bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early Consolidation with Myeloablative Radiochemotherapy Followed by Autologous Stem Cell Transplantation in First Remission Significantly Prolongs Progression-Free Survival in Mantle Cell Lymphoma - Long Term Follow up of a Prospective Randomized Trial of the European MCL Network.
Authors: Dreyling Martin H. , Lenz Georg , Schiegnitz Eva , van Hoof Achiel , Gisselbrecht Christian , Pfreundschuh Michael , Metzner Bernd , Truemper Lorenz H. , Reiser Marcel , Steinhauer Hjalmar B. , Boiron Jean-Michel , Boogaerts Marc A. , Aldaoud Ali , Silingardi Vittorio , Kluin-Nelemans Hanneke C. , Hasford Joerg , Parwaresch Reza , Michael Unterhalt , Wolfgang Hiddemann 
Published: October 2019

Abstract
Mantle cell lymphoma (MCL) is a distinct subtype of malignant lymphoma with an especially poor prognosis and a median survival of only 3–4 years. In 1996, the European MCL Network initiated a randomized trial to improve the otherwise dismal outcome of MCL, comparing early consolidation with myeloablative radiochemotherapy (TBI 12 gray, cyclophosphamide 120 mg/kg bw) followed by autologous stem cell transplantation (ASCT) to a conventional a -interferon maintenance (6x106 IE IFNa 3x weekly) in first remission after a CHOP-like induction regimen. Until March 2004, a total of 269 previously untreated patients (up to 65 years) were randomized upfront. 189 (82%) of 230 patients with advanced stage MCL completed initial induction chemotherapy and 142 (75%) achieved either a complete (45 pts., 24%) or partial response (97 pts, 51%). 122 pts proceeded to consolidation therapy, 62 pts received ASCT consolidation and 60 patients were assigned to IFN maintenance.
Patients in the ASCT study arm experienced a significantly longer progression-free survival (PFS) as compared to patients in the IFNa arm. The PFS at 2 years was 73% after ASCT as compared to only 43% in the IFNa arm (p = 0.0108). Similar results were achieved in the intent to treat analysis of all initially randomised MCL patients (p=0.0001). Accordingly, this advantage resulted in a trend towards an improved overall survival (OS) in the ASCT arm. After a follow-up of up to nearly 7 years (median follow-up of patients: 2.8 years), 3 year survival after ASCT was 83% in comparison to 77% under IFNa maintenance (p = 0.18). As expected, acute toxicity was higher in the ASCT group with an early mortality of 4.8%, whereas long-term effects were more frequently encountered under IFNa maintenance.
Conclusion : In first line treatment of advanced stage MCL, dose-intensified consolidation with myeloablative radiochemotherapy followed by ASCT after CHOP-like induction results in a significant prolongation of PFS. Current study concepts evaluate the benefits of combined immuno-chemotherapy to further improve the overall survival.
Risk Factors of Myelodysplastic Syndromes (MDS): A Case-Control Study.
Authors: Strom Sara S. , Gu Yun , Gruschkus Stephen K. , Estey Elihu H. 
Published: October 2019

Abstract
Little is known about the etiology of MDS. A hospital-based case control study was conducted to investigate the association between lifestyle characteristics and MDS risk. Cases included 354 newly diagnosed adult de novo MDS cases registered at M. D. Anderson Cancer Center (MDACC) between 1996 and 2003. Four hundred and fifty two age-, sex- and race-matched healthy controls were recruited among visitors to MDACC who accompanied patients to different clinics excluding the Leukemia clinic. A validated questionnaire was used to collect demographic and epidemiological information including lifetime history of smoking, alcohol drinking and occupational history. Multivariate logistic regression analysis adjusting for all variables simultaneously was used. The distribution by FAB type was 102 (29%) RA/RARS, 43 (12%) CMML and 209 (59%) RAEB/RAEB-T. The mean age of patients was 64 years (range: 24 to 89), the male to female ratio was 2.72, and 94% of cases were whites. Abnormal cytogenetics was found in 49% of the patients. Multivariate logistic regression analysis was performed among all MDS cases and among each FAB type. For all MDS combined, having a first degree relative diagnosed with a hematopoietic cancer (Odds ratio (OR)=1.92, 95% CI: 1.11–3.33), having ever smoked (OR=1.65, 95% CI: 1.19–2.29), having been exposed to agricultural chemicals (OR=4.57, 95% CI: 1.78–11.7) and solvents (OR=2.08, 95% CI: 1.22–3.54) were associated with MDS risk. Wine drinkers had a reduced risk of MDS as compared to those who never drank alcohol (OR=0.54, 95%: 0.37–0.79). For the RA/RARS type, smoking (OR=2.16, 95% CI: 1.3–3.6) and having been exposed to agricultural chemicals (OR=4.64, 95% CI: 1.27–16.9) were the only two risk factors identified. Wine drinkers were at reduced risk (OR=0.51, 95% CI: 0.29–0.91). For the RAEB/RAEBT type, a positive family history of hematopoietic cancer (OR=2.16, 95% CI: 1.17–3.98), smoking (OR=1.55, 95% CI: 1.05–2.30) and exposure to agricultural chemicals (OR=4.12, 95% CI: 1.51–11.3) or solvents (OR=2.83, 95% CI: 1.59–5.05) were independent risk factors. Also drinking wine seemed to reduce the risk by almost 50% (OR=0.51, 95% CI: 0.32–0.81). We also found a joint effect between smoking and chemical exposures with the largest OR found among smokers who were also exposed to solvents or agricultural chemicals as compared to never smokers without chemical exposures (OR=3.22, 95% CI: 2.11–4.92, Trend test: p<0.0001). Results from this large study suggest that several factors play a role in predisposing to MDS with possible joint effects. Risk profiles seem to differ by FAB type. Further population-based studies are needed to confirm these findings. Supported by NCI grants CA91340 and CA 100632.
