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Germline DDX41 variants are the most common mutations predisposing to acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) in adults, but the causal variant (CV) landscape and clinical spectrum of hematologic malignancies (HMs) remain unexplored. Here, we analyzed the genomic profiles of 176 patients with HM carrying 82 distinct presumably germline DDX41 variants among a group of 9821 unrelated patients. Using our proposed DDX41-specific variant classification, we identified features distinguishing 116 patients with HM with CV from 60 patients with HM with variant of uncertain significance (VUS): an older age (median 69 years), male predominance (74% in CV vs 60% in VUS, P = .03), frequent concurrent somatic DDX41 variants (79% in CV vs 5% in VUS, P < .0001), a lower somatic mutation burden (1.4 ± 0.1 in CV vs 2.9 ± 0.04 in VUS, P = .012), near exclusion of canonical recurrent genetic abnormalities including mutations in NPM1, CEBPA, and FLT3 in AML, and favorable overall survival (OS) in patients with AML/MDS. This superior OS was determined independent of blast count, abnormal karyotypes, and concurrent variants, including TP53 in patients with AML/MDS, regardless of patient’s sex, age, or specific germline CV, suggesting that germline DDX41 variants define a distinct clinical entity. Furthermore, unrelated patients with myeloproliferative neoplasm and B-cell lymphoma were linked by DDX41 CV, thus expanding the known disease spectrum. This study outlines the CV landscape, expands the phenotypic spectrum in unrelated DDX41-mutated patients, and underscores the urgent need for gene-specific diagnostic and clinical management guidelines.

In this paper, we emphasize that the thermodynamic basis of displacement concept is finite equilibrium region and quasi-static process. By considering the dynamic process of a particle system undergoing reversible deformation under external force, the spatial and temporal distributions of mesoscopic mass, mesoscopic mass flow, mesoscopic energy, and mesoscopic stress are calculated using corresponding mesoscopic theory (e.g., Hertz contact mechanics). Their macroscopic correspondence is calculated by means of coarse-grained average, and the resulting macroscopic mass and mass flow are substituted into the equation that defines the displacement, and the displacement is calculated by integration.

Acute myeloid leukemia (AML) with RARG rearrangement has clinical, morphologic, and immunophenotypic features similar to classic acute promyelocytic leukemia. However, AML with RARG rearrangement is insensitive to all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) and carries a poor prognosis. We initiated a global cooperative study to define the clinicopathological features, genomic and transcriptomic landscape, and outcomes of AML with RARG rearrangements collected from 29 study groups/institutions worldwide. Thirty-four AML with RARG rearrangements were identified. Bleeding or ecchymosis was present at 18 (54.5%) patients. Morphology diagnosed as M3 and M3v accounted for 73.5% and 26.5% of cases, respectively. Immunophenotyping showed following characteristics: positive for CD33, CD13, and MPO but negative for CD38, CD11b, CD34, and HLA-DR. Cytogenetics showed normal karyotype in 38% and t(11;12) in 26% of patients. The partner genes of RARG were diverse and included CPSF6 (n=14), NUP98 (n=11), HNRNPc (n=6), HNRNPm (n=1), PML (n=1), and NPM1 (n=1). WT1- and NRAS/KRAS-mutations were common co-mutations. None of the 34 patients responded to ATRA and/or ATO. Death within 45 days from diagnosis occurred in 10 patients (~29%). At the last follow-up, 23 patients had died, and the estimated 2-year cumulative incidence of relapse, event-free survival, and overall survival were 68.7%, 26.7%, and 33.5%, respectively. Unsupervised hierarchical clustering using RNA-seq data from 201 AML patients showed that 81.8% of the RARG fusion samples clustered together, suggesting a new molecular subtype. RARG rearrangement is a novel entity of AML that confers a poor prognosis.

