UK Biobank, and then used a Mendelian randomisation (MR) approach to assess causality in the UK Biobank, FinnGen consortium, and combined analyses incorporating additional consortia data for five cancers. In MR meta-analyses, case numbers for cancers of breast, ovary, uterus, cervix, prostate, bladder and urinary tract, colorectum, and lung ranged between 6000 and 148,000 cases, and between 780 and 1342 cases for cancers of the liver, mouth, stomach and diffuse large B-cell lymphoma.
In observational analyses, milk consumption was associated with higher risk of bladder and urinary tract cancer (OR 1.23, 95% CI 1.03-1.47), but not with any other cancer. This association was not confirmed in the MR analysis, and genetically predicted milk consumption showed a significant association only with lower risk of colorectal cancer (0.89, 0.81-0.98 per additional 50 g/day). In the MR analyses conducted among individual cohorts, genetically predicted milk consumption provided evidence for an association with lower colorectal cancer in the FinnGen cohort (0.85, 0.74-0.97), and in the UK Biobank greater risk of female breast cancer (1.12, 1.03-1.23), and uterine cancer in pre-menopausal females (3.98, 1.48-10.7).
In a comprehensive survey of milk-cancer associations, we confirm of a protective role of milk consumption for colorectal cancer. Our analyses also provide some suggestion for higher risks of breast cancer and premenopausal uterine cancer, warranting further investigation. |
The dual role of CD70 in B-cell lymphomagenesis. | CD70 is a costimulatory molecule that is transiently expressed on a small set of activated lymphocytes and is involved in T-cell-mediated immunity. However, the role of CD70 in B-cell malignancies remains controversial.
We investigated the clinical relevance of CD70 genetic alterations and its protein expression in two diffuse large B-cell lymphoma (DLBCL) cohorts with different ethnic backgrounds. We also performed transcriptomic analysis to explore the role of CD70 alterations in tumour microenvironment. We further tested the blockade of CD70 in combination with PD-L1 inhibitor in a murine lymphoma model.
We showed that CD70 genetic aberrations occurred more frequently in the Chinese DLBCL cohort (56/233, 24.0%) than in the Swedish cohort (9/84, 10.8%), especially in those with concomitant hepatitis B virus (HBV) infection. The CD70 genetic changes in DLBCL resulted in a reduction/loss of protein expression and/or CD27 binding, which might impair T cell priming and were independently associated with poor overall survival. Paradoxically, we observed that over-expression of CD70 protein was also associated with a poor treatment response, as well as an advanced disease stage and EBV infection. More exhausted CD8
Our findings suggest that CD70 can play a role in either tumour suppression or oncogenesis in DLBCL, likely via distinct immune evasion mechanisms, that is, impairing T cell priming or inducing T cell exhaustion. Characterisation of specific dysfunction of CD70 in DLBCL may thus provide opportunities for the development of novel targeted immuno-therapeutic strategies. |
Summary of the current status of clinically diagnosed cases of Schnitzler syndrome in Japan. | Schnitzler syndrome is a rare disorder with chronic urticaria, and there is no report summarizing the current status in Japan.
A nationwide survey of major dermatology departments in Japan was conducted in 2019. We further performed a systematic search of PubMed and Ichushi-Web, using the keywords "Schnitzler syndrome" and "Japan" then contacted the corresponding authors or physicians for further information.
Excluding duplicates, a total of 36 clinically diagnosed cases were identified from 1994 through the spring of 2022, with a male to female ratio of 1:1. The median age of onset was 56.5 years. It took 3.3 years from the first symptom, mostly urticaria, to reach the final diagnosis. The current status of 30 cases was ascertained; two patients developed B-cell lymphoma. SchS treatment was generally effective with high doses of corticosteroids, but symptoms sometimes recurred after tapering. Colchicine was administered in 17 cases and was effective in 8, but showed no effect in the others. Tocilizumab, used in six cases, improved laboratory abnormalities and symptoms, but lost its efficacy after several years. Rituximab, used in five cases, was effective in reducing serum IgM levels or lymphoma mass, but not in inflammatory symptoms. Four cases were treated with IL-1 targeting therapy, either anakinra or canakinumab, and achieved complete remission, except one case with diffuse large B-cell lymphoma.
Since Schnitzler syndrome is a rare disease, the continuous collection and long-term follow-up of clinical information is essential for its appropriate treatment and further understanding of its pathophysiology. |
Quantitative evaluation of therapy options for relapsed/refractory diffuse large B-cell lymphoma: A model-based meta-analysis. | New therapies for relapsed/refractory diffuse large B-cell lymphoma (r/rDLBCL) have emerged in recent years, but there have been no comprehensive quantitative comparisons of the efficacy of these therapies. In this study, the efficacy characteristics of 11 types of treatment strategy and 63 treatment regimens were compared by model based meta-analysis. We found that compared with monotherapy, association therapy had significant benefits in terms of overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). However, whereas treatment regimens involving chemotherapy contributed to significant improvements in ORR and PFS, OS was not improved. In terms of treatment strategy, we identified chemotherapy in association with immunotherapy sequential autologous stem cell transplantation (ASCT), the association of two different types of immunotherapies, chemotherapy sequential ASCT, chemotherapy in association with immunotherapy, and chemotherapy in association with two types of immunotherapies as showing better efficacy. With respect to specific treatment regimens, we found that the following had better efficacy: rituximab in association with inotuzumab ozogamicin; rituximab in association with carmustine, etoposide, cytarabine, and melphalan sequential ASCT (R-BEAM+ASCT); lenalidomide in association with rituximab, etoposide, cisplatin, cytarabine, and methylprednisolone; iodine-131 tositumomab in association with BEAM sequential ASCT; and chemotherapy sequential chimeric antigen receptor T-cell immunotherapy, with median OS of 48.2, 34.2, 27.8, 25.8, and 25 months, respectively. Moreover, with respect to association therapy, there was a strong correlation between the 6-month PFS and 2-year OS. The findings of this study provide the necessary quantitative information for clinical practice and clinical trial design for the treatment of r/rDLBCL. |
Large B-cell lymphoma with IRF4 gene rearrangements: differences in clinicopathologic, immunophenotypic and cytogenetic features between pediatric and adult patients. | Large B-cell lymphoma (LBL) with interferon regulatory factor 4 (IRF4) rearrangement (LBL-IRF4), a provisional entity in the 2017 WHO classification, primarily arises in children and young adults and has a favorable prognosis. However, few studies have addressed the clinicopathologic and cytogenetic features of older adults with IRF4-rearranged B-cell lymphomas. From a database of all internal and external cases (08/01/2015 to 12/01/2020) on which interphase fluorescence in situ hybridization was performed at the Mayo Clinic, we identified 43 patients with B-cell lymphoma and IRF4 rearrangements. Consistent features included large cell morphology, expression of CD20, BCL6, and MUM1, and absence of MYC-R. All pediatric cases (n=12) arose in Waldeyer's ring (WR), cervical lymph node (CLN), or bowel, and lacked BCL6-R and BCL2-R, and all but one showed classic morphology. Adults with WR, CLN, or bowel involvement (n=22) were younger (median 32 years). Their lymphomas resembled pediatric cases morphologically and lacked BCL2-R, although 30% harbored BCL6-R (p=0.043). Lymphomas that involved other anatomic sites (n=9) arose in older adults (median 68 years; p=0.002) and often showed atypical morphology (p<0.001). All lacked BCL6-R and 2 of 4 harbored BCL2-R (p<0.001). LBL-IRF4 - arising in WR, CLN, or bowel may represent a distinct clinicopathologic entity characterized by pediatric/younger adult age, classic morphology, and lack of BCL2-R. In contrast, B-cell lymphomas with IRF4-R that arise in other sites usually involve older adults, are often morphologically atypical and/or harbor BCL2-R, and may be more akin to diffuse LBL, not otherwise specified. |
Potential Role of 68Ga-NOTA-Duramycin PET/CT Imaging for Early Response Evaluation in a Lymphoma Patient: A Case Report. | Duramycin, a 19 amino acids peptide, is known for its potential to target phosphatidylethanolamine. During cell death (apoptosis), rearrangement of membrane phospholipids results in the externalization of phosphatidylethanolamine to the outer leaflet of the cell membrane, which can be imaged using 68Ga-NOTA-duramycin. We report 68Ga-NOTA-duramycin imaging in a 50-year-old man with biopsy-proven diffuse large B-cell lymphoma planned for anthracycline-based chemotherapy. 68Ga-NOTA-duramycin PET/CT imaging along with 18F-FDG PET/CT was performed before and after 2 cycles of chemotherapy. The tracer avidity in interim 68Ga-NOTA-duramycin PET/CT showed its diagnostic potential to assess early response to chemotherapy. |
Ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone in patients with previously untreated non-germinal centre B-cell-like diffuse large B-cell lymphoma: A Chinese subgroup analysis of the phase III PHOENIX trial. | In this post hoc subgroup analysis of 200 patients enrolled in China from the phase III PHOENIX trial ( |
Identifying the Effect of COVID-19 Infection in Multiple Myeloma and Diffuse Large B-Cell Lymphoma Patients Using Bioinformatics and System Biology. | The severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), also referred to as COVID-19, has spread to several countries and caused a serious threat to human health worldwide. Patients with confirmed COVID-19 infection spread the disease rapidly throughout the region. Multiple myeloma (MM) and diffuse large B-cell lymphoma (DLBCL) are risk factors for COVID-19, although the molecular mechanisms underlying the relationship among MM, DLBCL, and COVID-19 have not been elucidated so far. In this context, transcriptome analysis was performed in the present study to identify the shared pathways and molecular indicators of MM, DLBCL, and COVID-19, which benefited the overall understanding of the effect of COVID-19 in patients with MM and DLBCL. Three datasets (GSE16558, GSE56315, and GSE152418) were downloaded from the Gene Expression Omnibus (GEO) and searched for the shared differentially expressed genes (DEGs) in patients with MM and DLBCL who were infected with SARS-CoV-2. The objective was to detect similar pathways and prospective medicines. A total of 29 DEGs that were common across these three datasets were selected. A protein-protein interaction (PPI) network was constructed using data from the STRING database followed by the identification of hub genes. In addition, the association of MM and DLBCL with COVID-19 infection was analyzed through functional analysis using ontologies terms and pathway analysis. Three relationships were observed in the evaluated datasets: transcription factor-gene interactions, protein-drug interactions, and an integrated regulatory network of DEGs and miRNAs with mutual DEGs. The findings of the present study revealed potential pharmaceuticals that could be beneficial in the treatment of COVID-19. |
Total Knee Arthroplasty Complicated by Diffuse Large B-Cell Lymphoma. | A 74-year-old male with a prior left total knee arthroplasty presented with deformity, loosening, pain, and stiffness associated with multiple raised, erythematous, cutaneous nodules about the anterior knee. Workup was concerning for infection, but the skin nodules were atypical. The patient was sent for biopsy which revealed cutaneous diffuse large B-cell lymphoma. The revision surgery was delayed, and the patient underwent chemotherapy/radiation with complete resolution of his lymphoma. He then underwent a successful aseptic revision total knee arthroplasty. Proper identification and treatment of rare cutaneous skin lesions about a prior surgical site can limit morbidity and result in more desirable outcomes. |
Circulating tumor DNA mutation profile is associated with the prognosis and treatment response of Chinese patients with newly diagnosed diffuse large B-cell lymphoma. | Characterization of gene mutation profiles can provide new treatment options for patients with diffuse large B-cell lymphoma (DLBCL). However, this method is challenged by the limited source of tissue specimens, especially those of DLBCL patients at advanced stages. Therefore, in the current study, we aimed to describe the gene mutation landscape of DLBCL using circulating tumor DNA (ctDNA) samples obtained from patients' blood samples, as well as to explore the relationship between ctDNA mutations and the prognosis and treatment response of patients with newly diagnosed DLBCL.
A total of 169 newly diagnosed Chinese DLBCL patients were included in this study, among which 85 patients were divided into a training set and 84 were assigned into a validation set. The mutation profile of a 59-gene panel was analyzed by targeted next generation sequencing (NGS) of the patients' ctDNA samples. Differences in clinical factors between patients with and without ctDNA mutations were analyzed. In addition, we also explored gene mutation frequencies between GCB and non-GCB subtypes, and the relationship between gene mutation status, clinical factors, mean VAF (variant allele frequencies) and the patients' overall survival (OS) and progression-free survival (PFS).
ctDNA mutations were detected in 64 (75.3%) patients of the training set and 67 (79.8%) patients of the validation set. The most commonly mutated genes in both sets were
We investigated the ctDNA mutation landscape in Chinese patients with newly diagnosed DLBCL and found that ctDNA could reflect tumor burden and patients with detectable ctDNA mutations trended to have shorter OS and PFS and a lower CR rate. |
Follicle Center Lymphoma (FCL) of the Lower Female Genital Tract (LFGT): A Novel Variant of Primary Cutaneous Follicle Center Lymphoma (PCFCL). | Primary cutaneous follicle center lymphoma has been distinguished from nodal follicular lymphoma (FL) based on genomic and clinical features. The nature of other extranodal FLs is not well defined. We report 15 cases of follicle center lymphoma involving the lower female genital tract. Cases were evaluated using an immunohistochemical panel for B-cell lymphoma, B-cell clonality, fluorescence in situ hybridization for BCL2 gene rearrangement, and next-generation sequencing. All patients had localized disease with no evidence of bone marrow involvement. Most cases (12/15, 80%) had a follicular pattern, at least focally. Large centrocytes were a prominent feature leading to concern for diffuse large B-cell lymphoma by referring pathologists. Neoplastic cells were positive for CD20 and BCL-6, while BCL-2 was positive in 2/15 (13%) cases. Fluorescence in situ hybridization for BCL2 gene rearrangement was negative in 10/11 (91%) cases. Next-generation sequencing performed in 10 cases revealed TNFRSF14 as the most frequently mutated gene in 6/10 (60%) cases. No case had CREBBP or KMT2D mutations as seen in nodal FL. None of the patients had progressive disease with durable complete remission achieved in 10/12 (83%) cases. The median follow-up period was 7.8 years (range: 0.2 to 20.5 y) with a 5-year overall survival of 100%. We conclude that follicle center lymphoma of the lower female genital tract is a novel variant of primary cutaneous follicle center lymphoma. Despite a frequent component of large cells, it is characterized by localized disease and low risk for dissemination. Awareness and recognition are important to distinguish these lesions from aggressive B-cell lymphomas. |
Diffuse large B-cell lymphomas, not otherwise specified, and emerging entities. | Diffuse large B-cell lymphoma (DLBCL) is an aggressive and heterogenous group of diseases and the most common subtype of non-Hodgkin lymphoma. In the past decade, there has been an explosion in molecular profiling that has helped to identify subgroups and shared oncogenic driving mechanisms. Since the 2017 World Health Organization (WHO) classification, additional studies investigating these genomic abnormalities and phenotypic findings have been reported. Here we review these findings in DLBCL and address the proposed changes by the 2022 International Consensus Classification. |
Plasmablastic Lymphoma of the Endometrium: A Rare Site for Primary Presentation. | Global incidence of non-Hodgkin's lymphoma (NHL) is 3% of which 1% occurs in extranodal lymphoma. Plasmablastic lymphoma (PBL) is a rare and aggressive variant of diffuse large B-cell lymphoma (DLBCL). It is usually seen in human immunodeficiency virus (HIV) infected patients. PBL occurring in extranodal site, particularly female genital tract, is very rare, and only few case reports have been reported. Here, we report a unique rare case of uterine PBL in an HIV/Epstein-Barr virus-negative patient that was initially diagnosed as endometrioid carcinoma. |
Dysregulation of FBW7 in malignant lymphoproliferative disorders. | The ubiquitin-proteasome system (UPS) is involved in various aspects of cell processes, including cell proliferation, differentiation, and cell cycle progression. F-box and WD repeat domain-containing protein 7 (FBW7), as a key component of UPS proteins and a critical tumor suppressor in human cancers, controls proteasome-mediated degradation by ubiquitinating oncoproteins such as c-Myc, Mcl-1, cyclin E, and Notch. It also plays a role in the development of various cancers, including solid and hematological malignancies, such as T-cell acute lymphoblastic leukemia, diffuse large B-cell lymphoma, and multiple myeloma. This comprehensive review emphasizes the functions, substrates, and expression of FBW7 in malignant lymphoproliferative disorders. |
Prognostic impact of peripheral eosinophil counts in patients with diffuse large B-cell lymphoma receiving chimeric antigen receptor T-cell therapy. | Chimeric antigen receptor (CAR) T-cell therapy is a breakthrough treatment for patients with relapsed or refractory diffuse large B-cell lymphoma. However, many patients do not achieve remission or relapse after remission. Previous studies have demonstrated that eosinophils have synergistic anti-tumor effects with CD8
We retrospectively analyzed the eosinophil counts of patients with diffuse large B-cell lymphoma and found it changed remarkably pre- and post-CAR T-cell therapy.
