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Primary adrenal lymphoma (PAL) is a rare entity that presents as unilateral or bilateral rapidly growing adrenal masses, with signs and symptoms most commonly related to adrenal insufficiency due to the mass effect on the surrounding tissues. Although steroeidogenesis has not been previously described in PAL, we herein report two cases of PAL presenting as adrenal incidentalomas (AIs) that demonstrated autonomous cortisol production. A 52-year-old woman presented with lumbar pain; a computed tomography (CT) scan demonstrated a left AI measuring 8.5 × 15 × 10 cm. Similarly, an 80-year-old woman presented with lumbar pain, demonstrating in a CT scan a bilateral AI (right: 9 × 6.5 cm, left: 3.6 × 3.2 cm). Both cases underwent a full hormonal evaluation according to the algorithm for the investigation of AIs, demonstrating increased 24-h cortisol excretion, suppressed fasting adrenocorticotropic hormone (ACTH) levels, and non-suppressed serum cortisol levels in both the overnight and the low-dose dexamethasone suppression tests, indicating autonomous cortisol secretion and Cushing's syndrome. In a relatively short time, both patients developed night sweats, and their clinical picture deteriorated, while the CT scans showed increased dimensions of the masses with radiological characteristics compatible to lymphoma. Both patients underwent ultrasound-guided biopsies (FNBs), revealing infiltration of the left adrenal by diffuse large B-cell lymphoma in the first case, whereas bilateral adrenal infiltration from the same histological type was noted in the second case. Subsequently, they were treated with immunochemotherapy, but the second patient died from an infection shortly after the initiation of the treatment. To our knowledge, this is the first report of PAL presenting with Cushing's syndrome due to autonomous cortisol production, indicating that neoplastic lymphoid cells in PAL might acquire the potential for steroidogenesis; therefore, more cases of PAL should be analyzed so as to further elucidate the complex pathogenesis and the natural course of this entity. [ABSTRACT FROM AUTHOR]

Simple Summary: Diffuse large B-cell lymphoma (DLBCL) is the most common high-grade non-Hodgkin lymphoma. The current treatment combining the anti-CD20 monoclonal antibody rituximab with chemotherapy is the gold standard for frontline treatment. Although the results for patients who relapse had been disappointing, the recent research explosion on novel agents for DLBCL has reignited the hope for these patients. This review aims to summarize the exciting research results of novel therapeutic agents recently approved or under investigation for the treatment of DLBCL. We focus on novel monoclonal antibodies conjugated to cytotoxic drugs and bispecific antibodies that have shown very promising results for patients in the relapsed/refractory setting. Although rituximab has revolutionized the treatment of diffuse large B-cell lymphoma (DLBCL), a significant proportion of patients experience refractory disease or relapse early after the end of treatment. The lack of effective treatment options in the relapsed/refractory (R/R) setting had made the prognosis of these patients dismal. The initial enthusiasm for novel anti-CD20 antibodies had been short-lived as they failed to prove their superiority to rituximab. Therefore, research has focused on developing novel agents with a unique mechanism of action. Among them, two antibody-drug conjugates, namely polatuzumab vedotin (PolaV) and loncastuximab tesirine, along with tafasitamab, an anti-CD19 bioengineered antibody, have been approved for the treatment of R/R DLBCL. Whereas PolaV has been FDA and EMA approved, EMA has not approved loncastuximab tesirine and tafasitamab yet. Results from randomized trials, as well as real-life data for PolaV have been promising. Novel agents as bispecific antibodies bridging CD3 on T-cells to CD20 have shown very promising results in clinical trials and are expected to gain approval for treatment of R/R DLBCL soon. As the therapeutic armamentarium against DLBCL is expanding, an improvement in survival of patients with R/R and higher cure rates might soon become evident. [ABSTRACT FROM AUTHOR]

End-of-treatment (EoT) PET/CT is used as a guide to omit radiotherapy (RT) patients with primary mediastinal large B-cell lymphoma (PMBCL). We present the mature and extended results of a retrospective study evaluating the prognostic significance of EoT-PET/CT after adequate response to R-CHOP. Among 231 consecutive PMLBCL patients, 182 underwent EoT-PET/CT and were evaluated according to the Deauville 5-point scale (D5PS) criteria. Freedom from progression (FFP) was measured from the time of PET/CT examination. Among 182 patients, 72 (40%) had D5PS score 1 (D5PSS-1), 33 (18%) had 2, 28 (15%) had 3, 29 (16%) had 4, and 20 (11%) had 5. The 5-year FFP was 97, 94, 92, 82, and 44% for D5PSS-1, D5PSS-2, D5PSS-3, D5PSS-4, and D5PSS-5, respectively. Among 105 patients with unequivocally negative PET/CT (D5PSS-1/D5PSS-2), 49 (47%) received RT (median dose 3420 cGy) and 56 (53%) did not with relapses in 0/49 vs. 4/56 patients (2 mediastinum and 2 isolated CNS relapses).The 5-year FFP for those who received RT or not was 100% versus 96%, when isolated CNS relapses were censored (p = 0.159). Among D5PSS-3 patients (27/28 irradiated-median dose 3600 cGy), the 5-year FFP was 92%. The 5-year FFP for D5PSS-4 and D5PSS-5 was 82 and 44%; 44/49 patients received RT (median dose 4000 and 4400 cGy for D5PSS-4 and D5PSS-5). Our study supports the omission of RT in a sizeable fraction of PET/CT-negative patients and definitely discourages salvage chemotherapy and ASCT in patients with PMLBCL who conventionally respond to R-CHOP, solely based on PET/CT positivity in the absence of documented progressive or multifocal disease. The persistence of positive PET/CT with D5PSS < 5 after consolidative RT should not trigger the initiation of further salvage chemotherapy in the absence of conventionally defined PD. [ABSTRACT FROM AUTHOR]

