[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.

Dual optical frequency combs with ultra-low relative phase jitters from 550 nm to 1020 nm for precision spectroscopy.

Here, ultra-low relative phase jitters over a wide optical spectrum were achieved for dual Ti:Sapphire optical frequency combs. The two optical frequency combs were independently phase-locked to a Sr optical lattice clock laser delivered through a commercial optical fiber network. We confirmed that the relative phase jitters between the two combs integrated from 8.3 mHz to 200 kHz were below 1 rad, corresponding to a relative linewidth of below 8.3 mHz, over the entire wavelength of the optical frequency combs ranging from 550 nm to 1020 nm. Our work paves the way for ultrahigh-precision dual-comb spectroscopy covering a wide optical spectral range with a simple setup, and provides an absolute optical frequency reference with great stability over a wide range of wavelengths.

[Late-onset refractory autoimmune hemolytic anemia following autologous hematologic recovery after allo-HSCT in aplastic anemia-PNH syndrome].

A 31-year-old man underwent allogeneic bone marrow transplantation (BMT) for the treatment of transfusion-dependent aplastic anemia (AA) after conditioning with a regimen including fludarabine, cyclophosphamide, and antithymocyte globulin. The patient developed a late graft rejection on day 103 and showed autologous hematologic recovery not requiring transfusions on day 76. Peripheral blood leukocytes were of 100% recipient origin on day 103, and paroxysmal nocturnal hematuria (PNH)-type granulocytes were detected 5 months after BMT. The patient suddenly experienced hemolytic symptoms triggered by cold stimulation, and was diagnosed with autoimmune hemolytic anemia (AIHA) 37 months after BMT. Although anemia was ameliorated by prednisolone (PSL), hemolytic attacks repeatedly occurred, which became refractory to corticosteroids. Moreover, the patient underwent a splenectomy for the steroid-resistant AIHA and achieved AIHA remission without the need for PSL at 53 months after BMT. The immune tolerance breakdown to erythrocyte antigens was thought to have occurred due to various factors including immune AA, medication, cold stimulation, and infection, leading to AIHA development in this case.

Chirped pulse amplification of an ultrahigh-repetition-rate Ti:sapphire frequency comb using a tapered semiconductor amplifier.

Chirped pulse amplification of a 1.6 GHz Ti:sapphire femtosecond frequency comb was achieved using a GaAs-based tapered semiconductor amplifier. The spectral component of 855-865 nm was coherently amplified up to 379 mW at 2.5 A, corresponding to a peak power of 1.48 kW and an average power of 150 µW per mode. A chirped Bragg grating was used for pulse stretching and compression, resulting in a 150mm×200mm compact amplification system. Competition between the amplified spontaneous emission and the coherent signal was observed at high driving currents. A numerical analysis was presented to account for the observed gain suppression. This amplification method is useful for the realization of high repetition rate frequency combs with a wider spectral range, including the UV and mid-infrared regions.

Measurement of complex refractive index with tunable extreme ultraviolet high harmonic source.

We report a broadband refractive index measurement method based on a higher harmonic generation tabletop coherent extreme ultraviolet source. We measured the complex refractive index of a sample material by measuring the interference pattern produced by a bare double slit and comparing this with the pattern produced by another double slit with one slit covered by the sample material. We validated the method by measuring the complex refractive index of aluminum in the photon energy range of 63-78 eV using a neon gas jet. The measurement system had errors of less than 0.02%.

Unmanipulated haploidentical hematopoietic stem cell transplantation using very low-dose antithymocyte globulin and methylprednisolone in adults with relapsed/refractory acute leukemia.

