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To overcome the delayed or failed engraftment after unrelated cord blood transplantation (CBT), we conducted a multicenter phase II study of intrabone single-unit CBT without antithymocyte globulin (ATG) for adult patients with hematological malignancies (UMIN-CTR, UMIN000020997). Sixty-four patients received an intrabone injection of unwashed (n = 61) or washed (n = 3) cord blood after local anesthesia. All injection-related adverse events were mild and resolved spontaneously. Sixty-two patients were evaluable for the efficacy of intrabone CBT of serological HLA-A, -B, and -DR ≥ 4/6 matched cord blood with a median number of 2.57 × 10^7/kg cryopreserved total nucleated cells. The probability of survival with neutrophil engraftment on day 28 was 77.4% (95% confidence interval, 67.0–85.8%), which exceeded the threshold value. The cumulative incidences of neutrophils ≥ 0.5 × 10^9/L on day 60 was 80.6% (68.2–88.6%), with a median time to recovery of 21 days after transplantation. The cumulative incidences of platelets ≥ 20 × 10^9/L and platelets ≥ 50 × 10^9/L on day 100 were 75.8% (62.6–84.9%) and 72.6% (59.4–82.1%), respectively, with median time to platelets ≥ 20 × 10^9/L and platelets ≥ 50 × 10^9/L of 38 and 45 days after transplantation, respectively. The cumulative incidences of grade II–IV and III–IV acute graft-versus-host disease were 29.0% and 6.5%, respectively. All responded to steroid therapy, and secondary treatments were not required. The present study suggests the efficacy of intrabone single-unit CBT without ATG in terms of early engraftment and controllable acute graft-versus-host disease.

A prospectively registered observational study was conducted to assess the significance of allogeneic hematopoietic stem cell transplantation from highly HLA-matched unrelated donors (UD) and cord blood (CB) on outcomes in adult acute leukemia (AL) and myelodysplastic syndrome (MDS). Between 2007 and 2015, 231 transplant-eligible patients were registered for a phase 2 study of alternative donor transplantation. After registration, a sufficient time period was given to find appropriate UD. Patients received CB transplantation (CBT) if an appropriate UD was unavailable. In total, 119 patients received CBT (106 AL and 13 MDS) and 91 patients received UD transplantation (UDT) (86 AL and 5 MDS). The median age was 39 years in both groups. The primary objective was overall survival (OS); secondary objectives included cumulative incidences of non-relapse mortality (NRM) and relapse, and disease-free survival. Diagnosis, disease status at transplantation, refined disease risk index, and hematopoietic cell transplant-specific comorbidity index did not differ between UDT and CBT. In multivariate analyses, graft source was not a significant risk factor for all objectives. In adjusted analyses, UDT and CBT showed similar OS, NRM, and relapse in this prospective study. CB can be a comparable alternative stem cell source to UD by achieving a timely transplant.

Almost comparable transplantation outcomes have been reported with HLA-matched unrelated donor transplantation (UDT) and cord blood transplantation (CBT). We conducted a prospective phase 2 study to assess the efficacy and safety of single-unit myeloablative CBT in adult leukemia and myelodysplastic syndrome. Because the day 180 survival of UDT was approximately 80%, we determined the alternative hypothesis of expected day 180 survival with a successful engraftment rate of 80% and set the null hypothesis of threshold rate at 65%. Sixty-two patients (median age, 37 years) were registered, including 28 with acute myelogenous leukemia, 25 with acute lymphoblastic leukemia, and 9 with myelodysplastic syndrome. Of 61 eligible patients, 52 were successfully engrafted and survived at day 180 (85%; 95% confidence interval, 74% to 93%). Single-unit CBT was judged to be effective because the null hypothesis was rejected (P.001). Furthermore, neutrophil engraftment was observed in 57 patients (92%); the incidences of grade II-IV acute and chronic graft-versus-host disease were 30% and 32%, respectively; and the cumulative incidences of nonrelapse mortality and relapse at 2 years were 18% and 13%, respectively. The present study showed favorable survival outcomes with single-unit CBT. Therefore, this method may be considered if a well-HLA-matched UDT cannot be obtained.

Invasive fungal infection (IFI) is a major life-threatening problem encountered by patients with hematological malignancies receiving intensive chemotherapy. Empirical antifungal agents are therefore important. Despite the availability of antifungal agents for such situations, the optimal agents and administration methods remain unclear. We conducted a prospective phase 2 study of empirical 1 mg/kg/day liposomal amphotericin B (L-AMB) in 80 patients receiving intensive chemotherapy for hematological malignancies. All enrolled patients were high-risk and had recurrent prolonged febrile neutropenia despite having received broad-spectrum antibacterial therapy for at least 72 hours. Fifty-three patients (66.3 %) achieved the primary endpoint of successful treatment, thus exceeding the predefined threshold success rate. No patients developed IFI. The treatment completion rate was 73.8 %, and only two cases ceased treatment because of adverse events. The most frequent events were reversible electrolyte abnormalities. We consider low-dose L-AMB to provide comparable efficacy and improved safety and cost-effectiveness when compared with other empirical antifungal therapies. Additional large-scale randomized studies are needed to determine the clinical usefulness of L-AMB relative to other empirical antifungal therapies.

The present study reports a rare case of bladder cancer that caused Trousseau's syndrome, a malignancy-associated hypercoagulative state leading to venous or arterial thrombosis. A 38-year-old Japanese female patient experienced a sudden onset of visual field defects and lower limb weakness. Cerebral magnetic resonance imaging revealed multi-regional hypointense areas compatible with acute cerebral infarction. Despite the repeated administration of anticoagulant treatment with heparin, the condition could not be adequately controlled and thromboembolic events occasionally recurred. Several tumor markers, including carbohydrate antigen 19–9, cancer antigen 125, carcinoembryonic antigen, cytokeratin 19 fragment and squamous cell carcinoma antigen levels, were elevated. Consequently, computed tomography scans were performed, which revealed a massive bladder tumor with multiple bone and lymph node metastases. The patient also exhibited other paraneoplastic disorders, including leukocytosis due to granulocyte colony-stimulating factor (G-CSF) production, and hypercalcemia due to parathyroid hormone-related protein (PTHrP) production. Transurethral resection of the bladder tumor was performed, and the tumor was pathologically confirmed as urothelial cell carcinoma. Immunohistochemical testing revealed positive staining for G-CSF and PTHrP. Despite undergoing gemcitabine/cisplatin-based systemic chemotherapy, the disease developed rapidly and the patient succumbed to the disease within 3 months of initial symptoms. The present case indicates that occult visceral malignancy should be considered in patients with unexplained thromboembolism.

