[Successful immunosuppressive therapy in female hemophilia A developing inhibitor after perioperative administration of factor VIII products].

A 62-year-old woman was diagnosed as a hemophilia A carrier (factor VIII activity 35%) on preoperative examination of an ovarian tumor. A total of 35,600 units of recombinant factor VIII products was administered perioperatively. On postoperative day 95, a subcutaneous hematoma formed and immunosuppressive therapy with prednisolone was started based on an APTT of 66 seconds, factor VIII (FVIII) activity of 3%, and FVIII inhibitor of 1 BU/ml. During this treatment, the patient was hospitalized due to ankle joint bleeds and required hemostatic treatment, but the inhibitor disappeared and FVIII activity recovered to 30% after postoperative day 438 with cyclophosphamide. F8 analysis revealed the patient carried a heterozygosity of p.Arg391Cys, which has previously been categorized as cross-reacting material (CRM)-positive severe hemophilia A. No high-risk mutations for inhibitor development were found. We also report the results of a desmopressin acetate hydrate test administered to the patient to prepare for future treatment in case of hemorrhage, since high-dose FVIII administration may have been a factor in inhibitor development.

Correlation of ex vivo and in vivo ammonia production with L-asparaginase biological activity in adults with lymphoid malignancies.

Silent inactivation of L-asparaginase (L-Asp) represents rapid clearance of L-Asp by anti-L-Asp IgG antibodies without clinical symptoms. Measurement of L-Asp activity is the gold standard for diagnosis of silent inactivation, but this test is not commercially available in Japan as of 2023. We evaluated ex vivo and in vivo ammonia production in relation to L-Asp activity. Blood samples from ten adult patients treated with L-Asp were collected to measure ammonia levels and L-Asp activity before the first dose and 24 h after the last dose of L-Asp, during each cycle of treatment. Plasma ammonia levels were analyzed immediately and 1 h after incubation at room temperature, and ex vivo ammonia production was defined as the increase in ammonia concentration. Ex vivo ammonia production correlated with L-Asp activity (R2 = 0.741), and ammonia levels measured immediately after blood collection were moderately correlated with L-Asp activity (R2 = 0.709). One patient with extranodal NK/T-cell lymphoma showed an increase in ammonia levels during the first cycle, but no increase in ammonia levels or L-Asp activity after L-Asp administration during the second cycle. Both ex vivo and in vivo ammonia production and surrogate markers are used for L-Asp biological activity.

Cartilage tissues regulate systemic aging via ectonucleotide pyrophosphatase/phosphodiesterase 1 in mice.

Aging presents fundamental health concerns worldwide; however, mechanisms underlying how aging is regulated are not fully understood. Here, we show that cartilage regulates aging by controlling phosphate metabolism via ectonucleotide pyrophosphatase/phosphodiesterase 1 (Enpp1). We newly established an Enpp1 reporter mouse, in which an EGFP-luciferase sequence was knocked-in at the Enpp1 gene start codon (Enpp1/EGFP-luciferase), enabling detection of Enpp1 expression in cartilage tissues of resultant mice. We then established a cartilage-specific Enpp1 conditional knockout mouse (Enpp1 cKO) by generating Enpp1 flox mice and crossing them with cartilage-specific type 2 collagen Cre mice. Relative to WT controls, Enpp1 cKO mice exhibited phenotypes resembling human aging, such as short life span, ectopic calcifications, and osteoporosis, as well as significantly lower serum pyrophosphate levels. We also observed significant weight loss and worsening of osteoporosis in Enpp1 cKO mice under phosphate overload conditions, similar to global Enpp1-deficient mice. Aging phenotypes seen in Enpp1 cKO mice under phosphate overload conditions were rescued by a low vitamin D diet, even under high phosphate conditions. These findings suggest overall that cartilage tissue plays an important role in regulating systemic aging via Enpp1.

The IL-17-IL-17RA axis is required to promote osteosarcoma progression in mice.

