Bendamustine-Based Regimens as Salvage Therapy in Refractory/Relapsed Multiple Myeloma Patients: A Retrospective Real-Life Analysis by the Polish Myeloma Group

Multiple myeloma (MM) is an incurable disease and patients become refractory to the treatment in the course of the disease. Bendamustine-based regimens containing steroids and other agents are among the therapeutic options offered to MM patients. Here, we investigated the safety and the efficacy of bendamustine used in patients with refractory/relapsed MM (RRMM). The patients were treated with bendamustine and steroids (n = 52) or bendamustine, steroids and immunomodulatory agents or proteasome inhibitors (n = 53). Response rates, progression-free survival (PFS), overall survival (OS) and frequency of adverse events were compared between both study groups. Most efficacy measurements were better in patients treated with three-drug regimens: overall response rate (55% versus 37%, p = 0.062), median PFS (9 months versus 4 months, p < 0.001), median OS survival (18 months versus 12 months, p = 0.679). The benefit from combining bendamustine and steroids with an additional agent was found in subgroups previously treated with both lenalidmide and bortezomib, with stem cell transplant and with more than two previous therapy lines. Toxicity was similar in both study groups and bendamustine-based therapies were generally well-tolerated. Our study suggests that bendamustine may be an effective treatment for patients with RRMM. Three-drug regimens containing bendamustine, steroids and novel agents produced better outcomes and had acceptable toxicity. The efficacy of bendamustine combined with steroids was limited.

Arc eruptions deliver ‘first blow’ in the pulsed end-Permian mass extinction

Brief pulses of intense magmatic activity (flare-ups) along convergent margins represent drivers for climatic excursions that can lead to major extinction events. However, correlating volcanic outpouring to environmental crises in the geological past is often difficult due to poor preservation of volcanic sequences. Herein, we present a high-fidelity, CA-TIMS U–Pb zircon record of an end-Permian flare-up event in Eastern Australia, that involved the eruption of >39,000–150,000 km3 of silicic magma in c. 4.21 million years. A correlated high-resolution tephra record (c. 260–249 Ma) in the proximal sedimentary basins suggests recurrence of eruptions from the volcanic field in intervals of ~51,000–145,000 years. Peak eruption activity at 253 Ma is chronologically associated with the pulsed stages of the Permian mass extinction event. The ferocity of the 253 Ma eruption cycle in Eastern Australia is identified as a driver of greenhouse crises and ecosystem stress that led to the reduction in diversity of genera and the demise of the Glossopteris Forests. Simultaneous global continental margin arc flare-up events could thus present an additional agent to trigger greenhouse warming and ecosystem stress that preceded the catastrophic eruption of the Siberian Traps.

EXPERIENCE OF USING KALFOSET IN COMPLEX THERAPY OF RETENTION OF HIGH PRODUCTIVE DAIRY CATTLE IN THE CONDITIONS OF JV KALUZHSKOE LLC

The article describes the experience of using the drug Kalfoset as an additional agent in a complex conservative treatment for the retention of the placenta in highly productive Holstein cattle in the conditions of the livestock complex of LLC JV Kaluzhskoe.

Water-Assisted Production of Polypropylene/Boehmite Composites

In this study polypropylene (PP) matrix-based boehmite alumina (BA) reinforced composites were prepared batchwise in an internal mixer. BA particles up to 10 wt.% were incorporated by 1. traditional melt mixing and 2. in a novel, Water-Assisted (WA) way, called fast evaporation mixing, during which BA was dispersed in PP with the use of an aqueous carrier medium. The WA way with pure water as medium proved to be ineffective because of the presence of the Leidenfrost effect. Therefore, an additional agent, carboxymethyl cellulose (CMC) was used to increase the boiling temperature of the water. Mechanical, morphological and thermal properties of the composites were determined. Scanning electron microscopy images revealed a partially dispersed structure of BA within the PP matrix in all cases, where aggregates and dispersed particles were identified as well. The size of the agglomerates observed was the smallest when BA was incorporated by being dispersed in water/CMC firstly. The mechanical tests results indicated that the reinforcing effect of BA was also most prominent in this case. However, CMC had an opposite effect on PP, than BA thus reducing the overall enhancement in mechanical properties. Differential scanning calorimetry showed an increase in the crystallinity ratio of PP with increasing BA content, which indicates a nucleating effect of BA.

