Outcomes of transplant-eligible patients with myelodysplastic syndrome with excess blasts registered in an observational study: The JALSG-CS11-MDS-SCT.

Allogeneic hematopoietic stem cell transplantation (allo-SCT) is the sole curative therapy for myelodysplastic syndrome (MDS). However, whether bridging therapy (BRT) including azacitidine (AZA) and combination chemotherapy (CCT) prior to allo-SCT should be performed is unclear. We analyzed BRT and the outcomes of patients with myelodysplastic syndrome with excess blasts (MDS-EB) who were ≤ 70 years old at the time of registration for a prospective observational study to clarify the optimal allo-SCT strategy for high-risk MDS. A total of 371 patients were included in this study. Among 188 patients (50.7%) who were considered for allo-SCT, 141 underwent allo-SCT. Among the patients who underwent allo-SCT, 64 received AZA, 29 received CCT, and 26 underwent allo-SCT without BRT as the initial treatment. Multivariate analysis identified BRT as an independent factor influencing overall survival (AZA vs. without BRT, hazard ratio [HR] 3.33, P = 0.005; CCT vs. without BRT, HR 3.82, P = 0.003). In multivariate analysis, BRT was independently associated with progression-free survival (AZA vs. without BRT: HR, 2.23; P = 0.041; CCT vs. without BRT: HR, 2.94; P = 0.010). Transplant-eligible patients with MDS-EB should undergo allo-SCT when clinically acceptable, and upfront allo-SCT without BRT may be superior to AZA or CCT.

Impact of low pharyngeal/esophageal pressure associated with sarcopenia on postendoscopic submucosal dissection pneumonia in patients with superficial esophageal cancer.

OBJECTIVES: The aging population, including patients with superficial esophageal cancer, encounters critical dysphagia- and postoperative pneumonia-related issues. Although endoscopic submucosal dissection (ESD) provides advantages over other modalities, older patients are at higher risk of postoperative pneumonia. Furthermore, the etiologies of pneumonia are complex and include patient- (such as sarcopenia) and treatment- (including ESD) related factors. Therefore, this study evaluated swallowing function in patients with superficial esophageal cancer and identified post-ESD pneumonia-associated factors. METHODS: Comprehensive swallowing function and sarcopenia were evaluated in patients pre-ESD and 2 months post-ESD using high-resolution manometry and several swallowing studies by multiple experts. The effects of mucosal resection and sarcopenia on swallowing function changes post-ESD, the relationship between preoperative swallowing function and sarcopenia, and the factors influencing postoperative pneumonia were investigated. RESULTS: Twenty patients were included in the study. Patients with preoperative sarcopenia had significantly lower pharyngeal/upper esophageal sphincter and tongue pressures than those without sarcopenia. However, ESD did not worsen pharyngeal or upper esophageal pressure. Post-ESD pneumonia incidence tended to be higher in patients with sarcopenia than in those without sarcopenia. The lower upper esophageal sphincter-integrated relaxation pressure (UES-IRP) was a significant factor in pneumonia development. Furthermore, the receiver operating characteristic curve for UES-IRP in pneumonia yielded an area under the curve of 0.82. CONCLUSIONS: Sarcopenia is associated with preoperative dysphagia, which increases post-ESD pneumonia risk. Therefore, postoperative pneumonia incidence is expected to increase with an aging population, making preoperative sarcopenia and swallowing function evaluation crucial.

Diversity in matrilineages among the Jomon individuals of Japan.

BACKGROUND: The Jomon period of Japan is characterised by a unique combination of sedentary and hunting/gathering lifestyles, spanning for more than 10,000 years from the final Pleistocene to the Holocene. The transition from the preceding Palaeolithic period to the Jomon period is known to have begun with the appearance of pottery usage. However, knowledge of the genetic background of the Jomon people is still limited. AIM: We aimed to determine the population-scale complete mitogenome sequences of the Initial Jomon human remains and compare the occurrence of mitochondrial haplogroups in the Jomon period from temporal and regional perspectives. SUBJECTS AND METHODS: For human remains dated to 8200-8600 cal BP, we determined their complete mitogenome sequences using target enrichment-coupled next-generation sequencing. RESULTS: We successfully obtained the complete mitogenome sequences with high depth of coverage and high concordance on consensus sequences. These sequences differed by more than three bases each, except for two individuals having completely identical sequences. Co-existence of individuals with haplogroups N9b and M7a was first observed at the same archaeological site from the Initial Jomon period. CONCLUSION: The genetic diversity within the population was not found to be low even in the Initial Jomon period.

