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Introduction: Bisphosphonates (BPs) are widely used for osteoporosis and cancer-induced bone diseases due to their antiresorptive properties, yet they pose risks such as medication-related osteonecrosis of the jaw (MRONJ)., Methods: We present a unique case of concurrent oral squamous cell carcinoma (SCC) and MRONJ in a 72-year-old female chronically treated with oral ibandronate for osteoporosis. Following a dental extraction, she developed a nonhealing wound in the maxilla. Following conservative treatment, the patient underwent a maxillectomy and extensive tissue reconstructions to control her infection and address suspicions of an underlying malignancy., Results: Histopathological examinations confirmed simultaneous osteonecrosis and well-differentiated SCC in the maxillary sinus and surrounding tissues. Despite multiple surgeries, the patient's disease progressed rapidly. Upon examining the literature for patients with a history of BP use diagnosed with MRONJ and/or SCC, a total of 16 cases report a diagnostic dilemma between MRONJ and locoregional SCC. Three of the 16 cases report a final diagnosis of concurrent MRONJ and SCC. This report is the fourth reported case of concurrency to date., Conclusions: The patient's complex clinical course underscores the diagnostic challenges and therapeutic dilemmas in managing concurrent MRONJ and SCC, highlighting the need for vigilant monitoring and interdisciplinary collaboration in similar cases., (© 2024 Wiley Periodicals LLC.)

Background: Continued advances in haematopoietic cell transplantation (HCT) for children with non-malignant diseases (NMDs) have led to a growing population of survivors in whom late occurring toxic effects remain a challenge. We investigated the incidence of and risk factors for post-transplant toxicities in a contemporary cohort of children and adolescents undergoing HCT for NMDs., Methods: In this retrospective cohort study, we extracted data from the Center for International Blood and Marrow Transplantation Research (CIBMTR) database to analyse timing and incidence of effects and risk factors associated with late effects of HCT for treatment of NMDs at age 21 years or younger. Late effects of interest were avascular necrosis, cataracts, congestive heart failure, myocardial infarction, diabetes, gonadal dysfunction, growth hormone deficiency, hypothyroidism, renal failure requiring dialysis, and neurological events (stroke and seizure). Cumulative incidence of each late effect was calculated at 5 years and 7 years after HCT. Risk factors were evaluated in Cox proportional hazards regression analyses. Main exposures were primary NMD, age, sex, ethnicity and race, insurance, donor and graft type, myoablative conditioning, total-body irradiation exposure, graft-versus-host disease (GVHD), and transplant year. Primary outcomes were rates, cumulative incidence probability (95% CI), and risk-factors for organ-specific late effects., Findings: Between Jan 1, 2000, and Dec 31, 2017, 7785 patients aged 21 years or younger underwent HCT. 1995 patients were ineligible or did not consent to be included. 5790 patients from 171 centres were included in the analysis. 3505 (60·5%) of 5790 patients were male and 2285 (39·5%) were female. 2106 (36·4%) patients were White, 771 (13·3%) were Hispanic, and 773 (12·7%) were Black. 1790 (30·9%) patients were non-USA residents. Median age at HCT was 5·5 years (range 0·0-21·0). 1127 (19%) of 5790 patients had one late effect, and 381 (7%) had at least two. At 7 years post-HCT, the cumulative incidence probability was 1·9 (95% CI 1·5-2·3) for cataracts, 4·9 (4·3-5·6) for diabetes, 2·6 (2·1-3·1) for gonadal dysfunction, 3·2 (2·7-3·8) for hypothyroidism, 5·0 (4·4-5·7) for growth disturbance, 8·1 (7·4-8·9) for renal failure, 1·6 (1·3-2·0) for avascular necrosis, 0·6 (0·4-0·8) for congestive heart failure, 0·2 (0·1-0·3) for myocardial infarction, and 9·4 (8·6-10·2) for neurological effects. Age 10 years or older at HCT, unrelated donor source, total-body irradiation, and GVHD were identified as risk factors for long-term effects., Interpretation: The findings highlight the need for, and access to, multidisciplinary and lifelong follow-up for children undergoing HCT for NMDs. As more children undergo treatment with cellular therapies for non-malignant conditions, further analyses of post-transplant data could increasingly guide treatment decisions and subsequent long-term surveillance., Funding: National Cancer Institute, National Heart, Lung and Blood Institute, National Institute of Allergy and Infectious Diseases, Health Resources and Services Administration, and Office of Naval Research., Competing Interests: Declaration of interests BKH reports compensation from Nkarta ad hoc advisory board; serving on the Data Safety Monitoring Committee for Angiocrine; speaker fees from Therakos/Mallinkrodt; ad hoc advisory board participation for Kadmon/Sanofi and Equilium; and consulting for Incyte. HS reports compensation (personal fees paid to institution) from Incyte, Janssen, Novartis, Sanofi, and the Belgian Hematological Society; research grants (paid to institution) from Novartis and the BHS; non-financial support from Gilead, Pfizer, European Society for Blood and Marrow transplantation (EBMT) and Center for International Bone Marrow Transplantation Research (CIBMTR); and serving as a volunteer for EBMT, CIBMTR, and The European Patients' Academy on Therapeutic Innovation. JJA reports advisory board participation for AscellaHealth and Takeda. AB reports consulting fees from Kite. NF reports advisory board participation and consulting for Incyte. RPG reports consulting for Antengene Biotech LLC, Ascentage Pharma Group, and NexImmune; serving as the Medical Director for FFF Enterprises; serving on the Board of Directors for Russian Foundation for Cancer Research Support; and Scientific Advisory Board participation for Nanexa and StemRad. SG reports Advisory Board participation for AstraZeneca, Sanofi, Bristol Myers Squibb, and KITE Pharma. GCH reports consultancy or advisory boards for Seattle Genetics, Daiichy, Jannsen, Ono, Astra Zeneca, Sobi, and RapaTherapeutics; stocks with Axim, Cellectis, CVS Health, Cardinal Health, Pfizer, Bluebird Bio, Charlotte's web, Medical PTTYS TR, Moderna, Viatris, Biogen, Merck, Micron Technology, Mustang Bio, Neogenomics, Opko Health, Zevra Therapeutics, Clovis Oncology, AImmune, Caretrust Reit, Angi, and GW Pharmaceuticals; and research funding from Astra Zeneca and Incyte. PAM reports serving on the Board of Directors for Orthogon Therapeutics. KCM reports research funding (clinical trial) from Incyte and the National Institutes for Health (NIH) and industry sponsored (clinical trial) from Elixirgen Therapeutics. TN reports research support (to the institution) for clinical trial from Novartis; research support (drug supply only) to the institution for clinical trial from Karyopharm; and advisory board participation for Medexus. SJR reports being a paid medical monitor for the RCI and BMT. AS reports compensation (consulting) for Spotlight Therapeutics, Medexus, Vertex Pharmaceuticals, Sangamo Therapeutics, and Editas Medicine; serving as a medical monitor for RCI BMT CSIDE clinical trial which receives financial compensation; research funding from CRISPR Therapeutics; honoraria from Vindico Medical Education; serving as the St Jude Children's Research Hospital site principal investigator of clinical trials for genome editing of sickle cell disease sponsored by Vertex Pharmaceuticals and CRISPR Therapeutics (NCT03745287), Novartis Pharmaceuticals (NCT04443907) and Beam Therapeutics (NCT05456880). The industry sponsors provide funding for the clinical trial, which includes salary support paid to Dr Sharma's institution. Dr Sharma has no direct financial interest in these therapies. CU reports honoraria (speakers' bureau) from Bluprint and Takeda. KMW reports grant review and research funding from the National Heart, Lung, and Blood Institute, Leukemia Lymphoma Society, Rising Tide, and NIH; philanthropy funds from the Hudgens society and Legacy Peach Bowl; and travel compensation from American Society for Transplantation and Cellular Therapy, American Society of Hematology, and Pediatric Transplantation & Cellular Therapy Consortium. RP reports compensation (advisory board) from Bluebird Bio; and research funding from Amgen. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The EBMT (European Blood and Marrow Transplantation Society) aims to connect patients, the scientific community, and other stakeholders to improve hematopoietic stem cell transplantation and cellular therapy outcomes. We performed a cross-sectional online survey to understand the perceptions regarding Patient Reported Outcomes (PROs) and Patient Active Involvement in Research (PAIR) in over 800 stakeholders (n = 813). Patients (n = 278) and health care professionals (HCPs) (n = 351) were compared. We observed high openness for EBMT PRO collection (n = 680, 84.5% across stakeholders' groups; patients n = 256, 93.1% versus HCPs n = 273, 78.4% [p < 0.001]) and PAIR (n = 702, 87.3% across stakeholder groups; patients n = 256, 92.4% versus HCPs n = 296, 85.8% [p = 0.009]), with a significantly higher proportion of patients expressing interest compared to HCPs. Priority domains for PROs data-collection identified were the assessment of symptom experience, psychosocial and cognitive functioning. The most important issues for patients specifically were the data-collection of PROs reflecting cognitive function, the option of reporting data at home, the importance of identifying actionable targets to improve their recovery, and receiving feedback on their input when participating in research projects. Our multistakeholder approach suggests an added value to embracing patient engagement in the development of meaningful research and service design within the transplantation and cellular therapy community., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Siblings of youth with cancer have heightened risk for poor long-term psychosocial outcomes. Although sibling psychosocial care is a standard in pediatric oncology, this standard is among those least likely to be met. To address barriers to providing sibling services, a blueprint for systematic psychosocial screening and support of siblings was developed based on feedback from a national sample of psychosocial providers., Procedure: Semi-structured interviews were conducted with a purposive sample of psychosocial care providers (N = 27) of various disciplines working in US pediatric cancer centers, varied in size, type, and extent of sibling support. Interviews queried providers' suggestions for the future of sibling psychosocial care and impressions of a blueprint for sibling service delivery, which was iteratively refined based on respondents' feedback. Interviews were analyzed using applied thematic analysis., Results: Based on existing literature and refined according to providers' recommendations, the Sibling Services Blueprint was developed to provide a comprehensive guide for systematizing sibling psychosocial care. The blueprint content includes: (i) a timeline for repeated sibling screening and assessment; (ii) a stepped model of psychosocial support; (iii) strategies for circumventing barriers to sibling care; and (iv) recommendations for how centers with varying resources might accomplish sibling-focused care. The blueprint is available online, allowing providers to easily access and individualize the content. Providers indicated enthusiasm and high potential utility and usability of the blueprint., Conclusions: The Sibling Services Blueprint may be a useful tool for systematizing sibling psychosocial care, promoting wider availability of sibling-focused services, and addressing siblings' unmet needs., (© 2024 Wiley Periodicals LLC.)

