Understanding CD30 biology and therapeutic targeting: a historical perspective providing insight into future directions.

CD30 is a member of the tumor necrosis factor receptor superfamily. It is characteristically expressed in certain hematopoietic malignancies, including anaplastic large cell lymphoma and Hodgkin lymphoma, among others. The variable expression of CD30 on both normal and malignant lymphoid cells has focused research efforts on understanding the pathogenesis of CD30 upregulation, its contribution to lymphomagenesis through anti-apoptotic mechanisms, and its effect on cell survival. Given the restriction of CD30 to certain tumor types, the logical extension of this has been to attempt to exploit it as a therapeutic target. The efficacy of naked anti-CD30 antibodies in practice was, however, modest. Moreover, combinations with bacterial toxins and radioimmunoconjugates have also had limited success. The development of the antibody-drug compound brentuximab vedotin (BV), however, has rejuvenated interest in CD30 as a tumor target. Phase I and II clinical trials in Hodgkin lymphoma, peripheral T-cell lymphoma, cutaneous T cell lymphoma, and even CD30-expressing B-cell lymphomas, have shown the compound is well tolerated, but more importantly, able to deliver meaningful disease control even in patients with multiply relapsed or refractory disease. FDA approval has been granted for its use in relapsed Hodgkin lymphoma and systemic anaplastic large cell lymphoma. A recent phase III trial of BV in cutaneous T-cell lymphoma has confirmed its superiority to standard of care therapies. In this manuscript, we explore the history of CD30 as a tumor marker and as a therapeutic target, both in the laboratory and in the clinic, with a view to understanding future avenues for further study.

Morbidity and mortality associated with rewarming hypothermic very low birth weight infants.

OBJECTIVES: In very low birthweight (VLBW) infants, hypothermia is associated with poor outcomes. The goal of this study is to assess the relationship between the rate of rewarming these babies and their outcomes. METHODS: This is a retrospective cohort study of 98 inborn VLBW infants who were hypothermic (<36°C rectally) upon admission to the NICU. A logistic regression model was used to examine the relationship between the rates of rewarming and time to achieve euthermia and the following outcomes: death, intraventricular hemorrhage, severe intraventricular hemorrhage, bronchopulmonary dysplasia, necrotizing enterocolitis and retinopathy of prematurity. RESULTS: Prolonged rewarming time was associate with increased odds of mortality (OR 1.273 95% CI 1.032-1.571). No associations between rewarming rates and any of the outcomes were seen. Once birthweight was included in a multiple logistic regression model, the association between mortality and rewarming time was no longer significant. Outcomes that were not associated with either rate or time of rewarming (even in a univariate model) were: bronchopulmonary dysplasia, intraventricular hemorrhage, severe intraventricular hemorrhage, necrotizing enterocolitis and retinopathy of prematurity. CONCLUSION: In moderately hypothermic VLBW infants, after accounting for birthweight, no association between rewarming and outcome is seen.

Whole-exome analysis reveals novel somatic genomic alterations associated with outcome in immunochemotherapy-treated diffuse large B-cell lymphoma.

Lack of remission or early relapse remains a major clinical issue in diffuse large B-cell lymphoma (DLBCL), with 30% of patients failing standard of care. Although clinical factors and molecular signatures can partially predict DLBCL outcome, additional information is needed to identify high-risk patients, particularly biologic factors that might ultimately be amenable to intervention. Using whole-exome sequencing data from 51 newly diagnosed and immunochemotherapy-treated DLBCL patients, we evaluated the association of somatic genomic alterations with patient outcome, defined as failure to achieve event-free survival at 24 months after diagnosis (EFS24). We identified 16 genes with mutations, 374 with copy number gains and 151 with copy number losses that were associated with failure to achieve EFS24 (P<0.05). Except for FOXO1 and CIITA, known driver mutations did not correlate with EFS24. Gene losses were localized to 6q21-6q24.2, and gains to 3q13.12-3q29, 11q23.1-11q23.3 and 19q13.12-19q13.43. Globally, the number of gains was highly associated with poor outcome (P=7.4 × 10(-12)) and when combined with FOXO1 mutations identified 77% of cases that failed to achieve EFS24. One gene (SLC22A16) at 6q21, a doxorubicin transporter, was lost in 54% of EFS24 failures and our findings suggest it functions as a doxorubicin transporter in DLBCL cells.

The role of front-line anthracycline-containing chemotherapy regimens in peripheral T-cell lymphomas.

