bluuebunny/crossref_metadata_2025_split huggingface dataset:
Downregulation of Peroxiredoxin III Contributes to Arsenic Trioxide-Induced Apoptosis in APL.
Authors: Vivas-Mejia Pablo , Ozpolat Bulent , Chen Xian , Lopez-Berestein Gabriel 
Published: October 2019

Abstract
Arsenic trioxide (ATO) induces differentiation and apoptosis in acute promyelocytic leukemia (APL). Compared with other leukemia cells, the APL-derived NB4 cells are particularly sensitive to ATO-induced apoptosis. Several reports indicate that in NB4 cells, apoptosis occurs in part by a mechanism that involves the inhibition of glutathione peroxidase, one of the enzymes that regulate the levels of H2O2 in the mitochondria, and that is present only at low levels in NB4 cells. Peroxirredoxin III (Prx III) is a mitochondria-specific H2O2-scavenger member of the thioredoxin-dependent peroxidases. NB4 cells express high levels of Prx III; however the role of Prx III in ATO-induced apoptosis in NB4 cells has not been investigated. We studied here whether Prx III is regulated during ATO-induced apoptosis in NB4 cells and whether the depletion of Prx III further sensitized these cells to ATO-induced apoptosis. The protein and mRNA levels of Prx III were decreased during ATO-induced apoptosis of NB4 cells. The down-regulation of Prx III occurred prior to the accumulation of reactive oxygen species, reduction in the mitochondrial membrane potential and apoptosis. Depletion of Prx III enhanced the ATO-induced mitochondrial damage, and also promoted cytochrome-c release, and caspase-3 and caspase-9 activation. Prx III is downregulated early during ATO-induced apoptosis, facilitating in this way the mitochondria-depending apoptotic events triggered by the accumulation of H2O2.
Traumatic Lumbar Puncture (TLP) Is Not Associated with Worse Outcome in Adults with Acute Lymphocytic Leukemia (ALL) or Burkitt-Type Leukemia/Lymphoma (BLL) Receiving Hyper-CVAD Regimens.
Authors: Atallah Ehab , O’Brien Susan , Kaled Susan , Lynn Alice , Cortes Jorge , Kantarjian Hagop , Thomas Deborah A. 
Published: October 2019

Abstract
Background: TLP has been associated with worse outcome in pediatric ALL patients (pts). However, this has not been well studied in adults with ALL or BLL. Our aim was to investigate the prognostic significance of CNS status at presentation in adult ALL pts undergoing frontline therapy with hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and cytarabine) or variations incorporating rituximab and/or imatinib. Pts were stratified to receive standard intrathecal treatments (IT) with methotrexate alternating with cytarabine based on CNS risk assessment (proliferative index ≥ 14% or serum lactate dehydrogenase ≥ 1400) [Cortes et al, Blood 86:2091, 1995]. Low risk pts received 6 IT, high or indeterminate risk 8 IT, and BLL 16 IT.
Methods and Results: Cerebrospinal fluid was assessed after IT approximately day 2 of induction therapy. CNS status at presentation was defined as: CNS 1 (not traumatic; < 10 RBCs/μL without leukemic blasts after cytocentrifugation); CNS 2 (not traumatic; < 5 WBCs/μL with leukemic blasts); CNS 3 (not traumatic; ≥ 5 WBCs/μL with leukemic blasts), TLP+ (traumatic, > 10 RBCs/μL with leukemic blasts). TLP- (traumatic without leukemic blasts). Two hundred eighty two pts were reviewed up to January 2007; the median age was 42 years (range, 15–84). Diagnosis was ALL in 229 (81%) and BLL in 53 (19%). In the ALL subset, 48 pts (17%) were Philadelphia positive. Median WBC and platelet count were 3.2 x 109/L and 65 x 109/L, respectively. At the time of first LP, 119 (42%) pts had circulating (PB) blasts. CNS risk was high in 34% (plus 17% with BLL), indeterminate in 20%, and low in 21%. The remainder (7%) had definitive CNS disease and were not classified. PB blasts and CNS risk did not appear to affect the CNS relapse rate. By multivariate analysis, age, thrombocytopenia, leukocytosis and presence of t(4;11) were associated with worse survival in this selected group, while CNS status at presentation was not (Table 1).
