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T- lymphoblastic leukemia / lymphoma (T-LL) is an aggressive malignancy of immature T-cells with poor overall survival (OS) and in need of new therapies. LIM-domain only 2 (LMO2) is a critical regulator of hematopoietic cell development that can be overexpressed in T-LL due to chromosomal abnormalities. Deregulated LMO2 expression contributes to T-LL development by inducing block of T-cell differentiation and continuous thymocyte self-renewal. However, LMO2 expression and its biologic significance in T-LL remain largely unknown. We analyzed LMO2 expression in 100 initial and follow-up biopsies of T-LL from 67 patients, including 31 (46%) early precursor T-cell (ETP)-ALL, 26 (39%) cortical and 10 (15%) medullary type. LMO2 expression was present in 50 (74.6%) initial biopsies with an average of 87% positive tumor cells (range 30% - 100%). LMO2 expression in ETP, medullary and cortical T-LLs was not statistically different. In patients with biopsies after initial therapy, LMO2 expression was stable. LMO2 expression was associated with longer OS (p=0.048) regardless of T-lymphoblast stage or other clinicopathologic features. These findings indicate that LMO2 is a promising new prognostic marker that could predict patients’ outcomes and potentially be targeted for novel chemotherapy, i.e. PARP1/2 inhibitors, which have been shown to enhance chemotherapy sensitivity in LMO2 expressing diffuse large B cell lymphoma (DLBCL) tumors by decreasing DNA repair efficiency.

Objective Von Hippel-Lindau (VHL) syndrome is a rare and complex disease. We described in 1996 a three generation VHL 2A kindred with 11 mutation carriers. We aim to share our experience regarding the long-term follow-up of this family and the management of all our other VHL patients focusing on frequently encountered neuroendocrine tumors: pheochromocytoma/paraganglioma and pancreatic neuroendocrine neoplasms (PNEN). Methods All VHL patients in follow-up at our tertiary center from 1980 to 2019 were identified. Clinical, laboratory, imaging and therapeutic characteristics were retrospectively analyzed. Results We identified 32 VHL patients in 16 different families, 7/16 were classified as VHL 2 subtype. In the previously described family, the 4 initially asymptomatic carriers developed a neuroendocrine tumor; 7 new children were born, 3 of them being mutation carriers; 2 patients died, one due to metastatic PNEN-related liver failure. Pheochromocytoma was frequent (22/32), bilateral (13/22;59%), often diagnosed in early childhood when active screening was timely performed, associated with paraganglioma in 5/22, rarely malignant (1/22) and recurred after surgery in some cases after more than 20 years. PNEN occurred in 8/32 patients (25%), and was metastatic in three. Surgery and palliative therapy allowed relatively satisfactory outcomes. Severe disabling morbidities due to central-nervous system and ophthalmologic hemangiomas, and other rare tumors as chondrosarcoma in 2 patients and polycythemia in 1 patient were observed. Conclusions Multidisciplinary approach and long-term follow-up is mandatory in VHL patients to manage the multiple debilitating morbidities and delay mortality in these complex patients.