Saturation prostate biopsy protocols have been developed to improve the prostate cancer (PCa) detection rate, particularly in the setting of repeat biopsies. The present study attempted to clarify the association between PCa detection and various risk factors in repeat saturation biopsies. A retrospective analysis was conducted on 78 Japanese patients for whom findings had caused suspicion of PCa despite previous negative prostate biopsies, and who consecutively underwent a 24-core transperineal repeat biopsy at Toyama University Hospital (Toyama, Japan). PCa was confirmed histologically in 16 of the 78 patients (20.5%). A univariate analysis revealed that the prostate-specific antigen (PSA) level at repeat biopsy was higher (P

Segmental ureterectomy (SU) represents a promising alternative for the treatment of upper tract urothelial carcinomas (UTUCs) as it is a less invasive procedure and guarantees the preservation of renal units. The present study evaluated oncological outcomes and renal functions following SU when compared with radical nephroureterectomy (RNU). A total of 26 patients with UTUCs who underwent SU (n=12) or RNU (n=14) were retrospectively evaluated. SU was performed in patients with clinically unifocal disease. In the SU group, the following surgeries were carried out: 7 direct ureterocystoneostomy, 1 reimplantation on psoas hitch bladder, 1 reimplantation on Boari flap bladder, 2 ureteral end-to-end anastomosis and 1 subtotal ureterectomy. In the SU group, tumors were low grade urothelial carcinoma (UC) in 6 patients, high grade UC in 5 patients and high grade UC with squamous cell differentiation in 1 patient, as well as ≤pT1 in 5, ≥pT2 in 6 and pTis in 1 patient; ‘p’ refers to the pathological state. The 5-year overall, cancer-specific, recurrence free and metastasis free survival in the SU group were 77.8, 87.5, 34.4 and 80.8%, respectively, which all exhibited no significant differences when compared with those of the RNU group. With regard to renal function, postoperative estimated glomerular filtration rates were preserved in the SU group. The present study demonstrated that SU does not result in poorer cancer control when compared with RNU. Thus, SU is an acceptable alternative to RNU in selected cases, as it is less invasive and preserves renal functions.

Background The prognosis of CML has dramatically improved with the introduction of imatinib. Patients diagnosed in chronic phase can live almost as long time as healthy people. However, adequate strategy of pregnancy under TKI treatment has not been established. Case report 31-year-old-female was introduced to us because of leukocytosis. She was diagnosed as CML CP. We let her visit OB-GYN clinic with her partner to preserve a fertilized egg. After its preservation, we initiated dasatinib as her first-line-treatment. She achieved CHR in a month, CCyR in 3 months, and MMR in 10 months. Therefore, her clinical course could be evaluated as optimal. However, she strongly requested to have a baby early. We switched her TKI from dasatinib to nilotinib for deeper molecular response. 5 months later, she accidentally became pregnant. She stopped taking nilotinib at 5th week of her pregnancy and selected to give a birth even with a risk: her disease had not reached DMR. Considering her disease status, it was impossible to stop all the treatment, so we initiated IFN-alpha, which was known not to cross the placenta. She did not experience any adverse event with it, and successfully gave birth to a 2500g baby without any abnormality. We checked MRD once in 3 months, her disease kept MR4.0 all the pregnancy period.[Discussion] Discontinuation of TKIs is under trial now. According to the JSH guideline, significant treatment duration (over 3 years) and DMR more than MR4.5 over 2 years are necessary conditions for planning pregnancy. But 2 and more years could be said too long for young women who hope for children. In this case, we switched TKIs for achieving DMR as early as possible. But unexpected pregnancy occurred in MMR. As a result, she gave a birth without any major event under IFN-alpha therapy. Conclusion The IFN-alpha therapy for pregnant female achieved safe and normal delivery.

Objective Conditioning regimens for hematopoietic stem cell transplantation (HSCT) are well known to cause severe gastrointestinal toxicities that often disturb the oral intake of the patients followed by poor nutrition and life-threatening infection. An oral elemental diet (ED) is an easily consumed and assimilated form of liquid nutrients mainly composed of amino acids. It alleviates the digestive loading from the intestine and is mainly used for enteral nutritional support in patients with Crohn's disease. We herein report, for the first time, the efficacy of ED for patients undergoing HSCT. Methods We evaluated the efficacy of ED in a prospective cohort study. The primary endpoint for this study was the hospitalization period. The secondary endpoint was the occurrence of oral mucositis, nausea, diarrhea and fever. Patients A total of 73 patients were consecutively enrolled between March 2011 and March 2013. Twenty-three patients underwent autologous HSCT and 50 patients underwent allogeneic HSCT. The first 21 patients did not receive ED (non-ED group; NEG) while in the successive 52 patients (ED group; EG), oral ED was started before conditioning and was continued until 28 days after transplantation. Results The patient characteristics were similar between the two groups. The mean duration of ED administration for EG was 28.7 days (range, 3-37 days), and the mean total-dose of ED administration was 1904 g (range, 240-2,960 g). The median hospitalization period was significantly shorter in EG compared to NEG, (34 days vs. 50 days; p=0.007). Grade 3-4 oral mucositis occurred less in EG than NEG (25% vs. 48%; p=0.06). Conclusion Oral ED may promote an early mucosal recovery and thereby shorten the duration of hospitalization.

Influence of melphalan plus fludarabine-conditioning regimen in elderly patients aged ⩾ 55 years with hematological malignancies

Little is known regarding the chimerism status after reduced-intensity conditioning transplantation when bone marrow is used as a stem cell source. We prospectively analyzed lineage-specific chimerism and retrospectively evaluated clinical outcomes in 80 adult patients who underwent unrelated donor bone marrow transplantation (URBMT) with fludarabine plus melphalan (FM) as the conditioning regimen. Mixed donor chimerism (MDC) was seen in 43 and 10 % of patients at days 14 and 28, respectively. Melphalan at ≤130 mg/m(2) was associated with an increased incidence of MDC at day 28 (P = 0.03). Patients with MDC at day 14 showed a marginally increased risk of primary graft failure and a marginally decreased risk of graft-versus-host disease. In multivariate analysis, MDC at day 14 was associated with higher overall mortality (hazard ratio (HR) = 2.1; 95 % confidence interval (CI), 1.1-4.2; P = 0.04) and relapse rate (HR = 3.0; 95 % CI, 1.2-7.5; P = 0.02), but not with non-relapse mortality (HR = 1.8; 95 % CI, 0.70-4.6; P = 0.23). Thus, the FM regimen yields prompt complete donor chimerism after URBMT, but the melphalan dose significantly impacts the kinetics of chimerism. Chimerism status evaluation at day 14 may be instrumental in predicting relapse after URBMT with the FM regimen.

