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Aggressive adult T-cell leukemia/lymphoma (ATL) is a hematological malignancy that is difficult to treat with chemotherapy alone, and allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative therapy. We conducted a multicenter, prospective, observational study to clarify the treatment outcomes of aggressive ATL in the current era. Between 2015 and 2018, 113 patients aged 70 years or younger with newly diagnosed aggressive ATL were enrolled. The median age at diagnosis was 61 years. Treatment outcomes were compared with those of 1792 ATL patients diagnosed between 2000 and 2013 in our previous retrospective study. The inclusion criteria were the same in both studies. The prospective cohort demonstrated better overall survival (OS) than the retrospective cohort (2-year OS, 45% vs 29%, respectively; P < .001), with a much higher proportion of patients receiving allo-HCT (80% vs 34%, respectively; P < .001) and a shorter interval from diagnosis to allo-HCT (median, 128 vs 170 days, respectively; P < .001). Among the 90 patients who received allo-HCT (cord blood, n = 30; HLA-haploidentical related donors, n = 20; other related donors, n = 14; other unrelated donors, n = 26), the 2-year probabilities of OS, non-relapse mortality (NRM), and disease progression were 44%, 23%, and 46%, respectively. OS and NRM did not differ statistically according to donor type. Our results suggest that increased application of allo-HCT improved the survival of patients with aggressive ATL. The use of cord blood or HLA-haploidentical donors may be feasible for aggressive ATL when HLA-matched related donors are unavailable. This study was registered at the UMIN Clinical Trials Registry as #000017672., (© 2021 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Tongue-hold swallow (THS) is a swallow exercise in which an individual swallows saliva while holding the anterior portion of the tongue between the front teeth. The effect of THS on pharyngeal contractile vigor is still unclear. The purpose of this study was to quantify THS using high-resolution manometry with a contractile integral analysis. Twenty-two healthy participants performed three different saliva swallow tasks: normal swallow, weak THS (in which the tongue was protruded 1 cm outside the upper incisors), and strong THS (in which the tongue was protruded 2 cm outside the upper incisors). The participants repeated each task twice randomly. Pharyngeal and upper esophageal sphincter metrics, including the pharyngeal contractile integral, were analyzed. Both weak and strong THS enhanced the velopharyngeal contractile integral and peak pressure compared with normal swallow (P < 0.01). THS also prolonged mesopharyngeal contraction (P < 0.01). Holding the tongue anteriorly during swallow requires significant biomechanical changes to pharyngeal contractile properties at the superior and middle pharyngeal constrictor levels; thus, it may serve as a resistance exercise for the muscles that are involved in bolus propulsion., (© 2021. The Author(s).)

Positive results from recent clinical trials have significantly expanded current therapeutic options for patients with chronic graft-versus-host disease (GVHD). However, new insights into the associations between clinical characteristics of chronic GVHD, pathophysiologic mechanisms of disease, and the clinical and biological effects of novel therapeutic agents are required to allow for a more individualized approach to treatment. The current report is focused on setting research priorities and direction in the treatment of chronic GVHD. Detailed correlative scientific studies should be conducted in the context of clinical trials to evaluate associations between clinical outcomes and the biological effect of systemic therapeutics. For patients who require systemic therapy but not urgent initiation of glucocorticoids, clinical trials for initial systemic treatment of chronic GVHD should investigate novel agents as monotherapy without concurrently starting glucocorticoids, to avoid confounding biological, pathological, and clinical assessments. Clinical trials for treatment-refractory disease should specifically target patients with incomplete or suboptimal responses to most recent therapy who are early in their disease course. Close collaboration between academic medical centers, medical societies, and industry is needed to support an individualized, biology-based strategic approach to chronic GVHD therapy., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. All rights reserved.)

Bronchiolitis obliterans syndrome (BOS) is a highly morbid form of chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT). Several plasma proteins have been identified as biomarkers for BOS after lung transplantation. The relevance of these biomarkers in BOS patients after allogeneic HCT has not been examined. We hypothesized that biomarkers associated with BOS after lung transplantation are also associated with BOS after allogeneic HCT. We tested plasma samples from 33 adult HCT patients who participated in a phase II multicenter study of fluticasone, azithromycin, and montelukast (FAM) treatment for new-onset BOS (NCT01307462), and matched control samples of HCT patients who had non-BOS chronic GVHD (n = 31) and those who never experienced chronic GVHD (n = 29) (NCT00637689 and NCT01902576). Candidate biomarkers included matrix metalloproteinase-9 (MMP-9), MMP-3, and chitinase-3-like-1 glycoprotein (YKL-40). MMP-9 concentrations were higher in the patients with BOS compared with those with non-BOS chronic GVHD (P = .04) or no chronic GVHD (P < .001). MMP-3 concentrations were higher in patients with BOS (P < .001) or non-BOS chronic GVHD (P < .001) compared with those with no chronic GVHD. YKL-40 concentrations did not differ statistically among the 3 groups. MMP-9 concentrations before starting FAM therapy were higher in patients who experienced treatment failure within 6 months compared with those with treatment success (P = .006), whereas MMP-3 or YKL-40 concentrations did not differ statistically between these 2 groups. Patients with an MMP-9 concentration ≥200,000 pg/mL before starting FAM therapy had worse overall survival compared with those with lower MMP-9 concentrations. Our data suggest that plasma MMP-9 concentration could serve as a relevant biomarker at diagnosis of BOS after allogeneic HCT for prognostication of survival and for prediction of treatment response. Further validation is needed to confirm our findings., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Purpose: This study aimed to describe recovery of dysphagia after stroke. We determined the proportion of stroke survivors with dysphagia on admission, discharge, and 6 months after stroke. Additionally, the factors affecting oral feeding 6 months after stroke were explored., Methods: A total of 427 acute stroke patients were recruited prospectively. Presence of dysphagia was evaluated on admission, weekly until recovery was achieved, and at discharge. We compared stroke survivors with dysphagia who had complete recovery, who had dysphagia but achieved oral feeding, and who required tube feeding. Patient-reported eating ability was evaluated at 6 months. Patients who achieved oral feeding by 6 months were compared to those who had persistent tube feeding need., Results: Fifty-five percent of stroke survivors had dysphagia on initial evaluation (3.1 ± 1.4 days after admission) and 37% at discharge (21.1 ± 12.4 days). At 6 months, 5% of patients required tube feeding. Among those who had dysphagia at initial evaluation, 32% had resolution of dysphagia within two weeks, 44% had dysphagia but started oral feeding before discharge, and 23% required alternative means of alimentation (nasogastric tube feeding, percutaneous endoscopic gastrostomy, parental nutrition) throughout hospitalization. At 6 months, 90% of stroke survivors who achieved oral feeding by discharge continued with oral feeding. Patients who achieved oral feeding after discharge had less cognitive impairments on admission and a higher speech therapist intervention rate after discharge., Conclusions: More than half of stroke survivors had dysphagia but the vast majority were able to return to oral feeding by 6 months. Cognitive function and dysphagia rehabilitation interventions were associated with return to oral feeding after hospital discharge., Competing Interests: Declaration of Competing Interest No conflict of interest declared., (Copyright © 2021 Elsevier Inc. All rights reserved.)

