bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical significance of extranuclear expression of hormone receptors in breast cancer
Authors: Kim R. , Kaneko M. , Arihiro K. , Emi M. , Tanabe K. , Murakami S. , Osaki A. , Inai K. 
Published: March 2020

644 Background: Hormone receptor (HR)-positive breast cancer cells grow through estrogen receptor (ER)-signaling pathways that mediate both genomic and nongenomic actions, which cross-talk with growth factors associated with resistance to tamoxifen. The aim of this study is to explore the clinical significance of extranuclear expression of ER and PR in the cross-talk between HR and growth factor signaling pathways. Methods: We examined the extranuclear expression of ER and PR in 219 primary breast cancers by immunohistochemical staining. Specimens showing such expression were further examined for the expression of pAkt and aromatase. Due to heterogeneity, staining was scored on the basis of intensity and distribution in the tumors. Results: Extranuclear expression of ER or PR was observed in 21 cases (9.5%), which included 4 cases (19.0%) for ER and 20 cases (95.2%) for PR. Among these patients, HER-2, pAkt, and aromatase-positivity were observed in 14 cases (66.6%), 13 cases (61.9%), and 14 cases (66.6%), respectively. On the basis of nuclear HR expression, 11 of these cases were categorized as ER-positive/PR-negative, while 2 were ER-negative/PR-positive. Of those 13 cases, increased pAkt staining was found in 11 cases (84.6%). In particular, among the 11 ER-positive/PR-negative, elevated pAkt and aromatase were found in 10 (90.9%; p<0.01) and 9 cases (81.8%), respectively. Conclusion: PR is more frequently expressed extranuclearly than ER in primary breast cancer, and extranuclear HRs cross-talk with the Akt/HER-2-signaling pathway and activation of aromatase, providing an explanation for the observation that aromatase inhibitors are more beneficial than tamoxifen for ER-positive/PR-negative patients. No significant financial relationships to disclose.
The influence of PET/Gallium (P/G) status and high-dose rituximab (HDR) in patients (pts) with aggressive, large, B-cell lymphoma (LBCL) receiving autologous stem cell transplants (ASCT)
Authors: Alousi A. M. , Saliba R. M. , Okoroji G. , Hosing C. , Samuels B. I. , Champlin R. E. , Khouri I. F. 
Published: March 2020

6518 Background: P/G status has been suggested to be an important predictor of outcome in pts with LBCL who receive an ASCT. Newer conditioning regimens which include HDR have been shown to improve results (Khouri, JCO, 2005). The influence of HDR on the outcome of pts based on P/G status has not been determined. Methods: A retrospective review of pts with chemo-sensitive, LBCL who received an ASCT on a research protocol at MD Anderson between 1995 and 2005 was performed. Results: A total of 188 pts were identified. Median age was 49 yrs with 108 (57%) male pts. 147 (78%) had de novo LBCL and 41 (22%) had an LBCL of follicular origin (LBCL-F). 83 (39%) pts received HDR with ASCT. At transplantation 95 pts (50%) were in PR, 71 pts (38%) in CRU and 22 pts (12%) in CR. 142 (76%) pts were P/G negative, 37 (20%) pts P/G positive and 9 (4%) pts unknown. The median follow-up was 44 months. Factors that were considered for outcome included: Age, IPI, # of prior chemotherapies, B2-microglobulin, disease status at transplant, HDR and P/G status. On multivariate analysis, P/G status and HDR were the only predictors for progression and PFS. Pts who were P/G negative and those that received HDR had a hazard ratio (HR) of 0.3 (p<0.001) and 0.5 (p=0.02) for progression, respectively. The cumulative incidence (CI) of progression and progression free survival (PFS) at 54 months according to HDR and P/G status are shown in the table below. P/G Status and HDR were also found to be predictive for pts with LBCL- F on univariate analysis, however due to the small numbers in this subset of pts, multivariate analysis could not be performed. Conclusions: These results suggest that pre-transplant P/G positive status increases the risk of progression of LBCL after ASCT. The addition of HDR to the transplant regimen decreases this risk irrespective of P/G status. [Table: see text] No significant financial relationships to disclose.
