A phase 1 study of the antibody-drug conjugate brentuximab vedotin with re-induction chemotherapy in patients with CD30-expressing relapsed/refractory acute myeloid leukemia.

BACKGROUND: Outcomes for patients with relapsed/refractory acute myeloid leukemia (R/R AML) remain poor. Novel therapies specifically targeting AML are of high interest. Brentuximab vedotin (BV) is an antibody-drug conjugate that is specific for human CD30. In this phase 1 dose escalation study, the authors evaluated the safety of BV combined with mitoxantrone, etoposide, and cytarabine (MEC) re-induction chemotherapy for patients with CD30-expressing R/R AML. METHODS: Using a standard dose escalation design, the authors evaluated 3 dose levels of BV (0.9 mg/kg, 1.2 mg/kg, and 1.8 mg/kg) administered once on day 1 followed by MEC on days 3 through 7. RESULTS: There were no dose-limiting toxicities noted and the maximum tolerated dose was not reached. The recommended phase 2 dose of BV was determined to be 1.8 mg/kg when combined with MEC. The side effect profile was similar to that expected from MEC chemotherapy alone, with the most common grade ≥3 toxicities being febrile neutropenia, thrombocytopenia, and anemia (toxicities were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). Among the 22 patients enrolled on the trial, the composite response rate was 36%, with a composite response rate of 42% noted among those who received the highest dose of BV. The median overall survival was 9.5 months, with a median disease-free survival of 6.8 months observed among responders. Approximately 55% of patients were able to proceed with either allogeneic hematopoietic stem cell transplantation or donor lymphocyte infusion. CONCLUSIONS: The combination of BV with MEC was found to be safe in patients with CD30-expressing R/R AML and warrants further study comparing this combination with the use of MEC alone in this population (ClinicalTrials.gov identifier NCT01830777). LAY SUMMARY: The outcomes for patients with relapsed/refractory acute myeloid leukemia (R/R AML) are exceptionally poor. New and emerging treatment combinations are actively being studied in an effort to improve outcomes. The authors examined the combination of brentuximab vedotin, an antibody product that recognizes a marker called CD30, with mitoxantrone, etoposide, and cytarabine (MEC), a common chemotherapy regimen, in patients with R/R AML that expressed the CD30 marker. The authors found that the combination was safe and well tolerated. Future studies comparing this new combination with the use of MEC alone can help to inform its effectiveness for this patient population.

Isocitrate dehydrogenase 1 and 2 mutations, 2-hydroxyglutarate levels, and response to standard chemotherapy for patients with newly diagnosed acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) cells harboring mutations in isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) produce the oncometabolite 2-hydroxyglutarate (2HG). This study prospectively evaluated the 2HG levels, IDH1/2 mutational status, and outcomes of patients receiving standard chemotherapy for newly diagnosed AML. METHODS: Serial samples of serum, urine, and bone marrow aspirates were collected from patients newly diagnosed with AML, and 2HG levels were measured with mass spectrometry. Patients with baseline serum 2HG levels greater than 1000 ng/mL or marrow pellet 2HG levels greater than 1000 ng/2 × 106 cells, which suggested the presence of an IDH1/2 mutation, underwent serial testing. IDH1/2 mutations and estimated variant allele frequencies were identified. AML characteristics were compared with the Wilcoxon test and Fisher's exact test. Disease-free survival and overall survival (OS) were evaluated with log-rank tests and Cox regression. RESULTS: Two hundred and two patients were treated for AML; 51 harbored IDH1/2 mutations. IDH1/2-mutated patients had significantly higher 2HG levels in serum, urine, bone marrow aspirates, and aspirate cell pellets than wild-type patients. A serum 2HG level greater than 534.5 ng/mL was 98.8% specific for the presence of an IDH1/2 mutation. Patients with IDH1/2-mutated AML treated with 7+3-based induction had a 2-year event-free survival (EFS) rate of 44% and a 2-year OS rate of 57%. There was no difference in complete remission rates, EFS, or OS between IDH1/2-mutated and wild-type patients. Decreased serum 2HG levels on day 14 as a proportion of the baseline were significantly associated with improvements in EFS (P = .047) and OS (P = .019) in a multivariate analysis. CONCLUSIONS: Among patients with IDH1/2-mutated AML, 2HG levels are highly specific for the mutational status at diagnosis, and they have prognostic relevance in patients receiving standard chemotherapy.

