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Recently, progression of disease within 24 months (POD24) has been demonstrated as a strong prognostic indicator in various types of malignant lymphoma. Peripheral T-cell lymphoma (PTCL) has an aggressive course and poor clinical outcomes. In this multicenter retrospective study, 111 consecutively registered patients with newly diagnosed PTCL were analyzed. Of these patients, 72 (64.9%) experienced POD24 (POD24 group), and the other 39 patients (35.1%) were analyzed as the no POD24 group. In the POD24 group, overall survival (OS) was significantly inferior to all patients, and in the no POD24 group, subsequent OS was significantly superior to the POD24 group, although the clinical characteristics between the POD24 group and no POD24 group were not significantly different. Twenty-three patients (20.7%) showed primary refractory disease to first-line therapy, and the prognosis was poor. The International Prognostic Index score and POD24 were identified as independent predictors in multivariate analysis for OS in all patients, and only performance status was an independent prognostic factor for OS in the POD24 group in multivariate analysis. In conclusion, the clinical significance of assessing POD24 in PTCL and the poor prognosis in patients with early disease progression were demonstrated.

We herein report a 64-year-old man who was treated with pembrolizumab for relapsed Hodgkin lymphoma. After the third administration of pembrolizumab, he showed acute anemia with a positive direct anti-globulin test. Because of the markedly erythroid hypoplasia, he was diagnosed with pure red cell aplasia (PRCA) caused by pembrolizumab. He was initially treated with prednisolone, but the reticulocytes decreased after tapering prednisolone. He then received high-dose intravenous immunoglobulin (IVIG) with prednisolone, and PRCA was successfully treated. Although the pathogenesis of PRCA caused by immune checkpoint inhibitors (CPIs) remains unclear, IVIG treatment may be effective for some steroid-refractory CPI-induced PRCA cases.

Purpose Vitamin D is a fundamental mediator of skeletal metabolism, but also plays an important role in the pathophysiology of multiple myeloma (MM). Recent studies have shown an association between vitamin D deficiency and racial outcomes in MM patients. The aim of this study was to clarify the prevalence of vitamin D deficiency among Japanese MM patients and the association between vitamin D status and clinical outcomesMethods We tested serum 25-hydroxyvitamin D (25(OH)D) levels in 68 MM patients at a single Japanese institution from December 2015 to March 2016.Results Median serum 25(OH)D level was 22 ng/mL, with 32% and 51% of patients showing vitamin D deficiency (Conclusion Most Japanese MM patients had less-than-sufficient levels of serum vitamin D, with one-third being deficient. Vitamin D deficiency also predicted poor overall survival in Japanese MM patients. Further studies are needed to investigate whether vitamin D supplementation can overcome the poor survival of MM patients.

There is a controversy which short term high dose dexamethasone therapy (HDD) or standard dose prednisolone therapy as the initial treatment leads to long term efficacy in idiopathic thrombocytopenic purpura (ITP) patients. We conducted a multicenter, prospective trial to determine the efficacy and safety of short-term HDD in ITP patients aged 18–80 years with platelet counts of

Febrile neutropenia, a serious complication that can occur during the treatment of hematological malignancies, can sometimes be fatal owing to fungal infection. Prospective randomized trials indicated the utility of liposomal amphotericin B or caspofungin as an empirical antifungal therapy. Itraconazole, a broad-spectrum tri azole antifungal agent, is poorly absorbed in the intestines after oral absorption and makes it difficult to achieve a stable serum drug concentration. Therefore, an intravenous formulation might offer a potentially safer and more effective alternative. To compare the efficacy and safety of empirical antifungal therapy, patients will be randomly assigned to either the liposomal amphotericin B 3.0 mg/kg once daily group or the intravenous itraconazole 200 mg dose group with five stratification factors (disease risk, previous antifungal prophylaxis, age, sex, and institute). The primary endpoint will be overall favorable response, comprising five secondary endpoints: successful treatment of baseline infection by the end of the treatment; absence of breakthrough infection; no discontinuation of the antifungal treatment due to drug-related toxicity; fever resolution during neutropenia; and 7-day survival after termination of the antifungal treatment. The target sample size of 850 subjects is sufficient to prove the non inferiority of itraconazole compared with liposomal amphotericin B, with a non-inferiority margin of 10%, one sided significance level of 5%, and power of 90%.

Elderly multiple myeloma (MM) patients, who are generally ineligible for transplantation, have high risks of death and treatment discontinuation, and require a regimen incorporating novel agents that balance safety, tolerability, and efficacy. We evaluated alternating bortezomib-dexamethasone and lenalidomide-dexamethasone treatments administered over a 63-day cycle in transplant-ineligible elderly patients with newly diagnosed MM. Subcutaneous bortezomib 1.3 mg/m2 was administered weekly on Days 1, 8, 15, and 22; oral lenalidomide 15 mg daily on Days 36-56; and oral dexamethasone 20 mg on Days 1, 8, 15, 22, 36, 43, 50, and 57 for 6 cycles. The primary endpoint was the overall response rate.

More than 40% of Japanese patients with multiple myeloma (MM) are over 75 years of age at diagnosis. Regardless of the treatment benefits, complications and relapses obstruct long-term survival. We conducted a phase II, open-label, single-arm, multicenter clinical trial to assess the efficacy and safety of alternating bortezomib-dexamethasone (Bd) and lenalidomide-dexamethasone (Ld) (Bd/Ld) treatment in MM patients aged over 75 years (MARBLE trial). Patients received Bd therapy from days 1 to 35 and Ld therapy from days 36 to 63. For Bd therapy, patients were administered bortezomib 1.3 mg/m

We retrospectively analyzed the risk factors for outcomes among patients with peripheral T-cell lymphoma not otherwise specified (PTCL-NOS, n = 100) and angioimmunoblastic T-cell lymphoma (AITL, n ...

