Comprehensive procedure for injecting Evusheld® for hematological diseases in a single institute.

Tixagevimab and cilgavimab (EVA, Evusheld®), monoclonal antibody combination treatments, consisted of two neutralizing antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). EVA showed prophylactic and therapeutic effects against coronavirus disease 2019. The Japanese Society of Hematology recommended EVA for such patients with active treatment, but each institution decided on comprehensive administration. We develop a systematic procedure for comprehensive EVA injection prophylactically in patients with hematological malignancies without any over/under-indication. We listed all patients with the required indications from November 2022 to March 2023. We included 178 cases, 84 females and 94 males, with a median age of 70 (range: 19-90) years. Underlying diseases are myeloid neoplasms in 36 (20%), lymphoid neoplasms in 75 (73%), and others. Indications were intensively hematological malignancy treatment, rituximab treatment within 12 months, burton kinase inhibitor treatment, after chimeric antigen receptor T cell immunotherapy, and after stem cell transplantation in 74 (41%), 73 (41%), 3 (2%), 5 (3%), and 23 (13%) cases, respectively. Of the 178 cases, 22 (12.4%) refused EVA injection. Further, 42 and 136 cases were administered outpatient and inpatient, respectively. Over 95% of the listed cases received EVA injection within 3 months. No severe toxicities were observed among them (N = 156), and 8 (5.2%) cases had breakthrough SARS-CoV-2 infection, which was significantly lower (P = 0.02) than those without EVA (4 [18.2%] of 22 cases). Both groups showed no moderate or severe infection cases. This single-center experience showed that comprehensive EVA injection management effectively generated safer completion with preferable clinical impact.

Graft-versus-host disease after autologous stem cell transplantation in a recipient who underwent allogeneic stem cell transplantation 20 years earlier.

A literature review does not provide information about the safety of autologous hematopoietic stem cell transplantation (HSCT) in a recipient who has previously received allogeneic HSCT. We treated a 69-year-old woman with diffuse large B cell lymphoma. The patient received autologous stem cell transplantation (ASCT) in the second complete remission of malignant lymphoma. The patient had undergone allogeneic hematopoietic SCT (allo-HSCT) for chronic myeloid leukemia 20 years ago. Chronic myeloid leukemia had been in complete remission for the previous 20 years. Thus, the patient received autologous and allogenic HSCT 20 years apart. ASCT involves the patient receiving "self" hematopoietic cells from an allogeneic donor. In other words, this is immunologically the second allo-HSCT. The allo-HSCT 20 years ago was undergone by a related healthy brother, a human leukocyte antigen (HLA) 8/8 full matched donor. The conditioning regimen was reduced-intensity consisting of fludarabine and busulfan. The patient did not experience acute or chronic graft-versus-host disease (GVHD) after allo-HSCT. The second transplantation, ASCT was performed to the MEAM conditioning regimen. Engraftment was uneventful, and complete donor chimerism had been achieved even after ASCT. She suffered from an acute gastric mucosal lesion 52 days after ASCT. Pathological finding of gastric mucosa was nonspecific acute gastritis with significant neutrophil infiltration. Sex chromosome analysis of gastric mucosa demonstrated that mucosal cells had XX signals, whereas infiltrating neutrophils had XY signals. We speculated the patient onset of an acute gastric GVHD in this recipient after the second transplantation. This case remarked infiltration of neutrophils triggered GVHD reaction by resetting allogeneic immune reaction after the second transplantation. We describe a rare occurrence of GVHD reaction in a recipient of ASCT following allo-HSCT.

Clinical effects of tacrolimus blood concentrations early after allogeneic hematopoietic stem cell transplantation.

