Artigos de revistas sobre o tema "Hl 4343"

Background: Recent research has focused on the potential benefits of physical activity in occupational settings in addition to leisure time. However, occupational physical activity (OPA) differs substantially for occupations that require heavy and repetitive physical work, such as nursing. We explored associations between leisure time and OPA and health outcomes in working nurses and midwives. Methods: Nurses who were enrolled in the Fit For the Future study (New South Wales, Australia) and who completed physical activity questionnaires (n = 4343) were classified according to high (HO) or low (LO) occupational and high (HL) or low (LL) leisure-time physical activity (LTPA): HO performed walking/heavy labor most/all of the time at work; HL met the guidelines of 150 minutes per week moderate to vigorous LTPA, creating 4 categories: HOLL, HOHL, LOHL, and LOLL. Results: HL predicted better self-rated health (unstandardized B = 0.51, 95% confidence interval, 0.44 to 0.57) and lower likelihood of ≥3 sick days in the past 12 months (OR: 0.71, 95% confidence interval, 0.61 to 0.83), whereas HO predicted higher likelihood of ≥3 sick days (OR: 1.17, 95% confidence interval, 1.01 to 1.35), adjusting for all variables. Conclusions: OPA may not confer the same health benefits as LTPA for nurses. Health-promoting interventions should emphasize the importance of achieving adequate moderate to vigorous LTPA for all, including those undertaking substantial OPA.

Introduction: Noise Induced Hearing Loss (NIHL) is a permanent sensorineural hearing loss (HL) which affects the quality of life of exposed individuals. Aim: To determine the prevalence of NIHL among sawmill workers at the Timber market and petty traders in Accra, Ghana, and to assess the difference in actual and self-reported HL among the sawmill workers. Methods: This was a comparative study of NIHL among sawmill workers at the Agbogbloshie Timber Market of Accra and petty traders whose work environment was situated remotely from the sawmill. Data was analysed using SPSS version 20.0. Demographic characteristics and pure tone audiometric testing of study participants were analysed and presented as mean±standard deviation, counts and percentages. Independent T-test was used in comparing pure tone hearing thresholds of sawmill workers and petty traders at various frequencies. Results: A total of 120 sawmill workers and 120 petty traders were studied. Sixty-four (53.3%) of the petty traders were females and all the sawmill workers were males. Mean age of the sawmill workers was 41.5±11.8 years. The prevalence of NIHL among the sawmill workers was 37.5% in the right ear and 43.3% in the left ear. Among the petty traders, the prevalence of NIHL was 12.5% in the right ear and 8.3% in the left ear. There was a statistically significant difference in NIHL between the sawmill workers and the petty traders (p-value = 0.0001). The prevalence of HL in the better ear for the sawmill workers and petty traders was 16.7% and 1.7% respectively. Sixty-nine (57.5%) sawmill workers self-reported HL compared to actual HL of 39 (32.5%) which showed a statistically significant difference (p-value = 0.011). Conclusions: The prevalence of NIHL among the sawmill workers was 37.5% and 43.3% in the right and left ears. There was a significant difference between actual and self-reported HL among the sawmill workers.

Two new species of the elongate snake eel genus Bascanichthys are described from the northwestern Pacific. Bascanichthys kabeyawan sp. nov. is described based on a single specimen collected from estuary of southern Taiwan. It is characterized by having head 4.6% TL; tail 52.3% TL; body depth at gill opening 1.1% TL; predorsal-fin length 58.4% HL; snout length 10.9% HL; body bicolored, head without bands; lateral-line pores anterior to anus 104; vertebral formula 4-103-224. Bascanichthys ryukyuensis sp. nov. is described based on two specimens collected from the shallow water of Okinawa-jima Island, Ryukyu Islands of southern Japan. It is characterized by having head 3.7–4.3% TL; tail 43.3–44.2% TL; predorsal-fin length 40.7–45.4% HL; snout length 11.3–13.1% HL; body pale brown, head without distinct dark bands after preservation; lateral-line pores anterior to anus 114–118; total vertebrae 207–216, mean vertebral formula 2-116-212; and dorsal-fin origin before middle of head.

OBJECTIVE: To evaluate changes in vertigo and hearing from patients with Ménière's disease managed by endolymphatic mastoid shunt (EMS). STUDY DESIGN: Case series with chart review. SETTING: Tertiary referral center. SUBJECTS AND METHODS: Data from 16 patients were analyzed using 1995 AAO–HNS criteria. RESULTS: Among 16 patients, six had class A vertigo control two years after treatment, five had class B, one class C, three class D, and one class F. At four years after surgery, seven patients had class A, four class B, three class C, and two class F. The mean functional level before surgery was 4.8 and improved to 2.9 and 2.6 at two years and four years after surgery, respectively. The bone conduction pure-tone averages (four frequencies) were 43.3 before surgery and improved to 33.5 dB HL and 35.5 dB HL at three and six months after surgery, respectively. At two years of follow-up, the hearing level was 38.6 dB HL and was not different from the preoperative hearing level. Two years after surgery, the hearing level gradually decreased and was 42.0 dB HL at five years of follow-up. CONCLUSION: EMS appears to be beneficial in the short term for the symptomatic patients.

Background: The COVID-19 pandemic has been disseminating fear in the community, which has affected people’s quality of life, especially those with health problems. Health literacy (HL), eHealth literacy (eHEAL), and digital healthy diet literacy (DDL) may have potential impacts on containing the pandemic and its consequences. This study aimed to examine the association between the fear of COVID-19 scale (FCoV-19S) and the health-related quality of life (HRQoL), and to examine the effect modification by HL, eHEAL, and DDL on this association. Methods: A cross-sectional study was conducted in 11 hospitals across Vietnam from 7 April to 31 May 2020. Data were collected on 4348 outpatients, including demographic characteristics, HL, eHEAL, DDL, FCoV-19S, and HRQoL. Multiple linear regression and interaction models were used to explore associations. Results: Patients with higher FCoV-19S scores had lower HRQoL scores (unstandardized coefficient, B = −0.78, p < 0.001). HL (B = 0.20, p < 0.001), eHEAL (B = 0.24, p < 0.001), and DDL (B = 0.20, p < 0.001) were positively associated with higher HRQoL scores. The negative impact of FCoV-19S on HRQoL was significantly attenuated by higher eHEAL score groups (from one standard deviation (SD) below the mean, B = −0.93, p < 0.001; to the mean, B = −0.85, p < 0.001; and one SD above the mean, B = −0.77, p < 0.001); and by higher DDL score groups (from one SD below the mean, B = −0.92, p < 0.001; to the mean, B = −0.82, p < 0.001; and one SD above the mean, B = −0.72, p < 0.001). Conclusions: eHealth literacy and digital healthy diet literacy could help to protect patients’ health-related quality of life from the negative impact of the fear of COVID-19 during the pandemic.