CNS status and risk of CNS relapse CNS status at 1st LP No. (%) %CNS Relapse CNS1 159 (56) 5 CNS2 13 (5) 15 CNS3 7 (3) 14 TLP+ 25 (9) 4 TLP− 78 (27) 4
Conclusion: CNS status at first LP does not appear to affect prognosis of adults with de novo ALL or BLL receiving frontline therapy with hyper-CVAD based regimens. TLP or the presence of PB blasts at the time of first LP does not appear to increase the risk of CNS relapse.
Impact on Quality of Life of Postconsolidation Immunotherapy with Histamine Dihydrochloride and Interleukin-2 in Acute Myelogenous Leukemia.
Authors: Wallhult Elisabeth , Whisnant John , Rowe Jacob M. , Szer Jeff , Bhagwat Dileep , Hellstrand Kristoffer , Nilsson Bo I. , Brune Mats L. 
Published: October 2019

Abstract
PURPOSE: To assess the impact on Quality of Life (QoL) of postconsolidation immunotherapy with histamine dihydrochloride (HDC) in combination with interleukin-2 (IL-2) in acute myelogenous leukemia (AML).
PATIENTS & METHODS: A multi-national randomized open-label phase 3 trial recruited 320 AML patients between 1998 and 2000. Patients were enrolled after termination of consolidation therapy, stratified by country and remission status (first or subsequent remission), and randomized to HDC/IL-2 treatment or no treatment (standard-of-care, control). The treatment was self-administered at home and included ten 3-week courses of HDC (0.5 mg sc bid; EpiCept Corporation) plus low-dose recombinant IL-2 (aldesleukin, 18,000 U/kg sc bid; Chiron Corp). Cycles 1–3 comprised 3 wks of treatment followed by 3 wks of rest, whereas in cycles 4–10 the rest periods were 6 wks. As reported previously (Blood2006; 108:88), the trial met the primary endpoint of prolonged leukemia-free survival (LFS) for all patients randomized (P=0.008). Assessment of QoL, a secondary trial endpoint, was performed using the validated EORTC-C30(v2) instrument at 8 pre-defined study visits: baseline; pre- and post-cycles 3, 5, and 8; and at 18 months. Data were analyzed as specified in the EORTC scoring manual for 9 scales (1 global, 5 functional, 3 symptom scales) and 6 single-symptom items. Comparisons were made between and within groups at
baseline vs. each visit, pre- vs. post-treatment, and baseline vs. end of treatment (18 months).
RESULTS: At least one questionnaire was completed by 285 patients (89%). Patients in both study arms increased or maintained QoL status from baseline to last evaluation with respect to global health status, physical, cognitive and role functioning, and financial issues, as well as symptoms of fatigue, nausea/vomiting, pain, diarrhea, and dyspnea. Comparisons of pre- vs. post-treatment QoL assessments showed transient increases in fatigue (P=0.008), nausea/vomiting (P=0.006), and appetite loss (P=0.005) in the treatment arm.
CONCLUSION: Post-consolidation immunotherapy with HDC/IL-2 self-administered at home by AML patients was associated with transient gastrointestinal symptoms and fatigue, but did not prevent recovery from induction/consolidation chemotherapy.
Intensity of FDG Uptake on PET Scan Varies by Histologic Subtype of Hodgkin Lymphoma.
Authors: Holalkere Nagaraj , Hochberg Ephraim P. , Takvorian Ronald , Blake Michael , Toomey Christiana , Michaelson James , Rahemtullah Aliyah , Abramson Jeremy S. 
