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Ogilvie, C., K. Lund, P. McKay, and M. Leach. "19 Extranodal or primary CNS DLBC lymphoma?" European Journal of Cancer Supplements 8, no. 4 (April 2010): 13. http://dx.doi.org/10.1016/s1359-6349(10)70690-x.
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Weyl Ben Arush, M., A. Hersalis Eldar, G. Abrahami, D. Attias, A. Ben Barak, R. Dvir, H. Gabriel, J. Kapelushnik, H. Kaplinsky, and S. Vilk-Revel. "Burkitt lymphoma in children: The Israel Society of Pediatric Hematology Oncology retrospective study." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 10051. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.10051.
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10051 Background: From 2000 to 2005, the Israel Society of Pediatric Hematology Oncology studied the results of the FAB-LMB 96 protocol in children with B cell lymphoma. Methods: Eighty eight patients (pts) were eligible, 63 boys, 25 girls, median age was 8.9 years. Fifty patients (57%) were classified as burkitt lymphoma, 5 (5.7%) as burkitt-like lymphoma, 22 (25%) as diffuse large B cell (DLBC), 9 (10.2%) as burkitt leukemia. Initial disease sites included the abdomen in 43%, head and neck in 45%, mediastinum in 7%. Stage I: 9.1%, Stage II in 28.4%, stage III in 45.5%, stage IV in 17%. Five pts had bone marrow involvement (BM) alone, 5 pts CNS alone and 4 both CNS and BM. Five children were treated according to group A, 69 pts group B and 14 pts group C. Results: At a median follow up of 3 years, Kaplan Meier for EFS and OS for all pts was respectively 88.6%, 90.9%, group A, 100%,100%, group B: 90%, 93%, group C 79%, 79%. In group A: there were neither events nor deaths in this group, 6 patients relapsed in group B, among them 4 patients had died, tumor lysis syndrome in 3 patients, death of toxicity in 1 patient. In group C, 3 patients had relapsed and died, no death of toxicity. EFS for LDH less then twice was 96.4%, EFS for LDH more than twice was 73.3% (p = 0.002). OS according to primary site: bone and ovary (100%), head and neck (95%), abdomen (92%) and mediastinum (50%) (p = 0.003). All of the mediastinal tumors were of DLBC origin, but when comparing the DLBC to other histologies, no significant difference in outcome were found.(DLBC: 81.8%, other B line: 90.9%). The OS for Arab ethnic origin is 79.2%, OS for Jewish is 95.3% (p = 0.02). Conclusions: In nonresected mature B cell lymphoma of childhood and adolescence with no BM or CNS involvement, a 93% cure rate was achieved. Patients with primary DLBC mediastinal mass had a significantly reduced overall survival, indicating the need for a different therapeutic approach. No significant financial relationships to disclose.
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Amorim, José M., Santiago Rosati, Ronit Agid, Vítor Mendes Pereira, and Timo Krings. "Treatment of an internal carotid artery aneurysm with a flow diverter through a double lumen balloon catheter." Interventional Neuroradiology 23, no. 3 (February 26, 2017): 255–59. http://dx.doi.org/10.1177/1591019917691238.
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Background Double lumen balloon catheters (DLBCs) are currently used in the treatment of intracranial aneurysms, especially when involving balloon or stent-assisted coiling. The existing DLBCs allow the delivery of self-expandable stents but do not offer the possibility to deploy flow-diverters. Despite the increasing use and success of flow-diverters, there have been numerous reports of procedural complications such as early in-stent thrombosis or delayed distal embolization. It seems that these complications can be avoided by correct stent positioning and adequate wall apposition, achieved either by manoeuvres with the microguidewire and/or microcatheter or by performing balloon angioplasty following an exchange guidewire manoeuvre. Objective Report the use of a new DLBC able to deliver a flow-diverter. Methods A 41-year-old woman presented to our hospital with binocular horizontal diplopia for two weeks and reduced visual acuity. A left internal carotid artery aneurysm involving the cavernous and ophthalmic segments was found, with a maximum height of 19 mm and a broad 8 mm neck. It presented extra- and intra-dural components and the parent vessel was significantly narrowed. A decision was made to perform endovascular treatment of the aneurysm with placement of a flow diverter through a DLBC. Results Patency and adequate expansion of the flow diverter with evident intra-aneurysmal contrast stasis was observed in the final angiogram. No peri-procedural complications were observed. Conclusion This is a technical note demonstrating the feasibility of a new device to deploy a flow diverter, aiming to improve wall apposition and stent configuration without the need of additional devices or exchange manoeuvres.
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Vanazzi, Anna, Pier Francesco Ferrucci, Chiara Maria Grana, Giancarlo Pruneri, Cristiano Crosta, Antonello Pinto, Marco Chinol, Liliana Calabrese, Giovanni Paganelli, and Giovanni Martinelli. "Efficacy of 90 Y - Ibritumomab Tiuxetan in Relapsed or Refractory Primary Gastric Non Hodgkin Lymphoma." Blood 112, no. 11 (November 16, 2008): 3063. http://dx.doi.org/10.1182/blood.v112.11.3063.3063.
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Abstract BACKGROUND: A prospective, single arm, open-label, phase II trial was performed to evaluate efficacy of 90Y-Ibritumomab Tiuxetan at conventional activity of 0,4 mCi/kg in Primary Gastric Non Hodgkin Lymphoma (NHL). PATIENTS AND METHODS: From May 2004 to May 2008, 13 patients affected by Primary Gastric NHL - either Mucosa Associated Lymphoid Tissue (MALT) or Diffuse Large B Cell (DLBC) NHL, relapsed/refractory disease - were enrolled to receive 90Y-Ibritumomab Tiuxetan at the activity of 0,4 mCi/kg. Median age was 57 ys (range 36–83), 6 female and 7 male. Nine out of 13 patients had gastric MALT NHL, the remaining 4 patients had DLBC NHL. At time of treatment 11 out of 13 patients had stage I/II, 2 patients had stage III/IV disease. Helicobacter Pylori was negative in all patients except one at time of treatment and positive at diagnosis in 5 of them. Median number of previous therapies received was 1 (1–4): all patients except 3 had received prior CT, 7 patients prior Rituximab, no one had received prior RT. RESULTS: Toxicities were primarily haematological and reversible. All patients had serial testing for HAMA and none developed antibodies to date. MALT-1 gene rearrangement was detected in 3 of the 9 cases analyzed, while none of the cases showed bcl-10 gene rearrangement. All patients are now evaluable for response: 10 out of 13 patients experienced a complete response (CR) (9 MALT, 1 DLBC); progressive disease (PD) was observed in 2 out of 13 patients, both DLBC NHL; finally another patient affected by DLBC NHL did not respond. After a median follow up of 24 months (range 3–50 months) 9 out of 10 CRs are disease free and 5 of them can be considered long term responders at 50, 43, 40, 32 and 31 months, respectively, following radioimmunotherapy (RIT). At the time of the analysis only 1 relapse occurred 17 months after RIT (MALT). Two patients - both DLBC - died due to disease progression. There was no statistically significant associations between response to RIT and the occurrence of the MALT-1 translocation. CONCLUSIONS: 90Y-Ibritumomab Tiuxetan seems to be very active in patients with primary gastric NHL relapsed or refractory to conventional systemic treatment, especially in gastric MALT NHL. Despite the relative short median follow-up (24 months), we observed durable long-term responses at least in 5 patients. High response rate and durable remissions could be related to the low tumor burden and consequently to higher absorbed doses to tumor, confirming the possible relationship between absorbed doses to tumor, efficacy and duration of response. If preliminary results can be confirmed in larger series, RIT could be offered as valid alternative approach in this setting because of its efficacy and low rate of side effects. These preliminary results warrant further studies.
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Tomas-Roca, Laura, Marta Rodriguez, Ruth Alonso-Alonso, Socorro M. Rodriguez-Pinilla, and Miguel Angel Piris. "Diffuse Large B-Cell Lymphoma: Recognition of Markers for Targeted Therapy." Hemato 2, no. 2 (May 14, 2021): 281–304. http://dx.doi.org/10.3390/hemato2020017.
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Diffuse large B-cell lymphomas (DLBCL)s, the most common type of Non-Hodgkin’s Lymphoma, constitute a heterogeneous group of disorders including different disease sites, strikingly diverse molecular features and a profound variability in the clinical behavior. Molecular studies and clinical trials have partially revealed the underlying causes for this variability and have made possible the recognition of some molecular variants susceptible of specific therapeutic approaches. The main histogenetic groups include the germinal center, activated B cells, thymic B cells and terminally differentiated B cells, a basic scheme where the large majority of DLBCL cases can be ascribed. The nodal/extranodal origin, specific mutational changes and microenvironment peculiarities provide additional layers of complexity. Here, we summarize the status of the knowledge and make some specific proposals for addressing the future development of targeted therapy for DLBC cases.
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Bishop, M. R., R. M. Dean, S. Steinberg, J. Odom, S. Z. Pavletic, C. Kasten-Sportes, N. Hardy, S. Pittaluga, R. Gress, and D. H. Fowler. "Reduced-intensity allogeneic stem cell transplantation for diffuse large B-cell lymphoma: Clinical evidence of a graft-versus-lymphoma effect." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 6546. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.6546.
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6546 Background: Despite being the most common non-Hodgkin’s lymphoma, there have been no specific reports on the use of reduced-intensity (RI) allogeneic stem cell transplantation (alloSCT) to treat patients (pts) with diffuse large B-cell lymphomas (DBCL). This may be due to a lack of definitive evidence for a therapeutic graft-versus-lymphoma (GVL) effect against DLBC. We undertook a retrospective analysis to assess clinical outcomes and evidence of a GVL effect in DLBC pts undergoing RI alloSCT. Methods: The analysis was limited to 18 pts with primary refractory (n = 6) or relapsed (n = 12) DLBC. The median age was 43 years (range: 31–61); median number of previous treatments was 3 (range: 2–9). Nine (50%) pts had undergone autologous transplantation. Three (16%) pts were determined to have chemo-sensitive disease to last treatment prior to RI alloSCT. All pts received a RI conditioning regimen consisting of fludarabine (30 mg/m2/d × 4d) and cyclophosphamide (1200 mg/m2/d × 4d) followed by a T-cell replete allograft from HLA-matched siblings. Results: Median potential follow-up from transplant is 43 months. Seven (39%) pts developed grade II-IV acute GVHD. Response at day +100 post-transplant was as follows: complete response (CR/CRu) = 5; partial response = 5; progressive disease = 8. Nine of 17 (53%) evaluable pts developed chronic GVHD. Median progression-free survival (PFS) was 4.8 months; however, PFS after 9 months post-transplant was 31% with 5 pts in continuous CR/CRu > 12 months post-transplant. Among 14 pts who were not in CR/CRu (n = 12) or progressed after achieving a CR/CRu (n = 2) at day +100 post-transplant, 8 (57%) subsequently achieved a CR/CRu after removal of immune suppression and/or donor lymphocyte infusion (DLI) ± chemotherapy. Seven of these 8 pts remain in continuous (median = 34 months; range: 6–55+) CR/CRu without further treatment. Median survival for all 18 pts was 19 months with survival probability of 40% plateauing at 25 months post-transplant. Conclusions: The clinical observations of sustained CR/CRu after withdrawal of immune suppression and DLI suggest that a GVL effect exists against DLBC. RI alloSCT should be considered as a treatment option for pts with primary refractory and relapsed DLBC. No significant financial relationships to disclose.
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Vanazzi, Anna, Pier F. Ferrucci, Chiara Grana, Giancarlo Pruneri, Cristiano Crosta, Antonello Pinto, Marco Chinol, Giovanni Paganelli, and Giovanni Martinelli. "Efficacy of 90Y-Ibritumomab Tiuxetan (Zevalin) in Refractory or Relapsed MALT Gastric Non Hodgkin’s Lymphoma." Blood 108, no. 11 (November 16, 2006): 2771. http://dx.doi.org/10.1182/blood.v108.11.2771.2771.
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Abstract Radio-immunotherapy (RIT) is an effective approach for patients with relapse-refractory NHL. The aim of RIT is to use the monoclonal antibody to target radiation to the tumor bulk while limiting exposure of normal tissues. Toxicity is prevalently hematologic, but transient and reversible. Zevalin in particular has demonstrated activity in follicular (FL) and diffuse large B-cell (DLBC) NHL, but data are still lacking in MALT NHL. In this setting of pts Zevalin could offer an alternative option to those pts who relapse or do not respond to conventional treatment. We report efficacy results of a pilot study of Zevalin delivered at conventional activity (0,4 mCi/kg) in gastric NHL pts resistant or refractory to conventional systemic treatment. From May 2004 to January 2006, 7 patients were enrolled. They all had gastric resistant-refractory CD-20 positive B-cell NHL: 2 DLBC and 5 MALT. Median age was 57 ys (range 36–64), 3 female and 4 male. At time of treatment 5 out of 7 patients had stage I/IIA (MALT), while 2 out of 7 pts had stage III/IV (DLBCL) of disease. Helicobacter Pylori was negative in all pts at time of treatment, positive at diagnosis in 3 out of 5 pts affected by MALT gastric NHL. Median number of previous therapies received was 2 (1–4): all of them had received prior CT, 3 prior Rituximab, no one had received prior RT. Toxicities were primarily haematological, as expected, and reversible. Response evaluation was performed two months after Zevalin administration by upper gastrointestinal endoscopy with multiple biopsy and endoscopic ultrasonography. All patients are now evaluable for response: 5 CR (all MALT), 2 PD (both DLBC NHL). All responders still maintain a CR at 27, 20, 16, 9 and 8 months after treatment. Conclusions: Zevalin seems to be very active in pts with MALT gastric NHL resistant or refractory to conventional systemic treatment. Its mechanism of action mimics conventional RT already known as valid option in MALT gastric NHL. If these preliminary results are confirmed in larger number of pts, one single administration of Zevalin delivered at conventional activity (0,4 mCi/kg) could be considered a possible alternative option in the treatment of such indolent disease.
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Abdulhaq, Haifaa, and Maher Albitar. "Using Targeted RNA Next Generation Sequencing and Differential Expression to Compare Primary Central Nervous System Lymphoma with CD+ DLBCL, Nodal DLBCL and EBV+ DLBCL." Blood 136, Supplement 1 (November 5, 2020): 22. http://dx.doi.org/10.1182/blood-2020-142235.
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Introduction:Primary central nervous system lymphoma (PCNSL) is a diffuse large B-cell lymphoma (DLBCL) with a tropism for the CNS microenvironment. Limited studies suggested differential expression of multiple extracellular matrix (ECM) and adhesions-related genes in PCNSL as compared to nodal DLBCL. We used next generation sequencing to evaluate expression profiles of 1408 genes and and performed differential expression profiling to compare PCNSL with nodal DLBCL, CD5+ DLBCL and EBV+ DLBCL. CD5+ DLBCL was selected because it is frequently ABC subtype. We also selected EBV+ DLBCL due to its poor outcome, similar to PCNSL. Methods:RNA was extracted from 30 formalin-fixed paraffin-embedded (FFPE) tissue samples from PCNSL patients and 23 FFPE tissue samples from cases with lymph node DLBCL-NOS, 8 samples CD5+DLBCL, 14 samples EBV+ DLBCL.. We sequenced the RNA using a 1408 gene panel (Illumina). Next Generation Sequencing was based on hybrid capture methodology. Total number of reads per sample must exceed 5 million to be accepted. RNA levels were quantified using FPKM. Levels of expression of each of the 1408 genes were compared between groups. The T-score is used to show differences. Considering the number of analyzed samples and to correct for multiple testing, only T-score less or greater than 3 was considered clinically significant. Results:PCNSL showed significant overexpression in 25 genes as compared with CD5+ DLBCL, while only 5 genes were highly expressed in PCNSL as compared with nodal DLBCL and 8 when compared with EBV+ DLBCL (Table below). Four genes were significantly less expressed in PCNSL as compared with CD5+ DLBCL, and only one gene when compared to nodal and EBV+ DLBCL. There was no significant difference in RNA expression of MYD88, CD79B, CARD11, KMT2D or SPP1 between PCNSL and DLBC-NOS, CD5+ DLBCL and EBV+ DLBCL . There was no significant difference between PCNSL and the other sub types in MYC, Ki67, BCL2, CD44, or CD274 (PD-L1) expression. Several genes emerged as highly expressed in PCNSL as compared with other subtypes of DLBCL (negative T-score). However, CLTC (Clathrin Heavy Chain) gene is uniquely highly overexpressed in PCNSL and not in any of the other 3 types of lymphoma. The CLTC gene is involved in anaplastic lymphoma as a partner gene for ALK (CLTC-ALK) in t(2,17) translocation. The SEPT2 (SEPTIN2) gene is uniquely highly expressed in PCNSL as compared with nodal and EBV DLBC lymphoma. SEPT2 gene plays significant role in Hodgkin lymphoma and in maintaining Reed-Stenberg cells . In contrast, VEGFC was significantly lower in PCNSL compared with nodal DLBCL. Conclusions:RNA molecular profiling suggests significant difference between PCNSL and CD5+ DLBCL and less difference when compared with nodal and EBV+ DLBCL. The strikingly high expression of CLTC gene in PCNSL suggests possible targeting of this gene might present a specific therapeutic approach for PCNSL. Figure Disclosures Abdulhaq: Novartis:Consultancy, Honoraria, Speakers Bureau;Astellas:Honoraria, Speakers Bureau;Amgen:Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Morphosys:Membership on an entity's Board of Directors or advisory committees, Research Funding;Oncopeptide:Research Funding.
