bluuebunny/crossref_metadata_2025_split huggingface dataset:
Diastolic Dysfunction Is an Independent Risk Factor for Death in Patients with Sickle Cell Disease.
Authors: Sachdev Vandana , Machado Roberto F. , Shizukudu Yukitaka , Rao Yesoda , Sidenko Stanislav , Ernst Inez , St. Peter Marilyn , Coles Wynona A. , Rosing Doug , Blackwelder William C. , Castro Oswaldo , Kato Gregory J. , Gladwin Mark T. 
Published: October 2019

Abstract
Background. Pulmonary hypertension, defined by an elevated pulmonary artery systolic pressure measured by Doppler-echocardiogram, has been identified as the major predictor of death in the adult sickle cell disease population. While diastolic dysfunction is also observed in this population, the prevalence in unselected patients, the association with high pulmonary artery systolic pressure, and the attributable mortality remain unknown.
Methods. Diastolic function parameters, pulmonary artery systolic pressures and right and left ventricular size and function were measured prospectively in 215 subjects with sickle cell disease. Associations between these parameters, lab and echocardiographic variables and prospective mortality were determined.
Results. Diastolic dysfunction, measured by conventional and tissue-Doppler echocardiography, was present in 19% of patients with sickle cell disease. Diastolic dysfunction and pulmonary hypertension were both present in approximately 11% of patients and diastolic dysfunction accounted for approximately 10–20% of the variability in tricuspid regurgitant jet velocity. Importantly, Cox Proportional Hazards analysis revealed that diastolic dysfunction, as reflected by low E/A ratio, was associated with prospective mortality with a risk ratio of 1.9 (95%CI 1.0 to 3.7; p=0.028), even after adjustment for tricuspid regurgitant jet velocity. While pulmonary hypertension remained the dominant determinant of mortality risk, even after adjustment for measures of diastolic function (adjusted rate ratio of 5.3; 95% CI= 1.9 to15.0; p<0.001), the risk was additive such that patients with both risk factors had an odds ratio for death of 10.1 (95% CI= 3.2 to 31.9; p<0.001).
Conclusions. Diastolic dysfunction and pulmonary hypertension due to other causes each contribute independently to prospective mortality in patients with sickle cell disease. Patients with both risk factors have an extremely poor prognosis. These data support the implementation of Doppler-echocardiographic screening of adult patients with sickle cell disease to identify individuals at high risk of death for intensified therapy.
Figure Figure
Impact of HLA Class I Typing-Resolution and Mismatches on Survival and Graft-Versus-Host Disease in Patients after Hematopoietic Stem Cell Transplantations from Unrelated Donors.
Authors: Markiewicz Miroslaw , Wojnar Jerzy , Krawczyk-Kulis Malgorzata , Wylezol Iwona , Giebel Sebastian , Holowiecki Jerzy 
Published: October 2019

Abstract
We analyzed 150 consecutive patients (pts) transplanted from unrelated donors (URD) at single institution- Silesian Medical Academy in Katowice- with use of the same standard operating procedure from February 1997 until December 2004 for CML (74 pts), AML (28), ALL (27), SAA (9), MDS (7), MM (1), NHL (1), PNH (1), OMF (1), bi-phenotypic AL (1). 92 pts were transplanted from matched donors, including 59 with complete 10 alleles (HLA-A,B,C,DRB1,DQB1) high resolution (HR) DNA-typing; and 33 with first class match established on base of low-resolution (LR) (13), serological (7) or un-complete typing without HLA-C (13) and second class HR typing. 58 pts were transplanted from mismatched donors (first class typing was HR in 43, LR in 14 and serological in 1 pt): 22 with single allelic mismatch (2 HLA-A, 7-B, 6-C, 7-DQB1), 33 with single HLA-C antigen mismatch and 3 with double mismatches (2 B+C, 1 C+C). Survival advantage at 4 years, although without statistical significance (p=0.16), was observed in the group of pts transplanted from 10/10 alleles matched donors (36+/− 11%) over those with mismatched donors (24+/− 11%). Oppositely, pts transplanted from matched donors who were not completely typed in HR did not achieve better survival (23+/− 17%). Poorest survival (13+/− 12%, p=0.007) was observed in patients transplanted from mismatched homozygous donors (n=10). The risk of acute GVHD grade 3–4 was increased (p=0.007) in pts with mismatched donors (31+/− 6%) when compared to matched completely typed in HR (10+/− 4%). Also the rate of graft failure tended to be lower in pts with matched than mismatched donors (5.1% versus 10.2%, p=0.25). In contrast, relapse rate was lower in mismatched (23+/− 10%) than in HR matched pts (34+/− 12%, p=0.55) what may reflect better GVL effect in mismatched transplant recipients. Unexpectedly, the rate of chronic GVHD was similar in pts with 10/10 alleles matched and mismatched donors (40+/− 10% versus 42+/− 9%, p=0.75). These results indicate that complete high resolution HLA class I typing is necessary for adequate selection of unrelated donors. Class I HLA-B and -C mismatches influence both survival and serious a-GVHD incidence.
