Lenalidomide, bortezomib, pegylated liposomal doxorubicin, and dexamethasone in newly diagnosed multiple myeloma: a phase 1/2 Multiple Myeloma Research Consortium trial

This phase 1/2 trial evaluated combination lenalidomide, bortezomib, pegylated liposomal doxorubicin, and dexamethasone (RVDD) in newly diagnosed multiple myeloma (MM) patients. Patients received RVDD at 4 dose levels, including the maximum tolerated dose (MTD). Patients with a very good partial response or better (≥ VGPR) after cycle 4 proceeded to autologous stem cell transplantation or continued treatment. The primary objectives were MTD evaluation and response to RVDD after 4 and 8 cycles. Seventy-two patients received a median of 4.5 cycles. The MTDs were lenalidomide 25 mg, bortezomib 1.3 mg/m(2), pegylated liposomal doxorubicin 30 mg/m(2), and dexamethasone 20/10 mg, as established with 3-week cycles. The most common adverse events were fatigue, constipation, sensory neuropathy, and infection; there was no treatment-related mortality. Response rates after 4 and 8 cycles were 96% and 95% partial response or better, 57% and 65% ≥ VGPR, and 29% and 35% complete or near-complete response, respectively. After a median follow-up of 15.5 months, median progression-free survival (PFS) and overall survival (OS) were not reached. The estimated 18-month PFS and OS were 80.8% and 98.6%, respectively. RVDD was generally well tolerated and highly active, warranting further study in newly diagnosed MM patients. This trial was registered at www.clinicaltrials.gov as NCT00724568.     

Perspective: Medical education in medical ethics and humanities as the foundation for developing medical professionalism

Medical education accreditation organizations require medical ethics and humanities education to develop professionalism in medical learners, yet there has never been a comprehensive critical appraisal of medical education in ethics and humanities. The Project to Rebalance and Integrate Medical Education (PRIME) I Workshop, convened in May 2010, undertook the first critical appraisal of the definitions, goals, and objectives of medical ethics and humanities teaching. The authors describe assembling a national expert panel of educators representing the disciplines of ethics, history, literature, and the visual arts. This panel was tasked with describing the major pedagogical goals of art, ethics, history, and literature in medical education, how these disciplines should be integrated with one another in medical education, and how they could be best integrated into undergraduate and graduate medical education. The authors present the recommendations resulting from the PRIME I discussion, centered on three main themes. The major goal of medical education in ethics and humanities is to promote humanistic skills and professional conduct in physicians. Patient-centered skills enable learners to become medical professionals, whereas critical thinking skills assist learners to critically appraise the concept and implementation of medical professionalism. Implementation of a comprehensive medical ethics and humanities curriculum in medical school and residency requires clear direction and academic support and should be based on clear goals and objectives that can be reliably assessed. The PRIME expert panel concurred that medical ethics and humanities education is essential for professional development in medicine.     

Ultrasound integrated backscatter tissue characterization of remote myocardial infarction in human subjects

To determine whether quantitative ultrasound tissue characterization differentiates normal myocardial regions from segments of remote infarction, 32 consecutive patients with a diagnosis of previous myocardial infarction were evaluated. Images were obtained in real time with a modified two-dimensional ultrasound system capable of providing continuous signals in proportion to the logarithm of integrated backscatter along each A line. In 15 patients, adequate parasternal long-axis images that delineated both normal and infarct segments were obtained with standard time-gain compensation. Image data were analyzed to yield both magnitude and delay (electrocardiographic R wave to nadir normalized for the QT interval) of the cyclic variation of backscatter. Cyclic variation was present in 55 of 56 normal myocardial sites, averaging (mean +/- SEM) 3.2 +/- 0.2 dB in magnitude and exhibiting a mean normalized delay of 0.87 +/- 0.03. The magnitude of cyclic variation in infarct segments was significantly reduced to 1.1 +/- 0.2 dB (42 sites), and the delay was markedly increased to 1.47 +/- 0.12 (21 sites) (p less than 0.0001 for both). In 20 of 42 infarct sites, no cyclic variation was detectable. Thus, ultrasound tissue characterization quantitatively differentiated infarct segments from normal myocardium in patients with remote myocardial infarction.     

What other biologic and mechanical factors might contribute to osteolysis?

An overwhelming consensus exists that wear particles are the primary driving force in aseptic loosening of orthopaedic implants. Nonetheless, considerable evidence has emerged demonstrating that various other factors can modulate the biologic activity of orthopaedic wear particles. Two of the most studied modulating factors are bacterial endotoxins and implant motion.     

What patient and surgical factors contribute to implant wear and osteolysis in total joint arthroplasty?

