bluuebunny/crossref_metadata_2025_split huggingface dataset:
FLIPI and F2 Index – Prognostic Indices in Advanced Stage Follicular Lymphoma
Authors: Unterhalt Michael , Hoster Eva , Dreyling Martin , Buske Christian , Hiddemann Wolfgang ,   on behalf of the German Low-Grade Lymphoma Study Group (GLSG)
Published: April 2020

Abstract
Background: The follicular lymphoma international prognostic index (FLIPI) has become a widely accepted tool for stratification of patients with follicular lymphoma according to their risk profiles (Solal-Celigny et al., Blood 2004). Its prognostic relevance has been proven in patients treated with standard chemotherapy as well as with immunochemotherapy (Buske et al., Blood 2006). Recently, a new prognostic index, the F2 index, has been proposed as possible alternative to the FLIPI (Federico et al., ICML-10, 2008). Methods: We used the collective of patients with advanced stage follicular lymphoma treated first-line within the recent trials of the GLSG to explore the prognostic relevance of the F2 prognostic index in comparison to the FLIPI. Outcome parameters were time to treatment failure (TTF) and overall survival (OS). Statistical methods included Kaplan-Meier plots to validate the prognostic indices and multiple Cox regression to explore the relevance of the prognostic factors.
Results: Of the 1562 patients, the F2 index could only be assessed in 758 patients (50%), of those 355 had had a treatment failure and 124 had died. The low number of evaluable patients was mainly due to the use of β2-microglobulin as prognostic factor, which was missing in 45% of the patients. The FLIPI could be assessed in 1424 patients (93%), of those 697 had had a treatment failure and 255 had died. The F2 index classified 7% of the patients as low risk, 58% as intermediate risk, and 35% as high risk, in comparison to 14%, 41% and 45% according to the FLIPI. Both F2 and FLIPI separated three risk groups with regard to TTF (p&lt;0.0001). However, the F2 index did not separate risk groups in the three FLIPI risk subgroups. In addition, in multiple regression analysis of the F2 and FLIPI prognostic factors, two of the three new F2 prognostic factors, namely bulk &gt; 6 cm and elevated β2-microglobulin showed no prognostic relevance for TTF. Furthermore, after backward elimination, all the FLIPI risk factors (age &gt; 60 years, LDH &gt; ULN, hemoglobin &gt; 120 g/l and more than 4 involved nodal regions) remained independently significant together with bone marrow involvement, whereas bulk &gt; 6cm and b2-microglobulin were of no relevance. With regard to OS, the FLIPI separated three groups, whereas according to the F2 index low and intermediate risk groups were overlapping.
Conclusion: The F2 index did not show superior relevance to the FLIPI in our evaluation and should not replace the FLIPI as prognostic index in follicular lymphoma in general. However, a simplification of the FLIPI with regard to the assessment of the number of involved nodal areas and the incorporation of the performance status would be challenging.
