Malignant B-cell Lymphoma Research Articles

Solitary pulmonary mass in a patient with a history of lymphoma: a case report

IntroductionWith the progress made in treatments, the survival rate for patients with malignant lymphoma in the last 30 years has significantly improved. However, the risk of experiencing a second primary malignancy or other disease has increased significantly.Case presentationA 44-year-old Mongolian man with a large mass in his right lower abdomen was admitted to our hospital 15 years previously. The mass was removed, and confirmed via pathological examination to be a malignant B-cell lymphoma in the appendix and distal small bowel. Post-operative chemotherapy with standard cyclophosphamide, hydroxydaunomycin, vincristine (Oncovin®) and prednisolone regimen was given for six cycles. No obvious recurrence was detected over the following 12 years. Subsequently, a mass in the right lung was found on a regular X-ray follow-up; our patient did not report chills, fever or cough. Chest computed tomography and positron emission tomography scans confirmed the mass. A primary lung carcinoma was considered to be the most likely diagnosis. However, after an exploratory thoracotomy and right upper lobectomy was performed a pathological examination of tissue samples demonstrated a lung cryptococcal granuloma, with positive staining for periodic acid Schiff and periodic acid-silver metheramine.ConclusionsCompared to the normal population, second primary malignancy (in particular leukaemia and lung cancer) in patients with malignant lymphoma during their long-term survival has been seen occasionally. However, other diagnoses should also be considered such as pulmonary cryptococcosis. Other than computed-tomography-guided needle biopsy, surgery for some patients is a much more appropriate choice, which could also help attain correct diagnosis and treatment.

Abstract 3159: Modulating therapeutic targets in B-cell lymphoma: Loss-of-function RNAi screen for CD20 regulators.

Abstract The surface glycoprotein CD20 is expressed on healthy and malignant B-cells and can be therapeutically exploited by monoclonal antibodies (e.g. Rituximab, Ofatumumab, GA-101). Stem cells and pro-B-cells are lacking CD20 surface protein, which allows the reestablishment of B-cell populations after treatment. Other cell lineages do not express CD20. Rituximab has revolutionized clinical practice in the treatment of malignant B-cell lymphoma. However, refractory lymphoma cells can lose the expression of CD20 after Rituximab exposure and B-cell lymphoma with low CD20 surface expression may be less responsive to treatment. Despite the widespread use of CD20 antibodies across lymphoma subtypes, little is known about the endogenous regulation of CD20. It was shown that several chemical compounds may modulate the surface density of CD20 (e.g. histone deacetylase inhibitors), but the regulatory network controlling CD20 levels is not understood. We aim to dissect the CD20 regulatome and to exploit the findings for novel therapeutic strategies. The CD20 regulatome is studied in a Burkitt lymphoma cell line (Raji) characterized by medium expression of CD20 in comparison to other lymphoma models. As a proof of principle, we were able to down-regulate the surface expression of CD20 assayed by FACS with four independent silencing triggers targeting CD20 mRNA. To discover novel regulators of CD20 expression, we performed an unbiased genome-wide RNAi screen. The screen hits are involved in diverse molecular mechanisms such as signaling, trafficking, chromatin remodeling and membrane composition. The group of genes decreasing the expression of CD20 expression can provide an insight into the physiological and pathological machinery involved in CD20 trafficking and processing. The strongest hit in this group, next to CD20 knockdown, is potentially involved in the direct transport of CD20 to the cell surface. Clinically most relevant is the group of genes where silencing increases the expression of CD20. The two strongest hits in this category are a transcription factor and a gene involved in signaling. Detailed molecular characterization of several chosen hits is currently ongoing. Their inhibition may lead to increased sensitivity to anti-CD20 antibodies and thus provide starting points for rational drug design. Citation Format: Mikolaj Slabicki, Leopold Sellner, Alexander Jethwa, Michael Boettcher, Thorsten Zenz. Modulating therapeutic targets in B-cell lymphoma: Loss-of-function RNAi screen for CD20 regulators. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3159. doi:10.1158/1538-7445.AM2013-3159

