bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sensitivity of refractory hairy cell leukemia to BRAF inhibition.
Authors: Dietrich Sascha , Lehners Nicola , Huellein Jennifer , Andrulis Mindaugas , Hundemer Michael , Jethwa Alexander , Capper David , Froehling Stefan , Kalle Christof V. , Ho Anthony D. , Glimm Hanno , Zenz Thorsten 
Published: March 2020

6519 Background: Thorough understanding of genetic lesions in cancer and targeted intervention against driver mutations are beginning to transform cancer treatment. An activating mutation of the BRAF serine/threonine protein kinase, BRAF V600E occurs in a proportion of malignant melanomas, and colorectal, thyroid, and other cancers. In hairy-cell leukemia (HCL), BRAF V600E is nearly always present, suggesting oncogene dependence. Methods: Here, we present a patient with HCL who was refractory to three lines of purine analogue-based treatment. The BRAF V600E mutation was demonstrated. After intensive counseling, the patient and his family provided written consent for vemurafenib (mutant BRAF-specific inhibitor) treatment. Results: Before vemurafenib treatment, the patient had subtotal bone marrow infiltration and massive splenomegaly (24.8 x 8.3 cm) leading to severe cytopenia (leukocytes 680/µl, hemoglobin 10.0 g/dl, platelets 36.000/µl). Treatment with vemurafenib was started with 240 mg twice daily and was slowly escalated to 1920 mg/d. Within two days of treatment, the spleen softened and decreased in size. Serum CD25 (sCD25) level fell rapidly from 24.800 U/ml to normal levels (<900), and platelets, hemoglobin, and leukocyte counts rose. After 16 days of vemurafenib treatment, the spleen size had shrunk to 14 x 5 cm. By day 28 of treatment (on 720 mg/d), platelet counts and sCD25 levels had normalized. Bone marrow infiltration by HCL had decreased from 70% to 20% on day 16 and complete remission was achieved on day 35. We terminated treatment on day 57 when there was no evidence of any circulating hairy cells by immunophenotyping. Conclusions: The striking therapeutic activity of vemurafenib in our patient provides the first in vivo evidence to substantiate the BRAF V600E allele as a driver and validates mutant BRAF as a therapeutic target in HCL. Proof of principle for a molecularly targeted therapy of HCL adds to the recent success of targeting oncogenic kinases in oncogene addicted malignancies. Given the rarity of HCL, introducing new therapeutic modalities may be challenging. Future studies are needed that compare short-term inhibition of BRAF with low doses of vemurafenib (or alternative BRAF inhibitors) and standard therapy.
Prognostic implication of monosomal karyotype in patients with acute myeloid leukemia who received allogeneic hematopoietic cell transplantation.
Authors: Choi Yunsuk , Kim Sung-Doo , Park Young-Hun , Lee Jae Seok , Kim Dae-Young , Lee Jung-Hee , Lee Kyoo-Hyung , Seol Miee , Lee Young-Shin , Kang Young-Ah , Jeon Mijin , Jung Ah Rang , Lee Je-Hwan 
Published: March 2020

6564 Background: Monosomal karyotype (MK), defined as at least two autosomal monosomies or one single autosomal monosomy with one or more structural cytogenetic abnormalities, has been associated with worse outcomes in acute myeloid leukemia (AML). We evaluated the prognostic impact of MK on outcomes after allogeneic hematopoietic cell transplantation (allo-HCT) in AML. Methods: We retrospectively analyzed 169 adult patients with AML, who received allo-HCT in the first complete remission (CR) between 2000 and 2009. All patients had cytogenetic results at the diagnosis of AML. Patients were classified as having good, intermediate, or poor risk cytogenetics according to the NCCN guideline, and MK status was also determined. Results: MK was observed in 12 patients (7.1%); of whom, 11 patients also had complex karyotype (CK). Compared to patients without MK, those with MK had significantly lower overall survival (OS) (62.2% vs. 0%) and event free survival (EFS) (58.9% vs. 0%), and higher relapse probability (RP) (22.9% vs. 66.7%) at 5 years (all, p<0.001). 22 patients with CK also showed inferior outcomes, but CK with MK was associated with more inferior outcomes than CK without MK. Multivariate analysis showed that MK had a significantly adverse impact on OS (hazard ratio [HR], 5.192; p<0.001), EFS (HR, 4.531; p<0.001), and RP (HR, 6.558; p<0.001) after allo-HCT (Table). Conclusions: MK is a major prognostic factor predicting extremely worse outcomes in AML patients who underwent allo-HCT in the first CR. [Table: see text]
Interim results of a phase I/II randomized study of clofarabine, idarubicin, and cytarabine (CIA) versus fludarabine, idarubicin, and cytarabine (FIA) for newly diagnosed or relapsed patients (pts) with acute myeloid leukemia (AML).