A 69-year-old man presented initially with back pain and incomplete bilateral lower limb paralysis. The level of prostate-specific antigen (PSA) in the patient was elevated to 167.0 ng/ml, and multiple bone metastases were detected. Thoracic laminectomy was performed in an emergency due to spinal decompression. Subsequently, the patient was diagnosed with prostate cancer from an examination of resected bone specimens. Combined androgen blockade with degarelix and bicalutamide was initiated in October 2013. Consequently, the serum PSA level decreased to

A 72-year-old man initially presented with lumbar and right chest pain, but was later found out to also have an elevated prostate-specific antigen (PSA) level at 2,000.0 ng/ml. Further evaluation disclosed metastatic prostate cancer involving the bones and lymph nodes. The patient was initially treated with combined androgen blockade (CAB) with leuprolide acetate and bicalutamide. After 6 months of CAB, the patient's PSA level began to rise from the nadir (85.1 ng/ml) to 113.3 ng/ml. Bicalutamide was withdrawn in anticipation of anti-androgen withdrawal syndrome and the PSA level declined temporally. However, it increased up to 517.0 ng/ml thereafter. Consequently, a year after CAB, abiraterone acetate (AA) was initiated at a standard dose of 1,000 mg daily in combination with 10 mg of prednisolone. PSA rapidly decreased to the nadir of 20.1 ng/ml thereafter. The PSA level remained stable until 2 years after AA administration. However, he decided to reduce the dose of AA to half of the standard dose (500 mg daily). Contrary to our expectations, the serum PSA level promptly decreased to a nadir of 8.1 ng/ml. Thereafter, the PSA level remained stable until 3 years and 9 months after AA administration. Subsequently, the patient stopped taking AA and prednisolone. However, to our surprise, the patient's serum PSA level decreased further to

The Japan Marrow Donor Program (JMDP) has facilitated unrelated peripheral blood stem cell transplantation (URPBSCT) since 2010. We conducted a prospective multicenter observational study to evaluate the feasibility of such transplantation. Between 2011 and 2014, 51 patients underwent URPBSCT from 8/8 allele-matched donors for hematological malignancies. The median age of the patients was 50 years; 21 had high-risk disease. Myeloablative conditioning regimens were used in 31 patients, and tacrolimus based graft-versus-host disease (GVHD) prophylaxis was used for all patients. The cumulative rate of engraftment was 96%. With a median follow-up period of 610 days for survivors, 100-day and 1-year overall survival rates were 86 and 59%, respectively. The cumulative incidence of non-relapse mortality and relapse at 1 year were 14 and 35%, respectively. The incidence of grade II to IV acute GVHD at 100 days and extensive type of chronic GVHD at 1 year were 25 and 32%, respectively. The probability of overall survival was comparable with that of bone marrow transplantation from HLA matched-unrelated donors in Japan, although the incidence of chronic GVHD was higher. Further follow-up with more patients is clearly warranted to establish the optimal use of URPBSCT together with the approaches of minimizing chronic GVHD.

Ureterosciatic herniation, the protrusion of the hernia sac through the sciatic foramen, is an extremely rare cause of ureteral obstruction. We describe a case revealed by severe left back pain in a 72-year-old female. She was referred to our hospital for urological assessment of left hydronephrosis observed by ultrasonography. Intravenous ureterography (IVU) showed findings compatible with a left sciatic ureter, a dilated ureter with a fixed kinking, which is known as the ‘curlicue' sign. We decided to attempt recovery of the herniated ureter using a retrograde approach. Ureteral stent placement was performed to decompress the dilated upper urinary tract. The ureterosciatic hernia was relieved with the passage of a flexible guide wire and a double-pigtail stent. Three months after ureteral stenting, she refused continuing to have an indwelling stent and the stent was removed. Thereafter, IVU revealed recurrent ureterosciatic hernia; however, there was no hydroureter or hydronephrosis. The patient is currently being under observation for 6 years after stenting and continues to be without hydronephrosis or symptoms. Placement of an internal stent possibly provides the rigidity to the ureter, thereby reducing the hernia and urinary obstruction. In the previous reports, most symptomatic patients have been treated surgically, with conservative therapy reserved for asymptomatic patients. For the patient who is elderly or a poor surgical candidate, retrograde stenting may provide safe reduction and efficacious treatment. This endourological approach provides a minimally invasive means for the management of urinary obstruction caused by ureterosciatic herniation.

To clarify the cooperative roles of recurrently identified mutations and to establish a more precise risk classification system in acute myeloid leukemia (AML), we comprehensively analyzed mutations in 51 genes, as well as cytogenetics and 11 chimeric transcripts, in 197 adult patients with de novo AML who were registered in the Japan Adult Leukemia Study Group AML201 study. We identified a total of 505 mutations in 44 genes, while only five genes, FLT3, NPM1, CEBPA, DNMT3A and KIT, were mutated in more than 10% of the patients. Although several cooperative and exclusive mutation patterns were observed, the accumulated mutation number was higher in cytogenetically normal AML and lower in AML with RUNX1-RUNX1T1 and CBFB-MYH11, indicating a strong potential of these translocations for the initiation of AML. Furthermore, we evaluated the prognostic impacts of each sole mutation and the combinations of mutations and/or cytogenetics, and demonstrated that AML patients could be clearly stratified into five risk groups for overall survival by including the mutation status of DNMT3A, MLL-PTD and TP53 genes in the risk classification system of the European LeukemiaNet. These results indicate that the prognosis of AML could be stratified by the major mutation status in combination with cytogenetics.

