bluuebunny/crossref_metadata_2025_split huggingface dataset:
WT1 heteroclitic epitope immunization following autologous stem cell transplantation in patients with high-risk multiple myeloma (MM).
Authors: Koehne Guenther , Devlin Sean , Chung David J. , Landau Heather Jolie , Korde Neha , Mailankody Sham , Hassoun Hani , Lesokhin Alexander M. , Lendvai Nikoletta , Giralt Sergio , Landgren Carl Ola 
Published: September 2018

8016 Background: Host T-cells mount immune responses (IR’s) against Wilms tumor 1 (WT1) in A*0201+MM pts through formation of WT1 peptide fragment (RMFPNAPYL)/HLA-A*0201 complex. We report initial results from MM pts immunized with the WT1 heteroclitic peptide mixture galinpepimut-S (GPS) after autoSCT. Methods: 16 MM pts underwent autoSCT with melphalan conditioning followed by (f/b) lenalidomide maintenance starting 3 months (mos) post-SCT. 13/16 pts presented with high-risk (HR) cytogenetics [t(4;14), t(14;16), del17p, 1q21/25 gain and/or del13q]. GPS was administered with montanide s.c. starting 2 wks post-SCT and q.2 wks thereafter x 6 initial doses f/b boosters q.4 wks x 6 additional doses. GM-CSF was given on days -2 and 0 of each cycle. GPS consisted of 4 peptides: WT1-A1: Y*MFPNAPYL; 427-L (long): RSDELVRHHNMHQRNMTKL; 331-L: PGCNKRYFKLSHLQMHSRKHTG, and 122A1-L: SGQAY*MFPNAPYLPSCLES. 2 of the 4 peptides were mutated at a single residue (*) to induce stronger HLA-binding/reduce tolerance. WT1-specific IR’s were assessed by intracellular IFN-g analyses post-challenge with PBMC’s pulsed with a ‘total pool’ of overlapping 15mers along the entire WT1 protein; or each of the 4 WT1 peptides in GPS; or the non-mutated (native) WT1 peptides corresponding to the 2 heteroclitic sequences. Results: 16 pts; median follow-up: 18 mos (range: 5-31 mos) for survivors; median age: 61.6 y. Overall survival (OS) and progression-free survival (PFS) (95% CI) at 18 mos: 0.88 (0.73-0.99) and 0.62 (0.42-0.97) respectively. Current median PFS: 23.6 mos (15.2 - not reached). No >G2 systemic side effects were observed, however, all pts developed local nodularity at the site of injections which resolved over 2 – 6 wks. Both CD8+ and CD4+ IR’s could be detected at various levels and were induced not only against the heteroclitic peptides (within GPS), but also against the corresponding native WT1 peptide sequences as well as the ‘total pool’ of WT1-derived overlapping peptides. Conclusions: Administration of the novel WT1 heteroclitic peptide immunizer GPS post auto SCT demonstrates favorable safety profile along with encouraging mPFS of currently 23.6 mos in this high-risk MM population. Clinical trial information: NCT01827137.
HDAC11 as a candidate therapeutic target in multiple myeloma.
Authors: Distler Allison , Brayer Jason B. , Meads Mark , Sahakian Eva , Powers John Joseph , Alsina Melissa , Nishihori Taiga , Baz Rachid C. , Pinilla-Ibarz Javier , Sotomayor Eduardo M. , Shain Kenneth H. 
