STUDY OF HEPATOPROTECTIVE ACTIVITY OF STINGLESS BEE PROPOLIS AGAINTS TOXICITY OF DRUGS

Objective: The aim of this study is to determine the effect of stingless bee propolis supplementation as a hepatoprotector on the prevention of DILI and the effect of healing and restoring nutrition for DILI patients due to drug induction. Methods: The literature review starts from problem identification, library data collection, reading, taking notes, analyzing, and processing the data obtained and then compiling it into a systematic review Results: The results of a literature study conducted show that propolis has a good hepatoprotective ability against drugs that cause DILI cases such as the anti-tuberculosis, antibiotic and antipyretic groups as indicated by the SGPT, SGOT, BT, GSH, and SOD values that are close to normal values. In addition, propolis supplementation can accelerate the healing and restoration of the nutritional status of DILI patients. All active compounds contained in propolis such as phytochemicals and lipopolysaccharides work to protect the liver from the toxic effects of DILI through antioxidant mechanisms. Conclusion: Overall, the data from this literature study show that the hepatoprotective activity of propolis has the potential to complement drug therapy to reduce hepatotoxic effects and can conclusively beneficial to accelerate the restoration of nutritional status for DILI patients.

Vincristine Sulfate Liposome Injection (VSLI, Marqibo®) in Combination with UK ALL-R3 Induction Chemotherapy for Children, Adolescents and Young Adults with Relapsed Acute Lymphoblastic Leukemia (ALL): A Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL) Consortium Trial

Introduction: Vincristine intensification has the potential to improve outcomes in ALL, but severe neurotoxicity has prohibited escalation beyond standard capped doses. Vincristine sulfate liposome injection, VSLI (Marqibo®) is a liposomal formulation of aqueous vincristine that optimizes pharmacokinetics, prolongs circulating half-life, increases tissue penetration, and may be better tolerated than standard vincristine. VSLI received accelerated FDA approval for adults with relapsed/refractory (r/r) ALL, at a dose of 2.25 mg/m 2/dose without a dose cap. A phase I trial of VSLI in children and young adults with r/r ALL demonstrated safety, tolerability, and evidence for single-agent activity (Shah NN, et al. Pediatric Blood Cancer, 2016). Studies of VSLI with combination chemotherapy in children have not been conducted. With emerging data supporting improved outcomes for patients (pts) with r/r ALL who proceed to immunotherapy with low-burden disease, identifying safe and effective reinduction regimens to reduce disease burden remains a priority. Methods: This multicenter pilot study conducted through the TACL consortium was designed to assess safety and feasibility of VSLI as replacement for standard vincristine with combination chemotherapy for individuals between the ages of 2-21 years with r/r ALL. Two dose levels of VSLI were utilized without a dose cap: Dose level 1 (DL1) 1.5 mg/m 2/dose; and Dose level 2 (DL2) 2.0 mg/m 2/dose. Treatment success was determined by both 1) the absence of a dose-limiting toxicity (DLT) (as defined by any > Grade 3 regimen related non-hematologic toxicity which precluded completion of the pre-specified treatment course or from proceeding to subsequent therapy within 7 weeks) and 2) completion of the prescribed treatment regimen. Adverse event grading was based on CTCAE v4.03. Bone marrow aspirate was used for standard morphologic assessment of response with central flow cytometric analysis for minimal residual disease (MRD) determination with a cut-off of <0.01% of mononuclear cells considered as MRD negative. This analysis reports the toxicities and feasibilities for Cohort A which constituted the 4-drug UK ALL-R3 induction regimen consisting of VSLI, dexamethasone, mitoxantrone, and asparaginase (pegaspargase or Erwinia). Results: A total of 10 pts with r/r B-ALL, median age 13.4 (range 5.0-17.3 years) were treated on Cohort A. Pts were heavily pre-treated, with 3 having relapsed after prior allogeneic stem cell transplantation; 8 of 10 had an M3 marrow (>/= 25% blasts). The first 4 pts were treated at DL1. All 4 were evaluable for toxicity and response and met the criteria for treatment success, facilitating dose escalation to DL2. At DL2, 4 pts were treated, with 2 experiencing DLT, including one grade (Gr) 5 event (Table 1). Two additional pts were subsequently treated at DL1 and achieved treatment success, confirming safety and feasibility of DL1 with a VSLI dose of 1.5 mg/m 2 in combination with UK ALL-R3 4-drug induction. Nine of 10 (90%) pts achieved a morphologic complete remission (CR), 5 of which were MRD negative. The median VSLI dose administered at DL1 was 2.3 mg (range, 1.8-3.2 mg) and at DL2 was 2.2 mg (range, 1.5-3.3 mg) demonstrating the feasibility of dosing beyond the standard vincristine dose-cap of 2 mg. Transient aspartate aminotransferase (AST) and alanine aminotransferase (ALT) elevations were seen in 8 pts, 6 of whom had a grade 1-2 toxicity. Gr 3 hepatic toxicities were seen in 3 pts: 1 each with ALT elevation and hyperbilirubinemia; ALT and AST elevation; gamma-glutamyl transferase elevation. Toxicities were generally consistent with the UK ALL-R3 regimen. Conclusions: In children with r/r ALL, the combination of UK ALL-R3 with VSLI was highly effective with an acceptable safety profile. DL1 (1.5 mg/m 2/dose) was found to be the maximum tolerated dose in combination with this intensive re-induction regimen. The trial continues to enroll at DL1 in the expansion phase to obtain additional safety and response data with this 4-drug regimen. Additionally, 2 cohorts have been added to gain further experience with VSLI in combination with 3-drug induction (Cohort B: UK ALL-R3 without mitoxantrone) and with ALL maintenance chemotherapy (Cohort C: dexamethasone, methotrexate, mercaptopurine). VSLI has potential as a vincristine dose-intensification strategy in combination with reinduction chemotherapy for r/r ALL in pediatric patients. Figure 1 Figure 1. Disclosures Hermiston: Novartis: Consultancy; Sobi: Consultancy. Whitlock: Amgen; Jazz Pharmaceuticals: Honoraria; Novartis: Research Funding; Sobi Pharmaceuticals: Consultancy. Silverman: Takeda, Servier, Syndax, Jazz Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Wayne: Spectrum/Acrotech: Research Funding; KITE/Gilead: Research Funding.

