bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genomic Imbalances Are Associated with Outcome of Helicobacter pylori Eradication in t(11;18)(q21;q21)-Negative Gastric MALT Lymphomas.
Authors: Fukuhara Noriko , Tagawa Hiroyuki , Nakamura Tsuneya , Inagaki Hiroshi , Morishima Yasuo , Nakamura Shigeo , Seto Masao 
Published: October 2019

Abstract
Background: Approximately 70% of low grade gastric mucosa-associated lymphoid tissue (MALT) lymphoma cases are successfully treated by H. pylori eradication. The MALT lymphoma resistant to this therapy needs an additional therapy. A part of the tumors transform to an aggressive lymphoma including diffuse large B-cell lymphoma (DLBCL). The t(11;18)(q21;q21) characteristic to MALT lymphoma is recognized as a marker for H. pylori independency, but this marker is found in only a half of the MALT lymphomas resistant to H. pylori eradication. Therefore the detailed genomic features of eradication resistant group as well as dependent group are needed to understand molecular basis.
Patients and Methods: We performed array-based comparative genomic hybridization for 30 gastric MALT lymphomas treated with H. pylori eradication. These included 10 cases of t(11;18)(q21;q21)-positive MALT group, 10 cases of t(11;18)(q21;q21)-negative MALT with H. pylori dependent group and 10 cases of t(11;18)(q21;q21)-negative MALT with H. pylori independent group. The presence of t(11;18)(q21;q21) was identified by a multiplex reverse transcriptase polymerase chain reaction of the API2-MALT1 chimeric transcript.
Results: Almost no significant genetic alterations were found in t(11;18)(q21;q21)-positive MALT lymphoma, whereas numerous genomic alterations were found in those without t(11;18)(q21;q21). These aberrations were mostly similar to those found in DLBCL (Tagawa et al., Blood 106:5, 2005). Trisomy 3 is most recurrent and 7q loss specific to SMZL is also recurrent. Within the t(11;18)(q21;q21)-negative MALT lymphoma group, presence of genomic imbalances is more frequent in H. pylori independent group (one of ten (10%) vs seven of ten (70%); p =0.019, two-sided fisher’s exact test). Neither locally advanced disease nor including large cell component is correlated with H. pylori independency, respectively.
Conclusions: Genomic imbalances are associated with H. pylori independency in t(11;18)(q21;q21)-negative gastric MALT lymphomas. Thus, the genomic imbalances may have a role in the acquisition of H. pylori-independent growth.
NOTCH2 Mutations in Marginal Zone Lymphoma.
Authors: Troen Gunhild , Wlodarska Iwona , Warsame Abdirashid , Llodrà Silvia H. , De Wolf-Peeters Christiane , Delabie Jan 
Published: October 2019

Abstract
Notch2 is a membrane receptor and transcription factor that is indispensable for marginal zone cell differentiation. Also, marginal zone cell lymphomas express increased levels of Notch2 when compared with other B-cell lymphomas. Of interest, activating mutations have previously been described for Notch1, a homologous transcription factor which is important for T-cell differentiation, in up to 50% of cases of acute T-lymphoblastic leukemia, and are thought to contribute to leukemogenesis. We therefore investigated whether activating mutations in the NOTCH2 gene could be identified, especially in marginal zone lymphoma (MZL). We analyzed 41 cases of MZL and 28 other B-cell lymphomas cases for the presence of potentially activating mutations in exons 26, 27 and 34 of the NOTCH2 gene. These exons code for the heterodimerization and the C-terminal transcriptional activation domains. We identified four cases with mutations among the MZL cases, but none in the other B-cell lymphoma cases. Mutations were found in two cases of splenic marginal zone lymphoma and two cases of extranodal marginal zone lymphoma of MALT type, respectively. To investigate whether elevated Notch2 expression in most of the other marginal zone lymphomas, as investigated by quantitative RT-PCR, was due to structural changes within the NOTCH2 locus, FISH analysis was performed. FISH analysis did not reveal structural changes of the NOTCH2 locus in any of the MZL cases. In conclusion, we have shown potentially oncogenic NOTCH2 mutations in 10% of MZL. It remains to be shown whether elevated Notch2 expression in most MZL can be caused by as yet other disease mechanisms.
