bluuebunny/crossref_metadata_2025_split huggingface dataset:
Semaphorin 4D to suppress bone formation in multiple myeloma.
Authors: Lontos Konstantinos , Adamik Juraj , Zhang Peng , Sun Quanhong , Roodman David , Suvannasankha Attaya , Galson Deborah Lynn 
Published: September 2018

8039 Background: Myeloma bone disease is characterized by osteoclast activation and long-term osteoblast suppression. We investigated if Semaphorin 4D (Sema4D; CD100) plays a role in these processes. Sema4D has been shown to be a potent osteoblast inhibitor (Negishi-Koga T et al, Nat Med. 2011). A study recently identified that the breast cancer cell line MDA-MB-231 utilizes Sema4D to create osteolysis (Yang Y et al, PLOS One 2016). There have been previous data that Sema4D is increased in the serum of myeloma patients (Terpos et al, Blood 2012) and that co-culturing myeloma cell lines with osteocytes increases the expression of Sema4D mRNA in both (Suvannasankha et al, Blood 2016). We sought to investigate if myeloma cells are using Sema4D to suppress bone formation and if they affect the levels of Sema4D produced by osteoclasts. Methods: We used lentivirus carrying shRNA for Sema4D or control (Scr) to knock down the level of the protein in the 5TGM1 murine myeloma cell line. Knockdown was verified by qPCR and Western Blot. We subsequently co-cultured the 5TGM1 cells with the MC3T3-subclone M4 (MC4) murine stromal cell line for 2 days, removed the myeloma cells and then differentiated the MC4 cells using ascorbic acid and β-glycerolphosphate. At day 5, we analyzed the cells for Runx2 (a critical gene for the differentiation of stromal cells into osteoblasts) expression utilizing qPCR. Also, we performed qPCR in primary osteoclast (OCL) mouse cells differentiating into OCL with RANKL with or without pre-treatment with myeloma-conditioned media for 3 days before the addition of RANKL. Results: When 5TGM1-Scr were co-cultured with MC4 cells the expression of Runx2 on day 5 was decreased (p=0.02). Strikingly, the 5TGM1-shSema4D cells when co-cultured with MC4s did not have the same effect and allowed the upregulation of Runx2 expression on day 5 (p=0.01). Myeloma-conditioned media increased Sema4D expression by OCL throughout the 5 days of differentiation 2 to 3-fold (p=0.01 for day 5). Conclusions: The myeloma cells seem to be utilizing Sema4D both directly and indirectly to inhibit bone formation. Targeted therapy against Sema4D may improve outcomes and fracture-free survival for multiple myeloma patients.
Rates of peripheral neuropathy (PN) in patients (Pts) with relapsed and refractory multiple myeloma (RRMM) treated with carfilzomib vs comparators in pivotal phase III trials.
Authors: Niesvizky Ruben , Hungria Vania , Ho Joy , Suvorov Aleksandr , White Darrell , Ben-Yehuda Dina , Zhou Lifen , Iskander Karim S. , Rosinol Laura 
Published: September 2018

8041 Background: PN is a dose-limiting toxicity for some anti-MM agents, such as the proteasome inhibitor (PI) bortezomib (V). Carfilzomib (K), a novel irreversible PI associated with low PN, was evaluated in 2 recent phase 3 studies in RRMM pts. Methods: This analysis evaluated PN rates in ASPIRE (K [27 mg/m2]-lenalidomide [R]-dexamethasone[d] [KRd] vs Rd in relapsed MM; Stewart 2015) and ENDEAVOR (Kd [K 56 mg/m2] vs Vd in RRMM; Dimopoulos 2016). We evaluated grade ≥2 PN during treatment, patient-reported outcomes (PROs; QLQ-C30 pain, FACT/GOG-neurotoxicity subscales), and progression-free survival (PFS) in pts with BL history of PN. Results: In ASPIRE, grade ≥2 PN rate was low (8.9% [KRd] vs 8.0% [Rd]; Table). Pain subscale scores were similar between arms. Median PFS was longer with KRd vs Rd for pts with BL grade ≥2 PN. In ENDEAVOR, grade ≥2 PN rate during the study (prespecified key secondary endpoint) was significantly lower with Kd vs Vd (6.0% vs 32.0%; Table). Pts had significantly improved pain and neurotoxicity subscale scores with Kd vs Vd. PFS improved with Kd vs Vd in pts with BL history of grade ≥2 PN (Table). Conclusions: In ENDEAVOR, Kd resulted in less PN vs Vd; in ASPIRE, PN rate was similar for KRd vs Rd. PFS was longer with KRd and Kd vs Rd and Vd, respectively, including in pts with BL grade ≥2 PN. Improved pain and neurotoxicity outcomes with K may be attributed to better disease control and/or lower PN rates. Clinical trial information: NCT01568866, NCT01080391. [Table: see text]
Racial differences in abnormalities by FISH in minorities with multiple myeloma: A single-center experience.
