The role of immune checkpoint inhibitors: Variable number of tandem repeat (VNTR) polymorphism in the second exon of the P-selectin glycoprotein ligand-1 (PSGL-1) gene polymorphism in multiple myeloma.

Somatic mutations and polymorphisms may play a role in multiple myeloma (MM) susceptibility and survival. One of the immune checkpoint inhibitors is P-selectin glycoprotein ligand-1 (PSGL-1); the majority of tumor-infiltrating leukocytes express PSGL-1, causing T cell and immune inhibition via PSGL-1 mediator molecules. We aimed to investigate the effect of variable number of tandem repeat (VNTR) polymorphism in the second exon of the PSGL-1 gene on MM susceptibility, response to treatment and survival in our patient group. A total of 238 patients diagnosed with MM between January 2010 and January 2021 and 162 healthy individuals as a control group were included in this cross-sectional study. The genotypes of the VNTR polymorphism in the second exon of the PSGL-1 gene were statistically compared between patients and healthy controls; the statistically significant effects of the genotypes on response to first-line treatment and survival were examined. The AC genotype was significantly higher in healthy controls compared to patients diagnosed with MM (p < 0.001). The median PFS in patients with AA/AB/AC was 56 months, while it was 100 months in patients with BB/CC. The hazard ratio of 1.34 for PFS was found to be clinically significant and having the BB/CC genotype could provide a longer PFS compared to others, but it was not statistically significant due to the sample size. Our study results will shed light on new study plans in terms of immune checkpoint target therapies among conventional treatment preferences in MM.

Effect of interleukin-2 (IL-2) polymorphisms on multiple myeloma: IL-2RA rs2104286, IL-2 rs2069762 and rs2069763 polymorphisms.

Interleukin-2 (IL-2) is a cytokine secreted from T helper type 1 cells and released after induction of T helper cells with major histocompatibility complexes or antigens presented by antigen presenting cells. IL-2 activity and gene polymorphisms have been studied in both solid and hematological malignancies. In the present study, it was aimed to examine the effects of IL-2RA rs2104286, IL-2 rs2069762 and rs2069763 polymorphisms on multiple myeloma (MM) susceptibility, progression-free survival (PFS) and overall survival (OS). A total of 300 patients diagnosed with MM in our clinic between January 2010 and January 2021, and 170 healthy individuals were included. In addition to the demographic data of the patients, MM subtypes, initial stages, prognostic index scores, laboratory results, treatment preferences, and survival data were recorded. The genotypes of the IL-2RA rs2104286, IL-2 rs2069762 and rs2069763 polymorphisms were statistically compared between patients and healthy controls to reveal their effects on MM susceptibility and survival. In the statistical analysis performed to examine the effect of IL-2RA rs2104286, IL-2 rs2069762 and rs2069763 polymorphisms on disease susceptibility, no significant difference was found between the patient and healthy control groups. Patients with the TG genotype of IL-2 rs2069762 had a significantly shorter median PFS and OS compared to others. Patients with the GG genotype of IL-2 rs2069763 had a significantly shorter median PFS compared to others. Having the TG genotype of IL-2 rs2069762 has been shown to be protective for short PFS and OS. Our study results will be guiding in terms of IL-2 based therapies, the future for MM and MM epigenetics.

Plerixafor in autologous stem cell transplantation: Does it affect engraftment kinetics?

Plerixafor increases stem cell mobilization by reversibly binding to the chemokine receptor CXCR4. In our study, we examined the results of mobilization with plerixafor and granulocyte colony-stimulating factor (G-CSF) and revealed their effects on autologous stem cell transplantation (ASCT) engraftment kinetics. The study included all cases of ASCT performed in the Adult Bone Marrow Transplantation Unit of xxx University between January 2014 and January 2022. It included a total of 300 patients. The total number of CD34 + cells collected was 7.44 ± 4.19 in patients with plerixafor and 9.53 ± 6.09 in patients without plerixafor. The mean neutrophil and platelet engraftment took longer in plerixafor-mobilized patients (neutrophil: 12 ± 4.1 vs. 10.2 ± 2.7 days; platelet: 21.6 ± 13.9 vs. 14.2 ± 5.9 days; p = 0.008 and p = 0.002). The number of febrile neutropenia attacks was significantly higher in plerixafor-mobilized patients (p = 0.04). In the chemo-mobilized patient subgroup, plerixafor-mobilized patients experienced more febrile neutropenia attacks (p = 0.04). The mean time to both neutrophil and platelet engraftment was longer in patients mobilized with plerixafor. In the subgroup of patients with MM, the mean time to platelet engraftment was longer in patients mobilized with plerixafor. Plerixafor and its effect on engraftment kinetics should be evaluated with further studies in a larger population with survival analysis.

