VD Groups Research Articles

Bionic Tiger-Bone Powder Improves Bone Microstructure and Bone Biomechanical Strength of Ovariectomized Rats.

ObjectiveTo study the curative effect of bionic tiger‐bone powder on osteoporosis in ovariectomized rats and investigate its mechanism.MethodsOverall, a 120 female Wistar rats were randomly divided into Sham (sham‐operated group), ovariectomy (OVX, ovariectomized group), TB (bionic tiger‐bone powder treatment group after ovariectomy) and TB + VD groups (bionic tiger‐bone powder + vitamin D treatment group after ovariectomy). The osteoporotic rat model was established 3 months after ovariectomy, and rats were intragastrically administrated with the corresponding drugs. Serum and bone tissue samples were collected from 10 rats in each group at weeks 4, 12 and 24 after intragastric administration. The bone microstructure of L6 vertebrae was analyzed by MicroCT, the biomechanical strength of left femurs was measured by the three‐point bending test, and serum bone metabolism markers (P1NP and CTX) were detected by ELISA. Changes in bone collagen were analyzed by Masson's trichrome staining and hydroxyproline detection, and members of the BMP2/SMAD/RUNX2 and OPG/RANKL/RANK signal pathways were detected by immunoblotting.ResultsCompared with the OVX group, the serum level of P1NP in the TB and TB + VD groups was higher (P < 0.05), while the CTX level was lower (P < 0.05). Bone collagen fiber structures in the TB and TB + VD groups were repaired, and the collagen content was significantly higher than that in the OVX group (P < 0.05). In the TB group, BMP‐2, P‐SMAD1/5, RUNX2 and OPG levels were increased in bone tissue (P < 0.01), RANKL levels were decreased (P < 0.01), and the bone microstructure and biomechanical strength were improved.ConclusionBionic tiger‐bone powder promotes osteogenesis by activating the BMP2/SMAD/RUNX2 signaling pathway, suppresses osteoclasts by downregulating the OPG/RANK/RANKL signaling pathway, increases bone collagen content, and improves bone microstructure and bone biomechanical strength.

Effects of supraphysiological vitamin D3 (cholecalciferol) supplement on normal adult rat ovarian functions.

This study measured the sequelae of cholecalciferol (VD3) therapy on ovarian functions in adult VD-replete rats (n = 48). The animals were distributed into the control and VD groups following estrous cycle synchronisation. The VD group received VD3 injections for 4 weeks (600IU/Kg; 3 times/week). Vaginal cytology and cycle durations were recorded throughout the study. Serum VD (25-OH VD), Ca2+, gonadotrophins (FSH & LH) and sex steroids (E2 & progesterone) were measured following euthanasia. Follicles and corpora lutea were counted in ovarian tissue sections. VD receptor, binding protein, Ca2+-sensing receptor and retinoid X receptor-α genes and proteins were measured by quantitative RT-PCR and immunohistochemistry. Serum VD, LH, E2 and progesterone levels were significantly higher, whereas FSH declined, in the VD group than controls. VD3 therapy was also associated with markedly higher rates alongside shorter durations of estrous cycles than controls. While serum Ca2+ levels were equal between the study groups, they correlated directly with serum 25-OH VD. The numbers of small and medium size ovarian follicles were equal in both study groups, whereas large follicles and corpora lutea counts were significantly higher in the VD group. The mRNAs and proteins of targeted molecules also increased substantially in the VD group than controls. In conclusion, treating VD-sufficient female rats with supraphysiological VD3 supplements was not associated with hypercalcaemia, and could contribute to ovarian functions by regulating the hypothalamic-pituitary-ovarian hormones and ovarian VD-related molecules. However, further studies are still needed to illustrate the clinical significance of VD3 in female reproduction.

Delayed Establishment of Gut Microbiota in Infants Delivered by Cesarean Section.

The maternal vaginal microbiome is an important source for infant gut microbiome development. However, infants delivered by Cesarean section (CS) do not contact the maternal vaginal microbiome and this delivery method may perturb the early establishment and development of the gut microbiome. The aim of this study was to investigate the early gut microbiota of Korean newborns receiving the same postpartum care services for two weeks after birth by delivery mode using fecal samples collected at days 3, 7, and 14. Early gut microbiota development patterns were examined using 16S rRNA gene-based sequencing from 132 infants either born vaginally (VD, n = 64) or via Cesarean section (CS, n = 68). VD-born neonates showed increased alpha diversity in infant fecal samples collated at days 7 and 14 compared to those from day 3, while those of CS infants did not differ (p < 0.015). Bacterial structures of infants from both groups separated at day 7 (p < 0.001) and day 14 (p < 0.01). The bacterial structure of VD infants gradually changed over time (day 3 vs. day 7, p < 0.012; day 3 vs. day 14, p < 0.001). Day 14 samples of CS infants differed from day 3 and 7 samples (day 3 vs. day 14, p < 0.001). VD infant relative abundance of Bifidobacterium (days 7, 14), Bacteroides (days 7, 14), and Lachnospiraceae (day 7) significantly increased compared to CS infants, with a lower abundance of Enterobacteriaceae (found in all periods of the CS group) (LDA > 3.0). Relative abundances of Bifidobacterium, Lactobacillus, and Staphylococcus were significantly increased in both VD and CS groups at day 14 (LDA > 3.0). Predicted functional analysis showed that VD infants had overrepresented starch/sucrose, amino acid and nucleotide metabolism in gut microbiota with depleted lipopolysaccharide biosynthesis until day 14 compared to CS infants. This study confirmed that delivery mode is the major determinant of neonatal intestinal microbiome establishment and provides a profile of microbiota perturbations in CS infants. Our findings provide preliminary insight for establishing recovery methods to supply the specific microbes missing in CS infants.