Coordinated Chromatin-Association of Fanconi Anemia Network Proteins Requires Replication-Coupled DNA Damage Recognition.
Authors: Sobeck Alexandra , Stone Stacie , deGraaf Bendert , Costanzo Vincenzo , deWinter Johan , Wang Weidong , Joenje Hans , Gautier Jean , Hoatlin Maureen E. 
Published: October 2019

Abstract
Fanconi anemia (FA) is a genetic disorder characterized by hypersensitivity to DNA crosslinking agents and diverse clinical symptoms, including developmental anomalies, progressive bone marrow failure, and predisposition to leukemias and other cancers. FA is genetically heterogeneous, resulting from mutations in any of at least eleven different genes. The FA proteins function together in a pathway composed of a mulitprotein core complex that is required to trigger the DNA-damage dependent activation of the downstream FA protein, FANCD2. This activation is thought to be the key step in a DNA damage response that functionally links FA proteins to major breast cancer susceptibility proteins BRCA1 and BRCA2 (BRCA2 is FA gene FANCD1). The essential function of the FA proteins is unknown, but current models suggest that FA proteins function at the interface between cell cycle checkpoints, DNA repair and DNA replication, and are likely to play roles in the DNA damage response during S phase. To provide a platform for dissecting the key functional events during S-phase, we developed cell-free assays for FA proteins based on replicating extracts from Xenopus eggs. We identified the Xenopus homologs of human FANCD2 (xFANCD2) and several of the FA core complex proteins (xCCPs), and biochemically characterized these proteins in replicating cell-free extracts. We found that xCCPs and a modified isoform of xFANCD2 become associated with chromatin during normal and disrupted DNA replication. Blocking initiation of replication with geminin demonstrated that association of xCCPs and xFANCD2 with chromatin occurs in a strictly replication-dependent manner that is enhanced following DNA damage by crosslinking agents or by addition of aphidicolin, an inhibitor of replicative DNA polymerases. In addition, chromatin binding of xFANCD2, but not xBRCA2, is abrogated when xFANCA is quantitatively depleted from replicating extracts suggesting that xFANCA promotes the loading of xFANCD2 on chromatin. The chromatin-association of xFANCD2 and xCCPs is diminished in the presence of caffeine, an inhibitor of checkpoint kinases. Taken together, our data suggest a model in which the ordered loading of FA proteins on chromatin is required for processing a subset of DNA replication-blocking lesions that are resolved during late stages of replication.
TNF-α Hypersensitivity of Fanconi Anemia Type C Deficient Cells Is Dependent on the Apoptosis Signal-Regulating Kinase 1 Signaling Pathway.
Authors: Haneline Laura S. , Bijangi-Vishehsaraei Khadijeh R. , Werne Adam , McKenzie Kristina Wilson , Davis Susanna , Ichijo Hidenori , Saadatzadeh Mohammad R. 