Objective:to compare diagnostic effectiveness of whole body diffusion-weighted imaging (DWI), other magnetic resonance imaging (MRI) pulse sequences and iliac wing trephine biopsy in the diagnosis of focal and diffuse bone marrow (BM) involvement in patients with lymphoma.Materials and methods.Prospective study included 130 patients with lymphoma who underwent whole-body MRI-DWI and iliac wing trephine biopsy before treatment (64 (49,2%) men, 66 (50,8%) women, middle age 43,3 ± 16,3 years, interval of 18–79 years). Hodgkin's lymphoma (HL) was at 57 (44%) patients, non-Hodgkin lymphomas (NHL) – at 73 (56%). Diagnostic effectiveness of T1- weighted images (T1-WI), STIR, DWI and FIESTA was analyzed. BM apparent diffusion coefficient (ADC) values were measured.Results.BM involvement was found in 42 patients, including 9 with HL and 33 with NHL. In HL, BM involvement was only focal. Diffuse involvement occurred more often (64%) in the NHL as compared to focal one. In focal involvement, all pulse sequences showed high diagnostic sensitivity (90–100%), BM biopsy sensitivity was 33% only. The proposed new criterion for the diagnosis of diffuse BM involvement in NHL – diffuse signal increase of the spine on DWI above renal parenchyma – has the highest sensitivity (90%) compared to T1-WI and STIR (67%) and FIESTA (71%) (p < 0.05). In NHL, the ADC value ≤0.575 • 10−3 mm2/s discrimi nates cases of diffuse involvement and absence of BM involvement with a sensitivity of 86% and a specificity of 68% (p < 0.0001). In HL, the diffuse BM signal increase on DWI is not indicative of involvement.Conclusion.All pulse sequences showed high effectiveness in the diagnosis of focal BM involvement in patients with lymphoma, iliac wing biopsy effectiveness was low. The proposed new DWI criterion for diagnosing diffuse BM involvement in NHL is the most sensitive one. A new algorithm based on whole body MRI-DWI for the diagnosis of BM involvement allows to reduce the need for BM biopsy without reducing the diagnostic effectiveness.

In current horticultural practice, potential acidity or basicity of fertilizers is estimated using Pierre's method (PM) expressed in calcium carbonate equivalents (CCE) per unit weight of fertilizer. PM was developed using mineral field soil systems and may be inaccurate for quantifying fertilizer acidity in containerized plant production given the widespread use of soilless substrates and fertigation. The PM-predicted acidity of an ammonium-based fertilizer was compared against experimental data obtained when ‘Ringo’ geraniums [Pelargonium ×hortorum (Bailey. L.H.)] and ‘Super Elfin’ impatiens [Impatiens wallerana (Hook. F.)] were grown in 70% peat:30% perlite (v:v) limed with either hydrated limestone only (HL) or a combination of carbonate and hydrated limestone (CHL). Plants in 10-cm-diameter (0.35 L) containers were top-irrigated with a total of 2.0 L over 6 weeks using a 15.2N–1.9P–12.6K fertilizer [100% of nitrogen (N) as NH4-N] applied with each irrigation at 100 mg N/L without leaching. According to PM, 61.8 meq of fertilizer acidity was applied per liter of substrate. During the experiment, the pH of the substrate decreased from 7.05 to 4.41 for the HL substrate and from 7.14 to 5.13 for the CHL substrate. A corresponding drop in substrate-pH was observed when 37.1 (HL) or 43.3 (CHL) meq of CCE from 0.5 N HCl was applied per liter of substrate in a laboratory titration of the same substrates without plants. Gasometric analysis of residual carbonate at Day 0 and at the end of the experiment quantified change in CHL substrate alkalinity with time, resulting in an estimated 30.7 meq of neutralized alkalinity. Using an electroneutrality approach that assumed anion uptake (NO3–, P2O5–) was basic, and cations (NH4+, K+) were potentially acidic, nutrient analysis of the substrate at the beginning and end of the experiment estimated that an average 48.5 meq of acidity was contributed by the fertilizer. Experimentally measured acidity values were 13.1 to 31.1 meq·L−1 of substrate lower for HL and CHL than those expected from PM, suggesting PM overestimated the amount of fertilizer acidity applied to the substrate. These results support the need for an alternative method to predict fertilizer acidity for plant production in soilless substrates.

Purpose: The aim of the study is to evaluate the prognostic value of a joint evaluation of PET and CT radiomics combined with standard clinical parameters in patients with HL. Methods: Overall, 88 patients (42 female and 46 male) with a median age of 43.3 (range 21–85 years) were included. Textural analysis of the PET/CT images was performed using freely available software (LIFE X). 65 radiomic features (RF) were evaluated. Univariate and multivariate models were used to determine the value of clinical characteristics and FDG PET/CT radiomics in outcome prediction. In addition, a binary logistic regression model was used to determine potential predictors for radiotherapy treatment and odds ratios (OR), with 95% confidence intervals (CI) reported. Features relevant to survival outcomes were assessed using Cox proportional hazards to calculate hazard ratios with 95% CI. Results: albumin (p = 0.034) + ALP (p = 0.028) + CT radiomic feature GLRLM GLNU mean (p = 0.012) (Area under the curve (AUC): 95% CI (86.9; 100.0)—Brier score: 3.9, 95% CI (0.1; 7.8) remained significant independent predictors for PFS outcome. PET-SHAPE Sphericity (p = 0.033); CT grey-level zone length matrix with high gray-level zone emphasis (GLZLM SZHGE mean (p = 0.028)); PARAMS XSpatial Resampling (p = 0.0091) as well as hemoglobin results (p = 0.016) remained as independent factors in the final model for a binary outcome as predictors of the need for radiotherapy (AUC = 0.79). Conclusion: We evaluated the value of baseline clinical parameters as well as combined PET and CT radiomics in HL patients for survival and the prediction of the need for radiotherapy treatment. We found that different combinations of all three factors/features were independently predictive of the here evaluated endpoints.

Abstract Background: Autologous stem cell transplantation (ASCT) has been used as a standard treatment in the management of patients (pts) with relapsed/refractory Hodgkin’s lymphoma (HL) in the last few decades. Long-term side effects of this treatment such as secondary malignancies (SM), organ failure and infertility attract scientific interest. Very little data is available on late events among pts with HL treated with ASCT. Material and Methods: We retrospectively analysed HL pts treated with an ASCT and registered in the European Group for Blood and Marrow Transplantation (EBMT) Database. Further inclusion criteria were: age at ASCT ≥ 18 years and time of transplantation between 1985 and 1995. Additionally, pts treated with tandem protocols have been excluded. The frequency of late events including incidence of secondary malignancies and non-relapse related mortality (NRM) was evaluated. Univariate and multivariate analyses of risk factors for SM and NRM were performed. Results: 2289 pts (median age at ASCT 30 years, range 18 – 70) were evaluated; 1408 (61.5%) pts were male. Most patients (76.9%) were in complete or partial remission at the time of transplantation and 23.1% of pts were transplanted with refractory or progressive disease. BEAM was the conditioning regimen most frequently used (57.3%) followed by CBV (29.4%) and other chemotherapy regimens (8.7%); TBI was given to 4.7% of pts. Median follow-up for all pts was 47 months (range 0 – 240). Progression free survival and overall survival at 5 years for the whole series were 39.9% and 46.8%, respectively. 988 pts (43.3%) relapsed after a median time of 8.5 months post-ASCT, 787 of them died and 201 are alive after a relapse. 312 pts died without previous relapse or progression (NRM). The main causes of death were relapse/progression (34%), transplant related mortality (11.4%) and SM (1.5%). Cumulative risk at 10 years for NRM was 14.4%. Sex, disease status at ASCT, year of ASCT (1985 – 1990 vs. 1990 – 1995), stem cell source (BM vs. PB), age > 40 years, conditioning with CBV, conditioning including TBI and time of ASCT after diagnosis > 48 months were significant prognostic factors in multivariate Cox regression analysis for NRM. SM were diagnosed in 74 pts (3.2%): solid tumours in 33 pts (1.4%), MDS/acute leukaemias in 35 pts (1.5%) and NHL in 6 pts. Cumulative risk at 10 years for SM was 4.4%, for solid tumours 2.2% and for MDS/acute leukaemia 1.7%. The significant risk factors in multivariate Cox regression analysis for SM were age at ASCT > 40 years, time from diagnosis to ASCT > 48 months and conditioning with CBV (p<0.05). Age > 40 years was the only significant risk factor for solid tumours and MDS/acute leukaemias in Cox multivariate analysis. Conclusions: ASCT remains the standard treatment for patients with refractory/relapsed HL. The cumulative risk at 10 years for NRM and for SM was 14.4% and 4.4%, respectively. The cumulative risk for SM among evaluated patients is higher compared with that reported among HL patients after first line treatment and is expected to increase over time due to the rather short median observation time and the slow progression of solid malignancies.

