Sequential Line Research Articles

Buffer clustering policy for sequential production lines with deterministic processing times

Buffer clustering policy for sequential production lines with deterministic processing times

Increasing economic burden of tyrosine kinase inhibitor treatment failure by line of therapy in chronic myeloid leukemia

Objective:To assess the economic burden of tyrosine kinase inhibitor (TKI) treatment failure in chronic myeloid leukemia (CML), by assessing all-cause health care resource use (HCRU) and costs in the year after treatment failure by line of therapy (LOT; 1L/2L/3L) using real-world data.Methods:Treatment episodes initiating a TKI of interest (index TKI) during June 2008–December 2011 were identified from the IMS PharMetrics Plus Health Plan Claims Database for adult patients with CML diagnosis (ICD-9-CM 205.1x), 120 days pre-index continuous enrollment (CE) and no clinical trial participation. Episodes experiencing treatment failure, defined as switch to a non-index TKI or discontinuation of index TKI (gap of ≥ 60 days), and with 1 year CE post-failure, were analyzed. LOT was determined by number of unique TKIs used in the pre-index. All-cause HCRU and costs (2012 USD) in the 1 year post-failure were assessed by LOT, and the comparisons between 1L and 2L failures were also adjusted using multivariate generalized linear models (GLMs) to control for underlying differences.Results:A total of 706 episodes were identified (518 1L; 180 2L; 8 3L). Unadjusted HCRU over 1 year post-failure increased significantly. This was accompanied by a significant increase in unadjusted mean costs for 2L failures vs. 1L failures ($99,624 vs. $78,667, p = 0.021, Δ$20,957). Following the adjustment using GLMs, adjusted mean costs were 38% higher (95% CI 1.14–1.68), driven primarily by use of medical services. In adjusted analyses, compared to 1L, 2L failures had: 45% more ambulatory visits (mean 31 vs. 21, 95% CI 1.26–1.66), 75% higher risk of hospitalization (33% vs. 23% hospitalized, 95% CI 1.16–2.64), and 73% higher medical costs (95% CI 1.31–2.29). Medical costs comprised a greater proportion of total costs in 2L vs. 1L (55% vs. 44%); pharmacy costs did not increase significantly.Conclusions:The economic burden over 1 year post TKI failure increased with each sequential line of TKI treatment failure.

Manual assembly cells vs. sequential line

Manufacturing line efficiency is an important issue directly influencing the profitability and competitiveness on the market. Comparison shows efficiency advantages for the cell-based manual assembly line in comparison with sequential line. Downsides of the cell-based line configuration are increased capital cost, larger footprint and increased complexity of the manufacturing task on each station.

Simulation of matrix-structured manufacturing systems

Increasing product variety, shorter product life cycles, and unknown future demands for each product type are key challenges of manufacturing companies. This paper describes the concept of matrix-structured manufacturing systems (MMS) which aims at providing high operational flexibility and scalability. The main goal of MMS is to eliminate a constant cycle time by providing redundant work stations for same operations as well as a flexible product routing. This enables to avoid starving and blocking and to achieve high system utilization while producing multiple product types with unknown demands and high volumes. The paper explains the main principles, elements, and control strategies of MMS and presents a simulation approach for the evaluation of MMS configurations. A case study shows the application of the simulation approach and how it can be used in the planning of MMS. The results reveal that a MMS configuration can lead to better utilizations of the exemplary manufacturing system in comparison to a sequential assembly line configuration.

Internally-represented space and its mirror-reversed image of the visuospatial representation: A possible association

