Therapy For Malignant Lymphoma Research Articles

Circulating free DNA and its potential in the diagnostics and therapy of malignant lymphoma

Circulating free DNA and its potential in the diagnostics and therapy of malignant lymphoma

Tissue Factor-Targeted "O2-Evolving" Nanoparticles for Photodynamic Therapy in Malignant Lymphoma.

Vascular-targeted PDT (vPDT) has produced promising results in the treatment of many cancers, including drug-resistant ones, but little is known about its efficacy in lymphoma. Unfortunately, the lack of a specific therapeutic target and a hypoxic microenvironment for lymphoma jeopardizes the efficacy of vPDT severely. In this study, we designed a lymphoma tissue factor-targeted “O2-evolving” strategy combining PDT with catalase and HMME-encapsulated, EGFP-EGF1-modified PEG-PLGA nanoparticles (CENPs) to boost PDT efficiency; this combination takes advantage of the low oxygen tension of lymphoma. In our results, CENPs accumulated effectively in the vascular lymphoma in vivo and in vitro, and this accumulation increased further with PDT treatment. Per positron emission tomography imaging, combining CENPs with PDT inhibited lymphoma glucose metabolism significantly. The expression of hypoxia-inducible factor (HIF)-1α in the entrapped catalase groups reduced markedly. These data show that the combined administration of PDT and CENPs can prompt tissue factor-cascade-targeted and self-supply of oxygen and that it has a good therapeutic effect on malignant lymphoma.

Serum Levels of CCL22 and CCL25 Might Predict Skin Rash Induction、the Common Adverse Event By Bendamustine Therapy in Malignant Lymphoma

Introduction: Bendamustine has been recently approved for the treatment of low-grade malignant lymphoma. In spite of the better efficacy, skin rash is the commonest adverse event by bendamustine in the treatment of malignant lymphoma. To understand the mechanism of the skin rash, we prospectively examine the relationship between skin rash and chemokines. Methods: After informed consent to the patients, who would received bendamustine (B) or bendmustine+rituximab (BR), the sera were collected before and after the treatment of B or BR. Cytokine/Chemokine array was performed by Bio-Plex system. Results: 20 patients with FL (n=18), MCL (n=1), and low-grade B-cell lymphoma (n=1) were enrolled in this study. All patients wee treated with B or BR regimen. 9 patients showed skin rash after the treatment of bendamustine. In Cytokine/Chemokine array, serum levels of CCL22 and CCL25 before the treatment were significantly higher in skin rash group (p=0.010738476 and p=0.030366028, respectively) (Figure 1 and 2), and serum levels of CXCL10 and CXCL11 after skin rash were higher significantly (p=0.000923527 and p=0.014890795, respectively). Conclusion: Serum levels of CCL22 and CCL25 might predict skin rash inductionAthe commonest adverse event by bendamustine and CXCL10 and CXCL11might contribute to induction of skin rash by bendamustine. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

FNC, a Novel Nucleoside Analogue, Blocks Invasion of Aggressive Non-Hodgkin Lymphoma Cell Lines Via Inhibition of the Wnt/β-Catenin Signaling Pathway

