Diffuse large B-cell lymphoma with MYC gene rearrangements: Current perspective on treatment of diffuse large B-cell lymphoma with MYC gene rearrangements; case series and review of the literature.

In the past decade, patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) were treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) therapy. Standard treatment is now changing as a result of deeper understanding of underlying biologic differences of such lymphomas. One of the most powerful predictors of an adverse outcome on R-CHOP therapy is the presence of a MYC gene rearrangement (MYC+ lymphoma). Determination of MYC gene rearrangement by FISH (fluorescent in situ hybridisation) has recently become a standard diagnostic procedure. In this paper, an overview of current literature on MYC function and MYC+ lymphoma patient outcome is presented. Furthermore, we present 26 patients from our tertiary referral centre who were diagnosed with MYC+ lymphoma between 2009 and 2014. In our patient series, we confirm the dismal prognosis of MYC+ lymphoma patients. Intensification of classical chemotherapy does not lead to better overall survival, justifying new treatment modalities. First line therapy should be more specifically targeted against MYC and the genes and proteins that are deregulated by MYC. To this end, the first clinical trial in which MYC+ patients will be offered targeted treatment has recently been launched.

Skin reactions due to low molecular weight heparin in pregnancy: a strategic dilemma.

INTRODUCTION: Heparin-induced allergic reactions may cause problems if heparin administration is needed for thrombo-embolic disease in pregnancy. CASE REPORTS: We report two cases of hypersensitivity to low molecular weight heparin (LMWH) in pregnancy. DISCUSSION: Alternative methods and new antithrombotic agents are discussed.

Giant liver hemangioma in three sisters.

We describe a patient, in whom giant liver hemangioma (GLH) was found by ultrasound study in screening for hypertension. Two of her sisters also had GLH. One of them had become symptomatic and the hemangioma was successfully removed. The other sisters were carefully watched. Our patient didn't need any intervention in 4 years of follow-up. The pathogenesis of GLH is still unknown. Recent investigations show a role of the TIE receptor/angiopoietin system in vascular malformations. In literature we only found two other reports about a familial occurrence of liver hemangiomas. A genetic defect in familial GLH has not yet been identified.

Iron deficiency anaemia in hospitalised patients: value of various laboratory parameters. Differentiation between IDA and ACD.

BACKGROUND: for the diagnostic evaluation of microcytic or normocytic anaemia in a heterogeneous group of patients, the value of newer parameters, such as zinc protoporphyrin (ZPP), plasma transferrin receptor (PtrfR) and PtrfR/ferritin ratio is not clear. We have performed a prospective study to determine the predictive value of these parameters and ferritin, for diagnosing iron deficiency anaemia (IDA). METHODS: sixty-two patients with Hb<8.2 (men) or <7.0 (women) and mean cell volume (MCV)<96 fl were included. Exclusion criteria were: known haematological disease, pregnancy, bone marrow suppression or iron therapy within the previous 7 days. Bone marrow examination was used as a golden standard to discriminate between IDA and non-IDA. RESULTS: twenty-four patients had depleted iron stores. We found that the reticulocyte response on iron supplementation correlated well with the iron-status of the bone marrow. Univariate analysis showed that ferritin, PtrfR/ferritin ratio, ZPP and PtrfR have significant predictive values for differentiating IDA from non-IDA. Interestingly, multivariate analysis revealed that ferritin was the only significant, independent predictor of IDA, with a cut-off point of 32 microg/l (sensitivity 79.2%, specificity 96.9%). CONCLUSIONS: the low sensitivity and specificity of ZPP, PtrfR and PtrfR/ferritin ratio render them insufficient to be used as a single 'best' test for the identification IDA in a non-selected group of anaemic patients and do not even add to the prediction if the value of ferritin is known.

Tropical pyomyositis in a temperate climate: a case report.