Newly Diagnosed Multiple Myeloma: How Many Drugs Are Enough?

The treatment of multiple myeloma (MM) has evolved over the past decade, yet it remains a chronic disease. Several trials of 4-drug induction regimens have resulted in deepening of disease response. With the emergence of multidrug regimens, questions have arisen regarding the role of autologous stem cell transplant (ASCT) in MM therapy and available treatment options after ASCT. Clinicians have also continued to improve the efficacy of maintenance therapies. In transplant-ineligible patients, the phases of treatment are less distinct; however, several regimens have demonstrated efficacy in this clinical setting. Future research should focus on individualizing treatment approaches.

Updates in the Treatment of Multiple Myeloma

The treatment of multiple myeloma is marked by many recent advances, but for newly diagnosed patients the standard of care for induction remains the combination of a proteasome inhibitor, immunomodulatory drug, and dexamethasone. The role of a 4-drug induction regimen is still being defined, but can be considered for patients with high-risk disease. For patients who are eligible to undergo stem cell transplant, this approach remains the preferred option, but transplant can be delayed until relapse if patients prefer. In those who are not eligible for transplant, based on impressive data with daratumumab/lenalidomide/dexamethasone, this triplet should be considered as initial therapy. In patients with relapsed disease, it is important to switch treatment to new drug classes; for this, multiple combinations can be recommended. Updated guidelines now include new drugs for refractory disease: selinexor and belantamab mafodotin, both listed as “other regimens” in the NCCN Guidelines, can be considered.