Abstract: Activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) is an inborn error of immunity that manifests as immune deficiency and dysregulation; symptoms include frequent infections and lymphoproliferation. In our dose-finding and phase 3 placebo-controlled trials, treatment with the selective PI3Kδ inhibitor leniolisib reduced lymphoproliferation and normalized lymphocyte subsets. Here, we present 6 years of follow-up from the 6 adult patients in the original dose-finding trial receiving leniolisib. We used data from the ongoing open-label extension study, which was supplemented at later time points by investigators, including health-related quality of life (HRQoL) assessed through a clinician-reported questionnaire. We observed improvements in HRQoL: 5 of 6 patients experienced an increase in physical capabilities and socialization, and a decrease in prescribed medications. Immune subsets improved in all patients: mean transitional B-cell levels decreased from 38.17% to 2.47% and the CD4:CD8 T-cell ratio normalized to 1.11. Manifestations seen before and within the first year of leniolisib exposure, such as infections and gastrointestinal conditions, attenuated after year 2, with few new conditions emerging out to year 6. Thrombocytopenia or lymphopenia remained present in half of patients at year 6. Of 83 adverse events through year 5, 90.36% were grade 1; none were grade 4/5 nor deemed leniolisib related. Collectively, we saw an enhancement in HRQoL as well as durable changes in lymphocyte subsets and clinical manifestations, further supporting the use of leniolisib as a long-term therapeutic option for the treatment of APDS. This trial was registered at www.ClinicalTrials.gov as #NCT02859727., (Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution.)

Abstract: Wiskott-Aldrich syndrome (WAS) is a multifaceted monogenic disorder with a broad disease spectrum and variable disease severity and a variety of treatment options including allogeneic hematopoietic stem cell transplantation (HSCT) and gene therapy (GT). No reliable biomarker exists to predict disease course and outcome for individual patients. A total of 577 patients with a WAS variant from 26 countries and a median follow-up of 8.9 years (range, 0.3-71.1), totaling 6118 patient-years, were included in this international retrospective study. Overall survival (OS) of the cohort (censored at HSCT or GT) was 82% (95% confidence interval, 78-87) at age 15 years and 70% (61-80) at 30 years. The type of variant was predictive of outcome: patients with a missense variant in exons 1 or 2 or with the intronic hot spot variant c.559+5G>A (class I variants) had a 15-year OS of 93% (89-98) and a 30-year OS of 91% (86-97), compared with 71% (62-81) and 48% (34-68) in patients with any other variant (class II; P < .0001). The cumulative incidence rates of disease-related complications such as severe bleeding (P = .007), life-threatening infection (P < .0001), and autoimmunity (P = .004) occurred significantly later in patients with a class I variant. The cumulative incidence of malignancy (P = .6) was not different between classes I and II. It confirms the spectrum of disease severity and quantifies the risk for specific disease-related complications. The class of the variant is a biomarker to predict the outcome for patients with WAS.

Background : The current high standards in orthognathic surgery demand surgical solutions that are both ⁠ functionally ⁠ effective and aesthetically pleasing. Our approach offers one for enhanced stability, attractiveness, and nerve protection ⁠ with improved accessibility ⁠ in the majority of orthognathic scenarios ⁠ compared to an inverted L osteotomy. Methods: A case series is presented to illustrate the application and outcomes of HSSO, an optimised approach that combines the advantages of a transoral inverted L osteotomy with specific enhancements and increased versatility, ⁠ with accessibility and exposure similar to a BSSO. Results: HSSO as a completely transoral technique, demonstrate the ability to perform significant counterclockwise rotations of the mandible, eliminating the need for trocars or skin incisions. We experinced high postoperative stability when HSSO was performed in conjunction with a three-piece LeFort 1 osteotomy on a dynamic opposing arch. In comparison to an inverted L approach, we postulated that HSSO offers advantages in stability, due to the increased segmental overlap of the proximal and distal segments of the mandible. This approach is designed to enhance the safety of the inferior alveolar nerve compared to traditional sagittal split methods. Furthermore, HSSO represents an alternative to total joint replacement in select cases of idiopathic condylar resorption and is effective for correcting mandibular asymmetries while maintaining jawline aesthetics. This is achieved through the manipulation of the mandibular angle, ramus height, and inferior border without creating a step deformity in the soft tissue. Conclusions: The outcomes of HSSO highlight its capacity to deliver predictable, functional, and aesthetically pleasing results, offering a viable alternative to more traditional orthognathic techniques.

As hematopoietic cell transplantation (HCT) and cellular therapy expand to new indications and international access improves, the volume of HCT performed annually continues to rise. Parallel improvements in HCT techniques and supportive care entails more patients surviving long-term, creating further emphasis on survivorship needs. Survivors are at risk for developing late complications secondary to pre-, peri- and post-transplant exposures and other underlying risk-factors. Guidelines for screening and preventive practices for HCT survivors were originally published in 2006 and updated in 2012. To review contemporary literature and update the recommendations while considering the changing practice of HCT and cellular therapy, an international group of experts was again convened. This review provides updated pediatric and adult survivorship guidelines for HCT and cellular therapy. The contributory role of chronic graft-versus-host disease (cGVHD) to the development of late effects is discussed but cGVHD management is not covered in detail. These guidelines emphasize special needs of patients with distinct underlying HCT indications or comorbidities (e.g., hemoglobinopathies, older adults) but do not replace more detailed group, disease, or condition specific guidelines. Although these recommendations should be applicable to the vast majority of HCT recipients, resource constraints may limit their implementation in some settings., (© 2024. The Author(s).)