Evaluation of abatacept for GVHD prophylaxis in patients with non-malignant diseases after hematopoietic stem cell transplantation

Graft-versus-host diseases (GVHD) is one of most significant complication after allogeneic hematopoietic stem cells transplantation (HSCT). T-cell activation is a major stage in the GVHD pathogenesis. T-cells require 2 signals for activation: cognate antigen/MHC binding T-cell receptors and positive costimulatory signals from antigen-presenting cells (APC). The predominant positive costimulatory signal to human CD4 T0-cells comes through the CD28 receptor. This signal can be blocked by fusion proteins (such as CTLA4-Ig). Abatacept is a soluble fusion protein, which links the extracellular domain of human CTLA-4 to the modified Fc portion of human IgG1. We present results of single-center prospective randomized study to evaluate the efficacy of adding abatacept to the GVHD prophylaxis protocol after hemopoietic stem cell transplantation in patients with non-malignant diseases. Study was approved by Ethics Committee and Scientific Council of the Institute (protocol # 9/2013 from 01.10.2013). During 4 years we included 62 patients, 30 of them received abatacept as additional agent. Cumulative incidence of acute GVHD was significantly lower in this group in compare with control group (p = 0,018). When we stratified patients in dependents of graft processing technology, we did not see any advantages of abatacept in patients after transplantation with TCRαβ+/СD19+ graft depletion. However, after HSCT with non-manipulated graft the abatacept showed significant efficacy in aGVHD prophylaxis compared with control group (p = 0,024). Abatacept can be recommended as effective additional agent for GVHD prophylaxis after allogeneic HSCT in patients with non-malignant diseases.

CLO19-026: Determining the Treatment Decision of Tumors With Mixed Response

Introduction: Individuals receiving systemic anticancer therapies for advanced solid tumors routinely undergo imaging studies to assess the efficacy of the treatment. Mixed response (MR) to cancer therapy is a common but poorly described phenomenon. There is a paucity of data regarding both the incidence and possible mechanisms of this clinical quandary. Potential etiologies include tumor heterogeneity, differences in tumor microenvironment, and discrepancies in drug delivery to different tumor deposits. It is also possible that MR simply reflects differences in the rate of resistance emerging. MR represents a therapeutic dilemma for the clinician. Methods: Mixed tumor response was defined as: One tumor decreasing in size; one tumor increasing in size (classified as RECIST response/progressions), One tumor stable; another tumor progressing, One tumor stable; another tumor responding, New tumor; another tumor responding or remaining stable. Between 2015 and 2017, 120 restaging CT scans were reviewed of patients who had received at least 1 line of therapy for advanced cancer diagnosis which showed MR; hematologic malignancies were excluded. Charts were reviewed to determine the clinical decision that was made at the time of the MR. Results: A total of 120 scans with MR were reviewed from various solid tumor diagnoses. 38 scans were excluded due to loss of follow-up or death. Of the remaining 82 scans, therapy was switched in 30, the same therapy was continued in 50, and an additional agent was added to the current treatment in 2 cases (Table). Of the patients in which treatment was switched, 20% (6/30) showed response to treatment on the following scan. Of the cases that were kept on current treatment, none showed response on the following restaging scan which was done 6–8 weeks later. There were 4 (10%) deaths prior to the next scan in the group that had treatment switched and similarly 5 deaths (10%) prior to the next scan in the group in which treatment remained the same. Conclusion: MR is associated with a poor prognosis, irrespective of treatment decisions. These data are retrospective and our sample size is small, so definitive conclusions cannot be drawn. However, changing therapy when a MR is observed may be of benefit to some patients. A prospective evaluation to more accurately describe and understand the MR phenomenon is warranted.

Virological and Immunological Outcomes of Coinfections

SUMMARYCoinfections involving viruses are being recognized to influence the disease pattern that occurs relative to that with single infection. Classically, we usually think of a clinical syndrome as the consequence of infection by a single virus that is isolated from clinical specimens. However, this biased laboratory approach omits detection of additional agents that could be contributing to the clinical outcome, including novel agents not usually considered pathogens. The presence of an additional agent may also interfere with the targeted isolation of a known virus. Viral interference, a phenomenon where one virus competitively suppresses replication of other coinfecting viruses, is the most common outcome of viral coinfections. In addition, coinfections can modulate virus virulence and cell death, thereby altering disease severity and epidemiology. Immunity to primary virus infection can also modulate immune responses to subsequent secondary infections. In this review, various virological mechanisms that determine viral persistence/exclusion during coinfections are discussed, and insights into the isolation/detection of multiple viruses are provided. We also discuss features of heterologous infections that impact the pattern of immune responsiveness that develops.