High-dose chemotherapy and autologous stem cell transplantation (ASCT) are too toxic for elderly patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Therefore, effective and tolerable regimens for elderly patients are urgently needed. The present phase II study assessed the efficacy and safety of dose-adjusted therapy with gemcitabine, dexamethasone, cisplatin, and rituximab (GDP-R) in this population. ASCT-ineligible elderly patients with relapsed or refractory DLBCL received dose-adjusted GDP-R in each 28-day cycle for up to six cycles. The primary endpoint was overall response rate (ORR), and secondary endpoints were complete response (CR) rate, progression-free survival (PFS), and safety. Thirty-three patients were enrolled and received dose-adjusted GDP-R. The median age was 75 years (range: 68-87 years). The ORR was 82.8% (90% confidence interval [CI], 67.1-93.0%), with a CR rate of 58.6% (90% CI, 41.7-74.1%). At a median follow-up of 20.9 months, the 2-year PFS rate was 46.8% (90% CI, 30.7-61.5%) and the 2-year overall survival rate was 63.2% (90% CI, 45.8-76.3%). The most frequently observed grade 4 adverse events were neutropenia (63.6%), thrombocytopenia (57.6%), and lymphocytopenia (39.4%). Dose-adjusted GDP-R is a promising salvage regimen for ASCT-ineligible elderly patients with relapsed DLBCL after rituximab-containing chemotherapy and warrants further investigation.

Standard therapy for idiopathic thrombocytopenic purpura (ITP) has not been established. We are conducting a multicenter, prospective trial to determine the efficacy and safety of short-term, high-dose dexamethasone therapy in ITP patients aged 18-80 years with platelet counts of

Rituximab has markedly improved the outcomes of B cell lymphoma, and its maintenance has been shown to be beneficial in low grade B cell lymphoma (LGBCL). We conducted a multicenter, phase II trial of intensive rituximab induction and maintenance therapy for LGBCL to optimize the rituximab monotherapy. Patients with newly diagnosed or rituximab naïve relapsed LGBCL received 8 weekly rituximab as induction, then continued maintenance therapy with rituximab for 4 weeks at 6-month intervals. The primary endpoint was the overall response rate (ORR). Forty-five patients were enrolled from 2005 to 2009 and 36 were eligible. The ORR was 83.3% (30/36) with a complete response rate of 72.2% (26/36). The 3-year progression-free survival (PFS) was 76.7% with a median follow-up of 43.0 months. Five grade three toxicities were observed (no grade 4). Our findings suggest that this regimen demonstrates high activity with durable PFS and minimal toxicity in LGBCL patients.

Single-nucleotide polymorphisms (SNPs) of the programmed cell death protein-1 (PDCD1), programmed cell death protein-1 ligand-1 (PDCD1LG1), and cytotoxic T lymphocyte-associated antigen-4 (CTLA4) genes are implicated in the pathogenesis of some cancers. We investigated the role of PDCD1, PDCD1LG1, and CTLA4 SNPs in MM pathogenesis and the susceptibility to and clinical features of multiple myeloma (MM). We obtained genomic DNA from 124 patients with MM and 211 healthy controls and detected PDCD1 (rs36084323, rs41386349, and rs2227982), PDCD1LG1 (rs2297136 and rs4143815), and CTLA4 (rs733618, rs11571316, rs231775, and rs3087243) genotypes using the polymerase chain reaction-restriction fragment length polymorphism method or the TaqMan allelic discrimination real-time PCR method. The patients with MM had a significantly higher frequency of the PDCD1 GCC/GCC haplotype (rs36084323/rs41386349/rs2227982) compared with the healthy controls. PDCD1 rs2227982 CC genotype was associated significantly with a higher frequency of bone lesions. Patients with PDCD1LG1 rs2297136 TT and TC types (high-expression types) showed lower albumin level than those with CC genotype. In addition, the PDCD1LG1 rs4143815 CC and CG types (high-expression types) were associated significantly with higher frequency of patients who were treated with thalidomide and/or bortezomib. However, there was no statistical significance between CTLA4 polymorphisms and clinical variables of patients with MM. There were no significant differences between all the polymorphisms and OS. Our study indicates that the PDCD1 haplotype is associated with a susceptibility to MM. The PDCD1 rs2227982 and PDCD1LG1 rs2297136 affect the clinical features of multiple myeloma patients.

Chemotherapy-induced nausea and vomiting (CINV) is a significant side effect in multiple myeloma (MM) patients receiving high-dose melphalan treatment followed by autologous stem cell transplantation (ASCT). We evaluated the efficacy and safety of a triple antiemetic combination of palonosetron, aprepitant, and low-dose dexamethasone in 24 MM patients who received melphalan conditioning (100 mg/m2 on days 1–2) before ASCT (on day 4). Intravenous palonosetron (0.75 mg on day 1), oral aprepitant (125 mg on day 1; 80 mg on days 2–4), and intravenous dexamethasone (6.6 mg on days 1–4) were administered for prevention of CINV. Complete response (no emesis and no rescue antiemetic) and complete control (no emesis, no rescue antiemetic, and no more than mild nausea) rates were 75 and 68% during the overall phase (0–120 h), while they were 88 and 86% in the acute phase (0–48 h), 75 and 68% in the delayed phase (48–120 h), and 67 and 59% in the extended phase (120–168 h), respectively. There were no serious adverse events related to the antiemetic therapy. In conclusion, the three-antiemetic regimen consisting of palonosetron, aprepitant, and dexamethasone was safe and effective for controlling CINV due to high-dose melphalan treatment, especially during the delayed phase.

