Survival outcomes in patients with acute myeloid leukaemia who received subsequent therapy for relapse in QUAZAR AML-001.

In the phase 3 QUAZAR AML-001 trial (NCT01757535) of patients with acute myeloid leukaemia (AML) in remission following intensive chemotherapy (IC) and ineligible for haematopoietic stem cell transplant (HSCT), oral azacitidine (Oral-AZA) maintenance significantly prolonged overall survival (OS) versus placebo. The impact of subsequent treatment following maintenance has not been evaluated. In this post hoc analysis, OS was estimated for patients who received subsequent AML therapy, and by regimen received (IC or lower-intensity therapy). First subsequent therapy (FST) was administered after treatment discontinuation in 134/238 Oral-AZA and 173/234 placebo patients. OS from randomization in patients who received FST after Oral-AZA versus placebo was 17.8 versus 12.9 months (HR: 0.82 [95% CI: 0.64-1.04], median follow-up: 56.7 months); OS from FST was similar between arms. Among patients who received injectable hypomethylating agents as FST, median OS was 8.2 versus 4.9 months in the Oral-AZA versus placebo groups (HR: 0.66 [95% CI: 0.41-1.06]). Forty-eight patients (16/238 Oral-AZA, 32/234 placebo) received HSCT following treatment discontinuation, including six Oral-AZA patients still in first remission; Oral-AZA OS benefit persisted when censoring these patients. Oral-AZA maintenance can prolong AML remission duration without negatively impacting survival outcomes after salvage therapies.

Extended exposure to low doses of azacitidine induces differentiation of leukemic stem cells through activation of myeloperoxidase.

Oral azacitidine (oral-Aza) treatment results in longer median overall survival (OS) (24.7 vs. 14.8 months in placebo) in patients with acute myeloid leukemia (AML) in remission after intensive chemotherapy. The dosing schedule of oral-Aza (14 days/28-day cycle) allows for low exposure of Aza for an extended duration thereby facilitating a sustained therapeutic effect. However, the underlying mechanisms supporting the clinical impact of oral-Aza in maintenance therapy remain to be fully understood. In this preclinical work, we explore the mechanistic basis of oral-Aza/extended exposure to Aza through in vitro and in vivo modeling. In cell lines, extended exposure to Aza results in sustained DNMT1 loss, leading to durable hypomethylation, and gene expression changes. In mouse models, extended exposure to Aza, preferentially targets immature leukemic cells. In leukemic stem cell (LSC) models, the extended dose of Aza induces differentiation and depletes CD34+CD38- LSC. Mechanistically, LSC differentiation is driven in part by increased myeloperoxidase (MPO) expression. Inhibition of MPO activity either by using an MPO-specific inhibitor or blocking oxidative stress, a known mechanism of MPO, partly reverses the differentiation of LSC. Overall, our preclinical work reveals novel mechanistic insights into oral-Aza and its ability to target LSC.

Oral azacitidine modulates the bone marrow microenvironment in patients with acute myeloid leukaemia in remission: A subanalysis from the QUAZAR AML-001 trial.

Oral azacitidine (Oral-AZA) maintenance therapy improved relapse-free (RFS) and overall survival (OS) significantly versus placebo for AML patients in remission after intensive chemotherapy (IC) in the phase 3 QUAZAR AML-001 study. Immune profiling was performed on the bone marrow (BM) at remission and on-treatment in a subset of patients with the aim of identifying prognostic immune features and evaluating associations of on-treatment immune effects by Oral-AZA with clinical outcomes. Post-IC, increased levels of lymphocytes, monocytes, T cells and CD34 + CD117+ BM cells were prognostically favourable for RFS. CD3+ T-cell counts were significantly prognostic for RFS in both treatment arms. At baseline, high expression of the PD-L1 checkpoint marker was identified on a subset of CD34 + CD117+ BM cells; many of which were PD-L2+. High co-expression of T-cell exhaustion markers PD-1 and TIM-3 was associated with inferior outcomes. Oral-AZA augmented T-cell numbers during early treatment, increased CD4+:CD8+ ratios and reversed T-cell exhaustion. Unsupervised clustering analysis identified two patient subsets defined by T-cell content and expression of T-cell exhaustion markers that were enriched for MRD negativity. These results indicate that Oral-AZA modulates T-cell activity in the maintenance setting of AML, and these immune-mediated responses are associated with clinical outcomes.

Prognostic impact of NPM1 and FLT3 mutations in patients with AML in first remission treated with oral azacitidine.