Chemotherapy is the primary therapy for malignant lymphoma (ML). However, the clinical outcome is still far from satisfactory. Consequently, an understanding of the mechanism of modulating cancer cell invasion, migration and metastasis is important for the development of more effective chemotherapeutic agents. FNC, 2'- deoxy- 2' -β- fluoro -4'- azidocytidine, a novel cytidine analogue, has demonstrated significantly inhibitory effects on proliferation of several non-Hodgkin lymphoma (NHL) cell lines. A previous study indicated that FNC effectively inhibited the growth of Raji and JeKo-1 cells in dose-time dependent effects with IC50 values of 0.2μM and 0.097μM, respectively. This study was focused on investigating the anti-invasive properties of FNC on NHL cells and its potential mechanisms of action. Cell adhesion and transwell chamber assays were utilized to investigate the anti-invasive effects of FNC on Raji and JeKo-1 cells. Real-time PCR and Western blotting were employed to qualify the expression of β-catenin, the glycogen synthase kinase-3 beta (GSK-3β), E-cadherin vascular endothelial growth factor (VEGF), matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9). The results revealed that FNC remarkably inhibited the adhesion, migration and invasion of two human aggressive non-Hodgkin lymphoma cell lines in a dose dependent manner. Furthermore, β-catenin, MMP-2, MMP-9, VEGF mRNA and protein levels were decreased after FNC treatment, while GSK-3β and E-cadherin increased. Our studies thus provide evidence and a rationale that FNC may offer an effective chemotherapeutic agent by regulating the invasion and metastasis of aggressive non-Hodgkin lymphoma via inhibition of the Wnt/β-catenin signaling pathway.

CD79B and MYD88 mutations in diffuse large B-cell lymphoma

Mutations in 2 upstream components of the nuclear factor κB (NF-κB) pathway, CD79B and MYD88, are important information for new target therapy in malignant lymphoma. We examined the prevalence and clinicopathologic characteristics of CD79B and MYD88 mutation in a cohort of Asian diffuse large B cell lymphoma (DLBCL) patients. CD79B and MYD88 mutations were analyzed by Sanger sequencing in 187 DLBCL tissue samples. CD79B immunoreceptor tyrosine-based activation motif spanning exon 5 and 6 and MYD88 TIR domain spanning exons 3, 4 and 5 were amplified and sequenced. The cell-of-origin was determined based on immunohistochemical stains for CD10, BCL-6 and MUM-1 by Hans' algorithm. CD79B was mutated in 16 cases (8.5%), mostly involving the first tyrosine (Y196) of immunoreceptor tyrosine-based activation motif. For MYD88, L265P mutation was found in 31 cases (out of 161, 19.3%). In 11 of these, a CD79B mutation coexisted, which constituted 69% of CD79B mutants and 36% of MYD88 L265P cases. Clinicopathologic comparison between the mutant and the wild-type group showed that the mean age was older for both CD79B (66 versus 58 years) and MYD88 L265P mutant groups (64 versus 58 years). Survival analyses showed that neither CD79B mutation nor MYD88 L265P was a significant prognostic indicator. In conclusion, CD79B and MYD88 mutations are associated with an older age at onset in DLBCL with a significant overlap, which did not affect the outcome of the disease.

Therapy in malignant lymphoma in 80 years or over

Therapy in malignant lymphoma in 80 years or over

68IN - Targeted Therapy in Malignant Lymphoma: Clinical Implications and Perspectives

ABSTRACT With a whole range of new drugs showing activity in different types of lymphoma, we question if any of these will make the new step forward as it has been the case with the introduction of doxorubicin, high-dose chemotherapy or rituximab. If we look at some most significant diseases, we can hope that for Hodgkin's lymphoma (HL) the advent of active drugs as brentixumab vedotin and panobinostat could make chemotherapy more effective, reducing the number of cycles needed or allowing the avoidance of drugs with long-term side effects. In the treatment of diffuse large B-cell lymphoma (DLBCL) what is needed is a drug improving on the cure rate. The new available substances have not yet shown to be so promising but not all of them have yet been combined with classical chemotherapy. Follicular lymphoma (FL) is a well controllable disease but we want a drug which will render this disease curable; in the meanwhile we hope that patient-friendly treatments will allow long-term maintenance and disease control. The combination of lenalidomide with rituximab, but also the new CAL 101, BTK inhibitors or inotuzumab ozogamicin could increase the possibility of prolonging the time without symptoms of disease or treatment. The impact of these drugs on survival though will be long to ascertain in such an indolent disease. Mantle cell lymphoma (MCL) remains rapidly progressing and difficult to treat. It is considered not curable and it will therefore be important ascertain the impact of bortezomib, temsirolimus, BTK and PI3K inhibitors or blinotumumab combined with standard treatment on survival or cure. Finally, peripheral T-cell lymphoma (PTCL) is an orphan disease compared to the B-cell lymphomas as it could not take advantage of the introduction of rituximab. In anaplastic large cell lymphoma (ALCL) brentuximab vedotin has shown very important activity and might make the difference, while the addition of pralatrexate, romidepsin or vorinostat could change the prognosis of the other entities. Despite many of these drugs having shown promising data, the challenge is now to combine them with standard treatment in order to obtain regimens which are more active but not more toxic. Phase II trials are ongoing to develop the optimal combination schedules. Disclosure M. Ghielmini: Member of advisory board for Roche, Lilly, BMS, Celgene, Pfizer, Jansen