Authors: Mathisen Michael , Kantarjian Hagop , Faderl Stefan , Garcia-Manero Guillermo , Ravandi Farhad , Kadia Tapan M. , Daver Naval Guastad , O'Brien Susan Mary , Dorkhom Stephan Joseph , Pierce Sherry , Lira Cynthia , Cortes Jorge E. , Jabbour Elias 
Published: March 2020

6607 Background: Outcomes of pts with AML remain suboptimal. The addition of cladribine to 3+7 has been shown to improve complete remission (CR) rates and 3-year survival. The aim of this study was to assess the efficacy and safety of idarubicin + cytarabine (IA, idarubicin 10 mg/m2 on days 1-3, cytarabine 1 g/m2 on days 1-5) combined with two other nucleoside analogs, clofarabine (C) or fludarabine (F), in pts with newly diagnosed and relapsed/refractory (RR) AML. Methods: Pts with newly diagnosed or RR non-M3 AML with normal organ function were eligible. Pts with RR disease were treated in the phase I portion defining the MTD of C. The starting dose of C was 15 mg/m2 with doses escalating to 25 mg/m2 on days 1-5 in subsequent cohorts. During phase II, patients were randomized in a Bayesian design to C at the MTD with IA or fludarabine (F) at 30 mg/m2 on days 1-5 with IA. Up to 6 consolidation cycles were planned according to an attenuated schedule using the same drugs. Dose adjustments were made for elderly pts or pts with poor PS. Results: 9 pts were enrolled in the phase I portion. The overall response rate (ORR) in this group was 44%. DLT were observed at C 20 mg/m2 and included hand/foot syndrome (HFS), elevated bilirubin, and prolonged myelosuppression. The MTD was 15 mg/m2 on days 1-5. 50 evaluable pts were enrolled (16 newly diagnosed, 34 RR) in the phase II. In the frontline cohort, median age was similar in both groups (C 56, F 55), as were the cytogenetic profiles. The CR rate was 100% in both groups (9 CIA, 7 FIA). Detailed efficacy information can be found in the Table. More than half of the RR cohort were receiving therapy as salvage 2 or higher, and most had short first CR durations. Notable toxicities included elevated liver function tests for both groups, and HFS in the C group. There were 4 deaths on study, though most pts were receiving therapy as second salvage and were over the age of 60. Conclusions: CIA and FIA are effective regimens for newly diagnosed or RR AML with manageable toxicity profiles. The ORR were 100% and 32% for newly diagnosed and RR AML pts, respectively, with low early mortality rates. The study is ongoing.
Post hoc analysis of relationship between baseline white blood cell count and renal and hepatic function and response in a randomized phase III trial of decitabine in patients age 65 or older with acute myeloid leukemia.