Breast implant-associated anaplastic large cell lymphoma (ALCL) is a distinctive type of T-cell lymphoma that arises around textured-surface breast implants. In a subset of patients, this disease can involve surrounding tissues, spread to regional lymph nodes, and rarely metastasize to distant sites. The aim of this study was to assess sequential pathologic specimens from patients with breast implant-associated ALCL to better understand the natural history of early-stage disease. To achieve this goal, we searched our files for patients who had breast implant-associated ALCL and who had undergone earlier surgical intervention with assessment of biopsy or cytologic specimens. We then focused on the patient subset in whom a definitive diagnosis was not established, and patients did not receive current standard-of-care therapy at that time. We identified a study group of ten patients with breast implant-associated ALCL in whom pathologic specimens were collected 0.5 to 4 years before a definitive diagnosis was established. A comparison of these serial biopsy specimens showed persistent disease without change in pathologic stage in three patients, progression in five patients, and persistence versus progression in two patients. Eventually, six patients underwent implant removal with complete capsulectomy and four underwent partial capsulectomy. Seven patients also received chemotherapy because of invasive disease, three of whom also received radiation therapy, two brentuximab vedotin after chemotherapy failure, and one allogeneic stem cell transplant. Eight patients achieved complete remission and two had partial remission after definitive therapy. At time of last follow-up, six patients were alive without disease, one had evidence of disease, one died of disease, and two patients died of unrelated cancers. In summary, this analysis of sequential specimens from patients with breast implant-associated ALCL suggests these neoplasms persist or progress over time if not treated with standard-of-care therapy.

Germline DDX41 variants in myeloid neoplasms (MNs) are not uncommon, and we explored the prevalence and characterized the clinical and pathologic features in a cohort of 3132 unrelated adult MN patients. By targeted next-generation sequencing, we identified 28 patients (20 men and 8 women) with pathogenic germline DDX41 variants who developed acute myeloid leukemia (AML), in which only 3 (11%) had a family history (FH) of MNs. A subacute clinical course of cytopenia (mean duration of 11.2 months, range 0-72 months) prior to the initial AML diagnosis was accompanied by a low blast count (median at 30%, range 20-70%) in hypocellular marrows (93% of all patients), in vast contrast to the typical proliferative subtypes of AML in the elderly. Most patients had a normal karyotype (75%) and acquired a second DDX41 variant (69%). A favorable overall survival (OS) was observed in comparison to that of common subtypes of AML with wild-type DDX41 in age-matched patients. Our study demonstrated that the frequent germline pathogenic DDX41 variants characterized a clinically distinct AML entity. Features characteristic of DDX41-mutated AML include male predominance, often lack of FH, indolent course, low proliferative potential, frequent somatic DDX41 variants, and a favorable OS.

Primary cutaneous anaplastic large-cell lymphoma and breast implant-associated ALCL (BIA-ALCL) are rare subtypes of anaplastic lymphoma kinase (ALK)-negative ALCLs originating from skin and breast implants, respectively. Herein, we report a unique case of cutaneous ALK-negative ALCL occurring in the skin of left medial breast from a patient with multiple rounds of bilateral breast implants and a history of breast carcinoma. The lymphoma cells are entirely confined to the lymphatic channels in the dermis, and the patient has no other areas of skin abnormality, no lymphadenopathy, peri-implant fluid accumulation, or masses from the bilateral capsules of implants. The differential diagnosis and its relationship with breast implants are further explored.

Monomorphic posttransplant lymphoproliferative disorders have been defined as lymphoid or plasmacytic proliferations that fulfill criteria for one of the B-cell or T/NK-cell neoplasms recognized in immunocompetent hosts in the current WHO Classification. Low-grade B-cell neoplasms have historically been excluded from this category, although rare reports of marginal zone lymphoma (MZL) have been described. We report 9 cases of posttransplant Epstein-Barr virus-negative MZL, all arising in solid organ transplant recipients (4 renal, 3 liver, 1 cardiac, and 1 liver, pancreas, and small bowel). Seven were extranodal MZL of mucosa-associated lymphoid tissue type, all of which had gastrointestinal involvement (4 colon, 1 duodenum, 1 stomach, and 1 oropharynx/base of tongue). Notably, the preferential involvement of intestine distinguishes posttransplant extranodal MZL from sporadic cases. Immunoglobulin light-chain restriction was seen in all cases, with polymerase chain reaction showing a monoclonal pattern in 7 of 8 cases with successful amplification of polymerase chain reaction products. A clonally unrelated recurrence was seen in one case. Next-generation sequencing identified recurrent mutations previously reported in MZL in 3/5 cases. MZL was diagnosed at least 1 year after solid organ transplant (median time to presentation, 84 mo; range, 13 to 108 mo). The median age was 44 (range, 9 to 73 y); the male: female ratio was 5:4. The mean follow-up was 33.4 months, with an indolent clinical course observed. A subset responded to reduction in immunosuppression and anti-CD20 therapy alone. These data support the designation of Epstein-Barr virus-negative MZL as an uncommon form of monomorphic posttransplant lymphoproliferative disorders.