Patients who achieved complete remission after CAR T-cell infusion had greater post-CAR T-eosinophil counts than those who did not. Kaplan-Meier curves showed that patients with greater eosinophil counts during the second month after CAR T-cell infusion had superior progression-free survival and overall survival compared with those with lower eosinophil counts.
For patients who responded to CAR T-cell therapy, eosinophil counts also can be used to predict 6-month duration of response. In conclusion, the post-CAR T-eosinophil count is associated with the prognosis of patients treated with CAR T-cell therapy and can be used to clinically identify patients who can achieve longer remission after CAR T-cell infusion. |
Anti-spike antibody response to the COVID vaccine in lymphoma patients. | Patients with hematologic malignancies have poor outcomes from COVID infection and are less likely to mount an antibody response after COVID infection. This is a retrospective study of adult lymphoma patients who received the COVID vaccine between 12/1/2020 and 11/30/2021. The primary endpoint was a positive anti-COVID spike protein antibody level following the primary COVID vaccination series. The primary vaccination series was defined as 2 doses of the COVID mRNA vaccines or 1 dose of the COVID adenovirus vaccine. Subgroups were compared using Fisher's exact test, and unadjusted and adjusted logistic regression models were used for univariate and multivariate analyses. A total of 243 patients were included in this study; 72 patients (30%) with indolent lymphomas; 56 patients (23%) with Burkitt's, diffuse large B-cell lymphoma (DLBCL), and primary mediastinal B-cell lymphoma (PMBL) combined; 55 patients (22%) with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL); 44 patients (18%) with Hodgkin and T-cell lymphomas (HL/TCL) combined; 12 patients (5%) with mantle cell lymphoma; and 4 patients (2%) with other lymphoma types. One-hundred fifty-eight patients (65%) developed anti-COVID spike protein antibodies after completing the primary COVID vaccination series. Thirty-eight of 46 (83%) patients who received an additional primary shot and had resultant levels produced anti-COVID spike protein antibodies. When compared to other lymphoma types, patients with CLL/SLL had a numerically lower seroconversion rate of 51% following the primary vaccination series whereas patients with HL/TCL appeared to have a robust antibody response with a seropositivity rate of 77% (p = 0.04). Lymphoma patients are capable of mounting a humoral response to the COVID vaccines. Further studies are required to confirm our findings, including whether T-cell immunity would be of clinical relevance in this patient population. |
Predictors of response to axicabtagene-ciloleucel CAR T cells in aggressive B cell lymphomas: A real-world study. | Chimeric antigen receptor T-cell (CAR T) therapy has shown promising efficacy in relapsed and refractory diffuse large B cell lymphoma (DLBCL). While most patients undergo CAR T infusion with active disease, the impact of some clinical variables, such as responsiveness to the pre-CAR T chemotherapy on the response to CAR T, is unknown. In this single-institution study, we studied the impact of several pre-CAR T variables on the post-CAR outcomes. Sixty patients underwent apheresis for axicabtagene-ciloleucel (axi-cel) and 42 of them (70.0%) had primary refractory disease. Bridging therapy between apheresis and lymphodepletion was given in 34 patients (56.7%). After axi-cel, the overall response rate was 63.3%. Responsiveness to the immediate pre-CAR T therapy did not show a significant association with response to axi-cel, progression-free (PFS) or overall (OS) survival. Multivariable analysis determined that bulky disease before lymphodepletion was independently associated with inferior outcomes, and patients that presented with high-burden disease unresponsive to immediate pre-CAR T therapy had a dismal outcome. This data supports proceeding with treatment in CAR T candidates regardless of their response to immediate pre-CAR T therapy. Interim therapeutic interventions should be considered in patients who have known risk factors for poor outcomes (bulky disease, high LDH). |
Diffuse Large B-Cell Lymphoma of Thyroid: A Case Report and Review of Literature. | Primary thyroid lymphoma is a rare malignancy, accounting for 1-2% of extra-nodal lymphomas and 1-5% of thyroid malignancies. Diffuse large B-cell lymphoma is the most common type of primary thyroid lymphoma. It usually presents with a rapidly enlarging neck mass with cervical lymphadenopathy. Though rare, early diagnosis of this condition is important because its management is quite different from the treatment of other thyroid neoplasms. It is usually treated by chemotherapy with or without radiotherapy. We present the case of a 43 years old male who presented with thyroid swelling which on histopathology and subsequent immunohistochemistry was confirmed as diffuse large B-cell lymphoma of the thyroid. |
Case report and review of the literature of primary central nervous system lymphoma of the fourth ventricle. | Primary central nervous system lymphoma of the fourth ventricle is very rare. We present a case of primary central nervous system lymphoma originating from the fourth ventricle and review cases reported in the literature.
A 54-year-old man with no previous medical history presented with headache and nausea. Magnetic resonance imaging showed a homogeneously enhancing tumor in the fourth ventricle and obstructive hydrocephalus. We performed biopsy of the tumor, which was diagnosed pathologically as diffuse large B-cell lymphoma. Although the tumor disappeared after 5 cycles of R-MPV regimen, the patient required repeated ventricular drainage and finally received a ventriculoperitoneal shunt. Complete response was achieved after 2 cycles of high-dose cytarabine chemotherapy with an autologous peripheral blood stem cell transplant. There was no sign of recurrence at 20 months after biopsy.
Morbidity arising due to radical resection/radiotherapy of resistant primary central nervous system lymphoma originating from the fourth ventricle could be prevented by ventriculoperitoneal shunting with chemotherapy and autologous blood stem cell transplantation. |
Plasmablastic Lymphoma in an Immunocompetent Patient: A Case Report and Literature Review. | Plasmablastic lymphoma (PBL) is considered an aggressive rare variant of diffuse large B-cell lymphoma that has a predilection to develop in immunocompromised patients, particularly HIV-positive individuals. This report highlights the development of such a rare and aggressive malignancy in a 55-year-old immunocompetent male. It outlines the atypical clinical presentation and pathological features of this disease entity. Overall prognosis and response to chemotherapy differ in the absence or presence of immunosuppression. This report includes a summary of the epidemiologic, clinical, and immunohistochemical characteristics of PBL based on a comprehensive review of the reported cases occurring in immunocompetent individuals. |
Primary splenic T-cell/histiocyte-rich B-cell lymphoma in a patient with recurrent hairy cell leukemia: a case report. | T-cell/histiocyte-rich B-cell lymphoma is a high-grade, morphologic variant of diffuse large B-cell lymphoma. T-cell/histiocyte-rich B-cell lymphoma. It is rare as a primary splenic involvement and is usually reported as a second malignancy after hairy cell leukemia. Here, we report the first case that describes the occurrence of primary splenic T-cell/histiocyte-rich B-cell lymphoma in a patient with a previous diagnosis of recurrent hairy cell leukemia. A 53-year-old male patient was diagnosed with hairy cell leukemia in 1996 and achieved complete remission with Pentostatin. Then, recurrence of hairy cell leukemia was diagnosed in 2015 and treated with Cladribine. In 2016, he presented with B symptoms and hypersplenism. Therapeutic and diagnostic splenectomy was performed. Histopathological study with immunohistochemistry evaluation revealed the presence of T-cell/histiocyte-rich B-cell lymphoma. Therefore, second malignancies should be considered in patients with a previous neoplasm when symptoms recur or develop. |
Healthcare Resource Utilization and Associated Costs of German Patients with Diffuse Large B-Cell Lymphoma: A Retrospective Health Claims Data Analysis. | Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin's lymphoma with increasing prevalence. Although the disease burden associated with DLBCL is high, only limited data on healthcare resource utilization (HCRU) and associated costs of German patients with DLBCL is available.
Using a large claims database of the German statutory health insurance with 6.7 million enrollees, we identified patients who were newly diagnosed with DLBCL between 2011 and 2018 (index date). Treatment lines were identified based on a predefined set of medication. HCRU and related costs were collected for the entire post index period and per treatment line.
A total of 2495 incident DLBCL patients were eligible for the analysis. The average follow-up time after index was 41.7 months. During follow-up, 1991 patients started a first-line treatment, 868 a second-line treatment, and 354 a third-line treatment. Overall, patients spent on average (SD) 5.24 (6.17) days per month in hospital after index. While on anti-cancer treatment, this number increased to nine (10.9) in first-line, 8.7 (13.7) in second-line, and 9.4 (15.8) in third-line treatments. Overall costs per patient per month (PPPM) increased from €421 (875.70) before to €3695 (4652) after index. While on a treatment line, PPPM costs were €17,170 (10,246) in first-line, €13,362 (12,685) in second-line, and €12,112 (16,173) in third-line treatments. Time-unadjusted absolute costs sum up to €59,868 (43,331), €35,870 (37,387), and €28,832 (40,540) during first-line, second-line, and third-line treatments, respectively. The main cost drivers were hospitalizations (71% of total costs) and drug acquisition costs (18% of total costs).
The financial burden of DLBCL in Germany is high, mainly due to hospitalization and drug costs. Therefore, there is a high medical need for new cost-effective therapeutic options that can lower the disease burden and remain financially viable to support the growing number of patients with this aggressive disease. |
Diabetes, Metformin Use, and Risk of Non-Hodgkin's Lymphoma in Postmenopausal Women: A Prospective Cohort Analysis in the Women's Health Initiative. | Epidemiologic evidence is limited about associations between T2DM, metformin, and the risk of non-Hodgkin's lymphoma (NHL). We aimed to examine associations between T2DM, metformin, and the risk of NHL in the Women's Health Initiative (WHI) Study. Information on T2DM status (diabetes status/types of antidiabetic drug use/diabetes duration) from study enrollment and during follow-up were assessed. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to evaluate associations of T2DM status with risks of overall NHL and its 3 major subtypes (diffuse large B-cell lymphoma (DLBCL), (n=476), follicular lymphoma (FL), (n=301), and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), (n=136)) based on multivariable-adjusted Cox proportional hazards models. During a median follow-up of 18.86-years (range, 0.01 to 25.13; SD±6.55), a total of 1,637 women developed NHL among 147,885 postmenopausal women. Women with T2DM and with self-reported oral medication use had 38% and 55% higher risk of DLBCL, respectively (multivariable-adjusted model HR=1.38, 95%CI (1.06-1.81) and HR=1.55, 95%CI (1.16-2.06)) compared to the reference group (nondiabetics/untreated diabetes). Risks of NHL and DLBCL (multivariable-adjusted model: HR=1.28, 95%CI (1.06-1.54) and HR=1.56, 95%CI (1.13-2.14), respectively) were significantly higher in associations with relatively short duration (≤7 years) of diabetes, compared to reference group. Additionally, an increased risk of DLBCL (HR=1.76, 95%CI (1.13-2.75)) was found in metformin users compared to the reference group. Postmenopausal women who had T2DM, who were oral antidiabetic drug users, especially metformin, and who had a shorter diabetes duration may have higher risks of DLBCL. Further well-designed research is needed to confirm our findings. This article is protected by copyright. All rights reserved. |
Clinical Characteristics, Outcomes, and Risk Factors for Patients with Diffuse Large B-Cell Lymphoma and Development of Nomogram to Identify High-Risk Patients. | To analyse the clinical features, outcomes, and risk factors of patients with diffuse large B-cell lymphoma (DLBCL) in China, with the aim to establish a new prognostic model based on risk factors.
Clinical features and outcomes of 564 patients newly diagnosed with DLBCL from Jan 2009 to May 2017 were analyzed retrospectively. Variables were screened by LASSO regression and nomogram was constructed.
The 5-year overall survival (OS) of the cohort was 75%. The 5-year OS of patients differentiated by International Prognostic Index (IPI) score was 90% (score 0-2), 73% (score 3), and 51% (score 4-5), respectively. Age > 60, Eastern Cooperative Oncology Group (ECOG) > 1, Ann Arbor stage III-IV, bone marrow involvement, low level of albumin (ALB), and lymphatic/monocyte ratio (LMR) were independent predictors of OS. The predictive model was developed based on factors including age, bone marrow involvement, LMR, ALB, and ECOG scores. The predictive ability of the model (AUC, 0.77) was better than that of IPI (AUC, 0.74) and NCCN-IPI (AUC, 0.69). The 5-year OS of patients in the low-, intermediate-, and high-risk groups identified by the new predictive model was 89%, 70%, and 33%, respectively.
The new prediction model had better predictive performance and could better identify high-risk patients. |
Mutational patterns along different evolution paths of follicular lymphoma. | Follicular lymphoma (FL) is an indolent disease, characterized by a median life expectancy of 18-20 years and by intermittent periods of relapse and remission. FL frequently transforms into the more aggressive diffuse large B cell lymphoma (t-FL). In previous studies, the analysis of immunoglobulin heavy chain variable region (IgHV) genes in sequential biopsies from the same patient revealed two different patterns of tumor clonal evolution: direct evolution, through acquisition of additional IgHV mutations over time, or divergent evolution, in which lymphoma clones from serial biopsies independently develop from a less-mutated common progenitor cell (CPC). Our goal in this study was to characterize the somatic hypermutation (SHM) patterns of IgHV genes in sequential FL samples from the same patients, and address the question of whether the mutation mechanisms (SHM targeting, DNA repair or both), or selection forces acting on the tumor clones, were different in FL samples compared to healthy control samples, or in late relapsed/transformed FL samples compared to earlier ones. Our analysis revealed differences in the distribution of mutations from each of the nucleotides when tumor and non-tumor clones were compared, while FL and transformed FL (t-FL) tumor clones displayed similar mutation distributions. Lineage tree measurements suggested that either initial clone affinity or selection thresholds were lower in FL samples compared to controls, but similar between FL and t-FL samples. Finally, we observed that both FL and t-FL tumor clones tend to accumulate larger numbers of potential N-glycosylation sites due to the introduction of new SHM. Taken together, these results suggest that transformation into t-FL, in contrast to initial FL development, is not associated with any major changes in DNA targeting or repair, or the selection threshold of the tumor clone. |
Diffuse Large B-cell Lymphoma Presenting as an "Oops" Lesion in the Nasolabial Fold: A Case Report. | Diffuse large B-cell lymphomas are the most common type of non-Hodgkin lymphoma. Because cutaneous lymphomas predominantly originate from the T cells, primary cutaneous diffuse large B-cell lymphomas are considered a rare subtype of extranodal diffuse large B-cell lymphomas that commonly involve the subcutaneous tissues of the trunk and extremities. To date, only a single case of facial primary cutaneous diffuse large B-cell lymphoma has been reported in the literature.
