Chromatin activation as a unifying principle underlying pathogenic mechanisms in multiple myeloma.

Multiple myeloma (MM) is a plasma cell neoplasm associated with a broad variety of genetic lesions. In spite of this genetic heterogeneity, MMs share a characteristic malignant phenotype whose underlying molecular basis remains poorly characterized. In the present study, we examined plasma cells from MM using a multi-epigenomics approach and demonstrated that, when compared to normal B cells, malignant plasma cells showed an extensive activation of regulatory elements, in part affecting coregulated adjacent genes. Among target genes up-regulated by this process, we found members of the NOTCH, NF-kB, MTOR signaling, and TP53 signaling pathways. Other activated genes included sets involved in osteoblast differentiation and response to oxidative stress, all of which have been shown to be associated with the MM phenotype and clinical behavior. We functionally characterized MM-specific active distant enhancers controlling the expression of thioredoxin (TXN), a major regulator of cellular redox status and, in addition, identified PRDM5 as a novel essential gene for MM. Collectively, our data indicate that aberrant chromatin activation is a unifying feature underlying the malignant plasma cell phenotype.

Bibliometric analysis of cancer care operations management: current status, developments, and future directions.

Around the world, cancer care services are facing many operational challenges. Operations management research can provide important solutions to these challenges, from screening and diagnosis to treatment. In recent years, the growth in the number of papers published on cancer care operations management (CCOM) indicates that development has been fast. Within this context, the objective of this research was to understand the evolution of CCOM through a comprehensive study and an up-to-date bibliometric analysis of the literature. To achieve this aim, the Web of Science Core Collection database was used as the source of bibliographic records. The data-mining and quantitative tools in the software Biblioshiny were used to analyze CCOM articles published from 2010 to 2021. First, a historical analysis described CCOM research, the sources, and the subfields. Second, an analysis of keywords highlighted the significant developments in this field. Third, an analysis of research themes identified three main directions for future research in CCOM, which has 11 evolutionary paths. Finally, this paper discussed the gaps in CCOM research and the areas that require further investigation and development.

A Review of Artificial Intelligence Applications in Hematology Management: Current Practices and Future Prospects.

BACKGROUND: Machine learning (ML) and deep learning (DL) methods have recently garnered a great deal of attention in the field of cancer research by making a noticeable contribution to the growth of predictive medicine and modern oncological practices. Considerable focus has been particularly directed toward hematologic malignancies because of the complexity in detecting early symptoms. Many patients with blood cancer do not get properly diagnosed until their cancer has reached an advanced stage with limited treatment prospects. Hence, the state-of-the-art revolves around the latest artificial intelligence (AI) applications in hematology management. OBJECTIVE: This comprehensive review provides an in-depth analysis of the current AI practices in the field of hematology. Our objective is to explore the ML and DL applications in blood cancer research, with a special focus on the type of hematologic malignancies and the patient's cancer stage to determine future research directions in blood cancer. METHODS: We searched a set of recognized databases (Scopus, Springer, and Web of Science) using a selected number of keywords. We included studies written in English and published between 2015 and 2021. For each study, we identified the ML and DL techniques used and highlighted the performance of each model. RESULTS: Using the aforementioned inclusion criteria, the search resulted in 567 papers, of which 144 were selected for review. CONCLUSIONS: The current literature suggests that the application of AI in the field of hematology has generated impressive results in the screening, diagnosis, and treatment stages. Nevertheless, optimizing the patient's pathway to treatment requires a prior prediction of the malignancy based on the patient's symptoms or blood records, which is an area that has still not been properly investigated.

Dissecting bloodstream infections in febrile neutropenic patients with hematological malignancies, a decade-long single center retrospective observational study (2009-2019).