BACKGROUND AIMS: Tacrolimus (TAC) plus short-term methotrexate (stMTX) is used for graft-versus-host disease (GVHD) prophylaxis after allogeneic hematopoietic stem cell transplantation (allo-HSCT). TAC blood concentrations are frequently adjusted to enhance the graft-versus-leukemia/lymphoma effect or attenuate severe GVHD. Limited information is available on the clinical impact of these adjustments and the optimal time to perform them in order to achieve good clinical outcomes. METHODS: We retrospectively analyzed 211 patients who underwent allo-HSCT at our institutes. RESULTS: Higher TAC concentrations in week 3 correlated with a significantly higher cumulative incidence of relapse (CIR) (P = 0.03) and lower nonrelapse mortality (P = 0.04). The clinical impact of high TAC concentrations in week 3 on CIR was detected in the refined disease risk index: low/intermediate (P = 0.04) and high (P < 0.01), and conditioning regimens other than cyclophosphamide/total body irradiation and busulfan/cyclophosphamide (P = 0.07). Higher TAC concentrations in week 1 correlated with a lower grade 2-4 acute GVHD rate (P = 0.01). Higher TAC concentrations in weeks 2 and 3 correlated with slightly lower (P = 0.05) and significantly lower (P = 0.02) grade 3-4 acute GVHD rates, respectively. Higher TAC concentrations in weeks 1 and 3 were beneficial for severe acute GVHD in patients with a human leukocyte antigen-matched donor (P = 0.03 and P < 0.01, respectively), not treated with anti-thymocyte globulin (P = 0.02 and P = 0.02, respectively), and receiving three stMTX doses (P = 0.03 and P = 0.02, respectively). CONCLUSIONS: The clinical impact of TAC concentrations varied according to patient characteristics, including disease malignancy, conditioning regimens, donor sources, and GVHD prophylaxis. These results suggest that TAC management needs to be based on patient profiles.

Association of Psychological Readiness to Return to Sports With Subjective Level of Return at 12 Months After ACL Reconstruction.

Background: Return-to-sports (RTS) rates after anterior cruciate ligament (ACL) reconstruction (ACLR) differ according to the level at which patients return. It is unclear whether the level of RTS is affected by psychological readiness to return. Purpose: To examine the association between psychological readiness to RTS and subjective RTS level 12 months after ACLR. Study Design: Case-control study; Level of evidence, 3. Methods: A total of 47 patients who underwent unilateral primary ACLR surgery were enrolled. Assessments at 6 and 12 months postoperatively consisted of knee strength testing (isokinetic quadriceps and hamstring strength), the International Knee Documentation Committee Subjective Knee Evaluation Form (IKDC-SKF), and the Anterior Cruciate Ligament-Return to Sport after Injury (ACL-RSI) scale to measure psychological readiness to RTS. Patients were assigned to 1 of 3 subgroups based on their subjective assessment of RTS level at 12 months postoperatively: RTS at or above preinjury level (RTS≥Pre; n = 19), RTS below preinjury level (RTS

Potential factors for and the prognostic impact of ascites after allogeneic hematopoietic stem cell transplantation.

Ascites is sometimes detected after allogeneic hematopoietic stem cell transplantation (allo-HSCT); however, since limited information is currently available, its clinical meaning remains unclear. Therefore, we herein examined potential factors for and the impact of ascites on the prognosis of patients after allo-HSCT at our institutes. Fifty-eight patients developed ascites within 90 days of allo-HSCT (small in 34 (16%), moderate-large in 24 (11%)). A multivariate analysis identified veno-occlusive disease/sinusoidal obstruction syndrome (p = 0.01) and myeloablative conditioning (p = 0.01) as significant potential factors for the development of small ascites. Thrombotic microangiopathy (TMA) (p < 0.01) was a significant potential factor for moderate-large ascites. The incidence of both small and moderate-large ascites correlated with lower overall survival (p = 0.03 for small ascites and p < 0.01 for moderate-large ascites) and higher non-relapse mortality rates (p = 0.03 for small ascites and p < 0.01 for moderate-large ascites). Lower OS and higher NRM rates correlated with the incidence of both small and moderate-large ascites. Further investigation is warranted to establish whether the clinical sign of ascites improves the diagnostic quality of TMA in a large-scale study.

Cetuximab Plus Concurrent Radiotherapy in Patients With Nasopharyngeal Carcinoma.