Cabozantinib is well tolerated in acute myeloid leukemia and effectively inhibits the resistance-conferring FLT3/tyrosine kinase domain/F691 mutation.

BACKGROUND: Cabozantinib, a tyrosine kinase inhibitor of FMS-like tyrosine kinase 3 (FLT3), MET, AXL, vascular endothelial growth factor receptor, and KIT, is approved for use in multiple malignancies. We assessed the safety and tolerability of cabozantinib in AML, given up-regulation of multiple relevant pathways. METHODS: Adults were eligible if they were 18 years old or older with relapsed/refractory AML or if they were 70 years old or older with newly diagnosed AML but were ineligible for conventional therapy. Cabozantinib was administered in 28-day cycles, and dose escalation occurred via cohorts. A pharmacodynamic evaluation of serial plasma samples via a plasma inhibitory assay (PIA) was used to assess FLT3-inhibitory activity in FLT3-mutant cell lines. RESULTS: Among 18 patients enrolled, 5 were found to harbor FLT3/ITD mutations. Sixteen patients (89%) had relapsed/refractory AML, and most were treated with 2 or more lines of prior treatment. No dose-limiting toxicities (DLTs) were detected at the first dose level (40 mg daily), but 2 patients experienced DLTs at the next level (60 mg daily). The remaining patients were then dosed at 40 mg daily, the maximum tolerated dose (MTD). Additional grade 2 or higher toxicities, possibly/probably related to cabozantinib, included fatigue, nausea, transaminitis, and electrolyte imbalance. No patients had a marrow response according to formal criteria, but 4 had peripheral blast reductions; 2 of these 4 patients transiently cleared circulating blasts. One patient experienced a reduction in marrow blasts, and 1 had stable disease. The FLT3-inhibitory activity of plasma samples, as assessed with the PIA, revealed potent and sustained inhibition in FLT3/ITD and, notably, F691 tyrosine kinase domain (TKD)-mutant cells. CONCLUSIONS: Cabozantinib is well tolerated in AML patients at an MTD of 40 mg daily and is a potent inhibitor of FLT3/ITD- and F691 TKD-altered tyrosine kinases. Cancer 2018;124:306-14. © 2017 American Cancer Society.

Phase I study of the aurora A kinase inhibitor alisertib with induction chemotherapy in patients with acute myeloid leukemia.

Aberrant expression of aurora kinase A is implicated in the genesis of various neoplasms, including acute myeloid leukemia. Alisertib, an aurora A kinase inhibitor, has demonstrated efficacy as monotherapy in trials of myeloid malignancy, and this efficacy appears enhanced in combination with conventional chemotherapies. In this phase I, dose-escalation study, newly diagnosed patients received conventional induction with cytarabine and idarubicin, after which alisertib was administered for 7 days. Dose escalation occurred via cohorts. Patients could then receive up to four cycles of consolidation, incorporating alisertib, and thereafter alisertib maintenance for up to 12 months. Twenty-two patients were enrolled. One dose limiting toxicity occurred at dose level 2 (prolonged thrombocytopenia), and the recommended phase 2 dose was established at 30mg twice daily. Common therapy-related toxicities included cytopenias and mucositis. Only three (14%) patients had persistent disease at mid-cycle, requiring "5+2" reinduction. The composite remission rate (complete remission and complete remission with incomplete neutrophil recovery) was 86% (nineteen of twenty-two patients; 90% CI 68-96%). Among those over age 65 and those with high-risk disease (secondary acute leukemia or cytogenetically high-risk disease), the composite remission rate was 88% and 100%, respectively. The median follow up was 13.5 months. Of those treated at the recommended phase 2 dose, the 12-month overall survival and progression-free survival were 62% (90% CI 33-81%) and 42% (90% CI 17-65%), respectively. Alisertib is well tolerated when combined with induction chemotherapy in acute myeloid leukemia, with a promising suggestion of efficacy. (clinicaltrials.gov Identifier:01779843).