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Laszlo, Daniele, Giancarlo Pruneri, Giovanna Andreola, Davide Radice, Liliana Calabrese, Alessandra Alietti, Alberto Agazzi, Anna Vanazzi, and Giovanni Martinelli. "Tissue Microarray (TMA) Study in DLBC Lymphomas (DLBCL): Could the Extranodal Origin Affect the Prognostic Impact of the Analysis?." Blood 108, no. 11 (November 1, 2006): 2037. http://dx.doi.org/10.1182/blood.v108.11.2037.2037.
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Abstract DLBCL can be divided into two prognostically different subgroups, germinal center B-cell-like (GCB) and activated B-cell-like (ABC), according to twodifferent gene patterns identified with cDNA microarray technology. Though valuable, this technology is expensive and not generally available. However, the identification of individual antigens related to different stages of B-cell differentiation using immunohistochemistry, can be used to assess the two profiles yielding comparable results with respect to cDNA microarray technique. We have retrospectively investigated 105 patients (pts) diagnosed with de novo DLBCL and treated at our centre between November 2001 and June 2004; the only inclusion criteria was the availability of a tissue biopsy at diagnosis. Median age was 62 (19–85); stage at diagnosis was I–II in 49 pts (47%), III in 14 pts (13%) and IV in 42 pts (40%); according to IPI, 74 (70%) pts were defined as low (0–2) and 31 (30%) as high risk (3–5). Interestingly, the majority (53%) of our pts, had a primary extranodal lymphoma at diagnosis. TMA analysis was performed with antibodies to CD10, bcl-6 and MUM1 allowing the following classification: 50 pts (48%) were considered having CGB lymphoma and 55 pts (52%) having ABC disease. According to IPI risk score, 38 pts with CGB and 36 with ABC lymphoma were at low risk (0–2) whereas 10 with CGB and 16 with ABC lymphoma were at high risk (3–5). All pts received a median of 6 cycles of a CHOP-like, antracycline-based polychemotherapy. Observed ORR was 89% (94/105); 62 (59%) pts achieved a CR, 32 (30.5%) a PR while 11 (10.5%) failed to respond to treatment. Median follow-up of the surviving pts was 45 months ( 5–110). The 3-year OS for the entire group was 71% and the 3-year EFS was 54%. In terms of CR, PD and resistance to therapy, no difference was observed between the two TMA types of DLBCL. Pts obtaining a CR after 1st line treatment were equally distributed in both groups (28.6% in CGB vs 30.5% in ABC) as were those not responding to therapy (3.8% in CGB versus 6.7% in ABC). A separate analysis in pts with stage IV disease at diagnosis was also performed and showed similar results (40.5% of CR, 23.8% of NR; no difference was observed between the two TMA defined subgroups). Pts who experienced a PD at any time, were equally distributed between the 2 subgroups, either if they relapsed after first line therapy (6 pts in CGB group , 10 in the ABC one) or after any other subsequent treatment (12 in the CGB group, 18 in the ABC one). Furthermore, 39 of 56 (69%) patients with extranodal presentation at diagnosis showed a CR independently of their subgroup distribution (37.5% in the CGL group vs 32.1% in the ABC one), and pts experiencing a PR were equally distributed between the two groups. Our data do not support the use of TMA to predict outcome in DLBCL. However, previously published data supporting the prognostic impact of TMA, have not enrolled pts with lymphomas of primary extranodal origin which, instead, were the majority in our study. Indeed, the study by Colomo et al, which enrolled 39% of pts affected by extranodal lymphomas, also failed to demonstrate a role of TMA in predicting outcome in DLBCL pts. Furthermore, the use of a limited number of antigens to define different subtypes of DLBCL may not be sufficient to identify the same patterns as defined by cDNA microarray technology.
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Rujirojindakul, Pairaya, Kumpol Aiempanakit, Kanita Kayasut, Arnuparp Lekhakula, and Hutcha Sriplung. "No Prognostic Impact of p53 and P-Glycoprotein Expression in Patients with Diffuse Large B-Cell Lymphoma." ISRN Oncology 2011 (December 22, 2011): 1–6. http://dx.doi.org/10.5402/2011/670358.
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The aim of this study was to determine the clinical significances of p53 and p-glycoprotein (P-gp) expression on outcome predictors for patients with DLBC. We assessed the immunohistochemical expression of p53 and P-gp using formalin-fixed, paraffin-embedded specimens in 108 patients diagnosed with de novo DLBC. A high expression of p53 was found in 53.7% of the patients. No expression of P-gp was demonstrated in any of the specimens. There were no significant differences in the complete remission (CR) rate (P=0.79), overall survival (OS) (P=0.73), or disease-free survival (DFS) (P=31) between the p53-positive and p53-negative groups. The final model from multivariate analysis that revealed poor performance status was significantly associated with CR (P<0.001) and OS (P<0.001). Moreover, the advanced stage was a significant predictor of DFS (P=0.03). This study demonstrated no impact of the expression of p53 on either response or survival rates.
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Markovic, O., M. Gotic, V. Cemerikic, A. Divac, and D. Marisavljevic. "Successful treatment of synchronous hairy cell leukaemia and diffuse large B cell lymphoma in a patient with severe hypercalcemia and extensive osteolytic lesions." Vojnosanitetski pregled, no. 00 (2021): 73. http://dx.doi.org/10.2298/vsp210118073m.
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Introduction: Although secondary malignancies usually occur at different times after HCL treatment, (simultaneous) occurrence of HCL and other malignancies at the same time is very rare. Synchronous hairy cell leukemia (HCL) and diffuse large B cell lymphoma (DLBCL) has not been described so far. Case report: We report a 62-years old female patient who presented with intense constitutional symptoms, hypercalcaemia, pancytopenia and osteolytic destruction of the left shoulder joint. Immunohistochemical analysis of the bone marrow revealed presence of two populations: a population of HCL cells and a population of DLBCL cells with the expression of c-myc and bcl-2 ("double expressor" DLBCL) and high proliferative activity (Ki-67+cells>90%). FISH analysis showed amplification of the bcl-2 gene. In addition, BRAF V600E mutation was detected. After intensive treatment with immunochemotherapy, radiotherapy and bisphosphonates patient achieved complete remission, lasting for more than two years. Conclusion: As the association of hairy cell leukemia and lymphoma is a very rare, diagnosis of synchronous occurrence of two lymphoproliferative diseases is diagnostic and therapeutic challenge. It remains unclear whether DLBC and HCL are derived from two different malignant clones or DLBCL developed by transformation of HCL as the result of clonal evolution of B-cell clone.
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Deutsch, Alexander, Ariane Aigelsreiter, Christine Beham-Schmid, Alfred Beham, Werner Linkesch, and Peter Neumeister. "Aberrant Somatic Hypermutation in Extranodal Marginal Zone B-Cell Lymphoma of MALT Type." Blood 106, no. 11 (November 16, 2005): 417. http://dx.doi.org/10.1182/blood.v106.11.417.417.
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Abstract Extranodal marginal zone B-cell lymphoma of mucosa associated lymphoid tissue (MALT lymphoma) accounts for approximately 7% to 8% of all non-Hodgkin lymphomas (NHLs) being the third most frequent histological subtype. The gastrointestinal tract - particularly the stomach - is the most common site of MALT lymphoma comprising 50% of all cases, but virtually every organ may be affected by this type of lymphoma. Transformation (or de novo emergence at extranodal sites) in diffuse large B-cell lymphoma (DLBCL) occurs but - according to the WHO criteria - is considered as separate entity. The understanding of the molecular biology of MALT lymphoma has significantly improved following the recent cloning of recurrent balanced translocations such as t(11;18) or t(14;18), but a mechanism for genome-wide instability during MALT lymphomagenesis has not been described. We have reported that the somatic hypermutation process (SHM) physiologically aimed at mutating the immunoglobulin variable gene (IgV) aberrantly targets multiple proto-oncogenes in >50% of DLCBL (Pasqualucci et al., Nature412:341, 2001). Consequently, multiple mutations are introduced in the 5′ region of genes including known proto-oncogenes such as PIM-1, PAX-5, Rho/TTF and c-MYC. To further investigate whether aberrant somatic hypermutation (ASHM) also occurs in MALT lymphoma, we studied the mutation profile of these genes in 17 MALT lymphomas (6 of gastric- and 11 of nongastric origin) and 18 extranodal DLBCL (10 gastric, 8 nongastric). Mutations in one or more genes were detected in 15 of 17 (88.2%) cases of MALT lymphoma and in all of 18 (100%) cases of extranodal DLBCL. 7 of 17 (41.2%) and 15 of 18 (83.3%) carried mutations in two or more genes in the MALT- and DLBC-lymphoma group, respectively. Overall, mutations in PIM-1 occurred in 5 of 17 (29.4%) cases with MALT lymphoma and in 10 of 18 (55.5%) in extranodal DLBCL cases. For PAX-5, the distribution of mutated cases between MALT- and DLBC-lymphoma was 6 of 17 (35.3%) and 10 of 18 (55.5%), for Rho/TTF 3 of 17 (17.6%) and 8 of 18 (44.4%) and for c-MYC 9 of 17 (52.9%) and 12 of 18 (66.6%), respectively. A total of 99 sequence variants were found in 35 cases, 29 in the MALT lymphomas and 70 in extranodal DLBCL. Although the mutations were almost exclusively single base pair substitutions (n=98 ), an insertion was also present (n=1). Mutations were of somatic origins, occur independent of chromosomal translocations to the Ig loci and share features of the IgV SHM process including bias for transition over transversion, preferential hotspot (RGYW/WRCY) targeting and restriction to the first 1–2Kb from the promoter. The mean mutation frequency in mutated MALT lymphomas was with 0.045 x10−2/bp 1.7 fold lower compared to 0.08 x10−2/bp in mutated extranodal DLBCL. Further in PIM-1, PAX-5 and c-MYC some of the mutations were found to affect coding exons, leading to amino acid exchanges, thus potentially altering gene function. These data indicate that aberrant SHM is associated with extranodal DLBCL and MALT lymphoma, likewise. By mutating regulatory and coding sequences of the targeted genes and by possibly favouring chromosomal translocations ASHM may represent a major contributor to their pathogenesis. ASHM may further support a model of MALT lymphomagenesis leading from an antigen driven lesion to transformed MALT lymphoma finally evolving to overt DLBCL.
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Ibrahim, E., and A. Ezzat. "Failure of the International Prognostic Index to prognosticate outcome in primary gastric DLBC lymphoma." Annals of Oncology 15, no. 5 (May 2004): 841. http://dx.doi.org/10.1093/annonc/mdh179.
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Ennishi, Daisuke, Anja Mottok, Kerry J. Savage, Susana Ben-Neriah, Hennady Shulha, Pedro Farinha, Fong Chun Chan, et al. "Comprehensive MYC and BCL2 Genetic Profiling in De Novo Diffuse Large B-Cell Lymphoma Demonstrates Clinically Relevant Genetic Alterations According to Cell of Origin Subtype." Blood 126, no. 23 (December 3, 2015): 109. http://dx.doi.org/10.1182/blood.v126.23.109.109.
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Abstract Background: MYC and BCL2 are critical driver genes for non-Hodgkin lymphoma including diffuse large B-cell lymphoma (DLBCL). However, the clinical impact of MYC and BCL2 genetic alterations, apart from translocations, has not been comprehensively investigated using high-resolution genetic assays, such as next generation sequencing and high-resolution SNP arrays. Moreover, correlations with cell of origin (COO) subtype, determined by gene expression profiling, have not been widely studied in a large homogeneously treated cohort. We determined the frequency and clinical impact of MYC and BCL2 genetic aberrations in DLBCL in a large population-based cohort uniformly treated with R-CHOP. Methods: We analyzed 347 newly diagnosed de novo DLBCL cases that were treated with R-CHOP in BC. Comprehensive clinical annotation was available through the BCCA Lymphoid Cancer Database. Deep targeted re-sequencing of the coding exons of MYC and BCL2 was performed using a Truseq Custom Amplicon assay (Illumina) on the Miseq platform. High-resolution copy number analyses were performed using Affymetrix SNP 6.0 arrays. Immunohistochemical staining and break-apart FISH assays for MYC and BCL2 were performed on tissue microarrays (n=332). Dual positivity for MYC (cut off; 40%) and BCL2 (cut off; 50%) proteins identified a dual protein expresser (DPE) phenotype. COO classification was achieved using the Lymph2Cx assay based on NanoString technology in 299 patients and the Hans algorithm in 32 cases with low tumor content (<40%). Results: COO determination revealed 193 cases to be GCB subtype, 107 cases ABC/non-GCB and 30 were unclassifiable. Using next generation sequencing, 310 SNVs were detected in MYC (29/347; 8% of cases) and BCL2 (88/347; 25% of cases), with mean redundant coverage depths of 633-fold. All MYC and 98% of BCL2 mutations were misssense mutations. Analysis of copy number alterations using GISTIC 2.0 revealed significant focal gain/amplification (gain/amp) peaks affecting 8q24, including the MYC locus (68/341; 20% of cases) and 18q21, including the BCL2 locus (82/341; 24% of cases). MYC and BCL2 translocations were detected in 38/283 (13%) and 90/300 (30%) of tumors, respectively. MYC gain/amp, BCL2 mutation, BCL2 translocations and double MYC/BCL2 translocation (DHIT) were seen significantly more often in GCB-DLBCL (26% vs 10%, p=0.001; 35% vs 11%, p<0.001; 44% vs 6%, p<0.001; and 13% vs 0%, p<0.0001, respectively), and BCL2 gain/amp was observed more commonly in ABC-DLBCL (44% vs 12%, p<0.001). MYC translocations were significantly associated with MYC protein expression in ABC, GCB and all cases (p<0.0001). On the other hand, BCL2 protein expression was significantly associated with BCL2 mutation and translocation in GCB-DLBCL (both, p<0.0001), and BCL2 gain/amp in ABC-DLBCL (p=0.0037). With a median follow up of 6.5 years for living patients, the presence of MYC translocation, BCL2 gain/amp and BCL2 mutation were associated with an inferior 5y-time to progression (TTP, 53% vs 30%, p=0.019; 60% vs 32%, p=0.009 and 52% vs 17%, p=0.026, respectively) in ABC subtype. In GCB subtype, BCL2 translocation, MYC gain/amp and MYC translocation were associated with an inferior 5y-TTP (85% vs 62%, p=0.001; 80% vs 63%, p=0.011; and 79% vs 61%, p=0.013, respectively). In a multivariate Cox model of TTP including IPI and DPE, BCL2 gain/amp remained prognostic (HR=2.4 [1.3-4.5], p=0.008) independent of IPI and DPE in ABC-DLBCL. In GCB-DLBCL, BCL2 translocation and/or MYC gain/amp showed strong prognostic value (HR=3.0 [1.4-6.4], p=0.006) independent of IPI and DPE. In the IPI high risk group (IPI=3-5), the presence of a BCL2 translocation and/or MYC gain/amp defined a remarkably poor outcome group in GCB-DLBCL (5y-TTP; 29%). Similar poor outcome was observed in ABC-DLBCL cases that harbored BCL2 gain/amp (5y-TTP; 22%). Conclusions: The DHIT genotype was only seen in GCB-DLBCL. High-resolution genomic assays identified extremely poor prognostic groups within each COO subtype on the basis of MYC and BCL2 genetic status in a large uniformly R-CHOP-treated population-based cohort of DLBCL. Figure 1. TTP according to MYC/BCL2 genetic alterations with IPI in ABC-DLBC (n=101) and GCB-DLBCL patients (n=166) treated with R-CHOP. Figure 1. TTP according to MYC/BCL2 genetic alterations with IPI in ABC-DLBC (n=101) and GCB-DLBCL patients (n=166) treated with R-CHOP. Disclosures Savage: Seattle Genetics: Honoraria, Speakers Bureau; BMS: Honoraria; Infinity: Honoraria; Roche: Other: Institutional research funding. Connors:Roche: Research Funding; Seattle Genetics: Research Funding. Scott:Celgene: Consultancy, Honoraria; NanoString: Patents & Royalties: Inventor on a patent that NanoString has licensed.
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Montes, Anel, Ma Andrade, Ilda Murillo, Luis Lopez-Gomez, Teresa Baringo, and Pilar Giraldo. "RIT with 90Y Ibritumomab Tiuxetan in Agressive Non-Hodgkin Lymphoma. Evaluation of Recent Outcomes in a Single Institution." Blood 120, no. 21 (November 16, 2012): 4883. http://dx.doi.org/10.1182/blood.v120.21.4883.4883.