Published: September 2018

8029 Background: Histone deacetylase (HDAC) inhibitors (HDI) have a therapeutic niche in multiple myeloma (MM) due to their ability to salvage proteasome inhibitor and immunomodulatory drug responsiveness in refractory patients, thus raising interest in this therapeutic class. Selective HDI may further improve therapeutic efficacy. Methods: B cell lymphopoiesis was evaluated using Tg-HDAC11-eGFP mice expressing eGFP regulated by the HDAC11 promoter and congenic mouse strains deficient in HDAC11 expression globally (B6.HDAC11-/-) or targeted to the B cell lineage (CD19Cre.HDAC11-/-). Molecular and pharmacologic means were used to impair HDAC11 in established MM cell lines. Viability was measured by activated caspase-3, Annexin/PI (A/PI) staining, and CCK-8 viability assay. Subcellular localization changes induced by HDI and identification of the novel binding partner IRF4 were assessed by proximity ligation assay (PLA). Results: Profound eGFP increases in PC of Tg-HDAC11-eGFP mice suggest HDAC11 influences late stage B cell development. In addition, HDAC11 deficiency results in dramatically reduced PC in the bone marrow and periphery. PC depletion in CD19Cre.HDAC11-/-mice suggests activity inherent in B cells rather than via externally derived signals. Quisinostat (QS), an HDI with enhanced HDAC11 selectivity, showed dose-dependent cytotoxicity in 10 MM cell lines (EC50 1-10nM). This activity was synergistic with bortezomib (BTZ) and carfilzomib (CFZ) in RPMI-8226 cells, while synergism was amplified in the BTZ-resistant RPMI-8226-B25 cell line. Exposure of RPMI-8226 cells to QS decreased detection of nuclear, but not cytosolic, HDAC11. Targeted siRNA–mediated silencing of HDAC11 in RPMI-8226 cells activated caspase-3 and reduced viability by A/PI staining. PLA of MM cell lines showed a novel interaction between HDAC11 and IRF4, an essential regulator of PC differentiation and MM survival, unmasking a potential mechanism for HDAC11-induced cytotoxicity in MM. This interaction was disrupted by QS. Conclusions: We show that HDAC11 inhibition reduces MM cell survival in vitro. Furthermore, we identify IRF4 as a binding partner for HDAC11 and propose this interaction as a candidate mechanism regulating PC maturation and MM survival.
Synergism of gambogenic acid with bortezomib induce apoptosis of multiple myeloma.
Authors: Chen Runzhe , Zhang Hongming , Liu Ping , Wu Xue , Chen Baoan 
Published: September 2018

8035 Background: Multiple myeloma (MM) is one of the most common primary tumors of the bone marrow that accounts for approximately 10% of all hematological cancer. Gambogenic acid (GNA) is one of the natural compound isolated from gamboge and has demonstrated advantages such as a more potent anticancer effect and less systemic toxicity according to early investigations. In this study, we hypothesized that GNA could synergistically potentiate BTZ-induced apoptosis of MM cells and that combining BTZ and GNA may provide a more effective approach to treat MM. Methods: CCK-8 assay, CI isobologram, flow cytometry, western blot, xenograft tumour models, TUNEL and immunochemistry were used in this study to detect to possible mechanisms of apoptosis led by GNA and BTZ in vitro and in vivo. Results: The percentage of MM.1S in G2/M phase after 48h of 4.0nM BTZ, 0.90μM GNA and combination treatment were 31.09±2.16%, 26.68±1.96% and 19.88±1.89% respectively. The percentage of MM.1S in G2/M phase of control group was 17.23±1.65%. The apoptosis rates of MM.1S cells for 48h were 6.57±0.15% in control group, 89.67±5.15% after treatment with 4.0nM BTZ, 97.80±0.81% after treatment with 0.90μM GNA, and 98.9±3.86% after treatment with 4.0nM BTZ plus 0.9μM GNA respectively. All the treatment groups showed a more significant apoptosis rate compared to that of the control group ( p<0.01). MM.1S tumors were implanted in BALB/Ca nu/nu male mice. The tumor weights of GNA and BTZ plus GNA groups decreased significantly when compared with those of control group (p<0.01 and p<0.001, respectively) and the tumor weight of combination group was significantly less than that of BTZ or GNA group (p<0.001). When mice were treated with BTZ combined with GNA, the tumor inhibition rate was 41.94%, whereas those of mice treated with BTZ or GNA alone were 9.68% and 19.35%, respectively. We also found that the combined treatment could induce more markedly increased apoptosis of MM.1S cells via the activation of PARP cleavage, P53, Caspase-3 cleavage and Bax and inhibition of Bcl-2 expression. Conclusions: Our data support that a synergistic antitumor activity exists between BTZ and GNA, and provide a rationale for successful utilization of dual BTZ and GNA in MM chemotherapy in the future.
CALGB/ECOG 100104 (Alliance) study: Lenalidomide (LEN) vs placebo (PBO) maintenance (maint) after stem cell transplant (SCT) for patients (pts) with multiple myeloma—Overall survival (OS) and progression-free survival (PFS) adjusted for treatment (tx) crossover (XO).