Published: October 2019

Abstract
Fanconi anemia (FA) is a chromosomal instability disorder characterized by a progressive bone marrow (BM) aplasia. Previous studies from our lab and others suggest that enhanced oxidant- and inhibitory cytokine-mediated apoptosis of hematopoietic stem/progenitor cells are important mechanisms in the pathogenesis of BM failure in FA. Recently, we showed that oxidant-induced apoptosis in Fancc −/− murine embryonic fibroblasts (MEFs) was mediated through hyperactivation of the redox-dependent protein, apoptosis signal-regulating kinase 1 (ASK1, Saadatzadeh et al, JBC 2004). Here, we tested whether alterations in ASK1 signaling also participate in the pro-apoptotic phenotype of primary Fancc −/− MEFs and progenitors in response to the inhibitory cytokine, TNF-α. To determine whether Fancc −/− MEFs exhibit altered ASK1 signaling after TNF-α treatment, we examined ASK1 activity using in vitro kinase assays. These studies demonstrated a 2–3 fold increase in TNF-α-induced ASK1 activity in Fancc −/− MEFs compared to WT (n=5). Consistent with ASK1 hyperactivation, we observed an increase in activation of the downstream stress kinases, c-jun N-terminal kinase and p38, in Fancc −/− MEFs compared to WT (n=5). Utilizing a dominant negative ASK1 cDNA to decrease ASK1 activity, we determined that TNF-α-induced apoptosis in Fancc −/− MEFs was ASK1 dependent (n=3, p<0.05). In addition, TNF-α-induced apoptosis in Fancc −/− MEFs was completely blocked by both antioxidants (selenomethionine and N-acetylcysteine, n=3, p<0.001) and the p38 inhibitor SB 203580 (n=6, p<0.001). To examine whether ASK1 has a critical role in the hypersensitivity of Fancc −/− progenitors to TNF-α-induced apoptosis, we crossed ASK1 knockout mice with Fancc mice to generate the following four experimental genotypes; WT, Fancc +/+;ASK1 −/−, Fancc −/−;ASK1 +/+, and Fancc −/−;ASK1 −/−. BM cellularity and progenitors/femur were similar between all genotypes (n=3). Interestingly, TNF-α hypersensitivity of Fancc −/− progenitors was restored to WT levels when ASK1 was deleted (n=3, p<0.05), suggesting that TNF-α-induced hypersensitivity of Fancc −/− progenitors is mediated through ASK1, similar to Fancc −/− MEFs. In addition, TNF-α-induced apoptosis in Fancc −/− progenitors was restored to WT levels after culturing with the p38 inhibitor SB 203580 (n=6, p<0.005). Since ASK1 activity is directly regulated by the cellular redox state, these data support the idea that aberrant redox regulation may be involved in the observed pro-apoptotic phenotype of Fancc −/− cells after exposure to inhibitory cytokines such as TNF-α. Collectively, these data suggest that inhibiting the ASK1 apoptotic pathway in Fancc −/− cells via antioxidants or small molecule inhibitors may protect Fancc −/− hematopoeitic stem/progenitors from an apoptotic fate and delay BM failure.
Hyperacute Graft-Versus-Host Disease: Analysis of Risk Factors, Clinical Manifestations and Outcomes.
Authors: Couriel Daniel R. , Saliba Rima , de Lima Marcos J. , Hosing Chitra , Andersson Borje , De Jesus Jorge , Mickler Kerry , Hsu Yvonne , Shpall Elizabeth J. , Ghosh Shubhra , Champlin Richard 
Published: October 2019

Abstract
Objective: To evaluate risk factors, clinical manifestations and outcome of hyperacute or early acute graft-versus host disease (GVHD), defined as that occurring within 14 days after hematopoietic stem cell (HSC) transplantation.
Methods: A total of 815 consecutive patients transplanted at UT MD Anderson Cancer Center between 1/1998 and 9/2002 were retrospectively analyzed.
Results: Of 381 patients presenting with acute GVHD, 22% (n=83) had biopsy-proven hyperacute GVHD. Grade I GVHD occurred in 12% of these patients, grade II in 53%, grade III in 13% and grade IV in 22%. The proportion of grade II-IV GVHD in this group was significantly higher (88%) than in the 298 patients presenting with acute GVHD between days 15 and 100 (64%, p value <0.001). The majority of patients with hyperacute GVHD had skin involvement (89%), followed by GI (43%), and liver GVHD (19%). Skin involvement was significantly more common (89% vs 76%, p value 0.01), and more severe (stage III or IV 63% vs 32%, p value <0.001) in the hyperacute group. There was no statistical difference in frequency and severity of visceral involvement. Risk factors for hyperacute GVHD were evaluated using Cox proportional hazards model. On univariate analysis, a mismatched (MM) related (HR=4.4, p value<0.001) matched unrelated (MUD) graft (HR=2.4, p value<0.001) and a myeloablative preparative regimen with or without TBI (HR=2.5, p value<0.001) were significantly associated with a higher rate of hyperacute GVHD. These effects remained significant in a multivariate model. Donor’s age greater than 40 years was associated with a lower rate of hyperacute GVHD (HR=0.6,p value=0.05), and there was a trend for increased rates for patients receiving sex mismatched grafts, solid tumor transplants or multiple (>5) chemotherapy regimens before transplant. Age, disease status, GVHD prophylaxis, or stem cell source (BM vs peripheral HSC) were not associated with hyperacute GVHD. Overall mortality was significantly higher within 6 months post transplant for patients with hyperacute GVHD (HR=2.2, p value <0.001) compared to all other patients, or to patients developing acute GVHD after day 14 (HR=1.6, p = 0.009). GVHD-related death was also significantly higher (HR=2.3, p=0.007) in the hyperacute GVHD group.