Background: Erdheim–Chester Disease (ECD) is a clonal non-Langerhans histiocytosis, classified as a macrophage-dendritic cell neoplasm in the 2016 WHO classification. The exact cell of origin of ECD is unknown, although some limited evidence suggests that it arises from myeloid progenitors. Case Presentation: A 43-year-old patient, diagnosed with BRAFV600E mutated ECD, developed NPM1+/FLT3+ acute myeloid leukemia (AML) with wild-type BRAF, 15 months after the initial ECD diagnosis. The patient received intensive chemotherapy plus midostaurin, followed by midostaurin maintenance. Six months into maintenance, the patient remains in complete remission with low-level measurable residual disease, whereas ECD shows a sustained partial metabolic response. Molecular karyotype at several distinct timepoints, namely ECD diagnosis, AML diagnosis, and following treatment of AML, highlighted a molecular signature, indicative of a persistent, underlying clonal hematopoiesis. Conclusion: This case report suggests that ECD and AML might represent an expansion of two distinct clones in a background of clonal hematopoiesis, indicating their shared origin. Moreover, molecular karyotype might serve as a strong, inexpensive tool for revealing clonal hematopoiesis in cases of negative targeted next-generation sequencing. Finally, the moderate response of ECD to midostaurin suggests that kinase inhibition might have a potential role in ECD treatment. [ABSTRACT FROM AUTHOR]

MicroRNA-92a-3p (miR-92a-3p) derives from the oncogenic miR-17/92 cluster and its highly homologous miR-106a/363 cluster. miR-92a-3p regulates the expression of key transcription factors such as HIF1 and inhibits SOCS1 to enhance the anti-apoptotic STAT3/IL6 signaling pathway. In this study, we assessed the putative usefulness of miR-92a-3p as a prognostic and/or diagnostic biomarker in chronic lymphocytic leukemia (CLL). For this purpose, total RNA was extracted from mononuclear cells isolated from the peripheral blood of 88 CLL patients and 36 non-leukemic blood donors, was polyadenylated and reversely transcribed. miR-92a-3p expression was quantified using an accurate qPCR method. miR-92a-3p levels were significantly lower in peripheral blood mononuclear cells of CLL patients. Overall survival (OS) analysis revealed that high miR-92a-3p expression predicts significantly prolonged OS of CLL patients. Interestingly, miR-92a-3p overexpression remains a significant prognosticator in subgroups of CLL patients with distinct prognosis. In conclusion, miR-92a-3p overexpression is a potential surrogate biomarker of favorable outcome of CLL patients. [ABSTRACT FROM AUTHOR]

Plasmablastic lymphoma (PBL) is a rare, aggressive type of B-cell non-Hodgkin lymphoma with the vast majority of patients responding poorly to treatment or progressing shortly thereafter. Cyclophosphamide-doxorubicin-vincristine-prednisolone (CHOP) or CHOP-like regimens have disappointing results in this setting. We report a case of PBL arising in a previously diagnosed myelodysplastic/myeloproliferative (MDS/MPN) with ring sideroblasts and thrombocytopenia (RS-T), HIV-negative patient treated with the combination of CHOP and bortezomib. The patient achieved complete metabolic response, which has lasted one year, longer by far than would have been expected with the sole use of CHOP. [ABSTRACT FROM AUTHOR]