Interleukin-10 (IL-10) and IL-10 receptor (IL-10R) single nucleotide polymorphisms have been implicated in the pathogenesis of many cancers. We investigated the influence of IL-10 -592C/A, IL-10RA I224V, and IL-10RB K47E on the risk of developing multiple myeloma (MM) and the clinical features of MM. We extracted the genomic DNA from 128 MM patients and 202 healthy controls and used polymerase chain reaction-restriction fragment length polymorphism method to detect IL-10 promoter -592C/A (rs1800872), IL-10RA (rs2228055), and IL-10RB K47E (rs2834167) genotypes. Overall survival (OS) was defined as the interval from the date of diagnosis to the date of death or last clinical appointment. No statistically significant difference was observed in the genotype and allele frequencies of IL-10 -592C/A, IL-10RA I224V, and IL-10RB K47E between MM patients and healthy controls. IL-10RA II genotype was significantly associated with a hemoglobin level lower than that of IV and VV genotypes (mean ± standard deviation, 9.21 ± 2.46 vs 10.3 ± 2.33 g/dL; P = .021). IL-10 -592 AA genotype was significantly associated with OS better than that of CA and CC genotypes (median OS, 74.5 vs 46.3 months; P = .047). We observed significant differences in survival between patients treated with thalidomide and/or bortezomib and those treated with conventional treatments (median OS, 74.5 vs 38.2 months; P = .021). Therefore, we also examined the effect of IL-10 and IL-10R polymorphisms on the clinical variables and OS of patients treated with thalidomide and/or bortezomib. In addition, IL-10RB EE genotype was significantly associated with poorer survival than KK and KE genotypes (median OS, 46.3 vs 78.8 months; P = .015). Our findings indicate that IL-10 and IL-10R gene polymorphisms may not contribute to the susceptibility to MM but may be associated with the severity and prognosis of MM. In particular, IL-10RB K47E polymorphism may contribute to the poor prognosis of MM patients treated with thalidomide and/or bortezomib.

In spite of recent development in the treatment armamentarium for multiple myeloma, overall survival (OS) still depends on risk status and sensitivity to treatment of each patient. We have evaluated the clinical relevance of the Revised International Staging System (R-ISS) by comparing it with the original ISS in 718 Japanese patients. The distribution of patients according to response was similar between the ISS and R-ISS stages. Treatment response was greatly influenced by initial treatment modalities and deeper response was observed more frequently in transplanted patients. The R-ISS discriminated the difference in OS between the stages more distinctly than the ISS (p = 9.0 × 10−15 and p = 4.0 × 10−10, respectively). Differences in OS were clarified by both R-ISS and ISS in non-transplanted patients (p = 2.4 × 10−12 and p = 1.4 × 10−8, respectively), but the ISS failed to distinguish the difference between the stages in transplanted patients (p = 0.13). In contrast, the R-ISS could at least discriminate the excellent prognosis of stage I patients whereas the distinction between stage II and III was not that clear (p = 0.033). The R-ISS stage II encompassed a large number of patients, and the prognosis was heterogeneous depending on the fulfillment of prognostic factors such as LDH and adverse cytogenetics. These results suggest that treatment factors and prognostic factors greatly affect the therapeutic response and outcome, and the R-ISS is superior to ISS in prognostication of both transplant-eligible and -ineligible patients in our current clinical practice.

We performed a phase 1 study to evaluate the safety and feasibility of bortezomib (BOR) with melphalan and dexamethasone (BMD) in patients with light chain amyloidosis (AL) without severe cardiac failure. Patients received BOR on a twice-weekly schedule (days 1, 4, 8, and 11 of 28-day treatment cycles) at planned doses of 1.0 (dose level 1) and 1.3 (dose level 2) mg/m(2) in combination with melphalan 8 mg/m(2) on days 1-4 and dexamethasone 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12. Dose-limiting toxicity (DLT) was evaluated at the end of cycle one, and treatment was continued for four cycles. Six patients were enrolled at dose level 1, and one showed DLT (grade 3: herpes zoster). Further 3 patients were enrolled at dose level 2, and none experienced DLT. Thus, the maximum tolerated dose was defined as BOR doses of 1.3 mg/m(2) for the twice-weekly schedule. A total of 32 cycles of BMD therapy were given, and the most common hematologic toxicity was thrombocytopenia (47%). Peripheral neuropathy was the most common non-hematologic toxicity (16%). We demonstrated that BMD is safe and tolerable for Japanese AL patients without severe cardiac damage.UMIN000006604.