Dynamics of molecular response to dasatinib (BMS-354825) in patients (pts) with chronic myelogenous leukemia (CML) resistant or intolerant to imatinib
Authors: Quintás-Cardama A. , Kantarjian H. , Jones D. , Talpaz M. , Jabbour E. , O’Brien S. , Luthra R. , Wierda W. , Nicaise C. , Cortes J. 
Published: March 2020

6525 Background: Mutations in the BCR-ABL kinase domain are a common mechanism (40%) of imatinib-resistance. Dasatinib is 300-fold more potent than imatinib against Abl and has activity against all BCR-ABL mutants, except T315I. We investigated the molecular response to dasatinib in pts with CML intolerant or resistant to imatinib. Methods: Fifty-three pts in chronic (CP) (n=29), accelerated (AP) (n=14) and blast (BP) (n=10) phase CML received dasatinib for a median of 22 wks (range, 7 to 42). Pts had received a median of 4 therapies (range, 1 to 8) including imatinib (n=53), IFN (n=32), and AMN107 (n=9). Imatinib was stopped (41 resistant and 12 intolerant) after a median of 34 mo (range, 2.5 to 82). Quantitative reverse transcription PCR in peripheral blood samples was performed prior to dasatinib and every 3 mo thereafter. Median BCR-ABL/ABL ratio (%) at dasatinib start was 78.34 (range, 0.009 to 100). Twenty-four of 42 assessed pts harbored 16 different BCR-ABL mutants. The most common mutations were H396R (n=5), G250E (n=4), and M351T (n=3). Results: BCR-ABL reductions occurred in 48 (90%) pts: <1-log in 12 (23%) pts (7 CP, 2 AP, 3 BP) after a median of 12 wks (range, 4 to 38); >1-log in 15 (28%) pts (5 CP, 6 AP, 4 BP) after a median of 12 wks (range, 4 to 35); >2-logs in 10 (19%) pts (7 CP, 2 AP, 1 BP) after a median of 14.5 wks (range, 4 to 36) and >3-logs in 9 (17%) pts (5CP, 3 AP, 1 BP) after a median of 16 wks (range, 4 to 36). BCR-ABL/ABL ratio <0.05 was seen in 5 (9.5%) CP pts. After a median follow-up of 26 wks (range, 6 to 41), 12 (23%) pts stopped dasatinib due to death (n=2), disease progression (n=6), BMT (n=1), or intolerance (n=3). Dose reductions (31/53, 58%) were associated with BCR-ABL increments in 13 pts (>1 log in 10). Twenty-nine (55%) pts had at least 1 follow-up PCR analysis after their lowest transcript level, and in 9 pts the BCR-ABL/ABL ratio increased >1 log (F359V, Y253H, S348L, H396P, F317L, G250E, F359C), in 4 pts >2 logs (E255V/K, V299L) and in 2 pts >3 logs (F359V, H396R). T315 mutants have not been detected. Conclusion: Dasatinib is associated with significant molecular responses in imatinib-resistant/intolerant CML across multiple BCR-ABL mutants. Longer follow-up is needed to define the stability and durability of these responses. [Table: see text]
Intravenous (i.v.) busulfan (Bu) plus melphalan (Mel) is a well-tolerated preparative regimen for stem cell transplantation (SCT) in patients (pts) with advanced lymphoid malignancies
Authors: Kebriaei P. , Madden T. , Thapar N. , Shpall E. , Hosing C. , Qazilbash M. , Thall P. , Khouri I. , Champlin R. , Jones R. , Andersson B. 
