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.

5-Aza-2'-Deoxycytidine Alters the Methylation Profile of Bortezomib-Resistant U266 Multiple Myeloma Cells and Affects Their Proliferative Potential.

Multiple myeloma (MM) is a plasma cell malignancy that accounts for 1% of all cancers and is the second-most-common hematological neoplasm. Bortezomib (BTZ) is a proteasome inhibitor widely implemented in the treatment of MM alone or in combination with other agents. The development of resistance to chemotherapy is one of the greatest challenges of modern oncology. Therefore, it is crucial to discover and implement new adjuvant therapies that can bypass therapeutic resistance. In this paper, we investigated the in vitro effect of methylation inhibitor 5-Aza-2'-deoxycytidine on the proliferative potential of MM cells and the development of resistance to BTZ. We demonstrate that alterations in the DNA methylation profile are associated with BTZ resistance. Moreover, the addition of methylation inhibitor 5-Aza-2'-deoxycytidine to BTZ-resistant MM cells led to a reduction in the proliferation of the BTZ-resistant phenotype, resulting in the restoration of sensitivity to BTZ. However, further in vitro and ex vivo studies are required before adjuvant therapy can be incorporated into existing treatment regimens.

VEGFR and DPP-IV as Markers of Severe COVID-19 and Predictors of ICU Admission.

The pathophysiology of the severe course of COVID-19 is multifactorial and not entirely elucidated. However, it is well known that the hyperinflammatory response and cytokine storm are paramount events leading to further complications. In this paper, we investigated the vascular response in the pathophysiology of severe COVID-19 and aimed to identify novel biomarkers predictive of ICU admission. The study group consisted of 210 patients diagnosed with COVID-19 (age range: 18-93; mean ± SD: 57.78 ± 14.16), while the control group consisted of 80 healthy individuals. We assessed the plasma concentrations of various vascular factors using the Luminex technique. Then, we isolated RNA from blood mononuclear cells and performed a bioinformatics analysis investigating various processes related to vascular response, inflammation and angiogenesis. Our results confirmed that severe COVID-19 is associated with vWF/ADAMTS 13 imbalance. High plasma concentrations of VEGFR and low DPP-IV may be potential predictors of ICU admission. SARS-CoV-2 infection impairs angiogenesis, hinders the generation of nitric oxide, and thus impedes vasodilation. The hypercoagulable state develops mainly in the early stages of the disease, which may contribute to the well-established complications of COVID-19.

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.

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.

Empirical investigations into Kruskal-Wallis power studies utilizing Bernstein fits, simulations and medical study datasets.

Bernstein fits implemented into R allow another route for Kruskal-Wallis power-study tool development. Monte-Carlo Kruskal-Wallis power studies were compared with measured power, a Monte-Carlo ANOVA equivalent and with an analytical method, with or without normalization, using four simulated runs, each with 60-100 populations (each population with N = 30,000 from a set of Pearson-type ranges): random selection gave 6300 samples analyzed for predictive power. Three medical-study datasets (Dialysis/systolic blood pressure; Diabetes/sleep-hours; Marital-status/high-density-lipoprotein cholesterol) were also analyzed. In three from four simulated runs (run_one, run_one_relaxed, and run_three) with Pearson types pooled, Monte-Carlo Kruskal-Wallis gave predicted sample sizes significantly slightly lower than measured but more accurate than with ANOVA methods; the latter gave high sample-size predictions. Populations (run_one_relaxed) with ANOVA assumptions invalid gave Kruskal-Wallis predictions similar to those measured. In two from three medical studies, Kruskal-Wallis predictions (Dialysis: similar predictions; Marital: higher than measured) were more accurate than ANOVA (both higher than measured) but in one (Diabetes) the reverse was found (Kruskal-Wallis: lower; Monte-Carlo ANOVA: similar to measured). These preliminary studies appear to show that Monte-Carlo Kruskal-Wallis power studies, based on Bernstein fits, might perform better than ANOVA equivalents in many settings (and provide reasonable results when ANOVA cannot be used); and both Monte-Carlo methods appeared to be considerably more accurate than the analytical version analyzed.

