bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bone Mineral Density in Transfusion Independent Thalassemia Patients.
Authors: Pakbaz Zahra , Zhang Zhe , Fung Ellen , Sweeters Nancy , Singer Sylvia , Vichinsky Elliott 
Published: October 2019

Abstract
Low bone mineral density (BMD) is commonly seen in regularly transfused thalassemia patients; however, there have been few reports for bone mineral density assessment in transfusion independent thalassemia patients. The present report includes the results of BMD assessments in patients with transfusion independent thalassemia who were referred to the bone density clinic through 2002–2006. BMD was evaluated by dual energy x-ray absorptiometry (DXA, Hologic Delphi A). A convenience sample of 24 patients (Females=15) with transfusion independent thalassemia were measured with a mean age of 22.1 ± 13.8 years. Subjects younger than 10 yrs old (n = 7) underwent scans for Lumbar spine (LS; L1-L4) and whole body (WB), patients ages 10–20 (n = 5) were assessed for LS, WB, and non-dominant hip, and for patients older than 20 (n = 12), LS and hip scans were completed. Z-scores specific for age and gender were generated using Zemel BS et al.(J. Bone Min Res 2004) database. Z-scores less than −2.0 were considered as low bone density. Calcium intake was assessed by a brief food frequency questionnaire. Past medical history, medications, history of fractures, and family history of osteoporosis were obtained by chart review and patient interview. Data is presented as Mean ± SD. T-test was used to assess differences in continuous variables. The mean LS Z-score (n = 24) was −1.5 ± 1.0 and the mean hip Z-score (n = 17) was −0.5 ± 1.1. Mean WB Z-score (n = 10) was −2.0 ± 1.2. There was a significant (p<0.001) difference between spine and hip Z-scores. Overall 46% had a Z-score less than −2.0. Thirty-three percent of patients have spine Z-scores of less than −2.0 and 25% spine Z-scores between −2.0 and −1.0. Average spine Z-score in patients younger than 10 years old (n=7) was −1.6 ± 0.5. In WB scans, 50% of the patients had WB Z-scores worse than −2.0. None of the young patients (5–9 yrs; n = 7) consumed inadequate intake of calcium (< 2/3 of RDA age specific) while 75% of patients ages 10–20 (n = 4) years old consumed inadequate intake of calcium (dietary + supplement). Neither spine nor hip Z-score was related to patients’ gender, age, and calcium intake. Two patients reported fractures in the past and two reported family history of osteoporosis. Six patients had delayed puberty and one has hypogonadism. Seven patients have short stature. This data suggests that low bone mass is not only a problem in transfused thalassemia patients, but is also observed in non-transfused patients. The significance and pathophysiology of low bone mass should be studied further in non-transfused patient population, especially in younger children.
Impact of Chemotherapy-Induced Anemia on Economic and Quality of Life Outcomes in Adults with Cancer.
Authors: Tran Kimbach T. , Stephens Jennifer M. , Liou Sarah Y. , Botteman Marc F. 
Published: October 2019

Abstract
OBJECTIVES: Anemia is one of the most common hematologic adverse events experienced by cancer patients. The incidence of chemotherapy-induced anemia is as high as 100% for Grade 1 to 2 and 80% for Grade 3 to 4 anemia, although it varies depending on the cancer type and treatment regimen administered. Anemia is associated with high healthcare costs as well as decreased quality of life. The objective of this study was to review the economic and quality of life (QoL) outcomes of anemia in cancer patients.
METHODS: A systematic search of the English-language literature published between 1990 and 2006 was conducted. Additional publications and conference proceedings were retrieved from the article bibliographies and included in the review. Articles selected include prospective or retrospective studies specifically designed to examine burden of illness, direct medical costs, indirect costs, cost drivers, or quality of life outcomes associated with chemotherapy-induced anemia in adult cancer patients. All original costs were reported, with adjusted figures (to 2006 dollars) presented in parentheses using the medical care component of the consumer price index from the US Bureau of Labor Statistics.
RESULTS: Of 183 abstracts screened, 36 met selection criteria and were reviewed in detail. Fifteen and 11 studies focused on economics and QoL burden associated with anemia, respectively. The average annual cost attributable to anemia ranges from $18,418 (2006 US$ $22,775) to $69,478 ($93,454) per patient. Inpatient and outpatient services account for a significant portion of the total costs of anemia. Other key cost drivers for anemia include the cost of erythropoietic drugs, which range from approximately $210 ($239) to $1,090 ($1,288) per week, and the cost of red blood cell (RBC) transfusions, which range from $232 ($323) to $512 ($712) per unit. Patients with hematologic malignancies require almost double the number of RBC units and have higher associated costs than patients with solid tumors. Indirect costs include lost work time due to fatigue for an average of 4.2 sick/vacation days per month. In addition to raising the cost of care, anemia affects patient QoL in the following key domains: energy/fatigue, role (ability to work), social function, and leisure activities. Furthermore, some patients may report daily fatigue, overall decreasing everyday QoL.
CONCLUSIONS: Anemia is a common hematologic adverse event experienced by cancer patients, resulting in significant health care costs, indirect costs, and decrements in patient QoL. In particular, patients with hematologic malignancies incur higher anemia-associated costs compared to patients with solid tumors. The economic burden of cancer treatment-induced anemia, as well as the impact on patient QoL, should be considered when making clinical decisions regarding the optimal treatment course for patients with cancer.
Microalbuminuria among Egyptian Children and Adult with Sickle Cell Hemoglobinopathy, Single Institution Study.
Authors: Ibrahim Wafaa E. , Abdelmonem Ashraf M. , Mahmoud Nermin H. , Mostafa Waleed 
Published: October 2019