Published: March 2020

6548 Background: High dose chemotherapy and SCT is an accepted treatment option for pts with relapsed lymphoid malignancies. However, relapse remains a significant problem. A double alkylating regimen of Bu and Mel has been suggested as an effective and myeloablative pre-transplant conditioning regimen. Historically, oral Bu was used and the combination resulted in considerable mucositis and VOD. An i.v. formulation of Bu has been developed that has less pharmacokinetic variability. We are investigating i.v. Bu-Mel in pts with lymphoid malignancies undergoing auto- or allo-SCT. Patients and Methods: The conditioning regimen consists of i.v. Bu 130 mg/m2 over 3 hr daily for 4 days, either as a fixed dose per BSA, or to target an average daily AUC of 5,000 μMol-min ± 12% determined by a test dose of i.v. Bu at 32 mg/m2 given 48 hours prior to the high dose regimen. After the 4 daily Bu doses, there is a rest day, followed by 2 daily doses of Mel at 70mg/m2. Stem cells are infused the following day. Dilantin is given for seizure prophylaxis. GVHD prophylaxis is tacrolimus and methotrexate for pts receiving allo-SCT. Results: Patient characteristics, engraftment, and regimen-related toxicities are listed below: Grade I or II mucositis was the most common regimen-related toxicity. There were no cases of VOD; reversible hyperbilirubinemia was observed in 3 pts receiving allo-SCT. No grade IV toxicity was noted, and there were no regimen-related deaths with longest follow-up of 10 months. All allo-SCT pts had 100% donor chimerism by day 30. 27 pts had i.v. Bu delivered per test dose guidance; 6 pts received fixed dose Bu at 130 mg/m2. The median daily systemic Bu exposure was 4867 μMol-min. Conclusion: Intravenous Bu-Mel is well tolerated, and enables prompt neutrophil and platelet engraftment. Individualized PK-directed dosing of i.v. Bu is feasible, and likely contributes to the low toxicity profile of this regimen. Longer time is needed to assess disease control. [Table: see text] No significant financial relationships to disclose.
Similarities and differences in aging and in malignant transformation of human hematopoietic stem cells
Authors: Lannert H. , Able T. , Franz T. , Hofmann R. , Lenze A. , Horsch K. , Eckstein V. , Saffrich R. , Ho A. D. 
Published: March 2020

6555 Background: The tracking of stem cell aging, differentiation and deterioration by gene expression profiling and proteome analysis allows the comparison of different stages. The overall aim of a proteomic study is characterization of the complex network of cell regulation. We focused our investigations on different subsets of highly enriched CD34+ stem cells from different human origins: fetal liver, cord blood, bone marrow (BM), and mobilized stem cells from peripheral blood (PBSC), as well as CD34+ leukemia cells, thus e.g. to identify pathways and new targets for leukemia therapy. Methods: Mononuclear cells were isolated by a standard Ficoll separation method from the different blood sources. An Auto-MACS (Miltenyi) and FACS Vantage SE cell sorter (Becton Dickinson) was used to highly enrich (>99%) CD34+ cells fractions. Sample preparation: Total RNA was isolated from sorted 1 × 10e6 cells by standard methods using RNA isolation kit (Qiagen). For gene expression analysis topic-defined PIQOR stem cell microarrays (936 genes) were performed. Proteomics started with the determination of protein concentrations, 2D-gel-electrophoresis were described in Proteome Works System (BioRad). Sypro ruby and/or coomasie stained gels were used for protein identification by Q-TOF analyses. The subcellular localization of the identified proteins were performed by fluorescence and confocal microscopy of all cell fractions. Results: 1. The microarray gene expression correlation shows many similarities between human healthy stem cells of different sources and ages, otherwise many differences: 125 upregulated genes (kinases: PAK1, ATM1, CDKN2A) and 32 downregulated genes (EBCTF, RAMP1) in malignant cells compared to healthy stem cells. 2. Proteomics analyses of the different cell fractions show a large overlap of the most dominant protein spots, >200 spots were identified by Q-TOF. For example stathmin (oncoprotein Op18) is expressed at very high levels in leukemia cells and in PBSCs but not in BM cells, additionally demonstrated by fluorescence microscopy. Conclusions: Combining genomics and proteomics assays, pathways e.g. Op18 for proliferation and migration of healthy (mobilized) CD34+ cells from bone marrow and malignant leukemia cells could be identified. No significant financial relationships to disclose.
