bluuebunny/crossref_metadata_2025_split huggingface dataset:
Detection of trastuzumab (T) level in human serum using quartz crystal microbalance (QCM) piezo-immunosensors by immobilization of a HER2 mimotope-derived synthetic peptide and its potential application in breast cancer.
Authors: Chisti Mohammad Muhsin , Shang Yuqin , Muslimani Alaa , Singh Pankaj R , Mernaugh Ray , Jaiyesimi Ishmael A. , Zeng Xiangqun 
Published: March 2020

628 Background: Varied clinico-pathological response to monoclonal antibodies like T has been reported either due to presence of antibodies, rapid clearance or low density of target receptor/antigens. This demands need for an assay to monitor serum T therapeutic levels to ensure appropriate dosage. Enzyme-linked immunosorbent assay (ELISA) is still the most widely used technique to detect T level in human serum which is expensive and time consuming. For the first time, we established a platform to detect T level by using a small (<2.2 kDa), inexpensive, highly stable HER2 mimotope-derived synthetic peptide immobilized on the surface of a gold quartz electrode. Methods: HER2 mimotope was used as a substitute for the HER2 receptor protein in QCM assays to detect T level. The validation samples were prepared from the standard T solution in 10% human serum at three concentrations (10, 20 and 40 ug/ml). The changes in frequencies (ΔF) of sera from 3 female patients , 61, 32 and 44 years old , with ER/PR positive, HER2/neu positive metastatic breast cancer were obtained by calculating the differences between frequency shifts in pre and post T infusion.T level was calculated by equation, (ΔF +1.0022) ÷ 0.9997 μg / ml. Results: We showed that assay sensitivity was dependent upon the amino acids used to tether and link the peptide to the sensor surface and the buffers used. QCM assay was capable of detecting T serum level as low as 0.038 nM (linear operating range of 0.038–0.859 nM). T levels of 3 patients were 43.34, 121.96 and 193.18 μg /ml corresponding to pre and post infusion ΔF of 3.33, 11.19 and 18.31 respectively. The time frame of assay was 20-30 minutes. These results were in concordance with previously published results using ELISA. Conclusions: For the first time, we have established a low cost, highly sensitive, fast, synthetic peptide based QCM assay which could be used as a basis for developing a new generation of affinity-based Immunosensor assays to monitor serum levels of T and other monoclonal antibodies, helping physicians to determine the clinical efficacy of these drugs and ensuring appropriate dosages.
Effect of heterogeneity of HER2 expression on brain metastases of breast cancer.
Authors: Hosonaga Mari , Arima Yoshimi , Sugihara Eiji , Kohno Norio , Saya Hideyuki 
Published: March 2020

635 Background: HER2-overexpressing or triple-negative [ER(-)/PR(-)/HER2(-)] breast cancers are associated with increased risk of brain metastases. The mechanisms leading to metastasis in each subtype are not well known. Methods: We introduced the wild-type HER2 gene into MDA-MB-231-luc-D3H2LN (231-Luc) cells, which are triple-negative breast cancer cells, and established HER2-expressing (63.2%) cells as 231-Luc-HER2 cells. We investigated the tumor formation following orthotopic inoculation and brain metastasis following intracardiac injection into nude mice. Metastasis was detected by bioluminescence imaging and confirmed in H&E staining and immunohistochemistry of vimentin and HER2 expressions. Flow cytometry analysis was used to detect the proportion of CD44+/CD24- cells, a maker for stem-like breast cancer cells. Results: 231-Luc-HER2 cells formed larger tumors in orthotopic xenograft models compared to 231-Luc cells, however, no significant difference was observed in proliferation in vitro. Neither 231-Luc-HER2 nor 231-Luc metastasized in the brain from the breast after orthotopic inoculation. After intracardiac injections of the 231-Luc-HER2 cells, brain metastasis developed (7/13 mice, 53.8%). Immunohistochemical analysis revealed that most metastasized cells expressed HER2, although we had injected a mixture of HER2-positive and HER2-negative cancer cells. Interestingly, administering Lapatinib, a dual EGFR and HER2 tyrosine kinase inhibitor, effectively prevented HER2-positive cells to colonize the brain. However, the HER2-negative 231-Luc-HER2 cells developed into brain metastases. In fact, the 231-Luc cells, which are HER2-negative, also metastasized in the brain (10/16 mice, 62.5%). Flow cytometry analysis of the 231-Luc-HER2 cells showed that HER2-positive cells decreased the population of CD44+/CD24- (HER2+/CD44+/CD24-: 86.8% and HER2-/CD44+/CD24-: 96.3%). Conclusions: The mechanism of brain metastases of HER2-positive breast cancer cells is different from that of HER2-negative breast cancer cells. It is therefore important to consider an additional therapeutic approach when dealing with HER2-negative cells in tumors having the heterogeneity of HER2 expression.