Acute mesenteric ischemia diagnosed using the aquarium sign: A case report.

RATIONALE: The diagnosis of mesenteric ischemia in critically ill patients remains challenging; however, the aquarium sign, comprising a large number of bubble images in the right cardiac chambers on echocardiography, may be used as a point-of-care ultrasound finding to diagnose acute mesenteric ischemia (AMI). PATIENT CONCERNS: A 65-year-old woman diagnosed with lymphoma was urgently admitted to the intensive care unit with suspected tumor lysis syndrome. High-dose vasopressor and inotropic agents were required to manage the patient's shock with marked lactic acidosis and peripheral hypoperfusion with mottled skin, and multidisciplinary treatment was initiated. By day 6, the lactate levels normalized and there were no abnormal abdominal findings. An echocardiogram was performed to examine the mass lesion associated with lymphoma in the right atrium and evaluate the hemodynamics; it revealed an "aquarium sign." Similar findings were found in the inferior vena cava and portal vein. DIAGNOSES: Contrast-enhanced computed tomography of the abdomen revealed hepatic portal vein gas, poor contrast of the colon wall, and intramural emphysema, and a diagnosis of AMI was made. Lower gastrointestinal endoscopy showed necrosis of the colon. INTERVENTIONS: The patient underwent urgent subtotal colorectal resection. OUTCOMES: Although a tracheostomy was required, the patient's general condition improved after surgery, and she was discharged to the ward without mechanical ventilatory support in the intensive care unit on Day 19. LESSONS: In patients with risk factors for AMI, repeated evaluation for the presence of aquarium signs by echocardiography may be warranted, even if there are no abdominal findings or abnormalities in biomarkers, such as lactate levels and trends. When the aquarium sign is found, AMI should be aggressively suspected, and a definitive diagnosis should be made to initiate early therapeutic intervention.

Long-term effectiveness and safety of high dose chemotherapy followed by autologous stem cell transplantation in daily practice in patients with diffuse large B-cell lymphoma.

We retrospectively evaluated long-term outcomes of high dose chemotherapy followed by autologous stem cell transplant (HDC/ASCT) in patients with diffuse large B-cell lymphoma (DLBCL). Between 2004 and 2020, 46 DLBCL patients received HDC/ASCT in our institution, including 12 patients (26.1%), who received as an upfront setting (UFS). At a median follow-up time of 69 months (range, 2-169 months), the 5-year progression-free survival (PFS) rates were 82.5% (95%CI, 46.1-95.3%) in the UFS, and 57.8% (95%CI, 38.1-73.2%) in the relapsed or refractory (R/R) patients (n=34), respectively. The 5-year PFS rates were 62.3% (95%CI, 34.0-81.3%) in primary resistant (n=13) or early relapsing (within 1 year from the initial diagnosis) patients (n=4), and 53.3% (95%CI, 25.9-74.6%) in those relapsing >1 year after the initial diagnosis (n=17), with no statistically significant difference (p=0.498). In R/R patients, multivariate analysis showed that the remission status before HDC/ASCT was an independent poor prognostic factor for progression-free survival (hazard ratio [HR], 17.0; 95%CI, 3.35-86.6; p=0.000630) and high-risk category in the international prognostic index for OS (HR, 9.39; 95%CI, 1.71-51.6; p=0.0100). The incidence of non-relapse mortality by 5 years, and 10 years were 12.2%, and 15.2%, respectively. Eleven patients (23.9%) developed second malignancies, which was the most frequent late complication after HDC/ASCT, with 5-year, and 10-year cumulative incidence of 16.9%, 22.5%, respectively. In conclusion, HDC/ASCT is effective for chemo-sensitive R/R DLBCL regardless of the timing and lines of therapy. However, careful observation is required, considering the long-term complications such as secondary malignancies.