Background: Siblings of children with cancer may experience adverse household economic consequences, but their financial outcomes in adulthood are unknown., Methods: A total of 880 siblings (aged 18-64 years) of adult-aged childhood cancer survivors were surveyed to estimate the prevalence of financial hardship by three established domains (behavioral, material, and psychological). For individual financial hardship items matching the contemporaneous National Health Interview Survey or Behavioral Risk Factor Surveillance System, siblings were compared with the general population by calculating adjusted prevalence odds ratios (ORs) to sample-weighted responses. Multivariable logistic regression models examined associations between sibling characteristics and each hardship domain and between sibling hardship and survivors' cancer/treatment characteristics., Results: Behavioral, material, and psychological hardship was reported by 24%, 35%, and 28%, respectively. Compared with national survey respondents, siblings were more likely to report worries about medical bills (OR, 1.14; 95% confidence interval [CI], 1.06-1.22), difficulty affording nutritious foods (OR, 1.79; 95% CI, 1.54-2.07), and forgoing needed medical care (OR, 1.38; 95% CI, 1.10-1.73), prescription medications (OR, 2.52; 95% CI, 1.99-3.20), and dental care (OR, 1.34; 95% CI, 1.15-1.57) because of cost. Sibling characteristics associated with reporting financial hardship in one or more domains included female sex, older age, chronic health conditions, lower income, not having health insurance, high out-of-pocket medical expenditures, and nonmedical/nonhome debt. No survivor cancer/treatment characteristics were associated with sibling financial hardship., Conclusions: Adult siblings of childhood cancer survivors were more likely to experience financial hardship compared with the general population. Childhood cancer may adversely affect entire households, with potentially lasting implications., (© 2023 American Cancer Society.)

Abstract: Allogeneic hematopoietic cell transplantation (HCT) can be complicated by life-threatening organ toxicity and infection necessitating intensive care. Epidemiologic data have been limited by single-center studies, poor database granularity, and a lack of long-term survivors. To identify contemporary trends in intensive care unit (ICU) use and long-term outcomes, we merged data from the Center for International Blood and Marrow Transplant Research and the Virtual Pediatric Systems databases. We identified 6995 pediatric patients with HCT aged ≤21 years who underwent first allogeneic HCT between 2008 and 2014 across 69 centers in the United States or Canada and followed patients until the year 2020. ICU admission was required for 1067 patients (8.3% by day +100, 12.8% by 1 year, and 15.3% by 5 years after HCT), and was linked to demographic background, pretransplant organ toxicity, allograft type and HLA-match, and the development of graft-versus-host disease or malignancy relapse. Survival to ICU discharge was 85.7%, but more than half of ICU survivors required ICU readmission, leading to 52.5% and 42.6% survival at 1- and 5-years post-ICU transfer, respectively. ICU survival was worse among patients with malignant disease, poor pretransplant organ function, and alloreactivity risk factors. Among 1-year HCT survivors, those who required ICU in the first year had 10% lower survival at 5 years and developed new dialysis-dependent renal failure at a greater rate (P<.001). Thus, although ICU management is common and survival to ICU discharge is high, ongoing complications necessitate recurrent ICU admission and lead to a poor 1-year outcome in select patients who are at high risk., (Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution.)

Objective: Using computer-assisted surgery (CAS) and patient-specific plates (PSP) in orthognathic surgery has shown improved accuracy and efficiency compared with traditional techniques. This study analyzed current global trends in planning and investigated the reasons for CAS and PSP use., Study Design: A survey of 29 multiple choice questions was distributed to AO Foundation Craniomaxillofacial e-mail subscribers biweekly between July 14, 2021 and September 2, 2021. Questions focused on specifics of respondents' preoperative workup, methods of data collection, and the use of cutting guides and patient-specific plates. Objective clinical outcomes and subjective surgeon reasons for use were also investigated., Results: Of the 557 responses, 420 (75.4%) participant responses were eligible for analyses. Most (302/420, 71.9%) respondents used CAS when performing orthognathic surgery, although regional differences were observed. Almost all respondents in North America implemented CAS in their surgery plan (44/46, 95.7%) compared with only 47.4% (18/38) in the Middle East/North Africa. Surgeons with 10 to 15 years of experience were far more likely to incorporate CAS. More than half (175/301, 58.1%) of CAS users also used PSP, of which 43% (68/158) did so for maxillary-only cases, 3.2% (5/158) used PSP for mandible-only surgeries, and 42.4% (67/158) used PSP for both. Surgeons' primary reasons for using CAS and PSP were accuracy (200/253, 79.1%), efficiency (196/253, 77.5%), and ease of preoperative planning (150/253, 59.3%). Most (77.9%) surgeons perceived that CAS was equal to or faster than traditional surgery., Conclusions: Our study shows differences in use regionally and with surgeon experience. Surgeons primarily use CAS and PSP in orthognathic surgery to increase accuracy and efficiency, minimize intraoperative deviations from the surgical plan, and reduce total surgical time., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Patient-reported outcomes (PROs) capture subjective social determinants of health (SDOHs), which can affect health outcomes through the stress response pathway. The conserved transcriptional response to adversity (CTRA) is a stress-mediated proinflammatory transcriptomic pattern that has been linked to adverse hematopoietic cell transplant (HCT) outcomes. This study examined the association of pretransplant CTRA with patient-reported SDOHs in allogeneic HCT recipients. In this cross-sectional study, pre-HCT SDOH-related PROs included the 36-Item Short Form Health Survey and the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT). CTRA was assessed by RNA sequencing of whole blood specimens, with mixed effects linear regression models relating CTRA expression to PRO scores while controlling for age, sex, race, disease, and performance status. Among 121 patients, the median age was 54 years, 42% were female, and 91% were White. CTRA was elevated in participants reporting lower scores on the FACT-BMT (P = .003), including the general (P = .003) and BMT-specific (P = .014) components. Effects were driven by the social well-being domain (P = .0001). This corresponded to an 8% to 15% difference in CTRA RNA expression across a 4 standard deviation range in patient-reported SDOHs. Ancillary bioinformatics analyses confirmed the association of well-being with reduced proinflammatory transcription pathway activity [cyclic AMP response element-binding protein, (CREB), NF-κB, and activating protein-1 (AP-1)]. In conclusion, HCT-treated patients who experience unfavorable social conditions show elevated CTRA expression in pretransplant blood samples. These data highlight the biologic sequelae of social well-being and community context and suggest a potential molecular mechanism for the impact of social gradients in HCT outcomes. Targeting this pathway could optimize outcomes in this high-risk population., (© 2023 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.)

