bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prediction and Optimization of the Therapeutic Effect of mTOR Inhibitors in Aggressive B-Cell Lymphomas
Authors: Bi Chengfeng , Zhang Xiaoyan , Xuan Zhang , Chan Wing C , McKeithan Timothy , Fu Kai 
Published: October 2019

Abstract
Mechanistic target of rapamycin complex 1 (mTORC1) is a central integrator of nutrient and growth factor inputs that controls cell growth in all eukaryotes. Rapamycin and its analogs (rapalogs) have been approved for the treatment of relapsed mantle cell lymphoma. A large proportion of aggressive B-cell lymphoma patients, however, respond poorly to rapalogs. The second generation of mTOR inhibitors function as ATP-competitive inhibitors (TORi), directly targeting the mTOR catalytic site. TORis have been proven to be more effective than rapalogs in cancer treatment. However, the mechanism underlying the cytotoxic effect of TORis in aggressive B-cell lymphomas remains unclear. In this study, we demonstrated that TORi-induced apoptosis is predominantly dependent on loss of mTORC1-mediated 4EBP phosphorylation. Knocking out Rictor, a key component of mTORC2, or inhibiting p70S6K has little effect on TORi-induced apoptosis. In contrast, increasing the EIF4E:4EBP ratio by either overexpressing EIF4E or knocking out 4EBP1/2 protected lymphoma cells from TORi-induced cytotoxicity. Furthermore, down-regulation of MCL1 and BCL-XL expression plays an important role in TORi-induced apoptosis whereas BCL-2, in cells with high expression, confers resistance to TORi treatment. Based on the mechanism study, we demonstrated that BH3 profiling, primarily NOXA and HRK stimulation, can effectively predict the cytotoxicity of the TORi in lymphoma cells. Also, in combination with pro-apoptotic drugs, especially BCL-2 inhibitors, the TORi exerted powerful anti-tumor effects both in vitro and in vivo. Taken together, this study provides mechanistic insight in TORi treatment in aggressive B-cell lymphoma and identified a mean to predict and improve its effectiveness clinically.

Disclosures
No relevant conflicts of interest to declare.
Iliopsoas Hemorrhage in Pediatric Patients with Hemophilia, Experience from One Centre
Authors: Türkkan Emine , Atay Didem Yalcin , Ocak Suheyla , Ozdemir Gul Nihal 
Published: October 2019

Abstract
Introduction: Iliopsoas hematoma is a serious, life threatening bleeding event in patients with hereditary clotting disorders and significantly associated with morbidity. It occurs most commonly in patients with severe hemophilia (Balkan et al Haemophilia 2005). In this review, we evaluated our patients with iliopsoas hematoma and compared with literature.
Methods: The eleven pediatric patients with hemophilia and iliopsoas hematoma treated in a research and training hospital in Istanbul, between 2005 and 2015 were enrolled. The clinical characteristics including symptoms, signs, complications, and treatment were analyzed retrospectively.
Results: We evaluated 14 episodes of iliopsoas hematoma from 11 patients (10 hemophilia A and 1 hemophilia B). All patients were male and the median age was 12 (8 -14) years old. Eight patients had one episode, three had two episodes. One patient had a high titer inhibitor against factor VIII. The hematoma was spontaneous and unilateral in all cases. The most common symptoms were hip pain and hip flexion contracture. Iliopsoas hematomas were confirmed by ultrasound, CT or MR scan. The treatment consisted of factor replacement and rehabilitation therapy. One patient needed erythrocytes transfusion. The mean duration of factor replacement therapy was 13.5 +/- 2.1 days. One severe hemophilia A patient with inhibitor treated with recombinant factor VIIa. Long term complications included paresthesia in 3 patients in the distribution of femoral nerve, quadriceps atrophy in 3 patients and permanent abnormal posture in one patient.
Conclusion: The psoas muscles are located in the iliopsoas compartment posterior to the transversalis fascia, which is the posterior boundary of the retro peritoneum. Presentation of iliopsoas hematomas is often non-specific with abdominal, pelvic, back or groin pain or swelling. If they are large, iliopsoas hematomas can present with constipation, urinary frequency or fever. They can even compress the femoral nerve and cause a femoral neuropathy . A delay in treatment may result in permanent femoral nerve palsy (Mannucci N Engl J Med 2004). In this report, we present our experience and treatment modality in 14 episodes of iliopsoas hematoma in pediatric hemophilia patients. Rehabilitation treatment with factor replacement is safe and effective therapy for patients with small hematomas and little or no neurological symptoms. More aggressive recommendations have been made for patients with large hematomas and severe neurological symptoms or hemodynamic instability. An early diagnosis allows early factor replacement therapy, and decreases the risk of recurrence and morbidity.

