The changing landscape of relapsed and/or refractory multiple myeloma (MM): fundamentals and controversies

The increase in the number of therapeutic alternatives for both newly diagnosed and relapsed/refractory multiple myeloma (RRMM) patients has widened the clinical scenario, leading to a level of complexity that no algorithm has been able to cover up to date. At present, this complexity increases due to the wide variety of clinical situations found in MM patients before they reach the status of relapsed/refractory disease. These different backgrounds may include primary refractoriness, early relapse after completion of first-line therapy with latest-generation agents, or very late relapse after chemotherapy or autologous transplantation. It is also important to bear in mind that many patient profiles are not fully represented in the main randomized clinical trials (RCT), and this further complicates treatment decision-making. In RRMM patients, the choice of previously unused drugs and the number and duration of previous therapeutic regimens until progression has a greater impact on treatment efficacy than the adverse biological characteristics of MM itself. In addition to proteasome inhibitors, immunomodulatory drugs, anti-CD38 antibodies and corticosteroids, a new generation of drugs such as XPO inhibitors, BCL-2 inhibitors, new alkylators and, above all, immunotherapy based on conjugated anti-BCMA antibodies and CAR-T cells, have been developed to fight RRMM. This comprehensive review addresses the fundamentals and controversies regarding RRMM, and discusses the main aspects of management and treatment. The basis for the clinical management of RRMM (complexity of clinical scenarios, key factors to consider before choosing an appropriate treatment, or when to treat), the arsenal of new drugs with no cross resistance with previously administered standard first line regimens (main phase 3 clinical trials), the future outlook including the usefulness of abandoned resources, together with the controversies surrounding the clinical management of RRMM patients will be reviewed in detail.

Construction of developmentally inspired periosteum-like tissue for bone regeneration

The periosteum, a highly vascularized thin tissue, has excellent osteogenic and bone regenerative abilities. The generation of periosteum-mimicking tissue has become a novel strategy for bone defect repair and regeneration, especially in critical-sized bone defects caused by trauma and bone tumor resection. Here, we utilized a bone morphogenetic protein-2 (BMP-2)-loaded scaffold to create periosteum-like tissue (PT) in vivo, mimicking the mesenchymal condensation during native long bone development. We found that BMP-2-induced endochondral ossification plays an indispensable role in the construction of PTs. Moreover, we confirmed that BMP-2-induced PTs exhibit a similar architecture to the periosteum and harbor abundant functional periosteum-like tissue-derived cells (PTDCs), blood vessels, and osteochondral progenitor cells. Interestingly, we found that the addition of chondroitin sulfate (CS), an essential component of the extracellular matrix (ECM), could further increase the abundance and enhance the function of recruited PTDCs from the PTs and finally increase the regenerative capacity of the PTs in autologous transplantation assays, even in old mice. This novel biomimetic strategy for generating PT through in vivo endochondral ossification deserves further clinical translation.

Bioethical Aspects in Modern Cardiosurgery of Coronary Artery Disease

The paper focuses on ethical issues, provides data on personality qualities and socio-ethical factors necessary for the professional activity of a cardiovascular surgeon. The aim. To identify the most relevant bioethical aspects, personality traits necessary for a cardiovascular surgeon to carry out his/her professional activities. Materials and methods. Analytical review of scientific publications was performed using the abstract database of scientific libraries, text database of medical and biological publications as well as analysis of observations of our own research works. Results. The main stages of development of surgical treatment of coronary artery disease in Ukraine are highlighted. Analysis of the basic bioethical aspects which take place in a profession of cardiovascular surgeon is carried out. Important personality traits which are necessary for professional activity in cardiac surgery are established. Ethical principles and problems that take place in modern cardiovascular surgery are analyzed. Autologous transplantation which takes place during reconstructive shunt surgery is emphasized. Conclusions. High-tech diagnostic and treatment technologies in cardiac surgery, their specificity, irreversibility of biomedical experience and certain event (intervention) to prolong life and improve health of the patient place new demands on the cardiac surgeon and require special responsibility. Today’s cardiac surgery requires not only high-tech skills in using modern methods of operations, responsibility, but also comprehensive support of aspects of biomedical ethics in the treatment of patients.

Ovarian Estrogen Synthesis Reduced by Peritoneal Endometriosis in Rat Autologous Transplantation Model

OBJECTIVE: To investigate the effects of peritoneal endometriosis on rat ovaries. METHODS: A rat model of peritoneal endometriosis was established by autologous transplantation. qPCR was performed to measure mRNA levels of steroid hormone and steroid synthesis-related genes in the ovaries of endometriosis rats. Immunohistochemistry was performed to characterize the distribution of FSHR in the ovaries of endometriosis rats. RNAseq was performed to find pathological changes in the ovaries of endometriosis rats. RESULTS: By qPCR, it was revealed that mRNA levels of steroid hormone synthesis-related genes were decreased in the ovaries of rats with endometriosis; With IHC, observed that FSHR expression was significantly decreased in the antral follicles of rats with endometriosis. RNAseq revealed that endometriosis affected transcription of the genes related to the microtubule structure and tight junctions of rat ovarian cells. CONCLUSION: Peritoneal endometriosis decreased the genic expression of ovarian steroid hormone synthetases and FSHR protein level in granulosa cells of antral follicles, and reduced the mRNA levels of the microtubule structure and tight junctions in rat ovarian cells, which contribute to the impairment of ovarian function.

