[Kidney transplantation for end-stage renal disease after third allogeneic hematopoietic stem cell transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia].

An 18-year-old man underwent allogenic bone marrow transplantation (BMT) for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). Ph+ALL relapsed 3 months after the first BMT, and the patient underwent a second BMT. However, Ph+ALL relapsed 4 months after the second BMT, and he received a haploidentical peripheral blood stem cell transplantation (haplo-PBSCT) from his father. Molecular complete remission was confirmed 29 days after haplo-PBSCT. However, the patient needed dialysis for end-stage renal disease due to thrombotic microangiopathy 3 years and 2 months after haplo-PBSCT. He received a kidney transplantation from his father 7 years and 10 months after haplo-PBSCT, and got off dialysis after the kidney transplantation. Immunosuppressive therapy with methylprednisolone, tacrolimus, and mycophenolate mofetil was started for kidney transplantation, but the dose of immunosuppressive agents was reduced successfully without rejection soon after kidney transplantation. The patient has maintained long-term remission since the haplo-PBSCT, and his kidney function was restored by the kidney transplantation from his father.

Intensified conditioning regimens improved disease-free survival and engraftment after unrelated single-unit cord blood transplantation but not after matched sibling or matched unrelated donor allogeneic hematopoietic cell transplantation.

The impact of conditioning intensity on different donor groups has been unclear in allogeneic transplantation. The objective of this study was to clarify the effect of conditioning intensity on disease-free survival (DFS), relapse, non-relapse mortality (NRM), neutrophil engraftment, and graft-versus-host disease for each donor type. We retrospectively evaluated the effect of conditioning intensity on transplant outcomes for patients with acute leukemia or myelodysplastic syndrome aged between 16 and 60 years in Japan using the transplant conditioning intensity (TCI) scoring system. A total of 8526 patients who received first allogeneic transplantation from 6/6 antigen-matched sibling donor (MSD, n = 2768), 8/8 allele-matched unrelated donor (MUD, n = 2357), and unrelated single-cord blood (UCB, n = 3401) were eligible for the analyses. Compared to conditioning with TCI score 4.0, which was corresponds to conventional myeloablative conditioning, including cyclophosphamide with total body irradiation 12 Gy or busulfan 12.8 mg, and was considered as the reference group in the multivariate analyses, intensified conditioning with TCI score ≥4.5 improved DFS (hazard ratio [HR],0.81, P < 0.001) and relapse rate (HR, 0.70, P < 0.001) but only after UCB transplants and not MSD and MUD transplants. In contrast, NRM was higher after intensified conditioning with TCI score ≥4.5 for MSD (HR, 1.39, P = 0.008) and MUD (HR, 1.47, P = 0.002) transplants but not UCB transplants (HR, 1.12, P = 0.240). Neutrophil engraftment was also significantly higher after intensified conditioning with TCI score ≥4.5 but only for UCB transplants (HR, 1.24, P < 0.001), whereas it was significantly lower after reduced-intensity conditioning with TCI score ≤3.5 for MSD transplants only (HR, 0.82, P < 0.001). These data demonstrated that an intensified conditioning regimen improved survival and engraftment rate only after a UCB transplants. Therefore, TCI scoring system could enable the optimization of conditioning intensity according to donor type, particularly in terms of survival and engraftment.

Phase I trial of myeloablative conditioning with 3-day total marrow and lymphoid irradiation for leukemia.

This prospective phase I trial aimed to determine the recommended dose of 3-day total marrow and lymphoid irradiation (TMLI) for a myeloablative conditioning regimen by increasing the dose per fraction. The primary end-point of this single-institution dose escalation study was the recommended TMLI dose based on the frequency of dose-limiting toxicity (DLT) ≤100 days posthematopoietic stem cell transplantation (HSCT); a 3 + 3 design was used to evaluate the safety of TMLI. Three dose levels of TMLI (14/16/18 Gy in six fractions over 3 days) were set. The treatment protocol began at 14 Gy. Dose-limiting toxicities were defined as grade 3 or 4 nonhematological toxicities. Nine patients, with a median age of 42 years (range, 35-48), eight with acute lymphoblastic leukemia and one with chronic myeloblastic leukemia, received TMLI followed by unrelated bone marrow transplant. The median follow-up period after HSCT was 575 days (range, 253-1037). Three patients were enrolled for each dose level. No patient showed DLT within 100 days of HSCT. The recommended dose of 3-day TMLI was 18 Gy in six fractions. All patients achieved neutrophil engraftment at a median of 19 days (range, 14-25). One-year overall and disease-free survival rates were 83.3% and 57.1%, respectively. Three patients experienced relapse, and no nonrelapse mortality was documented during the observation period. One patient died due to disease relapse 306 days post-HSCT. The recommended dose of 3-day TMLI was 18 Gy in six fractions. The efficacy evaluation of this regimen is currently being planned in a phase II study.

