bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I/II study of sunitinib and intensive chemotherapy in patients over 60 years of age with acute myeloid leukaemia and activating FLT3 mutations
Authors: Fiedler Walter , Kayser Sabine , Kebenko Maxim , Janning Melanie , Krauter Jürgen , Schittenhelm Marcus , Götze Katharina , Weber Daniela , Göhring Gudrun , Teleanu Veronica , Thol Felicitas , Heuser Michael , Döhner Konstanze , Ganser Arnold , Döhner Hartmut , Schlenk Richard F. 
Published: March 2015

SummaryAcute myeloid leukaemia (AML) with FLT3 mutation has a dismal prognosis in elderly patients. Treatment with a combination of FLT3 inhibitors and standard chemotherapy has not been extensively studied. Therefore, we instigated a phase I/II clinical trial of chemotherapy with cytosine arabinoside (Ara‐C)/daunorubicin induction (7+3) followed by three cycles of intermediate‐dose Ara‐C consolidation in 22 AML patients with activating FLT3 mutations. Sunitinib was added at predefined dose levels and as maintenance therapy for 2 years. At dose level 1, sunitinib 25 mg daily continuously from day 1 onwards resulted in two cases with dose‐limiting toxicity (DLT), prolonged haemotoxicity and hand‐foot syndrome. At dose level −1, sunitinib 25 mg was restricted to days 1–7 of each chemotherapy cycle. One DLT was observed in six evaluable patients. Six additional patients were treated in an extension phase. Thirteen of 22 patients (59%; 8/14 with FLT3–internal tandem duplication and 5/8 with FLT3‐tyrosine kinase domain) achieved a complete remission/complete remission with incomplete blood count recovery. For the 17 patients included at the lower dose level, median overall, relapse‐free and event‐free survival were 1·6, 1·0 and 0·4 years, respectively. Four out of five analysed patients with relapse during maintenance therapy lost their initial FLT3 mutation, suggesting outgrowth of FLT3 wild‐type subclones.
Four doses of unpegylated versus one dose of pegylated filgrastim as supportive therapy in R‐CHOP‐14 for elderly patients with diffuse large B‐cell lymphoma
Authors: Bozzoli Valentina , Tisi Maria C. , Maiolo Elena , Alma Eleonora , Bellesi Silvia , D'Alo’ Francesco , Voso Maria T. , Leone Giuseppe , Hohaus Stefan 
Published: March 2015

SummaryThe primary objective of this prospective, randomized study was to compare the efficacy of a reduced regimen of only four doses of unpegylated filgrastim from day +8 to +11 per cycle with a standard once per cycle administration of pegylated filgrastim to maintain dose‐intensity of R‐CHOP‐14 (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone given every 14 d) in previously untreated elderly patients with diffuse large B‐cell lymphoma (DLBCL). We included 51 patients (median age 66 years, range 60–76). Median dose intensity did not differ between the group of 24 patients receiving four doses of unpegylated filgrastim of each cycle (87·5%) and the group of 27 patients receiving pegylated filgrastim once per cycle on day 2 (89·4%) (P = 0·9). There was also no difference in the frequency of adverse events, such as episodes of neutropenic fever and unplanned hospitalizations. Patient characteristics that negatively influenced dose intensity were reduced performance status, advanced stage disease and poor‐risk International Prognostic Index, with Eastern Cooperative Oncology Group performance status ≥2 being the most significant factor. In conclusion, a limited support with 4 d of filgrastim appears to be equivalent to pegylated filgrastim administered once per cycle, and appears to be sufficient to maintain dose‐intensity of the R‐CHOP‐14 regimen in elderly patients with DLBCL without risk factors.
MYD88 L265P and CXCR4 mutations in lymphoplasmacytic lymphoma identify cases with high disease activity
Authors: Schmidt Janine , Federmann Birgit , Schindler Natalie , Steinhilber Julia , Bonzheim Irina , Fend Falko , Quintanilla‐Martinez Leticia 
Published: March 2015

