The Impact of the COVID-19 Pandemic on the Organization of Cardio-Hematology Care-A Polish Single Center Experience.

Background and Objectives: We present a retrospective report on the cardio-hematological care of hematology patients at a university hospital in Poland during the COVID-19 pandemic. Materials and Methods: The number of hospitalizations at the Hematology Department and cardio-hematology consultations throughout 2019 and 2020 was analyzed. The types of cardiac procedures, risk factors, and complications were also assessed. Results: A significant reduction in the number of hospitalizations was observed in 2020 as compared to 2019. However, there were no significant differences in the incidence of hematological diseases between both of the analyzed years. In 2019, 299 cardiac consultations were performed in hematological patients, and there was a total of 352 such consultations performed in 2020 (p = 0.042). Less high-risk tests (transesophageal and stress echocardiography) were performed in 2020, in favor of the use of cardiac computed tomography in cardiac diagnostics as it was safer during the pandemic. At least one cardiovascular risk factor during cardiac consultation was noted in 42% and 48% of hematological patients in 2019 and 2020, respectively. Among 651 examined hematological patients, the most common findings were mild cardiac complications of hemato-oncological treatment, which were found in 57 patients. Conclusions: This study seems to confirm that during a pandemic there is an increased demand for well-organized cardio-hematology consultations.

Case of Patient with AML with Complex Karyotype including Ultra-Rare t(4;8)(q32;q13), t(4;11)(q21;p15) and Familial Aggregation of Myeloid Malignancies.

We present a unique case of a young woman with acute myeloid leukemia (AML) with complex karyotype. The presence of the t(4;11)(q23;p15) is extremely rare in myeloid leukemias, while t(4;8)(q32;q13) has not yet been described in any leukemia reference. Another interesting issue is the familial aggregation of myeloid malignancies and worse course of the disease in each subsequent generation, as well as an earlier onset of the disease. Our report emphasizes the need for thorough pedigree examination upon myeloid malignancy diagnosis as there are relatives for whom counseling, gene testing, and surveillance may be highly advisable.

Secondary Hemophagocytic Syndrome in a Patient with Plasma Cell Myeloma and CNS Involvement Treated with Lenalidomide.

We present an extremely rare case report of a 29-year-old multiple myeloma patient with central nervous system involvement and secondary hemophagocytic lymphohistiocytosis (HLH). We observed that HLH was presumably triggered by the immunomodulatory drug-lenalidomide. HLH is frequently misdiagnosed or underdiagnosed. As HLH requires immediate treatment, our report emphasizes the need to consider HLH in the differential diagnosis when the condition of a patient receiving chemotherapy rapidly deteriorates and an infectious etiology is excluded. We furthermore discuss the pathogenesis of HLH, with particular emphasis on drugs affecting the immune system as well as possible therapeutic strategies.

COVID-19 during Early Phase of Autologous Stem Cell Transplantation.

We present one of few cases of COVID-19 occurrence during the early phase of autologous hematopoietic stem cell transplantation. We observed an interesting correlation between the patient's rapid clinical deterioration and myeloid reconstitution that cannot be assigned to engraftment syndrome. Our report emphasizes the need to investigate whether timely steroid therapy upon neutrophil engraftment in the setting of COVID-19 could limit the extent of lung injury and prevent ARDS. Furthermore, we discuss a significant issue of possible prolonged incubation of the virus in heavily pretreated hematological patients.

Local and Systemic Humoral Response to Autologous Lineage-Negative Cells Intrathecal Administration in ALS Patients.

Amyotrophic lateral sclerosis (ALS) remains a fatal disease with limited therapeutic options. Signaling via neurotrophins (NTs), neuroinflammation, and certain micro-RNAs are believed to play essential role in ALS pathogenesis. Lineage-negative stem/progenitor cells (Lin-) were obtained from bone marrow of 18 ALS patients and administered intrathecally. Clinical assessment was performed using ALS Functional Rating Scale (FRSr) and Norris scale. Protein concentrations were measured in plasma and cerebrospinal fluid (CSF) by multiplex fluorescent bead-based immunoassay. Gene expression in nucleated blood cells was assessed using gene microarray technique. Finally, miRNA expression was analyzed using qPCR in CSF and plasma samples. We observed a significant decrease of C-reactive protein (CRP) concentration in plasma on the seventh day from the application of cells. Gene array results revealed decreased expression of gene sets responsible for neutrophil activation. Further analysis revealed moderate negative correlation between CRP level in CSF and clinical outcome. Brain-derived neurotrophic factor (BDNF) concentrations in both plasma and CSF significantly correlated with the favorable clinical outcome. On a micro-RNA level, we observed significant increase of miR-16-5p expression one week after transplantation in both body fluids and significant increase of miR-206 expression in plasma. Administration of Lin- cells may decrease inflammatory response and prevent neurodegeneration. However, these issues require further investigations.