Abstract 4049: Early prediction of response to targeted drugs treatment in malignant lymphoma and sarcoma using in vivo proliferation marker 18F-FLT

Abstract Purpose: Last year we have shown that 18F-FLT is superior surrogate marker than 18F-FDG for very early response assessment to therapy in malignant Lymphoma. In this study, we use FLT-PET to predict the response of ewing sarcoma to different cancer therapy and investigate its relation to cancer cell death, especially apoptosis. Methods: FLT and/ or FDG PET were performed prior and early in each therapeutic course on SCID mice bearing with various tumor cells. Ewing sarcoma A673 was applied for investigation of the response to sorafenib treatment or Radiotherapy. GFP labelled Lymphoma cells (Myc449, Myc665) with or without transportation of Bcl2 gene was employed for the observation of cell death especially apoptosis after the treatment with aura kinase inhibitor or chemotherapy. Tumor-to-background ratios (TBR) of FLT-PET were compared to that of FDG-PET. PET findings were correlated with optical Imaging, histopathology and in vitro data comprising cellular tracer uptake, cell cycle related protein expression, cell cycle distribution and viability assessment. Results: In vitro study shows that sarcoma A673 cells were sensitive to all therapy. For in vivo studies, tumor volume of sorafenib treated animals showed modest increase of 0.1cm3 (range 0.02cm3 to 0.2cm3, SD=0.09) within the first week as opposed to a 15-fold increase in control mice. Median TBR of FLT-PET decreased significantly to 30.1% compared to baseline as early as 5d after therapy (range 11.3-53.5%, n=12, p=0.0004). On the other side, TBR in FDG-PET also showed the similar tendency (median TBR 74.6%, range 28.1%-131.8%, n=12, p=0.02). But the reduction of TBR in FLT was significantly stronger than that in FDG (p<0.001). In vitro study of lymphoma cells with Bcl2 transduction showed a strong anti- cell death ability, which will be served for the link between FLT PET and cell death. Conclusion: Compared with FDG-PET, FLT-PET is able to predict the response in the early therapeutic course and has a high specificity for the detection of ewing sarcoma. Continuing studies are intensively carried out to investigate FLT and FDG PET in relation to therapy-induced cell death. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4049. doi:1538-7445.AM2012-4049

IgG4-Related Tubulointerstitial Nephritis and Lymphadenopathy after Therapy for Malignant Lymphoma

We report a middle-aged Japanese man who had a past history of malignant lymphoma with tubulointerstitial nephritis (TIN) presenting a high serum immunoglobulin G4 (IgG4) concentration and bilateral kidney enlargement and swelling of many lymph nodes. Although lymph node biopsy was not evident of a recurrence of lymphoma, kidney biopsy showed prominent infiltration of IgG4-positive plasma cells in a tubulointerstitial lesion but not in glomeruli. We made a diagnosis of IgG4-related TIN and lymphadenopathy; administration of oral prednisolone improved his physical and laboratory parameters. This is the first report of a case of IgG4-related TIN and lymphadenopathy after therapy for malignant lymphoma.