MicroRNA-20b-5p (miR-20b-5p) is part of the miR-106a/363 cluster and a member of the cancer-related miR-17 family. miR-20b-5p regulates important transcription factors, including hypoxia-inducible factor 1 (HIF1) and signal transducer and activator of transcription 3 (STAT3). Recently, the dysregulation of miR-20b-5p expression has been observed in many B-cell lymphomas and T-cell leukemias. In this research study, we examined the putative prognostic value of miR-20b-5p in CLL. Therefore, total RNA was isolated from peripheral blood mononuclear cells (PBMCs) collected from 88 CLL patients; next, total RNA was polyadenylated and first-strand cDNA was synthesized, using an oligo-dT–adapter primer. miR-20b-5p expression was quantified using an in-house–developed real-time quantitative PCR assay. Kaplan-Meier OS analysis and bootstrap univariate Cox regression showed that high miR-20b-5p expression predicts better OS for CLL patients ( p <  0.001). Interestingly, miR-20b-5p overexpression retains its favorable prognostic role in CLL patients of intermediate risk or stratified according to established prognostic factors [CD38 expression and mutational status of the immunoglobulin heavy chain variable ( IGHV ) region]. In conclusion, miR-20b-5p is a potential independent molecular biomarker of favorable prognosis in CLL. [ABSTRACT FROM AUTHOR]

MicroRNA-155-5p (miR-155-5p) is a proinflammatory, oncogenic miRNA, involved in various physiological processes, including hematopoiesis, immunity, inflammation, and cell lineage differentiation. It regulates important transcription factors, such as E2F2, hypoxia-inducible factor 1 (HIF1), and FOXO3. Recently, the dysregulation of miR-155-5p expression has been linked to chronic lymphocytic leukemia (CLL) pathogenesis. In this research study, we investigated the potential diagnostic and prognostic value of miR-155-5p in CLL. To achieve our goal, we isolated total RNA from peripheral blood mononuclear cells (PBMCs) collected from 88 CLL patients and 36 nonleukemic blood donors and performed polyadenylation of total RNA and reverse transcription. Next, we quantified miR-155-5p levels using an in-house-developed real-time quantitative PCR method, before proceeding to extensive biostatistical analysis. Thus, it appears that miR-155-5p is significantly overexpressed in PBMCs of CLL patients and can distinguish them from nonleukemic population. Kaplan-Meier OS analysis and bootstrap univariate Cox regression showed that high miR-155-5p expression predicts inferior OS for CLL patients (p<0.001). Interestingly, miR-155-5p overexpression retains its unfavorable prognostic role in CLL patients stratified according to established prognostic factors [CD38 expression and mutational status of the immunoglobulin heavy chain variable region (IGHV)]. Thus, miR-155-5p appears as a promising, independent molecular biomarker of unfavorable prognosis in CLL. [ABSTRACT FROM AUTHOR]

The hypoxia inducible factor 1 (HIF1) is a heterodimeric transcription factor that ultimately regulates cellular responses to changes in oxygen tension. In this study, we examined the potential diagnostic and prognostic potential of the mRNA expression of HIF1 regulatory α-subunit ( HIF1A ) in chronic lymphocytic leukemia (CLL). For this purpose, total RNA was isolated from peripheral blood mononuclear cells collected from 88 CLL patients and 33 non-leukemic blood donors, and poly(A)-RNA was reversely transcribed. HIF1A mRNA levels were quantified using real-time PCR. Kaplan-Meier survival analysis showed that high HIF1A mRNA expression predicts inferior overall survival for CLL patients ( p = 0.001). Bootstrap univariate Cox regression analysis confirmed that HIF1A mRNA overexpression is a significant unfavorable prognosticator in CLL (hazard ratio = 3.75, bias-corrected and accelerated 95% confidence interval = 1.43–24.36, bootstrap p < 0.001), independent of other established prognostic factors, including CD38 expression, the mutational status of the immunoglobulin heavy chain variable region ( IGHV ), and the clinical stage (Binet or Rai stage) or risk group ( p < 0.001 in all cases). Interestingly, HIF1A mRNA positivity retains its unfavorable prognostic value in distinct subgroups of patients, stratified according to established prognostic factors. Thus, HIF1A mRNA overexpression can be regarded as a promising, independent molecular biomarker of unfavorable prognosis in CLL. [ABSTRACT FROM AUTHOR]

Anti-CD20-based chemo-immunotherapeutic regimens have been suggested to assist in the management of Epstein-Barr virus (EBV)-induced hemophagocytic lymphohistiocytosis (HLH) and EBV-associated post-transplant lymphoproliferative disorders (EBV-PTLD), by reducing EBV viral load and EBV-induced inflammation. Herein we report a fatal EBV-related HLH in the context of Hodgkin lymphoma (HL)-like Richter’s transformation of B chronic lymphocytic leukemia (B-CLL), two months after rituximab treatment. The complex balance between EBV driven T-cell stimulation and immunosuppressive therapy in the context of multiple immune deficits is discussed. [ABSTRACT FROM AUTHOR]

The article discusses the overexpression of BCL2L12 protein associated with favorable outcome in diffuse large B-cell lymphoma (DLBCL) patients treated with rituximab. The study included formalin-fixed paraffin-embedded tissue biopsies from newly diagnosed DLBCL patients, and other conventional chemotherapy treatments like cyclophosphamide, doxorubicin, and vincristine. Assessments performed include immunohistochemistry, RNA isolation from cultured cells, and multivariate Cox regression.