This study aimed to clarify the risk factors and prognosis associated with blood stream infection (BSI) in allogeneic hematopoietic cell transplantation (allo-HCT), and the relationship between BSI and acute graft-versus-host disease (aGVHD). This retrospective analysis included 11,098 patients in the Japanese national transplant registry. A total of 2172 patients developed BSI after allo-HCT, with 2332 identified pathogens. The cumulative incidences of BSI were 15.5% at 30 days and 20.9% at 100 days after allo-HCT. In a multivariate analysis, severe (grade III-IV) aGVHD was associated with a higher risk of BSI (vs. grade 0-I aGVHD: hazard ratio [HR] 3.34 [95% confidence interval (CI), 2.85-3.92; P < 0.001]). In a multivariate analysis, severe aGVHD before BSI was associated with a higher risk of overall mortality after BSI (vs. grade 0-I aGVHD: HR 2.61 [95% CI 2.18-3.11; P < 0.001]). In addition, BSI (vs. no-BSI: HR 1.20 [95% CI, 1.12-1.29; P < 0.001]) and severe aGVHD (vs. grade 0-I aGVHD: HR 1.97 [95% CI, 1.83-2.12; P < 0.001]) were independent risk factors for overall mortality after allo-HCT. In the setting of allo-HCT, severe aGVHD was associated with increases in both BSI incidence and post-BSI overall mortality. Furthermore, BSI was an independent risk factor for overall mortality., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Despite a strong association between acute graft-versus-host disease (GVHD) and cytomegalovirus reactivation (CMVR), the joint effect of acute GVHD and CMVR on nonrelapse mortality (NRM) has not been well studied., Methods: We evaluated the impact of CMVR on NRM stratified according to the development of acute GVHD using a landmark method. This study included 6078 patients who received their first allogeneic hematopoietic cell transplantation (HCT) with a preemptive strategy for CMVR between 2008 and 2017., Results: The cumulative incidences of grade 2-4 acute GVHD (G24GVHD), CMVR by day 100, and CMV disease by day 365 were 37.3%, 52.1%, and 2.9%, respectively. Patients with G24GVHD were associated with the subsequent development of CMVR, and the presence of CMVR also increased the risk of G24GVHD. In a landmark analysis at day 65, the cumulative incidence of NRM at 1 year was 5.4%, 10.0%, 13.9%, and 19.7% in patients with G24GVHD-/CMVR-, G24GVHD-/CMVR+, G24GVHD+/CMVR-, and G24GVHD+/CMVR+, respectively. In a multivariate analysis, CMVR was respectively associated with an increased risk of NRM by day 365 in patients without G24GVHD (hazard ratio [HR], 1.59; 95% confidence interval [CI], 1.24-2.05; P < .001) and with G24GVHD (HR, 1.34; 95% CI, 1.06-1.70; P = .014), but the interaction between G24GVHD and CMVR was not significant (P = .326). Subgroup analyses suggested that the joint effect of acute GVHD and CMVR might vary according to the baseline characteristics., Conclusions: These data regarding the close relationship between acute GVHD and CMVR should provide important implications for the treatment strategy after HCT., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Young adult (YA) survivors of allogeneic hematopoietic cell transplantation (HCT) are at risk for late psychosocial challenges, including the inability to return to work post-HCT. Work-related outcomes in this population remain understudied, however. We conducted this study to assess the post-HCT work status of survivors of allogeneic HCT who underwent HCT as YAs and to analyze the patient-, disease-, and HCT-related factors associated with their work status at 1 year post-HCT. Using Center for International Blood and Marrow Transplant Research data, we evaluated the post-HCT work status (full-time, part-time work, unemployed, or medical disability) of 1365 YA HCT survivors who underwent HCT between 2008 and 2015. Percentages of work status categories were reported at 4 time points: 6 months, 1 year, 2 years, and 3 years post-HCT. Percentages of post-HCT work status categories at the 1-year time point were also described in relation to survivors' pre-HCT work status categories. Factors associated with 1-year post-HCT work status (full-time or part-time work) were examined using logistic regression. From 6 months to 3 years post-HCT, the percentage of survivors working full-time increased from 18.3% to 50.7% and the percentage working part-time increased from 6.9% to 10.5%. Of patients in full-time work pre-HCT, 50% were unemployed or on medical disability at 1 year post-HCT. Female sex (odds ratio [OR], 0.55; 95% confidence interval [CI], 0.40 to 0.77), HCT Comorbidity Index score ≥3 (OR, 0.57; 95% CI, 0.39 to 0.82), pre-HCT unemployment (OR, 0.37; 95% CI, 0.24 to 0.56), medical disability (OR, 0.44; 95% CI, 0.28 to 0.70), development of grade III-IV acute graft-versus-host disease (OR, 0.52; 95% CI, 0.34 to 0.80), and relapse within 1 year post-HCT (OR, 0.34; 95% CI, 0.21 to 0.56) were associated with a lower likelihood of employment at 1 year post-HCT. Compared with myeloablative conditioning (MAC) with total body irradiation (TBI), MAC without TBI (OR, 1.71; 95% CI, 1.16 to 2.53) was associated with a greater likelihood of employment at 1 year post-HCT. Graduate school-level education (OR, 2.47; 95% CI, 1.49 to 4.10) was also associated with a greater likelihood of employment at 1 year post-HCT. Although the work status among YA HCT survivors continued to improve over time, a substantial subset became or remained unemployed or on medical disability. These findings underscore the need for effective interventions to support return to work in this population., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. All rights reserved.)

Allogeneic hematopoietic cell transplantation (allo-HCT) is potentially curative for certain hematologic malignancies and nonmalignant diseases. The field of allo-HCT has witnessed significant advances, including broadening indications for transplantation, availability of alternative donor sources, less toxic preparative regimens, new cell manipulation techniques, and novel GVHD prevention methods, all of which have expanded the applicability of the procedure. These advances have led to clinical practice conundrums when applying traditional definitions of hematopoietic recovery, graft rejection, graft failure, poor graft function, and donor chimerism, because these may vary based on donor type, cell source, cell dose, primary disease, graft-versus-host disease (GVHD) prophylaxis, and conditioning intensity, among other variables. To address these contemporary challenges, we surveyed a panel of allo-HCT experts in an attempt to standardize these definitions. We analyzed survey responses from adult and pediatric transplantation physicians separately. Consensus was achieved for definitions of neutrophil and platelet recovery, graft rejection, graft failure, poor graft function, and donor chimerism, but not for delayed engraftment. Here we highlight the complexities associated with the management of mixed donor chimerism in malignant and nonmalignant hematologic diseases, which remains an area for future research. We recognize that there are multiple other specific, and at times complex, clinical scenarios for which clinical management must be individualized., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Chronic graft-versus-host disease (GVHD) commonly occurs after allogeneic hematopoietic cell transplantation (HCT) despite standard prophylactic immune suppression. Intensified universal prophylaxis approaches are effective but risk possible overtreatment and may interfere with the graft-versus-malignancy immune response. Here we summarize conceptual and practical considerations regarding preemptive therapy of chronic GVHD, namely interventions applied after HCT based on evidence that the risk of developing chronic GVHD is higher than previously appreciated. This risk may be anticipated by clinical factors or risk assignment biomarkers or may be indicated by early signs and symptoms of chronic GVHD that do not fully meet National Institutes of Health diagnostic criteria. However, truly preemptive, individualized, and targeted chronic GVHD therapies currently do not exist. In this report, we (1) review current knowledge regarding clinical risk factors for chronic GVHD, (2) review what is known about chronic GVHD risk assignment biomarkers, (3) examine how chronic GVHD pathogenesis intersects with available targeted therapeutic agents, and (4) summarize considerations for preemptive therapy for chronic GVHD, emphasizing trial development, including trial design and statistical considerations. We conclude that robust risk assignment models that accurately predict chronic GVHD after HCT and early-phase preemptive therapy trials represent the most urgent priorities for advancing this novel area of research., (Copyright © 2021. Published by Elsevier Inc.)

Introduction: In autologous peripheral blood stem cell harvest (APBSCH), CD34-positive cells have been measured to assess the numbers of hematopoietic stem cells, but measurement requires specialized equipment. Recently, there was a report that peripheral blood hematopoietic progenitor cells (HPCs) are useful indicators of the presence of hematopoietic stem cells. We examined the usefulness of HPC monitoring to predict APBSCH timing., Methods: We retrospectively analyzed the relationship between HPC and collected CD34-positive cells in 84 consecutive patients who underwent APBSCH., Results: According to the receiver operating characteristics curve for the collection of ≥2 × 106 CD34-positive cells/kg, the HPC cut-off value on the day before collection was 21/μL, while that on the day of collection was 41/μL. No significant factors were found in the univariate analysis except for the HPC count on the day before collection (p < 0.001) and the day of collection (p < 0.001). According to the multivariate analysis, the HPC count on the day before collection (p < 0.001) and the day of collection (p < 0.001) were also factors that strongly influenced the quantity of CD34-positive cells collected., Conclusion: Our results suggest that the HPC count on not only the day of collection but also the day before collection is a good indicator for appropriate APBSCH timing., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Posttransplant cyclophosphamide (PTCy) graft-versus-host disease (GVHD) prophylaxis has enabled haploidentical (Haplo) transplantation to be performed with results similar to those after matched unrelated donor (MUD) transplantation with traditional prophylaxis. The relative value of transplantation with MUD vs Haplo donors when both groups receive PTCy/calcineurin inhibitor/mycophenolate GVHD prophylaxis is not known. We compared outcomes after 2036 Haplo and 284 MUD transplantations with PTCy GVHD prophylaxis for acute leukemia or myelodysplastic syndrome in adults from 2011 through 2018. Cox regression models were built to compare outcomes between donor types. Recipients of myeloablative and reduced-intensity regimens were analyzed separately. Among recipients of reduced-intensity regimens, 2-year graft failure (3% vs 11%), acute grades 2 to 4 GVHD (hazards ratio [HR], 0.70; P = .022), acute grades 3 and 4 GVHD (HR, 0.41; P = .016), and nonrelapse mortality (HR, 0.43; P = .0008) were lower after MUD than with Haplo donor transplantation. Consequently, disease-free (HR, 0.74; P = .008; 55% vs 41%) and overall (HR, 0.65; P = .001; 67% vs 54%) survival were higher with MUD than with Haplo transplants. Among recipients of myeloablative regimens, day-100 platelet recovery (95% vs 88%) was higher and grades 3 and 4 acute (HR, 0.39; P = .07) and chronic GVHD (HR, 0.66; P = .05) were lower after MUD than with Haplo donor transplantation. There were no differences in graft failure, relapse, nonrelapse mortality, and disease-free and overall survival between donor types with myeloablative conditioning regimens. These data extend and confirm the importance of donor-recipient HLA matching for allogeneic transplantation. A MUD is the preferred donor, especially for transplantations with reduced-intensity conditioning regimens.