Incidence of Catheter-Associated Bloodstream Infections in Stem Cell Recipients-Should We Be "PICCy"?

The management of patients undergoing HSCT requires a multipurpose central venous catheter. Peripheral catheters (PCs), such as peripherally inserted central catheters (PICCs) and MidLine catheters (MLCs), appear to be adequate vascular catheters to be used for stem cell infusion, although their utilization in this indication is not yet common. We analyzed the infectious complications such as blood stream infection (BSI), febrile neutropenia (FN) and central line-associated bloodstream infection (CLBSI) in patients undergoing stem cell infusion through PC and conventionally inserted central catchers (CICCs), and evaluated their impacts on transplantation outcomes. Our results reveal no statistically significant differences between different types of catheter in terms of FN, BSI and CLABSI. Moreover, transplantation outcomes were comparable between the groups. Interestingly, according to our data, there were no differences in terms of abovementioned infectious complications between individuals who received antibiotic prophylaxis and those who did not. Our study has shown that infection complications are independent of the intravenous device and antibiotic prophylaxis. Considering that PCs are not associated with life-threatening complications, they should be considered more frequently in the stem cell transplantation setting.

Lenalidomide in Multiple Myeloma: Review of Resistance Mechanisms, Current Treatment Strategies and Future Perspectives.

Multiple myeloma (MM) is the second most common hematologic malignancy, accounting for approximately 1% of all cancers. Despite the initial poor prognosis for MM patients, their life expectancy has improved significantly with the development of novel agents. Immunomodulatory drugs (IMiDs) are widely used in MM therapy. Their implementation has been a milestone in improving the clinical outcomes of patients. The first molecule belonging to the IMiDs was thalidomide. Subsequently, its novel derivatives, lenalidomide (LEN) and pomalidomide (POM), were implemented. Almost all MM patients are exposed to LEN, which is the most commonly used IMiD. Despite the potent anti-MM activity of LEN, some patients eventually relapse and become LEN-resistant. Drug resistance is one of the greatest challenges of modern oncology and has become the main cause of cancer treatment failures. The number of patients receiving LEN is increasing, hence the problem of LEN resistance has become a great obstacle for hematologists worldwide. In this review, we intended to shed more light on the pathophysiology of LEN resistance in MM, with particular emphasis on the molecular background. Moreover, we have briefly summarized strategies to overcome LEN resistance and we have outlined future directions.

Safety of Cryopreserved Stem Cell Infusion through a Peripherally Inserted Central Venous Catheter.

The management of patients undergoing stem cell transplantation requires a multipurpose central venous catheter (CVC) to facilitate drug administration, parenteral nutrition, transfusion of blood products, and collection of blood samples. Peripherally inserted central venous catheters (PICCs) appear to meet these requirements but are rarely used for stem cell infusion. We aimed to retrospectively assess the safety and feasibility of stem cell infusion through PICC and to evaluate its impact on transplantation kinetics. We retrospectively analyzed the outcomes of peripheral blood stem cell (PBSC) transplantation in patients receiving cryopreserved autologous or allogeneic PBSC by PICCs and compared the results with patients receiving transplants through a conventionally inserted central venous catheter (CICC). Despite statistically significant differences in CD34+ dose, infusion rate, and total length of administration, the clinical outcomes of transplantation, exemplified by platelet and neutrophil engraftment, along with the length of hospitalization, were not affected by the prolonged infusion time and lower infusion velocity in the PICC group. Our study showed that the clinical outcomes of PBSC transplantation did not differ between the PICC and CICC groups, suggesting that both types of catheters can be implemented in a PBSC transplantation setting.

Updates for the diagnosis and management of cardiac amyloidosis.