Long-term survivors of childhood cancer are at risk for financial hardship. However, it is not known if HCT leads to an incremental change in financial hardship for survivors who received it versus those who did not. We examined financial outcomes among adult survivors of childhood cancer who had undergone HCT. Using a cross-sectional survey in the Childhood Cancer Survivor Study population between 2017 and 2019, self-reported financial hardship was compared between survivors who received HCT, survivors treated without HCT ("non-HCT"), and siblings and categorized into 3 domains: material hardship/financial sacrifices, behavioral, and psychological hardship. The standardized score of each domain of financial hardship was calculated by adding the item responses and dividing by the standard deviation among siblings. Multivariable linear and logistic regression were used to evaluate associations between sociodemographic characteristics, cancer diagnosis, post-treatment complications, and financial hardship among survivors. The mean adjusted score for each hardship domain was not significantly different between HCT survivors (n = 133) and non-HCT survivors (n = 2711); mean differences were .18 (95% confidence interval [CI], -.05 to .41) for material hardship/financial sacrifices, .07 (95% CI, -.18 to .32) for behavioral hardship, and .19 (95% CI, -.04 to .42) for psychological hardship. Within specific items, a higher proportion of survivors treated with HCT reported greater financial hardship compared to non-HCT survivors. HCT survivors also had significantly higher mean domain scores compared to sibling controls (n = 1027) in all domains. Household income and chronic health conditions, but not HCT, were associated with financial hardship among all survivors. Adult survivors of childhood cancer treated with HCT do not report greater overall financial hardship compared to non-HCT survivors but do report greater overall financial hardship compared to sibling controls. Surveillance and intervention may be necessary for all survivors regardless of HCT status., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: While a single-stage free-flap reconstruction is the preferred approach for oromandibular defects, a multistaged approach may be necessary in rare cases. These patients can still be effectively restored with functional and aesthetic improvements., Methods: We report two cases with a history of bilateral failed fibula free flaps. We detail the multistaged reconstruction to repair these complex defects and discuss the considerations when planning such procedures., Results: Both patients successfully underwent a staged reconstruction with an iliac crest osteocutaneous flap following either a rectus abdominis or pectoralis major myocutaneous flap., Conclusion: Oromandibular reconstruction is an expected outcome in the contemporary management of oral cavity cancer and osteoradionecrosis. However, complications do occur and can be devastating. In cases of bilateral failed fibula free flaps, a staged approach is a favorable option. Moreover, the iliac crest provides an important reconstructive option with the documented potential for implant born dental rehabilitation., (© 2023 Wiley Periodicals LLC.)

Patients with hypomorphic mutations in the RAG1 or RAG2 gene present with either Omenn syndrome or atypical combined immunodeficiency with a wide phenotypic range. Hematopoietic stem cell transplantation (HSCT) is potentially curative, but data are scarce. We report on a worldwide cohort of 60 patients with hypomorphic RAG variants who underwent HSCT, 78% of whom experienced infections (29% active at HSCT), 72% had autoimmunity, and 18% had granulomas pretransplant. These complications are frequently associated with organ damage. Eight individuals (13%) were diagnosed by newborn screening or family history. HSCT was performed at a median of 3.4 years (range 0.3-42.9 years) from matched unrelated donors, matched sibling or matched family donors, or mismatched donors in 48%, 22%, and 30% of the patients, respectively. Grafts were T-cell depleted in 15 cases (25%). Overall survival at 1 and 4 years was 77.5% and 67.5% (median follow-up of 39 months). Infection was the main cause of death. In univariable analysis, active infection, organ damage pre-HSCT, T-cell depletion of the graft, and transplant from a mismatched family donor were predictive of worse outcome, whereas organ damage and T-cell depletion remained significant in multivariable analysis (hazard ratio [HR] = 6.01, HR = 8.46, respectively). All patients diagnosed by newborn screening or family history survived. Cumulative incidences of acute and chronic graft-versus-host disease were 35% and 22%, respectively. Cumulative incidences of new-onset autoimmunity was 15%. Immune reconstitution, particularly recovery of naïve CD4+ T cells, was faster and more robust in patients transplanted before 3.5 years of age, and without organ damage. These findings support the indication for early transplantation., (© 2023 by The American Society of Hematology.)

Background: Although providing sibling psychosocial services is a standard of care in pediatric oncology, initial survey research suggests that this standard is rarely achieved and siblings' support needs remain unmet. Which sibling psychosocial services are available and how centers provide such services is unknown. To identify targetable services gaps, this qualitative study characterizes current sibling psychosocial care practices at select pediatric cancer centers across the United States., Procedure: Semi-structured interviews were conducted with a purposive sample of psychosocial care providers (N = 27) working across the United States in pediatric oncology centers of varied sizes. Interviews queried providers regarding sibling-focused parent psychoeducation, psychosocial screening, comprehensive assessment, and psychosocial support offerings. Interview data were analyzed using Applied Thematic Analysis., Results: Across cancer centers, sibling care practices did not align with consensus-based recommendations. The nature and availability of sibling-focused psychoeducation, screening, assessment, and support were variable between and within centers. Siblings themselves were largely absent from sibling psychosocial care, and care was rarely sibling-specific. The flow of information about siblings was discontinuous and uncoordinated across the care continuum, resulting in psychosocial care provided reactively, typically in response to parental concerns., Conclusions: Sibling psychosocial care provision falls short of established care recommendations, leaving sibling psychosocial needs unmet. Findings highlight the need for tools and strategies to facilitate the implementation of sibling psychosocial care across the care continuum, to support siblings' psychosocial functioning across the life course., (© 2022 Wiley Periodicals LLC.)

Background: The current standard of documenting and communicating frozen section margin results is inefficient. We present a novel method of generating 3D digital models of gross tumor specimens to more clearly visualize histopathological margin results., Methods: Fifty-five head and neck specimens were scanned and virtually "inked" using 3D software. These 3D specimen maps were displayed in the operating room to provide the surgeon with a real-time specimen-to-defect relationship by which further resections could be guided., Results: Margin results were reported within an average of 34 min using the proposed workflow. The scanner rendered accurate models of specimens that exceeded 3.0 × 3.0 × 3.0 cm. Critical specimen features to consider were size, color, textural complexity, and the presence of discernible anatomic landmarks., Conclusions: Optical 3D scanning technology can improve the quality of head and neck margin documentation and the efficiency with which results are communicated between the pathologist and surgeon., (© 2022 Wiley Periodicals LLC.)

Study Design: Comparative cross-sectional., Objective: To measure the impact that COrona VIrus Disease-19 (COVID-19) has had on craniomaxillofacial (CMF) surgeons after 1 year and compare it with 2020 data by ( 1 ) measuring access to adequate personal protective equipment (PPE), ( 2 ) performance of elective surgery, and ( 3 ) the vaccination status. This should be investigated because most CMF surgeons felt that hospitals did not provide them with adequate PPE., Methods: The investigators surveyed the international AO CMF membership using a 30-item online questionnaire and compared it to a previous study. The primary predictor variable was year of survey administration. Primary outcome variables were availability of adequate personal protective equipment (adequate/inadequate), performance of elective surgery (yes/no), and vaccination status (fully vaccinated/partly vaccinated/not vaccinated). Descriptive and analytic statistics were computed. Binary logistic regression models were created to measure the association between year and PPE availability. Statistical significance level was set at P < .05., Results: The sample was composed of 523 surgeons (2% response rate). Most surgeons reported access to adequate PPE (74.6%). The most adequate PPE was offered in Europe (87.8%) with the least offered in Africa (45.5%). Surgeons in 2021 were more likely to report adequate PPE compared to 2020 (OR 3.74, 95% CI [2.59-4.39]). Most of the respondents resumed elective surgery (79.5% vs 13.3% in 2020) and were fully vaccinated (59.1%)., Conclusions: Most CMF surgeons now have access to adequate PPE, resumed elective surgery, and are either fully or partly vaccinated. Future studies should investigate the long-term impact of the fast-evolving COVID-19 pandemic on CMF surgeons., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome (WS) is a combined immunodeficiency caused by gain-of-function mutations in the C-X-C chemokine receptor type 4 (CXCR4) gene. We characterize a unique international cohort of 66 patients, including 57 (86%) cases previously unreported, with variable clinical phenotypes. Of 17 distinct CXCR4 genetic variants within our cohort, 11 were novel pathogenic variants affecting 15 individuals (23%). All variants affect the same CXCR4 region and impair CXCR4 internalization resulting in hyperactive signaling. The median age of diagnosis in our cohort (5.5 years) indicates WHIM syndrome can commonly present in childhood, although some patients are not diagnosed until adulthood. The prevalence and mean age of recognition and/or onset of clinical manifestations within our cohort were infections 88%/1.6 years, neutropenia 98%/3.8 years, lymphopenia 88%/5.0 years, and warts 40%/12.1 years. However, we report greater prevalence and variety of autoimmune complications of WHIM syndrome (21.2%) than reported previously. Patients with versus without family history of WHIM syndrome were diagnosed earlier (22%, average age 1.3 years versus 78%, average age 5 years, respectively). Patients with a family history of WHIM syndrome also received earlier treatment, experienced less hospitalization, and had less end-organ damage. This observation reinforces previous reports that early treatment for WHIM syndrome improves outcomes. Only one patient died; death was attributed to complications of hematopoietic stem cell transplantation. The variable expressivity of WHIM syndrome in pediatric patients delays their diagnosis and therapy. Early-onset bacterial infections with severe neutropenia and/or lymphopenia should prompt genetic testing for WHIM syndrome, even in the absence of warts., (© 2022. The Author(s).)