Feasibility of Seated Stepping and Handshaking as a Cardiopulmonary Exercise Testing: A Pilot Study.

Cardiopulmonary function is usually assessed by cardiopulmonary exercise testing (CPX) using a cycle ergometer (CE-CPX) or a treadmill, which is difficult in patients with lower extremity motor dysfunction. A stepping and handshaking (SHS) exercise has been developed that can be performed safely and easily while sitting on a chair. This study compared peak oxygen uptake (peak V.O2) between CE-CPX and SHS-CPX in healthy adults and investigated the safety and validity of SHS-CPX. Twenty young adults (mean age 27.8 ± 4.4 years) were randomly assigned to perform CE-CPX or SHS-CPX, with the other test to follow 1-2 weeks later. The peak V.O2, respiratory exchange ratio (RER), peak heart rate, blood pressure, and test completion time were compared between CE-CPX and SHS-CPX. All subjects completed the examination and met the criteria for peak V.O2. SHS-CPX and CE-CPX showed a strong correlation with peak V.O2 (r = 0.85, p < 0.0001). The peak V.O2 (40.4 ± 11.3 mL/min/kg vs. 28.9 ± 8.0 mL/min/kg), peak heart rate (190.6 ± 8.9 bpm vs. 172.1 ± 12.6 bpm), and test completion time (1052.8 ± 143.7 s vs. 609.1 ± 96.2 s) were significantly lower in the SHS-CPX (p < 0.0001). There were no adverse events. The peak V.O2 with SHS-CPX was equivalent to about 70% of that with CE-CPX despite the exercise being performed in a sitting position, suggesting its suitability as a submaximal exercise test.

Comparative Study of Muscle Hardness during Water-Walking and Land-Walking Using Ultrasound Real-Time Tissue Elastography in Healthy Young People.

Compared with land-walking, water-walking is considered to be beneficial as a whole-body exercise because of the characteristics of water (buoyancy, viscosity, hydrostatic pressure, and water temperature). However, there are few reports on the effects of exercise in water on muscles, and there is no standard qualitative assessment method for muscle flexibility. Therefore, we used ultrasound real-time tissue elastography (RTE) to compare muscle hardness after water-walking and land-walking. Participants were 15 healthy young adult males (24.8 ± 2.3 years). The method consisted of land-walking and water-walking for 20 min on separate days. The strain ratio of the rectus femoris (RF) and medial head of gastrocnemius (MHGM) muscles were measured before and immediately after walking using RTE to evaluate muscle hardness. In water-walking, the strain ratio significantly decreased immediately after water-walking, with p < 0.01 for RF and p < 0.05 for MHGM, indicating a significant decrease in muscle hardness after water-walking. On the other hand, land-walking did not produce significant differences in RF and MHGM. Muscle hardness after aerobic exercise, as assessed by RTE, was not changed by land walking but was significantly decreased by water walking. The decrease in muscle hardness induced by water-walking was thought to be caused by the edema reduction effect produced by buoyancy and hydrostatic pressure.

Long­term prognosis and comprehensive endoscopic treatment strategy for esophageal cancer, including salvage endoscopic treatment after chemoradiation therapy.

Endoscopic submucosal dissection (ESD) is the first treatment option for superficial squamous cell carcinoma of the esophagus (SSCE). Salvage endoscopic treatment for recurrent advanced esophageal cancer after chemoradiotherapy (CRT) has been reported. However, there are few reports on long-term prognosis after salvage endoscopic treatment in Japan. The present study investigated long-term treatment results after conventional ESD for SSCE and after salvage endoscopic treatment for locally recurrent lesions after CRT. Outcomes of esophageal ESD were retrospectively investigated at Nagasaki University Hospital and long-term prognosis after salvage endoscopic treatment for locally recurrence lesions after CRT was examined. The en-bloc curative resection rate was 89.5% (606/676) for conventional ESD. The 5-year cause-specific survival rate (CSS) was 98.5%. A total of 77 patients underwent salvage endoscopic treatment [ESD or photodynamic therapy (PDT)] for locally recurrent lesions after CRT. The 3-year CSS was 81.3 and 77.1% for salvage ESD and salvage PDT, respectively. SSCE management using ESD yielded high en-bloc curative resection and survival rates. Overall, establishing salvage endoscopic treatment made long-term control of the underlying disease possible, while also maintaining the quality of life for patients with recurrent advanced esophageal cancer deeper than patients with T1b who underwent CRT and patients with recurrence after additional CRT following ESD.

