bluuebunny/crossref_metadata_2025_split huggingface dataset:
Predicting Treatment Response and Survival of Multiple Myeloma with the Xbp-1 Co-Expression Gene Module
Authors: Lu Xuzhang , Xiaolong Fan , Zhuxia Jia , Jinyuan He , Xiaohui Cai 
Published: October 2019

Abstract
Multiple Myeloma (MM) is a B-cell malignancy characterized by monoclonal expansion and accumulation of abnormal plasma cells in bone marrow. The extensive biological and clinical heterogeneity of MM hinders effective treatment and etiology research. Several molecular classification systems for prognosis have been proposed, but they are not predictive for treatment response. XBP-1 is a critical molecule in coordinating normal plasma cell differentiation and survival because of its role in regulating the unfolded protein response. We identified a module of 100 genes co-expressed with XBP-1 (XBP-1-M) in the dataset GSE2658 by QlucoerOmics Explore 2.2 (Qlucore AB, Lund, Sweden) software. Using unsupervised consensus clustering, we assigned 264 MMs into XBP-1 low or XBP-1 high subtype in the validation dataset GSE9782. Patients in GSE9782 were randomly assigned into bortezomib or high-dose dexamethasone (Dex) treatment arms in the APEX 3 trial (039) (Blood 2007;109:3177-88). We integrated XBP-1-M clustering-based response analysis with the choice of treatment in GSE9782, XBP-1 high MMs had lower response rate (CR+PR) than XBP-1 low group (18.5% vs 59.67%, p<0.01). In the XBP-1 high MMs, significantly different response rate between bortezomib treatment and Dex treatment (36.34% vs 0%, p<0.05) was observed, while in the XBP-1 low MMs, no significantly different response between bortezomib treatment and Dex treatment (55.88% vs 61.18%, p>0.05) was noted. We further integrated XBP-1-M clustering-based survival analysis with the choice of treatment in GSE9782, XBP-1 high MMs showed significantly poorer progression-free survival (PFS) compared with XBP-1 low MMs during the 5-8 years follow-up, using either bortezomib(p=0.0071) or Dex (p=0.0011) regimen. In the patients treated with Dex regimen, XBP-1 high MMs showed significant poorer overall survival (OS) compared with XBP-1 low MMs (p=0.0316), while there were no differences in bortezomib regimen between XBP-1 high MMs and XBP-1 low MMs (p=0.224). Next, we integrated the XBP-1-M clustering-based genetic abnormality in GSE9782, there were higher frequencies of genetic abnormalities in XBP-1 high MMs than those in XBP-1 low MMs (1q gain 49.5% vs 12.6%, p<0.01; 17p del 21.9 % vs 3.2%, p<0.01; 13q del 58.1% vs 28.5%, p<0.05; t(4,14) 22.8% vs 15.8%, p<0.05; t(11,14) 31.4% vs 3.2%, p<0.01). The higher cytogenetic abnormalities may be related to the poorer treatment response and survival in patients with XBP-1 high expression. Therefore, we conclude that XBP-1-M may enable prediction of the treatment response and clinical outcome in multiple myeloma.

Disclosures
No relevant conflicts of interest to declare.
Retrospective Cohort Study Assessing the Prognostic Value of Baseline Necrosis on PET-CT in Hodgkin Lymphoma
Authors: Borges Nuno , Chen Isobel , Winn Luke , Osborne Wendy , Petrides George 
Published: October 2019

Abstract
Background: Identifying prognostic markers at diagnosis is essential to determine optimal tailored therapy for patients. The presence of necrosis has been shown to be associated with worse outcomes in patients with diffuse large B cell lymphoma. We aimed to determine whether necrosis at baseline correlated with clinical outcomes in patients with Hodgkin lymphoma.
Methods: Baseline PET-CT scans of patients diagnosed with Hodgkin lymphoma between January 2015 and December 2016 at a large UK teaching hospital were reviewed for evidence of tumour necrosis by a consultant radionuclide radiologist with a specialist interest in lymphoma. Potential necrosis identified on PET-CT was then confirmed both visually and quantitatively on baseline contrast enhanced CT. The presence or absence of necrosis was correlated with prognostic markers including Total Metabolic Volume (TMV), Total Lesion Glycolysis (TLG) and Hasenclever score as well as metabolic response, current remission status, relapse outcome and mortality.
Results: Fifty one patients' PET-CT scans were reviewed in total. Eight (15.6%) patients were confirmed to demonstrate necrosis both visually and using quantitative criteria. The presence of necrosis was associated with increased mortality (38%) vs no necrosis (9%). At end of treatment, a lower rate of complete metabolic response was achieved in the necrosis cohort (37%) compared with the no necrosis cohort (74%). This was statistically significant using Chi-square test with Yates correction (p=0.049). The presence of necrosis did not correlate with other prognostic markers (TMV, TLG or Hasenclever score).
Conclusion: This study has found that baseline necrosis correlated with both mortality and incomplete metabolic response following initial treatment. Tumour necrosis did not correlate with other prognostic markers and therefore may be able to be used as an independent assessment of prognosis to allow further tailoring of patient treatment. This study has identified a new potential independent prognostic marker in Hodgkin lymphoma. Prospective trials are required to confirm or refute these findings.

