Publications by authors named "Efstathios Kastritis"

275 Publications

Carfilzomib Improves Bone Metabolism in Patients with Advanced Relapsed/Refractory Multiple Myeloma: Results of the CarMMa Study.

Cancers (Basel) 2021 Mar 12;13(6). Epub 2021 Mar 12.

Department of Clinical Therapeutics, Alexandra General Hospital, School of Medicine, National and Kapodistrian University of Athens, PS 11528 Athens, Greece.

Carfilzomib with dexamethasone (Kd) is a well-established regimen for the treatment of relapsed/refractory multiple myeloma (RRMM). There is limited information for the effects of Kd on myeloma-related bone disease. This non-interventional study aimed to assess skeletal-related events (SREs) and bone metabolism in patients with RRMM receiving Kd, in the absence of any bone-targeted agent. Twenty-five patients were enrolled with a median of three prior lines of therapy; 72% of them had evidence of osteolytic bone disease at study entry. During Kd treatment, the rate of new SREs was 28%. Kd produced a clinically relevant (≥30%) decrease in C-telopeptide of collagen type-1 ( = 0.048) and of tartrate-resistant acid phosphatase-5b ( = 0.002) at 2 months. This reduction was at least partially due to the reduction in the osteoclast regulator RANKL/osteoprotegerin ratio, at 2 months ( = 0.026). Regarding bone formation, there was a clinically relevant increase in osteocalcin at 6 months ( = 0.03) and in procollagen type I N-propeptide at 8 months post-Kd initiation. Importantly, these bone metabolism changes were independent of myeloma response to treatment. In conclusion, Kd resulted in a low rate of SREs among RRMM patients, along with an early, sustained and clinically relevant decrease in bone resorption, which was accompanied by an increase in bone formation, independently of myeloma response and in the absence of any bone-targeted agent use.
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http://dx.doi.org/10.3390/cancers13061257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998249PMC
March 2021

Exercise-Induced Changes in Tumor Growth via Tumor Immunity.

Sports (Basel) 2021 Mar 30;9(4). Epub 2021 Mar 30.

Sports Performance Laboratory, School of Physical Education and Sport Science, National and Kapodistrian University of Athens, 17237 Athens, Greece.

Immunity in the tumor microenvironment plays a central role in tumor development. Cytotoxic immune cells act against tumors, while tumors manage to trigger immunosuppressive mechanisms for defense. One bout of physical exercise acutely regulates the immune system inducing short-term redistribution of immune cells among body organs. Repeated acute immune cell mobilization with continuing exercise training results in long-term adaptations. These long-term exercise-induced changes in the immune system arise both in healthy and in diseased populations, including cancer patients. Recent preclinical studies indicate that physical exercise may have a positive impact on intra-tumoral immune cell processes, resulting in tumor suppression. This short narrative review describes the effect of physical exercise on tumor growth as detected via changes in tumor immunity. Research evidence shows that exercise may improve tumor-suppressive functions and may reduce tumor-progressive responses and mechanisms of immune cells, controlling tumor development. Specifically, it seems that exercise in rodents triggers shifts in tumor infiltration of macrophages, neutrophils, natural killer cells, cytotoxic and regulatory T lymphocytes, resulting in tumor suppression. These recent promising data suggest that physical exercise could be combined with anticancer immunotherapies, although exercise parameters like intensity, duration, and frequency need to be evaluated in more detail. More research is needed to investigate the effect of exercise in other immune cell subtypes and their possible connection with tumor growth, whilst information from human tumors is also required.
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http://dx.doi.org/10.3390/sports9040046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065770PMC
March 2021

SARS-CoV-2 Infection Is Asymptomatic in Nearly Half of Adults with Robust Anti-Spike Protein Receptor-Binding Domain Antibody Response.

Vaccines (Basel) 2021 Mar 2;9(3). Epub 2021 Mar 2.

Department of Chemistry, NKUA, 15771 Athens, Greece.

Between June and November 2020, we assessed plasma antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid protein in 4996 participants (aged 18-82 years, 34.5% men) from the National and Kapodistrian University of Athens. The weighted overall prevalence was 1.6% and monthly prevalence correlated with viral RNA-confirmed SARS-CoV-2 infections in Greece, in the same period. Notably, 49% of seropositive cases reported no history of SARS-CoV-2 infection-related clinical symptoms and 33% were unsuspected of their previous infection. Additionally, levels of anti-SARS-CoV-2 antibodies against the spike-protein receptor-binding domain were similar between symptomatic and asymptomatic individuals, irrespective of age and gender. Using Food and Drug Administration Emergency Use Authorization-approved assays, these results support the need for such studies on pandemic evaluation and highlight the development of robust humoral immune responses even among asymptomatic individuals. The high percentage of unsuspected/asymptomatic active cases, which may contribute to community transmission for more days than that of cases who are aware and self-isolate, underscores the necessity of measures across the population for the efficient control of the pandemic.
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http://dx.doi.org/10.3390/vaccines9030207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998869PMC
March 2021

Recovery of Innate Immune Cells and Persisting Alterations in Adaptive Immunity in the Peripheral Blood of Convalescent Plasma Donors at Eight Months Post SARS-CoV-2 Infection.

Microorganisms 2021 Mar 6;9(3). Epub 2021 Mar 6.

Department of Clinical Therapeutics, Alexandra General Hospital, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece.