An In Vivo Model To Investigate the Nature of the Cell-of-Origin of Multiple Myeloma.
Authors: Asimakopoulos Fotios , Varmus Harold 
Published: October 2019

Abstract
Multiple myeloma (MM) and related plasma cell dyscrasias are characterized by monoclonal expansion of terminally differentiated plasma cells. However, it is puzzling how the quiescent plasma cell can be the source of often aggressive and relapsing neoplasms. We and others have postulated that the myeloma clonogenic progenitor may reside in a more immature compartment with greater self-renewal capacity, most probably a maturing plasmablast precursor in the germinal center. To investigate the nature of cell-of-origin for these diseases and the genetic requirements for pathogenesis, we have created a novel flexible mouse model system that enables the delivery of stochastic, sequential, somatic mutations to precisely defined compartments of the germinal center in secondary lymphoid tissues. To this end, we have used BAC transgenic technology to express distinct types of avian leukosis virus (ALV) receptors, TVA and TVB, in the expanding centroblast of the dark zone and the committed plasmablast of the light zone, respectively. Mammalian tissues are refractory to transduction by retroviruses of the ALV family unless they ectopically express the cognate avian-derived receptors. Thus, the coding sequences for the TVA receptor, fused to a fluorescent protein tag were placed under the control of transcription factor A-myb, expressed in centroblasts of the dark zone. Similarly, sequences encoding a fluorescent-tagged TVB receptor were placed under the control of transcription factor Blimp1, expressed in the earliest committed plasmablasts as well as mature plasma cells. Analysis of the Blimp1: TVB mice showed that expression of the avian retroviral receptor in the hematopoietic system is limited to the light zone of germinal centers, extrafollicular collections of CD138+ cells in the spleen and lymph nodes as well as long-lived bone marrow plasma cells. Analysis of A-myb: TVA transgenic mice demonstrated expression of the fusion receptor to be restricted to B cells in the immunized spleen but not T cells. Both transgenic systems have been crossed into an Ink4a/Arf-deficient background. We have been transducing plasma cell precursors generated in the course of immune responses to T-dependent antigens with retroviral vectors carrying genes important in myelomagenesis, such as cyclin D1 or c-Myc. Animals are being monitored for development of plasma cell dyscrasias by periodical serum protein electrophoresis (SPEP) and other assays.
Clinicopathological Features of Pyothorax-Associated Lymphoma; a Retrospective Survey Involving 98 Patients.
Authors: Narimatsu Hiroto , Ota Yasunori , Kami Masahiro , Takeuchi Kengo , Suzuki Ritsuro , Matsuo Keitaro , Kishi Yukiko , Hamaki Tamae , Tanaka Yuji , Nakamura Shigeo 
Published: October 2019

Abstract
Pyothorax-associated lymphoma (PAL) is a lymphoproliferative disorder developing in the pleural cavity after a long-standing history of pyothorax. The pathogenesis, clinical features and optimal treatment have not been clarified. To investigate clinicopathological features of pyothorax-associated lymphoma (PAL), we examined medical records of 98 patients (88 males and 10 females) with PAL at a median age of 70 (range, 51–86). Seventy-nine patients had a history of artificial pneumothorax. Median interval between diagnosis and artificial pneumothorax was 43 years (range, 19–64). At diagnosis, performance status was 0–1 (n=56) and 2–4 (n=42). Clinical stages were I (n=42), II (n=26), III (n=8) and IV (n=22). In situ hybridization using a probe for EBV-encoded RNA-1 demonstrated the presence of the EBV genome in the nucleus of tumor cells in 28 of 29 (88%) patients. Immunohistochemical studies revealed that 12 of 14 (86%) and 11 of 17 (65%) were positive for EBNA-2 and LMP-1, respectively. Seventeen were treated supportively. The other 81 received