Disclosures
Osborne: MSD: Honoraria; Roche: Honoraria; Takeda: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Servier: Honoraria. Petrides:Roche: Honoraria; GE Healthcare: Honoraria.
Treatment with Decitabine Followed By Prednisone for Myelodysplatic Syndrome Concomitant with Sjogren's Syndrome
Authors: Sun Xingfu , Li Jianyong , Lu Hua 
Published: October 2019

Abstract
Myelodysplastic Syndrome (MDS) is rarely concomitant with Sjögren's syndrome (SS) with only 9 previously reported cases in the literature. A case of a previously healthy 31-year-old Chinese female presenting with dysplasia affecting all three lineages without blasts excess showed by bone marrow examination is reported. Autoimmune workup revealed positive antinuclear antibodies and Anti-SSA. Lip biopsy revealed findings consistent with SS. A diagnosis of SS associated with MDS of the refractory cytopenia with multilineage dysplasia (RCMD) subtype was established, and decitabine for five days at 20mg/m2 per day was initiated with only slight increase in platelet counts. Four weeks later, another cycle of decitabine for five days at 20mg/m2 per day was performed. Unfortunately, infection occurred, and the patient suffered from thrombocytopenia and leucopenia. Then the patient received the treatment of Biapenem and Vancomycin Hydrochloride along with granulocyte colony stimulating factor followed by platelet infusion for two weeks. Significant clinical and laboratory response was achieved. In hopes of improving both response rates and durability of response, the third cycle of decitabine for five days at 20mg/m2 per day was performed with again an excellent clinical and laboratory response. However the patient refused further cycle of decitabine due to cost consideration, then prednisone at 10mg per day was used as a basic treatment for SS. It was an amazing feat that the patient was in a state of remission for two years. MDS with SS tends to be incurable. Decitabine alone with prednisone may serve as an effective option to those patients.

Disclosures
No relevant conflicts of interest to declare.
Stratification for Age in Transfusion-Dependent Thalassemia
Authors: Pepe Alessia , Pistoia Laura , Rocca Mario , Palazzi Giovanni , Sorrentino Francesco , Maggio Aurelio , Quarta Antonella , Cosmi Carlo , Argento Crocetta , Armari Sabrina , Peritore Giuseppe , Oliva Matteo , Positano Vincenzo , Meloni Antonella 
Published: October 2019

Abstract

Introduction. Transfusion-dependent β-thalassemia (TDT) is the most severe clinical form of β-thalassemia and requires regular long-term red cell transfusions for survival. This study aimed to examine the association of age with the presence of iron overload assessed by Magnetic Resonance Imaging (MRI) and cardiovascular and endocrine complications in TDT patients.
Methods. We considered all TDT patients enrolled in the Myocardial Iron Overload in Thalassemia (MIOT) project at the first MRI examination. Iron concentrations were measured by T2* multiecho technique. All complications were classified according to international guidelines.
Results. Three groups of patients were identified: age<12 years (group 0, N=53), age between 12-17 years (group 1, N=100) and age≥18 years (group 2, N=1857).
The number of transfusional units in the 12 months before the MRI scan resulted significantly lower in group 0 versus both group 1 (20.8±5.3 vs 34.8±10.6; P<0.0001) and group 2 (20.8±5.3 vs 39.2±10.9; P>0.0001) and in group 1 versus group 2 (P=0.021).
The Table shows the comparison of clinical characteristics among the 3 groups.
Serum ferritin levels were significantly higher in both groups 0 and 1 when compared to group 2. Liver aminotransferases were significantly lower in group 1 than in group 2.
The number of patients with MRI LIC (liver iron concentration) >3 mg/g dw was significantly higher in group 1 than in group 2 and the number of patients with global heart T2*<20 ms was significantly lower in group 0 than in group 2.
Among the endocrinopathies, hypogonadism, hypothyroidism and osteoporosis were significantly less frequent in groups 0 and 1 than in group 2 while diabetes was significantly less frequent only in group 1 when compared to group 2.
Frequency of heart failure was comparable among the groups while the frequency of arrhythmias was significantly lower in group 1 than in group 2.
The types of chelation regimens were significantly different among groups (<0.0001) (see Figure).
Conclusions. Younger patients had more hepatic iron, despite the significant lower transfusional burden. Cardiac iron overload occurs early in TDT patients but it is more frequent in older patients. Endocrinopathies (excluding diabetes) and cardiac complications become clinically evident during the second decade and are time-dependent processes. Our data suggest the need for an effective strategy to prevent iron overload since early childhood, in order to reduce its toxic effect and prevent the development of long-term complications.
Figure. Figure.

