Sphingosine-1-phosphate (S1P), a lipid mediator enriched in blood, controls the dynamic migration of osteoclast (OC) precursors (OPs) between the blood and bone, in part via the S1P receptor 1 ...(S1PR1) which directs positive chemotaxis toward S1P. We show that OPs also express S1PR2, an S1P receptor which mediates negative chemotaxis (or chemorepulsion). OP-positive chemotaxis is prominent in gradients with low maximal concentrations of S1P, whereas such behavior is minimal in fields with high maximal S1P concentrations. This reverse-directional behavior is caused by S1PR2-mediated chemorepulsion acting to override S1PR1 upgradient motion. S1PR2-deficient mice exhibit moderate osteopetrosis as a result of a decrease in osteoclastic bone resorption, suggesting that S1PR2 contributes to OP localization on the bones mediated by chemorepulsion away from the blood where S1P levels are high. Inhibition of S1PR2 function by the antagonist JTE013 changed the migratory behavior of monocytoid cells, including OPs, and relieved osteoporosis in a mouse model by limiting OP localization and reducing the number of mature OCs attached to the bone surface. Thus, reciprocal regulation of S1P-dependent chemotaxis controls bone remodeling by finely regulating OP localization. This regulatory axis may be promising as a therapeutic target in diseases affecting OC-dependent bone remodeling.
The introduction of rituximab for diffuse large B-cell lymphoma (DLBCL) has improved the disease’s overall prognosis. However, relapse in the central nervous system (CNS) is still an issue. We ...investigated the prognosis and risk factors of CNS recurrence in DLBCL. A total of 403 patients who were diagnosed with DLBCL without CNS involvement between January 1996 and April 2007 at our institution were included in the study. Subsequently, 42 experienced CNS relapse. Clinical information was gathered by chart review. The median disease-free interval to CNS relapse was 625 days. The mean survival periods after relapse in the cases with CNS and extra-CNS involvement were 513 and 1,615 days, respectively (
P
= 0.0004). Multivariate analysis identified age >60 years (
P
= 0.031), involvement in two or more extranodal sites (
P
= 0.040), bone marrow involvement (
P
= 0.036), an elevated serum lactate dehydrogenase (LDH) level (
P
= 0.016), and treatment without rituximab before CNS relapse (
P
= 0.027) as independent predictors of CNS relapse. We have shown that cases of DLBCL occurring in advanced age, involving two or more extranodal sites or the bone marrow, or showing an elevation of LDH have a higher risk of CNS relapse. Rituximab may prevent CNS relapse by reducing the recurrence of DLBCL at all sites. An effective CNS prophylaxis strategy should be determined according to the risk assessment of CNS relapse.
New drugs for multiple myeloma (MM) have dramatically improved patients’ overall survival (OS). Autologous stem cell transplantation (ASCT) remains the mainstay for transplant‐eligible MM patients. ...To investigate whether the post‐ASCT prognosis of MM patients has been improved by new drugs, we undertook a retrospective observational analysis using the Transplant Registry Unified Management Program database in Japan. We analyzed 7323 patients (4135 men and 3188 women; median age, 59 years; range 16‐77 years) who underwent upfront ASCT between January 2007 and December 2018. We categorized them by when they underwent ASCT according to the drugs’ introduction in Japan: group 1 (2007‐2010), group 2 (2011‐2016), and group 3 (2017‐2018). We compared the groups’ post‐ASCT OS. The 2‐year OS rates (95% confidence interval CI) of groups 1, 2, and 3 were 85.8% (84.1%‐87.4%), 89.1% (88.0%‐90.1%), and 92.3% (90.0%‐94.2%) (P < .0001) and the 5‐year OS (95% CI) rates were 64.9% (62.4%‐67.3%), 71.6% (69.7%‐73.3%), and not applicable, respectively (P < .0001). A multivariate analysis showed that the post‐ASCT OS was superior with these factors: age less than 65 years, performance status 0/1, low International Staging System (ISS) stage, receiving SCT for 180 days or less post‐diagnosis, better treatment response pre‐ASCT, later year of ASCT, and receiving SCT twice. A subgroup analysis showed poor prognoses for the patients with unfavorable karyotype and poor treatment response post‐ASCT. The post‐ASCT OS has thus improved over time (group 1 < 2 < 3) with the introduction of new drugs for MM. As the prognosis of high‐risk‐karyotype patients with ISS stage III remains poor, their treatment requires improvement.