Abstract
Introduction: Renal failure is one of the most serious complications of sickle cell diseases; it affects 5% – 18% and leads to early death. Protienuria is highly correlated with risk for future chronic renal failure.
Aim: to estimate the prevalence of microalbuminuria among Egyptian children and adults with sickle hemoglobinopathy, and to evaluate the effect ACE inhibitor on positive cases.
Subject and method: 60 patients (mean age 13.03±9.15) with sickle hemoglobinopathy were included. Patients were divided into 3 groups: sickle cell disease (group I) constituted 20%, Sickle ß-Thalassemia (group II) 46.6% and sickle cell trait (group III) 33.4%. Informed consent was obtained from patients and/or guardians and study approval by local IRB was obtained. Microalbuminuria was measured by turbidimetric assay in 24 hour urine collection. Patients with microalbuminuria were started on a 4 weeks trial of ACE inhibitor after excluding any contraindication for the drug. Patients were closely monitored for side effects and repeat microalbuminuria assay was done at the end of the trial period. Data were coded, entered and processed using SPSS (version 11).
Results: The prevalence of microalbuminuria was 32.5% in sickle cell disease, and sickle β thalassemia while in sickle cell trait was 5 % (p=0.02). The highest level of microalbuminuria (93.3+-146.27) was observed in sickle cell disease patients followed by sickle β thalassemia (63.82+-172.38) followed by sickle cell trait(18.75+-12.86).
Compared to patients with no microalbuminuria, the group with positive microalbuminuria was significantly older (18.31±4.48 vs. 9.24± 4.96 years), had higher number of blood transfusions / year (7.08±3.55 vs. 5.11±4.05), higher mean number of hemolytic crisis (2.38±1.98 vs. 1.11±1.19), higher mean number of pain crisis (2.92±1.61 vs. 2.2±1.48), and higher mean serum creatinine (0.63±0.31 vs. 0.47±0.19) (p<0.01).
After 4 weeks trial of ACE inhibitor there was a statistically significant reduction (77.9% reduction) in number of cases with microalbuminuria as well as level of microalbuminuria (dropped from 171.91 ± 251.60 to 27.11 ± 13.99) (p= 0.005). Conclusion: Microalbuminuria is a significant problem among patients with sickle cell disease. ACE inhibitors have significant impact on improving microalbuminuria.
Patients Mobilizing Large Numbers of CD34+ Cells ("Super-Mobilizers") Have Improved Survival in Autologous Stem Cell Transplantation for Lymphoid Malignancies.
Authors: Bolwell Brian J. , Pohlman Brad , Rybicki Lisa , Kalaycio Matt , Sobecks Ronald , Dean Robert M. , Bernhard Laura , Cherni Kelly , Ferraro Christina , Bates Jenny , Brown Stacey , Sweetenham John William 
Published: October 2019

