MYC+ diffuse large B-cell lymphoma is not salvaged by classical R-ICE or R-DHAP followed by BEAM plus autologous stem cell transplantation

Approximately 5-10% of diffuse large B-cell lymphomas (DLBCL) harbor a 8q24/MYC rearrangement (MYC(+)). We determined the prognostic significance of MYC rearrangement in patients with relapsed/refractory DLBCL prospectively treated by R-ICE or R-DHAP followed by high-dose therapy and autologous stem cell transplantation. Twenty-eight (17%) of the 161 patients analyzed presented a MYC(+) rearrangement, targeted as either simple hit (25%) or complex hits (n=75%) including MYC/BCL2, MYC/BCL6, and MYC/BCL2/BCL6. Results were statistically highly concordant in matched primary and relapsed biopsies (n = 45). Compared to the MYC(-) DLBCL patients, the MYC(+) DLBCL patients presented with a more elevated lactico-deshydrogenase level (P = .0006) and a more advanced age adjusted international prognostic index (P = .0039). The 4-year PFS and OS were significantly lower in the MYC(+) DLBCL patients than those in the MYC(-) DLBCL patients, with rates of 18% vs 42% (P = .0322), and of 29% vs 62% (P = .0113), respectively. Type of treatment, R-DHAP or R-ICE, had no impact on survivals, with 4-year PFS rates of 17% vs 19% and 4-year OS rates of 26% vs 31%. In conclusion, MYC rearrangement is an early event in DLBCL. MYC(+) DLBCL patients have a significant inferior prognosis than MYC(-) DLBCL patients. Their outcome was not influenced by the proposed salvage therapy.     

Spontaneous megakaryocyte colony formation in myeloproliferative disorders is not neutralizable by antibodies against IL3, IL6 and GM-CSF

Summary. Megakaryocyte progenitor growth in 42 patients with myeloproliferative disorders (MPD), including 23 essential thrombocythaemia (ET), eight polycythaemia vera (PV). six chronic myelogenous leukaemia (CML) and five primary myelofibrosis (PMF), was studied in vitro using plasma clot assay and serum-free agar culture. Spontaneous megakaryocyte colonies (CFU-MK) were found in 34/40 (80%) blood and 14/18 (77.8%) bone marrow plasma clot cultures, and also observed in 27/35 (77.1%) blood and 10/18 (55.6%) bone marrow serum-free agar cultures. In the blood of 27 patients with MPD (15 ET, four PV, four CML and four PMF) and the bone marrow of 10 patients (five ET, four CML and one PV), spontaneous colony formation was observed in both plasma clot and serum-free agar cultures. However, spontaneous CFU-MK was only found in plasma clot culture, but not in agar culture in two blood (one ET and one CML) and four bone marrow cultures (one ET, two PV, one CML). The colony numbers were greatly increased in the presence of aplastic anaemia serum (AAS) under both conditions. In 17 patients (12 ET, two CML and three PV) with spontaneous megakaryocyte colonies, anti-cytokine antibody neutralizing experiments were carried out in blood cultures. Anti-IL3, anti-IL6 and anti-GM-CSF antibody, alone or in combination, at different concentrations (1, 5 and 10 μg/ml), were added into plasma clot or agar cultures without exogenous stimulating growth factors. The results showed that the numbers of spontaneous megakaryocyte colonies were not significantly decreased in the presence of these monoclonal antibodies in the cultures. The data indicated that the megakaryocyte progenitor growth in MPD under in vitro conditions was heterogenous, and independent of exogenous stimulatory factors in most patients and that optimal megakaryocyte colony development in MPD still requires exogenous growth factors.     

Targeting Krasg12c‐mutant cancer with a mutation‐specific inhibitor

The RAS genes, which include H, N, and KRAS, comprise the most frequently mutated family of oncogenes in cancer. Mutations in KRAS – such as the G12C mutation – are found in most pancreatic, half of colorectal and a third of lung cancer cases and is thus responsible for a substantial proportion of cancer deaths. Consequently, KRAS has been the subject of exhaustive drug‐targeting efforts over the past 3–4 decades. These efforts have included targeting the KRAS protein itself but also its posttranslational modifications, membrane localization, protein–protein interactions and downstream signalling pathways. Most of these strategies have failed and no KRAS‐specific drugs have yet been approved. However, for one specific mutation, KRAS^G12C, there is light on the horizon. MRTX849 was recently identified as a potent, selective and covalent KRAS^G12C inhibitor that possesses favourable drug‐like properties. MRTX849 selectively modifies the mutant cysteine residue in GDP‐bound KRAS^G12C and inhibits GTP‐loading and downstream KRAS‐dependent signalling. The drug inhibits the in vivo growth of multiple KRAS^G12C‐mutant cell line xenografts, causes tumour regression in patient‐derived xenograft models and shows striking responses in combination with other agents. It has also produced objective responses in patients with mutant‐specific lung and colorectal cancer. In this review, we discuss the history of RAS drug‐targeting efforts, the discovery of MRTX849, and how this drug provides an exciting and long‐awaited opportunity to selectively target mutant KRAS in patients.     