The cognitive capacity for number representation is thought to be a functional isomorphism of space representation. Numbers are represented in a left-to-right-oriented mental number line and hemispatial neglect patients consistently demonstrate rightward midline shift of visuospace, the internal space and number representation. However, patients with pathologic pain in one limb showed a negative correlation between midline shift of the visuospace and number representation. The purpose of the present study is to ascertain whether such dissociation in accessing space and number representation is observed in another neuropathic pain condition, and then to propose a theoretical model regarding an intimate relationship between visuospace and internal space representations. Using patients with deafferentation pain caused by a nerve lesion in a limb, we investigated whether number representation is closely linked to space representation by evaluating visual subjective body-midline judgments in dark and light conditions (egocentric- and allocentric-spaces, respectively). We also used a number-interval-bisection task to analyze this question. All of the patients perceived allocentric-space accurately. Respective patients showed perceptual shifts in egocentric-space and number representation, however they did not demonstrate any trend of the shifted-direction. Direct comparison revealed that number representation is negatively correlated with not allocentric-space but egocentric-space: a leftward midline-shift of egocentric-space was linked with a rightward midline-shift of number bisection, and vice-versa. Internally-represented space demonstrated a mirror-reversed image of the visuospatial representation, similar to our previous finding. To explain the inverted representation, we can propose a theoretical model that spacing between mentally-aligned numbers in a left-to-right sequential line is anisometric.

Abstract CT127: Can potential curability be reached in high risk/metastatic breast cancer patients with a treatment optimization strategy that includes a novel GNT (gemcitabine, vinorelbine, docetaxel) in front line combination chemotherapy

Abstract Aiming at improving the therapeutic outcome of sequential taxane and anthracycline front line chemotherapy in breast cancer, G and N were incorporated into the taxane arm; GNT x 4 courses (G 1800-2500mg/m2, N 20-30mg/m2, T 100mg/m2, I.V. on day 1. GNT was administered sequentially with L-FAC x 4 courses; 72hr infusion of 400mg/m2/d 5-fluorouracil modulated by I.V. bolus 200mg/m2/d x 3 leucovorin. This was given concomitantly with 24hr d1 I.V. infusion 600mg/m2 cyclophosphamide, followed by 48hr I.V. infusion d2 + d3 60mg/m2 doxorubicin (ASCO 2006# 10741). Chemotherapy was given in a dose dense pattern with filgrastim support. As data became available, transtuzumab (for 1≤ year) was incorporated in HER2+ subset (15 patients) as of 11/2004, cis-platin (P) 70mg/m2/d1; GNTP in HER2+ and Triple negative (TN) subsets (20 patients) as of 5/2007 and bevacizumab 5mg/kg/wk I.V. in inflammatory and Stage IV HER2- subsets (6 patients) as of 10/2007. Hormone receptor positive (HOR+) subset (18 patients) received post chemotherapy hormone maintenance. Ten patients also received additional therapies. From 3/2001 to 2/2012, 52 patients (Median age 48) participated including the following stages: I; 3 (6%), II; 24 (46%), III; 17 (33%), IV; 8 (15%). The following subsets were represented; Triple negative 22 (42%), HER2+ 19 (37%), HER2-/HOR+ 11 (21%). Modified Blacks nuclear grade 3 was noted in 71% and Ki67 > 14% in 91%. 83% had breast conservation and 23 (44%) neoadjuvant chemotherapy; 87% achieved major pathologic response (14 PCR, 2 RCB1, 4 PET/CR/negative biopsy) at a median follow up of 75 months (m). Adjuvant chemotherapy follow up was longer at 116 m. At 81 m, 8/8 Stage IV patients achieved complete remission, though 1 patient (HER2+) had successfully treated intracranial relapse and another developed a second breast primary. At an overall follow up of 85 m (29-154), 4 relapses were observed; 2 HER+ (Stage III/without transtuzumab; Stage IV intracranial relapse only), 1 Inflammatory TN without PCR, 1 HOR+ late relapse > 10 year with short hormonal therapy. There were 3 deaths; 2 breast cancer related. Freedom from relapse for TN was 95% at 82 m, HER2+ 89% at 84 m, HER-/HOR+ 91% at 116 m. Dose dense limiting events included thrombocytopenia, muco-cutaneous reactions, and patient desired breaks. Other side effects noted were; decreased cardiac ejection fraction (2), decreased hearing (1), chronic peripheral neuropathy (2), AML (1), and MDS (1). Despite the limited study population number, this treatment approach resulted in high pathologic remission, complete remission in Stage IV and substantial freedom from relapse in high-risk and metastatic breast cancer subsets. This is highly suggestive that the natural history of aggressive breast cancer can be favorably influenced with this treatment approach. Citation Format: Khaled Jabboury, Lena Rogers, Krystal Sexton, Odelia Garcia. Can potential curability be reached in high risk/metastatic breast cancer patients with a treatment optimization strategy that includes a novel GNT (gemcitabine, vinorelbine, docetaxel) in front line combination chemotherapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT127. doi:10.1158/1538-7445.AM2015-CT127

3-D ice shape measurements using mid-infrared laser scanning.