Purpose: Ultrahigh resolution (UHR) HLA matching is reported to result in better outcomes following unrelated donor hematopoietic cell transplantation, improving survival and reducing post-transplant complications. However, most studies included relatively small numbers of patients. Here we report the findings from a large, multicenter validation study., Methods: UHR HLA typing was available on 5,140 conventionally 10 out of 10 HLA-matched patients with malignant disease transplanted between 2008 and 2017., Results: After UHR HLA typing, 82% of pairs remained 10 out of 10 UHR-matched; 12.3% of patients were 12 out of 12 UHR HLA-matched. Compared with 12 out of 12 UHR-matched patients, probabilities of grade 2-4 acute graft-versus-host disease (aGVHD) were significantly increased with UHR mismatches (overall P = .0019) and in those patients who were HLA-DPB1 T-cell epitope permissively mismatched or nonpermissively mismatched (overall P = .0011). In the T-cell-depleted subset, the degree of UHR HLA mismatch was only associated with increased transplant-related mortality (TRM) (overall P = .0068). In the T-cell-replete subset, UHR HLA matching was associated with a lower probability of aGVHD (overall P = .0020); 12 out of 12 UHR matching was associated with reduced TRM risk when compared with HLA-DPB1 T-cell epitope permissively mismatched patients, whereas nonpermissive mismatching resulted in a greater risk (overall P = .0003)., Conclusion: This study did not confirm that UHR 12 out of 12 HLA matching increases the probability of overall survival but does demonstrate that aGVHD risk, and in certain settings TRM, is lowest in UHR HLA-matched pairs and thus warrants consideration when multiple 10 out of 10 HLA-matched donors of equivalent age are available., Competing Interests: Stephanie J. LeeHonoraria: Wolters KluwerConsulting or Advisory Role: Incyte, Pfizer, EMD Serono, Kadmon, MSD Oncology, Sanofi, Genzyme, Regeneron, 4SCResearch Funding: Kadmon, Takeda, Amgen, Bristol-Myers Squibb, EMD Serono, MSD, Novartis, Incyte, Syndax, Pfizer, AstraZenecaPatents, Royalties, Other Intellectual Property: Patent pending for high-affinity T-cell receptors that target the Merkel polyomavirus Jeffrey AulettaConsulting or Advisory Role: MORE Health, AlloVir, AscellaHealth Vijaya R. BhattConsulting or Advisory Role: Abbvie, Incyte, Agios, Genentech, Rigel, Partnership for Health Analytic Research, LLC, Omeros, TakedaResearch Funding: Incyte, Tolero Pharmaceuticals, National Marrow Donor Program, Abbvie, Pfizer, Jazz PharmaceuticalsOther Relationship: Oncoceutics, Novartis, Pfizer Loren GragertOther Relationship: National Marrow Donor Program/Be The Match, United Network For Organ Sharing Yoshihiro InamotoHonoraria: Kyowa Kirin Co, Ltd, Astellas Pharma, Sumitomo Dainippon, Novartis, Chugai Pharma, Bristol-Myers Squibb, MSD K.K.Consulting or Advisory Role: Novartis, Janssen, Meiji Seika Kaisha Gerald P. MorrisResearch Funding: Ferring Inc, AmgenTravel, Accommodations, Expenses: Thermo Fisher Scientific Sophie PaczesnyPatents, Royalties, Other Intellectual Property: Dr Paczesny has a patent on “Methods of detection of graft-versus-host disease” licensed to Viracor-IBT Laboratories Ran ReshefConsulting or Advisory Role: Atara Biotherapeutics, Novartis, Bristol-Myers Squibb, Gilead Sciences, TScan TherapeuticsResearch Funding: Atara Biotherapeutics, Incyte, Pharmacyclics, Shire, Immatics, Takeda, Gilead Sciences, Precision Biosciences, Astellas Pharma, Bristol-Myers Squibb Bronwen E. ShawHonoraria: TherakosConsulting or Advisory Role: Orcabio Peter ShawConsulting or Advisory Role: NovartisOther Relationship: Link PharmaNo other potential conflicts of interest were reported.

Purpose: To identify the ocular surface changes of ocular graft-versus-host disease (GVHD) using anterior segment optical coherence tomography (AS-OCT) and examine the efficacy of disposable bandage soft contact lens (BSCL) treatment in ocular GVHD patients., Methods: This study is a prospective, Phase II clinical trial. Nineteen patients diagnosed with chronic GVHD based on the NIH criteria and ocular symptoms of NIH eye score 2 or greater were enrolled. Disposable BSCL was applied to the GVHD-affected eyes with topical antibiotic coverage. Ocular exams, eye symptom surveys, and AS-OCT were performed with signed informed consent. Patients were followed for one to three months., Results: Thirty-eight eyes of 19 patients with ocular GVHD underwent BSCL treatment in this study. AS-OCT scans were done in 14 out of 19 patients. The mean best-corrected visual acuity at enrollment, 2-week, and 4-week visits was 0.180, 0.128, and 0.163 logMAR, respectively. Twenty-four out of 25 eyes (96 %) that initially presented with conjunctival inflammation, twenty-three out of 30 eyes (76.7 %) that initially presented with punctate epithelial erosion, and 8 out of 15 (53.3 %) eyes that initially presented with filamentous keratopathy showed improvement after wearing BSCL for 2 to 4 weeks. AS-OCT revealed corneal epithelial irregularity, abnormal meibomian gland orifice, and conjunctival hyperemia, in patients with ocular GVHD., Conclusions: BSCL treatment provided significant subjective and objective improvements in ocular GVHD patients. Meanwhile, we found that AS-OCT can be a promising diagnostic tool to characterize the ocular surface changes associated with ocular GVHD.

Preventing chronic graft-versus-host disease (GVHD) remains challenging because the unique cellular and molecular pathways that incite chronic GVHD are poorly understood. One major point of intervention for potential prevention of chronic GVHD occurs at the time of transplantation when acute donor anti-recipient immune responses first set the events in motion that result in chronic GVHD. After transplantation, additional insults causing tissue injury can incite aberrant immune responses and loss of tolerance, further contributing to chronic GVHD. Points of intervention are actively being identified so that chronic GVHD initiation pathways can be targeted without affecting immune function. The major objective in the field is to continue basic studies and to translate what is learned about etiopathology to develop targeted prevention strategies that decrease the risk of morbid chronic GVHD without increasing the risks of cancer relapse or infection. Development of strategies to predict the risk of developing debilitating or deadly chronic GVHD is a high research priority. This working group recommends further interrogation into the mechanisms underpinning chronic GVHD development, and we highlight considerations for future trial design in prevention trials., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. All rights reserved.)

To elucidate the incidence, causes, and risk factors associated with readmission due to transplant-related complications, we studied 213 consecutive patients who were discharged without progression of primary disease after their first allogeneic hematopoietic cell transplantation at our center between 2013 and 2016. The median patient age was 50 years (range, 18-71 years). Eighty-three patients had AML or MDS, 66 had lymphoma, 28 had ALL, 23 had ATL, and 13 had other diseases. The median duration of hospitalization for transplantation was 56 days (range 27-325 days). The cumulative incidences of readmission due to transplant-related complications were 8% at 30 days, 16% at 100 days, and 25% at 1 year after discharge. The most frequent cause of readmission was infection, followed by graft-versus-host disease throughout the first year. In multivariate analysis, steroid use at discharge was the only risk factor associated with readmission within 30 days, and steroid use at discharge, absolute lymphocyte count < 500/µl at discharge, and documented bacterial infection during admission were risk factors associated with readmission within 1 year. Our results indicated that factors during hospitalization or discharge, but not at transplantation, were associated with readmission. Patients with these risk factors should be monitored carefully after discharge.

Letermovir has been approved for the prevention of cytomegalovirus (CMV) infection after allogeneic hematopoietic stem cell transplantation (HCT). Letermovir is a cytochrome P450 (CYP) 2C19 inducer. Voriconazole, which is a broad-spectrum triazole antifungal agent, is mainly metabolized by CYP2C19. Thus, voriconazole trough concentration may decrease due to the drug interaction between voriconazole and letermovir. This study aimed to clarify the effects of letermovir on voriconazole trough concentration in allogeneic HCT recipients. We retrospectively examined voriconazole trough concentration in 24 allogeneic HCT recipients who had letermovir for prevention of CMV infection. The median voriconazole C/D ratios significantly decreased after starting letermovir from 0.25 L/kg to 0.11 L/kg (p < 0.01), and increased after discontinuing letermovir from 0.15 L/kg to 0.24 L/kg (p = 0.02). The median fold change of voriconazole trough concentration during letermovir administration was 0.40. Our results suggest that voriconazole trough concentration decreases when voriconazole is combined with letermovir in allogeneic HCT recipients. Therefore, close therapeutic drug monitoring of voriconazole trough concentration is warranted in allogeneic HCT recipients after starting or discontinuing letermovir.

