Common Hematologic Malignancy Research Articles

Pseudokinase TRIB3 stabilizes SSRP1 via USP10-mediated deubiquitination to promote multiple myeloma progression.

Multiple myeloma (MM), the world's second most common hematologic malignancy, poses considerable clinical challenges due to its aggressive progression and resistance to therapy. Addressing these challenges requires a detailed understanding of the mechanisms driving MM initiation, progression, and therapeutic resistance. This study identifies the pseudokinase tribble homolog 3 (TRIB3) as a high-risk factor that promotes MM malignancy in vitro and in vivo. Mechanistically, TRIB3 directly interacts with structure-specific recognition protein 1 (SSRP1) and ubiquitin-specific peptidase 10 (USP10), facilitating the formation of a TRIB3/USP10/SSRP1 ternary complex. This complex stabilizes SSRP1 via USP10-mediated deubiquitination, thereby driving MM cell proliferation. Furthermore, a stapled peptide, SP-A, was developed, which effectively disrupts the TRIB3/USP10/SSRP1 complex, leading to a decrease in SSRP1 levels by inhibiting its stabilization through USP10. Notably, SP-A exhibits strong synergistic effects when combined with the proteasome inhibitor bortezomib. Given the critical role of the TRIB3/USP10/SSRP1 complex in MM pathophysiology, it represents a promising therapeutic target for MM treatment. In MM cells, TRIB3, USP10 and SSRP1 form a ternary complex and TRIB3 enhances the deubiquitinating effect of USP10 on SSRP1, leading to malignant progression of MM. In the case of drug intervention, SP-A attenuates the binding of SSRP1 and USP10 by inhibiting protein interactions between TRIB3 and SSRP1 and promoted SSRP1 protein degradation, leading to significant inhibition of MM development. Visual abstract created with Biorender.

Unusual synchronous and metachronous association of hematologic neoplasms with gynecologic neoplasms: Acaseseries and literature review.

The aim of the present study was to evaluate the occurrence of synchronous or metachronous hematologic and gynecologic malignancies. The medical database of the pathology department at a tertiary center was searched from 2016 to 2024 for cases involving both hematologic and gynecologic tumors. A literature search using Google Scholar and PubMed was also conducted between May and June 2024. Articles reporting surgical pathology data were included, while radiologic studies and those lacking pathology data were excluded. Cases involving one gynecologic cancer and one hematologic malignancy were analyzed. Three cases from our center and 25 cases from 15 English-language articles were identified. The mean age of the cases at diagnosis was 61.4 ± 9.4 years. A total of 19 patients (68%) were diagnosed with synchronous cancers, while the rest had metachronous diagnoses. Endometrial cancer was seen in 20 cases (71.4%): 14 synchronous and five metachronous endometrioid adenocarcinomas, and one unspecified metachronous endometrial cancer. This was followed by five cases of ovarian cancer (17.9%): three synchronous serous ovarian carcinomas, one metachronous serous ovarian carcinoma, and one synchronous ovarian adenocarcinoma. Additionally, there were two cases of cervical cancer (7.1%): one synchronous adenosquamous carcinoma and one metachronous invasive squamous carcinoma, and one case of carcinosarcoma (3.6%). Involvement of more than one site is possible for hematolymphoid cancer, commonly affecting the pelvic or para-aortic lymph nodes in 16 patients (57.1%), with other sites including the cervix (4 cases, 14.3%), ovary (4 cases, 14.3%), uterus (2 cases, 7.1%), iliac/inguinal lymph nodes (2 cases, 7.1%), fallopian tube (1 case, 3.6%), vagina (1 case, 3.6%), liver (1 case, 3.6%), abdomen (1 case, 3.6%), and appendix (1 case, 3.6%). Two cases were unspecified. Non-Hodgkin lymphoma (NHL), primarily of B cell lineage, was the most common hematologic malignancy (25 cases, 89.3%, with 22 cases being B cell lineage). In contrast, Hodgkin lymphoma was observed in two cases (7.1%), and acute leukemia in one case (3.6%). Among 21 patients with available follow-up data, eight died during the follow-up period. The co-occurrence of NHL, Hodgkin lymphoma, and acute leukemia with gynecologic cancers is rare. However, during surgery for gynecologic cancers, the potential of synchronous lymphoma should be considered, particularly in cases with unusual retroperitoneal lymphadenopathy.