Authors: Gonzalez Velez Miguel , Jaramillo Restrepo Valentina , Duma Narjust , Palascak Matthew , McKenna Marshall , Richter Joshua Ryan , Vesole David H. , Siegel David Samuel DiCapua , Biran Noa 
Published: September 2018

8044 Background: Racial disparities of FISH abnormalities in multiple myeloma (MM) have been well described in whites (W) but partially described in minorities (M) (Paulus et al, ASH 2016, 4432). We aimed to explore racial-based differences of FISH abnormalities using the largest cohort of m to date. Methods: CD-138 selected FISH was done on 799 consecutive patients (pts). Pts without symptomatic MM, and biopsy >6 months after diagnosis were excluded. The abnormalities evaluated included standard and intermediate risk: IGH rearrangements (IGH r), t(4;14), t(11;14), and high risk: t(14;20), t(14;16), del13q, del 17p, 1q21. Chi-square was used for statistical analysis. Due to smaller numbers, all m (Hispanic (H), Black (B), Asian (A) and Other (O)) were included into the same group for statistical analysis. Results: 482 pts were eligible, 343 (71%) were W, 52 (10%) H, 50 (10%) B, 19 (3%) A, and 18 (3%) O. Median age was 65 years, 54% were male, and 26% ISS stage 3. There were no were no statistically significant differences in FISH abnormalities between the m (Table1). Overall W had more abnormalities in IGH r, t(4;14), t(11;14), t(14:20), 1q21 gain compared to M. Most notably W had more IGH r (39% vs 28%; p=0.019) and t(11;14) (20% vs 12%; p=0.024). There were no statistically significant differences between W and m in the high risk FISH abnormalities. Conclusions: We had significant differences in FISH compared to M. W had more IGH r and t(11;14) than M, and there was no difference in high risk FISH abnormalities between W and M. This study confirms the biological racial disparities that exist in minorities with MM. Further studies with more inclusion of minorities are needed to elucidate these disparities and its effects on risk stratification and outcomes. [Table: see text]
Trends in survival and costs among US multiple myeloma patients.
Authors: Maiese Eric M , Evans Kristin , Chu Bong-Chul , Irwin Debra E. 
Published: September 2018

8046 Background: Survival among multiple myeloma (MM) patients has improved over time, but little is known about concurrent changes in healthcare costs. This study examined trends in both survival and healthcare costs over the same time periods in US MM patients. Methods: The MarketScan Commercial and Medicare claims dataset was used to identify 5199 adult patients diagnosed with MM from Jan. 2006 to Dec. 2014. Patients had no prior evidence of cancer, were continuously enrolled for >12 months prior to MM diagnosis, and were followed through the earliest event (death, end of enrollment, or end of the study period (9/30/2015)). Multivariate GLM and Cox proportional hazards models estimated healthcare costs and survival probabilities, respectively, for two time periods during which patients were diagnosed with MM (2006-2010 vs 2011-2014) while controlling for demographic and clinical characteristics. The recycled prediction method was used to calculate the incremental cost estimates between the time periods. Results: Patients diagnosed in 2011-2014 had a 35% lower risk of death compared to those diagnosed in 2006-2010 (HR [95% CI] = 0.65 [0.57-0.74]. Patients diagnosed in 2011-2014 had 18% (95% CI: 6-31%) higher all cause and 26% (95% CI: 6-50%) higher MM-related per patient per month costs compared to those diagnosed in 2006-2010 (Table). Conclusions: Among MM patients, survival has improved at a greater rate than the increase in healthcare costs. In addition to improvements in MM treatment, changes in overall disease management may have contributed to both the increased expenditures and survival improvements observed in this study. [Table: see text]
Mature overall survival (OS) results from the LUME-Meso study of nintedanib (N) + pemetrexed/cisplatin (PEM/CIS) vs placebo (P) + PEM/CIS in chemo-naïve patients (pts) with malignant pleural mesothelioma (MPM).