Abstract
We have anecdotally observed that many patients mobilized with Etoposide (VP) + filgrastim (G) collect very high numbers of CD34+ cells for autologous stem cell transplantation (ASCT). Some BMT centers have suggested that the cellular composition of an autologous graft may influence ASCT outcome. We therefore queried whether patients collecting high numbers of PBPCs (“super-mobilizers”) have a better outcome than other patients. We retrospectively reviewed 693 consecutive adult patients with Non-Hodgkin Lymphoma (NHL) or Hodgkin Lymphoma (HL) receiving an ASCT from 1/1994 through 12/2005 treated with a uniform preparative regimen of Busulfan, Cyclophosphamide and Etoposide (Bu/Cy/VP). Of these 693 patients, 350 were mobilized with VP (2 gm/m2) + G and comprised the study population. After receiving VP+G, patients were collected for a minimum of 2 days with a collection goal of 7 × 106 CD34+ cells/kg. A minimum collection of 2.0 × 106 cells was required to proceed to ASCT. Super-mobilizers were defined as collecting, and infusing, greater than 8 × 106 CD34+ cells/kg. 203 patients were super-mobilizers, while 147 collected between 2.0 and 7.95 CD34+ cells/kg. Pre-transplant performance status, LVEF, and DLCO were similar between the two groups. Super-mobilizers were slightly younger (mean 47 years old vs. 51 years old, p=0.003) and more likely to have received 2 or fewer prior chemotherapy regimens, (80% vs. 63%, p<0.001). 82% of the entire study population had NHL and 18% HL, and 83% had chemotherapy sensitive disease at the time of ASCT. The super-mobilizer group required fewer days of pheresis for mobilization (median 2 days vs. 5 days, p<0.001). The median CD34+ dose of the super-mobilizer group was 13.7 × 106/kg vs. 4.4 ×106/kg in the standard collecting group. The super-mobilizer group had a superior overall survival as shown graphically below:
Figure Figure
A multivariable analysis was performed, and revealed three variables associated with improved survival: disease status at transplant (comparing patients in remission vs. those with refractory disease, p=0.004), younger age at transplant (p=0.033), and CD34+ cell dose (>8 vs. <8, p=0.038). We conclude that patients mobilized with VP+G achieving robust CD34+ cellular mobilization have an improved outcome after ASCT. The mechanism of action of this phenomenon is conjectural; further studies are required to determine if the composition of the infused graft directly influences outcome, and, if so, what specific cellular components are important. However, collecting large numbers of CD34+ cells may be clinically beneficial (regardless of the specific mechanism of action) and may warrant a change in definition of collection end points.
Testing Standard and Genetic Markers in 220 Patients with Multiple Myeloma (MM) with Complete Data Sets: Superiority of Molecular Genetics.
Authors: Shaughnessy John D. , Haessler Jeffrey , Hanamura Ichiro , Huang Yongsheng , Stewart James P. , Zhan Fenghuang , Sawyer Jeffrey , Anaissie Elias , van Rhee Frits , Tricot Guido , Epstein Joshua , Zangari Maurizio , Pineda-Roman Mauricio , Hollmig Klaus , Crowley John , Barlogie Bart 
Published: October 2019

Abstract
Background: Many prognostic models have been proposed for staging patients with MM, most recently the ISS system utilizing B2M and albumin.
Patients and Methods: In the context of Total Therapy 2 (TT2) for newly diagnosed MM, we identified 220 patients in whom 4 standard prognostic factors (SPF: B2M, albumin, LDH, hemoglobin), imaging data (MRI-defined focal lesions [MRI-FL]), metaphase-derived cytogenetic abnormalities (CA), FISH-derived amp1q21 and del13q14, and gene expression profiling (GEP)-derived data are available. The baseline characteristics and clinical outcome of the 220 patients are similar to those of the entire population of 668 patients receiving TT2. The median follow-up of the 220 patients is 42mo compared to 52mo for all 668 patients. Five multivariate analysis-based prognostic models were derived, utilizing SPF only (model I), with progressive addition of CA (model II), MRI (model III), FISH (model IV) and GEP (model V).
Results: In model I, B2M, LDH and hemoglobin, but not albumin were independently significantly associated with overall survival (OS) (R2=22.5%); upon introduction of CA (model II) (p=.008), only LDH remained significant (p=.033) (R2=28.3%); addition of MRI (model III) was not significant (R2=31.1%); addition of FISH (model IV) was significant for amp1q21 (p=.003) but not for del13q13, with CA remaining significant (p=.023) (R2=38.1%); when GEP was added (model V), the 70 gene-derived model (p<.001) and FISH-based amp1q21 (p=.025) were the only significant variables associated with OS (R2=43.4%). Indeed when GEP was entered into the model first, its R2 value was 24.6%, with the addition of amp1q21 raising R2 to 31.8%, beyond which only minor contributions were made by the remaining 7 variables. With the combined use of GEP and amp1q21, 3 risk groups could be distinguished with 5-yr OS rates of 82% with GEP-low risk/no amp1q21 (n=107), 61% with GEP-low risk/amp1q21 (n=78) and 29% with GEP-high risk regardless of amp1q21 status (n=35).
Conclusion: Among an ever increasing prognostication armamentarium in MM, few studies have investigated the concurrent use of all reputedly important variables. Here, we clearly show, in a comparison of 5 prognostic models that, once molecular genetic variables were introduced, standard prognostic parameters provided little if any further contribution. Therefore, such genetic tests should be more widely performed in order to adequately evaluate the results of clinical therapeutic trials and identify robust high-risk subgroups for novel therapies with purportedly unique mechanisms of action.
Figure Figure
A Gene Expression Signature of Benign Monoclonal Gammopathy Evident in Multiple Myeloma Is Linked to Good Prognosis.
Authors: Zhan Fenghuang , Barlogie Bart , Arzoumanian Varant , Huang Yongsheng , Hollmig Klaus , Pineda-Roman Mauricio , Tricot Guido , van Rhee Frits , Zangari Maurizio , Dhodapkar Madhav , Shaughnessy John D. 
Published: October 2019