The randomized, placebo-controlled, phase 3 QUAZAR AML-001 trial (ClinicalTrials.gov identifier: NCT01757535) evaluated oral azacitidine (Oral-AZA) in patients with acute myeloid leukemia (AML) in first remission after intensive chemotherapy (IC) who were not candidates for hematopoietic stem cell transplantation. Eligible patients were randomized 1:1 to Oral-AZA 300 mg or placebo for 14 days per 28-day cycle. We evaluated relapse-free survival (RFS) and overall survival (OS) in patient subgroups defined by NPM1 and FLT3 mutational status at AML diagnosis and whether survival outcomes in these subgroups were influenced by presence of post-IC measurable residual disease (MRD). Gene mutations at diagnosis were collected from patient case report forms; MRD was determined centrally by multiparameter flow cytometry. Overall, 469 of 472 randomized patients (99.4%) had available mutational data; 137 patients (29.2%) had NPM1 mutations (NPM1mut), 66 patients (14.1%) had FLT3 mutations (FLT3mut; with internal tandem duplications [ITD], tyrosine kinase domain mutations [TKDmut], or both), and 30 patients (6.4%) had NPM1mut and FLT3-ITD at diagnosis. Among patients with NPM1mut, OS and RFS were improved with Oral-AZA by 37% (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.41-0.98) and 45% (HR, 0.55; 95% CI, 0.35-0.84), respectively, vs placebo. Median OS was improved numerically with Oral-AZA among patients with NPM1mut whether without MRD (48.6 months vs 31.4 months with placebo) or with MRD (46.1 months vs 10.0 months with placebo) post-IC. Among patients with FLT3mut, Oral-AZA improved OS and RFS by 37% (HR, 0.63; 95% CI, 0.35-1.12) and 49% (HR, 0.51; 95% CI, 0.27-0.95), respectively, vs placebo. Median OS with Oral-AZA vs placebo was 28.2 months vs 16.2 months, respectively, for patients with FLT3mut and without MRD and 24.0 months vs 8.0 months for patients with FLT3mut and MRD. In multivariate analyses, Oral-AZA significantly improved survival independent of NPM1 or FLT3 mutational status, cytogenetic risk, or post-IC MRD status.

Oral azacitidine prolongs survival of patients with AML in remission independently of measurable residual disease status.

Measurable residual disease (MRD) in patients with acute myeloid leukemia (AML) in remission after intensive chemotherapy is predictive of early relapse and poor survival. Postremission maintenance therapy that prolongs MRD negativity or converts MRD+ patients to MRD- status may delay or prevent relapse and improve overall survival (OS). In the phase 3 QUAZAR AML-001 trial, oral azacitidine (oral-AZA; formerly CC-486), a hypomethylating agent, significantly prolonged OS and relapse-free survival (RFS) compared with placebo in patients aged ≥55 years with AML in first remission after intensive chemotherapy who were not candidates for hematopoietic stem cell transplantation. In this trial, MRD (≥0.1% leukemic cells in bone marrow) was assessed by multiparameter flow cytometry in serial samples collected at baseline and on day 1 of every 3 cycles. As expected, baseline MRD status was significantly associated with both OS and RFS. Multivariate analyses showed oral-AZA significantly improved OS and RFS vs placebo independent of baseline MRD status. Oral-AZA treatment also extended the duration of MRD negativity by 6 months vs placebo and resulted in a higher rate of conversion from MRD+ at baseline to MRD- during treatment: 37% vs 19%, respectively. In the oral-AZA arm, 24% of MRD responders achieved MRD negativity >6 months after treatment initiation. Although presence or absence of MRD was a strong prognostic indicator of OS and RFS, there were added survival benefits with oral-AZA maintenance therapy compared with placebo, independent of patients' MRD status at baseline. Registered at clinicaltrials.gov as #NCT01757535.