Repeat hepatectomies for hepatic malignant lymphoma and hepatocellular carcinoma associated with chronic hepatitis C: report of a case

We report a case of repeat hepatectomies for hepatic malignant lymphoma and hepatocellular carcinoma (HCC). A 75-year-old man with chronic hepatitis C underwent partial hepatectomy for a 25mm hepatic tumor in S5. The histological diagnosis was diffuse large B-cell malignant lymphoma and as postoperative (18)F-fluorodeoxyglucose-positron emission tomography showed no hot spots, the mass was presumed to be primary hepatic lymphoma. Thus, adjuvant systemic chemotherapy was given following the hepatectomy. Abdominal ultrasonography, done 12months after the hepatectomy, showed a hepatic tumor in S6 and repeat partial hepatectomy was performed. This tumor was histologically diagnosed as HCC.

A model system for assessing and comparing the ability of exon microarray and tag sequencing to detect genes specific for malignant B-cells

BackgroundMalignant cells in tumours of B-cell origin account for 0.1% to 98% of the total cell content, depending on disease entity. Recently, gene expression profiles (GEPs) of B-cell lymphomas based on microarray technologies have contributed significantly to improved sub-classification and diagnostics. However, the varying degrees of malignant B-cell frequencies in analysed samples influence the interpretation of the GEPs. Based on emerging next-generation sequencing technologies (NGS) like tag sequencing (tag-seq) for GEP, it is expected that the detection of mRNA transcripts from malignant B-cells can be supplemented. This study provides a quantitative assessment and comparison of the ability of microarrays and tag-seq to detect mRNA transcripts from malignant B-cells. A model system was established by eight serial dilutions of the malignant B-cell lymphoma cell line, OCI-Ly8, into the embryonic kidney cell line, HEK293, prior to parallel analysis by exon microarrays and tag-seq.ResultsWe identified 123 and 117 differentially expressed genes between pure OCI-Ly8 and HEK293 cells by exon microarray and tag-seq, respectively. There were thirty genes in common, and of those, most were B-cell specific. Hierarchical clustering from all dilutions based on the differentially expressed genes showed that neither technology could distinguish between samples with less than 1% malignant B-cells from non-B-cells. A novel statistical concept was developed to assess the ability to detect single genes for both technologies, and used to demonstrate an inverse proportional relationship with the sample purity. Of the 30 common genes, the detection capability of a representative set of three B-cell specific genes - CD74, HLA-DRA, and BCL6 - was analysed. It was noticed that at least 5%, 13% and 22% sample purity respectively was required for detection of the three genes by exon microarray whereas at least 2%, 4% and 51% percent sample purity of malignant B-cells were required for tag-seq detection.ConclusionA sample purity-dependent loss of the ability to detect genes for both technologies was demonstrated. Taq-seq, in comparison to exon microarray, required slightly less malignant B-cells in the samples analysed in order to detect the two most abundantly expressed of the selected genes. The results show that malignant cell frequency is an important variable, with fundamental impact when interpreting GEPs from both technologies.

HDM2 antagonist MI-219 (spiro-oxindole), but not Nutlin-3 (cis-imidazoline), regulates p53 through enhanced HDM2 autoubiquitination and degradation in human malignant B-cell lymphomas