SummaryRecurrent mutations in MYD88 have been identified in >90% of lymphoplasmacytic lymphoma (LPL). Recently, WHIM (warts, hypogammaglobulinaemia, infections, myelokathexis) syndrome‐like mutations in CXCR4 have been described in 28% of LPL cases, and seem to impact clinical presentation and response to therapy. We investigated the presence of the MYD88 L265P mutation in 90 decalcified, formalin‐fixed, paraffin‐embedded (FFPE) bone marrow (BM) biopsies, including 51 cases of LPL, 14 cases of B‐cell chronic lymphocytic leukaemia (CLL), 13 cases of marginal zone lymphoma (MZL) and 12 normal controls. In addition, the C‐terminal domain of CXCR4 was sequenced in LPL cases. MYD88 L265P was found in 49/51 (96%) LPL cases and in 1/13 (7·6%) MZL (splenic type), whereas all CLL samples remained negative. The two MYD88 wild type LPL cases were associated with cold agglutinin disease. Mutations in CXCR4 were detected in 17/47 (36·2%) LPL cases, which showed a higher extent of BM infiltration and lower leucocyte counts (P = 0·02), haemoglobin (P = 0·05) and platelet counts (P = 0·01). In conclusion the detection of MYD88 L265P mutation in FFPE samples is reliable and useful for subtyping small B‐cell lymphomas in BM biopsies. In addition, the presence of CXCR4 mutations identifies a subgroup of LPL patients with higher disease activity.
Characterization of bone marrow mesenchymal stromal cells in aplastic anaemia
Authors: Hamzic Edita , Whiting Karen , Gordon Smith Edward , Pettengell Ruth 
Published: March 2015

SummaryIn aplastic anaemia (AA), haemopoietic activity is significantly reduced and generally attributed to failure of haemopoietic stem cells (HSC) within the bone marrow (BM). The regulation of haemopoiesis depends on the interaction between HSC and various cells of the BM microenvironment, including mesenchymal stromal cells (MSC). MSC involvement in the functional restriction of HSC in AA is largely unknown and therefore, the physical and functional properties of AA MSC were studied in vitro. MSC were characterized by their phenotype and ability to form adherent stromal layers. The functional properties of AA MSC were assessed through proliferative, clonogenic and cross‐over culture assays. Results indicate that although AA MSC presented typical morphology and distinctive mesenchymal markers, stromal formation was reduced, with 50% of BM samples failing to produce adherent layers. Furthermore, their proliferative and clonogenic capacity was markedly decreased (P = 0·03 and P = 0·04 respectively) and the ability to sustain haemopoiesis was significantly reduced, as assessed by total cell proliferation (P = 0·032 and P = 0·019 at Week 5 and 6, respectively) and clonogenic potential of HSC (P = 0·02 at Week 6). It was concluded that the biological characteristics of AA MSC are different from those of control MSC and their in vitro haemopoiesis‐supporting ability is significantly reduced.
Current approaches in the management of low risk Hodgkin lymphoma in children and adolescents
Authors: Giulino‐Roth Lisa , Keller Frank G. , Hodgson David C. , Kelly Kara M. 
Published: March 2015

SummaryThe outcome for children and adolescents with low risk Hodgkin lymphoma (HL) is excellent, with event‐free survival >85% and overall survival >95%. Historically, however, treatment has come at the cost of significant long‐term toxicity from chemotherapy, radiation or a combination of these. Recent treatment strategies have focused on maintaining high event‐free and overall survival while minimizing the use of therapy associated with late effects. The strategies used to achieve this vary greatly among paediatric cooperative groups and there is no one standard treatment for children with low risk HL. This review summaries recent clinical trials in paediatric low risk HL and addresses some of the important considerations when comparing trials, including differences in the definition of low risk HL, differences in outcome among histological subtypes and varying approaches to reduce or eliminate radiation therapy. Recommendations are provided for the treatment of children with low risk HL outside the setting of a clinical trial.
JAK1/2 inhibition impairs T cell function in vitro and in patients with myeloproliferative neoplasms
Authors: Parampalli Yajnanarayana Sowmya , Stübig Thomas , Cornez Isabelle , Alchalby Haefaa , Schönberg Kathrin , Rudolph Janna , Triviai Ioanna , Wolschke Christine , Heine Annkristin , Brossart Peter , Kröger Nicolaus , Wolf Dominik 
Published: March 2015