Neuroprotective effect of different physical exercises on cognition and behavior function by dopamine and 5-HT level in rats of vascular dementia

The aim of the present study is to evaluate neuroprotective effect of different physical exercises on cognition and behavior function by dopamine and 5-HT in rats of vascular dementia. Forty Sprague-Dawley rats were enrolled in this study and randomly divided into following 5 groups: control group (C group, n = 8), vascular dementia group (VD group, n = 8), treadmill exercise and vascular dementia group (TE-VD group, n = 8), in-voluntary exercise and vascular dementia group (IE-VD group, n = 8), voluntary exercise and vascular dementia group (VE-VD group, n = 8). The rats in TE-VD, IE-VD and VE-VD groups were received different physical exercise interventions, treadmill exercise, voluntary running exercise, involuntary running exercise respectively, total 4 weeks. Next, the rats in VE-VD, IE-VD, TE-VD and VD groups were received bilateral common carotids arteries operation to create vascular dementia model. Then, we use a passive avoid test to evaluate cognition and open field test to evaluate cognition autonomic activity in each group. The level in hippocampal dopamine and 5-HT were detected by microdialysis coupled with high performance liquid chromatography. Behavior results demonstrated that: compared with C group, the cognition in VD group significantly decreased (p < 0.001); compared with VD group, the cognition in VE-VD, IE-VD and TE-VD groups were significantly increased (p < 0.001). However, there are no significant difference between VE-VD, IE-VD and TE-VD groups (p> 0.05). In addition, hippocampal dopamine and 5-HT level significantly decreased in VD group when compared with C group (p < 0.001); hippocampal dopamine and 5-HT level in VE-VD, IE-VD and TE-VD groups were significantly increased when compared with VD group (p < 0.05). However, there are no significant difference between VE-VD, IE-VD and TE-VD groups (p> 0.05). Therefore, we concluded that different physical exercises, included treadmill exercise, in-voluntary exercise and voluntary exercise, all can protect cognition by up-regulate dopamine and 5-HT level in rats of vascular dementia.

Safety Profile for Lenalidomide-Based and Non-Lenalidomide-Based First-Line Therapy for Multiple Myeloma in Transplant Ineligible Patients: Real-World Evidence from a European Post-Authorization Safety Study

BACKGROUND: Real-world data can provide important information on the safety profile for recommended treatment options, but these data are collected infrequently. The ongoing post-authorization safety study (PASS) MM-034 (NCT03106324) is a prospective non-interventional study in patients (pts) with newly diagnosed multiple myeloma (NDMM) who are transplant ineligible. This study allows for the collection of robust safety data for currently recommended regimens for the management of these pts. Global guidelines recommend lenalidomide (LEN) regimens, such as LEN plus dexamethasone (DEX; Rd) and LEN plus bortezomib (BORT) plus DEX (Vd), and BORT regimens, including BORT plus melphalan plus prednisone (VMP). METHODS: Transplant-ineligible adult pts with NDMM initiating therapy in centers throughout Europe are being enrolled in the ongoing MM-034 trial. Pts receiving any first-line regimen are eligible, but the decision for which treatment regimen will be used must be made prior to study inclusion. The primary endpoint is the incidence of cardiovascular events. Secondary endpoints include the incidence of renal impairment, infections, and second primary malignancies. In this analysis, the safety profiles of Rd, Vd, and VMP were compared. RESULTS: As of April 12, 2019, 145 Rd, 53 Vd, and 83 VMP pts were enrolled in the study (evaluable cohort). At the time of data cutoff, treatment was ongoing in 64.8% of Rd pts, 41.5% of Vd pts, and 61.4% of VMP pts. Median age was 79 years in Rd pts and 75 years in both Vd and VMP pts. The proportion of pts with ISS stage III disease was higher in the Vd group (24.8% Rd vs 32.1% Vd vs 24.1% VMP), and more pts in the VMP group were male (49.7% Rd vs 58.5% Vd vs 65.1% VMP). Adverse events (AEs) of all grades confirmed the expected side effects. Any-grade neutropenia occurred in 7.6%, 11.3%, and 13.3% of Rd, Vd, and VMP pts, respectively, and thrombocytopenia occurred in 6.2%, 5.7%, and 12.0%, respectively. However, any-grade febrile neutropenia was seen only in the VMP group, at 2.4%, but not in the other 2 groups. Any-grade polyneuropathy was reported in 1.4% of Rd pts, but in 18.9% of Vd pts and 19.3% of VMP pts. Any-grade infections of all kinds occurred in 28.3% of Rd pts, 41.5% of Vd pts, and 20.5% of VMP pts, with pneumonia in 3.4%, 11.3%, and 2.4% of Rd, Vd, and VMP pts, respectively. Any-grade thrombosis was reported in 4.8% of Rd pts and 3.8% of Vd pts and in no VMP pts. Grade 3/4 AEs occurred in 42.8% of Rd pts, 52.8% of Vd pts, and 43.4% of VMP pts. Grade 3/4 neutropenia was reported in 4.8%, 9.4%, and 8.4% of Rd, Vd, and VMP pts, respectively, and thrombocytopenia in 2.8%, 0%, and 8.4%, respectively. Grade 3/4 infections were lower in Rd pts (6.9% vs 24.5% Vd and 12.0% VMP); pneumonia, the most important of these, was reported in 0.7%, 5.7%, and 2.4% of Rd, Vd, and VMP pts, respectively. Grade 3/4 peripheral neuropathy was not seen in the Rd group; however, it was reported in 3.8% of Vd pts and 2.4% of VMP pts. Grade 3/4 venous thrombosis was reported in only 0.7% of Rd pts, with no events reported in the Vd and VMP groups. CONCLUSIONS: The results from this analysis, along with those from a previous analysis of cardiovascular events in the LEN-treated and non-LEN treated cohorts of pts from the European PASS MM-034 study (De Stefano, EHA 2019), provide real-world evidence for the safety profile of Rd as first-line therapy and support the role of Rd in the treatment of pts with NDMM who are transplant ineligible. Disclosures Cavo: celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; bms: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; novartis: Honoraria; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Tromp:Janssen: Other: Grant. Dhanasiri:Celgene Corporation: Employment, Equity Ownership. Kueenburg:Celgene: Consultancy. Rosettani:Celgene International: Employment. Martin:Celgene: Employment. Pozzi:Celgene: Consultancy. Bacon:Celgene: Employment, Equity Ownership. Gamberi:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Front-line treatment (of any type) was at the discretion of the investigator.