[Tisagenlecleucel for relapsed/refractory diffuse large B-cell lymphoma: real-world data from single institute experience].

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the approach to patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL). This study retrospectively analyzed patients treated with commercially available tisagenlecleucel at our hospital and evaluated its safety and effectiveness. Of the 21 patients evaluated, any grade and grade ≥3 cytokine release syndrome (CRS) occurred in 85.7% and 9.5% of the patients, respectively. A total of 66.7% received tocilizumab and 28.6% received glucocorticoids for the treatment of CRS. The complete response (CR) rate at 3 months was 61.9% (95% confidence interval [CI] 38.4-81.9). After a median follow-up of 6.3 months following CAR-T infusion, the progression-free survival (PFS) and overall survival rates at 6 months were 53.1% (95%CI 28.3-72.7) and 69.2% (95%CI 43.7-84.9), respectively. Severe cytopenia and hypogammaglobulinemia occurred frequently following CAR-T infusion. Eight patients (38.1%) had comorbidities that would have made them ineligible for leukapheresis in the JULIET trial. However, the presence of comorbidities at the time of leukapheresis had no significant effect on the rates of CR, PFS, and adverse events. Tisagenlecleucel for r/r DLBCL in the real-world setting showed high efficacy and manageable safety profile comparable with the pivotal trial.

[Haploidentical hematopoietic stem cell transplantation for graft failure in myelodysplastic syndrome/myeloproliferative neoplasm-unclassifiable complicated with Stenotrophomonas maltophilia bacteremia].

A 60-year-old woman with myelodysplastic syndrome/myeloproliferative neoplasm-unclassifiable underwent unrelated bone marrow transplantation from a human leukocyte antigen (HLA) 8/8 allele-matched male donor. Neutrophil engraftment was achieved on day 29. Fluorescence in situ hybridization of sex chromosomes demonstrated complete donor chimerism. The red blood cell and platelet transfusion dependence continued, and the neutrophil count decreased gradually. Despite prolonged administration of broad-spectrum antibiotics for febrile neutropenia, blood cultures on days 46 and 58 returned positive for Stenotrophomonas maltophilia (SM). Contrast-enhanced computed tomography revealed multiple nodules of septic emboli in the lungs and kidneys, suggesting a disseminated SM infection. Antibiotic therapy was conducted based on antimicrobial susceptibility testing. However, the blood cell count failed to normalize and a secondary graft failure was diagnosed. A HLA-haploidentical peripheral-blood stem-cell transplantation from the patient's son was performed on day 134 after the initial transplantation. Neutrophil engraftment was achieved on day 11. Red blood cells and platelets were also engrafted. After the resolution of the SM bacteremia, the patient was discharged on day 63. The prognosis of the SM bacteremia with neutropenia is poor. Antibiotic treatment based on antimicrobial susceptibility testing and a second transplant from an HLA-haploidentical donor likely contributed to the successful outcome in this patient.

Impact of lung function impairment after allogeneic hematopoietic stem cell transplantation.

Late-onset noninfectious pulmonary complications (LONIPC) are a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). However, the clinical impact of lung function deterioration itself in long-term adult survivors of HSCT remains to be fully investigated. This retrospective, longitudinal study aimed to investigate pulmonary function following HSCT in terms of its change and the clinical significance of its decline. We examined 167 patients who survived for at least 2 years without relapse. The median follow-up period was 10.3 years. A linear mixed-effects model showed that the slope of pulmonary function tests values, including percent vital capacity (%VC), percent forced expiratory volume in one second (%FEV1), and FEV1/forced VC ratio (FEV1%), decreased over time. The cumulative incidence of newly obstructive and restrictive lung function impairment (LFI) at 10 years was 15.7% and 19.5%, respectively. Restrictive LFI was a significant, independent risk factor for overall survival (hazard ratio 7.11, P = 0.007) and non-relapse mortality (hazard ratio 12.19, P = 0.003). Our data demonstrated that lung function declined over time after HSCT and that the decline itself had a significant impact on survival regardless of LONIPC.

Ideal Body Weight Is Useful For Predicting Neutrophil Engraftment and Platelet Recovery for Overweight and Obese Recipients in Single-Unit Cord Blood Transplantation.