Abstract: Dysphagia is the difficulty in swallowing because of the presence of certain diseases; it particularly compromises the oral and/or pharyngeal stages. In severe acute respiratory syndrome coronavirus 2 infection, neuromuscular complications, prolonged bed rest, and endotracheal intubation target different levels of the swallowing network. Thus, critically ill patients are prone to dysphagia and aspiration pneumonia. In this review, we first discuss the possible cause and pathophysiology underlying dysphagia associated with coronavirus disease 2019, including cerebrovascular events, such as stroke, encephalomyelitis, encephalopathy, peripheral neuropathy, and myositis, that may lead to the dysphagia reported as a complication associated with the coronavirus disease 2019. Next, we present some recommendations for dysphagia evaluation with modifications that would allow a safe and comprehensive assessment based on available evidence to date, including critical considerations of the appropriate use of personal protective equipment and optimization individual's noninstrumental swallowing tasks evaluation, while preserving instrumental assessments for urgent cases only. Finally, we discuss a practical managing strategy for dysphagia rehabilitation to ensure safe and efficient practice in the risks of severe acute respiratory syndrome coronavirus 2 exposure, in which swallowing therapy using newer technology, such as telerehabilitation system or wearable device, would be considered as a useful option., Competing Interests: Financial disclosure statements have been obtained, and no conflicts of interest have been reported by the authors or by any individuals in control of the content of this article., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: To identify core practices for workforce management of communication and swallowing functions in coronavirus disease 2019 (COVID-19) positive patients within the intensive care unit (ICU)., Design: A modified Delphi methodology was used, with 3 electronic voting rounds. AGREE II and an adapted COVID-19 survey framework from physiotherapy were used to develop survey statements. Sixty-six statements pertaining to workforce planning and management of communication and swallowing function in the ICU were included., Setting: Electronic modified Delphi process., Participants: Speech-language pathologists (SLPs) (N=35) from 6 continents representing 12 countries., Interventions: Not applicable., Main Outcome Measures: The main outcome was consensus agreement, defined a priori as ≥70% of participants with a mean Likert score ≥7.0 (11-point scale: 0=strongly disagree, 10=strongly agree). Prioritization rank order of statements in a fourth round was also conducted., Results: SLPs with a median of 15 years of ICU experience, working primarily in clinical (54%), academic (29%), or managerial positions (17%), completed all voting rounds. After the third round, 64 statements (97%) met criteria. Rank ordering identified issues of high importance., Conclusions: A set of global consensus statements to facilitate planning and delivery of rehabilitative care for patients admitted to the ICU during the COVID-19 pandemic were agreed by an international expert SLP group. Statements focused on considerations for workforce preparation, resourcing and training, and the management of communication and swallowing functions. These statements support and provide direction for all members of the rehabilitation team to use for patients admitted to the ICU during a global pandemic., (Copyright © 2021. Published by Elsevier Inc.)

We reviewed blood product use in 729 consecutive allogeneic hematopoietic cell transplantation (allo-HCT) recipients at our center to assess the volume of red blood cells (RBCs) and platelets required after allo-HCT. The median number of bags required by day 30 was 4 for RBCs (range 0-22) and 9.5 for platelets (0-53). Multivariate analysis showed that related peripheral blood stem cell transplantation (PBSCT) required a significantly lower RBC transfusion volume by day 30 compared to unrelated bone marrow transplantation (UBMT). PBSCT from haplo-identical related donors and cord blood transplantation (CBT) required a significantly greater RBC transfusion volume. For platelet transfusion, related and unrelated PBSCT required a significantly lower volume than UBMT, and CBT a greater volume. Other factors independently associated with greater RBC transfusion volume were male sex, disease status other than complete remission, and major ABO mismatch. For platelet transfusion, these were male sex, disease status, and HCT-specific comorbidity index of 1. Although the burden of blood transfusions may not be the most important factor when choosing a donor type, our findings may provide a foundation for nationwide strategies to prepare blood products and inform aspects of national healthcare expenditures.

Objective: To elucidate the characteristics of recovery progression during long-term rehabilitation after moderate-to-severe traumatic brain injury., Methods: Longitudinal changes in consciousness, swallowing disorders, activities of daily living, and psychological and behavioural status were studied in 7 patients with moderateto-severe traumatic brain injury, using scores of the National Agency for Automotive Safety & Victim's Aid (NASVA score), Glasgow Coma Scale (GCS), Dysphagia Severity Scale (DSS), Eating Status Scale (ESS), Functional Independence Measure (FIM), Cognitive-related Behavioural Assessment (CBA), and Neuropsychiatric Inventory (NPI). Scores were collected every month until discharge (median 359 days after injury), or until the study end date for those patients who remained hospitalized (432 days)., Results: Patients were qualitatively classified into those who improved well in the early phase, in terms of consciousness, swallowing, and activities of daily living, and those with less or delayed improvement. Psychological and behavioural difficulties appeared to remain less improved than the other functions for longer periods in many patients. Statistical comparisons that included all 7 patients revealed a significant improvement in NASVA score, GCS, DSS, and ESS, but not in FIM, CBA, and NPI at discharge/at the last measurement compared with scores at admission., Conclusion: Swallowing function is more responsive to long-term rehabilitation in patients with moderate-to-severe traumatic brain injury, while neuropsychiatric and behavioural difficulties tend to persist for longer periods., Competing Interests: The authors have no conflicts of interest to declare., (Journal Compilation © 2021 Foundation of Rehabilitation Information.)

The role of hematopoietic cell transplantation (HCT) in the management of newly diagnosed adult acute myeloid leukemia (AML) is reviewed and critically evaluated in this evidence-based review. An AML expert panel, consisting of both transplant and nontransplant experts, was invited to develop clinically relevant frequently asked questions covering disease- and HCT-related topics. A systematic literature review was conducted to generate core recommendations that were graded based on the quality and strength of underlying evidence based on the standardized criteria established by the American Society of Transplantation and Cellular Therapy Steering Committee for evidence-based reviews. Allogeneic HCT offers a survival benefit in patients with intermediate- and high-risk AML and is currently a part of standard clinical care. We recommend the preferential use of myeloablative conditioning in eligible patients. A haploidentical related donor marrow graft is preferred over a cord blood unit in the absence of a fully HLA-matched donor. The evolving role of allogeneic HCT in the context of measurable residual disease monitoring and recent therapeutic advances in AML with regards to maintenance therapy after HCT are also discussed., (Copyright © 2020 The American Society for Transplantation and Cellular Therapy. All rights reserved.)

Many drugs are used for unapproved indications in Japan for post hematopoietic stem cell transplant (HCT) complications. To investigate unapproved or off-label drug usage for graft-versus-host disease (GVHD) and virus infections after allogeneic HCT, we analyzed the data of Japanese HCT registry. Between 2006 and 2017, 39,941 adults and children received HCT for a variety of disease and their transplant data were captured in the registry. Among them, 14,687 and 8914 patients receiving treatment for acute and/or chronic GVHD, 24,828 patients with cytomegalovirus (CMV) infection or receiving therapies for CMV, and 4943 who received treatment for other viral infections were included in the analyses of off-label or unapproved drugs. For GVHD, mycophenolate mofetil was the most frequently used off-label drug, followed by beclomethasone, infliximab, and etanercept. For viral infections other than CMV, foscarnet was the most frequently used off-label drug. Cidofovir, which is not approved for use in Japan, was mainly used for adenovirus infection. This study demonstrated that numerous off-label and unapproved drugs have been used as key drugs for GVHD and post-transplant viral infection, and the real world date in the transplant registry may serve as an important asset to regulatory purposes.

While TKI are the preferred first-line treatment for chronic phase (CP) CML, alloHCT remains an important consideration. The aim is to estimate residual life expectancy (RLE) for patients initially diagnosed with CP CML based on timing of alloHCT or continuation of TKI in various settings: CP1 CML, CP2 + [after transformation to accelerated phase (AP) or blast phase (BP)], AP, or BP. Non-transplant cohort included single-institution patients initiating TKI and switched TKI due to failure. CIBMTR transplant cohort included CML patients who underwent HLA sibling matched (MRD) or unrelated donor (MUD) alloHCT. AlloHCT appeared to shorten survival in CP1 CML with overall mortality hazard ratio (HR) for alloHCT of 2.4 (95% CI 1.2-4.9; p  = .02). In BP CML, there was a trend toward higher survival with alloHCT; HR = 0.7 (0.5-1.1; p  = .099). AlloHCT in CP2 + [HR = 2.0 (0.8-4.9), p  = .13] and AP [HR = 1.1 (0.6-2.1); p  = .80] is less clear and should be determined on a case-by-case basis.

