Detection of Circulating Tumor Cells in Patients with Small Choroidal Melanocytic Lesions.

PURPOSE: To determine the presence of circulating tumor cells (CTCs) in patients with indeterminate small choroidal melanocytic lesions (SCMLs). DESIGN: Retrospective case series. PARTICIPANTS: Forty-seven patients with choroidal melanocytic lesions 2.5 mm or less in tumor thickness and ≤ 10 mm in largest basal diameter (LBD). METHODS: Blood samples were analyzed for CTCs and the presence of monosomy-3 (M3) in CTCs. Tissue biopsy was performed in the patients who were CTC-positive (pCTC). MAIN OUTCOME MEASURES: Presence and M3 status of the CTCs with regard to the clinical characteristics and results from tissue biopsy. RESULTS: Median thickness of all (n = 47) lesions was 1.1 mm (range: 0.2-2.5 mm), and LBD was 5.6 mm (range: 2.0-10.0 mm). Circulating tumor cells were found in 25 patients (n = 25). This group was classified as pCTC and compared with the CTC-negative (nCTC) group consisting of 22 patients (n = 22). Median tumor dimensions in the pCTC versus the nCTC group were 1.6 mm (range: 0.6-2.5 mm) versus 0.5 mm (range: 0.2-2.5 mm) for thickness and 6.6 mm (range: 4.1-10.0 mm) versus 4.0 mm (range: 2.0-8.0 mm) for LBD, respectively. Both LBD and thickness were positively associated (P < 0.001) with the presence of CTC. Compared with the nCTC group, a higher percentage of the pCTC group exhibited LBD > 5 mm (36% vs. 88%), subretinal fluid (9.1% vs. 56%), orange pigment (4.5% vs. 60%), sonographic hollowness (9.1% vs. 60%), and the presence of multiple risk factors (0% vs. 68% for ≥3 factors) with P < 0.001 for all parameters. No significant difference was detected in the clinical parameters of the patients who had disomy-3 (D3) (n = 7) versus M3 (n = 17) in their CTC. The tissue biopsy confirmed the uveal melanoma (UM) in 22 of the 25 pCTC patients (88%), whereas no conclusive diagnosis could be determined in the remaining 3 cases because of insufficient or invalid material. CONCLUSIONS: We report compelling evidence for the potential of liquid biopsy as an additional tool to screen SCMLs for malignancy. These findings pave the way toward the implementation of liquid biopsy to detect small UM and monitor melanocytic lesions. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Mutational landscape of high-grade B-cell lymphoma with MYC-, BCL2 and/or BCL6 rearrangements characterized by whole-exome sequencing.

High-grade B-cell lymphoma accompanied with double/triple-hit MYC and BCL2 and/or BCL6 rearrangements (HGBLDH/ TH) poses a cytogenetically-defined provisional entity among aggressive B-cell lymphomas that is traditionally associated with unfavorable prognosis. In order to better understand the mutational and molecular landscape of HGBLDH/ TH we here performed whole-exome sequencing and deep panel next-generation sequencing of 47 clinically annotated cases. Oncogenic drivers, mutational signatures and perturbed pathways were compared with data from follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL). We find an accumulation of oncogenic mutations in NOTCH, IL6/JAK/STAT and NFκB signaling pathways and delineate the mutational relationship within the continuum between FL/DLBCL, HGBL-DH/TH and BL. Further, we provide evidence of a molecular divergence between BCL2 and BCL6 rearranged HGBL-DH. Beyond a significant congruency with the C3/EZB DLBCL cluster in BCL2 rearranged cases on an exome-wide level, we observe an enrichment of the SBS6 mutation signature in BCL6 rearranged cases. Differential gene set enrichment and subsequent network propagation analysis according to cytogenetically defined subgroups revealed an impairment of TP53 and MYC pathway signaling in BCL2 rearranged cases, whereas BCL6 rearranged cases lacked this enrichment, but instead showed impairment of E2F targets. Intriguingly, HGBL-TH displayed intermediate mutational features considering all three aspects. This study elucidates a recurrent pattern of mutational events driving FL into MYC-driven BCL2-rearranged HGBL, unveiling the mutational pathogenesis of this provisional entity. Through this refinement of the molecular taxonomy for aggressive, germinal center-derived B-cell lymphomas, this calls into question the current World Health Organization classification system, especially regarding the status of MYC/BCL6- rearranged HGBL.