Published: October 2019

Abstract
FDG-PET scanning has demonstrated utility in the staging and prognostication of Hodgkin lymphoma, but PET characteristics of discrete histologic subsets of Hodgkin lymphoma have never been reported. Further, while studies in this disease have focused on classical Hodgkin lymphoma, the PET features of nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) have not been addressed to date. NLPHL represents less than 5% of all cases of Hodgkin lymphoma and has distinct clinicopathologic features, natural history, and treatment from classical subtypes. Diagnosis may be difficult as it exists in a “gray zone” between Hodgkin and non-Hodgkin lymphomas (NHL), and shares immunophenotypic and histologic features with the T-cell rich variant of diffuse large B-cell lymphoma. Clinically, NLPHL follows a natural history more akin to indolent B-cell NHLs than to classical Hodgkin lymphomas. We retrospectively identified 7 cases of NLPHL diagnosed at our institution since 2003 with available PET staging data. Consistent with prior series of this disease, the majority of patients were male (6:1) and the median age was 32 years. All 7 patients presented with limited stage disease (3 stage I, 4 stage II) and without “B” symptoms. All 7 cases demonstrated increased FDG avidity on PET scanning. The mean Standard Uptake Value (SUV) max was 6.1 (range 1.1–8.8), and mean SUV mean was 5.6 (range 1.0–8.3). We compared these results to recently diagnosed patients with nodular sclerosis and mixed cellularity subtypes of classical Hodgkin lymphoma. Among 13 patients with nodular sclerosis Hodgkin lymphoma (NSHL), the mean SUV max was 10.1 (range 4.8–15.8), while among the 7 patients with mixed cellularity histology (MCHL), the mean SUV max was 5.6 (range 4.0–9.8). Patients with NLPHL had significantly decreased SUV max compared to NSHL patients (p=0.022), but were similar to patients with MCHL (Figure 1). Mixed cellularity histology similarly demonstrated significantly decreased SUV max compared to patients with nodular sclerosing disease (p=0.005). PET intensity therefore highlights differences between classical subtypes of Hodgkin lymphoma, as well as between classical and non-classical variants. When compared to published PET SUV data in aggressive B-cell lymphomas, the maximal SUVs we observe in NLPHL fall well below those reported in aggressive B-cell lymphomas, which may aid in the diagnosis of these occasionally similar appearing neoplasms. We conclude that PET scans identify differences in FDG avidity across classical and non-classical Hodgkin lymphoma subtypes, likely reflecting underlying biological differences. We also demonstrate for the first time that despite its indolent behavior, NLPHL is a uniformly FDG-avid neoplasm, and so PET scans may have a role in the staging and surveillance of this uncommon disease variant.
Figure Figure
Velcade®, Thalidomide, Dexamethasone (VTD) Induction Therapy Followed by Melphalan, Prednisone, Thalidomide (MPT) Maintenance as a First Line Treatment for the Patients (pts) with Multiple Myeloma (MM) Who Are Non-Transplant Candidates: Early Analysis from the Korean Multiple Myeloma Working Party.
Authors: Eom HyeonSeok , Kim Yeo-Kyeoung , Chung Jooseop , Kim Kihyun , Kim HyoJeong , Jin JongYul , Do Young-Rok , Oh Sukjoong , Kim HoYoung , Suh Cheolwon , Seong Chu-Myong , Kim Chul Soo , Lee Dong Soon , Lee Jae Hoon 
Published: October 2019

Abstract
VTD and MPT chemotherapies have been known to be active regimens in pts with MM. The objective of this study is to examine response and toxicities and to estimate survival of pts with VTD followed by MPT, who are non-transplant candidates with previously untreated MM. Total of 29 pts were enrolled from March, 2006 through August, 2007 and this study is still ongoing. 13 pts were men and 16 pts were women. The median age was 67 years (range, 61–75 years) and median follow up was 5 months (range, 1–16 months). Here 23 pts who completed at least first two cycles of VTD were analyzed. Pts received bortezomib (Velcade®) 1.3 mg/m2 on days 1, 4, 8, 11, thalidomide 100 mg daily, dexamethasone 40 mg on days 1–4 every 3 weeks for a maximum of 6 cycles of treatment, and thereafter melphalan 4 mg/m2 on days 1–7, prednisone 40 mg/m2 days 1–7, thalidomide 100 mg daily every 4 weeks for a maximum of 12 cycles. In these 23 pts, 92% of them showed responses (18% CR, 4% nCR, and 70% PR). 17 pts completed 4 cycles of VTD and all of them showed 100% response rates (CR 35%, nCR 18%, PR 47%). 13 out of 14 who completed 6 cycles of VTD showed responses (CR 50%, nCR 14%, PR 29%, PD 7%). It is too early to see whether improved response rate translates into improved overall survival (OS) and progression free survival (PFS). The median OS and PFS have not been reached yet. 11 pts (37%) stopped protocol therapy because of consent withdrawal (2 pts), death (4 pts), disease progression (2 pts) and severe adverse reaction (3 pts). The causes of death were infection-related in 2 pts who had been in remission. Other 2 pts were related to disease progression. Although peripheral neuropathy affected all of pts, only 20% of the pts were grade 3. The most common side effects of the chemotherapies greater than grade 3 were pneumonia (24%), asthenia (12%), diarrhea (16%), nausea (4%), thrombocytopenia (16%), neutropenia (12%) and anemia (12%). Although VTD followed by MPT chemotherapy in pts with previously untreated MM, who are non-transplant candidates showed high response rates with manageable toxicities, they showed high withdrawal rates from the study which attributed partly to the characteristics of the pts at baseline who were non-transplant candidates because of old age and morbidities, and a few major neuropathies. Follow up data will be presented.