BACKGROUND/AIM: Several reports have evaluated the efficacy and safety of concurrent radiotherapy with cetuximab (BRT) in patients with nasopharyngeal carcinoma (NPC). Combination therapy with cetuximab can be a treatment option for NPC. Although clinical data regarding the efficacy and safety of BRT without induction chemotherapy (ICT) or adjuvant chemotherapy is essential for the development of new therapeutic strategies, such data are rarely reported. PATIENTS AND METHODS: We retrospectively investigated a series of patients with NPC treated in our institution to evaluate the efficacy and safety of BRT. Eleven patients with newly diagnosed NPC were identified from an inpatient database from July 2015 to April 2018. Seven patients who received BRT were reviewed. RESULTS: All patients completed BRT without cessation of treatment. Six (85.7%) patients achieved a complete response and one (14.3%) achieved stable disease. The response rate was 85.7%. All patients with ≤T3 disease achieved a complete response. Both patients with T3 disease developed local recurrence, and one of the four patients with T1-2 disease developed distant metastases. The 1- and 3-year overall survival rates were 85.7% and 47.6%, respectively. The most common adverse events (AEs) were pharyngeal mucositis (100%), radiation dermatitis (100%), anorexia (28.6%), weight loss (28.6%), acneiform rash (28.6%), and dry mouth (28.6%). Grade 3 AEs were pharyngeal mucositis (42.9%), radiation dermatitis (28.6%), and anorexia (14.3%). No grade 4/5 AEs were observed. CONCLUSION: BRT for NPC was tolerable, but our findings suggest that BRT without induction chemotherapy or adjuvant chemotherapy is insufficient at least for ≥T3 disease.

WPOI-4/5 Correlates With Lymph Node Recurrence and Poor Prognosis in Early-stage Tongue Squamous Cell Carcinoma.

BACKGROUND/AIM: Neck management in patients with early-stage tongue cancer remains controversial. The worst pattern of invasion (WPOI) of the primary tumor has been associated with the incidence of regional metastasis. We investigated the prognostic role of WPOI, especially in relation to regional lymph node recurrence and disease-specific survival (DSS). PATIENTS AND METHODS: We retrospectively reviewed medical records and evaluated tumor specimens of 38 patients with early-stage tongue cancer who underwent primary tumor resection without elective neck dissection. RESULTS: Regional lymph node recurrence rates were significantly higher in patients with WPOI-4/5 compared with WPOI-1 to -3. The 5-year DSS rates were significantly higher for WPOI-1 to -3 than for WPOI-4/5. Notably, patients with WPOI-1 to -3 achieved a 100% 5-year DSS rate with salvage neck dissection and postoperative treatment, even those with cervical lymph node recurrence, whereas patients with WPOI-4/5 had a poorer prognosis. CONCLUSION: Patients with WPOI-1 to -3 tumors can be followed up without neck dissection until regional lymph node recurrence is detected, with a good course after salvage treatment. In contrast, patients with WPOI-4/5 tumors who are followed up until the appearance of regional lymph node recurrence have a poor prognosis, even with adequate treatment for recurrent disease.

Repetitive pitching decreases the elbow valgus stability provided by the flexor-pronator mass: the effects of repetitive pitching on elbow valgus stability.

BACKGROUND: Baseball pitching induces a large elbow valgus load, stressing the ulnar collateral ligament (UCL). Flexor-pronator mass (FPM) contraction contributes to valgus stability; however, repetitive baseball pitching may weaken the FPM contractile function. The present study investigated the effects of repetitive baseball pitching on the medial valgus stability measured using ultrasonography. We hypothesized that repetitive pitching would decrease elbow valgus stability. METHODS: This was a controlled laboratory study. Fifteen young male baseball players at the collegiate level (age: 23.0 ± 1.4 years) were enrolled. The medial elbow joint space was measured using ultrasonography (B-mode, 12-MHz linear array transducer) in the following three conditions: at rest (unloaded), under 3 kg valgus load (loaded), and under valgus load with maximal grip contraction to activate FPM (loaded-contracted). All measurements were performed before and after the pitching tasks, which comprised five sets of 20 pitches. Two-way repeated-measures analysis of variance was applied to determine changes in the medial elbow joint space. The post hoc test with Bonferroni adjustment was applied to assess the changes within the time and condition. RESULTS: The medial elbow joint space was significantly greater under the loaded than the unloaded and loaded-contracted conditions both before and after pitching (P < .001). In the loaded-contracted condition, the medial elbow joint space significantly increased after repetitive baseball pitching (P < .001). CONCLUSIONS: The results of the present study indicated that repetitive baseball pitching reduced the elbow valgus stability. This reduction could be attributed to the decreased FPM contractile function. Insufficient contraction may increase the tensile load on the UCL with pitching. FPM contraction plays a role in narrowing the medial elbow joint space; however, repetitive baseball pitching reduced the elbow valgus stability. It has been suggested that sufficient rest and recovery of the FPM function are required to reduce the UCL injury risk.