Exhaustion of tumour-infiltrating T-cell receptor repertoire diversity is an age-dependent indicator of immunological fitness independently predictive of clinical outcome in Burkitt lymphoma.

Burkitt lymphoma (BL) is an aggressive B-cell-malignancy derived from germinal-centre B-cells. Curative therapy traditionally requires intensive immunochemotherapy. Recently, immuno-oncological approaches, modulating the T-cell tumour response, were approved for the treatment of a variety of malignancies. The architecture of the tumour-infiltrating T-cell receptor (TCR) repertoire in BL remains insufficiently characterized. We therefore performed a large-scale, next-generation sequencing study of the complimentary-determining region (CDR)-3 region of the TCRß chain repertoire in a large cohort of all epidemiological subtypes of BL (n = 82) and diffuse large B-cell lymphoma (DLBCL; n = 34). Molecular data were subsequently assessed for correlation with clinical outcome. Our investigations revealed an age-dependent immunoprofile in BL as in DLBCL. Moreover, we found several public clonotypes in numerous patients suggestive of shared tumour neoantigen selection exclusive to BL and distinct from DLBCL regardless of Epstein-Barr virus and/or human immunodeficiency virus status. Compared with baseline, longitudinal analysis unveiled significant repertoire restrictions upon relapse (P = 0·0437) while productive TCR repertoire clonality proved to be a useful indicator of both overall and progression-free-survival [OS: P = 0·0001; hazard ratio (HR): 6·220; confidence interval (CI): 2·263-11·78; PFS: P = 0·0025; HR: 3·086; CI: 1·555-7·030]. Multivariate analysis confirmed its independence from established prognosticators, including age at diagnosis and comorbidities. Our findings establish the clinical relevance of the architecture and clonality of the TCR repertoire and its age-determined dynamics in BL.

Impact of treatment variability and clinicopathological characteristics on survival in patients with Epstein-Barr-Virus positive diffuse large B cell lymphoma.

Patients with EBV-positive diffuse large B cell lymphoma not otherwise specified (EBV+ DLBCL (NOS)) recurrently present with advanced age and reduced performance status. They are therefore insufficiently represented in clinical trials and treatment is likely to differ. Here we assess clinicopathological characteristics, therapeutic variability and clinical outcome in the largest consecutively diagnosed EBV+ DLBCL (NOS) cohort published to date (n = 80; median age 70 years; range 19-90). Centralized and systematic haematopathological panel review was performed. By immunohistochemistry 60/80 patients were CD30-positive. Further, we identified nine EBV+ DLBCL (NOS) patients with associated or composite peripheral T cell lymphoma at diagnosis or relapse (preceded by clonal T cell populations within the initial DLBCL biopsy in 4/5 cases). Most patients (80%) were treated with R-CHOP-type therapy and 16 patients received none or less intensiveprotocols. Upon univariate analysis both R-CHOP-type therapy (OS: P < 0.0001; PFS: P = 0.0617) and negativity for CD30 (OS: P = 0.0002; PFS: P = 0.0002) showed a protective 66 effect, maintained upon multivariate analysis. In a propensity-score matched analysis with a cohort of non-EBV+ DLBCL (NOS) patients, balanced for all revised-international prognostic index factors, we found an EBV-association to hold no significant impact on progression-free and overall survival whilst exhibiting a trend favouring EBV-negativity (OS: P = 0.116; PFS: P = 0.269). Our findings provide insight into the clinical course of EBV+ DLBCL (NOS), highlight the ramifications of CD30-expression and underline the superior therapeutic efficacy of R-CHOP immunochemotherapy. Alternative therapies, incorporating tumour biology (e.g. CD30 directed therapies) need to be explored in EBV+ DLBCL (NOS) patients. Moreover our data advert to the close relationship between EBV+ DLBCL (NOS) and peripheral T cell lymphomas.

Monosomy-3 Alters the Expression Profile of the Glucose Transporters GLUT1-3 in Uveal Melanoma.