Abstract 5302: Early prediction of response to therapy in malignant lymphoma using non-invasive [18F]FLT-PET imaging from animal to human model

Abstract Purpose: Preclinical and clinical studies have recently shown that the thymidine analogue [18F]fluorothymidine (FLT) accumulates in tumor tissue and enables non-invasive imaging of tumor proliferation, using positron emission tomography (PET). The aim of this study is to establish FLT-PET as an adequate and robust surrogate marker for very early response assessment to therapy in malignant Lymphoma. Methods: In animal models we assessed the thymidine metabolism in SCID mice bearing SUDHL-1 or Karpas 299 lymphoma prior to and early in the course of therapy with Hsp90 inhibitor NVP-AUY922 or mTOR inhibitor RAD001, using a small animal PET system. Tumor-to-background ratios (TBR) of FLT-PET were compared to that of FDG-PET. PET findings were correlated with histopathology and in vitro data comprising cellular tracer uptake, cell cycle related protein expression, cell cycle distribution and viability assessment. In human models, FLT-PET was performed additionally to routine staging procedures in 66 patients with malignant lymphoma undergoing R-CHOP chemotherapy. FLT-uptake was correlated with response and survival. Results: SUDHL-1 cells proved to be sensitive to both inhibitors whereas Karpas299 showed relative resistance to NVP-AUY922. Tumor volume in treated animals bearing SUDHL-1 lymphomas showed modest increase within the first week (median increase = + 25%, range -30% to + 80%, n=8) as opposed to a 3.8-fold increase in control mice. After 14 days a clear reduction of tumor mass was observed (median = – 25%, range -40% to + 30%, n=4). Median TBR of FLT-PET decreased significantly to 40% compared to baseline as early as 5d after therapy (range 32-67%, n=8, p=0,008). In contrast, TBR in FDG-PET did not show any clear tendency (median TBR 79%, range 36%-161%, n=8, p=0.73). According to our in vitro results, less effect was seen during treatment with AUY299 resulting in an increase of median TBR in FLT-PET to 154% (p=0,008, n=11) on day 2. In contrast, mice receiving RAD001 showed a stronger inhibition of tumor development and early FLT-PET imaging indicated a decrease of TBR to 78% (n=9, p=0.008). In human data, the initial SUVmesn in complete responders was significantly lower than in patients with progressive disease or partial response (p=0.049). Conclusion: FLT-PET has a high specificity for the detection of malignant lymphomas, both in animal xenotransplants model and in human disease. Compared with FDG-PET, FLT-PET is able to predict response to specific inhibitors treatment very early in the therapeutic course. Our human data indicate that high initial FLT uptake is a negative predictor of response to R-CHOP treatment in aggressive B-cell NHL. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5302. doi:10.1158/1538-7445.AM2011-5302

A case of discontinuation syndrome following the discontinuation of low-dose mirtazapine therapy in malignant lymphoma

We report the case of a 69-year-old woman with malignant lymphoma who suffered from major depressive disorder. A low dose of mirtazapine (15 mg/day) brought about dramatic improvement in her mental status. However, after discontinuation of the mirtazapine, anxiety, restlessness, irritability, nausea, insomnia, imbalance and sensory disturbances occurred. When mirtazapine therapy was restarted, these symptoms resolved completely. These findings suggest that discontinuing even a low dose of mirtazapine might result in discontinuation syndrome, particularly in patients in poor physical condition. To the best of our knowledge, this is the first report describing a discontinuation syndrome due to the discontinuation of a low dose of mirtazapine.