Inflammatory pseudotumor (IPT), also known as plasma cell granuloma, is a rare lesion of unknown etiology that occurs in many organs, especially in the lung. Here we report five cases of IPT arising in pulmonary artery mimicking chronic thromboembolic disease, not previously documented in the literature. Those cases were identified at our institute among over 2500 pulmonary endarterectomy (PEA) specimens acquired from 2000 to 2017. The cohort included three men and two women with a median age of 41 years (range: 23-54). All patients presented with dyspnea and radiologic findings of pulmonary artery thromboembolism, some concerning for intimal sarcoma. The duration between disease onset and PEA ranged from 6 months to approximately 3 years. Histologically, all cases showed proliferation of spindle cells with marked inflammatory infiltrates composed predominantly of plasma cells, histiocytes, and small lymphocytes. Ancillary studies were performed in each case and ruled out other possibilities, such as sarcoma, lymphoma, plasmacytoma, IgG4-related disease, and infection. IPT arising in pulmonary artery presenting clinically as acute or chronic thromboembolic disease is very unusual, in which clinical data, radiographic findings, and histopathologic features have to be integrated for reaching the proper diagnosis.

Primary mediastinal (thymic) large B-cell lymphoma (PMBL) is a subtype of uncommon aggressive large B-cell lymphomas primarily occurring in mediastinum although rare cases with non-thymic type of PMBL have been reported. Typical PMBL has characteristic clinical, morphological, and immunophenotypic features which the pathologists use as diagnostic paradigm in routine practice. However, the diagnosis can be occasionally challenging due to the overlapping clinicopathologic features with other lymphomas, among which are nodular sclerosis classic Hodgkin lymphoma, systemic diffuse large B-cell lymphoma (DLBCL) involving mediastinum, and B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classic Hodgkin lymphoma (gray zone lymphoma). Recent depictions of the characteristic genetic/ molecular aberrations and unique gene expression profiling in PMBL have provided a robust tool to significantly improve the diagnostic accuracy. In addition, the progresses in understanding the pathogenesis of PMBL have paved the way discovering novel therapeutic agents for patients with refractory/relapsed disease.

Objectives Castleman disease (CD) is a heterogeneous group of disorders involving systemic inflammation and lymphoproliferation. Recently, clonal mutations have been identified in unitcentric CD (UCD) and idiopathic multicentric CD (iMCD), suggesting a potential underlying neoplastic process. Methods Patients with UCD or iMCD with next generation sequencing (NGS) data on tissue DNA and/or circulating tumor DNA (ctDNA) were included. Results Five patients were included, 4 with iMCD and 1 with UCD. Four patients (80%) were women; median age was 40 years. Three of five patients (60%) had ≥1 clonal mutation detected on biopsy among the genes included in the panel. One patient with iMCD had a 14q32-1p35 rearrangement and a der(1)dup(1)(q42q21)del(1)(q42) (1q21 being IL-6R locus) on karyotype. This patient also had a NF1 K2459fs alteration on ctDNA (0.3%). Another patient with iMCD had a KDM5C Q836* mutation, and one patient with UCD had a TNS3-ALK fusion but no ALK expression by immunohistochemistry. Conclusions We report 4 novel somatic alterations found in patients with UCD or iMCD. The 1q21 locus contains IL-6R, and duplication of this locus may increase IL-6 expression. These findings suggest that a clonal process may be responsible for the inflammatory phenotype in some patients with UCD and iMCD.