Allogeneic hematopoietic stem cell transplantation (HSCT) could be the only curative therapy for patients with relapsed/refractory acute leukemia (RRAL). Many reports have described unmanipulated haploidentical HSCT (HID-HSCT) using high-dose antithymocyte globulin (ATG). However, the transplant outcomes of HID-HSCT using very low-dose ATG (thymoglobulin, 2-2.5 mg/kg) and methylprednisolone (mPSL, 1 mg/kg) for patients with RRAL have not been reported. We compared the outcomes of 46 patients with RRAL who underwent HID-HSCT using very low-dose ATG (thymoglobulin) and mPSL with the outcomes of 72 patients who underwent non-HID-HSCT. Patient characteristics differed regarding conditioning intensity (myeloablative; 19.6% in HID-HSCT vs. 61.1% in non-HID-HSCT, P < 0.001) and having undergone multiple HSCT (26.1% vs. 11.1%, P = 0.045). However, we found no significant differences in the 1-year overall survival (OS, 31.7% vs. 29.1%; P = 0.25), disease-free survival (DFS, 20.5% vs. 23.7%; P = 0.23), cumulative incidence of relapse (CIR, 40.0% vs. 42.8%; P = 0.92), non-relapse mortality (NRM, 39.5% vs. 33.5%; P = 0.22), or 100-day grade II-IV acute graft-versus-host disease (32.6% vs. 34.7%; P = 0.64) following HID-HSCT vs. non-HID-HSCT, respectively. Subgroup analysis stratified by disease and intensity of conditioning regimen demonstrated the same results between HID-HSCT and non-HID-HSCT. Furthermore, multivariate analysis showed that HID-HSCT was not an independent prognostic factor for OS (hazard ratio (HR) = 0.95 [95% confidence interval (CI), 0.58-1.58]), DFS (HR = 1.05 [95%CI, 0.67-1.68]), CIR (HR = 0.84 [95%CI, 0.48-1.47]), or NRM (HR = 1.28 [95%CI, 0.66-2.46]). In summary, transplant outcomes for RRAL were comparable in the HID-HSCT and non-HID-HSCT groups. HID-HSCT using very low-dose ATG and mPSL for RRAL may be a viable alternative to non-HID-HSCT.

Direct phase-locking of a Ti:Sapphire optical frequency comb to a remote optical frequency standard.

We report on an ultralow noise optical frequency transfer from a remotely located Sr optical lattice clock laser to a Ti:Sapphire optical frequency comb through telecom-wavelength optical fiber networks. The inherent narrow linewidth of the Ti:Sapphire optical frequency comb eliminates the need for a local reference high-finesse cavity. The relative fractional frequency instability of the optical frequency comb with respect to the remote optical reference was 6.7(1) × 10-18 at 1 s and 1.05(3) × 10-19 at 1,000 s including a 2.9 km-long fiber network. This ensured the optical frequency comb had the same precision as the optical standard. Our result paves the way for ultrahigh-precision spectroscopy and conversion of the highly precise optical frequency to radio frequencies in a simpler setup.

Dynamical Critical Behavior of an Attractive Bose-Einstein Condensate Phase Transition.

When matter undergoes a continuous phase transition on a finite timescale, the Kibble-Zurek mechanism predicts universal scaling behavior with respect to structure formation. The scaling is dependent on the universality class and is irrelevant to the details of the system. Here, we examine this phenomenon by controlling the timescale of the phase transition to a Bose-Einstein condensate using sympathetic cooling of an ultracold Bose thermal cloud with tunable interactions in an elongated trap. The phase transition results in a diverse number of bright solitons and gray solitons in the condensate that undergo attractive and repulsive interactions, respectively. The power law dependence of the average soliton number on the timescale of the phase transition is measured for each interaction and compared. The results support the Kibble-Zurek mechanism, in that the scaling behavior is determined by universality and does not rely on the interaction properties.

Disseminated adenovirus infection in a patient with relapsed refractory multiple myeloma undergoing autologous stem cell transplantation and pomalidomide/dexamethasone as salvage regimens.