We present a case of primary cutaneous diffuse large B-cell lymphoma presented with a small painless nodule in the right nasolabial fold that had persisted for 10 days in a 67-year-old man. Ultrasonographic findings of this lesion mimicked the features of a complicated epidermal inclusion cyst. Primary cutaneous diffuse large B-cell lymphoma was confirmed by an excisional biopsy of the mass Conclusion: The diagnosis of primary cutaneous diffuse large B-cell lymphomas presenting as "oops lesions" in daily clinical practice can be challenging due to their rarity and nonspecific clinical and radiological findings. Therefore, clinical suspicion and awareness are critical for the accurate diagnosis and management of patients with palpable soft tissue masses in the head and neck region. |
null | To develop a combined model incorporating the clinical and PET features for identifying patients with diffuse large B-cell lymphoma (DLBCL) at high risk of progression or relapse after first-line therapy, compared to International Prognostic Index (IPI) and Deauville score (DS) assessment.
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In the test set, the best combined model showed better discriminative power compared to IPI model, the best baseline clinical model, DS model, the best combined clinical model, and the best PET-based radiomics model (AUC 0.898 vs. 0.584, 0.695, 0.756, 0.824, 0.832; p < 0.001, 0.014, 0.018, 0.152, 0.042, respectively). The combined model was superior to other models for progression-free-survival prediction (C-index: 0.853 vs. 0.568, 0.666, 0.753, 0.808, 0.814, respectively).
A combined model for identifying patients at high risk of progression or relapse after first-line therapy was constructed, superior to IPI and DS assessment. |
Anti-CD19 chimeric antigen receptor T cells secreting anti-PD-L1 single-chain variable fragment attenuate PD-L1 mediated T cell inhibition. | Adoptive T cell therapy using second-generation anti-CD19 chimeric antigen receptor T cells (anti-CD19-CAR2-T) induced complete remission in many heavily pretreated patients with B cell acute lymphoblastic leukemia (B-ALL) or diffuse large B cell lymphoma (DLBCL). However, poor clinical efficacy was observed in treating aggressive B cell lymphomas (BCL). The limited T cell function was reported by programmed cell death protein 1 ligand (PD-L1) expressed on BCL cells bound to the PD-1 receptor on T cells. To overcome this problem, we generated anti-CD19-CAR4-T cells secreting anti-PD-L1 single-chain variable fragment (scFv), namely anti-CD19-CAR5-T cells, and evaluated their functions in vitro. Both anti-CD19-CAR-T cells contain an anti-CD19 scFv derived from a monoclonal antibody, FMC63, linked to CD28/4-1BB/CD27/CD3ζ. The secreting anti-PD-L1 scFv is derived from atezolizumab. Our results showed that secreted anti-PD-L1 scFv could bind to PD-L1 and block the binding of anti-PD-L1 monoclonal antibodies on PD-L1 |
Primary sinonasal lymphoma: A multi-institutional experience of clinical presentation, treatment, and outcomes. | Sinonasal lymphoma (SL) is a heterogenous, underrecognized neoplastic disorder with limited outcomes data. We sought to better define outcomes by subtype and treatment at two referral centers over the last two decades.
Demographics, clinicopathologic data, and treatment outcomes for patients treated for SL were queried from January 1, 2000 to December 31, 2021 at two tertiary academic medical centers.
84 patients were included, with an average age at diagnosis of 63.4 ± 15 years. There were 34 females (40.5%). The majority of patients had an ECOG score < 2 (76.2%) and the most common presenting symptom was facial swelling/pain (26.2%). The most common primary site was the nasal cavity (36.9%). Diffuse large B-cell lymphoma was the most common subtype (46.4%), followed by extranodal NK/T cell lymphoma (17.9%). Chemotherapy was the most common treatment strategy (n = 59, 70.2%), followed by radiation therapy (n = 35, 41.7%) and immunotherapy (n = 24, 28.6%). Disease-specific survival (DSS) at 1-, 5-, and 10-years were 85.7%, 73.6%, and 58.6%, respectively. Eighteen patients (21.4%) developed recurrence. On multivariate analysis, higher ECOG score (p < 0.0001) and history of head and neck radiation (p = 0.048) were associated with worse survival. Younger age was associated with greater risk of recurrence (p = 0.022) and male sex was associated with more treatment side effects (p = 0.012).
This is the largest multi-institutional analysis of SL characteristics and outcomes. Our work suggests that while disease control in the first 5 years is reasonable, 10-year outcomes remains challenging. Future studies investigating new treatment paradigms and risk stratification are needed. This article is protected by copyright. All rights reserved. |
Physical Activity Program for the Survival of Elderly Patients With Lymphoma: Study Protocol for Randomized Phase 3 Trial. | The practice of regular physical activity can reduce the incidence of certain cancers (colon, breast, and prostate) and improve overall survival after treatment by reducing fatigue and the risk of relapse. This impact on survival has only been demonstrated in active patients with lymphoma before and after treatment. As poor general health status reduces the chances of survival and these patients are most likely to also have sarcopenia, it is important to be able to improve their physical function through adapted physical activity (APA) as part of supportive care management. Unfortunately, APA is often saved for patients with advanced blood cancer. As a result, there is a lack of data regarding the impact of standardized regular practice of APA and concomitant chemotherapy as first-line treatment on lymphoma survival.
This study aimed to assess the impact of a new and open rehabilitation program suitable for a frail population of patients treated for diffuse large B-cell lymphoma (DLBCL).
PHARAOM (Physical Activity Program for the Survival of Elderly Patients with Lymphoma) is a phase 3 randomized (1:1) study focusing on a frail population of patients treated for DLBCL. The study will include 186 older adult patients with DLBCL (aged >65 years) receiving rituximab and chemotherapy. Overall, 50% (93/186) of patients (investigational group) will receive APA along with chemotherapy, and they will be supervised by a dedicated qualified kinesiologist. The APA program will include endurance and resistance training at moderate intensity 3 times a week during the 6 months of chemotherapy. The primary end point of this study will be event-free survival of the patients. The secondary end points will include the overall survival, progression-free survival, prevalence of sarcopenia and undernutrition, and patients' quality of life. This study will be conducted in accordance with the principles of the Declaration of Helsinki.
Recruitment, enrollment, and data collection began in February 2021, and 4 participants have been enrolled in the study as of July 2022. Data analysis will begin after the completion of data collection. Future outcomes will be published in peer-reviewed health-related research journals and presented at national congress, and state professional meetings. This publication is based on protocol version 1.1, August 3, 2020.
The PHARAOM study focuses on highlighting the benefits of APA intervention on survival during the period of first-line treatment of patients with DLBCL. This study could also contribute to our understanding of how an APA program can reduce complications such as sarcopenia in patients with lymphoma and improve their quality of life. By documenting the prevalence and relationship between sarcopenia and exercise load, we might be able to help physicians plan better interventions in the care of patients with DLBCL.
ClinicalTrials.gov NCT04670029; https://clinicaltrials.gov/ct2/show/NCT04670029.
DERR1-10.2196/40969. |
Lymphoma-associated mutations in autoreactive memory B cells of patients with Sjögren's syndrome. | We recently demonstrated that normal memory B lymphocytes carry a substantial number of de novo mutations in the genome. Here, we performed exome-wide somatic mutation analyses of bona fide autoreactive rheumatoid factor (RF)-expressing memory B cells retrieved from patients with Sjӧgren's syndrome (SS). The amount and repertoire of the de novo exome mutations of RF B cells were found to be essentially different from those detected in healthy donor memory B cells. In contrast to the mutation spectra of normal B cells, which appeared random and non-selected, the mutations of the RF B cells were greater in number and enriched for mutations in genes also found mutated in B-cell non-Hodgkin lymphomas. During the study, one of the SS patients developed a diffuse large B-cell lymphoma (DLBCL) out of an RF clone that was identified two years earlier in an inflamed salivary gland biopsy. The successive oncogenic events in the RF precursor clone and the DLBCL were assessed. In conclusion, our findings of enhanced and selected genomic damage in growth-regulating genes in RF memory B cells of SS patients together with the documented transformation of an RF-precursor clone into DLBCL provide unique novel insight into the earliest stages of B cell derailment and lymphomagenesis. This article is protected by copyright. All rights reserved. |
null | Some cells within a diffuse large B-cell lymphoma (DLBCL) have the genotype of a stem cell, the proportion of which is termed |
Diffuse large B-cell lymphoma and red cell autoimmunity: clinical role and pathogenesis. | Diffuse large B-cell lymphoma (DLBCL) is the most common form of B-cell non-Hodgkin lymphoma (B-NHL) with significant morbidity and mortality despite advancements in treatment. Lymphoma and autoimmune disease both result from breakdowns in normal cell regulatory pathways, and epidemiological studies have confirmed both that B-NHL is more likely to develop in the setting of autoimmune diseases and vice versa. Red cell immunity, as evidenced by direct antiglobulin test (DAT) positivity, has been linked to DLBCL and more recently the pathogenic causes of this association have begun to be better understood using molecular techniques. This project aimed to explore the relationship between red cell autoimmunity and DLBCL. DAT positivity was more common in DLBCL as compared to healthy controls (20.4% vs 3.7%, p=0.0005). Univariate analysis found a non-significant trend towards poorer overall survival in the DAT positive (DAT+) compared to the DAT negative (DAT-) groups (p=0.087). High throughput sequencing was used to compare mutations in DLBCL from DAT+ and DAT- patients. The most frequently mutated genes in 15 patient samples were KMT2D (n=13), MYOM2 (n=9), EP300 (n=8), SPEN (n=7), and ADAMTSL3 (n=7), which were mutated in both DAT+ and DAT- groups. BIRC3 (n=3), FOXO1 (n=3) and CARD11 (n=2) were found to be mutated only in samples from the DAT+ group. These gene mutations may be involved in disease development and progression, and potentially represent targets for future therapy. The immunoglobulin genotype IGHV4-34 is seen more frequently in DLBCL clones than in normal B cells and has intrinsic autoreactivity to self-antigens on red cells, which is largely mediated by two motifs within the first framework region (FR1); Q |
Radiation Therapy for Relapsed or Refractory Diffuse Large B-Cell Lymphoma: What Is the Right Regimen for Palliation? | To report objective response rates (ORR), time to local failure (TTLF), and overall survival (OS) among patients with relapsed or refractory diffuse large B-cell lymphoma after salvage- or palliative-intent radiation therapy (RT) and to investigate whether outcomes differed with conventional versus hypofractionated (≥2.5 Gy/fraction) RT.
A single-institution observational cohort study was performed for patients who completed a course of RT for relapsed or refractory diffuse large B-cell lymphoma between January 1, 2008, and April 1, 2020. Predictors of ORR, TTLF, and OS were calculated using univariable and multivariable regression models. The Kaplan-Meier method was used to estimate TTLF and OS, and log-rank analysis was used to compare outcomes. Equivalent dose in 2 Gy fractions (EQD2) was calculated using an α/β of 10.
One-hundred and sixty-nine patients were treated with 205 RT courses (73 [36%] salvage, 132 [64%] palliative), and hypofractionated RT was used in 100 RT courses (49%). Median RT dose was 30 Gy (range, 8-60 Gy). ORR was 60% for the total cohort (53% and 69% for palliative and salvage cohorts, respectively). Over a median follow-up time of 4 months, median OS in all patients was 5 months (3 and 22 months for palliative and salvage cohorts, respectively). No statistically significant differences in ORR, TTLF, and OS were observed with hypofractionation compared with conventional fractionation. EQD2 ≥35 Gy was associated with improved ORR (odds ratio, 3.79 [1.19-12.03];
Hypofractionation is not associated with differences in disease outcomes for patients with relapsed or refractory diffuse large B-cell lymphoma, while higher RT dose (EQD2 ≥35 Gy) may improve ORR and TTLF. Future work is warranted to elucidate the ideal dose and fractionation schema for such patients who will likely also undergo novel systemic agents and cellular therapies. |
Second Primary Malignancies in Diffuse Large B-cell Lymphoma Survivors with 40 Years of Follow Up: Influence of Chemotherapy and Radiation Therapy. | Previous studies have shown an increased risk of second primary malignancies (SPMs) in survivors of diffuse large B-cell lymphoma (DLBCL). Survivors live longer due to the intensification of and improvements in therapy; thus, we aimed to characterize SPM patterns in patients with DLBCL by treatment modality.
Standardized incidence ratio and absolute excess risk of SPMs were assessed in patients with primary DLBCL from 1975 to 2016 in the National Cancer Institute's Surveillance, Epidemiology, and End Results Program. A subgroup analyses based on, sex, race, age at the time of diagnosis, latency, and treatment modality were performed. Propensity score-adjusted cumulative incidence curves were generated, stratified by treatment and accounting for death as a competing risk.
In total, 45,946 patients with DLBCL were identified with a mean follow up of 70 months. Overall, 9.2% of patients developed an SPM with a standardized incidence ratio of 1.23 (95% confidence interval, 1.20-1.27). There was no difference in SPM risk between men and women or Black and White patients. Patients age <25 years were particularly susceptible to the development of SPMs, with a risk 2.5 times greater than patients aged 50 to 74 years. Temporal patterns showed increasing risk of solid malignancies and decreasing risk of hematologic malignancies over time, with bladder cancer posing the greatest absolute excess risk of any cancer type after 15 years. Patients treated with radiation therapy (RT), chemotherapy (CT), and chemoradiation therapy (CRT) all had an increased risk of SPM development compared with the general population. The cumulative incidence of SPMs was the lowest in patients treated with RT and the highest when treated with CRT. In the modern treatment era, the cumulative incidence of SPM for patients treated with CT versus CRT was not significantly different.