10/10 alleles matched mismatched p survival at 4 years 36+/− 11% 24+/− 11% 0.16 aGVHD grade 3–4 10+/− 4% 31+/− 6% 0.007 graft failure rate 5.1% 10.2% 0.25 relapse rate 34+/− 12% 23+/− 10% 0.55 cGVHD 40+/− 10% 42+/− 9% 0.75 10/10 alleles matched mismatched homozygous donors p survival at 4 years 36+/− 11% 13+/− 12% 0.007
Single Antigen Mismatched Related Donor Allogeneic Stem Transplants Have Similar Outcomes as Matched Unrelated Donor Allogeneic Stem Cell Transplants: A Single Center’s Experience.
Authors: Newton Benjamin , Sprague Kellie A. , Klein Andreas K. , Klingemann Hans G. , Chan Geoffrey W. 
Published: October 2019

Abstract
We retrospectively reviewed transplant outcomes of 32 patients who received an allogeneic stem cell transplant from single human leukocyte antigen (HLA) mismatched related family donors (MMRD), and compared them to 45 case-matched controls who received transplants from matched unrelated donors (MUD). Controls were matched for age, sex, disease type, disease status, CMV seropositivity, and type of conditioning regimen (full versus reduced intensity). Full donor neutrophil engraftment for MMRD and MUD transplants were achieved in 81% and 93% of patients respectively (p=0.1). Grade 2–4 acute graft-versus-host disease (GVHD) developed in 32% of MMRD transplants versus 42% for MUD transplants (p=0.43). Limited and extensive chronic GVHD developed in 22% and 19% of MMRD transplants versus 14% and 30% of MUD transplants (p=0.61). Day 100 transplant related mortality (TRM) for MMRD and MUD transplants were 31% and 33% respectively (p=0.69). Disease relapse occurred in 16% of MMRD transplants versus 13% in MUD transplants (p=0.87). Overall survival at 1 and 3 years for MMRD transplants were 53% and 40% versus 49% and 32% for MUD transplants (p=0.61). There were no statistically significant differences among HLA-A, HLA-B, and HLA-DR MMRD transplants in terms of neutrophil engraftment and grade 2–4 acute GVHD, but day 100 TRM among HLA-DR MMRD transplants were higher than among HLA-A and HLA-B MMRD transplants (50% versus 0% and 17% respectively, p=0.01). Overall survival at 3 years was 53% for HLA-A and HLA-B MMRD transplants, 30% for HLA-DR MMRD transplants, and 32% for MUD transplants (p=0.42). In conclusion, single antigen mismatched related donor allogeneic stem cell transplants have similar transplant outcomes as matched unrelated donor allogeneic stem cell transplants and usually takes a shorter amount of time to stem cell donation. HLA-DR mismatch transplants have higher day 100 TRM than Class I mismatch transplants. Single antigen mismatched related donors should be considered as donors for allogeneic stem cell transplantation.
MMRD vs MUD Transplants MMRD MUD P-value MMRD=mismatch related donor; MUD=matched unrelated donor N n=32 n=45 Median age 44 years 41 years P=0.14 High-Risk Disease 63% 71% P=0.51 CMV Seropositivity 45% 42% P=0.93 Full Conditioning 72% 76% P=0.72 Neutrophil Engraftment 81% 93% P=0.1 Grade 2–4 aGVHD 32% 42% P=0.43 Day 100 TRM 31% 33% P=0.69 Disease Relapse 16% 13% P=0.87 3-year OS 40% 32% P=0.6 Figure Figure
Autologous Stem Cell Transplantation as First-Line Therapy in Peripheral T-Cell Lymphomas. A Prospective Multicenter Study.
