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Introduction. The success of any organization depends on the level of its organizational culture. Healthcare institutions are no exception, especially in the context of the COVID-19 pandemic. Organizational culture is influenced by many factors, but one of the most important components in the development of organizational culture is the staff motivation. The purpose of the research is to analyze the relationship between the level of staff motivation and organizational culture of healthcare institutions. Results. Healthcare institutions in Ukraine have specific features in the structure of their staff. The formation of staff is regulated at the legislative level. It was found out that the studied healthcare institutions have different structure by category, age and work experience. It is proved that the development of organizational culture depends on the level of staff motivation. The level of staff motivation in some healthcare institutions in Kharkiv has been determined. Based on the proposed approach, the level of staff motivation can be high, sufficient and low. Providing survey, the main motivators and demotivators in the work of the staff are formed. It was outlined that the main motivator is material reward. It includes salaries, regular bonuses, gifts, etc. The intangible aspects of motivation consist of good working conditions, the presence of a social package, a normal work / home ratio, respect and trust in the team, gratitude and fairness of the leader. Among the demotivators, unsatisfactory wages, unsatisfactory working conditions and a negative climate in the team were noted. For developing the organizational culture, healthcare institution should improve the motivation system based on the main motivators and by eliminating the negative influence of the demotivators. Conclusions. Many factors influence the development of the organizational culture of healthcare institutions. Among them, staff motivation plays a significant role. Motivational measures should be based on certain motivators and demotivators of the staff of a particular healthcare institution. Keywords: motivation, development of organizational culture, motivators, demotivators, level of motivation, healthcare institution.

Purpose:Somatic mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), which encodes the p110α catalytic subunit of PI3K, are found in multiple human cancers. While recurrent mutations in PIK3CA helical, regulatory, and kinase domains lead to constitutive PI3K pathway activation, other mutations remain uncharacterized. To further evaluate their clinical actionability, we designed a basket study for patients with PIK3CA-mutant cancers with the isoform-specific PI3K inhibitor taselisib.Patients and Methods:Patients were enrolled on the basis of local PIK3CA mutation testing into one of 11 histology-specific cohorts and treated with taselisib at 6 or 4 mg daily until progression. Tumor DNA from baseline and progression (when available) was sequenced using a next-generation sequencing panel. Exploratory analyses correlating genomic alterations with treatment outcomes were performed.Results:A total of 166 patients with PIK3CA-mutant cancers were enrolled. The confirmed response rate was 9%. Activity varied by tumor type and mutant allele, with confirmed responses observed in head and neck squamous (15.4%), cervical (10%), and other cancers, plus in tumors containing helical domain mutations. Genomic analyses identified mutations potentially associated with resistance to PI3K inhibition upfront (TP53 and PTEN) and postprogression through reactivation of the PI3K pathway (PTEN, STK11, and PIK3R1). Higher rates of dose modification occurred at higher doses of taselisib, indicating a narrow therapeutic index.Conclusions:Taselisib had limited activity in the tumor types tested and is no longer in development. This genome-driven study improves understanding of the activity, limitations, and resistance mechanisms of using PI3K inhibitors as monotherapy to target PIK3CA-mutant tumors.

espanolUn factor importante en la formacion de una cultura organizativa es el analisis de los factores de motivacion que tienen impacto en la cultura organizativa. El objetivo de este trabajo es determinar los indicadores de motivacion que tienen un impacto significativo en la cultura organizativa de la empresa. La implementacion de la funcion motivacional de la cultura organizacional implica el uso de indicadores motivacionales monetarios y no monetarios. La motivacion de los empleados de forma listada permite desarrollar una cultura organizativa eficaz. El uso de los motivadores sugeridos para aumentar la eficacia de la cultura organizativa permite aumentar significativamente la eficacia de la gestion del personal en la empresa. Para la formacion competente de la cultura organizativa en Ucrania, junto con los indicadores monetarios, las empresas deberian implementar indicadores no monetarios y motivadores especificos que tienen un impacto significativo en la cultura organizativa. En el futuro, la lista de indicadores de motivacion permitira elaborar una lista de medidas eficaces para mejorar la cultura organizativa de la empresa. EnglishAn important factor in formation an organizational culture is the analysis of motivational factors that have impact on organizational culture. This paper aims to determine motivational indicators that have a significant impact on the organizational culture of the enterprise. Implementation of the motivational function of organizational culture implies the use of monetary and non-monetary motivational indicators. Motivation of employees in a listed way allow to develop effective organizational culture. The use of the suggested motivators for increasing efficiency of organizational culture makes it possible to significantly increase the effectiveness of personnel management in the company. For competent formation of the organizational culture in Ukraine together with monetary indicators companies should implement non-monetary indicators and specific motivators which have significant impact on the organizational culture. In the future, the list of motivational indicators will allow to develop a list of effective measures to improve the organizational culture of the company.