Guidelines for the diagnosis and management of multiple myeloma in China (2024 revision)

Multiple myeloma (MM), an incurable clonal plasma cell dysplasia, is the second most common hematological malignancy in many countries, mainly developing in the elderly population. With the emergence of novel agents and laboratory methods, the diagnosis and treatment of MM have been significantly improved. In this version of the "Guidelines for the diagnosis and management of multiple myeloma in China (2024 revision)", several examination items have been updated in the diagnostic section; the definition of ultra high-risk MM has been proposed in the risk stratification section; for patients with equal or more than second-line relapse, chimeric antigen receptor T cell therapy and a bispecific T-cell engager have been added; and the treatment recommendations have been listed at different levels based on the best available evidence.

Global patterns of leukemia by subtype, age, and sex in 185 countries in 2022.

In 2022, leukemia ranked as the second most common hematological malignancy after non-Hodgkin lymphoma worldwide. However, updated global estimates of leukemia incidence by subtype are unavailable. We estimated leukemia incidences for different leukemia subtypes by country, world region, and human developmental index using data from the Cancer Incidence in Five Continents databases combined with the GLOBOCAN 2022 estimates of leukemia in 185 countries. We estimated sex-specific age-standardized rates (ASRs) per 100 000 for children (0-19 years) and adults (20+ years). In adults, the most common leukemia worldwide was AML (males:38%, ASR = 3·1; females:43%, ASR = 2·4), followed by CLL (males:28%, ASR = 2·2; females:24%, ASR = 1·3). In very high HDI countries, the ASR of CLL was higher than the ASR of AML among males (5·2 versus 4·3, respectively) and similar among females (2·9 and 3·0, respectively). In children, the most common leukemia was ALL (boys:70%, ASR = 2·4; girls:68%, ASR = 1·8) followed by AML (boys:22%, ASR = 0·76; girls:25%, ASR = 0·65). ALL proportions varied across world sub-regions from 57to78% among boys, and from 49 to 80% among girls. Our findings suggest clear geographical patterns of leukemia subtypes in adults and children. Further research into underlying causes that explain these variations is needed to support cancer control strategies for prevention and plan national healthcare needs.

Can you Diagnose Immune Thrombocytopenia in Myeloma? A Case of Thrombocytopenia in a Patient with Multiple Myeloma.

Multiple myeloma is the second most common haematological malignancy and is associated with a broad group of pathologies, including, in some cases, autoimmune manifestations. Thrombocytopenia in multiple myeloma is common due to therapy or bone marrow plasmacytosis, but the association of immune thrombocytopenia with multiple myeloma is rare.Raising clinicians' awareness of the association of multiple myeloma with immune thrombocytopenia is essential for a rapid differential diagnosis. This can alter therapeutic possibilities and consequent patient prognoses.