Authors: Reimer Peter , Ruediger Thomas , Schertlin Tobias , Geissinger Eva , Weissinger Florian , Einsele Hermann , Mueller-Hermelink Hans Konrad , Wilhelm Martin 
Published: October 2019

Abstract
Peripheral T-cell lymphomas (PTCL) are rare diseases representing only 10–15% of all non Hodgkin’s lymphomas and show a poor outcome following conventional chemotherapy. Long-term remissions are achieved in only 15 to 35% of patients following conventional chemotherapy. However, the impact of more aggressive therapeutic approaches such as high-dose therapy with autologous stem cell transplantation (ASCT) as first-line therapy is poorly defined mainly due to the lack of prospective PTCL-restricted studies. Therefore, in 2000 we initiated the first prospective PTCL-restricted multicenter study in PTCL. The results of the first 30 patients (pts) have recently been published. Here we update our data on all pts. entering the study.
Study design: Pts. < 65 years with PTCL of all subtypes without primary cutaneous lymphoma and ALK1+ anaplastic large cell lymphoma were included. Treatment consisted of 4–6 courses of CHOP followed by DexaBEAM or ESHAP regimens before collection of stem cells. Subsequently, pts. underwent total body irradiation (TBI) and high dose cyclophosphamide (60 mg/kg body weight) chemotherapy with ASCT.
Patient characteristics: From 6/00 to 7/05 75 pts. (65% male) with a median age of 50 years were enrolled. Main subtypes were Peripheral T-cell lymphoma not otherwise specified (NOS, 41%) and Angioimmunoblastic T-cell lymphoma (AIL, n= 31%). According to the Ann Arbor classification, 75% of the pts had stage III/IV disease. The International Prognostic Index (IPI) was low/low intermediate in 51% and high intermediate/high in 49% of pts, respectively.
Results: So far 65 pts are eligible for evaluation. Forty pts could be transplanted (62%). After a median follow-up of 10 months post-transplant 22 pts (42%) are in sustained remission and 8 pts (15%) have relapsed. Treatment-related mortality was 2/65 (3%, one secondary AML, one multiorgan failure). Twenty-five pts (38%) did not proceed to ASCT mainly due to progressive disease (n= 18). Treatment-related toxicity was comparable to other high-dose studies in B-cell lymphomas. The IPI does not seem to have a significant impact on response to therapy, progression during CHOP therapy, or relapse rate following ASCT.
Conclusion: Our data confirm the feasibility and efficacy of first line ASCT following myeloablative radiochemotherapy in PTCL. A sustained remission seems achievable for a significant proportion of pts. However, additional treatment strategies are required to prevent early progression before myeloablative therapy. Longer follow up is necessary to confirm long term remission rates.
Efficacy of High-Dose Therapy and Autologous Stem Cell Transplantation for Chemoresistant Hodgkin’s Lymphoma.
Authors: Metcalfe Tracee L. , Gooley Ted A. , Press Oliver W. , Pagel John M. , Petersdorf Stephen H. , Bensinger William , Holmberg Leona , Maloney David G. , Gopal Ajay K. 
Published: October 2019

Abstract
High-dose therapy (HDT) with autologous stem cell transplantation (ASCT) is the standard treatment for patients (pts) with chemosensitive relapsed or refractory Hodgkins lymphoma (HL). Unfortunately, there are few established options for HL pts with chemoresistant disease and data regarding the efficacy of HDT and ASCT in this setting are limited. One hundred and seventy-two patients underwent HDT followed by ASCT for HL at our centers between 1971 and 2005. Of these, 66 pts (38.6%) had chemoresistant disease defined as < 50% reduction in the size of the tumor with the chemotherapy regimen immediately preceding HDT. The baseline characteristics of these pts included: median age = 34 years (yrs) (range, 14–59 yrs), male = 39 (59%), stage I/II= 15 (23%), stage III = 17 (26%), Stage IV = 34 (51.5%), ≥ 5cm tumor bulk = 23 (35%), > 1 extranodal site of disease (ENS) = 13 (20%), median # of prior regimens = 2 (range 1–5), and prior radiation (RT) = 34 (52%). Histologies included nodular sclerosis (NS) in 53 (80%), mixed-cellularity in 11 (17%), and lymphocyte predominant in 2 (2%). Twenty-seven pts (41%) received TBI-based preparative regimens and 39 (59%) underwent non-TBI conditioning with the most common chemo-only regimen of bulsulfan, melphalan, thiotepa used in 19 pts.The estimated 5-year overall (OS) and progression-free survival (PFS) of this cohort was 31% and 18%, respectively with a median follow-up of 2.6 yrs among surviving pts (Figure). Twenty-two (56%) of the 39 deaths were due to relapse and 17 (44%) resulted from non-relapse causes including: 7 infections, 5 pulmonary, 1 cardiac, 1 hepatic, 1 renal, and 2 (5%) unknown causes. Multivariable modeling utilizing the above baseline criteria identified factors that were statistically significantly associated with inferior OS and PFS. These included: NS histology (OS: HR=3.8, p=0.03; PFS: HR=2.5, p=.03), non-TBI conditioning (OS: HR=2.6, p=0.009; PFS: HR=2.1, p=.02), 2 or more ENS (OS: HR=4.1, p=.0005; PFS: HR=3.7, p=0.0008); and male gender (OS: HR=2.0, p=.05; PFS: HR=2.0, p=.03) These data suggest that HDT and ASCT may result in prolonged remissions and survival for a significant minority of chemoresistant HD pts, with improved outcomes observed in those treated with TBI-based regimens, non-NS histology, female gender, and fewer ENS, though novel improved therapies for these patients are still required.