Phase 1 Study of Weekly Vincristine Sulfate (VCR) Liposomes Injection (VSLI, Marqibo™) Plus Dexamethasone in Adults with Relapsed or Refractory Acute Lymphoblastic Leukemia (ALL)
Authors: Thomas Deborah A. , Kantarjian Hagop M , Stock Wendy , Heffner Leonard , Hirabayashi Sue , Lu Biao , Deitcher Steven R. , O’Brien Susan 
Published: April 2020

Abstract
Novel formulations of standard chemotherapy allowing increased drug delivery without additional toxicity may improve outcomes for patients with relapsed or refractory acute lymphoblastic leukemia (ALL). Vincristine sulfate liposomes injection (VSLI, Marqibo®) is VCR encapsulated in sphingomyelin (55%)/cholesterol (45%) nanoparticle liposomes called Optisomes™. Pharmacokinetic studies have shown that the altered distribution and elimination phases of VSLI may lead to increased VCR exposure compared to traditional VCR, and may account for the increased efficacy observed in preclinical models. Activity of VCR is dose and time-dependent, but neurotoxicity limits dosing to 1.4 mg/m2 (capped at 2.0 mg). VSLI, however, may be given without dose capping. We conducted a phase 1, open-label, dose-escalation study of VSLI in adults with relapsed or refractory ALL to determine the safety, maximum tolerated dose (MTD), and activity of this formulation. Subjects received VSLI intravenously weekly at doses of 1.5, 1.825, 2.0, 2.25 or 2.4 mg/m2. Dexamethasone 40 mg was given days 1–4 and 11–14 of each 4 week cycle. Thirtysix eligible subjects, all of whom had been previously treated with VCR, received at least 1 dose of VSLI. All were Philadelphia chromosome negative except for one. Median number of doses received for all subjects was 4; total medium cumulative dose was 9.09 mg/m2 (19.20 mg). MTD of VSLI was 2.25 mg/m2 based on dose-limiting toxicities of grade 3 motor neuropathy, grade 4 seizure and grade 4 hepatotoxicity observed in 1 subject each at the 2.4 mg/m2 dose level. The most common toxicities (constipation [67%], fatigue [61%], pyrexia [50%], anemia [50%], peripheral neuropathy [50%; mostly grade 1–2]) were as expected. Complete response (CR) was achieved in 7 of 36 (19%) subjects based on intent to treat analysis (Table). Overall response rate (including 1 PR) was 22%. Four subjects (11%) achieved hematologic improvement, 13 (36%) had stable disease, and 9 (25%) progressed. CR rate was 29% for the 7 subjects treated with VSLI as second salvage. Five of 7 subjects who achieved CR were able to undergo allogeneic stem cell transplant (SCT). In conclusion, VSLI appears to be an effective therapeutic option which may permit potentially curative SCT. A phase 2 international multi-center trial of single agent VSLI in subjects with relapsed ALL is currently accruing.
Table. VSLI Clinical Activity (CR) by Dose Level and Salvage Status
1.5 mg/m2 n = 5 1.825 mg/m2 n = 3 2 mg/m2 n = 3 2.25 mg/m2 n = 18 2.4 mg/m2 n = 7 Total n = 36 1st salvage 1/1 0/1 -- 2/7 1/4 4/13 (31) 2nd or later salvage 1/4 1/2 0/3 1/11 0/3 3/23 (13)
Direct Transcriptional Repression of BCL2 by BCL6 in Germinal Centre B Cells and Its Disruption in B Cell Lymphomas with BCL2 Locus Alterations
Authors: Piovan Erich , Saito Masumichi , Basso Katia , Novak Urban , Shen Qiong , Pasqualucci Laura , Dalla-Favera Riccardo 
Published: April 2020

Abstract
The human proto-oncogene BCL6 encodes a BTB/POZ-zinc finger transcriptional repressor that is required for germinal centre (GC) development and is expressed in the majority of normal GC B cells and in the majority of B cell lymphoma (B-NHL), including follicular lymphoma (FL) and a subset of diffuse large B cell lymphomas (DLBCLs). Deregulation of BCL6, by chromosomal translocation or somatic hypermutation, is implicated in the pathogenesis of B-NHL. The precise function of BCL6 in GC development and lymphomagenesis is still unclear also due to the very few direct BCL6 target genes that have been identified. In order to identify physiologically relevant BCL6 direct target genes, we used a novel approach combining high-throughput biochemical (ChIP-on-chip), bioinformatics (ARACNe) (Basso et al., Nature Genetics, 2005) and gene expression profile analysis (Klein et al., Proc. Natl. Acad. Sci., 2004) of normal GC B cells. The results (see abstract by Saito et al.) have identified a core of