Objectives: The demethylating factor 5-Azacytidine (5-AZA) improves survival of patients with myelodysplastic syndromes (MDS) in randomized control trials but the results in 'real life' are controversial. Methods: In this retrospective study, we evaluated the outcome of 56 high-risk MDS patients who were treated with 5-AZA between 2005 and 2013. 5-AZA was administered in an outpatient basis at a dose 75 mg/m2 s.c. with the following schedule: 5 days on/weekend off/2 days on (5/2/2). Results: The overall response rate (ORR) was 50%; 21.2% patients achieved complete response (CR), 3.8% partial response (PR), and 25% hematologic improvement (HI); 34.6% had stable disease (SD) and 15.4% showed progressive disease (PD). The estimated median event free survival (EFS) and overall survival (OS) were 11 and 17 months, respectively. Interestingly, the estimated time to acute myeloid leukemia transformation was 30 months, which refers to patients who responded to AZA treatment or remained stable. Patients who responded to the 5-AZA achieving CR, PR, and HI had better EFS and OS compared to the patients who had SD or PD. In addition, Δ WHO Classification-based Prognostic Score System (ΔWPSS), which represents the improvement of WPSS risk group before and after treatment, was associated with significantly improved OS and better EFS. Finally, the response to treatment was not associated with the expression of p53. Conclusions: In conclusion, 5-AZA is an effective treatment for high-risk MDS. Improved OS and EFS were found mainly in patients who responded to the treatment while ΔWPSS seems to represent a promising future prognostic tool. [ABSTRACT FROM AUTHOR]

Abstract: The expression of activated forms of key proteins of the DNA damage response machinery (pNBS1, pATM and γH2AX) was assessed by means of immunohistochemistry in bone marrow biopsies of 74 patients with de novo myelodysplastic syndromes (MDS) and compared with 15 cases of de novo acute myeloid leukemia (AML) and 20 with reactive bone marrow histology. Expression levels were significantly increased in both MDS and AML, compared to controls, being higher in high-risk than in low-risk MDS. Increased pNBS1 and γH2AX expression possessed a significant negative prognostic impact for overall survival in MDS patients, whereas pNBS1 was an independent marker of poor prognosis. [Copyright &y& Elsevier]

Abstract: Mir-17-5p and mir-20a, members of the mir-17-92 family, down-regulate E2F1, which is over-expressed in myelodysplastic syndromes (MDS). Moreover, let-7a down-regulates KRAS, which is aberrantly expressed in MDS. We evaluated the expression of the aforementioned microRNAs in CD34+ cells of 43 MDS patients using real-time PCR and their target proteins (E2F1, MYC, BCL2, CCND1, and KRAS) by Western blot. Mir-17-5p and mir-20a were under expressed in high risk MDS patients, compared to low risk MDS patients. Similarly, let-7a was under expressed in patients with intermediate or high-risk karyotype. Interestingly, there was an inverse correlation between microRNA and the expression levels of their targets. Importantly, mir-17-5p and mir-20a constitute favorable prognostic factors in MDS, since their expression was associated with increased overall survival of MDS patients. [Copyright &y& Elsevier]

errant activation of phosphoinositide-3 kinase/Akt (PI3K/Akt) and mammalian target of rapamycin (mTOR) signaling is implicated in the pathogenesis of mantle cell lymphoma (MCL). We previously showed oncogenic activation of PI3K/Akt pathway in a subset of MCL patients. In this study, we investigated downstream the immunohistochemical expression of pmTOR [indicative of mTOR complex 1 (mTORC1) activation status] as well as of hypoxia-inducible factor 1 alpha (HIF-1α), hypoxia-inducible factor 2 alpha (HIF-2α), p53, and p21 in the same series of MCL patients. Additionally, correlation of these proteins with activated Akt (pAkt) and established histological prognostic factors was examined. Thirty-five tissue samples (28 classical type and seven blastoid variant) were included. The neoplastic cells expressed pmTOR in 61.7%, HIF-1α in 73.5%, HIF-2α in 23.5%, and p53 in 18.2% of patients, while p21 was negative in all examined samples. In addition, 72% of patients who expressed HIF-1α had also pmTOR expression ( p = 0.041). HIF-1α expression was also correlated to an elevated (≥30%) Ki-67 ( p = 0.031) and blastoid variant of disease ( p = 0.017). In conclusion, we report for the first time common expression of HIF-alphas, especially HIF-1α, in MCL patients. Furthermore, an overall activation of mTORC1→HIF-1α axis and a potential role of pmTOR in the regulation of HIF-1α in MCL patients are suggested. Finally, HIF-1α appears to be associated with more aggressive disease. A pathogenetic role for both mTORC1 and HIF-1α in MCL is implied, which will possibly lead to more efficient target therapies. [ABSTRACT FROM AUTHOR]

