Translocation In Patients Research Articles

SAT-004-Bacterial translocation in patients with liver cirrhosis and variceal bleeding

SAT-004-Bacterial translocation in patients with liver cirrhosis and variceal bleeding

Application of Fluorescence in situ Hybridization in Detection of PML/RARA Translocation in Patients with Acute Promyelocytic Leukemia

Background: Acute promyelocytic leukaemia (APML) is a sub-type of acute myeloid leukaemia (AML). APML accounts for 10% of all AML diagnosis. Diagnosis is made by presence of abnormal promyelocytes in circulating blood and bone marrow smear and presence of PML RARA fusion transcript which is responsible for leukemogenesis. Fluorescence in situ Hybridisation (FISH) plays key role in confirming diagnosis by detecting PML/RARA (15;17) translocation which will help in deciding treatment and prognosis in patients diagnosed with APML. Aims and objectives: To estimate presence of PML/RARA translocation in patients diagnosed with APML using FISH. Materials and methods: Bone marrow samples of 20 patients diagnosed with APML was collected for standardized lymphocyte culture method followed by standard protocol for FISH using commercially available probes for PML /RARA gene. Ethical clearance was obtained from institutional ethical committee. Results: Out of 20 patients, 18 patients had shown positive result for PML/RARA translocation. Hence 90% of patients showed positive results for fusion gene. Conclusion: Detection of PML/ RARA translocation helps in rapid diagnosis as well as treatment of patient with APML. Further it will also help in prognosis and follow up to detect residual disease in these patients.

PD-L1 Expression Is Low in Large B-Cell Lymphoma with MYC or Double-Hit Translocation

Introduction: In large B-cell lymphoma (LBCL) MYC translocation and MYC/BCL2 or BCL6 double hit (DH) is associated with poor prognosis and there is an unmet need for novel treatment targets in this patient group. Treatment targeting the PD-L1/PD-1 pathway has been successfully introduced in Hodgkin lymphoma and solid cancers but are still poorly elucidated in LBCL. PD-L1 expression might predict response to treatment targeting the PD-L1/PD-1 pathway. We therefore investigated the relationship between PD-L1 protein and mRNA expression levels and MYC and DH translocation in LBCL.Material and Methods: MYC, BCL2 and BCL6 translocations were detected by fluorescent in situ hybridization in tissue samples from 130 patients randomly selected from two cohorts of patients with LBCL: 49 patients with MYC translocation of whom 36 patients had DH and 81 without MYC translocation. PD-L1 protein expression was detected by immunohistochemistry (IHC) in tissue samples from 77 patients and PD-L1 mRNA expression by next-generation RNA sequencing (NGS) in another 77 patients. 24 patients overlapped, i.e. were analysed with both IHC and NGS. Nonparametric tests were performed to evaluate intergroup differences.Results: PD-L1 protein expression level was lower in patients with MYC translocation (n=42, median=3,3%, IQR 0,0-10,8) or DH (n=31, median=3,3%, IQR 0,0-10,0) compared to patients with no MYC translocation (n=35, median=16,7%, IQR 3,3-30,0) or DH (n=46, 13,3%, IQR 2,5-30,0), P=0.004 and P<0,001 respectively (Fig.1). PD-L1 mRNA expression was also significantly lower in patients with MYC translocation or DH, P=0,001 and P=0,006 respectively. Higher PD-L1 protein and mRNA expression levels were associated with non-GC-type compared to GC-type DLBCL, P= 0,004 and P=0,002 respectively.Conclusions: We report a highly significant association between low PD-L1 expression and MYC and DH translocation in patients with LBCL. Our findings may indicate that patients with MYC or DH translocation may benefit less from treatment with PD-L1/PD-1-inhibitors compared to patients without these translocations. This should be evaluated in larger, prospective, consecutive trials. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

363TiP - Phase Ib/IIa study of RX-5902, a novel orally bioavailable inhibitor of phosphorylated P68, which prevents nuclear β-catenin translocation in patients with triple negative breast cancer

363TiP - Phase Ib/IIa study of RX-5902, a novel orally bioavailable inhibitor of phosphorylated P68, which prevents nuclear β-catenin translocation in patients with triple negative breast cancer