The Role and Mechanism of NDUFS2 in FLT3-Mutated Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a common hematologic malignancy characterized by poor prognosis and high recurrence rates. Disease relapse and the lack of precise treatment tailored to each patient pose challenges in AML treatment. The mitochondria, crucial for cellular energy center and signaling, are essential for maintaining the metabolic flexibility of tumor cells. However, their complex and elusive functions in cancer pose challenges for targeted mitochondrial therapies. Therefore, there is an urgent need to discover new mitochondrial-targeted drugs and novel targeted therapeutic strategies for AML. In this study, we explored the expression of NDUFS2 in AML using real-time quantitative PCR and immunohistochemistry. Subsequently, we performed knockdown and overexpression experiments of NDUFS2 in MOLM-13 and MV4-11 cell lines and assessed its effects on AML cell proliferation, apoptosis, cell cycle, reactive oxygen species (ROS) levels, and mitochondrial membrane potential using flow cytometry. Additionally, we evaluated the impact of NDUFS2 on mitochondrial morphology using transmission electron microscopy and confocal microscopy. Seahorse energy metabolism assay kits were utilized to examine the influence of NDUFS2 on AML cell energy metabolism, while mitochondrial complex I and II assay kits were employed to assess its effect on mitochondrial enzyme activity. Furthermore, Western blot analysis was conducted to evaluate the effects of NDUFS2 knockdown on the AMPK pathway, endoplasmic reticulum stress pathway, and apoptosis pathway in AML cells, with reverse validation performed using AMPK and PERK inhibitors. Finally, we established xenograft models of FLT3-mutated AML tumor cells to investigate the impact of NDUFS2 on tumor growth and the synergistic effect of NDUFS2 with FLT3 inhibitor Gilteritinib against FLT3-mutated AML. Concurrently, we developed xenograft models of relapsed/refractory FLT3-mutated AML patients to explore the synergistic effect of mitochondrial complex I inhibitor IACS-010759 with Gilteritinib against relapsed/refractory FLT3-mutated AML. We validated that NDUFS2 exhibits the highest expression level in AML, especially in FLT3-mutated AML cells. Knockdown of NDUFS2 inhibited the proliferation of FLT3-mutated AML cell lines, caused cell cycle arrest, induced mitochondrial fission, decreased mitochondrial membrane potential, increased ROS levels, impaired the function of mitochondrial complex I, altered cellular energy metabolism by reducing oxidative phosphorylation (OXPHOS) levels, and activated the AMPK/PERK pathways, leading to apoptosis. Knockdown of NDUFS2 enhanced the cytotoxicity of Gilteritinib against FLT3-mutated AML cells, and the combination of NDUFS2 knockdown and Gilteritinib reduced mitochondrial membrane potential, increased ROS levels, and activated the AMPK/PERK pathways to induce cell apoptosis. In vivo experiments confirmed that knockdown of NDUFS2 enhanced the antitumor effect of Gilteritinib. Furthermore, IACS-010759 and Gilteritinib exhibited synergistic activity against FLT3-mutated AML by synergistically inducing cell apoptosis, inhibiting cell proliferation, affecting mitochondrial function, activating the AMPK/PERK pathways. In vivo experiments in mice also confirmed the synergistic killing effect on FLT3-mutated AML tumor cells without affecting normal hematopoiesis or the normal function of other organs. We found that NDUFS2 is associated with the prognosis of AML and is highly expressed in FLT3-mutated AML. Knockdown of NDUFS2 suppresses the proliferation of FLT3-mutated AML cells, induces excessive ROS production, disrupts mitochondrial membrane potential, inhibits the enzyme activity of mitochondrial complex I, thereby suppressing OXPHOS, decreasing ATP production, and activating the AMPK/PERK pathways, ultimately leading to cell apoptosis. Targeting NDUFS2 can exert synergistic anti-FLT3-mutated AML effects with FLT3 inhibitors by activating the AMPK/PERK pathways. Additionally, the inhibition of mitochondrial complex I by the inhibitor IACS-010759 can synergize with Gilteritinib to combat FLT3-mutated AML. This indicates that NDUFS2 may serve as a potential target for the treatment of FLT3-mutated AML and enhance the sensitivity of targeted drugs to FLT3-mutated AML.

PPM1D/Wip1 is amplified, overexpressed, and mutated in human non-Hodgkin's lymphomas.