Difference in Z scores of placental weight and fetal/placental weight ratio by mode of delivery.

The difference of placental weight (PW) and fetal/placental weight ratio (F/P) Z scores by mode of delivery is unclear. To investigate such differences and the actual conditions underlying the imbalance between fetal and placental growth. The data from Japanese database 2013 were assessed. Light-for-dates (LFD, n = 12 884), appropriate-for-dates (n = 114 464) and heavy-for-dates (n = 13 164) from 140 512 placentas/infants of mothers delivered a singleton infant. Using Z scores of PW and F/P based on the standard curves of a sex-, parity- and gestational-age-specific PW and F/P, the rate of inappropriately heavy placenta according to the mode of delivery (vaginal [VD] vs cesarean [CS]) was investigated. (i) The PW and F/P were heavier and bigger in VD than in CS, in each subgroup. In the LFD groups, the PW Z score in VD was higher than that in CS, whereas the F/P Z score was lower than in VD than that in CS. (ii) Data of single regression analyses between the PW Z score and F/P Z score in VD groups were different from those in CS, especially in LFD infants. (iii) In the LFD subgroups, the rates of inappropriately heavy placenta in VD (n = 7781) and CS (n = 5103) were 0.54% and 0.86%, respectively. Difference in the mode of delivery influenced the PW and F/P, and the rate of inappropriately heavy placenta is associated with mode of delivery among LFD infants. This methodology might give us a clue to search a useful way for identifying the high-risk groups requiring postnatal counseling.

PF595 POMALIDOMIDE + BORTEZOMIB + LOW‐DOSE DEXAMETHASONE AFTER ONE PRIOR LINE OF THERAPY IN PATIENTS WITH LENALIDOMIDE‐PRETREATED MULTIPLE MYELOMA: SUBGROUP ANALYSIS OF THE PHASE 3 OPTIMISMM TRIAL

Background:Lenalidomide (LEN) is an established treatment (Tx) option for newly diagnosed multiple myeloma; however, patients (pts) for whom LEN is no longer a Tx option, including those who have become refractory to LEN, represent a clinically relevant pt population that is growing globally. Results of the phase 3 registrational trial (San Miguel J, et al. Lancet Oncol. 2013;14:1055–1066) showing a significant improvement in progression‐free survival (PFS) and overall survival with pomalidomide (POM) + low‐dose dexamethasone (LoDEX) vs high‐dose dexamethasone in heavily pretreated (median of 5 prior regimens) pts with relapsed or refractory MM (RRMM), most (95%) of whom were refractory to LEN, led to the approval of POM + LoDEX in RRMM. Pomalidomide, bortezomib, and low‐dose dexamethasone (PVd) has demonstrated encouraging activity in early‐phase clinical trials in LEN‐refractory pts. In the phase 3 OPTIMISMM trial (NCT01734928), PVd demonstrated a significantly improved PFS compared with bortezomib and low‐dose dexamethasone (Vd) in intent‐to‐treat population of pts who received 1–3 prior regimens and were 100% LEN pretreated; 70% of pts were LEN refractory.Aims:To compare the efficacy and safety of PVd vs Vd in LEN‐refractory and LEN‐nonrefractory pts treated with 1 prior line of therapy (LOT).Methods:Pts were randomized 1:1 to receive PVd or Vd in 21‐day cycles: POM 4 mg/day on days 1–14 (PVd arm only); bortezomib (BORT) 1.3 mg/m2 on days 1, 4, 8, and 11 of cycles 1–8 and on days 1 and 8 of cycles 9+; and DEX 20 mg/day (10 mg/day if aged &gt; 75 yrs) on the days of and after BORT. The primary endpoint was PFS.Results:As of October 26, 2017, 226 out of 559 pts enrolled had 1 prior LOT (111 PVd; 115 Vd). Among these pts, 129 (57.1%) were LEN refractory (64 PVd; 65 Vd) and 97 (42.9%) were LEN nonrefractory (47 PVd; 50 Vd). In LEN‐refractory pts median age was 68.0 vs 69.0 yrs, 57.8% vs 58.5% were male, and 56.3% vs 47.7% had prior BORT in the PVd vs Vd groups. In LEN‐nonrefractory pts, median age was 66.0 vs 65.5 yrs, 63.8% vs 38% were male, and 66.0% vs 72.0% had prior BORT. After 1 prior LOT, PVd vs Vd significantly improved PFS (median, 17.8 vs 9.5 mos [P = .0276] in LEN‐refractory and 22.0 vs 12.0 mos [P = .0491] in LEN‐nonrefractory pts; Table 1); median follow‐up 16.4 mos. PVd also significantly improved ORR in LEN‐refractory and LEN‐nonrefractory pts compared with Vd (Table 1). In LEN‐refractory pts, the most common grade 3 or 4 treatment‐emergent adverse events (TEAEs) with PVd vs Vd were neutropenia (35.9% vs 12.9%), thrombocytopenia (17.2% vs 22.6%), and anemia (17.2% vs 8.1%); 29.7% vs 21.0% had grade 3 or 4 infections. Among LEN‐nonrefractory pts, the most common grade 3 or 4 TEAEs were neutropenia (36.2% vs 6.3%) and thrombocytopenia (23.4% vs 18.8%). Grade 3 or 4 infections occurred in 27.7% vs 8.3% of pts. LEN‐refractory pts had a median Tx duration of 9.7 with PVd vs 6.1 mos with Vd. In LEN‐nonrefractory pts, median Tx duration of Pvd vs Vd was 13.6 vs 6.6 mos.Summary/Conclusion:In LEN‐refractory and ‐nonrefractory pts after 1 prior LOT, PVd reduced the risk of progression and death by 45% and 46% vs Vd, respectively. Further, in both subgroups, second‐line Tx with PVd significantly improved ORR and led to deeper responses compared with Vd. TEAEs with PVd therapy were generally consistent with the known profiles of POM, BORT, and DEX. These data further demonstrate that PVd is effective and tolerable in pts for whom LEN is no longer a Tx option, including LEN‐refractory pts, supporting its use as second‐line therapy in RRMM.image