Disclosures
No relevant conflicts of interest to declare.
Leukemia Cells Attenuate the Response of Leukemia-Associated Macrophages to LPS By Down Regulation of TLR4
Authors: Liao Jinfeng , Wang Rong , Yang Feifei , Feng Wenli , Yang Xiao , Wang Lina , Zheng Guoguang 
Published: October 2019

Abstract
Tumor-associated macrophages (TAMs) play important roles on tumor progress in solid tumors. Two therapeutic methods targeting TAMs, i.e. depleting TAMs and ¡°re-educating¡± TAMs to anti-tumoral M1 phenotype, have been proposed. LPS, which can stimulate macrophages to M1 phenotype, was suggested for anti-tumoral therapy. Recently, we reported leukemia-associated macrophages (LAMs), which showed leukemia-promoting effects, in leukemic microenvironment. In this study, we investigate whether LAMs can be re-educated by LPS in vitro.
THP-1 cells were treated with PMA for 48 hours for differentiation to macrophages. Then macrophages were treated with LPS for 24hrs directly (M¦Õ-LPS) or after cocultured with K562 or Jurkat cells for 48hrs (LAM-LPS). BrdU incorporation assay and TUNEL assay were used to detect the proliferation and apoptosis respectively. Significant decrease of BrdU positive rate was detected in M¦Õ-LPS while little change was detected in LAM-LPS. The TUNEL positive rates of both M¦Õ-LPS and LAM-LPS decreased. The expression of polarization related genes was studied by real time PCR. Increase of most M1 phenotype genes was detected and little difference of most M2 phenotype genes was detected in M¦Õ-LPS, whereas little difference of both M1 and M2 phenotype genes was detected in TAM-LPS. To further investigate the mechanism, Western blot was used to detect the M1 polarization determining transcription factor STAT1 among different groups. Drastic increase of p-STAT1 was detected in M¦Õ-LPS while little change was detected in LAM-LPS. These data suggested that LAMs had attenuated response to LPS. MAPK signal pathways were also examined by Western blot analysis. ERK, JNK and P38 pathway were significantly activated in M¦Õ-LPS, which was not observed in LAM-LPS. In order to further investigate the mechanism, real time PCR was used to detect the expression of LPS receptor complex: TLR4, CD14 and MD2. The results showed that TLR4 was decreased in LAM cocultured with both leukemia cells when macrophages without coculture or LPS treatment were set as control. Decrease of TLR4 was also observed in M¦Õ-LPS and LAM-LPS.
Our results suggested that leukemia cells attenuate the response of LAMs to LPS by down regulation of TLR4.

Disclosures
No relevant conflicts of interest to declare.
Presepsin (soluble CD14 subtype) Is Available in Febrile Neutropenic Patients with Hematological Malignancy As Diagnosis and Assesment Biomarker of Infections
Authors: Oyake Tatsuo , Masuda Takayuki , Sugawara Norifumi , Asahi Maki , Suzuki Yuzo , Okano Yoshiaki , Fujishima Yukiteru , Aoki Yusei , Kowata Shugo , Ito Shigeki , Ishida Yoji 
Published: October 2019