Activity of blinatumomab in lymphoblastic leukemia with impaired T-cell immunity due to congenital immunodeficiency

Blinatumomab, a single-chain, bispecific, T-cell–engaging antibody targeting CD19, is effective in B-precursor acute lymphoblastic leukemia (BCP-ALL), even in the context of chemotherapy-related partial T-cell immunodeficiency. We report 2 patients with BCP-ALL and congenital T-cell immunodeficiency, who obtained an excellent response to blinatumomab. The first, a 6-year-old girl with Schimke immuno-osseous dysplasia (SIOD) and combined immunodeficiency disorder (CID) obtained a minimum residual disease–negative (MRD−) remission of high hyperdiploid BCP-ALL with blinatumomab. At last follow-up, the remission had been sustained for 14 months from diagnosis. The second was a 9-year-old boy with Omenn syndrome and CID who received a mismatched bone marrow transplant from his mother at the age of 4 months and was diagnosed with t(3;11)+ (KMT2A-LARS2) BCP-ALL 9 years after his transplant. He received a 4-drug induction followed by blinatumomab for persistent MRD as a chemotherapy-sparing bridge to transplant and achieved an MRD− remission. T-lymphopenia, whether congenital or acquired, does not compromise the efficacy of blinatumomab.

Comparative Study of Effect of Etomidate Versus Propofol plus Ketamine on Haemodynamic Response to Laryngoscopy and Endotracheal Intubation

BACKGROUND Laryngoscopy and endotracheal intubation, a painful procedure, frequently used in airway management is commonly associated with undesired haemodynamic changes like hypertension, tachycardia and arrythmias. Thus, this study was designed to compare haemodynamic stability to laryngoscopy and intubation using single drug induction with etomidate and combined drug induction with propofol and ketamine. METHODS This was a double blind randomised controlled trial, a total of 90 patients of both sexes, aged between 18 - 60 years, who were scheduled for elective surgeries under general anaesthesia in regional institute of medical sciences (RIMS) operation theatre (OT) were divided into two groups. Group PK received propofol (1.5 mg / kg) + ketamine (0.5 mg / kg) and Group E received etomidate (0.3 mg / kg) as induction agents. The haemodynamic parameters (systolic blood pressureSBP, diastolic blood pressure-DBP, mean arterial pressure-MAP, heart rate-HR) were recorded before induction, immediately after induction, 1, 3 and 5 mins after intubation. Side effects like myoclonus and post-operative nausea and vomiting were also noted. RESULTS SBP, DBP, MAP which were recorded, before induction considered as the baseline, and after induction, were comparable between the two groups. SBP, DBP and MAP compared at 1, 3 and 5 mins after intubation showed statistically significant difference between the two groups with propofol-ketamine group showing better haemodynamic stability. The HR between both the groups at various time intervals were comparable and not considered statistically significant. The side effect associated after induction was myoclonus in 14 patients in Group E i.e. 31 % and post-operative nausea vomiting was observed in 8 patients in Group E i.e. 18 %. CONCLUSIONS Thus, in view of haemodynamic stability during laryngoscopy, intubation and side effect profile; propofol and ketamine combination proves to be a better alternative compared to etomidate according to our study. KEYWORDS Propofol, Ketamine, Etomidate, Haemodynamic Stability

Novel Insight into Multi-Hit Multiple Myeloma Based on "Two-Hit" Theory of Cancer Causation