A general approach based on mid-infrared (MIR) laser scanning is proposed to measure the 3-D ice shape no matter whether the ice is composed of clear ice, rime ice, mixed ice, or even supercooled water droplets or films. This is possible because MIR radiation penetrates ice and water only within a depth of less than 10 micrometers. First, an MIR laser point scanning technique is implemented and verified on transparent glass and clear ice. Then, to improve efficiency, an MIR laser line scanning method is developed and validated on different models. At last, several sequential MIR laser line scans are applied to trace the 3-D shape evolution of the continuous ice accretion on an airfoil in an icing wind tunnel. The ice growth process can be well observed in the results. The MIR scan shows a good agreement with the traditional visible laser scan on a plastic replication of the final ice shape made by the mold and casting method.

Reduced Circulating Memory B-Cells Account for Humoral Immune Defects in Multiple Myeloma, Associated with Infective Risk and Poor Vaccination Responses

Multiple myeloma (MM) is characterized by an increased risk of infection due to the immunosuppressive effect of the disease and conjointly of therapy. Furthermore, there is impaired responses to vaccination to counter the infection risk. The factors that underpin defective B-cell homeostasis and effective humoral immunity are not clear, nor are the extent of the defects. Also, the level of impaired humoral immunity in MGUS is not fully understood. The aim of this study was to delineate the circulating B-cell populations and recall antibody responses in patients with MGUS & MM, compared to age-matched controls, correlating with the responsiveness to vaccinations, incidence of infective complications and concomitant therapy. We performed comprehensive B-cell immunophenotyping by multi-parameter flow cytometry of peripheral blood samples from patients with MGUS (n=16), asymptomatic MM (n=18) and MM (n=108) with a median age of 63 years (range 38-94) comparing them to age-matched controls (n=9). B-cell subsets included naïve (CD19+CD27-), memory (CD19+CD27+; non-switch CD19+IgD+CD27+, switch CD19+IgD-CD27+), transitional (CD19+CD27-CD24hiCD38hi) & regulatory (CD19+CD27+CD24hi) B-cells. Serum uninvolved total IgG, IgM & IgA levels along with vaccine-specific antibody responses were analysed. There is a progressive decrease in the uninvolved immunoglobulin classes with significant reduction in total IgA (p=0.006) and IgM levels (p=0.007) in aMM/MM compared to MGUS & control (Figure 1). When anti-pneumococcal antibodies were measured, only 30% of aMM/MM patients had adequate protective levels compared to 79% of age-matched controls, with 40% of aMM/MM patients with inadequate levels experiencing recurrent respiratory tract infections compared to 25% of aMM/MM patients with adequate proactive antibodies. Patients with MGUS, aMM and MM have lower total B-cell numbers compared to controls (1-way ANOVA p=0.004; Figure 1). The reduction in B-cell numbers were primarily the consequence of reduced memory B-cells (percentage and absolute 1-way ANOVA p<0.0001), noted in both MGUS and aMM/MM but a progressive reduction with increasing disease activity (MGUS>aMM>MM). Furthermore, a correlation with total IgG levels & memory B-cell numbers is evident (r2=-0.053) & progressive reduction in memory B-cell numbers is seen with advancing cycles of therapy. The ratio of switch:non-switch memory B-cells is unaltered (control 1.05, MGUS 0.53, aMM 1.41 & MM 1.49; 1-way ANOVA p=ns). Conversely, there is a compensatory increase in the percentage of transitional B-cells when increasing disease stage is compared to controls (control 7.38% (95%ci 4.9,9.9) vs MGUS 14.0% (95%ci 7.4, 20.7) vs aMM 14.95% (95%ci 8, 21.9); 1-way ANOVA p<0.001) but a reduction is noted in MM (5.82%, 95%ci 4.5,7.2; p<0.0001), primarily being driven by sequential lines of therapy. As a consequence, the ratio of Memory:transitional B-cells is significantly reduced in aMM/MM compared to MGUS & controls (control 10.35, MGUS 20.46, aMM 7.74 & MM 4.57; 1-way ANOVA p=0.006), associated with increasing incidence of bacterial infections. A non-significant correlation is seen between transitional B-cells and total uninvolved immunoglobulin levels and with recall responses to vaccinations. There is a progressive decrease in the CD19+CD27+CD24hi B-cell subset between control and plasma cell dyscrasias (control 20.4% (95%ci 15.5,25.2), MGUS 14.0% (95%ci 7.4, 20.7), aMM 14.95% (95%ci 8, 21.9) & MM 5.82%, 95%ci 4.5,7.2; p<0.0001), primarily being driven by sequential lines of therapy and associated with increased incidence of infection. This study illustrates that patients with myeloma demonstrate reduced total circulating B-cells primarily as a consequence of reduced memory B-cells, associated with reduced immunoglobulin and recall antibody responses. This is associated with increased incidence of bacterial infections and is worsened by sequential exposure to lymphodepleting therapies. Of particular importance is the identified aberration in B-cell subsets seen in MGUS compared with age-matched control, indicative of humoral immune dysregulation highlighting that MGUS may not be an immunologically inert disorder. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