High‐throughput single‐cell cytometry technologies have significantly improved our understanding of cellular phenotypes to support translational research and the clinical diagnosis of hematological and immunological diseases. However, subjective and ad hoc manual gating analysis does not adequately handle the increasing volume and heterogeneity of cytometry data for optimal diagnosis. Prior work has shown that machine learning can be applied to classify cytometry samples effectively. However, many of the machine learning classification results are either difficult to interpret without using characteristics of cell populations to make the classification, or suboptimal due to the use of inaccurate cell population characteristics derived from gating boundaries. To date, little has been done to optimize both the gating boundaries and the diagnostic accuracy simultaneously. In this work, we describe a fully discriminative machine learning approach that can simultaneously learn feature representations (e.g., combinations of coordinates of gating boundaries) and classifier parameters for optimizing clinical diagnosis from cytometry measurements. The approach starts from an initial gating position and then refines the position of the gating boundaries by gradient descent until a set of globally‐optimized gates across different samples are achieved. The learning procedure is constrained by regularization terms encoding domain knowledge that encourage the algorithm to seek interpretable results. We evaluate the proposed approach using both simulated and real data, producing classification results on par with those generated via human expertise, in terms of both the positions of the gating boundaries and the diagnostic accuracy. © 2019 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of International Society for Advancement of Cytometry.

Heterozygous deletions within chromosome 20q, or del(20q), are frequent cytogenetic abnormalities detected in hematologic malignancies. To date, identification of genes in the del(20q) common deleted region that contribute to disease development have remained elusive. Through assessment of patient gene expression, we have identified STK4 (encoding Hippo kinase MST1) as a 20q gene that is downregulated below haploinsufficient amounts in myelodysplastic syndrome (MDS) and myeloproliferative neoplasm (MPN). Hematopoietic-specific gene inactivation in mice revealed Hippo kinase loss to induce splenomegaly, thrombocytopenia, megakaryocytic dysplasia, and a propensity for chronic granulocytosis; phenotypes that closely resemble those observed in patients harboring del(20q). In a JAK2-V617F model, heterozygous Hippo kinase inactivation led to accelerated development of lethal myelofibrosis, recapitulating adverse MPN disease progression and revealing a novel genetic interaction between these 2 molecular events. Quantitative serum protein profiling showed that myelofibrotic transformation in mice was associated with cooperative effects of JAK2-V617F and Hippo kinase inactivation on innate immune-associated proinflammatory cytokine production, including IL-1β and IL-6. Mechanistically, MST1 interacted with IRAK1, and shRNA-mediated knockdown was sufficient to increase IRAK1-dependent innate immune activation of NF-κB in human myeloid cells. Consistent with this, treatment with a small molecule IRAK1/4 inhibitor rescued the aberrantly elevated IL-1β production in the JAK2-V617F MPN model. This study identified Hippo kinase MST1 (STK4) as having a central role in the biology of del(20q)-associated hematologic malignancies and revealed a novel molecular basis of adverse MPN progression that may be therapeutically exploitable via IRAK1 inhibition.

Germline DDX41 variants in myeloid neoplasms (MNs) are not uncommon, and we explored the prevalence and characterized the clinical and pathologic features in a cohort of 3132 unrelated adult MN patients. By targeted next-generation sequencing, we identified 28 patients (20 men and 8 women) with pathogenic germline DDX41 variants who developed acute myeloid leukemia (AML), in which only 3 (11%) had a family history (FH) of MNs. A subacute clinical course of cytopenia (mean duration of 11.2 months, range 0-72 months) prior to the initial AML diagnosis was accompanied by a low blast count (median at 30%, range 20-70%) in hypocellular marrows (93% of all patients), in vast contrast to the typical proliferative subtypes of AML in the elderly. Most patients had a normal karyotype (75%) and acquired a second DDX41 variant (69%). A favorable overall survival (OS) was observed in comparison to that of common subtypes of AML with wild-type DDX41 in age-matched patients. Our study demonstrated that the frequent germline pathogenic DDX41 variants characterized a clinically distinct AML entity. Features characteristic of DDX41-mutated AML include male predominance, often lack of FH, indolent course, low proliferative potential, frequent somatic DDX41 variants, and a favorable OS.

