Favorable long-term outcome of patients with multiple myeloma using a frontline tandem approach with autologous and non-myeloablative allogeneic transplantation.

Despite survival improvement with novel agents and use of autologous hematopoietic stem cell transplantation (HSCT), cure of patients with multiple myeloma (MM) remains anecdotal. Initial observations suggested that chronic GvHD was accompanied by an anti-myeloma effect after myeloablative HSCT, but unfortunately this procedure was hampered by high non-relapse mortality (NRM). To maximize the anti-myeloma effect and minimize NRM, we developed a non-myeloablative (NMA) regimen associated with a high incidence of chronic GvHD and tested its efficacy on patient survival and disease eradication. From 2001 to 2010, 92 patients aged ⩽ 65 years with a compatible sibling donor received autologous HSCT followed by an outpatient NMA allogeneic HSCT using a conditioning of fludarabine and cyclophosphamide. Patient median age was 52 years and 97% presented Durie-Salmon stages II-III disease. After a median follow-up of 8.8 years, probability of 10-year progression free and overall survival were 41% and 62%, respectively. Although the cumulative incidence of extensive chronic GvHD was high (at 79%), the majority of long-term survivors were off immunosuppressive drugs by year 5 and NRM was low (at 10%). Together, our results suggest that potential MM cure can be achieved with NMA transplantation regimens that maximize graft-versus-myeloma effect and minimize NRM.

Circulating miRNAs as sensitive and specific biomarkers for the diagnosis and monitoring of human diseases: promises and challenges.

The regulation and modulation of gene expression has been a central focus of modern biomedical research ever since the first molecular elucidation of DNA. The cellular mechanisms by which genes are expressed and repressed hold valuable insight for maintaining tissue homeostasis or conversely provide mechanistic understanding of disease progression. Hence, the discovery of the first miRNA in humans roughly a decade ago profoundly shook the previously established dogmas of gene regulation. Since, these small RNAs of around 20 nucleotides have unquestionably influenced almost every area of medical research. This momentum has now spread to the clinical arena. Hundreds of papers have already been published shedding light on the mechanisms of action of miRNAs, their profound stability in almost every bodily fluid and relating their presence to disease state and severity of disease progression. In this review, we explore the diagnostic potential of miRNAs in the clinical laboratory with a focus on studies reporting the detection of miRNAs in blood and urine for investigation of human disease. Sensitivities, specificities, areas under the curve, group descriptions and miRNAs of interest for 69 studies covering a broad range of diseases are provided. We discuss the practicality of miRNAs in the screening, diagnosis and prognosis of a range of pathologies. Characteristics and pitfalls of miRNA detection in blood are also discussed. The topics covered here are pertinent in the design of future miRNA-based detection strategies for use in clinical biochemistry laboratory settings.

The platelet contribution to cancer progression.

Traditionally viewed as major cellular components in hemostasis and thrombosis, the contribution of platelets to the progression of cancer is an emerging area of research interest. Complex interactions between tumor cells and circulating platelets play an important role in cancer growth and dissemination, and a growing body of evidence supports a role for physiologic platelet receptors and platelet agonists in cancer metastases and angiogenesis. Platelets provide a procoagulant surface facilitating amplification of cancer-related coagulation, and can be recruited to shroud tumor cells, thereby shielding them from immune responses, and facilitate cancer growth and dissemination. Experimental blockade of key platelet receptors, such as GP1b/IX/V, GPIIbIIIa and GPVI, has been shown to attenuate metastases. Platelets are also recognized as dynamic reservoirs of proangiogenic and anti-angiogenic proteins that can be manipulated pharmacologically. A bidirectional relationship between platelets and tumors is also seen, with evidence of 'tumor conditioning' of platelets. The platelet as a reporter of malignancy and a targeted delivery system for anticancer therapy has also been proposed. The development of platelet inhibitors that influence malignancy progression and clinical testing of currently available antiplatelet drugs represents a promising area of targeted cancer therapy.