Chlorpromazine cooperatively induces apoptosis with tyrosine kinase inhibitors in EGFR-mutated lung cancer cell lines and restores the sensitivity to gefitinib in T790M-harboring resistant cells.

We previously reported that the antipsychotic drug chlorpromazine (CPZ), which inhibits the formation of clathrin-coated vesicles (CCVs) essential for endocytosis and intracellular transport of receptor tyrosine kinase (RTK), inhibits the growth/survival of acute myeloid leukemia cells with mutated RTK (KIT D816V or FLT3-ITD) by perturbing the intracellular localization of these molecules. Here, we examined whether these findings are applicable to epidermal growth factor receptor (EGFR). CPZ dose-dependently inhibited the growth/survival of the non-small cell lung cancer (NSCLC) cell line, PC9 harboring an EGFR-activating (EGFR exon 19 deletion). In addition, CPZ not only suppressed the growth/survival of gefitinib (GEF)-resistant PC9ZD cells harboring T790 M, but also restored their sensitivities to GEF. Furthermore, CPZ overcame GEF resistance caused by Met amplification in HCC827GR cells. As for the mechanism of CPZ-induced growth suppression, we found that although CPZ hardly influenced the phosphorylation of EGFR, it effectively reduced the phosphorylation of ERK and AKT. When utilized in combination with trametinib (a MEK inhibitor), dabrafenib (an RAF inhibitor), and everolimus (an mTOR inhibitor), CPZ suppressed the growth of PC9ZD cells cooperatively with everolimus but not with trametinib or dabrafenib. Immunofluorescent staining revealed that EGFR shows a perinuclear pattern and was intensely colocalized with the late endosome marker, Rab11. However, after CPZ treatment, EGFR was unevenly distributed in the cells, and colocalization with the early endosome marker Rab5 and EEA1 became more apparent, indicating that CPZ disrupted the intracellular transport of EGFR. These results suggest that CPZ has therapeutic potential for NSCLC with mutated EGFR by a novel mechanism different from conventional TKIs alone or in combination with other agents.

C-type lectin-like receptor 2 specifies a functionally distinct subpopulation within phenotypically defined hematopoietic stem cell population that contribute to emergent megakaryopoiesis.

C-type lectin-like receptor 2 (CLEC-2) expressed on megakaryocytes plays important roles in megakaryopoiesis. We found that CLEC-2 was expressed in about 20% of phenotypical long-term hematopoietic stem cells (LT-HSCs), which expressed lower levels of HSC-specific genes and produced larger amounts of megakaryocyte-related molecules than CLEC-2low LT-HSCs. Although CLEC-2high LT-HSCs had immature clonogenic activity, cultured CLEC-2high LT-HSCs preferentially differentiated into megakaryocytes. CLEC-2high HSCs yielded 6.8 times more megakaryocyte progenitors (MkPs) and 6.0 times more platelets 2 weeks and 1 week after transplantation compared with CLEC-2low LT-HSCs. However, platelet yield from CLEC-2high HSCs gradually declined with the loss of MkPs, while CLEC-2low HSCs self-renewed long-term, indicating that CLEC-2high LT-HSCs mainly contribute to early megakaryopoiesis. Treatment with pI:C and LPS increased the proportion of CLEC-2high LT-HSCs within LT-HSCs. Almost all CLEC-2low LT-HSCs were in the G0 phase and barely responded to pI:C. In contrast, 54% of CLEC-2high LT-HSCs were in G0, and pI:C treatment obliged CLEC-2high LT-HSCs to enter the cell cycle and differentiate into megakaryocytes, indicating that CLEC-2high LT-HSCs are primed for cell cycle entry and rapidly yield platelets in response to inflammatory stress. In conclusion, CLEC-2high LT-HSCs appear to act as a reserve for emergent platelet production under stress conditions.