BACKGROUND: The use of ill-suited antibiotics is a significant risk factor behind the increase in the mortality, morbidity, and economic burden for patients who are under treatment for hematological malignancy (HM) and bloodstream infections (BSI). Such unfitting treatment choices intensify the evolution of resistant variants which is a public health concern due to possible healthcare-associated infection spread to the general population. Hence, this study aims to evaluate antibiograms of patients with BSI and risk factors associated with septicemia. METHODS: A total of 1166 febrile neutropenia episodes (FNE) among 513 patients with HM from the National Center for Cancer Care and Research (NCCCR), Qatar, during 2009-2019 were used for this study. The socio-demographic, clinical, microbial, and anti-microbial data retrieved from the patient's health records were used. RESULTS: We analyzed the sensitivity of gram-negative and gram-positive bacilli reported in HM-FN-BSI patients. Out of the total 512 microorganisms isolated, 416 (81%) were gram-negative bacteria (GNB), 76 (15%) were gram-positive bacteria (GPB) and 20 (4%) were fungi. Furthermore, in 416 GNB, 298 (71.6%) were Enterobacteriaceae sp. among which 121 (41%) were ESBL (Extended Spectrum Beta-Lactamase) resistant to Cephalosporine third generation and Piperacillin-Tazobactam, 54 (18%) were Carbapenem-resistant or multidrug-resistant organism (MDRO). It's noteworthy that the predominant infectious agents in our hospital include E. coli, Klebsiella species, and P. aeruginosa. Throughout the study period, the mortality rate due to BSI was 23%. Risk factors that show a significant correlation with death are age, disease status, mono or polymicrobial BSI and septic shock. CONCLUSION: Decision pertaining to the usage of antimicrobials for HM-FN-BSI patients is a critical task that relies on the latest pattern of prevalence, treatment resistance, and clinical outcomes. Analysis of the antibiogram of HM-FN-BSI patients in Qatar calls for a reconsideration of currently followed empirical antibiotic therapy towards better infection control and antimicrobial stewardship.

Consensus-Based Guidelines for Acute Myeloid Leukemia Management in Gulf Cooperation Council Countries: Addressing Unmet Regional Needs and the Changing AML Landscape.

PURPOSE: AML is a heterogeneous hematologic malignancy. Region-specific recommendations for AML management can enhance patient outcomes. This article aimed to develop recommendations for the Gulf Cooperation Council (GCC) countries. METHODS: Ten AML panel members from Kuwait, Oman, Qatar, and the United Arab Emirates (KOQU) participated in a modified two-round Delphi process. The panel first identified the unmet regional needs and finalized a list of core variables. Next, they voted on iterative statements drawn from international recommendations and provided feedback via a questionnaire. Consensus voting ≤70% was discussed, and additional clinical decision making statements were suggested. At round closure, a consensus vote took place on revised statements. RESULTS: The panel reached ≥97.8% consensus on AML management. The panel agreed to use international risk stratification categories for personalized treatment of AML. The presence of ≥10% blasts for recurrent genetic abnormalities was required for a diagnosis of AML. Key consensus was reached for different treatment stages. The panel noted that older patients pose a challenge because of poor cytogenetics and genetic anomalies and require different treatment approaches. The panel recommended venetoclax-hypomethylating agents; fludarabine, cytarabine, idarubicin, and granulocyte colony-stimulating factor; and targeted therapy for AML relapsed/refractory disease. Supportive care is considered on the basis of prevailing organisms and drug resistance. CONCLUSION: The GCC KOQU's consensus-based recommendations for managing AML include an evidence-based and region-specific framework.

Real world evidence of epidemiological trends, clinical presentation, and prognostic outcomes of multiple myeloma (2007-2021).