Authors: Nowak Anna K. , Grosso Federica , Steele Nicola , Novello Silvia , Popat Sanjay , Greillier Laurent , John Tom , Leighl Natasha B. , Reck Martin , Pavlakis Nick , Soerensen Jens Benn , Planchard David , Ceresoli Giovanni Luca , Hughes Brett Gordon Maxwell , Mazieres Julien , Socinski Mark A. , Velema Derek , von Wangenheim Ute , Morsli Nassim , Scagliotti Giorgio V. 
Published: September 2018

8506 Background: LUME-Meso is a Phase (Ph) II/III, double-blind, randomized study. N targets MPM by inhibiting VEGFR 1–3, PDGFR α/β, FGFR 1–3, Src and Abl kinases. Primary analysis of the Ph II data demonstrated improved progression-free survival (PFS; hazard ratio [HR]=0.56; 95% confidence interval [CI] 0.34–0.91; p=0.017). Mature Ph 2 OS and updated PFS results are reported here. Methods: Pts with unresectable MPM (ECOG PS 0–1) were stratified by histology (epithelioid/biphasic) and randomized 1:1 to receive ≤6 cycles PEM (500 mg/m2)/CIS (75 mg/m2) Day 1 + N or P (200 mg bid, Days 2–21), followed by N or P monotherapy until progression or toxicity. The primary endpoint was PFS. The primary OS analysis and updated PFS analysis were performed as predefined. Results: 87 pts were randomly assigned (N=44, P=43). OS benefit favored N over P treatment (HR=0.77; 95% CI 0.46–1.29; p=0.319; 62 [71%] OS events) and was greatest in epithelioid pts (HR=0.70; 95% CI 0.40–1.21; p=0.197) with a median (m) OS gain of 5.4 months (mOS [95% CI]: 20.6 [16.2–28.8] N vs 15.2 [12.2–23.6] P). Updated PFS results (HR=0.54; 95% CI 0.33–0.87; p=0.010) also showed greatest benefit for epithelioid pts (HR=0.49; 95% CI 0.30–0.82; p=0.006) with a mPFS gain of 4.0 months (mPFS [95% CI]: 9.7 [7.2–12.4] N vs 5.7 [5.5–7.0] P). Improved forced vital capacity, objective response rates and duration of response were also observed with N treatment. Drug-related adverse events (AEs) in N- vs P-treated pts were 97.7% vs 97.6%. Grade ≥3 AEs of note included neutropenia (27.3% vs 4.9%), ALT (11.4% vs 0) and GGT (6.8% vs 0) elevations, and diarrhea (6.8% vs 0). AEs led to trial discontinuation in only 3 (6.8%) N vs 7 (17.1%) P pts. Conclusions: Mature Ph II OS data show that adding N to standard 1st-line treatment gives a strong signal towards improved OS. Updated PFS confirmed the primary analysis; AEs were manageable. The greatest clinical benefit was observed in pts with epithelioid histology. Median survival of 20.6 months in epithelioid pts treated with N is unprecedented in advanced MPM trials. Ph III is actively recruiting in this pt population. Clinical trial information: NCT01907100.
Neoadjuvant nivolumab in early-stage, resectable non-small cell lung cancers.
Authors: Chaft Jamie E. , Forde Patrick M. , Smith Kellie Nicole , Anagnostou Valsamo , Cottrell Tricia , Taube Janis M. , Rekhtman Natasha , Merghoub Taha , Jones David Randolph , Hellmann Matthew David , Yang Stephen C. , Broderick Stephen , Rusch Valerie W. , Velculescu Victor E. , Topalian Suzanne Louise , Pardoll Drew M. , Brahmer Julie R. 