Abstract
Monoclonal gammopathy of undetermined significance (MGUS) can progress to multiple myeloma (MM), often through a phase of smoldering MM (SMM). We hypothesized that a molecular signature of MGUS may be detectable in a subset of patients with MM. Applying Significance Analysis of Microarrays, 52 genes, involved in important pathways related to cancer, were found to be differentially expressed between plasma cells from 22 healthy subjects, 24 strictly defined MGUS/SMM and 351 symptomatic MM (P < .001). Unsupervised hierarchical clustering of 351 MM and 44 cases of MGUS and 16 cases of MM with a MGUS history, created two major cluster branches, one containing 82% of the MGUS cases and 28% of the MM, termed MGUS-like MM (MGUS-L MM). Using the same clustering approach on an independent cohort of 213 MM revealed 27% were MGUS-L. The MGUS-L MM signature was associated with a higher prevalence of low-risk clinical and molecular features and superior survival (P < .01), despite a lower incidence of complete remission (P = .006). The MGUS-L signature was also seen in 15 of 20 patients surviving more than 10 years after autotransplant. These data reveal molecular switches associated with the development and progression of plasma cell dyscrasias.
Nifuroxazide Inhibits STAT3 Function and Shows Potent Anti-Tumor Activity Against Multiple Myeloma.
Authors: Nelson Erik A. , Hideshima Teru , Gashin Laurie , Walker Sarah R. , Lynch Rebecca A. , Chauhan Dharminder , Anderson Kenneth C. , Frank David A. 
Published: October 2019

Abstract
Activation of the transcription factor STAT3 is essential for the pathogenesis of many cancers, including multiple myeloma. While normal cells can tolerate a reduction in STAT3 function, tumors often require constitutive STAT3 signaling for survival. Thus, identifying drugs that inhibit STAT3 activity may provide new therapeutic agents useful for cancer treatment. We have developed a high throughput cell-based screen to identify drugs that inhibit STAT3-dependent transcriptional activity. To assure the specificity of these drugs for STAT3 function, we performed a counter screen assessing NF-kappaB-dependent transcriptional activity. To bypass the difficulties inherent in the development of novel small molecules for clinical use, we analyzed a library of 1120 drugs that are either FDA approved, or are otherwise known to be safe in humans. From this screen, we identified nifuroxazide, a drug used to treat dehydration associated with diarrheal illness, as a potent inhibitor of STAT3 transcriptional activity. By contrast, nifuroxazide has no effect on NF-kappaB-dependent transcription. Myeloma cells containing constitutive STAT3 activation show decreased STAT3 tyrosine phosphorylation when incubated with 10 uM nifuroxazide. In addition, expression of STAT3 target genes necessary for myeloma survival, including bcl-x, mcl-1, and cyclin D1, is markedly reduced by 10 uM nifuroxazide. To determine whether these effects of nifuroxazide on STAT3 signaling alter cell viability, we utilized U266 myeloma cells, which depend on STAT3 activation for survival. U266 viability is inhibited by nifuroxazide at an EC50 of approximately 3 uM. Notably, RPMI 8226 myeloma cells, which do not contain activated STAT3, are not affected by comparable concentrations of nifuroxazide. In addition, this dose has no effect on normal peripheral blood mononuclear cells. Given that myeloma cells receive survival signals from bone marrow stromal cells, we determined if nifuroxazide affects myeloma survival in stromal cell co-cultures. Nifuroxazide is effective at reducing U266 viability in the presence of bone marrow stromal cells at an EC50 of approximately 3 uM. Thus, screening for compounds that inhibit STAT3 transcriptional activity is useful in identifying potential drugs for myeloma therapy. Through this approach, we have identified a novel STAT3 inhibitory function for nifuroxazide. Nifuroxazide inhibits STAT3 mediated survival of myeloma cells and may be useful, either alone or in combination with other drugs, for the treatment of patients with multiple myeloma.
HGF Inhibits BMP-Induced Osteoblastogenesis: Implications for the Bone Disease in Multiple Myeloma.
Authors: Standal Therese , Abildgaard Niels , Fagerli Unn-Merete , Stordal Berit , Hjertner Oyvind , Borset Magne , Sundan Anders 
Published: October 2019