PF596 EFFICACY AND SAFETY OF DARATUMUMAB, BORTEZOMIB, AND DEXAMETHASONE (D‐VD) IN RELAPSED OR REFRACTORY MULTIPLE MYELOMA (RRMM): UPDATED SUBGROUP ANALYSIS OF CASTOR BASED ON CYTOGENETIC RISK

Background:Patients (pts) with multiple myeloma associated with high cytogenetic risk abnormalities have poor outcomes. In CASTOR, D‐Vd prolonged progression‐free survival (PFS) vs bortezomib and dexamethasone (Vd) alone, and exhibited a manageable safety profile in pts with RRMM. We conducted a subgroup analysis of D‐Vd vs Vd in CASTOR, based on cytogenetic risk.Aims:The purpose of this analysis was to determine the efficacy and safety of D‐Vd in CASTOR based on cytogenetic risk status.Methods:Eligible pts received ≥1 prior line of therapy. Cytogenetic risk was based on a combined analysis of next‐generation sequencing (NGS) and fluorescence in situ hybridization (FISH)/karyotype testing. High‐risk pts had t(4;14), t(14;16), or del17p abnormalities. Standard (std)‐risk pts were confirmed negative for all 3 abnormalities. Minimal residual disease (MRD; 10–5) was assessed via NGS using clonoSEQ® assay V2.0.Results:In CASTOR (D‐Vd, n = 251; Vd, n = 247), high‐risk was confirmed in 26.7% and 25.9% of pts in the D‐Vd and Vd groups, respectively. At a median follow up of 40.0 months (mo), D‐Vd prolonged PFS vs Vd in pts with high‐ (median 13.4 vs 7.2 mo; HR, 0.40 [95% CI, 0.24–0.65]; P = 0.0002) or std‐risk (median 18.4 vs 6.8 mo; HR, 0.28 [95% CI, 0.20–0.37]; P &lt;0.0001). Higher ORR was seen with D‐Vd vs Vd (high risk: 84.8% vs 60.0%; P = 0.0226; std risk: 85.4% vs 65.0%; P &lt;0.0001), including deep responses of ≥CR (high risk: 33.3% vs 8.3%; std risk: 29.9% vs 10.2%) and ≥VGPR (high risk: 65.2% vs 35.0%; P = 0.0049; std risk: 64.3% vs 28.0%; P &lt;0.0001). Higher rates of MRD negativity (high risk: 17.9% vs 0%; P = 0.0003; std risk: 13.3% vs 2.4%; P = 0.0003), and sustained MRD negativity for ≥6 mo (high risk: 16.4% vs 0%; P = 0.0006; std risk: 6.1% vs 1.8%; P = 0.0859) and ≥12 mo (high risk: 7.5% vs 0%; P = 0.0581; std risk: 1.8% vs 0%; P = 0.2477) were seen with D‐Vd vs Vd. D‐Vd significantly prolonged PFS vs Vd in pts with one prior line of therapy only (high risk: median 20.1 vs 8.4 mo; HR, 0.30 [95% CI, 0.14–0.64]; P = 0.0012; std risk: median 32.6 vs 7.9 mo; HR, 0.18 [95% CI, 0.11–0.29]; P &lt;0.0001; Figure). Additionally, D‐Vd significantly prolonged PFS2 (high risk: median 27.9 vs 18.6 mo; HR, 0.59 [95% CI, 0.37–0.94]; P = 0.0258; std risk: median 40.1 vs 21.6 mo; HR, 0.43 [95% CI, 0.32–0.59]; P &lt;0.0001) regardless of cytogenetic risk status.Additional data including safety analyses will be presented.Summary/Conclusion:Adding daratumumab to Vd demonstrates significant efficacy in pts with high‐risk RRMM including PFS2. Among high‐risk RRMM pts, MRD negativity was only achieved with D‐Vd. These findings support use of D‐Vd for high‐risk RRMM. NCT02136134image

Efficacy and safety of daratumumab, bortezomib, and dexamethasone (D-Vd) in relapsed or refractory multiple myeloma (RRMM) based on cytogenetic risk: Updated subgroup analysis of CASTOR.