Authors: Delaunay Jacques , Mazur Grzegorz , Minden Mark D , Wierzbowska Agnieszka , Jones Mark M. , Tarassoff Peter G. , Kantarjian Hagop 
Published: March 2020

6632 Background: A phase III trial (NCT00260832) in patients (N=485) ≥65y with newly diagnosed acute myeloid leukemia (AML) was conducted (Kantarjian, JCO; in press). Every 4 wk, patients received decitabine (DAC) 20 mg/m2 (1-h intravenous infusion, 5 successive days) or treatment choice (TC) with either supportive care or cytarabine (20 mg/m2 subcutaneous injection daily, 10 successive days). This post hoc analysis examined whether baseline (BL) renal and hepatic function and white blood cell (WBC) counts were associated with response to DAC or TC. Methods: For patients with available data, BL WBC count and markers of renal function (blood urea nitrogen [BUN], creatinine) and liver function (ALT, AST, albumin) were tabulated for patients with/without a response to DAC or TC. Response was defined as morphologic complete remission (CR), CR with incomplete blood count recovery (CRi), or partial remission (PR). Results: Nonresponders had a higher mean BL creatinine vs responders (86.78 vs 80.23 mmol/L, respectively; P=.005); with no differences in BL BUN levels. There were no other between-group differences. Conclusions: This analysis suggests that there is no relationship between BL WBC or hepatic function and response to treatment with DAC or TC. Although there was no difference in BL BUN, higher mean creatinine levels in nonresponders may suggest a prognostic relationship but further studies are needed to clarify. [Table: see text]
High-throughput targeted resequencing of lung adenocarcinoma.
Authors: Kim Byung Chul , Kim Eun-Hye , Ghim Byoung-Chul , Choi So-Jung , Lee Jinseon , Kim Jhingook 
Published: March 2020

7053 Background: The mutational profiles are crucial for cancer diagnosis and classification, which lead to tailoring the best therapeutic strategy to each patient. Here, we present target sequencing of 30 hot spot genes in lung adenocarcinoma to identify new hot spot mutations in never-smoker, female lung adenocarcinoma patients. Methods: We targeted 30 genes that are known to be mutated frequently in lung adenocarcinoma. The exome capture was done using selector technology and sequencing was done using Illumina GA IIx Genome Analyzer. Exomic short reads from Illumina Pipeline 1.4 were aligned to human genome (NCBI build 36) with BWA 0.5.0. Variations and small indels were called by Samtools 0.1.7 and filtered by custom R scripts. Potential effects of these identified alterations were assessed with sequence analysis. Results: On average, 1.5 billion bases were uniquely mapped, and mean depth and coverage of exon regions were 38X and 96%, respectively. Filtering of data against public SNP database (dbSNP130), resulted in ~2,000 novel genetic alterations per sample, including single nucleotide variations, and small insertion and deletions in protein-coding regions. Among them, there were novel variants in LTK and EPHA5 genes. Conclusions: Our results demonstrated the feasibility of high-throughput mutation profiling with lung adenocarcinoma samples. We identified novel variants in hot target genes, which may provide an insight into the tumorigenesis signaling of lung adenocarcinoma.
Are the presenting characteristics and prognosis of primary salivary gland-type lung cancers (SG) similar to those of other non-small cell lung cancers (NSCLC)?
Authors: Varlotto John M. , Ali Suhail M. , DeCamp Malcolm M. , Flickinger John Charles , Recht Abram , Lake Jessica , Ramakrishna Satvik , Lipton Allan , Zander Dani , Reed Michael , Toth Jennifer , Belani Chandra Prakash 
Published: March 2020

7054 Background: SG, both adenoid cystic (ACC) and mucoepidermoid (ME) sub-types, are rare lung cancers. We choose to investigate the incidence of these rare sub-types and assess their difference in presentation and prognostic characteristics in comparison to adenocarcinomas (Ad) and squamous cell carcinomas (SCC) during the same time period. Methods: The SEER-17 database was used to collect data during the years 1988-2008. Differences between populations were determined by the chi-square test. Survival curves were generated as Kaplan-Meier techniques. Cox proportional hazards test was used to compare survival differences. Results: During the 20-year study period, ACC (n =100) and ME (n= 178) accounted for 0.03% and 0.06% of NSCLCs. Mean follow-up was 34.5 months for all patients. In comparison to ACC, patients with ME were significantly more likely to be younger (52 yr vs. 60yr), Asian(11.7% vs. 7%), have Stage I disease (62.9% vs 24.0%), and less likely to be in the mainstem bronchi (17.2% vs. 6.3%). In comparison to patients with patients presenting with either SCC or Ad, both ME and ACC were significantly less likely to present with Stage IV disease (26.6% SCC, 41.29% Ad, 16.73% SG), have nodal involvement (35.1% SCC, 27.4% Ad, 23.37% SG), and be older (70 SCC, 68 Ad, 58 years SG). Stratified by stage and treatment, there was no survival (OS) or disease-specific survival difference (DSS) between ACC and ME. The OS of the combined group of ME and ACC was significantly better stage per stage than either Ad (Hazard ratio (HR) range = 0.26- 041), and SCC (HR range = 0.17-0.56). Lung Cancer-Specific survival at 2,3,5 years for surgically-resected Stage I ACC and ME were 83.5%, 80.4%, and 80.4%; and 82.6%, 78.0% and 78%, respectively. Conclusions: Patients with ACC and ME have rare sub-types of lung cancer that present differently and have better survival than patients presenting with either of the more common histologic sub-types (SCC and Ad) of NSCLC. We encourage prospective, multi-institutional studies of these rare sub-types so that care can be optimized. Optimal care may differ for SG because of their stage per stage better prognosis than other NSCLCs.