CD34+ myeloma cells with self-renewal activities are therapy-resistant and persist as MRD in cell cycle quiescence.

Side population (SP) is known to include therapy-resistant cells in various cancers. Here, we analyzed SP using multiple myeloma (MM) samples. The SP accounted for 2.96% in MM cells from newly diagnosed MM (NDMM). CD34 was expressed in 47.8% of SP cells, but only in 2.11% of bulk MM cells. CD34+ MM cells expressed more immature cell surface markers and a gene signature than CD34- MM cells. CD34+ but not CD34- MM cells possessed clonogenic activities and showed long-term self-renewal activities in xenotransplantation assays. Similarly, whereas 2.20% of MM cells were CD34+ in NDMM (n = 38), this proportion increased to 42.6% in minimal residual disease (MRD) samples (n = 16) (p < 0.001) and to 17.7% in refractory/relapsed MM (RRMM) (n = 30) (p < 0.01). Cell cycle analysis showed that 24.7% of CD34+ MM cells from NDMM were in G0 phase while this proportion was 54.9% in MRD (p < 0.05) and 14.5% in RRMM, reflecting the expansion of MM. Together, CD34+ MM cells with long-term self-renewal activities persist as MRD in cell cycle quiescence or remain as therapy-resistant cells in RRMM, substantiating the necessity of targeting this population to improve clinical outcomes of MM.

Individual readiness for transplantation medicine of laypersons and the number of deceased organ donors: a cross-sectional online survey in Japan, South Korea and Taiwan.

OBJECTIVES: The gap between the numbers of organ donors and recipients is a common problem worldwide. This study was designed to investigate the importance of 'individual readiness', a here introduced novel concept in transplantation medicine and a measure of positive attitudes towards organ donation and transplantation. DESIGN: A cross-sectional online survey was used to collect the research data. PARTICIPANTS: The participants were recruited by a Japanese research company and affiliates in South Korea and Taiwan and fulfilled the following criteria: (1) laypersons aged 18-75 years, (2) residents of the countries and (3) understood the questions in their native languages. PRIMARY OUTCOME MEASURES: The survey investigated the interest and attitude of individuals regarding transplantation medicine by asking multiple choice questions. Based on answers concerning attitude, a positive group was identified as willing to be organ donors and recipients, and a non-positive group was identified as unwilling to be donors and recipients. The ratio between the positive and non-positive group, the P/N ratio, was introduced as an index of individual readiness. RESULTS: 1500 samples were included in this analysis. Individuals with interest agreed more with statements on organ donation than those without interest, and the P/N ratio per country was compatible with the actual deceased organ donors rate per million population (ADODR). CONCLUSIONS: Interest in transplantation medicine was associated with positive attitudes, and positive attitudes were associated with a higher ADODR. These results support that individual readiness is an important determinant for the number of donors. The P/N ratio can be used as an index to assess individual readiness in organ transplantation, at least in countries with minor to moderate popularisation. Further studies of individual readiness using the P/N ratio should be undertaken to develop policies and initiatives for increasing organ donations.

Decreased expression of T-cell-associated immune markers predicts poor prognosis in patients with follicular lymphoma.