8040 Background: MM patients (pts) with high cytogenetic risk have poor outcomes. In CASTOR, D-Vd prolonged progression-free survival (PFS) vs bortezomib and dexamethasone (Vd) alone, and exhibited tolerability in RRMM pts. We conducted a subgroup analysis of D-Vd vs Vd in CASTOR, based on cytogenetic risk. Methods: Pts received ≥1 prior line of therapy. Cytogenetic risk was based on a combined analysis of next-generation sequencing (NGS) and fluorescence in situ hybridization/karyotype testing. High-risk pts had t(4;14), t(14;16), or del17p abnormalities. Standard (std)-risk pts were confirmed negative for all 3 abnormalities. Minimal residual disease (MRD; 10–5) was assessed via NGS using clonoSEQ assay V2.0. Results: In CASTOR (D-Vd, n = 251; Vd, n = 247), high-risk was confirmed in 26.7% and 25.9% of pts in the D-Vd and Vd groups, respectively. At a median follow up of 40.0 months (mo), D-Vd prolonged PFS vs Vd in pts with high- (median 13.4 vs 7.2 mo; HR, 0.40 [95% CI, 0.24-0.65]; P = 0.0002) or std-risk (median 18.4 vs 6.8 mo; HR, 0.28 [95% CI, 0.20-0.37]; P &lt; 0.0001). Higher rates of ORR, MRD negativity, and sustained MRD negativity were seen with D-Vd vs Vd (Table). D-Vd prolonged PFS in first relapse pts (high risk: median 20.1 vs 8.4 mo; HR, 0.30 [95% CI, 0.14-0.64]; P = 0.0012; std risk: median 32.6 vs 7.9 mo; HR, 0.18 [95% CI, 0.11-0.29]; P &lt; 0.0001) and PFS2 vs Vd (high risk: median 27.9 vs 18.6 mo; HR, 0.59 [95% CI, 0.37-0.94]; P = 0.0258; std risk: median 40.1 vs 21.6 mo; HR, 0.43 [95% CI, 0.32-0.59]; P &lt; 0.0001) regardless of risk. Additional data will be presented. Conclusions: Adding daratumumab to Vd demonstrates significant efficacy in high-risk RRMM. Among high-risk pts, MRD negativity was only achieved with D-Vd. These findings support use of D-Vd for high-risk RRMM. Clinical trial information: NCT02136134. [Table: see text]

652: Impact of mode of delivery on neonatal microbial millieu

Mode of delivery has been linked to differences in neonatal microbiota. Given the potential role of the microbiome in neonatal and childhood health, we sought to evaluate whether mode of delivery (MOD) was associated with the bacterial profile in neonates as determined by blood culture. This is a secondary analysis of a multicenter trial evaluating magnesium for fetal neuroprotection in pregnancies at high risk for preterm delivery. We included singleton, non-anomalous, live-born gestations with blood cultures drawn at birth. The primary exposure was MOD. The primary outcome was positive neonatal blood cultures. Latency antibiotics were defined as receipt of ampicillin and erythromycin. Secondary outcomes included neonatal sepsis and microorganisms cultured. Multivariable regression models were used to assess factors related to positive blood cultures and gram-negative aerobes. Of 1804 included subjects, 671 (37.2%) delivered by cesarean (CD), 1133 (62.8%) delivered vaginally (VD), and 294 (16.3%) had positive blood cultures. Mean gestational age at delivery was 29.2 +/-2.8 weeks vs. 29.7 +/-2.7 in the CD and VD groups, respectively (p<0.01). Neonates born by CD were more likely to have positive blood cultures (19.4% vs. 14.5%, p < 0.01) and sepsis (20.7% vs. 16.1%, p=0.01). The most common organism among both CD and VD was coagulase negative Staphylococcus. Adjusting for confounders, CD remained an independent risk factor for positive blood cultures (aOR 1.43, 95% CI 1.06-1.93) (Table 2), even when stratifying by chorioamnionitis. Administration of latency antibiotics was protective (aOR 0.29, 95% CI 0.16-0.53). Notably, CDs were associated with a lower odds of gram negative aerobe colonization (aOR = 0.47, 95% CI 0.25-0.92). CD was associated with an increased risk of positive neonatal blood cultures compared to VD. These findings suggest that MOD may modulate the microbial profile in neonates, and given the potential role of the microbiome in development of obesity, asthma, and allergies, may have longstanding impacts on child health. Further study is needed to understand if these changes persist beyond the newborn period.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Canadian Retrospective Multicentric Study Comparing the Combination of Bortezomib, Cyclophosphamide and Dexamethasone (Cybord) Versus Bortezomib, Thalidomide and Dexamethasone (VTD) Versus Bortezomib and Dexamethasone (Vd) in Patients with Newly Diagnosed Multiple Myeloma Eligible for Autologous Hematopoietic Stem Cell Transplantation (HCT)