Ixazomib in addition to chemotherapy for the treatment of acute lymphoblastic leukemia in older adults.

We sought to assess the safety of adding ixazomib, an oral proteasome inhibitor, to a multi-agent treatment regimen for older adults with acute lymphoblastic leukemia (ALL). Patients 51 to 75 years of age with newly diagnosed ALL were screened. Induction consisted of prednisone (P), vincristine (V), and doxorubicin (D). For BCR-ABL1+ patients, dasatinib was added. On Days 1, 8, 15 of induction, ixazomib was given orally. After induction patients received 1 cycle of consolidation in which ixazomib was given on Days 1, 8, 15. After consolidation, patients in remission (CR) were offered stem cell transplantation. Among the 19 patients treated, 15 (79%) [90% CI, 58-92%] achieved CR or CRi. At 2 years, the overall survival was 47% [95%CI, 29-72%]. In this study the dose of 2.3 mg of ixazomib in combination was the MTD for older patients with ALL and is the recommended dose for future phase 2 studies.

A nonrandomized phase I and biomarker trial of regorafenib in advanced myeloid malignancies.

We conducted a single-center, open-label, dose escalation, and expansion phase I trial of the antiangiogenic multikinase inhibitor regorafenib in patients with advanced myeloid neoplasms. We enrolled 16 patients with relapsed/refractory acute myeloid leukemia (AML), myeloproliferative neoplasms (MPN), chronic myelomonocytic leukemia (CMML), or myelodysplastic syndrome (MDS). A 3 + 3 dose escalation design was used with two planned dose levels (120 or 160 mg daily) and one de-escalation level (80 mg daily). An additional 10 patients were treated on an expansion cohort. The recommended phase two dose of regorafenib was 160 mg daily, with no dose-limiting toxicities. The best overall disease response by International Working Group criteria included one partial and stable disease in 11 patients. Tissue studies indicated no change in Ras/mitogen-activated protein kinase (MAPK) pathway activation in responders. Pharmacodynamic changes in plasma VEGF, PlGF, and sVEGFR2 were detected during treatment. Baseline proinflammatory and angiogenic cytokine levels were not associated with clinical response. Single-agent regorafenib demonstrated an acceptable safety profile in relapsed/refractory myeloid malignancy patients. Most patients achieved stable disease, with modest improvements in cell counts in some MDS patients. Biomarker studies were consistent with on-target effects of regorafenib on angiogenesis. Future studies should investigate the role of regorafenib in combination therapy approaches.

A rare complication of a hemodialysis tunneled catheter: Case report of a superior vena cava and right atrium candida endocarditis.

Infections remain an important cause of death among hemodialysis patients. This population have a higher risk of candidemia. Candida endocarditis it´s a rare but frequently fatal complication of candidemia. A 64 year-old female presented with a purulent discharge at the insertion site of a hemodialysis tunneled cuff catheter. A catheter related bloodstream infection was suspected, cultures were obtained and wide-spectrum antibiotic therapy was administered. A multi sensitive Candida albicans was isolated. Transesophageal echocardiography showed a large vegetation located in the superior vena cava, in probable relation with a previous catheter. The first approach was antifungal treatment. Due to non-response, she did a surgical removal of the vegetation. Culture of the vegetation showed the same as the blood cultures. After one year she has no signs of relapse. To improve the prognosis of this high mortality condition a high index of suspicion is necessary for early diagnosis and timely intervention.

Kidney Transplant From Elderly Donors: A Center Experience.