Background: Evidence about the impact of marital status before hematopoietic cell transplantation (hct) on outcomes after hct is conflicting., Methods: We identified patients 40 years of age and older within the Center for International Blood and Marrow Transplant Research registry who underwent hct between January 2008 and December 2015. Marital status before hct was declared as one of: married or living with a partner, single (never married), separated or divorced, and widowed. We performed a multivariable analysis to determine the association of marital status with outcomes after hct., Results: We identified 10,226 allogeneic and 5714 autologous hct cases with, respectively, a median follow-up of 37 months (range: 1-102 months) and 40 months (range: 1-106 months). No association between marital status and overall survival was observed in either the allogeneic ( p = 0.58) or autologous ( p = 0.17) setting. However, marital status was associated with grades 2-4 acute graft-versus-host disease (gvhd), p < 0.001, and chronic gvhd, p = 0.04. The risk of grades 2-4 acute gvhd was increased in separated compared with married patients [hazard ratio (hr): 1.13; 95% confidence interval (ci): 1.03 to 1.24], and single patients had a reduced risk of grades 2-4 acute gvhd (hr: 0.87; 95% ci: 0.77 to 0.98). The risk of chronic gvhd was lower in widowed compared with married patients (hr: 0.82; 95% ci: 0.67 to 0.99)., Conclusions: Overall survival after hct is not influenced by marital status, but associations were evident between marital status and grades 2-4 acute and chronic gvhd. To better appreciate the effects of marital status and social support, future research should consider using validated scales to measure social support and patient and caregiver reports of caregiver commitment, and to assess health-related quality of life together with health care utilization., Competing Interests: CONFLICT OF INTEREST DISCLOSURES We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare that we have none., (2020 Multimed Inc.)

We conducted a multicenter study on anti-programmed cell death-1 monoclonal antibodies (anti-PD-1 mAbs) before/after allogeneic hematopoietic cell transplantation (allo-HCT) for Hodgkin lymphoma. Anti-PD-1 mAbs were administered to 25 patients before allo-HCT and to 20 after allo-HCT. In pre-allo-HCT setting, the median interval from the last administration to allo-HCT was 59 days. After allo-HCT, 12 patients developed non-infectious febrile syndrome requiring high-dose corticosteroid. The cumulative incidences of grade II-IV acute graft-versus-host disease (aGvHD) were 47.1%. Eight patients who had GvHD prophylaxis with post-transplant cyclophosphamide (PTCy) had less frequent aGvHD (grade II-IV, 14.6% versus 58.8%; P = 0.086). The 1 year overall survival (OS), relapse/progression, and non-relapse mortality rates were 81.3%, 27.9%, and 8.4%. In post-allo-HCT setting, the median interval from allo-HCT to the first administration was 589 days. The overall and complete response rates were 75% and 40%. At 100 days after anti-PD-1 therapy, the cumulative incidences of grade II-IV aGvHD, moderate-to-severe chronic GvHD, and grade 3-4 immune-related toxicity were 15.0%, 30.0%, and 30.0%. While the 1 year relapse/progression rate was 47.4%, the 1 year OS probability was 89.7%. In conclusion, immune-related complications were frequent despite modifications of GvHD prophylaxis or anti-PD-1 mAb dosing. In anti-PD-1-mAb-pretreated patients, PTCy-based GvHD prophylaxis may be effective.

Allogeneic hematopoietic stem cell transplantation (HCT) remains the only potentially curative option for myelodysplastic syndromes (MDS). Mortality after HCT is high, with deaths related to relapse or transplant-related complications. Thus, identifying patients who may or may not benefit from HCT is clinically important. We identified 1514 patients with MDS enrolled in the Center for International Blood and Marrow Transplant Research Registry and had their peripheral blood samples sequenced for the presence of 129 commonly mutated genes in myeloid malignancies. A random survival forest algorithm was used to build the model, and the accuracy of the proposed model was assessed by concordance index. The median age of the entire cohort was 59 years. The most commonly mutated genes were ASXL1(20%), TP53 (19%), DNMT3A (15%), and TET2 (12%). The algorithm identified the following variables prior to HCT that impacted overall survival: age, TP53 mutations, absolute neutrophils count, cytogenetics per International Prognostic Scoring System-Revised, Karnofsky performance status, conditioning regimen, donor age, WBC count, hemoglobin, diagnosis of therapy-related MDS, peripheral blast percentage, mutations in RAS pathway, JAK2 mutation, number of mutations/sample, ZRSR2, and CUX1 mutations. Different variables impacted the risk of relapse post-transplant. The new model can provide survival probability at different time points that are specific (personalized) for a given patient based on the clinical and mutational variables that are listed above. The outcomes' probability at different time points may aid physicians and patients in their decision regarding HCT., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. All rights reserved.)

To investigate which reduced-intensity conditioning (RIC)/reduced-toxicity conditioning (RTC) is superior for umbilical cord blood transplantation (UCBT) for lymphoid malignancies, we retrospectively compared three widely used RIC/RTC regimens: fludarabine/melphalan/total body irradiation (FM-TBI, n = 524), fludarabine/cyclophosphamide/total body irradiation (FC-TBI, n = 96), and fludarabine/busulfan/total body irradiation or melphalan (FB-based, n = 159). Among patients with acute lymphoblastic leukemia (ALL) (n = 314), there were no differences in overall survival (OS) by conditioning regimen. Among patients with malignant lymphoma (ML) (n = 465), FM-TBI and FC-TBI regimens had similar OS, whereas FB-based regimen had lower OS (hazard ratio [HR], 1.73; P < 0.01) than did FM-TBI regimen due to higher non-relapse mortality (HR, 1.72; P = 0.02). In addition, mycophenolate mofetil-containing GVHD prophylaxis was associated with better OS than methotrexate-containing GVHD prophylaxis among patients who received FM-TBI (HR, 0.65; P = 0.03) and FC-TBI (HR, 0.25; P < 0.01) regimens due to a decreased relapse risk. In summary, our results suggest that all three RIC/RTC regimens have comparable clinical outcomes in ALL, while the FM-TBI or FC-TBI regimens combined with mycophenolate mofetil-containing GVHD prophylaxis is preferable in RIC/RTC-UCBT for ML. Large prospective studies are warranted to confirm these results.

Objective: This study investigated the effects of bolus consistency on pharyngeal volume during swallowing using three-dimensional kinematic analysis., Methods: Eight subjects (2 males and 6 females, mean ± SD 44 ± 10 years old) underwent a 320-row area detector scan during swallows of 10 mL of honey-thick liquid and thin liquid. Critical event timing (hyoid, soft palate, UES) and volume of pharyngeal cavity and bolus were measured and compared between two swallows., Results: The pharynx is almost completely obliterated by pharyngeal constriction against the tongue base for both consistencies. There were no significant differences in maximum volume, minimum volume and pharyngeal volume constriction ratio values between thick and thin liquids. However, the pattern of pharyngeal volume change (decrease) was different. For thick liquids, the air volume started to decrease before the onset of hyoid anterosuperior movement and decreased rapidly after onset of hyoid anterosuperior movement. During thin liquid swallowing, air volume remained relatively large throughout the swallow and started to decrease later when compared to swallowing thick liquids. At onset of UES opening, the bolus volume was not significantly different between thin and thick liquids; however, air volume was significantly larger when swallowing thin liquids, which made the total volume of the pharyngeal cavity larger., Conclusion: This difference between the two consistencies is associated with differences in tongue motion to propel the bolus and clear the pharynx from possible residue., (© 2020 John Wiley & Sons Ltd.)

Bone health disturbances commonly occur after hematopoietic cell transplantation (HCT) with loss of bone mineral density (BMD) and avascular necrosis (AVN) foremost among them. BMD loss is related to pretransplantation chemotherapy and radiation exposure and immunosuppressive therapy for graft-versus-host-disease (GVHD) and results from deficiencies in growth or gonadal hormones, disturbances in calcium and vitamin D homeostasis, as well as osteoblast and osteoclast dysfunction. Although the pathophysiology of AVN remains unclear, high-dose glucocorticoid exposure is the most frequent association. Various societal treatment guidelines for osteoporosis exist, but the focus is mainly on menopausal-associated osteoporosis. HCT survivors comprise a distinct population with unique comorbidities, making general approaches to bone health management inappropriate in some cases. To address a core set of 16 frequently asked questions (FAQs) relevant to bone health in HCT, the American Society of Transplant and Cellular Therapy Committee on Practice Guidelines convened a panel of experts in HCT, adult and pediatric endocrinology, orthopedics, and oral medicine. Owing to a lack of relevant prospective controlled clinical trials that specifically address bone health in HCT, the answers to the FAQs rely on evidence derived from retrospective HCT studies, results extrapolated from prospective studies in non-HCT settings, relevant societal guidelines, and expert panel opinion. Given the heterogenous comorbidities and needs of individual HCT recipients, answers to FAQs in this article should be considered general recommendations, with good medical practice and judgment ultimately dictating care of individual patients. Readers are referred to the Supplementary Material for answers to additional FAQs that did not make the core set., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Post-transplantation cyclophosphamide (PTCy) is a new method to prevent graft-versus-host disease after allogeneic hematopoietic cell transplantation. Although the use of dexamethasone is recommended as prophylaxis against chemotherapy-induced nausea and vomiting (CINV) for patients who receive high-dose cyclophosphamide, corticosteroids cannot be used during PTCy administration to exploit depletion of alloreactive T cells. Thus, CINV may not be adequately controlled in this situation. We retrospectively examined antiemetic efficacy of the combination of a 5-hydroxytryptamine-3 receptor antagonist (5-HT 3 RA) and a NK 1 receptor antagonist (NK 1 RA) in 36 patients who received PTCy, and compared this efficacy with that of the same combination together with dexamethasone in 27 patients conditioned with cyclophosphamide and total body irradiation (CY/TBI). The proportion of patients who had no vomiting during the acute phase of PTCy administration was 81%, and was lower than 100% in the CY/TBI group (p = 0.02). Our results suggest that prevention of CINV using 5-HT 3 RA and NK 1 RA during PTCy administration is suboptimal and that addition of antiemetic is necessary in patients who receive PTCy.