Delaying therapy in Pts age ≥ 65 with untreated AML
Authors: Estey E. , Giles F. , Garcia-Manero G. , Kantarjian H. 
Published: March 2020

6560 186 pts age ≥ 65 with untreated normal karyotype AML given ara-C-containing Rx at MDA from 1996–2005 had course 1(C1) CR and death rates of 57% and 13%, while in 133 pts with abnormalities of chromosomes 5 and/or 7 (−5/−7) the C1 CR rate was essentially identical to the C1 death rate (30% and 27%). Knowledge of cytogenetics, while thus valuable in planning Rx, may not be available for ≥ 1 week after presentation, raising questions as to the advisability of waiting this long to begin Rx. We previously reported a multivariate analysis in 197 pts, median age 64 and with presenting WBC < 50,000, given idarubicin + ara-C for untreated AML at M.D. Anderson between 2001- and 2004, finding that the independent predictors of CR were age and cytogenetics but not the number of days from MDA presentation to MDA Rx (Estey et al. 2004 ASH meeting,abstract #879). Because Rx was delayed for > 1 week in only small numbers of older pts we now extend these observations to 684 pts age ≥ 65 with untreated AML and presenting WBC < 50,000 given induction Rx (± ara-C) at MDA since 1996. Time from MDA presentation to Rx was < 1 week in 423, 1–2 weeks in 126, 2 weeks-1 month in 80, and > 1 month in 55. This time was not affected by age, bilirubin, creatinine, or by whether induction Rx contained ara-C. However, 7% of pts Rxed within 2 weeks of diagnosis had performance status 3–4 vs. only 1% of pts Rxed after a delay of > 14 days (p = 0.008), leading us to limit analysis to pts with performance status 0–2. Results were as follows: Although CR rates were higher, results were qualitatively similar considering only pts given ara-C-containing Rx. Recognizing the potential influence of unrecorded covariates, the data suggest that delay of Rx in pts age ≥ 64 with untreated AML, WBC count < 50,000, and performance status < 3 does not affect outcome of induction therapy, a possibility given more credence by the several days that elapse between diagnosis of AML by referring physicians and MDA presentation. Delaying Rx allows knowledge of cytogenetic status, thus permitting investigational Rx, or supportive care only, to be directed to pts with -5/-7. [Table: see text] No significant financial relationships to disclose.
A phase I trial of bexarotene, a retinoid X receptor agonist, in relapsed or refractory non-M3 acute myeloid leukemia (AML)
Authors: Tsai D. E. , Luger S. M. , Loren A. W. , Kemner A. , Thompson J. , Schuster S. J. , Perl A. , Porter D. L. , Bagg A. , Carroll M. 