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Abstract Abstract 4883 Diffuse Large B Cell (DLBC) and Mantle Cell Lymphoma (MCL), are two subtypes of aggressive non-Hodgkin lymphoma (A-NHL),that frequently present as advanced systemic disease limiting the use of involved field radiation. They are also predominant in advanced age population non suitable for intensive therapy such as stem cell transplantation. Their aggressive systemic behavior, confer high rates of relapse and short overall survival. The development of radioimmunotherapy brings a new therapeutic approach for both types of A-NHL. We present the results derived from a single-institute use of 90Y-Ibritumomab Tiuxetan (90Y-IT) (Zevalin®) in DLBC and MCL, both as consolidation therapy in first complete response (C-1CR) after chemoimmunotherapy and as second line treatment in relapsed disease (RD). Patients and Methods: we included 19 patients with A-NHL, 10 MCL and 9 DLBCL, treated with 90Y-IT according to a multidisciplinary clinical protocol, between September 2005 and February 2012. Inclusion criteria were: histological confirmed CD20+ MCL or DLBCL, with absolute neutrophil count (ANC) ≥ 1.5 × 109/L, absolute platelet count (APC) ≥ 100 × 109/L, ≤ 25% bone marrow CD20+ lymphocytes, in Complete Remission (CR) after first line chemoimmunotherapy or with relapsed disease. All patients received two prior 250 mg/m2 Rituximab doses, followed by 0.4 mCi /kg IV 90Y-IT. Response was evaluated by PET/TC 12 weeks after treatment. Major endpoints were: objective response rate (ORR), overall survival (OS), progression free survival (PFS), and safety. Other clinical prognostic factors were taken into account upon their possible influence in treatment value. Results: 18 of 19 patients treated with 90Y-IT completed follow-up and were taken into analysis, 10 MCL (52.6%) and 9 DLBCL (47.4%); M/F distribution 10/9 (73.6/26.4%); Overall ECOG 0–1 82.35%. Mean follow-up time: 46.8 months. 8 patients were treated as C-1CR, 4 MCL and 4 DLBCL. For MCL mean age was 66.9 (53–79) years. MIPI score distribution: 0–3 (70.0%), >3 (30.0%). Status before 90Y-IT was: C-1CR 3; relapsed in CR after chemotherapy 3; relapsed/refractory with active disease after chemotherapy (PR) 4. Previous chemotherapeutic schedules: ≤2 (50 %). Overall response (80.0%) 7 CR; 1 PR. Mean estimated OS since 90Y-IT: 57.0 months (52.4–61.6), median OS: 59 months (34.8–86.1) and mean PFS: 24.9 months (95% CI: 14.3–35.6); median PFS: 22 months (95% CI: 1.9–42.0). For DLBCL: mean age 53 (35–87) years. IPI-R score distribution: 0–2 (33.3%), >2 (66.7%). Status before 90Y-IT was: C-1CR 5; relapse/refractory with active disease after chemotherapy (PR) 4; Previous chemotherapeutic schedules ≤2 (77.8%). Overall responses (88.8%) 5 CR; 3 PR. Mean OS since 90Y-IT: 49.2 months (42.8–55.6); median OS: NR and mean PFS: 39 months (95% CI: 22.6–55.4). Until analysis 11 patients have relapsed (57.8%), 8 MCL (80%) and 3 DLBCL (37.5%). Four patients had died, 3 because of disease progression even after several chemotherapeutic treatments. In respect to safety: thrombocytopenia was the most frequent hematologic toxicity presented in 63.1%, grade 3–4 in 21%, with median time to presentation of 2.8 weeks and median time for recovery of 3 weeks. Neutropenia occurred in 52.6%, grade 3–4 in 21%, with median time for recovery of 2 weeks. 1 patient (5.2%) required red cell transfusion and 4 (21.5%) needed platelet transfusion. The most frequent non hematologic toxicity was asthenia. One MCL patient who relapsed 28 months and received 2 more chemotherapy schedules has been diagnosed, four years after 90Y-IT as lung carcinoma. Conclusions: 90Y-IT is a safe and effective consolidation therapy in A-NHL, that allows sustained CR and extends PFS with a low toxicity profile. There are needed further studies to evaluate the impact of radioimmunotherapy in A-NHL. This worh has bee partially sponsored by a grant from FEHHA Disclosures: No relevant conflicts of interest to declare.
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Herrero, J., J. Gómez-Codina, M. Provencio, A. Rueda, M. Llanos, P. Sabín, F. Lobo, D. Vicente, F. García-Arroyo, and C. Iglesias. "A Phase II Study with Cyclophosphamide, Vincristine, Liposomal Doxorubicin (Myocet™), and Prednisone Plus Rituximab, Administered in a Two Weeks Regimen (R-COMP-14) as Primary Treatment for NHL: Efficacy and Safety Interim Analysis." Blood 110, no. 11 (November 16, 2007): 1368. http://dx.doi.org/10.1182/blood.v110.11.1368.1368.
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Abstract BACKGROUND: R-CHOP every 21 days is the standard front line therapy for CD20+ aggressive B-cell non-Hodgkin lymphoma (DLBCL). Intensification of R-CHOP from 21 to 14 days courses with growth factors prophylaxis has shown better outcome and acceptable tolerability. Liposomal doxorubicin (Myocet™) has demonstrated significant less cardiotoxicity than standard doxorubicin. The aim of the study is to assess the efficacy and safety of dose dense R-CHOP regimen modified with Myocet™ (R-COMP-14) in newly diagnosed aggressive DLBCL. Pegfilgrastim was administered to provide prophylactic neutropenia support. METHODS: Between Dec 04 and Aug 07, 47 patients (pats.) were included in the trial. Interim analysis results of the first 36 evaluable pats. completing the study are reported. CD20+, newly diagnosed DLBC non-Hodgkin lymphoma pats. were treated with Rituximab (375 mg/m2), Cyclophosphamide (750 mg/m2), Vincristine (1.4 mg/m2; max. 2 mg), Myocet™ (50 mg/m2) on day 1 and oral Prednisone (100 mg) on days 1 to 5. Pegfilgrastim was administered on day 2 at standard dose. A maximum of 8 cycles, administered every 14 days, were given. Response was assessed at cycle 3, and patients with complete or partial response received 5 additional courses. Pats. characteristics at baseline were: Median age of 55 years (range 27–65); Ann Arbor stage I-II (IPI >1) 38.2%, III 29.4%, IV 32.4%; Extranodal involvement was present in 54.3% pats. ECOG 0: 44.4%, ECOG 1: 41.7%; ECOG 2: 13.9%. Median basal LVEF was 65% (range 40–80). RESULTS: The median relative intensity per week of the chemotherapy regimen was 93.7%. A total of 228 cycles were given, 11 (4.8%) were delayed and 9 cycles (3.9%) were dose reduced mainly due to haematological toxicity. Twenty-four patients (66.7%) completed 8 cycles of treatment. Patients withdrew the study because of investigator or patient decision (7 pats.), unrelated adverse events (2 pats.), haematological or gastrointestinal toxicity (2 pats.) and progression disease (1 pat.). Tolerability: Haematological Grade 3–4 toxicity was: Febrile neutropenia in 2.7% cycles; neutropenia in 3.0% cycles; anaemia in 0.8% cycles and thrombocytopenia in 0.4% cycles. Non-haematological G 3–4 toxicities were gastrointestinal, emesis, nausea/vomiting, hepatic, and asthenia observed in 1.1% of the cycles each; G 3 neurotoxicity and infection were observed in one cycle each. No additional G 3–4 toxicities were recorded. Median LVEF at final visit was 63% (range 52–76). No cardiac episode was observed. Efficacy: Overall response rate was 83.4% (95% CI: 67.2%–93.6%). 24 pts. (66.7%) achieved a complete response (CR/uCR) and 6 pts. (16.7%) a partial response (PR); 2 pats (5.6%) had stable disease and 4 (11.1%) progression disease. CONCLUSIONS: Dose dense R-CHOP modified with liposomal doxorubicin (R-COMP-14) and supported with prophylactic pegfilgrastim is an effective treatment for DLBC non Hodgkin lymphoma, that shows good tolerability profile and no cardiac events. The good efficacy and safety results justifie continuation until the foreseen 75 patients.
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Albitar, Maher, Zijun Yidan Xu-Monette, Babak Shahbaba, Ivan De Dios, Yingjun Wang, Deng Manman, Alexandar Tzankov, et al. "Cell of Origin Classification of DLBCL Using Targeted NGS Expression Profiling and Deep Learning." Blood 134, Supplement_1 (November 13, 2019): 2891. http://dx.doi.org/10.1182/blood-2019-126927.
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Introduction: Targeted RNA sequencing using Next Generation Sequencing (NGS) has significant advantages over transcriptome sequencing. In addition to information on mutations, fusion and alternative splicing, RNA quantification using targeted RNA sequencing is sensitive, reproducible and provides better dynamic range. We used targeted RNA sequencing for RNA profiling of diffuse large B-cell lymphoma (DLBCL) and explored its utility in the sub-classification of DLBC to ABC and GCB. Method: RNA extracted from 441 FFPE lymphnode samples with DLBC lymphoma and sequenced targeting 1408 genes. These cases were previously subclassified as ABC vs GCB using expression profiling and immunohistochemistry. We first normalized RNA expression data to PAX5 expression, then we tried to narrow down important markers using univariate significance tests. Setting the cutoff for false discovery rate at 0.0001, 48 variables remained significant, including 46 RNA levels and two genes (MYD88 and EZH2) mutation status. Using 60% of samples as training set, we used multiple statistical approaches for classification. Deep learning emerged as the best approach. We used autoencoder with 5 hidden layers and developed a model for classification of ABC vs GCB. To further improve on classification, we divided patients in each subgroup based on survival using simple tree model. In this tree model, expression level of CD58 emerged as a powerful prognostic marker for the ABC group and RLTPR expression in the GCB group. Results: Using probability of scoring developed based on deep learning and logestic regression, approximately 30% of the cases had a score between 0.5 and 0.75. For the remaining 70% of patients, the ABC vs GCB classification showed sensitivity and specificity of 96% and 97% for the testing set. We also applied the same approach to 60 independent cases classified using NanoString (Lymph2Cx). Our model showed sensitivity and specificity of 96% and 97% in the NanoString independent cases. Using the tree model for further classification of the ABC and GCB classes, CD58 mRNA levels separated the ABC group into two subgroups (ABC1 and ABC2) and RLTPR mRNA separated the GCB into two subgroups (GCB1 and GCB2) with significant difference in overall survival (P=0.0010) and progression-free survival (PFS) (P=0.0027). Conclusion: Targeted RNA sequencing is very reliable and practical for the subclassification of DLBCL and can provide clinical-grade reproducible test for prognostically subclassification of DLBCL. Figure Disclosures Albitar: Genomic Testing Ccoperative: Employment, Equity Ownership. De Dios:Genomic Testing Ccoperative: Employment. Tam:Takeda: Consultancy; Paragon Genomics: Consultancy. Hsi:Abbvie: Research Funding; Eli Lilly: Research Funding; Cleveland Clinic&Abbvie Biotherapeutics Inc: Patents & Royalties: US8,603,477 B2; Jazz: Consultancy. Ferreri:Roche: Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Kite: Consultancy. Piris:Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Lecture Fees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jansen: Membership on an entity's Board of Directors or advisory committees, Other: Lecture Fees; Nanostring: Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees; Kura: Research Funding. Kantarjian:Ariad: Research Funding; Agios: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Novartis: Research Funding; BMS: Research Funding; Takeda: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Research Funding; Jazz Pharma: Research Funding; Cyclacel: Research Funding; Immunogen: Research Funding; Amgen: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Astex: Research Funding.
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Pfreundschuh, Michael, Carsten Mueller, Samira Zeynalova, Gerhard Held, Viola Poeschel, Carsten Zwick, Tanja Rixecker, Norbert Schmitz, and Niels Murawski. "Differential impact of sex in young and elderly patients with DLBC: Correlation with rituximab (R) pharmacokinetics." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 8570. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.8570.
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8570 Background: Sex and weight independently influence R clearance in elderly DLBCL pts (Mueller et al., Blood 2012). Methods: We analyzed the impact of sex on R pharmacokinetics and outcome of 1,222 elderly pts of the RICOVER-60, 823 young (18 to 60 years) aaIPI=0,1 pts of the MInT, and 375 aaIPI=2,3 pts of the Mega-CHOEP trials. R pharmacokinetics was determined by ELISA in 33 young and 49 elderly patients. Population pharmacokinetic modeling was performed with nonlinear mixed-effect modeling software (NONMEM VI). Results: R clearance was independent of tumor mass (IPI), but weakly correlated (0.2, R2linear=0.045) with increasing age in male, and moderately inversely correlated (-0.5, R2linear=0.207) with age in female DLBCL patients, resulting in similar R clearances in young female and male patients (9.88 vs. 10.38 ml/h; p=0.238), but a significantly faster R clearance in elderly males compared to females (10.50 vs 8.25 ml/h; p=0.006). In the RICOVER-60 trial, elderly females had a higher 3-year PFS (68% vs. 61%) and OS (74% vs. 68%) than male pts. due to a greater outcome improvement by the addition of R in females. In a multivariable analysis adjusting for IPI, the hazard for progression in male compared to female pts. was not significantly increased after CHOP (HR=1.1; p=0.348), but was significantly higher after R-CHOP (OR=1.6; p=0.004). In contrast, young males treated in the MInT and Mega-CHOEP trials benefitted as much as females from the addition of rituximab, with a similar hazard for male pts. after CHOP and R-CHOP (HR=1.2) with no significant difference to female patients (HRPFS=1.2, p=0.552; HROS=1.0; p=0.898). Conclusions: While no differences in R clearance and benefit from rituximab were found in young female compared to male patients, the reduced benefit of adding R to CHOP in elderly male DLBCL pts. who have a shorter rituximab serum half life and hence lower serum levels suggests that this subpopulation is suboptimally dosed when R is given based on body surface area at 375 mg/m2. Ongoing studies of the DSHNHL investigate whether higher R doses for pts. with a shorter R serum half life can improve the outcome of the respective patients. Supported by Deutsche Krebshilfe and Roche.
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McQuellon, R. P., G. B. Russell, M. T. Jesse, C. R. Thomas, and Y. Keung. "Factors associated with long-term survival following stem cell transplantation (SCT) for non-Hodgkin lymphoma." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 18504. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.18504.
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18504 Background: Psychosocial variables have been associated with survival in stem cell transplantation recipients. The purpose of this study was to examine the relationship between clinical, psychosocial, and demographic variables and long-term survival. Methods: Autologous SCT recipients with NHL (n=315) from 1/92 - 4/05 (mean age = 51.6 yrs (±12); 35% F; 7% AA; median survival/follow-up = 4.4/ 6.1 yrs) completed the Center for Epidemiologic Studies-Depression Scale, Functional Assessment of Cancer Therapy- BMT (FACT-BMT; physical well-being, PWB), Profile of Mood States, and the Medical Outcomes Study Social Support Survey (MOS-SS) prior to transplantation. Clinical and demographic data were abstracted from the patient’s record. Cox’s proportional hazards regression models were used to assess the effect of the following variables on survival: clinical - histological subtypes (HS) [anaplastic large cell (ALC), diffuse large B-cell (DLBC), mantle cell (MC), indolent, and aggressive], grade, stage, type of conditioning regimen (TC), chemosensitivity (CS), number of chemotherapy regimens (1–7) prior to SCT (NCR); demographic - age, race, gender; and psychosocial - depressed mood, general distress, quality of life, and social support. Measures with a univariate p-value <0.2 were fit in a backwards stepwise regression; remaining variables had a p-value < 0.05. Results: The included univariate model variables (p-values) were: HS (0.0004), grade (0.004), TC (0.14), CS (0.0001), NCR (0.02), PWB (0.03), FACT-BMT subscale (0.16), SS-Emotional (0.05), SS-affection (0.13). In the regression model, predictors of survival were: HS (<0.0001), median survival = ALC 1.9, DLBC 2.7, aggressive 3.3, MC 5.1, indolent 8.4 yrs; CS (0.008); NCR (0.03), and PWB(0.03). Conclusions: Clinical variables were the most predictive of survival. Psychosocial variables were not associated with survival. No significant financial relationships to disclose.
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Avivi, Irit, Carme Canals, Goli Taghipour, Dietger Niederwieser, Lothar Kanz, Gerhard Ehninger, Jurgen Finke, et al. "Matched Unrelated Donor Stem Cell Transplantation for Patients with Diffuse Large Cell B Cell Lymphoma: A Retrospective Analysis of 118 Patients Registered through the European Group for Blood and Marrow Transplantation (EBMT)." Blood 108, no. 11 (November 16, 2006): 602. http://dx.doi.org/10.1182/blood.v108.11.602.602.