Osteosarcoma is rare but is the most common bone tumor. Diagnostic tools such as magnetic resonance imaging development of chemotherapeutic agents have increased the survival rate in osteosarcoma patients, although 5-year survival has plateaued at 70%. Thus, development of new treatment approaches is needed. Here, we report that IL-17, a proinflammatory cytokine, increases osteosarcoma mortality in a mouse model with AX osteosarcoma cells. AX cell transplantation into wild-type mice resulted in 100% mortality due to ectopic ossification and multi-organ metastasis. However, AX cell transplantation into IL-17-deficient mice significantly prolonged survival relative to controls. CD4-positive cells adjacent to osteosarcoma cells express IL-17, while osteosarcoma cells express the IL-17 receptor IL-17RA. Although AX cells can undergo osteoblast differentiation, as can patient osteosarcoma cells, IL-17 significantly inhibited that differentiation, indicating that IL-17 maintains AX cells in the undifferentiated state seen in malignant tumors. By contrast, IL-17RA-deficient mice transplanted with AX cells showed survival comparable to wild-type mice transplanted with AX cells. Biopsy specimens collected from osteosarcoma patients showed higher expression of IL-17RA compared to IL-17. These findings suggest that IL-17 is essential to maintain osteosarcoma cells in an undifferentiated state and could be a therapeutic target for suppressing tumorigenesis.

Transthyretin amyloid deposition in ligamentum flavum (LF) is significantly correlated with LF and epidural fat hypertrophy in patients with lumbar spinal stenosis.

Lumbar spinal stenosis (LSS) is a degenerative disease characterized by intermittent claudication and numbness in the lower extremities. These symptoms are caused by the compression of nerve tissue in the lumbar spinal canal. Ligamentum flavum (LF) hypertrophy and spinal epidural lipomatosis in the spinal canal are known to contribute to stenosis of the spinal canal: however, detailed mechanisms underlying LSS are still not fully understood. Here, we show that surgically harvested LFs from LSS patients exhibited significantly increased thickness when transthyretin (TTR), the protein responsible for amyloidosis, was deposited in LFs, compared to those without TTR deposition. Multiple regression analysis, which considered age and BMI, revealed a significant association between LF hypertrophy and TTR deposition in LFs. Moreover, TTR deposition in LF was also significantly correlated with epidural fat (EF) thickness based on multiple regression analyses. Mesenchymal cell differentiation into adipocytes was significantly stimulated by TTR in vitro. These results suggest that TTR deposition in LFs is significantly associated with increased LF hypertrophy and EF thickness, and that TTR promotes adipogenesis of mesenchymal cells. Therapeutic agents to prevent TTR deposition in tissues are currently available or under development, and targeting TTR could be a potential therapeutic approach to inhibit LSS development and progression.

Remnant tissue enhances early postoperative biomechanical strength and infiltration of Scleraxis-positive cells within the grafted tendon in a rat anterior cruciate ligament reconstruction model.

When ruptured, ligaments and tendons have limited self-repair capacity and rarely heal spontaneously. In the knee, the Anterior Cruciate Ligament (ACL) often ruptures during sports activities, causing functional impairment and requiring surgery using tendon grafts. Patients with insufficient time to recover before resuming sports risk re-injury. To develop more effective treatment, it is necessary to define mechanisms underlying ligament repair. For this, animal models can be useful, but mice are too small to create an ACL reconstruction model. Thus, we developed a transgenic rat model using control elements of Scleraxis (Scx), a transcription factor essential for ligament and tendon development, to drive GFP expression in order to localize Scx-expressing cells. As anticipated, Tg rats exhibited Scx-GFP in ACL during developmental but not adult stages. Interestingly, when we transplanted the flexor digitorum longus (FDP) tendon derived from adult Scx-GFP+ rats into WT adults, Scx-GFP was not expressed in transplanted tendons. However, tendons transplanted from adult WT rats into Scx-GFP rats showed upregulated Scx expression in tendon, suggesting that Scx-GFP+ cells are mobilized from tissues outside the tendon. Importantly, at 4 weeks post-surgery, Scx-GFP-expressing cells were more frequent within the grafted tendon when an ACL remnant was preserved (P group) relative to when it was not (R group) (P vs R groups (both n = 5), p<0.05), and by 6 weeks, biomechanical strength of the transplanted tendon was significantly increased if the remnant was preserved (P vsR groups (both n = 14), p<0.05). Scx-GFP+ cells increased in remnant tissue after surgery, suggesting remnant tissue is a source of Scx+ cells in grafted tendons. We conclude that the novel Scx-GFP Tg rat is useful to monitor emergence of Scx-positive cells, which likely contribute to increased graft strength after ACL reconstruction.