Disclosures
Pepe: Chiesi Farmaceutici S.p.A., ApoPharma Inc., and Bayer: Other: No profit support.
Quality of Life in Pediatric Acute Myeloid Leukemia: A Report from the Children's Oncology Group
Authors: Nagarajan Rajaram , Alonzo Todd A , Gerbing Robert B , Johnston Donna , Aplenc Richard , Kolb E. Anders , Meshinchi Soheil , Barakat Lamia , Sung Lillian 
Published: October 2019

Abstract
Background: Objectives were to describe guardian proxy-reported quality of life (QoL) during chemotherapy for pediatric acute myeloid leukemia (AML) and to identify treatment and demographic factors associated with worse QoL.
Methods: Children's Oncology Group phase 3 AAML1031 study was a randomized trial for de novo AML patients age 0-30 to receive standard AML therapy with and without bortezomib. Patients with high risk FLT3-internal tandem duplication high allelic ratio (ITD HAR) were allocated to receive sorafenib in addition to the standard chemotherapy. Patients enrolled on the AAML1031 study who were 2-18 years of age at diagnosis with English or Spanish-speaking guardians were eligible to participate in the QoL portion of the study which included the PedsQL 4.0 Generic Core Scales, PedsQL 3.0 Acute Cancer Module and PedsQL Multidimensional Fatigue Scale. QoL assessments were obtained at four timepoints - at diagnosis and following completion of second, third and fourth (final) course of therapy. Guardians provided proxy assessments for all patients, while self-report for patients 5 years of age or older who could understand English was optional. This analysis focused on guardian proxy-reported QoL for patients who did not have FLT3-ITD HAR. In addition to demographic and treatment related factors, the total number of non-hematological grade 3-4 CTCAE (Common Terminology Criteria for Adverse Events) toxicities occurring during the time frame of QoL assessments was examined as a potential predictor of QoL.
Results: There were a total of 4105 QoL submissions and there were 3513 non-hematological grade 3-4 CTCAE toxicities reported: 1339 submissions at diagnosis with 1088 toxicities reported, 1112 submissions following the second course with 721 toxicities, 929 submissions following third course with 911 toxicities, and 725 submissions following the fourth course with 793 toxicities.
In repeated measures linear regression the number of submitted CTCAE toxicities was significantly associated with worse physical health (β±standard error (SE) -3.00±0.69; P<0.001) and general fatigue (β±SE -2.50±0.66; P<0.001). Older age was significantly associated with general fatigue (β±SE -0.58±0.25; P=0.022). In contrast, gender, risk status, bortezomib assignment, duration of neutropenia, private insurance status, white race and Hispanic ethnicity were not associated with physical health, psychosocial health or fatigue.
Conclusions: The number of CTCAE toxicities was an important factor influencing physical QoL and fatigue among children on treatment for AML. Identifying novel approaches for reducing toxicities should be a priority to potentially improve QoL.