Mucosal Barrier Injury Laboratory Confirmed Bloodstream Infections

To increase the awareness of the new CDC survey definition of Mucosal Barrier Injury Laboratory-Confirmed Bloodstream Infection (MBI-LCBI). We included a comparison of the definition of Central Line-Associated Bloodstream Infection (CLABSI), with a high sensitivity but low specificity and Catheter-Related Bloodstream Infection (CRBSI). There are other parameters like the difference between the size of the inoculum (catheter lumen vs peripheral), that increased specificity and is useful for research and clinical decisions. Also, MBI-LCBI secondary to bacterial translocation in patients who had received myeloablative chemotherapy with severe neutropenia is not related to central venous catheter care. This new survey definition is useful for better classification of nosocomial bloodstream infections among patients receiving myeloablative chemotherapy and has impacted diminishing the incidence of CLABSI, which has probably has been overestimated in patients with hematological malignancies. The concept of MBI-LCBI should not be limited to survey purposes; it is also useful for clinical decisions. We propose to incorporate a second set of blood cultures obtained 48 hours after antibiotic treatment onset, one through the line of the CVC and another one at a peripheral site; if negative, it avoids unnecessary removal of the catheter in patients with severe neutropenia or, on the contrary, if positive blood cultures persist after 48 hours of antimicrobial therapy, there is a clear indication for central venous catheter removal. The definition of MBI-LCBI avoids over-diagnosis of CLABSI in patients receiving myeloablative chemotherapy with severe neutropenia.

Beneficial Effect of Alcohol Withdrawal on Gut Permeability and Microbial Translocation in Patients with Alcohol Use Disorder.

The human intestinal microbiota exerts beneficial or harmful effects in several disorders. Many factors, including alcohol consumption, may influence its composition and trigger bacterial translocation. Excessive alcohol consumption increases gut permeability and translocation of endotoxin into peripheral circulation. Although plasma endotoxin concentrations have been measured often, quantitative changes following alcohol withdrawal have never been described in subjects with alcohol use disorder (AUD). The aim of this study was to measure microbial translocation (MT) and gut permeability markers in patients with AUD, to compare these markers to healthy controls (HC) and to monitor markers during the first 6weeks of abstinence. Sixty-five patients with AUD and hospitalized for alcohol withdrawal were included. Epidemiological, clinical, biological, and addictological data were gathered. Blood samples were collected at baseline, then 3 and 6weeks after alcohol withdrawal. A hundred healthy volunteers were used as controls. Three markers of MT were monitored in plasma samples: sCD14 and lipopolysaccharide-binding protein (LBP) were quantified using ELISA, and 16S rDNA was quantified using real-time polymerase chain reaction. Zonulin and intestinal fatty acid binding protein (I-FABP) blood levels were also monitored as indirect markers of gut permeability, using ELISA. At baseline, LBP, 16S rDNA, sCD14 and I-FABP markers were significantly higher in patients with AUD than in HC. Six weeks after alcohol withdrawal plasma levels of sCD14 and LBP decreased significantly. Cannabis consumption and body mass index (BMI) before alcohol withdrawal influenced baseline MT levels and the decrease in MT markers after 6weeks. Finally, markers of MT and gut permeability did not correlate with each other before and after alcohol withdrawal. Before alcohol withdrawal, MT markers were higher in patients with AUD than in HC. After 6weeks of abstinence, an improvement in MT markers was observed. Our data suggest that there is a link between MT, its improvement, BMI, and cannabis consumption.

The Influence of Carbon Dioxide Pneumoperitoneum on Systemic Inflammatory Response Syndrome and Bacterial Translocation in Patients With Bacterial Peritonitis Caused by Acute Appendicitis.