Lenalidomide treatment in combination with dexamethasone and/or chemotherapy is associated with a significant risk of venous thromboembolism (VTE) in patients with multiple myeloma (MM). However, the incidence of asymptomatic VTE in lenalidomide-treated MM patients remains unclear. A total of 80 relapsed and refractory MM patients treated with lenalidomide-containing regimens in a single institution between July 2010 and July 2014 were retrospectively analyzed. Of these, eight patients had asymptomatic VTE before starting lenalidomide. The remaining 72 patients received thromboprophylaxis with low-dose aspirin (100 mg daily) and monitoring of plasma D-dimer levels on each visit. During the median follow-up time of 7.3 months (range 1.0-43.5 months), 29 patients (40.3 %) showed an elevation of D-dimer (≥2.5 μg/mL), and 13 (18.1 %) showed asymptomatic VTE in a lower extremity. Median time to asymptomatic VTE events from initiation of lenalidomide treatment was 3.0 months (range 1.0-13.1 months). All patients having an asymptomatic VTE continued lenalidomide treatment on warfarinization (target international normalized ratio 1.5-2.5), and none of them developed symptomatic VTE. In conclusion, an asymptomatic VTE event occurred in 18 % of Japanese MM patients receiving lenalidomide-containing therapy despite aspirin prophylaxis. Serial monitoring of plasma D-dimer levels and early intervention may help to prevent symptomatic or lethal VTE events.

Recent studies have revealed the clinical and biological features of stage I follicular lymphoma (FL), but information about patients with stage I FL who underwent total resection after tissue biopsy is limited. Among 305 FL patients diagnosed between 2001 and 2013, clinical stage I disease was observed in 36 patients. Of these, 18 patients underwent total resection after diagnostic tissue biopsy. We used (18)F-fluorodeoxyglucose positron emission CT for staging assessment in 13 of 18 patients (72.2%). The median age was 56.5 years. Six patients (33.3%) were male. The soluble interleukin-2 receptor alpha concentration was significantly lower than in patients with residual disease. Among these 18 patients, 7 patients (38.9%) were treated with a “watch-and-wait” (WW) policy, 7 (38.9%) were treated with involved-field irradiation, and 4 (22.2%) received systemic chemotherapy. Patients with resected disease were treated with significantly different strategies from those with residual disease (p = 0.0026). Five patients experienced relapse during follow-up (median follow-up: 48.2 months). All relapses were distant from the primary site, irrespective of treatment strategy. Among all stage I patients, disease resection was not a significant factor for survival (p = 0.9294). Collectively, the choice of treatment strategy was significantly influenced by patient status. Resection status was not significantly associated with survival after several treatment strategies.

Clinical information regarding non-Hodgkin lymphoma (NHL) in adolescents and young adults (AYA) is lacking. We retrospectively analyzed 1426 consecutively registered patients with newly diagnosed NHL. Of 798 DLBCL patients, 42 (5.3%) were identified as AYA (16–39 years). The characteristics of AYA DLBCL patients showed no significant differences compared to older adult DLBCL patients (age ≥ 40 years). Progression-free survival (PFS) and overall survival (OS) in AYA were similar to those in patients aged 40–60 years. However, in older adult groups, PFS and OS were significantly different according to the age group (40–60, 61–79, and ≥ 80 years). In univariate analysis in AYA, performance status, clinical stage, International Prognostic Index (IPI), and age-adjusted IPI significantly affected both PFS and OS. In multivariate analysis, only clinical stage was identified as an independent predictor among AYA. In conclusion, disease characteristics and outcomes of DLBCL in AYA were nearly the same as those in older adults.

Single nucleotide polymorphisms (SNPs) in interleukin 17 (IL17A) and IL-23 receptor (IL23R) are involved in the pathogenesis of many cancers and autoimmune diseases. We investigated the influence of IL17A and IL23R SNPs on the risk of developing multiple myeloma (MM) and its clinical features. We obtained genomic DNA from 120 patients with MM and 201 healthy controls and detected IL17A -197 G/A (rs2275913) and IL23R H3Q (rs1884444) genotypes using the polymerase chain reaction-restriction fragment length polymorphism method. There were no significant differences in the genotype and allele frequencies of IL17A -197 G/A and IL23R H3Q between the controls and patients with MM. Compared with the GG and GA genotypes, the IL17A AA genotype was significantly associated with lower hemoglobin levels. The IL23R HH genotype was significantly associated with higher frequency of bone lesions and plasmacytoma than the HQ and QQ genotypes. We observed significant differences in overall survival (OS) between patients treated with thalidomide and/or bortezomib and those treated conventionally. Therefore, we also examined the effect of IL17A and IL23R polymorphisms on the clinical variables and OS in patients treated with thalidomide and/or bortezomib. We observed that the IL23R HH genotype was significantly associated with poor survival compared with the QH and HH genotypes in these patients. Our findings indicate that IL17A -197 G/A and IL23R H3Q are not associated with susceptibility to MM. However, IL-17 and IL-23R polymorphisms may affect severity, bone lesions, and extra-medullary disease in patients with MM. Moreover, IL23R polymorphisms may contribute to poor prognosis in patients with MM treated with thalidomide and/or bortezomib.

We evaluated the prognostic significance of the serum level of the soluble form of interleukin-2 receptorα (sIL-2Rα) and investigated its association with CD25 expression on tumor cells in diffuse large B-cell lymphoma (DLBCL). Three hundred and thirty-eight adult patients with newly diagnosed DLBCL were eligible for this retrospective study. 32.2% of patients were treated with CHOP-like regimen and 67.8% with R-CHOP-like regimen. CD25 expression on the surface of tumor cells was evaluated in 143 cases and its relationship with sIL-2Rα level was also investigated. Both overall survival (OS) and progression-free survival (PFS) were poorer in patients with higher sIL-2Rα, in both R-CHOP and CHOP groups. sIL-2Rα > 1,000 U/mL and performance status (PS) ≥ 2 were independently associated with poorer OS, and sIL-2Rα > 1,000 U/mL, age > 60 years, and ≥ 2 extranodal sites were independently associated with poorer PFS in the R-CHOP group. The sIL-2Rα level was higher in the CD25-positive group than in the CD25-negative group in stage 3 or 4 disease (p = 0.010). Multiple linear regression analysis showed CD25 expression to be independently correlated with sIL-2Rα levels. High sIL-2Rα is an important risk factor for survival in DLBCL treated with not only CHOP-like, but also R-CHOP-like regimens, regardless of the tumor's expression of CD25.

