bluuebunny/crossref_metadata_2025_split huggingface dataset:
High Altitude: A Hyper Coagulable State: Results of a Prospective Cohort Study.
Authors: Kotwal Jyoti , Chopra G. S. , Kotwal A. , Sharma Y. V. , Bhardwaj J. R. 
Published: October 2019

Abstract
Thrombosis has been recognized as a complication of rapid ascent as well as long-term stay at high altitude (HA). Researchers have presented conflicting results and majority of them studied only short-term stay. A prospective cohort study was carried out at a height of 3500 m to study the hematological factors, which may lead to increased propensity to thrombosis on prolonged stay at HA. The subjects were healthy low landers (initial N=38, complete follow up N=32) in age group of 20–40 years, inducted to HA and investigated at induction and subsequently at 3 and 8 months. The comparison cohort was age and sex matched low landers not inducted to HA. Bleeding time, clotting time, hemoglobin (Hb), HCT, platelet count, prothrombin time, APTT, fibrinogen, d-dimers. Protein C, protein S, anti-thrombin III levels, APC resistance, PAI-1, Beta thromboglobulin (BTG) and PF4 were estimated. On induction to HA the mean Hb, platelet count, fibrinogen levels, PAI-1 levels and levels of platelet activation factors were in normal range and not statistically different from those at low altitude (P>0.05). None of the subjects had thrombophilia. There was no statistically significant change in Protein C, Protein S, AT III levels, APC resistance, BT, CT, PT and APTT. The mean values were: Hb (13.9, 15.6, 16.6 gm/dl); platelet count (255, 309, 343 x 103/mm3); fibrinogen (253, 304, 346 mg/dl); BTG (30.3, 38.5, 47.3 IU/ml); PF 4 (3.9, 7.6, 13.7 IU/ml) and; PAI-1 (23.7, 40.1, 49.3 ng/ml), at (induction, 3 months, 8 months) respectively. The P value for all was 0.000 by repeated measure analysis. The high Hb itself is unlikely to be the single cause of the thrombotic tendency at HA as its maximum value was 18.0 gm/dl. Erythrocytosis and hyper viscosity are known to activate platelets, however, platelet activation may be the result of hypoxic stress and injury to platelets or endothelium. An important finding of the study was the rise in PAI-1 levels that correlated with rise in fibrinogen levels and duration of stay at HA (Figure 1 and 2). The endothelial injury and clotting activation followed by increased fibrinolysis maintains homeostasis. We hypothesize that increased PAI-1 level tilts the balance by decreasing fibrinolytic activity and increasing propensity to thrombosis. Hypoxia during surgery is known to cause raised postoperative PAI-1 levels leading to a tendency of postoperative thrombosis. The prolonged hypoxia in a lowlander staying in HA may have a similar effect. By virtue of increased platelet count, hematocrit, platelet activation factors, PAI-1 and fibrinogen, prolonged stay at HA is a pro thrombotic state. Thus, there may be a role for antiplatelet drugs in prevention in view of the platelet hyperactivity and interventional trials with homocysteine lowering vitamins or aspirin also need to be considered.
Is Cladribine, a Treatment for Chronic Lymphocytic Leukemia, a DNA Methylation Inhibitor?.
Authors: Yu Margaret K. , Wade Mark , Moore Brent C. , Fitzpatrick Frank A. 
Published: October 2019