Context Mosunetuzumab (Mosun), a full-length, humanized, IgG1 CD20xCD3 bispecific antibody, showed promising efficacy/safety for R/R B-NHL (NCT02500407; Assouline, et al. ASH 2020). Mosun combined with the anti-CD79b antibody-drug conjugate Pola showed synergistic anti-lymphoma activity in a mouse xenograft model, supporting the Phase Ib/II, open-label, multicenter trial of Mosun-Pola for R/R B-NHL (GO40516, NCT03671018). Objective To present early clinical data from the Phase Ib cohort of GO40516. Methods Patients with R/R follicular lymphoma (FL, grade 1–3a) or aggressive NHL (aNHL), including de novo diffuse large B-cell lymphoma (DLBCL), transformed FL (trFL), and grade 3b FL (FL3b), received Cycle (C)1 step-up doses of Mosun on Day (D)1 (1 mg) and D8 (2 mg), and target dose on C1D15, continuing from C2D1. Mosun was given every 21 days for eight cycles, continuing for ≤17 cycles. Pola (1.8 mg/kg) was administered with Mosun on D1 of six cycles. Results As of November 17, 2020, 22 patients received Mosun-Pola (Mosun target doses: 9 mg, n=7; 20 mg, n=3; 40 mg, n=6; 60 mg [D1 dose 30 mg from C3 onward], n=6). Patients had DLBCL (n=12), FL (n=3), FL3b (n=3), and trFL (n=4). Median age: 70 (38–81) years; median 3 (1–10) prior lines of therapy; prior chimeric antigen receptor T-cell (CAR-T) therapy (n=7; 32%). Median follow-up duration: 9.6 (0.7–23.7) months. Most frequent treatment-related adverse events (AEs): neutropenia (45.4%), fatigue, nausea, and diarrhea (all 36.4%). Cytokine release syndrome was observed in two patients (9.1%; both grade 1 [Lee, et al. Biol Blood Marrow Transplant 2019]). One dose-limiting toxicity (grade 3 new-onset atrial fibrillation) was observed in the 40 mg cohort; maximum tolerated dose not exceeded. Most common grade ≥3 AE: neutropenia (n=8; 36.4%). Two (9.3%) grade 5 AEs occurred (sudden cardiac death [n=1]); respiratory failure [n=1]); neither was deemed treatment-related. Complete responses were achieved with Mosun-Pola in patients with R/R aNHL (n=9; 47.4%), prior CAR-T therapy (n=2; 28.6%) and FL (n=3; 100%). Conclusions These data indicate that Mosun-Pola has an acceptable safety profile and shows promising efficacy in patients with predominantly aggressive R/R NHL. The Phase II expansion cohort in patients with R/R DLBCL is ongoing, with no requirement for mandatory hospitalization.

SCLC is frequently associated with paraneoplastic syndromes, including dermatomyositis. Patients with malignancy-associated dermatomyositis express a specific autoantibody pattern usually positive for anti–transcription intermediary factor 1-γ (TIF1-γ), suggesting anti–TIF1-γ plays a role in development of malignancy-associated dermatomyositis. We present a case of a patient with SCLC, paraneoplastic dermatomyositis, positive anti–TIF1-γ, and a point mutation in TIF1-γ coding gene, with prominent clinical response to chemoradiation. We suggest that this point mutation is pathogenic, providing evidence for the development of paraneoplastic dermatomyositis through immune cross-reactivity.

Compartment-specific resistance to cancer therapy remains poorly understood. We utilized orthotopic xenografts of human double-hit lymphoma (DHL) to interrogate responses across involved sites. We identified resistance to multiple chemotherapies and the anti-CD52 antibody Alemtuzumab within the bone marrow (BM) that depended on extensive lymphoma involvement and impaired antibody-dependent cellular phagocytosis. This resistance was overcome by high doses of alkylating agents, including cyclophosphamide (CTX), which exhibited >80-fold in vivo synergy with Alemtuzumab. CTX induced ER stress in BM DHL cells leading to ATF4- mediated paracrine secretion of VEGF-A and massive macrophage infiltration. Macrophages from DHL-engrafted, CTX-treated mice had increased phagocytic capacity for lymphoma cells that was reversed by VEGF-A blockade and required SYK phosphorylation. A subset of these macrophages, defined by surface CD36/FcgRIV and a distinct transcriptional state, were “superphagocytic.” Together, our findings define a unique mechanism through which high-dose alkylating agents can overcome therapy-resistant niches by ER stress-induced activation of phagocytosis.

Human herpesvirus type 8, also known as Kaposi's sarcoma-associated herpesvirus (HHV-8/KSHV) has been associated with several lymphoproliferative disorders including Kaposi's sarcoma, primary effusion lymphoma (PEL), cases of multicentric Castleman's disease (MCD) including plasmablastic lymphoma associated with MCD, and germinotropic lymphoproliferative disorder. These lymphoproliferative disorders, with the exception of the latter, usually arise in HIV-positive or profoundly immunosuppressed patients. Herein, we describe an unusual large B-cell lymphoma in a 43year-old male infected with HIV who presented with multiple lymphadenopathies. The tumor cells were positive for EBV, HHV-8/KSHV, CD20 (small subset), PAX5, and IgM and negative for CD138, and IgG. This lymphoma is difficult to classify following the 2008 WHO criteria and expands the current spectrum of viral-associated lymphomas.