Late Complications of Radiation Therapy for Malignant Lymphoma of the Thyroid

Late Complications of Radiation Therapy for Malignant Lymphoma of the Thyroid

Prediction of Lymph Node Manifestations in Malignant Lymphoma

Comparison of 2-dimensional and semiautomated 3-dimensional (3D) measurements to distinguish between benign and malignant lymph nodes in patients with malignant lymphoma. Whole-body positron emission tomography-computed tomography (PET-CT) was performed in 33 patients before therapy for malignant lymphoma. Two hundred fifty-seven peripheral lymph nodes (mean size, 13.4 +/- 5.4 mm) were evaluated independently by 2 radiologists, both manually and with the use of semiautomated segmentation software. Long-axis diameter (LAD), short-axis diameter (SAD), maximal 3D diameter, volume, and elongation were measured. Positron emission tomography-CT and PET-CT follow-up and/or histology served as the reference standard. Statistical analysis encompassed intraclass correlation coefficients and receiver operating characteristic curves. The standard of reference revealed involvement in 116 (45%) of 257 lymph nodes. Manual and semiautomated LAD and SAD showed good correlation with intraclass coefficients of 0.85 and 0.72, respectively. Semiautomated prediction of malignant lymph nodes revealed the highest areas under the receiver operating characteristic curves for volume (0.760; 95% confidence interval [CI], 0.639-0.887) followed by SAD (0.740; 95% CI, 0.616-0.862). The findings for LAD (0.722; 95% CI, 0.588-0.855), maximal 3D diameter (0.697; 95% CI, 0.565-0.830), and lymph node elongation (0.605; 95% CI, 0.466-0.745) were significantly lower (P < 0.05). Volumetric lymph node analysis is significantly superior compared with established LAD in the prediction of lymph node involvement and therefore can add to the definition of peripheral lymphoma target lesions.

悪性リンパ腫治療後に発症した慢性骨髄性白血病に対するinterferon-α hydroxycarbamide併用著効例

悪性リンパ腫治療後に発症した慢性骨髄性白血病に対するinterferon-α hydroxycarbamide併用著効例

Hämatopoetische Stammzelltransplantation

The hematopoietic stem cell transplantation (HSCT) has become a standard therapy for many inherited and acquired disorders of the bone marrow and immune system. Autologous HSCT is mainly done as part of the primary therapy in multiple myeloma and as part of relapse therapy in malignant lymphoma. In contrast, allogeneic HSCT is predominantly performed in patients with acute leukemias. The selection process for allogeneic HSCT takes disease-specific as well as patient-specific factors into account. Risk factors which can predict for poor response to chemotherapy can now be identified in acute myeloid as well as lymphoid leukemia, based on phenotype, cytogenetics, molecular genetics and response to therapy. In these patients allogeneic HSCT can improve overall survival from 0-20% to 30-60%. New conditioning protocols have now raised the upper age limit for transplantation to 70 years. In elderly patients the selection of patients based on absence of comorbidities becomes especially important. The increasing number of long-term survivors requires knowledge of organ-specific late toxicities including secondary malignancies.

Preclinical Rationale for the Use of the Multikinase Inhibitor Sorafenib in the Treatment of Human Lymphomas