We describe a patient who developed repeated rituximab-induced serum sickness (RISS) followed by anaphylaxis soon after the third administration of rituximab at relapse. A 65-year-old woman with Sjögren's syndrome and relapsed mucosal associated lymphoma tissue (MALT) lymphoma of the lung underwent rituximab monotherapy (375 mg/m(2)/week). Several days after the second exposure to rituximab, she developed a rash, fever, and arthralgia. These symptoms showed relief, but a severe anaphylactic reaction occurred when she was treated with rituximab for the third time. Although a rare complication in patients with lymphoma, clinicians should be aware of RISS symptoms and avoid repeatedly administering rituximab to such patients.

Interleukin-10 (IL-10) and IL-10 receptor (IL-10R) single nucleotide polymorphisms have been implicated in the pathogenesis of many cancers. We investigated the influence of IL-10 -592C/A, IL-10RA I224V, and IL-10RB K47E on the risk of developing multiple myeloma (MM) and the clinical features of MM. We extracted the genomic DNA from 128 MM patients and 202 healthy controls and used polymerase chain reaction-restriction fragment length polymorphism method to detect IL-10 promoter -592C/A (rs1800872), IL-10RA (rs2228055), and IL-10RB K47E (rs2834167) genotypes. Overall survival (OS) was defined as the interval from the date of diagnosis to the date of death or last clinical appointment. No statistically significant difference was observed in the genotype and allele frequencies of IL-10 -592C/A, IL-10RA I224V, and IL-10RB K47E between MM patients and healthy controls. IL-10RA II genotype was significantly associated with a hemoglobin level lower than that of IV and VV genotypes (mean ± standard deviation, 9.21 ± 2.46 vs 10.3 ± 2.33 g/dL; P = .021). IL-10 -592 AA genotype was significantly associated with OS better than that of CA and CC genotypes (median OS, 74.5 vs 46.3 months; P = .047). We observed significant differences in survival between patients treated with thalidomide and/or bortezomib and those treated with conventional treatments (median OS, 74.5 vs 38.2 months; P = .021). Therefore, we also examined the effect of IL-10 and IL-10R polymorphisms on the clinical variables and OS of patients treated with thalidomide and/or bortezomib. In addition, IL-10RB EE genotype was significantly associated with poorer survival than KK and KE genotypes (median OS, 46.3 vs 78.8 months; P = .015). Our findings indicate that IL-10 and IL-10R gene polymorphisms may not contribute to the susceptibility to MM but may be associated with the severity and prognosis of MM. In particular, IL-10RB K47E polymorphism may contribute to the poor prognosis of MM patients treated with thalidomide and/or bortezomib.

l-[3-18F]-alpha-methyltyrosine (18F-FAMT) is an amino-acid tracer for positron emission tomography (PET), with uptake related to overexpression of L-type amino-acid transporter 1 and proliferative activity in tumour cells. This study evaluated the diagnostic performance of 18F-FAMT PET compared with 2-[18F]-fluoro-2-deoxy-d-glucose (18F-FDG) PET in patients with multiple myeloma (MM). Eleven patients with MM (newly diagnosed, n = 3; relapsed after treatment, n = 8) underwent whole-body 18F-FAMT and 18F-FDG PET within a 2-week interval. Magnetic resonance imaging (MRI) of the spine was also performed to assess patterns of bone marrow infiltration. Tracer uptake was semi-quantitatively evaluated using maximal standardized uptake value (SUVmax). Mean SUV was also determined for normal bone marrow and the aortic arch as mediastinal background SUV to calculate lesion-to-bone marrow (L/B) and lesion-to-mediastinum (L/M) ratios, respectively. Those values were statistically compared using Student’s t test. In 8 patients showing focal infiltration on MRI, 34 FDG-avid bone lesions were identified, with each showing increased FAMT uptake. Mean SUVmax and L/B ratio of FDG (3.1 ± 1.2 and 3.3 ± 1.9, respectively) were significantly higher than those of FAMT (2.0 ± 1.0 and 2.6 ± 1.1, respectively; p

Objectives: Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by the production of autoreactive antibodies against platelet antigens. Although dysfunction of multiple aspects of cellular immunity is considered to be important in the pathogenesis of ITP, it has not been clarified which cell types play a principal role. Methods: We enrolled 46 untreated patients with chronic ITP and 47 healthy adult volunteers, and investigated by flow cytometry the percentage and absolute number of cells in their peripheral blood that participate in the regulation of cellular immunity. These included plasmacytoid dendritic cells (pDCs), myeloid dendritic cells (mDCs), natural killer (NK) cells, natural killer T (NKT) cells, regulatory T (Treg) cells, and Th17 cells. Results: We found a significant reduction in the absolute number of pDCs, but not of mDCs, in patients with ITP when compared with healthy controls (P

To the Editor,Panobinostat (LBH589, FARYDAK®) is a nonselective histone deacetylase inhibitor that has shown synergistic anti-myeloma activity in combination with bortezomib [1]. In a pivotal phase...