Lenalidomide/Dexamethasone Improves Response and Prolongs Time to Progression, Even in Patients with IgA Multiple Myeloma: A Sub-Analysis of the MM-009/010 Studies.
Authors: Foa Robert , Weber Donna , Dimopoulos Meletios , Olesnyckyj Marta , Yu Zhinuan , Zeldis Jerome , Knight Robert , Chanan-Khan Asher Alban 
Published: October 2019

Abstract
Background: Historically, patients with IgA multiple myeloma (MM) respond poorly to treatment. In 2 recent phase III trials, Lenalidomide (Len) in combination with Dexamethasone (Dex) led to an overall response (OR) rate of approximately 60% (61% in MM-009 and 60% in MM-010), a complete response (CR) rate of about 15% (14% and 16%, respectively), an overall survival (OS) of at least 29.5 months (29.5 and not yet reached), and a median time to progression (TTP) of at least 11.1 months (11.1 months and 11.3 months, respectively) in patients with relapsed/refractory MM. In both studies, OR, CR, OS and TTP were significantly better with Len/Dex than with Dex alone. Here, we assess the impact of IgA disease on the efficacy and tolerability of treatment with Len/Dex versus Dex alone.
Methods: Data were pooled from the MM-009 and MM-010 studies. Patients were randomized to receive Len (25 mg/day on days 1–21 of each 28-day cycle) or placebo. Both groups received Dex 40mg PO q.d. on days 1–4, 9–12, and 17–20 (for the first four cycles). After four cycles, Dex 40 mg/day was administered only on days 1–4. Response to therapy, TTP, OS, and adverse events were assessed. Response rate and TTP were based on data obtained before unblinding (June 2005 [MM-009] and August 2005 [MM-010]).
Results: Of 154 patients with IgA at baseline, 72 were treated with Len/Dex and 82 with Dex alone. Among those without IgA, 281 received Len/Dex and 269 received Dex alone. Baseline characteristics were balanced between treatment groups. Len/Dex was associated with a significantly higher OR and longer median TTP than Dex alone in patients with and without IgA (Table). In the non-IgA group, patients treated with Len/Dex had a significantly longer OS than those treated with Dex alone. Response, TTP and OS were comparable between IgA and non-IgA patient groups. There was no difference in the incidence of adverse events between patients with and without IgA. Among those with IgA, the most common grade 3–4 adverse events with Len/Dex and Dex alone were neutropenia (37.5% and 2.4%), thrombocytopenia (16.7% and 8.5%), and anemia (11.1% and 7.3%). The respective rates for patients without IgA were 46.5% and 14.5%, 12.1% and 5.7%, and 11.0% and 5.7%.
Conclusion: In patients with and in those without IgA MM, Len/Dex treatment induces a high response rate and a prolonged TTP compared with Dex.