Impact of a third dose of anti-SARS-CoV-2 vaccine in hematopoietic cell transplant recipients: A Japanese multicenter observational study.

This prospective observational study aimed to assess the serological response and safety after the third booster shot of SARS-CoV-2 mRNA vaccines in 292 hematopoietic cell transplant (HCT) recipients. In our patients, mild systemic reactions were present in 10-40% and GVHD aggravation in 1.1%. Overall, clinically relevant response (>250 U/mL) was observed in 93.1% of allogeneic (allo)-HCT recipients and 70.6% of autologous (auto)-HCT recipients, respectively. Of note, detectable antibody response with any titer following the first two doses was a powerful predictor for adequate response after booster shot in both cohorts. For such patients, 98.8% of allo- and 92.3% of auto-HCT recipients obtained clinically relevant response after dose 3. In addition, continued systemic steroid and/or calcineurin inhibitors at the booster shot significantly correlated with serological response. These findings highlighted that booster vaccination efficiently improved serological response without safety concerns and thus recommended for the majority of HCT recipients.

A machine learning-based scoring system and ten factors associated with hip fracture occurrence in the elderly.

Hip fractures are fragility fractures frequently seen in persons over 80-years-old. Although various factors, including decreased bone mineral density and a history of falls, are reported as hip fracture risks, few large-scale studies have confirmed their relevance to individuals older than 80, and tools to assess contributions of various risks to fracture development and the degree of risk are lacking. We recruited 1395 fresh hip fracture patients and 1075 controls without hip fractures and comprehensively evaluated various reported risk factors and their association with hip fracture development. We initially constructed a predictive model using Extreme Gradient Boosting (XGBoost), a machine learning algorithm, incorporating all 40 variables and evaluated the model's performance using the area under the receiver operating characteristic curve (AUC), yielding a value of 0.87. We also employed SHapley Additive exPlanation (SHAP) values to evaluate each feature importance and ranked the top 20. We then used a stepwise selection method to determine key factors sequentially until the AUC reached a plateau nearly equal to that of all variables and identified the top 10 sufficient to evaluate hip fracture risk. For each, we determined the cutoff value for hip fracture occurrence and calculated scores of each variable based on the respective feature importance. Individual scores were: serum 25(OH)D levels (<10 ng/ml, score 7), femoral neck T-score (<-3, score 5), Barthel index score (<100, score 3), maximal handgrip strength (<18 kg, score 3), GLFS-25 score (≥24, score 2), number of falls in previous 12 months (≥3, score 2), serum IGF-1 levels (<50 ng/ml, score 2), cups of tea/day (≥5, score -2), use of anti-osteoporosis drugs (yes, score -2), and BMI (<18.5 kg/m2, score 1). Using these scores, we performed receiver operating characteristic (ROC) analysis and the resultant optimal cutoff value was 7, with a specificity of 0.78, sensitivity of 0.75, and AUC of 0.85. These ten factors and the scoring system may represent tools useful to predict hip fracture.

Association between personality traits and glycemic control after inpatient diabetes education.

Aims: The longitudinal effect of personality traits on glycemic control is unclear. This prospective observational study explored the relationship between personality traits and glycemic control in patients with uncontrolled diabetes after inpatient diabetes education. Methods: Patients with diabetes mellitus (HbA1c ≥ 7.5%, measured by high-performance liquid chromatography) who received inpatient diabetes education were scored on the Big Five personality traits: neuroticism, extraversion, openness, agreeableness, and conscientiousness. Multiple linear analysis was used to determine whether any personality traits were independently associated with HbA1c on admission and HbA1c change from admission to 1, 3, and 6 months after discharge. Results: One hundred seventeen participants (mean age 60.4 ± 14.5 years; 59.0% male) were enrolled. HbA1c values on admission and 1, 3, and 6 months after discharge were 10.2 ± 2.1%, 8.3 ± 1.4%, 7.6 ± 1.4%, and 7.7 ± 1.5%, respectively. Multiple linear analysis showed that no personality traits were associated with HbA1c on admission. Neuroticism was negatively associated with the HbA1c change from admission to 3 months (ß = -0.192, P = 0.025) and 6 months after discharge (ß = -0.164, P = 0.043). Conclusions: Neuroticism was associated with good long-term glycemic control after inpatient diabetes education.