BACKGROUND: Disseminated adenovirus (ADV) infection is a fatal complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), however, it is rare following autologous peripheral blood stem cell transplantation (auto-PBSCT) or chemotherapy alone. CASE: A 66-year-old Japanese female with relapsed and refractory multiple myeloma (RRMM) received auto-PBSCT, achieving partial response. To obtain a greater response, pomalidomide/dexamethasone was started on day 28 after auto-PBSCT, but was stopped on day 41 due to thrombocytopenia, fever, and gross hematuria. Additionally, she complained of abdominal pain on day 46. Blood tests revealed elevation of transaminases and alkaline phosphatase. There was no evidence of bacterial or fungal infections or progression of MM. ADV titer in urine and serum were 3.41 × 105 copies/mL and 6.76 × 103 copies/mL, respectively. CT scans revealed cystitis, urethritis, and peritonitis. Since more than two organs were infected with ADV, she was diagnosed with disseminated ADV disease. After 5 weeks of supportive care, all symptoms resolved. ADV titer decreased to 5.90 × 102 copies/mL in urine and became negative in serum on day 80. However, she succumbed to the MM a little more than a month later. CONCLUSION: Disseminated ADV infection can occur even in non-allogeneic transplant settings, such as in severely immunocompromised patients with MM who receive auto-PBSCT and repeated salvage therapies. Although it is a rare event, the mortality rate of this disease is very high, and hence, early diagnosis and interventions are needed in suspected cases.

[Transfusion-associated circulatory overload with pulmonary alveolar hemorrhage following allogeneic bone marrow transplantation].

A 51-year-old man underwent allogeneic bone marrow transplantation (BMT) for recurrent acute myeloid leukemia. Although the patient developed slight edema, pleural effusion, and cardiac effusion 6 months after BMT, his clinical condition improved with furosemide treatment. The patient was transfused with red blood cells for the management of anemia 8 months after BMT. He developed acute respiratory failure with pulmonary alveolar hemorrhage 80 min after the transfusion. He was diagnosed with transfusion-associated circulatory overload (TACO) due to the presence of acute pulmonary congestion and depressed left ventricular systolic function. Reduced circulatory load due to sufficient furosemide led to ventilator weaning 3 days later. Other causes of pulmonary alveolar hemorrhage were excluded, and the patient's condition improved by cardiac failure treatment only. This clinical course indicated that pulmonary alveolar hemorrhage would breakdown the blood vessels due to acute pulmonary congestion. Chemotherapy and prolonged anemia are high risks for cardiac failure in patients with hematological malignancies. Therefore, the possibility of cardiac failure is considered when patients with hematological malignancies have fluid retention, such as cardiac enlargement, edema, and pleural effusion. Moreover, the body fluids should be monitored before and after blood transfusion.

Clinical impact of pre-transplant gut microbial diversity on outcomes of allogeneic hematopoietic stem cell transplantation.

Post-transplant microbial diversity in the gastrointestinal tract is closely associated with clinical outcomes following allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, little is known about the impact of the fecal microbiota before allo-HSCT. We analyzed fecal samples approximately 2 weeks before conditioning among 107 allo-HSCT recipients between 2013 and 2015. Microbial analysis was performed using 16S rRNA gene sequencing. Operational taxonomic unit-based microbial diversity was estimated by calculating the Shannon index. Patients were classified into three groups based on the diversity index: low (<2), intermediate (2, 3), and high (>3) diversity (18 (16.8%), 48 (44.9%), and 41 (38.3%) patients, respectively). There were no significant differences in the 20-month overall survival, cumulative incidence of relapse, and non-relapse mortality among three groups. The cumulative incidence of grade II to IV acute graft-versus-host disease (aGVHD) was similar among the three groups (low 55.6%; intermediate 35.4%; high 48.8%, p = 0.339, at day 100). Furthermore, we found no differences in the cumulative incidence of grade II to IV acute gastrointestinal GVHD among the three groups (low 38.9%; intermediate 21.3%; high 24.4%, p = 0.778, at day 100). Regarding the composition of microbiota before allo-HSCT, aGVHD patients showed a significantly higher abundance of phylum Firmicutes (p < 0.01) and a lower tendency for Bacteroidetes (p = 0.106) than non-aGVHD patients. Maintenance of Bacteroidetes throughout allo-HSCT may be a strategy to prevent aGVHD.

Gut microbiota and acute graft-versus-host disease.