Authors: McCarthy Philip L. , Holstein Sarah A. , Jung Sin-Ho , Cooper Miranda , Gibson Craig J , Stadtmauer Edward Allen , Winograd Benjamin , Richardson Paul G. 
Published: September 2018

8037 Background: At a prespecified interim analysis (Dec 2009), the phase 3 CALGB study results surpassed the prespecified superiority boundary (significantly improved PFS for LEN maint vs PBO after SCT) and the majority of PBO arm pts without progressive disease (PD) crossed over to LEN maint. An updated analysis (cutoff Mar 2015), showed significantly longer OS with LEN maint (HR, 0.56; 95% CI, 0.42-0.76). We examined the effect of LEN vs PBO on OS and PFS from randomization, adjusting for XO effects. Methods: The rank-preserving structural failure time model (RPSFTM; Robins, Commun Stat Theory Methods, 1991) was used for XO adjustment; the iterative parameter estimation (IPE; Branson, Stat Med, 2002) algorithm was used as validation. Survival was portioned assuming a residual LEN effect after discontinuation. A landmark analysis was also performed at the Dec 2009 interim for pts who remained on Tx. Results: Pts were randomized to LEN maint (n = 231) and PBO (n = 229) (intent-to-treat [ITT] population); 76 pts without PD crossed over from PBO to LEN. Median time from randomization to XO was 11.5 mos. The relative Tx effect for OS and PFS increased for LEN vs PBO when adjusting for XO using RPSFTM and IPE (Table). The landmark analysis at the Dec 2009 interim (PBO XO, n = 76; No XO, n = 34) showed the Tx effect is not dissimilar to the ITT analysis (HR 0.53; 95% CI, 0.25-1.13). Sensitivity analyses showed consistent results. Conclusions: Adjusting for the potential diluting effects of XO reduced median OS and PFS with PBO, and improved the Tx effect in the ITT analyses for OS and PFS for LEN vs PBO maint after SCT. The statistical significance of the ITT analyses was maintained throughout. Support: U10CA180821, U10CA180882, CA180820. Clinical trial information: NCT00114101. [Table: see text]
Gefitinib (G) versus vinorelbine+cisplatin (VP) as adjuvant treatment in stage II-IIIA (N1-N2) non-small-cell lung cancer (NSCLC) with EGFR-activating mutation (ADJUVANT): A randomized, Phase III trial (CTONG 1104).
Authors: Wu Yi-Long , Zhong Wenzhao , Wang Qun , Xu Song-Tao , Mao Wei-Min , Wu Lin , Shen Yi , Liu Yong-Yu , Chen Chun , Cheng Ying , Xu Lin , Wang Jun , Fei Ke , Li Xiao-Fei , Li Jian , Huang Cheng , Liu Zhi-Dong , Chen Ke-Neng , Yan Hong-Hong , Yang Xue-Ning 
Published: September 2018

8500 Background: Cisplatin-based adjuvant chemotherapy is standard of care for patients (pts) with stage II-IIIA non-small cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors have shown no benefits in the adjuvant setting for pts with unselected resected NSCLC in the BR19 and RADIANT trials. ADJUVANT (NCT01405079) is the first randomized trial to compare gefitinib (G) with vinorelbine+cisplatin (VP) in completely resected pathological stage II-IIIA (N1-N2) NSCLC with EGFR-activating mutation. Methods: Completely resected stage II-IIIA (N1-N2) NSCLC pts with EGFR-activating mutation were randomized 1:1 to receive G (250 mg once daily) for 24 months or vinorelbine (25 mg/m2 Day 1 and Day 8) plus cisplatin (75 mg/m2 Day 1) every 3 weeks for 4 cycles. Stratification factors were lymph node status (pN1/N2) and EGFRmutation status. The primary endpoint was disease-free survival (DFS) in the intent-to-treat population. Results: A total of 222 pts were randomly assigned (Sep 19 2011 to Apr 24 2014). Baseline characteristics were balanced. At the time of data cutoff, the median duration of treatment was 21.9 months in the G arm, and 4 cycles in the VP arm. The median follow-up period was 36.5 months (range 0.1 to 62.8). G had significantly longer median DFS (28.7 months, 95% confidence interval [CI] 24.9 to 32.5) than VP (18.0 months, 95% CI 13.6 to 22.3; hazard ratio 0.60; 95% CI 0.42 to 0.87; p= 0.005). 3-year DFS was significantly better with G (34.0% vs 27.0%; p= 0.013). The number of overall survival events was 76 (34.2%). In the subgroup analysis of patients treated with G, lymph node status (pN1/N2) demonstrated significant correlation with DFS ( p< 0.05). Grade 3 or higher adverse events were less common with G than with VP (12.3% vs 48.3%; p< 0.001). No interstitial lung disease was observed with G. Conclusions: Adjuvant G significantly prolonged DFS compared with VP in pts with resected stage II-IIIA (N1-N2) NSCLC with EGFR-activating mutation. Adjuvant gefitinib should be considered as an important option for stage II-IIIA lung cancer pts with EGFR mutation. Clinical trial information: NCT01405079.