Abstract Introduction. Allogeneic stem cell transplantation (allo-SCT) is a well established therapeutic alternative for those patients with refractory Hodgkin’s lymphoma (HL) who relapse after an autologous stem cell transplantation (ASCT), have chemosensitive disease and a HLA compatible donor available. The impact of the intensity of the conditioning regimen in the outcome of this procedure is still not well understood. An initial retrospective analysis from the European Group for Blood and Marrow Transplantation (EBMT) Lymphoma Working Party (LWP) (Sureda et al, JCO 2010) that compared myeloablative (MAC) with reduced intensity conditioning (RIC) protocols indicated that the high non-relapse mortality (NRM) associated to MAC-SCT translated into a non-significant improvement in progression free survival (PFS) for RIC recipients in spite of the higher relapse rate of the latter. As NRM for MAC-SCT might have decreased over time due to better patient selection, HLA typing and peri-transplant supportive measures, we hypothesize that overall results of more intensive protocols could compare better to RIC-SCT in recent years. Patients and Methods. We have included in this analysis adult patients with multiply relapsed classical HL treated with an allo-SCT between January 2006 and December 2010 and reported to the EBMT Database. Only first and second allo-SCT was included. Tandem ASCT-allo-SCT was excluded as well as cord blood transplantations and haplo-identical SCT. A total of 313 patients met the inclusion criteria (63 patients treated with a MAC and 250 patients treated with a RIC, definitions following the EBMT criteria). There were 173 males (55%) and 140 females (45%) with a mean age at diagnosis of 29 years and at SCT of 33 years. Mean time from diagnosis to SCT was of 43.3 months. 153 patients (49%) were chemorefractory at the time of allo-SCT and 166 patients (53%) had already failed a prior ASCT. Peripheral blood (PB) was used as the source of stem cells in 88% of the patients. Comparing MAC with RIC groups, the latter one was significantly older at allo-SCT (31 years vs 34 years, p=0.01), had a longer time interval between diagnosis and allo-SCT and preferentially received mobilized PB stem cells (82% vs 91%, p=0.01). There were also more prior autograft failures in the RIC group (56% vs 42%, p=0.006). Results. With a median follow up for alive patients of 32.5 (9.7 – 52.9) months, overall survival (OS) was 75% and 65%, PFS, 54% and 39%, NRM 11% and 12% and relapse rate after SCT of 37% at 1 year. There were no significant differences in NRM between MAC and RIC patients. Relapse rate was higher in the RIC group, although these differences did not reach statistical significance (55% vs 40% at 24 months, p=0.1). This lower relapse rate translated into an improvement in PFS for the MAC group (48% vs 37% at 24 months, p=0.08) with no differences in terms of OS (71% for MAC vs 61% for RIC at 24 months, p=0.4). Multivariate analysis after adjusting for disease status at the time of SCT showed that the use of RIC protocols was the only independent adverse prognostic factor associated to a higher relapse rate after SCT [HR 0.68, 95%CI (0.38 – 0.98), p=0.04] and to a lower PFS after the procedure [HR 0.65, 95%CI (0.43 – 0.98), p=0.04]. The intensity of the conditioning regimen did not have any impact n NRM in the multivariate analysis. Chemosensitive disease at SCT was the only independent prognostic factor for OS after SCT in the multivariate analysis [HR 1.70, 95%CI (1.17 – 2.46), p=0.005]. Conclusions. This retrospective analysis shows that NRM after MAC protocols is not a significant clinical issue when allografting patients with HL nowadays. On the other hand, using MAC decreases the relapse risk in this highly resistant population of patients, translating into a significant improvement of PFS. MAC protocols should be considered when designing prospective clinical trials in patients with HL candidates for an allogeneic stem cell procedure. Disclosures No relevant conflicts of interest to declare.

Background: There are not many population-based epidemiological studies on the association between self-reported hearing problems and measured hearing thresholds in older adults. Previous studies have shown that the relationship between self-reported hearing difficulties and measured hearing thresholds is unclear and, according to our knowledge, there are no previous population-based studies reporting hearing thresholds among subjects with hyperacusis. Purpose: The aim was to investigate the prevalence of self-reported hearing problems, that is, hearing difficulties, difficulties in following a conversation in noise, tinnitus, and hyperacusis, and to compare the results with measured hearing thresholds in older adults. Research Design: Cross-sectional, population-based, and unscreened. Study Sample: Random sample of subjects (n = 850) aged 54-66 yr living in the city of Oulu (Finland) and the surrounding areas. Data Collection and Analysis: Otological examination, pure tone audiometry, questionnaire survey Results: The prevalence of self-reported hearing problems was 37.1% for hearing difficulties, 43.3% for difficulties in following a conversation in noise, 29.2% for tinnitus, and 17.2% for hyperacusis. More than half of the subjects had no hearing impairment, or HI (BEHL[better ear hearing level]0.5–4 kHz < 20 dB HL) even though they reported hearing problems. Subjects with self-reported hearing problems, including tinnitus and hyperacusis, had significantly poorer hearing thresholds than those who did not report hearing problems. Self-reported hearing difficulties predicted hearing impairment in the pure-tone average at 4, 6, and 8 kHz, and at the single frequency of 4 kHz. Conclusions: The results indicate that self-reported hearing difficulties are more frequent than hearing impairment defined by audiometric measurement. Furthermore, self-reported hearing difficulties seem to predict hearing impairment at high frequencies (4–8 kHz) rather than at the frequencies of 0.5–4 kHz, which are commonly used to define the degree of hearing impairment in medical and legal issues.