Response to upfront azacitidine in juvenile myelomonocytic leukemia in the AZA-JMML-001 trial.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy for most children with juvenile myelomonocytic leukemia (JMML). Novel therapies controlling the disorder prior to HSCT are needed. We conducted a phase 2, multicenter, open-label study to evaluate the safety and antileukemic activity of azacitidine monotherapy prior to HSCT in newly diagnosed JMML patients. Eighteen patients enrolled from September 2015 to November 2017 were treated with azacitidine (75 mg/m2) administered IV once daily on days 1 to 7 of a 28-day cycle. The primary end point was the number of patients with clinical complete remission (cCR) or clinical partial remission (cPR) after 3 cycles of therapy. Pharmacokinetics, genome-wide DNA-methylation levels, and variant allele frequencies of leukemia-specific index mutations were also analyzed. Sixteen patients completed 3 cycles and 5 patients completed 6 cycles. After 3 cycles, 11 patients (61%) were in cPR and 7 (39%) had progressive disease. Six of 16 patients (38%) who needed platelet transfusions were transfusion-free after 3 cycles. All 7 patients with intermediate- or low-methylation signatures in genome-wide DNA-methylation studies achieved cPR. Seventeen patients received HSCT; 14 (82%) were leukemia-free at a median follow-up of 23.8 months (range, 7.0-39.3 months) after HSCT. Azacitidine was well tolerated and plasma concentration--time profiles were similar to observed profiles in adults. In conclusion, azacitidine monotherapy is a suitable option for children with newly diagnosed JMML. Although long-term safety and efficacy remain to be fully elucidated in this population, these data demonstrate that azacitidine provides valuable clinical benefit to JMML patients prior to HSCT. This trial was registered at www.clinicaltrials.gov as #NCT02447666.

Quantification of azacitidine incorporation into human DNA/RNA by accelerator mass spectrometry as direct measure of target engagement.

We report an accelerator mass spectrometry (AMS) assay to quantify azacitidine (Aza) incorporation into DNA and RNA from human acute myeloid leukemia (AML) cells, mouse bone marrow (BM) and peripheral blood mononuclear cells (PBMCs). Aza, a cytidine nucleoside analogue, is a disease modifying pharmacological agent used for treatment of myelodysplastic syndromes (MDS) and AML. Our assay was able to directly quantify the complex of Aza incorporated into DNA/RNA, via isolation of DNA/RNA from matrix (i.e., cancer cells, BM and PBMC) and subsequent measurement of total radioactivity (i.e., 14C-Aza) by using AMS. The sensitivity of the method was able to quantify as little as a single Aza molecule incorporated into DNA with approximately 2 × 107 nucleotides from PBMCs. An in vivo mouse model was used for establishing the lower limits of quantification (LLOQs) for Aza incorporated into DNA/RNA in mouse PBMCs (∼ 3.7 × 105) and BM (∼27.8 mg) collected 24 h post-dose after total exposure of 18 nCi/mouse (Aza 1 mg/kg). The LLOQs for PBMC analysis were 2.5 picogram equivalents per microgram (pgEq/µg) DNA and 0.22 pgEq/µg RNA, and for BM analysis were 1.7 pgEq/µg DNA and 0.22 pgEq/µg RNA. A linear relationship (i.e., ∼10-fold) was established of radioactive dose from 14C-Aza 17 nCi/mouse to 188 nCi/mouse and AMS response (i.e., 14C/12C ratio ranging from 2.45 × 10-11 to 2.50 × 10-10), as Aza was incorporated into DNA in mouse BM. The current method enables the direct measurement of Aza incorporation into DNA and RNA from patient PBMCs and BM to provide dosing optimization, and to assess target engagement with as little as ∼5 mL whole blood and ∼3 mL of BM from patients.

PCA062, a P-cadherin Targeting Antibody-Drug Conjugate, Displays Potent Antitumor Activity Against P-cadherin-expressing Malignancies.

The cell surface glycoprotein P-cadherin is highly expressed in a number of malignancies, including those arising in the epithelium of the bladder, breast, esophagus, lung, and upper aerodigestive system. PCA062 is a P-cadherin specific antibody-drug conjugate that utilizes the clinically validated SMCC-DM1 linker payload to mediate potent cytotoxicity in cell lines expressing high levels of P-cadherin in vitro, while displaying no specific activity in P-cadherin-negative cell lines. High cell surface P-cadherin is necessary, but not sufficient, to mediate PCA062 cytotoxicity. In vivo, PCA062 demonstrated high serum stability and a potent ability to induce mitotic arrest. In addition, PCA062 was efficacious in clinically relevant models of P-cadherin-expressing cancers, including breast, esophageal, and head and neck. Preclinical non-human primate toxicology studies demonstrated a favorable safety profile that supports clinical development. Genome-wide CRISPR screens reveal that expression of the multidrug-resistant gene ABCC1 and the lysosomal transporter SLC46A3 differentially impact tumor cell sensitivity to PCA062. The preclinical data presented here suggest that PCA062 may have clinical value for treating patients with multiple cancer types including basal-like breast cancer.

Phase III, Randomized, Placebo-Controlled Trial of CC-486 (Oral Azacitidine) in Patients With Lower-Risk Myelodysplastic Syndromes.