SummaryRuxolitinib (INCB018424) is the first JAK1/JAK2 inhibitor approved for treatment of myelofibrosis. JAK/STAT‐signalling is known to be involved in the regulation of CD4+ T cells, which critically orchestrate inflammatory responses. To better understand how ruxolitinib modulates CD4+ T cell responses, we undertook an in‐depth analysis of CD4+ T cell function upon ruxolitinib exposure. We observed a decrease in total CD3+ cells after 3 weeks of ruxolitinib treatment in patients with myeloproliferative neoplasms. Moreover, we found that the number of regulatory T cells (Tregs), pro‐inflammatory T‐helper cell types 1 (Th1) and Th17 were reduced, which were validated by in vitro studies. In line with our in vitro data, we found that inflammatory cytokines [tumour necrosis factor‐α (TNF), interleukin (IL)5, IL6, IL1B] were also downregulated in T cells from patients (all P < 0·05). Finally, we showed that ruxolitinib does not interfere with the T cell receptor signalling pathway, but impacts IL2‐dependent STAT5 activation. These data provide a rationale for testing JAK inhibitors in diseases triggered by hyperactive CD4+ T cells, such as autoimmune diseases. In addition, they also provide a potential explanation for the increased infection rates (i.e. viral reactivation and urinary tract infection) seen in ruxolitinib‐treated patients.
Clinical and laboratory characterization of 114 cases of Castleman disease patients from a single centre: paraneoplastic pemphigus is an unfavourable prognostic factor
Authors: Dong Yujun , Wang Mingyue , Nong Lin , Wang Lihong , Cen Xinan , Liu Wei , Zhu Sainan , Sun Yuhua , Liang Zeyin , Li Yuan , Ou Jinping , Qiu Zhixiang , Ren Hanyun 
Published: March 2015

SummaryThis study retrospectively collected the clinical and laboratory data of 114 patients with Castleman disease (CD) from a single medical centre. Clinical classification identified 62 patients (54·4%) with unicentric Castleman disease and 52 (45·6%) with multi‐centric Castleman disease. Pathological classification revealed 68 cases (59·6%) of hyaline vascular variant, 16 (14·1%) mixed cellular variant (Mix) and 30 (26·3%) plasmacytic variant. Clinical complications occurred in 69 CD patients, including 37 cases of paraneoplastic pemphigus (PNP) and 25 cases with renal complications. Haematological involvement, pleural effusion and/or ascites and POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes) were also found. Univariate analysis showed that presence of clinical complications and PNP were both risk factors relating to CD patient survival. Prognostic factors showing P < 0·15 in univariate analysis and those with clinical significance were subjected to multivariate analysis using a Cox regression model. PNP presence and age over 40 years both significantly adversely affected survival. Thus, only presence of PNP was identified as an independent unfavourable survival risk factor in both univariate and multivariate analyses. Overall, the present data provide a panoramic description of CD cases and emphasize that the presence of PNP is an adverse prognostic factor.
Ofatumumab retreatment and maintenance in fludarabine‐refractory chronic lymphocytic leukaemia patients
Authors: Österborg Anders , Wierda William G. , Mayer Jiří , Hess Georg , Hillmen Peter , Schetelig Johannes , Schuh Anna , Smolej Lukáš , Beck Christian , Dreyfus Brigitte , Hellman Andrzej , Kozlowski Piotr , Pfreundschuh Michael , Rizzi Rita , Spacek Martin , Phillips Jennifer L. , Gupta Ira V. , Williams Vanessa , Jewell Roxanne C. , Nebot Noelia , Lisby Steen , Dyer Martin J. S. 
Published: March 2015

SummaryThere are limited data on retreatment with monoclonal antibodies (mAb) in patients with chronic lymphocytic leukaemia (CLL). In a pivotal study, ofatumumab (human anti‐CD20 mAb) monotherapy demonstrated a 47% objective response rate (ORR) in fludarabine refractory CLL patients. From this study, a subset of 29 patients who had at least stable disease and then progressed were retreated with eight weekly ofatumumab infusions (induction treatment period), followed by monthly infusions for up to 2 years (maintenance treatment period). The ORR after 8 weeks of induction retreatment was 45% and 24% had continued disease control after maintenance at 52 weeks. Efficacy and safety of the retreated patients were compared with their initial results in the pivotal study. Response duration was 24·1 months vs. 6·8 months; time to next therapy was 14·8 months vs. 12·3 months; and progression‐free survival was 7·4 months vs. 7·9 months (medians). Upon retreatment, 72% had infusion reactions, mostly Grade 1–2. Three patients had fatal infections. In summary, ofatumumab retreatment and maintenance therapy was feasible in patients with heavily pretreated CLL and appeared to result in more durable disease control than initial ofatumumab treatment in this subset of patients who may have a more favourable disease profile.
Fatigue in immune thrombocytopenia
Authors: Hill Quentin A. , Newland Adrian C. 
Published: March 2015