Monosomy-3 in uveal melanoma (UM) cells increases the risk of fatal metastases. The gene encoding the low-affinity glucose transporter GLUT2 resides on chromosome 3q26.2. Here, we analyzed the expression of the glucose transporters GLUT1, GLUT2, and GLUT3 with regard to the histological and clinical factors by performing immunohistochemistry on the primary tumors of n = 33 UM patients. UMs with monosomy-3 exhibited a 57% lower immunoreactivity for GLUT2 and a 1.8×-fold higher ratio of GLUT1 to total GLUT1-3. The combined levels of GLUT1-3 proteins were reduced in the irradiated but not the non-irradiated tumors with monosomy-3. GLUT3 expression was stronger in the irradiated samples with disomy-3 versus monosomy-3, but the ratio of the GLUT3 isoform to total GLUT1-3 did not differ with regard to the monosomy-3 status in the irradiated or non-irradiated subgroups. Systemic metastases were associated with the presence of monosomy-3 in the primary and circulating tumor cells as well as a higher GLUT1 ratio. Upregulation of the high-affinity glucose transporter GLUT1 possibly as a compensation for the low-affinity isoform GLUT2 may be enhancing the basal glucose uptake in the UM cells with monosomy-3. Prevention of hyperglycemia might, therefore, be a valuable approach to delay the lethal UM metastases.

Hodgkin lymphoma as a novel presentation of familial DICER1 syndrome.

UNLABELLED: DICER1 germline mutations are associated with an inherited cancer syndrome, most commonly presenting with pleuropulmonary blastoma (PPB), ovarian sex cord tumors, thyroid cysts/goitre, and cystic nephroma. We describe the occurrence of a Hodgkin lymphoma (HL) of the T cell phenotype in a family with DICER1 syndrome. The patient presented with PPB Type I and HL. Immunohistochemical staining of the Hodgkin and Reed-Sternberg cells revealed CD30, TGP, CD2, CD3, CD15, and IRF4 positivity and weekly positivity of PAX5. T cell receptor repertoire analysis suggested HL of T cell origin, which is in contrast to common B cell-derived HL. The mother had been diagnosed with thyroid cysts, one sister had died from a primitive neuroectodermal tumor, and a brother had died from PPB Type III. Two mutational events were revealed in all affected family members; a single bp deletion, c.5299delC, leading to a frameshift and premature stop in exon 24 and a heterozygous variant (c.4616C>T; p.Thr1539Met) located in exon 23 of the DICER1 gene. This variant is predicted to be benign by in silico analysis. CONCLUSION: Future studies looking for DICER1 mutations in HL cases of the T cell phenotype will be important to confirm its association with constitutional DICER1 syndrome. WHAT IS KNOWN: • DICER1 germline mutations are associated with an inherited cancer syndrome, most commonly pleuropulmonary blastoma, ovarian sex cord tumors, thyroid cysts/goitre, and cystic nephroma. • Hodgkin lymphoma is one of the most frequent types of malignant lymphomas and typically arises sporadically. T cell-derived Hodgkin lymphomas are exceptionally rare. What is New: • DICER1 syndrome may have an even broader phenotypic spectrum and seems to be associated with rare forms of T cell Hodgkin lymphoma.

MicroRNA profiling of low-grade and transformed nodal marginal zone lymphoma reveals a similar signature pattern distinct from diffuse large B cell lymphoma.

BACKGROUND/AIMS: As critical post-transcriptional regulators of gene expression, microRNAs are involved in several cellular processes of vital impact including cell growth and apoptosis. Many hematologic malignancies exhibit distinct microRNA signatures. MicroRNA implication in the pathogenesis of nodal marginal zone lymphoma (NMZL), however, remains widely elusive. METHODS: Comprehensive morphologic, immunophenotypic and cytogenetic studies were carried out on a cohort of NMZL (n = 30) incorporating indolent as well as transformed MZL. In addition, microRNA signatures were generated, employing a quantitative real-time polymerase chain reaction approach. These were then compared to signatures from cases of diffuse large B cell lymphoma (DLBCL) alongside reactive lymph node controls. RESULTS: While microRNA signatures of low-grade and transformed NMZL did not differ significantly, several microRNAs were differentially expressed between transformed NMZL and DLBCL, hinting at molecularly distinct mechanisms of lymphomagenesis and indicating the biological disparity of transformed NMZL from DLBCL. CONCLUSION: In the light of the unresolved issue regarding the classification of marginal zone-derived transformed B-cell neoplasms, microRNAs may be a valuable aid in discriminating NMZL from DLBCL.