Published: September 2018

8508 Background: Anti-PD-1 therapy produces objective and often durable responses in ~20% of unselected patients (pts) with metastatic non-small cell lung cancer (NSCLC). However, the role of PD-1 blockade in treating resectable NSCLC is unknown. This is the first study to test nivolumab in the neoadjuvant setting. This trial design provides an opportunity to examine anti-PD-1 mechanism of action and immunologic correlates of outcomes. Methods: Patients with Stage IB - IIIA NSCLC received 2 doses of nivolumab 3mg/kg over 4 weeks before surgery. The primary endpoint was safety in 20 patients with resected NSCLC. Efficacy was explored using objective pathologic response criteria. Correlative studies of the tumor immune microenvironment, tumor mutation and predicted neoantigen loads, and changes in T cell receptor (TCR) clonality in tumor and blood pre and post treatment were conducted. Results: 22 pts were treated. Nivolumab was well-tolerated and no surgeries were delayed. 1 pt withdrew from study preop without progression or toxicity. Among the 21 attempted resections, 1 tumor was unresectable. 9/21 (43%, 95% CI 24-63%) had a major pathologic response ( < 10% viable tumor cells in resection specimen). With a median postop follow-up of 9 months, 18 pts (86%) remain alive and recurrence free. Pre-treatment tumor exome sequencing showed a correlation between both tumor mutation and predicted neoantigen loads with pathologic response. Multiplex immunohistochemistry of pre- and post-treatment tumors showed an influx of PD-1+CD8+ T cells into responding tumors. TCR sequencing demonstrated that expanded peripheral T cell clones after treatment match clones found in the tumor. Conclusions: Neoadjuvant nivolumab in resectable NSCLC did not delay surgery. Major pathologic response rate was encouraging and compares favorably to outcomes with cisplatin-based neoadjuvant chemotherapy. Genomic analyses suggest that higher mutational and neoantigen burden could result in deeper pathologic response. Immunologic analyses support the detection of intra-tumoral T cell clones in the blood after treatment with nivolumab and may provide further insight into the molecular and immunologic features of response and non-response to PD-1 blockade. Clinical trial information: NCT02259621.
Treatment of lung cancer patients in multidisciplinary (MDC) and serial care (SC) clinics.
Authors: Ray Meredith , Faris Nicholas Ryan , Rugless Stewart Fedoria Elaine , Smeltzer Matthew , Boateng Nana , Meadows Meghan Brooke , Foust Courtney , Jackson Bianca , Patel Anita , Fehnel Carrie , Houston-Harris Cheryl , Signore Raymond S , Robbins Edward T , Osarogiagbon Raymond U. 
Published: September 2018

8522 Background: MDC may improve the quality of care for complex diseases. We compared the use of stage-appropriate treatment for lung cancer patients in a co-located MDC to serially-referred (SC) patients within the same healthcare system. Methods: Prospective cohort study of newly-diagnosed lung cancer patients enrolled before onset of treatment from MDC or the standard clinics (SC). Eligible pts had ECOG PS 0-2. Stage-appropriate treatment selection was determined using National Comprehensive Cancer Network (NCCN) guidelines based on clinical stage just before treatment onset. Differences in stage-based treatment rates were calculated using Chi-squared tests. Results: 162 had MDC and 317 SC. Compared to serial care patients, MDC patients were more likely black (37% v 30%) female (51% vs 48%), older (median 69 vs median 66) and less likely commercially insured (36% v 43%). Surgical resection was more frequently used for early stage patients in MDC: 72% v 58% for stage IA/IB (p = 0.2259); 58% v 31% for stage IIA/B and IIIA (T3N1M0) (p = 0.0375). MDC patients also had trends towards higher rates of recommended concurrent chemoradiation therapy for stage IIIA (T4N0-1M0) (75% vs 53%) (p = 0.5835), IIIB (T1-3N3, T4N2) (78% v 68%), but equal rates of concurrent chemoradiation therapy for stage IIIA (T1-3N2M0) (68% vs 68%). Stage IV patientss were more likely to receive chemotherapy or targeted therapy in MDC v SC (87% vs 80%) (p = 0.3795). Conclusions: Lung cancer patients in the MDC model are more likely to receive recommended stage-appropriate treatment than those in the usual serial care model, despite relatively adverse demographic characteristics. Clinical trial information: NCT02123797.