Introduction: We report the results of a prospective study of long-tern treatment with single-agent thalidomide in patients who had responded in a preceding trial of the use of thalidomide for relapsed/refractory myeloma. Patients and Methods: Nineteen patients were enrolled: 11 patients (57.9%) treated at a dosage of 100 mg/day; 2 patients (10.5%) at a dosage of 200 mg/day; 2 patients (10.5%) at a dosage of 300 mg/day; and 4 patients (21.1%) at a dosage of 400 mg/day. The median follow-up from the start of the preceding study was 3.0 years. At the time of entry to this study, 5 patients (26.3%) had partial response (PR), another 5 patients (26.3%) had a minimal response (MR), and the remaining 9 patients (47.4%) had shown no change (NC). Results: The cumulative MR rate was 78.9% (at the 32nd week) and the cumulative PR rate was 47.4% (at the 112th week). The median progression-free survival was 104 weeks and the median time to next treatment was 144 weeks. No patients experienced grade 4 or greater hematologic toxicity or grade 3 or greater non-hematologic toxicity. Conclusion: Long-term thalidomide maintenance therapy induced an increase in response rate, suppressed the progression to active myeloma without severe adverse events, and contributed to long survival with good activities of daily living.

【背景・目的】 抗レトロウイルス療法を継続中のHIV (human immunodeficiency virus) 感染者の一部では血液中のウイルス量が十分抑制されているにもかかわらず, CD4陽性T細胞の回復が十分でない症例が認められるため, この要因について検討をした. 【対象と方法】 群馬大学医学部附属病院及び関連施設において, 抗HIV療法下で5年以上の長期間にわたってウイルス血症が検出限界以下と良好にコントロールされているHIV感染者46名におけるCD4陽性T細胞数の回復と, 治療開始時の年齢, CD4陽性T細胞数, 治療レジメン, 性別との関係について相関をみた. 【結 果】 CD4陽性T細胞数の回復が不十分なグループ (CD4数

Hypercholesterolemia is one of the most representative disorders of the common diseases. To evaluate the prevalence of hypothyroidism in the population of adult hypercholesterolemia, we prospectively examined the thyroid function in patients with untreated or treated hypercholesterolemia as a multi-center survey. Subjects were the patients who were treated with some antilipemic agents or the untreated patients whose total cholesterol (TC) was over 220 mg/dL and/or LDL-cholesterol (LDL-C) over 140 mg/dL. Among 737 cases recruited, 725 cases (300 males and 425 females) participated in the survey including the thyroid function test. The patient's backgrounds include hypertension (51%), diabetes mellitus (49%), fatty liver (17%), smoking (15%), and habitual drinking (10%). The 72% of the patients were treated with some antilipemic agents and the mean values of TC, LDL-C, triglyceride (TG), HDL-cholesterol (HDL-C), and LDL-C/HDL-C ratio (L/H) were 204.5 mg/dL, 119.6 mg/dL, 144.4 mg/dL, 60.7 mg/dL and 2.25, respectively. The primary hypothyroidism was seen in 27 cases (3.7%) (11 males, 16 females) with subclinical hypothyroidism in 17 cases (2.4%) and overt hypothyroidism in 10 cases (1.4%). The central hypothyroidism was seen in 4 cases (0.6%). The prevalence of hypothyroidism was 4.3% in patients with hypercholesterolemia. Taking account of the large number of patients with dyslipidemia and importance of avoiding unnecessary administration and associated adverse effects, evaluation of the thyroid function could be warranted in patients with dyslipidemia although cost-benefit issues waits further investigation.

The efficacy and safety of high-dose chemotherapy with tandem autologous peripheral blood stem cell transplantation (auto-PBSCT) were evaluated in a multicenter clinical study of patients with advanced multiple myeloma. Eligible patients (n = 40) were consecutively enrolled in the phase I/II study and received 2-4 cycles of vincristine-adriamycin-dexamethasone regimen. The responding patients underwent PBSC harvesting following high-dose cyclophosphamide and filgrastim administration. The first auto-PBSCT (n = 32) following high-dose melphalan (200 mg/m(2)) was performed within 2 months of PBSC harvesting; the second auto-PBSCT (n = 28) was scheduled 3-6 months later. Treatment-related mortality was 2.5% (n = 1) throughout the protocol. Grade 4 nonhematologic toxicity occurred in 12.5 and 14.3% of the first and second auto-PBSCT patients, respectively. All but one patient (who died) achieved hematopoietic recovery. For the 28 patients completing the second auto-PBSCT, the results were favorable with a response rate of 65% (complete response rate = 27.5%, n = 11); the five-year progression-free survival and overall survival were 20.3 and 66.5%, respectively. In conclusion, high-dose chemotherapy with tandem auto-PBSCT is feasible and safe with a favorable response rate in treating advanced multiple myeloma in Japan.

Paraneoplastic neuropathies have rarely been reported in patients with hematological malignancies. We report herein the case of a 65-year-old Japanese woman with chronic myelomonocytic leukemia (CMML) accompanying chronic inflammatory demyelinating polyneuropathy (CIDP). She had been diagnosed with refractory anemia and subsequently developed CMML with cytogenetic abnormalities including t(3;8)(q26;q24). While regenerating bone marrow following induction chemotherapy, she complained of numbness in the lower legs and then became unable to walk. Clinical and electrophysiological features were consistent with CIDP. Intravenous immunoglobulin treatment was insufficient, although corticosteroids reduced neurological symptoms. This case suggests CIDP as one of the autoimmune phenomena associated with myelodysplastic syndrome and immunosuppressive treatment represents an effective therapy.