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Abstract Matched unrelated donor stem cell transplantation (MUD-SCT) may provide a treatment option for patients with diffuse large B cell lymphoma (DLBC) who have failed other conventional therapies and do not have a compatible sibling donor available. We present data of 118 DLBC patients, 69 males and 49 females, aged 18 to 66 years (median 43 years), treated with a MUD-SCT between January 1997 and July 2005 and reported to the EBMT registry. Median time from diagnosis to MUD-SCT was 25 months (range, 3 – 205), and 64% of the cases had failed a previous autologous transplant (ASCT). At allogeneic transplantation, 25% of the patients had chemorefractory disease. Peripheral blood was the source of hematopoietic stem cells in 70% of the cases and reduced intensity conditioning regimens (RIC) were used in 52% of the cases. After a median follow up of 26 months, the estimated 2-year non-relapse mortality (NRM), relapse rate (RR), progression free survival (PFS) and overall survival (OS) for the whole series were 29%, 35%, 36% and 43%, respectively. Grade II–IV acute graft-versus-host-disease developed in 32% of patients. Patients selected for RIC protocols were older (median age of 44 years vs 38 years, p = 0.02) and more heavily pre-treated; 75% had failed a previous autograft compared with 53% in the conventionally treated group (CC) (p = 0.01). Despite these unfavorable factors, the 2-yr NRM for RIC patients was significantly lower than in CC patients: 19% vs 39% (p = 0.03). Unfortunately, this advantage was offset by an increased RR in this group of patients (2-yr RR: 46% vs 24%, p = 0.2), resulting in a very similar PFS and OS for both types of conditioning regimens. The prognostic factor with highest impact on PFS was refractory disease at transplantation (RR = 1.8; 95%CI 1.1 −3.1, p = 0.02). The 2-year PFS for patients transplanted with sensitive disease was 40% irrespective of the conditioning regimen used. In sensitive patients undergoing a RIC transplant, the NRM was significantly lower with respect to CC regimen (14% vs 38%, p = 0.02), resulting in an improved PFS and OS (41% vs 37% and 50% vs 46% respectively). PFS in patients transplanted with refractory disease was generally poor (25% at 2 years). However, CC seemed to provide a better outcome than RIC (2-yr PFS of 35% vs 16%). In conclusion, MUD-SCT constitutes a treatment option for patients with DLBCL failing other conventional treatments, particularly for those patients being allografted in sensitive disease. The high RR observed with reduced intensity protocols does not allow to demonstrate a clear long-term benefit of this approach in this setting.
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Walewski, J., G. Mead, A. Jack, S. Barrans, J. Radford, S. Clawson, S. Stenning, and W. Qian. "Defining Burkitt’s lymphoma (BL) with cytogenetics: LY10, a prospective clinicopathological study of dose-reduced (dr) CODOX-M/IVAC in patients with 100% Ki-67 staining B-cell non-Hodgkin’s lymphoma (NHL)." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 7557. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.7557.
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7557 Background: Previous studies suggest that CODOX-M/IVAC is effective therapy for BL (Ann Onc 2002 13:1264–74), however the diagnosis of BL in this and other studies was not based on modern immunochemistry and cytogenetics and is unreliable. To re-evaluate this question we prospectively studied a population of patients (pts) with aggressive B-cell lymphoma (100% Ki-67+) uniformly treated with dr CODOX-M/IVAC. Methods: Pts ≤65 years with B-cell lymphomas showing 100% Ki-67, considered fit for chemotherapy, received either dr CODOX-M x 3 or dr CODOX-M/IVAC x 4 according to a modified international prognostic index (IPI). Chemotherapy was modified by methotrexate dose reduction to 3g/m2. Pts >65 years had further dose reductions; unfit pts were studied pathologically only. Tumours were characterised using both an extended panel of antibodies and interphase FISH on paraffin sections for the presence of the C-MYC and BCL-2 rearrangements. Results: Of 126 pts reviewed centrally, 5 were ineligible; 53 were diagnosed as BL, each based on the combination of the presence of re-arrangement of C-MYC as a sole abnormality, germinal centre phenotype and p53 abnormality. The final 68 cases were highly heterogenous with respect to tumour phenotype and cytogenetics and were diagnosed as diffuse large B-cell lymphoma (DLBCL). Median age (all pts) was 44 years (range 17–83), with 23 aged >65. Compared with the DLBCL pts, BL pts were significantly younger (mean 38yrs vs 53 yrs, p < 0.001), had more marrow involvement (45% vs 24%, p = 0.02) and male predominance (83% vs 65%, p = 0.03). Of 104 pts entered into the clincal study, 32 pts (10 BL, 22 DLBCL, IPI 0,1) received dr CODOX-M x 3 and 72 (39 BL, 33 DLBCL, IPI >1) received dr CODOX-M/IVAC x 4. With median follow-up of 15 months (range 1 to 37), 1 year progression-free survival was 58%, 95% CI 48%-68% (54% BL vs 62% DLBCL) and 1 year survival 61% 95% CI 51%-71% (55% BL vs 66% DLBC). Conclusions: The study shows Ki67 is not an accurate approach to the diagnosis of BL and the use of immunocytochemistry and FISH is essential. BL and DLBCL as defined differ markedly clinically. Preliminary data suggest that dr CODOX-M/IVAC has similar activity in both histologies. No significant financial relationships to disclose.
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Cunningham, D., P. Smith, P. Mouncey, W. Qian, C. Pocock, K. M. Ardeshna, J. Radford, J. Davies, A. McMillan, and D. Linch. "A phase III trial comparing R-CHOP 14 and R-CHOP 21 for the treatment of patients with newly diagnosed diffuse large B-cell non-Hodgkin's lymphoma." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 8506. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.8506.
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8506 Background: The addition of rituximab to standard therapy with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP21) has resulted in improved survival outcomes in the treatment of diffuse large B-cell non-Hodgkin's lymphoma (DLBC NHL). In addition, the administration of CHOP as a 14 day cycle (CHOP14) has shown benefit over standard CHOP21 chemotherapy. This randomised study was designed to evaluate the toxicity and survival outcomes achieved with the addition of rituximab to CHOP14 (R-CHOP14), as compared to standard therapy (R-CHOP21) in newly diagnosed DLBC NHL. Methods: Patients were randomised to receive either eight cycles of standard R-CHOP21 or six cycles of R-CHOP14 (+ G-CSF) with two additional cycles of single agent rituximab. Randomisation was stratified by age (≤60 vs >60), WHO performance status (0–1 vs 2) and LDH level (normal vs raised). The primary endpoint is overall survival. The study was powered to detect an improvement in 2-year survival in the R-CHOP14 arm of 8% (70% to 78%) with 5% significance and 90% power (2-sided). Results: Recruitment is complete with 1080 patients randomised. Patient characteristics in the R-CHOP21 and R-CHOP14 arms are; IPI score of ≥4 17%:15%, stage III/IV disease 63%:62%, B symptoms 44%:47%, bulk disease 51%:48%. Median age is 61 years in both arms. 82% of patients in the R-CHOP21 arm completed study therapy as compared to 89% in the R-CHOP14 arm. Reported grade III/IV toxicities in the R-CHOP21 and R-CHOP14 arms are; neutropenia 57%:31%, thrombocytopenia 5%:9%, Infection 22%:17%, cardiac 1%:2%, nausea & vomiting 8%:8%, mucositis 2%:3%. The radiological complete response rate (CR/CRu) is 47% in both treatment arms. With a median follow-up 14 months 805 patients remain alive. Conclusions: Results indicate that R-CHOP14 can be delivered as effectively as R-CHOP21 with comparable levels of acute toxicity. Final analysis will be performed when 330 deaths have occurred. No significant financial relationships to disclose.
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Shah, Binay K., Amir Bista, and Sandhya Sharma. "Unstaged Diffuse Large B Cell Lymphoma in the United States: Predictors and Patient Outcomes." Blood 126, no. 23 (December 3, 2015): 2109. http://dx.doi.org/10.1182/blood.v126.23.2109.2109.
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Abstract Background: Treatment and prognosis of diffuse large B cell lymphoma (DLBCL) depends on the stage of lymphoma. We conducted this study to examine unstaged DLBCL in the United States. Methods and methodology: We used Surveillance Epidemiology and End Result (SEER) 18 registries to select patients with DLBCL diagnosed during January 2000 to December 2012. We used LRD Summary stage 2000 was used to determine stage of the disease - localized, regional, distant or unstaged. We used Logistic regression to investigate factors associated with unstaged DLBCL. We used Cox Proportional Hazard model to compare survival outcomes. Results: Among 67765 patients, 3194 (4.71%) were unstaged. Age (60+years), "Others" and Caucasian races, single or single/divorced/widow marital status, metropolitan residence, median household income> $50,000, lymph node as the primary site and cased with other primaries before diagnosis of DLBCL were the factors associated with unstaged cases (Table 1). The 5- year relative survival rate for unstaged patients was inferior to those with localized and regional disease, and superior to those with distant disease (HRs of 0.58, 0.66 and 1.24 for localized, regional and distant respectively when compared to unstaged cases). Conclusion: In this large population-based study, 4.71% patients with DLBCL had unstaged disease. Patients with unstaged DLBC had significantly inferior survival rates compared to patients with localized and regional stage. Table 1. Factors associated with unstaged DLBCL cases Parameters Unadjusted OR (95% CI) P value Adjusted OR (95% CI) P value Age (60+ Vs. <60 years) 1.478 (1.363 - 1.602) <0.001 1.458 (1.335 - 1.592) <0.001 Sex (Female Vs. Male) 1.063 (0.990 - 1.141) 0.093 0.983 (0.911 - 1.059) 0.646 Race Caucasians Reference Reference African American 0.804 (0.691 - 0.935) 0.005 0.835 (0.715 - 0.974) 0.022 Others 1.109 (0.976 - 1.261) 0.112 1.257 (1.104 - 1.431) 0.001 Marital Status Married Reference Reference Single 1.026 (0.927 - 1.135) 0.662 1.208 (1.086 - 1.345) 0.001 Single/divorced/widow 1.249 (1.152 - 1.355) <0.001 1.185 (1.087 - 1.291) <0.001 Rural/Urban Rural Reference Reference Urban 0.878 (0.651 - 1.183) 0.393 0.896 (0.661 - 1.214) 0.479 Metropolitan 0.882 (0.667 - 1.165) 0.882 1.028 (0.767 - 1.379) 0.852 Median annual household income Upto 25,000 Reference Reference >25,000-50,000 01.009 (0.753 - 1.354) 0.951 0.927 (0.675 - 1.271) 0.636 >50,000 0.758 (0.563 - 1.021) 0.068 0.673 (0.486 - 0.933) 0.017 Sequence (Not first or only primary vs. first or only primary) 1.261 (1.156 - 1.377) <0.001 1.219 (1.115 - 1.334) <0.001 Site of primary Lymph nodes Reference Reference Extra-lymphatic 0.760 (0.704 - 0.821) <0.001 0.748 (0.693 - 0.808) <0.001 Unknown primary 6.295 (4.569 - 8.672) <0.001 6.727 (4.865 - 9.300) <0.001 Disclosures No relevant conflicts of interest to declare.
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Mounier, Nicolas, Christian Gisselbrecht, Jean-Emmanuel Filmont, Xavier Cuenca, Laure Deville, Pauline Brice, Josette Briere, et al. "Impact of Pre-Transplantation and Post-Transplantation Positron Emission Tomography (PET) Using 18-Fluorodeoxyglucose in Lymphoma Patients Treated with Autologous Stem Cell Transplantation." Blood 108, no. 11 (November 16, 2006): 3055. http://dx.doi.org/10.1182/blood.v108.11.3055.3055.
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Abstract Introduction : Assessment of therapeutic response using 18-Fluoro-deoxy-glucose (FDG) positron emission tomography (PET) is useful to determine prognosis in lymphoma. In poor prognosis lymphoma patients, it may have an important value in the pre-transplant evaluation and help to transplant-decision making. But the impact on patient outcome of post-transplant assessment is unknown. Patients and methods: In our department, between July 2004 and December 2005, 60 consecutive patients (M/F ratio= 37/23) who achieved tumor response and received high-dose chemotherapy plus autologous-stem-cell transplantation (ASCT) were prospectively explored with PET, prior to ASCT (after 3–4 chemotherapy cycles) and 100 days after ASCT. PET images were evaluated without knowledge of conventional imaging and clinical history. Presence (PET positive) or absence (PET negative) of abnormal FDG uptake was related to event-free survival (EFS) and overall survival (OS). Results :50 patients had non-Hodgkin lymphoma (20 diffuse-large-B-cell (DLBCL), 8 mantle-cell, 16 follicular, 4 T-large-cell, 2 Burkitt) and 10 Hodgkin’s lymphoma. Median age was 52 ranging from 19 to 68 years. At diagnosis, 9 patients had 2–4 performance status, 40 elevated LDH, 30 extranodal involvement and 53 staged 3–4. Tumor bulk was above 10 cm in 14 patients. 22 patients received front-line ASCT mainly after ACVBP (n=14) or CHOP. Platinum-based salvage chemotherapy (DHAP, n= 26) was the most frequently used for 27 relapses and 11 refractory diseases. 40 patients received Rituximab with chemotherapy. Prior ASCT, there were 31 complete remission (CR), 23 uncertain CR and 6 partial remission. Conditioning regimen was BEAM in 39 patients; Zevalin BEAM in11, Total Body Irradiation was used in 10. 44 patients (75%) were pre-ASCT-PET negative and 48 (80%) post-ASCT-PET negative. 6 patients (10%) converted from pre-ASCT-PET positive to post-ASCT-PET negative (2 Hodgkin, 1 mantle, 2 follicular, 1 DLBC) and 2 patients (3%) converted from pre-ASCT-PET negative to post-ASCT-PET positive (1 pulmonary infection, 1 early relapse in DLBC). One year after ASCT, 10 patients died (OS 80%) and 17 relapsed (EFS 67%). OS was estimated to 90% in pre-ASCT-PET-negative patients vs. 51 % in PET-positive (p=0.0003), EFS was 75% vs. 43%, respectively (p=0.001). OS was estimated to 87% in post-ASCT-PET-negative patients vs. 48% in PET-positive (p<0.0001), EFS was 77% vs. 25%, respectively (p<0.0001). There was no difference within histological subtypes or front-line vs. relapse/refractory. The only adverse prognostic factors in multivariate analysis was PET positive either pre ASCT (relative risk=4) or post ASCT (relative risk=12). Conclusion: A positive PET after induction chemotherapy indicates a high risk of ASCT failure; in addition, this risk of failure is increased by a positive PET after ASCT. In pre-ASCT-PET-positive patients, more experimental approaches are needed. In pre-ASCT-PET-negative patients, post-ASCT-PET assessment may be omitted.
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Bier, Clerilei Aparecida, Rogério Simões, Isabella Dabrowski, and Carlos Alberto Zapata Carubelli. "Promoção do desenvolvimento local sustentável: estudo comparativo das iniciativas do Brasil e da União Europeia." Revista Grifos 29, no. 50 (June 6, 2020): 7. http://dx.doi.org/10.22295/grifos.v29i50.5219.
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A partir das noções de desenvolvimento local e desenvolvimento sustentável, buscou-se analisar neste artigo, utilizando-se do método de Estudo Comparado, duas iniciativas de desenvolvimento local sustentável que tem como ponto central a participação cidadã e o envolvimento da comunidade, e atuação conjunta com a administração pública por meio da coordenação eficiente de governos locais para o desenvolvimento dos objetivos traçados. Revelou-se no estudo da iniciativas DLBC – Desenvolvimento local de base comunitária aplicada no Brasil pelo Governo Federal em comunidades brasileiras pelo projeto de cooperação técnica INCRA/IICA, e iniciativa denominada LEADER – Liaison Entre Actions pour le Développement de l’Economie Rurale desenvolvida pela União Europeia, que uma estrutura de governança pautada na mobilização das energias da sociedade, nas suas capacidades e potencialidades bem como na atuação do Estado é pedra angular das mudanças sociais e econômicas pretendidas no processos de desenvolvimento local sustentável e fortalecimento das instituições locais com a conscientização dos envolvidos
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Costa, Luciano J., Ivana N. Micallef, David J. Inwards, Patrick B. Johnston, Luis F. Porrata, and Stephen M. Ansell. "Time of Relapse after Initial Therapy Significantly Adds to the Prognostic Value of the IPI-R in Patients with Relapsed DLBCL Undergoing Autologous HSC Transplantation." Blood 110, no. 11 (November 16, 2007): 1897. http://dx.doi.org/10.1182/blood.v110.11.1897.1897.
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Abstract Background: High-dose chemotherapy and hematopoietic stem cell (HSC) transplantation is curative in about 40% of patients with relapsed chemosensitive diffuse large B cell lymphoma (DLBCL). The international prognostic index obtained at the time of relapse (IPI-R) and the time from initial treatment to relapse (TTR) have been suggested in different series to be predictors of outcome after HSC transplantation. We explored the concomitant effect of IPI-R and TTR on therapeutic outcome in a modern and uniform cohort of patients with relapsed chemosensitive DLBC undergoing high-dose chemotherapy and peripheral HSC transplantation. Methods: Retrospective analysis of 80 consecutive patients treated at Mayo Clinic, Rochester, MN between 2001 and 2006 who received a peripheral HSC transplant (except for 3 patients who receive bone marrow) after being conditioned with BCNU, etoposide, cytarabine and melphalan (BEAM) for relapsed chemosensitive DLBCL. Results: Median follow-up of survivors was 31.4 months, Median age at the time of transplant was 62 (interquartile range 53–65; range 26–77), 65% were males; median number of prior chemotherapy regimens was 2. All patients had received at least one previous anthracycline-based regimen, 78% had been previously exposed to rituximab and all achieved at least CRu after the initial treatment. The median time from diagnosis to relapse was 19 months (interquartile range 10–43), 25% of patients had a high or high-intermediate IPI-R. The median survival from the time of transplant for patients with TTR>18 months v. ≤ 18 months was not reached and 50 months respectively (P=0.005). Median survival for patients with high or high-intermediate IPI-R at the time of relapse (IPI score ≥3) was 23.3 months and not reached for patients with low or low-intermediate IPI (P=0.01). These two factors were independent in multivariate analysis with RR for death of 1.8 (1.2–2.9; P=0.004) for TTR ≤ 18 months and 1.7 (1.1–2.5; P=0.017) for high or high-intermediate IPI and therefore combined in a prognostic system were patients with none (n=32), one (n=39) or two (n=9) of these prognostic factors had median disease free survival not reached v. 50 months v. 3.3 months (P=0.001) and overall survival not reached v. 50 months v. 5 months (P=0.0001) (Figure). Conclusion: TTR and IPI-R provide an easy and powerful prognostic system in patients with DLBCL undergoing modern high-dose chemotherapy with HSC support. Figure Figure
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Kharfan-Dabaja, Mohamed A., Cheryl Tate, Janelle Perkins, Teresa Field, Hugo F. Fernandez, Melissa Alsina, Ernesto Ayala, et al. "Administration of Rituximab 375 Mg/m2 on Days +1 and +8 after Allogeneic Hematopoietic Stem Cell Transplantation (allo-HCT) Regimens for Patients with Advanced CD20+ Lymphoid Malignancies." Blood 112, no. 11 (November 16, 2008): 4323. http://dx.doi.org/10.1182/blood.v112.11.4323.4323.