A phase II trial of azacitidine (NSC-102816) and gemtuzumab ozogamicin (NSC-720568) as induction and post-remission therapy in patients of age 60 and older with previously untreated non-M3 acute myeloid leukemia: SWOG S0703 protocol—Report on the good-risk patients.
Authors: Nand Sucha , Gundacker Holly , Godwin John E. , Willman Cheryl L. , Norwood Thomas , Erba Harry Paul , Howard Dianna S. , Coutre Steven E. , Othus Megan , Appelbaum Frederick R. 
Published: March 2020

6502 Background: In pts with AML, response rates to standard chemotherapy decrease and early death rates increase with age. Whereas pts < 56 yrs of age have a complete remission (CR) rate of 65% and 30 day mortality risk of <3%, the respective figures are 33% and 31% in pts > 75 yrs. This trial was designed to improve safety and efficacy by using agents with low toxicity, different mechanisms of action and possible synergy. The treatment could be given in the outpatient setting. Methods: Newly diagnosed pts with non-M3 AML, 60 yrs or older, were treated as follows: Induction: Hydroxyurea 1500 mg b.i.d till WBC <10,000/mcL, followed by azacitidine 75 mg/m2/day s/cu or iv days 1-7, gemtuzumab ozogamicin (GO) 3mg/m2 on D8. Induction treatment was repeated for residual disease on D14. Pts achieving CR received a consolidation treatment identical to the induction treatment. This was followed by 4 cycles of azacitidine 75/m2/day, D1-7, given q 4 weeks. Subsequent therapy was optional. Promoter and global methylation studies were performed at defined time points. Results: Pts were stratified into good risk (age 60-69 or Zubrod 0-1) and poor risk (age ≥70 and Zubrod 2 or 3) groups. The results presented here are from the good risk cohort. Eighty-three pts were entered of whom 79 are evaluable. Median age was 71 yrs (60-88) and 49 were males. Thirty-five achieved CR/CRi (44%: 95% CI 33%-56%). Median overall survival was 11 months and median relapse-free survival with patients achieving a CR/CRi was 8 months. Six patients (8%), 3 with disease progression, died within 30 days of registration. The main non-hematologic toxicity was neutropenic fever (Grade 3 or higher), seen in 27 patients. Conclusions: The combination of hydroxyurea, azacitidine and GO is associated with a low induction mortality, can be given in the outpatient setting and produces results which compare favorably with standard chemotherapy regimens in elderly patients with AML. Our results are sufficiently encouraging to warrant further studies of this approach. Clinical Trials.govIdentifier: NCT00658814.
Dasatinib versus imatinib (IM) in newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): DASISION 3-year follow-up.