The role of adjuvant chemotherapy in stage IB non-small cell lung cancer: A decision, effectiveness, and cost-effectiveness analysis.
Authors: Hudson Jessica Lynn , Aung Wint Y , Santos Carlos AQ , Chang Su-Hsin , Olsen Margaret A , Meyers Bryan F , Morgensztern Daniel , Puri Varun 
Published: September 2018

8526 Background: Despite complete surgical resection (SR), half of stage I non-small cell lung cancer (NSCLC) patients die from systemic relapse. An independent risk factor for systemic progression is pathologic stage IB subtype (T2aN0M0, AJCC 7). The role of adjuvant chemotherapy (AC) in stage IB NSCLC is controversial. We studied the effectiveness and cost-effectiveness of AC after SR in stage IB NSCLC. Methods: Propensity score matching was performed on the National Cancer Database (2004-2011). The Kaplan-Meier method generated conditional probabilistic incremental 1- to 5-year survival after SR stratified by receipt of AC. Medicare allowable charges for SR, AC, and their respective complications were used. Decision analysis modeling and microsimulation were performed to account for proportions of chemotherapeutic agents administered in real-world settings. The incremental cost-effectiveness ratio (ICER) was calculated over a 5-year horizon. Probabilistic and two-way sensitivity analyses were performed. Results: 3662 of 18709 patient (19.6%) who met inclusion criteria received AC for SR stage IB NSCLC, with usage ranging from 15-27% annually. After propensity score matching, an overall survival benefit of AC was conferred over SR alone (at 5 years: 68.9% vs 60.4%, p < 0.001). The incremental cost of AC over SR alone was $11,541. The incremental effectiveness of AC was 0.28 life-years, with an ICER of $41,218. In two-way sensitivity analysis, AC plus SR dominated for the entire range of cost and survival estimates. In probabilistic sensitivity analysis, AC plus SR dominated the model above a willing-to-pay threshold of $16,000. AC costs could nearly double and the ICER remained under conventional thresholds. However, only 3 of the 4 common AC regimens were cost effective. Conclusions: In stage IB NSCLC, surgery is insufficient to render a cure. The addition of AC to SR extends life-expectancy and is cost-effective compared to SR alone. These conclusions are valid over a range of clinically meaningful variations in cost and treatment outcomes, though a cost-conscious approach is needed when selecting an AC regimen. This represents a novel change in the treatment of stage IB NSCLC.
Randomized phase II trial of S-1 plus cisplatin or docetaxel plus cisplatin with concurrent thoracic radiotherapy for inoperable stage III non-small cell lung cancer (TORG1018).