Background: Multiple myeloma (MM) is the second most common hematologic cancer. The management of this disease consists of induction therapy followed by autologous hematopoietic stem cell transplantation (HCT). There is no standard of care as for the best induction regime. Recently, the first phase III study (Moreau P and all.) comparing two chemotherapy triplets in transplant-eligible patients, suggested a superiority of VTD over VCD. Although VTD was associated with better treatment response rates, the survival data remains to be seen. We wanted to retrospectively compare 3 Bortezomib-based therapies using response rates (RR), progression-free survival (PFS) and overall survival (OS). Bortezomib-Cyclophosphamide-Dexamethasone (CyBorD) remains the standard in Canada.Method: A total of 75 patients induced between 2010 and 2016 were analyzed. Their charts were reviewed and the data was retrospectively collected. Three distinct treatment groups were included : Vd (19), CyBorD (39) and VTD (17).The main outcome was treatment response rate, 2-year progression-free survival rate (PFS) and 2-year overall survival rate (OS). The secondary outcome was median PFS.Results: Patient characteristics are presented below (table 1). The difference between the treatment response rates were non-statistically significant but demonstrated a favorable trend towards VTD as the VGPR rate was 58.8%, 65% and 88.1% respectively in the Vd, CyBoRD and VTD groups (table 2 and 3). Median progression-free survival was significantly longer in the group that received VTD than in the group that received CyBord (3.58 years vs. 2,80 years; P = 0.03). The 2-year overall survival rate was 88,9%, 96,3% et 93,3% respectively in the 3 groups (table 4).Conclusion: The data from this retrospective study supports the superiority of the VTD induction regimen compared with CyBorD and Vd in terms of response rate and progression-free survival. However, there is no major difference in overall survival over the time period observed. [Display omitted] DisclosuresLeblanc:Amgen Canada: Membership on an entity's Board of Directors or advisory committees; Takeda Canada: Membership on an entity's Board of Directors or advisory committees; Celgene Canada: Membership on an entity's Board of Directors or advisory committees; Janssen Inc.: Membership on an entity's Board of Directors or advisory committees. Boudreault:Celgen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees.

The effects of vitamin D supplementation on healthy and hypercholesterolemic rabbits on levels of OSI and paraoxonase

Abstract Objective Conflicting data are available in literature regarding the effects of vitamin D (VitD) supplementation diet on lipid panel. Therefore, we had the purpose to evaluate the effects of VitD supplementation on lipid panel by a controlled experimental study, and those of VitD supplementation on oxidative stress index (OSI) and paraoxonase-1 (PON1) values in healthy and hypercholesterolemic male rabbits. Methods Thirty New Zealand rabbits were randomly separated into control, VD, HC+VD and HC groups. Control and VD groups were fed with standard chow, whereas HC+VD and HC groups were fed with 0.5% cholesterol chow a period of 8 weeks. During this period, VD and HC+VD groups were orally administered with 300 IU/kg/day VitD. Results The increase in serum total cholesterol (TC) and OSI level of HC group were significant compared to those in HC+VD group. Decreases in serum HDL-cholesterol (HDL-C) and TC levels of VD group were significant within the groups. Conclusion Without any doubt it is important that applied VitD level should be in the ideal range for healthy living. However, it is also necessary to increase the serum HDL-C level (and hence PON1), which is decreases as a result of VitD supplementation. Therefore, we believe that during VitD supplementation, regular physical activity should be performed to increases serum HDL-C.

Acute Vitamin D₃ Supplementation in Severe Obesity: Evaluation of Multimeric Adiponectin.

Obesity predisposes to vitamin D deficiency (VDD) and glucose abnormalities. It is currently debated if vitamin D administration may improve glucose homeostasis by interacting with modulators of insulin sensitivity, such as adiponectin and its oligomers. In a 4-week inpatient study on a metabolic rehabilitation program, consisting of individualized caloric restriction and aerobic physical exercise in obese subjects with VDD, we assessed the acute effects of 600,000 IU cholecalciferol given per os VD group, 12 subjects; body mass index (BMI) 42.7 ± 1.3 kg/m2) or placebo per os (PL group, 12 subjects, BMI 39.8 ± 0.9 kg/m2) on high (HWM-A), medium (MMW-A), and low molecular weight adiponectin (LMW-A), as quantified by western immunoblot (WIB) and ELISA. During the 4-week study, dieting promoted a similar magnitude of weight loss in VD and PL groups. Compared to the PL group, cholecalciferol administration increased 25(OH)Vit D levels (p < 0.001) and promoted a significant increase of HMW-A expression analyzed by WIB (p = 0.02). In parallel, a significant decrease of leptin/HMW-A ratio (p < 0.05), a biomarker of metabolic homeostasis, was observed. During the study, changes of MMW-A and LMW-A occurred independently of cholecalciferol administration, and were likely explained by weight loss. At odds with these findings, the ELISA assessment of adiponectin oligomers showed no modifications in the VD group or PL group. Current findings suggest that acute cholecalciferol administration selectively modifies HMW-A and the leptin/HMW-A ratio.

Therapeutic evaluation of sorafenib for hepatocellular carcinoma using contrast-enhanced ultrasonography: Preliminary result.