Figure Figure
Differential Expression of Hem1 and CTLA-4 in B-CLL Patients with High and Low CD38 Expression.
Authors: Joshi Avadhut D. , Dickinson John D. , Lynch James C. , Bierman Philip J. , Bociek Gregory R. , Devetten Marcel P. , Armitage James O. , Joshi Shantaram S. 
Published: October 2019

Abstract
B chronic lymphocytic leukemia (B-CLL) is the most common leukemia in the elderly with heterogeneous clinical outcome. Rai stage, immunoglobulin heavy chain mutation status, Zap-70 expression, CD38 expression and chromosome abnormalities are used as prognostic markers. Among these, CD38, a differentiation marker of T lymphocytes, has been reported to have a role in B-CLL pathogenesis. High CD38 expression is associated with an unfavorable clinical course with advanced disease stage, poor responsiveness to therapy, short time to first treatment, and shorter survival, whereas B-CLL patients with low CD38 expression required minimal or no treatment, remained treatment free for longer time and had better survival. However, the molecular basis for the association of CD38 expression and clinical course of B-CLL patients is not known. Therefore, in this study we classified 35 B-CLL patients into CD38 high (>30%) and CD38 low (<30%) expressions, and the clinical course was correlated with gene expression profile using oligonucleotide DNA microarrays consisting 10,000 genes. There was a significant difference in CD38 expression levels in patients with good clinical outcome (mean CD38 ~ 20%) compared to poor clinical outcome (mean CD38 ~ 46%). Median time to treatment with high CD38 expression was 30 months compared to 69 months for low CD38 expressing patients. Significance analysis of microarray (SAM) identified 52 differentially expressed genes. From these genes, Hem1 and CTLA-4 were further studied because the Hem1 expression is limited to hematopoietic cells and CTLA-4 is involved in modulation of immune response. Also, CTLA-4 is a member of the immunoglobulin superfamily involved in the cell cycle regulation and prolongs the progression through the G1 phase of the cell cycle. The differential expression of Hem1 and CTLA-4 was also confirmed by semi-quantitative RT-PCR. Hem1 was found to be over expressed in B-CLL patients with higher CD38 expression compared to lower CD38 expression, whereas CTLA-4, was over expressed in B-CLL patients with lower CD38 expression compared to patients with high CD38 expression thus confirming the microarray results. Furthermore, to determine whether the expression levels of these two genes are associated with disease progression in B-CLL, log rank test was applied across the expression of Hem1 and CTLA-4 and disease progression. The higher expression of Hem1 was associated with shorter time to treatment (Figure 1), whereas lower expression of CTLA-4 was associated with shorter time to treatment (Figure 2). Thus, these results while confirming the prognostic value of CD38 expression, demonstrate the possible molecular basis of CD38 mediated clinical course in B-CLL patients involving key genes such as Hem1 and CTLA-4.
Figure 1 Figure 1. Figure 2 Figure 2.
Congenital Dysfibrinogenemia - Clinical Manifestations in Relation to the Fibrinogen Gene Mutation.
Authors: Miesbach Wolfgang A. , Galanakis D. K. , Scharrer Inge 
Published: October 2019

Abstract
The congenital dysfibrinogenemia is a rare clotting disorder which is based on a structural defect in the fibrinogen molecule. Approximately 350 cases of unrelated families with dysfibrinogenemia have been reported. Of these, the structural defects have been determined in nearly 170 families.