To explore the influence of carbon dioxide pneumoperitoneum (CDP) on system inflammatory response syndrome (SIRS) and bacterial translocation (BT) in patients with bacterial peritonitis (BP) caused by acute appendicitis (AA). Eighty-six consecutive subjects were randomly divided into the laparoscopy and laparotomy groups (n = 44 and n = 42, respectively). The levels of white blood cells (WBC), C-reactive protein (CRP), tumor necrosis factor α (TNF-α), and interleukin 6 (IL-6) of the 2 groups were tested preoperatively and at days 1, 2, and 4 after surgery. Blood and secretion culture was performed to verify whether septicemia or incision infection occurred, respectively. And the abdominal ultrasound or computed tomography scanning was used to diagnose peritoneal abscess for the suspected patients. The essential risk factors related to the aggravation of SIRS were analyzed through analysis of variance and binary logistic regression. The postoperative blood levels of WBC, CRP, TNF-α, and IL-6 on day 4 in the laparoscopy group were significantly lower than those in the control group (all Ps < .05). The differences in incidence rates of septicemia and peritoneal abscess between the CDP and control groups were not statistically significant ( P > .05). Nevertheless, the incision infection rate in the laparoscopy group was apparently lower than that in the control group (4.55% vs 19.04%, P = .047). Analysis of variance and binary logistic regression showed that the non-pneumoperitoneum, pathological type of appendicitis, and multidrug resistant infections were the 3 major risk factors for SIRS (the P values were .001, .019, and .012, respectively). It was found that CDP is safe for BP and could be a potential protective factor to mitigate BP effectively, indicating that the performance of laparoscopy operation under CDP is feasible to control SIRS; at the same time, CDP would not raise the incidence rate of BT.

Does bacterial translocation influence the postoperative infections in splenectomized patients after abdominal trauma?

BackgroundSome studies suggested that after abdominal trauma, postoperative infections are associated with bacterial translocation, whereas others have not replicated these findings. We have assessed the bacterial translocation and postoperative infections in patients undergoing splenectomy after abdominal trauma, using a very homogeneous study population. MethodsWe consecutively studied, in a prospective observational clinical study, 125 patients who required urgent surgical treatment (splenectomy) following blunt abdominal trauma. For bacterial translocation identification, tissue samples were taken from liver, spleen and mesenteric lymph nodes (MLNs). Postoperative infectious complications in these patients were registered, confirmed by a positive culture obtained from the septic focus. Associations between clinical variables, bacterial translocation presence, and postoperative infection development were established. ResultsBacterial translocation was detected in 47 (37.6%) patients. Postoperative infections were present in 29 (23.2%) patients. A significant statistical difference was found between postoperative infections in patients with bacterial translocation evidence (22 of 47 patients: 46.8%) in comparison with patients without bacterial translocation (7 of 78 patients: 8.9%) (P < 0.05). After multivariate adjustment analysis: a) the bleeding ≥ 1500 mL was significantly associated with the risk of bacterial translocation and, b) bacterial translocation was significantly associated with the risk of postoperative infections. Bacterial strains isolated from infection sites were the same as those cultured in MLNs in 48.3% of the cases (n = 14 of 29). ConclusionsThere is higher risk of bacterial translocation in patients who required urgent surgical treatment (splenectomy) following blunt abdominal trauma and it is associated with a significant higher number of postoperative infections.

Prognostic Impact of Chromosomal Translocations in 751 Korean Patients with Primary Myelodysplastic Syndrome