Peripheral T-cell lymphomas (PTCLs) are a heterogenous group of aggressive non-Hodgkin's lymphomas that are incurable in the majority of patients with current therapies. Outcomes associated with anthracycline-based therapies are suboptimal, but remain the standard of care for most patients, even though the benefits of this approach remain uncertain. This study retrospectively examined outcomes in a cohort of North American PTCL patients treated with both anthracycline- and nonanthracycline-containing regimens. The incorporation of anthracycline-containing regimens was associated with improved progression-free survival (PFS) and overall survival (OS). Patients treated with nonanthracycline-containing regimens were more likely to have high-risk features and were less likely to undergo high-dose therapy and stem cell transplantation. However, anthracycline use remained an independent predictor of improved PFS and OS when adjusting for these confounding variables. Anthracycline-based regimens and consolidation with high-dose therapy and autologous stem cell transplantation in appropriately selected patients remains a viable option for patients unable to participate in a clinical trial. Long-term disease-free survival is not optimal, highlighting the need for an improved understanding of disease pathogenesis, and the development of novel therapeutic strategies.

Bevacizumab versus ranibizumab in the treatment of exudative age-related macular degeneration: a retrospective study of 58 patients.

AIM: To compare the efficacy and safety of bevacizumab versus ranibizumab in the treatment of patients with neovascular age-related macular degeneration (AMD). PATIENTS AND METHODS: Retrospective case-controlled series of 30 patients treated with intravitreal bevacizumab and 28 patients treated with intravitreal ranibizumab for exudative AMD. Main outcomes measured included best-corrected visual acuity (BCVA), central macular thickness (CMT) and foveal thickness, quantity of subretinal fluid, neovessel size and total number of injections over the first year treatment period. A secondary outcome was the report of any adverse events in both groups. RESULTS: BCVA stabilized and increased from LogMAR 0.70 to 0.47 in the bevacizumab group and from 0.55 to 0.54 in the ranibizumab group (P>0.05). CMT decreased in the bevacizumab group from 369 to 284 µm and in the ranibizumab group from 340 to 271 µm (P>0.05). The number of injection was significantly lower (4.8) in the bevacizumab group than in the ranibizumab group (5.8) (P<0.05). No serious ocular adverse events were noted in both groups. CONCLUSION: This retrospective study failed to show a difference in visual and anatomic outcomes between bevacizumab and ranibizumab. The number of re-treatment was lower in the bevacizumab group (P=0.03).

[Prospective study of 34 retinal detachments associated with giant retinal tear]. / Etude prospective de 34 décollements de rétine par déchirure géante.

PURPOSE: To report the anatomical and functional outcomes of vitrectomy with silicone oil tamponade in the treatment of retinal detachment associated with giant retinal tears due to various factors. METHODS: We prospectively followed 34 eyes of 33 patients with giant retinal tear. That underwent vitrectomy, injection of perfluorocarbon liquids and silicone oil tamponade. Scleral buckle was associated with vitrectomy in cases of inferior giant retinal tear; 26,5 % and 11,8 %, respectively, demonstrated pseudophakia and aphakia. Seven eyes (20,5 %) had a history of trauma (blunt injuries in four and a penetrating injury in three) and, 14 eyes (41,2 %) had severe myopia. One patient developed a bilateral giant retinal tear during the follow-up. RESULTS: Retinal attachment was obtained in 33 (97 %) of 34 eyes, with a mean follow-up of 14,5+/-6 months. Retinal detachment reoccurred in four eyes (11,6 %) under silicone oil, in one eye (2,9 %) during the silicone removal, and in two eyes (5,8 %) after silicone removal and cataract surgery. Silicone oil was removed from all eyes (4,3+/-1 months). The most frequent postoperative complication was cataract in ten of 18 phakic eyes (55,5 %). Functional success with visual acuity 0,4 or better was obtained in 18 cases (52,96 %). CONCLUSION: Pars plana vitrectomy with silicone oil tamponade proved to be highly effective in giant retinal tears in terms of the anatomical and functional results. The analysis of recurrent retinal detachment allowed us to refine the technique and to suggest scleral buckle in one case of inferior retinal tear with laser over 360 degrees .

Mesenchymal progenitor cells in red and yellow bone marrow.