Authors: Hochhaus Andreas , Shah Neil P. , Cortes Jorge E. , Baccarani Michele , Bradley-Garelik M. Brigid , Dejardin David , Kantarjian Hagop 
Published: March 2020

6504 Background: In the phase 3 DASISION trial of dasatinib v IM in patients (pts) with newly diagnosed CML-CP, dasatinib had higher 12-month rates of complete cytogenetic response (CCyR) and major molecular response (MMR) (Kantarjian, NEJM 2010;362:2260). By 12 months confirmed CCyR (cCCyR) rates for dasatinib v IM were 77% v 66%, P=0.001, meeting the primary endpoint. Methods: Pts were randomized to receive dasatinib 100 mg once daily (QD; n=259) or IM 400 mg QD (n=260). Results: Minimum 24-month follow-up (median 26.6 months) is reported here. 24-month molecular response rates were higher for dasatinib v IM: MMR (BCR-ABL ≤0.1%) 64% v 46%, P<0.0001; MR4 (BCR-ABL ≤0.01%) 29% v 19%, P=0.0053; MR4.5 (BCR-ABL ≤0.0032%) 17% v 8%, P=0.0032. MMR rates were higher for dasatinib in all Hasford risk groups (high 73% v 56%; intermediate 61% v 50%; low 73% v 56%). Of pts who achieved MMR at 12 months, on dasatinib v IM, 97% v 92% had maintained their MMR at 24 months, respectively. Pts receiving dasatinib v IM had faster responses; median time to CCyR and MMR was 3.2 v 6.0 and 15 v 36 months, respectively. In an intent-to-treat analysis, fewer pts receiving dasatinib (n=9; 3.5%) transformed to accelerated/blast phase v IM (n=15; 5.8%) on study or during follow-up after discontinuation. 24-month overall and progression-free survival were similar for dasatinib v IM: 95.4% v 95.2% and 93.7% v 92.1% (follow-up is ongoing). Few additional adverse events (AEs) were reported between 12 and 24 months in both arms, with grade 3/4 nonhematologic AE rates ≤1%. In each arm, 10 pts had a BCR-ABL mutation detected at time of discontinuation. For dasatinib v IM, 23% v 25% discontinued treatment for drug-related AEs (7% v 5%), progression (5% v 7%), failure (3% v 4%), unrelated AEs (2% v <1%), death (2% v <1%), and other (4% v 8%). Few pts discontinued between 12 and 24 months for dasatinib (n=19; 7%) and IM (n=16; 6%). Conclusions: Updated data with minimum 36-month follow-up will be presented, including mutation analyses in pts who discontinued, progressed, or had suboptimal response. Pts receiving dasatinib had a lower transformation rate and higher molecular responses v pts receiving IM, supporting the use of dasatinib in newly diagnosed CML-CP.
Efficacy and tolerability of lenalidomide (LEN) in patients (pts) 75 and older versus those younger than 75 with RBC transfusion-dependent low/int-1-risk MDS and del 5q.
Authors: Fenaux Pierre , Guerci-Bresler Agnes , Muus Petra , Sekeres Mikkael A. , Giagounidis Aristoteles , Deeg H Joachim , Greenberg Peter , Skikne Barry , Yu Xujie , List Alan F. 
Published: March 2020

6522 Background: LEN is the approved treatment for pts with RBC transfusion-dependent Low/Int-1-risk MDS and del 5q. In 2 multicenter trials (MDS-003/-004) LEN lead to RBC transfusion independence (TI) for ≥ 26 wks in 35–58% of pts and cytogenetic response (CyR) in 25–73%. Most common grade (G) 3–4 adverse events (AE) were neutropenia and thrombocytopenia, a safety concern in elderly pts. We evaluated efficacy and tolerability of LEN in pts ≥ 75 y vs < 75 y in MDS-003/-004 trials. Methods: Pts received LEN 5 mg × 28 d, 10 mg × 21 d, or 10 mg × 28 d (all 28 d cycles). Dose reductions were required for G4 neutropenia (both trials) and platelet counts < 30 x 109/L (MDS-003) or < 25 x 109/L (MDS-004). Results: 32% of the 286 pts were ≥ 75 y. Baseline (BL) characteristics, LEN treatment, and optional G-CSF use are shown in Table. In pts ≥ 75 y vs < 75 y: RBC-TI ≥ 26 wks was 39 vs 47% (P = NS); CyR was 64 vs 54% (P = NS); 2-y AML progression rates were 10 vs 19% (P = NS); 2-y overall survival rates were 62 vs 73% (P = .001); G3–4 AE: neutropenia (63 vs 76%; P = .024), thrombocytopenia (56 vs 49%; P = NS), infection (36 vs 20%; P = .003); median time to recovery to ANC > 1 x 109/L was 0.7 vs 0.7 mo (P = NS) and to platelet counts > 100 x 109/L was 3.3 vs 1.7 mo (P = NS). 59% pts ≥ 75 y and 49% pts < 75 y discontinued LEN due to AE (33 vs 26%; P = NS), lack of effect (32 vs 49%; P = NS), or death (15 vs 6%; P = NS). Dose reduction and discontinuation rates are shown in Table. Conclusions: Pts ≥ 75 y and < 75 y had comparable response and AML progression rates. In pts ≥ 75 y, LEN appears to be well tolerated but the higher infection rate justifies close follow-up. [Table: see text]
Stage I findings of a two-stage phase II study to assess the efficacy, safety, and tolerability of barasertib (AZD1152) compared with low-dose cytosine arabinoside (LDAC) in elderly patients (pts) with acute myeloid leukemia (AML).