Background: Dysphagia is a common problem in patients with a history of stroke. In Japan, a reclined position is commonly used as a compensatory technique to address this problem., Objective: To evaluate the effect of reclined position on swallowing function in patients with stroke who had dysphagia., Methods: A retrospective analysis was carried out on the videofluoroscopic examination of swallowing (VF) of 4ml honey-thick liquid swallows collected over 9 years. Penetration-aspiration scale (PAS) and residue scores were compared for the following: a body position at 90° upright (90°U) and 60° reclining (60°R) groups, as well as 60°R and 45° reclining (45°R) groups., Results: Two hundred and five records from 98 subjects were reviewed. These included patients with ischaemic stroke (62%), haemorrhagic stroke (32%) and subarachnoid haemorrhage (6%). PAS scores were lower when the body was in a more reclined position (P < .001). The amount of residue in the valleculae and pyriform sinus also reduced in the more reclined position (P < .001). The deeper bolus head at swallowing onset was positively correlated with severe PAS (P < .001)., Conclusions: These findings suggest that in patients with stroke who had dysphagia, a reclined position may be useful in reducing the risk of penetration and aspiration, and in decreasing the amount of residue in the pharyngeal area. The depth of the bolus head at the onset of swallowing increases the severity of penetration and aspiration., (© 2020 John Wiley & Sons Ltd.)

Posttransplant lymphoproliferative disorder (PTLD) after allogeneic hematopoietic cell transplantation (HCT) is usually donor derived, associated with Epstein-Barr virus (EBV), and of B-cell origin. T-cell PTLD (T-PTLD) after allogeneic HCT is extremely rare. Four of 1015 (0.39%) allogeneic HCT patients were diagnosed with T-PTLD; peripheral T-cell lymphoma-not otherwise specified, anaplastic large cell lymphoma, monomorphic T-cell PTLD and polymorphic PTLD with chronic active EBV infection-like symptoms. Three of the four patients developed T-PTLD within 6 months after HCT from HLA-mismatched unrelated donor. Three (75%) and 4 (100%) cases were positive for EBV-encoded small RNA in situ hybridization and EBV-DNA load in peripheral blood, respectively. Chimerism analysis showed that 75% of T-PTLD tissues (3/4) were recipient derived. T-PTLD was refractory to salvage chemotherapy and fatal in all four patients. Including the 10 patients in the literature, the median interval from HCT to diagnosis of T-PTLD was 5 months (range 1-72 months), 55% were negative for EBV, and 56% were recipient-derived. T-PTLD, which often occurred early after allogeneic HCT, was more likely to be EBV negative and recipient derived than B-cell PTLD after allogeneic HCT. Like T-PTLD after solid organ transplant, T-PTLD after allogeneic HCT demonstrated morphological heterogeneity and poor prognosis.

Objective: Head lift exercise is a widely known form of training in the rehabilitation of patients with dysphagia. This study aimed to compare muscular strength reinforcement training of the suprahyoid muscles using repetitive peripheral magnetic stimulation (rPMS) with head lift exercises in a randomized controlled trial., Materials and Methods: Twenty-four healthy adults were randomly assigned to either the magnetic stimulation group (M group) or the head lift exercise group (H group). Both groups underwent training five days a week for two weeks. The primary outcome was the cervical flexor strength, and secondary outcomes were jaw-opening force, tongue pressure, muscle fatigue of the hyoid and laryngeal muscles, displacement of the hyoid bone and opening width of the upper esophageal sphincter (UES) while swallowing 10 mL of liquid, training performance rate, and pain., Results: No dropouts were reported during the two-week intervention period. Cervical flexor strength significantly increased solely in the M group. Tongue pressure significantly improved in both groups. There were no significant differences in the jaw-opening force, median frequency rate of the anterior belly of the digastric muscle, sternohyoid muscle, sternocleidomastoid muscle, anterior and superior hyoid bone displacement, and UES opening width in both groups., Conclusions: Two-week rPMS of the suprahyoid muscles increased the strength of these muscles compared with the head lift exercise during the same period., (© 2019 International Neuromodulation Society.)

Swallowing disorder or dysphagia is quite common in hospitalised patients. Using fibre-optic endoscopic evaluation of swallowing (FEES) is one of the clinical standards for evaluating swallowing disorder to prevent serious consequences such as aspiration pneumonia. This study aimed to determine the prevalence and the associated risk of dysphagia in hospitalised patients by using FEES finding. We retrospectively analysed the FEES records from the patients who were screened and suspected of swallowing problems by a certified nurse of dysphagia nursing (CNDN). The FEES findings were compared between dysphagia and without dysphagia to evaluate the associated risk of dysphagia. Six-hundred and nine FEES records were analysed. We found dysphagia 76% in patients who suspected swallowing problems by CNDN. FEES was assessed after the subjects had been admitted for 22 days on average. There was no difference in age between dysphagia and without dysphagia participants. However, the advanced age (age > 85 years old) increased the odd of dysphagia 1.18, P = .03. The primary disease of the subjects was mainly cerebrovascular disease (24%) and pneumonia (22%). Abnormal FEES findings including soft palate elevation, velopharyngeal contraction, whiteout, volitional cough, glottis closure during breath holding, cough reflex and presence of secretion in pharynx were found in hospitalised patients with dysphagia. The prevalence of dysphagia was high in hospitalised patients. Hence, screening the swallowing problem by nurse and FEES evaluation is essential to detect and prevent the complication in the patient who has dysphagia., (© 2020 John Wiley & Sons Ltd.)

There is a lack of large comparative study on the outcomes of reduced intensity conditioning (RIC) in acute myeloid leukemia (AML) transplantation using fludarabine/busulfan (FB) and fludarabine/melphalan (FM) regimens. Adult AML patients from Center for International Blood and Marrow Transplant Research who received first RIC allo-transplant between 2001 and 2015 were studied. Patients were excluded if they received cord blood or identical twin transplant, total body irradiation in conditioning, or graft-versus-host disease (GVHD) prophylaxis with in vitro T-cell depletion. Primary outcome was overall survival (OS), secondary end points were leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and GVHD. Multivariate survival model was used with adjustment for patient, leukemia, and transplant-related factors. A total of 622 patients received FM and 791 received FB RIC. Compared with FB, the FM group had fewer transplant in complete remission (CR), fewer matched sibling donors, and less usage of anti-thymocyte globulin or alemtuzumab. More patients in the FM group received marrow grafts and had transplantation before 2005. OS was significantly lower within the first 3 months posttransplant in the FM group (hazard ratio [HR] = 1.82, P < .001), but was marginally superior beyond 3 months (HR = 0.87, P = .05). LFS was better with FM compared with FB (HR = 0.89, P = .05). NRM was significantly increased in the FM group during the first 3 months of posttransplant (HR = 3.85, P < .001). Long-term relapse was lower with FM (HR = 0.65, P < .001). Analysis restricted to patients with CR showed comparable results. In conclusion, compared with FB, the FM RIC showed a marginally superior long-term OS and LFS and a lower relapse rate. A lower OS early posttransplant within 3 months was largely the result of a higher early NRM.