A substantial increase in the interest in transthyretin cardiac amyloidosis (ATTR-CA) is a result of the constantly growing number of patients, the use of clear diagnostic protocols and the availability of the first selective drug for these patients. This has also raised the awareness of the disease among physicians of all specialties. The topic is particularly relevant to cardiologists, who use non-invasive multimodal imaging in their daily practice. The differential diagnosis of the causes of myocardial hypertrophy includes arterial hypertension, hypertrophic cardiomyopathy, aortic stenosis (AS), athletic heart syndrome, Fabry disease, and cardiac amyloidosis (CA). It turns out that in patients with myocardial hypertrophy >15 mm, amyloidosis is the most common cause of left ventricular (LV) hypertrophy. In parallel, CA is one of the most common infiltrative diseases leading to a clinical picture that may mimic heart failure with preserved ejection fraction (HFpEF). The accumulation of amyloid in the extracellular space impairs the diastolic function of the myocardium, which is observed as the restrictive cardiomyopathy phenotype. In advanced cases, the LV systolic function is also impaired. Moreover, protein deposits contribute to the disturbances of calcium metabolism and cell metabolism as well as to cardiotoxicity, leading to edema and damage to cardiomyocytes.

microRNAs as the biomarkers of chemotherapy-induced peripheral neuropathy in patients with multiple myeloma.

Multiple myeloma (MM) is a malignant, incurable neoplastic disease. The currently used treatment significantly improves the prognosis and extends the survival time of patients. Unfortunately, a common side effect of the therapy is peripheral neuropathy, which may lead to dose reduction or complete treatment discontinuation/modification. In this study, we examined the changes in plasma levels of circulating miRNAs in myeloma patients to define potential factors characteristic for drug-induced peripheral neuropathy (DiPN). Global miRNA expression profile in the plasma of patients with MM during treatment was determined using miRNA microarray technology. Receiver operating characteristic (ROC) analysis allowed the identification of three miRNAs (miR-22-3p; miR-23a-3p; miR-24-3p) that could be a potential biomarker of PN. The most promising results were obtained for miR-22-3p, which was characterized by ROC area under curve (AUC) = 0.807. Our results suggest a relationship between the DiPN in patients with MM and the level of selected miRNAs in the plasma.

Long-Term Effects of Adjuvant Intravitreal Treatment with Autologous Bone Marrow-Derived Lineage-Negative Cells in Retinitis Pigmentosa.

BACKGROUND: Autologous bone marrow-derived lineage-negative (Lin-) cells present antiapoptotic and neuroprotective activity. The aim of the study was to evaluate the safety and efficacy of novel autologous Lin- cell therapy during a 12-month follow-up period. METHODS: Intravitreal injection of Lin- cells in 30 eyes with retinitis pigmentosa (RP) was performed. The fellow eyes (FEs) were considered control eyes. Functional and morphological eye examinations were performed before and 1, 3, 6, 9, and 12 months after the injection. RESULTS: Patients whose symptoms started less than 10 years ago gained 14 ± 10 letters, while those with a longer disease duration gained 2.86 ± 8.54 letters compared to baseline at the 12-month follow-up (p = 0.021). There were significantly higher differences in response densities of P1-wave amplitudes in the first ring of multifocal ERGs in treated eyes than FE recordings in all follow-up points were detected. Accordingly, the mean deviation in 10-2 static perimetry improved significantly in the treated eyes compared with fellow eyes 12 months after the procedure. The QoL scores improved significantly and lasted until the 9-month visit. CONCLUSION: Lin- cell-based therapy is safe and effective, especially for a well-selected group of RP patients who still maintained good function of the foveal cones.

Adjuvant Lineage-Negative Cell Therapy as a Potential Silencer of the Complement-Mediated Immune System in ALS Patients.