시설토마토에서 황색트랩을 이용한 담배가루이 표본조사법

The sweetpotato whitefly (SPW), Bemisia tabaci Gennadius, is a major pest in tomato greenhouses on Jeju Island because they transmit viral diseases. To develop practical sampling methods for adult SPWs, yellow-color sticky traps were used in commercial tomato greenhouses throughout the western part of Jeju Island in 2011 and 2012. On the basis of the size and growing conditions in the tomato greenhouses, 20 to 30 traps were installed in each greenhouse for developing a sampling plan. Adult SPWs were more attracted to horizontal traps placed 60 cm above the ground than to vertical trap placed 10 cm above the plant canopy. The spatial patterns of the adult SPWs were evaluated using Taylor`s power law (TPL) and Iwao`s patchiness regression (IPR). The results showed that adult SPWs were aggregated in each surveyed greenhouse. In this study, TPL showed better performance because of the coefficient of determination (). On the basis of the fixed-precision level sampling plan using TPL parameters, more traps were required for higher precision in lower SPW densities per trap. A sequential sampling stop line was constructed using TPL parameters. If the treatment threshold was greater than 10 maximum adult SPWs on a trap, the required traps numbered 15 at a fixed-precision level of 0.25. In estimating the mean density per trap, the proportion of traps with two or more adult SPWs was more efficient than whole counting: ${\ln}(m)

Progression-Free Survival Remains Poor Over Sequential Lines of Systemic Therapy in Patients With BRAF-Mutated Colorectal Cancer

BackgroundBRAF mutations occur in 5% to 10% of metastatic colorectal cancers and are biomarkers associated with a poor prognosis. However, the outcomes with standard chemotherapy over sequential lines of therapy in a large cohort of patients with BRAF-mutant tumors have not been described. Patients and MethodsWe searched the M.D. Anderson Cancer Center databases for patients with colorectal cancer and identified BRAF mutations between December 2003 and May 2012. Patients were analyzed for clinical characteristics, PFS, overall survival, and chemotherapeutic agents used. Survival was estimated according to the Kaplan–Meier method. ResultsAmong the 1567 patients tested for BRAF mutations at our institution, 127 (8.1%) had tumors with BRAF mutations. The 71 patients who presented with metastatic disease received a median of 2 lines of chemotherapy. For the first 3 lines of chemotherapy, median PFS was 6.3 months (n = 69 patients; 95% confidence interval [CI], 4.9-7.7 months), 2.5 months (n = 58 patients; 95% CI, 1.8-3.0 months), and 2.6 months (n = 31 patients; 95% CI, 1.0-4.2 months), respectively. Median PFS was not affected by the backbone chemotherapeutic agent in the first-line setting, whether oxaliplatin-based or irinotecan-based (6.4 months vs. 5.4 months, respectively; P = .99). ConclusionPFS is expectedly poor for patients with BRAF-mutated metastatic colorectal cancer. Despite the ascertainment bias present (with testing preferentially performed in patients suitable for clinical trials in refractory disease), these data provide historic controls suitable for future study design and support the idea that novel therapeutic options are essential in this population.

