In situ mantle cell neoplasia (isMCN) and leukemic non-nodal mantle cell lymphoma (nnMCL) are classified as an indolent subtype of mantle cell lymphoma (MCL). The tumor cells of isMCN are restricted to the inner layer of the lymphoid tissue mantle zone, exhibiting an in situ pattern histologically. On the other hand, nnMCL is distributed in the peripheral blood, bone marrow and sometimes the spleen, but lymphadenopathy or systemic organ involvement is rare. We report a case of isMCN in a submandibular lymph node resected from a 65-year-old Japanese male. The tumor cells were positive for cyclin D1 (CCND1) and SOX11 expression, and were restricted to the mantle zone area of the lymph node. However, tumor cells were also detected in the stomach mucosa, bone marrow tissue and peripheral blood, suggesting nnMCL. isMCN and nnMCL may have a partly overlapping disease spectrum, although the correlation between these two subtypes has not been well described. This present case demonstrated characteristics overlapping between isMCN and nnMCL.

Keywords: SOX11; cyclin D1; in situ mantle cell neoplasia; leukemic non-nodal mantle cell lymphoma.

Mantle cell lymphoma (MCL) usually harbors the t(11;14)(q13;q32) with overexpression of CCND1 mRNA and transcription of the cyclin D1 nuclear protein. Regardless of CCND1 status, most MCLs also express the SOX11 nuclear protein, which is thus helpful in the diagnosis of the rare CCND1-negative MCLs. Recently, SOX11 has been reported to be often negative in MCLs clinically resembling marginal zone lymphoma and recently defined as "leukemic non-nodal" MCL in the incoming revision of the WHO classification of lymphoid tumors, for which the bone marrow biopsy is commonly the first diagnostic approach. Due to the less aggressive clinical behavior of the latter MCLs, the reliable determination of the SOX11 antigen in decalcified tissue is mandatory. To this end, since little data are available in the literature, four commercially available anti-SOX11 antibodies (two polyclonal and two monoclonal) were tested on 21 positive staging bone marrow (BM) biopsies from cyclin D1/SOX11-positive MCL patients (17 fixed in B5, 4 in 10% buffered formalin) and on 9 positive BM biopsies from leukemic non-nodal MCL patients. The results were compared for specificity, sensitivity, staining strength and degree of an additional staining on myeloid precursors, also evaluating possible impact of the different fixatives used. Non-mantle cell lymphomas were also tested to address specificity. All reagents showed high sensitivity but the monoclonal code CMC38221001 provided the highest specificity and the lowest degree of non-lymphoid staining on myeloid cells. Formalin fixation generally improved the performance of most antibodies when compared to B5 fixation.

Pleomorphic mantle cell lymphoma (PMCL) can closely mimic diffuse large B-cell lymphoma (DLBCL) morphologically, and expression of CD5 and cyclin D1 is helpful for differential diagnosis. To date, no cases of CD5/cyclin D1 double-negative PMCL have been reported. Four cases of B-cell lymphoma with an immunophenotype of CD5(-) cyclin D1(-) SOX11(+) and morphologic features compatible with DLBCL were included. Two were previously identified, and the other 2 were screened from 500 cases of B-cell lymphoma. We analyzed their clinicopathologic, immunophenotypic, genetic, and gene expression features. Cases of cyclin D1-positive PMCL, cyclin D1-negative PMCL, germinal center B-cell (GCB) DLBCL, and activated B cell (ABC) DLBCL were also studied for comparison. Similar to other PMCL cases, these 4 patients were mainly elderly male individuals with an aggressive clinical course. None of these tumors had detectable translocations involving CCND1, CCND2, CCND3, CCNE1, CCNE2, MYC, BCL2, or BCL6. The genome-wide copy number profile of these 4 cases was similar to that of cyclin D1-negative PMCL. None of these tumors had high expression of cyclin D1, cyclin D2, or cyclin D3. Similar to cyclin D1-negative PMCL, these cases had higher expression of cyclin E1 and cyclin E2 compared with cyclin D1-positive PMCL. The gene expression pattern of these tumors was also similar to that of cyclin D1-negative PMCL. Here we report for the first time 4 cases of CD5/cyclin D1 double-negative PMCL. SOX11 positivity is useful to identify these rare tumors, and further genetic and gene expression analysis can be used to confirm the diagnosis.

Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma characterized by overexpression of cyclin D1 resulting from t(11;14)(q13;q32) translocation. Herein, we report 3 cases of MCL with features of plasma cell-type Castleman disease (CD). The 3 patients were all men, ranging from 51 to 74 years in age, and they all presented with systemic lymphadenopathy with anemia, hypoalbuminemia, elevated serum levels of C-reactive protein, and polyclonal hypergammaglobulinemia. Lymph node biopsy specimens of the 3 cases showed histological features of plasma cell-type CD, including atrophic germinal centers and interfollicular plasmacytosis, with no light chain restriction. However, flow cytometric analysis demonstrated an abnormal B-cell population with CD5 expression, and further analysis using cyclin D1 immunostaining highlighted a neoplastic component that was restricted to the mantle zone. These neoplastic cells were immunohistochemically positive for CD20, CD5, and SOX11, and negative for CD3, CD10, and HHV8. The Ki67 index was low. All patients were finally diagnosed with MCL. This rare type of MCL can be misdiagnosed clinically and histologically as CD. Therefore, it is important to recognize this rare type of MCL, and careful examination is required using both histological and flow cytometric analyses.

DNA methylation is an epigenetic mechanism controlling gene expression without affecting DNA sequences, and aberrant DNA methylation patterns are features of a number of diseases. Notably, epigenetic errors in cancer cells have been intensively studied over the last two decades in humans; however, little is known concerning dogs and cats. To analyze DNA methylation and gene expression changes in feline lymphoma cells, we added the DNA methylation inhibitor 5-aza-2'-deoxycytidine (5-aza) to three cell lines (3281 and FT-1 cells derived from T-cell lymphoma and MS4 cells derived from B-cell lymphoma). Adding 5-aza significantly retarded cell growth in a dose-dependent manner in all cell lines, and there were aberrant gene expression patterns. Transcription factor Sox11 expression in 3281 cells was de-repressed by 5-aza treatment, and subsequent promoter DNA demethylation was analyzed by bisulfite sequencing. Cell cycle analysis suggested that inhibition of cell growth was due to DNA replication arrest, and this supported the result of increased expression of p27kip1 gene which disturbed cells of 3281 and FT-1 entering the S phase. In this study, 5-aza suppressed the growth of feline lymphoma cells, but further experiments with normal lymph cells are necessary to confirm specificity of this drug treatment and to expand it for clinical use.

Mesenchymal stem cells (MSCs) are promising cells to treat cartilage defects due to their chondrogenic differentiation potential. However, an inflammatory environment during differentiation, such as the presence of the cytokine TNFα, inhibits chondrogenesis and limits the clinical use of MSCs. On the other hand, it has been reported that exposure to TNFα during in vitro expansion can increase proliferation, migration, and the osteogenic capacity of MSCs and therefore can be beneficial for tissue regeneration. This indicates that the role of TNFα on MSCs may be dependent on the differentiation stage. To improve the chondrogenic capacity of MSCs in the presence of an inflamed environment, we aimed to determine the effect of TNFα on the chondrogenic differentiation capacity of MSCs. Here, we report that TNFα exposure during MSC expansion increased the chondrogenic differentiation capacity regardless of the presence of TNFα during chondrogenesis and that this effect of TNFα during expansion was reversed upon TNFα withdrawal. Interestingly, pre-treatment with another pro-inflammatory cytokine, IL-1β, did not increase the chondrogenic capacity of MSCs indicating that the pro-chondrogenic effect is specific for TNFα. Finally, we show that TNFα pre-treatment increased the levels of SOX11 and active β-catenin suggesting that these intracellular effectors may be useful targets to improve MSC-based cartilage repair. Overall, these results suggest that TNFα pre-treatment, by modulating SOX11 levels and WNT/β-catenin signaling, could be used as a strategy to improve MSC-based cartilage repair.