The overall survival of patients with multiple myeloma (MM) after autologous stem cell transplantation has improved over time along with the introduction of new drugs for the treatment of MM.
TO THE EDITOR A 68-year-old man was admitted to our clinic because of vomiting. He had no notable past history. He was a social drinker, and developed abdominal distension for a few weeks before ...admission. Ileus was found in the small intestine on computed tomography (CT) of the abdomen. An intestinal tube was inserted, but his symptom remained. Further examination revealed that the cause of ileus was a tumor mass in the small intestine. Laparoscopic-assisted partial excision of small intestine was performed. The pathological diagnosis of the small intestinal mass was diffuse large B-cell lymphoma (DLBCL) , germinal center B-cell-like. He was referred to the hematological division for additional chemotherapy.
CASE REPORT A 73-year-old Japanese man was referred to our clinic with general malaise. He had a history of diabetes mellitus and hypertension of longer than 10 years. He presented with ...lymphadenopathy and liver dysfunction. Laboratory examination demonstrated a WBC count of 23.6×109/L with 10% abnormal lymphocytes having basophilic irregular nuclei, aspartate aminotransferase of 124U/L (normal range: 5-40U/L), alanine transaminase of 166U/L (5-35U/L), total bilirubin of 4.1mg/dL (1.0-0.3mg/dL), creatinine of 1.46mg/dL (0.6-1.1mg/dL) and soluble interleukin-2 receptor (sIL-2R) of 15,889U/mL (122-496U/mL). Serological tests for HBV, HCV and HTLV-1 were all negative. The physical examination revealed bilateral cervical lymph node swelling, multiple abdominal skin pigmentation and peripheral edema. On computed tomography (CT) of the trunk, generalized multiple lymphadenopathy with mild splenomegaly was noted. Biopsy specimens of cervical lymph nodes and abdominal skin exhibited monotonous infiltration of medium to large-sized lymphocytes with a phenotype of CD3+, CD5+, CD10-, CD20-, CD79a-, CD30-, CD56-, Bcl6-, granzyme B-, CD45RO-, CCR4+ and TdT-.
Novel therapeutic drugs have dramatically improved the overall survival of patients with multiple myeloma. We sought to identify the characteristics of patients likely to exhibit a durable response ...to one such drug, elotuzumab, by analyzing a real-world database in Japan. We analyzed 179 patients who underwent 201 elotuzumab treatments. The median time to next treatment (TTNT) with the 95% confidence interval was 6.29 months (5.18-9.20) in this cohort. Univariate analysis showed that patients with any of the following had longer TTNT: no high risk cytogenic abnormalities, more white blood cells, more lymphocytes, non-deviated κ/λ ratio, lower β
microglobulin levels (B2MG), fewer prior drug regimens, no prior daratumumab use and better response after elotuzumab treatment. A multivariate analysis showed that TTNT was longer in patients with more lymphocytes (≥ 1400/μL), non-deviated κ/λ ratio (0.1-10), lower B2MG (< 5.5 mg/L) and no prior daratumumab use. We proposed a simple scoring system to predict the durability of the elotuzumab treatment effect by classifying the patients into three categories based on their lymphocyte counts (0 points for ≥ 1400/μL and 1 point for < 1400/μL) and κ/λ ratio (0 points for 0.1-10 and 1 point for < 0.1 or ≥ 10) or B2MG (0 points for < 5.5 mg/L and 1 point for ≥ 5.5 mg/L). The patients with a score of 0 showed significantly longer TTNT (p < 0.001) and better survival (p < 0.001) compared to those with a score of 1 or 2. Prospective cohort studies of elotuzumab treatment may be needed to validate the usefulness of our new scoring system.
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