BackgroundLymphomas frequently retain wild-type (wt) p53 function but overexpress HDM2, thereby compromising p53 activity. Therefore, lymphoma is a suitable model for studying the therapeutic value of disrupting the HDM2-p53 interaction by small-molecule inhibitors (SMIs). HDM2 have been developed and are under various stages of preclinical and clinical investigation. Previously, we examined the anti-lymphoma activity of MI-319, the laboratory grade of a new class of HDM2 SMI, the spiro-oxindole, in follicular lymphoma. Since then, MI-219, the clinical grade has become readily available. This study further examines the preclinical effects and mechanisms of MI-219 in a panel of human lymphoma cell lines as well as a cohort of patient-derived B-lymphcytes for its potential clinical use.ResultsPreclinical assessment of MI-219 was evaluated by means of an in vitro and ex vivo approach and compared to Nutlin-3, the gold standard. Characterization of p53 activity and stability were assessed by quantitative PCR, Western blot, and immunoprecipitation. Biological outcome was measured using Trypan blue exclusion assay, Annexin V/PI, PARP and caspase-3 cleavage. Surprisingly, the overall biological effects of Nutlin-3 were more delayed (48 h) while MI-219 triggered an earlier response (12-24 h), predominantly in the form of apoptotic cell death. Using a cell free autoubiquitination assay, neither agent interfered with HDM2 E3 ligase function. MI-219 was more effective in upregulating wt-p53 stabilization compared to Nutlin-3. MI-219, but not Nutlin-3, enhanced the autoubiquitination and degradation of HDM2.ConclusionsOur data reveals unexpected differences between MI-219 and the well-studied Nutlin-3 in lymphoma cell lines and patient samples. We suggest a novel mechanism for MI-219 that alters the functional activity of HDM2 through enhanced autoubiquitination and degradation. Additionally, this mechanism appears to correspond to biological outcome. Our results provide evidence that different classes of HDM2 SMIs elicit molecular events that extend beyond HDM2-p53 dissociation which may be of biological and potentially therapeutic importance.

Identification of a glutathione peroxidase inhibitor that reverses resistance to anticancer drugs in human B-cell lymphoma cell lines

Cancer cells isolated from two patients with malignant non-Hodgkin B-cell lymphomas that became resistant to chemotherapy during clinical treatment were made ⩾fourfold resistant in culture to anticancer drugs, that is cisplatin, etoposide, methotrexate and bortezomib. Because most resistant lines showed significantly increased expression of the anti-oxidative enzyme glutathione peroxidase 1 (GPx1), GPx1 was investigated as a target for inhibitor development. Virtual screening of a library of diverse structures by docking them to the active site of the X-ray crystal structure of bovine GPx1 uncovered compounds that might block the enzyme. An enzyme assay confirmed an acylhydrazone heterocycle (3) with GPx inhibitory activity. Combinations of 3 with the anticancer drugs listed above led to reversal of resistance in the lymphoma cell lines.

Primary Hepatic Marginal Zone B Cell Lymphoma : A Case Report and Review of the Literature

Primary hepatic lymphoma (PHL) is a very rare malignancy, and constitutes about 0.016% of all cases of non-Hodgkin's lymphoma and is often misdiagnosed. The optimal therapy is still unclear and the outcomes are uncertain. Among PHLs, a primary hepatic low-grade marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) is extremely rare. We present a case of primary hepatic lymphoma (MALT lymphoma) treated with surgical resection and adjuvant chemotherapy. A 38-year-old Korean man, who was diagnosed with chronic hepatitis B 20years ago, was admitted for liver biopsy after liver lesions were detected on follow-up computed tomography scan (CT). Liver biopsy revealed the diagnosis of marginal zone B-cell malignant lymphoma (MALT lymphoma). The preoperative clinical staging was IE, given that no additional foci of lymphoma were found anywhere else in the body. The patient underwent left hemihepatectomy. Subsequently, the patient received two cycles of CHOP (cyclophosphamide, adriamycin, vincristine, and prednisone) regimen. After 15months of follow-up, the patient is alive and well without any evidence of disease recurrence. Although the prognosis is variable, good response to early surgery combined with postoperative chemotherapy can be achieved in strictly selected patients.

Excellent Long-Term Survival of Patients with Waldenström‘s Macroglobulinemia (WM) treated in Private Oncology Practices and a University hospital with different Treatment Strategies