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Abstract We evaluated the safety of adding rituximab 375 mg/m2 only on days +1 and +8 following allo-HCT in 18 patients (M=12, F=6), median age 56 (41–66) years, with advanced CD20+ lymphoid malignancies [CLL=9 (CR2=3, PR2=3; ≥PR3=3); Mantle cell lymphoma (MCL)= 5 (CR1=1, PR2=2, ≥PR3=2); follicular (FL)=3 (CR3=2, ≥PR3=1); DLBC NHL=1 (≥PR3=1). Source of stem cells consisted of matched-related (MRD)=11 (61%), matched-unrelated (MUD)=5 (28%), or mismatched-unrelated (MMUD)=2 (11%) donors. Conditioning regimens consisted of fludarabine plus targeted doses of IV busulfan (FLU-BU) (N=11) or 200 cGy TBI (N=4), or cyclophosphamide (FLU-CY) (N=1). ATG was administered on days −3 and −1 in 2 MMUD cases (FLU-BU-ATG). Fifteen patients received rituximab on day +1 (±3) and all on day +8 (±3). GVHD prophylaxis was tacrolimus plus mycophenolate mofetil (N=11) or methotrexate (N=7). Non-relapse mortality at 100 days was 6%. Median time to neutrophils and platelets engraftment was 15 (6–27) days and 12.5 (9–18) days, respectively. Eight patients never dropped platelets below 20,000/uL. Median CD3 and CD33 chimerisms at day +90 (±10) were 89% (50%–100%) and 100% (15%–100%), respectively. DLI was required in 2 patients (FLU-BU=1, FLU-TBI=1) due to poor CD3 engraftment. Response rates after 90 days post allo-HCT, according to diagnosis, were as follows: CLL (evaluable=8/9; CR=7/8; PR=1/8); MCL (evaluable=4/5; CR=4/4); FL (CR=3/3); DLBC (PD=1/1). Twelve (67%) patients remain alive in remission at a median follow up of 9.4 (2.3–42.3) months. The incidence of grade 0,I, II, and III–IV acute GVHD (aGVHD) was 6%, 33%, 50%, and 11%, respectively. Time to onset of aGVHD was 29 (16–77) days. The incidence of chronic GVHD (cGVHD), per NIH consensus criteria, was as follows in 15 evaluable patients: no cGVHD= 27%, mild= 33%, moderate= 13%, and severe=27%. These findings suggest that administration of rituximab 375 mg/m2 only on days +1 and +8 is safe. Response rates are encouraging; but controlled studies will be needed to conclusively determine the effect of post-transplant rituximab on efficacy.
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Spina, Michele, Ferdinando Martellotta, Massimiliano Berretta, Ernesto Zanet, Arben Lleshi, Vincenzo Canzonieri, Pietro Bulian, Michele Bibas, Andrea Antinori, and Umberto Tirelli. "Phase II Study of Intrathecal Long Acting Liposomal Cytarabine (Depocyte®) In the Prophylaxis of Lymphomatous Meningitis In HIV-Related Non-Hodgkin's Lymphoma." Blood 116, no. 21 (November 19, 2010): 1750. http://dx.doi.org/10.1182/blood.v116.21.1750.1750.
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Abstract Abstract 1750 Background: Around 5% of patients with aggressive non-Hodgkin's lymphoma (NHL) develop central nervous system (CNS) progression or relapse during the course of their disease. Patients with human immunodeficiency (HIV)-related NHL often develop CNS progression despite the use of adequate prophylaxis. Liposomal cytarabine has show a significant activity in lymphomatous meningitis but there are limited data in the prophylactic setting. Methods: Since May 2006, we are running a prospective phase II study of intrathecal liposomal cytarabine (Depocyte®) at the dose of 50 mg in 40 patients with HIV-NHL with the aim to evaluate the feasibility and activity of this drug in the prevention of lymphomatous meningitis. Results: Thirty-five patients were males and the median age was 44 years (range 18–69 yrs). As far as the histological subtype of NHL, 47% of patients had a diffuse large B-cell (DLBC) NHL and 40% Burkitt NHL. Stage III-IV was diagnosed in 80% of patients and 68% of DLBC were age-adjusted IPI 2 or more. An extranodal involvement was diagnosed in 70% of patients (gastrointestinal 30%, bone 27%, spleen 10%, liver 22%, bone marrow 17%). Liposomal cytarabine was well tolerated with headache grade I to III being the most frequent side effect in only 37% of patients. Less common toxicity (all grade I) included cortical changes (5%), fever (3%), vomiting (3%), hypertension (3%), chills (3%). With a median follow up of 12.4 months only one patient (3%) with Burkitt lymphoma developed a combined systemic and meningeal relapse. Moreover, in our experience previously the present study, we used methotrexate as practical use in 426 HIV-NHL with a meningeal progression or relapse of 14% (p=0.09). The use of a liposomal formulation allowed to significantly reduce the number of lumbar injections in comparison to the standard schedules (approximately of 50%) with an improvement of quality of life of patients and with a reduction of professional exposure risk for health care staff. Discussion: In this first prospective study on prophylaxis of lymphomatous meningitis in HIV-NHL reported in the literature, liposomal cytarabine seems safe and active and it reduces of approximately 50% the number of lumbar punctures and exposure risk for health staff as well. Disclosures: No relevant conflicts of interest to declare.
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Hussain, Sabir, Arif Alam, Amar Lal, Hani Y. Osman, Asad Khan, and Khaled Al Qawaksmeh. "Outcome of Patients with Diffuse Large B Cell Lymphoma Treated in a Tertiary Care Centre in Uae; A Retrospective Review." Blood 126, no. 23 (December 3, 2015): 5077. http://dx.doi.org/10.1182/blood.v126.23.5077.5077.
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Abstract Background: Diffuse large B cell lymphoma is the most frequent Haematological Malignancy in UAE. DLBC lymphoma treatment and outcome are well established. Most of reported outcome data is from North America or Europe. Because of lack of reported literature from Middle East, a retrospective data collection and review was performed in Tawam Hospital to evaluate the outcome of DLBC lymphoma. Methods: Retrospective chart review of all diffuse large B cell lymphoma patients treated from January 1, 2008 till December 30, 2012 at Tawam Hospital, a Tertiary Care Oncology Centre in UAE. Results: A total of 99 patients were identified with diffuse large B cell lymphoma. The median age was 48 (17 to 85). 59% of patients were male with a male to female ratio of 1.4. There were 17 (17%) stage I cases, 27 (27%) stage II cases, 23 (23%) stage III cases, and 30 (30%) stage IV cases. The stage was not documented in 2 (2%) patients. International Prognostic Index (IPI) score was documented in 80 (80%) patients. 28 (35%) of patients had low IPI score (0 or 1 risk factor), 33 (41%) patients had low intermediate IPI score (2 risk factor), 8 (10%) patients had high Intermediate IPI score (3 risk factors) and 11 (14%) patients had high IPI score (4 and 5 risk factors). 88 (89%) patients completed planned treatment: either R-CHOP or R-CHOP like chemotherapy. Involved field radiation therapy (IFRT) was given in limited stage and bulky disease. 11 (11%) patients didn't have a complete treatment. 3 patients received only R-CVP, 4 patients received only 1 cycle R-CHOP, 1 patient did not receive any treatment, 1 patient received only palliative Radiotherapy, 1 patient received Rituximab and palliative RT and 1 patient received only Dexamethasone and Rituximab. Relapse-free patients had median follow up of 31 months (1 to 67). 19 (26%) had less than 12 months follow up after completion of chemotherapy. Patients with documented relapses or primary refractory disease had relapse or progression at a median follow up of 14 month (1 to 43). There were 3 (10%) relapses in Low IPI score, 8 (24%) in low intermediate group, 4 (50%) in high intermediate group and 6 (54%) in high risk group. Discussion: Our data showed more young patients, median age 48, as compared to SEER data median age 65 and male predominance (59%), slightly higher as compared to SEER data (55%). These findings may be related to the demographics of UAE. UAE relatively have young and male predominance partly due to large number of expatriate population. Distribution of IPI score in our data is different as compared to the reported data; low risk 35% vs 52%, low intermediate 41% vs 21%, high intermediate 10% vs17%, and high risk 14% vs10%. Our data is missing reporting of IPI score in 20% of cases, may explain party the above difference. As median follow up of patient without relapse was 34 months, so comparison was made with 3 years progression free survival data reported in literature. Relapse free survival in the Low risk group 90% is comparable to reported 3 years progression free survival of 87% , low intermediate 76% as compared to reported 75%, in High intermediate and High risk group 50% and 46% are close to reported 59% (3) and 50% . The difference in high intermediate and high risk group as compared to reported survival in literature may be due to small number of patients in these groups. Conclusion: Outcome of DLBC lymphoma in our single centre retrospective review is relatively similar to reported outcome in literature. Median age is lower as compared to SEER data. Disclosures No relevant conflicts of interest to declare.
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Pfreundschuh, Michael, Carsten Mueller, Samira Zeynalova, Gerhard Held, Viola Poeschel, Carsten Zwick, Marcel Reiser, et al. "Evidence for rituximab (R) underdosing in subpopulations of elderly patients with DLBC: Results of the RICOVER-60 study of the DSHNHL." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 8024. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.8024.
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8024 Background: Gender and weight independently influence R clearance and R serum elimination half life (Mueller et al., Blood 2012). To investigate whether the differences in R pharmacokinetics translate into different outcomes, we analyzed elderly patients (pts) with different R pharmacokinetics treated in the RICOVER-60 study. Methods: 1222 elderly pts. (61-80 y) were randomized to receive 6 or 8 cycles of CHOP-14 with or without R given on days 1, 15, 29, 43, 57, 71, 85, and 99. For this study, subgroup analyses were performed for pts with faster R clearance: elderly male (vs. female) pts and elderly weighty (upper quartile: >77kg) vs. slim (lower quartile: ≤60 kg) female pts. Results: Elderly females had a slower R clearance (8.21 ml/h vs. 12.68 ml/h; p=0.003) and a prolonged R half life compared to men (t1/2ß=30.7 vs. t1/2ß=24.7 d; p=0.003). Female pts had a higher 3-year PFS (68% vs. 61%; p=0.062) and OS (74% vs. 68% p=0.086). The differences in outcome were due to a greater outcome improvement by the addition of R in females: the difference in 3-year PFS between female and male pts was 5.1% (p=0.448) in pts. receiving CHOP-14 only and 7.7% (p=0.053) when R was added. In a multivariate analysis the relative risk for progression in male compared to female patients was not significantly elevated after CHOP-14 (1.1; p=0.348), but was significantly higher after R-CHOP-14 (1.6; p=0.004). With respect to weight, addition of R resulted in a significantly improved 3-year PFS (74% vs. 49%; p=0.006) in female pts with a body weight within the lower quartile (≤60 kg) who have an R serum half life of >38.1 days, while there was no improvement by the addition of R (72% vs. 71%; p=0.816) in female pts. with a body weight within the upper quartile (>77kg), who have a serum half life of <29.3 days. Conclusions: The reduced benefit of adding R to CHOP in elderly DLBCL pts. with a shorter rituximab serum half life (and hence lower serum levels) suggests that the respective subpopulations (males and weighty females) are underdosed when R is dosed based on body surface area at 375 mg/m2. Ongoing studies of the DSHNHL investigate whether higher R doses for pts with a shorter R serum half life can improve the outcome of the respective pts.
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Hu, Jianda, Ting Yang, Xiaozhu Yang, Na Xian, Yanxin Chen, Peifang Jiang, and Gangxiong Huang. "Repeat Infusion of CD19-Specific Chimeric Antigen Receptor T-Cell Could Improve the Efficacy with Consistent Safety in Relapsed/Refractory Diffuse Large B-Cell Lymphoma." Blood 132, Supplement 1 (November 29, 2018): 5385. http://dx.doi.org/10.1182/blood-2018-99-119100.
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Abstract Backgroun d Patients with relapse and/or chemo-refractory (R/R) diffuse large B cell lymphoma (DLBCL) are often fail to conventional therapy and suffer dismal prognosis. Recently CD19-targeted immunotherapy using chimeric antigen receptor (CAR)-modified T cells (CART cells) has produced the most promising clinical outcomes in patients with R/R B-cell leukemia and lymphoma, including R/R DLBCL, with overall response rate (ORR) at 50%-80%. However, a part of R/R DLBCL patients, who had restricted durability of clinical response after CD19-specific CART (CD19-CART) cell therapy were at the risks of disease progression. Considering the majority of the existing studies generally used a single infusion of CART cells, with a limited remission duration in which 20%-40% R/R DLBCL patients lost response within 6 months, the purpose of this study is to investigate whether repeat infusions could raise therapeutic response and extend its persistence, and thus improve the clinical outcomes in R/R DLBCL patients. Herein, we conducted a clinical trial (ClinicalTrials.gov Identifier: NCT03391726) to evaluate the efficacy and safety of repeat infusion of CD19-CART cells to patients with R/R DLBCL. Methods Following chemotherapy consisting of cyclophosphamide and fludarabine for lymphodepletion, the enrolled R/R DLBCL patients received an infusion of CD19-CART cells at a dose of 0.7-6×106 cells/kg. The CD19-CART cells were generated by modifying autologous T cells with a lentiviral vector encoding a CAR comprising a murine derived anti-CD19 scFv, 4-1BB and CD3ζ domains. Four of eight (50.0%) patients were given a repeat infusion of CART cells at 3 to 10 months after the initial infusion. R esults From June 2017 to July 2018, eight patients (median age, 52 years; range, 27-70 years) with R/R DLBCLs that were relapsed or resistant to primary or salvage chemotherapy or local radiotherapy, or fail to other clinical trial were enrolled (5 cases of DLBCL; 1 case of DLBCL with central nervous system infiltration;1 case of primary central nervous system lymphoma (PCNSL); 1 case of primary mediastinal large B cell lymphoma (PMBL)). Patients were evaluated for efficacy and safety at four weeks after initial infusion. 1/8(12.5%) patients reached complete remission (CR), 5/8(62.5%) patients had a partial remission (PR), while 2/8(25.0%) patients had stable disease (SD). The ORR (CR and PR) was 75.0% (6 of 8). With a median follow-up of 8.5 months, among 4 patients who had received a second infusion of the CART cells, 1 patient with RR DLBC remained in CR, 1 patient with primary refractory DLBCL remained in PR with constant improvement in symptom and iconography, 1 patient with primary refractory DLBCL had SD after initial infusion and reached PR after a second infusion, and 1 patient with PCNSL remained in SD. Of the 4 patients receiving single infusion of CART cells, 2 patients with primary refractory DLBCL remained in PR, 1 patient with RR DLBCL with CNSL infiltration was SD and 1 patient with refractory PMBL developed to progress disease after reaching PR and finally died. Overall survival (OS) and progression free survival (PFS) rates at 12 months were 87.5 % and 87.5 %, respectively. The most common adverse events of grade 3 or higher during the treatments were neutropenia and anaemia (in 87.5% and 25% of the patients, respectively). Grade 1 cytokine release syndrome (CRS) was observed in 5/8 (62.5%) patients. Neither CRS of > grade 2 nor neurologic events occurred in any patients. No prolonged B cell aplasia and hypogammaglobinemia was observed in repeat infusion patients. Conclusion Patients with R/R DLBCL who were treated CD19-CART cells had promising clinical responses with a safety profile. A repeat infusion of CD19-CART cells may lead to prolonged persistence, and sustained responses without elevated side effect. The tendency of improved OS by repeat infusion need to be further evaluated in more patients. Figure. Figure. Disclosures No relevant conflicts of interest to declare.
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Ramadan, Khaled M., Kevin W. Song, Joseph M. Connors, Abdul Al-Tourah, Randy D. Gascoyne, Michael J. Barnett, Stephen H. Nantel, et al. "Comparison of Outcome Between Refractory/Relapsed De Novo Diffuse Large B-Cell and Transformed Lymphoma Using Related and Unrelated Allogeneic Hematopoietic SCT." Blood 112, no. 11 (November 16, 2008): 2173. http://dx.doi.org/10.1182/blood.v112.11.2173.2173.
