Greenberg, Alexandra J.

AbstractTranslational stories range from straightforward to complex. In this commentary, the story of the rapid and successful translation of rituximab therapy for the treatment of non‐Hodgkin's lymphoma (NHL) is examined. Development of this monoclonal antibody therapy began in the late 1980s. In 1994, rituximab received its first approval for the treatment of NHL by the United States Food and Drug Administration (FDA). Rituximab has since been approved for additional indications and has transformed medical practice. However, the social and political implications of these rapid successes are only beginning to become clear. In this commentary, key events in the rapid translation of rituximab from the bench to bedside are highlighted and placed into this historical framework. To accomplish this, the story of rituximab is divided into the following six topics, which we believe to be widely applicable to case studies of translation: (1) underlying disease, (2) key basic science, (3) key clinical studies in translation, (4) FDA approval process, (5) changes to medical practice, and (6) the social and political influences on translation.

AbstractThe introduction of novel immunomodulatory drugs (IMiDs) has dramatically improved the survival of patients with multiple myeloma (MM). While it has been shown that patients with specific cytogenetic subtypes, namely t(4;14), have the best outcomes when treated with bortezomib‐based regimens, the relationship between cytogenetic subtypes and response to IMiDs remains unclear. Using DNA synthesis assays, we investigated the relationship between cytogenetic subtype and lenalidomide response in a representative panel of human myeloma cell lines (HMCLs). We examined HMCL protein expression levels of the lenalidomide target cereblon (CRBN) and its downstream target interferon regulatory factor‐4 (IRF4), which have previously been shown to be predictive of lenalidomide response in HMCLs. Our results reveal that lenalidomide response did not correlate with specific cytogenetic translocations. There were distinct groups of lenalidomide‐responsive and non‐responsive HMCLs, as defined by inhibition of cellular proliferation; notably, all of the hyperdiploid HMCLs fell into the latter category. Repeated dosing of lenalidomide significantly lowered the IC50 of the responsive HMCL ALMC‐1 (IC50 = 2.6 μm vs. 0.005 μm, P < 0.0001), but did not have an effect on the IC50 of the non‐responsive DP‐6 HMCL (P > 0.05). Moreover, no association was found between lenalidomide responsiveness and CRBN and IRF4 expression. Our data indicate that lenalidomide sensitivity is independent of cytogenetic subtype in HMCLs. While CRBN and IRF4 have been shown to be associated with response to lenalidomide in patients, these findings do not translate back to HMCLs, which could be attributable to factors present in the bone marrow microenvironment.

AbstractWe previously reported an increased risk of monoclonal gammopathy of undetermined significance (MGUS) in first‐degree relatives of MGUS and multiple myeloma patients. Here, we examine whether primary cytogenetic categories of myeloma differ between patients with and without a family history of MGUS or myeloma. We studied 201 myeloma patients with available data on family history and molecular cytogenetic classification. Myeloma with trisomies was more common in probands who had an affected first‐degree relative with MGUS or myeloma compared with those without a family history (46.9% vs. 33.5%, P = 0.125); however, the difference was not statistically significant. Additional studies on the cytogenetic types of myeloma associated with familial tendency are needed.

AbstractElectrical stimulation of the brain has a 2000 year history. Deep brain stimulation (DBS), one form of neurostimulation, is a functional neurosurgical approach in which a high‐frequency electrical current stimulates targeted brain structures for therapeutic benefit. It is an effective treatment for certain neuropathologic movement disorders and an emerging therapy for psychiatric conditions and epilepsy. Its translational journey did not follow the typical bench‐to‐bedside path, but rather reversed the process. The shift from ancient and medieval folkloric remedy to accepted medical practice began with independent discoveries about electricity during the 19th century and was fostered by technological advances of the 20th. In this paper, we review that journey and discuss how the quest to expand its applications and improve outcomes is taking DBS from the bedside back to the bench.