Medical Face Masks Do Not Affect Acid-Base Balance Yet Might Facilitate the Transmission of Staphylococcus aureus in Hospital Settings during the COVID-19 Pandemic.

INTRODUCTION: Due to the SARS-CoV-2 coronavirus pandemic, the wearing of masks has become a common phenomenon. Most of the undesirable effects of using a protective face covering are usually related to the prolonged time of its wearing, and the adverse consequences of face coverings should be considered two-fold. The aim of the study was to evaluate the rate of contamination of the three types of face coverings (surgical, N95, and FFP2 masks) with the microorganism-aerobic bacteria, yeasts, and molds-after the 3 h exposure time. The study aimed to investigate the effects of wearing FFP2 masks (KN95) on respiratory function and the acid-base balance of the human body. RESULTS: The presence of S. aureus was confirmed in both nasal carriers and non-carriers which may demonstrate the cross-contamination and spread of this bacterium via hands. S. aureus was found on external and internal surfaces of face masks of each type, and therefore could also be transmitted via hands from external sources. The 3 h exposure time is not sufficient for Gram-negative rods and mold contamination. Moreover, there were no significant differences in most of the parameters studied between the first and second examinations, both in spirometry and capillary blood gas analysis (p > 0.05).

Vitamin D and K Supplementation Is Associated with Changes in the Methylation Profile of U266-Multiple Myeloma Cells, Influencing the Proliferative Potential and Resistance to Bortezomib.

Multiple myeloma (MM) is a plasma cell malignancy that, despite recent advances in therapy, continues to pose a major challenge to hematologists. Currently, different classes of drugs are applied to treat MM, among others, proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies. Most of them participate in an interplay with the immune system, hijacking its effector functions and redirecting them to anti-MM activity. Therefore, adjuvant therapies boosting the immune system may be potentially beneficial in MM therapy. Vitamin D (VD) and vitamin K (VK) have multiple so called "non-classical" actions. They exhibit various anti-inflammatory and anti-cancer properties. In this paper, we investigated the influence of VD and VK on epigenetic alterations associated with the proliferative potential of MM cells and the development of BTZ resistance. Our results showed that the development of BTZ resistance is associated with a global decrease in DNA methylation. On the contrary, both control MM cells and BTZ-resistant MM cells exposed to VD alone and to the combination of VD and VK exhibit a global increase in methylation. In conclusion, VD and VK in vitro have the potential to induce epigenetic changes that reduce the proliferative potential of plasma cells and may at least partially prevent the development of resistance to BTZ. However, further ex vivo and in vivo studies are needed to confirm the results and introduce new supplementation recommendations as part of adjuvant therapy.

Epigenetic Alterations as Vital Aspects of Bortezomib Molecular Action.

Bortezomib (BTZ) is widely implemented in the treatment of multiple myeloma (MM). Its main mechanism of action is very well established. BTZ selectively and reversibly inhibits the 26S proteasome. More precisely, it interacts with the chymotryptic site of the 20S proteasome and therefore inhibits the degradation of proteins. This results in the intracellular accumulation of misfolded or otherwise defective proteins leading to growth inhibition and apoptosis. As well as interfering with the ubiquitin-proteasome complex, BTZ elicits various epigenetic alterations which contribute to its cytotoxic effects as well as to the development of BTZ resistance. In this review, we summarized the epigenetic alterations elicited by BTZ. We focused on modifications contributing to the mechanism of action, those mediating drug-resistance development, and epigenetic changes promoting the occurrence of peripheral neuropathy. In addition, there are therapeutic strategies which are specifically designed to target epigenetic changes. Herein, we also reviewed epigenetic agents which might enhance BTZ-related cytotoxicity or restore the sensitivity to BTZ of resistant clones. Finally, we highlighted putative future perspectives regarding the role of targeting epigenetic changes in patients exposed to BTZ.

The Evidence That 25(OH)D3 and VK2 MK-7 Vitamins Influence the Proliferative Potential and Gene Expression Profiles of Multiple Myeloma Cells and the Development of Resistance to Bortezomib.