Many controlled clinical trials have proven that rituximab improves the clinical outcome of patients with mature B cell lymphoma. This study was conducted to assess the contribution of rituximab in the actual clinical practice. Patients with newly diagnosed mature B cell lymphoma treated at 20 National Hospital Organization hospitals from January 2000 to December 2004 were consecutively registered. Rituximab was approved in September 2002 for indolent B cell lymphoma and in September 2003 for aggressive B cell lymphoma in Japan. The patients were divided into two groups depending on whether they received induction therapy containing rituximab. The endpoint was to evaluate the rituximab benefit based on 2-year progression-free survival (PFS) and 2-year overall survival (OS). A total 1126 patients received chemotherapies. Of these, 762 were diagnosed as diffuse large B cell lymphoma (DLBCL) and 215 as follicular lymphoma (FL). PFS and OS were markedly improved in the rituximab group compared with the non-rituximab group in patients with DLBCL (both P < 0.001) and in patients with FL (P < 0.001 and P = 0.003 respectively). Rituximab, when used for remission induction therapy, significantly improved the clinical outcome of the mature B cell lymphoma patient in actual clinical practice.

There have been conflicting reports over the JAK2-V617F mutation status of platelets in chronic myeloproliferative diseases (CMPDs). The aim of this study was to analyse JAK2-V617F status, not only in granulocytes but also in platelets. The JAK2-V617F mutation was analysed in both granulocytes and platelets in 115 patients with CMPDs using direct sequencing. JAK2-V617F was detected in granulocytes from 71 of those patients, all 71 of whom also had platelet JAK2-V617F expression. The remaining 44 patients showed negative JAK2-V617F expression on granulocytes, but positive JAK2-V617F expression was detected on the platelets from nine of the 33 essential thrombocythaemia (ET) patients, one of the eight polycythaemia vera patients, and two of the three primary myelofibrosis patients. When ET patients were divided into three groups according to granulocyte and platelet JAK2-V617F status (both-positive, platelets-only positive and both-negative), the both-positive and platelets-only positive groups shared the clinical features of higher white blood cell count and frequent thrombosis. These results suggest that analysis of platelets is a more sensitive approach for detecting JAK2-V617F in CMPD patients than analysis of granulocytes. They also suggest that previous reports of the incidence of JAK2-V617F in CMPD patients, obtained using only analysis of granulocytes, could be underestimations.

Bortezomib is one of the most widely used novel drugs for the treatment of multiple myeloma (MM). However, twice-weekly intravenous administration is associated with innegligible adverse events and treatment discontinuation. We therefore evaluated the long-term efficacy and feasibility of reduced frequency treatment with intravenous bortezomib in elderly patients with relapsed and/or refractory MM. A total of 47 bortezomib-naive patients (median age 75 years) received bortezomib (1.3 mg/m2, intravenously) and dexamethasone (20 mg) on days 1, 8, and 15 of every 4-week cycle. Twenty-six patients completed the planned 8 cycles. Best responses were stringent complete response (sCR) in 5 patients, very good partial response (VGPR) in 3, PR in 15, stable disease (SD) in 18, and disease progression (PD) in 6, respectively. Median progression-free and overall survivals were 9.6 and 35.1 months, respectively. After progression, 11 patients were retreated with bortezomib-based regimens and another 24 patients with immunomodulatory drugs. Multivariate analysis revealed that ISS 3, t(4;14), and

To determine the clinical significance of the T helper 1(Th1)/T helper 2 (Th2) ratio in multiple myeloma, the intracellular IFN-gamma and IL-4 were analyzed by flow cytometry in 56 patients with multiple myeloma. The mean Th1/Th2 ratio of cases in the initial diagnosis phase and the refractory phase were higher than that of the control group. The mean serum beta-2-microglobulin in the high Th1/Th2 subgroup was significantly higher than that in the normal Th1/Th2 subgroup (P < 0.05). In conclusion, the Th1/Th2 ratio was closely related to the disease status of multiple myeloma.

We compared the effect of high-dose therapy together with autologous peripheral blood stem cell transplantation (autoPBSCT) in 60 patients with multiple myeloma (MM) with 90 patients who underwent conventional chemotherapy. We scored the prognostic factors according to our reported classification system that includes measurements of serum albumin, serum beta-2-microglobulin, and morphology of myeloma cells selected by multivariate analysis. We separated the patients into three risk groups at stratification level I (low, intermediate and high) and into two risk groups at stratification level II (low and high). AutoPBSCT tended to be as effective for high, as for low-risk patients in level I, and was obviously as helpful for high, as for low-risk patients in stratification II. In conclusion, high-risk patients with MM should be treated with high-dose therapy accompanied with autoPBSCT like low-risk patients.