Background: Multiple myeloma (MM) is one of the most common hematological malignancies globally, and it is projected to increase in the coming years. It occurs more frequently in males and affects older individuals. Presenting symptoms can range from being asymptomatic to severely debilitating. The objective of this study was to determine the epidemiology, clinical features, and prognostic outcomes of patients with MM in the only tertiary cancer hospital in Qatar. Methods: Patients with symptomatic myeloma diagnosed at the National Center for Cancer Care and Research in Qatar between 2007 and 2021 were included. Data on demographics, laboratory work, bone marrow analysis, radiology, and given treatment were collected. Descriptive statistics, survival curves, and multivariable cox regression were used to identify independent mortality risk factors. Results: During the study period of 15 years, a total of 192 patients were diagnosed with MM. The incident rate of myeloma cases in 2021 was 8 patients per million. The median age of patients was 57 years [range 22-88], with 68% being above the age of 50 years at diagnosis. The majority of patients were male (71%) and (85%) were expats. At the time of diagnosis, most patients [n = 169 (88%)] had bone lesions, and 27% had extramedullary plasmacytoma. Anemia, hypercalcemia, and spinal cord compression were reported in 53%, 28%, and 7% of patients, respectively, at presentation. The monoclonal immunoglobulin subtypes were IgG, IgA, and free light chain in 52%, 16%, and 26% of patients, respectively. The overall median survival was 103 months (95% CI 71-135 months). In a multivariate cox-regression analysis for risk factors, only high serum calcium (≥ 2.7 mmol/L) was associated with increased mortality (HR: 2.54, 95% C.I.: 1.40-4.63, p = 0.002). Patients who received an autologous stem cell transplant (ASCT) had significantly better overall survival. Conclusion: In this comprehensive study of patients with MM treated in a country with a small and young general population, centralized hematology care, and free cancer care, we found a low but increasing incidence of MM and a good overall survival. Hypercalcemia was confirmed as a negative risk factor. ASCT had a significant positive impact on survival and should be provided to all patients eligible for this treatment, even in the era of novel agents.

Erythema nodosum following treatment with dasatinib plus chemotherapy in a patient with myeloid blast phase of chronic myeloid leukemia.

Erythema nodosum (EN) is a type of panniculitis occurring due to various conditions. It can be associated with certain malignancies or manifest as a side effect of drugs. This article presents a unique case of EN in a patient with chronic myeloid leukemia (CML-blast phase) following dasatinib and chemotherapy. Timely recognition and appropriate management are crucial to alleviate symptoms and consider potential drug-induced etiology.

Refractory cold agglutinin disease successfully treated with daratumumab. A case report and review of literature.

BACKGROUND: Cold agglutinin disease (CAD) is immune-mediated hemolytic anemia. The disease is caused by cold reactive autoantibodies that induce hemolysis through the activation of the complement pathway. Most patients with CAD are elderly, and half may have refractory CAD that may not respond to the first-line treatment option (i.e. rituximab). Some cases are refractory to multiple lines of therapy, including chemotherapeutic agents, which might be toxic, especially for elderly patients. Daratumumab is a human monoclonal antibody targeting CD 38 glycoprotein, a transmembrane protein highly expressed in lymphoid and plasma cells. Daratumumab is currently approved for treating multiple myeloma and is used mainly as a combination therapy with other agents. CASE PRESENTATION: Our patient is a 69-year-old female diagnosed with CAD after presenting with severe anemia and significant circulatory symptoms. Rituximab was not effective in controlling her disease, and she refused other available chemotherapeutic agents due to their side effects profile. We used daratumumab combined with erythropoietin, which led to a dramatic response measured by stabilizing her hemoglobin levels and transfusion independence. CONCLUSION: Our case is the third reported case of refractory CAD successfully treated with daratumumab, which suggests that daratumumab might be a potential agent for the treatment and control of refractory Cold Agglutinin Disease.

An Artificial Intelligence-Based Diagnostic System for Acute Lymphoblastic Leukemia Detection.

This study suggests a novel Acute Lymphoblastic Leukemia (ALL) diagnostic model, built solely on complete blood count (CBC) records. Using a dataset comprised of CBC records of 86 ALL and 86 control patients respectively, we identified the most ALL-specific parameters using a feature selection approach. Next, Grid Search-based hyperparameter tuning with a five-fold cross-validation scheme was adopted to build classifiers using Random Forest, XGBoost, and Decision Tree algorithms. A comparison between the performances of the three models demonstrates that Decision Tree classifier outperformed XGBoost and Random Forest algorithms in ALL detection using CBC-based records.