Persisting alterations and unique immune signatures have been previously detected in the peripheral blood of convalescent plasma (CP) donors at approximately two months after initial SARS-CoV-2 infection. This article presents the results on the sequential analysis of 47 CP donors at a median time of eight months (range 7.5-8.5 months) post infection, as assessed by flow cytometry. Interestingly, our results show a significant variation of the relevant immune subset composition among CP donors. Regarding innate immunity, both non-classical monocytes, and CD11b- granulocytes had fully recovered at eight months post COVID-19 infection. Intermediate monocytes and natural killer (NK) cells had already been restored at the two-month evaluation and remained stable. Regarding adaptive immunity, the COVID-19-related skewed Th1 and Th2 cell polarization remained at the same levels as in two months. However, low levels of total B cells were detected even after eight months from infection. A persisting reduction of CD8+ Tregs and changes in the NKT cell compartment were also remarkable. CP donors present with a unique immune landscape at eight months post COVID-19 infection, which is characterized by the notable restoration of the components of innate immunity along with a persisting imprint of SARS-CoV-2 in cells of the adaptive immunity.
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http://dx.doi.org/10.3390/microorganisms9030546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000115PMC
March 2021

Continuing Cancer Therapy through the Pandemic While Protecting Our Patients: Results of the Implementation of Preventive Strategies in a Referral Oncology Unit.

Cancers (Basel) 2021 Feb 12;13(4). Epub 2021 Feb 12.

Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Alexandra Hospital, Athens 11528, Greece.

Cancer patients infected with SARS-CoV-2 have worse outcomes, including higher morbidity and mortality than the general population. Protecting this vulnerable group of patients from COVID-19 is of the utmost importance for the continuous operation of an oncology unit. Preventive strategies have been proposed by various societies, and centers around the world have implemented these or modified measures; however, the efficacy of these measures has not been evaluated. In our center, a referral oncology/hematology unit in Athens, Greece, we implemented strict protective measures from the outset of the pandemic in the country and we have prospectively recorded the epidemiological characteristics of COVID-19. Among 11,618 patient visits performed in our unit, 26 patients (case-to-visit ratio of 0.22%) were found positive for SARS-CoV-2, including 4 (1%) among 392 patients that were screened before starting primary systemic treatment. Among patients tested positive for SARS-CoV-2, 22 were symptomatic at the time of diagnosis; subsequently, 12 required hospitalization and 5 died due to COVID-19. Detailed contact tracing indicated that there was no in-unit transmission of the infection. Thus, strict implementation of multilevel protective strategies along with a modestly intense screening program allowed us to continue cancer care in our unit through the pandemic.
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http://dx.doi.org/10.3390/cancers13040763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918613PMC
February 2021

Carfilzomib-induced endothelial dysfunction, recovery of proteasome activity, and prediction of cardiovascular complications: a prospective study.

Leukemia 2021 May 15;35(5):1418-1427. Epub 2021 Feb 15.

Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.

Carfilzomib (CFZ) improves survival in relapsed/refractory multiple myeloma but is associated with cardiovascular adverse events (CVAEs). We prospectively investigated the effect of CFZ on endothelial function and associations with CVAEs. Forty-eight patients treated with Kd (CFZ 20/56 mg/m and dexamethasone) underwent serial endothelial function evaluation, using brachial artery flow-mediated dilatation (FMD) and 26S proteasome activity (PrA) measurement in PBMCs; patients were followed until disease progression or cycle 6 for a median of 10 months. FMD and PrA decreased acutely after the first dose (p < 0.01) and FMD decreased at cycles 3 and 6 compared to baseline (p ≤ 0.05). FMD changes were associated with CFZ-induced PrA changes (p < 0.05) and lower PrA recovery during first cycle was associated with more prominent FMD decrease (p = 0.034 for group interaction). During treatment, 25 patients developed Grade ≥3 CVAEs. Low baseline FMD (HR 2.57 lowest vs. higher tertiles, 95% CI 1.081-6.1) was an independent predictor of CVAEs. During treatment, an acute FMD decrease >40% at the end of first cycle was also independently associated with CVAEs (HR = 3.91, 95% CI 1.29-11.83). Kd treatment impairs endothelial function which is associated with PrA inhibition and recovery. Both pre- and posttreatment FMD predicted CFZ-related CVAEs supporting its role as a possible cardiovascular toxicity biomarker.
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http://dx.doi.org/10.1038/s41375-021-01141-4DOI Listing
May 2021

Overweight/Obesity and Monoclonal Gammopathy of Undetermined Significance.

Clin Lymphoma Myeloma Leuk 2021 Jan 15. Epub 2021 Jan 15.

Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece; Plasma Cell Dyscrasias Unit, Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.

Background: Obesity and high body mass index (BMI) are associated with increased incidence of multiple myeloma (MM). MM usually evolves from a precursor asymptomatic disease, namely monoclonal gammopathy of undetermined significance (MGUS). MGUS progresses to MM at a 1% annual rate; however, risk factors predisposing to MGUS are not completely understood. We conducted a systematic review to assess the relationship between obesity and high BMI with MGUS prevalence and progression to MM. To our knowledge, this is the first systematic review evaluating the role of obesity in MGUS.

Patients And Methods: We searched the Medline database and ClinicalTrials.gov for studies investigating BMI and obesity association with MGUS incidence and progression. The algorithm consisted of a predefined combination of the words "obesity," "obese," "body mass index," "overweight," "diet," "nutrition," "food," "dietary," "adiponectin," "monoclonal gammopathy," and "MGUS".