Pyomyositis is an abscess-forming infection of large skeletal muscles, usually with Staphylococcus aureus. Although it is common in the tropics and relatively rare in temperate climates, imported cases due to growing global mobility may be expected to increase its incidence outside tropical regions. Early diagnosis and correct management are imperative in this potentially fatal disorder, and require a high degree of clinical suspicion. A case report is presented demonstrating typical aspects of diagnosis and treatment.

Skin lesions and an intrathoracic mass.

We describe a case of thoracic actinomycosis in a previously healthy man. The clinical features were a paramediastinal mass with skin lesions due to haematogenic dissemination. After parasternal mediastomy, the diagnosis was made. After treatment with penicillin, there was complete recovery.

Distinct chromosomal abnormalities in murine leukemia virus-induced T- and B-cell lymphomas.

We performed a cytogenetic study on 16 murine mature B-cell lymphomas and 10 T-cell lymphomas, using G-banding techniques. All tumors, with the exception of 3 spontaneous B-cell tumors, were induced by various slowly transforming murine leukemia viruses (MuLV). Metaphases were obtained from primary (10 B-cell tumors) and first or second transplant generation lymphomas (6 B-cell and 10 T-cell tumors), all of which were well characterized with respect to phenotypic, histologic and genotypic features. In the T-cell tumors we found relatively simple karyotypic abnormalities, including various numerical aberrations, such as trisomy 15, in line with many earlier reports. However, the majority of B-cell tumors showed a great variety of both structural and numerical chromosomal anomalies. Three B-cell lymphomas had an apparently normal karyotype. No single cytogenetic abnormality occurred commonly in the B-cell lymphomas, but some structural abnormalities were found in more than one stemline, in particular, ins (II) (A1; A2) in 3 tumors, and deletions involving the D-region of chromosome 14 in 3 other lymphomas. These cytogenetic results clearly indicate that the pathogenic mechanisms involved in MuLV-induced (long latency) B-cell lymphomagenesis and (short latency) T-cell lymphomagenesis differ considerably.

Retrovirally induced murine B-cell tumors rarely show proviral integration in sites common in T-cell tumors.

The molecular etiology of retrovirally induced T-cell tumors has been shown in many cases to involve proviral integration near a cellular oncogene, c-myc, N-myc, Pim-1 and pvt-1 being frequent targets for insertional activation. Murine B-cell tumors induced by infection with murine leukemia virus have been studied for rearrangements in these and other loci. In contrast to the T-cell lymphomas, tumors of the B-cell lineage, either early B-cell tumors induced in nude mice or late B-cell tumors in immunocompetent mice, did not show disruption of N-myc or Pim-1 in any of the tumors studied, although those lymphomas had acquired many new proviruses. The loci c-abl, bcl-2, fis-1, c-erbB, c-myb, and neu were likewise not involved. Rearrangement of c-myc was seen in 1 out of 71 and rearrangement of the pvt-1 locus in 4 out of 73 (5%) of the B-cell tumors. Thus it appears that mechanistic differences exist in the development of T-cell tumors and B-cell tumors caused by the same etiological agent.

Primary virus-induced lymphomas evade T cell immunity by failure to express viral antigens.

T lymphoma induction by the mink cell focus-inducing murine leukemia virus MCF 1233 in C57BL/10 and C57BL/6 mice is influenced by a strongly Th-dependent, H-2I-A-restricted antiviral immune response (25). We compared the MHC class I as well as viral env and gag antigenic cell surface profiles of frequent T lymphomas of H-2I-A nonresponder-type mice to that of rare T lymphomas of H-2I-A responder-type mice. Membrane immunofluorescence studies, with a panel of anti-env mAbs (reactive with the highly conserved gp70f epitope, the p15Ec epitope, and the gp70-p15E complex), a polyclonal anti-p30 serum, and anti-H-2 class I mAbs, showed that all 17 nonresponder tumors tested expressed high levels of both env and gag viral proteins, and 15 of these 17 nonresponder tumors expressed high levels of H-2 class I K and D antigens. In contrast, 10 of 11 responder lymphomas lacked env and/or gag determinants. The only responder lymphoma with both strong env and gag expression failed to express H-2K and -D antigens. Preferential loss of env or gag expression did not correlate with H-2 class I allelic specificities. Both responder and nonresponder T lymphoma DNA contained multiple, predominantly MCF-like, newly acquired proviral integrations. Differences in viral antigen cell surface expression were confirmed at cytoplasmic and RNA levels. The amounts of 8.2- and 3.2-kb viral RNA were greatly reduced in two responder lymphomas when compared with four nonresponder lymphomas. In both responder lymphomas, aberrantly sized viral RNA species were found. Upon in vivo passage of these responder lymphomas in either immunocompetent or T cell-deficient nu/nu mice, it was found that various molecular mechanisms may underlie the lack of viral antigen expression at the cell surface of these lymphomas. One lymphoma re-expressed viral antigens when transplanted with nu/nu mice, whereas the other remained stably gag negative. The combined findings indicate that an H-2I-A-regulated antiviral immune response not only strongly reduces T lymphoma incidence, but also forces T lymphomas that still arise to poorly express viral antigens, thus explaining their escape from immunosurveillance.