Abstract Abstract 4333 Introduction L-asparaginase (L-Aspa) is one of the standard components of acute lymphoid leukemia (ALL) therapy. Its efficacy as an antineoplasic agent is due to its capacity to deplete plasmatic asparagine, starving the leukemic cells and subsequently inhibiting protein synthesis. In vitro studies have already shown the sensitivity to L-Aspa of leukemic cells from patients with acute myeloid leukemia (AML), depending on the French-American-British (FAB) subtype (Zwaan et al., 2000; Okada et al., 2003). Despite promising results in clinical trials (Capizzi et al., 1988; Wells et al., 1993), L-Aspa has only been used scarcely in the treatment of AML, mainly because of the adverse effects observed commonly that impair its use. The existence of a new formulation of L-Aspa (L-Aspa encapsulated in heterologous red blood cells) with a better safety profile allows considering its use for the treatment of AML (Godfrin et al., 2012). The sensitivity to L-Aspa may be inversely correlated to their expression of asparagine synthetase (ASNS, an enzyme catalyzing the intracellular synthesis of asparagine). The aim of this study was to investigate the potential of L-Aspa for AML treatment by determining the leukemic cell expression of ASNS and their sensitivity to L-Aspa. Materials and methods Studies were performed on an AML cell line (HL-60) and on leukemic cells isolated from the bone marrow of AML patients by Ficoll density gradient. The IC50 (concentration inhibiting 50% of cell viability) was determined in vitro by incubating various concentrations of L-Aspa with the cells and measuring the cell viability with a cell counting kit (CCK-8 viability assay). ASNS expression was determined by western-blot. Results As a preliminary, determination of IC50 for the HL-60 cell line demonstrated that these cells were equally sensitive to L-Aspa than the ALL cell line MOLT-4 in vitro(0.23 IU/mL versus 0.19 IU/mL, respectively). The expression of ASNS in the HL-60 cell line was low in comparison with other cancer cell lines. Concerning blasts isolated from AML patients, 2/3 patients displayed an IC50 < 0.01 IU/mL whereas 1/3 displayed an IC50 as low as 0.13 IU/mL, which means a high sensitivity to L-Aspa. All these patients were negative for ASNS expression. On 6 patients tested for ASNS expression, 5 had their blasts negative whereas one was positive. Patients with blasts negative for ASNS expression were all affected by FAB M5 or M1 AML whereas patient with blasts positive was diagnosed with a M2 AML. Conclusion Both AML cell line and cells isolated from AML patients were sensitive to L-Aspa. In all clinical cases, high sensitivity and/or lack of ASNS expression were linked to a FAB M5 or M1 AML, consistent with data from literature suggesting a higher sensitivity of M1, M4 and M5 AML subtypes. The only clinical case positive for ASNS expression was a FAB M2 AML, consistent with literature that indicates an in vitro resistance of the M2 AML subtype to L-Aspa. Globally, these results suggest that L-Aspa is effective for killing AML cells with low/no ASNS expression. Thus, thanks to its low toxicity profile, L-Aspa may be considered as a potential therapy for FAB subtypes or individuals characterized by low/no ASNS expression. Based on the epidemiology of AML subtypes (Selter et al., 2011), L-Aspa therapy may be beneficial for 50% of patients with AML. These results finally highlight the necessity of the determination of the grade and/or the expression of ASNS in leukemic cells to select AML patients at potential for L-Aspa therapies. Disclosures: Berlier: ERYTECH Pharma: Employment. Aguera:ERYTECH Pharma: Employment. Campion:ERYTECH Pharma: Employment. Gay:ERYTECH Pharma: Employment. Godfrin:ERYTECH Pharma: COO Other.

Abstract Background and Aims High dose chemotherapy followed by autologous stem cell transplant (ASCT) is an effective treatment for many patients with haematological malignancies. Adequate stem cell mobilization (SCM) and collection are essential for a successful ASCT. Unfortunately, a small group of patients fail to mobilize sufficient stem cell for transplant. In order to explore factors influencing SCM we conducted a retrospective analysis on a large series of candidates for ASCT in a Portuguese transplantation center. Patients and Methods We analyzed 233 patients who underwent consecutively SCM from 2007 to 2012. Patients with CD34+ <10/μL in peripheral blood at maximum stimulation were considered non-mobilizers (NM) and patients that didn’t harvest the minimal count of 2×10^6 CD34+/kg at maximum number of aphaeresis cycles were considered poor mobilizers (PM). Patient diagnosis, sex, age, body weight, previous radiotherapy, number of cycles of previous chemotherapy, status disease at mobilization and premobilization platelet count, prior use of fludarabine or alkylating agents were analyzed for correlation with mobilization. Results Two patients received granulocyte colony-stimulating factor (G-CSF), all others received G-CSF plus chemotherapy (G+C) for the initial mobilization. 68 patients had non-Hodgkin’s lymphoma (NHL), 23 Hodgkin’s lymphoma (HL), 94 multiple myeloma (MM), 46 acute myeloid leukemia (AML) and 2 non-hematological malignancies (NHM). The median age was 54 years (min-max: 18-69) and 108 were females. A successful SCM was achieved in 217 patients (93.1%) and the NM ratio differed with respect to diagnosis (NHL: 11.7%, AML: 9.5%, HL: 9%, MM: 2.1%, NHM: 0%). At univariate analysis NM was significantly associated with the number of cycles of previous chemotherapy (p=0.003), status disease at mobilization (p=0.000) and prior use of fludarabine (p=0.013). Multivariate analysis confirmed the higher number of cycles of previous chemotherapy (p=0.002) and prior use of fludarabine (p=0.000) as negative predictive factors for SCM. For the 217 patients who underwent stem cell collection, 504aphaeresis were performed. Median number of aphaeresis necessary to harvest 2×10^6 CD34+/kg was 2 (min-max:1-6). Median CD34+/kg harvested was 4.6x10^6 (min-max:1.82-52.7), with 43.3% patients collecting 2x10^6 CD34+/kg in one aphaeresis. MM patients had the highest total CD34 cell yield (median 6.9x10^6 CD34+/kg, min-max: 2-52.7) and required less aphaeresis to collect 2×10^6 CD34+/kg. At univariate analysis diagnosis of MM (p=0.000), status disease at mobilization (p=0.007) and the number of cycles of previous chemotherapy (p=0.002) were significantly associated with PM. Multivariate analysis confirmed the diagnosis of MM (p=0.000) and the lower number of cycles of previous chemotherapy (p=0.002) as favorable predictive factors for the total CD34+ cell yield. Grade III or IV hematopoietic toxicity of chemotherapy had no significant effect on the SCM. Incidence of febrile neutropenia was similar in all patients without morbidity. There was no mortality associated with SCM. Conclusions G+C SCM appears to be safe in all patients without major toxicity or morbidity. Our results enhances the need for effective first-line mobilization agents in patients with higher number cycles of chemotherapy and use of fludarabine prior SCM; these patients probably would benefit for a early SCM in order to achieve a higher CD34+ cell yield. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 1371 Aberrant signal transduction pathways influence metabolic changes in neoplastic cells. It is well established, in fact, that cancer cells are characterized by a pro-glycolytic metabolic phenotype and recent evidences confirmed that also leukemia cells may switch to a non-oxidative metabolism. Among the different substrates used to sustain the anabolic processes and to keep the tricarboxylic acid cycle (TCA) active, the fatty acid oxidation (FAO) may represent an alternative carbon source. The carnitine palmitoyl transferase 1a (CPT1a) catalyzes the first step of FAO, by loading long chain fatty acyl groups onto carnitine, transporting them through the mitochondrial membrane. Moreover, CPT1a has been previously demonstrated to interact with members of the apoptotic machinery, such as Bcl-2 and t-Bid, and its inhibition can cause an accumulation of the toxic metabolite palmitate, resulting in mitochondrial damage and cell death. In diabetic patients the use of a recently discovered antihyperglycemic agent characterized by the selective and reversible inhibition of CPT1a has been reported. Therefore, we aimed in this study to investigate the in vitro anti-leukemic effect of the CPT1a inhibition. Particularly, we evaluated the activity of two CPT1a-inhibitors, the novel ST1326 (kindly provided by Sigma-Tau) and the previously known Etomoxir on the proliferation and apoptosis of leukemia cell lines and primary cells obtained from patients affected by acute leukemias. The drug concentration inducing a 50% cell killing (IC50) was calculated from the dose-response curve. The cytotoxic drug effects on leukemia cell lines (HL-60, HL-60/MX2, U937, K562, CEM S, CEM R, MOLT-4) and primary cells of acute myeloid (AML) and lymphoid (ALL) leukemia were evaluated using the MTT test. Flow cytometry techniques Acridine-Orange staining, AnnexinV binding assay and Chloromethyl-X-Rosamine (CMXRos)/MitoTracker Green (MTGreen) staining were used to examine cell cycle changes, apoptosis and the loss of mitochondrial membrane potential (ΔΨm). We evaluated the activity of ST1326 (1–50 μM) on leukemia models, demonstrating a dose- and time-dependent cell growth arrest, caused by mitochondrial damage and apoptosis induction. In fact, 6 hours of ST1326 exposure were able to induce a dramatic loss of ΔΨm, as observed in MOLT-4 cells (cells affected increased from 15% in the control to 59.7% at 50 μM). Following 72 hours of ST1326 exposure, the same cells showed then an increase in the subG1 peak from a baseline value of 10% to 8.1%, 7.3%, 10.5%, 37% and 95.8% at 1, 5, 10, 20 and 50 μM, respectively (IC50= 39.2 μM). Etomoxir failed to show any activity (data not shown). The myeloid cell lines HL60, HL60/MX2 and U937 were more sensitive to ST1326, showing an IC50 of 11.8, 8.2 and 8.8 μM, respectively. A milder activity was found in the other lymphoid-derived model, the CEM S cell lines (IC50= 71.1 μM). Instead, both the lymphoid CEM R and the myeloid K562 cell lines proved resistant (IC50= n.d.). We then exposed in vitro (72 hours) primary cells from 12 AML and found in all a significant pro-apoptotic activity (AnnexinV positive cells): from 23.27% ± 13.63 (control) to 36.59% ± 19.97 (p=0.23), 40.51% ± 18.66 (p=0.0074), 43.43% ± 19.81 (p=0.0071) and 75.30% ± 11.52 (p=0.00018) following 72 hours of exposure to 5, 10, 20 and 50 μM ST1326, respectively. ALL primary samples (6/8 samples), instead, showed a significant (p<0.005) increase of the sub-G1 DNA apoptotic cells only at the higher ST1326 dose (from 38.9% ± 23.7 to 68.9% ± 23.4 of cells at 50 μM). In conclusion, ST1326 shows a high in vitro pro-apoptotic activity on acute leukemia models and on primary cells, especially in AML, prompting further studies to better define this novel approach based on the targeted inhibition of metabolic pathways in leukemia treatment. Disclosures: Petrucci: Jansse-Cilag, Celgene: Honoraria. Nicolai:Sigma Tau Pharmaceutical Industries SpA: Employment. Tafuri:Sigma Tau Pharmaceuticals: Research Funding.