Results: Overall, 12 articles were retrieved, including 11 eligible articles and 1 clinical trial. More than 57,068 patients were evaluated in this systematic review. Discrepancies between the identified studies were noted. Multiple studies support the notion that obesity or high BMI are positively linked to MGUS prevalence and transition to MM. In contrast, other studies revealed no such association. Visceral adipose tissue metabolic activity and decreased adiponectin concentrations were identified as biomarkers of MGUS progression to MM.

Conclusion: Obesity and increased BMI seem to be implicated both in MGUS development and progression to MM. Further studies should be designed to confirm this hypothesis.
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http://dx.doi.org/10.1016/j.clml.2021.01.008DOI Listing
January 2021

Liver and Gastrointestinal Involvement: Update.

Hematol Oncol Clin North Am 2020 12 31;34(6S):e1-e13. Epub 2020 Dec 31.

Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece.

The organs affected most commonly by AL amyloidosis are the kidneys and heart, however, liver and gastrointestinal (GI) tract are also commonly affected. Symptoms of GI amyloidosis often mimic those of other GI disorders; having a keen awareness of the need to evaluate for amyloidosis is critical in avoiding delay in diagnosis and intervention. GI and liver involvement is associated with significant complications, and challenges in symptomatic management. As with all AL-related organ disease, early systemic treatment can prevent progression of tissue damage and improve outcomes.
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http://dx.doi.org/10.1016/j.hoc.2020.11.001DOI Listing
December 2020

Practical recommendations for the diagnosis and management of transthyretin cardiac amyloidosis.

Heart Fail Rev 2021 Jan 15. Epub 2021 Jan 15.

Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Athens, Greece.

Cardiac amyloidosis (CA) is an infiltrative restrictive cardiomyopathy caused by accumulation in the heart interstitium of amyloid fibrils formed by misfolded proteins. Most common CA types are light chain amyloidosis (AL) caused by monoclonal immunoglobulin light chains and transthyretin amyloidosis (ATTR) caused by either mutated or wild-type transthyretin aggregates. Previously considered a rare disease, CA is increasingly recognized among patients who may be misdiagnosed as undifferentiated heart failure with preserved ejection fraction (HFPEF), paradoxical low-flow/low-gradient aortic stenosis, or otherwise unexplained left ventricular hypertrophy. Progress in diagnosis has been due to the refinement of cardiac echocardiographic techniques (speckle tracking imaging) and magnetic resonance (T1 mapping) and mostly due to the advent of bone scintigraphy that has enabled noninvasive diagnosis of ATTR, limiting the need for endomyocardial biopsy. Importantly, proper management of CA starts from early recognition of suspected cases among high prevalence populations, followed by advanced diagnostic evaluation to confirm diagnosis and typing, preferentially in experienced amyloidosis centers. Differentiating ATTR from other types of amyloidosis, especially AL, is critical. Emerging targeted ATTR therapies offer the potential to improve outcomes of these patients previously treated only palliatively.
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http://dx.doi.org/10.1007/s10741-020-10062-wDOI Listing
January 2021

Whole-Body Low-Dose CT in Multiple Myeloma: Diagnostic Value of Appendicular Medullary Patterns of Attenuation.

AJR Am J Roentgenol 2021 03 13;216(3):742-751. Epub 2021 Jan 13.

First Department of Radiology, School of Medicine, National and Kapodistrian University of Athens, Areteion Hospital, 76, Vas Sophias Ave, 11528, Athens, Greece.

The purpose of this article is to analyze whole-body low-dose CT-detected appendicular medullary patterns of attenuation in patients with newly diagnosed multiple myeloma and to determine the diagnostic performance of whole-body low-dose CT in detecting diffuse marrow infiltration. A total of 76 patients with myeloma who underwent whole-body low-dose CT and spinal MRI at initial assessment were retrospectively analyzed. The medullary cavities of femurs and humeri were evaluated qualitatively and quantitatively on CT. Medullary attenuation and SD-to-mean attenuation ratio were recorded for each long bone. The pattern of marrow involvement on spinal MRI was used as reference. The chi-square test was used to evaluate the relationship between the CT-based appendicular medullary cavity pattern and the MRI pattern, and ROC analysis was performed to assess the diagnostic accuracy of CT attenuation measurements for the differentiation between diffuse and mixed CT-based appendicular medullary cavity patterns. Medullary attenuation differed significantly among mixed, nodular, and diffuse CT-based appendicular medullary cavity patterns in the femurs (mean, 34.23 HU and range, 15-61 HU; mean, 66.26 HU and range, 26-104 HU; mean, 92.80 HU and range, 53-127 HU, respectively) and humeri (mean, 22.18 HU and range, 9-41; mean, 61.18 HU and range, 23-93 HU; mean, 77.50 and range, 25-105 HU, respectively). To discriminate between diffuse and mixed CT-based appendicular medullary cavity patterns, optimal cutoff attenuation values were 63 HU (sensitivity, 97.7%; specificity, 100.0%) for the femurs, and 52 HU (sensitivity, 97.4%; specificity, 100.0%) for the humeri. A total of 24 of 30 (80.0%) patients with a diffuse MRI pattern showed a diffuse CT-based appendicular medullary cavity pattern on whole-body low-dose CT, and all patients with a diffuse CT-based appendicular medullary cavity pattern also showed a diffuse pattern on MRI. According to analysis of peripheral medullary patterns of attenuation, whole-body low-dose CT can identify patients with multiple myeloma with diffuse marrow involvement.
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http://dx.doi.org/10.2214/AJR.20.23204DOI Listing
March 2021

Insights to SARS-CoV-2 life cycle, pathophysiology, and rationalized treatments that target COVID-19 clinical complications.