Demyelination reduces brain parenchymal stiffness quantified in vivo by magnetic resonance elastography.

The detection of pathological tissue alterations by manual palpation is a simple but essential diagnostic tool, which has been applied by physicians since the beginnings of medicine. Recently, the virtual "palpation" of the brain has become feasible using magnetic resonance elastography, which quantifies biomechanical properties of the brain parenchyma by analyzing the propagation of externally elicited shear waves. However, the precise molecular and cellular patterns underlying changes of viscoelasticity measured by magnetic resonance elastography have not been investigated up to date. We assessed changes of viscoelasticity in a murine model of multiple sclerosis, inducing reversible demyelination by feeding the copper chelator cuprizone, and correlated our results with detailed histological analyses, comprising myelination, extracellular matrix alterations, immune cell infiltration and axonal damage. We show firstly that the magnitude of the complex shear modulus decreases with progressive demyelination and global extracellular matrix degradation, secondly that the loss modulus decreases faster than the dynamic modulus during the destruction of the corpus callosum, and finally that those processes are reversible after remyelination.

Lymphoepithelioma-like carcinoma and simultaneous marginal zone lymphoma of the skin: a case report.

Lymphoepithelioma-like carcinoma (LELC) of the skin is a rare malignant epithelial neoplasm, which shows histological resemblance of nasopharyngeal carcinoma (Schmincke-Regaud tumor). Similar tumors have been reported at a variety of sites, including salivary gland, tonsil, thymus, stomach, and uterus. Extracutaneous LELC shows frequently an association with Epstein-Barr virus, whereas Epstein-Barr virus in LELC of the skin has been described only once till now. LELC of the skin usually presents as a papulonodular lesion on the head or neck of patients above 50 years of age. Here, we describe a collision tumor with an LELC and a marginal zone lymphoma of the skin in a 75-year-old female patient. To our knowledge, this is the first reported case of an association between these 2 malignancies, and the possibility of a causal relationship is discussed.

Intravascular natural killer cell lymphoma mimicking mycosis fungoides: a case report and review of the literature.

Intravascular lymphoma is a rare entity. Most cases constitute a variant of extranodal diffuse large B-cell lymphoma, and only 10% of the published cases are of T-cell or histiocytic origin. Even fewer cases of intravascular natural killer (NK) cell lymphoma have been reported. To date, only the intravascular lymphoma of B-cell linage is recognized as a distinct entity by the WHO Classification. Here, we report the clinical, morphological, immunohistochemical, and molecular findings of a 72-year-old male patient with intravascular NK-cell lymphoma of the skin who initially presented with red skin efflorescences suspicious of mycosis fungoides. A skin biopsy revealed large cell infiltrates of NK/T-cell phenotype (CD3ε, CD4, CD8, CD56, and TIA-1), which were localized strictly intravascularly and which were positive for Epstein-Barr virus nucleic acid EBER (Epstein-Barr virus-encoded small RNA). Molecular studies revealed a germline configuration for the T-cell receptor consistent with the possibility of an NK-cell origin. At the beginning, the disease appeared to be limited to the skin with no sign of bone marrow involvement or leukemic dissemination. Chemotherapy was initiated; however, the patient subsequently developed meningiosis lymphomatosa with recurrent epileptic episodes and bone marrow infiltration with pancytopenia 7 months after primary admission. Finally, the patient passed away in a septic shock.

Radiation-Induced DNA Damage in Uveal Melanoma Is Influenced by Dose Delivery and Chromosome 3 Status.