Potential function of Scx+/Sox9+ cells as progenitor cells in rotator cuff tear repair in rats.

Tendons and their attachment sites to bone, fibrocartilaginous tissues, have poor self-repair capacity when they rupture, and have risks of retear even after surgical repair. Thus, defining mechanisms underlying their repair is required in order to stimulate tendon repairing capacity. Here we used a rat surgical rotator cuff tear repair model and identified cells expressing the transcription factors Scleraxis (Scx) and SRY-box 9 (Sox9) as playing a crucial role in rotator cuff tendon-to-bone repair. Given the challenges of establishing stably reproducible models of surgical rotator cuff tear repair in mice, we newly established Scx-GFP transgenic rats in which Scx expression can be monitored by GFP. We observed tissue-specific GFP expression along tendons in developing ScxGFP transgenic rats and were able to successfully monitor tissue-specific Scx expression based on GFP signals. Among 3-, 6-, and 12-week-old ScxGFP rats, Scx+/Sox9+ cells were most abundant in 3-week-old rats near the site of humerus bone attachment to the rotator cuff tendon, while we observed significantly fewer cells in the same area in 6- or 12-week-old rats. We then applied a rotator cuff repair model using ScxGFP rats and observed the largest number of Scx+/Sox9+ cells at postoperative repair sites of 3-week-old relative to 6- or 12-week-old rats. Tendons attach to bone via fibrocartilaginous tissue, and cartilage-like tissue was seen at repair sites of 3-week-old but not 6- or 12-week-old rats during postoperative evaluation. Our findings suggest that Scx+/Sox9+ cells may function in rotator cuff repair, and that ScxGFP rats could serve as useful tools to develop therapies to promote rotator cuff repair by enabling analysis of these activities.

Prevalence and risk factors of osteonecrosis of the femoral head in patients with ANCA-associated vasculitis: a multicentre cohort study.

OBJECTIVE: We aimed to determine the prevalence and risk factors for osteonecrosis of the femoral head (ONFH) in a multicentre cohort of patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). METHODS: One hundred and eighty-six AAV patients who underwent radiographs and MRI screening of bilateral hip joints at more than 6 months after initial remission induction therapy (RIT) were retrospectively assessed for the presence of ONFH. RESULTS: Among 186 AAV patients, 33 (18%) were diagnosed with ONFH. Among the patients with ONFH, 55% were asymptomatic and 64% had bilateral ONFH. Seventy-six per cent of ONFH joints were in precollapse stages (stage ≤2), whereas 24% of ONFH joints were in collapse stages (stage ≥3). Moreover, 56% of the precollapse stage joints were already at risk of future collapse (type ≥C-1). Even in asymptomatic ONFH patients, 39% of the precollapse stage joints were type ≥C-1. Prednisolone dose of ≥20 mg/day on day 90 of RIT was an independent risk factor for ONFH in AAV patients (OR 1.072, 95% CI 1.017 to 1.130, p=0.009). Rituximab use was a significant beneficial factor against ONFH (p=0.019), but the multivariate analysis rejected its significance (p=0.257). CONCLUSION: Eighteen per cent of AAV patients developed ONFH, and two-thirds of the ONFH joints were already in collapse stages or at risk of future collapse. Prednisolone dose of ≥20 mg/day on day 90 of RIT was an independent risk factor for ONFH. A rapid reduction of glucocorticoids in RIT and early detection of precollapse ONFH by MRI may decrease and intervene ONFH development in AAV patients.

Clinical significance of cytomegalovirus (CMV) pp65 antigenemia in the prediction of CMV infection during immunosuppressive therapy for rheumatic disease.

To investigate the risk factors for CMV infection and to clarify the cut-off count of CMV pp65 antigenemia predicting clinical symptoms related to CMV infection in patients with rheumatic disease. We retrospectively analyzed 261 patients with rheumatic disease who were treated with immunosuppressive therapy. CMV infection was defined as positive > 1 CMV-positive cell per two slides (CMV pp65 antigenemia C10/C11). Patients with CMV infection were divided into two groups based on the presence of antiviral treatment for CMV disease. We determined a cut-off value of CMV-positive cells for the diagnosis of CMV disease. CMV infection was observed in 141 cases (54%). In a multivariate analysis, CMV infection was associated with three following factors: Age > 60 years (OR 1.87 [95% CI 1.04-3.36]); lymphocyte counts < 1000/µL (OR 3.34 [95% CI 1.88-6.05]); steroid pulse therapy (OR 2.60 [95% CI 1.27-5.55]). The cut-off level of CMV pp65 antigenemia indicating CMV disease was five positive cells average two slides by using receiver operating characteristic curve analysis (AUC 0.95, sensitivity 0.94, specificity 0.80). Age > 60 years, lymphocytopenia (< 1000/µL) and steroid pulse therapy are risk factors of CMV infection. We recommend that CMV pp65 antigenemia of > 5 cells average two slides (C10/C11) in patients with rheumatic disease should be the treated with antiviral drugs.