Elemental depth imaging of solutions for monitoring corrosion process of steel sheet by confocal micro X-ray fluorescence

Non-destructive and non-contact analysis has been in demand on numerous occasions. Confocal micro X-ray fluorescence analysis enables depth-selective elemental analysis of solid samples in the laboratory. In this paper, we applied this technique for imaging elemental distributions in solutions. A low-carbon steel sheet was placed in artificial seawater (NaCl: 3.5 mass%), and the corrosion process in the solution was observed. A depth image of Fe Kα intensity in the NaCl solution was obtained by using this technique. The Fe Kα intensity in the solution was measured with corrosion time by sequential line analysis at a fixed lateral position. The corrosion of Fe from the steel sheet, the migration of Fe ions in solution, and their condensation near a polymer window were successfully monitored. Copyright © 2014 John Wiley & Sons, Ltd.

UV irradiations induce variations of ferromagnetism and resistivity in nitrogen doped ZnO films

Abstract The saturated room-temperature ferromagnetism observed from nitrogen-doped zinc oxide (ZnO:N) increases significantly after ultraviolet light (UV) irradiation. During the period of irradiation, the resistivity as a function of time decreases dramatically and reaches saturation eventually. The log scale of the resistivity as a function of irradiation time reveals two sequential linear lines with different slops. Both of linear lines correspond to different dominant transports which result from some electrons recombination captured by the impurity band induced from the N doping. Similarly, the reverse properties of resistivity change appear at the samples after turning off the UV irradiation. The experiments convince us of the magnetic mechanism arising from the Coulomb excitation.

Identification of myelodysplastic syndromes patients

Myelodysplastic syndromes (MDS) are an heterogeneous group of hematological malignancies characterized by ineffective hematopoiesis and peripheral cytopenias, with a variable risk of developing acute myeloid leukemia. An accurate diagnosis is the basis of the possible selection of the most appropriate therapy. The most important parameters for an accurate prognosis and therapy are the biological characteristics of the disease, the clinical presentation, the fragility of the patient and the presence of comorbidities. MDS are mainly geriatric diseases and the presence of comorbidities and patient's poor performance status adversely affect the prognosis. Our group has proposed a system to identify the patients who have low probabilities to achieve benefit from treatment with azacitidine. A number of validated prognostic scores exist in MDS. The most widely used, although dated, is the International Prognostic Scoring System (IPSS). On IPSS scores we still base therapeutic choices. Recently a revised IPSS has been built on a larger cohort of patients still to be further validated, also in MDS treated patients. We at present can predict response to azacitidine and survival in patients treated with this drug. The goals of MDS therapy are for low-risk patients: improving quality of life through the improvement of hematopoiesis and for high risk patients: prolong survival and delay progression to acute myeloid leukemia. Currently, according to the calculated IPSS risk of the patient, age, biological parameters and comorbidities we may propose individualized therapies, which may vary from watch-and-wait to hypomethylating agent therapy, to an allogeneic transplant. Moreover, the new concept of sequential lines of therapy has gained consideration.