NGR-hTNF as second-line treatment in malignant pleural mesothelioma (MPM).
Authors: Rossoni Gilda , Gregorc Vanesa , Viganò Maria Grazia , Bulotta Alessandra , Ghio Domenico , Lambiase Antonio , Bordignon Claudio 
Published: March 2020

7076 Background: NGR-hTNF exploits the asparagine-glycine-arginine (NGR) peptide for selectively targeting tumor necrosis factor (TNF) to cancer endothelial cells. Tumor hypervascularity is an independent predictor of poor overall survival (OS) in MPM patients (pts). Methods: We report long-term results of a phase II trial that assessed NGR-hTNF in MPM pts with performance status (PS) ≤ 2 and radiologic progressive disease (PD) after a pemetrexed-based regimen. NGR-hTNF was given at 0.8 µg/m2 every 3 weeks (q3w) in 43 pts and weekly (q1w) in 14 pts. Primary endpoint was progression free survival (PFS), with restaging done q6w by MPM-modified RECIST criteria, while secondary aims included disease control (DC) rate and OS. We also tested the impact on outcome of neutrophil to lymphocyte ratio (NLR) at baseline (median 3; interquartile range 2-5). Median follow-up was 32.5 months (95% CI 27.5-37.5). Results: Baseline characteristics were (n=57): median age 57 years; M/F 35/22; PS 0/1-2 31/26; EORTC score good/poor 45/12. Median treatment free interval on prior therapy was 4.3 months. Only one drug-related grade ≥ 3 adverse events (AEs) was noted, common grade 1/2 AEs being transient chills (75%). No higher toxicity was reported using the q1w schedule. Median PFS was 2.8 months (95% CI 2.2-3.3). DC rate was 46% (95% CI 32-59; 26/57 pts; 1 partial response, 25 stable diseases) and was maintained for a median time of 4.7 months (95% CI 4.0-5.4). OS rates at 1 and 2 years were 47% and 16%, respectively. Median OS was longer in pts with DC than in those with early PD (16.2 and 8.3 months, respectively; p=.02). According to schedule, 6-month PFS rates were 11% and 36% and 2-year OS rates were 12% and 29% for q3w and q1w, respectively. In pts with DC, median PFS were 4.4 and 9.1 months and median OS were 13.3 and 24.8 months for q3w and q1w, respectively. By Cox analyses, a PS of 0 (p=.01) and a low baseline NLR (p=.004) were the only variables associated with improved OS. Median OS in pts stratified by NLR ≤ 2, 3 to 4, and ≥ 5 were 15.7, 10.5, and 4.2 months, respectively (p=.0002 for trend). Conclusions: NGR-hTNF showed promising PFS and OS in this study. A double-blind phase III trial is currently testing best investigator choice ± NGR-hTNF q1w in pemetrexed-pretreated MPM pts (NCT01098266).