Introduction Chromosomal translocations are rare in myelodysplastic syndrome (MDS) and their impact on overall survival (OS) and response to hypomethylating agents (HMA) is unknown.Methods The prognostic impact of the revised International Prognostic Scoring System (IPSS-R) and for chromosomal translocations was assessed in 751 patients from the Korea MDS Registry. Patients with secondary MDS, chronic myelomonocytic leukaemia, and patients with AML and a BM blast count of 20-30% who were classified as having refractory anaemia with excess blast (RAEB)-t according to the French-American-British classification were excluded. Cytogenetic aberrations were counted following the International Working Group on MDS Cytogenetics (IWGMC) consensus guidelines. Complex karyotype (CK) was defined as having 3 or more chromosomal abnormalities. Monosomal karyotype (MK) was defined as the presence of 2 or more autosomal monosomies or 1 single autosomal monosomy in combination with structural abnormalities.Results The median age of the patients was 65 years, and 457 (61.9%) were male. The median follow-up time was 71.7 months for survivors (range, 0.1 - 230.5). The most common WHO subtype was refractory cytopaenia with multilineage dysplasia (29.7%), followed by RAEB-1 (19.8%), RAEB-2 (18.4%), refractory cytopaenia with unilineage dysplasia (15.4%), and MDS-unclassifiable (11.9%). More than half of patients received disease-modifying treatment; 381 (50.7%) received hypomethylating agents (HMAs), and 83 (11.1%) received haematopoietic stem cell transplantation (HSCT). IPSS-R effectively discriminated patients according to leukaemia evolution risk and OS.We identified 40 patients (5.3%) carrying translocations. Among these, 46 translocations involving 72 breakpoints were identified including balanced translocations in 13 (28.3%) and unbalanced translocation in 33 (71.7%). Translocations were found as a part of CK in 30/46 cases (65.2%) and as a part of MK in 21/46 (45.7%). Frequently involved chromosomes were chromosome 7 (n = 13); ch1 (n = 12); ch5 (n = 9); ch12 (n = 6); ch6, ch11, and ch14 (n = 5); ch10 and ch20 (n = 4); and ch16, ch17, and X (n = 3) in decreasing order. To the best of our knowledge, 43 (93.5%) of the 46 translocations have not been previously described in MDS, nor in AML or CMML. Patients with translocation also had a higher percentage of BM blasts and included a significantly larger proportion of RAEB-1 and RAEB-2. Translocation presence was associated with a shorter OS (median, 12.0 versus 79.7 months, P < 0.01), and multivariate analysis demonstrated that translocations (hazard ratio [HR] 1.64 [1.06-2.63]; P = 0.03) as well as age, sex, IPSS-R, and CK were independent predictors of OS. In the IPSS-R high and very high risk subgroup (n = 260), translocations remained independently associated with OS (HR 1.68 [1.06-2.69], P = 0.03) whereas HMA treatment was not associated with improved survival (median OS, 20.9 versus 21.2 months, P = 0.43). However, translocation carriers exhibited enhanced survival following HMA treatment (median 2.1 versus 12.4 months, P = 0.03).Conclusion Our data suggest that chromosomal translocation is an independent predictor of adverse outcome and has an additional prognostic value in discriminating patients with MDS having higher risk IPSS-R who could benefit from HMA treatment. Further studies in other populations are needed to validate the clinical relevance of translocation in patients with MDS. DisclosuresLee:Amgen: Membership on an entity's Board of Directors or advisory committees.

MiRNA profiling, detection of BRAF V600E mutation and RET-PTC1 translocation in patients from Novosibirsk oblast (Russia) with different types of thyroid tumors.

BackgroundThe postoperative typing of thyroid lesions, which is instrumental in adequate patient treatment, is currently based on histologic examination. However, it depends on pathologist’s qualification and can be difficult in some cases. Numerous studies have shown that molecular markers such as microRNAs and somatic mutations may be useful to assist in these cases, but no consensus exists on the set of markers that is optimal for that purpose. The aim of the study was to discriminate between different thyroid neoplasms by RT-PCR, using a limited set of microRNAs selected from literature.MethodsBy RT-PCR we evaluated the relative levels of 15 microRNAs (miR-221, −222, −146b, −181b, −21, −187, −199b, −144, −192, −200a, −200b, −205, −141, −31, −375) and the presence of BRAF(V600E) mutation and RET-PTC1 translocation in surgically resected lesions from 208 patients from Novosibirsk oblast (Russia) with different types of thyroid neoplasms. Expression of each microRNA was normalized to adjacent non-tumor tissue. Three pieces of lesion tissue from each patient (39 goiters, 41 follicular adenomas, 16 follicular thyroid cancers, 108 papillary thyroid cancers, 4 medullary thyroid cancers) were analyzed independently to take into account method variation.ResultsThe diagnostic classifier based on profiling of 13 microRNAs was proposed, with total estimated accuracy varying from 82.7 to 99 % for different nodule types. Relative expression of six microRNAs (miR-146b, −21, −221, −222, 375, −199b) appeared significantly different in BRAF(V600E)-positive samples (all classified as papillary thyroid carcinomas) compared to BRAF(V600E)-negative papillary carcinoma samples.ConclusionsThe results confirm practical feasibility of using molecular markers for typing of thyroid neoplasms and clarification of controversial cases.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2240-2) contains supplementary material, which is available to authorized users.