Abstract
Multiple myeloma is a hematological malignancy characterized by accumulation of malignant plasma cells in the bone marrow. Most patients develop osteolytic lesions, caused by an uncoupling of bone formation from bone resorption. In patients with osteolytic lesions the osteoblasts are fewer and less active. HGF (Hepatocyte Growth Factor) is produced by the malignant plasma cells and is found at high concentrations in the bone marrow of most patients with multiple myeloma. In this study we show that HGF inhibited BMP-induced expression of alkaline phosphatase and mineralization in human mesenchymal stem cells (MSC) and the murine myoid cell line C2C12. Furthermore, the expression of the osteoblast-specific transcription factors Runx2 and Osterix was reduced by HGF treatment. HGF inhibited BMP-induced differentiation of MSC partly by keeping the cells in a proliferative, undifferentiated state. The in vitro data was supported by the observation of a negative correlation between HGF and a marker of osteoblast activity, bone specific alkaline phosphatase (rho=−0,45, p=0,008), in sera from 34 myeloma patients. These observations suggest that HGF inhibits bone formation in multiple myeloma.
SB431542, a TGF-Beta Receptor Kinase Inhibitor, Restores Bone Formation Which Ameliorates Myeloma-Induced Microenvironment.
Authors: Takeuchi Kyoko , Abe Masahiro , Oda Asuka , Amou Hiroe , Hiasa Masahiro , Asano Jin , Kitazoe Kenichi , Hashimoto Toshihiro , Ozaki Shuji , Kido Shinsuke , Inoue Daisuke , Matsumoto Toshio 
Published: October 2019

Abstract
Multiple myeloma (MM) cells stimulate bone resorption and concomitantly suppress bone formation, leading to devastating bone destruction. TGF-beta, a potent inhibitor for terminal osteoblasts (OB) maturation and mineralization, is abundantly produced and released from bone tissues through enhanced bone resorption, and activated by osteoclasts (OC)-derived acids and MMPs in MM bone lesions. In the present study we investigated the impact of TGF-beta inhibition on induction of bone formation in MM as well as the effects of matured OB on MM growth. TGF-beta completely suppressed BMP-2-induced mineralized nodule formation by OB cultured in osteogenic media supplemented with beta-glycerophosphate and vitamin C. SB431542, an inhibitor of TGF-beta type I receptor kinase, potently suppressed induction of Smad6 by TGF-beta, which inhibits BMP-2 signaling. SB431542 along with BMP-2 abolished such TGF-beta actions and enhanced mineralized nodule formation more than BMP-2 alone. Notably, addition of SB431542 antagonized the inhibitory effects of conditioned media from MM cell lines (RPMI8226 and U266) and bone marrow plasma from patients with MM, resulting in restoration of the BMP-induced mineralized nodule formation. Furthermore, MC3T3-E1 cells matured by BMP-2 enough to exhibit mineralized nodules suppressed the proliferation of 5TGM1 MM cells in sharp contrast to stromal cells as well as untreated or TGF-beta-treated undifferentiated MC3T3-E1 cells that promote MM cell growth and survival. Interestingly, 5TGM1 MM cell growth was also potently suppressed by MC3T3-E1 cells cultured with BMP-2 in the absence of beta-glycerophosphate to achieve OB maturation without formation of mineralized nodules, suggesting a responsible role for OB-derived non-mineralized factors associated with terminal differentiation of OB. In addition, the induction of OB maturation down-regulated the production by OB of IL-6 and up-regulated osteoprotegerin, an inhibitor for osteoclastogenesis. Taken together, blockade of TGF-beta actions release OB from the differentiational arrest in MM bone disease and thus can be a good therapeutic maneuver restoring bone formation as well as suppressing osteoclastogenesis to ameliorate bone destruction and at the same time suppressing MM expansion by disrupting the MM-induced microenvironment which can be called as MM niche.