Multiple myeloma (MM) remains an incurable hematological malignancy. Bortezomib (BTZ) is a proteasome inhibitor widely used in MM therapy whose potent activity is often hampered by the development of resistance. The immune system is vital in the pathophysiology of BTZ resistance. Vitamins D (VD) and K (VK) modulate the immune system; therefore, they are potentially beneficial in MM. The aim of the study was to evaluate the effect of BTZ therapy and VD and VK supplementation on the proliferation potential and gene expression profiles of MM cells in terms of the development of BTZ resistance. The U266 MM cell line was incubated three times with BTZ, VD and VK at different timepoints. Then, proliferation assays, RNA sequencing and bioinformatics analysis were performed. We showed BTZ resistance to be mediated by processes related to ATP metabolism and oxidative phosphorylation. The upregulation of genes from the SNORDs family suggests the involvement of epigenetic mechanisms. Supplementation with VD and VK reduced the proliferation of MM cells in both the non-BTZ-resistant and BTZ-resistant phenotypes. VD and VK, by restoring proper metabolism, may have overcome resistance to BTZ in vitro. This observation forms the basis for further clinical trials evaluating VD and VK as potential adjuvant therapies for MM patients.

CXCL8, CCL2, and CMV Seropositivity as New Prognostic Factors for a Severe COVID-19 Course.

The exact pathophysiology of severe COVID-19 is not entirely elucidated, but it has been established that hyperinflammatory responses and cytokine storms play important roles. The aim of this study was to examine CMV status, select chemokines, and complement components in COVID-19, and how concentrations of given molecules differ over time at both molecular and proteomic levels. A total of 210 COVID-19 patients (50 ICU and 160 non-ICU patients) and 80 healthy controls were enrolled in this study. Concentrations of select chemokines (CXCL8, CXCL10, CCL2, CCL3, CCR1) and complement factors (C2, C9, CFD, C4BPA, C5AR1, CR1) were examined at mRNA and protein levels with regard to a COVID-19 course (ICU vs. non-ICU group) and CMV status at different time intervals. We detected several significant differences in chemokines and complement profiles between ICU and non-ICU groups. Pro-inflammatory chemokines and the complement system appeared to greatly contribute to the pathogenesis and development of severe COVID-19. Higher concentrations of CXCL8 and CCL2 in the plasma, with reduced mRNA expression presumably through negative feedback mechanisms, as well as CMV-positive status, correlated with more severe courses of COVID-19. Therefore, CXCL8, CCL2, and CMV seropositivity should be considered as new prognostic factors for severe COVID-19 courses. However, more in-depth research is needed.

VISIA Skin Analysis System as a Tool to Evaluate the Reduction of Pigmented Skin and Vascular Lesions Using the 532 Nm Laser.

Purpose: Esthetic medicine is a rapidly developing field of medicine that is not only beneficial in terms of external appearance, but also significantly improves overall quality of life. Currently, pigmented and vascular skin lesions are more prevalent due to multiple environmental factors and are a characteristic manifestation of skin aging. The development of modern laser therapy has contributed to the successful management of multiple skin conditions. The aim of our study was to show the effect of concomitant reduction of both vascular and hyperpigmented skin lesions located on the facial area after repetitive 532 nm laser therapy and to emphasize that the detection of such observation was possible due to the implementation of System of Skin Analysis and Assessment. Patients and Methods: We retrospectively analyzed 100 patients' records with "VISIA" Skin Analysis System after 532nm laser therapy. Results: Laser therapy significantly decreased VISIA scores for all tested lesions, ie, macules, pigmented and vascular lesions (p<0.0001 for all). The efficacy of laser treatment was not significantly different regarding skin phototype (p>0.05) and did not correlate with age of participants (p>0.05). The more laser sessions were performed, the higher improvement in vascular lesion VISIA scores was observed (r=0.26, p=0.0097). Conclusion: 532 nm laser therapy is effective regarding vascular and hyperpigmented skin lesions located on the facial area. The System of Skin Analysis and Assessment is a good tool to test the treatment efficacy during regular follow-up procedure.

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.

Clinicopathological Prognostic Factors Determining Outcomes of Treatment in Gastric Cancer Surgery.

