Promising new drugs are being evaluated for treatment of multiple myeloma (MM), but their impact should be measured against the expected outcome in patients failing current therapies. However, the natural history of relapsed disease in the current era remains unclear. We studied 286 patients with relapsed MM, who were refractory to bortezomib and were relapsed, refractory, or ineligible, to an IMiD (Immunomodulatory Drug), with measurable disease and ECOG PS of 0, 1 or 2. The date patients satisfied the entry criteria was defined as time zero (T0). The median age at diagnosis was 58 years and time from diagnosis to T0 was 3.3 years. Following T0, 213 (74%) patients had a treatment recorded with one or more regimens (median=1; range 0-8). The first regimen contained bortezomib in 55 (26%) patients and an IMiD in 70 (33%). A minor response or better was seen to at least one therapy after T0 in 94 patients (51%) including >=partial response in 69 (38%). The median overall survival and event free survival from T0 were 9 and 5 months respectively. This study confirms the poor outcome once patients become refractory to current treatments. The results provide context for interpreting ongoing trials of new drugs.

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Trafficking of human CD34 ؉ stem/progenitor cells (HSCs/HPCs) is regulated by chemokines, cytokines, proteolytic enzymes, and adhesion molecules. We report that the adhesion receptor CD44 and its major ligand, hyaluronic acid (HA), are essential for homing into the bone marrow (BM) and spleen of nonobese diabetic/ severe combined immunodeficient (NOD/ SCID) mice and engraftment by human HSCs. Homing was blocked by anti-CD44 monoclonal antibodies (mAbs) or by soluble HA, and it was significantly impaired after intravenous injection of hyaluronidase. Furthermore, stromal cellderived factor-1 (SDF-1) was found to be a rapid and potent stimulator of progenitor adhesion to immobilized HA, leading to formation of actin-containing protrusions with CD44 located at their tips. HPCs migrating on HA toward a gradient of SDF-1 acquired spread and polarized morphology with CD44 concentrating at the pseudopodia at the leading edge. These morphologic alterations were not observed when the progenitors were first exposed to anti-CD44 mAbs, demonstrating a crosstalk between CD44 and CXCR4 signaling. Unexpectedly, we found that HA is expressed on human BM sinusoidal endothelium and endosteum, the regions where SDF-1 is also abundant. Taken IntroductionThe outcome of hematopoietic stem cell transplantation is influenced by the ability of the cells to home and repopulate their specialized bone marrow (BM) niches. The crosstalk between the hematopoietic stem/progenitor cells (HSCs/HPCs) and the microenvironment, which regulates homing to the BM, is not fully elucidated. Data indicate that transplanted HSCs/HPCs lodge into their BM niches by a sequence of highly regulated events that mimic the migration of leukocytes to inflammatory sites. This process includes tethering and rolling on E-and P-selectins, firm adhesion to the vessel wall, transendothelial extravasation, and migration through the extracellular matrix (ECM). [1][2][3] This multistep process is mediated by an interplay between chemokines, growth factors, proteolytic enzymes, and adhesion molecules. 4,5 The chemokine stromal cell-derived factor-1 (SDF-1), also named CXCL-12, and its receptor, CXCR4, play key roles in human HSC trafficking and repopulation. 6 This chemokine, expressed by both human and murine BM endothelium and stroma, 7,8 is the most powerful chemoattractant of HSCs/HPCs 9,10 that also regulates their survival. 11,12 It induces the integrin-mediated firm arrest of human HPCs under physiologic shear flow, facilitates their transendothelial migration, 3,8 and regulates homing 13 and BM engraftment. 14 Furthermore, SDF-1 is also required for the retention of murine stem and progenitor cells within the BM. 15,16 HSCs/HPCs express several types of adhesion molecules that are responsible for cell-cell and cell-ECM interactions 17 ; among them CD44 is of particular interest.The importance of CD44 in cell migration is reported for a variety of normal and malignant cells. 18 CD44 is a multifunctional and multistructural receptor that has a large array of isoforms....