Prophylactic cranial irradiation (PCI) versus observation in radically treated stage III non-small cell lung cancer (NSCLC): A randomized phase III NVALT11 study.
Authors: Groen Harry J.M. , Dingemans Anne-Marie C. , Belderbos Jose , Tissing-Tan Caroline , Herder Gertruda , Haitjema Tjeerd , Ubbels Fred , Lagerwaard Frank J , El Sharouni Sherif , Stigt Jos , Smit Egbert F. , van Tinteren Harm , van de Noort Vincent , De Ruysscher Dirk 
Published: September 2018

8502 Background: Brain metastases are one of the major sites of tumor failure in patients (pts) with radically treated stage III NSCLC. The value of PCI in these pts remains unsettled. This study is designed to investigate whether PCI reduces the incidence of symptomatic brain metastases (sBM). Methods: Pts were randomized between observation and PCI after concurrent or sequential chemo-RT with or without surgery. PCI dose was left to the physician(36 Gy/18F, 30 Gy/12F, 30 Gy/10F). Pts were registered before randomization, those progressing after chemo-RT were not randomized. Pts were followed for sBM (defined as increased intracranial pressure, headache, nausea, vomiting, cognitive, affective disturbances, seizures, focal neurological symptoms andMRI/CT), side effects, survival, quality of life (QLQ-C30, EuroQol 5D). The primary endpoint is the proportion of patients developing sBM. Randomizing 300 pts the study has 90% (2-sided p = 0.05) power to detect 17% decrease in pts developing sBM at 24 months (mo). Results: Between 2009 and 2015, 195 pts were registered, 175 were randomized, 87 received PCI and 88 pts were in the observation arm. In 2013 due to slow accrual, it was decided to reduce the number of randomized pts to 175 pts. With 75 events a 2-sided log-rank test would have 80% power to detect HR 0.52 and alpha 0.05. One pt in PCI arm was withdrawn after randomization. Pts characteristics were male (n = 114, 66%); adeno/squa/other 72 (41%), 62 (36%), 40 (23%); PS 0/1/2 66 (38%), 99 (57%), 9 (5%); stage IIIA/B 93 (53%), 80 (46%), unknown 1 (1%). Median follow up was 48.5 mo (95% CI, 39 - 54). Proportion of pts with sBM was 4/86 (4.6%) in PCI and 25/88 (28.4 %) in observation (p < 0.00001). Seven (8.1%) pts in PCI and 26 (29.7%) pts in observation arm had BM on imaging (p < 0.001). Median time to sBM was not reached in either arm. Median OS was 24.2 mo in PCI and 21.9 mo in observation arm (p = 0.52). Global QoL at 3 mo was worse in PCI arm (p = 0.02) but not afterwards. Conclusions: PCI significantly decreases the proportion of patients developing both symptomatic BM without influencing overall survival. PCI decreases 3 months global quality of life measures but not beyond. Clinical trial information: NTR 1601.
Multi-modality therapy for stage IIIa N2 non-small cell lung cancer: Does the answer lie in the components?