Purpose: The purpose of this study was to analyze the extent of DNA breaks in primary uveal melanoma (UM) with regard to radiotherapy dose delivery (single-dose versus fractionated) and monosomy 3 status. Methods: A total of 54 patients with UM were included. Stereotactic radiotherapy (SRT) was performed in 23 patients, with 8 undergoing single-dose SRT (sdSRT) treatment and 15 receiving fractionated SRT (fSRT). DNA breaks in the enucleated or endoresected tumors were visualized by a TUNEL assay and quantified by measuring the TUNEL-positive area. Protein expression was analyzed by immunohistochemistry. Co-detection of chromosome 3 with proteins was performed by immuno-fluorescent in situ hybridization. Results: The amount of DNA breaks in the total irradiated group was increased by 2.7-fold (P < 0.001) compared to non-irradiated tissue. Tumors treated with fSRT were affected more severely, showing 2.1-fold more DNA damage (P = 0.007) compared to the cases after single (high) dose irradiation (sdSRT). Monosomy 3 tumors showed less DNA breaks compared to disomy 3 samples (P = 0.004). The presence of metastases after radiotherapy correlated with monosomy 3 and less DNA breaks compared to patients with non-metastatic cancer in the combined group with fSRT and sdSRT (P < 0.05). Conclusions: Fractionated irradiation led to more DNA damage than single-dose treatment in primary UM. As tumors with monosomy 3 showed less DNA breaks than those with disomy 3, this may indicate that they are less radiosensitive, which may influence the efficacy of irradiation.

Genome-wide DNA methylation-analysis of blastic plasmacytoid dendritic cell neoplasm identifies distinct molecular features.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) constitutes a rare and aggressive malignancy originating from plasmacytoid dendritic cells (pDCs) with a primarily cutaneous tropism followed by dissemination to the bone marrow and other organs. We conducted a genome-wide analysis of the tumor methylome in an extended cohort of 45 BPDCN patients supplemented by WES and RNA-seq as well as ATAC-seq on selected cases. We determined the BPDCN DNA methylation profile and observed a dramatic loss of DNA methylation during malignant transformation from early and mature DCs towards BPDCN. DNA methylation profiles further differentiate between BPDCN, AML, CMML, and T-ALL exhibiting the most striking global demethylation, mitotic stress, and merely localized DNA hypermethylation in BPDCN resulting in pronounced inactivation of tumor suppressor genes by comparison. DNA methylation-based analysis of the tumor microenvironment by MethylCIBERSORT yielded two, prognostically relevant clusters (IC1 and IC2) with specific cellular composition and mutational spectra. Further, the transcriptional subgroups of BPDCN (C1 and C2) differ by DNA methylation signatures in interleukin/inflammatory signaling genes but also by higher transcription factor activity of JAK-STAT and NFkB signaling in C2 in contrast to an EZH2 dependence in C1-BPDCN. Our integrative characterization of BPDCN offers novel molecular insights and potential diagnostic applications.

MicroRNA expression and JAK2 allele burden in bone marrow trephine biopsies of polycythemia vera, essential thrombocythemia and early primary myelofibrosis.

BACKGROUND/AIMS: MicroRNAs (miRNAs) play an important role in cellular differentiation and cancer pathogenesis. However, their role in promoting the malignant phenotype of myeloproliferative diseases and their importance for differential diagnosis of early-stage chronic myeloproliferative diseases (CMPDs) remains widely obscure. METHODS: In this study, we systematically evaluated the differential expression of miRNAs previously described to be associated with myelopoiesis and myeloproliferative pathogenesis by quantitative RT-PCR in polycythemia vera, essential thrombocythemia, early primary myelofibrosis (PMF) and normal hematopoiesis. Our goal was to establish certain miRNAs as potential markers for CMPDs to facilitate the differentiation between these diseases and to further investigate molecular differences between the subtypes of myeloproliferative neoplasia. RESULTS: An aberrant expression of miRNAs 10a and 150 could be demonstrated for essential thrombocythemia and PMF as well as for polycythemia vera and PMF, respectively. The expression of miR-150 could further be shown to correlate with both JAK2 allele burden and peripheral blood counts. CONCLUSION: Thus, the miRNAs investigated in this study seem to be potential marker oncomiRs in the differential diagnosis of CMPDs and possibly hold potential for the elucidation of a JAK2-independent mechanism of pathogenesis.

Molecularly Stratified Treatment Options in Primary Refractory DLBCL/HGBL with MYC and BCL2 or BCL6 Rearrangements (HGBL, NOS with MYC/BCL6).