Abstract Abstract 4346 The pharmacokinetic profile of BAX 855, a longer acting PEGylated variant of Baxter’s recombinant FVIII based on the ADVATE™ manufacturing process, was assessed in comparison to ADVATE™ after a single intravenous bolus injection at a target dose of 200 IU/kg BW in mice and rats and 350 IU/kg BW in cynomolgus monkeys. Mean residence time (MRT), terminal half-life (HL), total clearance standardized per kg body mass (Cl), the AUC0-tlast (the area under the concentration vs. time curve from 0 to the last measured time point), the in vivo recovery (IVR) and volume of distribution at steady state (Vss) for FVIII activity (mice and cynomolgus monkey), FVIII antigen (rats) and FVIII-bound PEG were evaluated in all three models. Blood was sampled at baseline and each of the time points after a single intravenous bolus injection of BAX 855 or ADVATE™. A serial sacrifice design was used for the PK in mice. Sixteen FVIII ko mice (B6;129S4-F8tm2Kaz; m/f) for BAX 855 and eight FVIII ko mice for ADVATE™ per time point were bled by cardiac puncture under anesthesia for blood sampling 5 minutes – 48 hours after a single intravenous bolus injection. A single treatment design was used for the single dose PK in Sprague Dawley rats: 8m + 8f for BAX 855 and 4m + 4f for ADVATE™. A single treatment design was also used for the cynomolgus monkeys: 4m + 4f for BAX 855 and 2m + 2f for ADVATE™. Blood samples were drawn from rats and cynomolgus monkeys for citrated plasma (for analysis of baseline FVIII levels) before administration and 5 minutes - 48 hours (rats) and 5 minutes to 96 hours (cynomolgus monkeys) after administration. The citrated plasma samples were analyzed for FVIII activity (chromogenic assay) in mice and cynomolgus monkeys, for FVIII–bound PEG (using a PEG-FVIII ELISA) in all models and FVIII antigen (using a FVIII ELISA) in rats. In all three models a prolongation in MRT of Baxter’s and Nektar’s new BAX 855 compared with ADVATE™ could be demonstrated. FVIII activity analysis showed an increase of MRT in mice from 4.9 to 7.9 hours and in cynomlogus monkeys from 7.5 to 11.5 hours. This prolongation was also reflected in the terminal half-lives (4.3 to 5.9 hours in mice and 5.7 to 9.4 hours in cynomolgus monkeys). According to this prolongation a lower clearance [mL/h/kg] could be observed for BAX 855 than for ADVATE™ (22.1 to 12.2 in mice and 8.1 to 4.9 in monkeys). Similar levels in all PK parameters could be shown when measuring FVIII-bound PEG in all three preclinical models and FVIII antigen analysis in rats. These PK data provide evidence that PEGylation of human rFVIII increases the circulation time. Disclosures: Hoebarth: Baxter Innovations GmbH: Employment. Kubik:Baxter Innovations GmbH: Employment. Wolfsegger:Baxter Innovations GmbH: Employment. Lawo:Baxter Innovations GmbH: Employment. Weber:Baxter Innovations GmbH: Employment. Gritsch:Baxter Innovations GmbH: Employment. Hoellriegl:Baxter Innovations GmbH: Employment. Schiviz:Baxter Innovations GmbH: Employment. Ehrlich:Baxter Innovations GmbH: Employment. Scheiflinger:Baxter Innovations GmbH: Employment. Turecek:Baxter Innovations GmbH: Employment. Schwarz:Baxter BioScience: Employment. Muchitsch:Baxter Innovations GmbH: Employment.