aggressive treatments; chemotherapy (n=52), radiotherapy (n=7), surgery (n=4) and combination (n=18). Response rates to chemotherapy, radiotherapy, and chemoradiotherapy were 56%, 71%, and 83%, respectively. Five-year overall survival was 0.35 (95% confidence interval, 24–45%). The 5-year overall survival rates were 0.47 (95% CI, 0.30– 0.63), 0.35 (95% CI, 0.16– 0.54) and 0.15 (95% CI, 0.04–0.33) in patients with stages I, II and I-IV disease, respectively (Figure 1). Overall survival are different among the three groups (p <0.0001). Causes of deaths were PAL (n=39), respiratory failure (n=13), and others (n=12). Multivariate analysis identified prognostic factors for overall survival; lactate dehydrogenase levels (hazard ratio (HR)=2.36, p=0.013), sex (female vs. male) (HR=0.15, p=0.01), performance status (2–4 vs. 0–1) (HR=2.20, p=0.02), clinical stages (III/IV vs. I/II) (HR=1.95, p=0.037) and chemotherapy (HR=0.31, p=0.01). Most patients with PAL are elderly, and have comorbidities, while some of them achieve durable remission with appropriate treatments. These findings prompt us to establish an optimal treatment strategy based on risk stratification of individual patients.
Figure Figure
High Dose Cytarabine Salvage Regimen Combined with Bortezomib Is Feasible and Highly Effective in Relapsed Mantle Cell Lymphoma.
Authors: Weigert Oliver , Weidmann Eckhart , Mueck Rudolf , Bentz Martin , von Schilling Christoph , Rohrberg Robert , Jentsch-Ullrich Kathleen , Unterhalt Michael , Hiddemann Wolfgang , Dreyling Martin H. 
Published: October 2019

Abstract
Introduction: Mantle cell lymphoma (MCL) is a subtype of malignant lymphoma with an especially poor prognosis. However, molecular targeted therapy may alter the natural history of disease. Bortezomib (BZ) is a potent, selective and reversible inhibitor of the 26S proteasome thereby interfering with intracellular protein homeostasis. Various clinical phase II trials revealed significant efficacy of BZ monotherapy in relapsed MCL with approximately 40% response rate, but rare CR and short duration of response. Based on our preclinical data demonstrating synergy of BZ and cytarabine (Ara-C) we performed a pilot study to explore the clinical impact of such combined approach.
Treatment: 2 g/m2 Ara-C was applied on day 2 and 3 (1 g/m2 in patients with impaired hematopoiesis or age >60 years) combined with BZ 1.5 mg/m2 iv bolus (day 1 and 4). In addition, dexamethasone 40 mg was given over a 4 day period. R was added to the outlined regimen in 6 patients (375 mg/m2). Treatment was repeated in 3 week intervals for a total of 4 cycles with staging procedures performed after 2 and 4 cycles.
Results: After informed consent 8 patients with relapsed or refractory advanced stage MCL were treated accordingly to the outlined protocol. Median age was 65 years (54–76), 5 patients were male. Median number of prior systemic therapies was 4 (2–7). All patients had previously been treated with CHOP and at least one rituximab (R)-containing regimen, 2 patients previously failed BZ monotherapy, and none of them was considered eligible for myeloablative treatment. Currently data from 7 patients are available for analysis of toxicity and response. At time of analysis, a total of 22 cycles has been applied with a median follow-up of 214 days (119–366). As expected, hematologic toxicity CTC grade III/IV occurred in all 7 patients, but only one case of neutropenic fever (grade 3) and no major bleeding were observed. Ara-C dose was reduced in 5 patients. Two patients developed new onset or worsening of preexisting polyneuropathy. Dose of BZ had to be reduced in 1 patient and stopped after cycle 2 in another patient with preexisting polyneuropathy. Of note, 2 patients developed herpes zoster (grade 2). In 3 patients treatment was stopped after cycle 2 due to insufficient response (progressive disease, stable disease and minimal response, respectively). In the 4 patients completing 4 cycles 1 CR and 3 PR were archieved.
