bluuebunny/crossref_metadata_2025_split huggingface dataset:
Disease Burden of Chronic Lymphocytic Leukemia within the European Union.
Authors: Watson Louise , Wyld Peter , Catovsky Daniel 
Published: October 2019

Abstract
Introduction: While Chronic Lymphocytic Leukemia (CLL) is considered a rare disease, to our knowledge the current prevalence of the condition within the European Union (EU) member states is not published. Understanding the number of individuals with CLL is vital to assess disease burden within the wider population.
Methods: Using 2002 data from the International Agency for Research on Cancer (IARC), we estimated the number of individuals with CLL (ICD-10 C91.1) from those reported for all leukemias (C91–95) and extrapolated the figures by the population increase within the EU between 2002 and 2006, the last year with fully updated Community population estimates. One-year and 5-year partial prevalence estimates are reported (i.e. the number of individuals still living 1 and 5 years post diagnosis). We then applied proportional estimates from the literature to assess those requiring immediate treatment, those under observation and their likely progression rates.
Results: We found that within the 27 EU states plus Iceland, Norway and Lichtenstein, 1-year and 5-year CLL partial prevalence estimates totalled approximately 13,952 and 46,633 individuals respectively in 2006. If we apply Rai or Binet staging to the 1-year estimate, up to 45% of patients will be Stage III/IV or B/C and require immediate treatment. Thus 6,278 individuals may be treated within the first year of diagnosis. Of 55% (7673) under observation, by five years up to 33% (2,532) may have more advanced disease with increased risk of mortality.
Conclusion: While CLL is a rare disease, the number of individuals burdened by the disease within the EU is considerable and thousands of patients require treatment and physician care, which has cost implications for member states.
Imatinib Is Cost-Effective Comparing to Interferon-(IFN) for Patients with Newly Diagnosed Chronic-Phase (CP) Chronic Myeloid Leukemia (CML) from the Chinese Public Healthcare System Perspective.
Authors: Wang Chun , Chen Zi , Feng Weiwei 
Published: October 2019

Abstract
Background: Imatinib, a break-through oral molecular targeted therapy, has demonstrated impressive and durable responses as well as survival advantage compared to IFN based treatment in newly diagnosed CP CML (1, 2, 3). However, imatinib has not been registered on the Chinese National Reimbursement Drug List (RDL) whereas IFN has solely based on the drug price. Although IFN plus Ara-C has shown better efficacy than IFN alone, IFN is normally used alone to treat CP CML in China. The objective of this study was to conduct a cost-effective analysis comparing imatinib with IFN alone in newly diagnosed CP CML from the Chinese public healthcare systems perspective.
Methods: The 60-month data from the International Randomized Interferon versus STI571 Study (IRIS) was used to estimate survival for imatinib and utility values for survival. Since patients received IFN with Ara-C, and most patients randomized to receive IFN plus Ara-C crossed over to the alternate treatment imatinib in IRIS, historical data from the literature was used to estimate survival for IFN alone. Survival estimates were based on published survival curves for patients who achieved and those who did not achieve a complete cytogenetic response. Lifetime costs of treatment containing drug costs, office visits, lab tests, and hospitalizations were estimated based on treatment protocols from tier 3 hospitals in China. Incremental cost-effectiveness ratio (ICER), which is the difference in costs divided by the difference in quality adjusted life years (QALY) between imatinib and IFN, was calculated. All costs and outcomes were discounted at a rate of 3.5% per annum following the UK Health Technology Assessment recommendation.
Results: Total survival was estimated to be 19 and 9 for patients treated with imatinib and IFN, respectively. The discounted QALYs were 11.83 with imatinib and 5.41 with IFN. The discounted lifetime costs of treatment were RMB1169,661 with imatinib and RMB715,983 with IFN. The ICER for imatinib comparing with IFN was RMB70,510 per QALY.