A COVID-19 mystery: multisystem inflammatory syndrome in adults (MIS-A) associated with splenic rupture.

Severe inflammation and one or more extrapulmonary organ dysfunctions have been observed in those who had recently developed COVID-19, except for a macrophage activation syndrome-like picture. A 50-year-old female patient was admitted to the emergency department with fever and a history of COVID-19 infection. More than one area of hemophagocytosis was found in the bone marrow aspiration. The HLH-2004 protocol was started with neurological involvement and she underwent splenectomy due to massive intra-abdominal bleeding secondary to splenic laceration on the 3rd day. Multiple microthrombosis and infarcts were observed in the splenectomy specimen. At the 4th week of the treatment, she was discharged with oral agents. Splenic microthrombosis and splenic rupture due to "multisystem inflammatory syndrome in adults" are the most important findings of this report.

Role of cytokines in multiple myeloma: IL-1RN and IL-4 VNTR polymorphisms.

INTRODUCTION: The IL-1 receptor antagonist (IL-1Ra or IL-1RN) is a member of the IL-1 superfamily that functions as a competitive antagonist of the cell surface IL-1 receptor, thereby regulating various immune and inflammatory responses related to IL-1. IL-1 induces tumor growth and metastasis, while IL-1RN inhibits the secretion of IL-1α and IL-6 in cancer cells. Interleukin-4 (IL-4) is a potent anti-inflammatory cytokine, can be secreted by many types of immune cells. In this study, it was aimed to reveal the effects of IL-1RN and IL-4 VNTR polymorphisms on disease development and survival in patients with multiple myeloma (MM). MATERIAL AND METHODS: In this study, 244 patients diagnosed with MM in hematology clinic between January 2010 and January 2021, and 179 healthy individuals were included. The genotypes of the IL-1RN VNTR polymorphism were statistically compared before treatment between patients having undergone stem cell transplantation and healthy controls, as were the genotypes of IL-4 VNTR polymorphism. Additionally, the statistically significant effects of these genotypes on survival were examined. RESULTS: In the statistical analysis of the distribution of IL-1RN VNTR gene variants, 1/3 and 1/4 genotypes were found to be significantly higher in patients with MM compared to the healthy controls (p = 0.035). There was no significant difference between the MM patient group and the healthy controls in terms of IL-4 VNTR genotype distribution. PFS of patients with IL-1RN VNTR non-2-allele carrier genotypes was significantly shorter, but no significant effect was found on OS (p = 0.03, p = 0.786, respectively). Patients with IL-1RN VNTR non-2-allele carrier genotypes had 1.718-fold increased risk of shorter PFS. CONCLUSIONS: In conclusion, with this study, the effects of IL-1RN VNTR and IL-4 VNTR polymorphisms on MM were evaluated for the first time in the literature. This study will shed light on ones on cytokine-MM relationship and epigenetic mechanisms.

Importance of mannose-binding lectin2 polymorphism (rs1800450) in infections in children.

PURPOSE: Mannose-binding lectin (MBL) is a serine protease belonging to the collectins and an important factor in the inherited immune system. We aimed to reveal the distribution of different MBL2 genotypes in patients diagnosed with acute bronchiolitis and pneumonia. MATERIAL AND METHODS: A total of 147 patients who applied to Paediatric Emergency between 01.12.2019 and 31.12.2020 were included in the study. Patients were divided into two subgroups: Bronchiolitis and pneumonia. RESULTS: AA genotype was found to be significantly higher in healthy controls (p = 0.039). In the pneumonia group, both AB/BB genotype was significantly higher compared to healthy controls (p = 0.001). While the AA genotype was more common in patients with acute bronchiolitis, AB/BB genotypes were more common in the pneumonia group (p = 0.001). The presence of fever, crepitation, tachypnoea, pathological x-ray finding, and high leukocyte count are significantly more common in patients with AA genotype, while more than 3 days of follow-up duration and severe clinical picture were more common in patients with AB/BB genotypes (p < 0.05, for all). CONCLUSIONS: Genotypes with low MBL expression were significantly more common in patients with pneumonia and severe infection. All these results reveal the importance of MBL polymorphisms and their expression in infections.