Authors: Martinelli Giovanni , Kantarjian Hagop , Jabbour Elias , Quintas-Cardama Alfonso , Ando Kiyoshi , Bay Jacques-Olivier , Wei Andrew , Gröpper Stefanie , Owen Kate , Pike Laura , Schmitt Nicola , Stockman Paul , Giagounidis Aristoteles 
Published: March 2020

6527 Background: Barasertib is the pro-drug to barasertib-hQPA, a selective Aurora B kinase inhibitor with preliminary anti-AML activity in a Phase I/II study (Löwenberg et al. Blood 2011;118:6030). Methods: AML pts aged ≥60 y considered unsuitable for intensive chemotherapy were randomized 2:1 to open-label barasertib 1200 mg (7-day iv infusion) or LDAC 20 mg (sc twice daily for 10 days) in 28-day cycles (NCT00952588). The primary endpoint was improved objective complete response rate (OCRR: CR + CRi [Cheson criteria, but requiring CRi confirmation ≥21 days after first appearance, with partial recovery of platelets and neutrophils]). Secondary endpoints included duration of response (DoR), overall survival (OS) and safety. Results: 74 pts (barasertib, 48; LDAC, 26) received treatment and all completed ≥1 cycle. A significant improvement in OCRR was observed with barasertib (35.4% [17/48] vs 11.5% [3/26]; difference, 23.9% [95% CI, 2.7-39.9]; P<0.05); barasertib responses were seen in all cytogenetic risk groups and appeared to be durable (median DoR [range], 82 [28-321] days; vs LDAC 30-85 days). Although not formally sized to compare OS data, a trend favoring barasertib was observed (HR=0.88, 95% CI, 0.49-1.58; P=0.663; median OS, 8.2 vs 4.5 mo). Stomatitis and febrile neutropenia were the most common adverse events (AEs) in the barasertib arm with higher incidences vs LDAC (71% vs 15%; 67% vs 19%, respectively). Grade ≥3 AEs with a greater incidence in the barasertib arm were febrile neutropenia (50% vs 19%), stomatitis (29% vs 0%) and pneumonia (25% vs 8%); grade ≥3 infection rates were also higher with barasertib (40% vs 23%). For both arms, there were similar discontinuation rates due to AEs (barasertib 8.3% vs LDAC 7.7%), deaths due to AEs (12.5% vs 11.5%) and 30-day mortality (12.5% vs 15.4%). Cumulative toxicities were not observed with barasertib treatment. Conclusions: In this population with poor prognosis using standard chemotherapy, barasertib showed a significant improvement in OCRR vs LDAC, and a safety profile that was manageable and consistent with previous studies.
Impact of donor source on allogeneic stem cell transplantation for Philadelphia chromosome-negative acute lymphoblastic leukemia.