Marrow cavities in all bones of newborn mammals contain haematopoietic tissue and stromal microenvironment that support haematopoiesis (haematopoietic microenvironment), known as red bone marrow (BM). From the early postnatal period onwards, the haematopoietic microenvironment, mainly in tubular bones of the extremities, is replaced by mesenchymal cells that accumulate lipid drops, known as yellow BM, whereas haematopoietic tissue gradually disappears. We analysed the ability of mesenchymal cell progenitors in red and yellow BM to produce bone and haematopoietic microenvironment in vivo after transplantation into normal or haematopoietically deficient (irradiated and old) recipients. We found that (1) normal substitution of red with yellow BM results from a gradual loss of mesenchymal stem cells (MSCs) capable of developing bone and haematopoietic microenvironment; (2) the mesenchymal cell population in tubular bones still containing active haematopoietic tissue gradually becomes depleted of MSCs, starting from a young age; (3) haematopoietic microenvironment is incapable of self-maintenance and its renewal depends on the presence of precursor cells; (4) the mesenchymal cell population remaining in areas with yellow BM contains cells able to develop functionally active haematopoietic microenvironment in conditions of haematopoietic insufficiency. Our data also indicate the possible existence of bi-potential stromal precursor cells producing either bone in normal, or bone together with active haematopoietic microenvironment in irradiated or old recipients. This study opens a spectrum of opportunities for the extension of haematopoietic territories by substituting the fat contents of BM cavities with haematopoietic tissue, thereby improving haematopoiesis compromised by cytotoxic treatments, irradiation, ageing, etc.

Proinflammatory cytokines in a mouse model of central retinal artery occlusion.

PURPOSE: To analyze cytokines in the retina and serum in an experimental model of central retinal artery occlusion (CRAO) in mice. METHODS: CRAO was induced by laser activation of intravenously injected rose bengal, a photosensitive dye, in 60 C57Bl/6 mice. mRNA and protein levels of macrophage inhibitory protein-2 (MIP-2), interleukin-6 (IL-6), and tumor necrosis factor- alpha (TNF-alpha) were analyzed using real-time polymerase chain reaction, and western blot, respectively. Cytokine levels in serum were measured by ELISA. Analysis was performed at various time intervals from CRAO induction. RESULTS: In the retina, MIP-2 and IL-6 mRNA expression decreased 3 h after induction of CRAO and increased thereafter, peaking at 12-24 h. By 7 days, levels were again mostly undetectable. TNF-alpha mRNA expression increased at 3 h and decreased to control levels at 7 days. At the protein level, all cytokines were present at 3 h, following similar patterns to their respective gene expression thereafter. In serum, MIP-2 and TNF-alpha levels peaked early, and decreased to control levels at 12 h, with a second late rise of TNF-alpha. IL-6 levels increased between 3 and 12 h and decreased at 24 h. CONCLUSIONS: Temporal variations in cytokines were observed following the induction of CRAO, both at the retinal mRNA expression and protein levels. These temporal changes, and the variable effects of the cytokines at the different time intervals, should be taken into account during the formulation of therapeutic strategies.

Recurrent translocations involving the IRF4 oncogene locus in peripheral T-cell lymphomas.

Oncogenes involved in recurrent chromosomal translocations serve as diagnostic markers and therapeutic targets in hematopoietic tumors. In contrast to myeloid and B-cell neoplasms, translocations in peripheral T-cell lymphomas (PTCLs) are poorly understood. Here, we identified recurrent translocations involving the multiple myeloma oncogene-1/interferon regulatory factor-4 (IRF4) locus in PTCLs. IRF4 translocations exist in myeloma and some B-cell lymphomas, but have not been reported earlier in PTCLs. We studied 169 PTCLs using fluorescence in situ hybridization and identified 12 cases with IRF4 translocations. Two cases with t(6;14)(p25;q11.2) had translocations between IRF4 and the T-cell receptor-alpha (TCRA) locus. Both were cytotoxic PTCLs, unspecified (PTCL-Us) involving bone marrow and skin. In total, 8 of the remaining 10 cases were cutaneous anaplastic large-cell lymphomas (ALCLs) without TCRA rearrangements (57% of cutaneous ALCLs tested). These findings identified IRF4 translocations as a novel recurrent genetic abnormality in PTCLs. Cytotoxic PTCL-Us involving bone marrow and skin and containing IRF4/TCRA translocations might represent a distinct clinicopathologic entity. Translocations involving IRF4 but not TCRA appear to occur predominantly in cutaneous ALCLs. Detecting these translocations may be useful in lymphoma diagnosis. Further, due to its involvement in translocations, MUM1/IRF4 protein may play an important biologic role in some PTCLs, and might represent a possible therapeutic target.