Effects of reciprocating motion parameters on lubricating properties of tripod sliding universal joints

Purpose – This paper aims to clarify the effects of the reciprocating motion parameters on the lubricating performance of the tripod sliding universal joint (TSUJ). These parameters mainly include the frequency and amplitude of the reciprocating motion. This work will explain how the film thickness and pressure as well as the temperature vary with the frequency and amplitude of the reciprocating motion in order to improve the lubricating performance of the TSUJ and extend its working life. Design/methodology/approach – Based on the simplified geometrical model derived from the main mating surfaces, the effects of the frequency and amplitude on the pressure and film thickness as well as the temperature are theoretically investigated. In this work, multi-level method, multilevel multi-integration method and sequential line sweeping method were applied to solving Reynolds equation, the elastic deformation of the bounding surfaces and temperature, respectively. Findings – The overall film thickness increases with the increase of the amplitude or frequency. The consumed time of the rippled film passing through the contact zone hardly depends on the amplitude or frequency. The variation of the film or temperature lags behind the variation of the entrainment velocity. Increasing amplitude or frequency increases the temperature. The effect of the amplitude or frequency on the pressure focuses mainly on the second pressure peak. Originality/value – TSUJ is a new-type tripod joint and the obtained results are of great value for its design and application.

Disease management patterns for postmenopausal women in Europe with hormone-receptor-positive, human epidermal growth factor receptor-2 negative advanced breast cancer

Background:International guidelines for hormone-receptor-positive (HR+), human epidermal growth factor receptor-2 negative (HER2−) advanced breast cancer (BC) recommend sequential lines of hormonal therapy (HT), and only recommend chemotherapy for patients with extensive visceral involvement or rapidly progressive disease. This study evaluated actual physician-reported treatments for advanced BC in Europe.Methods:We conducted a retrospective chart review of 355 postmenopausal women with HR+, HER2− advanced BC who progressed on ≥1 line of HT (adjuvant or advanced) and completed ≥1 line of chemotherapy (advanced). Treatment choice was evaluated for each line of therapy.Results:Of 355 patients, 111 (31%) received first-line chemotherapy, whereas 218 (61%) and 26 (7%) switched from HT to chemotherapy in second and third line, respectively. More patients receiving first-line HT had bone metastases (73% vs 27% chemotherapy). Patients treated with first-line chemotherapy had more brain (12% vs 3% HT) or extensive liver (13% vs 6% HT) metastases. Subgroup analysis of 188 patients who received first-line HT and had de novo advanced BC or relapsed/recurrent disease more than 1 year after adjuvant therapy found that the majority (89%; n = 167) of these patients switched to chemotherapy in second line. However, among these 167 patients, 27% had no significant changes in metastases between first and second line. Among the 73% of patients who had significant changes in metastases, 20% had no brain metastases or extensive visceral disease.Conclusions:Our study suggests that the guideline-recommended use of multiple HT lines is open to interpretation and that optimal treatment for European postmenopausal women with HR+, HER2− advanced BC who responded to HT may not be achieved.

Abstract B10: Acquired resistance to afatinib plus cetuximab in EGFR-mutant lung adenocarcinoma may be mediated by EGFR overexpression and overcome by the mutant-specific EGFR inhibitor, AZD9291.