J Biomed Sci 2021 Jan 12;28(1). Epub 2021 Jan 12.

Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, 11528, Athens, Greece.

Background: Gaining further insights into SARS-CoV-2 routes of infection and the underlying pathobiology of COVID-19 will support the design of rational treatments targeting the life cycle of the virus and/or the adverse effects (e.g., multi-organ collapse) that are triggered by COVID-19-mediated adult respiratory distress syndrome (ARDS) and/or other pathologies.

Main Body: COVID-19 is a two-phase disease being marked by (phase 1) increased virus transmission and infection rates due to the wide expression of the main infection-related ACE2, TMPRSS2 and CTSB/L human genes in tissues of the respiratory and gastrointestinal tract, as well as by (phase 2) host- and probably sex- and/or age-specific uncontrolled inflammatory immune responses which drive hyper-cytokinemia, aggressive inflammation and (due to broad organotropism of SARS-CoV-2) collateral tissue damage and systemic failure likely because of imbalanced ACE/ANGII/AT1R and ACE2/ANG(1-7)/MASR axes signaling.

Conclusion: Here we discuss SARS-CoV-2 life cycle and a number of approaches aiming to suppress viral infection rates or propagation; increase virus antigen presentation in order to activate a robust and durable adaptive immune response from the host, and/or mitigate the ARDS-related "cytokine storm" and collateral tissue damage that triggers the severe life-threatening complications of COVID-19.
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http://dx.doi.org/10.1186/s12929-020-00703-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801873PMC
January 2021

Peripheral Blood Immune Profiling of Convalescent Plasma Donors Reveals Alterations in Specific Immune Subpopulations Even at 2 Months Post SARS-CoV-2 Infection.

Viruses 2020 12 25;13(1). Epub 2020 Dec 25.

Department of Clinical Therapeutics, Alexandra General Hospital, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece.

Immune profiling of patients with COVID-19 has shown that SARS-CoV-2 causes severe lymphocyte deficiencies (e.g., lymphopenia, decreased numbers, and exhaustion of T cells) and increased levels of pro-inflammatory monocytes. Peripheral blood (PB) samples from convalescent plasma (CP) donors, COVID-19 patients, and control subjects were analyzed by multiparametric flow cytometry, allowing the identification of a wide panel of immune cells, comprising lymphocytes (T, B, natural killer (NK) and NKT cells), monocytes, granulocytes, and their subsets. Compared to active COVID-19 patients, our results revealed that the immune profile of recovered donors was restored for most subpopulations. Nevertheless, even 2 months after recovery, CP donors still had reduced levels of CD4 T and B cells, as well as granulocytes. CP donors with non-detectable levels of anti-SARS-CoV-2-specific antibodies in their serum were characterized by higher Th9 and Th17 cells, which were possibly expanded at the expense of Th2 humoral immunity. The most noticeable alterations were identified in previously hospitalized CP donors, who presented the lowest levels of CD8 regulatory T cells, the highest levels of CD56CD16 NKT cells, and a promotion of a Th17-type phenotype, which might be associated with a prolonged pro-inflammatory response. A longer follow-up of CP donors will eventually reveal the time needed for full recovery of their immune system competence.
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http://dx.doi.org/10.3390/v13010026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7824046PMC
December 2020

Significant reduction in the visits to the emergency room department during the COVID-19 pandemic in a tertiary hospital in Greece: Indirect victims of the pandemic?

Medicine (Baltimore) 2020 Dec;99(52):e23845

Department of Clinical Therapeutics, National and Kapodistrian University of Athens, "Alexandra" Hospital, Greece.

Abstract: COVID-19 pandemic caused a major crisis, affecting and straining health care systems, including some very advanced ones. The pandemic may have also indirectly affected access to health care for patients with other conditions, not related to COVID-19, even in countries not overwhelmed by an outbreak.We analyzed and compared visits to the emergency room (ER) department during the same calendar period of 2019 and 2020 (from March 1 to March 31 of each year) in our hospital, a medium size, tertiary center, located in the center of Athens, which is not a referral center for COVID-19.Total ER visits were reduced by 42.3% and the number of those requiring hospitalization by 34.8%. This reduction was driven by lower numbers of visits for low risk, non-specific symptoms and causes. However, there was a significant decrease in admissions for cardiovascular symptoms and complications (chest pain of cardiac origin, acute coronary syndromes, and stroke) by 39.7% and for suspected or confirmed GI hemorrhage by 54.7%. Importantly, number of ER visits for infections remained unchanged, as well as the number of patients that required hospitalization for infection management; only few patients were diagnosed with COVID-19.During the initial period of the pandemic and lock-down in Greece, there was a major decrease in the patients visiting ER department, including decrease in the numbers of admissions for cardiovascular symptoms and complications. These observations may have implications for the management of non-COVID-19 diseases during the pandemic.
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http://dx.doi.org/10.1097/MD.0000000000023845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769364PMC
December 2020

A prognostic index predicting survival in transformed Waldenström macroglobulinemia.

Haematologica 2020 Nov 12;Online ahead of print. Epub 2020 Nov 12.

Bing Center for Waldenström Macroglobulinemia, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.