Abstract
Chronic lymphocytic leukemia is a heterogenous B lymphocyte disorder with a variable natural history. Like other Malignancies, key regulatory genes like the tumor suppressor, p16, and the mismatch repair gene, hMLH1, are frequently silenced by DNA methylation in patients with chronic lymphocytic leukemia (CLL). Although focal hypermethylation is found, global genomic DNA is hypomethylated compared to genomic DNA from healthy volunteers. Inhibition of DNA methylation may help CLL cells regain normal cellular function. Few studies have been done evaluating DNA methylation of CLL cells likely in part due to the difficulty in establishing a CLL cell line without altering DNA methylation. In addition, the primary cells do not divide in vitro, making the assessment of effect of a DNA methylation inhibitor very difficult. Of the ten samples tested from patients with CLL, we have not found p16 or hMLH1 expression by western blotting. Since 2-Chlorodeoxyadenosine (Cladribine) is already used clinically for treatment of CLL and may deplete available methyl donors, we asked if Cladribine is effective because of its inhibitory effect on DNA methylation in leukemia cells. To further evaluate the role of DNA methylation in CLL, we assessed the effect of 5-aza-2′-deoxycitidine (Decitabine), a DNA methyltransferase inhibitor compared to Cladribine in HT-29 cells. HT-29 cells do not express p16 and MAGE because of DNA methylation of the promoters. Assessment of global DNA methylation is done using reversed-phase high-performance liquid chromatography. Our results reveal that daily doses of 300nM Cladribine modestly inhibited global DNA methylation by 20+/−14% at 72 hours (n=3), while daily doses of 500nM Decitabine inhibited global DNA methylation by 75+/−9% at 72 hours (n=3). This results in re-expression of MAGE-1, a gene silenced by DNA methylation in all somatic tissues and p16, only in the Decitabine treated cells. We also evaluated the Cdx-2 promoter, an intestinal restricted gene silenced by DNA methylation in HT-29 cells. Decreased methylation of two regions of the Cdx-2 promoter was seen in the cells treated with Decitabine compared to the control cells. Cladribine treated cells had no effect on the Cdx-2, and may actually increase DNA methylation (result of 20 sequences). These results could be explained by the marked growth inhibitory effect of Cladribine at 300nM. We chose to evaluate Cladribine at 300nM because this plasma concentration is obtainable in patients treated with 0.1mg/kg of Cladribine, a dose frequently used in treatment of hairy cell leukemia. Cells with decreased DNA methylation after treatment with Cladribine may have died at the 72 hour time point.
Natural History of 656 Patients with Non IgM MGUS.
Authors: Nobile Carolina , Petrucci Maria T. , Bartolozzi Francesco , Levi Anna , De Muro Marianna , Tirindelli Maria C. , Del Bianco Patrizia , Gallucci Cristiano , Mandelli Franco , Avvisati Giuseppe 
Published: October 2019

Abstract
A monoclonal gammopathy of undetermined significance (MGUS) occurs in about 1% of the population over 50 years of age. Of these, about 20% evolves in Multiple Myeloma (MM); however, so far, predictive parameters of progression have not yet been identified.The aim of this study was to analyse the natural history of a cohort of non IgM MGUS and to identify whether or not there were laboratory parameters at diagnosis which can be utilized as prognostic markers of stable MGUS or progression to MM. From February 1974 to July 2001, 656 non IgM MGUS, whose clinical history was concluded (lost to follow up or died), have been followed at the Hematology of the University “La Sapienza” in Rome. The duration of follow up ranged from 2 months to 324 months, male/female ratio was 1.14, median age was 65 years (range 19–92). In each patient we evaluated: hemoglobin, platelet count, serum protein electrophoresis, serum concentration of monoclonal protein, serum calcium, creatinine, uric acid, BUN and percentage of bone marrow plasma cells.A monoclonal component (MC) of IgG type was documented in 543 patients (83%) while in 106 (16%) it was of IgA type, 6 patients had biclonal MC and 1 had a λ light chain MC; BJ proteinuria was detected in 78 (11%) patients at diagnosis.
After a median follow up of 60.1 months (range 2–324) the MC remained stable in 496 patients (75%), whereas in 160 cases (25%) increased to evolve in MM. According to the literature, cumulative probability of progression to MM was 3%, 7% and 17% at 5, 10 and 15 years respectively. Differently from what observed by other investigators, in this cohort of pts, the MGUS of IgA type was not associated with a higher risk of progression to MM. The median time of progression to MM was 60.7 months (range 3–256) and factors associated with a more rapid progression to MM were advanced age and a higher number of bone marrow plasmacells. At diagnosis of MM, the concentration of the serum MC was significantly higher (P<0.003) in patients who evolved from MGUS than in those with a newly diagnosed MM. None of the studied parameters at diagnosis of MGUS were predictive of evolution to MM even though, levels of MC <2.4 g/dl and bone marrow plasmacell infiltration <9% indicated a slower progression to overt MM.
Significant and Morbid Changes in Heart Rate Variability Precedes and Complicates Symptomatic Hypotension in Peripheral Blood Stem Cell Apheresis.
Authors: Nakamae Hirohisa , Terada Yoshiki , Akahori Mika , Nakane Takahiko , Hagihara Kiyoyuki , Takeoka Yasunobu , Hasegawa Taro , Ohta Kensuke , Yamane Takahisa , Hino Masayuki 
Published: October 2019