Keywords: SOXC transcription factors; cartilage; chondrogenesis; mesenchymal stem cells; regenerative medicine; tissue engineering; tumor necrosis factor-alpha.

BACKGROUND

Composite mantle cell lymphoma (MCL) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is rare, as less than 20 cases have been reported so far. However, this entity may be under-diagnosed because the two lymphomas are very similar in morphology and immunophenotype. Previous cases were mostly diagnosed with immunohistochemistry, but flow cytometry may play an important role in the detection of two tumors in the same specimen, thus achieving an accurate diagnosis. By definition, a composite lymphoma is two demarcated lymphomas occurring at the same anatomic site. Therefore, immunohistochemistry is still needed to identify the topographic relation of these two tumors. Our reported case illustrates the pitfalls in the diagnostic process and we recommend two standard panels with new markers for an accurate diagnosis of this composite lymphoma.

METHODS

FACSCanto II is used with antibodies, including CD5, CD10, CD19, CD20, CD22, CD23, CD43, CD79b, CD200, kappa, and lambda. Immunohistochemical stains include PAX-5/CD5 dual stain, Cyclin D1, SOX11, and LEF-1.

RESULTS

CLL/SLL is positive for CD5, CD19, CD23, CD43, and CD200, with dim expression of CD20, CD22, CD79b, and kappa. MCL is positive for CD5, CD19, CD20, CD22, CD79b, kappa, and negative for CD23, CD43, and CD200. Immunohistochemical stains show that PAX-5/CD5 stains the entire tumor population. Cyclin D1 and SOX11 only stain the central portion that represents MCL and LEF-1 stains the periphery that represents CLL/SLL.

CONCLUSIONS

We recommend the use of the above panels for flow cytometry and immunohistochemistry, respectively. LEF-1 is specific for CLL/SLL; and CD200 is helpful to distinguish CLL/SLL from MCL. © 2017 International Clinical Cytometry Society.

The development of cervical cancer (CC) is a multi‑gene, multi‑step carcinogenic process that involves complex genetic and epigenetic mechanisms. SRY‑related HMG‑box gene 11 (SOX11) is a member of the SOX family of transcription factors with an emerging crucial role in the development of various tumor types. To elucidate the function of SOX11 in cervical carcinogenesis, the expression level of SOX11 during the development of human CC was analyzed by immunohistochemistry and western blot analysis. Additionally, the methylation status of the SOX11 was examined using bisulfite sequencing and methylation‑specific polymerase chain reaction. The SOX11 expression and promoter methylation in human CC cell lines were also determined. The effect of SOX11 expression restoration after 5‑aza‑2'‑deoxycytidine (5‑Aza‑dC) treatment on the CC cell proliferation ability was evaluated in CC cell lines. SOX11 was highly expressed in normal cervix (NC) and precancerous low‑grade squamous intraepithelial lesions, but weakly expressed or virtually absent in precancerous high‑grade squamous intraepithelial lesions and CC, which is consistent with the result of the western blot analysis. Hypermethylation of the SOX11 promoter was detected in CC, which was significantly higher than that in NC samples at each CpG site. The expression level of SOX11 in the CC cell lines was downregulated compared with the positive control, Tera‑1human teratoma cell line. Upon 5‑Aza‑dC treatment, SOX11 expression was significantly upregulated in the CC cell lines at the mRNA and protein levels, and cell proliferation was inhibited. The results indicated that the downregulation of SOX11 in CC is due to the hypermethylation of the SOX11 promoter region. Thus, SOX11 methylation may have a role in the growth of CC cells and cervical carcinogenesis.