Context.—Recent advances in comprehensive genomic profiling by next-generation sequencing have uncovered the genomic alterations at the molecular level for many types of tumors; as such, numerous small specific molecules that target these alterations have been developed and widely used in the management of these cancers.Objective.—To provide a concise molecular genomic update in solid, bone and soft tissue tumors, hematopoietic as well as lymphoid malignancies; discuss its clinical applications; and familiarize practicing pathologists with the emerging cancer biomarkers and their diagnostic utilities.Data Sources.—This review is based on the National Comprehensive Cancer Network guidelines and peer-reviewed English literature.Conclusions.—Tumor-specific biomarkers and molecular/genomic alterations, including pan-cancer markers, have been significantly expanded in the past decade thanks to large-scale high-throughput technologies and will continue to emerge in the future. These biomarkers can be of great value in diagnosis, prognosis, and/or targeted therapy/treatment. Familiarization with these emerging and ever-changing tumor biomarkers will undoubtedly aid pathologists in making accurate and state-of-the-art diagnoses and enable them to be more actively involved in the care of cancer patients.

The pathogenesis of follicular lymphoma is a multi-step process, in which chromosomal translocation between immunoglobulin heavy chain (IgH) and anti-apoptotic B-cell lymphoma 2 (BCL2), namely IgH-BCL2, is an earliest step, followed by other genetic/genomic alterations including but not limited to mutation of CREB binding protein (CREBBP). MHC class II transactivator (CIITA) is a transcription regulator responsible for expression of MHC class II molecules including HLA-DR in human. We report herein a novel fusion gene involving CIITA and CREBBP in a patient with a low-grade follicular lymphoma (FL) but with high Ki-67 proliferation index. In addition, our patient also harbors CREBBP mutation. Together, we postulate that total loss of CREBBP function may contribute, in part, to the lymphoma genesis. Furthermore, this patient has addition rare (TBL1XR1-TP63) and common (IgH-BCL2) chromosomal translocations and multiple mutations including BCL2, BRAF, MUTYH, and STAT6.

Since the first reported case in 1997, over 600 women with breast implant-associated anaplastic large cell lymphoma (BI ALCL) have been reported. BI ALCL is a CD30-positive T-cell lymphoma that carries clonal T-cell receptor gene rearrangements, and a subset of cases harbors mutations in the JAK-STAT signaling pathway. Rarely, other histologic types of lymphoma have been reported in association with breast implants, including fewer than 10 cases of B-cell origin. Here, we describe three additional patients with B-cell lymphoma occurring around breast implants. Two of these patients developed extranodal marginal zone lymphoma in the peri-implant capsule, one of which had a concurrent ALCL within the superficial lining of the capsule. The third patient presented with diffuse large B-cell lymphoma inside the breast parenchyma surrounding her implant. Determining the etiology and risk factors for the development of B-cell lymphomas associated with breast implants remains challenging, given the wide spectrum of histologic features and the rarity of these neoplasms. Ultimately, we document three new cases of B-cell lymphoma arising around breast implants and highlight their clinical and pathologic features in order to expand our understanding of this rare disease presentation.

While the majority of NK/T-cell neoplasms are unfavorable in clinical outcome, a few pathologic variants demonstrate relatively indolent behavior. These include primarily four types of tissue-based T-cell or NK-cell lymphoproliferative disorders and two leukemic forms of T-cell or NK-cell lymphoproliferative disorder. The diagnostic criteria and other clinicopathologic features of these entities are discussed as question and answer format.

InGaN/GaN multiquantum well (MQW) structures have been grown on cone-shaped patterned sapphire substrates (CPSS) by metalorganic chemical vapor deposition (MOCVD). From the transmission electron microscopy (TEM) results, we found that most of the threading dislocations (TDs) in the trench region of the CPSS were bent by lateral growth mode. Also the staircase-like TDs were observed near the slant region of the cone pattern, they converged at the slope of the cone patterned region by staircase-upward propagation, which seems to effectively prevent TDs from vertical propagation in the trench region. The associated dislocation runs up into the overgrown GaN layer and MQW, and some (a+c) dislocations were shown to decompose inside the multi-quantum well, giving rise to a misfit segment in the c-plane and a V-shape defect. From cross-sectional TEM, we found that all V defects are not always connected with TDs at their bottom, some V defects are generated from the stacking mismatch boundaries induced by stacking faults which are formed within the MQW due to the strain relaxation.