ALS remains a fatal, neurodegenerative motor neuron disease. Numerous studies seem to confirm that innate immune system is involved in the pathophysiology of ALS. Hence, the assessment of the complement system and attempts to modify its activity remain the target of medical intervention in ALS. In the present study, three intrathecal administrations of autologous bone marrow-derived lineage-negative (Lin-) cells were performed every 6 weeks in 20 sporadic ALS patients. The concentrations of various complement components in the cerebrospinal fluid and plasma at different time points after cell injection were quantified using a Luminex multiplex. The results of the complement system were correlated with the level of leukocytes, neutrophils, lymphocytes, fibrinogen and CRP in the peripheral blood and the functional status of ALS patients using Norris and ALS-FRSr scales. The study showed a statistically significant decrease in plasma C3b concentration in all 7th days after cell application. In parallel, a peak decrease in neutrophil count and CRP level was observed on days 5-7, with a simultaneous maximum clinical improvement on days 7-28 of each Lin- cell administration. Adjuvant Lin- cell therapy appears to have the silencing potential on the complement-mediated immune system and thus suppress pro-inflammatory reactions responsible for neurodegeneration. However, further in-depth studies are necessary to address this issue.

The Potential Role of Proinflammatory Cytokines and Complement Components in the Development of Drug-Induced Neuropathy in Patients with Multiple Myeloma.

The launch of novel chemotherapeutic agents-in particular, proteasome inhibitors and immunomodulatory drugs-dramatically changed multiple myeloma (MM) therapy, improving the response rate and prolonging progression-free survival. However, none of the anti-MM drugs are deprived of side effects. Peripheral neuropathy (PN) seems to be one of the most pressing problems. Despite extensive research in this area, the pathogenesis of drug-induced peripheral neuropathy (DiPN) has not yet been fully elucidated. In the present study, we aimed to assess the potential relationship between proinflammatory factors and the development of PN in MM patients with particular emphasis on the application of VTD (bortezomib, thalidomide, dexamethasone) regimen. Our analysis identified increased concentrations of CCL2, IL-1ß, and IFN-γ in plasma of MM patients during treatment, both with and without symptoms of PN, compared with untreated neuropathy-free MM patients. At the same time, the plasma concentration of IL-1ß in patients with neuropathy was significantly increased compared with patients without PN before and during treatment. Moreover, the results were enhanced at the transcript level by performing global mRNA expression analysis using microarray technology. The most significant changes were observed in the expression of genes responsible for regulating immunological and apoptotic processes. An in-depth understanding of the mechanisms responsible for the development of DiPN might in the future reduce the incidence of PN and accelerate diagnosis, allowing the choice of neuropathy-free treatment strategies for MM.

Repeated Application of Autologous Bone Marrow-Derived Lineage-Negative Stem/Progenitor Cells-Focus on Immunological Pathways in Patients with ALS.

Therapeutic interventions in amyotrophic lateral sclerosis (ALS) are still far from satisfying. Immune modulating procedures raise hopes for slowing the disease progression. Stem cell therapies are believed to possess the ability to regulate innate and adaptive immune response and inflammation processes. Hence, three intrathecal administrations of autologous bone marrow-derived lineage-negative (Lin-) cells were performed every six weeks in 40 sporadic ALS patients. The concentrations of inflammatory-related proteins and expression profiles of selected miRNA in the cerebrospinal fluid (CSF) and plasma at different timepoints post-transplantation were quantified by multiplex Luminex and qRT-PCR. The global gene expression in nucleated blood cells was assessed using the gene microarray technique. According to the ALS Functional Rating Scale (FRSr), the study population was divided into responders (group I, n = 17) and non-responders (group II, n = 23). A thorough analysis of the pro-inflammatory expression profiles, regulated miRNA pathways, and global gene expression profiles at the RNA level revealed the local and systemic effects of Lin- cell therapy on the immune system of patients with ALS. The autologous application of Lin- cells in CSF modulates immune processes and might prevent the progression of neurodegeneration. However, further in-depth studies are necessary to confirm the findings, and prolonged intervention is needed to maintain therapeutic effects.

Humoral Influence of Repeated Lineage-Negative Stem/Progenitor Cell Administration on Articulatory Functions in ALS Patients.