Although allogeneic stem cell transplantation (allo-SCT) is a potentially curative treatment for various hematological diseases, acute graft-versus-host disease (GVHD) is a major cause of morbidity and mortality, and its management is clinically important. Advances in biological techniques have led to great progress in understanding the complex interactions between the host and the gut microbiota. The gut microbiota clearly modulates the immune response and is associated with the pathogenesis of various disorders. Also in allo-SCT, both preclinical and clinical results indicate that the gut microbiota is closely associated with the development of acute GVHD and transplant outcomes. These results led to the idea that improvement in quantitative and/or qualitative abnormalities of microbiota (dysbiosis) may be a new treatment strategy for acute GVHD. Evaluations of therapies targeting the gut microbiota such as probiotics or fecal microbiota transplantation have just begun. Furthermore, intervention in the gut microbiota with a nutritional approach including prebiotics, postbiotics, and antibiotics selection may also be another promising treatment option for acute GVHD.

Predictive implications of albumin and C-reactive protein for progression to pneumonia and poor prognosis in Stenotrophomonas maltophilia bacteremia following allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Stenotrophomonas maltophilia (S. maltophilia) bacteremia causes significant morbidity and mortality in immunocompromised hosts. However, incidence and risk factors for mortality in S. maltophilia bacteremia following allogeneic hematopoietic stem cell transplantation (allo-HSCT) remain controversial. The primary aim of this study is to clarify factors associated with poor prognosis of allo-HSCT recipients with S. maltophilia bacteremia. METHODS: From January 2005 to December 2014, patients with hematological diseases and S. maltophilia bacteremia at a single transplantation center in Japan were examined for incidence and 90-day mortality. Prognostic factors associated with 90-day mortality among allo-HSCT recipients were analyzed by log-rank test, and significant variables in the univariate analysis were included in the multivariate Cox proportional-hazards regression model. RESULTS: A total of 65 patients, including 47 patients undergoing allo-HSCT, developed S. maltophilia bacteremia. The incidence of S. maltophilia bacteremia was significantly higher in allo-HSCT recipients compared to patients not receiving allo-HSCT (6.53 vs. 0.36 per 100 admissions, respectively; p < 0.01). The overall 90-day mortality in allo-HSCT recipients was 43%. Independent risk factors for 90-day mortality were low serum albumin (<3.0 g/dl) (HR = 10.86; 95% CI, 3.27-36.12) and high serum C-reactive protein (CRP) (≥10.0 mg/dl) (HR = 3.28; 95% CI, 1.00-10.72). Among 9 patients with both high CRP and low albumin, 5 had pneumonia at the onset of bacteremia and the remaining 4 patients developed pneumonia in a median of 3 days (range, 1 to 8 days) even under effective treatment. All 9 patients eventually died in a median of 2 days (range, 2 to 32 days). The probabilities of developing pneumonia in patients with or without high CRP and low albumin levels were 100% (9/9) and 10.5% (4/38), respectively (p < 0.01). CONCLUSIONS: Allo-HSCT recipients had higher rates of S. maltophilia bacteremia than did patients not receiving allo-HSCT. High serum CRP and low serum albumin at the onset of bacteremia are predictive of disease progression to pneumonia and poor prognosis.

[Disseminated fusariosis in patients with acute leukemia: a retrospective analysis of three cases].

We report three cases of fusariosis that occurred during the treatment of acute leukemia, during the past 5 years at our institution. Case 1: A 70-year-old male with relapsed and refractory acute lymphoblastic leukemia (ALL) developed fever and multiple nodular lesions in both the lungs. Blood culture that was subsequently obtained revealed Fusarium species. Treatment with liposomal-amphotericin B (L-AMB) was ineffective, and the condition of the patient deteriorated rapidly leading to death. Case 2: A 28-year-old male with T-ALL developed echthyma gangrenosum (EG) ulcers on the scrotum during conditioning for transplantation. Antifungal therapy with L-AMB was ineffective, and later, itraconazole and micafungin (MCFG) were introduced. However, the engraftment was not achieved, and the patient died on day 27. Microbiological examination of EG samples collected on day 13 revealed infection by Fusarium species post mortem. Case 3: A 50-year-old male with blast crisis of chronic myeloid leukemia developed EG primarily on the trunk during chemotherapy. The patient died without any response to L-AMB and MCFG. A culture obtained from EG on day 19 yielded Fusarium species, post mortem. The prognosis of fusariosis is extremely poor. However, skin lesions such as EG may assist in the early diagnosis of the disseminated disease.