Disclosures
No relevant conflicts of interest to declare.
Real-World Efficacy of Anti-Fungal Prophylaxis in Patients Treated for Acute Gastrointestinal Graft-Versus-host Disease (GI-GVHD)
Authors: Yuan Yin , Scott Ashleigh P 
Published: October 2019

Abstract
Aim
Allogeneic progenitor cell transplant (HPCT) recipients who develop acute gastrointestinal graft-versus-host disease (GI-GVHD) are at increased risk of developing invasive fungal infections (IFI). Randomised control trial data supports the use of mould-active fungal prophylaxis in HPCT patients with grade II-IV GVHD (Ullman et al. 2007). We aimed to assess our unit's use of anti-fungal prophylaxis and describe the incidence and species of breakthrough IFI in patients with GI-GVHD.
Method
We conducted a retrospective audit of patients who underwent HPCT at our institution between 2011-2016 and identified those who were treated for acute GI-GVHD using a minimum of prednisone 1mg/kg or equivalent. For those patients the following details were collected: presence of any prior IFIs, anti-fungal prophylaxis before and after initiation of steroids, and the incidence of new IFIs within 6 months of commencing steroids.
Result
Of the 551 HPCT performed during this period, 74 evaluable patients were treated for GI-GVHD. All patients received anti-fungal prophylaxis prior to steroid commencement (66.2% received fluconazole, 10.8% posaconazole, 20.2% voriconazole and 2.7% other). Post steroids 35.1% remained on fluconazole, 21.6% received posaconazole, 35.1% received voriconazole, and 8.1% received other anti-fungals. Of the 26 patients remaining on fluconazole, 9 were transitioned to mould-active prophylaxis at a later time.
Twelve patients (16.2%) experienced a breakthrough IFI (6 definite and 6 probable). In the 42 patients receiving posaconazole or voriconazole, 7 (16.7%) experienced breakthrough IFI, compared with 3 (11.5%) in the fluconazole cohort. Two other cases occurred in patients who received caspofungin. Notably, patients receiving mould-active fungal prophylaxis developed mucormycosis, Fusarium and Scedosporium infections whereas fluconazole lead to invasive aspergillosis.
Conclusion
Despite anti-fungal prophylaxis, real-world GI-GVHD patients remain at particularly increased risk of developing IFI. Anti-mould prophylaxis is associated with lower incidence of invasive aspergillosis but higher incidence of non-Aspergillus mould. Further studies investigating optimal anti-mould strategies are warranted.

Disclosures
No relevant conflicts of interest to declare.
Bortezomib-Based Chemotherapy Reduces Early Mortality and Improves Outcomes in Patients with Ultra-High-Risk Light-Chain Amyloidosis
Authors: Shen Kaini , Zhang Congli , Feng Jun , Zhang Lu , Cao Xinxin , Zhou Daobin , Li Jian 
Published: October 2019

Abstract
【Introduction】Patients with amyloid light-chain (AL) amyloidosis who have advanced cardiac damage are at risk of premature mortality. Currently, bortezomib is the mainstay in the treatment of AL amyloidosis, but the benefits of bortezomib in patients with ultra-high-risk AL amyloidosis have not been proved definitively. In current study, we aimed to establish the effects of bortezomib on early mortality, treatment responses and long-term outcomes in this very high-risk population.
【Methods】We performed a retrospective analysis of patients newly diagnosed with ultra-high-risk (defined by 2004 Mayo Stage IIIb or 2012 Mayo stage IV criteria) AL amyloidosis who received a bortezomib-based regimen or supportive treatment from January 1, 2009 to April 1, 2018 in our hospital. Kaplan-Meier survival curves were plotted. Between-group comparisons of progression-free survival (PFS) and overall survival (OS) were conducted with the log-rank test. To examine the impact of treatment on patients who survived long enough to have potentially benefited from therapy, a 6-month landmark analysis was performed among patients surviving at least 6 months from the start of treatment.
【Results】Patients receiving bortezomib-containing chemotherapy (n = 62) and patients receiving no chemotherapy (n = 24) were included. The overall median age at presentation was 59 years (range 37-81 years), with a male: female ratio of 2.2:1. Organ involvement included the heart (100%), kidney (68.6%) and liver (25.6%). The median number of chemotherapy cycles was four (range 1-12). The overall hematological response rate in the bortezomib group was 59.3%, with 42.6% achieving a complete response, 7.4% having a VGPR. A cardiac response was observed in 36.7% of patients. With an overall median follow-up of 24.3 months, median OS was 30 months in the bortezomib group and 2 months in the control group (p < 0.001) (Figure 1-A), and median PFS was 15.8 months (bortezomib) and 2 months (control; p < 0.001) (Figure 1-B). The early-death rate (within 6 months of diagnosis) was 32.3% (bortezomib) and 66.7% (control; p < 0.001). In a landmark analysis assessing outcomes in patients surviving beyond 6 months, the 2-year OS and PFS in the bortezomib group were 77.3% and 65.8%, respectively.
【Conclusions】Bortezomib-based regimens can help to reduce early mortality and improve long-term survival in patients with ultra-high-risk AL amyloidosis, especially in those who achieve a threshold hematological response. We recommend that both physicians and patients should always consider chemotherapy, regardless of the disease stage, as long as treatment-related complications are controllable.
Figure 1. Figure 1.