Induction Chemotherapy With 5-Fluorouracil, Cisplatin, and Cetuximab in Advanced Head and Neck Squamous Cell Carcinoma.

BACKGROUND/AIM: Chemoradiotherapy (CRT) with high-dose cisplatin has become the standard of care for larynx preservation in patients with locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). However, the long-term results are unsatisfactory. Induction chemotherapy (ICT) with docetaxel/cisplatin/5-fluorouracil (TPF) is associated with hematologic toxicity, and a safer therapy with comparable efficacy is desired. We conducted a pilot study to investigate the efficacy and safety of 5-fluorouracil/cisplatin/cetuximab (FPE) therapy as a candidate regimen for ICT in comparison with TPF. PATIENTS AND METHODS: Patients with stage cN2/3 LA-SCCHN of the larynx/oropharynx/hypopharynx were treated with FPE or TPF followed by radiotherapy. We reviewed patients' medical records and evaluated treatment efficacy and safety retrospectively. RESULTS: The response rates for ICT and ICT-radiotherapy were 71% and 93%, respectively, in the FPE group and 90% and 89%, respectively, in the TPF group. The 1-year progression-free and overall survival rates were 57% and 100%, respectively, in the FPE group and 70% and 90%, respectively, in the TPF group. TPF was linked to significantly higher rates of Grade 3/4 hematologic toxicity during ICT. The rates of Grade 3 or higher toxicity did not differ between the two groups during radiotherapy. CONCLUSION: The efficacy of ICT was comparable between the FPE and TPF groups, whereas FPE was associated with less toxicity. It is suggested that FPE therapy is an alternative ICT regimen to TPF therapy, but further long-term follow-up is needed.

Repeated spontaneous remission of acute myeloid leukemia in response to various infections: a case report.

BACKGROUND: Acute myeloid leukemia (AML) is a progressive hematological malignancy that can be fatal when left untreated. However, spontaneous remission is rarely observed in the presence of infectious diseases. CASE PRESENTATION: We treated an 80-year-old woman with AML who spontaneously underwent remission after infections. Spontaneous remission was observed after each of three independent clinical infections caused by different pathogens-nontuberculous Mycobacterium infection, pulmonary aspergillosis, and Escherichia coli bacteremia. All infections were treated promptly with antimicrobials. Mycobacterium avium infection was treated with azithromycin, rifampin, and ethambutol. Pulmonary aspergillosis was treated with itraconazole followed by voriconazole. E. coli infection was treated with meropenem. During each infectious episode, leukemic cells disappeared from the patient's peripheral blood and pancytopenia improved without routine blood transfusion. These clinical effects lasted for several months. The patient has survived for > 2 years beyond the median survival time of end-stage AML. Thus, this case represents an immunological antileukemic effect of systemic infections. CONCLUSIONS: We have discussed a common mechanism of spontaneous remission of AML without chemotherapy, clinically exhibited by infection immunology. We believe that infections exert a limited immunological effect against AML, which may prolong survival among elderly individuals with AML.

Electromyographic activities of glenohumeral joint muscles during shoulder forward flexion with isometric horizontal abduction loading.