Comparison of treatment patterns, health care utilization, and direct costs in elderly patients with distant-stage small cell lung cancer (SCLC) versus non-small cell lung cancer (NSCLC) using the SEER-Medicare database.
Authors: Karve Sudeep , Price Gregory , Davis Keith L. , Pohl Gerhardt , Smyth Emily Nash 
Published: March 2020

7101 Background: Limited data exist on real-world treatment patterns, healthcare utilization, and associated costs of advanced SCLC among elderly patients in the US, and there are no recent comparisons between patients with advanced SCLC and advanced NSCLC. Methods: We retrospectively analyzed administrative claims data for elderly patients (≥65 years) from the linked Surveillance, Epidemiology and End Results (SEER)-Medicare database for 2000-2008. Patients with a new diagnosis of distant stage lung cancer receiving cancer-directed therapy (ie, surgery, radiation, biologics, and/or chemotherapy) were grouped by tumor type (SCLC [n=5,855] vs NSCLC [n=24,090]). Survival was compared using Kaplan-Meier Log-rank; categorical measures with Chi-square statistics; and continuous measures with t-tests. Results: Compared to SCLC patients, a significantly greater proportion of patients with NSCLC received radiation therapy (75.6% vs 65.4%; p<0.001) and surgery (13.6% vs 7.8%; p<0.001). Chemotherapy was received by 85.5% of SCLC patients and 60.3% of NSCLC patients (p<0.001). Significantly higher proportions of SCLC patients also received red blood cell (20.7% vs 10.9; p<0.001) and platelet transfusions (5.6% vs 1.8%; p<0.001) as well as growth factor support (58.9% vs 39.5%; p<0.001). Survival did not differ significantly between groups (p=0.424), with the mean (10.4 months vs 11.1 months) and median (7.4 months vs 5.9 months) survival for SCLC and NSCLC noted accordingly. Total lifetime lung cancer-related costs ($44,167 vs $37,932; p<0.001) and all-cause costs ($70,548 vs $67,175; p<0.001) per patient for SCLC exceeded those for NSCLC. The primary drivers of cost included resource utilization across 3 care settings: hospitalizations, office visits, and hospital outpatient visits. Conclusions: Overall total lifetime and disease-related costs per advanced SCLC and NSCLC patient were high, and costs for SCLC exceeded those for NSCLC. Survival estimates coupled with per patient costs for both cancers underscores the unmet medical need for patients with distant stage SCLC and NSCLC.
Phase II study of the HSP90 inhibitor AUY922 in patients with previously treated, advanced non-small cell lung cancer (NSCLC).
Authors: Garon Edward B. , Moran Teresa , Barlesi Fabrice , Gandhi Leena , Sequist Lecia V. , Kim Sang-We , Groen Harry J.M. , Besse Benjamin , Smit Egbert F , Kim Dong-Wan , Akimov Mikhail , Avsar Emin , Bailey Stuart , Felip Enriqueta 
Published: March 2020

7543 Background: AUY922 is a highly potent, non-geldanamycin, HSP90 inhibitor. A Phase I study in advanced solid tumors provided a recommended Phase II dose of 70 mg/m2. HSP90 acts as a chaperone of client proteins, including those relevant in NSCLC pathogenesis. This Phase II study assessed AUY922 in pts with previously treated advanced NSCLC stratified by molecular status. Methods: Pts with advanced NSCLC who progressed following ≥2 prior lines of chemotherapy, received AUY922 70 mg/m2 as a 1-hr infusion once-weekly. Pts were assigned to 4 strata: EGFR activating mutations (EGFR mut), KRAS mut, ALK rearranged (ALK+), or EGFR/KRAS/ALK wild type (wt). Phase II Bayesian hypothesis testing design allowed sharing of information between strata based on assessing similarity in observed response data. Primary endpoint was confirmed (RECIST) objective response rate (ORR) or stable disease (SD) at 18 wks. Secondary endpoints included OS, PFS, and