L-type amino-acid transporter 1 (LAT1) plays a key role in cell growth and survival. To determine the prognostic significance of LAT1 in multiple myeloma (MM), we investigated the expression of LAT1 and its functional subunit, 4Fc heavy chain (CD98), on myeloma cells by immunohistochemistry in 100 newly diagnosed MM patients. High expression (moderate or strong staining intensity) of LAT1 and CD98 was detected in 56% and 45% of patients, respectively. The LAT1 expression score was positively correlated with Ki-67 index (r = 0.631, P < 0.001), and there was a statistically significant difference in Durie–Salmon stage between patients with high and low LAT1 expression (P = 0.03). In 43 patients treated with melphalan and prednisolone, the overall response rate was significantly higher in the high LAT1 expression group (60.0%) than in the low LAT1 expression group (17.6%) (P = 0.03). Multivariate analysis confirmed that high expression of LAT1 was a significant prognostic factor for predicting poor overall survival independently from the International Staging System (both P = 0.01). Here, we show that the overexpression of LAT1 is significantly associated with high proliferation and poor prognosis in newly diagnosed MM patients. Thus, LAT1 may be a promising pathological marker for identifying high-risk MM.

Various prognostic markers for multiple myeloma (MM) have been identified, and stratification using these markers is considered important to optimize treatment strategies. The international staging system (ISS) is now a widely accepted prognostic staging system for MM patients; however, its validity is controversial in the era of new therapeutic regimens, since ISS had been established before introduction of new agents. We retrospectively reviewed prognostic factors in order to seek out an alternative staging system more suitably applied to MM patients treated with novel agents. We analyzed 178 newly diagnosed MM patients who received either conventional chemotherapy without novel agents (CT; n = 79) or chemotherapy with novel agents (NT; n = 99). Although median overall survival (OS) of patients treated with CT is significantly different depending on stages of ISS, ISS had no effect on OS among patients treated with NT. Meanwhile, we identified hemoglobin (Hb) and plasmacytoma as independent risk factors for OS in patients who received NT. Using these two parameters, we stratified NT patients into three stages; stage 1 (Hb≥10 g/dL and absence of plasmacytoma), stage 2 (not stage 1 or 3), and stage 3 (Hb

We studied tumor cell invasions of bone marrow and peripheral blood in patients with various types of advanced non-Hodgkin's lymphoma by amplifying complementarity determining region III using the polymerase chain reaction (PCR) method and developing patient-specific probes. After molecular engineering, we could detect tumor cells in bone marrow from seven of 11 cases and in peripheral blood from six of 11 cases, despite negative results in four cases studied morphologically. Indolent cases were more likely to yield positive results than aggressive cases. The reason may be different biological behaviors among the histological types.

非ホジキンリンパ腫intermediate grade 36例にCOPBLAM/MEVMP療法 (cyclophosphamide, vincristine, prednisolone, bleomycin, doxorubicin, procarbazine/mitoxantrone, etoposide, vindesine, meth-otrexate, prednisolone) を試みた.症例は男21例, 女15例で, 年齢は16から69歳 (中央値52歳), 臨床病期はI期1, II期5, III期10, IV期20例であった.全症例の完全寛解率 (CR) は69%, 5年生存率56%, 5年Event free survival (EFS) 42%であり, International Indexのlowとintermediate lowを合わせた5年生存率は71%, highとintermediate highを合わせた群では33%であった.副作用として骨髄抑制, 口内炎がみられ, 後半のMEVMPで目立ったが耐えうるものであった.MTX投与時期に若干の改良が必要であるが, 有用な治療法の一つと考えられた.

We evaluated the prognostic significance of the serum level of the soluble form of interleukin-2 receptorα (sIL-2Rα) and investigated its association with CD25 expression on tumor cells in diffuse large B-cell lymphoma (DLBCL). Three hundred and thirty-eight adult patients with newly diagnosed DLBCL were eligible for this retrospective study. 32.2% of patients were treated with CHOP-like regimen and 67.8% with R-CHOP-like regimen. CD25 expression on the surface of tumor cells was evaluated in 143 cases and its relationship with sIL-2Rα level was also investigated. Both overall survival (OS) and progression-free survival (PFS) were poorer in patients with higher sIL-2Rα, in both R-CHOP and CHOP groups. sIL-2Rα1,000 U/mL and performance status (PS) ≥ 2 were independently associated with poorer OS, and sIL-2Rα1,000 U/mL, age60 years, and ≥ 2 extranodal sites were independently associated with poorer PFS in the R-CHOP group. The sIL-2Rα level was higher in the CD25-positive group than in the CD25-negative group in stage 3 or 4 disease (p = 0.010). Multiple linear regression analysis showed CD25 expression to be independently correlated with sIL-2Rα levels. High sIL-2Rα is an important risk factor for survival in DLBCL treated with not only CHOP-like, but also R-CHOP-like regimens, regardless of the tumor's expression of CD25.

We report three patients with pulmonary disorders associated with myelodysplastic syndromes (MDS). All three patients had symptoms of pyrexia and respiratory discomfort. One patient had pulmonary eosinophilia with bilateral pleural effusion, one had interstitial pneumonia, and one had bilateral pleural effusion caused by systemic vasculitis. Elevated C-reactive protein (CRP) levels, polyclonal hypergammaglobulinemia, and morphological abnormalities in peripheral blood were observed in all three patients. The bone marrow of these patients revealed trilineage dysplasia and eosinophilia. Cytogenetic analysis showed [46,XY,-7,+der(1q;7p)]. Antibiotic treatment was not effective. However, improvement was dramatic after corticosteroid treatment; CRP levels were reduced and the hypergammaglobulinemia was improved. These cases suggest that MDS with [-7,+der(1q;7p)] may be correlated with bone marrow eosinophilia and that an immunologic abnormality may be involved in the pulmonary disorders.