• PMLBCL rarely extends to extranodal subdiaphragmatic (ES) sites at diagnosis. • Among 455 patients, 32 (7%) had such localization at baseline. • Kidney, liver, and adrenals were most frequently involved. • ES site involvement had not independent prognostic impact beyond that of stage IV. [ABSTRACT FROM AUTHOR]

Papageorgiou SG, Pappa V, Papageorgiou E, Tsirigotis P, Kontsioti F, Panani A, Dervenoulas J, Economopoulos T. Absence of p16 and p27 gene rearrangements and mutations in de novo myelodysplastic syndromes. Eur J Haematol 2005: 75: 193–198. © Blackwell Munksgaard 2005. Myelodysplastic syndromes (MDS) represent a group of clonal hematopoietic disorders characterized by dyshemopoiesis and frequent evolution to acute leukemia. Tumor suppressor gene inactivation may be involved in MDS pathogenesis. The two families of cyclin-dependent kinase inhibitors (CDKIs) (INK4 family of p15, p16, p18 and p19 and CIP/KIP family of p21, p27 and p57) that negatively regulate cell cycle progression are known tumor suppressor genes. To determine whether genetic alterations of p16 and p27 genes play an important role in MDS pathogenesis, we examined DNA from 51 patients classified as 17 refractory anemias (RA), four refractory anemias with ringed sideroblasts (RARS), 19 refractory anemias with an excess of blasts (RAEB), 5 refractory anemias with excess of blasts in transformation (RAEB-t) and 6 chronic myelomonocytic leukemias (CMML). Southern blot analysis detected no homozygous deletions of p16 and p27. Polymerase chain reaction–single-strand conformation polymorphism (PCR–SSCP) and sequencing did not reveal point mutations for both genes with the exception of two allelic polymorphisms, namely a C → G transition at 447 bp of p16exon3 and a T → A transition at 791 bp of p27exon1 genes. Our results suggest that mutations of p16 and p27 genes resulting in abnormal p16 and p27 proteins do not represent a mechanism of gene inactivation involved in the pathogenesis of MDS. [ABSTRACT FROM AUTHOR]

Objective: 3′ tRNA‐derived fragments (3′ tRFs) are important epigenetic regulators in normal and pathological conditions. In this study, we aimed to explore the potential value of a 3′ tRF as a prognostic and/or screening biomarker for B‐cell chronic lymphocytic leukemia (B‐CLL). Methods: Publicly available next‐generation sequencing data from 20 B‐CLL cases were analyzed, followed by prediction of targets of the most abundantly and ubiquitously expressed 3′ tRFs, leading to selection of tRF‐LeuAAG/TAG. PBMCs were isolated from blood samples of 91 B‐CLL patients and 43 non‐leukemic donors, followed by total RNA extraction, in‐vitro polyadenylation, and first‐strand cDNA synthesis. Next, a real‐time quantitative PCR (qPCR) assay was developed for the accurate quantification of tRF‐LeuAAG/TAG and applied in all samples, prior to biostatistical analysis. Results: High tRF‐LeuAAG/TAG levels are associated with inferior overall survival (OS) of B‐CLL patients. The unfavorable significance of tRF‐LeuAAG/TAG was independent of established prognostic factors in B‐CLL. Stratified Kaplan‐Meier OS analysis uncovered the unfavorable prognostic role of high tRF‐LeuAAG/TAG levels for patients in Binet A or Rai I stage, negative CD38 expression, mutated, or unmutated IGHV genomic locus. Conclusion: Our approach revealed the independent prognostic value of a particular 3′ tRF, derived from tRNALeuAAG and tRNALeuTAG (tRF‐LeuAAG/TAG) in B‐CLL. [ABSTRACT FROM AUTHOR]

Background: The landscape of first-line treatment for acute myeloid leukemia (AML) patients ineligible for intensive chemotherapy has changed remarkably after venetoclax approval. Accumulating real-world data further apprises us with more knowledgeable use. To assess the efficacy and safety challenges in the real-life setting of the combination of hypomethylated agent (HMA) and venetoclax, we conducted a multi-center retrospective study. Methods: Forty adult AML patients treated with the combination of HMA and venetoclax as a first-line treatment after full approval (2020) were included. To confirm VIALE-A results, this group was compared to a historical cohort of 17 chemotherapy-ineligible AML patients treated with HMA monotherapy before 2020. Results: The combination of HMA-venetoclax achieved a composite complete response rate of 86.8% (p < 0.001), median overall survival, and event-free survival of 33.8 and 19.7 months, respectively, in a median follow-up of 17.8 months (pos < 0.001, HR = 0.276, CI: 0.132–0.575, pEFS = 0.004, HR = 0.367, CI: 0.174–0.773). High rates of neutropenia (90%) and consequent infection rates (57.5%) were noted. Only 55% of our patients received antifungal prophylaxis, as its use remains controversial, and invasive fungal infections were presented in 7.5%. Conclusions: Evidently, venetoclax-HMA yields high response rates and profound survival benefits in real life and has changed our approach to alternative chemotherapy options. [ABSTRACT FROM AUTHOR]