bona fide target genes whose promoter is bound by BCL6, whose transcription is dynamically linked to BCL6, and whose expression is down-regulated in GC B cells. Among the genes meeting these stringent criteria, we found BCL2, encoding the anti-apoptotic molecule whose expression is deregulated by chromosomal translocations or gene amplification in the majority of FL and in a subset of DLBCL. Further investigations showed that BCL6 represses BCL2 transcription by binding specific DNA sites within the BCL2 promoter region. Suppression of BCL6 expression via specific siRNAs leads to increased levels of BCL2, and, conversely, constitutive BCL6 expression prevents B cell receptor (BCR)-induced upregulation of BCL2 in B cells. Consistent with a physiological role for BCL6- mediated BCL2 suppression, immunohistochemical analysis shows that BCL2 expression is absent in GC B cells where BCL6 is highly expressed. Notably, the comparative analysis of BCL6 and BCL2 expression in B-NHL cell lines showed a conserved inverse correlation between BCL6 and BCL2 levels in cell lines carrying a normal BCL2 locus. However, cell lines carrying chromosomal translocations or amplifications affecting the BCL2 gene displayed the pathologic co-expression of both proteins, suggesting that the alterations affecting the BCL2 locus prevent BCL6-mediated suppression. These results indicate that one critical role of BCL6 is the modulation of antiapoptotic function in GC B cells via BCL2 transcriptional repression, suggesting a mechanism by which B cells may die in the GC if not rescued by BCR and CD40 engagement, both of which downregulate BCL6 while inducing BCL2 expression. Alterations of the BCL2 locus may contribute to lymphomagenesis by making the gene resistant to suppression by BCL6, and therefore allowing B cells to avoid apoptosis in the absence of antigen- and T-cell-mediated rescue.
Secondary Acute Myeloid Leukemia (sAML) Treated with Amonafide (AS1413) + Cytarabine: Durable Responses in Poor-Risk AML
Authors: Allen Steven L , Erba Harry P , Rizzieri David A. , O’Donnell Margaret , Powell Bayard , Lundberg Ante S , Bennett John M , Capizzi Robert L 
Published: April 2020

Abstract
Background: Secondary acute myeloid leukemia (sAML), evolving from prior MDS or leukemogenic therapy (tAML), is associated with a poor prognosis. Many sAML patients are elderly with significant comorbidities. The incidence of unfavorable cytogenetics and expression of multidrug resistance (MDR) phenotype is higher in sAML blasts. Amonafide (AS1413) is a DNA intercalating agent and unique topoisomerase II (Topo II) inhibitor that, unlike the classical Topo II inhibitors (DNR, IDA, mitoxantrone, etoposide), does not affect the DNA/Topo II cleavable complex that results in DNA fragmentation. It does not act as either a substrate or an inhibitor of the MDR efflux pump, P-glycoprotein (Pgp), nor is it cross-resistant with classical Topo II inhibitors. A complete remission (CR) rate of 38.6%, with an additional 3.4% of patients achieving CRp, has previously been reported for this phase II trial. Updated findings from this trial including duration of remission data are reported here.
Methods: Patients received a 4 hr infusion of amonafide 600 mg/m2/day × 5 and continuous IV infusion cytarabine 200 mg/m2/day × 7. 14 patients received a second course on day 14 for persistent leukemia. Patients received consolidation with stem cell transplant or intermediate/high dose cytarabine, depending on age. Central bone marrow review was performed for patients in CR. The primary endpoint was CR + CRp. Secondary endpoints included duration of CR/CRp. The last patient was treated in December 2006.
Results: 88 patients were enrolled; median age was 62.5 (range 23–87); prior MDS, 48.9%, (43/88); tAML, 51.1% (45/88); unfavourable cytogenetics, 46.6% (41/88). The most common non-hematologic grade ≥ 3 AEs seen were febrile neutropenia (35.2%), hypotension (15.9%), pneumonia (14.8%), hypokalemia (12.5%), and bacteremia (11.4%). Death rate within 28 days was 20.5%. Overall CR + CRp rate: 42.0% (37/88), including 38.6% (34/88) CR; 3.4% (3/88) CRp. CR by age &lt; 60: 39.4% (13/33); ≥ 60: 43.6% (24/55). 30/37 patients received post-remission therapy with BMT (7), high/intermediate dose cytarabine (21) or both (2).