BACKGROUND: Isometric horizontal abduction loading has been applied to improve imbalanced scapular muscle activities during shoulder exercises; however, the effect on glenohumeral joint muscle activity remains unclear. The purpose of this study was to investigate the changes in electromyographic activity of shoulder muscles during forward flexion with isometric horizontal abduction loading in healthy participants. METHODS: Thirteen healthy men were recruited for this study. Participants performed shoulder forward flexion with isometric horizontal abduction loading using an elastic band (Flex-band condition) and forward flexion without shoulder loading (Normal-flex condition). Muscle activities were evaluated while maintaining shoulder flexion at 60°, 90°, 120°, and 150° (static task) and during active shoulder flexion from 0° to maximum elevation (dynamic task). Surface electrodes were placed on the deltoid, pectoralis major, infraspinatus, and teres minor muscles to measure the activities of the shoulder muscles during each task. The muscle activities during the static task were compared using a 2-way analysis of variance with repeated measures of the 2 factors, loading condition and flexion position, and a paired t test was used for comparisons between the 2 conditions during the dynamic task (significance level set at P < .05). RESULTS: For the static task, the Flex-band condition significantly increased the deltoid middle and posterior activities by 2-15 times and the infraspinatus and teres minor activities by 2-3 times compared with the Normal-flex condition at all positions. In contrast, the Flex-band condition significantly decreased (by about half) the activities of the deltoid anterior (at 120° and 150°) and pectoralis major (at all positions) compared with the Normal-flex condition. For the dynamic task, the Flex-band condition significantly increased the deltoid middle, deltoid posterior, infraspinatus, and teres minor activities by 2-7 times and decreased the deltoid anterior activity by approximately two-thirds. CONCLUSIONS: Applying isometric horizontal abduction loading during shoulder forward flexion may be useful in improving the imbalanced muscle activities of the glenohumeral joint, such as excessive activity of the deltoid anterior and pectoralis major and dysfunction of the deltoid middle, deltoid posterior, and shoulder external rotator muscles. Shoulder forward flexion with horizontal abduction loading could be available for exercise in patients who have massive rotator cuff tears or who have undergone rotator cuff repair and shoulder arthroplasty.

Prognostic impact of the simple L-index and absolute lymphocyte count early after allogeneic hematopoietic stem cell transplantation.

BACKGROUND AIMS: The L-index, designed as a quantitative parameter to simultaneously assess the duration and severity of lymphopenia, and absolute lymphocyte count (ALC) have a prognostic impact after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, discrepancies have been reported in the impact of ALC, and limited information is currently available on the L-index. METHODS: To search for a better clinical tool, the authors retrospectively compared the simple L-index at 30 days (sL-index(30)), which aims to make the original L-index more compact, and ALC at 30 days (ALC(30)) after allo-HSCT in 217 patients who underwent allo-HSCT at the authors' institutions. RESULTS: Median sL-index(30) was 11 712 (range, 4419-18 511) and median ALC(30) was 404 (range, 0-3754). In a multivariate analysis, higher sL-index(30) was associated with a significantly higher cumulative incidence of relapse (CIR) (hazard ratio [HR], 1.01, 95% confidence interval [CI], 1.00-1.02, P = 0.02 for every increase of 100 in sL-index(30)) as well as non-relapse mortality (NRM) (HR, 1.02, 95% CI, 1.00-1.03, P = 0.01 for every increase of 100 in sL-index(30)). Although higher ALC(30) was associated with significantly lower CIR (HR, 0.94, 95% CI, 0.89-1.00, P = 0.04 for every increase of 100/µL in ALC(30)), it was not extracted as an independent risk factor for NRM (HR, 0.96, 95% CI, 0.88-1.05, P = 0.39). Higher sL-index(30) was associated with a slightly higher rate of grade 3-4 acute graft-versus-host disease (GVHD) (HR, 1.02, 95% CI, 1.00-1.04, P = 0.12 for every increase of 100 in sL-index(30)) but not chronic GVHD (HR, 1.00, 95% CI, 0.99-1.01, P = 0.63). ALC(30) was not associated with rates of grade 3-4 acute GVHD (HR, 1.02, 95% CI, 0.88-1.17, P = 0.81) or chronic GVHD (HR, 1.02, 95% CI, 0.98-1.06, P = 0.34). In a receiver operating characteristic curve, the cutoff values of sL-index(30) and ALC(30) for CIR were 9000 and 500, respectively, and the cutoff value of sL-index(30) for NRM was 12 000. CONCLUSIONS: sL-index(30) is a promising tool that may be applied to various survival outcomes. A large-scale prospective study is needed to clarify whether medical interventions based on sL-index(30) values will improve the clinical prognosis of patients.