Amyotrophic lateral sclerosis (ALS) remains a fatal, neurodegenerative disease frequently leading to dysarthria and impaired swallowing. Better understanding of ALS pathophysiology is prompting the use of humoral cell therapies. Hence, a repeated cellular therapy was applied to ALS patients as an attempt to prevent speech deterioration. Autologous bone marrow-derived lineage-negative (Lin-) cells were intrathecally administered three times at six-week intervals to 42 sporadic ALS patients. Patients were examined for articulatory functions using subjective (VHI) and objective (FDA) scales. Selected trophic, proinflammatory factors and expression profiles of miRNA were measured in cerebrospinal fluid (CSF) and plasma by multiplex Luminex and q-PCR in different timepoints. Of the 42 patients who received the Lin- cells, 6 showed improvement in articulatory functions, 27 remained stable, and 9 deteriorated after 18 weeks of therapy according to FDA scale. Clinical improvement was particularly evident by the 7th day of each cell application and concerned better cough and swallow reflex, soft palate, laryngeal time, pitch, and volume. These results correlated with significant changes in the concentration of various trophic and proinflammatory factors and miRNA expression profiles. A multiple application of Lin- cells proved to be safe and feasible. The repeated procedure can potentate a humoral effect and prevent speech deterioration. A short-lasting trophic effect of each Lin- cells administration was observed on local and systemic level. However, further in-depth studies are necessary to sustain the beneficial effect.

Influence of Lineage-Negative Stem Cell Therapy on Articulatory Functions in ALS Patients.

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal, neurodegenerative disease, leading to loss of muscle strength and motor control. Impaired speech and swallowing lower the quality of life and consequently may induce acute respiratory failure. Bone marrow-derived stem and progenitor cells (SPCs) may be a valuable source of trophic factors. In this study, we assessed whether adjuvant cellular therapy could affect the levels of selected neurotrophins and proinflammatory factors in the cerebrospinal fluid (CSF) and subsequently prevent the deterioration of articulation. MATERIALS AND METHODS: The study group consisted of 32 patients with sporadic ALS who underwent autologous lineage-negative (Lin-) stem cell intrathecal administration to the spinal canal. Lin- cells were aspirated from the bone marrow and isolated using immunomagnetic beads and a lineage cell depletion kit. Patients were examined for articulatory functions by means of the Voice Handicap Index (VHI) questionnaire and Frenchay Dysarthria Assessment (FDA). In parallel, we carried out the analysis of selected trophic and proinflammatory factors in CSF utilizing multiplex fluorescent bead-based immunoassays. RESULTS: Of the 32 patients who received the Lin- progenitor cell therapy, 6 (group I) showed improvement in articulatory functions, 23 remained stable (group II), and 3 deteriorated (group III) on the 28th day. The improvement was particularly noticeable in a better cough reflex, laryngeal time, and dribble reflex. A statistically significant lower level of brain-derived neurotrophic factor (BDNF) was observed on day 0 in group I compared to group II. The CSF concentrations of C-reactive protein (CRP) in group I significantly decreased 7 days after Lin- SPC transplantation. On the contrary, a significant increase in the tumor necrosis factor receptor (TNF-R) level was confirmed among patients from group I with improvement of dribble and coughing reflex, tongue movements, and respiration on the 7th day, as well as on day 28 including dribble reflex solely. CONCLUSIONS: An application of Lin- stem cells could potentate the beneficial humoral effect. The prevention of deterioration of articulatory functions in ALS patients after applying adjuvant Lin- stem cell therapy seems to be promising. Although the procedure is safe and feasible, it requires further in-depth studies.

Influence of AIF1 Gene Polymorphisms on Long-Term Kidney Allograft Function.

BACKGROUND Allograft inflammatory factor (AIF-1) is a recently studied cytoplasmic protein encoded by the AIF1 gene in humans. The main function of AIF-1 is in the chronic inflammatory process. The aim of this study was to examine the impact of the rs2269475: C>T, rs2736182: G>A, and rs2259571: A>C AIF1 gene polymorphisms on long-term kidney allograft function and graft loss after kidney transplantation. MATERIAL AND METHODS The study enrolled 269 white kidney allograft recipients (165 males, 104 females, mean age 47.63±12.96 years, after transplantation performed between 2000 and 2006). The rs2269475: C>T, rs2736182: G>A, and rs2259571: A>C AIF1 gene polymorphisms were genotyped with TaqMan genotyping assays using a 7500 FAST Real-Time PCR System (Applied Biosystems, USA). RESULTS Creatinine concentrations at 12, 24, 36, 48, and 60 months after transplantation did not differ significantly between the studied genotypes of AIF1 polymorphisms. Cox regression analysis showed no statistically significant associations between the risk of graft loss/return to dialysis and the examined polymorphisms. CONCLUSIONS The results of our study suggest that the AIF1 gene polymorphisms have no influence on long-term kidney allograft function.