Kaplan-Meier estimate of the proportion of responders in continuous CR/CRp at 18 months is 41% for all sAML patients, and is similar for all poor-risk subgroups including age ≥ 60, 43%; tAML, 57%; and unfavorable cytogenetics, 38%. Median overall survival is 209 days for all patients and 400 days for patients with CR/CRp.
Conclusions: Durable CRs have been achieved in patients with sAML/tAML treated with amonafide plus cytarabine. This efficacy was similar across subgroups independent of age or the presence of various poor risk characteristics. Phase III evaluation of amonafide plus cytarabine vs. daunorubicin plus cytarabine (3+7) is currently underway.
Duration of Remission Duration of Remission
Clinical Predictors of Prophylaxis Use Prior to the Onset of Acute Venous Thromboembolism in Hospitalized Patients: Swiss Venous ThromboEmbolism Registry (SWIVTER)
Authors: Kucher Nils , Spirk David , Kalka Christoph , Mazzolai Lucia , Nobel Daniel , Banyai Martin , Frauchiger Beat , Bounameaux Henri 
Published: April 2020

Abstract
Background: Venous thromboembolism (VTE) prophylaxis among hospitalized patients remains underutilized. We investigated the use of appropriate prophylaxis and predictors for using prophylaxis prior to the onset of acute VTE.
Methods: In 14 academic and non-academic Swiss hospitals, 567 consecutive patients (306 medical and 261 surgical patients) with objectively confirmed acute VTE and hospitalization within 30 days prior to the VTE event were enrolled. Data on acute and chronic comorbidities, VTE risk factors, and prophylaxis use prior to VTE were prospectively recorded.
Results: Among the 567 patients (62±16 years), deep vein thrombosis (DVT) alone was diagnosed in 222 (39%), acute pulmonary embolism (PE) in 218 (38%), and PE plus DVT in 127 (22%). Overall, prophylaxis was used in 329 (58%) patients prior to the VTE event. Among the medical patients, 146 (48%) received prophylaxis, and among the surgical patients, 183 (70%) received prophylaxis (p &lt;0.001). The indication for prophylaxis was present in 262 (86%) medical patients and in 217 (83%) surgical patients. Among the patients with an indication for prophylaxis, 135 (52%) of the medical patients and 165 (76%) of the surgical patients received prophylaxis (p &lt;0.001). Admission to the intensive care unit (OR 3.28, 95% CI 1.94–5.57), recent surgery (OR 2.28, 95% CI 1.51–3.44), bed rest &gt;3 days (OR 2.12, 95% CI 1.45–3.09), obesity (OR 2.01, 95% CI 1.03–3.90), prior DVT (OR 1.71, 95% CI 1.31–2.24), and prior PE (OR 1.54, 95% CI 1.05–2.26) were independent predictors of prophylaxis. In contrast, cancer (OR 1.06, 95% CI 0.89–1.25), age (OR 0.99, 95% CI 0.98–1.01), acute heart failure (OR 1.13, 95% CI 0.79–1.63), and acute respiratory failure (OR 1.19, 95% CI 0.89–1.59) were not predictive of prophylaxis.
Conclusions: Although an indication for prophylaxis was present in most patients who suffered acute VTE as a complication during or shortly after hospitalization, almost half did not receive any form of prophylaxis. Future effort should focus on the improvement of prophylaxis in hospitalized patients, particularly in patients with cancer, acute heart or respiratory failure, and in the elderly.