BACKGROUND: There is growing evidence supporting multidisciplinary molecular tumor boards (MTB) in solid tumors whereas hematologic malignancies remain underrepresented in this regard. OBJECTIVE: The present study aimed to assess the clinical relevance of MTBs in primary refractory diffuse large B-cell lymphomas/high-grade B-cell lymphomas with MYC and BCL2 rearrangements (prDLBCL/HGBL-MYC/BCL2) (n = 13) and HGBL, not otherwise specified (NOS), with MYC and BCL6 rearrangements (prHGBL, NOS-MYC/BCL6) (n = 6) based on our previously published whole-exome sequencing (WES) cohort. PATIENTS AND METHODS: For genomic analysis, the institutional MTB WES pipeline (University Cancer Center Schleswig-Holstein: UCCSH), certified for routine clinical diagnostics, was employed and supplemented by a comprehensive immunohistochemical work-up. Consecutive database research and annotation according to established evidence levels for molecularly stratified therapies was performed (NCT-DKTK/ESCAT). RESULTS: Molecularly tailored treatment options with NCT-DKTK evidence level of at least m2A were identified in each case. We classified mutations in accordance with biomarker/treatment baskets and detected a heterogeneous spectrum of targetable alterations affecting immune evasion (IE; n = 30), B-cell targets (BCT; n = 26), DNA damage repair (DDR; n = 20), tyrosine kinases (TK; n = 13), cell cycle (CC; n = 7), PI3K-MTOR-AKT pathway (PAM; n = 2), RAF-MEK-ERK cascade (RME; n = 1), and others (OTH; n = 11). CONCLUSION: Our virtual MTB approach identified potential molecularly targeted treatment options alongside targetable genomic signatures for both prDLBCL/HGBL-MYC/BCL2 and prHGBL, NOS-MYC/BCL6. These results underline the potential of MTB consultations in difficult-to-treat lymphomas early in the treatment sequence.

Primary refractory plasmablastic lymphoma: A precision oncology approach.

Introduction: Hematologic malignancies are currently underrepresented in multidisciplinary molecular-tumor-boards (MTB). This study assesses the potential of precision-oncology in primary-refractory plasmablastic-lymphoma (prPBL), a highly lethal blood cancer. Methods: We evaluated clinicopathological and molecular-genetic data of 14 clinically annotated prPBL-patients from initial diagnosis. For this proof-of-concept study, we employed our certified institutional MTB-pipeline (University-Cancer-Center-Schleswig-Holstein, UCCSH) to annotate a comprehensive dataset within the scope of a virtual MTB-setting, ultimately recommending molecularly stratified therapies. Evidence-levels for MTB-recommendations were defined in accordance with the NCT/DKTK and ESCAT criteria. Results: Median age in the cohort was 76.5 years (range 56-91), 78.6% of patients were male, 50% were HIV-positive and clinical outcome was dismal. Comprehensive genomic/transcriptomic analysis revealed potential recommendations of a molecularly stratified treatment option with evidence-levels according to NCT/DKTK of at least m2B/ESCAT of at least IIIA were detected for all 14 prPBL-cases. In addition, immunohistochemical-assessment (CD19/CD30/CD38/CD79B) revealed targeted treatment-recommendations in all 14 cases. Genetic alterations were classified by treatment-baskets proposed by Horak et al. Hereby, we identified tyrosine-kinases (TK; n=4), PI3K-MTOR-AKT-pathway (PAM; n=3), cell-cycle-alterations (CC; n=2), RAF-MEK-ERK-cascade (RME; n=2), immune-evasion (IE; n=2), B-cell-targets (BCT; n=25) and others (OTH; n=4) for targeted treatment-recommendations. The minimum requirement for consideration of a drug within the scope of the study was FDA-fast-track development. Discussion: The presented proof-of-concept study demonstrates the clinical potential of precision-oncology, even in prPBL-patients. Due to the aggressive course of the disease, there is an urgent medical-need for personalized treatment approaches, and this population should be considered for MTB inclusion at the earliest time.

Polyclonal Immunotactoid Glomerulopathy Associated with Monoclonal Gammopathy of IgM Type and Underlying Plasmacellular Disease: Successful Treatment with Rituximab Alone.