Evaluation of JAK2 V617F mutation and BCR-ABL translocation status in the work-up of MPN: A hospital-based study in Lebanon

Context: With the advent of targeted therapy, the identification of JAK2 gene V617F mutation and BCR-ABL translocation has changed the course of myeloproliferative Neoplasias (MPN). Objective: The aim of the study was to assess the prevalence of the JAK2 mutation and BCR-ABL translocation in patients referred to Saint George Hospital, Beirut, Lebanon for suspicion of MPN. Methods: JAK2 V617F mutation was screened using allele-specific PCR. Fusion gene transcripts for BCR-ABL translocation were analyzed according to standardized RT-PCRs following the report of BIOMED-1 concerted action (Leukemia 1999). Results: BCR-ABL translocation and JAK2 mutation were examined in 760 consecutive patients referred for MPN suspicion. Out of these, 38.51% were positive for JAK2 V617F and 13.81% for BCR-ABL translocation and 0.13% positive for both JAK2 and BCR-ABL (P210 b3a2) while 47.55% were negative. Fusion transcript analysis of BCR-ABL corresponding to P210 was 97.4% (60.5% b3a2, 39.5% b2a2), P190 was 1.3% (e1a2) and P230 was 1.3%. Conclusion: To our knowledge, the presented epidemiological data are the first ones reported in the Lebanese population. These results confirm the value of including additional markers in the work-up of MPN to cover some of the negative cases. JAK2 exon 12/exon13, MPL, calreticulin genes mutations are currently evaluated worldwide. Our next step will be to implement those new markers in order to evaluate their prevalence and their benefit in our population.

Successful treatment of hydroxyurea-associated chronic leg ulcers and squamous cell carcinoma in a patient with essential thrombocythemia

Context: With the advent of targeted therapy, the identification of JAK2 gene V617F mutation and BCR-ABL translocation has changed the course of myeloproliferative Neoplasias (MPN). Objective: The aim of the study was to assess the prevalence of the JAK2 mutation and BCR-ABL translocation in patients referred to Saint George Hospital, Beirut, Lebanon for suspicion of MPN. Methods: JAK2 V617F mutation was screened using allele-specific PCR. Fusion gene transcripts for BCR-ABL translocation were analyzed according to standardized RT-PCRs following the report of BIOMED-1 concerted action (Leukemia 1999). Results: BCR-ABL translocation and JAK2 mutation were examined in 760 consecutive patients referred for MPN suspicion. Out of these, 38.51% were positive for JAK2 V617F and 13.81% for BCR-ABL translocation and 0.13% positive for both JAK2 and BCR-ABL (P210 b3a2) while 47.55% were negative. Fusion transcript analysis of BCR-ABL corresponding to P210 was 97.4% (60.5% b3a2, 39.5% b2a2), P190 was 1.3% (e1a2) and P230 was 1.3%. Conclusion: To our knowledge, the presented epidemiological data are the first ones reported in the Lebanese population. These results confirm the value of including additional markers in the work-up of MPN to cover some of the negative cases. JAK2 exon 12/exon13, MPL, calreticulin genes mutations are currently evaluated worldwide. Our next step will be to implement those new markers in order to evaluate their prevalence and their benefit in our population.

Arpin contributes to bacterial translocation and development of severe acute pancreatitis.

To assess the impact of Arpin protein and tight junction (TJ) proteins in the intestinal mucosa on bacterial translocation in patients with severe acute pancreatitis (SAP). Fifty SAP patients were identified as study objects and then classified into two groups according to the presence of bacterial translocation (BT) in the blood [i.e., BT(+) and BT(-)]. Twenty healthy individuals were included in the control group. BT was analyzed by polymerase chain reaction, colonic mucosal tissue was obtained by endoscopy and the expression of TJ proteins and Arpin protein was determined using immunofluorescence and western blotting. Bacterial DNA was detected in the peripheral blood of 62.0% of patients (31/50) with SAP. The expression of TJ proteins in SAP patients was lower than that in healthy controls. In contrast, Arpin protein expression in SAP patients was higher than in healthy controls (0.38 ± 0.19 vs 0.28 ± 0.16, P < 0.05). Among SAP patients, those positive for BT showed a higher level of claudin-2 expression (0.64 ± 0.27 vs 0.32 ± 0.21, P < 0.05) and a lower level of occludin (OC) (0.61 ± 0.28 vs 0.73 ± 0.32, P < 0.05) and zonula occludens-1 (0.42 ± 0.26 vs 0.58 ± 0.17, P = 0.038) expression in comparison with BT (-) patients. Moreover, the level of Arpin expression in BT (+) patients was higher than in BT (-) patients (0.61 ± 0.28 vs 0.31 ± 0.24, P < 0.05). Arpin protein affects the expression of tight junction proteins and may have an impact on BT. These results contribute to a better understanding of the factors involved in bacterial translocation during acute pancreatitis.