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Abstract No data are available in the literature comparing the outcome of myeloablative allogeneic SCT (allo-SCT) for patients with refractory/relapsed de novo diffuse large B-cell lymphoma (DLBCL) and transformed lymphoma (TNHL). We hypothesized that outcomes would be similar for these 2 groups. In this single centre, population based study, a total of 71 such patients underwent allo-SCT (Oct 87 to Feb 07), 40 (56%) with TNHL and 31 (44%) with DLBCL. The 2- and 5-y OS for the whole group is 46% and 41% respectively, with median follow up for surviving pts of 67 months (range 13 – 183 m). The 1-y cumulative incidence (CI) of relapse and TRM for the whole group is 27% and 27% respectively. There were no significant differences between baseline characteristics for the two groups including: median age at diagnosis, stage, B-symptoms, IPI at diagnosis, number of prior therapies, CMV status of donor and recipient, donor type, level of HLA matching and conditioning regimen. Median age at SCT was 58 for TNHL compared to 50 for DLBCL (p<0.001) and more patients received prior rituximab therapy in the TNHL group (35%) compared to the DBCL group (13%), (p=0.03). Sixteen of 31 patients (53%) with DLBCL and 11 of 40 (27.5%) with TNHL are alive. Overall (OS) and event-free survival (EFS) are superior for the DLBCL group compared to the TNHL group mainly due to lower risk of therapy related mortality (TRM). OS for the DLBCL and TNHL groups at 2-y and 5-y are 55% vs 40% and 55% vs 28% respectively, (p=0.05). EFS for the DLBCL and TNHL groups at 2-y and 5-y are 52% vs 35% and 48% vs 27% respectively, (p=0.1). The CI of disease relapse post allogeneic stem cell transplantation for the DLBCL and TNHL groups are similar at 1-y: 32% vs 23% and at 5-y: 36% vs 36% respectively, (p=0.9). TRM is significantly lower for the DLBCL compared to the TNHL group with 1- and 5-year CI - TRM at 16% vs 35% and 16% vs 38% respectively, (p=0.04). Early complications post-allogeneic stem cell transplantation (Bearman toxicity criteria) were similar in both groups. The CI of grades II–IV acute graft host disease (aGvHD) is41% for DLBCL and 60% for TNHL (p=0.08). The cumulative incidence of aGvHD grades III/IV was lower in the DLBCL group (7%) compared to the TNHL group (25%), (p=0.049). The cumulative incidence of chronic GvHD (cGvHD) at 3 years was non-significantly higher in the DLBCL (48%) compared with the TNHL group (27%) (p=0.14). In summary, patients with refractory/relapsed de novo DLBCL treated with allogeneic SCT have better outcome compared to those with TNHL. There is a plateau on the survival curve at 50% for DLBC NHL, with good long-term disease-free survival. The same is not true with allo HSCT for T NHL, whereby a continuous pattern of failure is seen. Table: Basic characteristics of follicular and transformed groups. Parameter TNHL (%) DLBCL (%) P-Value *at diagnosis Patient number 40 (56) 31 (44) 0.342 (Ho: porp=0.5) Gender: Male/Female; Ratio 27/13 (67.5/32.5); 2/1 16/15 (52/48); 1:1 Chi-squared test: 0.174 Age (years): Median / Range 44 / 28 – 58 38 / 15 – 50 t test (equal means): <0.001 Donor Type: Sibling/ unrelated 25 / 15 (62.5 / 37.5) 25 / 6 (81 / 19) Chi-squared test: 0.10 Stage: * Fisher test: 0.296 I/II/III/VI 2/2/6/30 (5/5/15/75) 1/5/7/18 (3/16/23/58) IPI (number of factors)(0–1 vs 2–5) * Chi-squared test:0.4 0/1 5/13 (12.5/32.5) 3/8 (10/26) 2/3 15/5 (37.5/12.5) 7/9 (23/29) 4/5 2/0 (5/0) 4/0 (13/0) Figure Figure
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Carreras, Joaquim, Yara Y. Kikuti, Sílvia Beà, Masashi Miyaoka, Shinichiro Hiraiwa, Haruka Ikoma, Ryoko Nagao, et al. "Clinicopathological characteristics and genomic profile of primary sinonasal tract diffuse large B cell lymphoma (DLBCL) reveals gain at 1q31 and RGS1 encoding protein; high RGS1 immunohistochemical expression associates with poor overall survival in DLBC." Histopathology 70, no. 4 (January 9, 2017): 595–621. http://dx.doi.org/10.1111/his.13106.
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Montalbán, Carlos, Antonio Díaz-López, Heidys Garrote Santana, Julián Matias Freue, Lourdes López, Raquel De Oña, Ana M. Martín Moreno, et al. "Validation of the NCCN-IPI for Diffuse Large B-Cell Lymphoma (DLBCL) in a Nation-Wide Spanish Series of 1885 Patients. the Geltamo-IPI Project." Blood 126, no. 23 (December 3, 2015): 3955. http://dx.doi.org/10.1182/blood.v126.23.3955.3955.
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Abstract The development of the NCCN International Prognostic Index (NCCN-IPI) for patients with DLBCL treated in the rituximab era improves discrimination when compared to the original IPI model. The aim of the present study is to validate the results of the NCCN-IPI in a large independent series of patients in a different geographical area. Materials & Methods. This nation-wide retrospective study includes 2156 patients with de novo DLBCL diagnosed in 20 (mostly) large academic Spanish centers within the Grupo Español de Linfomas y Transplante de Médula Osea (GELTAMO) network between 1998 to July 2014. Patients had to be ≥ 18 years-old, treated with rituximab plus chemotherapy (R-CHOP or variants and also more intense treatments) and a minimum of 1 year of follow-up; all histological subtypes of DLBCL and primary extranodal cases were acceptable, with the only exclusion of primary testicular or CNS sites. In the whole series the scoring of the IPI and NCCN-IPI indexes were used and 5-year Overall Survival (5y-OS) estimated with the Kaplan-Meier method and compared with the log-rank test. Results. Debugging the database resulted in a final working series that included 1885 patients. The demographics of the series were comparable to the NCCN series: NCCN/GELTAMO male gender(%) 54 vs 50.4, Age(y) 57 vs 60, LDH>1(%) 50 vs 54.7, Ann Arbor stage III-IV (%) 59 vs 62.5, ECOG PS≥2(%) 11 vs 30, extranodal disease(%) 36 vs 40.7. The IPI scoring (1760 patients) significantly separated the four risk groups, low (LR, 33.6% of the patients), low/intermediate (LI, 22.7%), intermediate/high (HI, 25.1%) and high (HR, 18.6%) with significantly different (p<0.001 in the global and pairwise comparisons) 5y-OS 5 (88, 77, 68 and 51%, respectively) (Figure 1). The NCCN-IPI (1773 patients) also significantly (p<0.001 in the global and pairwise comparisons) separated the four risk groups (L 12,7%, LI 34.5%, HI 37% and H 15.8%) with 5y-OS (%) of 93, 84, 67 and 49, respectively (Figure 2), comparably to the published data (Table 1). Conclusions. NCCN-IPI for the prognosis of DLBC lymphoma treated with chemo-immunotherapy has been validated in a large independent Spanish series. However, in our population the NCCN-IPI is not more powerful than the IPI for predicting survival. Figure 1. Figure 1. Figure 2. Figure 2. Figure 3. Figure 3. Disclosures López-Guillermo: Roche, Celgene, Mundipharma, Gilead, Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dlouhi:Gilead: Equity Ownership. Martín García:Servier, Gilead: Consultancy. Sancho:CELLTRION, Inc.: Research Funding.
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Ferman, Tanis J., Naoya Aoki, Bradley F. Boeve, Jeremiah A. Aakre, Kejal Kantarci, Jonathan Graff-Radford, Joseph E. Parisi, et al. "Subtypes of dementia with Lewy bodies are associated with α-synuclein and tau distribution." Neurology 95, no. 2 (June 19, 2020): e155-e165. http://dx.doi.org/10.1212/wnl.0000000000009763.
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ObjectiveTo determine whether Lewy body disease subgroups have different clinical profiles.MethodsParticipants had dementia, autopsy-confirmed transitional or diffuse Lewy body disease (TLBD or DLBD) (n = 244), or Alzheimer disease (AD) (n = 210), and were seen at least twice (mean follow-up 6.2 ± 3.8 years). TLBD and DLBD groups were partitioned based on the presence or absence of neocortical neurofibrillary tangles using Braak staging. Four Lewy body disease subgroups and AD were compared on clinical features, dementia trajectory, and onset latency of probable dementia with Lewy bodies (DLB) or a DLB syndrome defined as probable DLB or dementia with one core feature of parkinsonism or probable REM sleep behavior disorder.ResultsIn TLBD and DLBD without neocortical tangles, diagnostic sensitivity was strong for probable DLB (87% TLBD, 96% DLBD) and the DLB syndrome (97% TLBD, 98% DLBD) with median latencies <1 year from cognitive onset, and worse baseline attention-visual processing but better memory-naming scores than AD. In DLBD with neocortical tangles, diagnostic sensitivity was 70% for probable DLB and 77% for the DLB syndrome with respective median latencies of 3.7 years and 2.7 years from cognitive onset, each associated with tangle distribution. This group had worse baseline attention-visual processing than AD, but comparable memory-naming impairment. TLBD with neocortical tangles had 48% diagnostic sensitivity for probable DLB and 52% for the DLB syndrome, with median latencies >6 years from cognitive onset, and were cognitively similar to AD. Dementia trajectory was slowest for TLBD without neocortical tangles, and fastest for DLBD with neocortical tangles.ConclusionsThe phenotypic expression of DLB was associated with the distribution of α-synuclein and tau pathology.
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Sucularli, Ceren, Ugur Toprak, and Melda Arslantas. "Gene expression data analysis for characterizing shared and type specific mechanisms of HCC and B-CLL." Turkish Journal of Biochemistry 44, no. 1 (September 10, 2018): 86–97. http://dx.doi.org/10.1515/tjb-2018-0039.
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Abstract Background Comparing gene expression profiles using gene expression datasets of different types of tumors is frequently used to identify molecular mechanisms of cancer. This study aimed to find shared and type specific gene expression profiles of hepatocellular carcinoma (HCC) and B-cell chronic lymphocytic leukemia (B-CLL). Material and methods Gene expression microarrays for HCC and B-CLL and RNA-sequencing expression data for liver HCC and lymphoid neoplasm diffuse large B-cell lymphoma (DLBC) were analyzed and differentially expressed probe sets or genes for each cancer type were detected. Probe sets and genes that were shared or specifically expressed in both cancer types were identified. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) terms for Biological Process (BP) annotations were performed. Results According to our analysis shared upregulated genes were mainly annotated in cell cycle processes. Some of the genes that changed only in HCC were annotated in cell cycle and metabolic processes, and some of the genes, altered only in B-CLL, were annotated in immune response and hemopoiesis. Conclusion These results contribute to cancer research that aim to find the conserved gene expression profiles in different cancer types and widen the knowledge of HCC and B-CLL specific mechanisms.
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Lal, Amar, Nehal Masood, and Salman Adil. "Extranodal-NHL: Outcomeand Comparison with Nodal NHL. Single Institution Experience Year: 1988–2004." Blood 108, no. 11 (November 16, 2006): 4755. http://dx.doi.org/10.1182/blood.v108.11.4755.4755.
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Abstract Background & Objective: Non-Hodgkin’s lymphoma (NHL) arising in an extra nodal (EN) site is not uncommon and its natural history and treatment is clearly characterized in the literature. Data on EN-NHL and comparison with N-NHL with relation to survival and prognostic factors is scarce in our part of the world. The primary objective of this study was to analyze the anatomic distribution, clinical features and outcome of Diffuse large B-cell lymphoma (DLBCL) patients according to the primary site (extra nodal vs nodal) with applicability of International Prognostic Index (IPI). Methods: From 1988 to 2004, 711 cases of NHL were diagnosed at our Institute. Out of these 145 (20%) patients were excluded as they were other than DLBCL hitopathology. Five hundreds fifty-seven (80%) patients were analyzed for the clinico-pathologic characteristics, treatment outcome and prognostic factors affecting overall survival. Ann Arbor staging system was used for staging with bone marrow biopsy, chest and abdominal radiography/CT. Results: Median age was 48.7 ± 15.3 years; the M: F ratio was 2:1. The distribution according to the primary site was: lymph node, 322 cases (58%) of these 145 cases (44%) stage IV, 76 cases (23%) Stage III, 60 cases (18%) stage II and 47 cases(15%) stage I; and EN sites, 235 (42%), including gastro-intestinal tract (44%) followed by upper aerodigestive tract (19%), bones (08%), spine (05%), and unusual sites less than 3% each as breast, CNS, testis, lungs and skin. The median survival rate was 4.8 and 6.3 years in NL and ENL respectively vary according to primary site/stage of the lymphoma. In the univariate analysis age less than 60 years, early stage I -II, extra nodal involvement primarily gastric or bone, 0–1 extra nodal site, 0–1 PS, lack of B symptoms, normal LDH level has been associated with good prognosis. In the multivariate analysis age, PS, stage and level of LDH were the main variables to predict OS; no nodal or extranodal site maintained their prognostic value. Conclusion: Our data correspond with series from west increasing incidence extranodal lymphoma due to improved diagnostic techniques and superior results with chemotherapy by preserving the organ. Few patients with bowel obstruction or cord compression lymphoma required surgery for diagnosis or relief of symptoms. There is significant difference from western data in histologies DLBC-NHL is the most common histologies in our study. Overall survival patients with EN-NHL were similar to nodal NH-Lymphoma but largely depended on IPI.
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Lal, A., S. Adil, and N. Masood. "Extranodal NHL- A retrospective review of clinico-pathologic features and outcome and comparison with nodal NHL. Single institution experience years: 1988–2004." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 17542. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.17542.
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17542 Background: Non-Hodgkin’s lymphoma (NHL) arising in an extra nodal (EN) site is not uncommon and its natural history and treatment is clearly characterized in the literature. Data on EN-NHL and comparison with N-NHL with relation to survival and prognostic factors is scarce in our part of the world. The primary objective of this study was to analyze the anatomic distribution, clinical features and outcome of DLBCL patients according to the primary site with applicability of International Prognostic Index (IPI). Methods: From 1988 to 2004, 557 patients were analyzed for the clinico-pathologic characteristics, treatment outcome and prognostic factors affecting overall survival. Results: Median age was 48.7 ± 15.3 years ; the M: F ratio was 2:1. The distribution according to the primary site was: lymph node, 322 cases (58%) of these 145 cases (44%) stage IV, 76 cases (23%) Stage III, 60 cases (18%) stage II and 47 cases(15%) stage I ; and EN sites, 235 (42%), including GIT (44%) followed by upper aerodigestive tract (19%), bones (08%), spine (05%), and 3% each as breast, CNS, testis,lungs. The median survival rate was 4.8 and 6.3 years in NL and ENL respectively vary according to primary site/stage of the lymphoma. In the univariate analysis age less than 60 years, early stage I-II, extra nodal involvement primarily gastric or bone, 0–1 extra nodal site, 0–1 PS, lack of B symptoms, normal LDH level has been associated with good prognosis. In the multivariate analysis age, PS, stage and level of LDH were the main variables to predict OS; no nodal or extranodal site maintained their prognostic value. Conclusion: Our data correspond with series from west increasing incidence extranodal lymphoma due to improved diagnostic techniques and superior results with chemotherapy by preserving the organ. Few patients with bowel obstruction or cord compression lymphoma required surgery for diagnosis or relief of symptoms. There is significant difference from western data in histologies DLBC-NHL is the most common histologies in our study. Overall survival patients with EN-NHL were similar to nodal NH-Lymphoma but largely depended on IPI. No significant financial relationships to disclose.
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Bergstedt, Helena, Benjamin M. Jones, Kenneth Hinkel, Louise Farquharson, Benjamin V. Gaglioti, Andrew D. Parsekian, Mikhail Kanevskiy, et al. "Remote Sensing-Based Statistical Approach for Defining Drained Lake Basins in a Continuous Permafrost Region, North Slope of Alaska." Remote Sensing 13, no. 13 (June 29, 2021): 2539. http://dx.doi.org/10.3390/rs13132539.
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Lake formation and drainage are pervasive phenomena in permafrost regions. Drained lake basins (DLBs) are often the most common landforms in lowland permafrost regions in the Arctic (50% to 75% of the landscape). However, detailed assessments of DLB distribution and abundance are limited. In this study, we present a novel and scalable remote sensing-based approach to identifying DLBs in lowland permafrost regions, using the North Slope of Alaska as a case study. We validated this first North Slope-wide DLB data product against several previously published sub-regional scale datasets and manually classified points. The study area covered >71,000 km2, including a >39,000 km2 area not previously covered in existing DLB datasets. Our approach used Landsat-8 multispectral imagery and ArcticDEM data to derive a pixel-by-pixel statistical assessment of likelihood of DLB occurrence in sub-regions with different permafrost and periglacial landscape conditions, as well as to quantify aerial coverage of DLBs on the North Slope of Alaska. The results were consistent with previously published regional DLB datasets (up to 87% agreement) and showed high agreement with manually classified random points (64.4–95.5% for DLB and 83.2–95.4% for non-DLB areas). Validation of the remote sensing-based statistical approach on the North Slope of Alaska indicated that it may be possible to extend this methodology to conduct a comprehensive assessment of DLBs in pan-Arctic lowland permafrost regions. Better resolution of the spatial distribution of DLBs in lowland permafrost regions is important for quantitative studies on landscape diversity, wildlife habitat, permafrost, hydrology, geotechnical conditions, and high-latitude carbon cycling.