The present study aimed to determine the usefulness of contrast-enhanced ultrasonography (CEUS) with Sonazoid in evaluating the therapeutic response to sorafenib for hepatocellular carcinoma (HCC). In total, 26 patients with advanced HCC who received sorafenib and were followed up by CEUS were enrolled in the present study. CEUS was performed prior to and within 2-4 weeks of treatment, and the images of the target lesion in the post-vascular phase with a re-injection method were analyzed. The presence (+) or absence (-) of intratumoral necrosis and the intratumoral vascular architecture on micro-flow imaging (MFI) were compared prior to and subsequent to treatment. Target lesions that exhibited non-enhancement after re-injection were considered to indicate intratumoral necrosis. The intratumoral vascular architecture was classified into three groups, as follows: Vd, the intratumoral vessels visually narrowed or decreased; Vnc, the vessels remained unchanged; and Vi, the vessels were thickened or increased. Survival curves were estimated using the Kaplan-Meier method and compared using the log rank test between the intratumoral necrosis (+) and (-) groups, and among the Vd, Vnc and Vi groups. P<0.05 was considered to indicate a statistically significant difference. The number of patients in the intratumoral necrosis (+) and (-) groups was 8 and 18 patients, respectively, and the median survival time (MST) was 7.2 months [95% confidence interval (CI), 2.2-12.2] and 9.5 months (95% CI, 5.1-13.8), respectively (P=0.44). The MFI findings were observed in 11 patients in the Vd group, 10 patients in the Vnc group and 5 patients in the Vi group. The MSTs in the Vd, Vnc and Vi groups were 15.6 months (95% CI, 5.0-23.3), 11.0 months (95% CI, 3.5-17.6) and 3.6 months (95% CI: 1.2-6.0), respectively. The P-value for the differences between the Vd and Vnc groups, Vd and Vi groups, and Vnc and Vi groups were 0.78, 0.016 and 0.047, respectively, which indicated that the survival time decreased significantly in the Vi group. Evaluation of intratumoral vascular architecture using MFI demonstrates promise for assessing the therapeutic response to sorafenib in patients with HCC.

요양시설 치매노인의 치매유형에 따른 행동심리증상 특성과 간호제공자의 업무 부담감

Abstract The purpose of this study was to examine different patterns of behavioral and psychological symptoms ofdementia (BPSD) and caregiver burden according to dementia type. Data were collected from June 2014 to December2014 from five nursing homes. In all, 214 patients [131 patients with Alzheimer's disease (AD) and 83 patients withVascular dementia (VD)] were included in the study. BPSD and caregiver burden data were examined using NPI-NH (Neuropsychiatric Inventory Nursing Home Version). According to the results, both the AD and VD group showed the highest frequency in apathy/indifference and the frequency of anxiety, elation/euphoria, and irritability/lability wassignificantly higher in the AD group than in the VD group. The difference in total BPSD composite scores between the AD and VD groups was not significant but agitation/aggression was significantly higher in the AD group thanin the VD group. The mean score for caregiver burden was significantly higher in the AD group than in the VD group,particularly in agitation/aggression. In conclusion, BPSD differed according to dementia type, and nurses should provide specific interventions to control BPSD; a program to reduce caregiver burden according to dementia type is also needed.

Serial Echocardiographic Assessment of Patients (Pts) with Relapsed Multiple Myeloma (RMM) Receiving Carfilzomib and Dexamethasone (Kd) Vs Bortezomib and Dexamethasone (Vd): A Substudy of the Phase 3 Endeavor Trial (NCT01568866)

Serial Echocardiographic Assessment of Patients (Pts) with Relapsed Multiple Myeloma (RMM) Receiving Carfilzomib and Dexamethasone (Kd) Vs Bortezomib and Dexamethasone (Vd): A Substudy of the Phase 3 Endeavor Trial (NCT01568866)

Bortezomib-Containing Regimens (BCR) for the Treatment of Non-Transplant Eligible Multiple Myeloma