Key Points Brentuximab vedotin is active in primary effusion lymphoma, a rare CD30-positive lymphoma with an extremely poor prognosis.

Flow cytometry is used in cell-based diagnostic evaluation for blood-borne malignancies including leukemia and lymphoma. The current practice for cytometry data analysis relies on manual gating to identify cell subsets in complex mixtures, which is subjective, labor-intensive, and poorly reproducible. This article reviews recent efforts to develop, validate, and disseminate automated computational methods and pipelines for cytometry data analysis that could help overcome the limitations of manual analysis and provide for efficient and data-driven diagnostic applications. It demonstrates the performance of an optimized computational pipeline in a pilot study of chronic lymphocytic leukemia data from the authors' clinical diagnostic laboratory.

Context.—Different types of mature B-cell lymphomas, including plasma cell neoplasms, exhibit distinct immunohistochemical profiles, which enable them to be correctly diagnosed. However, except for rare examples of lymphoma-specific immunohistochemistry, such as cyclin D1 in mantle cell lymphoma and annexin A1 in hairy cell leukemia, immunohistochemical profiles of mature B-cell lymphomas overlap and lack specificity.Objectives.—To systemically review immunohistochemical features associated with commonly encountered mature B-cell lymphomas based on the presence or absence of CD5 and CD10; to review the immunophenotypic profile of plasma cells derived from plasma cell myelomas and B-cell lymphomas; and to review a group of rare, aggressive B-cell lymphomas with antigen expression features of plasma cells.Data Sources.—Published and PubMed-indexed English literature was reviewed.Conclusions.—Although the presence or absence of CD5 and CD10 expression should be included in the initial immunohistochemistry screening panel for mature B-cell lymphomas, appropriate and judicial use of other B-cell antigens is necessary to ensure correct diagnoses. Furthermore, although the status of CD5 and CD10 expression is associated with certain prototypes of B-cell lymphomas, their expression is not specific. Plasma cells from plasma cell neoplasias and B-cell lymphomas exhibit overlapping but relatively distinct immunophenotypes; thus, a panel of immunohistochemical markers (CD19, CD45, CD56, and CD117) can be employed for their proper identification. Lastly, CD138 staining results are almost always positive in a group of aggressive B-cell lymphomas with plasmablastic features, including plasmablastic plasma cell myeloma, plasmablastic lymphoma, and ALK-1+ large B-cell lymphoma.

In 2018, the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) updated the guidelines for diagnosis, indications for treatment, response assessment, and supportive management of patients with chronic lymphocytic leukemia. Included were definitions for response, which incorporated consideration of the significance of minimal residual disease. Here we discuss the clinical significance of complete response or partial response, as defined in the 2018 iwCLL guidelines, and the relative value of assessing for minimal residual disease.

Thoracic extramedullary hematopoiesis (EMH) is a rare manifestation in patients with myeloproliferative neoplasm. A 76-year-old woman with a long-standing history of polycythemia vera presented with a 2-month history of worsening dyspnea and left-sided wheezing. A chest computed tomography showed an ill-defined soft tissue mass encasing the left mainstem bronchus causing airway obstruction, associated with paratracheal and paraesophageal lymphadenopathy. Endobronchial ultrasound-guided fine needle aspiration of the soft tissue mass and mediastinoscopy with excisional biopsy of a paratracheal lymph node demonstrated EMH with increased myeloid blasts. A bone marrow biopsy confirmed postpolycythemic myelofibrosis consistent with progression of polycythemia vera to myelofibrosis. We describe the bronchoscopic management of a case of EMH presenting as a mediastinal mass, mimicking malignancy.