River beds are one of the most dynamic geographical features on the surface of the earth, accompanied by constant movements and displacements. They respond well to the dynamics of temperature and climatic conditions, changes and variability of meteorological conditions, as well as human load. Increasing rainfall during the season, the recurrence of abnormal seasons lead not only to an increase in the water level in the channel, but also to an increase in both the number and width of the river's hoses, contributes to the change of the location of the main channel, accompanied by watering old women and floodplains, the accumulation of sediment and the increase of washouts. Horizontal displacements of the channel significantly affect the cultural and natural landscapes and human economic activity. Conversely, human activity, in particular, mining and large-scale hydrotechnical works in the valleys, also change their course. Insufficient study and research of riverbed issues can lead to the flooding of large areas, which is particularly dangerous for settlements. The current insufficient number of existing hydrological posts, the reduction of field research opportunities, the deterioration of the quality and the inaccessibility of hydrometeorological, mapping information, and for most water bodies simply the lack of data leads to the impossibility of a comprehensive hydrological and morphological study of the river basin and the assessment of intensities. For this reason, in most of the works encountered and related to similar issues, a small local body of water or a section of the main channel or its tributary is selected for research. An important problem is also the comparison of the morphometric characteristics of the river network on topographic maps and plans of different scale series. The river meandering close to reality can only be displayed on large-scale maps. The smaller the scale of the map, the more straightened or generalized the drawing of the rivers. Therefore, it is advisable to carry out such assessments and study of horizontal displacements of the channel on the cartographic material of one scale series. The horizontal displacements of the Prut River bed within the city of Chernivtsi were investigated using topographic maps and plans of different scale, for more than 160 years of observations. About 15 km of the Prut River bed has been digitized. For a better and more detailed analysis of the change in horizontal displacements of the riverbed, the study area was divided into three sections - West, Central, and East. The choice of a place of division is caused by features of the winding channel. The search of maps of different scales in previous years for this territory made it possible to compare the horizontal displacements of the Prut River bed both in time and in space. Topographic maps of 1: 100000 scale in 1982, 1:50000 - 1940 and 1977 and 1:25000 of 1947 and 1957, maps of the Austrian monarchy of 1:75000 - 1855 were found. Analysis of the spatial-temporal changes of horizontal displacements of the Prut River bed by space images and topographic maps during the 161-year observation period showed significant differences in terms of the most meandering channel and its size and shape. Using time analysis, it was found that the highest meandering of the channel was observed in the middle of the twentieth century and amounted to 1.33 and decreased to 1.12 as of 2016. Virtually unchanged, in terms of horizontal displacements, the channel remained in the central part of the study area. In the eastern and western parts, the tortuosity coefficient is increased due to the meandering of the channel and due to the presence of the sleeves, especially in the Kalichanka area. For the western part, the greatest changes are observed in the area of the Prut River near the villages of Lenkivtsi and Streletsky Kut. The highest values of deviations of the channel from the current location are in the range of 300-400 meters.

Polymeric semiconductors exhibit exceptionally long spin lifetimes, and recently observed micrometre spin diffusion lengths in conjugated polymers demonstrate the potential for organic spintronics devices. Weak spin–orbit and hyperfine interactions lie at the origin of their long spin lifetimes, but the coupling mechanism of a spin to its environment remains elusive. Here, we present a systematic study of polaron spin lifetimes in field-effect transistors with high-mobility conjugated polymers as an active layer. We demonstrate how spin relaxation is governed by the charges’ hopping motion at low temperatures, whereas an Elliott–Yafet-like relaxation due to a transient localization of the carrier wavefunctions is responsible for spin relaxation at high temperatures. In this regime, charge, spin and structural dynamics are intimately related and depend sensitively on the local conformation of polymer backbones and the crystalline packing of the polymer chains. The long spin lifetimes observed in polymeric semiconductors hold promise for potential applications. A careful study untangles the main mechanism behind them.