Perioperative changes in cardiac biomarkers in juvenile cats during neutering.

Perioperative myocardial injury (PMI) is commonly caused by myocardial ischemia that develops during or after non-cardiac surgery. It occurs in 17.9% of human patients after non-cardiac surgery due to elevated high-sensitive perioperation cardiac troponin. However, PMI has not been demonstrated in cats. To investigate its occurrence, this study aimed to analyze the perioperative changes in cardiac biomarkers and clinical data, including measurement of vital signs, echocardiography, blood pressure, electrocardiogram, X-ray, and anesthetic profile, in 30 juvenile cats under neutering surgery. All cats had increased high-sensitive cardiac troponin I (hs-cTnI) postsurgery compared with presurgery. In particular, 48% of cats (14/29) showed elevated hs-cTnI over a reference range after surgery. In all groups, hs-cTnI and systolic arterial blood pressure (SAP) were significantly higher at 0 h and 18 h postoperation than at preoperation. A significant positive correlation was found between hs-cTnI and SAP at 18 h postoperation. Atrial natriuretic peptides, heart rate, and left ventricular wall thickness were markedly higher at 0 h postoperation than at preoperation; however, respiratory rate and body temperature were significantly lower at 0 h postoperation than at preoperation. Anesthetic time and hs-cTnI were significantly higher at 18 h postoperation in females than in males. Significant positive correlations were observed between hs-cTnI and anesthetic time at 18 h postoperation in females. These results indicate that postoperative hs-cTnI level can greatly increase in juvenile cats and hs-cTnI measurement at perioperation is potentially beneficial for early detection and evaluation of the presence of PMI.

Factor VII Deficiency Due to Compound Heterozygosity for the p.Leu13Pro Mutation and a Novel Mutation in the HNF4 Binding Region (-58G>C) in the F7 Promoter.

We investigated the molecular basis of factor VII (FVII) deficiency in a Japanese patient and identified compound heterozygous mutations. Factor VII activity and antigen levels in the patient were less than 5.0% and 6.5% of controls, respectively. All exons, exon-intron boundaries, and the 5' promoter region of F7 from genomic DNA were amplified using polymerase chain reaction (PCR). Sequencing analysis of PCR fragments revealed that the patient was heterozygous for a known T to C substitution at nucleotide position 38, which resulted in the p.Leu13Pro missense mutation (Factor VII Morioka) in the signal peptide region, and a novel mutation in the 5' promoter region (-58G>C). An electrophoretic mobility shift assay showed that the mutation in the promoter region reduced the binding of hepatocyte nuclear factor (HNF). It is presumed that the reduced binding of HNF-4 to the F7 promoter region reduces F7 transcription and thus reduces the synthesis and expression of FVII.

[FLT3-ITD and NPM1 mutation positive acute myeloid leukemia with cuplike blasts mimicking acute promyelocytic leukemia].