In this large population-based study, we demonstrate unique SPM risk patterns based on age, latency, and treatment modality that have important implications for the treatment and screening of patients diagnosed with DLBCL. |
Cardiac involvement of diffuse large B-cell lymphoma presenting as various arrythmias. | Symptomatic cardiac involvement of malignant lymphoma is rare. Silent invasion of malignant lymphoma makes it difficult to diagnose it in the early phase of clinical course. We describe a case with cardiac involvement of diffuse large B-cell lymphoma presenting various types of arrythmias that were not diagnosed until autopsy. |
How I treat Elderly Patients with DLBCL in the frontline setting. | Diffuse large B-cell lymphoma (DLBCL) is an aggressive but potentially curable disease and is most common in older people. Rituximab-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) is the standard of care for fit patients without cardiac contraindications. In each individual elderly patient the potential gains of treatment should be balanced against the risks of treatment related morbidity and mortality. A simplified comprehensive geriatric assessment or easily performed assessments such as gait speed and grip strength can be helpful to assess the fitness of an elderly patient. Pre-phase with corticosteroids, rigorous supportive care including G-CSF prophylaxis and careful monitoring can be important to prevent adverse events. In unfit elderly patients a dynamic dosing strategy is often applied. For very elderly patients (≥ 80 years) a dose reduced regimen (R-miniCHOP) is recommended. When anthracyclines are contraindicated, doxorubicin can be replaced by etoposide or gemcitabine. Most frail patients do not benefit from chemotherapy. Further progress can be expected from non-chemotherapy based therapies, such as bispecific antibodies, antibody-drug conjugates and immunomodulatory agents. This article provides an overview of first line treatment in elderly patients with DLBCL and our approach to the management of these challenging patients. |
Deep learning-based classifier of diffuse large B-cell lymphoma cell-of-origin with clinical outcome. | Diffuse large B-cell lymphoma (DLBCL) is an aggressive form of non-Hodgkin lymphoma with poor response to R-CHOP therapy due to remarkable heterogeneity. Based on gene expression, DLBCL cases were divided into two subtypes, i.e. ABC and GCB, where ABC subtype is associated with poor outcomes. Due to its association with clinical outcome, this classification, also known as cell-of-origin (COO), is an efficient way to predict the response to R-CHOP therapy. Previous COO classification methods have some shortcomings, e.g. limited number of samples in the training dataset. These shortcomings challenge the robustness of methods and make it difficult to implicate these methods at clinical level. To overcome the shortcomings of previous methods, we developed a deep learning-based classifier model on a cohort of 381 DLBCL patients using expression data of 20 genes. We implemented multilayer perceptron (MLP) to train deep learning-based classifier, named MLP-COO. MLP-COO achieved accuracy of 99.70% and 94.70% on training and testing datasets, respectively, with 10-fold cross-validation. We also assessed its performance on an independent dataset of 294 DLBCL patients. On independent dataset, we achieved an accuracy of 95.90% with MCC of 0.917. To show its broader applicability, we used this classifier to predict the clinical outcome using survival data from two large cohorts of DLBCL patients. In survival analysis, MLP-COO recapitulates the survival probabilities of DLBCL patients based on their COO in both cohorts. We anticipate that MLP-COO model developed in this study will benefit in the accurate COO prediction of DLBCL patients and their clinical outcomes. |
Hemophagocytic lymphohistiocytosis secondary to diffuse large B-cell lymphoma presenting with recurrent multi-territory infarcts: A case report. | Lymphoma-associated hemophagocytic syndrome is a life-threatening disease with poor prognosis and may present as ischemic stroke. We report a case of a 56-year-old female with recurrent multi-territory infarcts caused by diffuse large B-cell lymphoma with secondary hemophagocytic lymphohistiocytosis. She had been diagnosed with ischemic stroke and hemophagocytic syndrome probably secondary to Epstein-Barr virus infection 3 months previously and treated with Dexamethasone and Aspirin. High resolution vessel wall magnetic resonance imaging showed vessel wall thickening at some intracranial vessels suggesting vasculitis. Abdominal computed tomography scan revealed splenomegaly, multiple bilateral small nodules of the lung, multiple liver lesions, multiple bilateral renal masses, gastric wall thickening and multiple nodules in the omentum. Cerebrospinal fluid cytology showed increased cerebrospinal-fluid protein level. Hemophagocytosis was showed on bone marrow aspirate cytology. Gastric tissue biopsy revealed large B cell lymphoma. Chemotherapy was not given because the patient had severe pneumonia and sepsis. The patient died 28 days after the definitive diagnosis was confirmed. Ischemic stroke in our patient with diffuse large B-cell lymphoma may be due to vasculitis or intravascular large B-cell lymphoma. |
A Practical Review of the Presentation, Diagnosis, and Management of Cutaneous B-Cell Lymphomas. | This review of cutaneous B-cell lymphoma (CBCL) is focused on the clinical presentation, treatment, and workup of each type of lymphoma. Part 1 is an overview of each of the CBCLs, including clinical presentation, recent advances in the pathobiology, and evidence regarding treatment strategies. Part 2 is a detailed guide to the steps in diagnosis and workup of a newly diagnosed CBCL according to the International Society for Cutaneous Lymphoma/European Organization for Research and Treatment of Cancer and NCCN guidelines. |
Dual PI3Kδγ inhibition demonstrates potent anticancer effects in diffuse large B-cell lymphoma models: Discovery and preclinical characterization of LL-00084282. | Phosphoinositide 3-kinase (PI3K) pathway mediates key signaling events downstream to B-cell receptor (BCR) for survival of mature B-cells, and overexpression or overactivation of PI3Kδ is crucial for B-cell malignancies such as diffuse large B-cell lymphoma (DLBCL). Small molecule PI3Kδγ inhibitors, with a known potential to reduce activated B-cell (ABC)-DLBCL transformation, form an important class of therapeutics approved for follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL). In this study, we describe discovery of a potent, selective and efficacious dual PI3Kδγ inhibitor, LL-00084282, having a differentiated efficacy profile in human ABC- and germinal center B-cell (GCB)-DLBCL cell lines. LL-00084282 displayed high potency and superior PI3Kδγ engagement with excellent selectivity over other PI3K isoforms at both IC |
Fc receptor-like 1 (FCRL1) is a novel biomarker for prognosis and a possible therapeutic target in diffuse large B-cell lymphoma. | Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin's lymphoma, which can involve various types of mature B-cells. Considering that the incidence of DLBCL has increased, additional research is required to identify novel and effective prognostic and therapeutic molecules. Fc receptor-like 1 (FCRL1) acts as an activation co-receptor of human B-cells. Aberrant expression of this molecule has been reported in a number of B-cell-related disorders. Moreover, the clinical significance and prognosis value of FCRL1 in DLBCL are not completely identified.
In this study, the expression levels of FCRL1 were determined in thirty patients with DLBCL and 15 healthy controls (HCs). In addition, the correlation between FCRL1 expressions with clinicopathological variables of DLBCL patients were examined. Then, the potential roles of FCRL1 in proliferation, apoptosis, and cell cycle distribution of B-cells from DLBCL patients were determined using flow cytometry analysis, after knockdown of this marker using retroviral short hairpin RNA interference. Quantitative real time-PCR, western blotting, and enzyme-linked immunosorbent assay were also used to identify the possible effects of FCRL1 knockdown on the expression levels of BCL-2, BID, BAX, intracellular signaling pathway PI3K/p-Akt, and p65 nuclear factor-kappa B (NF-κB) in the B-cells of DLBCL.
Statistical analysis revealed higher levels of FCRL1 expression in the B-cells of DLBCL patients compared to HCs at both protein and mRNA levels. A positive correlation was observed between the FCRL1 expression and some clinicopathological parameters of DLBCL patients. In addition, FCRL1 knockdown significantly decreased cell proliferation and stimulated apoptosis as well as G1 cell cycle arrest in the B-cells of DLBCL patients. The levels of p65 NF-κB and PI3K/p-Akt expressions were markedly reduced after knockdown of FCRL1 expression.
These results suggested that FCRL1 could be a potential novel biomarker for prognosis and/or a possible effective therapeutic target for treatment of patients with DLBCL. |
Selective Inhibition of Bruton's Tyrosine Kinase by a Designed Covalent Ligand Leads to Potent Therapeutic Efficacy in Blood Cancers Relative to Clinically Used Inhibitors. | Bruton's tyrosine kinase (BTK) is a member of the TEC-family kinases and crucial for the proliferation and differentiation of B-cells. We evaluated the therapeutic potential of a covalent inhibitor (JS25) with nanomolar potency against BTK and with a more desirable selectivity and inhibitory profile compared to the FDA-approved BTK inhibitors ibrutinib and acalabrutinib. Structural prediction of the BTK/JS25 complex revealed sequestration of Tyr551 that leads to BTK's inactivation. JS25 also inhibited the proliferation of myeloid and lymphoid B-cell cancer cell lines. Its therapeutic potential was further tested against ibrutinib in preclinical models of B-cell cancers. JS25 treatment induced a more pronounced cell death in a murine xenograft model of Burkitt's lymphoma, causing a 30-40% reduction of the subcutaneous tumor and an overall reduction in the percentage of metastasis and secondary tumor formation. In a patient model of diffuse large B-cell lymphoma, the drug response of JS25 was higher than that of ibrutinib, leading to a 64% "on-target" efficacy. Finally, in zebrafish patient-derived xenografts of chronic lymphocytic leukemia, JS25 was faster and more effective in decreasing tumor burden, producing superior therapeutic effects compared to ibrutinib. We expect JS25 to become therapeutically relevant as a BTK inhibitor and to find applications in the treatment of hematological cancers and other pathologies with unmet clinical treatment. |
Oral Chemotherapy Application in Elderly Patients With Diffuse Large B-Cell Lymphoma: An Alternative Regimen in Retrospective Analysis. | A combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is considered the standard treatment for diffuse large B-cell lymphoma (DLBCL). However, no standard treatment has been established for older patients (age ≥ 75 years). This study retrospectively analyzed different treatment strategies in older patients with DLBCL with different chemotherapy regimens and compared the survival rate of patients using oral or intravenous form cyclophosphamide and etoposide in a single center.
We reviewed the records of older patients with DLBCL, aged ≥ 75 years, from January 2010 to August 2019. The different treatment combinations, clinical characteristics, response rates, and toxicity profiles were analyzed. The median overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier (KM) method. Cox regression model was used to identify the risk factors.
Eighty-four patients were included. One-quarter of the patients received cytoreduction treatment because of their poor medical condition at the time of diagnosis. Twenty-six percent of the patients were aged ≥ 85 at the time of diagnosis and 46.7% completed the treatment course. Patients receiving non-anthracycline-containing (non-ACR) treatment had worse Charlson comorbidity index, worse PFS, lower body mass index, or were older. The mean anthracycline accumulative dose in the anthracycline-containing (ACR) group was 134 mg/m
The toxicity, efficacy, and KM curve for OS and PFS in the non-ACR group were lower compared to ACR group, without statistical significance. R-CVOP had similar OS with R-mini-CHOP in our study. The result does not mean etoposide could totally substitute for anthracycline, but etoposide did have lower early progression rate (12.5%), and it may be an option for frail patients with comorbidity. Oral form cyclophosphamide and etoposide could be considered as a substitute for intravenous administration because of the similar effect and toxic profile. |
Immunophenotypic characterisation of non-Hodgkin lymphomas at a tertiary hospital in Ghana. | Non-Hodgkin lymphomas (NHLs) are a heterogeneous group of clonal lymphoid tumours originating from lymphocytes. They constitute about 90% of an estimated 3%-4% worldwide distribution of malignant lymphomas among various cancers. Despite the continuous rise and associated deaths, research on NHLs, and in particular the area of immunophenotypic spectrum is limited in Ghana and sub-Saharan Africa.
A retrospective, descriptive study in which archived tissue blocks of histologically diagnosed NHLs at a tertiary hospital in Accra, Ghana, were used. Antigenic phenotypes were determined by immunohistochemistry.
A total of 66 cases of NHLs, with a mean age of 50.2 ± 16.1 years, were selected for the study. Among the targeted markers, cluster of differentiation 20 (CD20) was the most commonly expressed in 89.4% (59) cases. Immunohistochemistry studies revealed a greater proportion of B cell lymphomas of 89.4%. Five subtypes were successfully identified, of which diffuse large B cell lymphoma constitutes the predominant group (40.9%). A significant association was observed between phenotypic cell types and outcomes of NHLs (
Adult NHLs were mostly due to the malignant transformation of B cells with diffuse large B cell lymphoma being the commonest subtype. The present study therefore serves as preliminary data for further research towards the adoption of an improved treatment regimen and management of NHLs. |
Primary Bone Marrow Lymphoma: De Novo and Transformed Subtypes. | Diffuse large B-cell lymphoma (DLBCL) is well known for selectively involving certain extranodal locations such as the central nervous system (CNS), testes, and skin. DLBCL or high-grade B-cell lymphoma selectively involving the bone marrow is rare and has been sparsely reported in the medical literature. We report two cases of lymphoma presenting with primary bone marrow involvement without evidence of involvement of any other sites. The first case represents de novo DLBCL. The patient achieved complete remission with initial treatment, had a bone marrow-only relapse three years later, and achieved a second complete remission following non-transplant salvage therapy. The second case had findings consistent with "double hit" Richter's transformation of chronic lymphocytic leukemia with translocation of |
T-cell immunoglobulin mucin molecule-3, transformation growth factor β, and chemokine-12 and the prognostic status of diffuse large B-cell lymphoma. | The effects of T-cell immunoglobulin mucin molecule-3 (Tim-3), transforming growth factor β (TGF-β), and chemokine-12 (CXCL12) expression on the prognosis of patients with diffuse large B-cell lymphoma (DLBCL) have not been elucidated.
To examine the correlation between Tim-3, TGF-β and CXCL12 expression and DLBCL prognosis.
Lymph node tissues of 97 patients with DLBCL and 93 normal-response hyperplastic lymph node tissues treated from January 2017 to May 2019 were selected as the DLBCL and control groups, respectively. The expression of Tim-3, TGF-β, and CXCL12 was detected immunohistochemically. Patients were followed up for 3 years, and progression-free survival was recorded. Cox multifactorial analysis was performed to analyze the risk factors for poor prognosis.
The positive expression rates of Tim-3, TGF-β, and CXCL12 were higher in DLBCL tissues than in non-cancerous (control) tissues (
DLBCL tissues exhibit high positive expression of Tim-3, TGF-β, and CXCL12, and a high expression of all three indicates a poor prognosis. |
Molecular and clinical diversity in primary central nervous system lymphoma. | Primary central nervous system lymphoma (PCNSL) is a rare and distinct entity within diffuse large B cell lymphoma presenting with variable response rates probably to underlying molecular heterogeneity.
To identify and characterize PCNSL heterogeneity and facilitate clinical translation, we performed a comprehensive multi-omic analysis (whole-exome sequencing, RNA-seq, methyl-seq, and clinical features) in a discovery cohort of 147 fresh-frozen immunocompetent PCNSLs and a validation cohort of formalin-fixed, paraffin-embedded (FFPE) 93 PCNSLs with RNA-seq and clinico-radiological data.
Consensus clustering of multi-omics data uncovered concordant classification of four robust, non-overlapping, prognostically significant clusters (CS). The CS1 and CS2 groups presented an immune-cold hypermethylated profile but distinct clinical behavior. The "immune-hot" CS4 group, enriched with mutations increasing the JAK-STAT and NF-κB activity, had the most favorable clinical outcome while the heterogeneous-immune CS3 group had the worse prognosis probably due to its association with meningeal infiltration and enriched HIST1H1E mutations. The CS1 was characterized by high Polycomb repressive complex 2 activity and CDKN2A/B loss leading to higher proliferation activity. Integrated analysis on proposed targets suggests potential use of immune checkpoint inhibitors/JAK1 inhibitors for CS4, cyclin D-Cdk4,6 plus PI3K inhibitors for CS1, lenalidomide/demethylating drugs for CS2, and EZH2 inhibitors for CS3. We developed an algorithm to identify the PCNSL subtypes using RNA-seq data from either FFPE or FF tissue.