• A qPCR assay was developed for the quantification of a new mt-tRNA-derived fragment. • i-tRF-PheGAA can distinguish between CLL patients and normal controls. • An association was observed between i-tRF-PheGAA expression and CLL clinical stage. • Patients overexpressing i-tRF-PheGAA show significantly poorer overall survival. • The prognostic power of i-tRF-PheGAA is independent of established prognosticators. Chronic lymphocytic leukemia (CLL) is the most common leukemia among adults. The prognosis of CLL patients varies considerably. Transfer RNA-derived RNA fragments (tRFs) constitute a class of small non-coding RNA fragments excised from mature tRNAs and pre-tRNAs located in nuclei as well as in mitochondria. In this study, the clinical utility of i-tRF-PheGAA, a novel mitochondrial tRF, was investigated in CLL. Peripheral blood mononuclear cells (PBMCs) were isolated from 91 CLL patients and 43 non-leukemic controls. Total RNA was isolated from each sample, polyadenylated at the 3′ end and reversely transcribed. An in-house developed real-time quantitative PCR assay was developed and applied, and the results were biostatistically analyzed. For the normalization of the i-tRF-PheGAA expression levels, the expression of a small nucleolar RNA (RNU48) was used as reference. Mann-Whitney U test showed that i-tRF-PheGAA can distinguish between CLL samples and normal controls (p < 0.001). As determined by Kaplan-Meier survival analysis, overexpression of i-tRF-PheGAA was related to poor overall survival of the CLL patients (p < 0.001). Univariate bootstrap Cox regression analysis exhibited a higher hazard ratio of 7.95 (95% CI = 2.37–26.72, p < 0.001) for patients with positive i-tRF-PheGAA expression status. Multivariate bootstrap Cox regression analysis showed that the prognostic value of this tRF is independent of clinical stage, mutational status of the immunoglobulin heavy chain variable (IGHV) genetic locus, and CD38 expression status (p = 0.010). Our results show that i-tRF-PheGAA can serve as a molecular biomarker of poor prognosis in CLL, alongside with the existing factors for CLL prognosis. [ABSTRACT FROM AUTHOR]

Background: Tissue kallikrein and kallikrein-related peptidases (KLKs) compose a family of serine endopeptidases with much clinical interest in oncology, as their potential as diagnostic and/or prognostic molecular biomarkers in several human malignancies has already been evidenced. However, none of the members of this family has ever been studied in hematological malignancies. Based on our preliminary results regarding the differential mRNA expression of several KLK genes in peripheral blood mononuclear cells (PBMCs) of patients with chronic lymphocytic leukemia (CLL) compared to healthy blood donors, we decided to study the diagnostic and prognostic potential of KLK14 mRNA expression in CLL. Methods: Total RNA was isolated from 69 CLL patients and 31 non-leukemic blood donors. After reverse transcription of poly(A)-RNA, KLK14 mRNA levels were quantified using a sensitive and accurate quantitative real-time PCR (qPCR) methodology. Results: According to ROC analysis, KLK14 mRNA overexpression successfully discriminated CLL patients from normal population (area under the curve [AUC] 0.89, 95% confidence interval [CI] 0.83-0.95, p < 0.001). Moreover, although not clearly related to clinical staging or other prognostic factors including IGHV mutational status and CD38 expression, strong KLK14 mRNA expression was shown to predict reduced overall survival of CLL patients (p = 0.026) using Kaplan-Meier survival analysis. The unfavorable prognostic value of KLK14 mRNA overexpression in CLL patients' PBMCs was independent of established prognostic factors of the disease, as shown by multivariate Cox regression analysis (hazard ratio [HR] 14.65, 95% CI 1.81-118.36, p = 0.012). Conclusions: KLK14 mRNA expression merits further investigation as a potential prognostic biomarker of overall survival of patients with CLL. [ABSTRACT FROM AUTHOR]