PURPOSE: Treatment options are limited for patients with lower-risk myelodysplastic syndromes (LR-MDS). This phase III, placebo-controlled trial evaluated CC-486 (oral azacitidine), a hypomethylating agent, in patients with International Prognostic Scoring System LR-MDS and RBC transfusion-dependent anemia and thrombocytopenia. METHODS: Patients were randomly assigned 1:1 to CC-486 300-mg or placebo for 21 days/28-day cycle. The primary end point was RBC transfusion independence (TI). RESULTS: Two hundred sixteen patients received CC-486 (n = 107) or placebo (n = 109). The median age was 74 years, median platelet count was 25 × 109/L, and absolute neutrophil count was 1.3 × 109/L. In the CC-486 and placebo arms, 31% and 11% of patients, respectively, achieved RBC-TI (P = .0002), with median durations of 11.1 and 5.0 months. Reductions of ≥ 4 RBC units were attained by 42.1% and 30.6% of patients, respectively, with median durations of 10.0 and 2.3 months, and more CC-486 patients had ≥ 1.5 g/dL hemoglobin increases from baseline (23.4% v 4.6%). Platelet hematologic improvement rate was higher with CC-486 (24.3% v 6.5%). Underpowered interim overall survival analysis showed no difference between CC-486 and placebo (median, 17.3 v 16.2 months; P = .96). Low-grade GI events were the most common adverse events in both arms. In the CC-486 and placebo arms, 90% and 73% of patients experienced a grade 3-4 adverse event. Overall death rate was similar between arms, but there was an imbalance in deaths during the first 56 days (CC-486, n = 16; placebo, n = 6), most related to infections; the median pretreatment absolute neutrophil count for the 16 CC-486 patients was 0.57 × 109/L. CONCLUSION: CC-486 significantly improved RBC-TI rate and induced durable bilineage improvements in patients with LR-MDS and high-risk disease features. More early deaths occurred in the CC-486 arm, most related to infections in patients with significant pretreatment neutropenia. Further evaluation of CC-486 in MDS is needed.

Combined oral 5-azacytidine and romidepsin are highly effective in patients with PTCL: a multicenter phase 2 study.

Peripheral T-cell lymphomas (PTCLs) are uniquely vulnerable to epigenetic modifiers. We demonstrated in vitro synergism between histone deacetylase inhibitors and DNA methyltransferase inhibitors in preclinical models of T-cell lymphoma. In a phase 1 trial, we found oral 5-azacytidine and romidepsin to be safe and effective, with lineage-selective activity among patients with relapsed/refractory (R/R) PTCL. Patients who were treatment naïve or who had R/R PTCL received azacytidine 300 mg once per day on days 1 to 14, and romidepsin 14 mg/m2 on days 8, 15, and 22 every 35 days. The primary objective was overall response rate (ORR). Targeted next-generation sequencing was performed on tumor samples to correlate mutational profiles and response. Among 25 enrolled patients, the ORR and complete response rates were 61% and 48%, respectively. However, patients with T-follicular helper cell (tTFH) phenotype exhibited higher ORR (80%) and complete remission rate (67%). The most frequent grade 3 to 4 adverse events were thrombocytopenia (48%), neutropenia (40%), lymphopenia (32%), and anemia (16%). At a median follow-up of 13.5 months, the median progression-free survival, duration of response, and overall survival were 8.0 months, 20.3 months, and not reached, respectively. The median progression-free survival and overall survival were 8.0 months and 20.6 months, respectively, in patients with R/R disease. Patients with tTFH enjoyed a particularly long median survival (median not reached). Responders harbored a higher average number of mutations in genes involved in DNA methylation and histone deacetylation. Combined azacytidine and romidepsin are highly active in PTCL patients and could serve as a platform for novel regimens in this disease. This trial was registered at www.clinicaltrials.gov as #NCT01998035.

Anatomical variations and congenital anomalies of the ribs revisited by multidetector computed tomography / Variantes anatômicas e anomalias congênitas dos arcos costais revisitadas por meio da tomografia computadorizada de multidetectores

Abstract As they are asymptomatic or have a nonspecific, anatomical variations of the ribs are usually detected as incidental findings on imaging studies. They may be isolated changes or can be related to anomalies or clinical syndromes. Such variations are easily overlooked on conventional radiography and computed tomography if they are not actively investigated, mainly because most indications for a chest X-ray studies aim to evaluate the lung parenchyma and mediastinal structures. The objective of this pictorial essay was to use multislice computed tomography images to illustrate the imaging aspects of the main anatomical variations and congenital anomalies of the ribs.