BACKGROUND: Renal transplantation is the treatment of choice in end-stage renal disease. With the aging of the population and better medical care available, the number of high-risk patients in terms of age and comorbidities on transplant waiting lists is increasing. Due to severe organ shortage, the use of expanded criteria and elderly donors is also increasing. We will review the outcomes of graft function and survival from a series of transplants from elderly deceased donors and compare the characteristics of the organs from donors older and younger than 70 years. METHODS: We collected data from our transplant unit from 1993 until May 2019 and considered 2 groups of donors: donors A (aged ≥70 years) and donors B (aged <70 years). RESULTS: The donors A group had more comorbidities with consequently higher Kidney Donor Profile Index scores than the donors B group, although there was no statistical difference regarding pre-donation serum creatinine level. Among transplant recipients, we also considered 2 groups, according to the age of the organ received: recipients A and recipients B. No difference was found between groups regarding the number of HLA mismatches, incidence of delayed graft function, number of hospitalizations, or incidence of acute rejection. Recipients' age, cold ischemia time, and graft function 1 year after transplant were worse in the recipients A group. CONCLUSIONS: Although kidney graft function was worse in recipients from elderly donors, this difference had no clinical relevance, showing a possible benefit in patient survival compared with permanence in dialysis, so this type of transplant could be considered for older recipients.

Safe Use of Infected Donor Organs in Kidney Transplantation.

INTRODUCTION: Organ availability is limited in the face of the growing number of candidates. Using organs from individuals with an infection at the time of transplantation emerged as a possible but controversial solution. MATERIALS AND METHODS: Retrospective analysis of patients submitted to kidney transplantation in Hospital Garcia de Orta (Almada, Portugal) from January 2008 to March 2019, comparing outcomes between recipients of organs from donors with an active infection and noninfected donors in the referred interval. RESULTS: An active infection in the donor was identified in 55 cases (28.4%) from a total of 194 transplants. The most frequent site of infection was the lung (n = 30), followed by the urinary tract (n = 13); 9 donors (16.4%) had documented bacteremia. None of the identified microorganisms were multidrug-resistant. All recipients from an infected donor received adequate antibiotic prophylaxis (mean duration of 11.1 ± 3.0 days). No significant differences between groups were found regarding patients' demographics, cold ischemia time, duration of hospital stay, delayed graft function, rejection episodes, noninfectious complications, or patient and graft survival. Basiliximab was the preferred induction agent in both groups but was used in a larger proportion of recipients in the infected donor group (87.0% vs 60.6%; P = .001). The rate of infectious complications was significantly lower in the infected donor group (14.5% vs 42.4%; P = .001), and none of the previously isolated agents in the donor was found in the recipient. CONCLUSION: Kidney transplant using infected donors can be performed safely, without worse organ-specific or recipient outcomes, if certain conditions are considered.

Alisertib plus induction chemotherapy in previously untreated patients with high-risk, acute myeloid leukaemia: a single-arm, phase 2 trial.

BACKGROUND: Increased aurora A kinase (AAK) expression occurs in acute myeloid leukaemia; AAK inhibition is a promising therapeutic target in this disease. We therefore aimed to assess the activity of alisertib combined with 7 + 3 induction chemotherapy in previously untreated patients with high-risk acute myeloid leukaemia. METHODS: We did a single-arm, phase 2 trial of patients recruited from the Dana-Farber/Harvard Cancer Center in the USA. Eligible patients had previously untreated acute myeloid leukaemia, an Eastern Cooperative Oncology Group performance status of 0-2, and were at high risk of disease as defined by the presence of an adverse-risk karyotype, the presence of secondary acute myeloid leukaemia arising from previous myelodysplastic syndrome or myeloproliferative neoplasm, the presence of therapy-related acute myeloid leukaemia, or being 65 years or older. Enrolled patients received 7 + 3 induction chemotherapy of continuous infusion of cytarabine (100 mg/m2 per day on days 1-7) and intravenous bolus of idarubicin (12 mg/m2 per day on days 1-3). Oral alisertib (30 mg) was given twice per day on days 8-15. Patients could receive up to four consolidation cycles with cytarabine and alisertib, and alisertib maintenance for 12 months. The primary endpoint was a composite including the proportion of patients achieving complete remission and those with a complete remission with incomplete neutrophil or platelet count recovery. Analyses were per-protocol. This study is registered with Clinicaltrials.gov, number NCT02560025, and has completed enrolment. FINDINGS: Between Dec 31, 2015, and Aug 1, 2017, we enrolled a total of 39 eligible patients. 19 (49%) of 39 patients had secondary acute myeloid leukaemia and three (8%) had therapy-related acute myeloid leukaemia. At mid-induction, 33 (85%) of 39 patients showed marrow aplasia, six (15%) received re-induction. The median follow-up was 13·7 months (IQR 12·7-14·4). Composite remission was 64% (two-stage 95% CI 48-79), with 20 (51%) of 39 patients achieving complete remission and five (13%) achieving complete remission with incomplete neutrophil or platelet count recovery. The most common grade 3 or 4 adverse events included febrile neutropenia (16 [41%] of 39), neutropenia (12 [31%]), thrombocytopenia (13 [33%]), anaemia (11 [28%]), anorexia (nine [23%]), and oral mucositis (four [10%]). No treatment-related deaths were observed. INTERPRETATION: These results suggest that alisertib combined with induction chemotherapy is active and safe in previously untreated patients with high-risk acute myeloid leukaemia. This study met criteria to move forward to a future randomised trial. FUNDING: Millennium Pharmaceuticals.