Cost-Effectiveness Analysis of Transplantation-Ineligible Elderly Patients With Acute Leukemia Harboring a Molecular Target: Ph-Positive Acute Leukemia and FLT3-Mutated Acute Myeloid Leukemia.

Background: Tyrosine kinase inhibitors (TKIs) and FMS-like tyrosine kinase 3 (FLT3) inhibitors are promising agents for Ph-positive acute leukemia (Ph+ AL) and FLT3 mutated acute myeloid leukemia (FLT3-AML), respectively. Methods: We examined the cost-effectiveness ratio (CER) of dasatinib and ponatinib for Ph+ AL and the cost-effectiveness of gilteritinib and quizartinib for FLT3-AML in elderly patients. Molecular therapy can fit the elderly population better than chemotherapy (CT). Results: The daily drug cost of dasatinib, ponatinib, gilteritinib, and quizartinib was $240, $170, $524, and $479 in terms of treatment maintenance dose, respectively. Treatment of Ph+ AL with stem cell transplantation (SCT), CT, dasatinib, and ponatinib yielded CERs of $322,375, $34,928, $61,104, and $46,234, respectively. The CERs for FLT3-AML treated with SCT, CT, gilteritinib, and quizartinib were $355,270, $42,717, $94,987, and $90,080, respectively. Treatment of elderly patients with TKIs and FLT3 inhibitors remained expensive and inferior to conventional CT. Conclusion: Although TKIs and FLT3 inhibitors have an inferior CER than does conventional CT, their promising survival benefit with better QOL can offer a profound advantage. TKI or FLT3 inhibitor monotherapy is recommended as an alternative treatment option for unfit (vulnerable) elderly patients with Ph+ AL or FLT3-AML.

Evaluation of performance of pelvic CT-MR deformable image registration using two software programs.

We assessed the accuracy of deformable image registration (DIR) accuracy between CT and MR images using an open-source software (Elastix, from Utrecht Medical Center) and a commercial software (Velocity AI Ver. 3.2.0 from Varian Medical Systems, Palo Alto, CA, USA) software. Five male patients' pelvic regions were studied using publicly available CT, T1-weighted (T1w) MR, and T2-weighted (T2w) MR images. In the cost function of the Elastix, we used six DIR parameter settings with different regularization weights (Elastix0, Elastix0.01, Elastix0.1, Elastix1, Elastix10, and Elastix100). We used MR Corrected Deformable algorithm for Velocity AI. The Dice similarity coefficient (DSC) and mean distance to agreement (MDA) for the prostate, bladder, rectum and left and right femoral heads were used to evaluate DIR accuracy. Except for the bladder, most algorithms produced good DSC and MDA results for all organs. In our study, the mean DSCs for the bladder ranged from 0.75 to 0.88 (CT-T1w) and from 0.72 to 0.76 (CT-T2w). Similarly, the mean MDA ranges were 2.4 to 4.9 mm (CT-T1w), 4.6 to 5.3 mm (CT-T2w). For the Elastix, CT-T1w was outperformed CT-T2w for both DSCs and MDAs at Elastix0, Elastix0.01, and Elastix0.1. In the case of Velocity AI, no significant differences in DSC and MDA of all organs were observed. This implied that the DIR accuracy of CT and MR images might differ depending on the sequence used.

Risk Factors for and the Prognostic Impact of Pericardial Effusion after Allogeneic Hematopoietic Stem Cell Transplantation.