Background Mammalian target of rapamycin (mTOR) inhibitor-associated stomatitis (mIAS) is a frequent adverse event (AE) associated with mTOR inhibitor therapy and can impact treatment adherence. The objectives are to evaluate two steroid-based mouthrinses for preventing/ameliorating mIAS in patients with metastatic breast cancer (MBC) treated with everolimus. Materials and Methods This prospective, randomized phase II study enrolled 100 postmenopausal patients with hormone receptor-positive MBC within the US Oncology Network who were initiating therapy with an aromatase inhibitor + everolimus (AIE; 10 mg/day). Patients were randomized to prophylactic therapy with one of two oral rinses (Arm 1: Miracle Mouthwash [MMW] 480 mL recipe: 320 mL oral Benadryl [diphenhydramine; Johnson & Johnson, New Brunswick, NJ, USA], 2 g tetracycline, 80 mg hydrocortisone, 40 mL nystatin suspension, water; or Arm 2: prednisolone [P] 15 mg/5 mL oral solution, 1.8% alcohol). Patients were instructed to swish/expectorate 10 mL of the assigned rinse for 1–2 minutes four times daily starting with day 1 of AIE treatment, for the first 12 weeks. Results A total of 100 patients received treatment (49 MMW; 51 P). The incidence of stomatitis/oral AEs during the first 12 weeks was 35% (n = 17/49) and 37% (19/51) in the MMW and P arms, respectively. The incidence of grade 2 oral AEs was 14% (7/49) and 12% (6/51) with MMW or P, respectively. There were two grade 3 oral AEs (MMW arm) and no grade 4 events. There was one everolimus dose reduction (MMW) and six dose delays (four MMW, two P) and one dose reduction + delay (MMW) during the first 12 weeks of treatment. No patients stopped steroid mouthwash therapy because of rinse-related toxicity. Conclusion Prophylactic use of steroid-containing oral rinses can prevent/ameliorate mIAS in patients with MBC treated with AIE. MMW + hydrocortisone is an affordable option, as is dexamethasone oral rinse. Implications for Practice This prospective phase-II study showed that two steroid-containing mouthrinses substantially reduced incidences of all-grade and grade ≥2 stomatitis and related oral adverse events (AEs), and the number of everolimus dose-delays and/or dose-reduction in metastatic breast cancer (MBC) patients receiving everolimus treatment plus an aromatase inhibitor. Both oral rinses were well tolerated and demonstrated similar efficacy. Prophylactic use of steroid mouth rinse provides a cost-effective option that substantially decreases the incidence and severity of mammalian target of rapamycin (mTOR) inhibitor-associated stomatitis and related oral AEs as well as the need for dose modification in MBC patients undergoing treatment with an mTOR inhibitor.

In this study, electron trapping phenomena in amorphous polymer electrets were studied using a solid-state electron affinity analysis by means of molecular dynamics simulations parametrized with ab initio calculations. Negatively charged amorphous systems of a cyclic transparent optical polymer (CYTOP) with different end groups were reproduced by molecular dynamics simulations parametrized by density functional theory analysis. Quantum mechanical calculations were performed for electron trapping sites to determine the electron affinity of an isolated molecule. The influence of the amorphous system surrounding the trapping site was considered by accounting for electrostatic interactions with surrounding molecules and multipole induction. A series of analyses were carried out to mimic the conformational diversity of the amorphous system. The calculated solid-state electron affinities were found to adopt a Gaussian-type distribution and were in good accordance with the experimental data for surface potential and thermally stimulated discharge spectra, indicating the reliability of the present analysis for predicting the charging performance of amorphous polymer electrets.

Somatic mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (Patients were enrolled on the basis of localA total of 166 patients withTaselisib had limited activity in the tumor types tested and is no longer in development. This genome-driven study improves understanding of the activity, limitations, and resistance mechanisms of using PI3K inhibitors as monotherapy to target

We develop a generic coarse-grained model of soluble conjugated polymers, capable of describing their self-assembly into a lamellar mesophase. Polymer chains are described by a hindered-rotation model, where interaction centers represent entire repeat units, including side chains. We introduce soft anisotropic nonbonded interactions to mimic the potential of mean force between atomistic repeat units. The functional form of this potential reflects the symmetry of the molecular order in a lamellar mesophase. The model can generate both nematic and lamellar (sanidic smectic) molecular arrangements. We parametrize this model for a soluble conjugated polymer poly(3-hexylthiophene) (P3HT) and demonstrate that the simulated lamellar mesophase matches morphologies of low molecular weight P3HT, experimentally observed at elevated temperatures. A qualitative charge-transport model allows us to link local chain conformations and mesoscale order to charge transport. In particular, it shows how coarsening of lamellar domains and chain extension increase the charge carrier mobility. By modeling large systems and long chains, we can capture transport between lamellar layers, which is due to rare, but thermodynamically allowed, backbone bridges between neighboring layers.

International audience; We highlight the influence of processing conditions on polymorphism and structure formation on the mesoscale for the family of PCPDTBT polymers with branched alkyl side chains. Direct correlations of morphology to the chemical structure and to transistor device performance are established. We found that up to four different packing motifs could be realized depending on the polymer derivative and the processing conditions: amorphous, π-stacked, cross-hatched and dimer-containing polymorphs. While C- and F-PCPDTBT display similar packing behavior organizing in π-stacked and dimer-like structures, Si-PCPDTBT gives rise to cross-hatched structures upon simple deposition from solution. The observed differences in chain packing for C-/F-PCPDTBT versus Si-PCPDTBT are attributed to differences in backbone conformations and aggregation behavior in solution. The effect of polymorphism on charge transport is probed using field-effect transistors, in which both π-stacked and cross-hatched polymer chain arrangements yield the highest hole mobilities. Mesoscopic morphology and mobility simulations rationalize our experimental findings by relating mobility to distributions of electronic coupling elements between the chains.