EED (embryonic ectoderm development) is a core component of the Polycomb repressive complex 2 (PRC2) which catalyzes the methylation of histone H3 lysine 27 (H3K27) during the process of self-renewal, proliferation, and differentiation of embryonic stem cells. However, its function in the mammalian nervous system remains unexplored. Here, we report that loss of EED in the brain leads to postnatal lethality, impaired neuronal differentiation, and malformation of the dentate gyrus. Overexpression of Sox11, a downstream target of EED through interaction with H3K27me1, restores the neuronal differentiation capacity of EED-ablated neural stem/progenitor cells (NSPCs). Interestingly, downregulation of Cdkn2a, another downstream target of EED which is regulated in an H3K27me3-dependent manner, reverses the proliferation defect of EED-ablated NSPCs. Taken together, these findings established a critical role of EED in the development of hippocampal dentate gyrus, which might shed new light on the molecular mechanism of intellectual disability in patients with EED mutations.

Neurons in the central nervous system (CNS) lose their intrinsic ability and fail to regenerate, but the underlying mechanisms are largely unknown. Polycomb group (PcG) proteins, which include PRC1 and PRC2 complexes function as gene repressors and are involved in many biological processes. Here we report that PRC1 components (polycomb chromobox (CBX) 2, 7, and 8) are novel regulators of axon growth and regeneration. Especially, knockdown of CBX7 in either embryonic cortical neurons or adult dorsal root ganglion (DRG) neurons enhances their axon growth ability. Two important transcription factors GATA4 and SOX11 are functional downstream targets of CBX7 in controlling axon regeneration. Moreover, knockdown of GATA4 or SOX11 in cultured DRG neurons inhibits axon regeneration response from CBX7 downregulation in DRG neurons. These findings suggest that targeting CBX signaling pathway may be a novel approach for promoting the intrinsic regenerative capacity of damaged CNS neurons.

The SoxC transcription factors (Sox4, Sox11, and Sox12) play important roles in the development of the vertebrate eye and retina. However, their expression and function during retinal and optic nerve regeneration remain elusive. In this study, we investigated the expression and possible functions of the SoxC genes after retinal and optic nerve injury in adult zebrafish. We found that among the five SoxC members, Sox11b was strongly induced in BrdU-positive cells in the inner nuclear layer (INL) after retinal injury, and morpholino-mediated Sox11b-knockdown significantly reduced the number of proliferating cells in the INL at 4 days post-injury. After optic nerve lesion, both Sox11a and Sox11b were strongly expressed in retinal ganglion cells (RGCs), and knockdown of both Sox11a and Sox11b inhibited RGC axon regrowth in retinal explants. Our study thus uncovered a novel expression pattern of SoxC family genes after retinal and optic nerve injury, and suggests that they have important functions during retinal and optic nerve regeneration.

SOX11, belonging to the family of genes SOXC, is a transcript factor involved in the embryonic neurogenesis and tissue remodeling, also participating in the control of cell proliferation. Its role in lymphomagenesis still remains unknown. Recent studies have shown aberrant SOX11 nuclear protein expression as well as mRNA levels in patients with mantle cell lymphoma (MCL). Although the majority of these lymphomas have an aggressive clinical course, there is a subgroup of patients with an indolent clinical evolution, suggesting a greater heterogeneity of this disease. Currently, there are contradictions regarding the association of SOX11 gene expression and outcome in MCL, while some authors have related the lack of SOX11 expression with good prognosis, others find it associated with an adverse clinical course. This difference in the gene expression could be associated to epigenetic mechanisms such as modifications at the histone level and DNA methylation that would allow the aberrant expression of this gene in some lymphoid neoplasias, including LCM. More knowledge of gene SOX11 in LCM will lead to a greater understanding of those mechanisms involved in the pathogenesis and progression of this lymphoma, also the involvement of SOX11 in these processes.