Because cord blood (CB) units are usually selected based on the cell dose per kilogram, overweight (body mass index [BMI] ≥25 kg/m2to < 30 kg/m2) and obese (30 kg/m2 ≤ BMI) recipients tend to have difficulty in getting appropriate CB units. In general, actual body weight (ABW) is used for CB unit selection. However, ideal body weight (IBW) has been reported to be more closely correlated with successful engraftment after autologous, allogeneic bone marrow, and peripheral blood stem cell transplantation than ABW. We conducted this analysis to clarify the threshold of CD34+ cell doses based on ideal body weight (CD34IBW) and to compare the outcomes among the groups stratified by the threshold according to actual body weight (CD34ABW) and CD34IBW for overweight and obese recipients in cord blood transplantation (CBT). We retrospectively analyzed 650 overweight and obese recipients who received single-unit CBT. To focus on the recipients who received a low CD34+ cell dose/kg, those who received 1.5×105 CD34+ cells/ABW or more were excluded. Using a cut-off of 0.8×105 CD34+ cells/kg, we compared the outcomes in 3 groups with low CD34ABW and low CD34IBW (CD34Low/Low), low CD34ABW but high CD34IBW (CD34Low/High), and high CD34ABW and high CD34IBW (CD34High/High). Hematopoietic recoveries were significantly delayed in the CD34Low/Low group compared with those in the CD34Low/High group (hazard ratio [HR] 0.67 for neutrophil, P < .001; HR 0.72 for platelet, P = .014), whereas those were comparable in the CD34Low/High and CD34High/High groups (HR 1.22 for neutrophil, P = .16; HR 1.29 for platelet, P = .088). Moreover, the CD34Low/High group demonstrated longer overall survival than the CD34Low/Low group (HR 1.48, P = .011) and comparable survival to the CD34High/High group (HR 0.93, P = .68). This finding may address the lack of availability of CB units for some overweight and obese recipients for whom suitable donors are unavailable. Further investigations are warranted to evaluate the appropriateness of ABW and IBW.

Risk and Predictive Factors for Candidemia After Allogeneic Hematopoietic Cell Transplantation: JSTCT Transplant Complications Working Group.

Although antifungal prophylaxis that covers Candida species is a standard of care in allogeneic hematopoietic cell transplantation (HCT), candidemia mainly caused by non-albicans Candida species still occurs and is associated with a high mortality rate. This study aimed to evaluate the risk factors for candidemia after allogeneic HCT. Particularly, we evaluated the impact of patient factors such as hematopoietic cell transplantation-specific comorbidity index (HCT-CI) and performance status (PS) in addition to well-recognized risk factors including donor type, delayed engraftment, and graft-versus-host disease (GVHD). By using data from a Japanese transplant registry database, we analyzed 26,236 pediatric and adult patients with hematological malignancies who underwent their first allogeneic HCT. The posttransplant period was divided into early (days 0-40), late (days 41-100) and very late (days 101-365) phases. The 1-year cumulative incidence of candidemia was 1.8%. When we analyzed pretransplantation factors, age ≥40 years (hazard ratio [HR] 1.85), male (HR 1.34), HCT-CI (HCT-CI 1-2, HR 1.56; HCT-CI ≥ 3, HR 2.21), PS ≥ 2 (HR 2.01), high-risk disease (HR 1.78) and donor type including HLA-mismatched related donor (MMRD) (HR 1.96), HLA-mismatched unrelated donor (HR 2.05), and cord blood (CB) (HR 2.85) were significantly associated with an increased incidence of candidemia. Focusing on the early phase (days 0-40), HCT-CI, PS, high-risk disease and CB transplantation together with engraftment and severe acute GVHD significantly affected the development of candidemia. In the late phase (days 41-100), higher HCT-CI, male, and donor type including MMRD, and CB were associated with the occurrence of candidemia together with acute GVHD and disease relapse. In the very late phase (days 101-365), HCT-CI ≥ 3 and high-risk disease significantly affected the occurrence of candidemia together with acute and chronic GVHD, and disease relapse. In addition to well-recognized risk factors including donor type, engraftment and GVHD, patient factors such as HCT-CI and PS were associated with the development of candidemia, which suggests that severely ill patients with transplantation-associated complications are more likely to develop candidemia.

Allogeneic Hematopoietic Cell Transplantation from Alternative Donors in Acute Myelogenous Leukemia: A Comparative Analysis.