BACKGROUND/AIM: The purpose of this study was to examine the impact of clinicopathological prognostic factors on tumor resectability, perioperative complications, and 5-year survival rates in patients with gastric cancer treated surgically. PATIENTS AND METHODS: A cohort of 834 patients operated on for gastric cancer between 2007 and 2016 was analyzed. RESULTS: Patients over 70 years of age manifested a significantly higher rate of overall complications, systemic complications, surgical complications, perioperative mortality, and a worse 5-year survival. The diffuse type according to the Lauren classification was an independent prognostic factor for perioperative mortality. TNM stage significantly influenced resectability and 5-year survival rates. Furthermore, the presence of distant metastases (M1 stage) significantly increased the rates of overall complications, systemic complications, and perioperative mortality. CONCLUSION: Although TNM stage was the most important prognostic factor for resectability, perioperative complications and 5-year survival, other clinicopathological prognostic factors, such as age, and Lauren type also significantly affected treatment outcomes in gastric cancer surgery.

Brain-derived neurotrophic factor: focus on the pathogenesis of multiple myeloma and the development of treatment-induced peripheral neuropathy.

For many years, intensive research has been carried out on the in-depth understanding of the pathogenesis of multiple myeloma (MM). Nevertheless, the multifactorial nature of the disease, the development of drug resistance, and the side effects of therapy, make it difficult to effectively treat patients. One of the many factors involved in the pathogenesis of MM is brain-derived neurotrophic factor (BDNF). This factor is widely described as a neuroregenerative and neuroprotective agent, but it also regulates non-neuronal cell functions, such as proliferation, apoptosis, and viability. Therefore, BDNF appears to be a good therapeutic target in MM. On the other hand, its decreased concentration during treatment closely correlates with the development of peripheral neuropathy (PN). BDNF dualism requires a detailed understanding of its action on individual molecular mechanisms. Perhaps the optimization of the BDNF level will contribute to the improvement of MM treatment and the reduction of chemotherapy side effects.

Vitamin D as a Potential Player in Immunologic Control over Multiple Myeloma Cells: Implications for Adjuvant Therapies.

Multiple myeloma (MM) is a plasma cell malignancy with multifactorial etiology. One of the underlying mechanisms is immune system dysregulation. Immunotherapy is being widely introduced into various MM treatment protocols. Nevertheless, little is known about boosting the immune system with supportive treatment. Although classical actions of vitamin D (VD) are very well established, their non-classical actions related to the modulation of the immune system in MM are still a subject of ongoing research. In this literature review, we intend to summarize research conducted on VD and MM, both in vitro and in vivo, with particular emphasis on immune system modulation, the induction of the differentiation of malignant MM cells, synergic activity with anti-MM drugs, and MM-associated peripheral neuropathy.

Bortezomib-Induced Epigenetic Alterations in Nerve Cells: Focus on the Mechanisms Contributing to the Peripheral Neuropathy Development.

Bortezomib-induced peripheral neuropathy (BiPN) occurs in approximately 40% of patients with multiple myeloma. The induction of severe neuropathy entails the dose reduction or complete elimination of bortezomib (BTZ). Interestingly, discontinuation of BTZ mostly results in a reduction or complete resolution of peripheral neuropathy (PN) symptoms. Therefore, it is likely that the BiPN mechanisms are based on temporary/reversible changes such as epigenetic alterations. In this study, we examined the effect of treating nerve cells, differentiated from the Lund human mesencephalic (dLUHMES) cell line, with several low-dose BTZ (0.15 nM) applications. We showed a significant decrease in global histone H3 acetylation as well as histone H3 lysine 9 acetylation. Moreover, analysis of the genetic microarray showed changes mainly in epigenetic processes related to chromatin rearrangement, chromatin silencing, and gene silencing. GSEA analysis revealed three interesting signaling pathways (SIRT1, B-WICH and, b-Catenin) that may play a pivotal role in PN development. We also performed an analysis of the miRNA microarray which showed the interactions of miR-6810-5p with the genes MSN, FOXM1, TSPAN9, and SLC1A5, which are directly involved in neuroprotective processes, neuronal differentiation, and signal transduction. The study confirmed the existence of BTZ-induced complex epigenetic alterations in nerve cells. However, further studies are necessary to assess the reversibility of epigenetic changes and their potential impact on the induction/resolution of PN.

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.