Abstract
Peripheral blood stem cell harvest (PBSCH) has been widely performed for rescue following high-dose chemotherapy or as an alternative to BMT for allogeneic stem cell transplantation. However, severe complications, which caused sudden death, were reported in PBSCH from healthy donors. Recent cumulative evidence shows that decrease in cardiovascular signal variability of the R-R period (heart rate variability, HRV) is strongly associated with sudden death and/or cardiac event after a myocardial infarction. Furthermore, usefulness of HRV as a clinical tool has been explored in numerous conditions such as hypertrophic cardiomyopathy, obstructive sleep apnea, diabetic neuropathy, and various neurological alterations. Two types, time domain and frequency domain, are included in HRV analysis. In this study, we investigated HRV during and after apheresis for PBSCH in 23 cases [8 autologous transplant patients, 15 allogeneic transplant donors; 8 men, 15 women; median age 47 years (27–55)]. Date from 24-hour ambulatory ECG recordings were analyzed with R-R data analysis software (MemCalc/CHIRAM version 1, Suwatrust, Tokyo, Japan). Acknowledged simple markers in time domain analysis are the standard deviation of all normal beats (SDNN) and the square root of the mean of the sum of squared differences between adjacent normal-to-normal intervals (r-MSSD). On the other hand, markers in frequency domain analysis include LH, low frequency power (0.04–0.15Hz); HF, high frequency power (0.15–0.4 Hz); LH/HF ratio; VLF, very low frequency power (0.003–0.04 Hz); and ULF, ultra low frequency power (<0.0033 Hz). These power spectrum analyses of HRV are used to investigate sympathovagal balance, autonomic cardiovascular control and/or target function impairment. Among frequency domain analysis markers, VLF or ULF reportedly have particular prognostic value in all causes of mortality after myocardial infarction. In our study, SDNN, r-MSSD, HF, VLF, and ULF significantly and markedly decreased to morbid levels during apheresis (all P<0.001). Of 23 harvest cases, symptomatic hypotension occurred during apheresis in 2 cases and after apheresis in one case. Notably, in these 3 cases, SDNN and VLF had already begun to decrease about 5–10 minutes before significant symptomatic hypotension occurred (P=0.03, P=0.04, respectively). Our results suggested that morbidly decreased HRV indicates serious cardiovascular load and suppression of the parasympathetic nervous system in apheresis for PBCSH. HRV analysis might be a useful tool to prevent donors from severe autonomic cardiovascular complications in PBCSH.
Valgancyclovir Significantly Reduced Reactivation of CMV Following Mini-Transplantation with MAP (Mitoxantrone, Ara-C, and Pentostatin) Regimen.
Authors: Qureshi Anila , Seiter Karen , Ahmed Tauseef , Nelson John , Liu Delong 
Published: October 2019

Abstract
CMV reactivation remains a significant morbidity following allogeneic transplantation. IV gancyclovir may cause myelosuppresion and renal toxicity. It is reserved for the therapy of CMV reactivation. We initiated prophylaxis with Valgancyclovir (Valcyte, manufactured by Hoffman-LaRoche), an oral pro-drug of gancyclovir, against CMV reactivation in patients with CMV exposure history. The Valgancyclovir was given as 450 mg po BID three times a week when post-transplant WBC exceed 1500. In this study, 50 patients who received mini-allogeneic hematopoietic stem cell transplantation following MAP regimen (mitoxantrone, AraC, pentostatin) were included for analysis. 30 patients had prior exposure to CMV (pre-transplant CMV IgG + for patient and /or donor), 20 patients had no evidence of prior exposure. Among the 30 patients who had exposure, 10 patients had antigenemia. Among the 20 patients who did not have exposure history, 2 had CMV antigenemia. Among the 30 patients who had exposure, 19 received Valgancyclovir prophylaxis, 10 received acyclovir, and 1 received gancyclovir. 2 of 19 patients (10%) among the valgancyclovir group had CMV antigenemia, whereas 8 of 11 (72%) who did not receive valgancyclovir prophylaxis had CMV antigenemia (table 1). We conclude that valgancyclovir prophylaxis significantly reduced CMV reactivation (p=0.0009) in patients who had history of CMV exposure and received mini-transplantation after MAP conditioning regimen.
CMV reactivation post-minitransplantation with MAP regimen
*CMV-Ag + CMV-Ag − *p=0.0009 Valgancyclovir n=19 2 17 Acyclovir /Gancyclovir n=11 8 3
Successful Re-Engraftment after Second Allogeneic Transplantation for Graft Failure in Patients with Refractory Hematologic Malignancies.
Authors: Gabriel Don A. , Coghill James , Shea Thomas C. , Comeau Terrance , Irons Robert , Krasnov Carol 
Published: October 2019