Purpose: Adoptive cell therapy with autologous tumor-infiltrating lymphocytes (TIL) has shown promising results in metastatic melanoma patients. Although objective response rates of over 50% have been reported, disadvantages of this approach are the labor-intensive TIL production and a very high drop-out rate of enrolled patients, limiting its widespread applicability.Previous studies showed a clear correlation between short TIL culture periods and clinical response. Therefore, we used a new TIL production technique using unselected, minimally cultured, bulk TIL (Young-TIL). The use of Young-TIL is not restricted to human leukocyte antigen (HLA)-A2 patients.The purpose of this study is to explore the efficacy and toxicity of adoptively transferred Young-TIL following lympho-depleting chemotherapy in metastatic melanoma patients, refractory to interleukin-2 and chemotherapy.Experimental Design: Young-TIL cultures for 90% of the patients were successfully generated, enabling the treatment of most enrolled patients. We report here the results of 20 evaluated patients.Results: Fifty percent of the patients achieved an objective clinical response according to the Response Evaluation Criteria in Solid Tumors, including two ongoing complete remissions (20+, 4+ months) and eight partial responses (progression-free survival: 18+, 13+, 10+, 9, 6+, 4, 3+, and 3 months). All responders are currently alive. Four additional patients showed disease stabilization. Side effects were transient and manageable.Conclusion: We showed that lympho-depleting chemotherapy followed by transfer of short-term cultured TIL can mediate tumor regression in 50% of metastatic melanoma with manageable toxicity. The convincing clinical results combined with the simplification of the process may thus have a major effect on cell therapy of cancer. Clin Cancer Res; 16(9); 2646-55. ©2010 AACR.

Hematopoietic stem cells rarely contribute to hepatic regeneration, however, the mechanisms governing their homing to the liver, which is a crucial first step, are poorly understood. The chemokine stromal cell-derived factor-1 (SDF-1), which attracts human and murine progenitors, is expressed by liver bile duct epithelium. Neutralization of the SDF-1 receptor CXCR4 abolished homing and engraftment of the murine liver by human CD34 + hematopoietic progenitors, while local injection of human SDF-1 increased their homing. Engrafted human cells were localized in clusters surrounding the bile ducts, in close proximity to SDF-1-expressing epithelial cells, and differentiated into albumin-producing cells. Irradiation or inflammation increased SDF-1 levels and hepatic injury induced MMP-9 activity, leading to both increased CXCR4 expression and SDF-1-mediated recruitment of hematopoietic progenitors to the liver. Unexpectedly, HGF, which is increased following liver injury, promoted protrusion formation, CXCR4 upregulation, and SDF-1-mediated directional migration by human CD34 + progenitors, and synergized with stem cell factor. Thus, stress-induced signals, such as increased expression of SDF-1, MMP-9, and HGF, recruit human CD34 + progenitors with hematopoietic and/or hepatic-like potential to the liver of NOD/SCID mice. Our results suggest the potential of hematopoietic CD34 + /CXCR4 + cells to respond to stress signals from nonhematopoietic injured organs as an important mechanism for tissue targeting and repair.

Apoptosis prevents osteoporosis G randmothers everywhere know well that estrogen defi cits lead to osteoporosis. Now, the molecular basis for this debilitating bone loss is fi nally identifi ed. Estrogen is needed to kill off bone-destroying osteoclasts, show Takashi Nakamura, Shigeaki Kato (University of Tokyo, Japan), and colleagues. The root cause of osteoporosis has been diffi cult to pin down, in part because bones are not frail in female mice lacking estrogen receptors. These mice make extra androgen, which builds bone in male mice and might compensate for bone loss in the mutant females. To avoid the androgen rise, Kato's group knocked out estrogen receptors only in mature osteoclasts, which accumulate in osteoporotic bones. These female mutants developed rickety bones due to losses within the central bone shafts. The authors then isolated osteoclasts to determine why they are so abundant in diseased bone. Microarray analyses revealed that estrogen induced apoptotic proteins, including Fas ligand, that were not induced in the estrogen-blind osteoclasts. Men who have estrogen receptor mutations develop osteoporosis. But male mice were not affected by the loss of estrogen receptors in osteoclasts. Perhaps the androgen-headed pathway is more dominant in mice than in humans. Currently, potential drugs to treat osteoporosis are screened through mice whose ovaries have been removed. Screens for the induction of Fas ligand in cultures of estrogen-blind osteoclasts should be much simpler.

Regulation of the availability of chemokine SDF-1 (CXCL12) in bone marrow is still not fully understood. Here we describe a unique function for the chemokine receptor CXCR4 expressed on bone marrow endothelial cells, which efficiently internalize circulating SDF-1, resulting in its translocation into the bone marrow. Translocated SDF-1 increased the homing of transplanted human CD34(+) hematopoietic progenitors to the bone marrow. The chemokine transporter function of CXCR4 was a characteristic of endothelial and stromal cells but not of hematopoietic cells. Thus, chemokine translocation across the blood-bone marrow barrier allows effective transfer of functional SDF-1 from the periphery to the stem cell niche in the bone marrow during both homeostasis and 'alarm' situations.

Preoperative imaging prevented operations and storage of tissue with cancer. Evaluation of stored ovarian tissue for MRD using sensitive markers is essential to increase safety and to prevent reimplantation of tissue with malignant cells.