Post-transplantation cyclophosphamide (PTCy) has been shown to effectively control graft-versus-host disease (GvHD) in haploidentical (Haplo) transplantations. In this retrospective registry study, we compared GvHD organ distribution, severity, and outcomes in patients with GvHD occurring after Haplo transplantation with PTCy GvHD prophylaxis (Haplo/PTCy) versus HLA-matched unrelated donor transplantation with conventional prophylaxis (MUD/conventional). We evaluated 2 cohorts: patients with grade 2 to 4 acute GvHD (aGvHD) including 264 and 1163 recipients of Haplo and MUD transplants; and patients with any chronic GvHD (cGvHD) including 206 and 1018 recipients of Haplo and MUD transplants, respectively. In comparison with MUD/conventional transplantation ± antithymocyte globulin (ATG), grade 3-4 aGvHD (28% versus 39%, P = .001), stage 3-4 lower gastrointestinal (GI) tract aGvHD (14% versus 21%, P = .01), and chronic GI GvHD (21% versus 31%, P = .006) were less common after Haplo/PTCy transplantation. In patients with grade 2-4 aGvHD, cGvHD rate after Haplo/PTCY was also lower (hazard ratio [HR] = .4, P < .001) in comparison with MUD/conventional transplantation without ATG in the nonmyeloablative conditioning setting. Irrespective of the use of ATG, non-relapse mortality rate was lower (HR = .6, P = .01) after Haplo/PTCy transplantation, except for transplants that were from a female donor into a male recipient. In patients with cGvHD, irrespective of ATG use, Haplo/PTCy transplantation had lower non-relapse mortality rates (HR = .6, P = .04). Mortality rate was higher (HR = 1.6, P = .03) during, but not after (HR = .9, P = .6) the first 6 months after cGvHD diagnosis. Our results suggest that PTCy-based GvHD prophylaxis mitigates the development of GI GvHD and may translate into lower GvHD-related non-relapse mortality rate., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Competing Interests: The authors declare no conflict of interest.

Open-mouth deformity after mandibular resection presents a challenge for surgeons and patients, contributing to significant functional and cosmetic morbidity. We present an innovative surgical technique to prevent or correct open-mouth deformity. Tensor fascia lata slings were utilized in combination with maxillomandibular fixation to surgically correct or prevent open-mouth deformity in four patients who had previously undergone mandibulectomy or at the time of a contralateral mandibulectomy following prior hemimandibulectomy and reconstruction. Two patients achieved favorable outcomes, including oral competence and improved resting jaw position, while open-mouth deformity could not be corrected for one patient. Another patient remains in the early postoperative period following a secondary procedure to correct open-mouth deformity. Open-mouth deformity is a functional/aesthetic problem that has not been addressed in the literature. Use of tensor fascia lata slings to suspend the mandible is a novel approach to the surgical management of open-mouth deformity., (© 2022 Wiley Periodicals LLC.)

Male-specific late effects after hematopoietic cell transplantation (HCT) include genital chronic graft-versus-host disease (GvHD), hypogonadism, sexual dysfunction, infertility, and subsequent malignancies. They may be closely intertwined and cause prolonged morbidity and decreased quality of life after HCT. We provide a systematic review of male-specific late effects in a collaboration between transplant physicians, endocrinologists, urologists, dermatologists, and sexual health professionals through the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research, and the Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation. The systematic review summarizes incidence, risk factors, screening, prevention and treatment of these complications and provides consensus evidence-based recommendations for clinical practice and future research., (© 2022. The Author(s).)

Background: Activated phosphoinositide 3 kinase (PI3K) -delta syndrome (APDS) is an inborn error of immunity with variable clinical phenotype of immunodeficiency and immune dysregulation and caused by gain-of-function mutations in PIK3CD . The hallmark of immune phenotype is increased proportions of transitional B cells and plasmablasts (PB), progressive B cell loss, and elevated levels of serum IgM., Objective: To explore unique B cell subsets and the pathomechanisms driving B cell dysregulation beyond the transitional B cell stage in APDS., Methods: Clinical and immunological data was collected from 24 patients with APDS. In five cases, we performed an in-depth analysis of B cell phenotypes and cultured purified naïve B cells to evaluate their survival, activation, Ig gene class switch recombination (CSR), PB differentiation and antibody secretion. We also analyzed PB differentiation capacity of sorted CD27 - IgD - double-negative B (DNB) cells., Results: The patients had increased B cell sizes and higher proportions of IgM + DNB cells than healthy controls (HC). Their naïve B cells exhibited increased death, impaired CSR but relatively normal PB differentiation. Upon stimulation, patient's DNB cells secreted a similar level of IgG but a higher level of IgM than DNB cells from HC. Targeted therapy of PI3K inhibition partially restored B cell phenotypes., Conclusions: The present study suggests additional mechanistic insight into B cell pathology of APDS: (1) decreased peripheral B cell numbers may be due to the increased death of naïve B cells; (2) larger B cell sizes and expanded DNB population suggest enhanced activation and differentiation of naïve B cells into DNB cells; (3) the impaired CSR yet normal PB differentiation can predominantly generate IgM-secreting cells, resulting in elevated IgM levels., Competing Interests: JEW is a consultant on APDS and leniolisib with Pharmin (Netherlands). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Min, Lai, Csomos, Wang, Liu, Meng, Sun, Hou, Ying, Zhou, Sun, Hui, Ujhazi, Gordon, Buchbinder, Schuetz, Butte, Walter, Wang and Wang.)

Objective: To characterize the prevalence and predictors of concerns regarding future health and cancer risk among siblings of childhood cancer survivors., Methods: This study reports longitudinal data (baseline and follow-up) from 3969 adult siblings (median age = 29 [range 18-56] years) of long-term survivors of childhood cancer (median time since diagnosis 19.6 [9.6-33.8] years). Self-reported future health and cancer risk concerns (concerned vs not concerned) were assessed. Demographics and health data reported by both the siblings and their matched cancer survivors were examined as risk factors for health concerns using multivariable logistic regression., Results: Percentage of siblings reporting future health and cancer risk concerns, respectively, decreased across decade of survivors' diagnosis: 1970s (73.3%; 63.9%), 1980s (67.2%; 62.6%), and 1990s (45.7%; 52.3%). Risk factors associated with future health concerns included sibling chronic health conditions (grade 2 Odds Ratio [OR]=1.57, 95% CI: 1.12-2.20; grades 3-4 OR=1.86, 95% CI: 1.18-2.94; compared to less than grade 2). Risk factors associated with future cancer concerns included sibling chronic health conditions (grade 2 OR=1.43, 95% CI: 1.05-1.94; grades 3-4 OR=1.64, 95% CI: 1.09-2.47; compared to less than grade 2)., Conclusions: Sibling concerns regarding future health and cancer have diminished in recent decades. There are subgroups of siblings that are at-risk for future health and cancer risk concerns., Implications for Cancer Survivors: Routine screening of concerns in at-risk siblings of survivors of childhood cancer may benefit the siblings of cancer survivors. These individuals may benefit from early interventions during diagnosis and treatment of their siblings., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Wiskott-Aldrich syndrome (WAS) serves as the prototype of how variants in a gene, which encodes a protein central to actin cytoskeletal homeostasis can manifest clinically in a variety of ways including infection, atopy, autoimmunity, inflammation, bleeding, neutropenia, non-malignant lymphoproliferation, and malignancy. Despite the discovery of the WAS gene almost 30 years ago, our understanding of the pathophysiological mechanisms underlying WAS continues to unfold., Areas Covered: This review will provide an overview of the approach to the diagnosis of WAS as well as the management of its associated complications. Advances in the use of allogeneic hematopoietic stem cell transplantation (HSCT) and gene therapy as well as the associated challenges unique to WAS will be discussed., Expert Opinion: Basic research, combined with clinical research focusing on longitudinal analysis of WAS patients, will help clarify determinants that influence WAS pathogenesis as well as clinical complications and outcomes. Advances in curative approaches including the use of alternative donor HSCT for WAS continue to evolve. Gene therapy employing safer and more effective protocols ensuring full correction of WAS will provide life-saving benefit to WAS patients who are unable to undergo HSCT.