safety/tolerability. Results: A total of 112 pts (median age 60 years; 45% male; 86% adenocarcinoma; 28 [25%] pts KRAS mut; 35 [31%] EGFR mut; 14 [12%] ALK+; 31 [28%] EGFR/KRAS/ALK wt) were treated at the December 16th 2011 cutoff. Most pts were heavily pretreated: 61% had received ≥3 prior systemic regimens; 64% had WHO PS 1 or 2. Mean duration of exposure was 9.1 wks. The most frequent adverse events (AEs, any grade [Gr]) were diarrhea (73%), visual AEs (71%), and nausea (43%). Most AEs were Gr 1/2; Gr 3/4 AE’s were rare (all <10%). The study is ongoing, and 29 pts were still receiving treatment at the cutoff date. Preliminary clinical activity of AUY922 (RECIST; investigator assessed) was seen with partial responses in 13/101 (13%) pts: 2/8 (25%) ALK+ pts, 6/33 (18%) EGFR mut pts, 4/30 (13%) EGFR/KRAS/ALK wt pts, 0/26 (0%) KRAS mut pts, and 1/4 (25%) pts of unknown status. In ALK+ pts, responses were seen in crizotinib (CRZ)-naive pts, and SD was seen with tumor shrinkage in CRZ-resistant pts. PFS data will be presented. Conclusions: AUY922 had an acceptable safety profile and demonstrated preliminary activity in heavily pretreated pts with advanced NSCLC. This trial demonstrates clinical activity of AUY922 in EGFR mut and EGFR/KRAS/ALK wt NSCLC pts in addition to ALK+ pts.
Afatinib monotherapy in patients with metastatic squamous cell carcinoma of the lung progressing after erlotinib/gefitinib (E/G) and chemotherapy: Interim subset analysis from a phase III trial.
Authors: Kim Joo-Hang , Grossi Francesco , De Marinis Filippo , Cobo Manuel , Yang James Chih-Hsin , Ragulin Yury , Bondarenko Igor N. , Chand Vikram K. , Wang Bushi , Gracien Edith , Schuler Martin H. 
Published: March 2020

7558 Background: Patients with squamous NSCLC have limited treatment options. For those deriving benefit from EGFR TKIs, it is unclear whether sustained ErbB family blockade offers benefit upon progression. We evaluated afatinib, an irreversible blocker of EGFR (ErbB1), HER2 (ErbB2) and ErbB4 receptor tyrosine kinases, in patients with metastatic NSCLC who had failed chemotherapy and E/G. Here we describe a pre-specified analysis of those with squamous histology in Part A. Methods: This randomized Phase III, open-label, multi-center trial enrolled patients with pathologically confirmed metastatic NSCLC after failing ≥1 line of cytotoxic chemotherapy and E/G. In Part A, patients received oral afatinib 50 mg until disease progression. Those with clinical benefit (≥12 wks) who progressed were eligible to receive afatinib plus paclitaxel or investigator’s choice chemotherapy (Part B). Primary endpoint was PFS (RECIST 1.1). Following an amendment, an interim analysis of Part A was performed to assess afatinib monotherapy. Results: Patient enrolment into Part A was from April 2010 to May 2011. Of 1154 afatinib-treated patients, 91 (8%) had squamous histology; 18/91 and 40/91 had CR/PR and SD on prior E/G, respectively (by investigator). Median age was 63 yrs, 71% were male, 76% were current/ex-smokers. Median PFS on afatinib was 3.7 mths in the squamous histology subset. Of 91 patients, 42 had PFS ≥3 mths; 13 had PFS of ≥6 mths. In evaluable patients (n=77), 1 CR and 3 PRs were confirmed; 51 and 22 patients had best overall response of SD and PD, respectively. Of the 31 patients with PD on prior E/G with no intervening chemotherapy, 10 achieved confirmed disease control (2 PR; 8 SD) on afatinib. Most commonly reported grade 3/4 adverse events (AEs) in Part A were diarrhea (13%) and rash/acne (12%). The safety profile in the squamous histology subset was similar to that observed for the whole trial. Conclusions: Afatinib monotherapy demonstrated encouraging activity in treatment-refractory NSCLC patients with squamous histology that merits further evaluation.