M. J. Kersten

Expression of Epstein-Barr virus latent genes and adhesion molecules in AIDS-related non-Hodgkin's lymphomas: correlation with histology and CD4-cell number

In patients with the acquired immunodeficiency syndrome, the incidence of non-Hodgkins lymphoma is increased. Two major subgroups of AIDS-related NHL (ARL) have been defined: Burkitt-type NHL (BL) and polymorphic centroblastic/immunoblast-rich large cell lymphomas (CB/IB LCL). These subgroups differ in their association with the Epstein-Barr virus (EBV) and thus possibly in their pathogenesis. We studied the expression of EBER (EBV small RNAs), and EBV latent antigens LMP-1 and EBNA-2 in 43 cases of ARL and related this to histology and immune status (CD4-cell count). In addition, in 19 cases the expression of adhesion molecules (LFA-1 (CD18), ICAM-1 (CD54), alpha4beta1 integrin (CD49d/CD29), L-selectin (CD62L) and CD44) was studied. We found major differences between the two subgroups. Patients with BL had significantly higher CD4-cell counts; only 40% of their lymphomas were EBV-positive, and when EBV-positive, were of the type I latency phenotype. Expression of adhesion molecules important for immune recognition was absent or low in all BL. In contrast, the majority of CB/IB LCL were EBER-positive (79%). 58% of EBV-positive LCL (particularly those in patients with CD4-cell counts below 0.2 x 10(9)/1) had a type II or III latency phenotype. Most LCL showed expression of LFA-1, ICAM-1 and alpha4beta1 integrin. CD44s expression was restricted to CB/IB LCL, in whom high expression of the metastasis-associated exon v6-containing CD44 variant was also observed. The observed EBV-latency types and full expression of adhesion molecules suggest that defective Epstein-Barr virus immunity is important in the pathogenesis of CB/IB large cell lymphomas.

Treatment of AIDS-related non-Hodgkin's lymphoma with chemotherapy (CNOP) and r-hu-G-CSF: Clinical outcome and effect on HIV-1 viral load

PURPOSE The optimal treatment of AIDS-related NHL (ARL) has yet to be defined. The purpose of this study was 1) to evaluate the efficacy and toxicity of the CNOP-regimen (cyclophosphamide, mitoxantrone, vincristine, and prednison) in combination with G-CSF; and 2) to study the effect of this regimen on HIV-1 viral replication. PATIENTS AND METHODS A phase II study was performed in 21 previously untreated patients with ARL. RESULTS Based on intention to treat, the response rate was 43%: four complete and five partial remissions. Median survival was only five months. Only one patient had an opportunistic infection during treatment; three patients had localized infections and one episode of septicaemia was seen. Remarkably, during treatment, in 94% of cases p24 antigen levels either remained undetectable or showed a substantial decrease, even though antiretroviral therapy had been discontinued just prior to the first cycle of chemotherapy in all patients. HIV-1 RNA load decreased or remained unchanged in 82% of patients and increased in three patients. CONCLUSIONS Our data demonstrate, 1) that the CNOP-regimen in combination with G-CSF, although associated with a low risk of both opportunistic and bacterial infections, can not be recommended in the treatment of ARL; but 2) that G-CSF can be used safely to sustain haematopoiesis in patients with ARL treated with chemotherapy.

The pan phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor SAR245409 (voxtalisib/XL765) blocks survival, adhesion and proliferation of primary chronic lymphocytic leukemia cells.

The phosphoinositide 3-kinases (PI3Ks) are critical components of the B-cell receptor (BCR) pathway and have an important role in the pathobiology of chronic lymphocytic leukemia (CLL). Inhibitors of PI3Kδ block BCR-mediated cross-talk between CLL cells and the lymph node microenvironment and provide significant clinical benefit to CLL patients. However, the PI3Kδ inhibitors applied thus far have limited direct impact on leukemia cell survival and thus are unlikely to eradicate the disease. The use of inhibitors of multiple isoforms of PI3K might lead to deeper remissions. Here we demonstrate that the pan-PI3K/mammalian target of rapamycin inhibitor SAR245409 (voxtalisib/XL765) was more pro-apoptotic to CLL cells—irrespective of their ATM/p53 status—than PI3Kα or PI3Kδ isoform selective inhibitors. Furthermore, SAR245409 blocked CLL survival, adhesion and proliferation. Moreover, SAR245409 was a more potent inhibitor of T-cell-mediated production of cytokines, which support CLL survival. Taken together, our in vitro data provide a rationale for the evaluation of a pan-PI3K inhibitor in CLL patients.

Seronegative lyme neuroborreliosis in a patient using rituximab

A 66-year-old woman presented with severe shooting pains throughout her back and legs, followed by progressive deafness, weight loss and headache. She had a history of marginal zone B-cell lymphoma stage IV-B, for which she was successfully treated with immunochemotherapy and rituximab maintenance therapy. A relapse was suspected, but chemotherapy was not administered, since, despite elaborate investigations, malignancy could not be proven. Because of a history of tick bites she was tested for antibodies against Borrelia burgdorferi in serum and cerebrospinal fluid (CSF), which were negative. However, a B burgdorferi PCR on CSF came back positive. The patient was treated for seronegative Lyme neuroborreliosis with ceftriaxone intravenously and dramatically improved. This case presentation demonstrates that, in immunocompromised patients, it is important not to solely rely on antibody testing and to use additional diagnostic tests to avoid missing or delaying the diagnosis.

Reversible posterior leucoencephalopathy syndrome associated with bortezomib in a patient with relapsed multiple myeloma

Reversible posterior leucoencephalopathy syndrome (RPLS) is a potentially fatal but reversible clinico-radiological syndrome with symptoms of headache, altered mental functioning, visual changes and seizures in association with typical posterior cerebral white matter lesions. RPLS is associated with the use of cytotoxic drugs, usually in combination with high blood pressure. We report a case of RPLS that we believe is associated with bortezomib, a proteasome inhibitor with proapoptotic and antiangiogenic properties approved for the treatment of relapsed multiple myeloma, and speculate about the possible mechanisms leading to RPLS. Clinicians should be aware of the potential association between RPLS and bortezomib because timely recognition and appropriate treatment are important in the prevention of irreversible neurological complications.