Lateral flow assay (LFA) in the diagnosis of COVID-19-associated pulmonary aspergillosis (CAPA): a single-center experience.

BACKGROUND: Invasive pulmonary aspergillosis (IPA) is seen during coronavirus-2019 (COVID-19), has been reported in different incidences, and is defined as COVID-19-associated pulmonary aspergillosis (CAPA). Detection of galactomannan antigen is an important diagnostic step in diagnosing IPA. Enzyme-linked immunoassay (ELISA) is the most frequently used method, and lateral flow assay (LFA) is increasingly used with high sensitivity and specificity for rapid diagnosis. The present study aimed to compare the sensitivity of LFA and ELISA in the diagnosis of CAPA in COVID-19 patients followed in our hospital's ICU for pandemic (ICU-P). METHODS: This study included patients with a diagnosis of COVID-19 cases confirmed by polymerase chain reaction and were followed up in ICU-P between August 2021 and February 2022 with acute respiratory failure. The diagnosis of CAPA was based on the European Confederation of Medical Mycology (ECMM) and the International Society for Human and Animal Mycology 2020 (ECMM/ ISHAM) guideline. Galactomannan levels were determined using LFA and ELISA in serum samples taken simultaneously from the patients. RESULTS: Out of the 174 patients followed in the ICU-P, 56 did not meet any criteria for CAPA and were excluded from the analysis. The rate of patients diagnosed with proven CAPA was 5.7% (10 patients). A statistically significant result was obtained with LFA for the cut-off value of 0.5 ODI in the diagnosis of CAPA (p < 0.001). The same significant statistical relationship was found for the cut-off value of 1.0 ODI for the ELISA (p < 0.01). The sensitivity of LFA was 80% (95% CI: 0.55-1.05, p < 0.05), specificity 94% (95% CI: 0.89-0.98, p < 0.05); PPV 53% (95% CI: 0.28-0.79, p > 0.05) and NPV was 98% (95% CI: 0.95-1.01, p < 0.05). The risk of death was 1.66 (HR: 1.66, 95% CI: 1.02-2.86, p < 0.05) times higher in patients with an LFA result of ≥ 0.5 ODI than those with < 0.5 (p < 0.05). CONCLUSIONS: It is reckoned that LFA can be used in future clinical practice, particularly given its effectiveness in patients with hematological malignancies and accuracy in diagnosing CAPA.

Enigma of COVID-19: is "multisystem inflammatory syndrome in adults" (MIS-A) predictable?

BACKGROUND: Severe inflammation and one or more extrapulmonary organ dysfunctions have been reported and this clinical picture is defined as "multisystem inflammatory syndrome in adults" (MIS-A) in severe coronavirus disease-2019 (COVID-19). We aimed to determine the effect of LDH/lymphocyte ratio (LLR) on the development of MIS-A. METHODS: The data of 2333 patients were retrospectively analyzed. RESULTS: MIS-A rate was found to be 9.9% and MIS-A related mortality was 35.3%. LRR level above 0.24 was found to predict MIS-A development with 70% sensitivity and 65.2% specificity. The risk of MIS-A development was found to be 3.64 times higher in those with LRR levels above 0.24 compared to those with 0.24 and below. In patients with MIS-A, LRR level above 0.32 predicts mortality with 78% sensitivity and 70% specificity. CONCLUSIONS: Early detection of MIS-A with high sensitivity and specificity in a practical ratio is very important in terms new studies.

Association of mannose-binding lectin 2 (MBL2) and suppressor of cytokine signaling-1 (SOCS1) gene variants in children with febrile neutropenia.