Bacterial Translocation as a Cause of Postoperative Sepsis in Surgical Patients Undergoing Laparotomy

Introduction: Bacterial translocation is the invasion of indigenous intestinal bacteria through the gut mucosa to normally sterile tissues and the internal organs. Objective of the study is to examine the spectrum of bacteria involved in translocation in surgical patients undergoing laparotomy and to determine the relation between nodal migration of bacteria and the development of postoperative septic complications.&#x0D; Methods: Mesenteric lymph nodes (MLN)culture was done in patients undergoing elective and emergency surgeries fulfilling the inclusion criteria.&#x0D; Results:Bacterial translocation was identified in 22 (44.8%) patients. The most common organism identified was Escherichia coli (n=11, 50%). Both enteric bacteria, typical of indigenous intestinal flora, and non-enteric bacteria were isolated. Postoperative septic complications developed in four (11%) patients. Septic morbidity was more frequent when a greater diversity of bacteria resided within the mesenteric lymph nodes.&#x0D; Conclusion: Bacterial translocation is associated with an increase in the development of postoperative sepsis in surgical patients. The organisms responsible for septic morbidity are similar in spectrum to those observed in the mesenteric lymph nodes. These data strongly support the gut origin hypothesis of sepsis in humans. Besides, there is increased bacterial translocation in patients undergoing emergency procedures.&#x0D; Keywords: bacteria • laparotomy • postoperative • sepsis • translocation

Spontaneous Mutations of Bcor and Jak1/2 genes Lead to an Aggressive Leukemia of B-1 Progenitor B Cells

NUP98 gene fusions, generated by non-random chromosomal translocations, are associated with a wide spectrum of high risk hematologic malignancies and have been shown to alter normal hematopoietic stem and progenitor cell (HSPC) gene expression programs. A recurrent t(11;17)(p15;p13) translocation in patients with AML leads to the production of a NUP98–PHF23 (NP23) fusion gene. The consequent NP23 fusion protein retains the PHD domain, known to bind H3K4me3, and is thought to have aberrant chromatin regulation properties. We have generated a transgenic mouse model of the NUP98-PHF23 gene fusion which develops a range of hematologic malignancies, most commonly pre-T LBL and AML. However, approximately 10% of NP23 mice develop an aggressive B-1 progenitor acute lymphoblastic leukemia (pro B-1 ALL).B-1 and B-2 lymphocytes have distinct developmental pathways and are thought to represent arms of the innate and adaptive immune systems, respectively. Mature B-2 lymphocytes predominate in the peripheral circulation, and are characterized by expression of B220; whereas B-1 lymphocytes are more prevalent in the pleural and peritoneal cavities, and do not express B220. Murine B cell malignancies typically stain positive for B220, and represent transformed B-2 cells. In the present study, NP23 progenitor ALLs displayed an immunophenotype (Lin-B220- CD19+ AA4.1+) that was identical to that of the recently described B-1 progenitor cell. All B-1 progenitor ALLs exhibited clonal rearrangements of the IgH gene locus. Specifically, these rearrangements involve favored usage of 3’ VH regions, similar to observations with fetal B-1 progenitor cells, further supporting the notion that these are leukemias of B-1 progenitors. Using whole exome sequencing, we found acquired mutations in the BCL6 interacting corepressor (Bcor) gene in 5 out of 7 B-1 progenitor leukemias. The mutations were all frame shift or nonsense mutations, and were located within a 9 bp “hot spot” in Bcor exon 8. In addition, 4 of 7 cases had somatic mutations of Janus kinase 1 (Jak1) or 2 (Jak2), and 7/7 cases showed hyperphosphorylation of Stat3 or Stat5, consistent with the contention that the Jak1/2 mutations are activating mutations, and leading to a hypothesis that the NP23 pro B-1 ALLs which do not harbor Jak1/2 mutations may have acquired an unidentified mutation in the Jak-Stat pathway. Of note, Jak1/2 mutations have previously been identified in a subset of high-risk pediatric B-cell precursor ALL patients. The striking correlation between Bcor and Jak1/2 mutations, occurring specifically in a subset of NP23 leukemias, implies that these three mutations (NP23, Bcor, and Jak1/2) collaborate and provide the oncogenic setting for B-1 progenitor transformation. DisclosuresNo relevant conflicts of interest to declare.