Abstract EGFR mutant lung cancers are highly sensitive to first generation EGFR tyrosine kinase inhibitors (TKIs; gefitinib and erlotinib), but resistance invariably develops. In the majority of patients, disease progression is mediated by a second-site T790M mutation in EGFR. T790M-mediated acquired resistance can be overcome by the combination of the second-generation EGFR TKI, afatinib, with the anti-EGFR monoclonal antibody, cetuximab, in both preclinical models and humans. However, patients still develop acquired resistance to second-line anti-EGFR combination therapy. In order to develop therapeutic strategies for patients whose tumors progress on afatinib/cetuximab, we have modeled resistance using xenografts of PC-9/BRc1 cells (EGFR exon 19 deletion/T790M) treated chronically with the drug combination. Over the course of four months, 4 of 10 animals developed acquired resistance. Xenograft tumors still displayed features of adenocarcinoma only, and mutational analysis did not detect any common secondary hotspot mutations found in lung adenocarcinomas. Analysis of two cell lines derived from resistant tumors by array comparative genomic hybridization (aCGH) suggests that resistant tumors developed additional amplification at the EGFR locus. Fluorescence in situ hybridization (FISH) of all lines confirmed sustained amplification of EGFR in resistant cell lines, and immunoblotting of cell lysates showed increased EGFR protein expression relative to parental cells and vehicle-treated controls. Strikingly, all xenograft-derived cell lines displayed in vitro sensitivity to AZD9291, a third-generation, mutant-specific EGFR TKI. Finally, in vitro comparison of afatinib/cetuximab with AZD9291 in PC-9/BRc1 cells suggests that AZD9291 may even be more potent than afatinib/cetuximab in the setting of T790M-mediated acquired resistance to first and second-generation EGFR TKIs. Confirmatory xenograft experiments are planned, and experiments are ongoing, including with additional cell lines. Collectively, these data suggest that EGFR overexpression may be a mechanism of acquired resistance to afatinib/cetuximab combination therapy, and that resistance may still be overcome by mutant-specific EGFR small molecule inhibitors. Thus, patients with EGFR mutant lung cancers may benefit from sequential lines of therapy (erlotinib-&amp;gt;afatinib/cetuximab-&amp;gt;AZD9291) targeting EGFR. Further work is needed to discern specific indications for afatinib/cetuximab versus AZD9291 as therapy for patients with acquired resistance to EGFR TKIs. Citation Format: Catherine B. Meador, Hailing Jin, Elisa de Stanchina, Valentina Pirazzoli, Marc Ladanyi, Lu Wang, Xi Chen, Rosana Eisenberg, Darren Cross, William Pao. Acquired resistance to afatinib plus cetuximab in EGFR-mutant lung adenocarcinoma may be mediated by EGFR overexpression and overcome by the mutant-specific EGFR inhibitor, AZD9291. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr B10.

Erythroblastic Synartesis in a Patient With Low Grade B Cell Lymphoma

Erythroblastic synartesis is a very rare form of acquired dyserythropoiesis. It is characterized by ineffective erythropoiesis due to abnormal aggregates of erythroid precursors in the bone marrow. An autoimmune etiology has been implicated with several cases having an IgG kappa paraprotein. The first case was described in 1973 and a total of 9 cases have been reported to date. There appears to be an association with lymphoproliferative and autoimmune disorders and treatment with steroids, rituximab and other immunosuppressants have been utilized with varying degrees of benefit. We here describe a new case of erythroblastic synartesis in a 59-year African-American man who presented with an IgG kappa paraprotein and an associated low grade B-cell lymphoma. The condition in this patient has proved relatively treatment refractory over the course of almost four years, necessitating multiple sequential lines of therapy with steroids, rituximab, erythropoietin and cyclosporine. A review of the previously published reports will be provided in addition to the current case presentation. J Hematol. 2014;3(1):13-18 doi: http://dx.doi.org/10.14740/jh113w

One Line Does Not Make a Picture: Real-World Cost-Effectiveness Of Multiple Myeloma Treatments Using a Full Disease Model