Conclusions: Hyperacute GVHD occurs in a substantial proportion of patients undersgoing HSC transplant, even prior to neutrophil engraftment. Skin involvement, grades 3–4 GVHD and a higher mortality are common features of this syndrome . Patients at high risk or with a diagnosis of hyperacute GVHD should be included in clinical studies whenever possible.
VPAC1 Receptor-Mediated Regulation of Megakaryopoiesis.
Authors: Freson Kathleen , Thys Chantal , Wittevrongel Christine , De Vos Rita , Vermylen Jos , Hoylaerts Marc F. , Van Geet Chris 
Published: October 2019

Abstract
Identification of the regulatory pathways that direct megakaryopoiesis and platelet production is essential for the development of novel strategies to treat life threatening bleeding complications in bone marrow suppressed patients. We demonstrated that megakaryocytes and platelets express the Gs-coupled VPAC1 receptor, for which both PACAP and VIP are specific agonists. We have further identified a bleeding tendency and found three copies of the PACAP gene in two related patients with severe mental retardation, responsible for elevated PACAP plasma levels and associated increased platelet cAMP concentrations, resulting in strongly reduced platelet aggregation (JCI, 2004, 113, 905). In this study, we have further demonstrated a fundamental role for the VPAC1 signalling pathway during megakaryocyte maturation and platelet formation. Patients with PACAP overexpression have mild thrombocytopenia, a normal platelet survival and relatively small platelets with an MPV of 8.2 fL (normal MPV 9-13 fL). FACS analysis of the patients’ platelets showed reduced expression of GPIX and GPIIIa. Electron microscopy of bone marrow of patients and of mice, specifically overexpressing PACAP in megakaryocytes revealed the presence of early megakaryocyte progenitors but almost not of mature megakaryocytes. Immature megakaryoblasts seemed to have reduced levels of rough endoplasmic reticulum cisternae and free ribosomes. To further study the modulating role of VPAC1 in thrombopoiesis, control mice were therefore subcutaneously injected with neutralizing polyclonal or monoclonal anti-PACAP, anti-VIP or anti-VPAC1 antibodies. Injection of these antibodies in all cases led to increased platelet counts, compared to control antibodies (monoclonal anti-PACAP antibody: 1194 ± 237 x 109 plt/L; control antibody: 722 ± 178 x 109 plt/L; p=0.01, unpaired t-test at day 7 after injection). This strategy was also capable of reducing the drop in platelet count in busulfan treated mice (polyclonal anti-PACAP antibody: 561 ± 121 x 109 plt/L; control antibody: 349 ± 65 x 109 plt/L; p=0.033, unpaired t-test at day 29 or day 18 after respectively antibody and busulfan injection). In addition, bone marrow examination of mice injected with monoclonal anti-PACAP or anti-VPAC1 antibodies revealed an increase in megakaryocyte numbers and showed a marked expansion and mobilization of megakaryocyte progenitor cells. Mice injected with a monoclonal anti-VPAC1 antibody showed an increase of about 50% in bone marrow CFU-MK. In conclusion, we provide evidence that the VPAC1 pathway modulates normal megakaryopoiesis. Further studies are needed to evaluate whether this pathway can be safely manipulated in man in the treatment of thrombocytopenia.
Asn 505 Mutation of the C-MPL Gene, A Cause of Familial Essential Thrombocythemia, Induces the Autonomous Homodimerizaton of the C-Mpl Independent of Ligand Stimulation.