Wip1, is a p53-dependent Ser/Thr phosphatase involved in the timely termination of DDR. The PPM1D gene encoding Wip1 is deregulated and thus gained an oncogene character in common human solid tumors and cell lines. This study assessed the oncogenic potential of the PPM1D gene in human non- Hodgkin's lymphomas (NHL), the most common hematological malignancy worldwide. FFPE human lymphoid hyperplasia (LH) (n = 17) and NHL tumor lymph node samples (n = 65) and human NHL cell lines were used to assess the oncogenic potential of the PPM1D gene in the present study. Copy number gain and mRNA expression analysis of the PPM1D/Wip1 gene were assessed by qRT-PCR analysis. Mutational analysis of Exon 6 of the PPM1D gene was performed by PCR amplification and Sanger sequencing. Expressions of Wip1 and p53 proteins were assessed by immunohistochemistry and Western blot analysis. We found that PPM1D gained gene copy number in NHL tumors by 0.7-8 times compared to the control (p < 0.01). Increased PPM1D/Wip1 gene copy number was associated with higher mRNA and protein expression in human NHL samples (p < 0.01). Overexpression of Wip1 in NHL tumors and NHL cell lines was associated with amplification level and was unaffected by p53 status. Furthermore, a heterozygous type insertion mutation was detected in exon 6 (c.1553_1554insA) of the PPM1D gene particularly in DLBCL samples. Wip1 may have oncogenic potential, perhaps playing a role in the onset and progression of human NHL. The possible significance of Wip1 overexpression to chemotherapy response in NHL remains an intriguing question that requires more exploration.

Clinical characteristics and risk factors of infection in initially treated patients with multiple myeloma during the induction period

BackgroundMultiple myeloma (MM) is a common hematologic malignancy and immune dysfunction is a hallmark of the disease. It leads to an increased infection risk, which is still a major cause of mortality. The infection spectrum and characteristics have evolved with the introduction of novel agents. An understanding of risk factors that increasing susceptibility to infection is critical in fighting them. This retrospective study aimed to identify risk factors associated with infection and develop nomogram to qualify the risk of infection. MethodsWe retrospectively reviewed the data of patients who were diagnosed with MM between April 1, 2018 and December 31, 2021 in our department. Independent predictors for infection were determined by the univariate and multivariate logistic regression analysis. Nomogram was established and evaluated by receiver operating characteristic (ROC) curve, calibration curve and decision curve analysis (DCA). ResultsA total of 230 MM patients who were diagnosed or treated in our department were included. Infections were identified in 37.4% of MM patients in the first treatment course. The most common infection was the pulmonary infection. The first treatment course had the highest infection rate. With three or more comorbidities, anemia, high LDH level and high β2-MG level were independent risk factors for infection in MM patients during the induction period. The area under the curve (AUC) of nomogram was 0.746 (95% CI: 0.679-0.814). The calibration curve and DCA indicated the good performance of the nomogram. ConclusionMultiple myeloma patients with one or more of these mentioned risk factors should be monitored with particular care in order to decrease the incidence and severity of infective complications. Nomogram was established to predict the incidence of infection in MM patients. Nomogram has satisfactory accuracy, and clinical utility may benefit for clinical decision-making.

Atypical Presentation of Multiple Myeloma: From Heart Failure to Multiple Myeloma

Multiple myeloma (MM) is a hematological malignancy commonly associated with bone pain, hypercalcemia, and renal failure. However, its presentation can occasionally mimic other medical conditions, which may delay diagnosis. This case report describes a patient who was initially diagnosed and treated for heart failure but was later found to have MM, highlighting the importance of considering MM in the differential diagnosis of heart failure. A 56-year-old lady presented with recurrent episodes of shortness of breath, orthopnea, paroxysmal nocturnal dypsnea and bilateral lower limb swelling which she had been treated for decompensated heart failure with optimal therapy. She denied any family history of cardiovascular disease personal history of underlying medical condition and was a nonsmoker. This patient was diagnosed with multiple myeloma and probability of concomitant cardiac amyloidosis and commenced on bortezomib, thalidomide and dexamethasone (VTD) regime and standard optimal therapy of heart failure but her condition deteriorated. After a few days of starting chemotherapy, patient demised despite all the resuscitative effort. Multiple myeloma is common hematological malignancy with its distinct clinical features of “CRAB”, however, more attention and alertness should also be exercised by clinicians as to be able to diagnose it early.

Polatuzumab Vedotin for Diffuse Large B-Cell Lymphoma: Innovation's Allure versus a Time-Honored Tradition

AbstractChemotherapy with R-CHOP (rituximab, cyclophosphamide, Adriamycin, vincristine, prednisolone) is the standard of care for patients with diffuse large B-cell lymphoma as the first-line therapy. The recent approval of polatuzumab as the first-line therapy after demonstration of its efficacy in the Polatuzumab Vedotin in Previously Untreated Diffuse Large B-Cell Lymphoma (POLARIX) trial is the first significant change in this treatment regimen over two decades. This concise appraisal of trial evidence and clinical context highlights the limited potential for a clinically significant benefit with the addition of polatuzumab to the first-line therapy for this common hematologic malignancy.