Background We determined the objective response rates produced by pegylated liposomal doxorubicin (PLD) plus carboplatin with/without trastuzumab (Herceptin). Patients and methods Patients with measurable disease were stratified by taxane treatment history and human epidermal growth factor receptor-2 status. Treatment: PLD 30 mg/m2 followed by carboplatin, day 1 of each 28-day cycle; human epidermal growth factor receptor-2 (HER2)-positive patients also received trastuzumab. Results Arm 1 received PLD plus carboplatin (N = 41 arm 1a, taxane naive; N = 42 arm 1b, taxane pretreated); Arm 2 patients received PLD plus carboplatin + Herceptin (N = 46). Overall response rates: 31%, 31%, and 56%, respectively. Median overall survival durations were not reached in arm 1a and were 13 and 33 months for arms 1b and 2. Median progression-free survival: 8, 5, 10 months, respectively. Grades 3–4 treatment-related toxic effects for arms 1a, 1b, 2, respectively, were neutropenia 22%, 31%, 35%; thrombocytopenia 34%, 26%, 17%; and fatigue 2%, 14%, 13%. Conclusions PLD plus carboplatin has moderate antitumor activity and excellent tolerability. Herceptin and PLD plus carboplatin in HER2-positive patients have antitumor activity without significant cardiac toxicity. Toxicity results suggest that PLD can be combined with Herceptin with minimal cardiac toxicity.

Background Concurrent chemoradiation with etoposide and cisplatin (EP/XRT) is standard treatment for inoperable stage III locally advanced non-small-cell lung cancer (LA-NSCLC). Consolidation docetaxel (D; Taxotere) after EP/XRT resulted in increased toxicity but no improvement in survival compared with observation (O). We report updated survival for the entire study population and include an analysis of efficacy and tolerability of EP/XRT with or without D in patients aged ≥ 70 years. Patients and methods Hoosier Oncology Group LUN 01-24 enrolled 243 patients with LA-NSCLC and randomized 166 after EP/XRT to three cycles of D versus O. the trial was terminated after an analysis of the first 203 patients demonstrated futility of D. Results Median survival time (MST) for the overall study population was 21.5 months, and 3-, 4-, and 5-year survival rates were 30.7%, 18.0%, and 13.9%, respectively. No differences in MST or 3-year survival were noted between D and O arms. Older patients had similar MST (17.1 versus 22.8 months for younger patients, P = 0.15) but higher rates of grade 3/4 toxicity and hospitalization during induction. Conclusions Consolidation docetaxel after EP/XRT does not improve survival in LA-NSCLC. Fit older adults with LA-NSCLC benefit from concurrent chemoradiation similarly as younger patients but experience higher rates of hospitalization and toxicity.

We performed a phase I trial of FANG vaccine, an autologous tumor-based product incorporating a plasmid encoding granulocyte-macrophage colony-stimulating factor (GMCSF) and a novel bifunctional short hairpin RNAi (bi-shRNAi) targeting furin convertase, thereby downregulating endogenous immunosuppressive transforming growth factors (TGF) β1 and β2. Patients with advanced cancer received up to 12 monthly intradermal injections of FANG vaccine (1 × 10(7) or 2.5 × 10(7) cells/ml injection). GMCSF, TGFβ1, TGFβ2, and furin proteins were quantified by enzyme-linked immunosorbent assay (ELISA). Safety and response were monitored. Vaccine manufacturing was successful in 42 of 46 patients of whom 27 received ≥1 vaccine. There were no treatment-related serious adverse events. Most common grade 1, 2 adverse events included local induration (n = 14) and local erythema (n = 11) at injection site. Post-transfection mean product expression GMCSF increased from 7.3 to 1,108 pg/10(6) cells/ml. Mean TGFβ1 and β2 effective target knockdown was 93.5 and 92.5% from baseline, respectively. Positive enzyme-linked immunospot (ELISPOT) response at month 4 was demonstrated in 9 of 18 patients serially assessed and correlated with survival duration from time of treatment (P = 0.025). Neither dose-adverse event nor dose-response relationship was noted. In conclusion, FANG vaccine was safe and elicited an immune response correlating with prolonged survival. Phase II assessment is justified.