Abstract
BACKGROUND: Febrile neutropenia (FN) is often observed in hematological malignancy (HEM). Although most are considered to be due to bacterial infections, it is often difficult to specify the focuses and pathogens of infections in FN patients. Presepsin (Pre-SEP) is a subtype of soluble CD14, which is a receptor for lipopolysaccharide (LPS)/LPS-binding protein complexes and is expressed on the myeloid and monocytic cells' surface. Recently, Pre-SEP has been shown to be a useful biomarker for assessing the severity of sepsis. However, little is known about the biological characteristics of Pre-SEP in FN patients. Therefore, we compared the Per-CEP to the established infection markers including procalcitonin (PCT) and C-reactive protein (CRP) continually in FN patients.
METHODS: We measured Pre-SEP concentration in the plasma, PCT and CRP on Day 0, 2, 4, 7 and 14 after the onset of FN and compared them to those of non-febrile neutropenic patients. Furthermore we evaluated the impact of Pre-SEP, PCT and CRP on the diagnosis and assessment of active infection status in FN, using the cut-off value by setting to 314 pg/ml, 0.50 ng/ml and 0.30 mg/ml. Correlation analysis was performed using Peason's correlation coefficient test.
RESULTS: Sixty-two hospitalized FN patients with HEM (AML 14, ALL 9, MDS 14, NHL 13, MM 8, ATL 2, others 2 cases) were treated according to IDSA guideline. Figure 1 showed the each data in Pre-SEP, PCT and CRP value on day 0, 2, 4, 7 and 14. The frequency of less than the cut-off value at day 0 of FN onset were 33.8 %, 77.4 % and 37.1 % in Pre-SEP, PCT and CRP respectively, indicating that Pre-SEP showed the highest sensitivity. On day 0, a significant correlation was not observed between Pre-SEP and PCT (P=0.457, correlation coefficient: 0.096) but it was observed between Pre-SEP and CRP (P<0.01, correlation coefficient: 0.599). However, on day 2 and 4, significant correlations were observed between Pre-SEP and PCT (P<0.01, correlation coefficient: 0.650, p<0.01, correlation coefficient: 0.702 respectively) as well as between Pre-SEP and CRP (P<0.01, correlation coefficient: 0.542, p<0.01, correlation coefficient: 0.722 respectively). These data strongly suggested that Pre-SEP and CRP were available early in FN for a diagnosis and assessment of infection. On day 7, the negative frequencies were 43.5 %, 88.7 % and 45.1 % in Pre-SEP, PCT and CRP. These data strongly suggested that more sensitive assessment of infection would be possible using Pre-SEP.
CONCLUSION: (1) Pre-SEP is available even in neutropenia. (2) Pre-SEP is a useful biomarker for infection on the onset of FN as well as CRP. (3) Pre-SEP can help more sensitive assessment of infection.
Figure 1. Figure 1.

Disclosures
No relevant conflicts of interest to declare.
Efficacy and Safety of Micafungin As Salvage Treatment for Invasive Fungal Disease in Patients with Hematologic Malignancies
Authors: Gao Li , Lin Ren , Dai Min , Sun Jing , Fan Zhiping , Zhang Yu , Zhou Hongsheng , Liu Qifa 
Published: October 2019

Abstract
Objective To explore the efficacy and safety of micafungin as salvage treatment for invasive fungal disease(IFD) in patients with hematologic malignancies.
Methods A retrospective, observational, sequential cohort study was performed between Feb 2012 and June 2015 at southern medical university nanfang Hospital. We selected a group of 51 patients who either refractory or intolerant to first-line antifungal therapies, received micafungin as salvage therapy. Of the 51 patients, IFD was proven in 5 and probable in 46 patients. The predominant cause for treatment switch to micafungin was refractory therapy in 33 patients, followed by intolerance in 15 patients or both in 3 patients. For their first-line antifungal therapies of IFD, 34 patients received voriconazole, 7 patients received itraconazole, 2 patients received amphotericin B,1 patients received caspofungin,1 patients received posaconazole and 6 patients received voriconazole combined amphotericin B. The median duration of antifungal treatment before salvage therapy was 26 days (range, 4 to 57 days). The successful resolution rates、the median time of micafungin treatment, the drug related adverse events and overall survival were assessed.
Results All of the patients were treated with 150 mg/d micafungin. The median time of micafungin treatment was 23 days (range,12-72 days). The success rate was 64.7%, including 16 achieved complete response, 17 achieved partial response and 18 patients had no overall response (failure in 9 patients, 2 patient with stable disease and 7 patients died). Only one patient experienced an adverse event. No patient discontinued micafungin therapy due to an adverse event.
Conclusions This study demonstrated that micafungin was efficacy and safety as salvage treatment IFD in patients with hematologic malignancies.