Conclusion: Salvage therapy with high-dose Ara-C combined with BZ in relapsed or refractory MCL was associated with considerable but manageable hematotoxicity and only few infectious complications. The high efficacy in heavily pretreated patients justifies a comparative trial of the European MCL Network evaluating a high-dose cytarabine containing regimen +/− BZ.
Oral Forodesine (Bcx-1777) Is Clinically Active in Refractory Cutaneous T-Cell Lymphoma: Results of a Phase I/II Study.
Authors: Duvic Madeleine , Forero-Torres Andres , Foss Francine , Olsen Elsie A. , Kim Youn 
Published: October 2019

Abstract
Background: Forodesine is a potent, rationally designed purine nucleoside phosphorylase (PNP) inhibitor that is orally bioavailable. IV forodesine has shown clinical activity in patients with cutaneous T-cell lymphoma (CTCL). The objective of this phase I/II study was to evaluate the safety, PK profile, and efficacy of oral forodesine in patients with refractory CTCL.
Methods: An open-label dose-escalation study of fordesine, 40 to 320 mg/m2 qd for 4 weeks, was undertaken to evaluate the safety and PK profile of oral forodesine, followed by an investigation of the expansion of the optimal biologic dose (dose with maximum PNP inhibition and elevation of plasma deoxyguanosine levels) to assess efficacy. Previously treated, refractory CTCL patients with stage IB or greater disease were eligible for participation. The primary end point was objective response (OR) = complete response [CR] plus partial response [PR], as measured by the severity-weighted assessment tool (SWAT; see Figure) and physicians’ global assessment (PGA)
Results: Overall, 37 patients were treated, including 14 patients in the dose-escalation portion of the study. No dose-limiting toxicities were observed with target doses of ≤320 mg/m2; thus, a maximum tolerated dose was never defined. Based on PK/PD results, an 80 mg/m2 qd dose was identified as the optimal biologic dose, and this ongoing study was expanded to enroll a total of 28 patients (median age, 64 yr; range, 28–81 yr). The OR rate was 53.6% (15/28 patients; 2 [7.1%] with a CR and 13 [46.4%] with a PR). The proportion of patients with stage IIB or greater disease was 19/28 (67.9%). Response in this population was seen in 10 (52.6%) of the 19 patients (1 [5.3%] with a CR and 9 [47.4%] with a PR). The percent change in SWAT score from baseline as a function of time demonstrated a progressive decrease over a 24-week period. To-date, 12 (42.9%) of 28 patients have completed ≥4 months of treatment. Safety data were recorded for all 37 patients treated with forodesine. The most common adverse events classified as grade 2 or less, without regard to causality, were nausea (30%), dizziness (22%), pruritus (22%), fatigue (19%), headache (19%), peripheral edema (19%), and pyrexia (16%). The only adverse event classified as grade 3 or greater, without regard to causality, and occurring in at least two patients, was lymphopenia, which was observed in two patients (5%).
Conclusions: Oral forodesine is effective in the treatment of refractory CTCL patients and has an encouraging safety profile.
SWAT SCORE: Percent Change from Baseline SWAT SCORE: Percent Change from Baseline
Romidepsin (Depsipeptide, FK228) Induces Clinically Significant Responses in Treatment-Refractory CTCL: Interim Report of a Phase II Multicenter Study.
Authors: Lerner Adam , Demierre M.F. , Whittaker S. , Robak T. , Baran E. , McCulloch W. , Prentice A.G. 
Published: October 2019

Abstract
Background: Romidepsin is a bicyclic peptide which inhibits Class I and II HDACs. An initial study by Piekarz et al noted frequent responses to romidepsin therapy in patients with CTCL (ASCO, 2004). The aim of the pivotal phase II study reported here is to confirm this clinical activity.