Authors: Spicer Jonathan David , Shewale Jitesh B. , Bott Matthew Joseph , Jones David Randolph , Vaporciyan Ara A. , Darling Gail Elizabeth , Swisher Stephen , Sepesi Boris 
Published: September 2018

8537 Background: Neoadjuvant chemoradiation prior to surgery offers excellent locoregional control, while neoadjuvant chemotherapy I meant to offer improved systemic therapy in stage IIIA N2 non-small cell lung cancer (NSCLC). Data are lacking to select the optimal regimen. We compared oncologic outcomes for stage IIIA N2 NSCLC utilizing granular data from three experienced lung cancer treatment centers. Methods: This collaborative retrospective study unites 3 major thoracic centers with differing approaches to IIIA N2 NSCLC. Patients undergoing surgical resection post-neoadjuvant chemotherapy (CxT) or concurrent chemoradiation (CxRT) were included. Primary outcomes were overall and disease- free survival (OS and DFS). Results: Demographic data and outcome data are in Table 1. There were no differences in 5-year OS (CxT 40% vs CxRT 42%, p=0.265) nor in DFS (CxT 30% vs 31%, p=0.275). Recurrence rates (CxT47%vsCxRT48%,p=0.799) and patterns were identical (Local: CxT 10% vs CxRT 8%; and Distant: CxT 30%vsCxRT29%,p=0.764). There was no difference in peri-operative mortality. To address potential bias from differing staging strategies, we excluded patients without invasive mediastinal staging and there were still no differences in OS (CxT 40% vs CxRT 42%, p=0.364) and DFS (CxT 30% vs CxRT 31%, p=0.332) Multivariable analysis identified pnemonectomy (HR1.66,p<0.001) and ypN2 (HR1.84,p<0.001) to be associated with overall survival. Conclusions: Both treatment strategies produce equivalent and better than expected outcomes compared to historical controls for IIIA N2 NSCLC. [Table: see text]
Results of stereotactic body radiation therapy (SBRT) for T2 lung cancer: Outcomes of longer term follow-up.
Authors: Shamp Stephen , Chang Tangel C. , Biswas Tithi , Linden Philip Aaron , Perry Yaron , Kazakov Jordan , Dowlati Afshin , Machtay Mitchell 
Published: September 2018

8542 Background: SBRT is a well-established, highly efficacious treatment for T1N0 non-small cell lung carcinoma (NSCLC). Its efficacy in T2N0 cancers is less clear. This is a review of our institutional experience with long-term follow-up. Methods: 45 patients with medically inoperable T2 N0/Nx M0 NSCLC who were treated with definitive SBRT between 2009 and 2013 were analyzed retrospectively. All patients underwent PET/CT staging and fiducial marker placement for image guided therapy with the Cyberknife platform. Radiation dose was 50 Gray in 5 fractions (N = 24), 50 Gray in 4 fractions (N = 11) or 54-60 Gray in 3 fractions (N = 10) delivered over 7 to 14 days. We analyzed overall survival from the date of start of SBRT, and we performed analyses actuarially using Cox regression analysis and Kaplan-Meier survival analysis for comparisons of hazard ratio (HR) among subgroups. Results: 45 patients were studied (median age 74). The 5-year actuarial overall survival was 18.7% (39.3% at 2 years), with most patients dying from lung cancer recurrence/progression outside of the treatment field. Subgroup analyses showed no statistically significant differences with respect to age, gender, histology, nominal radiation prescription dose, tumor diameter or PTV target volume (median PTV 87cc). There was statistically significantly better survival associated with increased maximum biologically effective dose (BED10) of radiation at the center of the tumor (p = 0.03). Conclusions: Unlike the outcomes for T1 NSCLC, our results in T2 NSCLC were disappointing, with a high rate of out-of-field failure and death from lung cancer. We stress the importance of diagnosis and treatment of NSCLC at the T1N0 stage. We suggest that patients with T2N0/Nx NSCLC be considered for SBRT dose intensification and/or combined modality therapy protocols.
Patterns of comorbidity, treatment, resource utilization, and referral in malignant pleural mesothelioma patients in the US.