Disclosures
No relevant conflicts of interest to declare.
Thymic Hyperplasia after Chemotherapy: Combined Experience of Two Centers
Authors: Dominguez-Perez Pamela , Maxey Nicole , Mohammadi Zeinab , Cortes Erasto , Antony Nishaal , Gupta Anuradha , Landeros Mark M , Campos-Gines Angel , Reiter Ethan , Arango Carmen , Gutierrez Javier , Morales Elena , Gonzalez Matilde , Herrada Juan 
Published: October 2019

Abstract
Background: Lymphoid tissue hyperplasia has been described in oncologic patients after receiving chemotherapy at different sites including: adenoids, tonsils, nasopharynx and thymus. Thymic hyperplasia has been reported more frequently in the pediatric age, associated most commonly with lymphomas. Biopsies of the thymic tissue show benign growth most likely due to a rebound effect after the chemotherapy treatments. Thymic hyperplasia occurring during cancer remission after chemotherapy treatment poses a diagnostic dilemma to clinicians. Our aim is to describe our experience with eight patients (pts) who were treated with chemotherapy and subsequently developed benign thymic hyperplasia.
Methods: Retrospective analysis.
Results: We reviewed the medical records of 8 consecutive pts seen in our two institutions between 2004 and 2015 who were referred with the diagnosis of breast cancer (7 pts) or lymphoma (1 pt). All pts were female; median age was 41 years, with an age range from 35 to 44. Each pt presented with benign thymic hyperplasia following the completion of chemotherapy treatments. The median time for diagnosis of thymic hyperplasia (demonstration of a new anterior mediastinal mass on follow-up CT scan) was 7 months following completion of chemotherapy, with a range of 1 to 11 months. In the first patient, the diagnosis was confirmed after thymic removal by thoracotomy and the remaining pts were followed up with serial computed tomography (CT) scans. All eight pts remain in complete remission from their primary cancers.
Conclusion: Thymic hyperplasia following chemotherapy treatment is an unusual benign phenomenon that merits awareness by clinicians in order to prevent unnecessary invasive and risky procedures.

Disclosures
No relevant conflicts of interest to declare.
Characterization of Phenotypic Expression of Inherited Fibrinogen Coagulopathy in Pakistani Index Patients
Authors: Naz Arshi , Khan Tehmina nafees sonia , Malik Noman A , Tariq Shahla , Saqlain Nazish , Shamsi Tahir 
Published: October 2019

Abstract
Background: Congenital afibrinogenemia is inherited as an autosomal recessive trait and consanguinity is common among affected families. Phenotypic expression of this particular factor deficiency is still not unanimously established in research literature globally as the disease manifests with variability in symptoms which may ranges from minimal bleeding to catastrophic hemorrhage.
Aim: To characterize the clinical manifestations of patients to set a standard parameter of bleeding severity in our local population.
Materials and Methods: This descriptive and cross sectional study was conducted at NIBD Karachi in collaboration with Chugtai's Lab and CHL Lahore in conformance with the Helsinki declaration. Consent was signed from all participants. Inclusion criteria for index patients specifically encompass the diagnosed cases of congenital afibrinogenemia excluding all acquired causes of this condition. Initially all the samples were processed at collection centers and platelet poor plasma and serum was separated and collected in labeled aliquots. Samples were transported to NIBD Karachi by maintaining cold chain. First line investigations including prothrombin time (PT), activated partial thromboplastin time (APTT) and fibrinogen levels by clauss method were performed to reconfirm the results. Grading of every individual's signs and symptoms depends upon severity of the disease and define here as per bleeding score [Tossetto et al]
Results: Total 18 patients were evaluated with mean age group10±2 yrs and 11 were males. Two patients were sibling. PT was >120s, APTT >180s and fibrinogen levels were (<0.2g/l).The most common symptom is umbilical bleeding (95%) followed by circumcision hemorrhage (90%) in males, cutaneous manifestations (85%) and epistaxis (68%). Grading of bleeding was done by WHO bleeding scale criteria and very well correlated with bleeding score and haemorrhagic manifestations exhibiting by patients. Severe bleeding patients were shown to have high bleeding scores along with II and III grades of bleeding .
Conclusion:The clinical manifestations of congenital afibrinogenemia in our local population are more or less same as reported in global literature. Due to the low prevalence rate of RBDs and the variability of bleeding manifestations are not well characterized clinically so far. Few exceptions do exists as we didn't find most of the rare complications in our set of patients.