INTRODUCTION: Febrile neutropenia (FEN) was reported in patients with solid malignancies at a rate of 5-10% and in patients with hematological malignancies at a rate of 20-25%. In our study, we aimed to investigate the effects of mannose-binding lectin 2 (MBL2) (rs1800450) and suppressor of cytokine signaling-1 (SOCS1) (rs33989964) gene variants on patients with FEN. METHODS: A total of 123 patients who applied to pediatric emergency department between December 2019-12/2020 included in the study. Thirteen patients were excluded from the study due to the inability to obtain DNA. Demographic-clinical features at initial diagnosis and genotype distributions were recorded. The control group consisted of volunteers with the same ethnicity, age and gender, no active infection, and no consanguinity. RESULTS: CA/CA genotype of SOCS1 was found to be significantly higher in the healthy control group (p = 0.028). AB/BB genotype of MBL2 was significantly higher in FEN patients with a MASCC score of high risk, AA genotype was found to be higher in patients with low risk (p = 0.001). While the rate of microbiologically documented infection (MDI) was significantly lower in patients with the AA genotype of MBL2, it was significantly higher in patients with AA/BB genotypes (p = 0.025). MDI rate in patients with the del/del genotype of SOCS1 was found to be significantly lower than in patients with CA/CA + CA/del genotypes (p = 0.026). CONCLUSIONS: In this study, it was revealed that low expression-related MBL2 genotypes were riskier for FEN and also, gene variants associated with high SOCS1 transcription were both protective against FEN and increased the rate of culture-negativity.

Efficacy of the lactate dehydrogenase (LDH)/lymphocyte ratio (LLR) to reduce the need for X-ray in pregnant patients with COVID-19.

OBJECTIVES: Pregnancy carries a significant risk for coronavirus disease-2019 (COVID-19) due to natural immunosuppression. A previous study from our center has shown that the lactate dehydrogenase (LDH)/lymphocyte ratio (LLR) can be used in the early diagnosis of COVID-19 and predicting mortality. Based on this, we aimed to determine the effect of LLR on early detection of critical pregnant women and mortality in COVID-19. METHODS: The data of 145 patients who were admitted to our hospital between March and December 2020; diagnosed with COVID-19 and hospitalized, were retrospectively analyzed. RESULTS: The median gestation period was 31 weeks (range: 5-41), 30.3% (n: 44) gave birth and 68.3% (n: 99) were pregnant. Median LLR was 0.13 (range: 0.04-0.70). The rate of cough (47% vs. 22.8%; p=0.003) was found to be high in patients with LLR>0.13. The patients were divided into subgroups. The proportion of patients without active complaints was higher in the Q1, followed by the Q4. The proportion of patients with an initial complaint of cough increased as LLR from Q1 to Q4, the distribution of other complaints did not differ between the quartiles. CONCLUSIONS: The higher rate of cough in the group with high LLR indicates that it may be an important indicator of lung involvement during pregnancy. The highest rate of non-treatment follow-up in the lowest LLR group proved that the LLR value at the time of diagnosis can be used as an important clinical marker in pregnant women.

A new parameter in multiple myeloma: CYP3A4*1B single nucleotide polymorphism.

Multiple myeloma (MM) is a disease caused by malignant plasma cells, causing free light chain release accompanying the increase in monoclonal immunoglobulin. Cytochrome P450 (CYP) is one of the large and functional enzyme families composed of various hemoproteins. This protein network has been shown to play a role in many treatment steps in current practices. We aimed to investigate the relationship between genotypes of CYP3A4*1B and treatment response and prognosis of MM. Seventy-two patients diagnosed with MM between January 2016 and 2020 and 100 healthy people to create a control group participated in our study. Genotypes were classified in 3 separate groups as NN, MN, and MM. Both PFS and OS were significantly higher in the NN genotype (p = 0.001, p = 0.014). Being under the age of 65 was 27.988 times more protective for OS and 4.496 times for PFS (p = 0.006, p = 0.017). NN genotype was shown to be 41.666-fold protective for OS and 3.144-fold protective for PFS (p = 0.004, p = 0.030). This study demonstrated that CYP3A4*1B NN genotype, which is an important cytochrome p450 member for the treatment of MM, was 41.666-fold protective for OS and 3.144-fold protective for PFS. It was shown in this study for the first time in the literature as a valuable contribution.