Introduction: The multikinase inhibitor Sorafenib (Nexavar, Bayer) exerts a remarkable activity against a variety of nonhematological tumors by blocking tumor cell proliferation and angiogenesis through the inhibition of the RAF/MEK/ERK pathway, as well as the receptor tyrosine kinases vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptor (PDGFR), c-KIT, Flt3, and RET. Several lines of evidence suggest that sorafenib might have a relevant clinical impact in the therapy of malignant lymphomas by overcoming the cytoprotective effects of ERK, Mcl-1, and Bcl-XL. However, preclinical data establishing a rationale for the clinical use of sorafenib in lymphomas are still lacking. The present studies aimed to investigate the activity and the mechanism(s) of action of sorafenib in human lymphomas.Methods: The effects of sorafenib were evaluated in vitro using a panel of six human cell lines of different phenotypes, including JVM-2 (B-Chronic Lymphocytic Leukemia), Granta-519 (Mantle Cell Lymphoma), DOHH2 (Follicular Lymphoma), SU-DHL-4V (Diffuse Large B-Cell Lymphoma), HD-MY-Z (Hodgkin Lymphoma), and KMS-11 (Multiple Myeloma) cell lines. Additionally, the antitumor efficacy and mechanism of action of sorafenib were investigated in vivo by means of five lymphoma xenograft models in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice.Results: In vitro, the response of cell lines to sorafenib (1–10 μM for 24–48 hours) was evaluated by detecting apoptotic cell death with the annexin-V/propidium iodide double staining assay, and viable cell countings with the Trypan blue dye exclusion test. All 6 cell lines responded to sorafenib with values of 50% inhibitory concentrations ranging from 1 to 7.5 μM. In contrast, normal CD34+ cells remain insensitive to the drug up to 15 μM. Despite significant rates of sorafenib-induced apoptosis were seen in all cell lines, activation of caspase-3 analyzed by fluorescent-activated cell sorter was only detected in DOHH-2 and JVM-2 cell lines. The phosphorylation status of mitogen-activated protein kinase (MAPK) was investigated using the human phospho-MAPK Array kit (R&D systems), analyzed with the open source imaging software ImageJ (http://rsb.info.nih.gov/ij/), and then validated by Western blotting. Sorafenib induced a significant reduction of pAkt1, pAkt2, and pAkt3 in SU-DHL-4V, Granta-519, and JVM-2 cell lines, whereas p38 phosphorylation levels were significantly reduced in all but one cell line (KMS-11). Reduced levels of pMEK, pERK1 and pERK2 were detected in SU-DHL-4V, KMS-11, Granta-519, and HD-MY-Z cell lines. Down-regulation of MCL-1 was seen in HD-MY-Z, JVM-2, and DOHH-2 cell lines. In vivo, the activity of sorafenib was evaluated in NOD/SCID mice bearing subcutaneous tumor nodules. Animals with tumors averaging from 140 to 160 mg were randomly grouped to receive sorafenib (90 mg/kg body weight, IP, once daily for 15 days) or control vehicle. Sorafenib significantly (P ≤0.001) reduced the growth of subcutaneous HD-MY-Z, KMS-11, Granta-519, SU-DHL-4V, and JVM-2 nodules, with values of tumor growth inhibition of 70%, 52%, 40%, 37%, and 24%, respectively. In control mice, TUNEL staining of tumor sections showed large areas of viable cells without significant necrosis, whereas a 2- to 5-fold increase of necrotic areas was detected in sorafenib-treated mice bearing the different lymphoma xenografts. Analysis of tumor vasculature by means of in vivo biotinylation of endothelial cells with sulfo-NHS-LC-biotin showed a 30% to 60% reduction of vessel density in sorafenib-treated mice bearing the different lymphoma xenografts.Conclusions: Sorafenib efficiently targets a variety of human lymphomas representative of different phenotypes by inhibiting tumor angiogenesis and directly affecting tumor cell survival. Our preclinical data establish a rationale for exploring the clinical activity of sorafenib in human lymphomas.

The Role of Imaging in Malignant Lymphoma: A Critical View on PET Scanning in Current Clinical Practice

SummaryTreatment and prognosis of malignant lymphomas depend on accurate staging and evaluation of clinical and histological features. Computed tomography (CT), magnetic resonance imaging and ultrasound are standard conventional imaging procedures for staging and, under certain circumstances, are supplemented by skeletal scintigraphy, biopsy from suspected areas of organ involvement and bone marrow biopsy. The determination of response to therapy, which is still the most important marker of prognosis [J Clin Oncol17 (1999) 1244], is usually performed at the end of therapy. However, this approach is being challenged (i) by the knowledge that the speed of tumour cell kill might be relevant particularly in high‐grade lymphomas, and (ii) by the application of modern immunological treatments with monoclonal antibodies whose efficacy may last substantially longer than the time period they are infused. Nuclear medicine imaging with positron emission tomography (PET) has become an increasingly used imaging method for the evaluation of lymphoma patients and is capable of more sensitive and accurate staging, early prediction of response and prognosis after 2–3 cycles of chemotherapy, and even predicting the relapse probability after the end of treatment [J Nucl Med47 (2006) 1326]. The main advantages of the technique are based on the detection of tumour‐specific metabolic cellular changes. Despite increased sensitivity in many but not all types of lymphoma, PET is not specific for tumour tissue and can be falsely interpreted. Additionally, the therapeutic consequences of the results of radioimaging are poorly defined despite the widespread use of the techniques, raising a number of unsolved problems. This article will review the use of PET and PET/CT in the staging and evaluation of response to therapy in malignant lymphoma and critically assess the pitfalls and advantages of this technique.