Leukemic, non-nodal mantle cell lymphoma (MCL) is a relatively indolent disease characterized by asymptomatic leukemic presentation, non-nodal disease distribution, and slow disease progression, particularly in comparison to that of classic nodal MCL. We studied 3 cases of leukemic, non-nodal MCL in which TP53, ATM, and/or 13q14 deletions were identified. All three patients had disease progression leading to treatment requirements in two of the patients at 5 and 18 months after initial diagnosis. The third patient also clinically progressed 25 months after initial diagnosis but was lost to follow up despite recommendation for initiation of therapy. We present these cases as potential evidence that while leukemic non-nodal MCL is typically an indolent disease compared to classically defined mantle cell lymphoma, cytogenetic heterogeneity exists and cases with TP53, ATM, and/or 13q14 deletions may have a relatively aggressive clinical course.

Tumefactive demyelination (TD) is a solitary cerebral demyelinating lesion clinically and radiologically mimicking brain tumors. It can occur in isolation or may be rarely associated with other demyelinating diseases. The underlying pathogenic mechanisms are unknown. We present the first report of TD following in-vitro fertilization (IVF) in a 36-year-old healthy woman who developed subacute right hemiparesis shortly after a scheduled IVF cycle. Evaluation revealed left hemispheric space-occupying lesion pathologically diagnosed as TD. Treatment with intravenous methylprednisolone promptly resulted in a clinical and radiological improvement maintained thereafter. This report confirms and expands the spectrum of inflammatory demyelinating conditions associated with IVF and suggests possible hormonal influence in the development of TD.

Lymphoplasmacytic lymphomas and marginal zone lymphomas of nodal, extra-nodal and splenic types account for 10% of non-Hodgkin lymphomas. They are similar at the cell differentiation level, sometimes making difficult to distinguish them from other indolent non-Hodgkin lymphomas. To better characterize their genetic basis, we performed array-based comparative genomic hybridization in 101 marginal zone lymphomas (46 MALT, 35 splenic and 20 nodal marginal zone lymphomas) and 13 lymphoplasmacytic lymphomas. Overall, 90% exhibited copy-number abnormalities. Lymphoplasmacytic lymphomas demonstrated the most complex karyotype (median=7 copy-number abnormalities), followed by MALT (4), nodal (3.5) and splenic marginal zone lymphomas (3). A comparative analysis exposed a group of copy-number abnormalities shared by several or all the entities with few disease-specific abnormalities. Gain of chromosomes 3, 12 and 18 and loss of 6q23-q24 (TNFAIP3) were identified in all entities. Losses of 13q14.3 (MIRN15A-MIRN16-1) and 17p13.3-p12 (TP53) were found in lymphoplasmacytic and splenic marginal zone lymphomas; loss of 11q21-q22 (ATM) was found in nodal, splenic marginal zone and lymphoplasmacytic lymphomas and loss of 7q32.1-q33 was found in MALT, splenic and lymphoplasmacytic lymphomas. Abnormalities affecting the nuclear factor kappa B pathway were observed in 70% of MALT and lymphoplasmacytic lymphomas and 30% of splenic and nodal marginal zone lymphomas, suggesting distinct roles of this pathway in the pathogenesis/progression of these subtypes. Elucidation of the genetic alterations contributing to the pathogenesis of these lymphomas may guide to design-specific therapeutic approaches.