What are the roles of global DNA and APC 2 gene promotor hypermethylation in multiple myeloma?

BACKGROUND: In today's practice, gene-based approaches come to the fore in the determination of prognosis and treatment preferences of multiple myeloma (MM). DNA methylation is one of the new approach parameters. DNA methylation occurs by the addition of a methyl group to cytosines in CpG dinucleotides. In this study, besides comparing the global DNA and APC 2 gene promotor hypermethylation between our patients with MM and healthy control group, we aimed to demonstrate the effect of hypermethylation on MM treatment responses and survival. METHODS AND RESULTS: 38 patients diagnosed with MM between January 2016 and January 2020 and 50 healthy controls were included in the study. The initial hypermethylation of the patients and the healthy control group were statistically analyzed. In addition, the increase in hypermethylation in the MM group before and after the first series of treatments were analyzed within themselves. There is a significant difference between the patients with MM diagnosis and the healthy control group in terms of the initial global hypermethylation (P = 0.001). In patients with MM, hypermethylation was significantly higher. Global hypermethylation in the post-treatment measurements was significantly increased in comparison to the pre-treatment state (P = 0.012). In terms of APC 2 promotor gene-specific hypermethylation, no significant differences were detected between pre- and post-treatment values (P = 0.368). CONCLUSIONS: This study represents valuable data with the initial global DNA hypermethylation results in the MM patient group and the increase in hypermethylation post-treatment. it will shed light on future studies.

Hemolytic anemia and plasma exchange.

Hemolytic anemia is a disease caused by autoantibodies and resulting in various complaints and clinical symptoms. In about half of cases, the cause of autoimmune hemolytic anemia can not be determined. Corticosteroids are the first-line treatment option for warm autoantibody-related hemolytic anemia. In patients who develop steroid side effects or do not respond adequately, other immunosuppressives may be preferred. In case a rapid response is required or fulminant hemolysis occur, human immunoglobulins (IVIGs) may be added to treatment. Finally, plasma exchange (PE) may additionally be utilised. The essence of PE is based on the removal of immune complexes, protein-bound toxins, autoantibodies and high molecular weight solutes and protein-bound solutes. The main clinical aim of the removal of solutes is usually to gain a faster response than immunosuppressive therapy. Studies related to hemolytic anemia and PE are usually based on case reports. Our case report is about a patient with severe IgG subtype hemolytic anemia. The treatment was started with 1 mg/kg methylprednisolone; to which there was no response with weekly rituximab 375 mg/m2 and IVIG administered. Because of unresponsiveness to all of the immunosuppresives, a total of 5 sessions of PE were added to the treatment procedure every other day. After these sessions, the requirement for transfusions has decreased and the patient underwent splenectomy. The patient is currently being followed up only on oral cyclosporine and the last hemoglobin level was 14.7 g /dl. In severe and refractory anemia, especially in the case of cardiovascular imbalance in fulminant hemolysis, PE may be preferred as a third series option after immunosuppressive treatments and play a role as a bridge to splenectomy.

Serum Aspergillus galactomannan lateral flow assay for the diagnosis of invasive aspergillosis: A single-centre study.

BACKGROUND: Aspergillus species meet the most important group of invasive fungal diseases (IFD) in immunosuppressed patients. Galactomannan is a polysaccharide antigen located in the wall structure of Aspergillus. The most commonly used method for antigen detection is enzyme-linked immunoassay (ELISA). Aspergillus galactomannan lateral flow assay (LFA) constitutes one of the new methods in the diagnosis of invasive aspergillosis (IA). The goal of this study was to demonstrate efficacy of LFA in our patients and to compare it to synchronous ELISA results. METHODS: Galactomannan antigen was examined using both LFA and ELISA in serum samples taken from patients who were followed up in our haematology clinic. All patients are classified in subgroups as 'proven', 'probable' and 'possible' patients according to the last EORTC / MSG guideline. Patients who met the 'proven' IA criteria were included in the study as the gold standard. RESULTS: A total of 87 patients were included in the study. Majority of patients had acute myeloid leukaemia (AML) (56.3%). Eleven (12.6%) were in 'proven' IA group. LFA test showed a superior diagnostic performance compared with ELISA (LFAAUC  = 0.934 vs ELISAAUC  = 0.545; p < .001). The LFA had a sensitivity of 90.9% and a specificity of 90.8% for '0.5 ODI' in predicting IA (PPV = 55.8%; NPV = 98.6%; p < .001). CONCLUSION: The most important finding of this study is that the specificity of LFA was found to be higher for cut-off value of 0.5. It is recommended to combine the methods in many studies to provide a better early diagnosis for IA.