Hematopoietic cell transplantation for sickle cell disease: updates and future directions

Excellent outcomes in hematopoietic cell transplantation (HCT) from HLA-identical siblings, improvements in conditioning regimens, novel graft-versus-host disease prophylaxis, and the availability of alternative donors have all contributed to the increased applicability and acceptability of HCT for sickle cell disease (SCD). In young children with symptomatic SCD with an available HLA-identical related donor, HCT should be carefully considered. HCT from alternative donors is typically undertaken only in patients with severe symptoms, causing or likely to cause organ damage, and in the context of clinical trials. Patients undergoing HCT for SCD require careful counseling and preparation. They require careful monitoring of unique organ toxicities and complications during HCT. Patients must be prospectively followed for a prolonged time to determine the long-term outcomes and late effects of HCT for SCD. Thus, there is a need for a universal, longitudinal clinical registry to follow patients after HCT for SCD in conjunction with individuals who do not receive HCT to compare outcomes. Antibody-based conditioning and ex-vivo umbilical cord blood expansion are likely to improve the availability and acceptability of HCT. In addition, new disease-modifying drugs and the emerging option of the autologous transplantation of gene-modified hematopoietic progenitor cells are likely to expand the available therapeutic options and make decision-making by patients, physicians, and caregivers even more complicated. Future efforts must also focus on determining the impact of socioeconomic status on access to and outcomes of HCT and the long-term impact of HCT on patients, families, and society.

Theoretical and Experimental Research on Multi-Layer Vessel-like Structure Printing Based on 3D Bio-Printing Technology

Cardiovascular disease is the leading cause of death worldwide. Traditional autologous transplantation has become a severe issue due to insufficient donors. Artificial blood vessel is an effective method for the treatment of major vascular diseases, such as heart and peripheral blood vessel diseases. However, the traditional single-material printing technology has been unable to meet the users’ demand for product functional complexity, which is not only reflected in the field of industrial manufacturing, but also in the field of functional vessel-like structure regeneration. In order to achieve the printing and forming of multi-layer vessel-like structures, this paper carries out theoretical and experimental research on the printing and forming of a multi-layer vessel-like structure based on multi-material 3D bioprinting technology. Firstly, theoretical analysis has been explored to research the relationship among the different parameters in the process of vessel forming, and further confirm the synchronous relationship among the extrusion rate of material, the tangential speed of the rotating rod, and the movement speed of the platform. Secondly, sodium alginate and gelatin have been used as the experimental materials to manufacture the vessel-like structure, and the corrected parameter of the theoretical analysis is further verified. Finally, the cell-loaded materials have been printed and analyzed, and cell viability is more than 90%, which provides support for the research of multi-layer vessel-like structure printing.

Consensus on Indications for Hematopoietic Stem Cell Transplantation in Pediatrics. Update 2020: Central Nervous System Tumors and Retinoblastoma

The indications for hematopoietic stem cell transplantation in solid tumors in children do not change a lot since our first Brazilian consensus publication in 2009. In this article, we are going to review indications to hematopoietic stem cell transplantation in solid tumors. For the consensus, a review was made using the most relevant articles, and a series of meetings was done to discuss the recommendations. In some indications, autologous transplantation is no longer used as a treatment option, however we chose to review these diseases and keep them as a non-recommendation. In this article we are going to review CNS tumors and retinoblastoma

Growth kinetics and phenotypic markers expression in human dermal stem cells

Human dermal stem cells (DSCs) have generated significant interest in the field of regenerative medicine due to their prospects of autologous transplantation. The present study evaluated the growth kinetics and phenotypic markers expression in human DSCs. The primary cultures of DSCs (n=3) were established by explant culture and characterization of the cells was carried out by assessing morphology, viability, proliferation rate, population doubling time (PDT), cell cycle status and the expression of cell surface markers such as CD29, CD73, CD90 and CD166. The cells released from tissue explants showed spindleshaped fibroblast morphology with the mean percentage viability varying between 93.43% and 100% from passages 1 to 4. DSCs displayed a strong and steady proliferative potential with an average PDT of 42.55 hrs. Cell cycle profile of DSCs demonstrated the majority of cells (59.80% to 76.29%) at G0/G1 phase. Further, the phenotypic profile of markers confirmed the stromal origin of DSCs by exhibiting positivity for CD29, CD73, CD90 and CD166. In conclusion, the growth kinetics and expression of phenotypic markers are consistent with the notion that skin dermis contains a population of stem cells and can serve as a potential autologous source for therapeutic applications.

An Analysis of the Progression of Conjunctivalisation after Transplantation of Cultivated Corneal Epithelium

Purpose. To analyse the recurrence of superficial neovascularisation after previous corneal surface reconstruction with cultivated corneal epithelial cells. Materials and Methods. Forty-eight eyes underwent autologous transplantation of cultivated corneal epithelium to treat partial or total limbal stem cell deficiency caused by chemical or thermal injury. The carrier for the epithelial sheets was a denuded amniotic membrane. Follow-up was conducted for up to 120 months. Recurrent revascularisation (measured in terms of clock hours affected) was evaluated with slit-lamp examination and the support of confocal microscopy. Results. During the long-term observation, only 7 eyes had stable epithelia with no neovascularisation from the conjunctiva. Nineteen eyes developed pathologic vessels in 1 quadrant, with additional 4 eyes developing them in 2 quadrants. Twelve patients developed subtotal or total conjunctivalisation of the corneal surface. They were referred for second cultivated epithelium transplantation (3 patients), allogenic keratolimbal transplantation (7 patients), or keratoprosthesis (2 patients). Six patients withdrew consent. The use of confocal scans of up to 100 µm in resolution enabled the detection of pathologic microvasculature originating from the conjunctiva and the exclusion of stromal vascular ingrowth. Conclusions. Local ingrowth of the conjunctiva is a common complication after the transplantation of cultivated epithelial cells. Severe and progressive vascularisation inevitably leads to graft failure. However, if local ingrowth stops before reaching the central cornea, the treatment even with this complication can be considered a success.