Total joint arthroplasty has been a successful operation for decades. Our current patients are younger and more active than those in the past. They place higher demands on themselves and have expectations commensurate with their lifestyles. Time-limited longevity with the large number of anticipated total joint replacement procedures and their potential burden to health care is a growing concern. In the past two decades, implant wear and osteolysis have been identified as major causes for the failure of otherwise well-functioning implants. Osteolysis can be divided into several categories: patient-specific, implant-specific, and the result of surgical factors. Although these categories are interrelated and not mutually exclusive, they enable us to build a framework in which to further advance our understanding of osteolysis and apply this information in a clinically relevant manner.     

How have new sterilization techniques and new forms of polyethylene influenced wear in total joint replacement?

Polyethylene has undergone many changes over the past several decades, including changes in consolidation processes, resin types, sterilization methods, packaging, and the extent of cross-linking. We believe that new sterilization techniques and forms of polyethylene have generally improved wear performance. Polyethylene sterilized without the use of radiation has been shown to have relatively high rates of wear in vivo. Ram-extruded polyethylene sterilized via gamma irradiation in air has been the most commonly used bearing material in the past several decades. Recently, components molded and gamma-sterilized without oxygen as well as highly cross-linked material have found increased clinical use. Exposure of polyethylene to radiation, either to sterilize it or to intentionally cross-link it, has been shown to improve the wear performance of the material. Newer second-generation methods of cross-linking polyethylene include the use of vitamin E, which quenches free radicals and demonstrates promise in providing low wear and desirable mechanical properties.     

How do alternative bearing surfaces influence wear behavior?

Metal, ceramic, and polyethylene liners represent contemporary bearing choices for total joint replacement. Each has limitations in terms of design, sensitivity to manufacturing, and surgical placement. With polyethylene, larger femoral heads represent a design restriction and a potential wear issue. One side benefit is that polyethylene does not click, squeak, or create stripe wear. The attraction of hard-on-hard bearings (metal-on-metal, ceramic-on-ceramic) is that their typically ultra-low wear alleviates concerns with large femoral head designs. However, hard-on-hard bearings produce stripe wear due to the effects of the rigid liner edge. Slight subluxation (microseparation) during swing phase of gait can result in stripe wear on the ball and liner rim. In addition, high levels of implant wear with vertically placed cups can be anticipated. Currently, only alumina-on-alumina bearings can claim virtually no biologic risk. Thus, the role of laboratory studies is to isolate relevant aspects of performance by cup design and to predict the risk-benefit ratios in patients requiring total hip replacement.     

How have wear testing and joint simulator studies helped to discriminate among materials and designs?

Historically, hip joint simulators most often have been used to model wear of a bearing surface against a bearing surface. These simulators have provided highly accurate predictions of the in vivo wear of a broad spectrum of bearing materials, including cross-linked polyethylenes, metal-on-metal, ceramic-on-ceramic, and others in development. In recent years, more severe conditions have been successfully modeled, including jogging, stair climbing, ball-cup micro separation, third-body abrasion, and neck-socket impingement. These tests have served to identify improved materials and to eliminate some with inadequate wear resistance prior to their clinical use. Simulation of the knee joint is inherently more complex than it is for the hip. It is more difficult to compare the results of laboratory tests with actual clinical performance, due to the lack of accurate in vivo measures of wear. Nevertheless, knee simulators, based on force control or motion control, have successfully reproduced the type of surface damage that occurs in vivo (eg, burnishing, scratching, pitting) as well as the size and shapes of the resultant wear particles. Knee simulators have been used to compare molded versus machined polyethylene components, highly cross-linked polyethylenes, fixed versus mobile bearings, and oxidized zirconia and other materials, under optimal conditions as well as more severe wear modes, such as malalignment, higher loading and activity levels, and third-body roughening.     

How do material properties influence wear and fracture mechanisms?

The wear and fracture mechanisms of ultra-high-molecular-weight polyethylene (UHMWPE) hip and knee implant components are of great interest. The material properties of UHMWPE are affected by ionizing radiation as used for sterilization and cross-linking. Cross-linking with high-dose irradiation has been shown to improve the wear resistance of UHMWPE. However, cross-linking leads to a loss in properties such as ductility and resistance to fatigue crack propagation. Highly cross-linked UHMWPE may be more susceptible than conventional UHMWPE to fracture under severe clinical conditions (eg, impingement). Contemporary hip and knee simulator studies provide good information with which new UHMWPE formulations can be screened for clinical wear performance. However, comparable methodologies are lacking for screening UHMWPEs for fracture resistance. Mechanical tests as well as computational material and structural models should be developed to evaluate the combined effect of material and geometry (structure) on fracture resistance under clinically relevant loading conditions.