Resumo As variantes anatômicas dos arcos costais são, geralmente, achados incidentais nos exames de imagem, em razão do seu comportamento assintomático ou quadro inespecífico, podendo constituir alterações isoladas ou relacionadas a anomalias e síndromes clínicas. Essas alterações são facilmente negligenciadas na radiografia convencional e na tomografia computadorizada se não forem investigadas ativamente, principalmente quando a maioria das indicações do estudo radiológico do tórax tem como objetivo a avaliação do parênquima pulmonar e das estruturas mediastinais. O objetivo deste artigo é demonstrar, por meio da tomografia computadorizada multidetectores, os aspectos de imagem das principais variantes anatômicas e anomalias congênitas dos arcos costais.

Design, Synthesis, and Structure-Activity Relationships of Novel Tetrahydroisoquinolino Benzodiazepine Dimer Antitumor Agents and Their Application in Antibody-Drug Conjugates.

A series of tetrahydroisoquinoline-based benzodiazepine dimers were synthesized and tested for in vitro cytotoxicity against a panel of cancer cell lines. Structure-activity relationship investigation of various spacers guided by molecular modeling studies helped to identify compounds with picomolar activity. Payload 17 was conjugated to anti-mesothelin and anti-fucosylated monosialotetrahexosylganglioside (FucGM1) antibodies using lysosome-cleavable valine-citrulline dipeptide linkers via heterogeneous lysine conjugation and bacterial transglutaminase-mediated site-specific conjugation. In vitro, these antibody drug conjugates (ADCs) exhibited significant cytotoxic and target-mediated selectivity on human cancer cell lines. The pharmacokinetics and efficacy of these ADCs were further evaluated in gastric and lung cancer xenograft models in mice. Consistent pharmacokinetic profiles, high target specificity, and robust antitumor activity were observed in these models after a single dose of the ADC-46 (0.02 µmol/kg).

Oral 5-azacytidine and romidepsin exhibit marked activity in patients with PTCL: a multicenter phase 1 study.

The peripheral T-cell lymphomas (PTCLs) are uniquely sensitive to epigenetic modifiers. Based on the synergism between histone deacetylase inhibitors and hypomethylating agents that we established in preclinical PTCL models, we conducted a phase 1 study of oral 5-azacytidine (AZA) and romidepsin (ROMI) in patients with advanced lymphoid malignancies, with emphasis on PTCL. According to a 3 + 3 design, patients were assigned to 1 of 7 cohorts with AZA doses ranging from 100 mg daily on days 1 to 14 to 300 mg daily on days 1 to 21, ROMI doses ranging from 10 mg/m2 on days 8 and 15 to 14 mg/m2 on days 8, 15, and 22, with cycles of 21 to 35 days. Coprimary end points included maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). We treated a total of 31 patients. The MTD was AZA 300 mg on days 1 to 14 and ROMI 14 mg/m2 on days 8, 15, and 22 on a 35-day cycle. DLTs included grade 4 thrombocytopenia, prolonged grade 3 thrombocytopenia, grade 4 neutropenia, and pleural effusion. There were no treatment-related deaths. The combination was substantially more active in patients with PTCL than in those with non-T-cell lymphoma. The overall response rate in all, non-T-cell, and T-cell lymphoma patients was 32%, 10%, and 73%, respectively, and the complete response rates were 23%, 5%, and 55%, respectively. We did not find an association between response and level of demethylation or tumor mutational profile. This study establishes that combined epigenetic modifiers are potently active in PTCL patients. This trial was registered at www.clinicaltrials.gov as NCT01998035.

Sufentanil during anesthetic induction of remifentanil-based total intravenous anesthesia: a randomized controlled trial / Sufentanil durante a indução da anestesia intravenosa total à base de remifentanil: ensaio clínico randômico