Deep Learning-Based Integration of Morphology and Immunophenotype Predicts Molecular Genetic Subtypes of Multiple Myeloma

Abstract Multiple myeloma, the second most common hematologic malignancy, is characterized by recurrent molecular genetic variants which portend important prognostic and therapeutic implications. These variants, which include chromosomal aneuploidies, translocations, and other structural changes, are currently identified by performing karyotyping and fluorescence in situ hybridization analysis on bone marrow biopsy samples. Comprehensive variant testing for full characterization of multiple myeloma cases can take days to weeks, is costly, and is not available to all patients. Past studies have explored to what extent cellular morphologic information from bone marrow aspirates or immunophenotypic information from flow cytometry can predict these genetic variants via the use of machine learning algorithms. However, the integration of multiple hematopathology data modalities using machine learning towards improving the diagnosis and characterization of hematologic neoplasms has yet to be explored. To this end, we developed a deep learning-based algorithm which, for individual patients, integrates tens-of-thousands of cell images from Wright-stained bone marrow aspirate smears with hundreds-of-thousands of events from myeloma flow cytometry panels to predict the presence or absence of particular molecular genetic variants among 85 cases of multiple myeloma. Attention-based multi-instance learning models were developed utilizing convolutional neural networks to analyze cell image data and multi-layer perceptrons to analyze flow cytometry data. Models trained solely on cell image data showed variable performance in predicting genetic subtypes of multiple myeloma cases: t(11;14), AUROC = 0.795; 1q+, AUROC = 0.743; del(17p), AUROC = 0.520. Similar models trained solely on flow cytometry data showed fair performance for all subtypes: t(11;14), AUROC = 0.761; 1q+, AUROC = 0.761; del(17p), AUROC = 0.787. However, models which combine features among high-attention events from both cell image and flow cytometry data yield significantly improved performance: t(11;14), AUROC = 0.892; 1q+, AUROC = 0.789; del(17p), AUROC = 0.876. Similarly, models trained to predict established prognostic classifications of multiple myeloma cases performed best when cell image and flow cytometry data is integrated: cell images alone, AUROC = 0.721; flow cytometry alone, AUROC = 0.827; both data combined, AUROC = 0.839. Additional improvements in prognostic classification were obtained when utilizing a Kronecker product to more completely utilize pairwise interactions between cell image and flow cytometry features: AUROC = 0.864. This study is, to our knowledge, the first to utilize deep learning to integrate multiple hematopathology data modalities towards automated diagnosis or subclassification of hematologic neoplasms in individual patients. The results of this study demonstrate the feasibility of accurately predicting molecular genetic subtypes of multiple myeloma cases solely from cell morphology and flow cytometric information. With further refinement, these promising models could be applied in low resource settings as well as research settings to better understand the biological relationship between plasma cell genetics with morphology and immunophenotype.

The role of nutrition and gut microbiome in the progression of multiple myeloma and its precursor disease.

Multiple myeloma (MM) is the second most common hematological malignancy, characterized by unregulated monoclonal proliferation in the bone marrow. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are premalignant conditions that can progress to MM. Identifying etiological risk factors for MM and its precursor diseases is crucial for prevention. Obesity, diet, vitamin D levels, and gut microbiota alterations have been identified as lifestyle factors affecting MM and MGUS risk. Upon disease onset, treatment strategies aim to reduce disease burden, enhance prognosis, and optimize patients' quality of life. Nutrition and body weight have been shown to affect disease progression and treatment outcomes. MM patients often present with vitamin D, vitamin B12, and folate deficiencies, which worsen disease prognosis. High body mass index is linked to increased death rates among MM patients and an increased risk of MGUS transformation to MM. Gut microbiota has also been associated with disease progression and response to treatment. This literature review aims to summarize the available evidence regarding the impact of nutrition and nutritional status on MM patients beyond prevention, highlighting the significance of gut microbiome and dysbiosis in MM progression.