Background: Among HLA-well-matched unrelated donor (UD) and umbilical cord blood (CB), HLA-8/8 allele-matched UD transplantation (UDT) showed superior overall survival (OS) to 7/8 allele-matched UDT and CBT, while a similar OS has been demonstrated between the HLA-7/8 allele-matched UDT and the CBT. However, a fair comparison between UDT and CBT is difficult, because graft availability and time required for donor-search is completely different. Once patients relapsed during UD-search period, most of those patients would choose immediate CBT. This means that patients who maintained CR in UD group may have more favorable characteristics, because those patients have been longer in remission and selected as a group of patients who maintained CR. Thus we thought that the factor of "donor-search duration" is important upon conducting a comparative study between UDT and CBT. We planned a clinical study that also taken "donor-search duration" into consideration to compare CBT outcomes with HLA well-matched UDT in a prospective trial setting. Purpose: The purpose of the current study is to compare the transplant outcomes of HLA-well-matched UDT with those of CBT in a prospective trial. Patients and Methods: From 2007 to 2015, 231 patients were provisionally registered for a single-arm phase 2 study of CBT (manuscript submitted). All provisionally registered patients were subjects of current study (Figure 1). After provisional registration, we attempted to find appropriate UD within a decent time period. After approximately 180 days of donor-search, patients received CBT if an appropriate UD was not available. In total, 91 patients received UDT, and 119 patients received CBT. Six patients withdrew and three died before transplantation. Twelve patients did not receive either UDT or CBT, but five received HLA-mismatched SCT from family donor (seven chose not to receive allogeneic SCT). Of 119 CBT recipients, 62 patients were eligible and registered to a phase 2 clinical trial reported elsewhere. Herein we analyzed transplant outcomes of 91 UDT and 119 CBT (UDT group; 49 AML, 37 ALL, 5 MDS: CBT group; 68 AML, 38 ALL, 13 MDS). Risk factors were analyzed by cox proportional hazard model, and survival estimates were depicted by Kaplan-Meier estimation and tested by log-rank test. Results: Patient age was median 39 yrs in both UDT and CBT (p=0.80). Patient body weight was median 59kg (37-90kg) in UDT, and median 55kg (35-90kg) in CBT (p=0.10). Sixty-six of 91 (72.5%) in UDT and 114 of 119 (95.8%) in CBT received myeloablative conditioning. More than 90% of patients received Tacrolimus and short-term methotrexate as GVHD prophylaxis in both UDT and CBT. Days from provisional registration to transplant were median 126 days (range, 77-261 days) in UDT, and median 99 days (8-286 days) in CBT (p Conclusion: Taken donor-search period into consideration, OS after UDT and CBT were similar in a prospective clinical study. CB may be the comparable alternative donor source to UDT. Disclosures Terakura: Novartis: Honoraria; Astellas Pharma Inc.: Honoraria; Amgen Astellas BioPharma K.K.: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Yakult Honsha, Co., Ltd.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria. Nishida:Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria; MSD K.K.: Consultancy, Honoraria; Amgen Astellas BioPharma K.K.: Honoraria. Sawa:Mundi Pharma: Honoraria; Bristol-Myers Squibb: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Sanofi: Honoraria; Astellas Pharma Inc.: Honoraria; Ono Pharmaceutical Co., Ltd: Honoraria; Otsuka Pharmaceutical: Honoraria; Kyowa-Hakko Kirin: Honoraria; Novartis: Honoraria; Shire: Honoraria; Eisai: Honoraria; Mochida: Honoraria; Pfizer Japan Inc.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Nippon Shinyaku: Honoraria; MSD: Honoraria; Asahi-Kasei: Honoraria; Takeda: Honoraria; Celgene: Honoraria. Miyao:Bristol-Myers Squibb: Honoraria; Celgene Corporation: Honoraria; Novartis: Honoraria. Ozawa:Pfizer Japan Inc.: Honoraria; Kyowa-Hakko Kirin: Honoraria; Astellas Pharma Inc.: Honoraria; Novartis: Honoraria. Goto:Celgene Co., Ltd.: Honoraria; JCR Pharmaceuticals Co., Ltd.: Honoraria; Novartis Pharma Co., Ltd.: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria. Onishi:Sumitomo Dainippon Pharma: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; ONO PHARMACEUTICAL CO., LTD.: Honoraria; Nippon Shinyaku: Honoraria; Kyowa-Hakko Kirin: Honoraria; Pfizer Japan Inc.: Honoraria; Astellas Pharma Inc.: Honoraria; Celgene: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Novartis Pharma: Honoraria; Takeda Pharmaceutical Co., Ltd.: Research Funding; MSD: Honoraria, Research Funding. Fukuhara:Janssen Pharma: Honoraria; Eisai: Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria; AbbVie: Research Funding; Celgene Corporation: Honoraria, Research Funding; Zenyaku: Honoraria; Bayer: Research Funding; Nippon Shinkyaku: Honoraria; Kyowa-Hakko Kirin: Honoraria; Mochida: Honoraria; Mundi: Honoraria; Ono Pharmaceutical Co., Ltd.: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Gilead: Research Funding; Solasia Pharma: Research Funding. Fujii:Novartis Pharma Co., Ltd.: Honoraria; Kyowa-Hakko Kirin Co., Ltd.: Honoraria. Iida:Chugai Pharmaceutical Co., Ltd.: Research Funding. Endo:Ono: Research Funding. Onizuka:Sumitomo Dainippon Pharma: Research Funding; Astellas: Research Funding; Novartis: Research Funding; pfizer: Research Funding; Chugai Pharma: Research Funding; Bristol-Myers Squibb: Research Funding. Iyama:Otsuka Pharmaceutical Co., Ltd.: Honoraria; Otsuka Pharmaceutical Factory: Honoraria; Astellas Pharma: Honoraria; Daiichi Sankyo: Honoraria; Allexion Pharma: Honoraria; CSL Behring: Honoraria. Nakamae:Japan Blood Products Organization: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyowa-Hakko Kirin Co.,Ltd: Honoraria; Nippon Shinyaku: Honoraria; Bristol-Myers Squibb: Honoraria; Shire Japan KK.: Honoraria; Pfizer Japan Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas Pharma Inc.: Research Funding; Alexion: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Novartis: Honoraria, Research Funding; Takeda Pharmaceutical Co., Ltd.: Honoraria. Nagata:Janssen Pharmaceutical K.K.: Honoraria; Bristol-Myers Squibb K.K.: Honoraria; Ono Pharmaceutical Co., Ltd: Honoraria; Novartis Pharma K.K.: Honoraria; Celgene K.K.: Honoraria; Takeda Pharmaceutical Co., Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kurahashi:Novartis Pharma Co., Ltd.: Honoraria; Bristol-Myers Squibb, Ltd.: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Takeda Pharmaceutical Co., Ltd: Honoraria. Suzuki:Celgene: Honoraria; Eisai: Honoraria; Novartis: Honoraria; Bristol-Myers Squibb: Honoraria; Kyowa Hakko Kirin: Honoraria; Chugai Pharmaceutical Co.,Ltd.: Honoraria; Meiji Seika: Honoraria; Merck Sharp & Dohme: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria; ONO Pharmaceutical Co., Ltd.: Honoraria; Janssen: Honoraria; AbbVie: Honoraria. Atsuta:Mochida Pharmaceutical Co. Ltd: Honoraria; Kyowa Kirin Co., Ltd: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Janssen Paharmaceutical K.K.: Honoraria. Miyamura:Bristol-Myers Squibb: Honoraria; Novartis: Honoraria; Pfizer Japan Inc.: Honoraria; Otsuka Pharmaceutical: Honoraria; Takeda Pharmaceutical: Honoraria; Kyowa-Hakko Kirin Co., Ltd: Honoraria; CHUGAI PHARMACEUTICAL CO., LTD.: Honoraria; Astellas Pharma Inc.: Honoraria; Celgene: Honoraria. Murata:Bristol-Myers Squibb, Ltd.: Honoraria; Kyowa-Hakko Kirin Co., Ltd.: Honoraria; Celgene Co., Ltd.: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Consultancy, Honoraria; GSK Co., Ltd.: Consultancy; Astellas Pharma Inc.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; JCR Pharmaceuticals Co., Ltd.: Honoraria; Novartis Pharma Co., Ltd.: Honoraria; MSD Co., Ltd.: Honoraria.

Tissue microarrays were constructed using prostate needle biopsy specimens obtained from 58 patients who underwent radical prostatectomy for localized or locally advanced prostate cancer (PC). We used the spiral array (SA) technique, a novel approach for tissue array construction in a spiral form, which has advantages over small needle biopsy specimens. Roll-shaped tissue pieces produced by slicing a prostate biopsy tissue block and trimming the cancer segment were used to obtain a tissue array block. Cancer segments measuring >3 mm were incorporated into the tissue arrays. Cancer fragments (n=253) were obtained from formalin-fixed, paraffin-embedded needle biopsy specimens. The median number of cancer fragments per patient was four (1-8, min-max). On SA, the median number of confirmed cancer fragments per patient was four (1-7) and 224 cancer fragments (88.5%) were confirmed histologically. Each core of reeled tissue contained at least one cancer fragment. The expressions of multiple prognostic molecular markers for PC (Ki-67, p53 and bcl-2) were immunohistochemically measured using the SA. The Ki-67 and bcl-2 expressions were significantly associated with the Gleason score (GS). A univariate analysis identified Ki-67, bcl-2 and GS as significant predictors of cancer-specific survival, p53 and bcl-2 as significant predictors of overall survival and Ki-67, adjuvant androgen deprivation and GS as significant predictors of biochemical progression. In a multivariate analysis, p53 was independently associated with overall survival, while adjuvant androgen deprivation and GS were associated with biochemical progression. These results indicate that SA has potential as a new tool for translational research on PC.