Background: PIK3CA, a gene that encodes the α-isoform of the catalytic subunit of Class I PI3K (PI3Kα), is frequently mutated or amplified in solid tumors. Taselisib is an oral, potent, selective inhibitor of Class I PI3Kα, γ, and δ isoforms with enhanced activity against PIK3CA-mutated cancer models. Preclinical and clinical data demonstrated that single-agent taselisib has activity in multiple PIK3CA-mutated tumor types. Methods: This open-label phase I study (Cohort X of PMT4979g; NCT01296555) enrolled patients (pts) with PIK3CA-mutated tumors who had progressed after, or failed to respond to, at least one prior treatment regimen and were not candidates for regimens known to provide clinical benefit. Pts received single-agent taselisib (4 or 6 mg tablet, daily). Eleven subcohorts comprised various solid tumor types: endometrial, bladder, head and neck squamous cell carcinoma (HNSCC), cervical, gastric/gastroesophageal junction, small cell lung, triple-negative breast, colorectal (excluding KRAS-mutated tumors), squamous (excluding histologies in the other subcohorts), ovarian, and pts with PIK3CA mutant tumors not otherwise specified (excluding breast, colorectal, and non-small-cell lung cancers). Tumor tissue (archival or fresh) was assessed centrally for PIK3CA mutation or amplification. The primary endpoint was tolerability and safety of taselisib. Other endpoints included assessment of antitumor activity per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. Results: At data cutoff (May 1, 2017), 146 pts have been enrolled. Overall, the most common adverse events (AEs; ≥30% of pts) were diarrhea (58.2%), nausea (39.0%), hyperglycemia (31.5%), and fatigue (30.8%). Ninety-four pts (64.4%) experienced ≥1 grade ≥3 AE and 53 pts (36.3%) had grade ≥3 AEs related to taselisib. Sixty-eight pts (46.6%) had serious AEs (SAEs) and the most common SAEs (>2 pts) related to taselisib treatment were colitis (5.5%), diarrhea (4.1%), and hyperglycemia (3.4%). Nine pts (6.2%) had grade 5 events; one AE with a fatal outcome (0.7%) was assessed by the investigator as related to taselisib (septic shock). AEs that led to dose reduction, interruption, or withdrawal were reported in 34 pts (23.3%), 59 pts (40.4%), and 14 pts (9.6%), respectively. Overall, confirmed response rates were 8.9% (n=13) and clinical benefit rates (confirmed response or without disease progression for ≥6 months) were 12.3% (n=18). Confirmed responses were observed in pts with endometrial cancer (2/10 [20.0%]), HNSCC (4/21 [19.0%]), and cervical cancer (2/19 [10.5%]), as well as other tumor types. Conclusions: Single-agent taselisib had an acceptable safety profile (with AEs that were generally reversible and manageable; no new safety signals were identified) and preliminary clinical activity in pts with PIK3CA-mutated locally advanced or metastatic solid tumors. Citation Format: Komal Jhaveri, Dejan Juric, Cristina Saura, Andrés Cervantes, Anton Melnyk, Manish R. Patel, Mafalda Oliveira, Valentina Gambardella, Vincent Ribrag, Cynthia X. Ma, Raid Aljumaily, Philippe L. Bedard, Jasgit C. Sachdev, John Bond, Surai Jones, Timothy R. Wilson, Michael C. Wei, José Baselga. A phase I basket study of the PI3K inhibitor taselisib (GDC-0032) in PIK3CA-mutated locally advanced or metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT046.

e15100 Background: Vigil is an immuno-stimulatory autologous tumor cell therapy, which uses patient tumor cells transfected with a plasmid encoding genes to upregulate GM-CSF and down regulate TGFβ 1&2. It is administered monthly by intra-dermal injection. In Phase I and IIa trials patients with over 19 different tumor types were safely treated. Rapid and durable systemic immune activation was demonstrated using an IFNγ ELISPOT assay. Methods: Data are summarized for a group of 9 patients with advanced colorectal cancer followed for up to 3.5 years. Results: Six women and 3 men with Stage III or IV colorectal cancer were treated between March, 2010 and September, 2013. Six patients received Vigil as a monotherapy and 3 in combination with FOLFOX chemotherapy. Results: Demographics and treatment details are displayed below. Two patients with Stage III disease received combination therapy after complete surgical resection, and remain disease free over 3 years from surgery. The patients received 9 and 12 Vigil injections with a brisk and durable ELISPOT reactions. Conclusions: Preliminary results suggest that Vigil can be combined safely with FOLOX chemotherapy and still elicit a systemic immune response. Long term disease free survival has been observed in several patients justifying further exploration of this combination. More detailed molecular characterization and neoantigen identification of patient tumor will be undertaken in future studies. A combination with immune checkpoint inhibitors may also be explored. [Table: see text]