Conclusion: The World Health Organization (WHO) considered a cost-effectiveness ratio (CER) of less than three times the GDP per capita as cost effective in developing countries (4). Based on the 2006 GDP per capita for China US$7,700 (5), the WHO CER for China would be RMB175,167. The ICER for imatinib over IFN was RMB70,510 which is less than half of the WHO CER threshold. Therefore, imatinib is cost-effective comparing with IFN in newly diagnosed CP CML from the Chinese public healthcare system’s perspective.
Day Hospital Approach to Uncomplicated Vaso-Occlusive Crises in Children with Sickle Cell Disease.
Authors: Raphael Jean L. , Kamdar Aditi , Mueller Brigitta U. 
Published: October 2019

Abstract
Day hospital management for patients with sickle cell disease experiencing uncomplicated vaso-occlusive pain crises has been described in adult populations as an alternative care delivery system. To date, there are no published studies addressing the utility of this model in pediatric populations. We retrospectively studied all admissions to the Day Hospital at the Texas Children’s Sickle Cell Center since its inception in 2000. A Day Hospital admission was defined as a minimum of two consecutive days of aggressive pain management as an outpatient, including intravenous hydration and analgesics, supported by home treatment over night with oral analgesic and anti-inflammatory agents. We gathered data on demographics, sickle cell genotype, incoming pain scale, provider type (physician versus nurse practitioner), home treatment with narcotics prior to presentation, average daily dose of narcotics administered during admission, length of stay, admission charges, return rate to the emergency department within 48 hrs, and transfer rate from Day Hospital to inpatient care. A total of 35 patients accounted for 80 visits during the study period (2000–2006). Approximately 83% of patients had sickle cell anemia (HbSS). The mean baseline hemoglobin for patients was 9.1 g/dl. Patients were seen equally by physicians and nurse practitioners. Approximately 93% of visits were preceded by home narcotic use within 24hrs of presentation. The mean incoming pain score was 7.9 on a scale from 1 to 10. The mean length of stay was 2.4 days. The return rate for emergency care within 48 hours was 6%. Approximately 40% of patients admitted to the Day Hospital were transferred to inpatient care for unresolved pain or increasing medical needs. We conclude that a dedicated Day Hospital facility has the potential to provide patient-centered, effective, and timely management of vaso-occlusive crises in children as well as adults. It may serve as an alternative to emergency and inpatient care for children with mild to moderate pain. Future studies should compare day hospital care to inpatient hospitalization for differences in length of stay, cost, patient satisfaction, and quality of life.
Long-Term Follow-Up of 132 Immunocompetent Primary Central Nervous System Lymphomas Treated at Leon Berard Cancer Centre: Proposition of a New Prognostic Model.
Authors: Ghesquieres Herve , Sunyach Marie Pierre , Drouet Youenn , Sebban Catherine , Chassagne Catherine , Jouanneau Emmanuel , Honnorat Jerome , Biron Pierre , Blay Jean-Yves 
Published: October 2019

Abstract
This study was aimed at analyzing long-term data on survival, relapse, and treatment-related neurotoxicity in all patients with newly diagnosed primary CNS lymphoma (PCNSL) and patients specifically treated with the C5R protocol (Blay et al, Blood86:2922,1995). We also identified prognostic factors of survival in order to propose a predictive model.132 patients with PCNSL seen at Leon Berard cancer centre between 1984 and 2006 were analyzed. Median age was 59 years (range: 26–81); 49% of the patients had a performance status (PS) of 2 to 4; 8% had leptomeningeal and ocular involvement. Initial treatment was chemotherapy and radiotherapy in 122 patients and chemotherapy alone in 10. Fifteen patients did not receive high-dose methotrexate as part of initial chemotherapy. The median overall (OS) and progression-free survival (PFS) for the whole series were 21.6 and 13.3 months for a median follow-up of 84.2 months. Twenty-five (19%) patients experienced toxic death, 24 (18%) progressed during treatment and 39 (30%) relapsed. Neurotoxicity was observed in 16% of the patients. Of the 49 patients receiving the intensive C5R protocol, 6 (12%) experienced toxic death, 3 (6%) progressed during treatment, 17 (35%) relapsed and 14% developed leukoencephalopathy. Median OS and PFS for patients treated with the C5R protocol were 73.8 and 44.4 months, respectively. Univariate analysis of the whole series showed that age over 60 years, elevated serum LDH, PS greater than 1 and the International Extranodal Lymphoma Study Group score were prognostic factors for OS and PFS, but not the presence of deep or multiple lesions or a high CSF protein level. The backward regression model integrating age, serum LDH, number and location of lesions, and CSF protein level showed that age, serum LDH and a tumor location within deep regions were predictive of OS and PFS. Four prognostic groups presenting 0, 1, 2 or 3 factors could be significantly distinguished regarding OS and PFS.