Background: We investigated how urinary, sexual, and testicular functions and generic health-related quality of life (HR-QOL) affect each other in aged men. Methods: Ninety patients who were negative for cancer on prostate biopsies were enrolled in this study. The mean patient age was 66±7 years (mean±s.d.). The mean prostate volume was 44.3±21.9 mL, and the mean serum total testosterone (TT) level was 3.63±1.18 ng/mL. Before conducting the prostate biopsies, the patients were asked to complete questionnaires, including the International Prostate Symptom Score (I-PSS), UCLA Prostate Cancer Index (UCLA-PCI), and the Rand Medical Outcome Study 36-Item Short Form (SF-36), to evaluate urinary symptoms, sexual function, and generic HR-QOL. The relationships between these parameters were analyzed. Other objective variables, such as the prostate volume, maximal urinary flow (Qmax), postvoid residual urine volume, and age, were also evaluated. Results: The TT level was found to be related to the I-PSS Q6...

Purpose: Retroperitoneal neural tumor (RNT) is rarely excised laparoscopically, and the laparoscopic management of RNT remains controversial. We herein report 4 cases of laparoscopic excision of RNT that resulted in diverse clinical outcomes. Patients and Methods: Between August 2005 and January 2011, we performed laparoscopic excision of RNT in 4 patients. The mean tumor size was 4.5 cm. The mean operative time was 297 minutes and the mean amount of blood loss was 55 ml. The surgeries were uneventful, with no operative complications or evidence of intra-abdominal bleeding. However, 2 patients required reoperation for delayed hemorrhage and urinoma formation, respectively. Results: The postoperative pathological diagnoses were schwannoma in 3 patients and ganglioneuroblastoma in 1 patient. All patients were well with no signs of peripheral neuropathy or radiculopathy, and CT and/or 18F-FDG PET/CT performed during follow-up indicated no evidence of disease. Conclusions: Obtaining extensive preoperative knowledge of the source neural and vascular anatomy of the tumor is important for the surgical planning of laparoscopic resection of RNT. When a great deal of care is taken to divide the tumor and the source nerves and vital vessels, safe execution of RNT can be achieved for minimal postoperative mortality and morbidity.

Impact of T-cell chimerism on relapse after cord blood transplantation for hematological malignancies: Nagoya Blood and Marrow Transplantation Group study

Objectives: We evaluated the effectiveness of antimuscarinic treatment on disease-specific and generic quality of life (QoL) in females with clinically diagnosed overactive bladder (OAB) by prospectively analyzing improvements in the overactive bladder symptom score (OABSS) and the Rand Medical Outcomes Study 36-Item Short Form Health Survey (SF-36). Methods: We prospectively recruited newly diagnosed female patients with OAB. Pretreatment disease-specific symptoms were documented, and generic QoL questionnaires were administered. All subjects received solifenacin 5 mg/day for >8 weeks. Symptoms and general health-related QoL (HRQoL) were assessed using the OABSS and SF-36, respectively. Other objective variables, such as maximum urinary flow rate and postvoid residual urine volume, were also evaluated. Results: Seventy-eight subjects met all inclusion criteria and no exclusion criteria. After 8 weeks, the mean OABSS decreased by approximately 50% compared with baseline (from 9.1 ± 2.8 to 4.5 ± 3.6). All individual scores in OABSS improved after administration of solifenacin. Before treatment, the scores of the study subjects in all SF-36 domains were significantly worse than the age- and gender-adjusted Japanese national norms (P < 0.01), except the vitality (VT) scale. Intra-group comparisons between age groups showed worse mental health (MH) scores in all age groups. In the OAB group, three mean SF-36 scales (physical function [PF], VT, and MH) significantly improved after treatment. Conclusion: Treatment of OAB with solifenacin is associated with significant improvement in generic HRQoL and disease-specific symptoms at 8 weeks after drug administration. Particularly for generic HRQoL as measured by the SF-36, solifenacin treatment effectively improves three SF-36 scores: PF, VT, and MH.

Background Because of the less graft-facilitating effect by bone marrow (BM), we need to assess a dosage of conditioning more accurately particularly in combination with reduced-intensity conditioning. Thus we examined that modified continual reassessment method (mCRM) is applicable for deciding appropriate conditioning of allogeneic BM transplantation. Patients and methods The conditioning regimen consisted of i.v. fludarabine (125 mg/m2) plus an examination dose of i.v. melphalan. The primary endpoint was a donor-type T-cell chimerism at day 28 with successful engraftment defined as >90% donor cells. Five patients per dose level were planned to be accrued and chimerism data were used to determine the next dose. Results Seventeen patients were enrolled at doses between 130 and 160 mg/m2. The dose was changed from 160 to 130 mg/m2 (second level) after five full-donor chimerisms. With one patient of 0% chimera in the second level, the dose was increased to 135 mg/m2 (third level). Following five full-donor chimerisms in the third level, the study was complete as projected. Conclusions mCRM was shown to be a relevant method for dose-finding of conditioning regimen. The melphalan dose of 135 mg/m2 was determined as the recommended phase II dose to induce initial full-donor chimerism.

611 Background: Hypertension (HT) is an established risk factor for developing renal cell carcinoma (RCC), and a relationship between the renin-angiotensin system and RCC has been emphasized. However, information about the impact of HT on treatment outcomes of patients after RCC surgery is limited. The present study aimed to clarify the impact of HT on the recurrence and survival of patients with RCC after surgery. Methods: Relationships between HT and clinical data including treatment outcomes were retrospectively analyzed in 149 patients (male, n = 112; female, n = 37; median age, 63 y; range, 29-86 y at the time of surgery) who underwent surgery between 2010 and 2016 at our hospital. Data were statistically analyzed using JMP version 9.0. Results: During a median follow-up period of 30.9 months, 28 and 16 patients experienced recurrence and died, respectively. Patients (n = 15) with Stage IV RCC were excluded from the analysis of recurrence. Five-year overall (OS) and recurrence-free (RFS) survival rates of the entire cohort were 80.8% and 76.1%, respectively. Kaplan-Meier analysis did not uncover a relationship between HT and OS, but the RFS rate was significantly lower for patients with HT than without HT (P = 0.0468). Tumor stage and the prevalence of proteinuria were significantly higher in the group with HT. The prevalences of vessel invasion (P = 0.0582) and low pre-surgical hemoglobin values (P = 0.0585) tended to be significantly higher for patients with HT. Conclusions: Patients with HT had significantly worse RFS rates, a more advanced stage of disease at the time of surgery, and a tendency towards a higher rate of vessel invasion. Further investigations are warranted to determine how HT promotes cancer progression.