Authors: Ding Jianmin , Komatsu Hirokazu , Iida Shinsuke , Wakita Atsushi , Nitta Masakazu , Miyazaki Hiroshi , Ueda Ryuzo 
Published: October 2019

Abstract
The c-MPL gene and its ligand, thrombopoietin (TPO), regulate the proliferation and differentiation of megakaryocytes and platelets. We previously found a dominant-positive activating mutation of the c-MPL gene as a cause of familial essential thrombocythemia. This mutation (Ser505 to Asn505) was located in the transmembrane domain of the c-MPL. The Ba/F3 cells expressing the mutant allele of Asn505 acquired interleukin-3 (IL-3)-independent survival capacity and the autonomous phosphorylation of Mek1/2 and Stat5b in the absence of IL-3 (Blood 103; 4198, 2004). The mechanism underlying how c-Mpl with Asn505 induces constitutive phosphorylation of Mek and Stat5b remains unknown. However, it is assumed that dimerization of c-Mpl molecules may be accelerated as a result of this specific mutation, as in the cases of mutations of c-kit and Neu at their transmembrane domains. Thus we examined the status of dimer formation of the c-Mpl molecules in the Ba/F3 cells with the Asn505 cells in the presence and absence of IL-3 or Tpo using the cell surface chemical cross-linking assay. As a result, in wild-type (Ser505) c-Mpl-expressing Ba/F3 cells, homodimeric signals of the c-Mpl proteins were detected only in the presence of IL-3 or Tpo, whereas mutant (Asn505) c-Mpl-expressing Ba/F3 cells harbored constitutively homodimeric signals even in the absence of IL-3 or Tpo. These observations suggest that mutant c-Mpl with Asn505 can activate the downstream signals involved in the Tpo-c-Mpl signaling pathway mediated by the formation of autonomous homodimerizaton independent of ligand stimulation. As asparagine (Asn) is well known to provide a strong free energy of association by forming interhelical hydrogen bonds in a hydrophobic environment, the Asn505 mutation in the transmembrane domain of the c-MPL is thought to drive strong interactions (dimerizations) among the c-Mpl molecules, leading to the activation of the Tpo-c-Mpl signaling and consequently autonomously activated megakaryocytopoiesis with the excessive production of platelets. The disulfide-bonded homodimerization may be also induced by the Asn505 mutation. Further investigation of this issue is now in progress.
Combination Therapy with Rituximab and Fludarabine in Waldenstrom’s Macroglobulinemia.
Authors: Treon Steven P. , Branagan Andrew , Wasi Parveen , Emmanouilides Christos A. , Frankel Stanley R. , Lister Andrew , Morel Pierre , Matous Jeffrey , Enschede Sari Heitner , Kimby Eva 
Published: October 2019

Abstract
Rituximab and Fludarabine are active in Waldenstrom’s macroglobulinemia (WM) producing major response rates of 40–70%. Both pre-clinical and clinical studies in related low-grade B-cell malignancies suggest that additive, and even synergistic benefit with combination Fludarabine and Rituximab may result. As such, we conducted this combination study with Rituximab and Fludarabine in WM patients. WM patients who had received < 2 prior therapies, and who had not previously been treated with any nucleoside analogue or Rituximab were eligible. Intended therapy was as follows:
Weeks 1–4 Rituximab (375 mg/m2/week)
Weeks 5, 9, 13 Fludarabine daily for 5 days (25 mg/m2)
Weeks 17, 18 Rituximab (375 mg/m2/week)
Weeks 19, 23, 27 Fludarabine daily for 5 days (25 mg/m2)
Week 30, 31 Rituximab (375 mg/m2/week)
Patients were evaluated at week 12, and if they did not progress were eligible for further therapy and were evaluable for response. 43 WM patients were enrolled with a median age of 61 (range 52–75 yrs), and median prior therapies of 1 (range 0–2). 40/43 patients continued on therapy beyond week 12. Two patients (1 PR, 1 SD) died after completing protocol therapy including one elderly patient who had an influenza pneumonia and another debilitated patient who may have had a secondary malignancy. Delays in therapy due to neutropenia were common, and 58% of patients experienced Grade III/IV neutropenia. Protocol therapy was truncated after the 4th and 5th courses of fludarabine in several patients for persistent neutropenia and/or thrombocytopenia despite delays in therapy and/or use of G-CSF support. Other complications included: Herpes zoster outbreak in 3 of the first 21 patients, before prophylactic acyclovir or equivalent was initiated; parasthesias (n=3); pneumonitis (n=2); development of bladder cancer (n=1) and a high grade lymphoma (n=1); subdural hemorrhage in a patient who had a 3-fold increase in serum viscosity following the first 4 infusions of Rituximab. On an intent to treat basis, 39/43 (90.1%) patients demonstrated a response. Response categories were as follows: CR (n=3); PR (n=32); MR (n=4). One patient remains in stable disease at 20+ months. At a median follow-up of 17 months, 36 of 39 responding patients remain in remission. Rituximab in combination with fludarabine is highly active and produces durable responses in WM.