Abstract▪2671▪This icon denotes a clinically relevant abstract Background:WM is a rare type of malignant B-cell lymphoma, defined as a lymphoplasmocytic lymphoma in bone marrow and a monoclonal gammopathy of immunoglobulin-M (IgM) type. Due to the paucity of large clinical trials, a standard treatment regimen is still controversial. The purpose of this study was to compare the standard treatment and outcome of patients (pts) treated in private oncology practices (PP) and a university hospital (UH) in a region of southern Germany (Nordbaden). Methods:We retrospectively reviewed the charts of all pts with WM of the last 2 decades of 4 PP in Mannheim, Heidelberg, Karlsruhe and Speyer and the department of hematology of the University of Heidelberg. Results:170 patients with WM could be identified, 74 from PP, 96 from the UH. The median age of the 170 pts was 63.3 years (range 29.1–88.5). The clinical symptoms were splenomegaly in 21.2%, hyperviscosity in 15.9%, lymphadenopathy in 15.9%, and polyneuropathy in 11.2%. 12.9% had a previous phase of IgM-MGUS. Pts from PP were older (median 65.3 vs. 62.5, p=0.01). Mean hemoglobine level at diagnosis was lower in pts from UH (11.4 vs. 12.2, p=0.04). There was no significant difference in mean platelet count, IgM and ß2-microglobuline level at diagnosis. 54% of pts from PP have received treatment during the observation time, as compared to 78.1% of the UH (p<0.001). The most common first line treatment protocols of PP were Chlorambucil (17/40, 42.5%), Bendamustin (17.5%) and Rituximab(R)-Bendamustin (17.5%). The UH most commonly administered R-Pentostatin-Cyclophosphamide (28%), Chlorambucil (17.3%) and COP (16%). 35% of the treated pts of PP have received R, as compared to 62.6% of the pts of the UH (p<0.001). 60% of the treated pts of PP have received Bendamustin, as compared to 8% of the pts of the UH (p<0.001). The time to first treatment was significantly shorter in pts from the UH (median 13.7 mo.) as compared to PP (52.9 mo.) (p=0.05). Median overall survival of all pts was 25.0 yrs and did not differ between PP and UH. Conclusion:Pts with WM treated in PP were older and had higher initial hemoglobin levels as compared to pts from the UH. Treatment differs significantly between PP and UH. Time to first treatment was significantly shorter in pts from UH. Overall survival was excellent, and better than reported previously. Disclosures:Hensel:Roche: Honoraria, Research Funding; Mundipharma: Research Funding.

An Unusual Case of Gastrointestinal Non-Hodgkinʼs Lymphoma Associated with Helicobacter pylori in a Patient with Peripheral B-Cell Lymphoma

Purpose: The simultaneous occurrence of non-Hodgkin lymphoma (NHL) and primary cancers is rare. Primary gastric lymphoma is the most frequent extra-nodal primary site for non-Hodgkin's lymphoma (NHL). Although uncommon, the incidence of primary Gastric-Non Hodgkin Lymphoma (PG-NHL) is increasing in United States. It is known to have different clinical behavior from lymph node NHL. PG-NHL of the mucosa associated lymphoid tissue (MALT) develops on the background of a chronic Helicobacter pylorii (H. pylori) infection. Case: An 83-year-old female with a past medical history of hypertension and peripheral B-cell Lymphoma diagnosed and treated 5 years prior was admitted with abdominal pain associated with weight loss and generalized weakness. Review of systems was negative. On physical examination, everything was unremarkable including a normal abdominal exam. Laboratory tests were significant for anemia. CT scan revealed marked gastric wall thickening and adenopathy. On further evaluation, EGD showed gastritis and large necrotic, ulcerated mass. On biopsy, it was consistent with Malignant Large B-cell Lymphoma. Our case also demonstrates the importance of follow-up of patients not only for the relapse of primary disease but also for the development of secondary malignancy which can be diagnosed at an early, treatable stage. Conclusion: Primary GI-NHL is a heterogeneous disease entity with considerable therapeutic options including surgical debulking and systemic chemotherapy for most patients. Peripheral B-cell lymphoma represent a distinct entity of B-NHL with characteristic morphologic and immunophenotypic features and particular chromosomal abnormalities, anda close histogenetic relationship between extranodal and nodal peripheral BCL is likely, although the clinical presentation may vary. Most probably multifocal clonal populations of lymphocytes develop, which progress to highly malignant lymphomas over many years, starting from a previous reactive disease, commonly an Helicobacter pylori-associated chronic gastritis or an organ related autoimmune disease.