SummaryFatigue is an important aspect of health‐related quality of life from the patient perspective and can have significant socio‐economic consequences. It is a common feature of chronic illnesses and a significant number of both adults and children with immune thrombocytopenia (ITP) suffer from fatigue. Reliable, validated fatigue scales have been developed for use in ITP. These will facilitate future investigation of its pathogenesis and the effectiveness of intervention. Acute inflammation acts on neural and endocrine systems resulting in ‘sickness behaviour’, an adaptive response to infection and injury. Inflammation is also thought to cause fatigue in chronic disease and immune dysregulation in ITP appears to have a number of pro‐inflammatory components. Clinicians should consider fatigue when assessing the burden of disease. Although effective ITP‐directed therapy can improve fatigue, a number of fatigue‐directed strategies may also need to be considered.
Secondary acute lymphoblastic leukaemia is constitutional and probably not related to prior therapy
Authors: Ganzel Chezi , Devlin Sean , Douer Dan , Rowe Jacob M. , Stein Eytan M. , Tallman Martin S. 
Published: March 2015

SummaryVery little is known about secondary acute lymphoblastic leukaemia (s‐ALL). This retrospective analysis studied a cohort of s‐ALL patients treated at a single centre between 1994 and 2013, while comparing therapy‐associated ALL (t‐ALL) and antecedent malignancy ALL (am‐ALL) patients. Thirty‐two patients with s‐ALL were identified. The overall incidence was 9·4% among ALL adults while T‐cell s‐ALL was rare (12% of s‐ALLs). The median time interval between two malignant diagnoses was 5·3 years (range: 0·1–28). In contrast to previous reports, most of the s‐ALLs were CD10 + and without KMT2A (MLL) abnormalities. The overall survival (OS) rates of the entire cohort at 12 and 24 months from ALL diagnosis was 49% and 25%, respectively. Most patients (n = 23, 72%) received prior chemo‐/radio‐therapy for their first malignancy (t‐ALL) and only 9 (28%) did not (am‐ALL). No significant difference was found in the incidence of B‐/T‐ lineage ALL, extramedullary disease, blood count, and the rate of Philadelphia‐positive ALL, nor in the rates of complete remission (P = 0·55) and OS (P = 0·97). This similarity, together with high incidence of family malignancy in both groups, raise the possibility that s‐ALL patients may have an inherent predisposition to malignancies and a history of previous therapy may be of lesser importance in the pathogenesis of s‐ALL.
Proteomic profiling of naïve multiple myeloma patient plasma cells identifies pathways associated with favourable response to bortezomib‐based treatment regimens
Authors: Dytfeld Dominik , Rosebeck Shaun , Kandarpa Malathi , Mayampurath Anoop , Mellacheruvu Dattatreya , Alonge Mattina M. , Ngoka Lambert , Jasielec Jagoda , Richardson Paul G. , Volchenboum Samuel , Nesvizhskii Alexey I. , Sreekumar Arun , Jakubowiak Andrzej J. 
Published: March 2015

SummaryToward our goal of personalized medicine, we comprehensively profiled pre‐treatment malignant plasma cells from multiple myeloma patients and prospectively identified pathways predictive of favourable response to bortezomib‐based treatment regimens. We utilized two complementary quantitative proteomics platforms to identify differentially‐regulated proteins indicative of at least a very good partial response (VGPR) or complete response/near complete response (CR/nCR) to two treatment regimens containing either bortezomib, liposomal doxorubicin and dexamethasone (VDD), or lenalidomide, bortezomib and dexamethasone (RVD). Our results suggest enrichment of ‘universal response’ pathways that are common to both treatment regimens and are probable predictors of favourable response to bortezomib, including a subset of endoplasmic reticulum stress pathways. The data also implicate pathways unique to each regimen that may predict sensitivity to DNA‐damaging agents, such as mitochondrial dysfunction, and immunomodulatory drugs, which was associated with acute phase response signalling. Overall, we identified patterns of tumour characteristics that may predict response to bortezomib‐based regimens and their components. These results provide a rationale for further evaluation of the protein profiles identified herein for targeted selection of anti‐myeloma therapy to increase the likelihood of improved treatment outcome of patients with newly‐diagnosed myeloma.
Immune checkpoint inhibition in lymphoid disease
Authors: Eyre Toby A. , Collins Graham P. 
Published: March 2015

SummaryIt has long been understood that the immune system has intrinsic anti‐tumour activity in humans, and that a key mechanism of tumour progression is the ability of a tumour to escape this immune surveillance. A number of attempts have been made to harness this anti‐tumour immunity in both solid tumour oncology and haematological malignancies with variable success. Examples include the use of allogeneic stem cell transplantation and donor lymphocyte infusion in haematological cancer and vaccine studies in solid tumours. Enhanced signalling of the Programmed cell death‐1 (PDCD1, PD‐1)/cytotoxic T‐lymphocyte‐associated protein 4 (CTLA4) ‘immune checkpoint’ pathway has emerged recently as a critical mechanism by which tumours can escape the natural anti‐tumour immune response. As such, novel therapies have been developed to help enhance this natural immunity by switching off the PDCD1/CTLA4 immune checkpoint pathway. The following review will discuss the pathobiology of these pathways and the exciting new data now available in lymphoid malignancies.
Peatland initiation and carbon dynamics in northeast China: links to Holocene climate variability
Authors: Xing Wei , Bao Kunshan , Guo Wenyong , Lu Xianguo , Wang Guoping 
Published: March 2015