Introduction In patients not eligible for transplant due to age and/or co-morbidities, the selection of up-front therapy needs to balance efficacy and toxicity. Recently, regimens with bortezomib, a proteasome inhibitor proven to be efficacious in myeloma, have been reported. Based on these findings, we aimed to evaluate the impact of different bortezomib combinations for the treatment of non transplant-eligible MM.Methods All- consecutive patients treated with bortezomib-containing regimens (BCR) at Tom Baker Cancer Center (TBCC) from 01/2006 to June/2015 were evaluated. Definitions of response and progression were used according to the EBMT modified criteria and a category of very good partial response (VGPR) was added. Two-sided Fisher exact test was used to test for differences between categorical variables. A p value of <0.05 was considered significant. Survival curves were constructed according to the Kaplan-Meier method and compared using the log rank test.Results 113 consecutive patients with MM received BCR. Thirty-three patients were treated with cyclophosphamide, bortezomib and dexamethasone (CyBorD), 41 with bortezomib, melphalan and prednisone (VMP) and 39 with bortezomib and dexamethasone (VD). Clinical characteristics are shown in Table 1. At the time of analysis, 20, 17 and 18 patients in the CyBorD, VMP and VD groups are still alive and 14, 33 and 30 have already progressed, respectively. ORR and VGPR rates were 93.9%/75.7%, 80%/53% and 76%/48% (p=0.001) for patients treated with CyBorD, VMP and VD, respectively. Median OS was NR for CyBorD, compared to 41months and 37 months for VMP and VD patients (p=0.6). Median PFS was 16.7 months for CyBorD compared to 17.5 months and 11 months for VMP and VD (P=0.6), respectively. The rate of treatment discontinuation and median number of cycles were: 9%, 26% and 12.8% and 6, 7.5 and 4 cycles for CyBorD, VMP and VD patients, respectively. Patients were to receive 6-9 cycles of treatment and the regimen could be continued to a maximum of 2 years at the discretion of the treating hematologist based on tolerability and response. Nine patients (27%) in the CyBorD group and 17 (41.4%) and 4 (10%) in the VMP and VD group received maintenance treatment. Median OS and PFS was longer for the group receiving maintenance (62 months vs 32 months and 23 months vs 10 months, p=0.007).In conclusion, bortezomib containing regimens are efficacious in the treatment of non-transplant eligible MM. Patients receiving maintenance appeared to exhibit longer PFS and OS. Very elderly patients should be subjected to frailty and comorbidity indexes aiming to decrease toxicity and prolong survival.Table 1Clinical CharacteristicsCharacteristicCyBorD, n=33VMP, n=41VD, n=39Age (median)585858GenderMaleFemale20 (60.6%)13 (39.4%)22 (53.6%)19 (46.4%)26 (66.6%)13 (33.4%)Hb (g/L)107110103Calcium (µmol/L)2.42.352.31Creatinine (µmol/L)115.5103108B2microglobulin (µmol/L)4.13.425.9Albumin (g/L)313130Stage IStage IIStage III6 (12.1%)14 (42.4%)13 (45.5%)9 (21.9%)19 (46.3%)13 (31.8%)4 (10.2%)16 (41%)18 (48.8%)LDH (IU/L)185179174BMPC (%)313033.5Heavy chain:IgGIgAFLC onlyIgDIgMBiclonal22470001914800021107010Light chain:KappaLambdaBiclonal161702912024150High riskStandard risk5 (15%) 286 (14.6%)358 (20%)31Ab: BMPC: Bone marrow plasma cells. [Display omitted] [Display omitted] [Display omitted] DisclosuresJimenez-Zepeda:Celgene: Honoraria; Amgen: Honoraria; J&J: Honoraria. Duggan:Jansen: Honoraria; Celgene: Honoraria. Neri:Celgene: Research Funding. Bahlis:Johnson & Johnson: Speakers Bureau; Johnson & Johnson: Consultancy; Amgen: Consultancy; Johnson & Johnson: Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Impact of 1, 25-(OH)2D3 on Left Ventricular Hypertrophy in Type 2 Diabetic Rats

To investigate the impact of 1, 25-(OH)2D3 on left ventricular hypertrophy (LVH) in type 2 diabetic rats. Type 2 diabetic mellitus (DM) model rats were established by intraperitoneally injecting with 30 mg/kg streptozotocin. After 8 weeks, 19 male rats were identified as diabetic with left ventricular hypertrophy (LVH) by ultrasound examination, and randomly assigned into three groups: untreated (DM-LVH, n=7), treated with insulin (DM-LVH+INS, n=6), and treated with 1, 25-(OH)2D3 (DM-LVH+VD, n=6). Healthy male rats were used as the controls group (n=6). The fasting blood glucose and the insulin level were determined weekly. The left ventricular mass index, myocardial collagen content, collagen volume fraction, and 1, 25-(OH)2D3-receptor level were determined by 4 weeks later. In the DM-LVH model group, the insulin level was significantly decreased compared with the non-diabetic control group (P<0.05), whereas the blood glucose, left ventricular mass index, myocardial collagen content, collagen volume fraction, and 1, 25-(OH)2D3-receptor expression were significantly increased (all P<0.05). In the DM-LVH+INS and DM-LVH+VD groups, the insulin levels were significantly increased compared with the DM-LVH model group (P<0.05), whereas the other parameters were significantly decreased (all P<0.05). 1, 25-(OH)2D3 could reverse LVH in diabetic rats and that the mechanism may involve stimulating insulin secretion and reducing blood glucose via direct up-regulation of 1, 25-(OH)2D3-receptor expression.

Histochemical examination of adipose derived stem cells combined with β-TCP for bone defects restoration under systemic administration of 1α,25(OH)2D3.

The purpose of this study was to evaluate the effects of osteogenic differentiated adipose-derived stem cell (ADSC) loaded beta-tricalcium phosphate (β-TCP) in the restoration of bone defects under intraperitoneal administration of 1α,25-dihydroxyvitamin D3(1α,25(OH)2D3). ADSCs were isolated from the fat tissue of 8 week old Wister rats and co-cultured with β-TCP for 21 days under osteogenic induction. Then the ADSC-β-TCP complexes were implanted into bone defects in the femora of rats. 1α,25(OH)2D3 (VD) or normal saline (NS) was administrated intraperitoneally every other day after the surgery. Femora were harvested at day 7, day 14 and day 28 post-surgery. There were 4 groups for all specimens: β-TCP-NS group; β-TCP-ADSC-NS group; β-TCP-VD group and β-TCP-ADSC-VD group. Alkaline phosphatase (ALP) was up-regulated obviously in ADSC groups compared with non-ADSC groups at day 7, day 14 and day 28, although high expression of runt-related transcription factor 2 (RUNX2) was only seen at day 7. Furthermore, the number of TRAP-positive osteoclasts and the expression of cathepsin K (CK) were significantly decreased in VD groups compared with non-VD groups at day 7 and day 14. As a most significant finding, the β-TCP-ADSC-VD group showed the highest BV/TV ratio compared with the other three groups at day 28. Taken together, ADSC-loaded β-TCP under the administration of 1α,25(OH)2D3 made a promising therapy for bone defects restoration.

Sa1421 Effect of Functional Relaxation on Patients Undergoing Colonoscopy: A Prospective Randomized Controlled Trial

Sa1421 Effect of Functional Relaxation on Patients Undergoing Colonoscopy: A Prospective Randomized Controlled Trial