Histological transformation into diffuse large B-cell lymphoma is a rare complication in patients with Waldenström macroglobulinemia (WM) usually associated with a poor prognosis. The objective of this study was to develop and validate a prognostic index for survival in transformed WM patients. Through this multicenter, international collaborative effort, we developed a scoring system based on data from 133 patients with transformed WM who were evaluated between 1995 and 2016 (training cohort). Univariate and multivariate analyses were used to propose a prognostic index with 2-year survival after transformation as an end-point. For external validation, a data set of 67 patients was used to evaluate the performance of the model (validation cohort). By multivariate analysis, three adverse covariates were identified as independent predictors of 2-year survival after transformation: elevated serum LDH (2 points), platelet count < 100 x 109/L (1 point) and any previous treatment for WM (1 point). Three risk groups were defined: low-risk (0-1 point, 24% of patients), intermediate-risk (2-3 points, 59%, hazard ratio (HR) = 3.4) and high-risk (4 points, 17%, HR = 7.5). Two-year survival rates were 81%, 47%, and 21%, respectively (P < 0.0001). This model appeared to be a better discriminant than the International Prognostic Index (IPI) and the revised IPI (R-IPI). We validated this model in an independent cohort. This easy-to-compute scoring index is a robust tool that may allow identification of groups of transformed WM patients with different outcomes and could be used for improving the development of risk-adapted treatment strategies.
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http://dx.doi.org/10.3324/haematol.2020.262899DOI Listing
November 2020

Deep Phenotyping Reveals Distinct Immune Signatures Correlating with Prognostication, Treatment Responses, and MRD Status in Multiple Myeloma.

Cancers (Basel) 2020 Nov 4;12(11). Epub 2020 Nov 4.

Department of Biology, School of Sciences, National and Kapodistrian University of Athens, 15784 Athens, Greece.

Despite recent advances, Multiple Myeloma (MM) remains an incurable disease with apparent heterogeneity that may explain patients' variable clinical outcomes. While the phenotypic, (epi)genetic, and molecular characteristics of myeloma cells have been thoroughly examined, there is limited information regarding the role of the bone marrow (BM) microenvironment in the natural history of the disease. In the present study, we performed deep phenotyping of 32 distinct immune cell subsets in a cohort of 94 MM patients to reveal unique immune profiles in both BM and peripheral blood (PB) that characterize distinct prognostic groups, responses to induction treatment, and minimal residual disease (MRD) status. Our data show that PB cells do not reflect the BM microenvironment and that the two sites should be studied independently. Adverse ISS stage and high-risk cytogenetics were correlated with distinct immune profiles; most importantly, BM signatures comprised decreased tumor-associated macrophages (TAMs) and erythroblasts, whereas the unique Treg signatures in PB could discriminate those patients achieving complete remission after VRd induction therapy. Moreover, MRD negative status was correlated with a more experienced CD4- and CD8-mediated immunity phenotype in both BM and PB, thus highlighting a critical role of by-stander cells linked to MRD biology.
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http://dx.doi.org/10.3390/cancers12113245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692501PMC
November 2020

Carfilzomib-associated renal toxicity is common and unpredictable: a comprehensive analysis of 114 multiple myeloma patients.

Blood Cancer J 2020 11 3;10(11):109. Epub 2020 Nov 3.

Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece.

Carfilzomib (CFZ) is a non-reversible proteasome inhibitor approved for the treatment of patients with relapsed and refractory myeloma (RRMM). Its use has been associated with cardiovascular toxicity but although recently a signal of clinically significant renal complications has also been identified, it is less extensively investigated. We analyzed data of 114 consecutive patients with RRMM who received CFZ-based regimens. Renal complications not related to MM progression were observed in 19 (17%) patients; thrombotic microangiopathy (TMA) was seen in 6 (5%) patients, albuminuria >1 gr/day in 7 patients (6%) and at least grade 3 acute kidney injury (AKI) which could not be otherwise explained in 6 patients (5%). A total of 15 patients discontinued CFZ and dosing was reinitiated at a lower level in one patient with AKI. Albuminuria was associated with focal segmental glomerulosclerosis in the renal biopsy (performed in a total of 6 patients). Renal complications during CFZ therapy are common, occur mostly early and are unpredictable. A potential effect of CFZ on the renal endothelium could be implicated in the pathogenesis of these complications and may also share common pathophysiology with cardiovascular effects of CFZ.
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http://dx.doi.org/10.1038/s41408-020-00381-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642386PMC
November 2020

Emerging treatment strategies for COVID-19 infection.

Clin Exp Med 2021 May 30;21(2):167-179. Epub 2020 Oct 30.

Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Alexandra General Hospital, 80 Vas. Sofias Avenue, 11528, Athens, Greece.

The new type of coronavirus (COVID-19), SARS-CoV-2 originated from Wuhan, China and has led to a worldwide pandemic. COVID-19 is a novel emerging infectious disease caused by SARS-CoV-2 characterized as atypical pneumonia. As of July 1, 2020, more than 10 million people worldwide had been infected with SARS-CoV-2. The typical manifestations of COVID-19 include fever, sore throat, fatigue, cough, and dyspnoea combined with recent exposure. Most of the patients with COVID-19 have mild or moderate disease, however up to 5-10% present with severe and even life-threatening disease course. The mortality rates are approximately 2%. Therefore, there is an urgent need for effective and specific antiviral treatment. Currently, supportive care measures such as ventilation oxygenation and fluid management remain the standard of care. Several clinical trials are currently trying to identify the most potent drug or combination against the disease, and it is strongly recommended to enroll patients into ongoing trials. Antivirals can be proven as safe and effective only in the context of randomized clinical trials. Currently several agents such as chloroquine, hydroxychloroquine, favipiravir, monoclonal antibodies, antisense RNA, corticosteroids, convalescent plasma and vaccines are being evaluated. The large numbers of therapeutic interventions aim to define the most efficacious regimen. The aim of this article is to describe the treatment strategies that have been used for COVID-19 patients and review all the available literature.
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http://dx.doi.org/10.1007/s10238-020-00671-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598940PMC
May 2021

Editorial: Exploiting the Immune System to Treat Multiple Myeloma: From Transplantation to Novel Treatment Approaches.