Diffusion coefficients in CO2/n-alkane binary liquid mixtures by molecular simulation.

The objective of this work was to determine Fick diffusion coefficients in CO2/n-alkane binary mixtures without experimental test. For doing so, Maxwell-Stefan (MS) diffusivity was calculated by molecular simulation. Simultaneously, a thermodynamic factor was estimated using the PC-SAFT (perturbed chain statistical associating fluid theory) equation of state (eos). The binary Fick diffusivities are calculated as the product of both quantities. The binary mixtures investigated contain CO2 and various n-alkanes (nC10, nC16, nC22, nC28, nC44), at their bubble pressure at varying temperatures between 298 and 373 K. The calculated values of Fick diffusivities were compared against the experimental ones for the systems where literature data exist. An average deviation of 26% was found for the CO2/n-decane and 15% for CO2/n-hexadecane mixtures. These results support that molecular simulation can be employed as a tool for the determination of Fick diffusivities in high pressure systems, like in oil reservoirs, without the need to construct a complicated and expensive experimental setup. This method only requires the phase behavior of the desired system, and it can be used for multicomponent mixtures. As an example, predictions of Fick diffusivities were done for CO2 binary mixtures with heavy n-alkanes (nC22, nC28, nC44).

Catheter-related bacteremia in hemodialysis: which preventive measures to take?

BACKGROUND: The use of tunneled hemodialysis catheters as definitive vascular access is becoming increasingly more widespread, reaching 25% of all dialysis patients in some countries. The rate of infectious morbidity and mortality is much higher when catheters are used than when patients are dialyzed through grafts or native fistulas, and it is generally agreed that implementing appropriate preventive measures would do more to lower its incidence. METHODS: A prospective, randomized, open-label, long-term follow-up clinical trial was conducted to compare the efficacy of dressing the exit site with antibiotic ointment (AO) versus catheter antimicrobial locking (AL) in preventing catheter-related bacteremia (CRB), both associated with strict standard precautions and appropriate catheter care. A total of 141 tunneled catheters, newly implanted in 116 consecutive patients, were followed during a 2-year period. Patients were randomly distributed into one of three arms, with group A receiving AO prophylaxis, group B treated with a heparin + gentamicin (5.2 mg/ml) lock (AL) and group C receiving both AO and AL prophylaxis. RESULTS: Group A had a significantly lower infection-free time survival curve (p < 0.02, Kaplan-Meier) with a catheter survival of 103.9 days and a significantly higher number of CRB (9 episodes, p < 0.02, chi(2)). Group B had 130.7 mean infection-free days and 1 episode of CRB. Group C had 127.3 mean infection-free days and 5 episodes of CRB. No toxicity or other adverse events were observed during this 2-year period, and the efficacy of the preventive measures remained stable throughout. CONCLUSION: Antimicrobial lock is superior to AO as a CRB preventive measure. The use of lock and ointment in the same catheter was not associated with additive effects.