Background: A recent study demonstrated that an increased number of CD68+ macrophages were correlated with primary treatment failure, shortened progression-free survival (PFS) and disease-specific survival (DSS) in patients with classical Hodgkin’s lymphoma (cHL). Patients and methods: The aim of the present study was to verify the relationship between the number of CD68+ and CD163+ macrophages with clinical outcomes in a cohort of 265 well-characterized patients with cHL treated uniformly with the standard doxorubicin, bleomycin, vinblastine and dacarbazine chemotherapy regimen. Two pairs of hematopathologists carried out independent pathological evaluations of tissue microarray slides. Results: There were no associations between clinical characteristics and the expression of CD68 or CD163. However, higher levels of CD68 and CD163 expression were correlated with the presence of Epstein‐Barr viruspositive Hodgkin tumor cells (P = 0.01 and 0.037, respectively). The expression of CD68 or CD163 was not associated with either the PFS or the DSS. Conclusion: CD68 and CD163 expression require further evaluation before their use can be recommended for prognostic stratification of patients with cHL.

Histological transformation, a pivotal event in the natural history of cancers including lymphomas, is typically associated with more aggressive clinical behavior. L3055, a B lymphoma cell line of germinal center (GC) origin, is dependent on follicular dendritic cells (FDCs) for survival and proliferation, similar to GC-B cells. However, L3055 cells become less FDC-dependent after prolonged culture, which is analogous to transformation in vivo. Comparison of two L3055 subclones (i.e., the FDC-dependent indolent clone 12 and the FDC-independent aggressive clone 33) by DNA microarray revealed that CD9 was the most differentially expressed gene (P = 0.05). L3055-12 expresses high levels of CD9 while L3055-33 does not. Reduced levels or loss of CD9 expression is also observed in other CD9-positive B lymphoma cell lines. The resultant CD9-negative cells grow faster than CD9-positive cells due to their greater resistance to apoptosis. Furthermore, CD9-negative cells are less dependent on FDCs for their survival and growth compared with CD9-positive cells. CD9 down-regulation in B lymphomas appears to be controlled epigenetically, mainly through histone modifications. These findings imply that CD9 is inversely correlated with B lymphoma progression, and CD9 inactivation may play an important role in B lymphoma transformation.

Listeria monocytogenes is a gram-positive bacterium with a predilection to infect the central nervous system, often affecting immunocompromised or elderly patients. The most common manifestations are meningitis and rhomboencephalitis. We report two cases of Listeria meningitis complicated by acute hydrocephalus several days after presentation and we further review the literature of similar cases. We conclude that acute hydrocephalus is a significant, not often recognized, complication of Listeria meningitis, usually occurring several days from onset when coverage did not include anti-Listeria antimicrobials. In high risk patients, meningitis combined with acute hydrocephalus is suggestive of LM infection. Keywords: Listeria monocytogenes meningitis, Hydrocephalus

Objective To determine the predictive value and the quality of supernatant sperm (SS) achieved by a simple laboratory technical modification after testicular sperm extraction (TESE). Design A retrospective analysis. Setting An IVF unit in a university medical center. Patient(s) Azoospermic patients undergoing TESE between January 2001 and December 2006. Intervention(s) Before the mechanical shredding, the testicular specimen in toto was placed in medium. The medium was spun and the pellet resuspended and transferred for SS detection. Then a wet preparation of the testicular tissue was shredded roughly and inspected for tissue sperm (TS) as described. Main Outcome Measure(s) Detection of SS versus TS, fertilization and pregnancy rates (PR) after intracytoplasmic sperm injection (ICSI) with SS versus TS. Result(s) The SS was detected in all specimens where TS was eventually found, independent of their testicular pathology. When the supernatant was spermatozoa-negative, no spermatozoa were detected in the tissue. For embryos derived from ICSI the fertilization rate of SS was significantly higher than TS (52% vs. 44%), whereas the PR was comparable. Conclusion(s) The SS serves as an excellent predictor of TESE outcome and as a superior source for fertilization. This modified technique enables faster decision of TESE outcome and an easier switch to donor sperm when available.