Basophils and plasmacytoid dendritic cells are potential sources for error in flow cytometric monitoring of patients receiving anti-CD22 therapies. AKA not all anti-CD22 antibodies are created equal

Basophils and plasmacytoid dendritic cells are potential sources for error in flow cytometric monitoring of patients receiving anti-CD22 therapies. AKA not all anti-CD22 antibodies are created equal

Primary B-cell lymphoma of the cauda equina, successfully treated with high-dose methotrexate plus high-dose cytarabine: a case report with MRI findings

Primary malignant lymphoma of the cauda equina is an extremely rare disease. Previously, there have been only 12 reported cases of malignant lymphoma of the cauda equina, and most cases relapsed early in the clinical course. So, the optimal treatment strategy for this condition has not been established yet and the prognosis is thought to be poor. We experienced a case of B-cell malignant lymphoma of the cauda equina, with rapid progression of the muscle weakness of the bilateral lower extremities, successfully treated with high-dose methotrexate plus high-dose cytarabine (Ara-C) chemotherapy, followed by radiotherapy and in complete remission without any recurrence signs, 1.5 years after the initial diagnosis. Intrathecal chemotherapy with MTX, Ara-C, and predonisolone was simultaneously performed. We should carefully continue to monitor the clinical course of our case, with the examinations of magnetic resonance imaging and cerebrospinal fluid in order not to overlook any subtle neurological changes or other clinical symptoms.

Modern concepts in the biology, diagnosis, differential diagnosis and treatment of primary central nervous system lymphoma

Recent studies addressing the molecular characteristics of PCNSL, which is defined as malignant B-cell lymphoma with morphological features of DLBCL, have significantly improved our understanding of the pathogenesis of this lymphoma entity, which is associated with an inferior prognosis as compared with DLBCL outside the CNS. This unfavorable prognosis stimulated intense efforts to improve therapy and induced recent series of clinical studies, which addressed the role of radiotherapy and various chemotherapeutic regimens. This review combines the discussion of diagnosis, differential diagnosis and recent progress in studies addressing the molecular pathogenesis as well as therapeutic options in PCNSL.

MRI patterns in recurrence of primary CNS lymphoma in immunocompetent patients

PurposePrimary CNS lymphomas (PCNSL) are highly malignant non-Hodgkin's B-cell lymphoma restricted to the CNS. While MRI features of PCNSL at initial presentation have been comprehensively described, literature on MRI-characteristics at relapse is sparse. The purpose of this study was to investigate anatomic location and contrast enhancement patterns at PCNSL recurrence by cranial MRI. MethodsSixteen immunocompetent patients (9 men, 7 women, median age 65 years) with histologically proven PCNSL and initial response to a standardized polychemotherapy, but suffering from a relapse were consecutively recorded. Native and contrast-enhanced MRI examinations carried out at initial presentation and at time of relapse were compared. Anatomical site of parenchymal enhancement, frequency and presence of non-parenchymal contrast enhancement (i.e. ventricular, superficial, subependymal) patterns at initial presentation and at relapse were recorded and compared. ResultsLocal recurrence was found at the site of the initial tumor presentation in four of the 16 cases. Six of 11 patients presenting a unilateral PCNSL at initial presentation had a bilateral involvement at relapse. In two cases, recurrence appeared solely on the contralateral side without involvement of the hemisphere initially affected. At both dates, subependymal enhancement was the most often found non-parenchymal pattern (six at initial presentation, and five at relapse). The number of patients with a ventricular contrast enhancement increased from one at initial presentation to four at relapse. ConclusionsPCNSL tend to recur in different parenchymal anatomic sites as compared with the site of the initial tumor presentation. Contrast-enhancing non-parenchymal lesions are also frequent and might change their pattern at relapse.

Hypercalcemia and large abdominal mass.