Purpose: There is no consensus on the best choice of an alternative donor (umbilical cord blood [UCB], haploidentical, one-antigen mismatched [7/8]-bone marrow [BM], or 7/8-peripheral blood [PB]) for hematopoietic cell transplantation (HCT) for patients lacking an HLA-matched related or unrelated donor., Methods: We report composite end points of graft-versus-host disease (GVHD)-free relapse-free survival (GRFS) and chronic GVHD (cGVHD)-free relapse-free survival (CRFS) in 2,198 patients who underwent UCB (n = 838), haploidentical (n = 159), 7/8-BM (n = 241), or 7/8-PB (n = 960) HCT. All groups were divided by myeloablative conditioning (MAC) intensity or reduced intensity conditioning (RIC), except haploidentical group in which most received RIC. To account for multiple testing, P < .0071 in multivariable analysis and P < .00025 in direct pairwise comparisons were considered statistically significant., Results: In multivariable analysis, haploidentical group had the best GRFS, CRFS, and overall survival (OS). In the direct pairwise comparison of other groups, among those who received MAC, there was no difference in GRFS or CRFS among UCB, 7/8-BM, and 7/8-PB with serotherapy (alemtuzumab or antithymocyte globulin) groups. In contrast, the 7/8-PB without serotherapy group had significantly inferior GRFS, higher cGVHD, and a trend toward worse CRFS (hazard ratio [HR], 1.38; 95% CI, 1.13 to 1.69; P = .002) than the 7/8-BM group and higher cGVHD and trend toward inferior CRFS (HR, 1.36; 95% CI, 1.14 to 1.63; P = .0006) than the UCB group. Among patients with RIC, all groups had significantly inferior GRFS and CRFS compared with the haploidentical group., Conclusion: Recognizing the limitations of a registry retrospective analysis and the possibility of center selection bias in choosing donors, our data support the use of UCB, 7/8-BM, or 7/8-PB (with serotherapy) grafts for patients undergoing MAC HCT and haploidentical grafts for patients undergoing RIC HCT. The haploidentical group had the best GRFS, CRFS, and OS of all groups.

To identify plasma biomarkers associated with fibrotic mechanisms of chronic graft-versus-host disease (GVHD), we used multiplex mass spectrometry with pooled samples for biomarker discovery in comparing proteomic profiles between patients with newly diagnosed sclerotic chronic GVHD (n = 21), those with newly diagnosed nonsclerotic chronic GVHD (n = 33), and those without chronic GVHD (n = 20). Immunoassay was used to measure protein concentrations of individual discovery samples and 186 independent verification samples. The discovery mass spectrometry analysis identified 2 candidate proteins with at least 1.5-fold difference in sclerotic GVHD: Dickkopf-related protein 3 (DKK3) and interleukin-1 receptor accessory protein (IL1RAP). Analysis of individual discovery samples by immunoassay showed that DKK3, a modulator of the Wnt signaling pathway, was a biomarker for both sclerotic and nonsclerotic chronic GVHD. Verification analysis of 186 patients confirmed that elevated plasma DKK3 concentrations were associated with chronic GVHD, regardless of the presence or absence of sclerosis, and that the area under the receiver operating characteristic curve was 0.85 for association of DKK3 concentrations with chronic GVHD. Multiple linear regression analysis showed that chronic GVHD with or without steroid treatment and patient age were independently associated with DKK3 concentrations. Patients with high DKK3 concentrations had a higher nonrelapse mortality than those with low concentrations. The lower IL1RAP concentrations in patients with sclerotic GVHD compared with other conditions in the discovery cohort were not confirmed in the verification cohort. DKK3 is a novel biomarker for chronic GVHD. Further studies are needed to determine the biological functions of DKK3 in the pathogenesis of chronic GVHD., (© 2020 by The American Society of Hematology.)

We examined the risk of subsequent neoplasms (SNs) and late mortality in children and adolescents undergoing allogeneic hematopoietic cell transplantation (HCT) for nonmalignant diseases (NMDs). We included 6028 patients (median age, 6 years; interquartile range, 1-11; range, <1 to 20) from the Center for International Blood and Marrow Transplant Research (1995-2012) registry. Standardized mortality ratios (SMRs) in 2-year survivors and standardized incidence ratios (SIRs) were calculated to compare mortality and SN rates with expected rates in the general population. Median follow-up of survivors was 7.8 years. Diagnoses included severe aplastic anemia (SAA; 24%), Fanconi anemia (FA; 10%), other marrow failure (6%), hemoglobinopathy (15%), immunodeficiency (23%), and metabolic/leukodystrophy syndrome (22%). Ten-year survival was 93% (95% confidence interval [95% CI], 92% to 94%; SMR, 4.2; 95% CI, 3.7-4.8). Seventy-one patients developed SNs (1.2%). Incidence was highest in FA (5.5%), SAA (1.1%), and other marrow failure syndromes (1.7%); for other NMDs, incidence was <1%. Hematologic (27%), oropharyngeal (25%), and skin cancers (13%) were most common. Leukemia risk was highest in the first 5 years posttransplantation; oropharyngeal, skin, liver, and thyroid tumors primarily occurred after 5 years. Despite a low number of SNs, patients had an 11-fold increased SN risk (SIR, 11; 95% CI, 8.9-13.9) compared with the general population. We report excellent long-term survival and low SN incidence in an international cohort of children undergoing HCT for NMDs. The risk of SN development was highest in patients with FA and marrow failure syndromes, highlighting the need for long-term posttransplantation surveillance in this population.

With increasing focus on the importance of long-term survivorship care after allogeneic hematopoietic cell transplantation (allo-HCT), more institutions have been establishing long-term follow-up (LTFU) clinics. Currently, however, with varying volumes of HCT procedures and resources, there is no standardized operation of these clinics in HCT centers. We conducted a nationwide questionnaire survey to characterize the current operation of LTFU clinics in Japan. We targeted 271 HCT centers (189 adult and 82 pediatric) that registered allo-HCT cases to the national transplant registry database. The response rate was 69%, and 117 of the 188 participating centers (62%) had an established LTFU clinic. The most frequent reason cited for not operating an LTFU clinic was a "lack of human resources," especially nurses. Most centers with an LTFU clinic targeted allo-HCT recipients, although autologous HCT survivors were followed up at 18% of adult centers and 48% of pediatric centers. Ninety-two percent of centers did not terminate LTFU at a specific time point, and 56% recommended that patients visit the LTFU clinic beyond 5 years after HCT. Fifteen of 20 pediatric centers indicated that they did not routinely refer survivors who underwent HCT at a young age to an adult HCT center for their adulthood LTFU. We found that staffing and standard practices varied widely among centers, and that most centers continued to see long-term HCT survivors at their own outpatient clinics. The development of common LTFU tools may help standardize LTFU practices and facilitate efficient transitions., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Cytogenetic risk stratification at diagnosis has long been one of the most useful tools to assess prognosis in acute lymphoblastic leukemia (ALL). To examine the prognostic impact of cytogenetic abnormalities on outcomes after allogeneic hematopoietic cell transplantation, we studied 1731 adults with Philadelphia-negative ALL in complete remission who underwent myeloablative or reduced intensity/non-myeloablative conditioning transplant from unrelated or matched sibling donors reported to the Center for International Blood and Marrow Transplant Research. A total of 632 patients had abnormal conventional metaphase cytogenetics. The leukemia-free survival and overall survival rates at 5 years after transplantation in patients with abnormal cytogenetics were 40% and 42%, respectively, which were similar to those in patients with a normal karyotype. Of the previously established cytogenetic risk classifications, modified Medical Research Council-Eastern Cooperative Oncology Group score was the only independent prognosticator of leukemia-free survival ( P =0.03). In the multivariable analysis, monosomy 7 predicted post-transplant relapse [hazard ratio (HR)=2.11; 95% confidence interval (95% CI): 1.04-4.27] and treatment failure (HR=1.97; 95% CI: 1.20-3.24). Complex karyotype was prognostic for relapse (HR=1.69; 95% CI: 1.06-2.69), whereas t(8;14) predicted treatment failure (HR=2.85; 95% CI: 1.35-6.02) and overall mortality (HR=3.03; 95% CI: 1.44-6.41). This large study suggested a novel transplant-specific cytogenetic scheme with adverse [monosomy 7, complex karyotype, del(7q), t(8;14), t(11;19), del(11q), tetraploidy/near triploidy], intermediate (normal karyotype and all other abnormalities), and favorable (high hyperdiploidy) risks to prognosticate leukemia-free survival ( P =0.02). Although some previously established high-risk Philadelphia-negative cytogenetic abnormalities in ALL can be overcome by transplantation, monosomy 7, complex karyotype, and t(8;14) continue to pose significant risks and yield inferior outcomes., (Copyright© 2020 Ferrata Storti Foundation.)

Induced contraction of the suprahyoid muscles via magnetic stimulation is considered to be effective for the rehabilitation of dysphagia. In our previous study, a magnetic stimulation coil with a U-shaped core for stimulating the suprahyoid muscles was developed based on the results of numerical analysis using a simplified human head model. It was confirmed that magnetic stimulation by the coil causes large contraction of the muscles. However, the human head has a complex structure that includes bone structures through which current cannot easily pass. To accurately predict the current density distribution induced by magnetic stimulation, a model that accurately describes the human head is required for numerical analysis. Therefore, in this study, numerical analysis using the finite element method with a human head model that includes the bone structure obtained from computed tomography scans was performed. The results for the model with bone structure show that the coil with a U-shaped core can stimulate the motor points of the suprahyoid muscles in the middle of the submental region. When compared with the current density observed in a model without the bone structure, that in the model with the bone structure was reduced by 29% at a point 20 mm below the mandibular surface. It is thus necessary to perform a numerical analysis using a model with the bone structure to obtain accurate analysis results.