The classification of primary cutaneous large B-cell lymphoma (PCLBCL) is based on standard morphology, immunohistochemistry, and clinical presentation. There are two major subtypes in the current WHO-EORTC classification: follicle center lymphoma and diffuse large B-cell lymphoma, leg-type (DLBCL-LT). The goals of this study were to examine a series of DLBCLs to determine (1) whether the immunohistochemical paradigm of germinal center B-cell and non-germinal center B-cell types of systemic DLBCL could be applied to PCLBCL; (2) whether application of the newly described germinal center B-cell marker, human germinal center-associated lymphoma (HGAL) also discriminates between these types as a further support for germinal center B-cell origin for primary cutaneous center lymphoma; and (3) whether any of these biologic markers were of prognostic significance. To this end, 32 cases of diffuse PCLBCL (22 primary cutaneous follicular center lymphomas and 10 DLBCL-LT) were classified based on the WHO-EORTC criteria and studied for expression of CD20, BCL2, BCL6, CD10, MUM-1, and HGAL by immunohistochemistry. Results were correlated with clinical features. HGAL and BCL6 expression and germinal center B-cell phenotype were associated with primary cutaneous follicular center lymphoma. The combination of HGAL and BCL6 positivity had the highest sensitivity (88%) and specificity (100%) for predicting subtype compared to either marker alone. Both HGAL and BCL6 were associated with the germinal center B-cell phenotype. The correlation of HGAL expression with the germinal center B-cell phenotype demonstrates the role of this marker in the classification of cutaneous large B-cell lymphomas. BCL6 expression was the only immunohistochemical marker associated with overall survival. Characterizing PCLBCLs with markers of B-cell maturation stage is a useful framework for studying, classifying, and clinically stratifying these lymphomas.

We report 10 children (7 male, 3 female), 3 homozygous for c.319C>T mutation and 7 heterozygous for c.319C>T on one allele and c.625G>A variant on the other in the short-chain acyl-CoA dehydrogenase (SCAD) gene (ACADS). All were of Ashkenazi Jewish origin in which group we found a c.319C>T heterozygote frequency of 1:15 suggesting the presence of a founder mutation or selective advantage. Phenotype was variable with onset from birth to early childhood. Features included hypotonia (8/10), developmental delay (8/10), myopathy (4/10) with multicore changes in two and lipid storage in one, facial weakness (3/10), lethargy (5/10), feeding difficulties (4/10) and congenital abnormalities (3/7). One female with multiminicore myopathy had progressive external ophthalmoplegia, ptosis and cardiomyopathy with pneumonia and respiratory failure. Two brothers presented with psychosis, pyramidal signs, and multifocal white matter abnormalities on MRI brain suggesting additional genetic factors. Two other infants also had white matter changes. Elevated butyrylcarnitine (4/8), ethylmalonic aciduria (9/9), methylsuccinic aciduria (6/7), decreased butyrate oxidation in lymphoblasts (2/4) and decreased SCAD activity in fibroblasts or muscle (3/3) were shown. Expression studies of c.319C>T in mouse liver mitochondria showed it to be inactivating. c.625G>A is a common variant in ACADS that may confer disease susceptibility. Five healthy parents were heterozygous for c.319C>T and c.625G>A, suggesting reduced penetrance or broad clinical spectrum. We conclude that the c.319C>T mutation can lead to wide clinical and biochemical phenotypic variability, suggesting a complex multifactorial/polygenic condition. This should be screened for in individuals with multicore myopathy, particularly among the Ashkenazim.

Diffuse large B cell lymphoma (DLBCL) is a subtype of non-Hodgkin lymphoma (NHL), characterized by a markedly heterogeneous clinical course and response to therapy that is not appreciated with standard histopathologic and immunophenotypic evaluations. Recent studies have focused on the use of genome-scale expression profiles that provide a snap fingerprint of the tumor and identifying tumors with similar genetic alterations and clinical features. Gene expression studies have the ability to recognize distinct subgroups of patients based on similar molecular characteristics and markedly different outcomes that were independent of the International Prognostic Index (IPI). Further, DNA microarray studies also allow identification of new prognostic biomarkers in DLBCL. However, new methods for immunohistochemical analysis of tissue microarray and RNA extraction from paraffin-embedded blocks are required to overcome the major pitfall of this technology—the requirement for fresh tissue. Herein, we summarize the progress made in better prediction of prognosis of DLBCL patients as a result of gene expression profiling.