Antimicrobial Stewardship: A Game Changer in the Fight against Carbapenem-Resistant Enterobacteriaceae (CRE) among Children with Cancer

Abstract Background Carbapenem-resistant Enterobacteriaceae (CRE) is an emerging threat among pediatric cancer patients, with a high mortality rate. A previous study in our center reported that 254 patients with CRE BSI were diagnosed from (2013-2018) with mortality from CRE BSI being 30%. Previous colonization was reported in 35% of those patients. Time to start adequate antibiotics is an independent prognostic factor for patients with CRE BSI, (48%) of patients started active treatment after 48h from culture and associated with higher mortality when compared to patients who started treatment earlier. Our recommendations include antimicrobial stewardship for early detection through routine screening and timely adequate therapy that may impact the outcome for such high-risk patient groups. Methods This prospective study included all pediatric cancer patients with (CRE) bloodstream infections (BSI) at a children’s cancer hospital in Egypt (2020–2022) with adopting antimicrobial stewardship program goals by (1) applying routine screening by rectal swab for high-risk patients and starting active treatment for patients colonized by CRE. (2) Introduction of PCR-based method (Cepheid XpertCarba-R assay) is developed for detecting carbapenemase genes with the availability of results within one hour which can allow for rapid time to start active treatment in less than 48h. Results One hundred and fifty pediatric cancer patients with CRE BSI were identified; 83% had hematological malignancies, and 17% had solid tumors. Acute myeloid leukemia was the most common hematological malignancy (47%). The main clinical features for acquiring CRE-BSI were prolonged neutropenia &amp;gt; 7 days (62%), previous Carbapenem exposure (82%), Quinilone prophylaxis (44%), central venous catheter use (40%), previous colonization with a resistant pathogen (35%) and ICU admission within 90 days (18%). E. coli was the most common isolated pathogen (65%), followed by Klebsiella pneumoniae (31%). Documented site of infection was reported with pneumonia in (32%), typhlitis in 15% skin soft tissue infection (57%), CNS infection (18%), and urinary tract infection in (10%). Time to start active antibiotics in less than 48h was reported in 89% with clinical cure reported in 71% and microbiological clearance was reported in in less than 7 days in 70% of patients. The need for ICU admission as sepsis related to CRE was reported in 29/150 (19%). The Gentopyic profile for CRE in our study reported that class B (69%) with NDM reported in 98/150 (65%) and VIM 6/150 (4%) was the most common carbanamases followed by Oxa-48 in 89/150(59%) of patients while KPC enzyme reported only in 6/150(4%). Day 30 mortality was reported in 23/150(15%). Upon multivariate analysis, patients with Klebsiella pneumoniae BSI, NDM genotype carbapenemases, CRE with aminoglycosides resistance or associated with pneumonia, and CRE patients who developed septic shock with the need for ICU admission were predictors of poor outcome. Conclusion CRE-BSI is a major threat among pediatric cancer patients in limited-resource countries and is considered a barrier against better outcomes. Antimicrobial stewardship through routine screening for colonization detection and Rapid diagnosis by using gene expert with rapid time to start adequate active antibiotics treatment is associated with improvement of outcome and decreasing mortality. Table 1: Comparison between retrospective study and prospective study (after adopting antimicrobial stewardship goals)

Progression of disease within 24 months (POD24) in multiple myeloma implicates poor prognosis and limitations of current prediction models for POD24

Multiple myeloma (MM) is a common hematological malignancy, and its prognostic factors have been extensively studied. Progression of disease within 24 months (POD24) suggests a poor prognosis in many malignancies, but is rarely mentioned in MM. This study aimed to investigate the prognostic value of POD24 in MM and risk factors of POD24, and to evaluate the predictive value of existing MM prognostic models for POD24. The research retrospectively analyzed the clinical data of MM patients and found that the occurrence of POD24 is an independent prognostic factor affecting overall survival in MM, while non-transplantion and genetic abnormality are independent risk factors for the occurrence of POD24. The existing prognostic models are not effective in predicting POD24. Therefore, it’s still necessary to explore a prognostic model that can predict POD24 more accurately.