Objective: We evaluated health-related quality of life (HRQOL) in Japanese men receiving androgen deprivation therapy (ADT) for prostate cancer. Methods: Fifty-six men were enrolled in this study. HRQOL was prospectively measured before ADT, and at 3, 6 and 12 months after treatment began, using a general (36-item Short-Form Health Survey) and disease-specific (the University of California, Los Angeles Prostate Cancer Index) HRQOL questionnaire. Results: In the general HRQOL questionnaire, patients with stage B (n = 22) or C (n = 17) disease showed a decline in vitality at 6 and 12 months (P

Aim: The clinical significance of the urinary white blood cell (U-WBC) count and serum C-reactive protein (CRP) level was evaluated in an effort to improve the efficiency of prostate biopsies. Methods: We enrolled 228 consecutive patients with serum prostate-specific antigen (PSA) ranging from 3.0 to 20.0 ng/mL, normal digital rectal examination findings, and who underwent prostate biopsies between January 2001 and August 2004. Of these, 157 patients had histologically confirmed benign prostatic disease and the remaining 71 patients had prostate cancer. Patients with a pretreatment U-WBC count ≤3 or >3/high power field were defined as non-pyuria and pyuria, respectively. The patients were also separated into two groups based on the serum CRP level prior to biopsy. Several clinical factors were compared among these subgroups. Results: Inflammation was histologically detected at rates of 58.1% and 34.1% in the pyuria and non-pyuria groups, respectively (P = 0.0014). The rates of cancer detection were significantly lower in the pyuria, than in the non-pyuria group (P = 0.0384). The cancer detection rates did not significantly differ according to serum CRP levels prior to biopsy. Conclusion: The U-WBC count appears to be a reliable indicator of minute prostatic inflammation. The serum PSA level was elevated in patients with asymptomatic prostatitis. Counting U-WBC is a simple, convenient and non-invasive method that should be valuable part of routine urological examinations.

The high incidence of tumor recurrence following transurethral resection (TUR) represents a major problem encountered in the management of bladder cancer. This study examined the efficacy of intravesical chemotherapy in superficial bladder cancer. We retrospectively analyzed 90 Japanese cases with low-grade superficial transitional cell carcinoma (stage T1, grades 1 and 2) who were rendered tumor-free by TURBT (TUR of bladder tumor) and who thereafter were treated with or without intravesical chemotherapy. Among them, instillation was terminated in 2 patients due to adverse effects (severe but reversible chemical cystitis). Remaining 88 patients were divided into 2 groups according to therapy: the TURBT-only group(n=46), defined as patients treated with TURBT alone, and the Instillation group(n=42), defined as patients treated with weekly intravesical instillation therapies using epirubicin plus Ara-C. Recurrence-free rate was significantly higher in the Instillation group than in the TURBT-only group (p=0.02, HR = 0.457). The 5-year recurrence-free rate was 58.5% for the Instillation group and 38.6% for the TURBT-only group. Our instillation schedule represents the most intensive regimen among previously reported therapies and resulted in a 54.3% decrease in incidence of tumor recurrence. We believe that the results of this study could provide useful information on management of bladder cancer.

Liver retraction is necessary for optimal exposure during laparoscopic right renal surgery. We described a patient who developed fulminant liver failure as a result of liver retractor-induced excessive ischemic changes in the right lobe of the liver. A 37-year-old male underwent a right side laparoscopic pyeloplasty for ureteropelvic junction obstruction. At the beginning of the operation, a small snake retractor was placed through a 5-mm port under direct vision. The liver was lifted in the appropriate direction to optimize exposure by using the laparoscope holder. The operation was prolonged. However, we achieved significant improvements in the efficiency of liver retraction using the holder. On the first postoperative day, the patient's serum levels of GOT, GPT and LDH had remarkably increased. A computerized tomogram confirmed the presence of excessive ischemic changes of the right lobe of the liver. Our method which used a laparoscope holder device for liver retraction maintained a better surgical field. However, neglecting to make minor adjustments to the positioning of the retractor can cause significant pressure on the liver parenchyma in a single area. As surgical procedures increase in complexity, the surgeon should keep these potential side effects in mind and shift the retraction point at regular intervals. In this report, we discussed various types of retractor-related liver injuries and their management, and highlighted the importance of intermittent release of retraction during prolonged surgery.

Treatment of primary central nervous system lymphoma (PCNSL) improved in recent years. However, the high neurotoxicity and low survival rates associated with this condition remain unresolved. We report 13 consecutive patients with PCNSL for whom upfront melphalan, cyclophosphamide, etoposide, and dexamethasone (known as LEED) followed by autologous stem-cell transplantation (ASCT) was planned at the Anjo Kosei Hospital. All patients were pathologically diagnosed with diffuse large B-cell lymphoma and were negative for human immunodeficiency virus. All patients were to receive three cycles of high-dose methotrexate-based induction chemotherapy, two cycles of high-dose AraC-based chemotherapy, and LEED followed by ASCT. All 13 patients achieved a partial response, and the 3-year overall survival (OS) rate was 76.2 %. Seven of the 13 patients were alive at the last follow-up, without any adverse events, including neurotoxicity. Six of the 13 (46.2 %) patients underwent ASCT and the 3-year OS rate was 80.0 %. Although this study included only a limited number of patients, these preliminary signs of efficacy and tolerability merit further consideration. To make further improvements in survival, the rate of patients undergoing ASCT should be increased. Other prospective studies involving greater numbers of patients are required to confirm these findings.

Empirical antifungal therapy is the current standard of care for patients with febrile neutropenia unresponsive to broad-spectrum antimicrobials. Although a number of antifungal agents are currently available, the need remains for effective but less toxic alternatives for this indication. We therefore conducted a phase 2 study of micafungin for 80 patients with hematologic diseases who were suffering from persistent or recurrent fever after at least 96 h of antibacterial therapy. The patients were treated with micafungin at a fixed dose of 150 mg/day. Of the 78 evaluable patients, 54 (69 %) achieved defervescence by the time of neutrophil recovery, and 56 (72 %) completed the treatment in accordance with the provision of the protocol. Four patients developed invasive fungal infection, nine changed antifungal therapy because of lack of efficacy, and three discontinued micafungin because of drug-related adverse events. Based on the composite end point taking account of these, the overall treatment success rate was 60 %, with the lower limit of a 90 % confidence interval (50.3 %) exceeding the predefined threshold success rate (50 %). These findings show the efficacy and safety of micafungin for empirical antifungal therapy in patients with persistent or recurrent febrile neutropenia, warranting further investigation of this drug in a phase 3 study.

Hemophagocytic syndrome (HPS) induced by uncontrolled macrophage activation and subsequent graft failure is a frequent and prominent complication after allogeneic stem cell transplantation (allo-SCT), a cause of severe morbidity and death, and a therapeutic challenge. Liposome-incorporated dexamethasone, dexamethasone palmitate (DP), shows greater efficacy against macrophages as compared to dexamethasone sodium phosphate (DSP). Based on our findings that DP achieves significantly larger decrease than DSP on the viability of primary human macrophages compared in vitro, we tested the effects of DP in patients with HPS. A decrease in number of macrophages in the bone marrow and prevention of engraftment failure were observed in all patients without any severe complications. In conclusion, these data provide a rationale for testing DP as a first-line treatment for patients with HPS after allo-SCT.