FMS-like tyrosine kinase 3 (FLT3) inhibitors improve the prognosis of FLT3-internal tandem duplication (ITD)-positive acute myeloid leukemia (AML). Case 1 is a 47-year-old male patient who presented with a white blood cell count (WBC) of 95,700/ml with 94% blast accompanied by cuplike nuclei, lactate dehydrogenase (LDH) of 2,434 IU/l, fibrin degradation products (FDP) of 476 mg/ml, and a bone marrow examination that revealed blastic marrow with chromosome 46, XY, positive FLT3-ITD, and positive nucleophosmin 1 (NPM1) mutation type A. Flow cytometry revealed that blasts were positive for CD33 and negative for CD34, CD117, and human leukocyte antigen-DR isotype (HLA-DR). The patient had no response to idarubicin combined cytarabine; however, qiuzartinib administration resulted in the first complete remission. Case 2 is a 71-year-old female patient, who presented with 94,900/ml of WBC with a 91% blast accompanied with cup-like nuclei, LDH of 19,03 IU/l, FDP of 112 mg/ml, and a peripheral blood examination that revealed chromosome 46, XX, positive FLT3-ITD, and positive NPM1 mutation type B. Flow cytometry revealed that blasts were positive for CD33 and negative for CD34, CD117, and HLA-DR. She had a partial response to venetoclax combined with azacytidine, and qiuzartinib administration resulted in the first complete remission. Both cases were CD34- and HLA-DR-negative with disseminated intravascular coagulation mimicking acute promyelocytic leukemia (APL). Additionally, recognizing the cuplike blasts is useful to differentiate FLT3 mutant AML from APL for the proper use of FLT3 inhibitors.

[Allogeneic hematopoietic stem cell transplantations for relapsed and refractory acute lymphoblastic leukemia following inotuzumab ozogamicin treatment].

Inotuzumab ozogamicin (InO) was administered in three cases of relapsed/refractory adult acute lymphoblastic leukemia (ALL) before allogeneic hematopoietic stem cell transplantation (allo-SCT). One case developed extremely severe sinusoidal obstruction syndrome (SOS) but recovered after receiving defibrotide therapy. A gap of 63 days in the SOS case was noted from the last administration of InO to allo-SCT, the duration was 133 and 86 days for the other two cases, and the remaining risk factors for SOS were comparable in the three cases. In contrast to gemtuzumab ozogamicin (GO), the interval between InO exposure and allo-SCT has not been reported as a risk for SOS. Nevertheless, this case suggests that the intervals should be as long as possible.

A case of lymphomatoid granulomatosis with central nervous system involvement successfully treated with IFNα.

Lymphomatoid granulomatosis (LYG) is a rare Epstein-Barr virus (EBV)-driven B-cell lymphoproliferative disease affecting mainly extranodal sites such as the lung, central nervous system (CNS), skin, kidney, and liver. We report a case of low-grade LYG involving the CNS that was successfully treated with interferon alpha (IFNα). A 69-year-old woman developed necrotic erythema of the skin and was initially diagnosed with pyoderma gangrenosum based on skin biopsy. She showed a limited response to prednisolone. Approximately 6 months after the initial onset, low-grade LYG was diagnosed after detection of CNS lesions on brain biopsy. The whole blood EBV-DNA load determined by real-time polymerase chain reaction was slightly elevated. Two months into IFNα therapy, skin and CNS lesions had responded favorably and the EBV-DNA load decreased. IFNα plays an important role in treatment of LYG through its antiproliferative, immunomodulatory, and anti-EBV effects. To our knowledge, this is the first case report of successful treatment with IFNα in Japan. Further investigation is necessary to determine optimal use of IFNα for LYG.

[Use of pegylated granulocyte colony-stimulating factor in dose-adjusted EPOCH-R therapy].

Dose-adjusted (DA)-EPOCH-R causes profound neutropenia requiring relatively long hospital stays with multiple doses of granulocyte colony-stimulating factor (G-CSF). A single-dose pegylated G-CSF (PEG-G-CSF) has been used for the treatment of chemotherapy-induced neutropenia. We retrospectively examined 15 patients (median age 61, range 33-75 years) treated with DA-EPOCH-R. In the first cycle of the DA-EPOCH-R therapy, a G-CSF preparation was used, and since the second cycle, the G-CSF and PEG-G-CSF use groups were divided. The median length of hospitalization after starting chemotherapy in the second-cycle DA-EPOCH-R was significantly shorter with PEG-G-CSF group (n=9) of 9 (7-13) days compared with G-CSF group (n=6) of 18 (15-22) days (P<0.001). Risk factors of febrile neutropenia, such as bone marrow invasion, performance status, serum albumin, and history of febrile neutropenia at the first DA-EPOCH-R cycle or previous chemotherapy were not significantly different for both groups, and the incidence of febrile neutropenia in PEG-G-CSF and G-CSF groups was 2.6% and 46.9%, respectively. These analyses suggest that PEG-G-CSF can be combined with DA-EPOCH-R without compromising treatment outcomes as compared with the daily dose of G-CSF.