Current ideas on the pathogenesis of osteoporosis in chronic lymphatic leukemia (literature review)

Background. Chronic lymphocytic leukemia (CLL) is the second most common hematological malignancy without a trend towards a decrease in its incidence. 66 % of patients with CLL experience bone fractures as a result of osteoporosis in all age groups, and the detection frequency is no more than 15 %. Insufficient understanding of the osteoporosis pathogenesis in CLL leads to problems in diagnosis, prevention and therapy.The aim of the study. To analyze modern data on the features of the osteoporosis pathogenesis in chronic lymphocytic leukemia.Results and discussion. Osteoporosis is formed when osteoresorption prevails over osteosynthesis due to intercellular interactions of bone tissue and the immune system, dysregulation of intracellular signaling pathways RANKL/RANK/OPG, Wnt, FoxO, RUNX2, initiated by cytokines, growth factors, prostaglandins, and hormones. The degree of osteoresorption in CLL is associated with the severity of the clinical course, chemotherapy and hormonal deprivation. The osteoporosis pathogenesis in CLL is considered as part of a complex set of events, including, firstly, the interaction between leukemic cells (overexpression of PTHrP, RANKL) and bone cells (synthesis of growth factors), which forms a vicious circle of osteoresorption and tumor growth. Secondly, pro-inflammatory markers in CLL (tumor necrosis factor α, interleukin (IL) 1β, IL-6, IL-8, IL-11, granulocyte-macrophage colony-stimulating factor, macrophage colony-stimulating factor, transforming growth factor β, prostaglandin E2) limit osteoblast-induced osteosynthesis and stimulate the expansion of osteoclasts from monocytic suppressor cells of myeloid origin with or without the participation of the RANKL/RANK system. Thirdly, oxidative stress in CLL and impaired efficiency of antioxidant protection with the participation of fibroblast growth factor 23, transcription factor Nrf-2 with activation of JNK, ERK1/2, NF-κB, and also an increase in the RANKL/OPG ratio lead to inhibition of osteoblastogenesis.Conclusion. Analyzing and systematizing data on the osteoporosis pathogenesis in CLL are instrumental for the development of diagnostic criteria for osteoporosis in chronic lymphocytic leukemia that are much-needed in clinical practice and for the improvement of therapeutic tactics.

The Role of Machine Learning in the Most Common Hematological Malignancies: A Narrative Review

The Role of Machine Learning in the Most Common Hematological Malignancies: A Narrative Review

Complex Relationships between Diagnostics and Survival in Chronic Lymphocytic Leukemia in Denmark, Finland, Norway, and Sweden.

Chronic lymphocytic leukemia (CLL) is a common hematological malignancy with highly variable clinical presentation. Many patients never require any treatment but for the others, chemotherapy, immunochemotherapy, and newer targeted therapies have changed the treatment landscape. Diagnostic age influences the applied treatment, and we thus wanted to analyze age-specific survival trends through 50 years up to 2020s. We used 1- and 5-year relative survival from the NORDCAN database, with data from Denmark (DK), Finland (FI), Norway (NO), and Sweden (SE). Because of the variable presentation of CLL, we also considered incidence and mortality trends. For comparison, US SEER data were used. The large age-specific survival differences in 1972-76 almost disappeared by 2017-21. While 5-year survival in younger patients exceeded 90%, for those diagnosed at age 80-89 years, survival reached 90% in DK and SE women, 80% in NO and SE men, but only 50% in FI. DK 5-year overall survival for men was 92.4%, and for women, it was 96.3%. These survival figures were higher than age-group-specific US survival data. The DK data are probably global top figures for national survival which could be achieved by boosting survival even among the oldest patients. The qualification to these figures and international comparisons is that survival needs to be considered in terms of incidence, which is high in DK and NO. Low survival of the FI 80-89-year-old patients, even in the first year after diagnosis, may suggest delayed diagnosis, which should call for a closer national scrutiny.