Authors: Kubota Kaoru , Shimokawa Tsuneo , Yamada Kazuhiko , Tanaka Hiroshi , Kishi Kazuma , Saito Haruhiro , Takiguchi Yuichi , Hosomi Yukio , Kato Terufumi , Nogami Naoyuki , Yamanaka Takeharu , Masuda Noriyuki , Watanabe Koshiro 
Published: September 2018

8534 Background: Concurrent chemoradiotherapy (CCRT) is standard of care in patients with inoperable stage III non-small cell lung cancer (NSCLC), however the best chemotherapy regimen has not been identified. The study was conducted to evaluate cisplatin plus S-1 (SP) or cisplatin plus docetaxel (DP) both with concurrent thoracic radiotherapy in patients with inoperable stage III NSCLC. Methods: Patients with inoperable stage III NSCLC were randomized to SP (S-1 40 mg/m2 twice a day on days 1-14 and 29-42 plus cisplatin 60 mg/m2 on days 1 and 29) or DP (docetaxel 50 mg/m2 and cisplatin 80 mg/m2 on days 1 and 29), stratified by institution, gender, histology, and stage. In both arms, concurrent radiotherapy began on day 1 (60 Gy/30 fr). After CCRT, patients in each group received two additional cycles of the consolidation chemotherapy. Primary endpoint was 2-year overall survival (OS), and secondary endpoints were OS, progression-free survival (PFS), toxicity profile, dose intensity and objective response rate (ORR). Results: From May 2011 to August 2014, 110 patients were enrolled from 19 institutions. Four patients (one in SP and 3 in DP) were ineligible, and 106 patients (53 in each arm) were evaluable for efficacy and safety. Patient characteristics were: male/female 83/23; median age 65 (range 42-74); performance status 0/1 59/47; IIIA/IIIB 59/47. With a median follow-up of 39.3 months, 2-year survival and median OS were 79% (95% CI: 66-88%) and 55.2 months in the SP arm and 69% (95% CI: 55-80%) and 50.8 months in the DP arm, respectively. ORR and median PFS in SP arm were 71.7% and 11.6 months, and ones in the DP arm were 67.9% and 19.9 months. Grade 3/4 leukopenia (62.3/34.0%) and neutropenia (56.6/28.3%) were significantly more frequent in DP arm than SP arm. Incidences of non-hematological toxicities including febrile neutropenia, anorexia, nausea, diarrhea, radiation pneumonitis and esophagitis tended to be higher in DP arm. No treatment-related death occurred. Conclusions: The 2-year OS favored for SP arm with less toxicity. We choose SP with concurrent thoracic radiotherapy as a future reference regimen. Clinical trial information: UMIN000005993.
Intratumor heterogeneity of stage IA lung adenocarcinoma by multiregion whole exome sequencing and association with survival.
Authors: Quek Kelly , Li Jun , Fujimoto Junya , Zhang Jianhua , Wang Jinliang , Chow Chi-Wan , Behrens Carmen , Little Latasha , Gumbs Curtis , Antonoff Mara , Kalhor Neda , Weissferdt Annikka , William William N. , Swisher Stephen , Lee J. Jack , Heymach John , Wistuba Ignacio Ivan , Futreal Andrew , Zhang Jianjun ,   Early NSCLC ITH Group
Published: September 2018

8545 Background: Our previous study has suggested that complex genomic intratumor heterogeneity (gITH) was associated with an increased risk of relapse in patients with localized lung adenocarcinomas (LUAD). We have launched a study to investigate molecular and immune profile ITH of Stage IA NSCLC (a patient population with no optimal biomarker to guide postsurgical therapy) to understand the molecular evolution during early carcinogenesis and to identify biomarkers for early detection and intervention. Here, we report the preliminary analysis on gITH. Methods: We performed multiregion whole exome sequencing on 30 Stage IA LUAD and matched normal lung tissue to a median sequencing depth of 494x. 15 patients have relapsed within 3 years post-surgery (cases) and 15 patients have not relapsed with a minimum of 5-year postsurgical follow up (controls). Cases and controls are 1:1 matched for the key prognostic factors including tumor size, smoking status, age, gender, ethnicity and lobectomy or wedge resection. Shannon diversity index (SDI) was used to quantify ITH in each individual tumor. Kaplan-Meier method was used to evaluate the relationship between ITH and disease-free survival (DFS) as well as overall survival (OS). Results: Consistent with our previous study, 108 of 110 (98.2%) canonical cancer gene mutations were shared events by all regions of individual tumor. Compared to non-relapsed controls, tumors from relapsed cases demonstrated significantly higher degree of ITH (SDI of 1.78 in cases vs 1.58 for controls, p = 0.016). Higher degree of gITH was associated with shorter DFS (p = 0.008) and shorter OS (p = 0.0153). Significantly higher mutation burden was observed in tumors from relapsed patients (median of 10.86 mutations per MB in cases vs 7.45 mutations per MB in controls, p = 0.03). Analysis of gITH on a larger cohort and on predicted neoantigen, methylation, gene expression and immune profiles are in progress. Conclusions: Majority of cancer gene mutations are clonal events during early carcinogenesis of LUAD. Complex gITH may be associated with more aggressive biology and inferior clinical outcome in patients with Stage IA LUAD, therefore, may be evaluated as a potential biomarker.