Objectives Plasma kallikrein, also known as Fletcher factor or kallikrein B1 (KLKB1), is a serine endopeptidase, like its homologs tissue kallikrein and kallikrein-related peptidases (KLKs). Its physiological role is to catalyze the release of kinins and other vasoactive peptides. Several KLKs have been proposed as putative tumor biomarkers with significant diagnostic and/or prognostic value in human malignancies arising from solid tumors; the most prominent example is the worldwide use of KLK3 (prostate-specific antigen, PSA) in prostate cancer diagnostics. The aim of this study was to analyze KLKB1 mRNA expression in B-cell chronic lymphocytic leukemia (CLL) patients and to examine its diagnostic value as a novel molecular biomarker in CLL. Design and methods Total RNA was isolated from peripheral blood mononuclear cells of sixty-nine patients previously diagnosed with CLL and thirty-one healthy blood donors. After cDNA preparation, a sensitive and cost-effective quantitative real-time PCR (qRT-PCR) methodology was developed and applied for KLKB1 mRNA quantification. Last, we carried out a biostatistical analysis to assess the clinical significance of KLKB1 mRNA expression. Results According to our findings, KLKB1 mRNA expression is significantly higher in CLL patients than in healthy blood donors. Furthermore, KLKB1 mRNA levels are negatively correlated with CD38 expression, an established prognostic biomarker in CLL. Most importantly, KLKB1 mRNA expression possesses important diagnostic value, distinguishing very efficiently CLL patients from non-leukemic population. Conclusions KLKB1 mRNA expression is a putative molecular biomarker in CLL, meriting investigation in large cohorts of CLL patients and non-leukemic controls. [ABSTRACT FROM AUTHOR]

Acute Myeloid Leukemia (AML) is a life-threatening disease whose induction treatment consists of combination chemotherapy with Idarubicin and Cytarabine for fit patients. Treatment failures are frequent, urging the need for novel treatments for this disease. The DNA Damage Response Mechanism (DDR) comprises numerous molecules and pathways intended to arrest the cell cycle until DNA damage is repaired or else drive the cell to apoptosis. AML-derived cell lines after treatment with Idarubicin and Cytarabine were used for studying the expression profile of 84 DDR genes, through PCR arrays. Utilizing de novo AML patient and control samples we studied the expression of PPP1R15A, CDKN1A, GADD45A, GADD45G, and EXO1. Next, we performed PPP1R15A silencing in AML cell lines in two separate experiments using siRNA and CRISPR-cas9, respectively. Our findings highlight that DDR regulators demonstrate increased expression in patients with high cytogenetic risk possibly reflecting increased genotoxic stress. Especially, PPP1R15A is mainly involved in the recovery of the cells from stress and it was the only DDR gene upregulated in AML patients. The PPP1R15A silencing resulted in decreased viability of Idarubicin and Cytarabine-treated cell lines, in contrast to untreated cells. These findings shed light on new strategies to enhance chemotherapy efficacy and demonstrate that PPP1R15A is an important DDR regulator in AML and its downregulation might be a safe and effective way to increase sensitivity to chemotherapy in this disease. [ABSTRACT FROM AUTHOR]

Acute cerebral ischemia with underlying myelodysplastic syndrome mimicking vaccine-induced immune thrombotic thrombocytopenia Keywords: ischemic stroke; multilineage dysplasia; myelodysplastic syndrome; thrombosis with thrombocytopenia syndrome; vaccine-induced immune thrombotic thrombocytopenia (VITT) EN ischemic stroke multilineage dysplasia myelodysplastic syndrome thrombosis with thrombocytopenia syndrome vaccine-induced immune thrombotic thrombocytopenia (VITT) e9 e12 4 04/13/22 20220501 NES 220501 We have read with great interest the article by Krzywicka et al. describing the clinical characteristics of cerebral venous sinus thrombosis (CVST) cases following SARS-CoV-2 vaccination of which the European Medicines Agency was notified [1]. Ischemic stroke, multilineage dysplasia, myelodysplastic syndrome, vaccine-induced immune thrombotic thrombocytopenia (VITT), thrombosis with thrombocytopenia syndrome. [Extracted from the article]

• An innovative qPCR method for quantification of i-tRF-GlyCCC levels was developed. • High i-tRF-GlyCCC expression predicts poor overall survival in CLL patients. • Prognostic significance of i-tRF-GlyCCC is independent of other prognostic factors. • i-tRF-GlyCCC is an unfavorable prognosticator in distinct subgroups of CLL patients Chronic lymphocytic leukemia (CLL) is one of the most common types of leukemia in adults. Several studies have identified various prognostic biomarkers in CLL. In this study, we investigated the potential value of an internal fragment of the tRNAs bearing the Glycine anticodon CCC (i-tRF-GlyCCC), which is a small non-coding RNA, as a prognostic and screening biomarker in CLL. For this purpose, blood samples were collected from 90 CLL patients and 43 non-leukemic blood donors. Peripheral blood mononuclear cells (PBMCs) were isolated, total RNA was extracted and in-vitro polyadenylated, and first-strand cDNA was synthesized using an oligo-dT–adaptor primer. A real-time quantitative PCR assay was developed and applied for the quantification of i-tRF-GlyCCC in our samples. The biostatistical analysis revealed that i-tRF-GlyCCC levels are significantly lower in PBMCs of CLL patients, compared to PBMCs of non-leukemic controls, and that i-tRF-GlyCCC could be considered as a screening biomarker. Kaplan-Meier overall survival (OS) analysis revealed reduced OS for CLL patients with positive i-tRF-GlyCCC expression (P = 0.001). Multivariate Cox regression confirmed its independent unfavorable prognostic power with regard to OS. In conclusion, i-tRF-GlyCCC may constitute a promising molecular biomarker in CLL, for screening and prognostic purposes. [ABSTRACT FROM AUTHOR]