Published: March 2020

6567 Background: In vitro, bexarotene inhibits the proliferation of non-M3 AML cell lines and induces differentiation of leukemic blasts. This phase I study was designed to evaluate the safety of escalating doses of bexarotene in patients with relapsed or refractory non-M3 AML. Methods: Bexarotene was administered orally daily until disease progression occurred. Five dose levels ranging from 100 to 300 mg/m2 were planned. Dose escalation occurred in cohorts of 3–6 patients based on dose-limiting toxicity. Results: Fourteen patients have been enrolled in 4 dose cohorts (100–250 mg/m2) with enrollment demographics: 8M/6F, median age 63 (range 51–76), 6 prior MDS, 6 primary refractory, median number of induction attempts 2, prior autologous stem cell transplant 4, 14 blood transfusion dependent, 12 platelet transfusion dependent, and 12 neutropenic. Two patients developed hypothyroidism. Despite prophylactic use of antihyperlipidemic agents, 4 patients developed grade 2 or 3 hypertriglyceridemia. Two patients developed a syndrome reminiscent of retinoic acid syndrome, consisting of dyspnea/hypoxia, pleural/pericardial effusions, weight gain/edema and dry cough in the setting of a rapidly rising neutrophil count. This syndrome resolved within 48 hours of stopping bexarotene and initiating steroids. One patient had a WBC rise from 1.7×103/μL (ANC 1,037/μL, 18% blasts) pre-bexarotene to 23.9×103/μL (ANC 19,368/μL, 3% blasts) during this syndrome. Flow cell sorted peripheral blood neutrophils all contained this patient’s original t(8;21) by FISH, suggesting differentiation of the leukemic blasts. Bone marrow blasts decreased to ≤5% in two patients. Three platelet transfusion dependent patients had increases in their platelet counts to a peak count of 40–292×103/μL on bexarotene. Conclusion: Daily oral bexarotene is well tolerated at the dose levels studied to date. Early evidence for activity has been seen as exemplified by improvement in platelet counts, decreased bone marrow blast counts, blast differentiation and possible retinoic acid syndrome. Patient enrollment is ongoing. [Table: see text]
Phase I study of a novel, pharmacokinetically derived schedule of flavopiridol in acute leukemias: Clinical efficacy including hyperacute tumor lysis, pharmacokinetics, and pharmacodynamics
Authors: Blum W. , Klisovic R. B. , Kefauver C. , Johnson A. , Phelps M. , Dalton J. T. , Lucas D. , Colevas A. D. , Grever M. R. , Marcucci G. , Byrd J. C. 
Published: March 2020

6568 Background: Flavopiridol is a cyclin dependent kinase inhibitor with in vitro activity in many cancer cell lines. However, phase I/II studies of either 24 or 72-hour continuous infusion schedules demonstrated no significant clinical activity. Discordant binding of flavopiridol to human plasma proteins as compared to fetal calf serum prompted us to perform pharmacokinetic modeling studies which suggested that optimal dosing would be a 30 min IV bolus followed by 4 hr IV infusion. With this schedule, our group has observed impressive clinical activity in refractory CLL. Methods: We intensified this schedule for relapsed or refractory adult AML and ALL patients (pts) to administer an IV bolus over 30 min followed by an infusion over 4 hrs on 3 consecutive days in a phase I trial. Results: To date, 10 pts have been treated at 2 dose levels. Pts had relapsed/refractory AML (N=6) or ALL (N=4) and were 25–77 yrs old. 4 pts received flavopiridol at 20 mg/m2 IV bolus and 30 mg/m2 infusion; 6 received 30 mg/m2 bolus followed by 35 mg/m2 infusion. The most significant toxicity was tumor lysis; treatment was well tolerated, and toxicities were similar to those previously reported by our group with the single day dosing schedule used in CLL. Plasma levels were 1–2 μM during the infusion (N=7) and declined with a terminal half life comparable to that previously reported with a 72 hr infusion. Significant anti-leukemic activity was seen in 5/7 evaluable pts at both dose levels. Tumor lysis was seen in both ALL and AML (see table ). Downregulation of Mcl-1 protein by immunoblotting was seen in 2/3 pts tested to date. Conclusions: Single agent flavopiridol given with this novel, pharmacologically modeled schedule has clinical activity in pts with relapsed/refractory ALL and AML. Further study in acute leukemia using this schedule is warranted; dose escalation to the current trial is ongoing. (NCI U01 CA 76576–05) [Table: see text] No significant financial relationships to disclose.
Comparison of 2 doses of daunorubicin(45mg/m2 vs 60mg/m2) in induction therapy of patients of de novo acute myeloid leukemia
Authors: Khattry N. , Kumar L. , Kumar R. , Patel C. , Raina V. , Sharma A. , Chandra P. , Bhutani M. , Sengar M. , Kochupillai V. 