We previously examined the utility of rituximab-bendamustine (RB) in patients with follicular lymphoma (FL) exhibiting less than optimal responses to 2 cycles of the R-CHOP chemotherapy regimen. The aim of this study was to identify molecular biomarkers that can predict prognosis in RB-treated patients in the context of the prospective cohort. We first analyzed the mutational status of 410 genes in diagnostic tumor specimens by target capture and Sanger sequencing. CREBBP, KMT2D, MEF2B, BCL2, EZH2, and CARD11 were recurrently mutated as reported before, however none was predictive for progression-free survival (PFS) in the RB-treated patients (n = 34). A gene expression analysis by nCounter including 800 genes associated with carcinogenesis and/or the immune response showed that expression levels of CD8+ T-cell markers and half of the genes regulating Th1 and Th2 responses were significantly lower in progression of disease within the 24-mo (POD24) group (n = 8) than in the no POD24 group (n = 31). Collectively, we selected 10 genes (TBX21, CXCR3, CCR4, CD8A, CD8B, GZMM, FLT3LG, CD3E, EOMES, GZMK), and generated an immune infiltration score (IIS) for predicting PFS using principal component analysis, which dichotomized the RB-treated patients into immune IIShigh (n = 19) and IISlow (n = 20) groups. The 3-y PFS rate was significantly lower in the IISlow group than in the IIShigh group (50.0% [95% CI: 27.1-69.2%] vs. 84.2% [95% CI: 58.7-94.6%], P = .0237). Furthermore, the IIS was correlates with absolute lymphocyte counts at diagnosis (r = 0.460, P = .00355). These results suggest that the T-cell-associated immune markers could be useful to predict prognosis in RB-treated FL patients. (UMIN:000 013 795, jRCT:051 180 181).

Dasatinib-based 2-step induction for adults with Philadelphia chromosome-positive acute lymphoblastic leukemia.

The standard treatment for adults with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) in Japan is imatinib-based chemotherapy followed by allogeneic hematopoietic stem cell transplantation (HSCT). However, ∼40% of patients cannot undergo HSCT in their first complete remission (CR1) because of chemotherapy-related toxicities or relapse before HSCT or older age. In this study, we evaluated dasatinib-based 2-step induction with the primary end point of 3-year event-free survival (EFS). The first induction (IND1) was dasatinib plus prednisolone to achieve CR, and IND2 was dasatinib plus intensive chemotherapy to achieve minimal residual disease (MRD) negativity. For patients who achieved CR and had an appropriate donor, HSCT during a consolidation phase later than the first consolidation, which included high-dose methotrexate, was recommended. Patients with pretransplantation MRD positivity were assigned to receive prophylactic dasatinib after HSCT. All 78 eligible patients achieved CR or incomplete CR after IND1, and 52.6% achieved MRD negativity after IND2. Nonrelapse mortality (NRM) was not reported. T315I mutation was detected in all 4 hematological relapses before HSCT. Fifty-eight patients (74.4%) underwent HSCT in CR1, and 44 (75.9%) had negative pretransplantation MRD. At a median follow-up of 4.0 years, 3-year EFS and overall survival were 66.2% (95% confidence interval [CI], 54.4-75.5) and 80.5% (95% CI, 69.7-87.7), respectively. The cumulative incidence of relapse and NRM at 3 years from enrollment were 26.1% and 7.8%, respectively. Dasatinib-based 2-step induction was demonstrated to improve 3-year EFS in Ph+ ALL. This study was registered in the UMIN Clinical Trial Registry as #UMIN000012173.

Population dynamics in the Japanese Archipelago since the Pleistocene revealed by the complete mitochondrial genome sequences.

The Japanese Archipelago is widely covered with acidic soil made of volcanic ash, an environment which is detrimental to the preservation of ancient biomolecules. More than 10,000 Palaeolithic and Neolithic sites have been discovered nationwide, but few skeletal remains exist and preservation of DNA is poor. Despite these challenging circumstances, we succeeded in obtaining a complete mitogenome (mitochondrial genome) sequence from Palaeolithic human remains. We also obtained those of Neolithic (the hunting-gathering Jomon and the farming Yayoi cultures) remains, and over 2,000 present-day Japanese. The Palaeolithic mitogenome sequence was not found to be a direct ancestor of any of Jomon, Yayoi, and present-day Japanese people. However, it was an ancestral type of haplogroup M, a basal group of the haplogroup M. Therefore, our results indicate continuity in the maternal gene pool from the Palaeolithic to present-day Japanese. We also found that a vast increase of population size happened and has continued since the Yayoi period, characterized with paddy rice farming. It means that the cultural transition, i.e. rice agriculture, had significant impact on the demographic history of Japanese population.