We retrospectively evaluated the outcome of oral low-dose dexamethasone (DXM) therapy for androgen-independent prostate cancer (AIPC). Between January 1999 and April 2006, 99 consecutive patients with AIPC were enrolled in this study. The median patient age was 70 years (range 46–86), and the median pretreatment prostate-specific antigen (PSA) level was 243 ng/ml (range 8.2–29600). Median follow-up was 41.9 months (range 11.4–170.4). Upon biochemical failure, patients were treated with oral low-dose DXM. A total of 40 of the 99 cases (40.4%) showed a ≥50% decrease in serum PSA levels (PSA responders). Twenty-five cases (25.2%) showed a

Aims Circadian clocks regulate daily rhythms of behavior and physiology such as the sleep–wake cycle and hormonal secretion. Numerous characteristics of the behavioral and physiological processes change with age. In this study, we evaluated the circadian clockwork in older people by measuring daily profiles of PERIOD ( PER ) gene expression in peripheral blood mononuclear cells (PBMCs). Main methods Blood samples were collected from 6 healthy older subjects (mean age 62 years) at 2-h intervals over a 24-h period under a semi-constant routine condition where masking effects are minimized. PBMCs were isolated from whole blood and temporal mRNA expression profiles of PER1 , PER2 , and PER3 were determined by RT-PCR. Phases of the PER rhythms, and times of sleep onset and offset were determined using data from those subjects who showed significant 24-h rhythms. The values for the parameters were compared between the older subjects and 8 young control subjects (mean age 21 years). Key findings Prominent daily rhythms of PER1 , PER2 , and PER3 mRNA levels, advanced sleep–wake timing and advanced phases of PER rhythms were observed in the older subjects compared to the young controls. There was no significant age-related phase difference in PER1 or PER2 rhythm with respect to sleep timing; however, PER3 expression pattern was altered in the older subjects. Significance This preliminary study shows that human circadian clockwork in PBMCs remains intact at least until the presenile stage and suggests that the altered PER3 expression pattern may reflect decreased homeostatic sleep drive in older people.

Dear Editor, A 64-year-old man was diagnosed with symptomatic multiple myeloma (MM) in June 2009. No extramedullary region including the testes was detected. Serum protein electrophoresis showed IgA-κmonoclonal protein. Durie-Salmon stagewas IIIA and International Staging System stage was II. Treatment was initiated with pulsed dexamethasone and bortezomib (1.3 mg/m) twice weekly with dexamethasone (20 mg on the day of bortezomib administration and the next day).Without any adverse events, he achieved very good partial response (VGPR) after three cycles of bortezomib therapy [1]. Subsequently, he received high-dose melphalan (200 mg/m) followed by autologous stem cell transplantation (ASCT) in November 2009. After ASCT, he was followed up without any therapeutic agents. However, in September 2010, he complained of hip pain, and serum IgA level was elevated to 2,014 mg/dl. As recurrence of MM was diagnosed, we started weekly bortezomib with dexamethasone. The patient soon experienced improvement of symptoms, and serum IgA decreased to normal levels. In July 2011, during weekly bortezomib and dexamethasone, the patient noticed enlargement of his scrotum. Magnetic resonance image revealed enlarged bilateral testes. Serum IgA levels and all other laboratory data were normal. Bilateral orchidectomy was performed in October 2011. Microscopic examination showed positive results for CD56, CD138, and IgA and κ light chain (Fig. 1a, b). The pathological diagnosis wasmetastasis of plasma cell myeloma to the bilateral testes, and the right spermatic cord had positive margins. In November 2011, serum IgA was elevated to 2,304 mg/dl. At relapse of systemicMM including spermatic margins after orchidectomy, a 28-day cycle of lenalidomide (25 mg on days 1–21) and dexamethasone (40 mg on days 1, 8, 15, and 22) was initiated [2]. Serum IgA levels decreased to 1,026 mg/dl and reached a plateau without stump recurrence of the spermatic cord. After 6 cycles of lenalidomide, the patient was treated with cyclophosphamide, vincristine, adriamycin, and dexamethasone (C-VAD) and achieved VGPR after two cycles of C-VAD therapy. In August 2012, he successfully underwent a second ASCT. Two months after ASCT, he started a 28-day cycle of lenalidomide maintenance therapy (10mg on days 1–21) [3]. As of the time of writing, the patient remains alive without recurrence.

A case of urethral leiomyoma is presented. The patient was a 48-year-old female who was hospitalized with a 4-year history of a progressively enlarging urethral mass. Based on clinical diagnosis of benign urethral tumor, local excision was performed. Histological diagnosis was urethral leiomyoma and the tumor cells demonstrated immunoreactivity for estrogen receptors. We report our experience of a leiomyoma of the urethra expressing estrogen receptors.

We report a primary adrenal leiomyosarcoma in a 59-year-old man. Computed tomography demonstrated a poorly enhanced mass, measuring 10 cm, between the left kidney and the normal left adrenal gland, with tumor thrombus in the inferior vena cava (IVC). The patient underwent left radical nephroadrenalectomy with IVC thrombectomy. The histological diagnosis was adrenal leiomyosarcoma. Adrenal leiomyosarcomas are extremely rare. Only seven cases have been reported previously in the English-language literature.

Repetition effect in event-related potentials (ERPs) was studied in 10 non-thought-disordered (non-TD) patients with schizophrenia, 8 thought-disordered (TD) patients with schizophrenia, and 10 normal control subjects while they performed a semantic categorization task with incidental word repetitions. All patients were in a stable or partially remitted stage. Although both healthy control and non-TD groups produced more positive ERPs to the repeated words than to the new words (ERP repetition effect) for 250-500 ms, the TD group did not show the ERP repetition effect. These findings suggest that the abnormal attenuation of the ERP repetition effect during semantic processing may be more prominent in schizophrenic patients with thought disorder than in those without the symptom.