Patients and methods:
We describe the clinical manifestations in 50 patients from 19 families from Frankfurt. Up to now the underlying structural defect could be found in 43/50 (86 %) of the patients and 14/19 (74 %) of the families (Galanakis, New York, von Depka, Hannover).
Results:
In 19 families, 50 patients were found with dysfibrinogenemia (52% female, age median: 52 years-old, 9 - 89 years old). The fibrinogen level, according to Clauss decreased in median with 51 mg% (15 – 86 mg/dl, norm: 150 – 450 mg/dl). The determination of the other fibrinogen levels resulted in the normal range. Fibrinogen according to Schulz: 240 mg/dl, immunological fibrinogen: 244 mg/dl. The Reptilase time was prolonged to 55 sec (median, norm: − 20 sec.). 50% of the patients stated a distinct bleeding tendency and mostly a tendency for haematoma (59%) and secondary haemorrhaging (45%). 13 patients had a thrombotic disease, of which 80% were arterially caused. 12 % of the patients stated a tendency for bleeding as well as for thrombosis. 19% of the patients had miscarriages, partly recurrent and 18/50 (36 %) of the patients were asymptomatic. Furthermore, it was observed that the clinical symptoms are often similar in the affected families. By administration of fibrinogen concentrates, the pregnancy in 4 patients who suffered from abortions in the first weeks of pregnancy resulted in healthy children. Fibrinogen was administered from the beginning of the pregnancy till the delivery (aiming fibrinogen levels of Clauss up to 100 mg%). In 11 of the families, an Aalpha 16 Arg-Cys mutation was found. In the other three families there were found gamma mutations, e.g., gamma 356 Ala-Thr, gamma 318–319 del and gamma 318 Ap-Gly. The clinical manifestations in the families with Aalpha 16 Arg-Cys mutation were bleeding (65 %), thrombosis (22 %) and abortions (16 %). 25 % were asymptomatic and 12 % of the patients experienced both, bleeding and thrombosis.
Conclusion:
The investigations of the Frankfurt patient group with dysfibrinogenemia showed a high rate of clinical manifestations, mostly the tendency for haematoma and secondary haemorrhaging. The tendency for thrombosis is concerned rather with the arterial vessels. The high tendency for miscarriage is striking, which makes the administration of fibrinogen concentrate during pregnancy necessary. The most common found fibrinogen mutation was at the Aaplha chain in position 16. In patients with this mutation mostly both, bleeding and thrombosis occurred. Thus, management of patients with this mutation may be complicated by the variablility of clinical manifestations of congenital dysfibrinogenemia.
The Prothrombin C>T Mutation at Position 20209 (F2 20209*T) Promotes 3′end mRNA Processing and Thus Contributes to Thrombophilia through Gain-of-Function.
Authors: Danckwardt Sven , Hartmann Kathrin , Ben-Tal Ofira , Hentze Matthias W. , Kulozik Andreas E. 
Published: October 2019

Abstract
The functional analysis of the common prothrombin (F2) 20210*A allele has recently revealed gain-of-function of 3′end processing as a novel genetic mechanism predisposing to human disease. Based on these observations we sought for the functional impact of a novel C>T mutation at position 20209 (F2 20209*T). This mutation affects the penultimate nucleotide of the 3′ untranslated region (UTR) of the F2 mRNA and has been reported to be associated with fetal loss, intrauterine growth retardation and a history of venous thrombosis. We have therefore systematically analyzed the functional effect of this polymorphism and show that the F2 20209*T mutation up-modulates the F2 mRNA expression and protein expression by ~1.4 fold which corresponds to the observation that the reported patients with the F2 20209*T allele tend to have moderate F2 level elevations, slightly above - but also within - the upper normal-range.
Furthermore, because of the critical position of the F2 20209*T allele we have analyzed the putative impact of this mutation on 3′end mRNA formation and show that this mutation represents a gain-of-function mutation, causing increased cleavage site recognition, increased 3′ end processing and increased mRNA accumulation neither affecting the poly(A) tail length nor the site of cleavage. Thus, this novel mutation falls into a general category of mutations in the F2 gene which contribute to thrombophilia by interfering with a tightly balanced architecture of non-canonical 3′end formation signals. This, together with previous results, demonstrates that the F2 cleavage site and adjacent parts of the 3′ flanking sequence represent an error-prone “vulnerable region” in which N>T mutations may give rise to clinically relevant gain-of-function phenotypes.