Machine Learning for Diagnosis and Screening of Chronic Lymphocytic Leukemia Using Routine Complete Blood Count (CBC) Results.

The comprehensive epidemiology and global disease burdens reported recently suggest that chronic lymphocytic leukemia (CLL) constitutes 25-30% of leukemias thus being the most common leukemia subtype. However, there is an insufficient presence of artificial intelligence (AI)-based techniques for CLL diagnosis. The novelty of this study is in the investigation of data-driven techniques to leverage the intricate CLL-related immune dysfunctions reflected in routine complete blood count (CBC) alone. We used statistical inferences, four feature selection methods, and multistage hyperparameter tuning to build robust classifiers. With respective accuracies of 97.05%, 97.63%, and 98.62% for Quadratic Discriminant Analysis (QDA), Logistic Regression (LR), and XGboost (XGb)-based models, CBC-driven AI methods promise timely medical care and improved patient outcome with lesser resource usage and related cost.

Prediction of Multiple Clinical Complications in Cancer Patients to Ensure Hospital Preparedness and Improved Cancer Care.

Reliable and rapid medical diagnosis is the cornerstone for improving the survival rate and quality of life of cancer patients. The problem of clinical decision-making pertaining to the management of patients with hematologic cancer is multifaceted and intricate due to the risk of therapy-induced myelosuppression, multiple infections, and febrile neutropenia (FN). Myelosuppression due to treatment increases the risk of sepsis and mortality in hematological cancer patients with febrile neutropenia. A high prevalence of multidrug-resistant organisms is also noted in such patients, which implies that these patients are left with limited or no-treatment options amidst severe health complications. Hence, early screening of patients for such organisms in their bodies is vital to enable hospital preparedness, curtail the spread to other weak patients in hospitals, and limit community outbreaks. Even though predictive models for sepsis and mortality exist, no model has been suggested for the prediction of multidrug-resistant organisms in hematological cancer patients with febrile neutropenia. Hence, for predicting three critical clinical complications, such as sepsis, the presence of multidrug-resistant organisms, and mortality, from the data available from medical records, we used 1166 febrile neutropenia episodes reported in 513 patients. The XGboost algorithm is suggested from 10-fold cross-validation on 6 candidate models. Other highlights are (1) a novel set of easily available features for the prediction of the aforementioned clinical complications and (2) the use of data augmentation methods and model-scoring-based hyperparameter tuning to address the problem of class disproportionality, a common challenge in medical datasets and often the reason behind poor event prediction rate of various predictive models reported so far. The proposed model depicts improved recall and AUC (area under the curve) for sepsis (recall = 98%, AUC = 0.85), multidrug-resistant organism (recall = 96%, AUC = 0.91), and mortality (recall = 86%, AUC = 0.88) prediction. Our results encourage the need to popularize artificial intelligence-based devices to support clinical decision-making.

Dasatinib-induced chylothorax: An unusual presentation of a common adverse event-A case report with literature review.

Tyrosine kinase inhibitors (TKIs) are the key agents for treating CML and BCR-ABL+ B-ALL. Dasatinib is a potent second-generation TKI. Here, we have discussed the case of a 51-year-old gentleman diagnosed with B-myeloid mixed-phenotype acute leukemia with t(9;22)(q34.1;q11.2); BCR-ABL1p210, in complete hematological, cytogenetic, and molecular remission, who developed chylothorax. Though pleural effusion is a commonly observed adverse effect of dasatinib therapy, chylothorax is rare. The ability of Dasatinib to inhibit multiple families of tyrosine kinases could be considered the etiology. Discontinuation of the drug resolved the symptom, but pleural effusion recurred once Dasatinib was resumed. Chylothorax induced by Dasatinib is a differential to be kept in mind, owing to the limited number of cases being reported.