Immunotactoid glomerulopathy (ITG) occurs infrequently and is characterized by organized IgG containing deposits. It most usually manifests as a concomitant disease of a broad spectrum of oncologic entities. We here present an exceptional case of ITG without glomerular light chain restriction secondary to a IgM kappa type monoclonal gammopathy of undetermined significance. Due to nephrotic syndrome and deterioration of kidney function a rituximab monotherapy was initiated without targeting the plasmacellular augmentation, which was confirmed as the underlying process. The treatment led to a long-term improvement of proteinuria and stabilization of glomerular filtration rate. Its therapeutic effect has to be attributed to immunomodulatory capacities and targeting of podocytes rather than to be interpreted as directed against a bone marrow or glomerular clone. We conclude that rituximab therapy may be a valuable part of the therapeutic options in ITG irrespective of the underlying oncologic entity.

Case Report: GNAQ- and SF3B1 Mutations in an Aggressive Case of Relapsing Uveal Ring Melanoma.

The molecular mechanisms for uveal ring melanoma are still unclear until today. In this case report, we describe a patient with a malignant uveal melanoma with exudative retinal detachment that had been treated with plaque brachytherapy, resulting in successful tumor regression. After 1 year, a ring-shaped recurrence with extraocular extension appeared, and the eye required enucleation. Histological and molecular genetic analyses revealed an epithelioid-cell-type melanoma with complete circumferential involvement of the ciliary body and, so far, unreported GNAQ and SF3B1 mutations in ring melanoma. Therefore, this report gives new genetic background information on this ocular tumor usually leading to enucleation.

Comparative analysis of international prognostic indices in gray-zone lymphoma.

Gray-zone lymphoma (GZL) reflects an aggressive B-cell neoplasm with features intermediate between diffuse large B-cell lymphoma (DLBCL) and classical Hodgkin lymphoma (cHL). The International Prognostic Index (IPI) and its derivatives (R-IPI, NCCN-IPI, and the Hasenclever IPS) have been established for DLBCL or cHL while the most suitable scoring system for GZL remains undetermined. In an exploratory multi-centric cohort of GZL (n = 61), we performed a comparative analysis of prognostic indices with regard to model fit and mutual concordance. The calculation of the corrected Akaike's information criterion (cAIC) and Harrel's concordance index (c-index) for each scoring system identified the NCCN-IPI to harbor the most convincing prognostic capabilities regarding both overall survival (OS) and progression-free survival (PFS) compared to its enhanced derivatives. The current results affirm the clinical utility of the NCCN-IPI and suggest its preferential use in clinical practice in GZL-patients.

Integrative genomic and transcriptomic analysis in plasmablastic lymphoma identifies disruption of key regulatory pathways.

Plasmablastic lymphoma (PBL) represents a clinically heterogeneous subtype of aggressive B-cell non-Hodgkin lymphoma. Targeted-sequencing studies and a single-center whole-exome sequencing (WES) study in HIV-positive patients recently revealed several genes associated with PBL pathogenesis; however, the global mutational landscape and transcriptional profile of PBL remain elusive. To inform on disease-associated mutational drivers, mutational patterns, and perturbed pathways in HIV-positive and HIV-negative PBL, we performed WES and transcriptome sequencing (RNA-sequencing) of 33 PBL tumors. Integrative analysis of somatic mutations and gene expression profiles was performed to acquire insights into the divergent genotype-phenotype correlation in Epstein-Barr virus-positive (EBV+) and EBV- PBL. We describe a significant accumulation of mutations in the JAK signal transducer and transcription activator (OSMR, STAT3, PIM1, and SOCS1), as well as receptor tyrosine-kinase RAS (ERBB3, NRAS, PDGFRB, and NTRK) pathways. We provide further evidence of frequent perturbances of NF-κB signaling (NFKB2 and BTK). Induced pathways, identified by RNA-sequencing, closely resemble the mutational profile regarding alterations accentuated in interleukin-6/JAK/STAT signaling, NF-κB activity, and MYC signaling. Moreover, class I major histocompatibility complex-mediated antigen processing and cell cycle regulation were significantly affected by EBV status. An almost exclusive upregulation of phosphatidylinositol 3-kinase/AKT/mTOR signaling in EBV+ PBL and a significantly induced expression of NTRK3 in concert with recurrent oncogenic mutations in EBV- PBL hint at a specific therapeutically targetable mechanism in PBL subgroups. Our characterization of a mutational and transcriptomic landscape in PBL, distinct from that of diffuse large B-cell lymphoma and multiple myeloma, substantiates the pathobiological independence of PBL in the spectrum of B-cell malignancies and thereby refines the taxonomy for aggressive lymphomas.