Comparison of graft-versus-host disease-free, relapse-free survival according to a variety of graft sources: antithymocyte globulin and single cord blood provide favorable outcomes in some subgroups.

Graft-versus-host disease-free relapse-free survival, which is defined as the absence of grade III-IV acute graft-versus-host disease, systemically treated chronic graft-versus-host disease, relapse, and death, is a novel, meaningful composite end point for clinical trials. To characterize risk factors and differences in graft-versus-host disease-free relapse-free survival according to a variety of graft sources, we analyzed 23,302 patients with hematologic malignancy that had a first allogeneic transplantation from 2000 through 2013 using the Japanese national transplant registry database. The 1-year graft-versus-host disease-free relapse-free survival rate was 41% in all patients. The rate was higher after bone marrow transplantation than after peripheral blood stem cell transplantation due to the lower risks of III-IV acute and chronic graft-versus-host disease. The rate was highest after HLA-matched sibling bone marrow transplantation. The rate after single cord blood transplantation was comparable to that after HLA-matched unrelated bone marrow transplantation among patients aged 20 years or under, and was comparable or better than other alternative graft sources among patients aged 21 years or over, due to the low risk of chronic graft-versus-host disease. Other factors associated with better graft-versus-host disease-free relapse-free survival include female patients, antithymocyte globulin prophylaxis (for standard-risk disease), recent years of transplantation, sex combinations other than from a female donor to a male patient, the absence of prior autologous transplantation, myeloablative conditioning, negative cytomegalovirus serostatus, and tacrolimus-based prophylaxis. These results provide important information to guide the choice of graft sources and are benchmarks for future graft-versus-host disease prophylaxis studies.

The clinical features of fatal cyclophosphamide-induced cardiotoxicity in a conditioning regimen for allogeneic hematopoietic stem cell transplantation (allo-HSCT).

Cyclophosphamide (CY) cardiotoxicity induces a rare lethal complication associated with its use. The minimum dose for cardiac toxicity is still not known, although there are no reports of CY toxicity at doses of less than 100 mg/kg. There are few studies of CY cardiotoxicity that included a large number of patients who received high-dose CY for conditioning for allogeneic stem cell transplant (allo-HSCT). To elucidate the clinical course, complications, true incidence, and risk factors, the cardiac events of 811 patients who received more than a total of 100 mg/kg of CY as conditioning for allo-HSCT were analyzed. Twelve of 811 recipients (1.5 %) developed fatal cardiac failure induced by CY at a median of 4 (range 2-8) days after the first administration of CY. Regarding the dose of CY, 8.5, 1.2, and 0 % of the patients developed cardiac failure among the patients treated with a total of 200, 120, and 100 mg/kg CY, respectively. On echocardiography, the E/A ratio shows diastolic dysfunction but not the ejection fraction changed in the early course. Moreover, a short time to the first symptom after the administration of CY tended to be associated with early death (p = 0.09). Eleven patients died from progressive acute cardiac failure at day 7 (5-30) after the first administration of CY, and only one patient survived. In summary, fatal CY cardiotoxicity with allo-HSCT is a rare complication, but it is associated with high mortality. The possibility of CY-induced cardiotoxicity must be considered early after the administration of CY.

Chronic myeloid leukemia relapsing ten years after allogenic bone marrow transplantation.