BackgroundAs with many types of cancer, treatment of multiple myeloma (MM) is characterised by sequential treatment lines consisting of innovative expensive drugs such as thalidomide, bortezomib and lenalidomide. While the cost-effectiveness of single treatments has been studied, a full disease model evaluating treatments sequentially is currently lacking. Therefore, we aimed to take a look at the big picture and calculate real-world costs and effects for commonly used treatment pathways for MM. MethodsWe developed a patient-level simulation (PLS) model for elderly (>65) MM patients diagnosed since 2004. Real-world data (N=621) including patient and disease characteristics, treatment information and outcomes as well as resource use was obtained from the Population based HAematological Registry for Observational Studies, PHAROS. Based on this information, a patient population was simulated. Parametric survival models including patient characteristics such as age, performance status, comorbidities, laboratory values and treatment were used to predict overall survival of commonly used treatment pathways. Five treatment categories were distinguished; Melphalan/Prednison, Thalidomide based regimens, Bortezomib based regimens, Lenalidomide based regimens and Other regimens not including a novel agent. Monthly costs, per treatment per line, were calculated based on real-world data. The sensitivity of parameters was explored through sensitivity analyses. ResultsMean age of our simulated population was 76 [SD: 6.25, Range 66-93] and 19 commonly used treatment pathways were observed. Average total costs from diagnosis till death ranged from $54,200 [SD: $10,990] (Melphalan/Prednison-Thalidomide-Other) to $172,346 [SD: $27,887] (Lenalidomide-Bortezomib-Other) while overall survival ranged from 29 [SD: 1.02] to 50 [SD 1.75] months for Melphalan/Prednison-Bortezomib-Lenalidomide and Lenalidomide-Bortezomib-Other, respectively. Total costs were especially induced by drug costs and inpatient hospital days. Substantial variation among the treatment pathways was observed with drug costs ranging from 7% ($3,980) of the total costs for Melphalan/Prednison-Thalidomide-Other compared to 53% ($88,058) of the total costs for Lenalidomide-Bortezomib-Thalidomide. In addition, inpatient day costs ranged from 68% ($37,113) of total costs for Melphalan/Prednison-Thalidomide-Bortezomib to 25% ($41,347) of the total costs for Lenalidomide-Bortezomib-Thalidomide. Costs per quality-adjusted-life-year (QALY) were between $29,060 [SD: $5,623] (Melphalan/Prednison-Thalidomide-Other) and $56,179 [SD: $9,190] (Lenalidomide-Bortezomib-Other). In addition to the 19 treatment pathways, we calculated the total costs and overall survival of treatment as observed in daily clinical practice, $79,203 [SD: $12,001] and 32 [SD: 1.33] months, respectively. Compared to real-world prescription, survival could be improved at a cost of $48,543 per QALY and $31,902 per life-year gained (Lenalidomide-Thalidomide-Bortezomib). ConclusionReal-world costs and effects of 19 treatment pathways for MM patients were calculated and revealed that real-world treatment could be improved at a cost of $48,543 per QALY and $31,902 per life-year gained. Our PLS model proved to be a reliable and robust approach to study entire treatment pathways for MM. Disclosures:Sonneveld:Jansssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Trabectedin in patients with metastatic soft tissue sarcoma

The aim of this study was to retrospectively evaluate the efficacy and safety of trabectedin treatment in patients with metastatic soft tissue sarcoma (STS) in the routine clinical setting. Further, the type and frequency of systemic treatments before commencing treatment with trabectedin and after its discontinuation, as well as the frequency of pulmonary metastasectomies, were analyzed. The current analysis includes retrospective data from consecutive STS patients treated with trabectedin at the Department of Medicine I, Division of Oncology, Medical University of Vienna, between January 2008 and December 2012. Patients were analyzed for median progression-free survival, overall survival (OS), and therapy-related toxicity. Data of 60 STS patients were included in the present analysis. In total, 198 cycles of trabectedin were administered, whereas the median number of cycles administered per patient was two (range 1-25). The median progression-free survival was 2.2 months and the median OS (mOS) was 11.8 months. mOS calculated from the first time point of detection of metastatic disease was 35.8 months. The 18 patients (30%) who underwent pulmonary metastasectomy had an mOS of 50.2 months. Further, trabectedin had a manageable toxicity profile comparable to data reported in previous phase II trials. Our findings support the use of trabectedin as an active and feasible therapeutic option among advanced, metastatic, and refractory STS patients. The good safety profile and lack of cumulative toxicity allow prolonged administration in highly pretreated patients. As visible from the present data, a considerable percentage of patients with advanced/metastatic STS benefit from sequential lines of drug therapy as well as pulmonary metastasectomy.

An intra-week efficiency analysis of bookie-quoted NFL betting lines in NYC

Abstract We analyze the intra-week evolution of bookie-quoted National Football League betting lines in New York City and its implications for market efficiency. Our unique data set includes three sequential lines: (i) an outlaw line set by a single agent at the beginning of the week; (ii) Tuesday's opening line shaped by bets from a group of eight to ten agents; and (iii) a game-time closing line shaped by the wider public. While forecast encompassing tests show that information content increases during the betting week, consistent with a reasonably well-functioning market, we also uncover significant evidence of pricing inefficiencies relating to sentiment measures. In addition, actual bets made by a number of professional gamblers appear profitable, pointing to the existence of superior analysts.