The integration of genome-wide data from multi-omics data revealed four molecular patterns in PCNSL with a distinctive prognostic impact that provides a basis for future clinical stratification and subtype-based targeted interventions. |
Polatuzumab vedotin, rituximab, and bendamustine combination in relapsed or refractory diffuse large B-cell lymphoma: a real-world data from Turkey. | Polatuzumab vedotin (Pola) with bendamustine and rituximab (BR) is a promising option for patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). We analyzed the data of 71 R/R DLBCL patients who had been treated with Pola-BR in the named patient program from March 2018 to April 2021 from 32 centers in Turkey. All patients received up to six cycles of Pola 1.8 mg/kg, rituximab 375 mg/m |
Aberrant synaptophysin expression in classic Hodgkin lymphoma. | Synaptophysin is an immunohistochemical marker for neuroendocrine differentiation and is widely used in pathologic diagnosis. Its expression in malignant lymphoma has not yet been described. However, we experienced an index case of classic Hodgkin lymphoma with synaptophysin expression. This experience prompted us to investigate synaptophysin expression in classic Hodgkin lymphoma.
Immunohistochemical staining of synaptophysin was performed in 59 diagnosed cases of classic Hodgkin lymphoma, 10 anaplastic large cell lymphomas, 16 diffuse large B-cell lymphomas, and 5 extranodal marginal zone lymphoma of the mucosa-associated tissue. Synaptophysin-positive cases were stained for both chromogranin and CD56a.
Of 59 classic Hodgkin lymphoma cases, 11 (19%) were positive for synaptophysin. None of the anaplastic large cell lymphomas expressed synaptophysin. Synaptophysin showed weak but specific expression in the cytoplasm of the Hodgkin lymphoma tumor cells. Other background inflammatory cells (such as macrophages, B-, and T-lymphocytes) were all negative for synaptophysin expression. Chromogranin and CD56a were not expressed in the synaptophysin-positive classic Hodgkin lymphomas.
Synaptophysin is an integral glycoprotein present in presynaptic vesicles of neurons and neuroendocrine cells. It is a diagnostic marker for neuroendocrine tumors. Aberrant synaptophysin expression has been reported in non-neuroendocrine tumors but not in lymphoma or leukemia. To the best of our knowledge, synaptophysin positivity has only been reported in a single case of precursor T-lymphoblastic leukemia/lymphoma to date. Our study showed that aberrant synaptophysin expression in classic Hodgkin lymphoma is an unexpectedly frequent finding. The mechanism underlying, and prognostic significance of, such aberrant expression is unclear. Thus, in a small biopsy, aberrant synaptophysin expression could be a diagnostic pitfall and should be carefully avoided. |
Genetic Profiling of Diffuse Large B-Cell Lymphoma: A Comparison Between Double-Expressor Lymphoma and Non-Double-Expressor Lymphoma. | Data are limited regarding the genetic profiling of diffuse large B-cell lymphoma (DLBCL) with double expression of MYC and BCL2 proteins without underlying rearrangements (double-expressor lymphoma [DEL]). This study aimed to describe the genetic profiling and determine the prognostic significance in patients with DEL and in those with non-DEL.
Capture-based targeted sequencing was performed on 244 patients with de novo DLBCL, not otherwise specified. Immunohistochemistry staining was performed for evaluating the MYC and BCL2 expression.
Among 244 patients, 46 patients had DEL, and 198 had non-DEL. KMT2D, CD58, EP300, PRDM1, TNFAIP3 and BCL2 gain or amplification (BCL2
There was difference in profiling of altered genes and signaling pathways between the DEL group and the non-DEL group. The presence of DEL alone should not be considered as an adverse prognostic indicator, and BCL2 alteration could define a subset of patients with poor prognosis within DEL. |
Minimal residual disease in patients with diffuse large B-cell lymphoma undergoing autologous stem cell transplantation. | Improved biomarkers are needed to guide the optimal use of autologous stem cell transplantation (ASCT) for patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). We hypothesized that minimal residual disease (MRD) identified using immunoglobulin high-throughput sequencing in apheresis stem cell (ASC) samples or post-ASCT peripheral blood mononuclear cell (PBMC) and plasma samples could predict relapse. We studied 159 patients with R/R DLBCL who underwent ASCT, of whom 98 had an ASC sample and 60 had post-ASCT surveillance samples. After a median post-ASCT follow-up of 60 months, the 5-year progression-free survival (PFS) was 48%. MRD was detected in 23/98 (23%) ASC samples and was associated with very poor PFS (5-year PFS 13% vs 53%, p<0.001) and inferior overall survival (52% vs 68%, p=0.05). The sensitivity and specificity of ASC MRD positivity for progression or death were 36% and 93%, respectively. Positive ASC MRD remained a significant predictor of PFS in a multivariable analysis (hazard ratio [HR] 3.7, p<0.001). Post-ASCT surveillance MRD testing from plasma, but not PBMC samples, reliably identified patients with impending relapse. A positive plasma MRD result was associated with inferior PFS (HR 3.0, p=0.016) on a multivariable analysis. The median lead time from MRD detection to relapse was 62 days (range 0-518 days). In conclusion, detection of MRD in ASC samples is associated with a very high relapse risk, justifying alternative treatment strategies or trials of novel consolidation options in those patients. Furthermore, post-ASCT MRD monitoring may facilitate trials evaluating early initiation of treatment at molecular relapse. This trial is registered at www.clinicaltrials.gov as NCT02362997. |
null | Primary hepatic lymphomas are rare hepatic malignancies which are often misdiagnosed preoperatively. Early accurate diagnosis is essential as the patients can be treated successfully with chemotherapy, eluding the need for surgery. We present a case of primary hepatic lymphoma which mimicked as focal nodular hyperplasia with normal biochemical tumor markers, and |
Real-world Outcomes of Relapsed/Refractory Diffuse Large B-cell Lymphoma Treated With Polatuzumab Vedotin-based Therapy. | After FDA and EMA approval of the regimen containing polatuzumab vedotin plus rituximab and bendamustine (PolaBR), eligible relapsed/refractory diffuse large B-cell lymphoma (DLBCL) patients in Italy were granted early access through a Named Patient Program. A multicentric observational retrospective study was conducted focusing on the effectiveness and safety of PolaBR in everyday clinical practice. Fifty-five patients were enrolled. There were 26 females (47.3%), 32 patients were primary refractory and 45 (81.8%) resulted refractory to their last therapy. The decision to add or not bendamustine was at physician's discretion. Thirty-six patients underwent PolaBR, and 19 PolaR. The 2 groups did not differ in most of baseline characteristics. The final overall response rate was 32.7% (18.2% complete response rate), with a best response rate of 49.1%. Median disease-free survival was reached at 12 months, median progression-free survival at 4.9 months and median overall survival at 9 months, respectively. Overall, 88 adverse events (AEs) were registered during treatment in 31 patients, 22 of grade ≥3. Eight cases of neuropathy occurred, all of grades 1-2 and all related to polatuzumab. The two groups of treatment did not differ for effectiveness endpoints but presented statistically significant difference in AEs occurrence, especially in hematological AEs, in AEs of grade equal or greater than 3 and in incidence of neuropathy. Our data add useful information on the effectiveness of Pola(B)R in the setting of heavily pretreated DLBCL and may also suggest a better tolerability in absence of bendamustine without compromise of efficacy. |
Concomitant Presence of Spermatic Cord and Testicular Non-Hodgkin's Lymphoma With Recurrence: A Case Report on a Rare Entity. | Primary testicular non-Hodgkin's lymphoma (PTNHL) with contiguous involvement of the spermatic cord is a rare occurrence and presentation of the disease, and it mostly involves elderly men between the sixth and eighth decades of life. PTNHL is a rare form of primary testicular malignancy that accounts for 1% of all non-Hodgkin's lymphoma cases and 5-10%of all testicular malignancies. This case report discusses a 73-year-old man who presented with right-sided inguinoscrotal swelling for six months, which had progressively increased in size. The patient was referred to the surgical department, and the examination revealed a hard-palpable mass with thickening of the cord. The initial imaging included an ultrasound, demonstrating a heteroechoic mass inseparable from the right testis with evidence of mild increased internal vascularity. Due to the high suspicion of malignancy, a right orchidectomy was performed. The patient subsequently developed another swelling after seven months, over the right inguinal region, which had progressively increased in size. MRI of the pelvis and CT of the abdomen and chest revealed a lobulated, intermediate intense lesion in the right inguinoscrotal region. This case report demonstrates the importance of radiological imaging in assessing and detecting the characteristics of concomitant lesions by using various imaging modalities and assessing the extent of spread. In addition, radiological imaging helps in the early diagnosis of the disease and facilitates prompt and early treatment to achieve favorable outcomes for the patient. The radiologist should include a differential diagnosis of PTNHL when imaging for a painless inguinoscrotal mass. |
Pituitary Infiltration by Lymphoma. | Lymphoma infiltration to the pituitary is rare. It represents less than 0.5% of all reported pituitary metastases (PMs). Here we present a case series of 3 patients with PMs from a systemic lymphoma. Also, we performed a literature review of the cases reported. We identified additional 31 cases in which non-Hodgkin lymphoma (NHL) was the most common (n = 28, 90%), with large B-cell NHL the most frequent histological subtype (n = 14, 45%). Central hypothyroidism (n = 21, 67%) was the most frequent pituitary deficiency followed by adrenal insufficiency (n = 19, 61%) and diabetes insipidus (DI; n = 18, 58%). Full endocrine recovery was found in only 12% (n = 4) of patients after treatment, and magnetic resonance imaging showed tumor regression in 22% of them. In our series, 2 patients were diagnosed with diffuse large B-cell lymphoma, and 1 had mixed cellularity of classic Hodgkin lymphoma. The mean age was 54 ± 6.92 years. Hypopituitarism and DI were present in all of them, with 100% of mortality because of advanced systemic disease. |
Case report: Hashimoto's thyroiditis after CD19 chimeric antigen receptor T-cell therapy. | Chimeric antigen receptor (CAR)-T cell therapy is a novel cell therapeutic approach that is increasingly being used to treat patients with relapsed refractory B-cell lymphoma. Despite the efficacy of CAR T cell therapy, it has various adverse effects that can affect any organ in the body. The application of immune checkpoint inhibitors such as programmed death 1 (PD-1), programmed death ligand 1 (PDL-1), and cytotoxic T-lymphocyte antigen 4 (CTLA-4) antibodies has previously been reported to be associated with immune-related adverse events such as thyroid dysfunction and thyroiditis. Reports of immune-related adverse reactions after CAR T therapy are currently extremely rare, with only one case of a cytokine storm (CRS) combined with severe arthritis in a patient with ALL after treatment. Here, we describe two cases of Hashimoto's thyroiditis secondary to CAR T therapy. Two patients with relapsed refractory diffuse large B-cell lymphoma developed elevated peroxidase and globulin antibodies secondary to CAR-T cell therapy and developed Hashimoto's thyroiditis. Complete remission was achieved in two patients at 1 and 3 months after CAR-T cell therapy. The inflammation of the thyroid tissue may be directly or indirectly related to CAR T cell therapy, and the mechanisms needs to be further investigated. |
Exploring the molecular mechanisms and shared gene signatures between rheumatoid arthritis and diffuse large B cell lymphoma. | The relationship between rheumatoid arthritis (RA) and diffuse large B-cell lymphoma (DLBCL) is well characterized, but the molecular mechanisms underlying this association have not been clearly investigated. Our study aimed to identify shared gene signatures and molecular mechanisms between RA and DLBCL. We selected multiple Gene Expression Omnibus (GEO) datasets (GSE93272, GSE83632, GSE12453, GSE1919) to obtain gene expression levels and clinical information about patients with RA and DLBCL. Weighted gene co-expression network analysis (WGCNA) was used to research co-expression networks associated with RA and DLBCL. Subsequently, we performed enrichment analysis of shared genes and screened the most significant core genes. We observed expression of the screened target gene, galectin 2 ( |
Impact of Epstein-Barr virus infection in patients with inflammatory bowel disease. | A high prevalence of Epstein-Barr virus (EBV) infection in patients with inflammatory bowel disease (IBD) has been reported in many case reports and studies; thus, the association between EBV and IBD has gained increasing attention. Patients with IBD are at an increased risk of opportunistic EBV infection owing to the common use of immunomodulators. EBV infection in IBD patients can cause various complications, including superimposed viral colitis, which is associated with chronicity, exacerbation, and poor prognosis of refractory IBD, and can induce progression to lymphoproliferative disorders, such as EBV-positive mucocutaneous ulcer (EBVMCU), lymphomatoid granulomatosis (LYG), hemophagocytic lymphohistiocytosis (HLH) and diffuse large B-cell lymphoma (DLBCL). It has been suggested to screen for EBV before initiating immunosuppressive therapy and monitor the status of EBV infection in patients with IBD, especially those who are EBV-seronegative and have a risk of primary EBV infection. Clinicians should also be careful of misdiagnosing IBD and EBV-associated lymphoproliferative diseases due to similarities in both clinical symptoms and endoscopic manifestations. Withdrawal of immunosuppressants has been shown to be an effective strategy to achieve remission of disease at the time of EBV diagnosis, but antiviral therapy remains controversial. The present review aims to describe the characteristics of the complications caused by EBV infection and generalize the recent research progress on and challenges caused by EBV infection in IBD patients. The literature for writing this review was collected from 'PubMed' research engine. The keywords 'inflammatory bowel disease and Epstein-Barr virus' or 'ulcerative colitis and Epstein-Barr virus' or 'Crohn's disease and Epstein-Barr virus' were used to collect the literature and relevant papers were collected to help writing this review. |
Primary spinal Non-Hodgkin Lymphoma presenting as impending cauda equina syndrome: A case report. | Malignant lymphoma (ML) can involve the central nervous system either primarily or by secondary spread, which tends to occur late in the disease as part of widespread dissemination. Lymphoma presenting as primary tumors of the spinal cord is extremely uncommon. Primary spinal lymphoma if detected early can have a good prognosis with no relapse after effective treatment.
A 32 years old male patient presented with the symptoms of impending cauda equina syndrome which was managed with surgery and chemotherapy. The patient was successfully treated without the relapse of his condition at his 6 months follow-up scan.Discussion: Primary spinal non-Hodgkin lymphoma is a rare entity among extranodal non-Hodgkin lymphoma. MRI is usually non-confirmatory and needs immunohistochemistry for the correct diagnosis. R-CHOP regimen is the standard chemotherapy regimen. Surgical decompression is required in cases of impending neurological injury along with radiotherapy.