Abstract Abstract 4347 Background: Chronic myeloid leukemia (CML) is a disease that is responsive to T-cell-mediated immunity. K562/granulocyte macrophage-colony stimulating factor (GM-CSF) is a vaccine derived from a CML cell line that produces GM-CSF and expresses several CML-associated antigens. An initial pilot study was performed in 19 patients in chronic phase CML who had achieved at least a major cytogenetic response on imatinib mesylate (IM) but had measurable molecular disease. The results suggested that immunotherapy resulted in a lowering tumor burden in the majority of patients (n = 13) with a total of 7 patients achieving undetectable bcr-abl levels by QT-PCR. (Smith, Clinical Cancer Research, 2010). This extension study evaluated the biologic impact of K562/GM-CSF given as a “booster” in subjects who completed the pilot study's scheduled 4 vaccinations and continued to have have persistent measurable disease or who lost their best response to the original therapy. Methods: This is a single-institution pilot study using open-label K562/GM-CSF vaccination as a “booster” in chronic phase CML patients who were previously treated with a full 4-vaccination course of therapy and continued to have measurable CML disease. Patients were stratified as having either responded to the initial set of vaccines and had subsequent loss of response or as having had no measurable response to therapy. None experienced significant adverse events in the first set of vaccinations. “Booster” treatment consisted of 4 doses of 1 × 108 irradiated K562/GM-CSF given every 3 weeks. Imatinib was continued through the study at the patients’ starting doses. Disease burden was measured using peripheral blood RT-PCR and FISH was every 3 months throughout the course of planned booster vaccinations for up to a year following the vaccination boost. Patients with evidence of advancing disease requiring adjustments to their IM dosing or those progressing to accelerated or blast phase were taken off study. Results: 11 patients met the eligibility to receive the booster vaccinations. Mean age was 54 (range 38–78) years. Median dose of IM therapy was 600 mg daily (range 400–800 mg). The median time from final vaccination in the pilot study to first booster vaccination was 24 (range 18–24) months. Duration of follow up was a median of 36 months (range 6–42 months). In general, the trend for lower disease burden following booster vaccines was significant by Generalize Estimating Equation using all study measures (p<0.009). Seven patients (63%) achieved their lowest levels of disease burden to date at a median of 5 (range 3–39) months following the initiation of their booster vaccinations with only 1 patient losing their “best” response as defined by a 10-fold increase in PCR value. One of the responding patients who had lost her complete molecular remission and became positive for 5 consecutive PCR readings prior to starting the booster immunizations was found to be undetectable after starting the booster treatments and has maintained negative PCR after the completion of the booster series (now at 1 year post booster). Three patients, all of whom qualified for the booster vaccines as “non-responders” to the initial immunizations, went off study secondary to progression of disease. Using sera from patients on the initial pilot study, antibodies against a total of 24 newly identified CML associated antigens were detected in post-vaccination > pre-vaccination samples. Of these, 15 antigens were recognized in 2 or more subjects. The influence of the vaccine boost series on antibody titer and on the induction of antibodies to antigens not previously recognized is under study. K562/GM-CSF immunotherapy given as a “booster” vaccination was associated with the lowering tumor burdens in 7 of 11 treated patients. Ongoing efforts to identify tumor-associated antigens that may be serving as immunologic targets is ongoing. Disclosures: Levitsky: HL vaccine: Patents & Royalties.

Abstract Background Combination therapy has proved to be a successful strategy and generally benefits from the crosstalk of antileukemic agents. However, the mechanisms of amplification remain mostly elusive and the outcome of relapsed or chemoresistant ALL and AML is still dismal. Therefore, drug discovery is not only challenged to address the identification of novel compounds and targets, but also to enhance the understanding of their molecular interaction pathways in order to exploit their potential for the translation into combination therapies. Screening small molecules that sensitize cancer cells towards Etoposide (VP-16) induced apoptosis, we recently introduced PS89 which targets protein disulfide isomerase (PDI) (Eirich et al, Angew Chem, 2014), a crucial enzyme for the maintenance of ER homeostasis and exciting novel target in cancer research (Xu et al, Drug Discov Today, 2014). Its chemosensitizing profile predestined PS89 for combination therapy and moreover called for the elucidation of critical networks integrated in the synergistic pro-apoptotic signaling. Methods Apoptosis of PS89 in combination with standard cytostatics (Daunorubicin/DNR, Etoposide/VP-16, Vincristine/VCR) was analyzed by flow cytometry in different leukemia cell lines and patient-derived xenograft (PDX) ALL and AML cells (Vick et al, PLoS One, 2014; Terziyska et al, PLoS One, 2012) versus lymphocytes of healthy individuals (at least n=3 biological replicates each). Activity-based protein profiling (ABPP) was applied in leukemic cells to identify the network of PS89 target proteins. Following interaction studies (STRING v10), biological validation of proposed communication pathways and time-dependent analysis of critical stress triggers was performed. Results The apoptosis rate of cytostatics was synergistically enhanced in several cell line models of acute leukemia, notably applying PS89 at subtoxic concentrations in all assays (Jurkat 0.5 µM VP-16 17.7% vs PS89+VP-16 51.8%; HL-60 10 nM DNR 14.4% vs PS89+DNR 43.3%; CCRF-CEM 1 nM VCR 12.8% vs PS89+VCR 46.6%). This approach was confirmed as a therapeutic advancement in the treatment of resistant cells (VCR-resistant CEM 0.5 µM VCR 3.8% vs PS89+VCR 36.1%) as well as Pre-B-ALL and T-ALL PDX cells (n=2 diagnosis samples, 5 nM VCR 14.2% vs PS89+VCR 43.6%) or AML PDX cells (n=4 relapse samples, 20 nM DNR 38.3% vs PS89+DNR 53.6%). While in vivo studies with PDX cells are ongoing, apoptotic effects of PS89 combinations were significantly lower in isolated lymphocytes of healthy individuals which are in line with the good in vivo tolerability of PS89 (30 mg/kg i. p. daily for 2 weeks). In a proteomics screen by ABPP in Jurkat cells, we identified the B-cell receptor-associated protein 31 (Bap31) as a further target of PS89 transducing apoptotic signals from the ER to mitochondria under ER stress (Namba et al, Cell Rep, 2013) and serving as a platform to activate caspase-8 (CASP8) following apoptotic stimuli (Iwasawa et al, EMBO J, 2011). In this regard, we proposed a distinct mechanistic pathway via the Bap31/CASP8 axis mediating the crosstalk of PDI inhibition and signaling of cytostatics. Indeed, apoptosis induced by PS89/VP-16 combination treatment in Jurkat cells was critically dependent on CASP8 activity (4.4-fold reduction with CASP8 inhibitor Z-IETD-FMK) and co-immunoprecipitation revealed that CASP8 cleavage at the Bap31 protein complex was only detectable in the presence of PS89. In turn, active CASP8 is able to cleave Bap31 (shown in PS89/VP-16 treated cells, Western Blot) leading to ER calcium release. We observed moreover, that loss of mitochondrial membrane integrity mediated concurrently by ER calcium and p53-dependent signaling was accompanied by elevation of reactive oxygen species (ROS) levels which provokes further ER stress and finally closes the feedback loop. Conclusion The strong antileukemic effects of the PDI inhibitor PS89 in combination with cytostatics are orchestrated by its direct target Bap31 which transduces apoptosis signals at the ER-mitochondrial interface and emphasizes the crucial role of this social network of cell death for synergistic drug combinations. Exploiting to tune these mutual amplification loops makes PS89 uniquely applicable at subtoxic concentrations and therefore a valuable novel option to sensitize acute leukemia cells towards established chemotherapeutics. Disclosures Braig: Dr Pfleger Foundation: Research Funding.