COVID-19 is an ongoing pandemic with high morbidity and mortality. Despite meticulous research, only dexamethasone has shown consistent mortality reduction. Convalescent plasma (CP) infusion might also develop into a safe and effective treatment modality on the basis of recent studies and meta-analyses; however, little is known regarding the kinetics of antibodies in CP recipients. To evaluate the kinetics, we followed 31 CP recipients longitudinally enrolled at a median of 3 days post symptom onset for changes in binding and neutralizing antibody titers and viral loads. Antibodies against the complete trimeric Spike protein and the receptor-binding domain (Spike-RBD), as well as against the complete Nucleocapsid protein and the RNA binding domain (N-RBD) were determined at baseline and weekly following CP infusion. Neutralizing antibody (pseudotype NAb) titers were determined at the same time points. Viral loads were determined semi-quantitatively by SARS-CoV-2 PCR. Patients with low humoral responses at entry showed a robust increase of antibodies to all SARS-CoV-2 proteins and Nab, reaching peak levels within 2 weeks. The rapid increase in binding and neutralizing antibodies was paralleled by a concomitant clearance of the virus within the same timeframe. Patients with high humoral responses at entry demonstrated low or no further increases; however, virus clearance followed the same trajectory as in patients with low antibody response at baseline. Together, the sequential immunological and virological analysis of this well-defined cohort of patients early in infection shows the presence of high levels of binding and neutralizing antibodies and potent clearance of the virus. [ABSTRACT FROM AUTHOR]

Extramedullary plasmacytoma (EMP) represents a distinct yet rare entity among the plasma cell neoplasms. Given its rarity, no therapeutic consensus has been met. We report the case of a 57-year-old man with a one-year history of nasal congestion and occasional dyspnoea. Imaging showed a hypermetabolic mass in the right nasopharynx extending backward towards the adjacent oropharynx, infiltrating the epiglottis. As incisional biopsy showed histologic and immunophenotypic features consistent with plasma cell neoplasm, whereas the possibility of a marginal zone lymphoma with plasmacytic differentiation was included in the differential diagnosis. A final diagnosis of EMP was reached by using flow cytometry (FC) of a cell suspension from the neoplastic tissue. The patient received local radiotherapy (RT) which resulted to complete remission. In conclusion, flow cytometry might serve as an auxiliary method in cases where immunohistochemistry cannot differentiate between a plasma cell dyscrasia and a B-non-Hodgkin lymphoma. In cases of an established diagnosis of solitary nasopharyngeal EMP RT represents an excellent treatment modality offering prolonged disease-free survival. [ABSTRACT FROM AUTHOR]

Simple Summary: The involvement of miRNAs in physiological cellular processes has been well documented. The development of B cells, which is dictated by a miRNA-transcription factor regulatory network, suggests a typical process partly orchestrated by miRNAs. Besides their contribution in normal hematopoiesis, miRNAs have been severally reported to be implicated in hematological malignancies, a typical example of which is B-cell chronic lymphocytic leukemia (B-CLL). Numerous studies have attempted to highlight the regulatory role of miRNAs in B-CLL or establish some of them as molecular biomarkers or therapeutic targets. Thus, a critical review summarizing the current knowledge concerning the multifaceted role of miRNAs in normal B-cell development and B-CLL progression, prognosis, and therapy, is urgent. Moreover, this review aims to highlight important miRNAs in both normal B-cell development and B-CLL and discuss future perspectives concerning their regulatory potential and establishment in clinical practice. MicroRNAs (miRNAs) represent a class of small non-coding RNAs bearing regulatory potency. The implication of miRNAs in physiological cellular processes has been well documented so far. A typical process orchestrated by miRNAs is the normal B-cell development. A stage-specific expression pattern of miRNAs has been reported in the developmental procedure, as well as interactions with transcription factors that dictate B-cell development. Besides their involvement in normal hematopoiesis, miRNAs are severally implicated in hematological malignancies, a typical paradigm of which is B-cell chronic lymphocytic leukemia (B-CLL). B-CLL is a highly heterogeneous disease characterized by the accumulation of abnormal B cells in blood, bone marrow, lymph nodes, and spleen. Therefore, timely, specific, and sensitive assessment of the malignancy is vital. Several studies have attempted to highlight the remarkable significance of miRNAs as regulators of gene expression, biomarkers for diagnosis, prognosis, progression, and therapy response prediction, as well as molecules with potential therapeutic utility. This review seeks to outline the linkage between miRNA function in normal and malignant hematopoiesis by demonstrating the main benchmarks of the implication of miRNAs in the regulation of normal B-cell development, and to summarize the key findings about their value as regulators, biomarkers, or therapeutic targets in B-CLL. [ABSTRACT FROM AUTHOR]