A multicenter phase II study of intrabone single-unit cord blood transplantation without antithymocyte globulin.

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 × 107/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 × 109/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 × 109/L and platelets ≥ 50 × 109/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 × 109/L and platelets ≥ 50 × 109/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.

Prospective evaluation of alternative donor from unrelated donor and cord blood in adult acute leukemia and myelodysplastic syndrome.

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.

Prospective Phase 2 Study of Umbilical Cord Blood Transplantation in Adult Acute Leukemia and Myelodysplastic Syndrome.

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.

Oncological and renal outcomes of segmental ureterectomy vs. radical nephroureterectomy for upper tract urothelial carcinoma.

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.

PSA response following the 'steroid switch' in patients with castration-resistant prostate cancer treated with abiraterone: A case report.

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 <1.0 ng/ml, but thereafter gradually increased. Subsequent bicalutamide withdrawal response was not observed, and switch of anti-androgen therapy to flutamide also resulted in a poor response. Then, abiraterone (1,000 mg daily) in combination with prednisolone (10 mg daily) was initiated when the level of PSA increased to 35.9 ng/ml in June 2015. The level of PSA decreased to the lowest point of 4 ng/ml; however, PSA level increased again to 21.7 ng/ml in April 2016. Consequently, a 'steroid switch' was attempted. Abiraterone therapy was continued, but concomitant corticosteroid was switched from prednisone to dexamethasone (1.0 mg per day). Fortunately, serum PSA level decreased promptly to the lowest point of 0.6 ng/ml. In the present case report, a review of recent literature was presented and potential explanations of the mechanism underlying the 'steroid switch' were described. Pharmacokinetic differences between dexamethasone and prednisolone may partially explain why the 'steroid switch' occurs. Other mechanisms may include the activation of the glucocorticoid receptor, mineralocorticoid receptor and/or mutant androgen receptor. Corticosteroids accelerate a number of transcription factors, cellular growth factors and cytokines, which may also be potential mechanisms. The 'steroid switch' at PSA progression might be a feasible option for therapy, which may delay the development of the disease. Although the underlying mechanisms require further study, clinicians should pay attention to this phenomenon.

Abiraterone acetate withdrawal syndrome: Speculations on the underlying mechanisms.

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 <1.0 ng/ml after AA discontinuation. His PSA remained <1.0 ng/ml without clinical or radiological progression for 1 year after AA withdrawal. Recently, it was reported that cessation of AA is associated with AA withdrawal syndrome in metastatic castration-resistant prostate cancer, defined as a PSA decrease after AA discontinuation, mimicking anti-androgen withdrawal syndrome. In the present study, explanations of the mechanisms underlying this phenomenon were explored, including mutant AR activation by alternative ligands.

Disseminated Cutaneous Infection of Mycobacterium colombiense in a Patient with Myelodysplastic Syndrome.

Mycobacterium colombiense (M. colombiense) is a member of the Mycobacterium avium complex (MAC). To our knowledge, this is the third case report of an M. colombiense infection. An 80-year-old man, immunocompromised by myelodysplastic syndrome (MDS), developed a skin rash with exfoliation and eruption on his face and scalp. Mycobacteria were detected in pus samples. Broad-range polymerase chain reaction (PCR) revealed the mycobacteria to be M. colombiense. The lesions resolved after daily administration of rifampicin, ethambutol, and clarithromycin. In conclusion, broad-range PCR identified this rare mycobacterium, allowing for the administration of appropriate combination antibiotic therapy.

Prospective observational study on the first 51 cases of peripheral blood stem cell transplantation from unrelated donors in Japan.

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.

A multicenter phase 2 study of empirical low-dose liposomal amphotericin B in patients with refractory febrile neutropenia.

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 Efficacy of an Oral Elemental Diet in Patients Undergoing Hematopoietic Stem Cell Transplantation.

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.

Trousseau's syndrome caused by bladder cancer producing granulocyte colony-stimulating factor and parathyroid hormone-related protein: A case report.

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.

Analysis of repeated 24-core saturation prostate biopsy: Inverse association between asymptomatic histological inflammation and prostate cancer detection.

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<0.01), the fPSA/tPSA ratio was lower (P=0.04), the total prostate volume was smaller (P=0.01) and the PSA density was higher (P<0.01) in PCa patients than in patients with benign prostatic disease (BPD). Histological inflammation was more frequently observed in BPD patients than in PCa patients (P<0.01). A multivariate analysis revealed that histological inflammation was the only independent predictor of the presence of a malignant lesion on repeat biopsy (odds ratio, 0.027; P=0.01). It must be considered that inflammation may cause a PSA increase in some patients with a negative initial biopsy, leading to unnecessary repeat biopsy.

Analysis of Japanese Patients Treated with or without Long-Term Epirubicin Plus Ara-C Intravesical Instillation Therapy for Low-Grade Superficial Bladder Cancer.

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.

Minimally Invasive Endourological Techniques may Provide a Novel Method for Relieving Urinary Obstruction due to Ureterosciatic Herniation.

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.

Chimerism status after unrelated donor bone marrow transplantation with fludarabine-melphalan conditioning is affected by the melphalan dose and is predictive of relapse.

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.