Front Oncol 2020 6;10:607571. Epub 2020 Oct 6.

Division of Hematology, Citta della Salute e della Scienza, University of Torino, Torino, Italy.

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http://dx.doi.org/10.3389/fonc.2020.607571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573349PMC
October 2020

Response of an oncology unit in the midst of the COVID-19 outbreak.

J Oncol Pharm Pract 2020 Dec 22;26(8):1947-1952. Epub 2020 Oct 22.

Department of Clinical Therapeutics, Alexandra General Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.

Coronavirus disease 19 (COVID-19) pandemic has caused an emergency in health systems worldwide. Apart from its apparent morbidity and mortality, COVID-19 has also imposed unique challenges in the management of cancer patients. We report here measures taken by a major oncology Unit in Greece to continue operation of the department while ensuring safety of the patients and health care professionals. The efficacy of these measures could serve as guidance for Oncology departments in view of a second wave of COVID-19 cases.
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http://dx.doi.org/10.1177/1078155220967973DOI Listing
December 2020

Consensus treatment recommendations from the tenth International Workshop for Waldenström Macroglobulinaemia.

Lancet Haematol 2020 Nov;7(11):e827-e837

Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Athens, Greece.

Waldenström macroglobulinaemia is an indolent B-cell lymphoma with clearly defined criteria for diagnosis, initiation of therapy, and response, which was established by consensus panels at previous International Workshops for Waldenström Macroglobulinaemia (IWWM). The treatment options for Waldenström macroglobulinaemia continued to be researched after the publication of the eighth IWWM consensus recommendations in 2016, and at the tenth IWWM in New York, USA (October, 2018) an international consensus panel was formed to update treatment recommendations. Participants were selected as members of the consensus panel based on their expertise on Waldenström macroglobulinaemia. The initial live discussion took place during the tenth IWWM meeting and two separate teleconferences were held in June, 2019, and January, 2020, to refine recommendations. No external or financial support was received for the elaboration of these recommendations. According to these updated consensus recommendations, alkylating drugs (bendamustine, cyclophosphamide) and proteasome inhibitors (bortezomib, carfilzomib, ixazomib), both in combination with rituximab, as well as BTK inhibitors (ibrutinib), alone or in combination with rituximab, are preferred first-line therapy options for symptomatic patients with Waldenström macroglobulinaemia. In previously treated patients with Waldenström macroglobulinaemia who had an initial durable response, reuse of a previous regimen or another primary therapy regimen are acceptable options. Novel BTK inhibitors (acalabrutinib, zanubrutinib, tirabrutinib) and the BCL2 antagonist venetoclax appear safe and active, and represent emerging options for the treatment of Waldenström macroglobulinaemia. The choice of therapy should be guided by the patient's clinical profile, genomic features, and drug availability.
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http://dx.doi.org/10.1016/S2352-3026(20)30224-6DOI Listing
November 2020

International Myeloma Working Group risk stratification model for smoldering multiple myeloma (SMM).

Blood Cancer J 2020 10 16;10(10):102. Epub 2020 Oct 16.

Clinica Universidad de Navarra, CIMA, CIBERONC, IDISNA, Pamplona, Spain.

Smoldering multiple myeloma (SMM) is an asymptomatic precursor state of multiple myeloma (MM). Recently, MM was redefined to include biomarkers predicting a high risk of progression from SMM, thus necessitating a redefinition of SMM and its risk stratification. We assembled a large cohort of SMM patients meeting the revised IMWG criteria to develop a new risk stratification system. We included 1996 patients, and using stepwise selection and multivariable analysis, we identified three independent factors predicting progression risk at 2 years: serum M-protein >2 g/dL (HR: 2.1), involved to uninvolved free light-chain ratio >20 (HR: 2.7), and marrow plasma cell infiltration >20% (HR: 2.4). This translates into 3 categories with increasing 2-year progression risk: 6% for low risk (38%; no risk factors, HR: 1); 18% for intermediate risk (33%; 1 factor; HR: 3.0), and 44% for high risk (29%; 2-3 factors). Addition of cytogenetic abnormalities (t(4;14), t(14;16), +1q, and/or del13q) allowed separation into 4 groups (low risk with 0, low intermediate risk with 1, intermediate risk with 2, and high risk with ≥3 risk factors) with 6, 23, 46, and 63% risk of progression in 2 years, respectively. The 2/20/20 risk stratification model can be easily implemented to identify high-risk SMM for clinical research and routine practice and will be widely applicable.
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http://dx.doi.org/10.1038/s41408-020-00366-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567803PMC
October 2020

Characterization of a PERK Kinase Inhibitor with Anti-Myeloma Activity.

Cancers (Basel) 2020 Oct 5;12(10). Epub 2020 Oct 5.

Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece.