Motivation Diagnosis of leukemia relies on accurate identification of leukemic cell populations. Flow cytometry (FCM) is a primary diagnostic assay routinely used in clinical practice. The assay workflows consist of multiple manual gating steps performed by technicians, followed by interpretation by hematopathologists. Challenges to this process include technical variability in manual gating, difficulty in identification of the atypical leukemic cells, and the growing number of antigens used for diagnosis. Methods Instead of conducting ad hoc analysis of individual samples, our proposed computational approach leverages preexisting clinical FCM data to improve robustness of the computational identification of leukemic cells. Instead of separating cell population identification and sample classification into two steps, our machine learning classification method optimizes them simultaneously, producing gating locations that are recognizable to hematopathologists. Results Our study consists of 10-color FCM data from blood or bone marrow samples of 129 random subjects for chronic lymphocytic leukemia (CLL) diagnosis. Our initial automated gating analysis rendered an accuracy of 89% matched the diagnosis of the hematopathologist. In the remaining cases with discrepant results, the misclassified CLL cells had atypical molecular phenotypes, making them difficult to identify. In our improved pipeline, we demonstrate that these atypical types of CLL cells can be clearly captured using a non-linear embedding dimensionality reduction step. Conclusion The results demonstrate the power of a novel computational analysis pipeline for improving the identification of aberrant leukemia cells for precision diagnosis.

Blue light-emitting diodes (LEDs) with an InGaN multi-quantum well (MQW) structure were fabricated on cone-shaped patterned sapphire substrate (PSS) using a single growth process of metal organic chemical vapor deposition (MOCVD). The PSS was proved to be an efficient method to decrease the threading dislocation (TD) density in GaN epifilm with the lateral growth mode on PSS. The LED designed on PSS increased the electroluminescene (EL) intensity. The internal quantum efficiency is increased by reducing the dislocation density, and light extraction efficiency is also enhanced owing to PSS.

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia. It is characterized by the accumulation of CD19+/CD5+ lymphocytes and can have variable outcomes. Richter syndrome (RS) is a lethal complication in CLL patients that results in aggressive B-cell lymphomas, and there are no tests to predict its occurrence. Because alterations in microRNA expression can predict the development and progression of several cancers, we investigated whether dysregulation of specific microRNAs can predict RS in CLL patients. Thus, we compared microRNA expression levels in samples from 49 CLL patients who later developed RS with samples from 59 CLL patients who did not. We found that high expression of miR-125a-5p or low expression of miR-34a-5p can predict ∼50% of RS with a false positive rate of ∼9%. We found that CLL patients predicted to develop RS show either an increase of miR-125a-5p expression (∼20-fold) or a decrease of miR-34a-5p expression (∼21-fold) compared with CLL patients that are not predicted to develop RS. Thus, miR-125a-5p and miR-34a-5p can be valuable predictor markers of RS and have the potential to provide physicians with information that can indicate the best therapeutic strategy for CLL patients.

Background We recently identified the human leukocyte immunoglobulin-like receptor B2 (LILRB2) and its mouse ortholog-paired Ig-like receptor (PirB) as receptors for several angiopoietin-like proteins (Angptls). We also demonstrated that PirB is important for the development of acute myeloid leukemia (AML), but exactly how an inhibitory receptor such as PirB can support cancer development is intriguing. Results Here, we showed that the activation of Ca (2+)/calmodulin-dependent protein kinases (CAMKs) is coupled with PirB signaling in AML cells. High expression of CAMKs is associated with a poor overall survival probability in patients with AML. Knockdown of CAMKI or CAMKIV decreased human acute leukemia development in vitro and in vivo. Mouse AML cells that are defective in PirB signaling had decreased activation of CAMKs, and the forced expression of CAMK partially rescued the PirB-defective phenotype in the MLL-AF9 AML mouse model. The inhibition of CAMK kinase activity or deletion of CAMKIV significantly slowed AML development and decreased the AML stem cell activity. We also found that CAMKIV acts through the phosphorylation of one of its well-known target (CREB) in AML cells. Conclusion CAMKs are essential for the growth of human and mouse AML. The inhibition of CAMK signaling may become an effective strategy for treating leukemia. Electronic supplementary material The online version of this article (10.1186/s13045-018-0574-8) contains supplementary material, which is available to authorized users.