An 85-year-old woman with chronic renal insufficiency presented with appetite loss and abdominal fullness. Laboratory data showed serum creatinine levels of 5.46 mg/dL, urea nitrogen 42 mg/dL, corrected calcium 15.3 mg/dL, intact PTH - parathyroid hormone 15.1 pg/mL (N 10–65), calcitriol 63.4 pg/mL (N 20–60), PTH-related protein 5.5 pmol/L (N < 1.0), cortisol of 4.3 pg/mL (N 6.2–19.4), ACTH - adrenocorticotropic hormone 304 pg/mL (N 7.2–63.3) and soluble interleukin-2 receptor of 2335 U/mL (N 206–713). These results signify that the patient suffered from exacerbation of chronic renal failure, adrenal insufficiency and severe hypercalcemia probably caused by excessive calcitriol and PTH-related protein. Magnetic resonance imaging and fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography imaging disclosed giant masses bilaterally in the adrenal glands (Figure 1A and B); the masses were histologically diagnosed as extranodal malignant B-cell lymphoma (Figure 2A), which was also positive for 25-hydroxyvitamin D3-1-alpha-hydroxylase (Figure 2B), suggesting extra-renal overproduction of calcitriol. Hypercalcemia was normalized (8.9 mg/dL) shortly after hydrocortisone and zoledronate treatment concomitant with serum calcitriol decline (20.6 pg/mL) and serum cortisol increase (16.3 pg/mL), although PTH-related protein remained high (5.5 pmol/L). Additionally, serum FGF23 - fibroblast growth factor 23 (FGF23) level decreased from 9050 to 258 pg/mL (N 10–50). The patient died 2 months after hospitalization due to lymphoma progression. Fig. 1. Imaging of the abdominal masses. (A) Magnetic resonance imaging and (B) fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography imaging revealed giant masses originating bilaterally in the adrenal glands and partially invading ... Fig. 2. Histopathology of the abdominal mass. Percutaneous biopsy of the adrenal glands was performed. Histological examination revealed the huge bilateral masses in the adrenal glands to be diffuse, large B-cell lymphoma (A), and lymphoma cells were stained ... Hypercalcemia is occasionally seen in malignant lymphoma [1]. Common causes of lymphoma-related hypercalcemia include overproduction of calcitriol and PTH-related protein and local osteolysis induced by inflammatory cytokines [2]. In the present case, hypercalcemia was caused by excessive calcitriol and PTH-related protein. Besides, adrenal insufficiency, which was normalized after hydrocortisone treatment, might also contribute to the development of hypercalcemia [3]. In addition, high serum FGF23 level decreased in parallel with the decline in serum calcitriol, indicating that endogeneous calcitriol overproduction stimulated the production of FGF23 in the bone.

The study of the origin and subdifferentiation of the malignant lymphoma diffuse large B-cell lymphoma

The study of the origin and subdifferentiation of the malignant lymphoma diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma of cerebellum five months after left atrial myxoma resection in an old woman

We describe a 70-year-old female patient with diffuse large B-cell lymphoma of the cerebellum; she received resection of a left atrial myxoma five months ago. To the best of our knowledge, to date no association of atrial myxoma with the malignant cerebellar diffuse large B-cell lymphoma has been reported in the literature, except for high level of interleukin-6 (IL-6) in the serum under both conditions. IL-6 as a pro-inflammatory cytokine has been shown to be associated with tumor progression, including inhibition of cancer cell apoptosis and stimulation of angiogenesis. IL-6 concentrations may provide possible aetiological links between atrial myxoma and cerebellar diffuse large B-cell lymphoma in our case.