Due to increased immunoglobulin production and uncontrolled proliferation, multiple myeloma (MM) plasma cells develop a phenotype of deregulated unfolded protein response (UPR). The eIF2-alpha kinase 3 [EIF2αK3, protein kinase R (PKR)-like ER kinase (PERK)], the third known sensor of endoplasmic reticulum (ER) stress, is a serine-threonine kinase and, like the other two UPR-related proteins, i.e., IRE1 and ATF6, it is bound to the ER membrane. MM, like other tumors showing uncontrolled protein secretion, is highly dependent to UPR for survival; thus, inhibition of PERK can be an effective strategy to suppress growth of malignant plasma cells. Here, we have used GSK2606414, an ATP-competitive potent PERK inhibitor, and found significant anti-proliferative and apoptotic effects in a panel of MM cell lines. These effects were accompanied by the downregulation of key components of the PERK pathway as well as of other UPR elements. Consistently, gene expression silencing significantly increased cell death in MM cells, highlighting the importance of PERK signaling in MM biology. Moreover, GSK2606414, in combination with the proteasome inhibitor bortezomib, exerted an additive toxic effect in MM cells. Overall, our data suggest that PERK inhibition could represent a novel combinatorial therapeutic approach in MM.
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http://dx.doi.org/10.3390/cancers12102864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601861PMC
October 2020

Circulating Soluble Urokinase-Type Plasminogen Activator Receptor Levels Reflect Renal Function in Newly Diagnosed Patients with Multiple Myeloma Treated with Bortezomib-Based Induction.

J Clin Med 2020 Oct 3;9(10). Epub 2020 Oct 3.

Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece.

(1) Background: Soluble urokinase-type plasminogen activator receptor (suPAR) has been implicated in the pathogenesis of kidney disease in different disease settings. The aim of this study was to investigate a possible link between suPAR circulating levels and renal impairment (RI) in newly diagnosed patients with symptomatic multiple myeloma (NDMM) before and after frontline therapy with bortezomib-based regimens. (2) Methods: We studied 47 NDMM patients (57% males, median age 69.5 years) before the administration of anti-myeloma treatment and at best response to bortezomib-based therapy. suPAR was measured in the serum of all patients and of 24 healthy matched controls, using an immuno-enzymatic assay (ViroGates, Denmark). (3) Results: suPAR levels were elevated in NDMM patients at diagnosis compared to healthy individuals ( < 0.001). suPAR levels strongly correlated with disease stage (-ANOVA < 0.001). suPAR levels both at diagnosis and at best response negatively correlated with estimated glomerular filtration rate (eGFR) values ( < 0.001). Interestingly, no significance changes in suPAR levels were observed at best response compared to baseline values ( = 0.31) among 18 responding patients with baseline eGFR < 50 mL/min/1.73 m. (4) Conclusions: SuPAR levels reflect renal function in NDMM patients treated with bortezomib-based induction. Responders may have elevated circulating suPAR levels, possibly reflecting persistent kidney damage, despite their renal response.
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http://dx.doi.org/10.3390/jcm9103201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600599PMC
October 2020

The Role of Low Dose Whole Body CT in the Detection of Progression of Patients with Smoldering Multiple Myeloma.

Blood Cancer J 2020 09 25;10(9):93. Epub 2020 Sep 25.

1st Department of Radiology, School of Medicine, Aretaieion Hospital, National and Kapodistrian University of Athens, Athens, Greece.

Multiple myeloma (MM) is the second most common hematological malignancy, characterized by plasma cell bone marrow infiltration and end-organ involvement. Smoldering MM (SMM) is an intermediate clinical entity between MGUS and MM, with a risk of progression to symptomatic disease 10% per year. Bone disease is the most frequent symptom of MM, with ~90% of patients developing bone lesions throughout their disease course. Therefore, imaging plays a crucial role in diagnosis and management. Whole-body low-dose CT (WBLDCT) is widely available and has been incorporated in the latest diagnostic criteria of the IMWG. The purpose of this study was to evaluate the role of WBLDCT in the early identification of lesions in patients with SMM who progress solely with bone disease. In total, 100 asymptomatic patients were consecutively assessed with WBLDCT from July 2013 until March 2020 at baseline, 1-year after diagnosis and every 1 year thereafter. Ten percent of patients were identified as progressors with this single imaging modality. This is the first study to evaluate prospectively patients with SMM at different time points to identify early bone lesions related to MM evolution. Serial WBLDCT studies can identify early myeloma evolution and optimize disease monitoring and therapeutic strategies.
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http://dx.doi.org/10.1038/s41408-020-00360-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519647PMC
September 2020

Seroprevalence of Antibodies against SARS-CoV-2 among the Personnel and Students of the National and Kapodistrian University of Athens, Greece: A Preliminary Report.

Life (Basel) 2020 Sep 21;10(9). Epub 2020 Sep 21.

Fourth Department of Propedeutic Internal Medicine, School of Medicine, University General Hospital Attikon, NKUA, 12462 Haidari, Greece.

Due to early implementation of public health measures, Greece had low number of SARS-CoV-2 infections and COVID-19 severe incidents in hospitalized patients. The National and Kapodistrian University of Athens (ΝΚUA), especially its health-care/medical personnel, has been actively involved in the first line of state responses to COVID-19. To estimate the prevalence of antibodies (Igs) against SARS-CoV-2 among NKUA members, we designed a five consecutive monthly serosurvey among randomly selected NKUA consenting volunteers. Here, we present the results from the first 2500 plasma samples collected during June-July 2020. Twenty-five donors were tested positive for anti-SARS-CoV-2 Igs; thus, the overall seroprevalence was 1.00%. The weighted overall seroprevalence was 0.93% (95% CI: 0.27, 2.09) and varied between males [1.05% (95% CI: 0.18, 2.92)] and females [0.84% (95% CI: 0.13, 2.49)], age-groups and different categories (higher in participants from the School of Health Sciences and in scientific affiliates/faculty members/laboratory assistants), but no statistical differences were detected. Although focused on the specific population of NKUA members, our study shows that the prevalence of anti-SARS-CoV-2 Igs for the period June-July 2020 remained low and provides knowledge of public health importance for the NKUA members. Given that approximately one in three infections was asymptomatic, continuous monitoring of the progression of the pandemic by assessing Ig seroprevalence is needed.
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http://dx.doi.org/10.3390/life10090214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555935PMC
September 2020

Emerging drugs for the treatment of Waldenström macroglobulinemia.