Primary spinal epidural diffuse large B-cell lymphoma should be considered as a differential diagnosis in patients presenting with back pain and symptoms of impending cauda equina syndrome. It is important to early detect and treat the disease to prevent permanent neurological injury and metastasis. |
B cell lymphoma 6A regulates immune development and function in zebrafish. | BCL6A is a transcriptional repressor implicated in the development and survival of B and T lymphoctyes, which is also highly expressed in many non-Hodgkin's lymphomas, such as diffuse large B cell lymphoma and follicular lymphoma. Roles in other cell types, including macrophages and non-hematopoietic cells, have also been suggested but require further investigation. This study sought to identify and characterize zebrafish BCL6A and investigate its role in immune cell development and function, with a focus on early macrophages. Bioinformatics analysis identified a homologue for BCL6A (<i>bcl6aa</i>), as well as an additional fish-specific duplicate (<i>bcl6ab</i>) and a homologue for the closely-related BCL6B (<i>bcl6b</i>). The human BCL6A and zebrafish Bcl6aa proteins were highly conserved across the constituent BTB/POZ, PEST and zinc finger domains. Expression of <i>bcl6aa</i> during early zebrafish embryogenesis was observed in the lateral plate mesoderm, a site of early myeloid cell development, with later expression seen in the brain, eye and thymus. Homozygous <i>bcl6aa</i> mutants developed normally until around 14 days post fertilization (dpf), after which their subsequent growth and maturation was severely impacted along with their relative survival, with heterozygous <i>bcl6aa</i> mutants showing an intermediate phenotype. Analysis of immune cell development revealed significantly decreased lymphoid and macrophage cells in both homozygous and heterozygous <i>bcl6aa</i> mutants, being exacerbated in homozygous mutants. In contrast, the number of neutrophils was unaffected. Only the homozygous <i>bcl6aa</i> mutants showed decreased macrophage mobility in response to wounding and reduced ability to contain bacterial infection. Collectively, this suggests strong conservation of BCL6A across evolution, including a role in macrophage biology. |
Identification of ATP1B1, a key copy number driver gene in diffuse large B-cell lymphoma and potential target for drugs. | Copy number variations (CNVs) participate in the development and progression of cancer by altering the expression levels of genes. However, it is unclear whether this correlation exists in diffuse large B-cell lymphoma (DLBCL).
Differentially expressed genes (DEGs) were identified from the GSE25638 and GSE56315 datasets. Modules that were highly related to DLBCL prognosis were obtained by Weighted Gene Co-expression Network Analysis (WGCNA). We performed an integrated analysis between CNV and differential gene expression in The Cancer Genome Atlas (TCGA) DLBCL. The DEGs were then overlapped with the module genes and expression-copy number variations-related (Exp-CNV-related) genes to obtain the common key genes. Time-dependent receiver operating characteristic (ROC) analysis was utilized to evaluate the accuracy of the key gene in predicting the prognosis of DLBCL. Next, we conducted a Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis to explore the key gene. The potential molecule drugs of the key gene were identified by Connectivity Map (Cmap) analysis.
A turquoise module with 160 genes was identified as the signature module. ATP1B1 is overexpressed in DLBCL cell lines, compared to Cluster of Differentiation 19+B (CD19+B) cells. The ROC curve indicated that ATP1B1 could be a biomarker for diagnosing DLBCL, and the forest map suggested that
ATP1B1 is a copy number driver gene that could potentially be adopted as a diagnostic biomarker and therapeutic target of DLBCL. |
null | Recent studies have highlighted the critical role of lysophosphatidylcholine acyltransferase 3 (
We explored the expression level and prognostic value of |
The path towards consensus genome classification of diffuse large B-cell lymphoma for use in clinical practice. | Diffuse large B-cell lymphoma (DLBCL) is a widely heterogeneous disease in presentation, treatment response and outcome that results from a broad biological heterogeneity. Various stratification approaches have been proposed over time but failed to sufficiently capture the heterogeneous biology and behavior of the disease in a clinically relevant manner. The most recent DNA-based genomic subtyping studies are a major step forward by offering a level of refinement that could serve as a basis for exploration of personalized and targeted treatment for the years to come. To enable consistent trial designs and allow meaningful comparisons between studies, harmonization of the currently available knowledge into a single genomic classification widely applicable in daily practice is pivotal. In this review, we investigate potential avenues for harmonization of the presently available genomic subtypes of DLBCL inspired by consensus molecular classifications achieved for other malignancies. Finally, suggestions for laboratory techniques and infrastructure required for successful clinical implementation are described. |
Activity and rational combinations of a novel, engineered chimeric, TRAIL-based ligand in diffuse large B-cell lymphoma. | TRAIL (TNF-related apoptosis inducing ligand) exhibits selective proapoptotic activity in multiple tumor types, while sparing normal cells. This selectivity makes TRAIL an attractive therapeutic candidate. However, despite encouraging activity in preclinical models, clinical trials with TRAIL mimetics/death receptor agonists demonstrated insufficient activity, largely due to emerging resistance to these agents. Herein, we investigated the cytotoxic activity of a novel, TRAIL-based chimeric protein AD-O51.4 combining TRAIL and VEGFA-derived peptide sequences, in hematological malignancies. We characterize key molecular mechanisms leading to resistance and propose rational pharmacological combinations sensitizing cells to AD-O51.4.
Sensitivity of DLBCL, classical Hodgkin lymphoma, (cHL), Burkitt lymphoma (BL) and acute myeloid leukemia (AML) to AD-O51.4 was assessed
AD-O51.4 exhibited low-nanomolar cytotoxic activity in DLBCL cells, but not in other lymphoid or AML cell lines. AD-O51.4 induced death-receptor (DR) mediated, caspase-dependent apoptosis in sensitive DLBCL cells, but not in primary resistant cells. The presence of DRs and caspase 8 in cancer cells was crucial for AD-O51.4-induced apoptosis. To understand the potential mechanisms of resistance in an unbiased way, we engineered AD-O51.4-resistant cells and evaluated resistance-associated transcriptomic changes. Resistant cells exhibited changes in the expression of multiple genes and pathways associated with apoptosis, endocytosis and HDAC-dependent epigenetic reprogramming, suggesting potential therapeutic strategies of sensitization to AD-O51.4. In subsequent analyses, we demonstrated that HDAC inhibitors, BCL2 inhibitors and endocytosis/dynamin inhibitors sensitized primary resistant DLBCL cells to AD-O51.4.
Taken together, we identified rational pharmacologic strategies sensitizing cells to AD-O51.4, including BCL2, histone deacetylase inhibitors and dynamin modulators. Since AD-O51.4 exhibits favorable pharmacokinetics and an acceptable safety profile, its further clinical development is warranted. Identification of resistance mechanisms in a clinical setting might indicate a personalized pharmacological approach to override the resistance. |
Clinicopathological Spectrum of Cutaneous Lymphomas and Distinction of Early Mycosis Fungoides from its Mimics-A Retro-Prospective Descriptive Study from Southern India. | Cutaneous lymphomas (CLs) could be either primary (PCL) or secondary; the former comprises cutaneous T-cell lymphomas (CTCLs) and cutaneous B-cell lymphomas (CBCLs). Mycosis fungoides (MF) is the most common PCL. Diagnosis of early MF and distinguishing it from benign inflammatory mimics is challenging. This study aims to assess the clinicopathological spectrum of CL and to characterize early MF from its mimics using clinical characteristics, histopathological features, and ancillary techniques.
This retro-prospective descriptive study was conducted in a tertiary-care institute, for over 5 years. Clinically as well as histopathologically suspected and biopsy-proven CL and their mimics were included. Cases were reviewed and subgrouped based on clinical and histopathological parameters and immunohistochemistry (IHC). Data were analyzed using descriptive statistics and a Chi-square test at a 5% level of significance.
Among PCL, CTCL comprised 84% (21/25) and CBCL was 16% (4/25); the most common CTCL was MF at 81% (17/21). Histologically, atypia of dermal infiltrate (100%), epidermotropism (91.7%), basal alignment of lymphocytes (91.7%), clear haloed cells (91.7%), wiry collagen (66.7%), grandiosity sign (50%), eccrine infiltration (66.7%), and follicular infiltration (50%) were significantly associated with early MF. Spongiosis (84.6%), pigment incontinence (84.6%), exocytosis (76.9%), and parakeratosis (76.9%) were significantly associated with inflammatory mimics. There was no significant difference in the downregulation pattern of CD7 (
MF was the most common PCL. Histological parameters showed a significant difference, whereas IHC did not show any significant difference between early MF and its mimics. |
Clinico-Dermoscopic-Pathological Features of a Rare Case of Locally Invasive Multifocal Primary Cutaneous Diffuse Large B Cell Lymphoma-Leg Type Over the Face and Scalp. | Primary cutaneous diffuse large B-cell lymphoma-leg type (PCDLBCL-LT) is characterized by diffuse monotonous proliferation of centroblasts and immunoblasts. It commonly presents as erythematous to violaceous nodules on one or both the legs and has a poor prognosis. We report the clinico-dermoscopic-pathological features and therapeutic response of a rare case of PCDLBCL-LT in a 62-year-old diabetic man, who presented with multifocal plaques, one lobulated and two arcuate-shaped, on the face and scalp. During the investigation, one of the plaques had eroded the underlying bone without any evidence of malignant cells in the cerebrospinal fluid. He was successfully treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) along with intrathecal methotrexate. |
Prostate primary intravascular large B-cell lymphoma: A case report. | Intravascular large B-cell lymphoma (IVLBCL) is a distinct subtype of extranodal diffuse large B-cell lymphoma (DLBCL) and mainly affects elderly population characterized by selective infiltration of neoplastic cells within the lumina of small vessels. Prostate primary IVLBCL is extremely rare. Herein we present a case of a 76-year-old male patient who was admitted with symptoms of severe lower urinary tract obstruction. IVLBCL was diagnosed based on histopathological and immunohistochemical examination of the precious tissue specimens though transurethral prostate resection. Awareness and accurate diagnosis are very important to guide the clinicals in formulation of diagnosis and treatment plan. |
A polyamine-centric, blood-based metabolite panel predictive of poor response to CAR-T cell therapy in large B cell lymphoma. | Anti-CD19 chimeric antigen receptor (CAR) T cell therapy for relapsed or refractory (r/r) large B cell lymphoma (LBCL) results in durable response in only a subset of patients. MYC overexpression in LBCL tumors is associated with poor response to treatment. We tested whether an MYC-driven polyamine signature, as a liquid biopsy, is predictive of response to anti-CD19 CAR-T therapy in patients with r/r LBCL. Elevated plasma acetylated polyamines were associated with non-durable response. Concordantly, increased expression of spermidine synthase, a key enzyme that regulates levels of acetylated spermidine, was prognostic for survival in r/r LBCL. A broad metabolite screen identified additional markers that resulted in a 6-marker panel (6MetP) consisting of acetylspermidine, diacetylspermidine, and lysophospholipids, which was validated in an independent set from another institution as predictive of non-durable response to CAR-T therapy. A polyamine centric metabolomics liquid biopsy panel has predictive value for response to CAR-T therapy in r/r LBCL. |
Isolated Primary Neurolymphomatosis in the Right Brachial Plexus Proven by Partial Nerve Biopsy. | Isolated primary neurolymphomatosis is a rare manifestation of lymphoma, which is challenging to diagnose as there is only involvement of the nervous system, and nerve biopsy is not frequently pursued due to the high risk of irreversible complications.
We present a case of isolated primary neurolymphomatosis of diffuse large B-cell lymphoma restricted to only the right brachial plexus and right axillary nerve. The clinical course has been indolent for several years. The initial examination, including MRI and the cerebrospinal fluid study, did not yield any evidence of malignancy. Eventually, due to the patient's symptom progression and the follow-up imaging findings, we conducted a partial nerve biopsy of the brachial plexus to confirm the malignancy. His neurological symptoms did not further deteriorate post-biopsy.
Isolated primary neurolymphomatosis with an indolent course is rare and challenging to diagnose. Serial MRI and fluorodeoxyglucose-positron emission tomography reveal clues for tumor involvement. Partial nerve biopsy or targeted fascicular nerve biopsy could be an alternative for achieving a pathologic diagnosis. |
Interim FDG-PET/CT for Response Assessment of Lymphoma. | The clinical use and prognostic value of interim FDG-PET/CT (iPET/CT), which is performed after treatment initiation but prior to its completion, varies by lymphoma subtype. Evidence supporting the prognostic value of iPET/CT is more robust for classical Hodgkin lymphoma (cHL), and in this lymphoma subtype, response-adapted treatment approaches guided by iPET/CT are a widely used standard of care for first-line therapy. The data supporting use of iPET/CT among patients with non-Hodgkin lymphoma (NHL) is less well-established, but failure to achieve complete metabolic response on iPET/CT is generally considered a poor prognostic factor with likely consequences for progression free survival. This review will present the available evidence supporting use of iPET/CT in lymphoma patients, particularly as it relates to prognostication and the ability to inform response-adapted treatment strategies. The latter will be addressed through a discussion on the major iPET-response adapted clinical trials with mention of ongoing trials. Special attention will be given to cHL and a few subtypes of NHL, including diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), and peripheral T cell lymphoma (PTCL). |
Carfilzomib Combined with Rituximab, Ifosfamide, Carboplatin, and Etoposide for Relapsed or Refractory DLBCL. | The CORAL study highlighted the need to develop novel salvage regimens in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) previously treated with R-CHOP. Carfilzomib (CFZ) can overcome rituximab-chemotherapy resistance in lymphoma pre-clinical models by targeting the ubiquitin-proteasome system (UPS). We conducted an investigator initiated, single-center, open-label, prospective phase 1 study evaluating the safety and efficacy of CFZ in combination with R-ICE in high-dose chemotherapy with autologous stem cell transplant (HDC-ASCT) eligible R/R DLBCL pts (NCT01959698). In the dose-escalation phase, 18 pts were enrolled at six dose levels with no dose-limiting toxicities noted. CFZ 45 mg/m2 was selected as the recommended dose for expansion. Eleven additional pts were enrolled in the dose-expansion phase. Overall response rate (ORR) was 66% (48% CR, 17% PR), 52% pts underwent HDC-ASCT. An ORR of 85% was observed in pts with non-germinal center B-cell-like (non-GCB) DLBCL compared to only 13% in GCB-DLBCL. Median PFS was 15.2 months (5.1 mo- not reached), and median OS was 22.6 months (6.8 mo- NR). Pts with non-GCB subtype had a significantly longer PFS (NR vs. 6.6 mo, p= 0.0001) and OS (NR vs. 6.6 mo, p= 0.001) than those with GCB-subtype. C-R-ICE is well tolerated in pts with R/R DLBCL with toxicities comparable to R-ICE therapy. Our data show that pts with non-GCB DLBCL benefit significantly from incorporating CFZ into second-line therapy and HDC-ASCT. |
BTG1 inactivation drives lymphomagenesis and promotes lymphoma dissemination through activation of BCAR1. | Understanding the functional role of mutated genes in cancer is required to translate the findings of cancer genomics into therapeutic improvement. BTG1 is recurrently mutated in the MCD/C5 subtype of diffuse large B cell lymphoma (DLBCL), which is associated with extranodal dissemination. There, we provide evidence that Btg1 knock-out accelerates the development of a lethal lymphoproliferative disease driven by Bcl2 overexpression. We further show that the scaffolding protein BCAR1 is a BTG1 partner. Furthermore, following BTG1 deletion or expression of BTG1 mutations observed in DLBCL patients, the overactivation of the BCAR1-RAC1 pathway confers increased migration ability in vitro and in vivo. These modifications are targetable with the SRC inhibitor dasatinib, which opens novel therapeutic opportunities in BTG1 mutated DLBCL. |
A phase 1/2 study of lenalidomide and obinutuzumab with CHOP for newly diagnosed DLBCL. | Diffuse large B-cell lymphoma (DLBCL) can be cured with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone immunochemotherapy (R-CHOP), but a third of patients experience refractory or relapsed disease after frontline R-CHOP. Randomized studies comparing R-CHOP with modified regimens replacing R with obinutuzumab (O) or adding lenalidomide (L) to R-CHOP have not resulted in improved outcomes, but the combination of L and O may enhance NK-cell mediated antibody dependent cellular toxicity when paired with CHOP. Here, we report on long term outcomes of a phase Ib/II study (NCT02529852) where 53 patients with newly diagnosed DLBCL received 6 cycles of LO-CHOP. End of treatment overall and complete response rates in the 50 evaluable patients were 98% and 90%, respectively. After a median follow up of 4.5 years, 4-year progression free and overall survival rates were 87.4% and 91.3%. Grade 3-4 adverse events were experienced by 70% of patients and included neutropenia (38%), thrombocytopenia (17%), fatigue (13%), neutropenic fever (13%), and infection (9%). Of 33 patients profiled with circulating tumor DNA (ctDNA) sequencing, 31 (94%) had detectable pre-treatment ctDNA with CAPP-Seq, 24/31 (77%) were classifiable by LymphGen classifier, and 15/20 (75%) and 12/17 (71%) patients achieved early and major molecular responses after 1 and 2 cycles, respectively. Using PhasED-Seq, 16/18 evaluable patients (89%) had no detectable ctDNA after at least 5 cycles of LO-CHOP. LO-CHOP demonstrates high efficacy and tolerability in newly diagnosed DLBCL, leading to a high rate of undetectable minimal residual disease by ctDNA by end of therapy. This trial is registered at www.clinicaltrials.gov as NCT02529852. |
Performance status, comorbidities, and cycles of methotrexate exert the greatest influence on outcomes of primary and secondary CNS lymphomas: the Lexington experience. | Primary central nervous system lymphoma (PCNSL) occurs primarily in older patients and has a worse prognosis than other extranodal lymphomas. Contemporary treatment is based on high-dose methotrexate (HD-MTX), which crosses the blood-brain barrier. Secondary CNS lymphoma (SCNSL) can occur concomitantly with systemic lymphoma or later at relapse and generally has a dismal outcome. We reviewed disease characteristics and outcomes of 103 patients (44 PCNSL and 59 SCNSL) treated at our center between 2015 and 2020. Median ages at diagnosis were 64 and 62 years, respectively. In both groups, diffuse large B cell lymphoma (DLBCL) was the major histologic type; in SCNSL, other types were also seen. SCNSL, in contrast with PCNSL, manifested with smaller tumors or cerebrospinal fluid positivity. For SCNSL the mean interval to brain involvement was 18 months (0-138). The overall survival had a trend to worse in SCNSL; median survival 11 months versus 61 months in PCNSL (p = 0.089). Progression-free survival was similar in both groups. A significant proportion of SCNSL patients with poor performance status could not obtain CNS-directed treatments. The strongest predictor of poor outcome was ECOG performance status 2 + at diagnosis for both groups. Charlson comorbidity index was predictive only for the PCNSL cohort. Tumor size was not prognostic for survival. The number of HD-MTX cycles correlated with survival, whereas the regimen itself and average cumulative dose of methotrexate did not play a role. Our study is in line with the recent literature and confirms ongoing challenges. We discuss how the outcomes of CNS lymphomas can be improved. |
Primary central nervous system lymphoma: advances in its pathogenesis, molecular markers and targeted therapies. | Primary central nervous system lymphoma (PCNSL) is a rare subtype of diffuse large B-cell lymphoma (DLBCL) located in the CNS with a less favorable prognosis. Recent information addressing the disease molecular heterogeneity is paving the way for tailored treatment strategies. This article reviews current work on the pathogenesis of the disease, potential biomarkers, and treatments.