Mantle cell lymphoma (MCL) is a mature B-cell neoplasm with a heterogeneous clinical and biological behavior. SOX11 oncogenic expression contributes to the aggressiveness of these tumors by different mechanisms including tumor and stromal cell interactions. However, the precise composition of the immune cell microenvironment of MCL, its possible relationship to SOX11 expression, and how it may contribute to tumor behavior is not well known. Here, we performed an integrative transcriptome analysis of 730 immune-related genes combined with the immune cell phenotype analysis by immunohistochemistry in SOX11+ and SOX11- primary nodal MCL cases and non-neoplastic reactive lymph nodes (RLN). SOX11+ MCL had a significant lower T-cell intratumoral infiltration compared to negative cases. A reduced expression of MHCI/II-like and T-cell costimulation and signaling activation related transcripts was significantly associated with poor clinical outcome. Moreover, we identified CD70 as a SOX11 direct target gene, whose overexpression was induced in SOX11+ but not SOX11- tumor cells by CD40L in vitro. CD70 was overexpressed in primary SOX11+ MCL and it was associated with an immune unbalance of the tumor microenvironment characterized by increased number of effector Treg cell infiltration, higher proliferation, and aggressive clinical course. CD27 was expressed with moderate to strong intensity in 76% of cases. Overall, our results suggest that SOX11 expression in MCL is associated with an immunosuppressive microenvironment characterized by CD70 overexpression in tumor cells, increased Treg cell infiltration and downmodulation of antigen-processing and -presentation and T-cell activation that could promote MCL progression and represent a potential target for tailored therapies.

Purpose of review: This review summarizes the unique presentation and management of the leukemic variant of mantle cell lymphoma (LV-MCL, also referred to as non-nodal MCL) and highlights the biologic and clinical differentiation from classical mantle cell lymphoma (cMCL) in biomarker expression, clinical features, prognosis, disease course, and treatment.

Recent findings: Several studies have evaluated the gene expression profile of mantle cell lymphoma, differentiating LV-MCL from cMCL. The typical immunophenotypic profile is CD5-positive, SOX 11-negative, CD23-low, CD200-low, and cyclin D1 overexpressed. LV-MCL commonly has mutated immunoglobulin heavy chain variable region genes. Data on treatment of LV-MCL is limited to retrospective analyses; the ideal treatment for these patients is unknown although many have a clinically indolent, asymptomatic presentation and often may be observed for an extended period without active treatment. LV-MCL is a clinically and biologically distinct entity. Clinically, it must be distinguished from chronic lymphocytic leukemia and cMCL. Future prospective, randomized clinical trials are required to optimize management, define the initial treatment, and appropriately sequence treatment modalities.

Keywords: Indolent mantle cell lymphoma; Leukemic variant mantle cell lymphoma; Non-nodal mantle cell lymphoma; Sox11 expression; TP53 mutation.

Mantle cell lymphoma (MCL) is considered one of the most aggressive lymphoid tumors. However, it sometimes displays indolent behavior in patients and might not necessitate treatment at diagnosis; this has been described as "smoldering MCL" (SMCL). There are significant differences in the diagnosis, prognosis, molecular mechanisms and treatments of indolent MCL and classical MCL. In this review, we discuss the progress in understanding the molecular mechanism of indolent MCL to provide insights into the genomic nature of this entity. Reported findings of molecular features of indolent MCL include a low Ki-67 index, CD200 positivity, a low frequency of mutations in TP53, a lack of SOX11, normal arrangement and expression of MYC, IGHV mutations, differences from classical MCL by L-MCL16 assays and MCL35 assays, an unmutated P16 status, few defects in ATM, no NOTCH1/2 mutation, Amp 11q gene mutation, no chr9 deletion, microRNA upregulation/downregulation, and low expression of several genes that have been valued in recent years (SPEN, SMARCA4, RANBP2, KMT2C, NSD2, CARD11, FBXW7, BIRC3, KMT2D, CELSR3, TRAF2, MAP3K14, HNRNPH1, Del 9p and/or Del 9q, SP140 and PCDH10). Based on the above molecular characteristics, we may distinguish indolent MCL from classical MCL. If so, indolent MCL will not be overtreated, whereas the treatment of classical MCL will not be delayed.

Keywords: Indolent; Molecular features; Smoldering mantle cell lymphoma.