Published: March 2020

6581 Background: Standard induction regimen for the management of acute myeloid leukemia (AML) includes 45 mg/m2 of daunorubicin (DNR) × 3 days and 100 mg/m2 of ara-c × 7 days. Recent studies suggest that higher doses of DNR may have better outcome. Randomized studies to objectively authenticate these observations to the best of our knowledge are not available. This study was undertaken as a preliminary trial to compare the induction remission rates and toxicity of 60 mg/m2 of DNR with standard dose of 45 mg/m2. Methods: Sixty newly diagnosed AML patients, except AML—M3, from January 2003—May 2005 were randomized to either 45mg/m2 (group A ) or 60 mg/m2 (group B) of DNR for three days. The dose of ara-c was 100mg/m2 for 7 days in both groups. All denovo AML patients with 0–2 performance status (ECOG) were included in the study. Results: Fifty six patients were evaluable, 30 in group A and 26 in group B. The baseline demographic and clinical characteristics were comparable. Twenty (67%) patients in group A and 23 (88%) in group B (p=0.05) achieved complete remission (CR). Fifteen (50%) patients in group A and 22 (84.6%) in group B (p=0.006) achieved remission after single course of induction chemotherapy. Nine patients (30%) in group A and 3 (11.5%) in group B died due to uncontrolled sepsis (p=0.09). Five patients, all belonging to Group A, had persistent disease at the time of death. Though there was no significant difference with respect to major organ toxicities in both the groups, duration of grade 4 thrombocytopenia and duration of admission were significantly greater in group A (P=0.02 and P=0.005 respectively). Conclusions: This study indicates that daunorubicin in the dose of 60 mg/m2 is superior to 45mg/m2 as a remission induction therapy for AML patients with good performance status. Further follow up is required to ascertain whether higher remission rate leads to higher disease free and over all survival. No significant financial relationships to disclose.
Preliminary activity of AMN107, a novel potent oral selective Bcr-Abl tyrosine kinase inhibitor, in newly diagnosed Philadelphia chromosome (Ph)-positive chronic phase chronic myelogenous leukemia (CML-CP)
Authors: Jabbour E. , Giles F. , Cortes J. , O’Brien S. , Ravandi F. , Borthakur G. , Garcia-Manero G. , Letvak L. , Salvado A. , Kantarjian H. 
Published: March 2020

6591 Background: AMN107 is a novel, highly selective oral Bcr-Abl inhibitor which is 20–50-fold more potent than imatinib. High response rates with AMN107 were observed in all CML phases post imatinib failure. Methods: Study Aims: Evaluate the efficacy of AMN107in newly diagnosed Ph-positive CML-CP. Study Group and Therapy: Patients with newly diagnosed Ph-positive CML-CP were treated with AMN107 400 mg orally twice daily. Results: So far, 13 patients have been treated; median age 49 (range 24 to 72). Sokal risk at pretreatment: low - 10, intermediate - 2, high - 1. Five have reached the 3 month evaluation: all 5 (100%) had a complete cytogenetic response [CGCR] (Ph 0%). This is compared with a CGCR at 3 months of 36% with imatinib 400 mg/d and 55% with imatinib 800 mg/d in historical data of newly diagnosed patients treated at M. D. Anderson. The median QPCR with AMN at 3 months was 0.67% (range 0.3 to 3.0), compared with a median QPCR of 8% with imatinib 800 mg daily. Grade 3–4 myelosuppression was observed in 3/13 and other grade 3–4 side effects in 1/13 requiring temporary AMN107 interruption for < 2 weeks and resumption at same dose level in the 3 patients with myelosuppression, and for 6 weeks+ in the patient with grade 3 elevation of liver enzymes which were reduced to grade 1 on last follow-up. One patient had a transient elevation of total bilirubin > 3 mg/L which was self limited with continued therapy. Conclusions: Early results with AMN107 400 mg orally twice daily are encouraging in newly diagnosed CML. [Table: see text]