Male-specific late effects after hematopoietic cell transplantation (HCT) include genital chronic graft-versus-host disease (GVHD), hypogonadism, sexual dysfunction, infertility, and subsequent malignancies, such as prostate, penile, and testicular cancer. These effects may be closely intertwined and cause prolonged morbidity and decreased quality of life after HCT. Here we provide a systematic review of male-specific late effects in a collaboration among transplantation physicians, endocrinologists, urologists, dermatologists, and sexual health professionals through the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and the Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation. We used a systematic review methodology to summarize incidence, risk factors, screening, prevention, and treatment of these complications and provide consensus evidence-based recommendations for clinical practice and future research. Most of the evidence regarding male GVHD is still based on limited data, precluding strong therapeutic recommendations. Therefore, we recommend systematic screening for male genital GVHD regularly and reporting of cases to large registries to allow for a better understanding. Future research also should address treatment, given the little published evidence currently available. Male-specific endocrine consequences of HCT include hypogonadism, which also may affect bone health. Given the scanty evidence, current recommendations for hormone substitution and/or bone health treatment are based on similar principles as for the general population. Following HCT, sexual health decreases, and this topic should be addressed at regular intervals. Future studies should focus on interventional strategies to address sexual dysfunction. Infertility remains prevalent in patients having undergone myeloablative conditioning, warranting the offer of sperm preservation for all HCT candidates. Most studies on fertility rely on descriptive registry analysis and surveys, underscoring the importance of reporting post-HCT conception data to large registries. Although the quality of evidence is low, the development of cancer in male genital organs does not seem more prevalent in HCT recipients compared with the general population; however, subsequent malignancies in general seem to be more prevalent in males than in females, and special attention should be given to skin and oral mucosa. Male-specific late effects, which likely are more underreported than female-specific complications, should be systematically considered during the regular follow-up visits of male survivors who have undergone HCT. Care of patients with male-specific late effects warrants close collaboration between transplantation physicians and specialists from other involved disciplines. Future research should be directed toward better data collection on male-specific late effects and on studies about the interrelationships among these late effects, to allow the development of evidence-based effective management practices., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Wiskott-Aldrich Syndrome Protein (WASP) deficiency causes Wiskott-Aldrich Syndrome (WAS), a sex-linked disorder characterized by combined immunodeficiency, microthrombocytopenia, and eczema. Like WASP-deficient humans, WASP-deficient mice produce normal numbers of functionally defective T cells. Here, we report a WAS patient with a novel germline frameshifting WAS mutation encoding a truncated form of WASP lacking the C-terminal cofilin homology (C) and the acidic region (A) domains (WASPΔCA). Although stably overexpressed in embryonic kidney cell lines, WASPΔCA was undetectable in circulating patient leukocytes. Deep sequencing, transcript profiling, and protein degradation analyses demonstrated patient lymphocytes employ an array of genetic, epigenetic, and proteasomal strategies to avoid expressing WASPΔCA., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Heterozygous germline mutations in cytotoxic T lymphocyte-associated antigen-4 (CTLA4) impair the immunomodulatory function of regulatory T cells. Affected individuals are prone to life-threatening autoimmune and lymphoproliferative complications. A number of therapeutic options are currently being used with variable effectiveness., Objective: Our aim was to characterize the responsiveness of patients with CTLA-4 insufficiency to specific therapies and provide recommendations for the diagnostic workup and therapy at an organ-specific level., Methods: Clinical features, laboratory findings, and response to treatment were reviewed retrospectively in an international cohort of 173 carriers of CTLA4 mutation. Patients were followed between 2014 and 2020 for a total of 2624 months from diagnosis. Clinical manifestations were grouped on the basis of organ-specific involvement. Medication use and response were recorded and evaluated., Results: Among the 173 CTLA4 mutation carriers, 123 (71%) had been treated for immune complications. Abatacept, rituximab, sirolimus, and corticosteroids ameliorated disease severity, especially in cases of cytopenias and lymphocytic organ infiltration of the gut, lungs, and central nervous system. Immunoglobulin replacement was effective in prevention of infection. Only 4 of 16 patients (25%) with cytopenia who underwent splenectomy had a sustained clinical response. Cure was achieved with stem cell transplantation in 13 of 18 patients (72%). As a result of the aforementioned methods, organ-specific treatment pathways were developed., Conclusion: Systemic immunosuppressants and abatacept may provide partial control but require ongoing administration. Allogeneic hematopoietic stem cell transplantation offers a possible cure for patients with CTLA-4 insufficiency., (Copyright © 2021. Published by Elsevier Inc.)

Background: Siblings of children with cancer are at increased risk for poor long-term psychosocial outcomes. The standard of psychosocial care in pediatric oncology calling for sibling support is not routinely implemented, often leaving siblings with unmet psychosocial needs. Barriers to implementing the sibling standard may exist at multiple levels. This study addresses research gaps regarding multilevel barriers to supporting siblings at the health care system, oncology center, and family levels., Procedure: Qualitative interviews were conducted with psychosocial care providers (N = 27; 18 psychologists, five social workers, three psychiatrists, and one child life specialist) employed at oncology centers within hospitals across the United States, varying in extent of sibling programming and center size. Interviews included questions about providers' roles, oncology center characteristics, existing psychosocial sibling services, barriers to providing systematic sibling assessment, and ideas about how to overcome barriers. Data were analyzed using applied thematic analysis., Results: Qualitative analysis revealed (a) barriers to providing sibling services occur at multiple levels (health care system, oncology center, family); (b) barriers at multiple levels frequently interact with one another; and (c) interacting barriers maintain a cycle: barriers to providing services contribute to limited provision of services, low service provision leads to limited utilization of existing services and underprioritization of siblings, and together this leads to siblings being off the radar, which further limits sibling service provision., Conclusion: Addressing health care system and oncology center barriers to implementing sibling assessment and support may be important potential targets for interventions to help ensure that siblings receive needed psychosocial assessment and support., (© 2021 Wiley Periodicals LLC.)

Chronic active Epstein-Barr virus (EBV) disease (CAEBV) is characterized by high levels of EBV predominantly in T and/or natural killer cells with lymphoproliferation, organ failure due to infiltration of tissues with virus-infected cells, hemophagocytic lymphohistiocytosis, and/or lymphoma. The disease is more common in Asia than in the United States and Europe. Although allogeneic hematopoietic stem cell transplantation (HSCT) is considered the only curative therapy for CAEBV, its efficacy and the best treatment modality to reduce disease severity prior to HSCT is unknown. Here, we retrospectively assessed an international cohort of 57 patients outside of Asia. Treatment of the disease varied widely, although most patients ultimately proceeded to HSCT. Though patients undergoing HSCT had better survival than those who did not (55% vs 25%, P < .01), there was still a high rate of death in both groups. Mortality was largely not affected by age, ethnicity, cell-type involvement, or disease complications, but development of lymphoma showed a trend with increased mortality (56% vs 35%, P = .1). The overwhelming majority (75%) of patients who died after HSCT succumbed to relapsed disease. CAEBV remains challenging to treat when advanced disease is present. Outcomes would likely improve with better disease control strategies, earlier referral for HSCT, and close follow-up after HSCT including aggressive management of rising EBV DNA levels in the blood., (© 2022 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.)