110 Background: Previously we described safety and evidence of activity to VigilÒ (FANGÒ) and identified relationship of survival advantage to ELISPOT “+” Vigil treated patients (Senzer N et al. Long Term Follow Up: Phase I Trial of “bi-shRNA furin/GMCSF DNA/Autologous Tumor Cell” Immunotherapy (FANG) in Advanced Cancer. J Vaccines Vaccine 2013; 4: 209. doi: 10.4172/2157-7560.1000209). We have updated survival and long-term ELISPOT assessment of this same group of patients. Methods: A non-randomized phase 1 trial of patient treated with Vigil immunotherapy (n=39) compared to a similar matched comparator (MC) group not treated with Vigil (n=35). Results: Trial results suggest survival benefit without evidence of Vigil related toxicity (no ≥ grade 3). γ-IFN ELISPOT served as a biomarker for response and shows correlation with survival. 22/30 evaluable Vigil-treated patients showed ELISPOT conversion (73%) from negative to positive (threshold of ≥10 spots from baseline) during treatment. Durable evidence of γIFN-secreting circulating cytotoxic T cells was observed (up to 30months from treatment start), suggesting induction of memory T effector cells. Survival correlation demonstrated significant benefit of ELISPOT “+” Vigil treated patients (median OS of 784 days, 26.1 months) compared to ELISPOT “-“ patients (median OS of 353 days, 11.77 moths), and supports immune-related survival benefit compared to MC (median OS of 122 days, 4 months), (Table). Conclusions: Vigil immunotherapy induces a significant immune response. Detailed analysis of the immune effector population phenotype is underway to determine optimal correlation with survival. Clinical trial information: NCT01061840. [Table: see text]

Study Background: Previously, we demonstrated safety and correlated induced immune response with survival in a Phase I study of FANG immunotherapy in advanced cancer patients. We now report long term follow-up (FU) of Phase I treated patients including assessment of relationships of dose, γIFN-ELISPOT response, and patient demographics to safety and survival. Methods: Safety, γIFN-ELISPOT response, and survival have been followed through 3+ years in advanced cancer patients who received ≥ 2-12 intradermal monthly injections of 1×107 or 2.5×107 cells/injection. Clinical and serological assessments were performed monthly, radiographic evaluations bimonthly, and γ-IFN-ELISPOT at baseline, and start of Cycle 2, 4, 6, 9, 12 then sequentially at FU. Results: Previously, we reported results on 45 patients with successful FANG construction followed for 1 year (28 treated (designated FANG); 17 not treated based on availability of other alternative treatments or failed manufacturing (designated No FANG)). We now report FU results through year 3 on those patients and an additional 29 patients (7 FANG, 22 No FANG) subsequently entered into Phase I study (total N=35 FANG; total N=39 No FANG). The median survival of the current expanded Phase I trial population is 562 days vs. 122 days (p=0.00001). This is similar to the originally published data from two years earlier. The γ-IFN-ELISPOT reaction was positive in 14 of the current FANG treated patients and negative in 12 FANG treated patients at Month 3 or less post first injection. Survival correlated with γ-IFN-ELISPOT reaction; median 836 days vs. 440 days with positive and negative ELISPOT respectively, (p=0.04). No long term adverse toxicity has been seen and there was no significant correlation of immune response or survival with either dose or demographics. Conclusions: Treatment with FANG vaccine continues to show long term safety and evidence of benefit in patients with many types of advanced cancer thereby justifying further efficacy testing.

TPS11621Background: The phosphoinositide 3-dependent kinase (PI3K) pathway is important for cancer growth, proliferation, and survival. PI3K is frequently activated in solid tumors due to amplifica...

Background Data support chemotherapy combined with antiangiogenic therapy in metastatic urothelial cancer (mUC) and muscle-invasive bladder cancer (MIBC). We investigated the efficacy and safety of gemcitabine, cisplatin, and sunitinib (GCS) in mUC and MIBC in parallel phase II trials. Patients and Methods Trial 1 enrolled 36 patients with mUC who were chemotherapy naive; trial 2 enrolled 9 patients with MIBC. The primary endpoints for trials 1 and 2 were response rate and pathologic complete response, respectively. GCS was given as first-line treatment for patients with mUC and as neoadjuvant therapy for patients with MIBC. The Simon minimax 2-stage design was used for an objective response rate in trial 1 and for the pathologic complete response rate in trial 2. Results The initial trial 1 GCS dose was gemcitabine 1000 mg/m 2 intravenously, days 1 and 8; cisplatin 70 mg/m 2 intravenously, day 1; and sunitinib 37.5 mg orally daily, days 1 to 14 of a 21-day cycle. These doses proved intolerable. The doses of gemcitabine and cisplatin were subsequently reduced to 800 and 60 mg/m 2 , respectively, without an improvement in drug delivery, and the trial was closed. This lower-dose regimen was applied in trial 2, which was stopped early due to excess toxicity. Grade 3 to 4 hematologic toxicities occurred in 70% (23/33) of patients in trial 1 and 22% (2/9) of patients in trial 2. In trial 1, the response rate was 49% (95% CI, 31%-67%); in trial 2, the pathologic complete response was 22% (2/9). Due to early closure secondary to toxicity, the sample sizes of both trials were small. Conclusions Delivery of GCS was hampered by excessive toxicity in both advanced and neoadjuvant settings.