Abstract Background Postoperative pain represents an important concern when remifentanil is used for total intravenous anesthesia because of its ultrashort half-life. Longer acting opioids, such as sufentanil, have been used during induction of remifentanil-based total intravenous anesthesia as a means to overcome this shortcoming. However, the effectiveness and safety of such strategy still lacks evidence from randomized clinical trials. Hence, we aimed to assess the postoperative analgesic efficacy and safety of a single dose of sufentanil administered during the induction of remifentanil-based total intravenous anesthesia. Methods Forty patients, scheduled for elective open abdominal surgery, were randomized to receive remifentanil-based total intravenous anesthesia with or without a single dose of sufentanil upon induction. We assessed the postoperative morphine consumption administered through a patient-controlled analgesia pump. Self-reported pain scores and the occurrence of nausea, vomiting, pruritus, agitation, somnolence and respiratory depression were also assessed up to 2 days after surgery. Results The mean difference between the sufentanil and control groups regarding morphine consumption in the post-anesthetic care unit and at 12, 24 and 48 h after surgery were -7.2 mg (95%CI: -12.5 to -2.1, p < 0.001), -3.9 mg (95%CI: -11.9 to 4.7, p = 0.26), -0.6 mg (95%CI: (-12.7 to 12.7, p = 0.80), and -1.8 mg (95%CI: (-11.6 to 15.6, p = 0.94), respectively. Neither self-reported pain nor the incidence of adverse events were significantly different between groups at any time point. Conclusion Our findings suggest that the administration of sufentanil during induction of remifentanil-based total intravenous anesthesia is associated with decreased early postoperative opioid consumption.

Resumo Justificativa A dor pós-operatória é uma grande preocupação quando o remifentanil é usado para anestesia intravenosa total devido à sua meia-vida ultracurta. Os opioides de ação mais longa, como o sufentanil, têm sido usados durante a indução de anestesia intravenosa total à base de remifentanil como um meio de superar essa deficiência. Porém, a eficácia e segurança de tal estratégia ainda precisam de evidências advindas de ensaios clínicos randômicos. Portanto, objetivamos avaliar a eficácia analgésica e a segurança pós-operatória de uma dose única de sufentanil administrada durante a indução de anestesia intravenosa total à base de remifentanil. Métodos Quarenta pacientes eletivamente agendados para cirurgia abdominal aberta foram randomizados para receber anestesia intravenosa total à base de remifentanil, com ou sem uma dose única de sufentanil, após a indução da anestesia. Avaliamos o consumo de morfina no pós-operatório, administrado através de uma bomba de analgesia controlada pelo paciente. Os escores de dor autorrelatados e a ocorrência de náusea, vômito, prurido, agitação, sonolência e depressão respiratória também foram avaliados até dois dias após a cirurgia. Resultados A diferença média entre os grupos sufentanil e controle em relação ao consumo de morfina em sala de recuperação pós-anestesia e após 12, 24 e 48 horas da cirurgia foi de -7,2 mg (IC 95%: -12,5 a -2,1, p < 0,001), -3,9 mg (IC 95%: -11,9 a 4,7, p = 0,26), -0,6 mg (IC 95%: (-12,7 a 12,7, p = 0,80) e -1,8 mg (IC 95%: -11,6 para 15,6, p = 0,94), respectivamente. Não houve diferença significativa tanto nos escores de dor autorrelatados, quanto na incidência de eventos adversos entre os grupos. Conclusão Nossos achados sugerem que a administração de sufentanil durante a indução de anestesia intravenosa total à base de remifentanil está associada à redução do consumo de opioides no pós-operatório imediato.

[Sufentanil during anesthetic induction of remifentanil-based total intravenous anesthesia: a randomized controlled trial]. / Sufentanil durante a indução da anestesia intravenosa total à base de remifentanil: ensaio clínico randômico.

BACKGROUND: Postoperative pain represents an important concern when remifentanil is used for total intravenous anesthesia because of its ultrashort half-life. Longer acting opioids, such as sufentanil, have been used during induction of remifentanil-based total intravenous anesthesia as a means to overcome this shortcoming. However, the effectiveness and safety of such strategy still lacks evidence from randomized clinical trials. Hence, we aimed to assess the postoperative analgesic efficacy and safety of a single dose of sufentanil administered during the induction of remifentanil-based total intravenous anesthesia. METHODS: Forty patients, scheduled for elective open abdominal surgery, were randomized to receive remifentanil-based total intravenous anesthesia with or without a single dose of sufentanil upon induction. We assessed the postoperative morphine consumption administered through a patient-controlled analgesia pump. Self-reported pain scores and the occurrence of nausea, vomiting, pruritus, agitation, somnolence and respiratory depression were also assessed up to 2 days after surgery. RESULTS: The mean difference between the sufentanil and control groups regarding morphine consumption in the post-anesthetic care unit and at 12, 24 and 48h after surgery were -7.2mg (95%CI: -12.5 to -2.1, p<0.001), -3.9mg (95%CI: -11.9 to 4.7, p=0.26), -0.6mg (95%CI: (-12.7 to 12.7, p=0.80), and -1.8mg (95%CI: (-11.6 to 15.6, p=0.94), respectively. Neither self-reported pain nor the incidence of adverse events were significantly different between groups at any time point. CONCLUSION: Our findings suggest that the administration of sufentanil during induction of remifentanil-based total intravenous anesthesia is associated with decreased early postoperative opioid consumption.