Background: Current definition of multi-hit multiple myeloma (MM) is based upon the number of high-risk cytogenetic abnormalities (CA). But we may overlook the influence of standard-risk CA and different concurrent patterns. In fact, standard-risk t(11;14) and del(13q) may bring extra danger when concurrent with other CA. And the concurrency of two secondary CA may do more harm to patients than that of one secondary CA with one primary CA. This study is to answer whether CA number or pattern exert an impact on outcomes of MM patients. Methods: This study was carried out based on the prospective, non-randomized clinical trial BDH 2008/02. 537 MM patients with complete cytogenetic data were enrolled, of whom 64% (341/537) patients were treated with bortezomib-based three-drug induction therapy, and the remaining patients with thalidomide-based therapy. Autologous stem cell transplantation (ASCT) was recommended post induction therapy in transplant-eligible patients, and all patients received maintenance therapy for two years. CA were divided into primary CA [pCA: any type of IgH breakage], and secondary CA [sCA: del(17p), del(13q), gain(1q) (≥3 copies)] Results: In the era of novel agents, patients with pCA only did not have outcomes different from those patients without any FISH abnormality. Patients with s1 CA or s1+p CA had hazard ratio for PFS or OS of 1.5-2.0. Patients with s2 CA or s2+p CA had hazard ratio for PFS or OS of 2.0-3.0. Patients with concurrent del(13q), del(17p) and gain(1q) (s3 CA) had hazard ratio for PFS of 3.11 and for OS of 3.00. Patients with s3+p CA had hazard ratio for PFS of 4.65 and for OS of 6.16. Based on these results, we divided patients into four subgroups: no CA or only pCA, s1 CA in the presence or absence of pCA, s2 CA in the presence or absence of pCA, and s3 CA in the presence or absence of pCA. Both the PFS and OS decreased in a stepwise fashion with the accumulation of CA (Figure 1). Therefore, we defined double-hit MM as any one sCA in the presence or absence of pCA. Triple-hit MM referred to two sCA plus pCA or not, and quadra-hit MM referred to three sCA plus pCA or not. Furthermore, we confirmed the prognostic independence of CA pattern in the multivariant analysis with International Staging System (ISS) and LDH (Table 1). Conclusion: In this study, we found that the primary CA as a whole lost its adverse effect when treated by bortezomib-based regimens. CA subtype conferred a prognostic value. In details, secondary CA imposed an accumulative risk to patients. For the first time, we indicated that double-hit or triple-hit MM should be defined upon the number of secondary CA. This definition coincides with the "Two-Hit" theory of cancer causation and fits well with MM evolution model. The prognostic significance of CA pattern needs validation in further prospective trials. Disclosures No relevant conflicts of interest to declare.

Drug-Induced Cell Viability Prediction from LINCS-L1000 through WRFEN-XGBoost Algorithm

BackgroundDifferent cell lines have different perturbation signatures under the action of specific compounds. Based on these perturbation signatures, it is very important to predict the cell viability and explore the biological molecular mechanism of action hidden under the phenotype. In the process of testing drug responses to the cancer, traditional experimental methods have been greatly hampered by the cost and sample size. At present, the public availability of large amounts of gene expression data makes it a challenging task to use machine learning methods to predict the drug sensitivity.ResultsIn this study, we developed the WRFEN-XGBoost cell viability prediction algorithm based on the LINCS-L1000 perturbation signatures. We integrateed the LINCS-L1000, CTRP and Achilles datasets and adopted a weighted fusion algorithm based on random forest and elastic net for key gene selection. Then, we combined the FEBPSO-XGBoost algorithm to predict the cell viability under the drug induction. Compared to other methods, our model achieved good results with 0.83 Pearson correlation. At the same time, we completed the drug sensitivity validation on the NCI60 and CCLE datasets, which further demonstrated the effectiveness of our method. ConclusionsOur results indicated that the proposed method could provide help to find the effective anti-cancer drugs and contributed to the medical research.