Background: Non-small cell lung cancer (NSCLC) is one of the most prevalent cancers. As reported, long non-coding RNAs (lncRNAs) induce various biological behaviors in cancers. LncRNA PCGEM1 prostate-specific transcript (PCGEM1) is reported to exert carcinogenic effect on certain cancers. Our research aimed to explore the role of PCGEM1 in NSCLC.

Methods: We enrolled forty NSCLC patients to explore PCGEM1 expression in clinical NSCLC tissues. Colony formation assay, CCK-8, Transwell assay were conducted to reveal cell proliferation, viability, migration and invasion. Luciferase reporter assay, RNA pull down, and RIP assay were performed to investigate the downstream axis of PCGEM1.

Results: PCGEM1 was significantly upregulated in NSCLC cells and tissues. Subsequently, in vitro loss-of-function experiments illustrated the carcinogenic role of PCGEM1 in NSCLC through promoting viability, proliferation, migration, and invasion. MiR-590-3p was confirmed to be a downstream gene of PCGEM1. Furthermore, SRY-box transcription factor 11 (SOX11) was verified to be a target of miR-590-3p. Additionally, rescue experiments indicated that miR-590-3p inhibitor or pcDNA3.1/SOX11 rescued the impacts of downregulated PCGEM1 on NSCLC cell proliferation, viability, migration and invasion.

Conclusions: LncRNA PCGEM1 aggravated proliferative and migrative abilities in NSCLC via the miR-590-3p/SOX11 axis.

Keywords: Non-small cell lung cancer; PCGEM1; SOX11; miR-590-3p.

Background: Coffin-Siris syndrome is a rare genetic disease with heterozygous variants in the ARID1A, ARID1B, ARID2, DPF2, SMARCA4, SMARCB1, SMARCE1 or SOX11 genes. It may manifest with somatic anomalies, deafness, urogenital malformations, recurrent infections, mental retardation, speech deficit, agenesis of the corpus callosum, convulsions, hypotonia, developmental delay, and scoliosis.

Case report: A 14-year-old boy with Coffin-Siris syndrome due to variants in the ARID1A gene was referred to the clinic. His rehabilitation over a 9-year period was described. The problem of assessment and the approach to rehabilitation was discussed, enabling a progressive remodelling of the cognitive-behavioural disorders that most hindered the possibility of his acquiring new skills and achieving social and family integration.

Clinical rehabilitation: A protracted, customised, multiprofessional rehabilitation approach, centred on realistic functional objectives, implemented with the direct involvement of the family and school, was the only way to achieve the maximum independence and social and family integration permitted by his residual disability.

Keywords: ARID1A; Coffin-Siris syndrome; behavioural rehabilitation; cognitive rehabilitation; rare genetic disease.

A 68-year-old male presents with generalized lymphadenopathy and fever of short duration. Axillary lymph node excision was performed and was sent for histopathological evaluation. Microscopic evaluation of the submitted lymph node revealed diffuse proliferation of intermediate-sized atypical lymphoid cells with round nuclei, irregular membranes, finely dispersed chromatin, and inconspicuous nucleoli. Mitotic figures were frequently seen. Immunohistochemical evaluation revealed diffuse expression of CD20, CD5, CD10, B-cell lymphoma 2 (Bcl2), and B-cell lymphoma 6 (Bcl6). Atypical lymphoid cells were negative for cyclin D1; however, showed diffuse and strong nuclear expression of SOX11. MIB1 proliferation index was high (Ki67: 90%-95%). Based on morphological features and immunohistochemical findings a diagnosis of "cyclin D1 negative aggressive blastoid variant of mantle cell lymphoma (MCL)" was offered. The classic morphology of MCL is seen in 90% of cases, while the remaining (∼10%) are considered as variants. A blastoid variant is an aggressive subtype that can lack expression of CD5 as well as cyclin D1, but instead expresses CD10, Bcl6, and CD23. SOX11 expression is seen in 90% cases of MCL and in almost 100% cases of cyclin D1 negative MCL. The current case highlights the unusual morphologic and aggressive variant of MCL and a significant role of SOX11 in its diagnosis.