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Kasanuki, Koji, Keith A. Josephs, Tanis J. Ferman, Melissa E. Murray, Shunsuke Koga, Takuya Konno, Nobutaka Sakae, et al. "Diffuse Lewy body disease manifesting as corticobasal syndrome." Neurology 91, no. 3 (June 13, 2018): e268-e279. http://dx.doi.org/10.1212/wnl.0000000000005828.
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ObjectiveTo describe clinical and pathologic characteristics of diffuse Lewy body disease (DLBD) manifesting as corticobasal syndrome (CBS).MethodsIn 523 autopsy-confirmed cases of DLBD, we identified 11 patients diagnosed with CBS. For comparison, we studied 22 DLBD brains with antemortem presentation of dementia with Lewy bodies (DLB). Given previous studies suggesting the importance of pathology in peri-Rolandic cortices in CBS, we used digital pathology to count Lewy bodies and to quantify intracytoplasmic and neuritic α-synuclein and phospho-tau burden in the motor cortex.ResultsDLBD patients with antemortem features of CBS were significantly younger at disease onset and less likely to have REM sleep behavior disorder than DLBD cases who met clinical criteria for DLB during life. Patients with DLBD manifesting as CBS had more Lewy bodies in the motor cortex than DLBD manifesting as clinically probable DLB. Three cases had concomitant progressive supranuclear palsy and 4 cases had concomitant Alzheimer disease as probable correlates of CBS.ConclusionThe neuropathology underlying CBS is heterogeneous, including corticobasal degeneration, Alzheimer disease, and progressive supranuclear palsy. This study suggests that atypical variants of Lewy body disease with severe peri-Rolandic Lewy-related pathology can present clinically as CBS. Patients with DLBD who present as CBS tend to have an earlier age at onset and are less likely to have clinical features of DLB, such as dream enactment behavior during sleep, visual hallucinations, and levodopa-responsive parkinsonism. Future studies with biofluid or molecular imaging biomarkers for α-synuclein will permit better recognition of this uncommon pathologic substrate of CBS.
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Gupta, Shweta, Shivi Jain, Sonia Sandhu, Shylendra Sreenivasappa, Shinoj Pattali, Tareq Braik, Margaret Telfer, Audrey French, and Paul G. Rubinstein. "A Retrospective Analysis of All Hematological Malignancies in Patients Infected with HIV, a Subset Analysis of the CHAMP Study (Cook County Hospital (CCH) AIDS Malignancy Project),." Blood 118, no. 21 (November 18, 2011): 3693. http://dx.doi.org/10.1182/blood.v118.21.3693.3693.
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Abstract Abstract 3693 Introduction: Stroger Hospital of Cook County (CCH) and the Ruth M. Rothstein CORE Center (CC) are the largest health provider for HIV + patients in Chicago and one of the largest in the United States. Together, the CC and CCH treats over 5500 HIV + individuals per year. Insights into the type of cancer and patient characteristics in the inner city and underserved populations have been underrepresented in the literature. To this end, a retrospective study of all HIV-associated cancers at CCH and the CC for the past 13 years was initiated, the CHAMP study (Stroger Hospital of C ook County (CCH) A IDS M alignancy P roject). In total, 413 malignancies were identified. Here we present the analysis of the HIV-associated hematological cancers of the CHAMP cohort. Methods: We identified via CCH and CC databases all HIV-infected patients with a cancer from 1998–2011. We then identified the HIV characteristics, cancer type, overall survival (OS) data, and patient demographics for all of hematological malignancies. Statistics: 149 patients were studied as a retrospective cohort for clinical presentation, prognostic characteristics, and OS. Survival data was analyzed using Kaplan-Meier analysis and Cox Proportional Hazards model. Results: In the CHAMP cohort, 149 HIV-associated hematological malignancies were identified, representing 16 cancers. The racial composition was 58% African American (AA), 25% Hispanic (Hsp), and 14% Caucasians with a Male (86%):Female (14%) ratio of 6:1. Of the 149 cancers, 71% (n=108) were ADC, non-hodgkins lymphoma. Diffuse large B cell lymphoma (DLBCL) 32%(n=49), Burkitt's lymphoma (BL) 15% (n=22), and primary CNS lymphoma (PCNSL) 8% (n=11) were the most common. Of the NADC, Hodgkin lymphoma (HL), 21%(n=32) was the most frequent. Seventy two percent of the patients with DLBC had stage III/IV disease, 50% had CD4 counts <100, and 75% had extra nodal disease. Sixty percent of the patients whose OS data were available, were still alive at 24 months, similar to historical controls. The average OS for BL and PCNSL was 18 and 6 months, respectively. Only two variables were found to adversely affect OS for DLBCL; the IPI score (p<0.034) and the CD4 count <200 (p < 0.027). No such factors were identified for BL. Survival for HL also equaled historical controls where 72% of the patients were alive at 24 months. As in DLBCL, the HL patients presented very late with aggressive disease. Fifty six percent of the HL patients had stage III/IV with 48% of these patients presented with an IPS score of 5 or 6. Primary effusion, follicular, T cell, plasmablastic lymphomas, multiple myeloma, multicentric castlemans, acute lymphoblastic and myeloid leukemias were all identified as 1–4% of the cases. The only form of myeloid leukemia identified was acute promyelocytic leukemia (n=2). CD4 counts for the various cancers showed specific trends, where 64% of PCNSL had CD4 #< 50, 54% DLBCL had CD4 # < 100, 55% of HL had CD4 # >150, and 58% of BL had CD4# > 200. In contrast to historical controls, the number of cases/year/individual and the average age/year of patients with DLBCL, BL, and PCNSL for the past 8 years have not changed. Thirty-six, 50, and 47% of the patients for DLBCL, BL, and PCNS lymphoma respectively, were diagnosed with AIDS at the time of diagnosis. Conclusions: In assessing the hematological cancers of the CHAMP cohort, we identified 149 patients encompassing 16 different malignancies. There were 83% minorities (58% AA, 25% Hsp) and 86% male, an overwhelming AA male condition, contrary to most studies. Compared to the AA population of Chicago of only 26%, a clear racial disparity exists. Of concern is that while the rates of NHL in HIV + patients have declined in almost every study; the rate of NHL in our cohort (inner city) has remained stable for the last 8 years. This could be secondary to our population that is HAART naïve or non compliant at presentation. For example, 36, 50, and 47% of the patients for DLBCL, BL, and PCNS lymphoma respectively, are diagnosed with AIDS at presentation. The OS data for HL, DLBCL, and PCNSL were equal to historical controls. We also showed that IPI score and a CD4 count below 200 were prognostic in determining OS in DLBCL. Late presentations were also seen in HL, where 48% of the patients with advanced stage had an IPS score of 5 or 6. Education and screening are needed to prevent late presentations of both HIV and lymphoma in the AA and Hsp communities. Disclosures: No relevant conflicts of interest to declare.
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Giordano, Giulio, Matteo Dell’Olio, Silvia Piano, Giuliana Farina, Antonio La Sala, Daniele Colaprete, Nicola Cascavilla, and Sergio Storti. "R-CHOP Modified with Pegilated Lyposomal Adriamycin in Elderly Diffuse Large B-Cell Non Hodgkin’s Lymphoma (DLBC-NHL) Therapy: An Attempt To Reduce Toxicity in Patients with Comorbidity." Blood 110, no. 11 (November 16, 2007): 4469. http://dx.doi.org/10.1182/blood.v110.11.4469.4469.
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Abstract The Combination of Rituximab and CHOP (R-CHOP) is the golden standard in young and elderly NHL therapy, safe and effective. We included pegylated lyposomial Adriamycin (Caelyx®) instead of conventional Adriamycin in R-CHOP regimen in order to reduce myocardic and organ toxicity and to enhance doxorubicin uptake in tumour mass in advanced stage DLBC-NHL of elderly patients with comorbidity. This study is a retrospective study including patients of two haematology centers. We analyzed 34 DLBCNHL patient treated with R-CCOP (Rituximab 375mg/sqm day 0, Caelyx® 30 mg/sqm day 1, cyclophosphamide 750 mg/sqm day 1, Vincristine 1 mg/sqm day 1, Prednisone 100 mg/day, days 1–5, recycle every 21 days). The median number of administered cycles was 6 (Range 4–11). G-CSF was administered according to international guidelines Their median age was 74.5 years old (Range 65–87), M/F:20/14, 19/34 (55%) patients presented stage III– IV disease. 8 (23%) had B symptoms and 11 (32%) extranodal disease.12/34 (35%) patients had IPI high-intermediate and 11/34 (32%) high. 17/34 (50%) showed comorbidity (hepatitis C, NIDDM, severe hypertension, aortic valve disease, atrial fibrillation, chronic renal failure). Median follow-up was 26 months (Range 9–36). Overall (OS) and progression-free survival (PFS) at 36 months were calculated using Kaplan-Mayer method. After R-CCOP therapy we obtained the complete remission in 24/34 (70%) of patients, a very good partial remission in 2/34 (5%). The disease progressed in 3/34 (8%). Five out of 34 (14%) dead (3 of these for disease progression). No severe treatment-related toxicities were observed, except G3-G4 WHO neutropenia in 17 patients (50%) and cardiotoxicity in 2 patients (6%) with pre-existing cardiopathy (bradycardia and atrial fibrillation with high heart rate respectively). Myocardial function was evaluated by 2D echocardiogram before and after chemotherapy treatment and was not impaired by pegylated lyposomial Adriamycin administration. 3% of patients presented severe mucositis and 9% non-fatal infections. We did not observe any thrombocytopenia, In our study OS and EFS at 36 months were respectively 83.7% (95%CI 70.4–97%) and 56% (95%CI 27–85%).Non-responding patients had extranodal, stage IV disease with B symptoms. Nevertheless, they maintained chemosensitivity to a second-line therapy. In elderly B-NHL patients with advanced stage of disease and comorbidity, R-CCOP seems to be safe, feasible and effective. These results confirm and improve in a larger cohort of patients those reported by Zaja, Tulpule and Coiffier in their previous series (see table). Zaja et al Tulpule et al Giordano et al Coiffier et al Treatment R-COP-Caelyx x6 R-COP-Caelyx x8 R-COP-Caelyx x4-11 R-CHOP x8 * in 2 pts with preexisting cardiopathy Patients 29 19 34 202 Caelyx mg/sqm 30 40 30 \ Doxorubicin mg/sqm \ \ \ 50 Age (median) 69 51 74.5 69 IPI (L/IL) 38% 47% 32% 46% IPI IH/H 62% 53% 68% 54% OR 76% 100% 76% 82% CR 59% 80% 71% 76% 2y EFS 65.5% NA (56% 3y) 60% TRM 0 0 0 12/202 (6%) Grade III/IV toxicity Neutropenia 86% 68% 50% 91% Thrombocytopenia 3% 5% 0% NA Mucositis 3% 0% 3% 3% Infection 3% 0% 9% 12% Cardiotocicity 0% 0% 6%* 8%
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Orme, Jacob, Jose Villasboas, and Haidong Dong. "Tumor ADAM10/ADAM17-Mediated PD-L1 Loss May Predict Poor Outcomes in Diffuse Large B Cell Lymphoma." Blood 134, Supplement_1 (November 13, 2019): 4120. http://dx.doi.org/10.1182/blood-2019-124189.
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Introduction Tumor surface matrix metalloproteases ADAM10 and ADAM17 are associated with poor outcomes in multiple malignancies. We previously showed that these proteases shed PD-L1 from lymphoma cell line Karpas-299 to produce soluble PD-L1 (sPD-L1) that induces CD8+ T cell apoptosis (1). While higher levels of soluble PD-L1 are associated with worse prognosis in patients with non-Hodgkin lymphoma treated with standard chemoimmunotherapy (cutoff of 1.52 ng/ml, 3-year OS of 76% versus 89%) (2), it is unknown whether the loss of PD-L1 on the surface of B cell lymphoma cells affects clinical outcomes. We hypothesized that tumors expressing low PD-L1 levels despite high PD-L1 mRNA levels would (1) produce higher ADAM10 or ADAM17 transcript levels and (2) predict poorer prognosis in diffuse large B cell lymphomas. Methods We queried the cancer genome atlas (TCGA) public database for cases of diffuse large B cell lymphoma (DLBCL) for which PD-L1 (CD274) protein levels are reported by reverse phase protein array (RPPA). We then queried TCGA for RNA-Seq data for CD274, ADAM10, and ADAM17 expressed as transcripts per million (FPKM). We re-normalized RPPA data and calculated a PD-L1 protein-to-mRNA ratio for each tumor sample. We then compared groups of high and low PD-L1 protein-to-mRNA ratios for ADAM10 and ADAM17 mRNA expression. We further compared groups of high and low PD-L1 protein-to-mRNA ratios for survival (adjusted for age at diagnosis). All statistical analyses were performed using R Statistical Software (R Foundation). Unpaired student's t-test assessed statistical differences in experimental groups except where otherwise indicated. Figures comprise box plots showing quartile values and individual data points. P<0.05 was considered statistically significant. In figures, p values are denoted <0.05 with *, <0.01 with **, and <0.001 with ***. Results Data were available for a total of 33 diffuse large B cell (DLBC) lymphomas. 18 of those samples were categorized as having low PD-L1 protein-to-mRNA ratios (cutoff 6.38e-6) with the remaining categorized as high ratio. DLBCL tumors demonstrating low PD-L1 protein-to-mRNA ratios expressed significantly higher ADAM10 (p=0.0237) and ADAM17 (p<0.0001) transcripts than tumors expressing low PD-L1 protein-to-mRNA ratios (Figure 1). Furthermore, patients with tumors demonstrating low PD-L1 protein-to-mRNA ratios experienced significantly poorer survival according to likelihood ratio (6.6, p=0.01) and log rank (4.67, p=0.03) tests (Figure 2). Conclusions Our findings may explain a crucial phenomenon seen in diffuse large B cell lymphoma, namely that many purportedly PD-L1-positive tumors appear to express PD-L1 but do not respond to PD-(L)1 inhibitor therapy (3,4). This may be caused by the activity of ADAM10 and ADAM17 to cleave PD-L1, which we previously showed in lymphoma cell line Karpas-299 (1). This posits pre-treatment ADAM10/ADAM17 inhibition to "boost" PD-(L)1 inhibitor therapy in lymphoma. Our results contrast with previous findings that PD-L1-positive DLBCL progression free survival is inferior to PD-L1-negative DLBCL (5). This may be due to different methods of protein detection (immunohistochemistry versus RPPA) and the lack of localization of PD-L1 expression in tumor cells versus the microenvironment. Notably, this study is only correlative with a limited case number. Larger prospective studies will be needed to further elucidate this relationship. Acknowledgments The results shown here are in whole or part based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga. References 1. Orme et al. AACR Adv Malig Lymphoma 2018. Pres 423 2. Rossille et al. Leukemia 2014. 28:2367-75. 3. Moskowitz et al. Blood 2014 124:290. 4. Armand et al. J Clin Oncol 2013. 31:4199-206. 5. Kiyasu et al. 2015.126:2193-201. Figure Disclosures No relevant conflicts of interest to declare.
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Hamarshi, Majdi SM, Maha abu Kishk, Mahmoud Mahafzah, and Jami Walloch. "Concurrent Chromosomal Alterations at 3q27, 8q24 and 18q21 in An Atypical Form of Burkitt’s Lymphoma." Blood 112, no. 11 (November 16, 2008): 5268. http://dx.doi.org/10.1182/blood.v112.11.5268.5268.