Methods: This single arm, open label study is enrolling mycosis fungoides (Stages IB-IVA) or Sezary syndrome patients from 30 centers in the UK, Germany, Poland and the US. Patients with biopsy-proven CTCL (centrally reviewed) that have failed at least one prior systemic therapy receive up to 6 cycles of romidepsin at 14 mg/m2 as a 4-hour IV infusion on Days 1, 8 and 15 q 28 days but may continue therapy if PR or CR is achieved. Eligibility criteria include adequate organ function and ECOG PS less than or equal to 1. Exclusion criteria include significant cardiovascular abnormalities or treatment with QTc-prolonging or CYP3A4-inhibiting drugs.
The primary endpoint is response rate as measured by a combination of imaging, circulating cell counts and a scoring instrument to determine average weighted skin involvement. Skin responses are confirmed by standardized photography. Where possible, correlative studies are performed including acetylation status, apoptotic markers and proteomic analyses. Target accrual is 64 evaluable patients.
Results: 45 patients have received treatment with 31 evaluable for efficacy. Preliminary results of responses are 1 CCR, 11 PRs, 17 SD and 2 PD for an ORR of 39% (duration 3–12 months). One PR became a CCR after more than 6 courses of treatment. In responding patients, time to response ranges from 1–3 cycles. In those patients with pruritus, relief of at least 30 mm from baseline (on a 100 mm VAS) or a VAS score of 0 (no itching) for at least 2 cycles, was seen in 14/26 patients (54%). Seven (7) patients withdrew with PD and 13 for other reasons. Most frequent toxicities are nausea/vomiting, fatigue, myelosuppression and asymptomatic ECG changes. 5 patients have withdrawn for toxicity and there have been no treatment-related deaths.
Conclusions: This study confirms the previously reported efficacy of romidepsin in treatment-refractory CTCL which includes relief of pruritus and a high response rate including one cCR. The low rate of treatment discontinuation due to side-effects and prolonged treatment duration of some patients illustrate that toxicity has been manageable. Accrual continues.
Treatment of Children & Adolescents with Early Stage Nodular Lymphocyte Predominant Hodgkin Lymphoma with a Low Intensity Short Duration Chemotherapy Regimen [CVP] - on Behalf of the EuroNet-PHL Group.
Authors: Shankar Ananth G. , Daw Stephen , Hall Georgina , Gorde-Grosjean Stephanie , Koerholz Christine Mauz , Korholz Dieter , Wallace William H. , Hasenclever Dirk , Landman-Parker Judith 
Published: October 2019

Abstract
Background: Nodular Lymphocyte Predominant Hodgkin’s Lymphoma (NLPHL) is a distinct clinicopathologic subtype of Hodgkin’s lymphoma [HL]. Reports in published literature suggest that very little, and occasionally, no chemotherapy is sufficient for long term survival in patients with LPHL and that this disease appears to have a more indolent course than classical HL. The optimum therapy for early stage NLPHL is not known, but it is likely that current therapy for classical Hodgkin’s lymphoma is unnecessarily toxic and intensive for this indolent, slowly progressive, CD 20 positive disease. Adverse treatment related late effects are the major causes of morbidity and death. Consequently children with early stage NLPHL represent ideal candidates for low intensity treatment.
Study Objectives: To assess whether a non-intensive chemotherapy regimen consisting of cyclophosphamide [500mg/m2 iv- day 1], vinblastine [6 mg/m2 iv-day1 & 8] and oral prednisolone [40 mg/m2 - days 1–7] (CVP) every 14–21 days, count dependent, could replace standard chemotherapy protocols used for classical HL without compromising efficacy in children and young people with NLPHL.
Patients and Methods: Between May 2004 and April 2006 18 patients with stages IA [n=12] and IIA [n=6] biopsy proven NLPHL were treated with 3 cycles of CVP chemotherapy. Three of the eighteen patients were initially treated with surgical resection alone and received CVP at first relapse. Ten patients were males and the median age at diagnosis was 10 years (range 7–15 years). Staging investigations at diagnosis included both conventional cross sectional as well as 18 fluro-deoxyglucose [FDG] PET imaging. Remission status at the end of 3 cycles of CVP was confirmed by both conventional cross sectional and PET imaging.