Disclosures
No relevant conflicts of interest to declare.
Platelet-Derived Microparticles May Influence Phenotypic Heterogeneity in Patients with Severe Hemophilia
Authors: Zhou Xuan , Qin Fangmei , Li Han , Li Zhitao , Liu Yang , Yi Zhengshan , Sun Jing 
Published: October 2019

Abstract
Large heterogeneity in bleeding phenotype is observed among patients with severe hemophilia A. Some severe patients do not require regular replacement therapy, so to address the factors influencing phenotypic Heterogeneity in Patients with Severe Hemophilia A seems particularly important. We first initiate a cohort study 0f 274 patients with severe hemophilia A who were treated at the hemophilia treatment centre at Nanfang hospital, then 209 patients were enrolled and their bleedings were recorded, finally 12.9% (12/209) of the patients were found to be mild phenotypes, which annual bleeding rate(ABR)were less than 6 times. We then use Flow-cytometric analysis to detect the platelet-derived microparticles (PMPs) among patients with mild phenotypes, patients with severe phenotypes (ABR more than 24) and the normal control group, megamix beads (0.5μm; BioCytex, Marseille, France), CD42a-PE, CD42b-PE, CD41b-PE (GPIX, platelet MPs [PMPs], BD, NJ, USA) were involved, then the results showed that there was no difference in the level of PMPs between hemophliac patients and the normal control group (P=0.317), however, the level of PMPs in patients with mild phenotypes were significantly higher than patients with severe phenotypes (3.65±1.38 vs 1.13±0.64, P<0.05).These findings indicated that 12.9% were mild phenotypes in 209 patients with severe hemophilia A, moreover, the platelet-derived microparticles which may influence phenotypic heterogeneity in patients with severe haemophilia A will be further study for individual treatment.

Disclosures
No relevant conflicts of interest to declare.
Quality of Life in Children with Rare Bleeding Disorders
Authors: Karimi Mehran , Mohtadi Hassan , Haghpanah Sezaneh , Akbari Mahboobeh 
Published: October 2019

Abstract
Background: Patients with rare bleeding disorders (RBDs) face with several problems due to the chronic feature of the disease. So their physical and mental health is affected. Objective: The aim of this study is to evaluate quality of life (QOL) in patients with RBDs using haemo-QOL questionnaire.
Methods: In this cross-sectional study, 52 consecutive children aged between4-18 years old with RBDs registered at the Haemophila center of Fars province in Southern Iran were investigated from January to April 2015. Quality of life was evaluated by expert nurses using haemo-QOL questionnaire in different age groups including 4-7, 8-12, and 13-16/18 years old. Final score range is defined between 0-100 and higher score of QOL shows worse condition. Disease severity was determined based on coagulation factor levels: mild >5%, moderate 1-5% and severe <1%. P value less than 0.05 was considered statistically significant.
Results: Mean age of the patients was 13.9 ± 4.5 ranged from 4 to 18 years old including 28 males and 24 females. The distribution of frequency of RBDs was as follow: Factor I deficiency 9; Factor V deficiency 2; Factor VII deficiency 15; Factor X deficiency7; Factor XI deficiency 8; Factor XIII deficiency 8; and combined Factor V&VIII deficiency 3 patients. Overall QOL of the patients was 41.15 ± 14.72. In Univariate analysis, from all evaluated variables only bleeding severity based on bleeding score showed a statistically significant correlation with QOL of the patients (r =0.298, P=0.032). In multiple linear regression models only degree of being bothered by the disease was determined as an independent influencing factor on QOL.
Conclusion: Based on our results, QOL of children with RBDs was correlated significantly with bleeding severity but not correlated with disease severity based on factor level. Due to chronicity and feature of bleeding disorders, more attention to different aspects of the disease is necessary to improve QOL of the patients with RBDs.

Disclosures
Karimi: Octapharma: Other: Investigator.