Point mutation of C-terminal region of CD20 molecule predicts rituximab-induced complement-dependent cytotoxicity and clinical response to rituximab in non-Hodgkin’s lymphoma

7563 Background: Although rituximab is commonly used as induction and maintenance therapy for malignant lymphoma, some patients become refractory to treatment and the mechanism of resistance is unclear. The aim of this study was to investigate the relationship between CD20 mutations and rituximab resistance. Methods: To investigate whether CD20 mutations affect response to rituximab, fresh CD19+ lymphoma cells were isolated from the lymph nodes, or bone marrow of 68 patients with NHL. The cells were subsequently sorted by flow cytometry. RNA was prepared from the isolated cells and RT-PCR was performed. The PCR products were sequenced, subcloned into an expression vector pTARGET, transfected into K562 cells. CD20 expression was examined by flow cytometry and laser scanning confocal microscopy. Results: In all 68 patients, overall response rate (CR+CRu+PR) to rituximab was 91.2% (62/68), but t four cases became PD after PR. DNA sequence analysis revealed that point mutations were mostly observed in three CD20 domains - extracellular/cytoplasmic domains, the third transmembrane domain and the C-terminal cytoplasmic domain. Two cases had point mutations in extracellular/cytoplasmic domains, one patient had point mutations in the transmembrane domain, four cases showed point mutations in the C-terminal cytoplasmic domain and six cases had non-specific CD20 mutations, which did not affect CD20 expression. 56 patients showed no mutations of CD20 gene. CD20 expression was very weak in patients with point mutations in the C-terminal cytoplasmic domain, whereas expression was increased in patients with point mutations in the transmembrane domain. Conclusions: Point mutations in CD20 may cause rituximab resistance and identification of CD20 mutations upon diagnosis may help to predict a patient’s response to rituximab. No significant financial relationships to disclose.

The potentials of proton beam radiation therapy in malignant lymphoma, thymoma and sarcoma

A group of Swedish oncologists and hospital physicists have estimated the number of patients in Sweden suitable for proton beam therapy. The estimations have been based on current statistics of tumour incidence, number of patients potentially eligible for radiation treatment, scientific support from clinical trials and model dose planning studies and knowledge of the dose-response relations of different tumours and normal tissues. Besides sarcomas of the base of skull, which are classical sites for proton beam therapy, it is estimated that about 40 patients yearly in Sweden with sarcomas at other sites are candidates for proton beam therapy. About 20 patients each with malignant lymphomas, chiefly in the mediastinum, and thymomas are also candidates to decrease doses to surrounding heart and lungs.

WHO-classification of malignant lymphomas

Because of the multiple developmental stages of lymphocytes and the complexity of the immune system,the corresponding neoplasms, the malignant lymphomas, represent a complex group of diseases. The clinical grouping of the KIEL-classification, distinguishing high grade from low grade lymphomas, has been abandoned in the WHO-classification as it is partly misleading. Especially,mantle cell lymphoma which, according to its morphology, represents a low grade lymphoma, is characterized by an extremely aggressive clinical course. The therapy of malignant non-Hodgkin lymphomas has become more and more diverse. The great advances in survival and quality of life of patients with malignant lymphomas have been reached in multiple clinical studies to optimize therapy and simultaneously set up standards of quality for the diagnosis and therapy of malignant lymphoma (see http://www.lymphome.de). Especially in the group of so-called low grade lymphomas according to the KIEL-classification, clinical studies in Germany follow different therapy concepts for each of the diseases. Therefore,patients should be treated within such a study.