Keywords: SOX11; blastoid; cyclin D1; lymphoma; mantle.

Interconnectivity between neocortical areas is critical for sensory integration and sensorimotor transformations^1-6. These functions are mediated by heterogeneous inter-areal cortical projection neurons (ICPN), which send axon branches across cortical areas as well as to subcortical targets^7-9. Although ICPN are anatomically diverse^10-14, they are molecularly homogeneous¹⁵, and how the diversity of their anatomical and functional features emerge during development remains largely unknown. Here we address this question by linking the connectome and transcriptome in developing single ICPN of the mouse neocortex using a combination of multiplexed analysis of projections by sequencing^16,17 (MAPseq, to identify single-neuron axonal projections) and single-cell RNA sequencing (to identify corresponding gene expression). Focusing on neurons of the primary somatosensory cortex (S1), we reveal a protracted unfolding of the molecular and functional differentiation of motor cortex-projecting ([Formula: see text]) ICPN compared with secondary somatosensory cortex-projecting ([Formula: see text]) ICPN. We identify SOX11 as a temporally differentially expressed transcription factor in [Formula: see text] versus [Formula: see text] ICPN. Postnatal manipulation of SOX11 expression in S1 impaired sensorimotor connectivity and disrupted selective exploratory behaviours in mice. Together, our results reveal that within a single cortical area, different subtypes of ICPN have distinct postnatal paces of molecular differentiation, which are subsequently reflected in distinct circuit connectivities and functions. Dynamic differences in the expression levels of a largely generic set of genes, rather than fundamental differences in the identity of developmental genetic programs, may thus account for the emergence of intra-type diversity in cortical neurons.

Mantle cell lymphoma (MCL) is a mature B-cell neoplasm characterized by t(11;14)(q13;q32) and cyclin D1 overexpression in >95% of cases. Classic MCL cases are composed of a monotonous population of small to medium-sized lymphocytes with irregular nuclear contours that are positive for cyclin D1 and SOX11, and negative for CD23 and CD200. By contrast, occasional MCL cases express CD23 and CD200 but lack of SOX11, and morphologically and immunophenotypically resemble chronic lymphocytic leukemia (CLL), termed as CLL-like MCL in this study. These neoplasms pose a diagnostic challenge and easy to be diagnosed as CLL in daily practice. We studied 14 cases of CLL-like MCL to define their clinicopathologic features and compared them with 33 traditional CLL cases. There were 8 men and 6 women with a median age of 62 years (range, 44-80). Compared with CLL, patients with CLL-like MCL have lower levels of peripheral blood and bone marrow involvement, and more frequently had mutated IGHV. Immunophenotypically, CLL-like MCL often showed moderate to bright expression of B-cell antigens and surface immunoglobulin light chain, dim and partial expression of CD23 and CD200, infrequent CD43 positivity, and lack of LEF1. The overall survival of patients with CLL-like MCL was similar to that of CLL patients. In conclusion, CD23+, CD200+, and SOX11-negative MCL closely resemble CLL, both clinically and pathologically, including a similar indolent clinical course. They may pose a diagnostic challenge. However, patients with CLL-like MCL also have distinctive immunophenotypic features that are useful to distinguish these neoplasms from CLL.

Keywords: Mantle cell lymphoma; chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL); flow cytometry; immunophenotypic variant.

Conventionally, mantle cell lymphoma (MCL) is an aggressive CD5-positive B-cell malignancy with poor prognosis and limited survival. However, a small subset of patients presents with indolent disease and can be managed on a 'watch and wait' approach. CD5-negative MCL has recently been recognized as a more favorable variant of MCL, but its clinical and biological implications remain ill-defined. We performed the most extensive review to-date of all reported cases of CD5-negative MCL and included unpublished cases diagnosed at our institutions to further characterize this disease subset. Based on our analysis of 356 cases of CD5-negative MCL, we conclude that median overall survival exceeds 14 years and is independent of favorable prognostic markers such as leukemic non-nodal disease, absence of SOX11, and low Ki-67.