Cyclin D1 C.870G>a Polymorphism in Patients with Multiple Myeloma after Allogeneic Stem Cells Transplantation

Introduction: Over the last decade, the cyclin D1 (CCND1) c.870G>A polymorphism has been variously reported to confer risk for a large number of cancers. Deregulation of a D-group cyclin is a key feature of multiple myeloma (MM). Previously published meta-analysis shown a relationship between CCND1 c.870G>A and risk of t(11;14) in MM (Wienhold, 2013). Allogeneic stem cell transplantation (AlloSCT) is a potential curative treatment for MM patients. There are no data with regard to the role of CCND1 c.870G>A polymorphism in stem cells donors and outcome of transplantation in MM patients.Methods: In this study we developed an endonuclease restriction method to identify CCND1 c.870G>A polymorphism. Directly Sanger sequencing were used to confirm the results.Results: At first, we analyzed 130 MM patients and 100 healthy donors as a control. CCND1 c.870G>A polymorphism was strongly associated with the t(11;14)(q13;q32) (P<0.001). In addition, we have analyzed CCND1 c.870G>A polymorphism 55 pairs of MM patients and their allogeneic stem cell donors, retrospectively. Interestingly, c.870G-genotype in related and unrelated donors was statistically correlated with poor outcome after AlloSCT (P<0.01). Moreover, only patients transplanted with “G-Genotype” donors developed secondary cancer after AlloSCT (P<0.01). No secondary tumors were diagnosed in the group of MM patients received grafts from “A-, AG-genotype” donors.Conclusion: Our data suggest the published data that constitutive genetic factor (CCND1 c.870 G>A polymorphism) is associated with a specific chromosomal translocation in patients with MM. Despite the fact that our group of patients after AlloSCT is small, we found a statistical association between the c.870G-genotype in donor and a poor prognosis after transplantation. DisclosuresNo relevant conflicts of interest to declare.

Long-term antibiotics and PPI's induce bacterial translocation in patients with cirrhosis: antibiotics are not always ANTI-biotics.

O’Leary JG, Reddy KR, Wong F, et al. Long-term use of antibiotics and proton-pump inhibitors predict development of infections in patients with cirrhosis. Clin Gastroenterol Hepatol 2014; pii: S1542-3565(14)01146X. doi: 10.1016/j.cgh.2014.07.060. [Epub ahead of print]. O’Leary et al. (1) prospectively analyzed 188 patients with cirrhosis who were hospitalized for infection from 12 centers (North American Consortium for the Study of End-Stage Liver Disease). They investigated and characterized risk factors for repeat infections in these patients. Patients were followed for 6 months after hospital discharge and data were analyzed on type of infections and factors associated with subsequent infections. Just after 6 months after hospital discharge, only 59% of them were alive and 14% had liver transplant.