Natural History of Mesenteric Venous Thrombosis: A Large Multicentre Study
Authors: Dentali Francesco , Ageno Walter , Witt Dan , Malato Alessandra , Clark Nathan , Garcia David , Siragusa Sergio , McCool Kathleen , Dyke Shannon , Crowther Mark A. 
Published: April 2020

Abstract
Introduction: Mesenteric venous thrombosis (MVT) is an uncommon but potentially life-threatening disease, accounting for 5–15% of mesenteric ischemic events. Most cases of MVT are either identified at laparotomy or at autopsy, with a mortality rate of approximately 50% in old series. Advances in imaging techniques have facilitated the early diagnosis of MVT and, thus, have contributed to a decrease in mortality in the more recent series. The treatment of MVT involves anticoagulation alone or in combination with surgery. Experts suggest that MVT can safely be managed without surgery if there is no evidence of bowel infarction. However, information on the natural history of MVT and on efficacy and safety of long term treatment with oral anticoagulant (OAT) is based on small uncontrolled series of patients with a limited follow up. Therefore, the aim of our study is to clarify the natural history of this disease in a large cohort of patients recently diagnosed with MVT.
Methods: The charts of all patients with splanchnic vein thrombosis who are currently attending or who have attended four anticoagulation clinics (Denver, Albuquerque, Varese and Palermo) were reviewed. At these centres, patients are regularly followed up for the monitoring of OAT and information on clinical events is documented and registered in a computerized database. All patients with objectively diagnosed MVT, were selected. The charts of eligible patients were reviewed for baseline clinical characteristics including sex, age, prior history of cardiovascular disease and use and type of anticoagulant therapy. Information on mortality and all objectively confirmed recurrent venous thromboembolic events were noted.
Results: Seventy seven patients (mean age 49.2 years; 45 males) were included. Thirteen patients had a previous thromboembolic event. Thirty two were idiopathic. Forty six patients were on long term OAT. Median follow up was 36 months (Range 2–204 months). Seven patients had a recurrent thromboembolic event (5 splancnic vein thromboses and two PEs) for an incidence rate of 23.4 events/1000 year patient. Two patients (2.6%) had a major bleeding event (one subdural haematoma and one gastroenteric bleeding). Five patients had a VTE recurrence when suspended OAT for an incidence rate of 45.9 events/1000 year patient. Seven patients (9.1%) died during follow up (4 were related to cancer).
Conclusion: patients with a previous episode of MVT have a low risk of recurrent thromboembolic events while on oral anticoagulant treatment. This risk is clearly increased after treatment is stopped. In these patients, long term anticoagulant therapy appears as a safe and effective option.
Substitution of Four Residues Revealed by High-Throughput Screening of Human Factor VIII A2 Domain Generated a Recombinant Molecule That Escapes to Anti-Factor VIII Antibodies
Authors: Plantier Jean-Luc , Saboulard Didier , Delcourt Marc , Enjolras Nathalie , Negrier Claude 
Published: April 2020

Abstract
Using Massive Mutagenesis technique® we performed a high-throughput alanine substitution of 206 residues between aminoacids 376 to 649 from factor VIII (FVIII) A2 domain. The pattern of activity and the levels of production of FVIII mutants were assessed following transient expression in COS-1 cells. FVIII mutants that kept at least 50% of wild-type activity were then screened in an inhibitor assay against total immunoglobulin G (IgG) fractions from patients with severe hemophilia A who had developed inhibitory antibodies (n=4; range 6–15 BU/mL) or a non immune IgG as control. In this assay, the cell culture supernatants containing FVIII were incubated in a volume of FVIII-depleted plasma for 1h30 in the presence of IgG. The residual activity was then measured in a chronometric assay. No single mutations were able to significantly allow FVIII to escape inhibitors. Four mutations (S409A, L462A, E507A, L629A) having a tendency to resist to inhibitors were selected