In the absence of HLA-matched related and unrelated donors, alternative donors must be found for patients in need of allogeneic hematopoietic cell transplantation (HCT). There are at least 3 donor options: a mismatched unrelated donor (MMUD), umbilical cord blood (UCB), and a haploidentical related donor (haplo); however, the optimal alternative donor type remains to be established. This study aimed to address how the outcomes of patients receiving these 3 alternative donor HCTs differ, and whether these outcomes change over time post-transplantation. We retrospectively analyzed Japanese nationwide transplantation registry data of adults with acute myelogenous leukemia (AML) undergoing allogeneic HCT while in first complete remission (CR) from an MMUD with a 7/8 match at the allele level (n = 601), with UCB (n = 1110), or from a haploidentical related donor (n = 221) between 2007 and 2018. For patients who underwent transplantation between 2007 and 2014, the 3-year overall survival (OS) for the MMUD, UCB, and Haplo groups was 60%, 54%, and 47%, respectively (P = .022). For those who underwent transplantation between 2015 and 2018, the 3-year OS in these groups was 60%, 66%, and 63%, respectively (P = .693). Multivariate analysis revealed that the risks of both overall mortality and nonrelapse mortality (NRM) were significantly lower in the later period than in the earlier period in the UCB group (hazard ratio [HR], 0.66 [P < .001] for OS; HR, 0.64 [P < .001] for NRM) and the Haplo group (HR, 0.58 [P = .019 for OS; HR, 0.39 [P = .004] for NRM), but not in the MMUD group (HR, 1.07 [P = .631] for OS; HR, 1.26 [P = .175] for NRM). The results of a test for interaction showed a significant difference in the effect of transplantation period on OS and NRM between the MMUD and UCB groups (P = .014 for OS; P = .004 for NRM) and between the MMUD and Haplo groups (P = .034 for OS; P = .003 for NRM). These findings demonstrate the recent improvements in the outcomes of UCB and Haplo transplantations in patients with AML in first CR that have resulted in a similar OS in patients undergoing HCT with grafts from MMUDs, UCB, and haploidentical donors in the later period of the study.

[Aggressive B-cell lymphoma with IGH/MYC, IGH/BCL2, and IGH/CCND1 translocations].

A 70-year-old man was admitted to our hospital due to fever, lymphadenopathy, and leukocytosis. White blood cell count was 22,700/µl with 92% blastoid cells. Bone marrow examination revealed abnormal lymphoid cell expansion. Abnormal cells expressed surface CD5 (dim), CD10, CD19, CD20, CD23 (dim) antigens, and kappa immunoglobulin light chains. Cytogenetic analysis of bone marrow cells at the time of diagnosis showed t (11:14) (q13;q32), t (14;18) (q32;q21), and t (8;14;18) (q24;q32;q21). Fluorescence in situ hybridization analyses of bone marrow identified translocations of IGH/MYC, IGH/BCL2, and IGH/CCND1. The patient was diagnosed with aggressive B-cell lymphoma with IGH/MYC, IGH/BCL2, and IGH/CCND1 translocation and was treated with various chemotherapies including R-CHOP, R-ESHAP, DA-EPOCH-R, R-hyper-CVAD, and radiotherapy. However, the lymphoma recurred after every chemotherapy session. Finally, he died after 6 months after first admission. Double-hit lymphoma/triple-hit lymphoma has previously been reported to present with an aggressive clinical course. In the present case, co-existence of IGH/CCND1, IGH/MYC, and IGH/BCL2 is very rare. Further clinical and biological investigations are necessary to establish an optimal treatment strategy.

Acute promyelocytic leukemia presenting as recurrent spinal myeloid sarcomas 3 years before developing leukemia: A case report with review of literature.

The de novo myeloid sarcoma (MS) type of acute promyelocytic leukemia (APL) is rare, and clinical features may differ from extramedullary diseases in advanced APL. Many cases occur as a spinal tumor, and some occur in the absence of bone-marrow diseases or coagulation abnormalities. Fluorescence in situ hybridization analysis of MS tissue is useful for accurate diagnosis, even in preserved tissue.

Postmortem CT is more accurate than clinical diagnosis for identifying the immediate cause of death in hospitalized patients: a prospective autopsy-based study.