Expert Opin Emerg Drugs 2020 12 21;25(4):433-444. Epub 2020 Sep 21.

Plasma Cell Dyscrasia Unit, Department of Clinical Therapeutics, National and Kapodistrian University of Athens , Athens, Greece.

Introduction: Waldenström's Macroglobulinemia (WM) is an indolent lymphoma with uniquely distinct and heterogenous clinical and genomic profiles. Clonal lymphoplasmacytic cells secrete monoclonal IgM. More than 90% of patients harbor a mutation in MYD88 gene, leading to the constitutive activation of downstream pathways, involving BTK-mediated signaling. The use of BTK inhibitors has changed the treatment landscape of WM and has paved the way for new approaches to therapy.

Areas Covered: WM is an orphan disease and ibrutinib is the only FDA/EMA approved agent. Currently established agent combinations will be reviewed with a focus on emerging therapeutic options. These include second generation inhibitors, agents that target other molecules in the BCR signaling pathway, CXCR4 inhibitors, proteasome inhibitors and anti-CD38 antibodies. The current research goal is to establish a combination that can induce deep and durable responses with minimal associated toxicity. In addition, agents that can overcome ibrutinib resistance or act in a synergistic manner with BTKi are under investigation.

Expert Opinion: The optimal therapeutic approach for WM patients is not currently established. The question of whether a combinatory (or synergistic) regimen to overcome resistance and allow for fixed- duration treatment will allow for deep/durable responses is being addressed in ongoing clinical trials.
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http://dx.doi.org/10.1080/14728214.2020.1822816DOI Listing
December 2020

Systemic AL Amyloidosis: Current Approaches to Diagnosis and Management.

Hemasphere 2020 Aug 10;4(4):e454. Epub 2020 Aug 10.

Plasma Cell Dyscrasia Unit, Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Athens, Greece.

AL amyloidosis is characterized by a low-level expansion of an indolent, small plasma cell clone that produces amyloidogenic light chains. Amyloid aggregates or preceding intermediaries cause direct cell damage through their proteotoxicity, and amyloid deposits distort tissue architecture, and, eventually, lead to organ impairment. It is a rare, underdiagnosed disease with a diverse clinical presentation depending on the organ tropism of the amyloid fibrils; cardiac and renal involvement is most common, but any organ can be affected, excluding the central nervous system. A high level of awareness and a systematic approach using newly emerging screening biomarkers is required to achieve early diagnosis. Management should be multidisciplinary as supportive management tailored to management of organ dysfunction is paramount to survival and minimization of treatment-associated toxicity. The initial therapeutic aim is to rapidly eliminate the clonal plasma cell that produces the circulating amyloid precursor and achieve a complete hematologic response, and if possible with undetectable minimal residual disease as assessed by next-generation methods (flow and sequencing), with minimal toxicity. Treatment is tailored to the initial risk assessment of the patients. Treatments are based on regimens adapted from the expanding options that are available for multiple myeloma patients and hematological response rates have improved. Organ response rates are strongly associated with deeper hematologic response but usually lag behind hematological response and are also dependent on the initial organ function reserve. Agents directed against the amyloid deposits have been explored to aid amyloid clearance and improve organ function, but data are still negative.
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http://dx.doi.org/10.1097/HS9.0000000000000454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430233PMC
August 2020

Daratumumab-based therapy for patients with monoclonal gammopathy of renal significance.

Br J Haematol 2021 Apr 23;193(1):113-118. Epub 2020 Aug 23.

Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece.

Treatment of the plasma cell clone in monoclonal gammopathy of renal significance (MGRS) is necessary in order to reduce toxic immunoglobulin load to the kidneys and salvage renal function. There are limited data on the use of daratumumab in patients with MGRS. We summarize our experience with the use of daratumumab-based therapy in 25 MGRS patients, 12 of whom were previously untreated. The median follow-up of the cohort is 14 months. The best overall haematologic response in evaluable patients was complete response (CR) in five (22%), very good partial response (VGPR) in five (22%) and partial response (PR) in seven (30%) patients for an overall response rate of 74%. Two of five patients in CR and two patients with initially detectable clones, but non-measurable immunoglobulins, had undetectable minimal residual disease (MRD) with next-generation flow cytometry (NGF) after therapy. Haematologic response rate for previously untreated patients was 83% vs. 69% for previously treated and for daratumumab combinations it was 91% vs. 64%, and with CR/VGPR 82% vs. 29%, compared to daratumumab monotherapy. At six months, 12/22 (55%) patients not on dialysis achieved a reduction of proteinuria >30%, of at least 0·5 g/24 h, without an estimated glomerular filtration rate (eGFR) reduction. The toxicity was mild and predictable. In conclusion, daratumumab-based therapy is a new option for patients with MGRS.
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http://dx.doi.org/10.1111/bjh.17052DOI Listing
April 2021