Overall Survival probability as a function of the number of risk factors among abnormal LDH, Age at diagnosis > 60 and deep lesion Overall Survival probability as a function of the number of risk factors among abnormal LDH, Age at diagnosis > 60 and deep lesion
This study allowed to identify a new prognostic model using 3 factors. This model has the interest to withdraw the PS which could be a subjective data and CSF protein level for which the accurate cutoff is not well known. This study also showed that, with a long follow-up, patients treated with the C5R protocol have excellent OS and PFS.
Pharmacologic Replacement of BIM BH3 Reactivates Apoptosis in Hematologic Cancer and Lymphoproliferative Disease.
Authors: LaBelle James L. , Fisher Jill K. , Katz Samuel G. , Bird Gregory H. , Lawrence Chelsea E. , Silverstein Amy M. , Walensky Loren D. 
Published: October 2019

Abstract
Selective targeting of deregulated apoptotic protein networks is a promising pharmacologic strategy for subverting diseases of unrestrained cellular survival, such as cancer. BCL-2 family protein interactions constitute a critical control point for the regulation of apoptosis. Whereas multidomain anti-apoptotic proteins such as BCL-2 guard against cell death, multidomain pro-apoptotic proteins such as BAX constitute a gateway to cell death through mitochondrial damage. The BH3-only proteins function as death sentinels situated throughout the cell, poised to transmit signals of cellular injury to multidomain members. BH3-only proteins deliver their death messages via their conserved alpha-helical BH3 domains. Whereas the indirect activator class of BH3-only proteins (e.g. BAD) counteract anti-apoptotic proteins, the direct activator subgroup (e.g. BIM) is believed to trigger apoptosis both by neutralizing anti-apoptotics and by directly activating the mitochondrial executioners BAX and BAK. The essential roles of BH3-only proteins in maintaining cellular homeostasis is highlighted by the development of autoimmune disease and cancer in mouse models of BH3-only protein deficiency. By inserting hydrocarbon “staples” into native BH3 peptide sequences, we have produced a chemical toolbox of stabilized alpha-helices of BCL-2 domains (SAHBs) to dissect apoptotic signaling pathways in vivo and explore the pharmacodynamic effects of “BH3 replacement” in cancer cells and mouse models of deregulated apoptosis. Whereas SAHBs display high affinity binding to anti-apoptotic targets, BID and BIM SAHBs also directly engage BAX and are thus especially potent in inducing apoptosis of a panel of leukemia and lymphoma cell lines. To evaluate the impact of selective BH3 replacement in vivo, we tested the capacity of BIM SAHB to reactivate apoptosis in the lymphoproliferative disease of Bim-/- mice. Strikingly, Bim-/- mice treated with BIM SAHB displayed marked influx of tingible-body macrophages into the lymphoid infiltrates of affected organs, with scattered cells throughout the infiltrate robustly positive for activated caspase-3, suggestive of SAHB induced apoptosis induction. Our studies highlight the therapeutic potential of BH3 replacement to circumvent apoptotic blockade and restore the death pathway in hematologic cancer and lymphoproliferative disease.
Gene Expression Profiling of Pulmonary Mucosa-Associated Lymphoid Tissue (MALT) Lymphoma Identifies New Diagnostic Markers, Biological Heterogeneity and Therapeutic Targets.