Purpose To present a case of T-cell chronic lymphocytic leukemia (T-CLL) manifesting as an intraocular lymphoma. Design Interventional case report. Methods We performed a vitreous biopsy in a 67-year-old woman who presented with blurred vision and vitreous cellular infiltration. Morphologic, immunohistochemical, flow cytometry, and molecular analysis by polymerase chain reaction of vitreous fluid, peripheral blood, bone marrow aspirate, and biopsy were performed. Results Cytofluorographic and molecular analysis of vitreous cells demonstrated a monoclonal T-cell population consistent with a T-cell intraocular lymphoma. Systemic evaluation established diagnosis of T-cell CLL. Conclusion T-CLL is a rare disease with an aggressive clinical course. We present a case of T-cell intraocular lymphoma as the initial manifestation of an otherwise asymptomatic T-CLL.

Introduction Myasthenia gravis (MG) is considered a paraneoplastic phenomenon of thymomas in 15% of patients. Co-existence of MG with extrathymic malignancies, and an increased risk of second malignancy in patients with thymoma have been reported. Data on clinical characteristics of MG patients with extrathymic malignancies and the role of concomitant diseases and their treatment are lacking. Methods The clinical records of 188 consecutive MG patients were studied retrospectively. We examined whether gender, age, generalized disease, seropositivity for acetyl-choline receptor antibodies, occurrence of thymoma, immunosuppressive therapy and occurrence of other autoimmune diseases determined an increased risk for development of extrathymic malignancy. Results This group followed the typical epidemiological characteristics of MG. Thirty-three patients (17.6%) had a thymoma. Twenty-nine patients (15.4%) had 30 extrathymic malignant tumors of various origins. Only four patients with extrathymic tumors had an associated thymoma. Tumors were diagnosed between 20 years prior to and 35 years after the appearance of MG. Older age of MG onset was the only risk factor identified for development of malignancy in MG. Discussion Extrathymic malignancies are common in MG patients, especially in the older age group. There are no specific clinical features of the subgroup of MG patients with cancer. Although MG is not a paraneoplastic phenomenon of extrathymic malignancy, the association between MG and malignancy may be due to a common background of immune dysregulation.

Background Central nervous system (CNS) involvement, a well-recognized complication of aggressive non-Hodgkin's lymphomas (NHL), has rarely been reported in indolent lymphomas. Large series have reported this complication in 3% of indolent NHLs, generally following histological transformation. Patients and methods We retrospectively reviewed the disease characteristics and clinical course in seven patients (six females, one male) with indolent B-cell lymphomas who developed CNS involvement during various stages of their illness. Results The median ages at diagnosis of systemic and CNS lymphoma were 60 and 63 years, respectively. Histologies were: small lymphocytic lymphoma (two), follicular lymphoma grade I (two), follicular lymphoma grade II (two) and unclear low-grade histology (one). There were diverse neurological symptoms. Two patients had parenchymal involvement, three had leptomeningial involvement and two had both. Systemic lymphoma was found in all patients, all but one having bone marrow involvement. Four patients had a transformation to high-grade histology. Six patients were treated with systemic and intra-cerebrospinal fluid chemotherapy, and two received radiotherapy as well. Five patients achieved CNS response. Survival was 1–9 years for treated patients (median 2 years). Three patients died of CNS disease. Conclusions CNS involvement is a rare and unexpected complication of indolent NHL, which should be considered in the differential diagnosis of patients presenting with new neurological signs. This condition is treatable and some patients have a long clinical course.

Higher grade histological transformation of follicular lymphoma (FL) to more aggressive diffuse large B-cell lymphomas (DLBCL) occurs in 10-60% of the cases. Review of the current knowledge of genetic and molecular alterations associated with the higher grade transformation of FCL suggests that the process that leads to clinically and phenotypically similar end-point can occur by functionally diverse genetic lesions. The most commonly identified genetic alterations associated with the FCL transformation are TP53 gene mutations, inactivation of CDKN2A and CDKN2B genes and deregulation of the C-MYC gene. These lesions affect different aspects of normal cell physiology (apoptosis, cell cycle control, and proliferation) and are potential targets for gene-specific therapies.