Throughout northeast China, the widely distributed peatlands have formed a large carbon (C) pool. However, the relationship between peatland initiation and climate controls is still poorly documented and understood. Understanding the responses of these C‐rich ecosystems to past climate change will provide useful insights into projecting the fate of peatland C in the future. In this study, we present a detailed historical reconstruction of peatland development in northeast China based on 312 basal peat dates, and examine the relationship between Holocene peatland dynamics and climate sensitivity. Our results indicate that peatland initiation started in the early Holocene, and that the majority of peatlands were initiated by and developed during the late Holocene. After the most intensive initiation period of 4.2–0.8 ka, the rate of peatland development slowed, which was concomitant with decreasing insolation and monsoon intensity. The widespread peatland initiation in the late Holocene might have been caused by the cool and moist climate patterns. The optimum timing of the peatland development was not uniform across northeast China, and these spatio‐temporal differences indicate the influences of regional climate and terrain on peatland initiation. Peat‐core data show variations in the long‐term apparent rate of C accumulation (LORCA) during the Holocene, with an average rate of 37.2 g C m−2 a−1. The peak LORCA occurred during 10.5–9.0 ka, probably in response to higher temperatures and stronger East Asia summer monsoon intensities. Both temperature and humidity are important factors influencing the peatland initiation and C dynamics in this region.
Elevated whole blood viscosity is associated with insulin resistance and non‐alcoholic fatty liver
Authors: Zhao Hong‐yan , Li Jing , Xu Min , Wang Tian‐ge , Sun Wan‐wan , Chen Ying , Bi Yu‐fang , Wang Wei‐qing , Ning Guang 
Published: March 2015

SummaryBackgroundAccumulating evidences demonstrate that abnormalities in whole blood viscosity (WBV) have been implicated in insulin resistance which may lead to non‐alcoholic fatty liver disease (NAFLD). However, epidemiological studies exploring the association between WBV and NAFLD were not available.ObjectiveOur objective was to evaluate the association between WBV levels and risk of prevalent NAFLD.DesignThis was a cross‐sectional population‐based study performed in Shanghai, China.PatientsA total of 8673 participants aged 40 years or older were included.MeasurementsWBV was calculated from haematocrit and plasma protein concentration, at a shear rate of 208−1 s, by a validated equation. NAFLD was diagnosed by hepatic ultrasound after the exclusion of alcohol abuse and other liver diseases. Insulin resistance (IR) was assessed by homeostasis model assessment (HOMA‐IR).ResultsThe overall prevalence of NAFLD was 30·2% in this population. With the increase of WBV level, participants have larger waist circumference (WC), more severe insulin resistance and the prevalence of NAFLD increased significantly with elevated WBV quartiles. Compared with those in the lowest quartiles, adults in the highest quartile of WBV levels have higher prevalence of NAFLD (adjusted odds ratio 1·77, 95% confidence interval [CI] 1·48–2·13) and IR (2·72, 95% CI 2·26–3·27).ConclusionsElevated WBV is associated with prevalence of NAFLD and IR in middle‐aged and elderly Chinese population.
Benefits and risks of immediately sequential bilateral cataract surgery: a literature review
Authors: Lansingh Van C , Eckert Kristen A , Strauss Glenn 
Published: March 2015

AbstractImmediately sequential bilateral cataract surgery (ISBCS) is a highly contended issue in ophthalmology, mainly due to the risk of bilateral endophthalmitis and financial penalties that many ophthalmologists face when performing simultaneous cataract surgeries. The purpose of this review is to understand the current status of the knowledge of ISBCS, mainly its benefits and risks and how they compare with the standard of care, delayed sequential bilateral cataract surgery. Evidence, although limited, increasingly supports ISBCS for providing faster rehabilitation, improved visual outcomes, and cost and time savings. Evidence does not support the fear of bilateral endophthalmitis resulting from the simultaneous procedure. However, stronger and greater evidence is needed before ISBCSs can be considered the standard of care. Where ISBCS can potentially create the most beneficial impact is in public eye health programmes in developing countries, but this has not yet been explored.