Major histocompatibility complex class II-regulated immunity to murine leukemia virus protects against early T- but not late B-cell lymphomas.

We studied the relative importance of class I and class II major histocompatibility complex (MHC) immunoregulation in the control of T- and B-cell lymphomas induced by murine leukemia virus. Previously, we have described a mink cell focus-inducing (MCF) murine leukemia virus, MCF 1233, which induces not only lymphoblastic T-cell lymphomas but also follicle center cell or lymphoblastic B-cell lymphomas. We now report that the outcome of neonatal infection with MCF 1233 in H-2-congenic C57BL/10 and C57BL/6 mice is decisively influenced by the H-2 I-A locus. A total of 64% of H-2 I-Ak, d mice [B10.BR, B10.D2, B10.A(2R), B10.A(4R), and B10.MBR] developed T-cell lymphomas after MCF 1233 infection (mean latency, 37 weeks). In contrast, H-2 I-Ab [B10, B10.A(5R), B6], H-2 I-Ab/k [(B10.A x B10)F1 and (B10 x B10.A)F1], and H-2 I-Abm12 (bm12) mice were resistant against T-cell lymphomagenesis, but 65% of these H-2 I-Ab, b/k, bm12 animals developed B-cell lymphomas (mean latency, 71 weeks). Animals of T-cell lymphoma-susceptible strains that escaped from T-cell lymphomagenesis developed B-cell lymphomas with similar frequency as animals of T-cell lymphoma-resistant strains, but with a shorter latency. H-2 class II-determined regulation of antiviral immunity was reflected in the presence of high titers of antiviral envelope antibodies in T-cell lymphoma-resistant B-cell lymphoma-susceptible H-2 I-Ab, b/k, bm12 mice, whereas in T-cell lymphoma-susceptible H-2 I-Ak,d mice no antiviral antibodies were found. At week 4 after neonatal MCF 1233 infection, a high percentage of thymocytes were virally infected in both T-cell lymphoma-susceptible and -resistant mice. However, T-cell lymphoma-resistant animals cleared the thymic infection between weeks 4 and 10 of age, coinciding with a sharp rise in serum levels of antiviral antibodies. We conclude that the pleiotropic effects of MCF 1233 infection in H-2-congenic mice result from MHC class II I-A-determined T-cell response differences.

Refinement and precision in the classification of murine lymphomas by genotyping with immunoglobulin and T cell receptor probes.