Ectopic TLX1 Expression Accelerates Malignancies in Mice Deficient in DNA-PK

The noncluster homeobox gene HOX11/TLX1 (TLX1) is detected at the breakpoint of the t(10;14)(q24;q11) chromosome translocation in patients with T cell acute lymphoblastic leukemia (T-ALL). This translocation results in the inappropriate expression of TLX1 in T cells. The oncogenic potential of TLX1 was demonstrated in IgHμ-TLX1Tg mice which develop mature B cell lymphoma after a long latency period, suggesting the requirement of additional mutations to initiate malignancy. To determine whether dysregulation of genes involved in the DNA damage response contributed to tumor progression, we crossed IgHμ-TLX1Tg mice with mice deficient in the DNA repair enzyme DNA-PK (PrkdcScid/Scid mice). IgHµ-TLX1TgPrkdcScid/Scid mice developed T-ALL and acute myeloid leukemia (AML) with reduced latency relative to control PrkdcScid/Scid mice. Further analysis of thymi from premalignant mice revealed greater thymic cellularity concomitant with increased thymocyte proliferation and decreased apoptotic index. Moreover, premalignant and malignant thymocytes exhibited impaired spindle checkpoint function, in association with aneuploid karyotypes. Gene expression profiling of premalignant IgHµ-TLX1TgPrkdcScid/Scid thymocytes revealed dysregulated expression of cell cycle, apoptotic and mitotic spindle checkpoint genes in double negative 2 (DN2) and DN3 stage thymocytes. Collectively, these findings reveal a novel synergy between TLX1 and impaired DNA repair pathway in leukemogenesis.

Pattern of microbial translocation in patients living with HIV‐1 from Vietnam, Ethiopia and Sweden

IntroductionThe role of microbial translocation (MT) in HIV patients living with HIV from low- and middle-income countries (LMICs) is not fully known. The aim of this study is to investigate and compare the patterns of MT in patients from Vietnam, Ethiopia and Sweden.MethodsCross-sectional samples were obtained from treatment-naïve patients living with HIV-1 and healthy controls from Vietnam (n=83; n=46), Ethiopia (n=9492; n=50) and Sweden (n=51; n=19). Longitudinal samples were obtained from a subset of the Vietnamese (n=24) in whom antiretroviral therapy (ART) and tuberculostatics were given. Plasma lipopolysaccharide (LPS), sCD14 and anti-flagellin IgG were determined by the endpoint chromogenic Limulus Amebocyte Assay and enzyme-linked immunosorbent assay.ResultsAll three biomarkers were significantly increased in patients living with HIV-1 from all countries as compared to controls. No differences were found between males and females. Vietnamese and Ethiopian patients had significantly higher levels of anti-flagellin IgG and LPS, as compared to Swedes. ART reduced these levels for the Vietnamese. Vietnamese patients given tuberculostatics at initiation of ART had significantly lower levels of anti-flagellin IgG and higher sCD14. The biomarkers were lower in Vietnamese who did not develop opportunistic infection.ConclusionsHigher MT is common in patients living with HIV compared to healthy individuals, and in patients from LMICs compared to patients from a high-income country. Treatment with tuberculostatics decreased MT while higher levels of MT are associated with a poorer clinical outcome.

Plasma l-citrulline concentrations and its relationship with inflammation at the onset of septic shock: A pilot study

PurposeHypocitrullinemia has been suggested to be a prognostic factor for patients in intensive care. The aim of this ancillary study of the Corticosteroids and Intensive Insulin Therapy for Septic Shock prospective study was to investigate plasma l-citrulline concentrations and its relationship with inflammation and digestive bacterial translocation in patients with septic shock multiorgan failure and without primary intestinal disease or chronic renal failure. MethodsSixteen adult patients were selected. They were studied on day (D) 0 at hours (H) 0, 6, 12, 18, and 24 and on D4 (H96). Selected plasma amino acids and proteins, proinflammatory (tumor necrosis factor α [TNF-α]) and anti-inflammatory (interleukin [IL] 10) cytokine concentrations, and bacterial translocation were measured. ResultsEight D14 survivors and 8 D14 nonsurvivors patients were studied. Citrulline was decreased on D0 (H0: 29 ± 10 vs nadir: 18 ± 6 μmol/L; P < .05). The citrulline nadir was lower (P < .01) in patients with digestive bacterial translocation than that in those without. Mean citrulline concentrations at H0 to H96 were not significantly different between survivors and nonsurvivors. In both groups, citrulline was significantly inversely correlated with C-reactive protein (r2 = 0.10, P < .01) on D0. No significant correlations were found between citrulline and albumin, transthyretin, TNF-α, IL-10, or TNF-α/IL-10 ratio. ConclusionsAt the onset of septic shock, plasma citrulline decreases and varies inversely with C-reactive protein and is lower when digestive bacterial translocation occurs. This finding could reflect an early acute intestinal dysfunction, but measurement of citrulline concentration does not appear to be able to predict the patients' mortality.