Rubella virus (RuV) has recently been found in association with granulomatous inflammation of the skin and several internal organs in patients with inborn errors of immunity (IEI). The cellular tropism and molecular mechanisms of RuV persistence and pathogenesis in select immunocompromised hosts are not clear. We provide clinical, immunological, virological, and histological data on a cohort of 28 patients with a broad spectrum of IEI and RuV-associated granulomas in skin and nine extracutaneous tissues to further delineate this relationship. Combined immunodeficiency was the most frequent diagnosis (67.8%) among patients. Patients with previously undocumented conditions, i.e., humoral immunodeficiencies, a secondary immunodeficiency, and a defect of innate immunity were identified as being susceptible to RuV-associated granulomas. Hematopoietic cell transplantation was the most successful treatment in this case series resulting in granuloma resolution; steroids, and TNF-α and IL-1R inhibitors were moderately effective. In addition to M2 macrophages, neutrophils were identified by immunohistochemical analysis as a novel cell type infected with RuV. Four patterns of RuV-associated granulomatous inflammation were classified based on the structural organization of granulomas and identity and location of cell types harboring RuV antigen. Identification of conditions that increase susceptibility to RuV-associated granulomas combined with structural characterization of the granulomas may lead to a better understanding of the pathogenesis of RuV-associated granulomas and discover new targets for therapeutic interventions., Competing Interests: MA is employed by Sidra Medicine and Hamad Medical Corporation, Qatar. HB is employed by Labor Berlin GmbH, Germany. JH received grants from Immune Deficiency Foundation, the US immunodeficiency network, Chao-physician Scientist award, the Texas Medical Center Digestive Diseases Center and the Jeffrey Modell Foundation. JH received honorarium, consultation fees from Horizon, Pharming, Baxalta, CSL Behring, the National guard, and Al-Faisal University Hospital. TPA received consultation fees from Horizon, Pharming, CSL Behring. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Perelygina, Faisthalab, Abernathy, Chen, Hao, Bercovitch, Bayer, Noroski, Lam, Cicalese, Al-Herz, Nanda, Hajjar, Vanden Driessche, Schroven, Leysen, Rosenbach, Peters, Raedler, Albert, Abraham, Rangarjan, Buchbinder, Kobrynski, Pham-Huy, Dhossche, Cunningham Rundles, Meyer, Theos, Atkinson, Musiek, Adeli, Derichs, Walz, Krüger, von Bernuth, Klein, Icenogle, Hauck and Sullivan.)

With improvement in survival after hematopoietic cell transplantation (HCT), it has become important to focus on survivors' psychosocial issues in order to provide patient-centered care across the transplant continuum. The goals of this article are to describe updates in the literature on certain psychosocial domains (emotional/mental health and social/financial) in HCT survivors, offer a brief overview of the status of the screening and management of these complications, and identify opportunities for future practice and research. An evidence-based approach to psychosocial care can be broken down as primary (promoting health, raising awareness, and addressing risk factors), secondary (screening and directing early pharmacological and nonpharmacological interventions), and tertiary (rehabilitating, limiting disability, and improving quality of life) prevention. Implementing such an approach requires close coordination between multiple stakeholders, including transplant center staff, referring hematologist/oncologists, and other subspecialists in areas such as palliative medicine or psychiatry. Innovative models of care that leverage technology can bring these stakeholders together to fulfill unmet needs in this area by addressing barriers in the delivery of psychosocial care., (Copyright © 2021 by The American Society of Hematology.)

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.)

To identify the clinical and pharmacological risk factors associated with tacrolimus pharmacodynamics for acute graft-versus-host disease (aGVHD) in pediatric patients receiving allogeneic hematopoietic stem cell transplantation (HSCT) from a matched related donor. A retrospective cohort single center chart review study was conducted with pediatric patients who received tacrolimus prophylaxis after allogeneic HSCT between January 1, 2017, and December 31, 2019. Potential risk factors were tested separately between aGVHD and non-aGVHD cohorts and were further analyzed in a logistic regression model with backward elimination and a partial least squares discriminant analysis. Thirty-three patient cases were included in our study and 52% (17/33) developed aGVHD while on tacrolimus prophylaxis. When tested independently, donor age and sibling versus parent donor/recipient relation were shown to be statistically significant between aGVHD and non-aGVHD patients (p < 0.005). Pharmacological factors associated with tacrolimus treatment failed to demonstrate a significant impact on patient's risk of aGVHD. Using a best fit logistic regression model that tested all the variables together, donor age was the only significant variable predicting patient's risk of aGVHD (p < 0.01). Donor relationship and donor age were unable to be evaluated separately and are therefore confounding variables. Among pediatric patients receiving allogeneic HSCT, aGVHD risk is significantly decreased by either sibling donor and/or younger donors. Although no conclusions were drawn on the effect of tacrolimus therapy (p = 0.08), results warrant additional research with a larger sample size to evaluate the accuracy of monitoring tacrolimus serum trough levels., (© 2021 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Systematic reviews apply rigorous methodologies to address a prespecified, clearly formulated clinical research question. The conclusion that results is often cited to more robustly inform decision making by clinicians, third-party payers, and managed care organizations about the clinical question of interest. Although systematic reviews provide a rigorous standard, they may be infeasible when the task is to create general disease-focused guidelines comprising multiple clinical practice questions versus a single major clinical practice question. Collaborating transplantation and cellular therapy society committees also recognize that the quantity and or quality of reference sources may be insufficient for a meaningful systematic review. As the conduct of systematic reviews has evolved over time in terms of grading systems, reporting requirements, and use of technology, here we provide current guidance on methodologies, resources for reviewers, and approaches to overcome challenges in conducting systematic reviews in transplantation and cellular therapy., (Copyright © 2020 The American Society for Transplantation and Cellular Therapy. All rights reserved.)

Purpose: Successful orthognathic surgery is fundamentally based on accurately carrying out the intended surgical plan intraoperatively. The purpose of this study was to evaluate the accuracy of bone-borne patient-specific maxillary cutting guides and 3-dimensional (3D)-printed plates in repositioning the maxilla during bimaxillary orthognathic surgery., Materials and Methods: This was a retrospective case series consisting of patients who had undergone Le Fort I osteotomy with a patient-specific cutting guide and 3D-printed plate as well as a bilateral sagittal split osteotomy and had 6-week postoperative cone-beam computed tomography studies. The primary outcome variable was the difference between the position of the postoperative maxilla and the virtually planned maxilla measured at 10 landmarks in 3 dimensions. Other study variables included the preoperative diagnosis and planned surgical movement at each landmark. Descriptive statistics were tabulated, and bivariate analyses were performed., Results: A total of 10 patients were included in this study. The mean age was 25.7 ± 8.1 years, and there were 5 female patients. The median planned surgical movement was 0.350 mm on the x-axis (right-left), 3.750 mm on the y-axis (anterior-posterior), and 1.704 mm on the z-axis (superior-inferior). The median absolute discrepancy between the postoperative position and the planned position on the x-axis, y-axis, and z-axis was 0.638, 0.798, and 0.481 mm, respectively. There was no significant difference in the discrepancies between the x-axis and y-axis (P = .575), x-axis and z-axis (P = .332), and y-axis and z-axis (P = .114)., Conclusions: Using a patient-specific cutting guide and 3D-printed plate when performing Le Fort I osteotomy allows for accurate 3-dimensional positioning of the maxilla in accordance with the surgical plan., (Copyright © 2020 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Systematic reviews apply rigorous methodologies to address a pre-specified, clearly formulated clinical research question. The conclusion that results is often cited to more robustly inform decision-making by clinicians, third-party payers and managed care organizations about the clinical question of interest. While systematic reviews provide a rigorous standard, they may be unfeasible when the task is to create general disease-focused guidelines comprised of multiple clinical practice questions versus a single major clinical practice question. Collaborating transplantation and cellular therapy societal committees also recognize that the quantity and or quality of reference sources may be insufficient for a meaningful systematic review. As the conduct of systematic reviews has evolved over time in terms of grading systems, reporting requirements and use of technology, here we provide current guidance in methodologies, resources for reviewers, and approaches to overcome challenges in conducting systematic reviews in transplantation and cellular therapy.