A case of grade1 follicular lymphoma diagnosed by laparoscopic lymph node resection: differentiating from late lymph node recurrence of endometrial cancer.

Follicular lymphoma is a common hematologic malignancy; however, it is less common among all malignant diseases and is difficult to suspect in advance due to the lack of specific clinical findings. Here, we report a case in which a late recurrence of corpus cancer was first suspected and finally diagnosed as follicular lymphoma. A 67-year-old female presented to our department with enlarged pelvic lymph nodes. She was diagnosed with breast cancer (HER2-posiotive with lymph node metastasis) and corpus cancer (endometrioid carcinoma grade 2, stage IA) 16years prior, received definitive therapy and was followed up. A positron emission tomography scan was performed, and an accumulation of 18F-fluorodeoxyglucose (FDG) was detected in multiple lymph nodes, including the lymph nodes with no change in size or enlargement. We performed laparoscopic resection of the enlarged and FDG-accumulated lymph nodes and a pathological examination. The patient was diagnosed with follicular lymphoma (FL) grade 1 and is currently under observation at the Department of Hematology. FL can be considered when there is a discrepancy between the change in lymph node size and the degree of FDG accumulation. A pathological examination is useful for accurate diagnosis. Therefore, it is important to consider tissue collection; however, care must be taken to minimize the invasiveness of the procedure for the patient.

Causal Relationship Between Gut Microbiota and Leukemia: Future Perspectives.

The gut microbiota plays a crucial role in maintaining homeostasis in the human gastrointestinal tract. Numerous studies have shown a strong association between the gut microbiota and the emergence and progression of various diseases. Leukemia is one of the most common hematologic malignancies. Although standardized protocols and expert consensus have been developed for routine diagnosis and treatment, limitations remain due to individual differences. Nevertheless, a large number of studies have established a link between the gut microbiota and leukemia, with disturbances in the gut microbiota directly or indirectly affecting the development of leukemia. However, the causal relationship between the two remains unclear, and studying and exploring the causal relationship may open up entirely new avenues and protocols for use in the prevention and/or treatment of leukemia, offering new insights into diagnosis and treatment. In this review, the intricate relationship between the gut microbiota and leukemia is explored in depth, including causal associations, metabolite effects, therapeutic applications, and complications. Based on the characteristics of the gut microbiota, the future applications and prospects of gut microbiota are discussed to provide useful information for clinical treatment of leukemia.

Sodium diethyldithiocarbamate trihydrate: an effective and selective compound for hematological malignancies.

Myeloid leukemias and lymphomas are among the most common and well-studied hematological malignancies. However, due to the aggressiveness and rapid progression of certain subtypes, treating these diseases remains a challenge. Considering the promising results of diethyldithiocarbamates in preclinical and clinical oncology trials, this study aimed to investigate the potential of sodium diethyldithiocarbamate trihydrate (DETC) as a prototype for developing new drugs to treat hematological malignancies. In silico analysis using SwissADME was conducted to evaluate the physicochemical characteristics and pharmacokinetic properties of DETC. An in vitro investigation utilizing the MTT assay assessed the cytotoxic effects of DETC on neoplastic and non-neoplastic cell lines. Selectivity was determined using a selectivity index and a hemolysis assay, while the mechanism of cell death in neoplastic cell lines was examined through flow cytometry analysis of pro-apoptotic and anti-apoptotic protein levels. The results demonstrated that the physicochemical characteristics of DETC are suitable for oral administration. Furthermore, the compound showed promising cytotoxic activity against human myeloid leukemia (K562) and Burkitt's lymphoma (Daudi) cell lines, with high selectivity for neoplastic cells over non-neoplastic cells of the bone marrow microenvironment (HS-5 cell line). Moreover, hemolysis was observed only at very high concentrations. The cytotoxicity mechanism of DETC against both neoplastic cell lines involved cell cycle arrest and the production of reactive oxygen species. In K562 cells, cell death was induced via apoptosis. Additional experiments are needed to confirm the exact mechanism of cell death in Daudi Burkitt's lymphoma cells.