Medication-related osteonecrosis of the jaw (MRONJ) and eNOS Polymorphisms in multiple myeloma patients: a single center experience.

BACKGROUND: Multiple myeloma (MM) constitutes approximately 10% of hematological malignancies. Bisphosphonates have established themselves in solid organ metastasis and multiple myeloma lytic bone lesions by inhibiting osteoclast activation. Medication-related osteonecrosis of the jaw (MRONJ) emerges as an important complication. Investigating host-based factors, and developing personal risk factors gain importance in the development mechanism of MRONJ. We aimed to reveal the different genotype polymorphisms, and clinical effects of eNOS in patients with a diagnosis of MRONJ in MM patients. METHODS: Medical records and blood samples were collected from 60 MRONJ patients with MM and 60 healthy controls. Inclusion criteria was having an exposed maxillofacial bone for more than eight weeks, a history of bisphosphonates, and no history of radiation therapy for the jaws. eNOS G894T and intron 4 VNTR were calculated by polymerase chain reaction and/or restriction fragment length polymorphism. RESULTS: eNOS G894T and VNTR genotypes and alleles were compared statistically with the healthy control group. There was no significant difference between the two groups. In comparison between G894T and clinical parameters, aphthous stomatitis was more common in TT genotype, while DMFT > 3 was more common in TG-GG genotype (p = 0.035, 0.023). CONCLUSIONS: eNOS induces osteogenesis in bone metabolism, with its regulatory effects on bone remodeling and also NO induced angiogenesis takes place indirectly with its protective effect on endothelial functions. We see that these polymorphisms affecting the entire process of bone remodeling and angiogenesis, especially mucosal damage, which is the triggering factor of MRONJ pathology, have been revealed in the MM patient group. Considering the MRONJ initiating factors, it is necessary to emphasize the importance of our study results. It should be seen as an important step for new studies towards MRONJ and its treatment.

Evaluation of Intraventricular/Intrathecal Antimicrobial Therapy in the Treatment of Nosocomial Meningitis Caused by Multidrug-Resistant Gram-Negative Bacteria after Central Nervous System Surgery.

INTRODUCTION: Postoperative meningitis (POM) is an infection with high mortality and morbidity following central nervous system surgery due to trauma or tumor. Intrathecal/intraventricular (IT/IVT) antibiotic administrations have been considered as the last treatment options for multidrug-resistance (MDR) Gram-negative bacteria that do not respond to intravenous (IV) regimens. IT/IVT can bypass the blood-brain barrier, obtain a more effective antibiotic concentration in CSF, and reduce systemic side effects. We aimed to determine the characteristics of postoperative patients who were diagnosed with MDR POM during follow-up in our intensive care unit (ICU). Material and Methods. In this study, POM patients who were followed up in ICU after the central nervous system intervention between January 2016 and December 2019 and whose MDR Gram-negative bacteria were isolated from CSF were evaluated. As soon as the patients were diagnosed with POM, a catheter was inserted and treatment was started. RESULTS: Microbiological eradication was achieved in 3 ± 0.8 days with 30 mg/day amikacin treatment in POM due to K. pneumoniae and 3.7 ± 1.95 days with colistin sodium 10 mg/day treatment in POM due to A. baumannii via IT/IVT catheter. IT/IVT treatment was utilized for a median of 10 days and continued until the defined cure criteria were achieved. While cure was achieved in 6 of 14 POM cases, 8 of them were exitus. Discussion and Conclusion. To avoid the severe consequences of postoperative meningitis, acting fast and adding IT/IVT methods to parenteral administration routes by considering the distribution of MDR microorganisms within the hospital while planning effective treatment will increase the clinical success.