The major limitation of cord blood transplantation (CBT) for adults remains the delayed hematopoietic recovery and higher incidence of graft failure, which result in a higher risk of early mortality in CBT. We evaluated early overall survival (OS), non-relapse mortality (NRM), neutrophil engraftment, acute graft-vs-host disease, and cause of early death among 9678 adult patients who received single-unit CBT in Japan between 1998 and 2017. The probability of OS at 100 days was 64.4%, 71.7%, and 78.9% for the periods 1998 to 2007, 2008 to 2012, and 2013 to 2017, respectively (P < .001). The cumulative incidences of NRM at 100 days during the same period were 28.3%, 20.8%, and 14.6%, respectively (P < .001). The cumulative incidences of neutrophil engraftment were also improved during the same period (P < .001). The most common cause of death within 100 days after CBT was bacterial infection in 1998 to 2007 and primary disease in the latter two time periods. Across the three time periods, the proportions of deaths from bacterial and fungal infection, graft failure, hemorrhage, sinusoidal obstructive syndrome, and organ failure decreased in a stepwise fashion. Landmark analysis of OS and NRM after 100 days showed that OS did not change over time in the multivariate analysis. Our registry-based data demonstrated a significant improvement of early OS after CBT for adults over the past 20 years. The landmark analysis suggested that improvement of early mortality could lead to an improvement of long-term OS after CBT., (© 2019 Wiley Periodicals, Inc.)

Posttransplant lymphoproliferative disorder (PTLD) is a serious complication after hematopoietic stem cell transplantation (HSCT). Several studies of risk factors for PTLD have been reported; however, the probability of, and risk factors for, PTLD in patients with lymphoma is unknown. Japanese nationwide transplant registry data from 5270 patients with lymphoma after allogeneic HSCT were analyzed. Mature B-cell, T/NK-cell, and T-cell lymphoblastic subtypes accounted for 49%, 26%, and 9.6% of lymphoma cases, respectively. Rituximab was used in 1678 lymphoma patients, most of whom (89%) received HSCT for mature B-cell lymphoma. Thirty-one patients with lymphoma developed PTLD, representing a probability of 0.77% at 2 years post-HSCT, which did not differ significantly from that in patients with other diseases (P = .98). Year of HSCT after 2010 (hazard ratio [HR] = 5.6, 95% confidence interval [CI], 1.48-21.3), antithymocyte globulin (ATG) use in the conditioning regimen (HR = 4.5, 95% CI, 1.61-12.5), and no rituximab use before HSCT (HR = 3.2, 95% CI, 1.26-7.90) were identified as risk factors for PTLD. Probabilities of PTLD at 1 year post-HSCT according to rituximab and ATG use were 0.23% (rituximab+, ATG-), 0.75% (rituximab-, ATG-), 1.25% (rituximab+, ATG+), and 3.53% (rituximab-, ATG+). Regarding lymphoma subtypes, patients with mature B-cell lymphoma had the lowest incidence of PTLD (0.35% at 2 years). Among high-risk patients receiving ATG, the mortality rate due to infection was elevated in those previously treated with rituximab (22%) relative to those without (14%); however, the difference was not significant (P = .10). Rituximab use before HSCT significantly reduces the risk of PTLD. Adding rituximab to the conditioning regimen is potentially a good strategy to prevent the development of PTLD in high-risk patients., (© 2020 John Wiley & Sons Ltd.)

There is marked paucity of data regarding late effects in adolescents and young adults (AYAs) who undergo myeloablative conditioning (MAC) allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML). We evaluated late effects and survival in 826 1-year disease-free survivors of MAC HCT for AYA AML, with an additional focus on comparing late effects based upon MAC type (total body irradiation [TBI] vs high-dose chemotherapy only). The estimated 10-year cumulative incidence of subsequent neoplasms was 4% (95% confidence interval [CI], 2%-6%); 10-year cumulative incidence of nonmalignant late effects included gonadal dysfunction (10%; 95% CI, 8%-13%), cataracts (10%; 95% CI, 7%-13%), avascular necrosis (8%; 95% CI, 5%-10%), diabetes mellitus (5%; 95% CI, 3%-7%), and hypothyroidism (3%; 95% CI, 2%-5%). Receipt of TBI was independently associated with a higher risk of cataracts only (hazard ratio [HR], 4.98; P < .0001) whereas chronic graft-versus-host disease (cGVHD) was associated with an increased risk of cataracts (HR, 3.22; P = .0006), avascular necrosis (HR, 2.49; P = .006), and diabetes mellitus (HR, 3.36; P = .03). Estimated 10-year overall survival and leukemia-free survival were 73% and 70%, respectively, and did not differ on the basis of conditioning type. In conclusion, late effects among survivors of MAC HCT for AYA AML are frequent and are more closely linked to cGVHD than type of conditioning., (© 2020 by The American Society of Hematology.)

It remains unknown whether the administration of tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1 after allogeneic hematopoietic cell transplantation (HCT) is associated with improved outcomes for patients with chronic myelogenous leukemia (CML). In this registry study, we analyzed clinical outcomes of 390 adult patients with CML who underwent transplantation between 2007 and 2014 and received maintenance TKI following HCT (n = 89) compared with no TKI maintenance (n = 301), as reported to the Center for International Blood and Marrow Transplant Research. All patients received TKI therapy before HCT. The majority of patients had a disease status of first chronic phase at HCT (n = 240; 62%). The study was conducted as a landmark analysis, excluding patients who died, relapsed, had chronic graft-versus-host disease, or were censored before day +100 following HCT. Of the 89 patients who received TKI maintenance, 77 (87%) received a single TKI and the other 12 (13%) received multiple sequential TKIs. The most common TKIs used for maintenance were dasatinib (n = 50), imatinib (n = 27), and nilotinib (n = 27). As measured from day +100, the adjusted estimates for 5-year relapse (maintenance, 35% versus no maintenance, 26%; P = .11), leukemia-free survival (maintenance, 42% versus no maintenance, 44%; P = .65), or overall survival (maintenance, 61% versus no maintenance, 57%; P = .61) did not differ significantly between patients receiving TKI maintenance or no maintenance. These results remained unchanged in multivariate analysis and were not modified by disease status before transplantation. In conclusion, our data from this day +100 landmark analysis do not demonstrate a significant impact of maintenance TKI therapy on clinical outcomes. The optimal approach to TKI administration in the post-transplantation setting in patients with CML remains undetermined., (Copyright © 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Patients with aggressive adult T-cell leukemia-lymphoma (ATL) have dismal outcomes with intensive chemotherapy. Early up-front allogeneic hematopoietic stem cell transplantation (allo-HSCT) is generally recommended. However, the choice of stem cell source, i.e., unrelated bone marrow transplant (UBMT) or cord blood transplantation (CBT), when an HLA-matched related donor is unavailable remains controversial. Thus, we undertook a decision analysis to compare the outcomes of two therapeutic strategies: chemotherapy followed by up-front UBMT at 6 months, and chemotherapy followed by up-front CBT at 3 months. Patients were stratified into low-, intermediate-, and high-risk groups according to the modified ATL-prognostic index. The model simulated life expectancy (LE) and quality-adjusted LE (QALE). LE following up-front UBMT was higher than that following up-front CBT in the low-risk group (2.63 vs. 2.28 years), but was comparable in the intermediate- (2.06 vs. 2.01 years) and high-risk groups (1.25 vs. 1.30 years). The Monte Carlo simulation for LE and QALE in each risk group showed that there was significant uncertainty in all categories. In conclusion, up-front UBMT was superior to up-front CBT in the low-risk group, but the strategies were comparable in the intermediate- and high-risk groups.

Follow-up is integral for hematopoietic cell transplantation (HCT) care to ensure surveillance and intervention for complications. We characterized the incidence of and predictors for being lost to follow-up. Two-year survivors of first allogeneic HCT (10,367 adults and 3865 children) or autologous HCT (7291 adults and 467 children) for malignant/nonmalignant disorders between 2002 and 2013 reported to the Center for International Blood and Marrow Transplant Research were selected. The cumulative incidence of being lost to follow-up (defined as having missed 2 consecutive follow-up reporting periods) was calculated. Marginal Cox models (adjusted for center effect) were fit to evaluate predictors. The 10-year cumulative incidence of being lost to follow-up was 13% (95% confidence interval [CI], 12% to 14%) in adult allogeneic HCT survivors, 15% (95% CI, 14% to 16%) in adult autologous HCT survivors, 25% (95% CI, 24% to 27%) in pediatric allogeneic HCT survivors, and 24% (95% CI, 20% to 29%) in pediatric autologous HCT survivors. Factors associated with being lost to follow-up include younger age, nonmalignant disease, public/no insurance (reference: private), residence farther from the tranplantation center, and being unmarried in adult allogeneic HCT survivors; older age and testicular/germ cell tumor (reference: non-Hodgkin lymphoma) in adult autologous HCT survivors; older age, public/no insurance (reference: private), and nonmalignant disease in pediatric allogeneic HCT survivors; and older age in pediatric autologous HCT survivors. Follow-up focusing on minimizing attrition in high-risk groups is needed to ensure surveillance for late effects., (Copyright © 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)