A 58-year-old female was diagnosed with Philadelphia chromosome positive chronic myeloid leukemia (CML) in blast crisis (BC) in 2004. The patient received imatinib, which quickly induced molecular remission, and subsequently underwent bone marrow transplantation (BMT) from an unrelated human leukocyte antigen (HLA)-identical donor. The post-transplant clinical course was essentially uneventful. In 2014, ten years after the BMT, the patient was admitted to our hospital complaining of lymphadenopathy, and blasts were observed in peripheral blood. The patient was diagnosed as having a CML relapse in myeloid BC, with leukemic infiltration in lymph nodes, and was treated with dasatinib. Subsequently, pleural effusion developed and nilotinib was administered, which induced normal blood counts without blasts and partial cytogenetic remission, one month after administration. Six months after the relapse, this patient underwent a second BMT from an HLA-matched unrelated donor. Recent studies have demonstrated the cumulative incidence of CML relapse more than five years after allogeneic hematopoietic stem cell transplantation (allo-HSCT) to be higher than in acute myeloid leukemia. Although rare, the possibility of late relapse should be considered in patients diagnosed with CML after allo-HSCT.

Retrospective analysis of clinical outcomes of the patients with chronic myeloid leukemia who stopped administration of tyrosine kinase inhibitors: a single institution experience.

We describe herein the clinical outcomes of 16 patients with chronic myeloid leukemia in the chronic phase who stopped the administration of tyrosine kinase inhibitors (TKI) after maintaining undetectable levels of major BCR-ABL1, based on real-time quantitative polymerase chain reaction, for prolonged periods (undetectable MR for a median of 2,100 days (822-4,068). The reasons for discontinuing TKI were enrollments in a clinical trial testing discontinuation of these agents (n=9), adverse effects (n=2) or financial problems (n=5). After TKI discontinuation, patients were followed for a median of 551 days (154-2,446). A total of 8 patients (50%) experienced molecular relapse after a median of 119 days (28-171). Among them, 6 patients who lost major molecular response (MMR) were treated with imatinib (n=2) or dasatinib (n=4), while 2 patients who lost undetectable MR after discontinuing TKI (1 each had taken bostinib and imatinib) but maintained MMR were carefully monitored without re-administration of TKI. Of 6 patients who re-started TKI, 4 (67%) achieved undetectable MR but the other 2 achieved only MMR. The results of this small, retrospective study may support the current understanding of treatment discontinuation, possibly leading to a sustained deep molecular response in some patients.

Donor cell leukemia with bone marrow necrosis.

A 60-year-old man with myelodysplastic syndrome underwent allogeneic transplantation of female umbilical cord blood in 2010 and sustained a complete remission. He experienced severe pain in his left hip joint and was admitted to the orthopedic surgery division of our institution in February 2015. After admission, he was suspected to have hemophagocytic syndrome (HPS) and was thus transferred to the hematology division. Bone marrow aspiration revealed hyper-cellular marrow filled with abnormal collapsed cells, consistent with bone marrow necrosis (BMN). As there was no evidence of infection, collagen disease, or occult cancer, he was diagnosed with HPS of unknown origin and treated with dexamethasone, cyclosporine A, and etoposide according to the HLH-2004 protocol. Although his general condition and laboratory findings showed amelioration, morphologically abnormal cells appeared in peripheral blood two weeks after treatment. Bone marrow aspiration showed BMN with increased abnormal cells, positive for CD117 and MPO. Sex chromosome FISH analysis revealed donor chimerism and cytogenetic analysis showed 46XX, +1, der (1;7) (q10;q10). He was diagnosed with donor cell leukemia (DCL) and received salvage chemotherapy. However, he died because of severe pneumonia and sepsis without neutrophil recovery at day 68. We herein report this rare case of DCL with BMN.

Selective generation of ultracold high-density 1s orthoexcitons in Cu2O with phase-modulated pulse using acousto-optic programmable filter.

Ultracold and high-density 1s orthoexcitons in semiconductor cuprous oxide are prepared via resonant two-photon absorption of a phase-tailored femtosecond pulse, by utilizing an acousto-optic programmable dispersive filter. The stability of the quantum degenerate exciton gas is studied using excitonic Lyman spectroscopy. A density of 10(16) cm(-3) is realized without creating hot carriers, and the Lyman spectrum remains unchanged at this density. This result assures the stability of a spontaneous Bose-Einstein condensate of excitons at sub-Kelvin temperatures.