Authors: Zauderer Marjorie Glass , Tsao Anne S. , Fennell Dean A , Wong William Bruce , Pattipaka Thirupathi , Bretscher Michael T , Peake Michael 
Published: September 2018

8554 Background: Malignant pleural mesothelioma (MPM) is a rare but aggressive cancer, which may be challenging to diagnose. The standard of care for MPM is cisplatin plus pemetrexed. In the recent phase III MAPS trial, addition of bevacizumab provided a significant survival benefit. There is limited data on real-world MPM treatment patterns to provide context to trial results. Consequently, the present study was conducted to evaluate treatment and referral patterns, co-morbidities and resource use in patients with MPM in the U.S. Methods: Patients ≥18 years old with a diagnosis of MPM between Jan 2004 and September 2015 were identified from the MarketScan claims database. Patients were required to have data for 12 months prior, and at least 3 months post, the diagnosis index date. Patients with other (non-MPM) cancers, malignant mesothelioma of non-pleural origin and those enrolled in clinical trials were excluded from the analysis. Treatment and resource utilization were identified by their corresponding HCPCS and DRG codes. Referral patterns were estimated starting from the first lung-related visit during the year preceding MPM diagnosis. Results: In the cohort of 1,869 patients, the median age was 71 years (range 61–79) and 65% were male. 4.1% of patients underwent radical surgery and of the remaining 96%, 15.6% had first-line chemotherapy, 33.2% had first-line chemotherapy plus radiotherapy, 11.7% received radiotherapy, and 39.5% received no chemotherapy or radiotherapy. The most common diagnosis on the first lung-related visit was pleural effusion (16.5%), followed by chest pain (10.7%), shortness of breath (9.6%) and cough (8.5%). The median time from first lung-related visit to MPM diagnosis was 77 days (mean 134 days, IQR 23–258). Conclusions: This real-world analysis showed that only a small proportion of MPM patients (~4%) received radical surgery and a large number of patients did not receive any treatment at all, indicating a large unmet need for effective treatments in this disease area. Additionally, the pathway to MPM diagnosis may be challenging in this population with a poor prognosis, often involving multiple healthcare contacts over an extended period of time.
Survival outcomes in extensive stage small cell lung cancer patients treated with thoracic radiation.
Authors: Higgins Kristin Ann , Zhang Xinyan , Jiang Renjian , Pillai Rathi Narayana , Owonikoko Taofeek Kunle , Steuer Conor Ernst , Saba Nabil F. , Pakkala Suchita , Patel Pretesh R , Belani Chandra Prakash , Khuri Fadlo Raja , Curran Walter John , Ramalingam Suresh S. , Behera Madhusmita 
Published: September 2018

8565 Background: The benefit of consolidation thoracic radiation in extensive stage small cell lung cancer (E-SCLC) remains unclear. This study utilized the National Cancer Database (NCDB) to evaluate overall survival outcome (OS) for patients receiving chemotherapy (CT) alone for E-SCLC versus CT + thoracic radiation (TRT). Methods: The NCDB was queried to capture patients (pts) with stage E-SCLC from 2010-2013. Patients with brain metastases at diagnosis were excluded, as were patients receiving radiation prior to initiation of chemotherapy. Univariate association of OS was assessed using Cox proportional hazards models and log-rank tests. A multivariable Cox proportional hazard model and Kaplan-Meier analyses were performed to compare treatment with CT only to CT + TRT. Propensity score matching method was also implemented to reduce treatment selection bias. All analyses were performed using SAS Version 9.4. Results: A total of 14,367 (12,019 received CT, 2,348 received CT + TRT) pts were included in the analysis. Patient characteristics included a median age of 66 years; 66 years for pts receiving CT, and 63 for pts receiving CT + TRT (p < 0.001). Male gender comprised 51% of pts; 52% in CT group versus 49% in CT + TRT (p < 0.001). Charlson-Deyo comorbidity score was zero in 53% of all patients; 52% in the CT group versus 57% of CT + TRT group (p < 0.001). In the CT + TRT group, the median total thoracic radiation dose was 45 Gy. On multivariate analysis, CT only was associated with an increased risk of death relative to CT+ TRT (HR 1.74 [1.65 – 1.84], p < 0.001). 5 year OS was 7% vs. 2% for CT + TRT versus CT alone (p < 0.001). On propensity matched analysis, CT + TRT was associated with better 5-year OS compared to CT alone (8% vs. 2%; p < 0.001). On multivariate analysis of propensity matched samples, chemotherapy alone continued to be associated with worse survival (HR 1.76 [1.62 – 1.91], p < 0.001). Conclusions: For E-SCLC, CT alone as standard of care is associated with worse survival relative to CT + TRT.