Despite 75 to 90 % physician accuracy in determining the underlying cause of death, precision of determination of the immediate cause of death is approximately 40 %. In contrast, two thirds of immediate causes of death in hospitalized patients are correctly diagnosed by postmortem computed tomography (CT). Postmortem CT might provide an alternative approach to verifying the immediate cause of death. To evaluate the effectiveness of postmortem CT as an alternative method to determine the immediate cause of death in hospitalized patients, an autopsy-based prospective study was performed. Of 563 deaths from September 2011 to August 2013, 50 consecutive cadavers undergoing hospital autopsies with consent for additional postmortem CT at the University of Fukui were enrolled. The accuracy of determination of the immediate cause of death by postmortem CT was evaluated in these patients. Diagnostic discrepancy was also compared between radiologists and attending physicians. The immediate cause of death was correctly diagnosed in 37 of 50 subjects using postmortem CT (74 %), concerning 29 cases of respiratory failure, 4 of hemorrhage, 3 of liver failure and 1 of septic shock. Six cases of organ failure involving 13 patients were not identified as the cause of death by postmortem CT. Regarding the immediate cause of death, accuracy of clinical diagnosis was significantly lower than that of postmortem CT (46 vs 74 %, P < 0.01). Postmortem CT may be more useful than clinical diagnosis for identifying the immediate cause of death in hospitalized patients not undergoing autopsy.

Feasibility of liver weight estimation by postmortem computed tomography images: an autopsy study.

Although organ weight gives pathologists information about the pathogenesis of diseases at autopsy, the knowledge is rarely helpful in postmortem virtual autopsy by computed tomography (CT). To investigate the feasibility of liver weight estimation based on liver volume estimated from three-dimensional CT images and the specific gravity of liver, thirty cadavers who died in the University of Fukui Hospital and whose family members agreed to postmortem CT and autopsy were prospectively enrolled. Mean specific gravity of liver was 1.054 ± 0.009 g/mL (95% confidence interval: 1.0507-1.0573 g/mL). The specific gravity was positively correlated to Hounsfield unit (HU) values of less than 40 (cases with moderate to severe fatty deposition) and remained stable between 1.05 to 1.065 g/mL for HU values greater than 40 (cases with mild or no fatty change). The liver weight estimated by our formula corresponded well to the actual liver weight, and the correlation coefficient was 0.96 (P < 1 × 10(-13) ). The estimated liver weight calculated from estimated liver volume and the specific gravity of 1.055 g/mL was highly accurate, whereas the specific gravity should be reduced by 2%-3% in patients with an HU value less than 40 due to fatty deposition.

[A simple method for generating temporal subtraction image in bone SPECT-initial evaluation in pelvic region-].

We proposed and optimized a simple method of temporal subtraction image between successive bone single photon emission computed tomography (SPECT) images for supporting interpretation of temporal changes, and we evaluated its clinical utility. This method consisted of image registration, count normalization, and image subtraction. For image registration, we used a BEAT-Tl software. For count normalization, a pixel value of the normal accumulation part in a SPECT image was used as a reference region. We evaluated accuracy of image registration and optimized the normalization procedure. The accuracy of image registration ranged within 1 pixel in all directions (x, y, x-axis, and rotation). As the reference region, the second lumbar vertebra showed the best results in terms of the normalization procedure. Our method simply allowed the production of a temporal subtraction image. Because the software used in this method can be used free, this method would be available in every institution.

[Result of the onsite dosimetry and questioning about quality assurance/ quality control of radiotherapy in the Hokuriku area - a comparison with past results -].

PURPOSE: To analyze temporal changes in human resources in the radiotherapy section, quality assurance/quality control (QA/QC) and dose difference for radiotherapy in the Hokuriku area based on the results of past investigations and our investigation. METHOD: We visited radiotherapy sections of 17 hospitals in the Hokuriku area (5 in Toyama, 9 in Ishikawa and 3 in Fukui) to measure the dose at the reference point of a linear accelerator (LINAC), as we asked questions to a radiotherapist about human resources, QA/QC of LINAC, etc. We compared our results with past reports (1992 to 2007) on the dose difference, human resources and frequency of dose monitor system calibration. RESULTS: The number of physicians has not changed since 1999, but the number of radiotherapists was significantly increased. Weekly dose monitor system calibration has been achieved in 80% of the institutions in our survey. This percentage was significantly higher than in the past surveys. The dose difference distribution from our onsite dosimetry did not significantly differ from that from the onsite dosimetry in 2007. 91% of the institutions have accomplished within 2% of the dose difference. CONCLUSION: We found that the number of physicians has not increased since 1999, but the number of radiotherapists has increased. We conclude that the increment of radiotherapists led to 80% achievement of the weekly dose monitor system calibration. Almost all institutions in Hokuriku area have properly performed QA of the dose monitor system.

[New patient positioning system for proton therapy combined with CT with a common treatment couch].

Exact reproducibility of patient positioning is a critical issue for proton therapy because of the sharp dose distribution. We constructed the first proton therapy system with a common couch for both CT and proton irradiation. In this paper, we report a brief overview of the instruments and the accuracy of mechanical positioning reproducibility.