Keywords: Lymphoma and Hodgkin disease; lymphocytes; prognostication.

We characterised patients with mantle cell lymphoma (MCL) with poor prognosis based on differences in immune infiltration. Different expressions of the tumour cell markers Cyclin D1 and sex-determining region Y-box transcription factor 11 (SOX11), and the immune markers cluster of differentiation 3 (CD3), CD4, CD8, CD25, forkhead box protein P3 (FoxP3), T-box transcription factor TBX21 (T-bet), programmed cell death protein 1 (PD-1), programmed-death ligand 1 (PD-L1) and CD163 were investigated for all-cause mortality in 282 patients with MCL and time-to-progression (TTP) in 106 clinical trial patients. With increasing age, a significantly lower infiltration of CD3⁺ T lymphocytes was seen. T-cell infiltration was independent of cellular tumour antigen p53 (p53) expression, Ki-67, morphology and frequency of tumour cells. The all-cause mortality was higher in patients with PD-L1-expression above cut-off [hazard ratio (HR) 1·97, 95% confidence interval (CI) 1·18-3·25, adjusted for sex and MCL International Prognostic Index (MIPI)] and a higher frequency of CD163⁺ cells (continuously, HR 1·51, 95% CI 1·03-2·23, adjusting for age, sex, morphology, Ki-67 and p53). In patients treated within the Nordic Lymphoma Group MCL2/3 trials, TTP was shorter in patients with a higher frequency of FoxP3⁺ cells (HR 3·22, 95% CI 1·40-7·43) and CD163⁺ cells (HR 6·09, 95% CI 1·84-20·21), independent of sex and MIPI. When combined a higher frequency of CD163⁺ macrophages and PD-L1⁺ cells or high CD163⁺ macrophages and FoxP3⁺ regulatory T cells indicated worse outcome independent of established risk factors. The T-cell infiltrate was in turn independent of molecular characteristics of the malignant cells and decreased with age.

Keywords: CD163; FoxP3; PD-1; PD-L1; mantle cell lymphoma; microenvironment.

Brian metastasis, which is diagnosed in 30% of triple-negative breast cancer (TNBC) patients with metastasis, causes poor survival outcomes. Growing evidence has characterized miRNAs involving in breast cancer brain metastasis; however, currently, there is a lack of prognostic plasma-based indicator for brain metastasis. In this study, high level of miR-211 can act as brain metastatic prognostic marker in vivo. High miR-211 drives early and specific brain colonization through enhancing trans-blood-brain barrier (BBB) migration, BBB adherence, and stemness properties of tumor cells and causes poor survival in vivo. SOX11 and NGN2 are the downstream targets of miR-211 and negatively regulate miR-211-mediated TNBC brain metastasis in vitro and in vivo. Most importantly, high miR-211 is correlated with poor survival and brain metastasis in TNBC patients. Our findings suggest that miR-211 may be used as an indicator for TNBC brain metastasis.

Mantle cell lymphoma has been recognized as a distinct entity from the other non-Hodgkin lymphomas in middle 1990's. It carries a worst prognosis among all mature B-cell malignancies. Cyclin D1 and recently SOX11 are the hallmarks for this disease. Even if it is highly responsive to induction treatment, it remains incurable, since it inevitably relapses. Highly aggressive approaches with stem cell transplantation can shift the survival curve for a bit, but even so the overall survival is not significantly improved in most of the cases. Small portion of patients with this heterogeneous disease have an indolent course with long-term survival. Conventional immunochemotherapy has reached its maximal possibilities, so novel target agents are absolutely warranted. The large number of ongoing early phase trials demonstrated promising results, especially emphasizing agents that target B-cell receptor. They are mostly investigated in relapsed/refractory disease, while front-line approaches with those agents need to be explored in future times.