Disclosures
No relevant conflicts of interest to declare.
Catabolic Flexibility Enhances Drug Resistance but Induces Selective Vulnerability to New Mitochondrial-Targeted Therapeutic Combinations in IDH Mutant Leukemia
Authors: Sarry Jean-Emmanuel , Recher Christian , Stuani Lucille , Portais Jean-Charles 
Published: October 2019

Abstract
Isocitrate dehydrogenases IDH1/2 mutations and its oncometabolite 2-HG have been of major clinical interest as they have been causally linked to the development of glioma and acute myeloid leukemia (AML). However, global impact of mutations in these two key metabolic enzymes on cellular metabolic networks and chemoresistance is not well defined. We hypothesized that key metabolic fluxes are selectively reprogrammed to maintain biosynthetic homeostasis and chemoresistance in IDH mutant acute myeloid leukemia cells. We show that metabolic reprogramming initiated by IDH1 mutation leads to marked increases in glucose, glutamine and fatty acid catabolism that along with enhancement of wild-type IDH enzyme activity contribute to provision of α-KG required for 2-HG synthesis and to replenish Krebs cycle intermediates for biosynthetic reactions, oxygen consumption and ATP production. Mechanistically, this occurs through both 2-HG-dependent histone methylation-driven CEBPα activation of FAO and reprogramming of systemic metabolic fluxes through other pathways that augment catabolic flexibility. This catabolic flexibility leads to the enhancement of Krebs cycle and OxPHOS activities that are not necessarily rescued by IDH mutant inhibitors. Similarly, generation of 2-HG reflects the catabolic flexibility of IDH1 mutant cells but its reduction does not necessarily reverse the mitochondrial OxPHOS phenotype or reduce cell proliferation and survival in IDH1 mutant cells. This also renders IDH1 mutant cells more resistant to conventional chemotherapy such as cytarabine. While catabolic flexibility is not druggable per se, its metabolic consequence (e.g. enhanced mitochondrial dependency) is a specifically targetable vulnerability in IDH1 mutant AML and mutant cells are more susceptible to mitochondrial inhibition by OxPHOSi (IACS-107839) and BCL2i (ABT-199) compared to WT cells. Treatment with mutant IDH1-specific inhibitors enhances anti-leukemic effects of OxPHOS inhibitors alone and in combination with cytarabine. Our findings also provide a strong scientific rationale for innovative combinatory targeted therapies to treat this subgroup of patients, especially those unresponsive to or relapsing from IDH mutant-specific inhibitors.

Disclosures
No relevant conflicts of interest to declare.
Whole Exome Sequencing Identifies a Novel Variant in the Pklr Gene Which Worsen the Anemia Status in a Congenital Dyserthropoietic Anemia Patient
Authors: Peng Ching-Tien 
Published: October 2019

Abstract
Congenital dyserythropoietic anemia (CDAs) is a group of hereditary disorders characterized by ineffective erythropoiesis and distinct morphological abnormalities of erythroblasts in the bone marrow. Diagnosis of CDA is based primarily on the morphology of bone marrow erythroblasts but genetic tests might have more and more important roles recently. Here, we describe a 31-year old female with atypical CDA under regular blood transfusions. The results of blood tests were as followed: RBC: 3080000/µL, Hb: 9.9 g/dL, Hct: 26.8%, MCV: 87.0 fl, MCH:32.2 pg, and MCHC: 36.9 g/L. In this study, analysis of CDA-related genes, including SEC23B, CDAN1, KLF1, and C15orf41, were analyzed by exome sequencing but no pathogenic variant was found. In additional, we analyzed RBC-related genes and a novel variant in the PKLR p.A468G (NP_000289) was found which was also confirmed by Sanger sequence. Variant of PKLR gene has been reported as the cause of pyruvate kinase (PK) deficiency anemia. PK deficiency is the most cause of congenital nonspherocytic hemolytic anemia with GMAF (global minor allele frequency) of 0.0001. The clinical features of PK-deficient patients are highly variable degree of chronic hemolysis with severe neonatal jaundice and fetal anemia at birth. In this case, PKLR p.A468G heterozygous variant was detected in a patient with PK deficiency, as an example of precision diagnosis by exome sequencing.

Disclosures
No relevant conflicts of interest to declare.