Purpose Concurrent chemoradiotherapy is standard treatment for patients with inoperable stage III non–small-cell lung cancer (NSCLC). A phase II study by the Southwest Oncology Group using consolidation docetaxel after cisplatin (P), etoposide (E), and radiation (XRT) resulted in a median survival time (MST) of 26 months. This randomized phase III trial evaluated whether consolidation docetaxel was responsible for this improved survival. Patients and Methods Eligible patients had stage IIIA or IIIB NSCLC, baseline performance status of 0 to 1, forced expiratory volume in 1 second ≥ 1 L, and less than 5% weight loss. Patients received P 50 mg/m2 intravenously (IV) on days 1, 8, 29, and 36 and E 50 mg/m2 IV on days 1-5 and 29-33 concurrently with chest XRT to 59.40 Gy. Patients who did not experience progression were randomly assigned to docetaxel 75 mg/m2 IV every 21 days for three cycles versus observation. The primary end point was to compare overall survival (Kaplan-Meier analysis). Results On the basis of evidence of futility, a data and safety monitoring board recommended early termination after an analysis of the initial 203 patients. Patient characteristics (n = 203) were as follows: 34% female; median age, 63 years; 39.4% stage IIIA; and 60.6% stage IIIB. One hundred forty-seven (72.4%) of 203 patients were randomly assigned to docetaxel (n = 73) or observation (n = 74). Grade 3 to 5 toxicities during docetaxel included febrile neutropenia (10.9%) and pneumonitis (9.6%); 28.8% of patients were hospitalized during docetaxel (v 8.1% in observation arm), and 5.5% died as a result of docetaxel. The MST for all patients (n = 203) was 21.7 months; MST was 21.2 months for docetaxel arm compared with 23.2 months for observation arm (P = .883). Conclusion Consolidation docetaxel after PE/XRT results in increased toxicities but does not further improve survival compared with PE/XRT alone in patients with stage III inoperable NSCLC.

3077 Background: Viagenpumatucel-L (HS-110), consists of an allogeneic NSCLC cell line, selected for high expression of a series of tumor antigens shared by NSCLC patients, which has been stably tr...

Meeting abstracts TG4010 immunotherapy product is a poxvirus (MVA) coding for MUC1 tumor-associated antigen and interleukin-2. A previous study showed that a normal baseline level of Triple Positive Activated Lymphocytes (TrPAL, CD16+CD56+CD69+) might be a predictive biomarker for TG4010 efficacy

Background: Trastuzumab (T) resistance may be due to aberrant signaling through the PI3K/Akt pathway. Pre-clinical and retrospective clinical data suggest that mTOR inhibition can overcome this mechanism of trastuzumab resistance. Ridaforolimus (R), an mTOR inhibitor, in combination with HER2 inhibition offers the potential for vertical pathway synergy.Methods: A single-arm, two-stage phase 2 trial was performed to evaluate R combined with T. Eligibility criteria included: female patients with HER2+ (IHC 3+ or FISH+) metastatic breast cancer (MBC), age ≥18 years, ECOG performance status ≤ 1, RECIST criteria measurable disease, LVEF ≥ 50%, who developed T resistance (defined as disease progression on T treatment with no more than 2 prior T regimens). R was administered orally at 40 mg once daily for 5 consecutive days per week. T was administered intravenously with a loading dose of 4 mg/kg followed by 2 mg/kg/wk. The treatment cycle for both agents was 4 weeks. In Stage 1 of the trial, 14 patients were assessed for safety after at least 1 cycle of therapy and objective response (OR) assessed every 2 cycles according to modified RECIST guidelines. At the time of the Stage 1 interim analysis, if one or more patients exhibited an OR, study enrollment continued to a total accrual of 33 patients. Patients continued study treatment until disease progression or other discontinuation criteria were met.Results: As of June 2009, 22 patients, median age 55 years (range 33-81), were enrolled. Thirteen and 9 pts had 1 and 2 prior T regimens, respectively. Nine patients discontinued prior to the first scheduled study assessment: 6 patients for progressive disease, 1 for AE (G2 stomatitis), 1 for a protocol violation (treatment with radiation), and 1 due to death from an intestinal perforation (diagnosed at autopsy; assessed by investigator as possibly related to R). One other patient discontinued after 7 months of treatment due to elevated transaminases related to R. Twelve patients remain on treatment. There were 2 PR (1 confirmed and 1 unconfirmed) among the first 14 patients. The prospectively defined Stage 1 safety review demonstrated mostly Grade 1/2 AEs that were within the expected safety profile of either study drug. Six related Grade 3 AEs (3 stomatitis/mucositis, 1 hyperglycemia, 1 neutropenia, and 1 dysphagia) were reported. There were no study related Grade 4 AEs. Ten SAEs have been reported in 5 patients; 2 were assessed by investigators as possibly related to R (death from intestinal perforation and venous thrombosis).Conclusions: R in combination with T is feasible and well tolerated with early evidence of encouraging anti-tumor activity in T resistant HER2+ MBC. Enrollment is ongoing and updated data will be presented. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3091.