Introduction: As previously reported, the combination of brentuximab vedotin with doxorubicin, vinblastine and dacarbazine (A+AVD) demonstrated a statistically significant improvement in modified progression free survival (modified PFS) compared with doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) in patients with newly diagnosed Stage III or IV classical HL in the phase 3 ECHELON-1 trial (NCT01712490). The benefit of A+AVD in the ITT population observed in the primary analysis was maintained at 3-years median follow-up [3-year PFS: A+AVD: 83.1% (79.9-85.9), ABVD: 76% (72.4-79.2)] and appears independent of interim PET status, disease stage, and prognostic risk factors. Here we present the efficacy and safety results of longer follow-up at a median 43.3 months. Methods: Newly diagnosed patients with Stage III or IV cHL were randomized 1:1 to receive A+AVD (n=664) or ABVD (n=670) intravenously on days 1 and 15 of each 28-day cycle for up to 6 cycles. The primary endpoint of the study was modified PFS per independent central review. The present follow-up PFS analysis is exploratory and per investigator assessment, with a cutoff date of June 17th, 2019. Patients with ongoing peripheral neuropathy (PN) at end of treatment were followed for resolution or improvement (defined as improved by ≥1 grade from worst grade as of the latest assessment) during the post-treatment follow-up period. Results: With a median follow-up of 43.3 months, the 42-month PFS per investigator for all patients was 82.4% (95% CI, 79.1-85.2) on the A+AVD arm and 76.2% (95% CI, 72.6-79.4) on the ABVD arm [overall HR 0.697 (95% CI, 0.547-0.890)]. Exploratory subgroup analyses of PET2(+) and PET2(-) patients showed a treatment effect in favor of A+AVD. The 42-month PFS in PET2(-) patients was 85.0% (95% CI, 81.6-87.7) for A+AVD and 79.6% (95% CI, 75.9-82.8) for ABVD [overall HR 0.695 (95% CI, 0.526-0.919)]; in PET2(+) patients 42-month PFS was 68.3% (95% CI, 54.5-78.7) for A+AVD and 51.5% (95% CI, 38.2-63.4) for ABVD [overall HR 0.552 (95% CI, 0.308-0.989)]. Upon continued follow-up, 81% (356/442) of patients with PN in the A+AVD arm had either complete resolution (64%, 283/442) or improvement (17%, 73/442) of their PN events compared with 83% (236/286) with either complete resolution (74%, 212/286) or improvement (8%, 24/286) in the ABVD arm. Among patients with ongoing PN after continued follow-up, the majority were Grade 1/2 events, with 89% (141/159; 59% Grade 1) and 95% (70/74; 65% Grade 1) on the A+AVD and ABVD arms, respectively. Overall survival data are not yet mature; per protocol, the final analysis will be performed after 112 deaths have occurred. Additional follow-up at an estimated median of ~4 years, including data from prespecified subgroups, will be presented. Conclusions: With a median follow-up of 43.3 months, A+AVD continues to provide a robust, durable benefit for patients with previously untreated Stage III or IV cHL compared with ABVD; the benefit is evident regardless of patient status at interim PET [PET2(+) or PET2(-)] and without the need for treatment intensification. PN continued to completely resolve or improve in patients on the A+AVD and ABVD arms. Together, these data further support the clinical advantages of A+AVD versus ABVD as treatment for patients with previously untreated Stage III or IV cHL. Disclosures Bartlett: Affimed Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Dynavax: Research Funding; Forty-Seven: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Immune Design: Research Funding; Janssen: Research Funding; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Medimmune: Research Funding; Merck: Research Funding; Millennium: Research Funding; Novartis: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Straus:Elsevier (PracticeUpdate): Consultancy, Honoraria; Hope Funds for Cancer Research: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria. Dlugosz-Danecka:Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Macrogenomics: Research Funding; Roche: Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau. Illes:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Feldman:Takeda: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Cell Medica: Research Funding; Amgen: Research Funding; Viracta: Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Honoraria, Other: Travel expenses, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Pharmacyclics: Honoraria, Other: Travel expenses, Speakers Bureau; Pfizer: Research Funding; Portola Pharma: Research Funding; Roche: Research Funding; Eisai: Research Funding; Corvus: Research Funding; Roche: Research Funding; AbbVie: Honoraria, Other: Travel expenses, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau; Kyowa Hakko Kirin: Research Funding; Trillium: Research Funding. Smolewski:Roche: Other: Travel Expenses. Savage:Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding; BMS, Merck, Novartis, Verastem, Abbvie, Servier, and Seattle Genetics: Consultancy, Honoraria. Walewski:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Takeda: Honoraria, Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria; Gilead: Other: Travel Expenses; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Zinzani:Portola: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy; Eusapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics: Honoraria, Speakers Bureau. Hutchings:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Genmab: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Novartis: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding. Radford:AstraZeneca: Equity Ownership, Research Funding; Novartis: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; ADC Therapeutics: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; GSK: Equity Ownership. Munoz:AstraZeneca: Speakers Bureau; Kite Pharma: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics LLC an AbbVie Company: Consultancy, Research Funding, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Fosunkite: Speakers Bureau; Kyowa: Consultancy, Honoraria, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Portola: Research Funding; Incyte: Research Funding. Kim:Roche: Research Funding; Kyowa-Kirin: Research Funding; Novartis: Research Funding; J&J: Research Funding; Mundipharma: Research Funding; Celltrion: Research Funding; Donga: Research Funding. Advani:Cell Medica, Ltd: Consultancy; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Kura: Research Funding; Infinity Pharma: Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Celmed: Consultancy, Membership on an entity's Board of Directors or advisory committees; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agensys: Research Funding; Stanford University: Employment, Equity Ownership; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Research Funding; Kyowa Kirin Pharmaceutical Developments, Inc.: Consultancy; Regeneron: Research Funding; Millennium: Research Funding; Janssen: Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Sciences, Inc./Kite Pharma, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forty-Seven: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ansell:Mayo Clinic Rochester: Employment; Affimed: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Mayo Clinic Rochester: Employment; Trillium: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Affimed: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment. Younes:Roche: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Curis: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Abbvie: Honoraria; Takeda: Honoraria; Pharmacyclics: Research Funding; AstraZeneca: Research Funding; Genentech: Research Funding; Biopath: Consultancy; Xynomics: Consultancy; Epizyme: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; HCM: Consultancy; BMS: Research Funding; Syndax: Research Funding. Gallamini:Takeda: Consultancy; Roche: Consultancy. Miao:Millennium Pharmaceuticals, Inc., Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment, Equity Ownership. Liu:Takeda: Employment. Fenton:Seattle Genetics, Inc.: Employment, Equity Ownership. Forero-Torres:Seattle Genetics: Employment, Equity Ownership, Honoraria, Research Funding.