Predictors of early death, serious hemorrhage, and differentiation syndrome in Japanese patients with acute promyelocytic leukemia.

Significant advancements have been achieved with regard to the outcomes of acute promyelocytic leukemia (APL) patients through the introduction of all-trans retinoic acid; however, early hemorrhagic death and differentiation syndrome remain the major causes of remission induction failure in patients with APL. To investigate early death, serious hemorrhage, and differentiation syndrome during remission induction therapy in terms of incidence, risk factors, influence on outcomes, and prophylactic effects of several new anticoagulants, the results of 344 patients enrolled in the Acute Promyelocytic Leukemia 204 study conducted by the Japan Adult Leukemia Study Group were analyzed. Early death was observed in 16 patients (4.7%), of whom 14 had serious hemorrhage and 2 had differentiation syndrome. Serious hemorrhage and differentiation syndrome of grade 2 or higher were observed in 21 and 54 patients, respectively. Patients who achieved complete remission had a 7-year disease-free survival of 84.8% if they did not experience serious hemorrhage and 40.0% if they experienced serious hemorrhage during remission induction therapy (P = 0.001). Risk factor analyses showed that higher white blood cell count was associated with early death, higher white blood cell count and lower platelet count with serious hemorrhage, and leukocytosis during induction therapy and higher body surface area with differentiation syndrome. In conclusion, these results indicate that patients with such high-risk features may benefit from more intensive supportive care. The hemorrhagic risk was not relieved by the introduction of new anticoagulants. Further studies are required to establish the predictive impact of body surface area on differentiation syndrome. This trial is registered with UMIN-CTR as C000000154 on September 13, 2005.

Targeted therapy for medullary and extramedullary relapse of FLT3-ITD acute myeloid leukemia following allogeneic hematopoietic stem cell transplantation.

We report a case with extramedullary tumors affecting the supraclavicular region that presented as a relapse of acute myeloid leukemia (AML) with FLT3-ITD mutation after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Treatment with gilteritinib resulted in remarkable response with disappearance of both the medullary and extramedullary tumors. Subsequently, a 2nd allo-HSCT was performed in an attempt to cure his AML and complete molecular response has been sustained with gilteritinib resumption without worsening GVHD. Targeted therapy with gilteritinib for medullary and extramedullary relapse of FLT3-ITD AML could be effective and suitable as a bridging therapy for allo-HSCT.

The Impact of Hemodialysis and Liver Cirrhosis on the Plasma Concentrations of Tyrosine Kinase Inhibitors in a Patient with Chronic Myeloid Leukemia.

We recently treated a chronic myeloid leukemia (CML) patient with liver and renal dysfunction, who was undergoing hemodialysis (HD). He was treated with 50 mg dasatinib (DAS) once daily just before HD. The maximum plasma concentration of DAS was 227 ng/mL on a non-HD day and 46.9 ng/mL on a HD day. He was subsequently treated with 200 mg bosutinib (BOS) once daily. The plasma concentration of BOS changed from 74.5 ng/mL before HD to 58.8 ng/mL after HD. Our results indicate that close monitoring of the plasma tyrosine kinase inhibitor concentrations should be considered in CML patients with organ impairment.

A study of 8,300-year-old Jomon human remains in Japan using complete mitogenome sequences obtained by next-generation sequencing.

Ancient human remains have been assigned to their mitochondrial DNA (mtDNA) haplogroups. To obtain efficiently deep and reliable nucleotide sequences of ancient DNA of interest, we achieved target enrichment followed by next-generation sequencing (NGS). Complete mitochondrial genome (mitogenome) sequences were obtained for three human remains from the Iyai rock-shelter site of the Initial Jomon Period in Japan. All the Jomon mitogenomes belong to haplogroup N9b, but no sequences among them were identical. High genetic diversity was clarified even among the Jomon human remains belonging to haplogroup N9b, which has been described as a haplogroup representing the Jomon people.