Pericardial effusion (PE) is a rare complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although the mechanisms underlying the onset of PE remain unclear, patients with PE after allo-HSCT have poor clinical outcomes. However, the prognostic impact of PE remains controversial, and risk factors have varied among studies. Therefore, we examined contributing as well as prognostic factors for PE. We retrospectively examined 243 patients who underwent allo-HSCT at the Faculty of Medicine, Kagawa University and Takamatsu Red Cross Hospital, Kagawa, Japan between 2000 and 2020. Forty-three patients (18%) were excluded owing to a lack of data on PE, and thus we ultimately analyzed 200 patients. We reviewed the findings of computed tomography (CT) scans, including chest CT, and echocardiography after allo-HSCT. Only cases in which a radiologist or echocardiography technician detected PE were assessed. PE was stratified into localized PE and whole-circumference PE. The median age at transplantation was 52 years (range, 16 to 74 years). The study cohort comprised 106 patients (53%) age more than 50 years, 88 females (44%), and 112 males (56%). Primary diseases were myeloid neoplasms in 122 patients (61%) and lymphoid neoplasms in 78 (39%). The conditioning regimen was myeloablative in 142 patients (71%) and nonmyeloablative in 58 (29%). The median duration of follow-up was 47 months (range, 1 to 209 months). Forty patients developed PE within 100 days; localized in 23 (12%) and whole circumference in 17 (9%). In a multivariate analysis, significant risk factors for the development of PE within 100 days were late neutrophil engraftment (hazard ratio [HR], 5.24; 95% CI, 1.92 to 14.30; P < .01) and thrombotic microangiopathy (TMA) (HR, 8.23; 95% CI, 1.42 to 47.60; P = .02). The incidence of whole- circumference PE correlated with a lower overall survival (OS) rate (HR, 3.10; 95% CI, 1.34 to 7.17; P < .01) and higher nonrelapse mortality (NRM) rate (HR, 2.94; 95% CI, 1.18 to 7.32; P = .02). In the subgroup analysis, significant risk factors for the development of PE within 365 days were late neutrophil engraftment (HR, 3.13; 95% CI, 1.08 to 9.02; P = .04), the occurrence of chronic graft-versus-host disease (GVHD) (HR, 3.57; 95% CI, 1.19 to 10.70; P = .02), and disease recurrence (HR, 4.98; 95% CI, 1.43 to 17.30; P = .01). The development of whole-circumference PE also correlated with a lower OS rate (HR, 3.83; 95% CI, 1.65 to 8.89; P < .01) and a higher NRM rate (HR, 83.21; 95% CI, 17.75 to 390.10; P < .01). The overall occurrence of acute (grade II to IV) GVHD, chronic GVHD, and TMA were 36% (72 of 200), 39% (78 of 200), and 10% (19 of 200), respectively. In the entire cohort, the 3-year OS rate was 55%, and 3-year relapse and NRM rates were 37 and 14%, respectively. The present results demonstrate that risk factors for PE varied according to the time after allo-HSCT, and that whole-circumference PE at any time correlated with lower OS and higher NRM rates. A large-scale prospective study is needed to verify risk factors for PE and clarify whether immunosuppressive interventions based on the onset of PE improve the clinical prognosis of patients.

A Case of Tyrosine Kinase Inhibitor-Resistant Chronic Myeloid Leukemia, Chronic Phase with ASXL1 Mutation.