Authors: Nishiwaki Satoshi , Miyamura Koichi , Ohashi Kazuteru , Kurokawa Mineo , Taniguchi Shuichi , Fukuda Takahiro , Ikegame Kazuhiro , Sakamaki Hisashi , Morishima Yasuo , Kato Koji , Suzuki Ritsuro , Tanaka Junji ,   Adult Acute Lymphoblastic Leukemia Working Group of the Japan Society for Hematopoietic Cell Transplantation
Published: March 2020

6533 Background: Although allogeneic stem cell transplantation (allo-SCT) could improve the outcome of adult Philadelphia chromosome-negative acute lymphoblastic leukemia [Ph(-) ALL], the impact of the donor source, particularly the position of cord blood (CB) transplantation, is still uncertain. Methods: We retrospectively analyzed 1726 adult Ph(-) ALL patients transplanted at the first time between 1998 and 2009 with myeloablative preparative regimens who were registered in the Japan Society for Hematopoietic Cell Transplantation database. Two hundred and thirty-three received CB transplantation [first complete remission (CR1): 95, subsequent CR: 53, non-CR: 85], 809 received allo-SCT from unrelated donor (URD) (CR1: 434, subsequent CR: 158, non-CR: 217), and 684 received allo-SCT from related donor (RD) (CR1: 388, subsequent CR: 89, non-CR: 207). Results: Overall survival (OS) in patients after CB transplantation in CR1 was comparable with that after allo-SCT from URD or RD [57% in CB, 64% in URD, and 65% in RD at 4 years, respectively, P=0.11]. Donor source was not a significant risk factor for OS in multivariate analysis. Although URD was a favorable factor for relapse and an unfavorable factor for non-relapse mortality (NRM), CB was not a significant factor for them [Relapse: 22% in CB, 17% in URD, and 24% in RD at 3 years, respectively (P=0.02); NRM: 27% in CB, 23% in URD, and 13% in RD at 3 years, respectively (P=0.0001)]. Among CB recipients in CR1, age at allo-SCT (45 years or older) was solely a significant adverse prognostic factor in multivariate analysis. Among patients younger than 45 years who received allo-SCT in CR1, OS after CB transplantation was significantly better than that after allo-SCT from mismatched URD (4-year OS: 68% vs. 49%, P=0.04). Similarly, OS was not different by donor source in subsequent CR or non-CR [Subsequent CR: 48% in CB, 39% in URD and 48% in RD, P=0.33; non-CR: 18% in CB, 21% in URD, and 15% in RD, P=0.20 at 4 years, respectively]. Conclusions: Allo-SCT using CB led to similar outcomes as either RD or URD in any disease status. CB transplantation is a good alternative for adult Ph(-) ALL patients without a suitable RD or URD.
Impact of treatment prior to allogeneic stem cell transplantation for myelodysplastic syndromes: A study on behalf of the SFGM-TC and the GFM groups.
Authors: Damaj Gandhi Laurent , Duhamel Alain , Robin Marie , Michallet Mauricette , Mohty Mohamad , Vigouroux Stephane , Beguin Yves , Garnier Alice , Lioure Bruno , El Cheikh Jean , Fegueux Nathalie , Cornillon Jerome , Francois Sylvie , Rubio Marie Therese , Huynh Anne , Park Sophie , Marolleau Jean pierre , Garnier Frederico , Fenaux Pierre , Yakoub-Agha Ibrahim 
Published: March 2020

6534 Background: Until the early 2000s, treatment prior to SCT varied according to cytogenetics and % BM blasts and was mainly induction-type chemotherapy (ICT). The role of Azacitidine (AZA) prior to transplant remains uncertain. Methods: 163 consecutive pts (M/F=104/67; age > 18) underwent alloSCT between 2005 and 2009 from sibling (n=96) or HLA- allele-MUD (10/10) (n=67). The SC source was blood (n=142) or marrow (n=21) and conditionings were myeloablative (n=33); nonmyeloablative (n=130). Pts who did not received neither prior ICT nor AZA were excluded since the main objective of this study was to investigate the impact of prior therapy on pts’ outcome. Results: At diagnosis, FAB/WHO was: 24 RA/RARS/RCMD, 52 RAEB-1, 74 RAEB-2, 13 RAEB-t/AML; Cytogenetic: fav (n=93), int (n=32), unfav (n=37). 