Authors: Chng Wee J. , Fonseca Rafael , Bergsagel Peter Leif , Vrana Julia A. , Kurtin Paul J. , Remstein Ellen , Dogan Ahmet 
Published: October 2019

Abstract
To further understand the molecular biology of mucosa-associated lymphoid tissue (MALT) lymphoma, we conducted a comprehensive gene expression study on the Affymetrix platform using total RNA extracted from biopsy specimen of 35 well-characterized pulmonary MALT lymphoma samples and compared them to gene expression profiles of a range of B and T cell lymphoma, such as Burkitt’s lymphoma, diffuse large B-cell lymphoma, Waldenstrom macroglobulinemia, chronic lymphocytic leukemia, multiple myeloma, and peripheral T-cell lymphoma, and normal cellular counterparts, such as different B-cell and T-cell populations, normal plasma cells and lung tussue. Analytical strategies were adopted to negate tissue specific effect such that our results can be generalized to MALT lymphoma from other anatomical sites. We further analyzed the data using functional tools such as gene-set enrichment analysis and gene ontology. Network/pathway analysis was performed using Metacore. Unsupervised clustering of whole dataset (including other lymphoid malignancies and normal cellular counterpart) using genes with variable expression, showed that compared to other B-cell lymphoid malignancies, MALT lymphoma have a prominent T-cell signature. Using established gene expression of different B-cell compartment, we confirmed that MALT has a marginal zone B-cell and memory B-cell cell-of-origin signature. Using ANOVA with post-hoc pair-wise comparison, we identified 4 novel transcripts over-expressed in MALT but not other B-cell tumors, and validated one of these using immunohistochemistry. MALT lymphoma with t(11;18) or t(14;18) over-expressed genes enriched for pathways other than the NFKB pathway such as JAK-STAT and SRC signaling pathways, which may represent novel therapeutic targets. We identified a number of genes with ‘outlier’ expression including RARA and RGS13. However, translocation involving RARA and the immunoglobulin heavy chain locus was not detected by FISH, suggesting other mechanisms of deregulating gene expression were involved. Using unsupervised clustering of only the MALT samples, we found that the molecular heterogeneity within MALT is composed of a group characterized by MALT1 translocations and another group with plasmacytic differentiation. Interestingly, further refinement of this grouping can be achieved by clustering the samples based on ‘outlier’ gene expression. Samples with MALT1 translocations have high expression of RARA, samples with plasmacytic differentiation have high FKBP11 expression and samples with high RGS13 expression tend to have trisomy 3 and reactive follicles. Our study therefore identified novel molecular markers, deregulated pathways and genetic defects in MALT. Furthermore, subgroups with distinct pathological features and anchored by unique pattern of ‘outlier’ gene expression were identified.
Evaluation of AMG 531 Efficacy in Nonsplenectomized Patients with Chronic Immune Thrombocytopenic Purpura (ITP) in a Randomized Placebo-Controlled Phase 3 Study.
Authors: Kuter David J. , Bussel James B. , Senecal Francis M. , Aledort Louis M. , Kessler Craig M. , Sanz Miguel A. , Liebman Howard A. , Slovick Frank T. , Kelly Reggie , Guo Matthew , Nichol Janet L. 