Randomised phase 2 study of pembrolizumab plus CC-486 versus pembrolizumab plus placebo in patients with previously treated advanced non-small cell lung cancer.

INTRODUCTION: Preclinical and early clinical studies suggest that combining epigenetic agents with checkpoint inhibitors can potentially improve outcomes in patients with previously treated advanced non-small cell lung cancer (NSCLC). This phase 2 trial examined second-line pembrolizumab + CC-486 (oral azacitidine) in patients with advanced NSCLC. METHODS: Patients with one prior line of platinum-containing therapy were randomised in a ratio of 1:1 to CC-486 or placebo, on days 1-14, in combination with pembrolizumab on day 1 of a 21-day cycle. The primary end-point was progression-free survival (PFS). Key secondary end-points included overall survival (OS), overall response rate (ORR) and safety. RESULTS: Among 100 patients randomised (pembrolizumab + CC-486: 51; pembrolizumab + placebo: 49), most were male (57.0%), were white (87.0%) and had Eastern Cooperative Oncology Group performance status 1 (68.0%). No significant difference in PFS was observed between the pembrolizumab + CC-486 and pembrolizumab + placebo arms (median, 2.9 and 4.0 months, respectively; hazard ratio [HR], 1.374; 90% confidence interval [CI], 0.926-2.038; P = 0.1789). Median OS was 11.9 months versus not estimable (HR, 1.375; 90% CI, 0.830-2.276; P = 0.2968); ORR was 20% versus 14%. Median treatment duration was shorter (15.0 versus 24.1 weeks), and the number of cycles was lower (5.0 versus 7.0) with pembrolizumab + CC-486 versus pembrolizumab + placebo. No new safety signals for CC-486 or pembrolizumab were detected. Treatment-emergent adverse events were more common in the pembrolizumab + CC-486 arm, particularly gastrointestinal, potentially impacting treatment feasibility. CONCLUSIONS: No improvement in PFS was observed with pembrolizumab + CC-486 versus pembrolizumab + placebo. Decreased treatment exposure due to adverse events may have impacted efficacy with pembrolizumab + CC-486.

A Novel, Fully Human Anti-fucosyl-GM1 Antibody Demonstrates Potent In Vitro and In Vivo Antitumor Activity in Preclinical Models of Small Cell Lung Cancer.

Purpose: The ganglioside fucosyl-GM1 (FucGM1) is a tumor-associated antigen expressed in a large percentage of human small cell lung cancer (SCLC) tumors, but absent in most normal adult tissues, making it a promising target in immuno-oncology. This study was undertaken to evaluate the preclinical efficacy of BMS-986012, a novel, nonfucosylated, fully human IgG1 antibody that binds specifically to FucGM1.Experimental Design: The antitumor activity of BMS-986012 was evaluated in in vitro assays using SCLC cells and in mouse xenograft and syngeneic tumor models, with and without chemotherapeutic agents and checkpoint inhibitors.Results: BMS-986012 showed a high binding affinity for FcγRIIIa (CD16), which resulted in enhanced antibody-dependent cellular cytotoxicity (ADCC) against FucGM1-expressing tumor cell lines. BMS-986012-mediated tumor cell killing was also observed in complement-dependent cytotoxicity (CDC) and antibody-dependent cellular phagocytosis (ADCP) assays. In several mouse SCLC models, BMS-986012 demonstrated efficacy and was well tolerated. In the DMS79 xenograft model, tumor regression was achieved with BMS-986012 doses of 0.3 mg/kg and greater; antitumor activity was enhanced when BMS-986012 was combined with standard-of-care cisplatin or etoposide. In a syngeneic model, tumors derived from a genetically engineered model of SCLC were treated with BMS-986012 or anti-FucGM1 with a mouse IgG2a Fc and their responses evaluated; when BMS-986012 was combined with anti-PD-1 or anti-CD137 antibody, therapeutic responses significantly improved.Conclusions: Single-agent BMS-986012 demonstrated robust antitumor activity, with the addition of chemotherapeutic or immunomodulatory agents further inhibiting SCLC growth in the same models. These preclinical data supported evaluation of BMS-986012 in a phase I clinical trial of patients with relapsed, refractory SCLC. Clin Cancer Res; 24(20); 5178-89. ©2018 AACR.