Congenital dyserythropoietic anemias (CDAs) are characterized by ineffective erythropoiesis and distinctive erythroblast abnormalities; the diagnosis is often missed or delayed due to significant phenotypic heterogeneity. We established the CDA Registry of North America (CDAR) to study the natural history of CDA and create a biorepository to investigate the pathobiology of this heterogeneous disease. Seven of 47 patients enrolled so far in CDAR have CDA-I due to biallelic CDAN1 mutations. They all presented with perinatal anemia and required transfusions during infancy. Anemia spontaneously improved during infancy in three patients; two became transfusion-independent rapidly after starting interferon-α 2 ; and two remain transfusion-dependent at last follow-up at ages 5 and 30 y.o. One of the transfusion-dependent patients underwent splenectomy at 11 y.o due to misdiagnosis and returned to medical attention at 27 y.o with severe hemolytic anemia and pulmonary hypertension. All patients developed iron overload even without transfusions; four were treated with chelation. Genetic testing allowed for more rapid and accurate diagnosis; the median age of confirmed diagnosis in our cohort was 3 y.o compared to 17.3 y.o historically. In conclusion, CDAR provides an organized research network for multidisciplinary clinical and research collaboration to conduct natural history and biologic studies in CDA., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Competing Interests: The authors declare no conflict of interest.

Newborn screening efforts focusing on the quantification of T cell receptor excision circles (TRECs), as a biomarker for abnormal thymic production of T cells, have allowed for the identification and definitive treatment of severe combined immunodeficiency (SCID) in asymptomatic neonates. With the adoption of TREC quantification in Guthrie cards across the USA and abroad, typical, and atypical SCID constitutes only ~ 10% of cases identified with abnormal TRECs associated with T cell lymphopenia. Several other non-SCID-related conditions may be identified by newborn screening in a term infant. Thus, it is important for physicians to recognize that other factors, such as prematurity, are often associated with low TRECs initially, but often improve with age. This paper focuses on a challenge that immunologists face: the diagnostic evaluation and management of cases in which abnormal TRECs are associated with variants of T cell lymphopenia in the absence of a genetically defined form of typical or atypical SCID. Various syndromes associated with T cell impairment, secondary forms of T cell lymphopenia, and idiopathic T cell lymphopenia are identified using this screening approach. Yet there is no consensus or guidelines to assist in the evaluation and management of these newborns, despite representing 90% of the patients identified, resulting in significant work for the clinical teams until a diagnosis is made. Using a case-based approach, we review pearls relevant to the evaluation of these newborns, as well as the management dilemmas for the families and team related to the resolution of genetic ambiguities.

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.)

Objective: A subset of patients who undergo major palatomaxillary reconstruction do not initially achieve their intended oncologic and/or reconstructive goals and require additional surgery. We aim to detail the unique management considerations in this patient population., Methods: We performed a retrospective review of patients who underwent palatomaxillary reconstruction by the senior author (m.l.u.) between 1998 and 2016., Results: Twenty-one patients required multiple reconstructions. The median time to second reconstruction was 17 months. The most common reason for a second reconstruction was for recurrent disease (10 of 21), followed by functional/aesthetic reasons (7 of 21) and osteoradionecrosis (4 of 21). Four patients went on to have a third reconstruction, and two underwent a fourth. A total of 27 reconstructions were performed, consisting of 20 soft tissue free flaps, four vascularized bone free flaps, and three locoregional flaps., Conclusion: This patient cohort represents unique oncologic and reconstructive challenges. With long-term follow-up, multiple reconstructions may be required to optimize oncologic and functional/aesthetic outcomes. This is the first series of its kind that details the reasons for, as well as the outcomes of, patients who required multiple reconstructive procedures following initial palatomaxillary reconstruction., Level of Evidence: 2B Laryngoscope, 130:2349-2353, 2020., (© 2019 The American Laryngological, Rhinological and Otological Society, Inc.)

Study Design: The COrona VIrus Disease-19 (COVID-19) pandemic has disrupted craniomaxillofacial (CMF) surgeons practice worldwide. We implemented a cross-sectional study and enrolled a sample of CMF surgeons who completed a survey., Objective: To measure the impact that COVID-19 has had on CMF surgeons by (1) identifying variations that may exist by geographic region and specialty and (2) measuring access to adequate personal protective equipment (PPE) and identify factors associated with limited access to adequate PPE., Methods: Primary outcome variable was availability of adequate PPE for health-care workers (HCWs) in the front line and surgeons. Descriptive and analytic statistics were computed. Level of statistical significance was set at P < .05. Binary logistic regression models were created to identify variables associated with PPE status (adequate or inadequate)., Results: Most of the respondents felt that hospitals did not provide adequate PPE to the HCWs (57.3%) with significant regional differences ( P = .04). Most adequate PPE was available to surgeons in North America with the least offered in Africa. Differences in PPE adequacy per region ( P < .001) and per country ( P < .001) were significant. In Africa and South America, regions reporting previous virus outbreaks, the differences in access to adequate PPE evaporated compared to Europe ( P = .18 and P = .15, respectively)., Conclusion: The impact of COVID-19 among CMF surgeons is global and adversely affects both clinical practice and personal lives of CMF surgeons. Future surveys should capture what the mid- and long-term impact of the COVID-19 crisis will look like., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)

Background: Melanoma risk is increased after allogeneic hematopoietic cell transplantation (HCT), but specific risk factors are unknown., Objective: Investigate risk factors for melanoma after allogeneic hematopoietic cell transplantation., Methods: We conducted a nested case-control study of 140 melanoma cases and 557 controls (matched by age at HCT, sex, primary disease, survival time) through the Center for International Blood and Marrow Transplant Research., Results: Melanoma risk was significantly increased among HCT survivors who received total body irradiation-based myeloablative conditioning (multivariable adjusted odds ratio [OR] = 1.77; 95% confidence interval [CI] = 1.00-3.15) or reduced-intensity conditioning containing melphalan (OR = 2.60; 95% CI = 1.13-6.02) or fludarabine (OR = 2.72; 95% CI = 1.02-7.30) versus busulfan-based myeloablative regimens; were diagnosed with acute graft-versus-host disease (GVHD) with stage 2+ skin involvement (OR = 1.92; 95% CI = 1.19-3.10), chronic GvHD without skin involvement (OR = 1.91; 95% CI = 1.03-3.57), or keratinocytic carcinoma (OR = 2.37; 95% CI = 1.16-4.83); and resided in areas with higher ambient ultraviolet radiation (ORtertile3 = 1.64; 95% CI = 1.01-2.67)., Limitations: Data on individual-level ultraviolet radiation exposure and clinical data on melanoma characteristics were lacking. Additionally, misclassification of melanoma is possible as not all pathology reports were available for review., Conclusion: These results emphasize the importance of adherence to current surveillance guidelines (routine skin examination, photoprotection recommendations), particularly for HCT survivors at highest risk., (Copyright © 2020. Published by Elsevier Inc.)

The COVID-19 pandemic is a global problem that has adversely and significantly impacted the safe practice of maxillofacial surgery. The risk lies in the heavy viral load in the oral/nasal/upper respiratory mucosal surfaces. Surgical procedures performed in this anatomic regional produce aerosalized viral particles which are highly infectious. Best practices and recommendations are outlined to mitigate the risk to the provider., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)