Abstract
Graft failure (GF), either primary or after transient engraftment, following matched, related allogeneic hematopoetic stem cell transplantation (HSCT) without T-cell depletion is usually less than 3% for hematological diseases. Graft failure using non-T-cell depleted unrelated donors in chronic myelogenous leukemia (CML) as reported by the national marrow registry is approximately 9.7%. For aplastic anemia, the incidence of graft failure is estimated to be 10%. In this report, we present 3 patients (Pts) with GF following unrelated ablative allogeneic HSCT (two with peripheral blood stem cells and one with bone marrow). Pt. 1 had transient engraftment and Pts 2 & 3 had primary GF. Their relevant demographics are as follows:
TABLE 1
Disease Unrelated Donor Age/Sex GVHD: BMT1 GVHD: BMT2 PTLD Pt1 CML, 1st Chronic Phase Matched 29/F None Grade II Yes Pt2 MDS Matched 57/M None None No Pt3 MDS/AML 1ag Mismatched 55/M None None No
All patients were initially conditioned with alemtuzumab (A) 30mg/day on days −8 to −6, fludarabine (F) 30mg/m2/day on days −7 to −3, and busulfan .8mg/kg x 16 doses (two patients) or x 8 doses (one patient) on days −5 to −2. Conditioning for HSCT #2 included cyclophosphamide 50mg/kg/day, Mesna 50mg/kg/day, and thymoglobulin 2.5mg/kg/day on days −5 to −2. Graft versus host disease (GVHD) prophylaxis included tacrolimus for both HSCT transplants, and low dose methotrexate (3 doses) combined with prednisone (2mg/kg) on days 0–18 followed by a two week taper for HSCT #2. The stem cell product and engraftment kinetics are shown below.

Significant toxicities after HSCT#2 have included successful resolution of PTLD in patient #1 (who also experienced infection with pulmonary respiratory syncitial virus, BK viruria, and fatty infiltration of the liver). BK viruria was noted in patient #2, as well as hypertension and a modest pericardial effusion with global hypokinesis (but with a normal ejection fraction). Hepatomegaly was documented, but no vaso-occlusive disease was established. Patient #3 developed a cardiac arrhythmia, hypertension, and BK viruria and remains Plt transfusion dependent. Patient #1 had grade II GVHD of the skin and gut, but patients 2 and 3 had none. GVHD has been <grade II. GF occurred in 3/17 Pts with MUD transplants that included alemtuzamab in the conditioning regimen. While GF is unacceptably high, it is encouraging that all 3 Pts. successfully completed 2nd MUD transplant with transfusion and cytokine independence using same donor preceded in Pts. 1 & 2 by depletion of anti-ABO incompatible antibodies in the recipient.[table2]
Correlation of Clinical Features with the Mutational Status of GM-CSF Signaling Pathway-Related Genes in Children with Juvenile Myelomonocytic Leukemia
Authors: Yoshida Nao , Yagasaki Hiroshi , Yoshimi Ayami , Takahashi Yoshiyuki , Xu Yinyan , Tanaka Makito , Watanabe Nobuhiro , Matsumoto Kimikazu , Kato Koji , Ueyama Junichi , Inada Hiroko , Goto Hiroaki , Yabe Miharu , Mimaya Junichi , Kikuchi Akira , Manabe Atsushi , Kojima Seiji 
Published: October 2019