IgA non-IgA Clinical response, % Len/Dex (n=72) Dex alone (n=82) P Len/Dex (n=281) Dex alone (n=269) P OR 68.1 18.3 <0.001 57.7 23.0 <0.001 CR 18.1 0 NS 14.2 2.6 NS PR 38.9 15.9 NS 35.6 19.3 NS Median TTP, wks 44.3 16.4 <0.001 52.1 20.1 <0.001 Median OS, wks 130.4 102.4 NS 156.0 136.1 <0.05
Varicella Zoster Virus Reactivation with the Use of Bortezomib in Relapsed or Refractory Multiple Myeloma Patients.
Authors: Kim Seok Jin , Lee Hyo-Jin , Kim Hawk , Kim Kihyun , Kwak Jae-Yong , Nam Seung-Hyun , Kwon Jung Hye , Sohn Sang Kyun , Won Jong-Ho , Lee Jae Hoon , Suh Cheolwon , Yoon Sung-Soo , Cha Yongjun , Kim Hye Jin , Kim Inho , Do Young-Rok , Lee Won-Sik , Joo Young-Don , Kim Hyo Jung ,   the Korean Multiple Myeloma Working Party (KMMWP)
Published: October 2019

Abstract
Bortezomib has been used for patients with relapsed or refractory multiple myeloma. However, considering most patients with multiple myeloma are elderly people, the management of bortezomib-induced adverse effects became important. Varicella zoster virus (VZV) reactivation was reported as another adverse event associated with bortezomib in the APEX trial. Although some concomitantly administered drugs such as steroid may induce herpes zoster, proteasome inhibition itself may be associated with VZV reactivation because NF-κB inactivation may reduce antiviral response, and proteasome inhibition may affect the cellular localization of VZV leading to nuclear accumulation of VZV. Therefore, we analyzed the incidence of VZV reactivation among 267 relapsed or refractory myeloma patients treated with bortezomib. All patients were treated with at least one kind of treatment other than bortezomib before bortezomib therapy. 58 cases of VZV reactivation was observed (21.72%, 58/267) during or after bortezomib treatment while only 25 cases were found during other treatments such as VAD, MP etc (9.36%, 25/267). The incidence of VZV reactivation was not different based on the type of regimen: bortezomib monotherapy (22.58%) vs. bortezomib combined with dexamethasone, alkylating agents or thalidomide (22.72%). The characteristics of patients were compared in table.
VZV reactivation (−) VZV reactivation (+) P value † number of prior VZV/total number of patients, ‡median (range), mean ± SD Age (median, range) 63 (43–82) 63 (37–82) n. s. Gender (male: female) 129:80 32:26 n. s. Number of prior zoster† 20/209 5/58 n. s. Disease duration (mean± SD) 3.57±3.01 years 2.33±1.99 years < 0.05 Number of prior treatment‡ 3 (1–7), 2.68±1.29 3 (1–7), 2.57±1.22 n. s.
The incidence of VZV reactivation was not related with the disease (D-S stage, type), health status (performance status, co-morbidity, social history, blood cell counts), and other toxicity associated with bortezomib. The median time and mean cycles to the onset of VZV reactivation after the first infusion of bortezomib were 46 days (7–560 days), and 2.58±1.97 cycles. Localized herpes zoster was dominant form, and most cases showed a good response to anti-viral therapeutics without significant sequela. In conclusion, bortezomib was associated with high incidence of VZV reactivation. However, considering the absence of factors predicting VZV reactivation, further study should be warranted to determine the routine use of anti-viral prophylaxis.
Rapid Remission Induction by VTD (Velcade, Thalidomide, Dexamethason) in Patients with Multiple Myeloma and High Tumor Burden at Diagnosis.
Authors: Odelga Viktoria , Ackermann Jutta , Sagaster Verena , Kaufmann Hannes , Zielinski Christoph , Drach Johannes 
Published: October 2019

Abstract
Background: VTD was reported to be an active salvage regimen in patients with relapsed/refractory multiple myeloma (MM). Since initial results with VTD as frontline therapy were also promising, we used VTD as induction treatment prior to autologous transplantation in MM patients with particularly high tumor burden.