Replacement of corn with mango meal for dairy goats / Sustitución de maíz por harina de mango para cabras lecheras / Substituição do milho pelo farelo de manga em cabras leiteiras

Summary Background: the high volume of mangos harvested during the season, associated with inappropriate management of the fruit after harvesting results in increased waste of this valuable resource. Mango fruit, rich in carbohydrates, has potential use in animal feeding. Objective: to evaluate the effect of replacing corn with whole mango meal (0, 330, 660, and 1000 g/Kg on dry matter basis) in the diets of dairy goats on rumen fermentation kinetics, intake, milk yield and composition, and economic results. Methods: eight lactating Saanen crossbred goats (48.7 ± 1.99 Kg body weight) were used in the experiment, which started 48 days postpartum and lasted until completing 124 days of lactation. The experimental design consisted of a double Latin square (4×4) with four treatments, four periods and four animals per square. Results: a reduction (p<0.05) was observed in gas production from total carbohydrates and fiber carbohydrates. Replacement of corn with whole mango meal showed no effect on DM intake (1,890 g/d), crude protein (278 g/d) and neutraldetergent fiber (959 g/d). Milk production (4% fat-corrected) and milk composition were not affected by the treatments, except for fat and myristoleic fatty acid contents. The economic evaluation showed a reduction in the total feeding cost and a better benefit:cost ratio. Conclusion: whole mango meal can replace corn up to 330 g/Kg in the diet of lactating goats.

Resumen Antecedentes: la alta producción de mango asociado con una gestión inadecuada durante la producción y pos-cosecha, resulta en un aumento de los residuos en el medio ambiente. Debido a que el mango es una fruta rica en carbohidratos (fuente de energía) es posible su utilización en la alimentación de los animales. Objetivo: evaluar el efecto de la sustitución de maíz con harina integral de mango (0, 330, 660 y 1000 g/Kg en base a materia seca) en las dietas de cabras lecheras sobre la cinética de fermentación ruminal, consumo, producción y composición láctea y evaluación económica de las dietas. Métodos: ocho cabras Saanen mestizas en lactación (48,7 ± 1,99 Kg de peso corporal) fueron utilizadas en el experimento desde el día 48 hasta el día 124 de lactancia. Se utilizó un diseño experimental doble cuadrado latino (4×4) con cuatro tratamientos, cuatro períodos y cuatro animales. Resultados: se observó una reducción (p<0,05) en la producción y volumen de gas de los carbohidratos totales y carbohidratos fibrosos. La sustitución de maíz con harina de mango integral no mostró ningún efecto sobre el consumo de materia seca (1890 g/d), proteína bruta (278 g/d) y fibra detergente neutra (959 g/d). La producción de leche (corregida al 4% de grasa) y su composición no fueron afectadas por los tratamientos, excepto para el contenido de grasa y ácido graso miristoleico. La evaluación económica mostró una reducción en el costo total de la alimentación y una mejor relación costo:beneficio. Conclusión: se recomienda sustituir el maíz por la harina de mango integral en hasta 330 g/Kg en las dietas de cabras lecheras.

Resumo Antecedentes: a elevada produção de manga associada a um manejo inadequado durante a produção e pós- colheita, resulta em aumento de resíduos no ambiente. Por ser uma fruta rica em carboidratos (fonte de energia) é possível a sua utilização na alimentação animal. Objetivo: avaliar o efeito da substituição do milho pelo farelo de manga integral (0, 330, 660 e 1000 g/Kg na matéria seca) na dieta de cabras leiteiras sobre a cinética de fermentação ruminal, consumo, produção e composição do leite, e também avaliação econômica das dietas. Métodos: oito cabras mestiças Saanen em lactação (48,7 ± 1,99 Kg de peso corporal) foram introduzidas no experimento 48 dias pós-parto e mantidas até 124 dias de lactação. Foi utilizado um delineamento em duplo quadrado Latino (4×4), com quatro tratamentos, quatro períodos e quatro animais por quadrado. Resultados: houve redução (p<0,05) na produção máxima de gás a partir dos carboidratos totais e o volume de gás produzido a partir de carboidratos fibrosos. A substituição do milho pelo farelo de manga integral não mostrou nenhum efeito sobre o consumo de matéria seca (1890 g/d), proteína bruta (278 g/d) e fibra em detergente neutro (959 g/d). A produção de leite corrigida para 4% de gordura e a composição do leite não foram afetadas pelos tratamentos, com exceção do teor de gordura e o ácido graxo miristoleico. A avaliação econômica mostrou uma redução no custo total da alimentação e uma melhor relação custo:benefício. Conclusão: recomenda-se substituir o milho pelo farelo de manga integral até 330 g/Kg na dieta de cabras leiteiras.