Abstract #6118 Background: PLD and Cb are active in metastatic breast cancer (MBC) but no data exist regarding the antitumor activity of the combination. Both agents are synergistic with H in preclinical studies. The primary objective of this study was to determine the objective response rates (ORR) produced by PLD+Cb ± H. Patients and Methods: 133 patients (pts) were registered to the study; 125 pts were treated and were stratified by HER2 status; 124 pts are currently evaluable for response. Pts had measurable disease per RECIST criteria and had received no more than 1 prior chemotherapy regimen for MBC; HER2+ pts received therapy first-line therapy for metastatic and 4% received prior adjuvant H. All pts received PLD 30 mg/m2 IV followed by Cb, AUC=5 IV on Day 1 of 28-day cycles. In addition to PLD+Cb, HER2+ pts received H on Day 1 and Day 15 (8 mg/kg IV first dose; 4 mg/kg IV subsequent doses). Results: 79 pts and 46 pts received at least 1 dose of study drug on PLD+Cb (Arm 1) and PLD+Cb+H (Arm 2), respectively. Median age was 56 years. Estrogen receptor (ER) or progesterone receptor (PR) + pts and ER and PR- pts in Arm 1/Arm 2 were 63%/55% and 36%/45%, respectively, 49%/43%; pts were treated with prior doxorubicin in Arm 1/Arm 2 and 51%/30%. With prior taxane in Arm 1/Arm 2, of 79 pts on Arm 1 evaluable for response, 27% had an objective response compared with 53% of the 45 pts currently evaluable on Arm 2. Median overall survival was 17 months in Arm 1 and as not been reached in Arm 2. Median PFS is 5 and 10 months for Arm 1 and 2, respectively. The most common Grade 3-4 treatment-related toxicities for Arm 1/Arm 2 were: neutropenia 23%/35%, leukopenia 13%/22%, thrombocytopenia 20%/17%, fatigue 6%/13%, and anemia 11%/9%. Conclusion: PLD+Cb in combination have moderate activity in MBC; also, the addition of H to PLD+Cb in HER2+ pts enhanced its activity. Preliminary toxicity results suggest that PLD can be safely combined with H with minimal cardiac toxicity. Final data analyses from this fully enrolled study will be reported at SABCS 2008. This research was supported, in part, by a research grant from Ortho Biotech Clinical Affairs, LLC, Bridgewater, NJ. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6118.

Background - A case of primary thyroid T cell lymphoma leading to lethal tracheal perforation during chemotherapy is described.

Molecular dynamics simulations are combined with solid-state NMR measurements to gain insight into the macroscopic structural composition of the π-conjugated polymer poly(2,5-bis(3-tetradecyl-thiophen-2-yl)thieno[3,2-b]thiophene) (PBTTT). The structural and dynamical properties, as established by the NMR analyses, were used to test the local structure of three constitutient mesophases with (i) crystalline backbones and side chains, (ii) lamellar backbones and disordered side chains, or (iii) amorphous backbones and side chains. The relative compositions of these mesophases were then determined from the deconvolution of the 1H and 13C solid-state NMR spectra and dynamic order parameters. Surprisingly, on the basis of molecular dynamics simulations, the powder composition consisted of only 28% of the completely crystalline mesophase, while 23% was lamellar with disordered side chains and 49% amorphous. The protocol presented in this work is a general approach and can be used for elucidating the relative com...

The solid-state morphology and photo-generated charge carrier dynamics in low-bandgap polymer: fullerene bulk heterojunction photovoltaic blends using the donor-acceptor type copolymers PCPDTBT or its silicon-substituted analogue PSBTBT as donors are compared by two-dimensional (2D) solid-state nuclear magnetic resonance (NMR) and femto-to microsecond broadband Vis-NIR transient absorption (TA) pump-probe spectroscopy. The 2D solid-state NMR experiments demonstrate that the film morphology of PCPDTBT:PC60BM blends processed with additives such as octanedithiol (ODT) are similar to those of PSBTBT:PC60BM blends in terms of crystallinity, phase segregation, and interfacial contacts. The TA experiments and analysis of the TA data by multivariate curve resolution (MCR) reveal that after exciton dissociation and free charge formation, fast sub-nanosecond non-geminate recombination occurs which leads to a substantial population of the polymer's triplet state. The extent to which triplet states are formed depends on the initial concentration of free charges, which itself is controlled by the microstructure of the blend, especially in case of PCPDTBT:PC60BM. Interestingly,PSBTBT:PC70BM blends show a higher charge generation efficiency, but less triplet state formation at similar free charge carrier concentrations. This indicates that the solid-state morphology and interfacial structures of PSBTBT:PC70BM blends reduces non-geminate recombination, leading to superior device performance compared to optimized PCPDTBT:PC60BM blends.