Downregulation of Lymphoid enhancer-binding factor 1 (LEF-1) expression (by immunohistochemistry and/ flow cytometry) in chronic Lymphocytic Leukemia with atypical immunophenotypic and cytologic features.

INTRODUCTION: Lymphoid enhancer-binding factor 1 (LEF-1) overexpression has been recently remarkably reported in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and has shown utility in distinguishing CLL/SLL from other B-cell lymphomas. CLL has a well-defined immunophenotype, yet, some cases of CLL demonstrate atypical morphology/ phenotype reflected by low Matutes score (atypical CLL). Till date, LEF1 expression has not been systematically studied in cases of CLL with atypical features. METHODS: In this study, LEF-1 expression was assessed by two different techniques, (immunohistochemistry and flow cytometry), to investigate the expression profile of LEF-1 in cases of CLL/SLL, in comparison with other low-grade B-lymphomas and CLL with atypical features, including atypical immunophenotype and CLL with increased prolymphocytes or morphologically atypical cells. RESULTS: We found that LEF-1 expression is downregulated in CLL with atypical immunophenotype/features compared to classic CLL; Chi-Square P < .0001. The ratio for LEF-1 expression in malignant B-cells/NK (by flow cytometry) in CLL/SLL with classic immunophenotype was higher than atypical CLL and is significantly higher in other small B-cell lymphomas (P < .01). Absence of LEF-1 expression in CLL/SLL is correlated (P < .05) with downregulation of CD5, CD23, CD200, expression of FMC7, brighter expression of CD79b, brighter expression of surface light chain, increased prolymphocytes and lower Matutes score. CONCLUSION: As downregulation of LEF-1 expression is well correlated with atypical CLL, we suggest adding LEF-1 to Matutes score as a beneficial marker to differentiate classic from atypical CLL LEF-1 could also serve as a potential prognostic indicator for CLL clinical course.

Characterization of complete lncRNAs transcriptome reveals the functional and clinical impact of lncRNAs in multiple myeloma.

Multiple myeloma (MM) is an incurable disease, whose clinical heterogeneity makes its management challenging, highlighting the need for biological features to guide improved therapies. Deregulation of specific long non-coding RNAs (lncRNAs) has been shown in MM, nevertheless, the complete lncRNA transcriptome has not yet been elucidated. In this work, we identified 40,511 novel lncRNAs in MM samples. lncRNAs accounted for 82% of the MM transcriptome and were more heterogeneously expressed than coding genes. A total of 10,351 overexpressed and 9,535 downregulated lncRNAs were identified in MM patients when compared with normal bone-marrow plasma cells. Transcriptional dynamics study of lncRNAs in the context of normal B-cell maturation revealed 989 lncRNAs with exclusive expression in MM, among which 89 showed de novo epigenomic activation. Knockdown studies on one of these lncRNAs, SMILO (specific myeloma intergenic long non-coding RNA), resulted in reduced proliferation and induction of apoptosis of MM cells, and activation of the interferon pathway. We also showed that the expression of lncRNAs, together with clinical and genetic risk alterations, stratified MM patients into several progression-free survival and overall survival groups. In summary, our global analysis of the lncRNAs transcriptome reveals the presence of specific lncRNAs associated with the biological and clinical behavior of the disease.

Acute Myeloid Leukemia in Qatar (2010-2016): Clinical, Biological, and Prognostic Factors and Treatment Outcomes.