Background: Oral elemental diet (ED) is easily assimilated form of liquid nutrients composed of amino acids, sugars, vitamins and minerals. It alleviates the digestive loading from the intestine and mainly used for enteral nutritional support in the treatment of patients with Crohn's disease. High dose alkylating agents and total body irradiation (TBI) commonly used in conditioning regimens for hematopoietic stem cell transplantation (HSCT) are well known to cause severe gastro intestinal toxicities including mucositis associated with oral pain which often disturb oral intake of the patient. Inadequate nutrition requiring total parenteral nutrition (TPN) prolongs hospitalization and life-threatening infection may result from bacterial translocation through damaged mucosal membranes. Objectives: To our best knowledge, there are no previous reports of the efficacy of ED in patients with HSCT. We conducted a prospective cohort study to determine whether ED improved patients' outcome. Patients: We enrolled 73 consecutive patients who underwent HSCT between Mar. 2011 and Mar. 2013 in Anjo Kosei Hospital. Fifty patients undergone allogeneic HSCT, and 23 patients undergone autologous HSCT. The sources of allogeneic HSCT were unrelated bone marrow (n=16), related peripheral blood stem cell (n=16), unrelated cord blood (n=18). Median age was 47 years old (range, 17-72 years). There were 41 male and 32 female patients. Patients had leukemia (n = 38), malignant lymphoma (n = 24), multiple myeloma (n = 7), and others (n = 3). At transplant, 52 patients were in complete remission (CR), 21 patients were in non-CR. Twenty-one patients who were transplanted before November 2011 did not receive any ED (non-ED group; NEG), and 52 patients transplanted afterward November 2011 received an ED as standard care (ED-group; EG). Methods: ED administration was initiated from day -8 to day -4 to all patients when conditioning regimens for HSCT began, and ended on day +28 after HSCT. The recommended dose was 80g (1255 kJ) daily for total oral ED intake. We didn’t exclude the intake after failure of ED administration, additional food intake, and total parenteral nutrition (TPN). Our standard practice for allogeneic HSCT has been to start TPN on day -1 and continue until patients achieve a documented caloric intake of 6279 kJ per day after engraftment. For autologous HSCT, our protocol has been to start TPN when patients fail to reach a documented caloric intake of 6279 kJ per day by food intake and continue until this level is reached. This study was approved by our institutional review board. Results: Patient characteristics were not significantly different between the two groups. The median days of ED administration was 30 days (range, 3–37 days). The median number of days of oral food intake for EG and NEG were 22 days (range, 2–37) and 25 days (range, 3–35 days) days, respectively (P = 0.90). There were no adverse events reported due to ED administration. Grade 3/4 oral mucositis occurred in 13 (25%) EG patients and 10 (48%) NEG patients (P=0.06). Mean duration of mucositis in EG and NEG were 2.8 days and 5.6 days (P=0.07), respectively. Grade 2 to 4 fever occurred in 43 (83%) EG patients and 14 (67%) NEG patients (P=0.13), and the mean duration of fever were 3.9 days and 5.0 days, respectively (P=0.95). Acute GVHD occurred in 8 (19%) EG patients and 7 (46%) NEG patients (P=0.21). The mean duration of patient hospitalization was 36.6 days in EG patients and 57.3 days in NEG patients (P=0.003). Day100 non-relapse mortalities were 4 (8%) in EG patients and 3 (14%) in NEG patients (P=0.40). Conclusions: Oral intake of ED in patients with HSCT significantly reduced the duration of hospitalization and showed the possibility to improve the occurrence of grade 3/4 oral mucositis without adverse events. Disclosures No relevant conflicts of interest to declare.

Background: Novel agents for multiple myeloma (MM) have been reported to increase complete remission (CR) rates compared with conventional chemotherapy. It is also estimated that deeper remission may improve survival in MM patients. We retrospectively evaluated the efficacy of novel agents combined induction chemotherapy to treat MM patients who are candidate for autologous stem cell transplant (ASCT). Patients and methods: Thirty seven newly diagnosed MM patients who underwent ASCT at our hospital from April 2004 to September 2012 were retrospectively analyzed. The 20 patients who underwent ASCT before July 2009 were treated with conventional induction Chemotherapy: doxorubicin, vincristine, dexamethasone (VAD) or cyclophosphamide plus VAD (C-VAD), and the recent 17 patients were treated with bortezomib and dexamethasone (BD) followed by ASCT. Results: The median age of patients were 61yr (range: 46-70). The median follow up time was 1041 days (range: 25-2804). There were no significant differences in the patient characteristics between those two groups other than the year of transplant. CR rate was significantly higher in BD group compared with conventional treatment group (56.3% vs. 15.0%, p Conclusion: Bortezomib combined induction chemotherapy for MM may improve survival by achieving deeper remission in ASCT setting.

Abstract 2273 Poster Board II-250 Background Development of reduced intensity conditioning (RIC) regimen has enabled older patients, who are not expected to tolerate the toxicity of myeloablative conditioning, to be treated with allogeneic HSCT. Because the risk of rejection after BMT is substantially higher than that of PBSCT in RIC transplantation, PBSC is commonly used for RIC transplantation. However, PBSCT from unrelated donors is not currently available in Japan. Therefore, a better dosage of conditioning to ensure engraftment in RIC with BM is needed. Here, we selected the fludarabine plus melphalan regimen which has sufficient potential to induce marrow engraftment if melphalan at 180mg/m2 is used, and planned further optimization of melphalan dosage. The rationale for modulating the dose of melphalan resulted from accumulated observations that melphalan is associated with toxicities, while fludarabine is not. Because the optimal dose of melphalan to minimize regimen-related toxicities and to enable sustained engraftment remains unknown to date, we investigated the recommended dose of melphalan in a phase I study. Patients and Methods To adjust the melphalan dose, we adopted a modified continual reassessment method (CRM) which has been hypothesized to allow a faster and more accurate dose reduction/escalation in patients needed to reach the recommended dose compared with classical algorithmic dose modification design. The conditioning regimen consisted of 125 mg/m2 intravenous fludarabine (day-6∼-2) in combination with the examination dose of intravenous melphalan (day-3, -2). Because the use of fludarabine at 125mg/m2 and melphalan at 180mg/m2 was known to induce reliable engraftment, we set the first dose level to receive 160mg/m2 of melphalan. The primary endpoint was an achievement of donor-type T-cell chimerism at day 28 with successful engraftment defined as 90% or more donor cells. Five patients were planned to be accrued for each dose level and chimerism data was used to determine the next dose. A maximum dose reduction of melphalan for the next level was limited to 30mg/m2 to avoid the potential risk of graft-failure. GVHD prophylaxis consisted of short term methotrexate and tacrolimus. The eligibility criteria were 1) patients with hematological malignancies, who have had more than 3 course of chemotherapy, 2) age, 55 to 65 years, or 40 to 54 years with substantial comorbidity (HCT-CI of 1 or more), 3) no prior stem cell transplantation. The protocol was approved by the Institutional Review Board of each institution. All patients and donors provided written informed consent. Results Seventeen patients were enrolled at doses between 130mg/m2 and 160mg/m2, including one protocol violation and one early death (brain hemorrhage). Both were unavailable for assessment according to the study definition in advance. Of the 15 evaluable patients (9 male, 6 female), the median age was 58 years old (range: 45-63), and their diagnosis were 10 AML, 2 NHL, 1 CML 1 ALL and 1 plasmacytoma. The dose was reduced from 160mg/m2 (level-1) to 130mg/m2 (level-2) after 5 consecutive full donor chimerism (all were 100% at day 28) were observed in level-1. In the level-2, we observed four patients with 100% chimera, and one with 0% chimera at day 28, which eventually resulted in graft-failure. Following the calculation by CRM from level-2, the examination dose was increased to 135mg/m2 (level-3). In the level-3, 5 consecutive full donor chimerism (four 100% and one 90.4%) were observed again. Because the next examination dose was calculated as within 5mg/m2 from the level-3 (135mg/m2), the study was complete as projected. We could not detect any significant difference among the dose levels in terms of toxicity, relapse rate or survival. Discussion Successful dose finding using modified CRM was accomplished. The strategy using engraftment as a primary endpoint instead of toxicity promotes a better chance to determine the optimal dosage compared with the classical phase I trial design with modified Fibonacci method. Our findings demonstrated the melphalan dose of 135mg/m2 in combination with fludarabine is able to induce initial full donor chimerism after unrelated donor BMT and is recommended for further phase II evaluation. Disclosures: No relevant conflicts of interest to declare.