CD40 expression by human bronchial epithelial cells

CD40 is a 50-kDa protein expressed on B cells, dendritic cells, monocytes and epithelial cells, but the distribution of CD40 expression in humans is not completely known. It binds to a ligand (CD40L) which is expressed essentially on activated T cells. The interaction between CD40 and CD40L plays important roles in immune responses. CD40 expression was investigated on bronchial tissues and human bronchial cell lines using immunohistochemistry, immunofluorescence staining and analysis with a cytometer, respectively. Constitutive CD40 expression, but not that of CD40L, was slightly detectable on normal human bronchial epithelial cells (HBEC) in situ and on an adult lung adenocarcinoma (SKLU1) cell line, while another cell line, a bronchial transformed SV40 cell line (WI26VA4), was negative for CD40. Among the various cytokines tested, only interferon (IFN)-gamma was found to induce CD40 expression on WI26VA4. Tumour necrosis factor (TNF)-alpha was the best cytokine able to up-regulate CD40 in SKLU1 cells. A combination of IFN-gamma and TNF-alpha was slightly more effective than the cytokine alone at up-regulating CD40 expression on both cell lines. We further investigated the functional consequences of CD40 ligation on both cell lines. These bronchial cells expressed CD40, HLADR and CD54 under basal conditions or when stimulated by cytokines. Stimulation through CD40 did not affect cell-surface-antigen expression on either cell line. The production of cytokines such as interleukin (IL)-6 and granulocyte macrophage-colony stimulating factor (GM-CSF) by HBEC has been described. SKLU1 and WI26VA4 cells released IL-6 and GM-CSF spontaneously. Whatever the case, CD40 engagement did not modulate spontaneous or TNF-alpha-induced production of these two cytokines. These data indicate for the first time that normal HBEC express CD40 in situ. Further investigations are required in order to determine the role of CD40 on normal HBEC.     

Methodological issues in the study of sexual abuse effects.

Despite its relative infancy, child abuse research has provided a substantial literature on the psychological sequelae of sexual molestation. These findings have been helpful in informing social policy and guiding mental health practice. Because of the recency of interest in this area, however, as well as the costs and time investment associated with more rigorous longitudinal research, many of these studies have used correlational designs and retrospective reports of abuse. The implications of this methodology are outlined, and remedies are suggested where possible.     

Spine stereotactic radiosurgery for metastases from hepatobiliary malignancies: patient selection using PRISM scoring

Journal of Neuro-Oncology - Glioblastoma multiforme (GBM) is one of the most devastating brain malignancies worldwide and is considered to be incurable. However, the mechanisms underlying its...     

Peripheral T-cell lymphoma with eosinophilia presenting as monoarthritis: a case study

Direct involvement of the joints is unusual in patients with non-Hodgkin's lymphoma (NHL). This may pose a diagnostic problem for pathologists, especially since synovial localization can disclose NHL. In the following case of T-cell NHL with eosinophilia, we point out the essential importance of clonality analysis on frozen tissue to distinguish between synovial NHL and specific inflammatory damage.     

Impact of integration of hygiene kit distribution with routine immunizations on infant vaccine coverage and water treatment and handwashing practices of Kenyan mothers

Integration of immunizations with hygiene interventions may improve use of both interventions. We interviewed 1361 intervention and 1139 comparison caregivers about hygiene practices and vaccination history, distributed water treatment and hygiene kits to caregivers during infant vaccination sessions in intervention clinics for 12 months, and conducted a followup survey of 2361 intervention and 1033 comparison caregivers. We observed significant increases in reported household water treatment (30% vs 44%, P < .0001) and correct handwashing technique (25% vs 51%, P < .0001) in intervention households and no changes in comparison households. Immunization coverage improved in both intervention and comparison infants (57% vs 66%, P = .04; 37% vs 53%, P < .0001, respectively). Hygiene kit distribution during routine immunizations positively impacted household water treatment and hygiene without a negative impact on vaccination coverage. Further study is needed to assess hygiene incentives, implement alternative water quality indicators, and evaluate the impact of this intervention in other settings.