and recombined two by two leading to a significant but insufficient resistance to anti-FVIII antibodies. The effect of the mutations was additive since a molecule (FVIII-4A2) combining the 4 substitutions significantly resisted to the inhibitory antibodies. Residual activity of FVIII-4A2 ranged from 8% to up to 82% of the initial activity depending on the inhibitor plasma whereas this residual activity never exceeded 30% for control wild-type FVIII. Following production by CHO cells, purified FVIII-4A2 demonstrated a similar pattern of resistance to the four IgG fractions already assayed. FVIII-4A2 was then assayed against 11 additional unrelated inhibitors (range 3–2662 BU/mL) and displayed also a resistance against 10 out of the 11 IgG fractions. The resistance was in all case only partial in relation with the likely presence of anti-C2 and/or anti-A3-C1 inhibitors within the IgG fractions. As detected in a solid-phase assay, the decrease in inhibitory effect was for some of the IgG fractions partly related to a decrease in their binding capacity. As a control experiment, FVIII-4A2 was poorly recognized by the monoclonal antibody GMA012 directed against the A2 domain. In contrast, the binding to ESH4, an anti-C2 monoclonal antibody was not affected. Such combination of mutations opened the perspective for the generation of a recombinant FVIII molecule that can be used as an effective substitutive FVIII therapy in patients with inhibitors.
Embryoid Body Defect in Mouse Rps19-Haploinsufficient Embryonic Stem Cell Model of Diamond Blackfan Anemia
Authors: Singh Sharon , Dsilva Sehba , Lipton Jeffrey Michael , Ellis Steven , Liu Johnson M. 
Published: April 2020

Abstract
Diamond Blackfan anemia (DBA) is an inherited bone marrow failure syndrome that is characterized by erythroid hypoplasia, risk of other cytopenias, congenital anomalies and a cancer predisposition. Thus far, all the genes identified as mutated in DBA encode ribosomal proteins (RPS19, RPS17, RPS24, RPL5, RPL11, and RPL35a). In the 25% of DBA patients with RPS19 mutations, haploinsufficiency of RPS19 has been linked to faulty ribosome biogenesis, which ultimately predisposes erythroid precursors to apoptosis through as yet unknown mechanisms. Previous attempts by others to apply targeted mutagenesis to Rps19 were unsuccessful because of compensatory Rps19 expression from the non-targeted allele. We have concentrated our efforts on characterizing the murine Rps19-mutated embryonic stem (ES) cell, S17-10H1, which was generated using a genetrap strategy. The gene-trap vector contains a strong splice acceptor-β-geo cassette-poly A termination, and following insertion, it should cause splicing with the exon upstream and termination at the poly A signal, effectively cutting Rps19 in half. S17-10H1 was sequenced using 3′ RACE (rapid amplification of cDNA ends) to confirm insertion of the vector between exons 2 and 3 of Rps19. PCR with primers against the β-geo sequence was also used to confirm insertion of the gene trap vector into the mutant ES cells. Western blot analysis of two different ES cell samples confirmed at least 50% less Rps19 protein than found in the wild-type parental ES cell line, AK7. The ES cells were subsequently induced to undergo primary differentiation into embryoid bodies (EBs). Although there was no significant difference in the EB size or shape at day 5 of culture, the number of EBs that formed in the mutant cultures was decreased by at least three-fold. Preliminary experiments indicated no obvious morphological differences in day 13 EBs derived from parental or mutant ES cells. We attempted to create chimeric mice by microinjection of the S17-10H1 cell line into 36 blastocysts. Six chimeric mice were set up in mating pairs with C57BL/6J partners. Analysis of more than 60 pups from the 60% chimeric male revealed a lack of germline transmission, possibly indicating that this mutation leads to embryonic lethality or inability to complete gametogenesis. We conclude that this ES cell differentiation model mimics the human disease in leading to Rps19 haploinsufficiency and provides a new and potentially powerful tool that can be used to elucidate molecular mechanisms and test potential therapies in DBA.