Abstract Background: Classical Hodgkin lymphoma (cHL) is characterized by chromosome 9p24.1 alterations (including amplification), leading to overexpression of the PD-L1 and PD-L2 immune checkpoint ligands. This genetically determined dependence on the PD-1 pathway makes cHL an attractive target for PD-1 blockade with the anti-PD-1 monoclonal antibody, pembrolizumab. In the phase 1b KEYNOTE-013 study, pembrolizumab demonstrated high antitumor activity (objective response rate [ORR] of 65%) in heavily pretreated patients with cHL. KEYNOTE-087 is a phase 2 study designed to further evaluate the efficacy and safety of pembrolizumab in different subgroups of patients with relapsed/refractory (R/R) cHL. Methods: KEYNOTE-087 (ClinicalTrials.gov, NCT02453594) is a multicenter, single-arm, multicohort phase 2 study of pembrolizumab in 3 cohorts of patients with R/R cHL: R/R cHL after autologous stem cell transplantation (ASCT) and subsequent brentuximab vedotin (BV) therapy (cohort 1); ineligibility for ASCT due to chemoresistance (no response to salvage chemotherapy) and BV therapy failure (cohort 2); and R/R cHL after ASCT but not treated with BV after ASCT (cohort 3). Patients received pembrolizumab at a fixed dose of 200 mg intravenously every 3 weeks. Response was assessed every 12 weeks according to the 2007 Revised Response Criteria for Malignant Lymphomas. The primary end point was ORR per blinded independent central review (BICR); secondary end points included ORR per investigator review (IR), complete remission rate (CRR), progression-free survival, and overall survival. All patients who received at least 1 dose of pembrolizumab were included in the analyses. Informed consent was obtained for all patients. Biomarkers included PD-L1/PD-L2 expression in formalin-fixed, paraffin-embedded tissue; flow cytometry-based evaluation of absolute and relative numbers of circulating NK cells and T-cell subsets (naive and memory T cells, activated T cells, and regulatory T cells); and gene expression using the NanoString and Illumina RNAseq platforms. The data cutoff date for these analyses was June 27, 2016. Results: Among 210 treated patients in cohorts 1 (n = 69), 2 (n = 81), and 3 (n = 60), all patients had refractory disease or relapsed HL. Of these, 98.6%, 96.3%, and 60.0% had received ≥3 prior lines of therapy, and by design 100% of patients in cohorts 1 and 2 had progressive disease after BV. 41.7% of patients received BV before ASCT in cohort 3. Per IR, ORR (95% CI) was 66.7% (54.3%-77.6%) in cohort 1 (46/69 patients), 65.4% (54.0%-75.7%) in cohort 2 (53/81 patients), and 68.3% (55.0%-79.7%) in cohort 3 (41/60 patients). The CRR was 29.0% in cohort 1, 24.7% in cohort 2, and 21.7% in cohort 3. Per BICR, the ORRs (95% CI) for each cohort were 72.5% (60.4%-82.5%), 65.4% (54.0%-75.7%), and 66.7% (53.3%-78.3%), respectively, and the CRRs were 21.7%, 22.2%, and 21.7%, respectively. A pooled analysis with hierarchical mutually exclusive categories of refractory disease (RD, n = 170) or relapse after ≥3 prior lines of therapy (Re ≥3, n = 40) was conducted across cohorts. Per BICR, ORR was 70.0% (62.5%-76.8%) in RD and 60.0% (43.3%-75.1%) in Re ≥3. Among patients with postbaseline assessment across all cohorts, 93.7% (192/205) experienced a decrease from baseline in tumor size (Figure). With a median of 9 treatment cycles, the most common treatment-related AEs (TRAEs) were pyrexia (11.0%), hypothyroidism (10.5%), diarrhea (6.7%), fatigue (6.7%), headache (6.2%), rash (6.2%), and nausea (5.7%). The most common grade 3/4 TRAEs were neutropenia (1.4%), thrombocytopenia (1.0%), and diarrhea (1.0%). Two patients died; neither death was considered to be treatment-related. At the time of analysis, 115 patients (80% of responders) had an ongoing response. Two hundred patients had evaluable pretreatment tumor tissue (archival or obtained for study) for biomarker analyses. Conclusions: PD-1 blockade with pembrolizumab had substantial clinical activity in subsets of heavily pretreated patients with cHL. Of note, pembrolizumab induced a high ORR in chemoresistant cHL. Additional results, including duration of response per BICR and biomarker analysis, will be presented at the meeting. Figure. Figure. Disclosures Moskowitz: Celgene: Consultancy; Genentech: Consultancy; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Research Funding. Zinzani:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sandoz: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees. Fanale:molecular templates: Research Funding. Armand:Merck & Co., Inc.: Consultancy, Research Funding; Roche: Research Funding; Infinity: Consultancy; BMS: Consultancy, Research Funding; Otsuka: Research Funding; Tensha: Research Funding; Sequenta: Research Funding; Sigma Tau: Research Funding. Radford:Takeda: Honoraria, Research Funding; Seattle Genetics: Honoraria; Novartis: Honoraria; GlaxoSmithKline: Equity Ownership; Astra Zeneca: Equity Ownership. Ribrag:Pharmamar: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; ArgenX: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; Esai: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Nanostring: Membership on an entity's Board of Directors or advisory committees. Vassilakopoulos:Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Genesis Pharma: Membership on an entity's Board of Directors or advisory committees. von Tresckow:Novartis: Consultancy, Other: travel grants, Research Funding; Takeda: Consultancy, Other: travel grants; Millenium: Consultancy. Shipp:Cell Signaling: Honoraria; Bayer: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Merck, Gilead, Takeda: Other: Scientific Advisory Board. Gustafson:Merck & Co., Inc.: Employment, Other: stock, stock options. Zhang:Merck: Employment, Other: stock, stock options. Ricart:Merck & Co.: Employment; Pfizer: Equity Ownership. Balakumaran:Merck & Co.: Employment, Other: stock, stock options. Chen:Merck: Consultancy, Research Funding; Genentech: Consultancy, Speakers Bureau; Millenium: Consultancy, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau.

A bridged peptide analog of RA-VII was designed, in which the α carbons of residues 1 and 4 were linked by a tetramethylene chain to restrict the conformational freedom of the backbone of the 18-membered cyclopeptide. This peptide analog was synthesized by a ring-closing metathesis reaction of [L-2-allylglycine-1, L-2-allylglycine-4]RA-VII and a subsequent hydrogenation of the resulting olefinic compound. Compared with RA-VII, the analog showed much weaker cytotoxic activity toward human promyelocytic leukemia HL-60 cells and human colon carcinoma HCT-116 cells, which may be accounted for by the difference in the orientation of the Tyr-6 phenyl ring plane between the analog and RA-VII.

Introduction: Hyperglycemia must be improved in acute stroke patients. However, effective treatment has not been established. Hypothesis: Moderate-carbohydrate (carbo) diet and sodium-glucose cotransporter 2 (SGLT2) inhibitors can lower blood glucose level (BGL) safely and soon in patients with oral ingestion and normal renal function. Methods: For the retrospective observational study, we included patients who 1) were admitted within 24 h of stroke onset between Jan 2011 and March 2019, 2) had not undergone insulin therapy, 3) presented hemoglobin A1c ≥ 6.5%, BGL ≥ 11.1 mmol/L, and estimated glomerular filtration rate ≥ 60 mL/min/1.73m2 at admission, 4) took diet and drugs orally during hospitalization, and 5) underwent blood examination on the 6th day. We classified patients into three groups: 60% carbo diet without SGLT2 (C60 group); 40% carbo diet without SGLT2 (C40 group); 40% carbo diet with SGLT2 (C40-SGLT2 group). We calculated daily carbo intake and evaluated sulfonylurea (SU) use during hospitalization, median BGL and median HL at admission and on the 6th day in three groups. Results: Of 5724 stroke patients, 84 patients met our inclusion criteria. There were 26 patients in the C60 group, 22 in the C40 group, and 36 in the C40-SGLT2 group. In three groups, median age was 70, 62, and 68 years, respectively, median body mass index was 24.1, 25.1, and 24.3 kg/m2, respectively, median daily carbo intake was 195, 140, and 140 g (p< 0.0001), respectively, 46%, 9%, and 0% of patients used SU (p< 0.0001), respectively, median BGL at admission were 14.2, 14.6, and 14.4 mmol/L, respectively, median HL at admission were 42.4, 44.1, and 43.3%, respectively, median BGL on the 6th day were 7.9, 8.2, and 6.4 mmol/L (p= 0.0003), respectively, and median HL on the 6th day were 40.5, 41.7, and 40.5%, respectively. BGL on the 6th day was decreased in three groups, and it was the most improved in the C40-SGLT2 group. BGL on the 6th day was not different between C60 and C40 groups; however, SU was seldom used in the C40 group. No dehydration occurred. Conclusion: SU was seldom necessary for the C40 group and unnecessary for the C40-SGLT2 group. SGLT2 inhibitors coupled with 40% carbo-diet lowered BGL safely and soon in patients with oral ingestion and normal renal function.