The current study retrospectively evaluated cytogenetic profiles, various prognostic factors, and survival outcomes in 128 acute myeloid leukemia (AML) patients (14 ≤ age ≤ 70 years) admitted to the National Center for Cancer Care and Research (NCCCR), Hamad Medical Corporation, Doha, Qatar, between January 2010 and December 2016. The median age at diagnosis was 43 years, and 80% were less than 60 years old; 75% of patients were male. Cytogenetic analysis was integrated into the World Health Organization 2008 classification and showed that the percentages of normal and abnormal karyotypes were similar, accounting for 48.4% of each group of patients. The AML risk stratification based on cytogenetic analysis resulted in the following distribution: 18% in the favorable risk group, 57% in the intermediate-risk group, 24% in the unfavorable risk group, and 1% unknown. Only 88 patients received therapy with curative intent; 67% achieved complete remission, increasing to 81% after inductions 1 and 2. The median overall survival (OS) and disease-free survival (DFS) in AML patients were 26.6 and 19.5 months, respectively. The 3-year OS and DFS were 40 and 36%, respectively. Prognostic factors including age, gender, white blood cell count, and risk stratification were not significantly associated with treatment outcomes, whereas response to treatment vs. failure was significantly associated with the outcome (p = 0.01). The current study supports the importance of cytogenetics as a useful tool in diagnosis, prognosis, and risk assessment in AML treatment.

Circulating tumor cells for comprehensive and multiregional non-invasive genetic characterization of multiple myeloma.

Multiple myeloma (MM) patients undergo repetitive bone marrow (BM) aspirates for genetic characterization. Circulating tumor cells (CTCs) are detectable in peripheral blood (PB) of virtually all MM cases and are prognostic, but their applicability for noninvasive screening has been poorly investigated. Here, we used next-generation flow (NGF) cytometry to isolate matched CTCs and BM tumor cells from 53 patients and compared their genetic profile. In eight cases, tumor cells from extramedullary (EM) plasmacytomas were also sorted and whole-exome sequencing was performed in the three spatially distributed tumor samples. CTCs were detectable by NGF in the PB of all patients with MM. Based on the cancer cell fraction of clonal and subclonal mutations, we found that ~22% of CTCs egressed from a BM (or EM) site distant from the matched BM aspirate. Concordance between BM tumor cells and CTCs was high for chromosome arm-level copy number alterations (≥95%) though not for translocations (39%). All high-risk genetic abnormalities except one t(4;14) were detected in CTCs whenever present in BM tumor cells. Noteworthy, ≥82% mutations present in BM and EM clones were detectable in CTCs. Altogether, these results support CTCs for noninvasive risk-stratification of MM patients based on their numbers and genetic profile.

Transcriptional profiling of circulating tumor cells in multiple myeloma: a new model to understand disease dissemination.

The reason why a few myeloma cells egress from the bone marrow (BM) into peripheral blood (PB) remains unknown. Here, we investigated molecular hallmarks of circulating tumor cells (CTCs) to identify the events leading to myeloma trafficking into the bloodstream. After using next-generation flow to isolate matched CTCs and BM tumor cells from 32 patients, we found high correlation in gene expression at single-cell and bulk levels (r ≥ 0.94, P = 10-16), with only 55 genes differentially expressed between CTCs and BM tumor cells. CTCs overexpressed genes involved in inflammation, hypoxia, or epithelial-mesenchymal transition, whereas genes related with proliferation were downregulated in CTCs. The cancer stem cell marker CD44 was overexpressed in CTCs, and its knockdown significantly reduced migration of MM cells towards SDF1-α and their adhesion to fibronectin. Approximately half (29/55) of genes differentially expressed in CTCs were prognostic in patients with newly-diagnosed myeloma (n = 553; CoMMpass). In a multivariate analysis including the R-ISS, overexpression of CENPF and LGALS1 was significantly associated with inferior survival. Altogether, these results help understanding the presence of CTCs in PB and suggest that hypoxic BM niches together with a pro-inflammatory microenvironment induce an arrest in proliferation, forcing tumor cells to circulate in PB and seek other BM niches to continue growing.

Highly Aggressive CD4-Positive Mast Cell Leukaemia (Leukaemic Variant) Associated with Isolated Trisomy 19 and Hemophagocytosis by Neoplastic Mast Cells: A Case Report with Challenging Experience and Review.