Sirolimus addition to tacrolimus-based immunosuppression induces complete remission of post-transplant lymphoproliferative disorder in a liver transplant recipient

Sirolimus addition to tacrolimus-based immunosuppression induces complete remission of post-transplant lymphoproliferative disorder in a liver transplant recipient

Bioengineering a Unique Deimmunized Bispecific Targeted Toxin That Simultaneously Recognizes Human CD22 and CD19 Receptors in a Mouse Model of B-Cell Metastases

A drug of high potency and reduced immunogenicity is needed to develop a targeted biological drug that when injected systemically can penetrate to malignant B cells. Therefore, a novel deimmunized bispecific ligand-directed toxin targeted by dual high-affinity single-chain Fvs (scFv) spliced to PE38 with a KDEL COOH-terminus was genetically engineered. The aims were to reduce toxin immunogenicity using mutagenesis, measure the ability of mutated drug to elicit antitoxin antibody responses, and show that mutated drug was effective against systemic B-cell lymphoma in vivo. Both human anti-CD22 scFv and anti-CD19 scFv were cloned onto the same single-chain molecule with truncated pseudomonas exotoxin (PE38) to create the drug. Site-specific mutagenesis was used to mutate amino acids in seven key epitopic toxin regions that dictate B-cell generation of neutralizing antitoxin antibodies. Bioassays were used to determine whether mutation reduced potency, and ELISAs were done to determine whether antitoxin antibodies were reduced. Finally, a powerful genetically altered luciferase xenograft model was used that could be imaged in real time to determine the effect on systemic malignant human B-cell lymphoma, Raji-luc. Patient B-lineage acute lymphoblastic leukemia, B-cell chronic lymphocytic leukemia, and B lymphoma were high in CD22 and CD19 expression. 2219KDEL7mut was significantly effective against systemic Raji-luc in mice and prevented metastatic spread. Mutagenesis reduced neutralizing antitoxin antibodies by approximately 80% with no apparent loss in in vitro or in vivo activity. Because 2219KDEL7mut immunogenicity was significantly reduced and the drug was highly effective in vivo, we can now give multiple drug treatments with targeted toxins in future clinical trials.

Malignant B-Cell Lymphoma with Mott Cell Differentiation in a Ferret (Mustela Putorius Furo)

A 3.5-year-old, male, neutered ferret (Mustela putorius furo) was presented with a 3-day history of lethargy and anorexia. Splenic aspirates revealed high numbers of intermediate-sized lymphocytes and Mott cells interpreted as lymphoma with Mott cells. The ferret was euthanized because of a poor clinical prognosis. Postmortem examination revealed markedly enlarged spleen and lymph nodes, with multifocal white nodules in the liver parenchyma. Histologically, the spleen had multifocal large nodules composed of neoplastic lymphocytes with frequent Mott cells. Similar neoplastic cells were present in the sections of liver, lymph nodes, and bone marrow. These cells were cluster of differentiation (CD)3-negative, CD79alpha-positive, and lambda light-chain-positive. Electron microscopy revealed that the cytoplasm of the neoplastic Mott cells had increased, disorganized, dilated, rough endoplasmic reticulum containing electron-dense immunoglobulin. On the basis of cytologic, histopathologic, immunohistochemical, and electron microscopic findings, a malignant B-cell lymphoma with Mott cell differentiation was diagnosed.

Anomalous expression of Thy1 (CD90) in B-cell lymphoma cells and proliferation inhibition by anti-Thy1 antibody treatment

The anti-CD20 monoclonal antibody (Ab) rituximab is accepted to be an effective therapeutic Ab for malignant B-cell lymphoma; however, discovery of other cell surface antigens is required for the option of antibody medicine. Considering that many tumor-associated antigens are glycans, we have searched glycoconjugates for the candidate antigens that therapeutic Abs target. To this end, we first focused on the difference in the glycogenes expression in terms of Epstein–Barr virus (EBV) infection of a Burkitt’s lymphoma cell line, Akata. Using DNA array, flow cytometry and Western blotting, we found that Thy1 was highly expressed in EBV-positive Akata cells. Subsequently, Thy1 was found to be expressed in other B-cell lymphoma cell lines: BJAB, MutuI, and MutuIII, irrespective of EBV infection. Treatment of these cells with an anti-Thy1 monoclonal antibody inhibited proliferation more strongly than the therapeutic Ab rituximab. The B-cell lymphoma cell lines were classified based on the extent of the proliferation inhibition, which was not correlated with the expression level of Thy1. It is suggested that stable residence of receptor tyrosine kinases in lipid rafts sustains cell growth in B-cell lymphoma cells.