Previous molecular classifications of PCNSL, built on DLBCL heterogeneity, did not properly address its intrinsic variability. Recent evidence has shown the existence of four different molecular PCNSL subtypes with associated multiomic characteristics, including prognostic relevance. Several studies have identified the tumor microenvironment (TME) as a driving prognostic factor in PCNSL. Therapy efforts continue mainly into targeting either the NF-κβ (nuclear factor kappa-light-chain enhancer of activated B cells) pathway or modulating the TME through immunomodulatory drugs (lenalidomide) or immunotherapy (antiprogrammed cell death 1/programmed cell death 1 ligand 1).
Despite the increasing understanding of PCNSL pathogenesis with recent studies, future efforts are still needed to yield diagnostic biomarkers to detect either PCNSL or its molecular subtypes and hence ease routine clinical use. |
Clinical application of 3D Slicer combined with Sina/MosoCam multimodal system in preoperative planning of brain lesions surgery. | To explore the clinical advantages of 3D Slicer combined with Sina/MosoCam multimodal system in preoperative planning of brain lesions surgery. By collecting the data of brain lesions patients undergoing craniotomy under the preoperative positioning of 3D Slicer combined Sina/MosoCam multimodal system in the people's Hospital of Wuhan University from January 2021 to October 2021, the preoperative planning of patients was introduced, and the size of surgical bone window, operation time, preoperative and postoperative neurological dysfunction were counted. We collected the case data of 35 patients who were reconstructed by 3D Slicer and located by Sina/MosoCam projection. There were 14 cases of malignant tumors (7 cases of glioma, 2 cases of diffuse large B-cell lymphoma, 5 cases of metastatic cancer) and 21 cases of benign tumors (17 cases of meningioma, 1 case of central neurocytoma, 2 cases of cavernous hemangioma and 1 case of arachnoid cyst). All 35 patients were located accurately before operation, the lesions were found quickly during operation, and the postoperative imaging data confirmed that the lesions were removed completely, of which 28 cases (80%) had significantly improved neurological symptoms one month after operation. 3D Slicer combined with Sina/MosoCam multimodal system has many advantages, such as simple and easy to learn, convenient operation, accurate positioning and free. It is considered to be a new technology that is practical, reliable, convenient for diagnosis and preoperative planning. It is suitable for popularization and use in neurosurgery and other operating rooms of all medical institutions. |
Low toxicity and excellent outcomes in patients with DLBCL without residual lymphoma at the time of CD19 CAR T-cell therapy. | CD19 chimeric antigen receptor (CAR) T-cell therapy represents a breakthrough for patients with relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL) inducing sustained remissions in these patients. However, CAR T-cells can result in significant toxicities. Pre-infusion disease burden is associated with toxicities and outcomes after CAR T-cell therapy. We identified 33 patients with R/R DLBCL treated at 8 academic centers who had no detectable disease at the time of CAR T-cell therapy. The median time from leukapheresis to CAR T-cell infusion was 48 (19-193) days. Nine patients received axicabtagene ciloleucel and 24 received tisagenlecleucel. There was no severe (grade≥3) cytokine release syndrome and only 1 patient developed severe neurotoxicity (grade 4). After a median follow-up of 16 months, 13 patients relapsed (39.4%) and 6 died (18.1%). One-year event-free survival and overall survival were 59.6% and 81.3%, respectively. Our findings suggest that, in patients with R/R DLBCL who have an indication for CAR T-cell therapy, treating patients in complete remission at time of infusion is feasible, safe, and associated with favorable disease control. Further exploration in a larger clinical trial setting is warranted. |
Development of combinatorial antibody therapies for diffuse large B cell lymphoma. | Diffuse large B-cell lymphoma (DLBCL), the most common form of lymphoma, is typically treated with chemotherapy combined with the immunotherapy rituximab, an antibody targeting the B cell receptor, CD20. Despite the success of this treatment regimen, approximately a third of DLBCL patients experience either relapse or have refractory disease that is resistant to rituximab, indicating the need for alternative therapeutic strategies. Here, we identified that CD74 and IL4R are expressed on the cell surface of both CD20 positive and CD20 negative B cell populations. Moreover, genes encoding |
Diffuse large B-cell lymphoma and new insights into its pathobiology and implication in treatment. | The most common non-Hodgkin lymphoma (NHL) subtype is diffuse large B-cell lymphoma (DLBCL). It accounts for roughly 30% of all cases of NHL affecting both nodal and extra nodal sites. There are molecular subtypes of DLBCL, germinal centre subtype (GCB), and activated B-cell (ABC), based on gene expression profiling (GEP), in accumulation to distinct morphological and clinicopathological subtypes. To prognosticate patients, the International Prognostication Index (IPI) and its variants are used. In ABC type DLBCL, limited stage disease is treated with a combination of abbreviated systemic chemotherapy (three cycles) and field radiation therapy. Although advanced stage disease is treated with a full course of chemotherapy as well as novel agents (Bortezomib, Ibrutinib, Lenalidomide). In this review study, we looked at the role of multiple aspects of genetic and microenvironment changes which have effects in DLBCL tumours. |
Inhibition of USP1 reverses the chemotherapy resistance through destabilization of MAX in the relapsed/refractory B-cell lymphoma. | The patients with relapsed and refractory diffuse large B-cell lymphoma (DLBCL) have poor prognosis, and a novel and effective therapeutic strategy for these patients is urgently needed. Although ubiquitin-specific protease 1 (USP1) plays a key role in cancer, the carcinogenic effect of USP1 in B-cell lymphoma remains elusive. Here we found that USP1 is highly expressed in DLBCL patients, and high expression of USP1 predicts poor prognosis. Knocking down USP1 or a specific inhibitor of USP1, pimozide, induced cell growth inhibition, cell cycle arrest and autophagy in DLBCL cells. Targeting USP1 by shRNA or pimozide significantly reduced tumor burden of a mouse model established with engraftment of rituximab/chemotherapy resistant DLBCL cells. Pimozide significantly retarded the growth of lymphoma in a DLBCL patient-derived xenograft (PDX) model. USP1 directly interacted with MAX, a MYC binding protein, and maintained the stability of MAX through deubiquitination, which promoted the transcription of MYC target genes. Moreover, pimozide showed a synergetic effect with etoposide, a chemotherapy drug, in cell and mouse models of rituximab/chemotherapy resistant DLBCL. Our study highlights the critical role of USP1 in the rituximab/chemotherapy resistance of DLBCL through deubiquitylating MAX, and provides a novel therapeutic strategy for rituximab/chemotherapy resistant DLBCL. |
mTOR inhibition amplifies the anti-lymphoma effect of PI3Kβ/δ blockage in diffuse large B-cell lymphoma. | Diffuse large B-cell lymphoma (DLBCL) is an aggressive disease that exhibits constitutive activation of phosphoinositide 3-kinase (PI3K) driven by chronic B-cell receptor signaling or PTEN deficiency. Since pan-PI3K inhibitors cause severe side effects, we investigated the anti-lymphoma efficacy of the specific PI3Kβ/δ inhibitor AZD8186. We identified a subset of DLBCL models within activated B-cell-like (ABC) and germinal center B-cell-like (GCB) DLBCL that were sensitive to AZD8186 treatment. On the molecular level, PI3Kβ/δ inhibition decreased the pro-survival NF-κB and AP-1 activity or led to downregulation of the oncogenic transcription factor MYC. In AZD8186-resistant models, we detected a feedback activation of the PI3K/AKT/mTOR pathway following PI3Kβ/δ inhibition, which limited AZD8186 efficacy. The combined treatment with AZD8186 and the mTOR inhibitor AZD2014 overcame resistance to PI3Kβ/δ inhibition and completely prevented outgrowth of lymphoma cells in vivo in cell line- and patient-derived xenograft mouse models. Collectively, our study reveals that subsets of DLBCLs are addicted to PI3Kβ/δ signaling and thus identifies a previously unappreciated role of the PI3Kβ isoform in DLBCL survival. Furthermore, our data demonstrate that combined targeting of PI3Kβ/δ and mTOR is effective in all major DLBCL subtypes supporting the evaluation of this strategy in a clinical trial setting. |
Hyperammonaemia syndrome in disseminated | Hyperammonaemia syndrome secondary to |
Primary lymphoma of the uterine cervix: a clinicopathologic study of 13 cases with review of additional 54 cases in the literature. | Primary lymphoma of the uterine cervix (LUCX) is extremely rare, and its diagnosis is challenging. However, its clinicopathological features have not been well characterized. Thirteen primary LUCX patients were retrospectively studied, and 54 patients from the literature were reviewed. Primary LUCX was identified in 0.22% (13/6000) of patients with uterine cervical malignancies in our institution. The patients' median age was 51 years (range: 22-85 years). All patients had a bulk of neoplasms in the uterine cervix. The median tumour diameter was 6 cm (range: 1.5-10 cm). Approximately 78.0% (39/50) of the patients initially presented with irregular vaginal bleeding or discharge. Moreover, 86.7% (39/45) had Ann Arbor stage I or II. Diffuse large B-cell lymphoma, not otherwise specified, was the most common type, accounting for 85.0% (57/67) of primary LUCX cases. Follicular lymphoma (7.5%, 5/67), extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (4.5%, 3/67), mantle cell lymphoma (MCL), blastoid variant (1.5%, 1/67), and peripheral T-cell lymphoma (1.5%, 1/67) were occasionally observed. Three patients (7.1%, 3/42) with DLBCL, NOS died from the disease during the follow-up period. Their 5-year overall survival (OS) rate was 93.5%. The patient with MCL, blastoid variant in our present cohort died of the disease 33 months after diagnosis. Primary LUCX is an extremely rare condition. The clinical symptoms are non-specific. DLBCL, NOS is the most common histologic type, showing a favourable outcome with accurate diagnosis and timely and optimal treatment. |
Poly zinc finger protein ZFP14 suppresses lymphomagenesis and abnormal inflammatory response via the HOXA gene cluster. | Poly zinc finger proteins (ZFP) that contain a KRAB (Krüppel-associated box) domain represent the largest class of transcription factors in higher organisms, but their roles in development and pathogenesis are largely undefined. ZFP14 (also known as ZNF531) contains thirteen zinc fingers and is highly conserved across species. Notably, we found that ZFP14 is frequently down-regulated in a multitude of human cancers, which correlates with poor prognosis of patients. Since ZFP14 has never been characterized, we generated a Zfp14-deficient mouse model to investigate the role of ZFP14 in development and pathogenesis. We showed that the mice deficient in Zfp14 had a short lifespan and were prone to diffuse large B-cell lymphoma (DLBCL), hyperplasia in multiple organs, systemic chronic inflammation, liver steatosis, and pancreatitis. Additionally, several pro-inflammatory cytokines, including IL-1β, IL18, and TNFα, were highly expressed in inflamed Zfp14 |
Immune scoring model based on immune cell infiltration to predict prognosis in diffuse large B-cell lymphoma. | Diffuse large B-cell lymphoma (DLBCL) is genetically heterogeneous in both pathogenesis and clinical symptoms. Most studies on tumor prognosis have not fully considered the role of tumor-infiltrating immune cells. This study focused on the role of tumor-infiltrating immune cells in the prognosis of DLBCL.
The GSE10846 data set from the National Center for Biotechnology Information's Gene Expression Omnibus was used as the training set, and the GSE53786 data set was used as the validation set. The proportion of immune cells in each sample was calculated with the CIBERSORT algorithm using R software. After 10 immune cells were screened out (activated memory CD4 positive T cells, follicular helper T cells, regulatory T cells, gamma-delta T cells, activated natural killer cells, M0 macrophages, M2 macrophages, resting dendritic cells, and eosinophils) by univariate Cox analysis, Lasso regression and random forest sampling analyses were performed, the intersecting immune cells were selected for multifactor Cox analysis, and a predictive model was constructed combined with clinical information. Predictive performance was assessed using survival analysis and time-dependent receiver operating characteristic curve analysis.