Abstract
Juvenile myelomonocytic leukemia (JMML) is a rare clonal myeloproliferative disorder that affects young children. It is characterized by specific hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF) in vitro. Mutations in RAS, NF1, or PTPN11 positioned in the GM-CSF signal pathway, are thought to be involved in the pathogenesis of JMML. However, no information is available on the relationship between these mutations and clinical features of JMML. The impacts of these mutations on clinical outcome also remain unclear. We tested 49 Japanese children with JMML for N-RAS, K-RAS, and PTPN11 mutations and evaluated their clinical significance. We also assessed correlations between mutational status and clinical and laboratory findings, including age at diagnosis, fetal hemoglobin (HbF), platelet count, and cytogenetic abnormality, all which have been proposed as prognostic factors for JMML. Of the 49 JMML patients, cytogenetic abnormalities were detected in 13, including 8 with monosomy 7. For 2 patients, a clinical diagnosis of neurofibromatosis type 1 (NF1) was confirmed. PTPN11 and N-/K-RAS mutations were found in 22 (45%) and 8 (16%) patients, respectively. Neither PTPN11 nor RAS mutations nor NF1 were present in 17 (35%) patients, and no simultaneous aberrations in these genes were found. In patients with the PTPN11 mutation, age at diagnosis was older (35 vs 11 months; P=0.001, or 12 months; P<0.01) and HbF level was higher (31 vs 10%; P=0.03, or 16%; P<0.01) than for patients with the RAS mutation or without any aberration, suggesting that the clinical outcome for patients with the PTPN11 mutation might be poorer, because a higher HbF level and older age have been reported to be poor prognostic factors. In fact, overall survival (OS) at 5 years was lower for patients with the PTPN11 mutation than for those without (20±9% vs 58±9%; P=0.02). In addition to PTPN11 mutation, age older than 24 months (P<0.01) and abnormal karyotype (P=0.02) were also associated with poor prognosis for OS. Of the 49 patients, 33 received stem cell transplantation (SCT). OS probabilities for patients with and without a mutation in PTPN11 at 5 years after SCT were 25±10% and 64±12%, respectively (P=0.04). More importantly, mutation in PTPN11 was the only unfavorable factor for relapse after SCT (P<0.01). Seven patients died owing to relapse and 12 from complications. All patients who died after relapse had a PTPN11 mutation. In summary, our results suggest that PTPN11-mutated JMML might be a distinct subgroup with specific clinical characteristics and a poor outcome.
HIV-Associated Non-Hodgkin Lymphoma in 114 Patients with Undetectable HIV Viral Load at NHL Diagnosis.
Authors: Oksenhendler Eric , Gerard Laurence , Galicier Lionel , Leturque Nicolas , Janin Anne , Meignin Veronique 
Published: October 2019

Abstract
Although the incidence of HIV-associated Non-Hodgkin lymphoma (NHL) has decreased since the use of combination antiretroviral therapy (cART) and survival has improved, NHL still represents one of the most frequent and severe complications in HIV-infected patients. Out of the 361 patients included in a cohort of HIV-NHL from 1996 to 2006, 114 patients had undetectable (? 500 copies/ml) plasma HIV-RNA. These patients were included in a study to analyze the characteristics of NHL over time according to the duration of HIV infection control. All available histological samples were reviewed by a single pathologist. Tumor was defined as virus-associated (VposNHL) if EBV (ISH, IHC or PCR) or HHV-8 (IHC or PCR) were detected in the tumor cells, and not virus-associated (VnegNHL) if nor EBV nor HHV8 were detected. Comparisons were performed using non parametric tests. All patients were treated with cART, with a median duration of 24 months (IQR, 2–119). The median duration of HIV replication control was 9.3 months (IQR, 0.13–90.5). Most cases (63%) had occurred within 18 months of HIV control versus only 37% after M18. When comparing characteristics of NHL in patients with less or more than 18 months of HIV control, the patients were older (52 years versus 41 years, P<10–4), have a longer median duration of HIV infection (4 years versus 2.4 years, P=.006), and a higher median CD4 cell count (346 × 106/L versus 275 × 106/L, P=.03) when HIV control was >18 months versus ?18 months. None of the NHL features (histology, phenotype, staging, ECOG, LDH, B symptoms) were different between the 2 groups. Virus-association could be assessed for EBV and HHV-8 in 96 cases (84%): 52 patients presented with a virus-associated tumor (31 EBV+, 13 HHV-8+, 8 both) and 43 tumors were not virus-associated. There was no difference in this repartition according to the duration of HIV control (P=.62).
VposNHL VnegNHL VundeterNHL HIV-RNA <500 cop/ml < 18 months 30 28 14 HIV-RNA <500 cop/ml > 18 months 16 13 4 Median CD4 cell count (×106/L) 280 290 317
Virus-associated tumors were neither associated with CD4 cell count (P=.86), nor with CD8 cell count (P=.78). In conclusion, NHL still occur in patients with HIV controled infection (30% of HIV-NHL), but within the first 18 months after plasma HIV-RNA becomes undetectable in most patients. After 18 months, the incidence dramaticaly decreased. However, characteristics of NHL and specifically the association with EBV and/or HHV-8 were not different according to the duration of control of HIV infection.