Results: 17 patients achieved a complete remission [CR] after 3 courses of CVP and 1 patient a very good partial remission [VGPR]. To date, only 1 patient has relapsed while all the remaining patients remain in continuous CR. Median duration of follow up is 12 months (range 2–26 months). The overall survival is 100% and event free survival is 94%. No significant early or late toxicity has been observed to date.
Conclusions: Nothithstanding the relatively short follow up period, CVP is an effective non toxic chemotherapy regimen with 95% of patients with early stage NLPHL achieving a CR after 3 courses. Based on these preliminary results, we have designed a prospective European study for patients with stage IA & IIA NLPHL to confirm these results in a larger cohort of patients.
High Anti-Lymphoma Activity of Bendamustine/Mitoxantrone/Rituximab (BMR) in Rituximab Pretreated Relapsed or Refractory Indolent Lymphomas. A Multicentre Phase II Study of the German Low Grade Lymphoma Study Group (GLSG).
Authors: Weide Rudolf , Hess Georg , Koeppler Hubert , Heymanns Jochen , Thomalla Joerg , Aldaoud Ali , Losem Christoph , Schmitz Stefan , Haak Ursula , Huber Christoph , Unterhalt Michael , Hiddemann Wolfgang , Dreyling Martin 
Published: October 2019

Abstract
Purpose: Bendamustine is a new anti-lymphoma agent with promising activity. Based on a preceeding phase I study the current trial explored Bendamustine in combination with Mitoxantrone and Rituximab (BMR) in patients with relapsed or refractory indolent lymphomas.
Patients and Methods: Patients with relapsed or refractory symptomatic stage III/IV indolent lymphomas with or without prior treatment with Rituximab were eligible. Therapy consisted of Bendamustine 90 mg/m2 days 1+2, Mitoxantrone 10 mg/m2 day 1, Rituximab 375 mg/m2 day 8. Treatment was repeated on day 29 for a total of 4 cycles.
Results: Between 04/03 and 07/04 62 patients were recruited from 24 participating institutions, 40% of whom had received prior Rituximab therapy. Median age was 67 years (40–83). Lymphoma subtypes were 30 follicular (FL), 18 mantle cell (MCL), 4 B-CLL with plasmacytic differentiation, 3 lymphoplasmacytic (LPL), 3 marginal zone (MZL), 2 diffuse large B-cell (DLBCL), 1 high grade lymphoma not otherwise specified and 1 hairy cell leukemia. The overall response rate (ORR) was 88% with 36% CR and 53% PR. ORR in Rituximab pretreated patients was 75% (38% CR, 38% PR). After a median observation time of 17 months (1 – 33), the estimated median progression free survival is 19 months. Treatment related toxicities of grade 3/4 comprized a reversible myelosuppression (10 % anemia, 78 % leukocytopenia, 46 % granulocytopenia, 16 % thrombocytopenia). However, unexpected hospitalisations were necessary after 10 of 231 cycles (4%) only.
Conclusion: BMR is a very effective new outpatient immuno-chemotherapy with low toxicity for patients with relapsed/refractory indolent lymphoma.
Response rates All patients FL MCL pretreated with Rituximab n 62 30 18 25 end of therapy without staging 3 3 0 1 evaluable patients 59 27 18 24 CR 21 (36%) 13 (48%) 6 (33%) 9 (38%) PR 31 (53%) 12 (44%) 8 (44%) 9 (38%) MR 1 (2%) 0 (0%) 1 (6%) 1 (4%) SD 0 (0%) 0 (0%) 0 (0%) 0 (0%) PD 6 (10%) 2 (7%) 3 (17%) 5 (21%) EX 0 (0%) 0 (0%) 0 (0%) 0 (0%) CR+PR 52 (88%) 25 (93%) 14 (78%) 18 (75%)
Figure Figure