In total, 539 samples were included in this study, and samples with p < .05 were retained using CIBERSORT. Univariate Cox analysis yielded 10 cell types that were associated with overall survival. Two kinds of immune cells were obtained by Lasso regression combined with the random forest method and were used to construct a prognostic model combined with clinical information. The reliability of the model was validated in two data sets.
The immune cell-based prediction model constructed by the authors can effectively predict the prognostic outcome of patients with DLBCL, whereas nomogram plots can help clinicians assess the probability of long-term survival. |
Outcomes of Autologous Stem Cell Transplantation as a Consolidative Strategy for the Treatment of Primary and Isolated Secondary Central Nervous System Diffuse Large B Cell Lymphomas. | Standard consolidation for primary diffuse large B cell lymphoma (DLBCL) of the central nervous system (CNS) (PCNSL) is not established. This single center, retrospective observational study aims to define the outcomes of consolidative high dose chemotherapy and autologous stem cell transplantation (HDC/ASCT) in patients with PCNSL and isolated secondary CNS DLBCL (SCNSL) and evaluate the prognostic factors.
All consecutive patients performed an HDC/ASCT for PCNSL or isolated SCNSLs between October 2012 and February 2022 were identified. Primary endpoints were progression-free survival (PFS) and overall survival (OS).
Among 35 patients included, 28 had PCNSL and 7 had isolated SCNSL. Median age was 51 (16-78). Males constituted 48.6%. Median follow-up after HDC/ASCT was 42.0 months. MATRIX (51.4%) and TEAM (80.0%) were the most frequent regimens of induction and conditioning, respectively. OS and PFS 1- and 2-year after HDC/ASCT were 68.0%, 57.0%, 58.0%, 48.0%, respectively. Increasing age, poor performance and comorbidities were associated with lower OS and PFS and higher non-relapse mortality (NRM). Complete response (CR) 1 at HDC/ACST was independently associated with higher OS and PFS [hazard ratio (HR): 4.67 and 6.99, respectively].
In patients < 60 years consolidative HDC/ASCT yields promising OS and PFS. Patients ≥ 60 years may less likely benefit from consolidative HDC/ASCT and should be studied further in trials of novel agents, lower doses of consolidative radiotherapy and dose-adjusted conditioning regimens. Not only age, but also comorbidities, clinical performance and response to induction correlate with outcomes. Patients with isolated SCNSL may achieve similar outcomes. |
Genomic Profiling Reveals Differences in Primary Central Nervous System Lymphoma and Large B-Cell Lymphoma, With Subtyping Suggesting Sensitivity to BTK Inhibition. | B-cell primary central nervous system (CNS) lymphoma (PCL) is diffuse large B-cell lymphoma (DLBCL) confined to the CNS. Less than 50% of patients with PCL achieve complete remission with current therapies. We describe the findings from comprehensive genomic profiling (CGP) of a cohort of 69 patients with PCL, 36 cases of secondary CNS lymphoma (SCL), and 969 cases of DLBCL to highlight their differences and characterize the PCL cohort. In addition, we highlight the differences in frequency of germinal center B-cell like (GCB) and non-GCB subtypes and molecular subtypes, particularly MCD and EZH subtypes, between PCL and DLBCL.
Sixty-nine cases of B-cell PCL, 36 cases of secondary CNS lymphoma (SCL), and 969 cases of DLBCL were evaluated by CGP of 405 genes via DNAseq and 265 genes via RNAseq for fusions (FoundationOne Heme). Tumor mutational burden (TMB) was calculated from 1.23 Mb of sequenced DNA.
Genomic alterations with significant differences between PCL and DLBCL included MYD88, ETV6, PIM1, PRDM1, CXCR4, TP53, and CREBBP, while only MYD88 was significantly different between SCL and DLBCL. PCL cases were significantly enriched for the MCD molecular subtypes, which have an excellent response to BTKi. We report a patient with a durable complete response to BTKi consistent with their genomic profile. EBV status, CD274 amplification, and TMB status suggest that 38% of PCL patients may benefit from ICPI; however further study is warranted.
CGP of PCLs reveals biomarkers, genomic alterations, and molecular classifications predictive of BTKi efficacy and potential ICPI efficacy. Given the limitations of standard of care for PCL, CGP is critical to identify potential therapeutic approaches for patients in this rare form of lymphoma. |
Case report: Ventricular primary central nervous system lymphoma with partial hypointensity on diffusion-weighted imaging. | Primary central nervous system lymphoma (PCNSL) is infrequent and represents 3. 1% of primary brain tumors. And the lesions that are restricted to the ventricular system, particularly the third ventricle, are even rarer. There are few pieces of literature or case reports to date. We report a case of PCNSL with partial hypointense on diffusion-weighted imaging (DWI) located in the lateral and third ventricles. Then we reviewed almost all case reports of ventricular PCNSLs in the last 20 years, discuss the imaging presentation, other ventricular tumors with similar imaging findings, and primary treatment measures.
A 78-year-old man presented with memory loss and poor responsiveness for one week without obvious precipitating factors. Magnetic resonance imaging (MRI) showed lesions in the third ventricle and left lateral ventricles, which were slightly hypointense on T1-weighted imaging (T1WI), and isointense to slightly hypointense on T2-weighted imaging (T2WI). On DWI, the left lateral ventricular lesion was hyperintense, while the third ventricular lesion was hypointense. After the surgical procedure, the pathology and immunohistochemistry revealed diffuse large B-cell lymphoma (DLBCL).
Ventricular PCNSL is quite rare, and may be confused with other tumors in the same position. However, PCNSL differs from other central nervous system tumors in that it is primarily treated with chemotherapy and/or radiation therapy. So, it is important to recognize PCNSL and differentiate it from other tumors, considering its implications for management planning. |
A Novel Prognostic Model for Patients with Primary Gastric Diffuse Large B-Cell Lymphoma. | Primary gastric diffuse large B-cell lymphoma (PG-DLBCL) is a common phenotype of extranodal non-Hodgkin's lymphoma (NHL). This research aims to identify a model for predicting overall survival (OS) and cancer-specific survival (CSS) in PG-DLBCL.
A total of 1716 patients diagnosed with PG-DLBCL between 1975 and 2017 were obtained from the SEER database and further randomly divided into the training and validating cohorts at a ratio of 7 : 3. Univariate and multivariate cox analyses were conducted to determine significant variables for the construction of nomogram. The performance of the model was then assessed by the concordance index (C-index), the calibration plot, and the area under the receiver operating characteristic (ROC) curve (AUC).
Multivariate analysis revealed that age, race, insurance status, Ann Arbor stage, marital status, chemotherapy, and radiation therapy all showed a significant association with OS and CSS. These characteristics were applied to build a nomogram. In the training cohort, the discrimination of nomogram for OS and CSS prediction was excellent (C-index = 0.764, 95% CI, 0.744-0.784 and C-index = 0.756, 95% CI, 0.732-0.780). The AUC of the nomogram for predicting 3- and 5-year OS was 0.779 and 0.784 and CSS was 0.765 and 0.772. Similar results were also observed in the internal validation set.
We have successfully established a novel nomogram for predicting OS and CSS in PG-DLBCL patients with good accuracy, which can help physicians to quickly and accurately complete the evaluation of survival probability, risk stratification, and therapeutic strategy at diagnosis. |
Outcomes of high‑dose methotrexate for CNS prophylaxis in diffuse large B‑cell lymphoma with an intermediate or high CNS‑International Prognostic Index: A single‑center retrospective cohort study. | Central nervous system (CNS) relapse in patients with diffuse large B-cell lymphoma (DLBCL) is rare (2-5% of cases), but is a devastating complication with a poor survival rate. The administration of high-dose methotrexate (HDMTX) for CNS prophylaxis in patients with DLBCL is controversial and variable in the literature. The present study aimed to evaluate the clinical outcomes of HDMTX CNS prophylaxis in patients with intermediate and high CNS-International Prognostic Index (IPI) DLBCL using real-world data. An observational retrospective cohort study was conducted of all patients with intermediate and high CNS-IPI DLBCL treated at Princess Noorah Oncology Center (King Abdulaziz Medical City, Jeddah, Saudi Arabia) between January 2010 and December 2020. Patients were treated with HDMTX either intravenously or intrathecally, according to the physician's evaluation of the patient. Data on patient clinical characteristics, CNS relapses, risk factors and survival rates were obtained from hospital records. Data were analyzed using Student's unpaired t-test and the χ |
Primary diffuse large B-cell lymphoma of the right kidney: a case report. | The existence of primary renal lymphoma (PRL) in the kidney has long been debated due to its extranodal location and lack of lymphatic channels. Primary renal lymphoma is extremely rare, accounting for less than 1%, and is frequently misdiagnosed as renal cell carcinoma (RCC). We present a 50-year-old man presenting with right flank pain in the last week. The computed tomography scan showed a large isodense right renal mass with a small para-aortic lymph node suspected of RCC. The patient underwent right radical nephrectomy and lymphadenectomy with an uneventful postoperative outcome. The histopathology and immunohistochemistry showed diffuse large B-cell lymphoma. Then, the patient received five-cycle chemotherapy and regional radiotherapy. Within five years of follow-up, no symptoms of recurrence. In conclusion, even though PRL is a rare tumor type. An effort should be made to make a preoperative diagnosis because PRL can be treated with systemic chemotherapy instead of other renal tumors requiring nephrectomy. |
High expression of AP2M1 correlates with worse prognosis by regulating immune microenvironment and drug resistance to R-CHOP in diffuse large B cell lymphoma. | First-line treatment with R-CHOP has cured 50%-60% patients of diffuse large B cell lymphoma (DLBCL), and more than one-third patients will eventually progressed to relapsed/refractory disease with dismal outcomes. Adaptor Related Protein Complex 2 Subunit Mu 1 (AP2M1) is required for the activity of a vacuolar ATPase and may also play an important role in regulating the intracellular trafficking and function of CTLA-4 protein. Herein, using both public databases and our own tumor samples, we aimed to demonstrate the prognostic role of AP2M1 and the potential tumor-promoting mechanisms in DLBCL.
Using public datasets of DLBCL from both GEO and TCGA databases, we analyzed the role of AP2M1 in mediating chemoresistance to R-CHOP and its correlation with various clinical parameters and prognosis. By using various R packages, we evaluated the role of AP2M1 on regulating tumor immune microenvironment. Moreover, tumor samples of DLBCL from Beijing TongRen Hospital were used to validate our findings by immunohistochemistry staining.
Expression of AP2M1 was significantly increased in DLBCL, which was correlated with poor prognosis and a variety of clinical indicators. On the basis of enrichment analysis, it was found that AP2M1 may be related to intracellular receptor signaling pathway. Through immune analysis and drug prediction, we found that the expression of AP2M1 affected the immune environment and drug response of DLBCL, which further revealed the important role of AP2M1 in DLBCL. By analyzing 61 patients treated uniformly with R-CHOP regimen in our center, we validated the above findings that high expression of AP2M1 correlated with inferior survival outcomes and affected sensitivity to R-CHOP treatment.
Expression of AP2M1 may affect the prognosis of DLBCL patients probably by affecting the immune environment and the responses to many drugs in treating DLBCL, indicating AP2M1 as a potential therapy target in DLBCL. |
T-cell counts in peripheral blood at leukapheresis predict responses to subsequent CAR-T cell therapy. | Prediction of responses to chimeric antigen receptor (CAR)-T cell therapies is essential to maximize their therapeutic efficacy for diffuse large B-cell lymphoma (DLBCL). While several tumor-intrinsic risk factors of resistance and/or early relapse have been identified, clinically useful markers that determine potential activity of CAR-T cells have not been fully investigated. T-cell property at the time of leukapheresis may serve as such a marker. Therefore, we evaluated the clinical impact of CD3 |
Rituximab PK and PKPD evaluation based on a study in diffuse large B-cell lymphoma: influence of tumor size on PK and assessment of PK similarity. | DRL-rituximab (DRL_RI, Dr. Reddy's Laboratories SA, Basel, Switzerland) is under development as a rituximab biosimilar. Study RI-01-002 (CTRI/2012/11/003129), comparing DRL_RI to the reference medicinal product MabThera® (RMP, Roche, Grenzach-Wyhlen, Germany), demonstrated pharmacokinetic (PK) equivalence and showed comparable pharmacodynamic, efficacy, safety, and immunogenicity profiles. We used data from the same study to perform population PK and pharmacokinetic-pharmacodynamic (PKPD) analyses: first exploring possible factors influencing the PK similarity assessment between products, then performing simulations to investigate the impact of tumor size on rituximab PK. Nonlinear mixed-effects models for PK, tumor size, tumor size-PK, and tumor response were developed independently. The final PK model included drug product as a dose scaling parameter and predicted a 6.75% higher dose reaching the system in RMP-treated patients. However, when tumor size was included in the tumor size-PK model, the drug product effect was no longer observed. The model rather indicated that patients with larger tumor size have higher clearance. Further simulations confirmed that higher baseline tumor size is associated to slightly lower rituximab exposure. Tumor response, described by a Continuous-time Markov model, did not differ between drug products. Both had higher effects during the first 20 weeks of treatment. Also, the model described a sub-population of non-responders to treatment (42%) with faster transitions to a worse state. The different rituximab exposure initially detected between drug products (6.75%) was shown using PK/PKPD analysis to be due to a tumor size imbalance between treatment groups. PK/PKPD analyses may contribute to PK similarity assessments. |
A bone-based 3D scaffold as an | About 30% of patients with diffuse large B-cell lymphoma (DLBCL) relapse or exhibit refractory disease (r/r DLBCL) after first-line immunochemotherapy. Bone marrow (BM) involvement confers a dismal prognosis at diagnosis, likely due to the interaction between neoplastic cells and a complex tumor microenvironment (TME). Therefore, we developed a 3D |
A retrospective cohort study of polatuzumab vedotin combined with immunochemotherapy in Chinese patients with relapse/refractory diffuse large B cell lymphoma. | There are no standard therapies for patients with relapse/refractory diffuse large B-cell lymphoma (R/R DLBCL) who are ineligible for transplantation. Recently, polatuzumab vedotin (pola) combined with rituximab and bendamustine (pola-BR) has been validated in clinical trials. However, pola is not approved in China and clinical data in Chinese population is still lacking. This study is intended to preliminarily evaluate the clinical effectiveness of this regimen in China.
This study retrospectively evaluated the efficacy and tolerability of pola-BR regimen in Chinese R/R DLBCL patients treated in a compassionate use program (CUP; pola CUP) after failing ≥2 prior regimens. Patients participated in CUP at 4 Chinese centers from December 2019 to July 2020 were enrolled. The outcomes were the overall response rate (ORR), complete response (CR) rate, and progression-free survival (PFS). Adverse events (AEs) were collected.
A total of 28 patients enrolled in the pola CUP were included. At data analysis cut-off (30 September 2020), the best overall response (BOR) rate was 71.4%, and a CR rate of 25.0% was obtained. The estimated median PFS of all patients was 200 [95% confidence interval (CI): 97 to not evaluable (NE)] days. The most common AEs were thrombocytopenia (32.1%), neutropenia (28.6%), and fever (14.3%). High-grade (grade ≥2) peripheral neuropathy (PN) was not observed.
These preliminary data suggested that the pola-BR regimen has promising efficacy and tolerable safety in Chinese transplantation ineligible R/R DLBCL patients. Hence, pola-BR may be an optional regimen. Considering the limited sample size and short follow-up, larger sample and long-term survival outcome studies are warranted. |
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