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Abstract Introduction: Chromosomal translocations are common in non-Hodgkin’s lymphomas (NHL), most frequently involving the genes bcl-2 in the t(14;18) of follicular lymphoma (FL), c-myc in the t(8;14) of Burkitt’s lymphoma (BL) and bcl-6 in the t(3;14) of follicular or diffuse large B-cell (DLBC) lymphoma. We report the clinical features, pathology and genetic findings in an exceedingly rare case of Burkitt’s lymphoma that showed concurrent involvement of these three chromosomal loci. Case Report: This is a 65 year old Caucasian female who presented with a rapidly growing right supraclavicular lymph node over a few weeks. FNA biopsy showed typical morphology of Burkitt’s lymphoma. Similar morphologic features were found on the bone marrow biopsy. There was widespread disease with no CNS involvement. Flow cytometry from peripheral blood and immunohistochemistry on the cellblock showed B-cell phenotype positive for CD 10, CD19, CD20 (negative CD20 by immunohistochemistry), HLA-DR, cytoplasmic CD79a, and negative for CD34 and TdT. The interesting finding was the lack expression of surface or cytoplasmic immunoglobulin and expression of weak Bcl-6. Almost 90–95% expressed Ki67. The cytogenetic analysis reportedly demonstrated a complex karyotype t(3;8;14), and t(14;18) involving c-myc (8q24), bcl-2 (18q21), and bcl-6 (3q27). After 7 cycles of hyper CVAD-R she had bone marrow biopsy which showed residual disease. She also had a biopsy confirmed relapse as left arm nodule and left leg nodular infiltrate at 8 and 12 months form the diagnosis, respectively. Discussion: This is a complex case of high grade B-cell lymphoma with morphology suggestive of Burkitt’s lymphoma. However the classification was challenging by the lack of surface immunoglobulin expression that might be expected in mature B-cell neoplasm “DLBCL, FL”, and the lack of TdT and CD34 that might be expected in precursor B-cell neoplasm “BL”. The diagnosis was highly dependent on the cytogenetic findings, which was significant for the presence of t(8;14) albeit in a three way translocation t(3;8;14), and t(14;18) involving c-myc (8q24), bcl-2 (18q21), and bcl-6 (3q27). The lymphoma was therefore described as “Burkitt’s transformation”. This is a rare translocation pattern, but has been described in follicular lymphoma, grade 3; diffuse large cell lymphoma; and Burkitt’s lymphoma. Conclusion: BL might lack surface immunoglobulin expression making the diagnosis of high grade B-cell lymphoma challenging if based on the morphology and immunophenotyping alone. The cytogentetic findings better delineate sub-types of lymphoma. Molecular evidence of multiple oncogene deregulations, especially when involving the c-myc gene, appears to be associated with a dire clinical outcome.
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Castelli, Roberto, Riccardo Schiavon, Carlo Preti, and Laurenzia Ferraris. "HIV-Related Lymphoproliferative Diseases in the Era of Combination Antiretroviral Therapy." Cardiovascular & Hematological Disorders-Drug Targets 20, no. 3 (November 26, 2020): 175–80. http://dx.doi.org/10.2174/1871529x20666200415121009.
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HIV-positive patients have a 60- to 200-fold increased incidence of Non-Hodgkin Lymphomas (NHL) because of their impaired cellular immunity. Some NHL are considered Acquired Immunodeficiency Syndrome (AIDS) defining conditions. Diffuse large B-cell Lymphoma (DLBC) and Burkitt Lymphoma (BL) are the most commonly observed, whereas Primary Effusion Lymphoma (PEL), Central Nervous System Lymphomas (PCNSL), Plasmablastic Lymphoma (PBL) and classic Hodgkin Lymphoma (HL) are far less frequent. Multicentric Castleman disease (MCD) is an aggressive lymphoproliferative disorder highly prevalent in HIV-positive patients and strongly associated with HHV-8 virus infection. In the pre-Combination Antiretroviral Therapy (CART) era, patients with HIV-associated lymphoma had poor outcomes with median survival of 5 to 6 months. By improving the immunological status, CART extended the therapeutic options for HIV positive patients with lymphomas, allowing them to tolerate standard chemotherapies regimen with similar outcomes to those of the general population. The combination of CART and chemotherapy/ immuno-chemotherapy treatment has resulted in a remarkable prolongation of survival among HIVinfected patients with lymphomas. In this short communication, we briefly review the problems linked with the treatment of lymphoproliferative diseases in HIV patients. Combination Antiretroviral Therapy (CART) not only reduces HIV replication and restores the immunological status improving immune function of the HIV-related lymphomas patients but allows patients to deal with standard doses of chemotherapies. The association of CART and chemotherapy allowed to obtain better results in terms of overall survival and complete responses. In the setting of HIVassociated lymphomas, many issues remain open and their treatment is complicated by the patient’s immunocompromised status and the need to treat HIV concurrently.
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Fan, Alice C., Debabrita Deb-Basu, Melissa Horoschak, Amy Shirer, David Voehringer, Roger O’Neill, and Dean W. Felsher. "Nano-Fluidic Detection of Oncoprotein Signaling in Preclinical and Patient Lymphoma Samples." Blood 108, no. 11 (November 16, 2006): 2527. http://dx.doi.org/10.1182/blood.v108.11.2527.2527.
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Abstract Inactivation of oncogenes can be an effective cancer therapy. Determining precise levels of oncogene expression is important in the development of drugs to target oncogenes. We have developed a novel automated nano-fluidic Western-blot-like technology to detect and quantify oncogene expression in small numbers of mouse and human hematopoietic tumor cells. To detect different levels of oncogene expression, we generated transgenic mice in which the MYC or BCL2 oncogenes are regulated conditionally via the Tetracycline Regulatory System (Tet-system). Using lymphoma- derived cell lines from these mice, we titrated the level of oncogene expression by adding different concentrations of doxycycline in vitro. We were able to distinguish among different levels of oncogene expression in cell lysates, with high sensitivity in as few as 400 cells by nano-fluidic detection. Next, lymphoma derived cell lines were injected subcutaneously into syngeneic mice. Upon tumor development, MYC or BCL2 oncogenes were inactivated in vivo. Both MYC and BCL2 levels decreased in serial fine needle aspirations (FNAs) of tumor nodules upon parallel analysis with nano-fluidic detection and Western blot. Finally, we used nano-fluidic detection to determine levels of MYC, BCL2, AKT and ERK in lymph node samples from patients with follicular, transformed DLBC, Burkitt’s, and mantle cell lymphomas. BCL2 was overexpressed in mantle cell and follicular lymphoma patients, confirmed by Western analysis, whereas MYC was found to be overexpressed in Burkitt’s lymphoma. These results demonstrate that nano-fluidic detection technology may be used both as a preclinical tool for the assessment of changes in oncoprotein signaling and as a clinical diagnostic modality on microscopic clinical specimens.
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Kamiyama, Kyohei, Motomasa Komuro, Tetsuro Endo, and Kazuyuki Aihara. "Classification of Bifurcations of Quasi-Periodic Solutions Using Lyapunov Bundles." International Journal of Bifurcation and Chaos 24, no. 12 (December 2014): 1430034. http://dx.doi.org/10.1142/s0218127414300341.
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In continuous-time dynamical systems, a periodic orbit becomes a fixed point on a certain Poincaré section. The eigenvalues of the Jacobian matrix at this fixed point determine the local stability of the periodic orbit. Analogously, a quasi-periodic orbit (2-torus) becomes an invariant closed curve (ICC) on a Poincaré section. From the Lyapunov exponents of an ICC, we can determine the time average of the exponential divergence rate of the orbit, which corresponds to the eigenvalues of a fixed point. We denote the Lyapunov exponent with the smallest nonzero absolute value as the Dominant Lyapunov Exponent (DLE). A local bifurcation manifests as a crossing or touch of the DLE locus with zero. However, the type of bifurcation cannot be determined from the DLE. To overcome this problem, we define the Dominant Lyapunov Bundle (DLB), which corresponds to the dominant eigenvectors of a fixed point. We prove that the DLB of a 1-torus in a map can be classified into four types: A+(annulus and orientation preserving), A-(annulus and orientation reversing), M (Möbius band), and F (focus). The DLB of a 2-torus in a flow can be classified into three types: A+× A+, A-× M (equivalently M × A-and M × M), and F × F. From the results, we conjecture the possible local bifurcations in both cases. For the 1-torus in a map, we conjecture that type A+and A-DLBs correspond to a saddle-node and period-doubling bifurcations, respectively, whereas a type M DLB denotes a double-covering bifurcation, and type F relates to a Neimark–Sacker bifurcation. Similarly, for the 2-torus in a flow, we conjecture that type A+× A+DLBs correspond to saddle-node bifurcations, type A-× M DLBs to double-covering bifurcations, and type F × F DLBs to the Neimark–Sacker bifurcations. After introducing the mathematical concepts, we provide a DLB-calculating algorithm and illustrate all of the above bifurcations by examples.
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Alexnder, Jacob M., Judith M. Joyce, Barry M. McCook, Norbert Avril, Stephanie R. Land, Mirsada Begovic, and Samuel A. Jacobs. "Correlation between Tumor Uptake on Indium-111 Ibritumomab Tiuxetan Imaging and Size on CT to Disease Response on FDG PET/CT Scans Obtained Pre- and Post-Yttrium-90 Ibritumomab Tiuxetan Therapy for Non-Hodgkin Lymphoma." Blood 106, no. 11 (November 16, 2005): 4781. http://dx.doi.org/10.1182/blood.v106.11.4781.4781.
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Abstract Background: Yttrium-90 ibritumomab tiuxetan (Zevalin, YZ), the first radioimmunotherapeutic agent approved for the treatment of relapsed or refractory B-cell non-Hodgkin Lymphoma (NHL), had an overall response rate of 80% vs 56% with rituximab alone based on CT assessment (IWRC criteria) without FDG PET correlation. Prior to the therapeutic administration of YZ, normal biodistribution must be confirmed by visual evaluation of whole-body In-111 Zevalin (IZ) images. Tumor uptake on IZ images has been noted to be variable and is not required to proceed with therapy. However, bulky lymphadenopathy has been reported to possibly predict poor response to radioimmunotherapy. We report our evaluation of the relation of tumor uptake on IZ images and size on CT scans to tumor response based on pre- and post-YZ therapy using FDG PET/CT scans. Methods: This retrospective review includes only patients with relapsed or refractory B-cell NHL treated with YZ who had fusion PET/CT scans pre- and post-YZ therapy and fulfilled all other standard eligibility critera for YZ. PET/CT scans were performed within 4 months prior and 8 months following IZ imaging and YZ therapy. The largest tumor mass on the pre-therapy CT was measured and categorized into subgroups of < or ≥5 cm. The IZ scans were reviewed for the presence or absence of tumor uptake over background activity. Response by CT was based on the IWRC criteria (CR/CRu, PR, Stable, and PD). Response on FDG PET was based upon comparison of the intensity of uptake in relation to adjacent background (CR, PR, Mixed and PD). Response rate comparisons by patient groups were performed with Fisher exact tests. Results: 24 patients (16M, 8F, 37–83 y.o.) fulfilled the criteria. The histologic diagnoses included: 14 follicular, 5 diffuse large B-cell, 4 mantle cell, and 1 MALT. All patients had increased FDG uptake in measurable CT lesions on the pre-therapy PET/CT scans. 14 IZ scans were positive, 10 were negative. Seven of 9 patients (78%) with lesions ≥5 cm had positive IZ versus 7 of 15 (47%) with lesions < 5 cm. The following tables display the cross-tabulation of tumor uptake on IZ, CT size, and the response to YZ. The overall response (ORR) based on FDG PET was 13/24 (54%) with a CR of 7/24 (29%) and a PR of 6/24 (25%). Excluding the patients with large cell histology, the ORR was 13/19 (68%). ORR for size ≥5 cm was 3/9 (33%) and for size <5 cm was 10/15 (66%), a suggestive but non-significant difference (p=0.2). The frequency of overall response was significantly reduced for large cell histology versus other histologies (p=0.011). The results show that those patients with tumor uptake on IZ imaging had significantly reduced overall response based on pre- and post-FDG PET/CT findings compared with patients without tumor uptake (p=0.047). Conclusions: The presence of tumor uptake on IZ imaging, tumor size (≥5 cm) and histology (large cell) may all adversely affect response to YZ. The identification of IZ tumor uptake may be related to large tumor size rather than tumor susceptibility to therapy. Responses (CR/CRu and PR) by PET # In+ In− CT≥5cm CT<5cm FL 9 4 5 1 8 DLBC 0 0 0 0 0 MCL 3 1 2 1 2 MALT 1 0 1 1 0 Nonresponses (Mixed and PD) by PET # In+ In− CT≥5cm CT<5cm FL 5 5 0 2 3 DLBC 5 3 2 3 2 MCL 1 1 0 1 0 MALT 0 0 0 0 0
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Schot, Bart W., Josée Zijlstra, Otto S. Hoekstra, Jan Pruim, Gustaaf W. van Imhoff, Wim Sluiter, John M. M. Raemaekers, et al. "Blinded Mid-Treatment FDG-PET in Newly Diagnosed Aggressive Non-Hodgkin Lymphoma (NHL): First Results of a Prospective Multicenter Study." Blood 108, no. 11 (November 1, 2006): 2400. http://dx.doi.org/10.1182/blood.v108.11.2400.2400.
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Abstract In aggressive B-cell NHL, determination of early response to induction therapy by FDG-PET may improve risk stratification. In a multicenter prospective trial in patients with aggressive NHL (stage II–IV) treated with 2 or 3 weekly (R)CHOP chemotherapy, FDG-PET was performed after the third cycle of chemotherapy. Both clinicians and nuclear medicine physicians were blinded for PET and clinical outcome, respectively. Clinical decisions were based on conventional diagnostic methods (CDM) only. In total 114 patients were included of which 95 were evaluable. 19 patients were excluded because of patient refusal (n=7), early progression (n=7) or logistical reasons (n=5). Median age was 55 yrs (range 20–82), 72% had DLBC-NHL, 76% IPI<3. The majority (85%) of patients completed chemotherapy according to protocol. 14(15%) went off protocol because of less than PR after 3 cycles of (R)CHOP or progression on treatment based on CDM or excess toxicity. CR(u) was reached in 60% of the patients. 34 (36%) patients relapsed and 2 patients died of NHL after a median follow-up of 26 months. PET was scored qualitatively using a Likert scale. PET after 3 courses was negative in 45 patients and positive in 50. 24/50 (48%) PET positive patients progressed or relapsed as compared to 10/45 (22%) PET negative patients. Median progression free survival (PFS) for PET positive versus PET negative patients was 19.8 months versus not yet reached (p=.0087). In a multivariate analysis, IPI and PET were independent predictors for PFS. These results corroborate and extend the evidence that mid-treatment FDG-PET is highly predictive for PFS and may be a useful tool for risk-adapted management of aggressive NHL.
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Albitar, Maher, Xu‐Monette Y. Zijun, Yingjun Wang, Deng Manman, Alexandar Tzankov, Carlo Visco, Govind Bhagat, et al. "MYC and BCL2 mRNA Expression As Determined By NGS Predicts Survival in DLBCL in GCB but Not in ABC Subgroup." Blood 134, Supplement_1 (November 13, 2019): 5092. http://dx.doi.org/10.1182/blood-2019-128492.
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Introduction: RNA expression profiling using Next Generation Sequencing (NGS) provides important and reproducible information on expression levels of various genes. We studied the expression levels of MYC and BCL2 in patients with diffuse large B-Cell lymphoma (DLBCL) using NGS targeted RNA sequencing. We correlated levels of expression of these genes with outcome. Methods: RNA extracted from 441 FFPE samples with DLBC lymphoma and sequenced targeting 1408 genes. The RNA sequencing is based on hybrid capture and the number of reads ranged from 5 to 10 million. RNA quantification was performed using Cufflinks. The RNA levels were normalized to PAX5 mRNA levels. Of these cases, 380 were subclassified as ABC or GCB using expression profiling. The rest were classified as "undetermined", therefore were not included in further analysis. All patients were treated with R-CHOP. Results: The expression of MYC and BCL2 mRNA was slightly higher in ABC as compared with GCB (P=0.01 and P=0.02, respectively). However, in the GCB subtype, patients with MYC expression above the median showed significantly shorter survival as compared with those below the median (P=0.0007, Log-rank test). In contrast, there was no significant difference in survival using median of MYC expression as cutoff in patients classified as ABC subtype (P=0.38). Using upper 15% cut-off point for BCL2 mRNA expression, GCB patients with high BCL2 expression had significantly shorter survival (P=0.005). In contrast, there was no significant difference in survival between high and low BCL2 expression groups in the ABC subtype (P=0.1). When both MYC and BCL2 are considered, patients with high expression of both BCL2 and MYC (double-RNA expression) had significantly shorter survival as compared with patients with low expression of both MYC and BCL2 (P=0.0009) when both GCB and ABC groups are considered. Patients with high BCL2 expression also had poor survival similar to those double-RNA expression. Considering only patients with GCB, high expressor of both MYC and BCL2 had significantly worse outcome (P=0.0015) as compared with low expressors of both MYC and BCL2, but patients with high BCL2 also had significantly poor outcome as compared to low expressor of both MYC and BCL2 (P=0.0005). In contrast, there was no difference in survival for high or low MYC and BCL2 expressor in the ABC group. Conclusion: The data support the concept that in DLBCL, MYC and BCL2 mRNA expression levels are clinically relevant in GCB, but not ABC subtype. Furthermore, targeted RNA sequencing might provide a reliable and practical objective approach for the subclassification of DLBCL and determining double-RNA expression lymphoma. Figure Disclosures Albitar: Genomic Testing Cooperative: Employment, Equity Ownership. Tam:Takeda: Consultancy; Paragon Genomics: Consultancy. Hsi:Abbvie: Research Funding; Eli Lilly: Research Funding; Cleveland Clinic&Abbvie Biotherapeutics Inc: Patents & Royalties: US8,603,477 B2; Jazz: Consultancy. Piris:Calgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jansen: Membership on an entity's Board of Directors or advisory committees, Other: Lecture Fees; Nanostring: Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees; Kura: Research Funding; Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Lecture Fees, Research Funding. Kantarjian:Immunogen: Research Funding; BMS: Research Funding; Cyclacel: Research Funding; Pfizer: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Ariad: Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria; AbbVie: Honoraria, Research Funding; Astex: Research Funding; Jazz Pharma: Research Funding; Novartis: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Research Funding.