BACKGROUND: Mast cell leukaemia is a unique disease among hematopoietic neoplasms, being one of the rarest leukaemia subtypes. In addition, its prompt diagnosis is usually challenging. This is due to its heterogeneity in clinical presentations and cytomorphological and immunophenotypical features together with potential associations with other hematologic neoplasms which can complicate the condition and delay accurate diagnosis. To the best of our knowledge, this is the first case report of CD4-positive mast cell leukaemia. CASE PRESENTATION: A 39-year-old male presented with acute onset of fever, abdominal pain, and generalized body aches of two-week duration. Peripheral blood smear showed circulating blasts (13%) with coarsely basophilic granulation. Bone marrow (BM) aspirate showed extensive infiltration with immature mast cells of blast-like morphology with trilineage dysplasia and evident hemophagocytic activity exhibited by histiocytes and neoplastic mast cells. BM biopsy was diffusely infiltrated with many atypical mast cells positive for CD45, CD117, mast cell tryptase, CD25, and CD4 with partial positivity for CD7 and CD30. Cytogenetics showed an abnormal karyotype: 47, XY, +1947, XY, +19[13]/46, XY[9]. Molecular analysis revealed a KIT D816V mutation consistent with a diagnosis of systemic mastocytosis, mast cell leukaemia. CONCLUSION: The expression of T-cell associated markers by abnormal mast cells is well documented; however, CD4 and CD7 expression have not previously been described in association with mast cell leukaemia. Coexpression of CD2, CD4, CD7, and CD30 by the mast cells particularly in skin lesions may provoke misinterpretation as a cutaneous T-cell neoplasm. To the best of our knowledge, this is the first report of CD4-positive mast cell leukaemia. Moreover, hemophagocytic mast cell leukaemia is a very rare morphologic variant, and possible correlation between this finding and expression of CD4 by neoplastic mast cells is a topic for further investigation.

Concomitant BRAF Mutation in Hairy Cell Leukemia and Papillary Thyroid Cancer: Case Report.

Hairy cell leukemia (HCL) is rare type of leukemia. This neoplasm is well-known to present with pancytopenia and splenomegaly. HCL is associated with BRAF mutation in 100% of cases. It is also associated with hematological and oncological malignancies such as melanoma and papillary thyroid cancer. Although the association of both cancers (HCL and papillary thyroid cancer) with BRAF mutation is well established in the literature, as far as we know it has not been reported before in the same patient. Here we report 48-year-old male diagnosed with HCL and papillary thyroid cancer and who is BRAF positive in both diagnostic tissues.

Acute Myeloid Leukemia With Inv(16)(p13q22) Associated With Hidden Systemic Mastocytosis: Case Report and Review of Literature.

Systemic mastocytosis (SM) is a condition associated with clonal neoplastic proliferation of mast cells. In up to 40% of systemic mastocytosis cases, an associated clonal hematological disease of non-mast cell lineage, such as acute myeloid leukemia (AML), is diagnosed before, simultaneously with, or after the diagnosis of SM. Herein, we report a case of a 30-year-old man diagnosed with AML with inv(16) (p13;q22) CBFB:MYH11. Associated mastocytosis was not noted at diagnosis and was only detected in the bone marrow at time of remission after successful chemotherapy. The diagnosis of mastocytosis was based on the demonstration of a multifocal dense mast cell infiltrate in the marrow biopsy with aberrant immunophenotype, with coexpression of tryptase, CD117, and CD25. The mast cells showed atypical morphology mostly with irregular nuclear contour, bilobed or multilobed nuclei with cytoplasmic hypogranulation or irregular metachromatic granule distribution, and some cells with eccentric nucleus or spindle shape. Reexamination of the pretherapeutic bone marrow with immunostain for tryptase and CD25 revealed that mastocytosis was present from the start but masked by extensive blast proliferation. This case indicates that mast cell infiltrates are sometimes underappreciated at the original diagnosis of AML with inv(16) and that the concurrent diagnosis of SM with AML requires a high index of suspicion supported with comprehensive morphologic and immunohistochemical evaluation for a neoplastic mast cell proliferation.