Hematological malignancies, including chronic myeloid leukemia (CML), exhibit ASXL1 mutations; however, the function and molecular mechanism of these mutations remain unclear. ASXL1 was originally identified as tumor suppressor gene, in which loss of function causes myelodysplastic syndrome (MDS). ASXL1 mutations are common and associated with disease progression in myeloid malignancies including MDS, acute myeloid leukemia, and similarly in CML. In MDS, ASXL1 mutations have been associated with poor prognosis; however, the impact of ASXL1 mutations in CML has not been well described. A 31-year-old male was diagnosed as CML-chronic phase (CP). Laboratory findings showed a white blood cell count of 187,200/µL, with asymptomatic splenomegaly. Blast count was 5.0% in peripheral blood and 7.3% in bone marrow. There was no additional chromosomal abnormality except for t(9;22)(q34;q11.2) by chromosomal analysis. At onset, the Sokal score was 1.4, indicating high risk. The patient received tyrosine kinase inhibitor (TKI) therapy, comprising nilotinib ∼600 mg/day, bosutinib ∼600 mg/day, ponatinib ∼45 mg/day, and dasatinib ∼100 mg/day. Nevertheless, after 1.5 years of continuous TKI therapy, the best outcome was a hematological response. Although additional chromosomal aberrations and ABL1 kinase mutations were analyzed repeatedly before and during TKI therapy, known genetic abnormalities were not detected. Thereafter, the patient underwent bone marrow transplantation from an HLA 7/8 matched unrelated donor (HLA-Cw 1 locus mismatch, graft-versus-host direction). The patient achieved neutrophil engraftment, 18 days after transplantation, leading to complete remission with an undetectable level of BCR-ABL1 mRNA. The patient, however, died from graft-versus-host disease and thrombotic microangiopathy after 121 days. Gene sequence analysis of his CML cell before stem cell transplantation revealed ASXL1 mutations. Physiologically, ASXL1 contributes to epigenetic regulation. In the CML-CP patient in this case report, ASXL1 mutation conferred resistance to TKI through obscure resistance mechanisms. Even though a molecular mechanism for TKI resistance in ASXL1 mutation in CML has remained obscure, epigenetic modulation is a plausible mode of CML disease progression. The clinical impact including prognosis of ASXL1 for CML is underscored. And the treatment strategy of CML with ASXL1 mutation has not been established. A discussion of this case was expected to facilitate treatment options.

Kinematics and muscle activities of the lower limb during a side-cutting task in subjects with chronic ankle instability.

PURPOSE: The purpose of the present study was to evaluate lower limb kinematics and muscular activities during walking, side-turning while walking, and side-cutting movement in athletes with chronic ankle instability and compare the results to those of athletes without chronic ankle instability. METHODS: Lower limb kinematics and muscular activities were evaluated in 10 athletes with chronic ankle instability and 10 healthy control athletes using a three-dimensional motion analysis system and surface electromyography during the 200-ms pre-initial contact (IC) and stance phases while walking, side-turning while walking, and side-cutting. RESULTS: During walking or side-turning while walking, there were no significant differences in kinematics or muscle activities between the subjects with and without chronic ankle instability. For the side-cutting task, however, ankle inversion angles during the 200-ms pre-IC and late stance phases [effect sizes (ESs) = 0.95-1.43], the hip flexion angle (ESs = 0.94-0.96) and muscular activities of the gastrocnemius medialis (ESs = 1.04-1.73) during the early stance phase were significantly greater in the athletes with chronic ankle instability than in the healthy control athletes. CONCLUSIONS: Alterations of kinematics in athletes with chronic ankle instability were found not only at the ankle but also at hip joints during the side-cutting movement. These alterations were not detected during walking or side-turning while walking. The findings of the present study indicate that clinicians should take into account the motion of the hip joint during the side-cutting movement in persons with chronic ankle instability. LEVEL OF EVIDENCE: III.

The effect of changing toe direction on knee kinematics during drop vertical jump: a possible risk factor for anterior cruciate ligament injury.

PURPOSE: The purpose of this study was to examine the effect of changing toe direction on knee kinetics and kinematics associated with anterior cruciate ligament injury during drop vertical jumps. METHODS: Fourteen females performed drop vertical jumps under three toe conditions (natural, toe-in, and toe-out). The knee kinetics and kinematics during landing were evaluated using a motion analysis system. Results under three toe conditions were compared using a one-way repeated measures analysis of variance and a post hoc Bonferroni test. RESULTS: Toe-in landing was associated with a significantly greater knee abduction angle, tibial internal rotation angle, and knee abduction moment than the natural and toe-out conditions. Toe-out landing was associated with significantly greater tibial internal rotational angular velocity. CONCLUSIONS: Changing toe direction significantly affects knee kinetics and kinematics during landing. It is important to avoid changing toe direction excessively inward or outward during landing to prevent the increases in knee abduction and tibial internal rotation which might increase the risk of ACL injury. LEVEL OF EVIDENCE: Prognosis, Level IV.