Published: October 2019

Abstract
AMG 531 is a novel platelet-stimulating peptibody that stimulates the thrombopoietin (TPO) receptor, and is being studied for its ability to increase production of platelets. Here we report efficacy data in nonsplenectomized patients from a randomized, double blind, placebo-controlled Phase 3 study designed to evaluate the efficacy and safety of AMG 531 in patients with chronic ITP. Sixty-two nonsplenectomized patients were enrolled (placebo, 21; AMG 531, 41) with a median age of 52 years (range 21 to 88) and a mean baseline platelet count of 18.3x109/L. Subcutaneous AMG 531 or placebo was administered weekly for 24 weeks at a starting dose of 1μg/kg, and adjusted to maintain a target platelet count of 50-200x109/L. One patient randomized to placebo received 3 doses of AMG 531 in error and was included in the efficacy analysis as a placebo. The primary study endpoint was the incidence of a durable platelet response, defined as a platelet count ≥50x109/L for ≥6 weeks during the last 8 weeks of the 24-week treatment period in the absence of rescue medications. Starting at a low dose of AMG 531 and gradually increasing it, as well as reducing the dose of steroids in certain patients, contributed to lower platelet counts early in the study. Twenty-five of the 41 patients (61.0%) receiving AMG 531 achieved a durable platelet response compared to 1/21 (4.8%) receiving placebo (p<0.0001). Overall response, defined as either durable or transient platelet response (≥4 weekly platelet responses), was observed in 36/41 (87.8%) patients receiving AMG 531, but was observed in only 3/21 (14.3%) placebo patients. The mean number of weekly platelet responses (platelet count ≥50x109/L) was significantly greater in patients receiving AMG 531 (15.2/24 weeks, 63%) compared to placebo (1.3/24 weeks, 5%) (p<0.0001). AMG 531 reduced the proportion of patients requiring ITP rescue medications, defined as either increase from baseline in dose of concurrent ITP medication or use of new medication to increase platelet counts. Thirteen of 21 (61.9%) placebo-treated patients received rescue medications compared to just 7/41 (17.1%) AMG 531-treated patients (p=0.0004). There were no treatment-related serious adverse events and no patients tested positive for neutralizing antibodies against either AMG 531 or endogenous TPO. In summary, as in previous studies, AMG 531 was well-tolerated while effectively increasing and sustaining platelet counts in nonsplenectomized patients with ITP. When compared to placebo, AMG 531 administration resulted in a higher mean platelet count, and was associated with less frequent use of rescue medications.
A Population (Registry) Based Analysis of the Impact of Bcr-Abl Specific Tyrosine Kinase Inhibition on Survival after Diagnosis of Philadelphia Chromosome Positive Chronic Myelogenous Leukemia..
Authors: Turner A. Robert , Hewitt Joanne D , Kamruzzaman Anmmd , Larratt Loree M. , Rusnak Deborah A. , Cox-Kennett Nanette , Belch Andrew R. 
Published: October 2019

Abstract
Specific tyrosine kinase inhibition (TKI) of the bcr-abl fusion protein in Philadelphia chromosome positive chronic myelogenous leukemia (CML) was introduced into general use in 2000 after a plenary abstract presentation to ASH in December 1999. Here we report the impact of the use of TKI on survival of all patients with CML in a total population based registry in the province of Alberta in Canada where BMT has been in use since 1980, α interferon +/− cytarabine since 1990 and TKI since 2000. All therapies have been fully funded by the public health care system in Alberta. Alberta’s population in 2000 was 2.97 million.
Prior to 2000, allogeneic stem cell transplant (BMT) was the only curative therapy available but its application was limited to a minority of patients with CML. Alpha interferon induced a cytogenetic remission in some CML and alpha interferon plus cytarabine prolonged survival in CML.
CML AML n 5 yr survival % BMT n 5 yr survival % BMT *59% of deaths occurred in the first year after diagnosis in the 2000–06 cohort 1980–89 303 40% NA 540 13% NA 1990–99 276 48% 25 692 15% 13 2000–06 216 83%* 8 680 25% 16 p<0.0001 p<0.0001
A 5 year survival for CML (1980–89) of 40% is consistent with published data. The 48% 5 year survival for CML (1990–99) reflects the benefit of interferon. The 5 year survival of acute myelogenous leukemia (AML) in Alberta is provided for comparison to reflect general improvement in care.
The proportion of AML patients who had a BMT did not significantly change while there was a significant reduction in numbers of CML transplanted in 2000–06. Transplant status did not significantly affect outcome in CML patients with 75% of non-BMT and 84% of BMT patients still alive at 5 years (p=0.08). In contrast, transplant status was statistically significant in AML, with 5 year survival of 49% in those treated with BMT, compared to 17% of those not transplanted (p<0.0001).
The results of this study show that TKI therapy (primarily imatinib) has had a major impact on the outcome of CML treatment in the province of Alberta. Long term survival, >80%, has been achieved and it appears that almost all of these patients can look forward to a normal life expectancy without the need for BMT.