Methods: Velcade was administered at 1.3 mg/m2 on days 1, 4, 8, and 11; thalidomide was given as a daily dose of 100 mg; dexamethasone (20 mg per os) was given on days 1, 2, 4, 5, 8, 9, 11, and 12. Four cycles were scheduled every 3 weeks.
Results: We here report on three patients (age 36, 38, and 50 years) with newly diagnosed MM and high tumor mass at presentation (patient 1: Bence-Jones kappa MM with 95% plasma cell infiltration, serum free-kappa light-chains 4000 mg/l; patient 2: IgG-kappa MM with serum IgG > 9000 mg/dl, bulky plasmacytomas in the iliac bones; patient 3: IgA-lambda MM with 70% plasma cells in the bone marrow, IgA 4500 mg/dl, plasmacytoma in the os sacrum > 10 cm in diameter). Genetically, all 3 patients corresponded to the hyperdiploid variant (multiple trisomies, absence of del(13q14) and del(17p13)); patient 1 also had a t(11;14) and gain of chromosome 1q21. VTD resulted in a paraprotein reduction of at least 75% already after cycle 1. Rapid tumor mass reduction was not associated with signs of tumor lysis, and patient 1 had a significant improvement in renal function (serum creatinine from 2.4 to 1.3 mg/dl). After 4 cycles of VTD, patients 1 and 2 achieved a CR including a normal kappa/lambda ratio in the free-light-chain assay (patient 3 still ongoing). Patients have already completed G-CSF primed peripheral stem cell collection and autologous transplantation. Toxicity of VTD was mild (transient nausea and diarrhea in patient 2), in particular no peripheral neuropathy (grade 2 or higher). 7 additional pts are still at an early phase of VTD treatment, and data will be available at the meeting.
Conclusion: Induction treatment with VTD results in an effective tumor mass reduction already within one cycle and should be further evaluated in MM patients in need of rapid disease control.
(−)-Epigallocatechin-3-Gallate (EGCG), Green Tea Component, Antagonize the Anti-Myeloma Activity of Proteasome Inhibitor PS-341 by Direct Chemical Interaction.
Authors: Kim Tae Young , Park Jongmin , Oh Bora , Min Hyun Jung , Jeong Tae-Sook , Lee Jae Hoon , Park Seung Bum , Lee Dong Soon ,   the Korean Multiple Myeloma Working Party (KMMWP)
Published: October 2019

Abstract
PS-341 (also known as bortezomib, Velcade®) has a remarkable anti-myeloma acitivity and is also potential candidate for the treatment of other tumors either alone or in combination with other chemotherapeutic agents. Investigations on the effectiveness of PS-341 in combination with other anti-neoplastic agents are currently under clinical trial. Since (−)-epigallocatechin-3-gallate (EGCG) has been reported its anti-cancer activity in various cancer types, we tried a co-treatment of PS-341 with EGCG on myeloma cells, expecting a synergistic effect. However, the anti-cancer activity of PS-341 was blocked by EGCG without any synergistic effect. At the early stage of our research, we suspected antioxidant function of EGCG is the main cause of antagonistic effect on PS-341-induced cell death. Thus we selected polyphenols showing strong antioxidant function including vitamin C. But, we did not obtain any consistant data that support the significant correlation of antioxidant function of polyphenols with antagonistic effects. Instead, the structural features of polyphenols showed striking correlations with antagonistic effect; especially the presence or absence of vicinal diol moiety on polyphenol was the key elements for the effective blocking on anti-cancer function of PS-341. We infer that vicinal diols on polyphenols interact with boronic acid of PS-341, which convert active triangular boronic acid (sp2 character) of PS-341 to inactive tetrahedral boronate (sp3 character) through direct chemical interaction. The equilibrium of this conversion is controlled by structures and concentration of polyphenols, and this conversion abolished the anti-myeloma activity of PS-341. We confirmed our hypothesis on direct chemical interaction of PS-341 with EGCG through 11B NMR experiment and cell viability assay data clearly support the antagonistic interaction between PS-341 and polyphenols in multiple myeloma cell lines and primary myeloma cells from patients. Based on our researches, restriction of the intake of natural polyphenols by food or vitamin supplements should be considered during the treatment with PS-341 in MM patients.
Figure Figure