Classifying patients in peritoneal dialysis by mass spectrometry-based profiling.

Protein equalization with dithiothreitol, protein depletion with acetonitrile and the entire proteome were assessed in conjunction with matrix assisted laser desorption ionization time of flight mass spectrometry-based profiling for a fast and effective classification of patients with renal insufficiency. Two case groups were recruited as proof of concept, patients with chronic glomerulonephritis and diabetic nephropathy. Two key tools were used to develop this approach: protein concentration with centrifugal concentrator tubes with 10 KDa cut-off membranes and chemical assisted protein equalization with dithiothreitol or chemical assisted protein depletion with acetonitrile. In-house developed software was used to apply principal component analysis and hierarchical clustering to the profiles obtained. The results suggest that chemical assisted protein equalization with dithiothreitol is a methodology more robust than the other two ones, as the patients were well grouped by principal component analysis or by hierarchical clustering.

Effect of electrolytes on bubble coalescence in columns observed with visualization techniques.

Bubble coalescence and the effect of electrolytes on this phenomenon have been previously studied. This interfacial phenomenon has attracted attention for reactor design/operation and enhanced oil recovery. Predicting bubble coalescence may help prevent low yields in reactors and predict crude oil recovery. Because of the importance of bubble coalescence, the objectives of this work were to improve the accuracy of measuring the percentage of coalescing bubbles and to observe the interfacial gas-liquid behavior. An experimental setup was designed and constructed. Bubble interactions were monitored with a visualization setup. The percentage of air bubble coalescence was 100% in distilled water, about 50% in 0.1 M sodium chloride (NaCl) aqueous solution, and 0% in 0.145 M NaCl aqueous solution. A reduction of the contact gas-liquid area was observed in distillate water. The volume of the resulting bubble was the sum of the original bubble volumes. Repulsion of bubbles was observed in NaCl solutions exceeding 0.07 M. The percentage of bubble coalescence diminishes as the concentration of NaCl chloride increases. High-speed video recording is an accurate technique to measure the percentage of bubble coalescence, and represents an important advance in gas-liquid interfacial studies.

[Democracy and conflict in pluralist contexts: an interview with Chantal Mouffe]. / Democracia y conflicto en contextos pluralistas: entrevista con Chantal Mouffe.

Chantal Mouffe, along with Argentinian political theorist Ernesto Laclau (1935-2014), laid down the bases of discourse theory in 1985. She later developed her work by exploring in more detail how discourse theory formulations influence the analysis of contemporary democracies. Approaching conflict as a product of the encounter with difference, Mouffe sees it as an indelible part of the constitution of social relationships. In this encounter with the author, we seek to reflect upon certain themes and problematics that are central to her work, and upon the implications of her theory for the field of contemporary education.

Democracia y conflicto en contextos pluralistas: entrevista con Chantal Mouffe / Democracy and conflict in pluralist contexts: an interview with Chantal Mouffe

Chantal Mouffe, junto al teórico político argentino Ernesto Laclau (1935-2014), lanzó, en 1985, las bases de la teoría del discurso. Luego, desarrolló su trabajo en el sentido de profundizar como influyen las formulaciones de la teoría del discurso en el análisis de las democracias contemporáneas. Abordando el conflicto como una producción del encuentro de la diferencia, Mouffe lo comprende como un aspecto indeleble en la constitución del social. En este encuentro con la autora, buscamos reflexionar algunos temas y problemáticas centrales de su trabajo, y las implicaciones de su teoría en el campo educacional contemporáneo.

Chantal Mouffe, along with Argentinian political theorist Ernesto Laclau (1935-2014), laid down the bases of discourse theory in 1985. She later developed her work by exploring in more detail how discourse theory formulations influence the analysis of contemporary democracies. Approaching conflict as a product of the encounter with difference, Mouffe sees it as an indelible part of the constitution of social relationships. In this encounter with the author, we seek to reflect upon certain themes and problematics that are central to her work, and upon the implications of her theory for the field of contemporary education.