98 pts received prior ICT (ICT-group) and 65 had received AZA, either alone (AZA-group; n=48) or AZA preceded or followed by intensive CT (AZA-chemo-group; n=17). In AZA groups, the drug was started 38 to 941 days from transplant and discontinued 6 to 438 days before transplant with a median number of 4 cycles (range 1-26). Overall, 119 pts were considered responders at SCT (CR, PR, mCR), including 33 (69%) treated with AZA-alone, 9 (53%) with AZA-chemo and 77(78%) with ICT.While there were no differences between AZA-group and ICT-group in terms of OS, EFS, relapse and NRM, having a poor risk cytogenetic and receiving AZA-chemo prior to SCT were, in multivariate analyses, the most important factors that adversely influenced OS with [HR=3.03; 95% CI 1.84-4.96] (p<.0001) and [HR=2.72; 95% CI, 1.38-5.35] (p=.004), respectively. Pts of AZA-chemo group had the same rate of relapse but significantly higher NRM rate (p=.059) than those who received either AZA or ICT alone. Conclusions: With the goal of down-staging underlying disease before allo-SCT, AZA treatment appears to be a valid therapeutic approach, but mainly in pts receiving AZA alone with an outcome at least equivalent to pts receiving ICT prior to SCT. Allo-SCT in pts who required both AZA and chemotherapy had less satisfactory outcomes, possibly reflecting additional toxicity and/or more resistant disease.
Impact of antithymocyte globulin (ATG)-containing conditioning regimens on patients undergoing allogeneic stem cell transplantation (allo-CST) for poor risk cytogenetic IPSS myelodysplastic syndrome (PRC-MDS): A report from the French Society of Stem Cell Transplantation and Cell Therapy (SFGM-TC).
Authors: Yakoub-Agha Ibrahim , Damaj Gandhi Laurent , Robin Marie , Vigouroux Stephane , Garnier Alice , Michallet Mauricette , El Cheikh Jean , Lioure Bruno , Bay Jacques-Olivier , Contentin Nathalie , Maillard Natacha , Deconinck Eric , Duhamel Alain , Mohty Mohamad 
Published: March 2020

6542 Background: Due to a risk of relapse of underlying disease in patients with PRC-MDS, the use of ATG, incorporated within the conditioning regimen prior to allo-SCT, is still controversial. Methods: Inclusion criteria included patients aged over 18 (n=101) who received allo-SCT transplanted between 1999 and 2009 from either a sibling (n=68) or HLA-allele-MUD (10/10) (n=33) for PRC-MDS. HLA matching was double-checked by the national Bone Marrow Donor Registry. Results: According to the FAB/WHO classification at diagnosis, 22 pts had RA/RARS/RCMD, 40 RAEB1, 30 REAB2 and 9 RAEB-t/AML. 34 pts had progressed to a more advanced disease before allo-SCT. At diagnosis, 89 patients had an IPSS int-2 or higher. At transplant, 36 pts were responders (CR, PR, CRm) and 62 with progressive disease (relapsed/refractory, untreated or stable disease without hematological improvement). Median age at transplantation was 54 years (range, 22-69). Pts received myeloablative conditioning (n=46) and nonmyeloablative (n=55). In this series, 48 patients received ATG as part of conditioning ('ATG' group), whereas 53 did not ('no-ATG’ group). As of April 1st 2011, 44 patients died of relapse and 22 of TRM. 3-year relapse, overall and event-free survival rates were not significantly different between the two groups. In contrast, the cumulative incidence of grade 2-4 acute GVHD was 48% in the no-ATG group and 30% ATG group (P <.005). Although the cumulative incidence of chronic GVHD was similar in the no-ATG and ATG groups, a trend for a lower TRM was observed in the ATG group (p=.06). In multivariate analysis, the absence of use of ATG was associated with an increased risk of acute grade 2-4 [HR = 1.92, p=.044]. Conclusions: The addition of ATG to the conditioning regimen resulted in a decreased incidence of acute GVHD without increasing relapse rates and compromising survival of patients undergoing allo-SCT for poor risk cytogenetic MDS.