Study of induced abortion based on the Georgian Birth Registry

Among the countries of the WHO European region, Georgia has the highest numbers of abortion and comprise 420 per 1 000 live births. According the national law and regulation it is necessary to have a mandatory waiting period for five days before the induced abortion. In this study, we aim to assess the usability of different methods and evaluate the effectiveness of mandatory waiting period of induced abortions. We provided retrospective study of secondary data based on cases, extracted from the Georgian Birth Registry. The main variables used for the descriptive statistics were: demographic information of selected cases, parity, gestational age, mode of abortion, real length of mandatory waiting period from registration till the induced abortion. In 2018, was registered 13 612 cases of induced abortion before gestation week 12. Of these, most cases were observed in two age groups: 27.6% was performed among women aged 25-29 and 27.5% among women aged 30-34. From total reported induced abortion cases, 5.4% were provided by dilatation and curettage (from these, 12.6% occurred before 6 weeks gestation), 41.4% was performed by aspiration (from these, 6% occurred at 10-11 weeks of gestation), and 53.2% provided using medical drug-induction (from these, 1.2% occurred at 10-11 weeks of gestation). Of all cases, 14.5% were primiparous women. In 29.3% of cases there were not observed obligatory waiting period before the abortion. 68% of total cases changed the geographical location for the performing induced abortion. According our results, the application of methods of induced abortion is not fully in line with the international recommendations. Additionally, there is violation of national law for keeping mandatory waiting period before induced abortion. The mandatory waiting period before the induced abortion is less effective in Georgia. Moreover, the share of induced abortions performed during the first pregnancy is high. Key messages Health promotion educational activities should be concerned on providing proper information about negative aspects of induced abortion and promote other ways of contraception. Medical personnel should have continues education to be well aware about application of different methodologies of induced abortion.

Outcomes with reduced intensity therapy in a low-risk subset of children with National Cancer Institute (NCI) standard-risk (SR) B-lymphoblastic leukemia (B-ALL): A report from Children’s Oncology Group (COG) AALL0932.

10509 Background: Post-hoc analysis of COG P9904 identified a low risk (LR) group of SR B-ALL patients aged 1-9.99 years with WBC < 50,000/µL, no CNS3, and either ETV6/RUNX1 or double trisomies (DT) of chromosomes 4 and 10 with day 8 peripheral blood (PB) and day 29 marrow (BM) minimal residual disease (MRD) < 0.01% who had a 5-year event-free survival (EFS) of 97±2% and overall survival (OS) 98.8±0.8%. Outstanding results were also obtained for LR patients on COG AALL0331 using CCG-based ALL therapy. AALL0932 tested prospectively whether LR B-ALL patients could attain a 5-year EFS ≥95% with these regimens. Methods: Following a 3-drug induction, eligible AALL0932 LR patients had NCI SR B-ALL (no testicular leukemia, unfavorable genetics or Down syndrome) with DT or ETV6/RUNX1 fusion, CNS1, no steroid pre-treatment, with Day 8 PB and Day 29 BM MRD < 0.01%. Between 2010-16, 603 LR patients were randomized to P9904-based regimen LR-M (n = 301) or CCG 1991/COG AALL0331-based regimen LR-C (n = 302). LR-M included 6 24-hour infusions of 1 gm/m2 of methotrexate (MTX) with leucovorin rescue, but no anthracyclines or alkylating agents. Maintenance followed with daily 6-mercaptopurine (6-MP) and weekly oral MTX, and every 16 week 7-day pulses of dexamethasone (DEX) with vincristine (VCR) on days 1 and 8. Boys and girls were treated for 2.5 years from diagnosis. LR-C had no 24-hour MTX infusions, but included 2 Interim Maintenance (IM) phases with VCR and escalating IV MTX without leucovorin rescue given every 10 days for 5 doses, flanking an 8-week Delayed Intensification (DI) phase that included DEX, VCR, pegasparagase, doxorubicin (75 mg/m2), cyclophosphamide (1 gm/m2) and 8 doses of low-dose cytarabine (75 mg/m2/dose). LR-C Maintenance included daily 6-MP and weekly oral MTX with 5-day pulses of DEX and 1 dose of VCR given every 12 weeks. Girls received 2 years and boys 3 years of therapy from the start of IM I. Results: Both regimens achieved outstanding outcomes: 5-yr disease-free survival (±SE) 98.8%±0.8% for LR-M and 98.5%±0.9% for LR-C (p = 0.67). Both had 5-yr OS 100%. Therapies were well tolerated with higher rates of mucositis (12.9 vs 6.3%; p = 0.008) and allergic reactions (2.3% vs 0%; p = 0.02) on LR-C. Conclusions: AALL0932 demonstrated that application of stringent risk criteria can identify a favorable B-ALL subgroup almost certain to be cured with either LR-M or LR-C, allowing physicians and families to select the optimal treatment approach in the future. Clinical trial information: NCT01190930.