Of 114 murine leukemia virus induced lymphomas and 12 lymphoid hyperplasias, T cell receptor beta-chain gene and immunoglobulin gene constellation (immunogenotype) was compared with histology and surface marker expression (immunomorphology). In 53 out of 114 lymphomas (45%), definite conclusions concerning cell lineage were possible only after genotyping. Fifteen follicular center cell lymphomas with a clear phenotype (13 tumors with B and 2 tumors with T cell markers) were genotypically classified in agreement with their phenotype. Of another 21 follicular center cell tumors (12 null cell tumors lacking T or B cell-specific antigens and 9 tumors phenotypically composed of mixtures of T and B cells), B cell lineage was determined upon genotyping in 17 cases. All 41 lymphoblastic tumors with a T cell phenotype and 6 out of 7 lymphoblastic tumors with a T cell phenotype and 6 out of 7 lymphoblastic tumors with a B cell phenotype, upon DNA analysis were indeed classified as T and B cell tumors, respectively. Of another 10 lymphoblastic tumors (phenotypically 4 null cell lymphomas, 6 mixtures of T and B cells) genotyping established lineage in 9 cases. Fifteen lymphoblastic neoplasms showing lineage infidelity because of simultaneous expression of a T (Thy-1) and a B cell (B220) marker were clearly of T cell genotype. Only 4 out of 114 lymphomas tested retained both Ig and T cell receptor genes in germline configuration, although 6 lymphomas in these series had both Ig and T cell receptor genes rearranged. Four of twelve lesions histologically classified as hyperplasias nevertheless contained a monoclonal B cell population at the DNA level. Immunogenotypic evaluation of lymphomas allows precise lymphoma lineage determination even in cases where marker analysis falls short, and is clearly superior in detecting mono- or oligoclonality in lymphomas versus polyclonality in benign lesions.

Imbalanced MHC class II molecule expression at surface of murine B cell lymphomas.

To study the role of class II MHC expression in mouse lymphomagenesis, we examined the cell surface expression of I-A/E antigens on 24 spontaneous or murine leukemia virus (MuLV)-induced mouse B10.A (I-Ak, I-Ek) B cell lymphomas. Two primary B10.A B cell lymphomas were observed with strong I-Ek expression but with only minimal cell surface I-Ak expression. Both tumors are readily transplantable in syngeneic mice, with maintenance of their I-A-, I-E+ phenotype. Strikingly, one I-A-, I-E+ B cell lymphoma contains a (11; 17) translocation with a breakpoint on chromosome 17 that is localized within or very close to the H-2 complex. DNA of both tumors contains normal restriction enzyme fragments of the A alpha and A beta genes. Northern blot analyses indicated that one I-A-, I-E+ tumor strongly expressed A alpha, E alpha, and E beta mRNAs but possessed only a weak expression of A beta mRNA. The other B cell lymphoma showed A beta, E alpha, and E beta mRNA expression but only minimal A alpha mRNA expression. In 11 primary B10.A B cell lymphomas with a normal I-A+, I-E+ phenotype, no imbalances in A alpha/A beta mRNA levels were observed. The implications of these findings for the role of class II MHC expression in mouse B cell lymphoma-genesis are discussed.

The H-2 complex regulates both the susceptibility to mouse viral lymphomagenesis and the phenotype of the virus-induced lymphomas.

Neonatal infection of C57BL/10 mice with cloned ecotropic and/or dualtropic mink cell focus-inducing (MCF) mouse leukaemia viruses (MuLV), induces a wide spectrum of different lymphomas of T, B, and non-T/non-B cell types. The H-2 complex has a marked influence on both the development of lymphoma incidence and lymphoma type. A study using the oncogenic MCF 1233 virus and a series of B10 congenic mice enabled the mapping of the following: Resistance to the early development of T cell lymphoma is controlled by the H-2I-A locus. Susceptibility to early T cell lymphomagenesis is associated with an I-A-regulated low anti-MCF 1233 envelope antibody response and persistent infection of the thymus. B10 (H-2b) mice, which are resistant to early T cell lymphomagenesis induced by MCF 1233 or other MuLV isolates, have high anti-MuLV envelope antibody responses which are I-A-regulated. These mice develop more B cell lymphomas late in life in contrast to the early development of T cell lymphoma in B10.A (H-2a) mice. The possible response mechanisms which underlie these observations, including: I-A-regulated immunoselection against MuLV antigens expressed by (pre) leukaemic T cells, aberrant expression of class II MHC antigens on some B cell lymphomas and I-A-regulated chronic immunostimulation of MuLV-expressing (pre) leukaemic B cells, are discussed.